Treatment of Tuberculosis

American Thoracic Society Documents
American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of Tuberculosis
This Ofcial Joint Statement of the American Thoracic Society, Centers for Disease Control and Prevention, and the Infectious Diseases Society of America was approved by the ATS Board of Directors October 2002, The Centers for Disease Control and Prevention October 2002, and the Council of the IDSA October 2002.
CONTENTS
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604 1. Introduction and Background . . . . . . . . . . . . . . . . . . . . 613 2. Organization and Supervision of Treatment 2.1. Role of the Health Department . . . . . . . . . . . . . . . 615 2.2. Promoting Adherence . . . . . . . . . . . . . . . . . . . . . . 615 3. Drugs in Current Use 3.1. First-Line Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . 619 3.2. Second-Line Drugs . . . . . . . . . . . . . . . . . . . . . . . . 623 4. Principles of Antituberculosis Chemotherapy 4.1. Combination Chemotherapy . . . . . . . . . . . . . . . . . 629 4.2. Optimum Duration of Treatment . . . . . . . . . . . . . 629 4.3. Intermittent Drug Administration . . . . . . . . . . . . . 630 5. Recommended Treatment Regimens 5.1. Evidence-based Rating System . . . . . . . . . . . 5.2. Recommended Regimens . . . . . . . . . . . . . . . 5.3. Deciding to Initiate Therapy . . . . . . . . . . . . . 5.4. Baseline and Follow-up Evaluations . . . . . . . 5.5. Identication and Management of Patients at Increased Risk of Relapse . . . . . . . . . . . . . . . 5.6. Denition of Completion of Therapy . . . . . . . 5.7. Interruptions in Therapy . . . . . . . . . . . . . . . . 6. Practical Aspects of Treatment 6.1. Drug Administration . . . . . . . . . . . . . . . . . 6.2. Fixed-Dose Combination Preparations . . . . 6.3. Management of Common Side Effects . . . . 6.4. Serum Drug Concentration Measurements . . . . . . . . . . . . . . . . . . . . . . 632 . 632 . 632 . 633
8.4. Culture-negative Pulmonary Tuberculosis in Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.5. Radiographic Evidence of Prior Tuberculosis: Inactive Tuberculosis . . . . . . . . . . . . . . . . . . . 8.6. Pregnancy and Breastfeeding . . . . . . . . . . . . . 8.7. Renal Insufciency and End-stage Renal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.8. Hepatic Disease . . . . . . . . . . . . . . . . . . . . . . . 8.9. Other Associated Disorders . . . . . . . . . . . . . . 9. Management of Relapse, Treatment Failure, and Drug Resistance 9.1. Relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2. Treatment Failure . . . . . . . . . . . . . . . . . . . 9.3. Management of Tuberculosis Caused by Drug-resistant Organisms . . . . . . . . . . . . . . 9.4. Role of Surgery in Multiple-Drug-Resistant Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . 9.5. Laboratory Considerations in Determining Drug Resistance . . . . . . . . . . . . . . . . . . . . .
. . 650 . . 650 . . 651 . . 652 . . 653 . . 653
. . . . 654 . . . . 654 . . . . 655 . . . . 657 . . . . 658
. . . . 634 . . . . 634 . . . . 634 . . . . . . . . . . . . . 636 . 636 . 636 . 637
7. Drug Interactions 7.1. Interactions Affecting Antituberculosis Drugs . . . . 638 7.2. Effects of Antituberculosis Drugs on Other Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638 8. Treatment in Special Situations 8.1. HIV Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642 8.2. Children and Adolescents . . . . . . . . . . . . . . . . . . . 645 8.3. Extrapulmonary Tuberculosis . . . . . . . . . . . . . . . . 646
10. Treatment of Tuberculosis in Low-Income Countries: Recommendations of the WHO and the IUATLD 10.1. Microbiological Tests for Diagnosis and Evaluation of Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659 10.2. Use of Chest Radiographs in Diagnosis and Follow-up of Patients Being Treated . . . . . . . . . 659 10.3. Initial Treatment Regimens . . . . . . . . . . . . . . . . 659 10.4. Approach to Previously Treated Patients . . . . . . 659 10.5. Monitoring of Outcomes of Therapy . . . . . . . . . 660 10.6. Recommended Doses of Antituberculosis Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 660 10.7. Drugs/Preparations Not Available in the United States . . . . . . . . . . . . . . . . . . . . . . . . . . . 660 10.8. Treating Pregnant Women . . . . . . . . . . . . . . . . . 660 10.9. Management of Common Adverse Reactions . . . 660 11. Research Agenda for Tuberculosis Treatment 11.1. New Antituberculosis Drugs . . . . . . . . . . . . . . . 660 11.2. Other Interventions to Improve the Efcacy of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . 661
Members of the adhoc statement committee have disclosed any direct commercial associations (financial relationships or legal obligations) related to the preparation of this statement. This information is kept on file at the ATS Headquarters. Am J Respir Crit Care Med Vol 167. pp 603662, 2003 DOI: 10.1164/rccm.167.4.603 Internet address: www.atsjournals.org
PURPOSE The recommendations in this document are intended to guide the treatment of tuberculosis in settings where mycobacterial cultures, drug susceptibility testing, radiographic facilities, and second-line drugs are routinely available. In areas where these resources are not available, the recommendations provided by the World Health Organization, the International Union against Tuberculosis, or national tuberculosis control programs should be followed.
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 167 2003
WHATS NEW IN THIS DOCUMENT The responsibility for successful treatment is clearly assigned to the public health program or private provider, not to the patient. It is strongly recommended that the initial treatment strategy utilize patient-centered case management with an adherence plan that emphasizes direct observation of therapy. Recommended treatment regimens are rated according to the strength of the evidence supporting their use. Where possible, other interventions are also rated. Emphasis is placed on the importance of obtaining sputum cultures at the time of completion of the initial phase of treatment in order to identify patients at increased risk of relapse. Extended treatment is recommended for patients with drug-susceptible pulmonary tuberculosis who have cavitation noted on the initial chest lm and who have positive sputum cultures at the time 2 months of treatment is completed. The roles of rifabutin, rifapentine, and the uoroquinolones are discussed and a regimen with rifapentine in a once-a-week continuation phase for selected patients is described. Practical aspects of therapy, including drug administration, use of xed-dose combination preparations, monitoring and management of adverse effects, and drug interactions are discussed. Treatment completion is dened by number of doses ingested, as well as the duration of treatment administration. Special treatment situations, including human immunodeciency virus infection, tuberculosis in children, extrapulmonary tuberculosis, culture-negative tuberculosis, pregnancy and breastfeeding, hepatic disease and renal disease are discussed in detail. The management of tuberculosis caused by drug-resistant organisms is updated. These recommendations are compared with those of the WHO and the IUATLD and the DOTS strategy is described. The current status of research to improve treatment is reviewed.
diagnostic and treatment services are available, and for monitoring the results of therapy. It is strongly recommended that patient-centered care be the initial management strategy, regardless of the source of supervision. This strategy should always include an adherence plan that emphasizes directly observed therapy (DOT), in which patients are observed to ingest each dose of antituberculosis medications, to maximize the likelihood of completion of therapy. Programs utilizing DOT as the central element in a comprehensive, patientcentered approach to case management (enhanced DOT) have higher rates of treatment completion than less intensive strategies. Each patients management plan should be individualized to incorporate measures that facilitate adherence to the drug regimen. Such measures may include, for example, social service support, treatment incentives and enablers, housing assistance, referral for treatment of substance abuse, and coordination of tuberculosis services with those of other providers.
Recommended Treatment Regimens
SUMMARY
Responsibility for Successful Treatment
The overall goals for treatment of tuberculosis are (1 ) to cure the individual patient, and (2 ) to minimize the transmission of Mycobacterium tuberculosis to other persons. Thus, successful treatment of tuberculosis has benets both for the individual patient and the community in which the patient resides. For this reason the prescribing physician, be he/she in the public or private sector, is carrying out a public health function with responsibility not only for prescribing an appropriate regimen but also for successful completion of therapy. Prescribing physician responsibility for treatment completion is a fundamental principle in tuberculosis control. However, given a clear understanding of roles and responsibilities, oversight of treatment may be shared between a public health program and a private physician.
Organization and Supervision of Treatment
Treatment of patients with tuberculosis is most successful within a comprehensive framework that addresses both clinical and social issues of relevance to the patient. It is essential that treatment be tailored and supervision be based on each patients clinical and social circumstances (patient-centered care). Patients may be managed in the private sector, by public health departments, or jointly, but in all cases the health department is ultimately responsible for ensuring that adequate, appropriate
The recommended treatment regimens are, in large part, based on evidence from clinical trials and are rated on the basis of a system developed by the United States Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA). The rating system includes a letter (A, B, C, D, or E ) that indicates the strength of the recommendation and a roman numeral (I, II, or III) that indicates the quality of evidence supporting the recommendation (Table 1). There are four recommended regimens for treating patients with tuberculosis caused by drug-susceptible organisms. Although these regimens are broadly applicable, there are modications that should be made under specied circumstances, described subsequently. Each regimen has an initial phase of 2 months followed by a choice of several options for the continuation phase of either 4 or 7 months. The recommended regimens together with the number of doses specied by the regimen are described in Table 2. The initial phases are denoted by a number (1, 2, 3, or 4 ) and the continuation phases that relate to the initial phase are denoted by the number plus a letter designation (a, b, or c ). Drug doses are shown in Tables 3, 4, and 5. The general approach to treatment is summarized in Figure 1. Because of the relatively high proportion of adult patients with tuberculosis caused by organisms that are resistant to isoniazid, four drugs are necessary in the initial phase for the 6-month regimen to be maximally effective. Thus, in most circumstances, the treatment regimen for all adults with previously untreated tuberculosis should consist of a 2-month initial phase of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) (Table 2, Regimens 13). If (when) drug susceptibility test results are known and the organisms are fully susceptible, EMB need not be included. For children whose visual acuity cannot be monitored, EMB is usually not recommended except when there is an increased likelihood of the disease being caused by INH-resistant organisms (Table 6) or when the child has adult-type (upper lobe inltration, cavity formation) tuberculosis. If PZA cannot be included in the initial phase of treatment, or if the isolate is resistant to PZA alone (an unusual circumstance), the initial phase should consist of INH, RIF, and EMB given daily for 2 months (Regimen 4). Examples of circumstances in which PZA may be withheld include severe liver disease, gout, and, perhaps, pregnancy. EMB should be included in the initial phase of Regimen 4 until drug susceptibility is determined. The initial phase may be given daily throughout (Regimens 1 and 4), daily for 2 weeks and then twice weekly for 6 weeks (Regimen 2), or three times weekly throughout (Regimen 3). For patients receiving daily therapy, EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate
American Thoracic Society Documents TABLE 1. INFECTIOUS DISEASES SOCIETY OF AMERICA/UNITED STATES PUBLIC HEALTH SERVICE RATING SYSTEM FOR THE STRENGTH OF TREATMENT RECOMMENDATIONS BASED ON QUALITY OF EVIDENCE*
Strength of the recommendation A. Preferred; should generally be offered B. Alternative; acceptable to offer C. Offer when preferred or alternative regimens cannot be given D. Should generally not be offered E. Should never be offered Quality of evidence supporting the recommendation I. At least one properly randomized trial with clinical end points II. Clinical trials that either are not randomized or were conducted in other populations III. Expert opinion * Reprinted by permission from Gross PA, Barrett TL, Dellinger EP, Krause PJ, Martone WJ, McGowan JE Jr, Sweet RL, Wenzel RP. Clin Infect Dis 1994;18:421.
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that the isolate is susceptible to INH and RIF. When the patient is receiving less than daily drug administration, expert opinion suggests that EMB can be discontinued safely in less than 2 months (i.e., when susceptibility test results are known), but there is no evidence to support this approach. Although clinical trials have shown that the efcacy of streptomycin (SM) is approximately equal to that of EMB in the initial phase of treatment, the increasing frequency of resistance to SM globally has made the drug less useful. Thus, SM is not recommended as being interchangeable with EMB unless the organism is known to be susceptible to the drug or the patient is from a population in which SM resistance is unlikely. The continuation phase (Table 2) of treatment is given for either 4 or 7 months. The 4-month continuation phase should be
used in the large majority of patients. The 7-month continuation phase is recommended only for three groups: patients with cavitary pulmonary tuberculosis caused by drug-susceptible organisms and whose sputum culture obtained at the time of completion of 2 months of treatment is positive; patients whose initial phase of treatment did not include PZA; and patients being treated with once weekly INH and rifapentine and whose sputum culture obtained at the time of completion of the initial phase is positive. The continuation phase may be given daily (Regimens 1a and 4a), two times weekly by DOT (Regimens 1b, 2a, and 4b), or three times weekly by DOT (Regimen 3a). For human immunodeciency virus (HIV)-seronegative patients with noncavitary pulmonary tuberculosis (as determined by standard chest radiography), and negative sputum smears at completion
TABLE 2. DRUG REGIMENS FOR CULTURE-POSITIVE PULMONARY TUBERCULOSIS CAUSED BY DRUG-SUSCEPTIBLE ORGANISMS
Initial Phase Regimen Drugs 1 INH RIF PZA EMB INH RIF PZA EMB INH RIF PZA EMB INH RIF EMB Interval and Doses (minimal duration) Seven days per week for 56 doses (8 wk) or 5 d/wk for 40 doses (8 wk) Regimen 1a 1b 1c** Seven days per week for 14 doses (2 wk), then twice weekly for 12 doses (6 wk) or 5 d/wk for 10 doses (2 wk), then twice weekly for 12 doses (6 wk) Three times weekly for 24 doses (8 wk) 2a 2b** Drugs Continuation Phase Interval and Doses, (minimal duration) Range of Total Doses (minimal duration) 182130 (26 wk) 9276 (26 wk) 7458 (26 wk) 6258 (26 wk) 4440 (26 wk) Rating* (Evidence) HIV A (I) A (I) B (I) A (II) B (I) HIV A (II) A (II)# E (I) B (II)# E (I)
INH/RIF Seven days per week for 126 doses (18 wk) or 5 d/wk for 90 doses (18 wk) INH/RIF Twice weekly for 36 doses (18 wk) INH/RPT Once weekly for 18 doses (18 wk) INH/RIF Twice weekly for 36 doses (18 wk) INH/RPT Once weekly for 18 doses (18 wk)
3a
INH/RIF Three times weekly for 54 doses (18 wk)
78 (26 wk)
B (I)
B (II)
Seven days per week for 56 doses (8 wk) or 5 d/wk for 40 doses (8 wk)
4a 4b
INH/RIF Seven days per week for 217 doses (31 wk) or 5 d/wk for 155 doses (31 wk) INH/RIF Twice weekly for 62 doses (31 wk)
273195 (39 wk) 118102 (39 wk)
C (I) C (I)
C (II) C (II)
Definition of abbreviations: EMB Ethambutol; INH isoniazid; PZA pyrazinamide; RIF rifampin; RPT rifapentine. * Definitions of evidence ratings: A preferred; B acceptable alternative; C offer when A and B cannot be given; E should never be given. Definitions of evidence ratings: I randomized clinical trial; II data from clinical trials that were not randomized or were conducted in other populations; III expert opinion. When DOT is used, drugs may be given 5 days/week and the necessary number of doses adjusted accordingly. Although there are no studies that compare five with seven daily doses, extensive experience indicates this would be an effective practice. Patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31-week; either 217 doses [daily] or 62 doses [twice weekly]) continuation phase. Five-day-a-week administration is always given by DOT. Rating for 5 day/week regimens is AIII. # Not recommended for HIV-infected patients with CD4 cell counts 100 cells/ml. ** Options 1c and 2b should be used only in HIV-negative patients who have negative sputum smears at the time of completion of 2 months of therapy and who do not have cavitation on the initial chest radiograph (see text). For patients started on this regimen and found to have a positive culture from the 2-month specimen, treatment should be extended an extra 3 months.
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TABLE 3. DOSES* OF ANTITUBERCULOSIS DRUGS FOR ADULTS AND CHILDREN

Doses Drug Preparation Adults/Children Daily First-Line Drugs 5 mg/kg (300 mg) 1015 mg/kg (300 mg) 1 /wk 2 /wk 3 /wk
Isoniazid
Rifampin
Rifabutin
Tablets (50 mg, 100 mg, 300 mg); elixir (50 mg/5ml); aqueous solution (100 mg/ml) for intravenous or intramuscular injection Capsule (150 mg, 300 mg); powder may be suspended for oral administration; aqueous solution for intravenous injection Capsule (150 mg)
Adults (max.) Children (max.)
15 mg/kg (900 mg)
15 mk/kg (900 mg) 15 mg/kg (900 mg) 2030 mg/kg (900 mg)
10 mg/kg (600 mg) 1020 mg/kg (600 mg)
10 mg/kg (600 mg) 10 mg/kg (600 mg) 1020 mg/kg (600 mg)
Rifapentine
Tablet (150 mg, film coated)
Pyrazinamide Ethambutol
Tablet (500 mg, scored) Tablet (100 mg; 400 mg)
Cycloserine
Capsule (250 mg)
Ethionamide
Tablet (250 mg)
Streptomycin
Amikacin/ kanamycin
Aqueous solution (1-g vials) for intravenous or intramuscular administration Aqueous solution (500 mg and 1-g vials) for intravenous or intramuscular administration
Appropriate dosing for children is unknown Adults 10 mg/kg (continuation phase) (600 mg) Children The drug is not The drug is not approved for use approved for use in children in children Adults See Table 4 Children (max.) 1530 mg/kg (2.0 g) Adults See Table 5 Children (max.) 1520 mg/kg daily (1.0 g) Second-Line Drugs Adults (max.) 1015 mg/kg/d (1.0 g There are no data to in two doses), usually support intermittent 500750 mg/d in administration two doses Children (max.) 1015 mg/kg/d (1.0 g/d) 1520 mg/kg/d (1.0 g/d), There are no data to Adults# (max.) usually 500750 mg/d support intermittent in a single daily dose administration or two divided doses# Children (max.) 1520 mg/kg/d (1.0 g/d) There are no data to support intermittent administration Adults (max.) ** ** Children (max.) Adults (max.) Children (max.) 2040 mg/kg/d (1 g) ** 1530 mg/kg/d (1 g) intravenous or intramuscular as a single daily dose ** **
Adults (max.) Children
5 mg/kg (300 mg) Appropriate dosing for children is unknown
5 mg/kg (300 mg) Appropriate dosing for children is unknown The drug is not approved for use in children See Table 4 50 mg/kg (4 g) See Table 5 50 mg/kg (4 g) There are no data to support intermittent administration There are no data to support intermittent administration There are no data to support intermittent administration ** 20 mg/kg ** 1530 mg/kg
5 mg/kg (300 mg) Appropriate dosing for children is unknown The drug is not approved for use in children See Table 4 See Table 5 There are no data to support intermittent administration There are no data to support intermittent administration There are no data to support intermittent administration ** **
Capreomycin
Aqueous solution (1-g vials) for intravenous or intramuscular administration
**
** 1530 mg/kg There are no data to support intermittent administration There are no data to support intermittent administration There are no data to support intermittent administration
** There are no data to support intermittent administration There are no data to support intermittent administration There are no data to support intermittent administration
p-Aminosalicylic Granules (4-g packets) can be mixed Adults acid (PAS) with food; tablets (500 mg) are still available in some countries, but not in the United States; Children a solution for intravenous administration is available in Europe Levofloxacin Tablets (250 mg, 500 mg, 750 mg); Adults aqueous solution (500-mg vials) for intravenous injection Children Moxifloxacin Tablets (400 mg); aqueous solution Adults (400 mg/250 ml) for intravenous injection Children Gatifloxacin Tablets (400 mg); aqueous solution Adults (200/20 ml; 400 mg/40 ml) for intravenous injection Children
1530 mg/kg/d (1 g) as a single daily dose 812 g/d in two or There are no data to three doses support intermittent administration 200300 mg/kg/d in two There are no data to to four divided doses support intermittent (10 g) administration 5001,000 mg daily
There are no data to support intermittent administration
400 mg daily
400 mg daily
* Dose per weight is based on ideal body weight. Children weighing more than 40 kg should be dosed as adults. For purposes of this document adult dosing begins at age 15 years. Dose may need to be adjusted when there is concomitant use of protease inhibitors or nonnucleoside reverse transcriptase inhibitors. The drug can likely be used safely in older children but should be used with caution in children less than 5 years of age, in whom visual acuity cannot be monitored. In younger children EMB at the dose of 15 mg/kg per day can be used if there is suspected or proven resistance to INH or RIF. It should be noted that, although this is the dose recommended generally, most clinicians with experience using cycloserine indicate that it is unusual for patients to be able to tolerate this amount. Serum concentration measurements are often useful in determining the optimal dose for a given patient. # The single daily dose can be given at bedtime or with the main meal. ** Dose: 15 mg/kg per day (1 g), and 10 mg/kg in persons more than 50 years of age (750 mg). Usual dose: 7501,000 mg administered intramuscularly or intravenously, given as a single dose 57 days/week and reduced to two or three times per week after the first 24 months or after culture conversion, depending on the efficacy of the other drugs in the regimen. The long-term (more than several weeks) use of levofloxacin in children and adolescents has not be approved because of concerns about effects on bone and cartilage growth. However, most experts agree that the drug should be considered for children with tuberculosis caused by organisms resistant to both INH and RIF. The optimal dose is not known. The long-term (more than several weeks) use of moxifloxacin in children and adolescents has not been approved because of concerns about effects on bone and cartilage growth. The optimal dose is not known. The long-term (more than several weeks) use of gatifloxacin in children and adolescents has not been approved because of concerns about effects on bone and cartilage growth. The optimal dose is not known.
American Thoracic Society Documents TABLE 4. SUGGESTED PYRAZINAMIDE DOSES, USING WHOLE TABLETS, FOR ADULTS WEIGHING 4090 KILOGRAMS
Weight (kg)* 4055 Daily, mg (mg/kg) Thrice weekly, mg (mg/kg) Twice weekly, mg (mg/kg) * Based on estimated lean body weight. Maximum dose regardless of weight. 1,000 (18.225.0) 1,500 (27.337.5) 2,000 (36.450.0) 5675 1,500 (20.026.8) 2,500 (33.344.6) 3,000 (40.053.6) 7690 2,000 (22.226.3) 3,000 (33.339.5) 4,000 (44.452.6)
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of 2 months of treatment, the continuation phase may consist of rifapentine and INH given once weekly for 4 months by DOT (Regimens 1c and 2b) (Figure 1). If the culture at completion of the initial phase of treatment is positive, the once weekly INH and rifapentine continuation phase should be extended to 7 months. All of the 6-month regimens, except the INH rifapentine once weekly continuation phase for persons with HIV infection (Rating EI), are rated as AI or AII, or BI or BII, in both HIV-infected and uninfected patients. The once-weekly continuation phase is contraindicated (Rating EI) in patients with HIV infection because of an unacceptable rate of failure/ relapse, often with rifamycin-resistant organisms. For the same reason twice weekly treatment, either as part of the initial phase (Regimen 2) or continuation phase (Regimens 1b and 2a), is not recommended for HIV-infected patients with CD4 cell counts 100 cells/ l. These patients should receive either daily (initial phase) or three times weekly (continuation phase) treatment. Regimen 4 (and 4a/4b), a 9-month regimen, is rated CI for patients without HIV infection and CII for those with HIV infection.
Deciding to Initiate Treatment
The decision to initiate combination antituberculosis chemotherapy should be based on epidemiologic information; clinical, pathological, and radiographic ndings; and the results of microscopic examination of acid-fast bacilli (AFB)stained sputum (smears) (as well as other appropriately collected diagnostic specimens) and cultures for mycobacteria. A puried protein derivative (PPD)-tuberculin skin test may be done at the time of initial evaluation, but a negative PPD-tuberculin skin test does not exclude the diagnosis of active tuberculosis. However, a positive PPD-tuberculin skin test supports the diagnosis of culture-negative pulmonary tuberculosis, as well as latent tuberculosis infection in persons with stable abnormal chest radiographs consistent with inactive tuberculosis (see below). If the suspicion of tuberculosis is high or the patient is seriously ill with a disorder, either pulmonary or extrapulmonary, that is thought possibly to be tuberculosis, combination chemotherapy using one of the recommended regimens should be initi-
ated promptly, often before AFB smear results are known and usually before mycobacterial culture results have been obtained. A positive AFB smear provides strong inferential evidence for the diagnosis of tuberculosis. If the diagnosis is conrmed by isolation of M. tuberculosis or a positive nucleic acid amplication test, treatment can be continued to complete a standard course of therapy (Figure 1). When the initial AFB smears and cultures are negative, a diagnosis other than tuberculosis should be considered and appropriate evaluations undertaken. If no other diagnosis is established and the PPD-tuberculin skin test is positive (in this circumstance a reaction of 5 mm or greater induration is considered positive), empirical combination chemotherapy should be initiated. If there is a clinical or radiographic response within 2 months of initiation of therapy and no other diagnosis has been established, a diagnosis of culture-negative pulmonary tuberculosis can be made and treatment continued with an additional 2 months of INH and RIF to complete a total of 4 months of treatment, an adequate regimen for culture-negative pulmonary tuberculosis (Figure 2). If there is no clinical or radiographic response by 2 months, treatment can be stopped and other diagnoses including inactive tuberculosis considered. If AFB smears are negative and suspicion for active tuberculosis is low, treatment can be deferred until the results of mycobacterial cultures are known and a comparison chest radiograph is available (usually within 2 months) (Figure 2). In low-suspicion patients not initially being treated, if cultures are negative, the PPD-tuberculin skin test is positive (5 mm or greater induration), and the chest radiograph is unchanged after 2 months, the three regimens recommended for the treatment of latent tuberculosis infection could be used. These include (1 ) INH for a total of 9 months, (2 ) RIF with or without INH for a total of 4 months, or (3 ) RIF and PZA for a total of 2 months. Because of reports of an increased rate of hepatotoxicity with the RIFPZA regimen, it should be reserved for patients who are not likely to complete a longer course of treatment, can be monitored closely, and do not have contraindications to the use of this regimen.
Baseline and Follow-Up Evaluations
Patients suspected of having tuberculosis should have appropriate specimens collected for microscopic examination and my-
TABLE 5. SUGGESTED ETHAMBUTOL DOSES, USING WHOLE TABLETS, FOR ADULTS WEIGHING 4090 KILOGRAMS
Weight (kg)* 4055 Daily, mg (mg/kg) Thrice weekly, mg (mg/kg) Twice weekly, mg (mg/kg) * Based on estimated lean body weight. Maximum dose regardless of weight. 800 (14.520.0) 1,200 (21.830.0) 2,000 (36.450.0) 5675 1,200 (16.021.4) 2,000 (26.735.7) 2,800 (37.350.0) 7690 1,600 (17.821.1) 2,400 (26.731.6) 4,000 (44.452.6)
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Figure 1. Treatment algorithm for tuberculosis. Patients in whom tuberculosis is proved or strongly suspected should have treatment initiated with isoniazid, rifampin, pyrazinamide, and ethambutol for the initial 2 months. A repeat smear and culture should be performed when 2 months of treatment has been completed. If cavities were seen on the initial chest radiograph or the acid-fast smear is positive at completion of 2 months of treatment, the continuation phase of treatment should consist of isoniazid and rifampin daily or twice weekly for 4 months to complete a total of 6 months of treatment. If cavitation was present on the initial chest radiograph and the culture at the time of completion of 2 months of therapy is positive, the continuation phase should be lengthened to 7 months (total of 9 months of treatment). If the patient has HIV infection and the CD4 cell count is 100/ l the continuation phase should consist of daily or three times weekly isoniazid and rifampin. In HIV-uninfected patients having no cavitation on chest radiograph and negative acid-fast smears at completion of 2 months of treatment, the continuation phase may consist of either once weekly isoniazid and rifapentine, or daily or twice weekly isoniazid and rifampin, to complete a total of 6 months (bottom). Patients receiving isoniazid and rifapentine, and whose 2-month cultures are positive, should have treatment extended by an additional 3 months (total of 9 months). *EMB may be discontinued when results of drug susceptibility testing indicate no drug resistance. PZA may be discontinued after it has been taken for 2 months (56 doses). RPT should not be used in HIV-infected patients with tuberculosis or in patients with extrapulmonary tuberculosis. Therapy should be extended to 9 months if 2-month culture is positive. CXR chest radiograph; EMB ethambutol; INH isoniazid; PZA pyrazinamide; RIF rifampin; RPT rifapentine.
cobacterial culture. When the lung is the site of disease, three sputum specimens should be obtained. Sputum induction with hypertonic saline may be necessary to obtain specimens and bronchoscopy (both performed under appropriate infection control measures) may be considered for patients who are unable to produce sputum, depending on the clinical circumstances. Susceptibility testing for INH, RIF, and EMB should be performed on a positive initial culture, regardless of the source of the specimen. Second-line drug susceptibility testing should be done only in reference laboratories and be limited to specimens from patients who have had prior therapy, who are contacts of patients with drug-resistant tuberculosis, who have demonstrated resistance to rifampin or to other rst-line drugs, or who have positive cultures after more than 3 months of treatment. It is recommended that all patients with tuberculosis have counseling and testing for HIV infection, at least by the time treatment is initiated, if not earlier. For patients with HIV infection, a CD4 lymphocyte count should be obtained. Patients with risk factors for hepatitis B or C viruses (e.g., injection drug use, foreign birth in Asia or Africa, HIV infection) should have serologic tests for these viruses. For all adult patients baseline measurements of serum amino transferases (aspartate aminotransferase [AST], alanine aminotransferase [ALT]), bilirubin,
alkaline phosphatase, and serum creatinine and a platelet count should be obtained. Testing of visual acuity and red-green color discrimination should be obtained when EMB is to be used. During treatment of patients with pulmonary tuberculosis, a sputum specimen for microscopic examination and culture should be obtained at a minimum of monthly intervals until two consecutive specimens are negative on culture. More frequent AFB smears may be useful to assess the early response to treatment and to provide an indication of infectiousness. For patients with extrapulmonary tuberculosis the frequency and kinds of evaluations will depend on the site involved. In addition, it is critical that patients have clinical evaluations at least monthly to identify possible adverse effects of the antituberculosis medications and to assess adherence. Generally, patients do not require follow-up after completion of therapy but should be instructed to seek care promptly if signs or symptoms recur. Routine measurements of hepatic and renal function and platelet count are not necessary during treatment unless patients have baseline abnormalities or are at increased risk of hepatotoxicity (e.g., hepatitis B or C virus infection, alcohol abuse). At each monthly visit patients taking EMB should be questioned regarding possible visual disturbances including blurred vision or scotomata; monthly testing of visual acuity and color discrimi-
TABLE 6. EPIDEMIOLOGICAL CIRCUMSTANCES IN WHICH AN EXPOSED PERSON IS AT INCREASED RISK OF INFECTION WITH DRUG-RESISTANT Mycobacterium Tuberculosis*
Exposure to a person who has known drug-resistant tuberculosis Exposure to a person with active tuberculosis who has had prior treatment for tuberculosis (treatment failure or relapse) and whose susceptibility test results are not known Exposure to persons with active tuberculosis from areas in which there is a high prevalence of drug resistance Exposure to persons who continue to have positive sputum smears after 2 months of combination chemotherapy Travel in an area of high prevalence of drug resistance * This information is to be used in deciding whether or not to add a fourth drug (usually EMB) for children with active tuberculosis, not to infer the empiric need for a second-line treatment regimen.
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Figure 2. Treatment algorithm for active, culturenegative pulmonary tuberculosis and inactive tuberculosis. The decision to begin treatment for a patient with sputum smears that are negative depends on the degree of suspicion that the patient has tuberculosis. The considerations in choosing among the treatment options are discussed in text. If the clinical suspicion is high (bottom), then multidrug therapy should be initiated before acid-fast smear and culture results are known. If the diagnosis is confirmed by a positive culture, treatment can be continued to complete a standard course of therapy (see Figure 1). If initial cultures remain negative and treatment has consisted of multiple drugs for 2 months, then there are two options depending on repeat evaluation at 2 months (bottom): (1 ) if the patients demonstrates symptomatic or radiographic improvement without another apparent diagnosis, then a diagnosis of culture-negative tuberculosis can be inferred. Treatment should be continued with isoniazid and rifampin alone for an additional 2 months; (2 ) if the patient demonstrates neither symptomatic nor radiographic improvement then prior tuberculosis is unlikely and treatment is complete once treatment including at least 2 months of rifampin and pyrazinamide has been administered. In low-suspicion patients not initially receiving treatment (top), if cultures remain negative, the patient has no symptoms, and the chest radiograph is unchanged at 23 months, there are three treatment options: these are (1 ) isoniazid for 9 months, (2 ) rifampin with or without isoniazid for 4 months, or (3 ) rifampin and pyrazinamide for 2 months. CXR Chest X-ray; EMB ethambutol; INH isoniazid; PZA pyrazinamide; RIF rifampin; Sx signs/symptoms. (It should be noted that the RIF/ PZA 2-month regimen should be used only for patients who are not likely to complete a longer course of treatment and can be monitored closely.)
nation is recommended for patients taking doses that on a milligram per kilogram basis are greater than those listed in Table 5 and for patients receiving the drug for longer than 2 months.
Identification and Management of Patients at Increased Risk of Treatment Failure and Relapse
The presence of cavitation on the initial chest radiograph combined with having a positive sputum culture at the time the initial phase of treatment is completed has been shown in clinical trials to identify patients at high risk for adverse outcomes (treatment failure, usually dened by positive cultures after 4 months of treatment, or relapse, dened by recurrent tuberculosis at any time after completion of treatment and apparent cure). For this reason it is particularly important to conduct a microbiological evaluation 2 months after initiation of treatment (Figure 1). Approximately 80% of patients with pulmonary tuberculosis caused by drug-susceptible organisms who are started on standard four-drug therapy will have negative sputum cultures at this time. Patients with positive cultures after 2 months of treatment should undergo careful evaluation to determine the cause. For patients who have positive cultures after 2 months of treatment and have not been receiving DOT, the most common reason is nonadherence to the regimen. Other possibilities, especially for patients receiving DOT, include extensive cavitary disease at the time of diagnosis, drug resistance, malabsorption of drugs, laboratory error, and biological variation in response. In USPHS Study 22, nearly 21% of patients in the control arm of the study (a continuation phase of twice weekly INH
and RIF) who had both cavitation on the initial chest radiograph and a positive culture at the 2-month juncture relapsed. Patients who had only one of these factors (either cavitation or a positive 2-month culture) had relapse rates of 56% compared with 2% for patients who had neither risk factor. In view of this evidence, it is recommended that, for patients who have cavitation on the initial chest radiograph and whose 2-month culture is positive, the minimum duration of treatment should be 9 months (a total of 84273 doses depending on whether the drugs are given daily or intermittently) (Figure 1 and Table 2). The recommendation to lengthen the continuation phase of treatment is based on expert opinion and on the results of a study of the optimal treatment duration for patients with silicotuberculosis showing that extending treatment from 6 to 8 months greatly reduced the rate of relapse (Rating AIII). The recommendation is also supported by the results of a trial in which the once weekly INHrifapentine continuation phase was extended to 7 months for patients at high risk of relapse. The rate of relapse was reduced signicantly compared with historical control subjects from another trial in which the continuation phase was 4 months. For patients who have either cavitation on the initial lm or a positive culture after completing the initial phase of treatment (i.e., at 2 months), the rates of relapse were 56%. In this group decisions to prolong the continuation phase should be made on an individual basis.
Completion of Treatment
A full course of therapy (completion of treatment) is determined more accurately by the total number of doses taken, not solely
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by the duration of therapy. For example, the 6-month daily regimen (given 7 days/week; see below) should consist of at least 182 doses of INH and RIF, and 56 doses of PZA. Thus, 6 months is the minimum duration of treatment and accurately indicates the amount of time the drugs are given only if there are no interruptions in drug administration. In some cases, either because of drug toxicity or nonadherence to the treatment regimen, the specied number of doses cannot be administered within the targeted period. In such cases the goal is to deliver the specied number of doses within a recommended maximum time. For example, for a 6-month daily regimen the 182 doses should be administered within 9 months of beginning treatment. If treatment is not completed within this period, the patient should be assessed to determine the appropriate action to take continuing treatment for a longer duration or restarting treatment from the beginning, either of which may require more restrictive measures to be used to ensure completion. Clinical experience suggests that patients being managed by DOT administered 5 days/week have a rate of successful therapy equivalent to those being given drugs 7 days/week. Thus, daily therapy may be interpreted to mean DOT given 5 days/week and the required number of doses adjusted accordingly. For example, for the 6-month daily regimen given 5 days/week the planned total number of doses is 130. (Direct observation of treatment given 5 days/week has been used in a number of clinical trials, including USPHS Study 22, but has not been evaluated in a controlled trial, thus, this modication should be rated AIII.) As an option, patients might be given the medications to take without DOT on weekends. Interruptions in treatment may have a signicant effect on the duration of therapy. Reinstitution of treatment must take into account the bacillary load of the patient, the point in time when the interruption occurred, and the duration of the interruption. In general, the earlier in treatment and the longer the duration of the interruption, the more serious the effect and the greater the need to restart therapy from the beginning.
Practical Aspects of Patient Management during Treatment
the hour of dosing is recommended. Administration with food is preferable to splitting a dose or changing to a second-line drug. Drug-induced hepatitis, the most serious common adverse effect, is dened as a serum AST level more than three times the upper limit of normal in the presence of symptoms, or more than ve times the upper limit of normal in the absence of symptoms. If hepatitis occurs INH, RIF, and PZA, all potential causes of hepatic injury, should be stopped immediately. Serologic testing for hepatitis viruses A, B, and C (if not done at baseline) should be performed and the patient questioned carefully regarding exposure to other possible hepatotoxins, especially alcohol. Two or more antituberculosis medications without hepatotoxicity, such as EMB, SM, amikacin/kanamycin, capreomycin, or a uoroquinolone (levooxacin, moxioxacin, or gatioxacin), may be used until the cause of the hepatitis is identied. Once the AST level decreases to less than two times the upper limit of normal and symptoms have signicantly improved, the rst-line medications should be restarted in sequential fashion. Close monitoring, with repeat measurements of serum AST and bilirubin and symptom review, is essential in managing these patients.
Treatment in Special Situations
The rst-line antituberculosis medications should be administered together; split dosing should be avoided. Fixed-dose combination preparations may be administered more easily than single drug tablets and may decrease the risk of acquired drug resistance and medication errors. Fixed-dose combinations may be used when DOT is given daily and are especially useful when DOT is not possible, but they are not formulated for use with intermittent dosing. It should be noted that for patients weighing more than 90 kg the dose of PZA in the three-drug combination is insufcient and additional PZA tablets are necessary. There are two combination formulations approved for use in the United States: INH and RIF (Rifamate) and INH, RIF, and PZA (Rifater). Providers treating patients with tuberculosis must be especially vigilant for drug interactions. Given the frequency of comorbid conditions, it is quite common for patients with tuberculosis to be taking a variety of other medications, the effects of which may be altered by the antituberculosis medications, especially the rifamycins. These interactions are described in Section 7 (Drug Interactions). Adverse effects, especially gastrointestinal upset, are relatively common in the rst few weeks of antituberculosis therapy; however, rst-line antituberculosis drugs, particularly RIF, must not be discontinued because of minor side effects. Although ingestion with food delays or moderately decreases the absorption of antituberculosis drugs, the effects of food are of little clinical signicance. Thus, if patients have epigastric distress or nausea with the rst-line drugs, dosing with meals or changing
HIV infection. Recommendations for the treatment of tuberculosis in HIV-infected adults are, with a few exceptions, the same as those for HIV-uninfected adults (Table 2). The INHrifapentine once weekly continuation phase (Regimens 1c and 2b) is contraindicated in HIV-infected patients because of an unacceptably high rate of relapse, frequently with organisms that have acquired resistance to rifamycins. The development of acquired rifampin resistance has also been noted among HIV-infected patients with advanced immunosuppression treated with twice weekly rifampin- or rifabutin-based regimens. Consequently, pa100/ l should receive daily or tients with CD4 cell counts three times weekly treatment (Regimen 1/1a or Regimen 3/3a). DOT and other adherence-promoting strategies are especially important for patients with HIV-related tuberculosis. Management of HIV-related tuberculosis is complex and requires expertise in the management of both HIV disease and tuberculosis. Because HIV-infected patients are often taking numerous medications, some of which interact with antituberculosis medications, it is strongly encouraged that experts in the treatment of HIV-related tuberculosis be consulted. A particular concern is the interaction of rifamycins with antiretroviral agents and other antiinfective drugs. Rifampin can be used for the treatment of tuberculosis with certain combinations of antiretroviral agents. Rifabutin, which has fewer problematic drug interactions, may also be used in place of rifampin and appears to be equally effective although the doses of rifabutin and antiretroviral agents may require adjustment. As new antiretroviral agents and more pharmacokinetic data become available, these recommendations are likely to be modied. On occasion, patients with HIV-related tuberculosis may experience a temporary exacerbation of symptoms, signs, or radiographic manifestations of tuberculosis while receiving antituberculosis treatment. This clinical or radiographic worsening (paradoxical reaction) occurs in HIV-infected patients with active tuberculosis and is thought to be the result of immune reconstitution as a consequence of effective antiretroviral therapy. Symptoms and signs may include high fevers, lymphadenopathy, expanding central nervous system lesions, and worsening of chest radiographic ndings. The diagnosis of a paradoxical reaction should be made only after a thorough evaluation has excluded other etiologies, particularly tuberculosis treatment failure. Nonsteroidal antiinammatory agents may be useful for
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symptomatic relief. For severe paradoxical reactions, prednisone (12 mg/kg per day for 12 weeks, then in gradually decreasing doses) may be used, although there are no data from controlled trials to support this approach (Rating CIII). Children. Because of the high risk of disseminated tuberculosis in infants and children younger than 4 years of age, treatment should be started as soon as the diagnosis of tuberculosis is suspected. In general, the regimens recommended for adults are also the regimens of choice for infants, children, and adolescents with tuberculosis, with the exception that ethambutol is not used routinely in children. Because there is a lower bacillary burden in childhood-type tuberculosis there is less concern with the development of acquired drug resistance. However, children and adolescents may develop adult-type tuberculosis with upper lobe inltration, cavitation, and sputum production. In such situations an initial phase of four drugs should be given until susceptibility is proven. When clinical or epidemiologic circumstances (Table 6) suggest an increased probability of INH resistance, EMB can be used safely at a dose of 1520 mg/kg per day, even in children too young for routine eye testing. Streptomycin, kanamycin, or amikacin also can be used as the fourth drug, when necessary. Most studies of treatment in children have used 6 months of INH and RIF supplemented during the rst 2 months with PZA. This three-drug combination has a success rate of greater than 95% and an adverse drug reaction rate of less than 2%. Although most treatment studies in children have used daily drug administration for the rst 2 weeks to 2 months, it appears that a three times weekly regimen from the beginning is equally efcacious. DOT should always be used in treating children. Because it is difcult to isolate M. tuberculosis from a child with pulmonary tuberculosis, it is frequently necessary to rely on the results of drug susceptibility tests of the organisms isolated from the presumed source case to guide the choice of drugs for the child. In cases of suspected drug-resistant tuberculosis in a child or when a source case isolate is not available, specimens for microbiological evaluation should be obtained via early morning gastric aspiration, bronchoalveolar lavage, or biopsy. In general, extrapulmonary tuberculosis in children can be treated with the same regimens as pulmonary disease. Exceptions are disseminated tuberculosis and tuberculous meningitis, for which there are inadequate data to support 6-month therapy; thus 912 months of treatment is recommended. The optimal treatment of pulmonary tuberculosis in children and adolescents with HIV infection is unknown. The American Academy of Pediatrics recommends that initial therapy should always include at least three drugs, and the total duration of therapy should be at least 9 months, although there are no data to support this recommendation. Extrapulmonary tuberculosis. The basic principles that underlie the treatment of pulmonary tuberculosis also apply to extrapulmonary forms of the disease. Although relatively few studies have examined treatment of extrapulmonary tuberculosis, increasing evidence suggests that 6- to 9-month regimens that include INH and RIF are effective. Thus, a 6-month course of therapy is recommended for treating tuberculosis involving any site with the exception of the meninges, for which a 9- 12-month regimen is recommended. Prolongation of therapy also should be considered for patients with tuberculosis in any site that is slow to respond. The addition of corticosteroids is recommended for patients with tuberculous pericarditis and tuberculous meningitis. Culture-negative pulmonary tuberculosis and radiographic evidence of prior pulmonary tuberculosis. Failure to isolate M. tuberculosis from persons suspected of having pulmonary tuberculosis on the basis of clinical features and chest radiographic examination does not exclude a diagnosis of active tuberculosis.
Alternative diagnoses should be considered carefully and further appropriate diagnostic studies undertaken in persons with apparent culture-negative tuberculosis. The general approach to management is shown in Figure 2. A diagnosis of tuberculosis can be strongly inferred by the clinical and radiographic response to antituberculosis treatment. Careful reevaluation should be performed after 2 months of therapy to determine whether there has been a response attributable to antituberculosis treatment. If either clinical or radiographic improvement is noted and no other etiology is identied, treatment should be continued for active tuberculosis. Treatment regimens in this circumstance include one of the standard 6-month chemotherapy regimens or INH, RIF, PZA, and EMB for 2 months followed by INH and RIF for an additional 2 months (4 months total). However, HIVinfected patients with culture-negative pulmonary tuberculosis should be treated for a minimum of 6 months. Persons with a positive tuberculin skin test who have radiographic evidence of prior tuberculosis (e.g., upper lobe bronodular inltrations) but who have not received adequate therapy are at increased risk for the subsequent development of tuberculosis. Unless previous radiographs are available showing that the abnormality is stable, it is recommended that sputum examination (using sputum induction if necessary) be performed to assess the possibility of active tuberculosis being present. Also, if the patient has symptoms of tuberculosis related to an extrapulmonary site, an appropriate evaluation should be undertaken. Once active tuberculosis has been excluded (i.e., by negative cultures and a stable chest radiograph), the treatment regimens are those used for latent tuberculosis infection: INH for 9 months, RIF (with or without INH) for 4 months, or RIF and PZA for 2 months (for patients who are unlikely to complete a longer course and who can be monitored closely) (Figure 2). Renal insufciency and end-stage renal disease. Specic dosing guidelines for patients with renal insufciency and end-stage renal disease are provided in Table 15. For patients undergoing hemodialysis, administration of all drugs after dialysis is preferred to facilitate DOT and to avoid premature removal of drugs such as PZA and cycloserine. To avoid toxicity it is important to monitor serum drug concentrations in persons with renal failure who are taking cycloserine or EMB. There is little information concerning the effects of peritoneal dialysis on clearance of antituberculosis drugs. Liver disease. INH, RIF, and PZA all can cause hepatitis that may result in additional liver damage in patients with preexisting liver disease. However, because of the effectiveness of these drugs (particularly INH and RIF), they should be used if at all possible, even in the presence of preexisting liver disease. If serum AST is more than three times normal before the initiation of treatment (and the abnormalities are not thought to be caused by tuberculosis), several treatment options exist. One option is to treat with RIF, EMB, and PZA for 6 months, avoiding INH. A second option is to treat with INH and RIF for 9 months, supplemented by EMB until INH and RIF susceptibility are demonstrated, thereby avoiding PZA. For patients with severe liver disease a regimen with only one hepatotoxic agent, generally RIF plus EMB, could be given for 12 months, preferably with another agent, such as a uoroquinolone, for the rst 2 months; however, there are no data to support this recommendation. In all patients with preexisting liver disease, frequent clinical and laboratory monitoring should be performed to detect druginduced hepatic injury. Pregnancy and breastfeeding. Because of the risk of tuberculosis to the fetus, treatment of tuberculosis in pregnant women should be initiated whenever the probability of maternal disease is moderate to high. The initial treatment regimen should consist
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of INH, RIF, and EMB. Although all of these drugs cross the placenta, they do not appear to have teratogenic effects. Streptomycin is the only antituberculosis drug documented to have harmful effects on the human fetus (congenital deafness) and should not be used. Although detailed teratogenicity data are not available, PZA can probably be used safely during pregnancy and is recommended by the World Health Organization (WHO) and the International Union against Tuberculosis and Lung Disease (IUATLD). If PZA is not included in the initial treatment regimen, the minimum duration of therapy is 9 months. Breastfeeding should not be discouraged for women being treated with the rst-line antituberculosis agents because the small concentrations of these drugs in breast milk do not produce toxicity in the nursing newborn. Conversely, drugs in breast milk should not be considered to serve as effective treatment for tuberculosis or for latent tuberculosis infection in a nursing infant. Pyridoxine supplementation (25 mg/day) is recommended for all women taking INH who are either pregnant or breastfeeding. The amount of pyridoxine in multivitamins is variable but generally less than the needed amount.
Management of Relapse, Treatment Failure, and Drug Resistance
Relapse refers to the circumstance in which a patient becomes and remains culture negative while receiving therapy but, at some point after completion of therapy, either becomes culture positive again or has clinical or radiographic deterioration that is consistent with active tuberculosis. In the latter situation rigorous efforts should be made to establish a diagnosis and to obtain microbiological conrmation of the relapse to enable testing for drug resistance. Most relapses occur within the rst 612 months after completion of therapy. In nearly all patients with tuberculosis caused by drug-susceptible organisms and who were treated with rifamycin-containing regimens using DOT, relapses occur with susceptible organisms. However, in patients who received self-administered therapy or a nonrifamycin regimen and who have a relapse, the risk of acquired drug resistance is substantial. In addition, if initial drug susceptibility testing was not performed and the patient fails or relapses with a rifamycin-containing regimen given by DOT, there is a high likelihood that the organisms were resistant from the outset. The selection of empirical treatment for patients with relapse should be based on the prior treatment scheme and severity of disease. For patients with tuberculosis that was caused by drugsusceptible organisms and who were treated under DOT, initiation of the standard four-drug regimen is appropriate until the results of drug susceptibility tests are available. However, for patients who have life-threatening forms of tuberculosis, at least three additional agents to which the organisms are likely to be susceptible should be included. For patients with relapse who did not receive DOT, who were not treated with a rifamycin-based regimen, or who are known or presumed to have had irregular treatment, it is prudent to infer that drug resistance is present and to begin an expanded regimen with INH, RIF, and PZA plus an additional two or three agents based on the probability of in vitro susceptibility. Usual agents to be employed would include a uoroquinolone (levooxacin, moxioxacin, or gatioxacin), an injectable agent such as SM (if not used previously and susceptibility to SM had been established), amikacin, kanamycin, or capreomycin, with or without an additional oral drug. Treatment failure is dened as continued or recurrently positive cultures during the course of antituberculosis therapy. After 3 months of multidrug therapy for pulmonary tuberculosis caused by drug-susceptible organisms, 9095% of patients will have negative cultures and show clinical improvement. Thus,
patients with positive cultures after 3 months of what should be effective treatment must be evaluated carefully to identify the cause of the delayed conversion. Patients whose sputum cultures remain positive after 4 months of treatment should be deemed treatment failures. Possible reasons for treatment failure in patients receiving appropriate regimens include nonadherence to the drug regimen (the most common reason), drug resistance, malabsorption of drugs, laboratory error, and extreme biological variation in response. If treatment failure occurs, early consultation with a specialty center is strongly advised. If failure is likely due to drug resistance and the patient is not seriously ill, an empirical retreatment regimen could be started or administration of an altered regimen could be deferred until results of drug susceptibility testing from a recent isolate are available. If the patient is seriously ill or sputum AFB smears are positive, an empirical regimen should be started immediately and continued until susceptibility tests are available. For patients who have treatment failure, M. tuberculosis isolates should be sent promptly to a reference laboratory for drug susceptibility testing to both rstand second-line agents. A fundamental principle in managing patients with treatment failure is never to add a single drug to a failing regimen; so doing leads to acquired resistance to the new drug. Instead, at least two, and preferably three, new drugs to which susceptibility could logically be inferred should be added to lessen the probability of further acquired resistance. Empirical retreatment regimens might include a uoroquinolone, an injectable agent such as SM (if not used previously and the patient is not from an area of the world having high rates of SM resistance), amikacin, kanamycin, or capreomycin, and an additional oral agent such as p-aminosalicylic acid (PAS), cycloserine, or ethionamide. Once drug-susceptibility test results are available, the regimen should be adjusted according to the results. Patients having tuberculosis caused by strains of M. tuberculosis resistant to at least INH and RIF (multidrug resistant [MDR]) are at high risk for treatment failure and further acquired drug resistance. Such patients should be referred to or consultation obtained from specialized treatment centers as identied by the local or state health departments or the Centers for Disease Control and Prevention. Although patients with strains resistant to RIF alone have a better prognosis than patients with MDR strains, they are also at increased risk for treatment failure and additional resistance and should be managed in consultation with an expert. Denitive randomized or controlled studies have not been performed to establish optimum regimens for treating patients with the various patterns of drug-resistant tuberculosis, thus, treatment recommendations are based on expert opinion, guided by a set of general principles specied in Section 9 (Management of Relapse, Treatment Failure, and Drug Resistance). Table 16 contains treatment regimens suggested for use in patients with various patterns of drug-resistant tuberculosis (all are rated AIII). The role of resectional surgery in the management of patients with extensive pulmonary MDR tuberculosis has not been established in randomized studies and results have been mixed. Surgery should be performed by surgeons with experience in these situations and only after the patient has received several months of intensive chemotherapy. Expert opinion suggests that chemotherapy should be continued for 12 years postoperatively to prevent relapse.
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Treatment of Tuberculosis in Low-Income Countries: Recommendations of the WHO and Guidelines from the IUATLD
To place the current guidelines in an international context it is necessary to have an understanding of the approaches to treatment of tuberculosis in high-incidence, low-income countries. It is important to recognize that the American Thoracic Society/ Centers for Disease Control and Prevention/Infectious Diseases Society of America (ATS/CDC/IDSA) recommendations cannot be assumed to be applicable under all epidemiologic and economic circumstances. The incidence of tuberculosis and the resources with which to confront the disease to an important extent determine the approaches used. Given the increasing proportion of patients in low-incidence countries who were born in high-incidence countries, it is also important for persons managing these cases to be familiar with the approaches used in the countries of origin. The major international recommendations and guidelines for treating tuberculosis are those of the WHO and of the IUATLD. The WHO document was developed by an expert committee whereas the IUATLD document is a distillation of IUATLD practice, validated in the eld. The WHO and IUATLD documents target, in general, countries in which mycobacterial culture, drug susceptibility testing, radiographic facilities, and second-line drugs are not widely available as a routine. A number of differences exist between these new ATS/CDC/IDSA recommendations, and the current tuberculosis treatment recommendations of the WHO and guidelines of the IUATLD. Both international sets of recommendations are built around a national case management strategy called DOTS, the acronym for directly observed therapy, short course, in which direct observation of therapy (DOT) is only one of ve key elements. The ve components of DOTS are (1 ) government commitment to sustained tuberculosis control activities, (2 ) case detection by sputum smear microscopy among symptomatic patients self-reporting to health services, (3 ) a standardized treatment regimen of 68 months for at least all conrmed sputum smearpositive cases, with DOT for at least the initial 2 months, (4 ) a regular, uninterrupted supply of all essential antituberculosis drugs, and (5 ) a standardized recording and reporting system that enables assessment of treatment results for each patient and of the tuberculosis control program overall. A number of other differences exist as well: The WHO and the IUATLD recommend diagnosis and classication of tuberculosis cases and assessment of response based on sputum AFB smears. Culture and susceptibility testing for new patients is not recommended because of cost, limited applicability, and lack of facilities. Chest radiography is recommended by both the WHO and IUATLD only for patients with negative sputum smears and is not recommended at all for follow-up. Both 6- and 8-month treatment regimens are recommended by the WHO. The IUATLD recommends an 8-month regimen with thioacetazone in the continuation phase for HIVnegative patients. For patients suspected of having or known to have HIV infection, ethambutol is substituted for thioacetazone The WHO and the IUATLD recommend a standardized 8-month regimen for patients who have relapsed, had interrupted treatment, or have failed treatment. Patients who have failed supervised retreatment are considered chronic cases and are highly likely to have tuberculosis caused by MDR organisms. Susceptibility testing and a tailored regimen using second-line drugs based on the test results are recommended by the WHO, if testing and sec-
ond-line drugs are available. The IUATLD recommendations do not address the issue. Neither baseline nor follow-up biochemical testing is recommended by the WHO and the IUATLD. It is recommended that patients be taught to recognize the symptoms associated with drug toxicity and to report them promptly.
A Research Agenda for Tuberculosis Treatment
New antituberculosis drugs are needed for three main reasons: (1 ) to shorten or otherwise simplify treatment of tuberculosis caused by drug-susceptible organisms, (2 ) to improve treatment of drug-resistant tuberculosis, and (3 ) to provide more efcient and effective treatment of latent tuberculosis infection. No truly novel compounds that are likely to have a signicant impact on tuberculosis treatment are close to clinical trials. However, further work to optimize the effectiveness of once-a-week rifapentine regimens using higher doses of the drug and using rifapentine in combination with moxioxacin is warranted, on the basis of experimental data. New categories of drugs that have shown promise for use in treating tuberculosis include the nitroimidazopyrans and the oxazolidinones. Experimental data also suggest that a drug to inhibit an enzyme, isocitrate lyase, thought to be necessary for maintaining the latent state, might be useful for treatment of latent tuberculosis infection. A number of other interventions that might lead to improved treatment outcome have been suggested, although none has undergone rigorous clinical testing. These include various drug delivery systems, cytokine inhibitors, administration of protective cytokines such as interferon- and interleukin-2, and nutritional supplements, especially vitamin A and zinc. Research is also needed to identify factors that are predictive of a greater or lesser risk of relapse to determine optimal length of treatment. Identication of such factors would enable more efcient targeting of resources to supervise treatment. In addition, identication of behavioral factors that identify patients at greater or lesser likelihood of being adherent to therapy would also enable more efcient use of DOT.
1. INTRODUCTION AND BACKGROUND

Since 1971 the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC) have regularly collaborated to develop joint guidelines for the diagnosis, treatment, prevention, and control of tuberculosis (1). These documents have been intended to guide both public health programs and health care providers in all aspects of the clinical and public health management of tuberculosis in low-incidence countries, with a particular focus on the United States. The most recent version of guidelines for the treatment of tuberculosis was published in 1994 (2). The current document differs from its predecessor in a number of important areas that are summarized in the boxed insert above. The process by which this revision of the recommendations for treatment was developed was modied substantially from the previous versions. For the rst time the Infectious Diseases Society of America (IDSA) has become a cosponsor of the statement, together with the ATS and CDC. The IDSA has had representation on prior statement committees but has not previously been a cosponsor of the document. Practice guidelines that serve to complement the current statement have been developed by the IDSA (3). In addition to the IDSA, representatives of the American Academy of Pediatrics (AAP), the (United States) National Tuberculosis Controllers Association (NTCA), the Canadian Thoracic Society (CTS), the IUATLD, and the WHO participated in the revision. By virtue of their different
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perspectives these committee members served to provide broader input and to help ensure that the guidelines are placed in an appropriate context. It should be emphasized that the current guidelines are intended for areas in which mycobacterial cultures, drug susceptibility tests, radiographic facilities, and second-line drugs are available, either immediately or by referral, on a routine basis. For this revision of the recommendations essentially all clinical trials of antituberculosis treatment in the English language literature were reviewed and the strength of the evidence they presented was rated according to the IDSA/USPHS rating scale (4).
of the structure and organization of treatment services, as well as the drugs that are used, to treat patients effectively. This philosophy is the core of the DOTS strategy (described in Section 10: Treatment of Tuberculosis in Low-income Countries: Recommendations of the WHO and the IUTLD), developed by the IUATLD and implemented globally by the WHO. Thus, although there are supercial differences in the approach to tuberculosis treatment between high- and low-incidence countries, the fundamental concern, regardless of where treatment is given, is ensuring patient adherence to the drug regimen and successful completion of therapy (6).
References
1. DuMelle FJ, Hopewell PC. The CDC and the American Lung Association/ American Thoracic Society: an enduring public/private partnership. In: Centers for Disease Control and Prevention: a century of notable events in TB control. TB Notes Newslett 2000;1:2327. 2. American Thoracic Society, Centers for Disease Control and Prevention. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 1994;149:13591374. www.thoracic.org/ adobe/statements/tbchild1-16.pdf 3. Horsburgh CR Jr, Feldman S, Ridzon R. Practice guidelines for the treatment of tuberculosis. Clin Infect Dis 2000;31:633639. 4. Gross PA, Barrett TL, Dellinger EP, Krause PJ, Martone WJ, McGowan JE Jr, Sweet RL, Wenzel RP. Purpose of quality standards for infectious diseases. Clin Infect Dis 1994;18:421. 5. Geiter LJ, editor. Ending neglect: the elimination of tuberculosis in the United States. Institute of Medicine, Committee on Elimination of Tuberculosis in the United States. Washington, DC: National Academy Press; 2000. www.nap.edu/catalog/9837.html 6. World Health Organization. What is DOTS? A guide to understanding the WHO-recommended TB control strategy known as DOTS. WHO/ CDS/CPC/TB/99.270. Geneva, Switzerland: World Health Organization; 1999. www.who.int/gtb/dots
PROVIDER RESPONSIBILITY Treatment of tuberculosis benets both the community as a whole and the individual patient; thus, any public health program or private provider (or both in a dened arrangement by which management is shared) undertaking to treat a patient with tuberculosis is assuming a public health function that includes not only prescribing an appropriate regimen but also ensuring adherence to the regimen until treatment is completed.
This revision of the recommendations for treatment of tuberculosis presents a signicant philosophic departure from previous versions. In this document the responsibility for successful treatment of tuberculosis is placed primarily on the provider or program initiating therapy rather than on the patient. It is well established that appropriate treatment of tuberculosis rapidly renders the patient noninfectious, prevents drug resistance, minimizes the risk of disability or death from tuberculosis, and nearly eliminates the possibility of relapse. For these reasons, antituberculosis chemotherapy is both a personal and a public health measure that cannot be equated with the treatment of, for example, hypertension or diabetes mellitus, wherein the benets largely accrue to the patient. Provider responsibility is a central concept in treating patients with tuberculosis, no matter what the source of their care. All reasonable attempts should be made to accommodate the patient so that a successful outcome is achieved. However, interventions such as detention may be necessary for patients who are persistently nonadherent. The recommendations in this statement are not applicable under all epidemiologic circumstances or across all levels of resources that are available to tuberculosis control programs worldwide. Although the basic principles of therapy described in this document apply regardless of conditions, the diagnostic approach, methods of patient supervision, and monitoring for response and for adverse drug effects, and in some instances the regimens recommended, are quite different in high-incidence, low-income areas compared with low-incidence, high-income areas of the world. A summary of the important differences between the recommendations in this document and those of the IUATLD and the WHO is found in Section 10 (Treatment of Tuberculosis in Low-income Countries: Recommendations of the WHO and the IUTLD). In the United States there has been a call for the elimination of tuberculosis, and a committee constituted by the Institute of Medicine (IOM) issued a set of recommendations for reaching this goal (5). The IOM committee had two main recommendations related to treatment of tuberculosis; rst, that all U.S jurisdictions have health regulations that mandate completion of therapy (treatment until the patient is cured); and second, that all treatment be administered in the context of patient-centered programs that are based on individual patient characteristics and needs. The IOM recommendations emphasize the importance
2. ORGANIZATION AND SUPERVISION OF TREATMENT

Successful treatment of tuberculosis depends on more than the science of chemotherapy. To have the highest likelihood of success, chemotherapy must be provided within a clinical and social framework based on an individual patients circumstances. Optimal organization of treatment programs requires an effective network of primary and referral services and cooperation between clinicians and public health ofcials, between health care facilities and community outreach programs, and between the private and public sectors of medical care. This section describes the approaches to organization of treatment that serve to ensure that treatment has a high likelihood of being successful. As noted previously, antituberculosis chemotherapy is both a personal health measure intended to cure the sick patient and a basic public health strategy intended to reduce the transmission of Mycobacterium tuberculosis. Typically, tuberculosis treatment is provided by public health departments, often working in collaboration with other providers and organizations including private physicians, community health centers, migrant health centers, correctional facilities, hospitals, hospices, long-term care facilities, and homeless shelters. Private providers and public health departments may cosupervise patients, assuring that the patient completes therapy in a setting that is not only mutually agreeable but also enables access to tuberculosis expertise and resources that might otherwise not be available. In managed care settings delivery of tuberculosis treatment may require a more structured public/private partnership, often dened by a contract, to assure completion of therapy. Regardless of the means by which treatment is provided, the ultimate legal authority for assuring that patients complete therapy rests with the public health system.
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2.1. Role of the Health Department
The responsibility of the health department in the control of tuberculosis is to ensure that all persons who are suspected of having tuberculosis are identied and evaluated promptly and that an appropriate course of treatment is prescribed and completed successfully (1, 2). A critical component of the evaluation scheme is access to procient microbiological laboratory services, for which the health department is responsible. The responsibilities of the health department may be accomplished indirectly by epidemiologic surveillance and monitoring of treatment decisions and outcome, applying generally agreedon standards and guidelines, or more directly by provision of diagnostic and treatment services, as well as by conducting epidemiologic investigations. Given the diverse sociodemographic characteristics of patients with tuberculosis and the many mechanisms by which health care is delivered, the means by which the goals of the health department are accomplished may be quite varied. In dealing with individual patients, approaches that focus on each persons needs and characteristics should be used to determine a tailored treatment plan that is designed to ensure completion of therapy (3). Such treatment plans are developed with the patient as an active participant together with the physician and/or nurse, outreach workers, social worker (when needed), and others as appropriate. Given that one-half the current incident cases of tuberculosis in the United States were born outside the United States (similar circumstances prevail in most other low-incidence countries), translation of materials into the patients primary language is often necessary to ensure his/ her participation in developing the treatment plan. Ideally, a specic case manager is assigned individual responsibility for assuring that the patient completes therapy. The treatment plan is reviewed periodically and revised as needed. These reviews may be accomplished in meetings between the patient and the assigned provider, as well as more formally through case and cohort evaluations. The treatment plan is based on the principle of using the least restrictive measures that are likely to achieve success. The full spectrum of measures that may be employed ranges from, at an absolute minimum, monthly monitoring of the patient in the outpatient setting to legally mandated hospitalization (4). Directly observed therapy (DOT) is the preferred initial means to assure adherence. For nonadherent patients more restrictive measures are implemented in a stepwise fashion. Any approach must be balanced, ensuring that the needs and rights of the patient, as well as those of the public, are met. Care plans for patients being managed in the private sector should be developed jointly by the health department and the private provider, and must address identied and anticipated barriers to adherence.
WHATS DOT? Direct observation of therapy (DOT) involves providing the antituberculosis drugs directly to the patient and watching as he/she swallows the medications. It is the preferred core management strategy for all patients with tuberculosis.
2.2. Promoting Adherence
Louis Pasteur once said, The microbe is nothing...the terrain everything (5). Assuming appropriate drugs are prescribed, the terrain (the circumstances surrounding each patient that may affect his or her ability to complete treatment) becomes the most important consideration in completion of tuberculosis treatment.
Many factors may be part of this terrain. Factors that interfere with adherence to the treatment regimen include cultural and linguistic barriers to cooperation, lifestyle differences, homelessness, substance abuse, and a large number of other conditions and circumstances that, for the patient, are priorities that compete with taking treatment for tuberculosis (6). Barriers may be patient related, such as conicting health beliefs, alcohol or drug dependence, or mental illness, or they may be system related, such as lack of transportation, inconvenient clinic hours, and lack of interpreters (7). Effective tuberculosis case management identies and characterizes the terrain and determines an appropriate care plan based on each of the identied factors. Additional advantages of the patient-centered approach are that, by increasing communication with the patient, it provides opportunities for further education concerning tuberculosis and enables elicitation of additional information concerning contacts. To maximize completion of therapy, patient-centered programs identify and utilize a broad range of approaches based on the needs and circumstances of individual patients. Among these approaches, DOT is the preferred initial strategy and deserves special emphasis. Although DOT itself has not been subjected to controlled trials in low-incidence areas (and, thus, is rated AII), observational studies and a metaanalysis in the United States strongly suggest that DOT, coupled with individualized case management, leads to the best treatment results (8 10). To date there have been three published studies of DOT in high-incidence areas, two of which (11, 12) showed no benet and one (13) in which there was a signicant advantage for DOT. What is clear from these studies is that DOT cannot be limited merely to passive observation of medication ingestion; there must be aggressive interventions when patients miss doses. Using DOT in this manner can only improve results. DOT can be provided daily or intermittently in the ofce, clinic, or in the eld (patients home, place of employment, school, street corner, bar, or any other site that is mutually agreeable) by appropriately trained personnel. DOT should be used for all patients residing in institutional settings such as hospitals, nursing homes, or correctional facilities, or in other settings, such as methadone treatment sites, that are conducive to observation of therapy (14). However, even in such supervised settings careful attention must be paid to ensuring that ingestion of the medication is, in fact, observed. It is essential that all patients being treated with regimens that use intermittent drug administration have all doses administered under DOT because of the potential serious consequences of missed doses. DOT also enables early identication of nonadherence, adverse drug reactions, and clinical worsening of tuberculosis. DOT provides a close connection to the health care system for a group of patients at high risk of other adverse health events and, thus, should facilitate identication and management of other conditions. The use of DOT does not guarantee ingestion of all doses of every medication (15). Patients may miss appointments, may not actually swallow the pills, or may deliberately regurgitate the medications. Consequently, all patients, including those who are being treated by DOT, should continue to be monitored for signs of treatment failure. DOT is only one aspect of a comprehensive patient-centered program that, in addition, includes incentives and enablers described subsequently (1620). Patients who are more likely to present a transmission risk to others or are more likely to have problems with adherence (Table 7) should be prioritized for DOT when resources are limited. When DOT is not being used, xed-dose combination preparations (see Section 6.2: Fixed-dose Combination Preparations) containing INH and RIF or INH, RIF, and PZA reduce the risk of the patient taking only one drug and may help prevent
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 167 2003 TABLE 7. PRIORITY SITUATIONS FOR THE USE OF DIRECTLY OBSERVED THERAPY
1. Patients with the following conditions/circumstances: Pulmonary tuberculosis with positive sputum smears Treatment failure Drug resistance Relapse HIV infection Previous treatment for either active tuberculosis or latent tuberculosis infection Current or prior substance abuse Psychiatric illnesses Memory impairment Previous nonadherence to therapy 2. Children and adolescents
the development of drug resistance. Combination formulations are easier to administer and also may reduce medication errors. Depending on the identied obstacles to completion of therapy, the treatment plan may also include enablers and incentives such as those listed in Table 8. Studies have examined the use of a patient-centered approach that utilizes DOT in addition to other adherence-promoting tools (9, 21, 22). These studies demonstrate, as shown in Figure 3, that enhanced DOT (DOT together with incentives and enablers) produces the highest treatment completion rates (in excess of 90% across a range of geographic and socioeconomic settings), and reinforces the importance of patient-related factors in designing and implementing case management (9, 23). Intensive educational efforts should be initiated as soon as the patient is suspected of having tuberculosis. The instruction should be at an educational level appropriate for the patient and should include information about tuberculosis, expected outcomes of treatment, the benets and possible adverse effects of the drug regimen, methods of supervision, assessment of response, and a discussion of infectiousness and infection control. The medication regimen must be explained in clear, understandable language and the verbal explanation followed with written
instructions. An interpreter is necessary when the patient and health care provider do not speak the same language. Materials should be appropriate for the culture, language, age, and reading level of the patient. Relevant information should be reinforced at each visit. The patients clinical progress and the treatment plan must be reviewed at least monthly to evaluate the response to therapy and to identify adherence problems. Use of a record system (Figure 4), either manual or computer-based, that quanties the dosage and frequency of medication administered, indicates AFB smear and culture status, and notes symptom improvement as well as any adverse effects of treatment serves to facilitate the regular reviews and also provides data for cohort analyses. In addition, adherence monitoring by direct methods, such as the detection of drugs or drug metabolites in the patients urine, or indirect methods, such as pill counts or a medication monitor, should be a part of routine management, especially if the patient is not being given DOT. Tracking patients is also a critical concern for those charged with assuring completion of treatment. It has been shown that patients who move from one jurisdiction to another before completion of therapy are much more likely to default than patients
TABLE 8. POSSIBLE COMPONENTS OF A MULTIFACETED, PATIENT-CENTERED TREATMENT STRATEGY

Enablers: Interventions to assist the patient in completing therapy* Transportation vouchers Child care Convenient clinic hours and locations Clinic personnel who speak the languages of the populations served Reminder systems and follow-up of missed appointments Social service assistance (referrals for substance abuse treatment and counseling, housing, and other services) Outreach workers (bilingual/bicultural as needed; can provide many services related to maintaining patient adherence, including provision of DOT, follow-up on missed appointments, monthly monitoring, transportation, sputum collection, social service assistance, and educational reinforcement) Integration of care for tuberculosis with care for other conditions Incentives: Interventions to motivate the patient, tailored to individual patient wishes and needs and, thus, meaningful to the patient* Food stamps or snacks and meals Restaurant coupons Assistance in finding or provision of housing Clothing or other personal products Books Stipends Patient contract
Definition of abbreviation: DOT Directly observed therapy. * Burman WJ, Cohn DL, Rietmeijer CA, Judson FN, Sbabaro JA, Reves RR. Noncompliance with directly observed therapy for tuberculosis: epidemiology and effect on the outcome of treatment. Chest 1997;111:11681173. Bayer R, Stayton C, Devarieux M, Healton C, Landsman S, Tsai W. Directly observed therapy and treatment completion in the United States; is universal supervised therapy necessary? Am J Public Health 1998;88:10521058. Vomink J, Matchaba P, Gainer P. Directly observed therapy and treatment adherence. Lancet 2000;355:13451350.
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TRACKING TUBERCULOSIS Inter- and intrastate notications constitute the key patient-tracking systems for patients moving within the United States. International notications can also be made, although specic tracking programs vary by country. Currently there are two formal patient-tracking systems in operation for patients moving across the United States Mexico boarder: TB Net, operated by the Migrant Clinician Network based in Austin, Texas (www.migrantclinician.org; telephone, 512327-2017) and Cure TB, managed by the San Diego County, California, Division of Tuberculosis Control (www.curetb.org; telephone, 619-692-5719).
Figure 3. Range and median of treatment completion rates by treatment strategy for pulmonary tuberculosis reported in 27 studies. DOT Directly observed therapy; n number of studies; Modified DOT DOT given only for a portion of the treatment period, often while the patient was hospitalized; Enhanced DOT individualized incentives and enablers were provided in addition to DOT. Reprinted by permission from Chaulk CP, Kazdanjian VA. Directly observed therapy for treatment completion of tuberculosis: consensus statement of the Public Health Tuberculosis Guidelines Panel. JAMA 1998;279:943948.
who do not move (24). Factors that have been shown to be associated with moving/defaulting include diagnosis of tuberculosis in a state correctional facility, drug and alcohol abuse, and homelessness. Communication and coordination of services among different sources of care and different health departments are especially important for patients in these groups as well as for migrant workers and other patients with no permanent home. Such communication may also be necessary across national boundaries, especially the United StatesMexico border, and there are systems in place to facilitate such communication and tracking.
Some patients, for example those with tuberculosis caused by drug-resistant organisms, or who have comorbid conditions, such as HIV infection, alcoholism, or other signicant underlying disorders, may need to be hospitalized in a facility where tuberculosis expertise is available and where there are appropriate infection control measures in place. Hospitalization may be necessary for nonadherent patients for whom less restrictive measures have failed (2527). Public health laws exist in most states that allow the use of detainment under these circumstances, at least for patients who remain infectious (28). Court-ordered DOT has been used successfully in some states as a less costly alternative. The use of these interventions depends on the existence of appropriate laws, cooperative courts, and law enforcement ofcials, and the availability of appropriate facilities. Health departments must be consulted to initiate legal action when it is necessary.
Figure 4. Example of flow chart for patient monitoring.
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States: is universal supervised therapy necessary? Am J Public Health 1998;88:10521058. Poszik CJ. Compliance with tuberculosis therapy. Med Clin North Am 1993;77:12891300. Lobue PA, Cass R, Lobo D, Moser K, Catanzaro A. Development of housing programs to aid in the treatment of tuberculosis in homeless individuals: a pilot study. Chest 1999;115:218223. Black B, Bruce ME. Treating tuberculosis: the essential role of social work. Soc Work Health Care 1998;26:5168. Moore RD, Chaulk CP, Grifths R, Cavalcante S, Chaisson RE. Costeffectiveness of directly observed versus self-administered therapy for tuberculosis. Am J Respir Crit Care Med 1996;154:10131019. Burman WJ, Dalton CB, Cohn DL, Butler RG, Reves RR. A costeffectiveness analysis of directly observed therapy versus self-administered therapy for treatment of tuberculosis. Chest 1997;112:6370. Davidson H, Smirnoff M, Klein SJ, Burdick E. Patient satisfaction with care at directly observed therapy programs for tuberculosis in New York City. Am J Public Health 1999;89:15671570. Cummings KC, Mohle-Boetani J, Royce SE, Chin DP. Movement of tuberculosis patients and the failure to complete antituberculosis treatment. Am J Respir Crit Care Med 1998;157:12491252. Oscherwitz T, Tulsky JP, Roger S, Sciortino S, Alpers A, Royce S, Lo B. Detention of persistently nonadherent patients with tuberculosis. JAMA 1997;278:843846. Singleton L, Turner M, Haskal R, Etkind S, Tricarico M, Nardell E. Long term hospitalization for tuberculosis control: experience with a medicalpsychosocial inpatient unit. JAMA 1997;278:838842. Gasner MR, Maw KL, Feldman GE, Fujiwara PI, Frieden TR. The use of legal action in New York City to ensure treatment of tuberculosis. N Engl J Med 1999;340:359366. Gostin LO. Controlling the resurgent tuberculosis epidemic: a 50 state survey of TB statutes and proposals for reform. JAMA 1993;269:255 261.
LEGAL ACTION FOR TUBERCULOSIS IN NEW YORK CITY: 19931999 Regulatory orders were issued for less than 4% of 8,000 patients. Detainment was based on tuberculosis status, not on sociodemographic factors. Legal orders varied: DOT150 patients Detainment139 patients Examination for tuberculosis ordered12 patients Completion of treatment ordered3 patients Less restrictive, court-ordered DOT was often as effective as detainment: 96% (excluding those who died or moved) completed treatment; 2% continued treatment for multidrug-resistant tuberculosis (from Gasner and coworkers [27])
18. 19.
20. 21.
22.
23.
24.
References
1. Centers for Disease Control and Prevention. Essential components of a tuberculosis prevention and control program. MMWR 1995;44(RR11):116. www.cdc.gov/nchstp/tb/ 2. Simone PM, Fujiwara PI. Role of the health department: legal and public health implications. In: Schlossberg D, editor. Tuberculosis and nontuberculous mycobacterial infections, 4th edition. Philadelphia: W. B. Saunders; 1999. p. 130139. 3. Etkind SC. The role of the public health department in tuberculosis control. Med Clin North Am 1993;77:13031314. 4. National Tuberculosis Controllers Association, National TB Nursing Consultant Coalition. Tuberculosis nursing: a comprehensive guide to patient care. Atlanta, GA: National Tuberculosis Controllers Association and National Tuberculosis Nursing Consultant Coalition; 1997. p. 6984. ` 5. Delhoume L. De Claude Bernard a dArsonval. Paris: J. B. Bailliere et Fils; 1939. p. 595. 6. Moss AR, Hahn JA, Tulsky JP, Daley CL, Small PM, Hopewell PC. Tuberculosis in the homeless: a prospective study. Am J Respir Crit Care Med 2000;162:460464. 7. Sumartojo E. When tuberculosis treatment fails: a social behavioral account of patient adherence. Am Rev Respir Dis 1993;147:13111320. 8. Chaulk CP, Moore-Rice K, Rizzo R, Chaisson RE. Eleven years of community-based directly observed therapy for tuberculosis. JAMA 1995;274:945951. 9. Chaulk CP, Kazandjian VA. Directly observed therapy for treatment completion of tuberculosis: census statement of the Public Health Tuberculosis Guidelines Panel. JAMA 1998;279:943948. 10. Weis SE, Slocum PC, Blais FX, King B, Nunn M, Matney GB, Gomez E, Foresman BH. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994;330:11791184. 11. Zwarenstein M, Schoeman JH, Vundule C, Lombard CJ, Tatley M. Randomised controlled trial of self-supervised and directly observed treatment of tuberculosis. Lancet 1998;352:13401343. 12. Walley JD, Khan MR, Newell JN, Khan MH. Effectiveness of the direct observation component of DOTS for tuberculosis: a randomised controlled trial in Pakistan. Lancet 2001;357:664669. 13. Kamolratanakul P, Sawert H, Lertmaharit S, Kasetjaroen Y, Akksilp S, Tulaporn C, Punnachest K, Na-Songkhla S, Payanandana V. Randomized controlled trial of directly observed treatment (DOT) for patients with pulmonary tuberculosis in Thailand. Trans R Soc Trop Med Hyg 1999;5:552557. 14. Snyder DC, Paz EA, Mohle-Boetani JC, Fallstad R, Balck RL, Chin DP. Tuberculosis prevention in methadone maintenance clinics: effectiveness and cost-effectiveness. Am J Respir Crit Care Med 1999;160:178 185. 15. Burman WJ, Cohn DL, Rietmeijer CA, Judson FN, Sbarbaro JA, Reves RR. Noncompliance with directly observed therapy for tuberculosis: epidemiology and effect on the outcome of treatment. Chest 1997;111: 11681173. 16. Volmink J, Matchaba P, Garner P. Directly observed therapy and treatment adherence. Lancet 2000;355:13451350. 17. Bayer R, Stayton C, Desvarieux M, Healton C, Landesman S, Tsai W. Directly observed therapy and treatment completion in the United
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26.
27.
28.
3. DRUGS IN CURRENT USE

Currently, there are 10 drugs approved by the United States Food and Drug Administration (FDA) for treating tuberculosis (Table 9). In addition, the uoroquinolones, although not approved by the FDA for tuberculosis, are used relatively commonly to treat tuberculosis caused by drug-resistant organisms or for patients who are intolerant of some of the rst-line drugs. Rifabutin, approved for use in preventing Mycobacterium avium complex disease in patients with HIV infection but not approved for tuberculosis, is useful for treating tuberculosis in patients concurrently taking drugs that have unacceptable interactions with other rifamycins. Amikacin and kanamycin, nearly identical aminoglycoside drugs used in treating patients with tuberculosis caused by drug-resistant organisms, are not approved by the FDA for tuberculosis. Of the approved drugs isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA) are considered rstline antituberculosis agents and form the core of initial treatment regimens. Rifabutin and rifapentine may also be considered rst-
TABLE 9. ANTITUBERCULOSIS DRUGS CURRENTLY IN USE IN THE UNITED STATES

First-line Drugs Isoniazid Rifampin Rifapentine Rifabutin* Ethambutol Pyrazinamide Second-line Drugs Cycloserine Ethionamide Levofloxacin* Moxifloxacin* Gatifloxacin* p-Aminosalicylic acid Streptomycin Amikacin/kanamycin* Capreomycin
* Not approved by the United States Food and Drug Administration for use in the treatment of tuberculosis.
American Thoracic Society Documents TABLE 10. CLINICAL HEPATITIS IN PERSONS TAKING ISONIAZID AND RIFAMPIN*
Drug INH INH plus other drugs, but not RIF INH plus RIF RIF plus other drugs, but not INH Number of Studies 6 10 19 5 Patients 38,257 2,053 6,155 1,264 Clinical Hepatitis (%) 0.6 1.6 2.7 1.1
619
Definition of abbreviations: INH isoniazid; RIF rifampin. * Reprinted by permission from Steele MA, Burk RF, Des Prez RM. Toxic hepatitis with isoniazid and rifampin: a meta-analysis. Chest 1991;99:465471.
line agents under the specic situations described below. Streptomycin (SM) was formerly considered to be a rst-line agent and, in some instances, is still used in initial treatment; however, an increasing prevalence of resistance to SM in many parts of the world has decreased its overall usefulness. The remaining drugs are reserved for special situations such as drug intolerance or resistance. The drug preparations available currently and the recommended doses are shown in Tables 3, 4, and 5.
3.1. First-Line Drugs
Fatal hepatitis: A large survey estimated the rate of fatal hepatitis to be 0.023%, but more recent studies suggest the rate is substantially lower (10, 11). The risk may be increased in women. Death has been associated with continued administration of INH despite onset of symptoms of hepatitis (12). Peripheral neurotoxicity (13, 14): This adverse effect is dose related and is uncommon (less than 0.2%) at conventional doses (1517). The risk is increased in persons with other conditions that may be associated with neuropathy such as nutritional deciency, diabetes, HIV infection, renal failure, and alcoholism, as well as for pregnant and breastfeeding women. Pyridoxine supplementation (25 mg/day) is recommended for patients with these conditions to help prevent this neuropathy (18). Central nervous system effects: Effects such as dysarthria, irritability, seizures, dysphoria, and inability to concentrate have been reported but have not been quantied. Lupus-like syndrome (19): Approximately 20% of patients receiving INH develop anti-nuclear antibodies. Less than 1% develop clinical lupus erythematosis, necessitating drug discontinuation. Hypersensitivity reactions: Reactions, such as fever, rash, Stevens-Johnson syndrome, hemolytic anemia, vasculitis, and neutropenia are rare. Monoamine (histamine/tyramine) poisoning: This has been reported to occur after ingestion of foods and beverages with high monoamine content but is rare (2022). If ushing occurs, patients should be instructed to avoid foods and drinks, such as certain cheeses and wine, having high concentrations of monoamines. Diarrhea: Use of the commercial liquid preparation of INH, because it contains sorbitol, is associated with diarrhea. Use in pregnancy. INH is considered safe in pregnancy, but the risk of hepatitis may be increased in the peripartum period (9, 23). Pyridoxine supplementation (25 mg/day) is recommended if INH is administered during pregnancy (18). It should be noted that multivitamin preparations have variable amounts of pyridoxine but generally less than 25 mg/day and, thus, do not provide adequate supplementation. CNS penetration. Penetration is excellent. Cerebrospinal uid (CSF) concentrations are similar to concentrations achieved in serum (24). Use in renal disease. (See Section 8.7: Renal Insufciency and End-stage Renal Disease.) INH can be used safely without dose adjustment in patients with renal insufciency (25) and with end-stage renal disease who require chronic hemodialysis (26). Use in hepatic disease. (See Section 8.8: Hepatic Disease.)
3.1.1. Isoniazid. Role in treatment regimen. Isoniazid (INH) is a rst-line agent for treatment of all forms of tuberculosis caused by organisms known or presumed to be susceptible to the drug. It has profound early bactericidal activity against rapidly dividing cells (1, 2). Dose. See Table 3. Adults (maximum): 5 mg/kg (300 mg) daily; 15 mg/kg (900 mg) once, twice, or three times weekly. Children (maximum): 1015 mg/kg (300 mg) daily; 2030 mg/kg (900 mg) twice weekly (3). Preparations. Tablets (50 mg, 100 mg, 300 mg); syrup (50 mg/ 5 ml); aqueous solution (100 mg/ml) for intravenous or intramuscular injection. Adverse effects. Asymptomatic elevation of aminotransferases: Aminotransferase elevations up to ve times the upper limit of normal occur in 1020% of persons receiving INH alone for treatment of latent tuberculosis infection (4). The enzyme levels usually return to normal even with continued administration of the drug. Clinical hepatitis: (See Table 10.) Data indicate that the incidence of clinical hepatitis is lower than was previously thought. Hepatitis occurred in only 0.10.15% of 11,141 persons receiving INH alone as treatment for latent tuberculosis infection in an urban tuberculosis control program (5). Prior studies suggested a higher rate, and a meta-analysis of six studies estimated the rate of clinical hepatitis in patients given INH alone to be 0.6% (68). In the meta-analysis the rate of clinical hepatitis was 1.6% when INH was given with other agents, not including RIF. The risk was higher when the drug was combined with RIF, an average of 2.7% in 19 reports (8). For INH alone the risk increases with increasing age; it is uncommon in persons less than 20 years of age but is nearly 2% in persons aged 5064 years (6). The risk also may be increased in persons with underlying liver disease, in those with a history of heavy alcohol consumption, and, data suggest, in the postpartum period, particularly among Hispanic women (9).
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The risk of drug accumulation and drug-induced hepatitis may be increased in the presence of hepatic disease; however, INH may be used in patients with stable hepatic disease. Laboratory and clinical monitoring should be more frequent in such situations. Monitoring. Routine monitoring is not necessary. However, for patients who have preexisting liver disease or who develop abnormal liver function that does not require discontinuation of the drug, liver function tests should be measured monthly and when symptoms occur. Serum concentrations of phenytoin and carbamazepine may be increased in persons taking INH. However, in combination therapy with RIF the effects of INH on serum concentrations of the anticonvulsants are limited by the decrease caused by RIF. Thus, it is important to measure serum concentrations of these drugs in patients receiving INH with or without RIF and adjust the dose if necessary. 3.1.2. Rifampin. Role in treatment regimen. Rifampin (RIF) is a rst-line agent for treatment of all forms of tuberculosis caused by organisms with known or presumed sensitivity to the drug. It has activity against organisms that are dividing rapidly (early bactericidal activity) (1) and against semidormant bacterial populations, thus accounting for its sterilizing activity (27). Rifampin is an essential component of all short-course regimens. Dose. See Table 3. Adults (maximum): 10 mg/kg (600 mg) once daily, twice weekly, or three times weekly. Children (maximum): 1020 mg/kg (600 mg) once daily or twice weekly. Preparations. Capsules (150 mg, 300 mg); contents of capsule may also be mixed in an appropriate diluent to prepare an oral suspension; aqueous solution for parenteral administration. Adverse effects (28). Cutaneous reactions (29): Pruritis with or without rash may occur in as many as 6% of patients but is generally self-limited (30). This reaction may not represent true hypersensitivity and continued treatment with the drug may be possible. More severe, true hypersensitivity reactions are uncommon, occurring in 0.070.3% of patients (17, 31, 32). Gastrointestinal reactions (nausea, anorexia, abdominal pain): The incidence is variable, but symptoms are rarely severe enough to necessitate discontinuation of the drug (2830). Flulike syndrome: This may occur in 0.40.7% of patients receiving 600 mg twice weekly but not with daily administration of the same dose (3134). Symptoms are more likely to occur with intermittent administration of a higher dose (29, 35). Hepatotoxicity: Transient asymptomatic hyperbilirubinemia may occur in as many as 0.6% of patients receiving the drug. More severe clinical hepatitis that, typically, has a cholestatic pattern may also occur (8, 36). Hepatitis is more common when the drug is given in combination with INH (2.7%) than when given alone (nearly 0%) or in combination with drugs other than INH (1.1%) (8). Severe immunologic reactions: In addition to cutaneous reactions and ulike syndrome, other reactions thought to be immune mediated include the following: thrombocytopenia, hemolytic anemia, acute renal failure, and thrombotic thrombocytopenic purpura. These reactions are rare, each occurring in less than 0.1% of patients (31, 32, 37). Orange discoloration of bodily uids (sputum, urine, sweat, tears): This is a universal effect of the drug. Patients should be
warned of this effect at the time treatment is begun. Soft contact lenses and clothing may be permanently stained. Drug interactions due to induction of hepatic microsomal enzymes: There are a number of drug interactions (described in Section 7: Drug Interactions, and Table 12) with potentially serious consequences. Of particular concern are reductions, often to ineffective levels, in serum concentrations of common drugs, such as oral contraceptives, methadone, and warfarin. In addition there are important bidirectional interactions between rifamycins and antiretroviral agents. Because information regarding rifamycin drug interactions is evolving rapidly, readers are advised to consult the CDC web site www.cdc.gov/ nchstp/tb/ to obtain the most up-to-date information. Use in pregnancy. RIF is considered safe in pregnancy (38). CNS penetration. Concentrations in the CSF may be only 1020% of serum levels, but this is sufcient for clinical efcacy. Penetration may be improved in the setting of meningitis (39). Use in renal disease. (See Section 8.7: Renal Insufciency and End-stage Renal Disease.) RIF can be used safely without dose adjustment in patients with renal insufciency and endstage renal disease (26, 40). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) Clearance of the drug may be impaired in the presence of liver disease, causing increased serum levels (40). However, because of the critical importance of rifampin in all short-course regimens, it generally should be included, but the frequency of clinical and laboratory monitoring should be increased. Monitoring. No routine monitoring tests are required. However, rifampin causes many drug interactions described in Section 7 (Drug Interactions) that may necessitate regular measurements of the serum concentrations of the drugs in question.
RIFABUTIN AND RIFAPENTINE The newer rifamycins, rifabutin and rifapentine, should be considered rst-line drugs in special situations: rifabutin for patients who are receiving medications, especially antiretroviral drugs, that have unacceptable interactions with rifampin or who have experienced intolerance to rifampin; and rifapentine, together with INH, in a oncea-week continuation phase for certain selected patients who meet specied criteria.
3.1.3. Rifabutin. Role in treatment regimen. Rifabutin is used as a substitute for RIF in the treatment of all forms of tuberculosis caused by organisms that are known or presumed to be susceptible to this agent. The drug is generally reserved for patients who are receiving any medication having unacceptable interactions with rifampin (41) or have experienced intolerance to rifampin. Dose. See Table 3. Adults (maximum): 5 mg/kg (300 mg) daily, twice, or three times weekly. The dose may need to be adjusted when there is concomitant use of protease inhibitors or nonnucleoside reverse transcriptase inhibitors. When rifabutin is used with efavirenz the dose of rifabutin should be increased to 450600 mg either daily or intermittently. Because information regarding rifamycin drug interactions is evolving rapidly readers are advised to consult the CDC web site, www.cdc.gov/ nchstp/tb/, to obtain the most up-to-date information. Children (maximum): Appropriate dosing for children is unknown.
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Preparations: Capsules (150 mg) for oral administration. Adverse effects: Hematologic toxicity: In a placebo-controlled, double-blind trial involving patients with advanced acquired immunodeciency syndrome (AIDS) (CD4 cell counts 200 cells/ml), neutropenia occurred in 25% compared with 20% in patients receiving placebo (p 0.03). Neutropenia severe enough to necessitate discontinuation of the drug occurred in 2% of patients receiving the drug (product insert B; Adria Laboratories, Columbus, OH). The effect is dose related, occurring more frequently with daily than with intermittent administration of the same dose (42). In several studies of patients with and without HIV infection, neither neutropenia nor thrombocytopenia was associated with rifabutin (4347). Uveitis: This is a rare (less than 0.01%) complication when the drug is given alone at a standard (300 mg daily) dose. The occurrence is higher (8%) with higher doses or when rifabutin is used in combination with macrolide antimicrobial agents that reduce its clearance (48). Uveitis may also occur with other drugs that reduce clearance such as protease inhibitors and azole antifungal agents. Gastrointestinal symptoms: These symptoms occurred in 3% of patients with advanced HIV infection given 300 mg/day (package insert). In subsequent studies no increased incidence of gastrointestinal symptoms was noted among patients taking rifabutin (43, 44, 4648). Polyarthralgias: This symptom occurred in 12% of persons receiving a standard 300-mg dose (package insert). It is more common at higher doses (48). Polyarthralgias have not been noted in more recent studies involving both HIV-infected and uninfected patients (43, 44, 46, 47). Hepatotoxity: Asymptomatic elevation of liver enzymes has been reported at a frequency similar to that of RIF (48). Clinical hepatitis occurs in less than 1% of patients receiving the drug. Pseudojaundice (skin discoloration with normal bilirubin): This is usually self-limited and resolves with discontinuation of the drug (49). Rash: Although initially reported to occur in as many as 4% of patients with advanced HIV infection, subsequent studies suggest that rash is only rarely (less than 0.1%) associated with rifabutin (46). Flulike syndrome: Flulike syndrome is rare (less than 0.1%) in patients taking rifabutin. Orange discoloration of bodily uids (sputum, urine, sweat, tears): This is a universal effect of the drug. Patients should be warned of this effect at the time treatment is begun. Soft contact lenses and clothing may be permanently stained. Use in pregnancy. There are insufcient data to recommend the use of rifabutin in pregnant women; thus, the drug should be used with caution in pregnancy. CNS penetration. The drug penetrates inamed meninges (50). Use in renal disease. (See Section 8.7: Renal Insufciency and End-stage Renal Disease.) Rifabutin may be used without dosage adjustment in patients with renal insufciency and endstage renal disease (50). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) The drug should be used with increased clinical and laboratory monitoring in patients with underlying liver disease. Dose reduc-
tion may be necessary in patients with severe liver dysfunction (50). Monitoring: Monitoring is similar to that recommended for rifampin. Although drug interactions are less problematic with rifabutin, they still occur and close monitoring is required. 3.1.4. Rifapentine. Role in treatment regimen. Rifapentine may be used once weekly with INH in the continuation phase of treatment for HIV-seronegative patients with noncavitary, drug-susceptible pulmonary tuberculosis who have negative sputum smears at completion of the initial phase of treatment (51). Dose. See Table 3. Adults (maximum): 10 mg/kg (600 mg), once weekly during the continuation phase of treatment. Data have suggested that a dose of 900 mg is well tolerated but the clinical efcacy of this dose has not been established (52). Children: The drug is not approved for use in children. Preparation. Tablet (150 mg, lm coated). Adverse effects. The adverse effects of rifapentine are similar to those associated with RIF. Rifapentine is an inducer of multiple hepatic enzymes and therefore may increase metabolism of coadministered drugs that are metabolized by these enzymes (see Section 7: Drug Interactions). Use in pregnancy. There is not sufcient information to recommend the use of rifapentine for pregnant women. CNS penetration. There are no data on CSF concentrations of rifapentine. Use in renal disease. (See Section 8.7: Renal Insufciency and End-stage Renal Disease.) The pharmacokinetics of rifapentine have not been evaluated in patients with renal impairment. Although only about 17% of an administered dose is excreted via the kidneys, the clinical signicance of impaired renal function in the disposition of rifapentine is not known. Use in hepatic disease. (See Section 8.8: Hepatic Disease.) The pharmacokinetics of rifapentine and its 25-desacetyl metabolite were similar among patients with various degrees of hepatic impairment and not different from those in healthy volunteers, even though the elimination of these compounds is primarily via the liver (53). The clinical signicance of impaired hepatic function in the disposition of rifapentine and its 25-desacetyl metabolite is not known. Monitoring. Monitoring is similar to that for RIF. Drug interactions involving rifapentine are being investigated and are likely to be similar to those of RIF. 3.1.5. Pyrazinamide. Role in treatment regimen. Pyrazinamide (PZA) is a rstline agent for the treatment of all forms of tuberculosis caused by organisms with known or presumed susceptibility to the drug. The drug is believed to exert greatest activity against the population of dormant or semidormant organisms contained within macrophages or the acidic environment of caseous foci (54). Dose. See Tables 3 and 4. Adults: 2025 mg/kg per day. Recommended adult dosages by weight, using whole tablets, are listed in Table 4. Children (maximum): 1530 mg/kg (2.0 g) daily; 50 mg/kg twice weekly (2.0 g). Preparations. Tablets (500 mg, scored). Adverse effects. Hepatotoxicity: Early studies (55, 56) using doses of 4070 mg/ kg per day reported high rates of hepatotoxicity. However, in treatment trials with multiple other drugs, including INH, liver toxicity has been rare at doses of 25 mg/kg per day
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or less (15, 34, 57). In one study, however, hepatotoxicity attributable to PZA used in standard doses occurred at a rate of about 1% (58). Gastrointestinal symptoms (nausea, vomiting): Mild anorexia and nausea are common at standard doses. Vomiting and severe nausea are rare except at high doses (59). Nongouty polyarthralgia: Polyarthralgias may occur in up to 40% of patients receiving daily doses of PZA. This rarely requires dosage adjustment or discontinuation of the drug (60). The pain usually responds to aspirin or other nonsteroidal antiinammatory agents. In clinical trials of PZA in the initial intensive phase of treatment, athralgias were not noted to be a signicant problem (15, 61). Asymptomatic hyperuricemia: This is an expected effect of the drug and is generally without adverse consequence (15, 62). Acute gouty arthritis: Acute gout is rare except in patients with preexisting gout (63), generally a contraindication to the use of the drug. Transient morbilliform rash: This is usually self-limited and is not an indication for discontinuation of the drug. Dermatitis: PZA may cause photosensitive dermatitis (59). Use in pregnancy. There is little information about the safety of PZA in pregnancy. However, when there are sound reasons to utilize a 6-month course of treatment, the benets of PZA may outweigh the possible (but unquantied) risk. The WHO and the IUATLD recommend this drug for use in pregnant women with tuberculosis (see Section 10: Treatment of Tuberculosis in Low-income Countries: Recommendations of the WHO and the IUATLD). CNS penetration. The drug passes freely into the CSF, achieving concentrations equivalent to those in serum (64). Use in renal disease. (See Section 8.7: Renal Insufciency and End-stage Renal Disease.) PZA is cleared primarily by the liver, but its metabolites are excreted in the urine and may accumulate in patients with renal insufciency (65). The dose may, therefore, need to be reduced in patients with renal insufciency. It should be administered at a reduced dose (2535 mg/ kg) three times a week after dialysis in patients with end-stage renal disease (Table 15) (26). The risk of hyperuricemia caused by PZA is increased in patients with renal insufciency. Use in hepatic disease. (See Section 8.8: Hepatic Disease.) Although the frequency is slightly lower than with INH or RIF, the drug can cause liver injury that may be severe and prolonged. If the drug is used in patients with underlying liver disease, laboratory and clinical monitoring should be increased. Monitoring. Serum uric acid measurements are not recommended as a routine but may serve as a surrogate marker for compliance. Liver chemistry monitoring should be performed when the drug is used in patients with underlying liver disease or when it is used with rifampin in treating latent tuberculosis infection. 3.1.6. Ethambutol. Role in treatment regimen. Ethambutol (EMB) is a rst line drug for treating all forms of tuberculosis. It is included in initial treatment regimens primarily to prevent emergence of RIF resistance when primary resistance to INH may be present. Ethambutol is generally not recommended for routine use in children whose visual acuity cannot be monitored. However, if a child has adult-type tuberculosis or disease that is suspected or proven to be caused by organisms that are resistant to either INH or RIF, EMB should be used (see Section 8.2: Children and Adolescents, and Table 6).
Dose. See Tables 3 and 5. Adults: 1520 mg/kg per day: Table 5 lists recommended dosages for adults, using whole tablets. Children (maximum): 1520 mg/kg per day (1.0 g); 50 mg/kg twice weekly (2.5 g). The drug can be used safely in older children but should be used with caution in children in whom visual acuity cannot be monitored (generally less than 5 years of age) (66). In younger children EMB can be used if there is concern with resistance to INH or RIF (Table 6). Preparations. Tablets (100 mg, 400 mg) for oral administration. Adverse effects. Retrobulbar neuritis: This is manifested as decreased visual acuity or decreased red-green color discrimination that may affect one or both eyes. The effect is dose related, with minimal risk at a daily dose of 15 mg/kg (67). No difference was found in the prevalence of decreased visual acuity between regimens that contained EMB at 15 mg/kg and those not containing the drug (68). The risk of optic toxicity is higher at higher doses given daily (18% of patients receiving more than 30 mg/kg per day) and in patients with renal insufciency. Higher doses can be given safely twice or three times weekly. Peripheral neuritis: This is a rare adverse effect (69). Cutaneous reactions: Skin reactions requiring discontinuation of the drug occur in 0.20.7% of patients (68). Use in pregnancy. EMB is considered safe for use in pregnancy (7072). CNS penetration. The agent penetrates the meninges in the presence of inammation but does not have demonstrated efcacy in tuberculous meningitis (73). Use in renal disease. (See Section 8.7: Renal Insufciency and End-stage Renal Disease.) EMB is cleared primarily by the kidneys. The dose or dosing interval should be adjusted when the creatinine clearance is less than 70 ml/minute (74). EMB should be administered at a dose of 1520 mg/kg three times a week by DOT after dialysis in patients with end-stage renal disease (Table 15) (26). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) EMB can be used safely in patients with hepatic disease. Monitoring. Patients should have baseline visual acuity testing (Snellen chart) and testing of color discrimination (Ishihara tests). At each monthly visit patients should be questioned regarding possible visual disturbances including blurred vision or scotomata. Monthly testing of visual acuity and color discrimination is recommended for patients taking doses greater than 1520 mg/kg, patients receiving the drug for longer than 2 months, and any patient with renal insufciency. Patients should be instructed to contact their physician or public health clinic immediately if they experience a change in vision. EMB should be discontinued immediately and permanently if there are any signs of visual toxicity.
ROLE OF FIXED-DOSE COMBINATION PREPARATIONS Fixed-dose combination preparations minimize inadvertent monotherapy and may decrease the frequency of acquired drug resistance and medication errors. These preparations should generally be used when therapy cannot be administered under DOT.
3.1.7. Fixed-Dose Combination Preparations. Role in treatment regimen. Two combined preparations, INH and RIF (Rifamate) and INH, RIF, and PZA (Rifater), are
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available in the United States. These formulations are a means of minimizing inadvertent monotherapy, particularly when DOT is not possible, and, therefore, may decrease the risk of acquired drug resistance (75). The use of xed-dose formulations may reduce the number of pills that must be taken daily. Constituent drugs are combined in proportions compatible with daily treatment regimens. Formulations for intermittent administration are not available in the United States. Preparations and dose. Rifamate: As sold in North America, each capsule contains RIF (300 mg) and INH (150 mg); thus, the daily dose is two capsules (600 mg of RIF and 300 mg of INH). Two capsules of Rifamate plus two 300-mg tablets of INH are used by some programs for intermittent therapy given twice weekly as DOT. Rifater: Each tablet contains RIF (120 mg), INH (50 mg), and PZA (300 mg). The daily dose is based on weight as follows: 44 kg or less, four tablets; 4554 kg, ve tablets; 55 kg or more, six tablets. To obtain an adequate dose of PZA in persons weighing more than 90 kg additional PZA tablets must be given. Adverse effects. See comments under individual drugs above. Use in pregnancy. Rifamate may be used in daily treatment of pregnant women. Rifater should not be used because it contains PZA. CNS penetration. See comments under individual drugs above. Use in renal disease. (See Section 8.7: Renal Insufciency and End-stage Renal Disease.) Rifamate may be used in persons with renal insufciency. Rifater should not be used because of the potential need for adjustment of the dose of PZA. Use in hepatic disease. (See Section 8.8: Hepatic Disease.) In patients with underlying hepatic disease it is advisable to treat with single-drug formulations until safety in an individual patient can be determined and a stable regimen established.
3.2. Second-Line Drugs
of 100200 mg/day (79). Rarely, cycloserine may cause peripheral neuritis. Use in pregnancy. Cycloserine crosses the placenta. There are limited data on safety in pregnancy; thus, it should be used in pregnant women only when there are no suitable alternatives (77). CNS penetration. Concentrations in CSF approach those in serum (77). Use in renal disease. (See Section 8.7: Renal Insufciency and End-stage Renal Disease.) The drug can accumulate in patients with impaired renal function and should be used cautiously in such patients. Generally, the dose should be reduced and serum concentrations measured. Cycloserine should not be used in patients having a creatinine clearance of less than 50 ml/ minute unless the patient is receiving hemodialysis. For patients being hemodialyzed the dose should be 500 mg three times a week or 250 mg daily (Table 15). Serum concentrations of the drug should be measured and the dose adjusted accordingly. Use in hepatic disease. (See Section 8.8: Hepatic Disease.) There are no precautions except for patients with alcohol-related hepatitis in whom there is an increased risk of seizures (77). Monitoring. Neuropsychiatric status should be assessed at least at monthly intervals and more frequently if symptoms develop. As note above, measurements of serum concentrations may be necessary until an appropriate dose is established. For patients taking phenytoin, serum concentrations of phenytoin should be measured. 3.2.2. Ethionamide. Role in treatment. Ethionamide (76, 77) is a second-line drug that is used for patients with drug-resistant tuberculosis disease caused by organisms that have demonstrated or presumed susceptibility to the drug. Dose: See Table 3. Adults (maximum): 1520 mg/kg per day (1.0 g/day), usually 500750 mg/day in a single daily dose or two divided doses. The single daily dose can be given at bedtime or with the main meal. There are no data to support intermittent dosing. Children (maximum): 1520 mg/kg per day (1.0 g/day). Preparations: Tablets (250 mg). Adverse reactions: Gastrointestinal effects: Ethionamide commonly causes profound gastrointestinal side effects, including a metallic taste, nausea, vomiting (that is often severe), loss of appetite, and abdominal pain (80). Symptoms may improve if doses are taken with food or at bedtime. Hepatotoxicity: Ethionamide is similar in structure to INH and may cause similar side effects. Hepatotoxicity occurs in about 2% of patients taking the drug (81, 82). Neurotoxicity: Neurotoxicity, including peripheral neuritis, optic neuritis, anxiety, depression, and psychosis, has been reported in 12% of patients taking shorter courses of the drug with higher rates reported with prolonged treatment (83, 84). Endocrine effects: Endocrine disturbances, including gynecomastia, alopecia, hypothyroidism, and impotence, have been described (85, 86). Diabetes may be more difcult to manage in patients taking ethionamide (77). Use in pregnancy. Ethionamide crosses the placenta and is teratogenic in laboratory animals. It should not be used in pregnancy. CNS penetration. CSF concentrations are equal to those in serum (77).
3.2.1. Cycloserine. Role in treatment regimen. Cycloserine (76, 77) is a secondline drug that is used for treating patients with drug-resistant tuberculosis caused by organisms with known or presumed susceptibility to the agent. It may also be used on a temporary basis for patients with acute hepatitis in combination with other nonhepatotoxic drugs. Dose. See Table 3. Adults (maximum): 1015 mg/kg per day (1,000 mg), usually 500750 mg/day given in two doses. Clinicians with experience with cycloserine indicate that toxicity is more common at doses over 500 mg/day. Serum concentration measurements aiming for a peak concentration of 2035 g/ml are often useful in determining the optimum dose for a given patient. There are no data to support intermittent administration. Children (maximum): 1015 mg/kg per day (1.0 g/day). Preparations. Capsules (250 mg). Adverse effects. Central nervous system effects: The central nervous system effects range from mild reactions, such as headache or restlessness, to severe reactions, such as psychosis and seizures. The drug may exacerbate underlying seizure disorders or mental illness. Seizures have been reported to occur in up to 16% of patients receiving 500 mg twice daily but in only 3% when receiving 500 mg once daily (78). Pyridoxine may help prevent and treat neurotoxic side effects and is usually given in a dosage
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Use in renal disease. (See Section 8.7: Renal Insufciency and End-stage Renal Disease.) For patients having a creatinine clearance of less than 30 ml/minute or who are receiving hemodialysis the dose should be reduced to 250500 mg/day (Table 15). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) Ethionamide should be used with caution in patients with underlying liver disease. Monitoring. Liver function tests should be obtained at baseline and, if there is underlying liver disease, at monthly intervals. The studies should be repeated if symptoms occur. Thyroidstimulating hormone should be measured at baseline and at monthly intervals. 3.2.3. Streptomycin. Role in treatment regimen. Streptomycin (SM) (76, 77, 8789) and EMB have been shown to be approximately equivalent when used in the initial phase of treatment with 6-month regimens. However, among patients likely to have acquired M. tuberculosis in a high-incidence country, the relatively high rate of resistance to SM limits its usefulness. Dose. See Table 3. Adults (maximum): 15 mg/kg per day (1 g/day) parenterally, usually given as a single daily dose (57 days/week) initially, and then reducing to two or three times a week after the rst 24 months or after culture conversion, depending on the efcacy of the other drugs in the regimen (90). For persons greater than 59 years of age the dose should be reduced to 10 mg/kg per day (750 mg). The dosing frequency should be reduced (i.e., 1215 mg/kg per dose two or three times per week) in persons with renal insufciency (see below, Use in Renal Disease) (91, 92). Children (maximum): 2040 mg/kg per day (1 g/day). Preparations. Aqueous solution in vials of 1 g (93). Adverse effects. Ototoxicity: The most important adverse reaction caused by SM is ototoxicity, including vestibular and hearing disturbances. The risk is increased with age (94) or concomitant use of loop-inhibiting diuretics (furosemide, ethacrynic acid). The risk of ototoxicity increases with increasing single doses and with the cumulative dose, especially above 100120 g. Neurotoxicity: SM relatively commonly causes circumoral parasthesias immediately after injection. Rarely, it may interact with muscle relaxants to cause postoperative respiratory muscle weakness. Nephrotoxicity: Nephrotoxicity occurs less commonly with SM than with amikacin, kanamycin, or capreomycin (95). Renal insufciency requiring discontinuation occurs in about 2% of patients (96). Use in pregnancy. SM is contraindicated in pregnancy because of the risk of fetal hearing loss (77, 97, 98). CNS penetration. There is only slight diffusion of SM into CSF, even in patients with meningitis (77, 99). Use in renal disease. (See Section 8.7: Renal Insufciency and End-stage Renal Disease.) SM should be used with caution in patients with renal function impairment because of the increased risk of both ototoxicity and nephrotoxicity. Because clearance is almost exclusively by the kidney, dosing adjustments are essential in patients with underlying renal insufciency, including the elderly and those undergoing hemodialysis. In such patients, the dosing frequency should be reduced to two or three times weekly, but the milligram dose should be maintained at 1215 mg/kg per dose to take advantage of the concentration-
dependent bactericidal effect (Table 15) (91, 92). Smaller doses may reduce the efcacy of this drug. The drug should be given after dialysis to facilitate DOT and to avoid premature removal of the drug (100). Serum drug concentrations should be monitored to avoid toxicity (91). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) No precautions are necessary. Monitoring. An audiogram, vestibular testing, Romberg testing, and serum creatinine measurement should be performed at baseline. Assessments of renal function, and questioning regarding auditory or vestibular symptoms, should be performed monthly. An audiogram and vestibular testing should be repeated if there are symptoms of eighth nerve toxicity. 3.2.4. Amikacin and kanamycin. Role in treatment regimen. Amikacin and kanamycin (76, 77, 101) are two closely related injectable second-line drugs that are used for patients with drug-resistant tuberculosis whose isolate has demonstrated or presumed susceptibility to the agents. There is nearly always complete cross-resistance between the two drugs, but most SM-resistant strains are susceptible to both (102). Because it is used to treat a number of other types of infections, amikacin may be more easily obtained, and serum drug concentration measurements are readily available. Dose. See Table 3. Adults (maximum): 15 mg/kg per day (1.0 g/day), intramuscular or intravenous, usually given as a single daily dose (57 days/ week) initially, and then reducing to two or three times a week after the rst 24 months or after culture conversion, depending on the efcacy of the other drugs in the regimen (90). For persons greater than 59 years of age the dose should be reduced to10 mg/kg per day (750 mg). The dosing frequency should be reduced (i.e., 1215 mg/kg per dose, two or three times per week) in persons with renal insufciency (see below, Use in Renal Disease) (91, 92). Children (maximum): 1530 mg/kg per day (1 g/day) intramuscular or intravenous as a single daily dose. Preparations. Aqueous solution for intramuscular or intravenous injection in vials of 500 mg and 1 g. Adverse effects. Ototoxicity: Amikacin and kanamycin may cause deafness, but they cause less vestibular dysfunction than SM (103, 104). Ototoxicity is more common with concurrent use of diuretics. In one report high-frequency hearing loss occurred in 24% of patients receiving amikacin, with higher rates occurring among those receiving longer treatment and/or higher doses (105), whereas a review of the literature found only 1.5% hearing loss (106). Nephrotoxicity: Amikacin and kanamycin may be more nephrotoxic than SM (95). Renal impairment was seen in 8.7% of patients receiving amikacin, with a higher frequency in patients with initially increased creatinine levels, patients receiving larger total doses, and patients receiving other nephrotoxic agents. A frequency of 3.4% was reported in patients with no risk factors (106, 107). Use in pregnancy. Both amikacin and kanamycin are contraindicated in pregnant women because of risk of fetal nephrotoxicity and congenital hearing loss (77). CNS penetration. Only low concentrations of the drugs are found in CSF, although slightly higher concentrations have been found in the presence of meningitis (77). Use in renal disease. (See Section 8.7: Renal Insufciency and End-stage Renal Disease.) Amikacin and kanamycin
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should be used with caution in patients with renal function impairment because of the increased risk of both ototoxicity and nephrotoxicity. Because clearance is almost exclusively by the kidney, dosing adjustments are essential in patients with underlying renal insufciency, including the elderly and those receiving hemodialysis. In such patients, the dosing frequency should be reduced to two or three times per week, but the dose should be maintained at 1215 mg/kg to take advantage of the concentration-dependent bactericidal effect (Table 15) (91, 92). Smaller doses may reduce the efcacy of this drug. The drug should be given after dialysis to facilitate DOT and to avoid premature removal of the drug (100). Serum drug concentrations should be monitored to avoid toxicity (91). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) No precautions are necessary. Monitoring. Monitoring should be performed as described for SM. An advantage of amikacin is that serum concentration measurements can be obtained routinely. Patients with severe hepatic disease, because of predisposition to hepato-renal syndrome, may be at greater risk for nephrotoxicity from amikacin/ kanamycin and should have renal function monitored closely. 3.2.5. Capreomycin. Role in treatment. Capreomycin is a second-line injectable drug that is used for patients with drug-resistant tuberculosis caused by organisms that have known or presumed susceptibility to the drug (108). Dose. See Table 3. Adults (maximum): 15 mg/kg per day (1.0 g/day), usually given as a single daily dose ve to seven times a week, and reduced to two or three times a week after the rst 24 months or after culture conversion, depending on the efcacy of the other drugs in the regimen (90). For persons greater than 59 years of age the dose should be reduced to 10 mg/kg per day (750 mg). The dosing frequency should be reduced to 1215 mg/kg two or three times per week in persons with renal insufciency (see below, Use in Renal Disease) (91, 92). Children (maximum): 1530 mg/kg per day (1 g/day) as a single daily or twice weekly dose. Preparations. Capreomycin is available in vials of 1 g for both intramuscular and intravenous administration. Adverse effects. Nephrotoxicity: Nephrotoxic effects may result in reduced creatinine clearance or potassium and magnesium depletion. Proteinuria is common (109). Signicant renal toxicity requiring discontinuation of the drug has been reported to occur in 2025% of patients (110, 111). Ototoxicity: Vestibular disturbances, tinnitus, and deafness appear to occur more often in elderly persons or those with preexisting renal impairment (111). Use in pregnancy. Capreomycin should be avoided in pregnancy because of risk of fetal nephrotoxicity and congenital hearing loss (77). CNS penetration. Capreomycin does not penetrate into the CSF (77). Use in renal disease. (See Section 8.7: Renal Insufciency and End-stage Renal Disease.) Capreomycin should be used with caution in patients with renal function impairment because of the increased risk of both ototoxicity and nephrotoxicity (112). Because capreomycin is nearly entirely cleared by the kidneys, dosing adjustments are essential in patients with underlying renal insufciency and end-stage renal disease, including patients undergoing hemodialysis. In such patients, the dosing frequency
should be reduced to two or three times weekly, but the milligram dose should be maintained at 1215 mg/kg per dose to take advantage of the concentration-dependent bactericidal effect (Table 15) (91, 92). Smaller doses may reduce the efcacy of this drug. The drug should be given after dialysis to facilitate DOT and avoid premature removal of the drug (100, 113). Serum drug concentrations should be monitored to avoid toxicity (91). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) No precautions are necessary. Monitoring. Monitoring should be performed as described for SM. In addition, serum potassium and magnesium concentrations should be measured at baseline and at least at monthly intervals. 3.2.6. p-Aminosalicylic acid. Role in treatment. p-Aminosalicylic acid (PAS) is an oral agent used in treatment of drug-resistant tuberculosis caused by organisms that are susceptible to the drug. Dose. See Table 3. Adults: 812 g/day in two or three doses. For PAS granules, 4 g three times daily has been the usual dosage (114, 115). However, it has been shown that administration of 4 g twice daily is adequate to achieve the target serum concentration (116). Children: 200300 mg/kg per day in two to four divided doses (117). Preparations. The only available formulation in the United States is granules in 4-g packets (Paser granules) (118). It was previously thought that the granules needed to be taken with acidic food (115); however, more recent data suggest that this is not necessary (C. Peloquin, personal communication). Tablets (500 mg) are still available in some countries. A solution for intravenous administration is available in Europe (119, 120). Adverse effects. Hepatotoxicity: In a review of 7,492 patients being treated for tuberculosis, 38 (0.5%) developed hepatitis, of which 28 cases (0.3%) were attributed at least in part to PAS (121). Gastrointestinal distress: This is the most common side effect of PAS (122). In a large study of INH and PAS 11% of patients had drug toxicity, mainly gastrointestinal intolerance to PAS (114). The incidence of gastrointestinal side effects is less with lower doses (8 g daily) and with the granular formulation of the drug. Malabsorption syndrome: This is characterized by steatorrhea and low serum folate levels (123). Hypothyroidism: This is a common side effect, especially with prolonged administration or concomitant use of ethionamide. It may be accompanied by goiter formation. Thyroid hormone replacement may be required. Thyroid function returns to normal after discontinuation of the drug (124). Coagulopathy: A doubling of the prothrombin time that seemed to be lessened by coadministration of streptomycin has been reported (125). Use in pregnancy. No studies have been done in humans; however, PAS has been used safely in pregnancy. The drug should be used only if there are no alternatives (see below) for a pregnant woman who has multidrug-resistant tuberculosis. CNS penetration. In the presence of inamed meninges, PAS concentrations are between 1050% of those achieved in serum (119). The drug has marginal efcacy in meningitis. Use in renal disease. (See Section 8.7: Renal Insufciency and End-stage Renal Disease.) Approximately 80% of the
626
drug is excreted in the urine (118). Unless there is no alternative, PAS is contraindicated in severe renal insufciency because of the accumulation of the acetylated form (123, 126, 127). Because both PAS and acetyl-PAS are removed by dialysis, the drug should be given after dialysis to facilitate DOT and avoid premature removal of the drug (126). Use in hepatic disease. (See Section 8.8: Hepatic Disease.) The clearance of PAS is not substantially altered in liver disease, suggesting that the drug may be used in usual doses but with increased laboratory and clinical monitoring (127). Monitoring. Hepatic enzymes and thyroid function should be measured at baseline. With prolonged therapy (i.e., more than 3 months) thyroid function should be checked every 3 months. 3.2.7. Fluoroquinolones. Role in treatment regimen. Of the uoroquinolones (128 131), levooxacin, moxioxacin, and gatioxacin have the most activity against M. tuberculosis. On the basis of cumulative experience suggesting a good safety prole with long-term use of levooxacin, this drug is the preferred oral agent for treating drug-resistant tuberculosis caused by organisms known or presumed to be sensitive to this class of drugs, or when rst-line agents cannot be used because of intolerance. Data on longterm safety and tolerability of moxioxacin and gatioxacin, especially at doses above 400 mg/day, are limited. Cross-resistance has been demonstrated among ciprooxacin, ooxacin, and levooxacin and presumably is a class effect (132). Fluoroquinolones should not be considered rst-line agents for the treatment of drug-susceptible tuberculosis except in patients who are intolerant of rst-line drugs. Dose. (See Table 3.) The doses given are for levooxacin. Adults: 5001,000 mg daily. Children: The long-term (more than several weeks) use of uoroquinolones in children and adolescents has not been approved because of concerns about effects on bone and cartilage growth. However, most experts agree that the drug should be considered for children with MDR tuberculosis. The optimal dose is not known. Preparations (Levooxacin). Tablets (250 mg, 500 mg, 750 mg); aqueous solution (500 mg) for intravenous administration. Adverse effects. The adverse effects (133) cited are for levooxacin. Gastrointestinal disturbance: Nausea and bloating occur in 0.5 1.8% of patients taking the drug. Neurologic effects: Dizziness, insomnia, tremulousness, and headache occur in 0.5% of patients. Cutaneous reactions: Rash, pruritis, and photosensitivity occur in 0.20.4% of patients. Use in pregnancy. This class of drugs should be avoided in pregnancy because of teratogenic effects (119, 134). CNS penetration. The concentration in CSF after administration of a standard dose of levooxacin is 1620% of that in serum (135). Interference with absorption. Because antacids and other medications containing divalent cations markedly decrease absorption of uoroquinolones, it is critical that any uoroquinolone not be administered within 2 hours of such medications (Section 7.1: Interactions Affecting Antituberculosis Drugs). Use in renal disease. (See Section 8.7: Renal Insufciency and End-stage Renal Disease.) The drug is cleared primarily (80%) by the kidney (135). Dosage adjustment (7501,000 mg three times a week) is recommended if creatinine clearance is
less than 50 ml/minute (Table 15) (136). It is not cleared by hemodialysis; supplemental doses after dialysis are not necessary (135). Use in hepatic disease. Drug levels are not affected by hepatic disease (135). It is presumed to be safe for use in the setting of severe liver disease, but as with all drugs, should be used with caution. Monitoring. No specic monitoring is recommended.
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Capreomycin kinetics in renal impairment and clearance by hemodialysis. Am Rev Respir Dis 1988;138:13121313. Storey PB. A comparison of isoniazidcycloserine with isoniazidPAS in the therapy of cavitary pulmonary tuberculosis. Am Rev Respir Dis 1960;81:868879. Peloquin CA, Henshaw TL, Huitt GW, Berning SE, Nitta AT, James GT. Pharmacokinetic evaluation of para-aminosalicylic acid granules. Pharmacotherapy 1994;14:4046. Peloquin CA, Berning SE, Huitt GW, Childs JM, Singleton MD, James GT. Once-daily and twice-daily dosing of p-aminosalicylic acid granules. Am J Respir Crit Care Med 1999;159:932934. American Academy of Pediatrics. Tuberculosis. In: Pickering LK, editor. Red book report of the Committee on Infectious Diseases, 25th edition. Elk Grove Village, IL: American Academy of Pediatrics; 2000. p. 593613. Anonymous. Pasera granules. In: Physicians desk reference, 54th edition. Montvale, NJ: Medical Economics Company; 2000. p. 14431445. Peloquin CA. Antituberculosis drugs: pharmacokinetics. In: Heifets LB, editor. Drug susceptibility in the chemotherapy of mycobacterial infections. Boca Raton, FL: CRC Press; 1991. Chapter 2. Fodor T, Pataki G, Schrettner M. PAS infusion in treatment of multidrug-resistant tuberculosis [letter]. Int J Tuberc Lung Dis 2000;4:187 188. Rossouw JE, Saunders SJ. Hepatic complications of antituberculous therapy. Q J Med 1975;XLIV:116. British Medical Research Council. Treatment of pulmonary tuberculosis with streptomycin and para-amino-salicylic acid. BMJ 1950;2:1073 1085. Jacobus DP. Para-amino-salicylic acid: multi-drug resistant [sic] Mycobacterium tuberculosis. Washington, DC. Crofton J. Drug treatment of tuberculosis. I. Standard chemotherapy. BMJ 1960;2:370373. Tarnoky AL, Steingold L. The action of p-aminosalicylic acid on prothrombin time in man. J Clin Pathol 1951;4:478486. Ogg CS, Toseland PA, Cameron JS. Pulmonary tuberculosis in patient on intermittent haemodialysis. BMJ 1968;2:283284. Held H, Fried F. Elimination of para-aminosalicylic acid in patients with liver disease and renal insufciency. Chemotherapy 1977;23:405415. Gillespie SH, Kennedy N. Fluoroquinolones: a new treatment for tuberculosis? Int J Tuberc Lung Dis 1998;2:265271. Kennedy N, Fox R, Kisyombe GM, Saruni AO, Uiso LO, Ramsay AR, Ngowi FI, Gillespie SH. Early bactericidal and sterilizing activities of ciprooxacin in pulmonary tuberculosis. Am Rev Respir Dis 1993; 148:15471551. Kennedy N, Berger L, Curram J, Fox R, Gutmann J, Kisyombe GM, Ngowi FI, Ramsay ARC, Saruni AOS, Sam N, et al. Randomized controlled trial of a drug regimen that includes ciprooxacin for the treatment of pulmonary tuberculosis. Clin Infect Dis 1996;22:827833. Fujiwara PI, editor. Clinical policies and protocols. New York: Bureau of Tuberculosis Control, New York City Department of Health; 1999. Sander CC. Review of preclinical studies with ooxacin. Clin Infect Dis 1991;14:526538. Ball P, Tillotson G. Tolerability of uorquinolone antibiotics: past, present, and future. Drug Saf 1995;13:343358. Lipsky BA, Baker CA. Fluoroquinolone toxicity proles: a review focusing on newer agents. Clin Infect Dis 1999;28:352364. Fish DN, Chow AT. The clinical pharmacokinetics of levooxacin. Clin Pharmacokinet 1997;32:101119. Anonymous. Ooxacin. Med Lett Drugs Ther 1991;33:7173.
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4. PRINCIPLES OF ANTITUBERCULOSIS CHEMOTHERAPY
EFFECTS OF ANTITUBERCULOSIS CHEMOTHERAPY Antituberculosis chemotherapy is designed to kill tubercle bacilli rapidly, minimize the potential for the organisms to develop drug resistance, and sterilize the hosts tissues. The achievement of these effects requires that a combination of agents with specic activities be administered for a sufciently long period of time. As a consequence of these effects, the patient is cured and has only a small likelihood of relapse.
4.1. Combination Chemotherapy
The primary goals of antituberculosis chemotherapy are to kill tubercle bacilli rapidly, prevent the emergence of drug resistance, and eliminate persistent bacilli from the hosts tissues to prevent relapse (1). To accomplish these goals, multiple antituberculosis drugs must be taken for a sufciently long time. The theoretical model of chemotherapy for tuberculosis is founded on current understanding of the biology of M. tuberculosis in the host and on the specic activities of antituberculosis drugs. This model is supported by data from numerous in vivo and in vitro studies. It is theorized that there are three separate subpopulations of M. tuberculosis within the host. These populations are dened by their growth characteristics and the milieu in which they are located (1). The largest of the subpopulations consists of rapidly growing extracellular bacilli that reside mainly in cavities. This subpopulation, because of its size, is most likely to harbor organisms with random mutations that confer drug resistance. The frequency of these mutations that confer resistance is about 10 6 for INH and SM, 10 8 for RIF, and 10 5 for EMB; thus, concurrent mutations to both INH and RIF, for example, would be 10 14, making simultaneous resistance to both drugs in an untreated patient a highly unlikely event (2). INH has been shown to possess the most potent ability to kill rapidly multiplying M. tuberculosis during the initial part of therapy (early bactericidal activity), thereby rapidly decreasing infectiousness (35). It is followed in this regard by EMB, RIF, and SM. PZA has weak early bactericidal activity during the rst 2 weeks of treatment (3, 6). Drugs that have potent early bactericidal activity reduce the chance of resistance developing within the bacillary population. Early experience in clinical trials demonstrated that multiple agents are necessary to prevent the emergence of a drug-resistant population as a consequence of the selection pressure from administration of a single agent. Shortly after the discovery of SM, it was demonstrated that treatment with this agent alone resulted in treatment failure and drug resistance (7). Subsequently, it was shown that the combination of PAS and SM substantially lessened the likelihood of acquired resistance and treatment failure (8). In modern regimens both INH and RIF have considerable ability to prevent the emergence of drug resistance when given with another drug. EMB and SM are also effective in preventing the emergence of drug resistance, whereas the activity of PZA in this regard is poor (9, 10). For this reason PZA should not be used with only one other agent when treating active tuberculosis. The rapidly dividing population of bacilli is eliminated early in effective therapy as shown by the early clinical responses and clearing of live bacilli from sputum within 2 months in about 80% of patients. The remaining subpopulations of M. tuberculosis account for treatment failures and relapses, especially when the
duration of therapy is inadequate. These residual populations include organisms that are growing more slowly, often in the acidic environment provided by areas of necrosis, and a group that is characterized by having spurts of growth interspersed with periods of dormancy. The sterilizing activity of a drug is dened by its ability to kill bacilli, mainly in these two subpopulations that persist beyond the early months of therapy, thus decreasing the risk of relapse (1). The use of drugs that have good sterilizing properties is essential for regimens as short as 6 months. RIF and PZA have the greatest sterilizing activity followed by INH and SM (11, 12). The sterilizing activity of RIF persists throughout the course of therapy, but this does not appear to be true for PZA. When given in RIF-containing regimens, PZA provides additive sterilizing activity only during the initial 2 months of therapy. The sterilizing activity of PZA may not be so limited in regimens where RIF cannot be used or is not effective, so regimens for MDR tuberculosis may include PZA for the full course of treatment if the isolate is susceptible to this agent.
4.2. Optimum Duration of Treatment
Truly effective chemotherapy for tuberculosis became available with the introduction of INH in the early 1950s. Adding INH to SM and PAS increased cure rates from about 70 to 95% but required treatment for 1824 months (13). Eventually, EMB replaced PAS as the companion agent for INH (14). Subsequent investigations of combination chemotherapy sought to identify regimens that were shorter and that could be given intermittently. The British Medical Research Council (BMRC) in East Africa (15) conducted the rst large-scale multicenter study of short-course (6-month) regimens. This study demonstrated that the addition of RIF or PZA to a base regimen of daily SM and INH increased the proportion of patients whose sputum cultures were negative by 2 months after the initiation of treatment and signicantly reduced the relapse rate. Moreover, the relapse rate of the short-course regimens was no greater than that of the standard 18-month regimen containing SM, INH, and thiacetazone (a drug used in many countries in place of PAS or EMB). In Hong Kong, administration of a 9-month regimen of SM, INH, and PZA daily, twice weekly, or three times weekly was associated with a relapse rate of only 56% (16). Unfortunately, all short-course regimens that did not include RIF required fully supervised therapy and SM had to be used for the entire 9 months. Subsequent investigations conducted by the British Thoracic Association demonstrated that SM (or EMB) was necessary only for the rst 2 months to achieve excellent results with a 9month treatment duration, using INH and RIF throughout (17, 18). The BMRC conducted studies in Hong Kong proving that EMB was roughly as effective as SM in the initial phase of therapy, thereby demonstrating that an all-oral regimen was effective (19). The addition of PZA to a regimen containing INH and RIF enabled further shortening of the duration of therapy to 6 months. The British Thoracic Association demonstrated that a regimen of INH and RIF for 6 months, supplemented during the rst 2 months with PZA and either EMB or SM, was as effective as a 9-month regimen of INH and RIF with EMB in the rst 2 months (18). Administration of PZA beyond the initial 2 months in an RIF-containing regimen had no additional benet. The efcacy of the treatment regimens was similar regardless of whether PZA was given for 2, 4, or 6 months (20). Subsequent studies of 6-month regimens have served to rene the approach used currently. USPHS Trial 21 compared selfadministered INH and RIF for 6 months plus PZA given during the initial 2 months with INH and RIF for 9 months (21). EMB
630
was added only if INH resistance was suspected. Patients taking the 6-month PZA-containing regimen had negative sputum cultures sooner after treatment was started than those treated for 9 months without PZA and relapse rates were similar for the two regimens (3.5 versus 2.8%). Investigators in Denver reported a low relapse rate (1.6%) when using a 62-dose, directly observed, 6-month regimen that consisted of 2 weeks of daily INH, RIF, PZA, and SM, 6 weeks of the same four drugs given twice weekly, and 18 weeks of twice weekly INH and RIF (22). Regimens less than 6 months in duration have been shown to have unacceptably high relapse rates among patients with smearpositive pulmonary tuberculosis (23, 24). However, in a study in Hong Kong among patients with smear-negative, culturepositive tuberculosis, the relapse rate was about 2% when using a 4-month regimen of daily SM, INH, RIF, and PZA (25); among smear-negative, culture-negative cases, the relapse rate was only 1%. In Arkansas, patients with tuberculosis who had negative smears and cultures were treated with INH and RIF given daily for 1 month followed by 3 months of twice weekly INH and RIF (26). Only 3 of 126 (2.4%) patients developed active tuberculosis during 3.5 years of follow-up. Thus, it appears that a 4-month, INH- and RIF-containing regimen is effective in culture-negative tuberculosis (see Section 8.4: Culture-negative Pulmonary Tuberculosis in Adults).
4.3. Intermittent Drug Administration
Nonadherence to the antituberculosis treatment regimen is well known to be the most common cause of treatment failure, relapse, and the emergence of drug resistance. Administration of therapy on an intermittent basis, as opposed to daily dosing, facilitates supervision of therapy, thereby improving the outcome. The concept of intermittent administration of antituberculosis drugs developed from early clinical observations and was supported by subsequent laboratory investigations. First, it was noted that a single daily dose of 400 mg of INH was more effective than the same total dose given in two divided doses (27). Second, in an early study from Madras, investigators demonstrated that fully supervised twice weekly therapy could be delivered to nonhospitalized patients and that the results were better than with a conventional self-administered daily regimen (28). These ndings, plus the laboratory results noted below, led to a series of clinical trials that compared daily and intermittent dosing of antituberculosis medications. In all of these studies, intermittent regimens were demonstrated to be as effective as daily regimens and no more toxic (20). In the laboratory it was noted that in vitro exposure of tubercle bacilli to drugs was followed by a lag period of several days before growth began again (postantibiotic effect) (2931). Thus,
it was concluded that maintaining continuous inhibitory drug concentrations was not necessary to kill or inhibit growth of M. tuberculosis. Studies in guinea pigs substantiated that INH could be given at intervals as long as 4 days without loss of efcacy; however, there was a signicant decrease in activity with an 8-day dosing interval (30, 31). The concept of intermittent drug administration continues to evolve. Studies have demonstrated that the frequency of drug administration in the continuation phase of treatment may be decreased to once a week when using INH and rifapentine for certain highly selected patients (3234). Because of the newness of these ndings the data are presented in some detail. The results from three open-label, randomized clinical trials indicate that rifapentine given with INH once a week is safe and effective when used for the treatment of selected, HIV-negative patients with pulmonary tuberculosis. In a study performed in Hong Kong, patients with pulmonary tuberculosis were allocated at random to receive 600 mg of rifapentine and 900 mg of INH given either once every week or once every 2 of 3 weeks for 4 months after completion of a standard 2-month initial phase (32). Overall, about 11% of patients in the two rifapentine arms failed or relapsed during a 5-year follow-up period, compared with 4% of the patients who received three times weekly INH RIF (control arm) in the continuation phase of treatment. Omitting every third dose of INHrifapentine did not appreciably increase the relapse rate, indicating that modest nonadherence may have a negligible effect. Multivariate analyses showed that the signicant prognostic factors were treatment arm, radiographic extent of disease (all three regimens), and sex (women fared better than men). The frequency of failures and relapses was also greater in all three arms if the 2-month culture was positive. The pivotal study for drug registration was conducted in North America and South Africa among HIV-negative patients with pulmonary tuberculosis (33). Patients in the experimental arm received directly observed twice weekly rifapentine together with daily self-administered INH, PZA, and EMB in the initial 2 months, followed by 4 months of once weekly directly observed rifapentine and INH. Patients in the control arm received a standard four-drug initial phase, followed by twice weekly INH RIF. Relapse rates during 2 years of follow-up were similar to those seen in the Hong Kong study (8.2% relapse in the experimental arm versus 4.4% in the control arm), and cavitary disease, sputum culture positivity at the end of the initial phase, and nonadherence with INH, EMB, and PZA in the experimental arm were signicantly associated with an increased probability of relapse. The third study was conducted by the CDC Tuberculosis Trials Consortium, and employed a design similar to the Hong
TABLE 11. RISK FACTORS FOR RELAPSE* BY CONTINUATION PHASE REGIMEN, RADIOGRAPHIC STATUS, AND 2-MONTH SPUTUM CULTURE: USPHS STUDY 22
Continuation Phase, INHRIF Twice Weekly Percentage Culture-Positive at 2 Months Cavity Yes No Yes 20.8 (48) 5.9 (17) No 4.7 (150) 1.7 (181) Cavity Yes No Continuation Phase, INHRPT Once Weekly Percentage Culture-Positive at 2 Months Yes 22.2 (72) 11.8 (17) No 9.1 (154) 1.9 (162)
Definition of abbreviations: INH Isoniazid; RIF rifampin; RPT rifapentine. Tuberculosis Trials Consortium. Rifapentine and isoniazid once a week versus rifampin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomized clinical trial. Lancet 2002;360:528534 and additional data (A. Vernon, personal communication). * Culture-positive relapse with restriction fragment length polymorphism match to initial isolate. INH-RIF twice weekly isoniazidrifampin for 16 weeks; INH-RPT once weekly isoniazidrifapentine for 16 weeks. Denominators in parentheses: number enrolled, completing treatment per protocol, and assessed for relapse.
631
of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Lancet 1973;1:13311339. Hong Kong Chest Service/British Medical Research Council. Controlled trial of 6-month and 9-month regimens of daily intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. Am Rev Respir Dis 1977;115:727735. British Thoracic and Tuberculosis Association. Short-course chemotherapy in pulmonary tuberculosis: a controlled trial by the British Thoracic and Tuberculosis Association. Lancet 1976;2:11021104. British Thoracic Association. A controlled trial of six months chemotherapy in pulmonary tuberculosis: second report-results during the 24 months after the end of chemotherapy. Am Rev Respir Dis 1982;126: 460462. Hong Kong Chest Service/British Medical Research Council. Five-year follow-up of a controlled trial of ve 6-month regimens of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1987;136:1339 1342. Hong Kong Chest Service/British Medical Research Council. Controlled trial of 2, 4, and 6 months of pyrazinamide in 6-month, three-timesweekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin, and pyrazinamide. Am Rev Respir Dis 1991;143:700706. Combs DL, OBrien RJ, Geiter LJ. USPHS tuberculosis short-course chemotherapy trial 21: effectiveness, toxicity, and acceptability. Report of nal results. Ann Intern Med 1990;112:397406. Cohn DL, Catlin BJ, Peterson KL, Judson FN, Sbarbaro JA. A 62-dose, 6-month therapy for pulmonary and extrapulmonary tuberculosis: a twice-weekly, directly observed, and cost-effective regimen. Ann Intern Med 1990;112:407415. East Africa/British Medical Research Council. Controlled clinical trial of ve short-course (4 month) chemotherapy regimens in pulmonary tuberculosis: second report of the 4th study. Am Rev Respir Dis 1981;123:165170. Singapore Tuberculosis Service/British Medical Research Council. Longterm follow-up of a clinical trial of 6-month and 4-month regimens of chemotherapy in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 1986;133:779783. Hong Kong Chest Service/British Medical Research Council. A controlled trial of 3-month, 4-month, and 6-month regimens of chemotherapy for sputum smear negative pulmonary tuberculosis: results at 5 years. Am Rev Respir Dis 1989;139:871876. Dutt AK, Moers D, Stead WW. Smear and culture negative pulmonary tuberculosis: four-month short course therapy. Am Rev Respir Dis 1989;139:867870. Tuberculosis Chemotherapy Centre, Madras. A concurrent comparison of isoniazid plus PAS with three regimens of isoniazid alone in the domiciliary treatment of pulmonary tuberculosis in South India. Bull World Health Organ 1960;23:535585. Tuberculosis Chemotherapy Centre, Madras. A concurrent comparison of intermittent (twice weekly) isoniazid plus streptomycin and daily isoniazid plus PAS in the domiciliary treatment of pulmonary tuberculosis. Bull World Health Organ 1964;31:247. Dickinson JM, Mitchison DA. In vitro studies on the choice of drugs for intermittent chemotherapy of tuberculosis. Tubercle 1966;47:370380. Dickinson JM, Ellard GA, Mitchison DA. Suitability of isoniazid and ethambutol for intermittent administration in the treatment of tuberculosis. Tubercle 1968;49:351366. Dickinson JM, Mitchison DA. Suitability of rifampicin for intermittent administration in the treatment of tuberculosis. Tubercle 1970;51: 8294. Tam CM, Chan SL, Kam KM, Goodall RL, Mitchison DA. Rifapentine and isoniazid in the continuation phase of treating pulmonary tuberculosis: nal report. Int J Tuberc Lung Dis 2002;6:310. Anonymous. Rifapentine (Priftin) data on le [package insert]. Kansas City, MO: Hoechst Marion Roussel; 1998. Benator D, Bhattacharya M, Bozeman L, Burman W, Catanzaro A, Chaisson R, Gordin F, Horsburgh CR, Horton J, Khan A, Stanton L, Vernon A, Villarino ME, Wang MC, Weiner M, Weis S. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomized clinical trial. Lancet 2002;360: 528534. Vernon A, Burman W, Benator D, Khan A, Bozeman L. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Lancet 1999;353: 18431847.
Kong trial, in which HIV-negative patients were allocated at random after successful completion of standard 2-month initial phase therapy (34). Again, results, as measured by rates of failure/relapse, were remarkably similar to the rst two trials, 9.2% in the experimental (INHrifapentine once weekly) arm compared with 5.6% in the control (INHRIF twice weekly) arm. However, as in the South Africa study, relapse was signicantly associated with the presence of cavitary lesions seen on the initial chest lm and sputum culture positivity at 2 months, both of which were more common in the rifapentine arm. With adjustment for these factors, the difference in outcome in the two arms was not statistically signicant. Relapse rates among patients who did not have cavitary disease and had negative sputum cultures at 2 months were low in both treatment arms. However, in patients who had both cavitation and a positive culture at 2 months the relapse rate in the rifapentine arm was 22% and in the twice weekly INHRIF arm was 21% (Table 11). In all of the cited studies, rifapentine was well tolerated, with the adverse events being similar to those occurring with RIF. A small number of HIVpositive patients were enrolled in the CDC study, but this arm was closed after the development of acquired rifampin resistance among relapse cases in the rifapentine arm (35).
References
1. Mitchison DA. Mechanisms of the action of drugs in short-course chemotherapy. Bull Int Union Tuberc 1985;60:3640. 2. David HL. Probability distribution of drug-resistant mutants in unselected populations of Mycobacterium tuberculosis. Appl Microbiol 1970;20:810814. 3. Jindani A, Aber VR, Edwards EA, Mitchison DA. The early bactericidal activity of drugs in patients with pulmonary tuberculosis. Am Rev Respir Dis 1980;121:939949. 4. Chan SL, Yew WW, Ma WK, Girling DJ, Aber VR, Felmingham D, Allen BW, Mitchison DA. The early bactericidal activity of rifabutin measured by sputum viable counts in Hong Kong patients with pulmonary tuberculosis. Tuber Lung Dis 1992;73:3338. 5. Sirgel FA, Botha FJH, Parkin DP, Van de Wal BW, Donald PR, Clark PK, Mitchison DA. The early bactericidal activity of rifabutin in patients with pulmonary tuberculosis measured by sputum viable counts: a new method of drug assessment. J Antimicrob Chemother 1993;32: 867875. 6. Botha FJH, Sirgel FA, Parkin DP, Van del Wal BW, Donald PR, Mitchison DA. The early bactericidal activity of ethambutol, pyrazinamide, and the xed combination of isoniazid, rifampicin, and pyrazinamide (Rifater) in patients with pulmonary tuberculosis. S Afr Med J 1996; 86:155158. 7. McDermott W, Muschenheim C, Hadley SF, Bunn PA, Gorman RV. Streptomycin in the treatment of tuberculosis in humans. I. Meningitis and generalized hematogenous tuberculosis. Ann Intern Med 1947;27: 769822. 8. Medical Research Council. Treatment of pulmonary tuberculosis with streptomycin and para-aminosalicylic acid. BMJ 1950;2:10731085. 9. East African/British Medical Research Council Pyrazinamide Investigation. A controlled comparison of four regimens of streptomycin plus pyrazinamide in the retreatment of pulmonary tuberculosis. Tubercle 1969;50:81112. 10. Matthews JH. Pyrazinamide and isoniazid used in the treatment of pulmonary tuberculosis. Am Rev Respir Dis 1960;81:348351. 11. East African/British Medical Research Council. Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for the treatment of pulmonary tuberculosis. Lancet 1974;2:11001106. 12. Hong Kong Chest Service/British Medical Research Council. Five year follow-up of a controlled trial of ve 6-month regimens of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1987;136:1339 1342. 13. Medical Research Council. Long-term chemotherapy in the treatment of chronic pulmonary tuberculosis with cavitations. Tubercle 1962;43:201. 14. Bobrowitz ID, Robins DE. Ethambutolisoniazid versus PASisoniazid in original treatment of pulmonary tuberculosis. Am Rev Respir Dis 1966;96:428438. 15. East African/British Medical Research Council. Controlled clinical trial
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5. RECOMMENDED TREATMENT REGIMENS

5.1. Evidence-based Rating System
To assist in making informed treatment decisions based on the most credible research results, evidence-based ratings have been assigned to the treatment recommendations (Table 1). The ratings system is the same as that used in the recommendations for treating latent tuberculosis infection, in which a letter indicating the strength of the recommendation, and a roman numeral indicating the quality of the evidence supporting the recommendation, are assigned to each regimen (1). Thus, clinicians can use the ratings to differentiate among recommendations based on data from clinical trials and those based on the opinions of experts familiar with the relevant clinical practice and scientic rationale for such practice when clinical trial data are not available.
5.2. Recommended Regimens
There are four basic regimens recommended for treating adults with tuberculosis caused by organisms that are known or presumed to be susceptible to INH, RIF, PZA, and EMB (Table 2). As noted below, children, depending on the circumstances, may not receive EMB in the initial phase of a 6-month regimen, but the regimens are otherwise identical. Each regimen has an initial phase of 2 months, followed by a choice of several options for the continuation phase of either 4 or 7 months. In Table 2 the initial phase is denoted by a number (1, 2, 3, or 4 ) and the options for the continuation phase are denoted by the respective number and a letter designation (a, b, or c ). DOT is the preferred initial management strategy for all regimens and should be used whenever feasible. All patients being given drugs less than 7 days per week (5, 3, or 2 days/week) must receive DOT. 5.2.1. Six-month regimens. The current minimal acceptable duration of treatment for all children and adults with culturepositive tuberculosis is 6 months (26 weeks). The initial phase of a 6-month regimen for adults should consist of a 2-month period of INH, RIF, PZA, and EMB given daily throughout (Regimen 1), daily for 2 weeks followed by two times weekly for 6 weeks (Regimen 2), or three times a week (Regimen 3). The minimum number of doses is specied in Table 2. On the basis of substantial clinical experience, 5 day-a-week drug administration by DOT is considered to be equivalent to 7 day-a-week administration; thus, either may be considered daily. Although administration of antituberculosis drugs by DOT at 5 days/week, rather than 7 days, has been reported in a large number of studies it has not been compared with 7-day administration in a clinical trial and therefore is rated AIII. The recommendation that a four-drug regimen be used initially for all patients is based on the current proportion of new tuberculosis cases caused by organisms that are resistant to INH (2). This recommendation is supported by a retrospective analysis of data from various BMRC studies indicating that in the presence of INH resistance there were fewer treatment failures and relapses if a regimen containing four drugs, INH, RIF, PZA, and EMB, was used in the initial phase (3). However, if therapy is being initiated after drug susceptibility test results are known and the organisms are susceptible to INH and RIF, EMB is not necessary. EMB can be discontinued as soon as the results of drug susceptibility studies demonstrate that the isolate is susceptible to the rst-line agents. In most situations these results are not available before 68 weeks after treatment is begun. The continuation phase of treatment should consist of INH and RIF given for a minimum of 4 months (18 weeks). Patients should be treated until they have received the specied total number of doses for the treatment regimen (Table 2). The continuation phase can be given daily (Regimen 1a), twice weekly
(Regimens 1b and 2a), or three times weekly (Regimen 3a). The continuation phase should be extended for an additional 3 months for patients who have cavitation on the initial or followup chest radiograph and are culture-positive at the time of completion of the initial phase of treatment (2 months). Patients who are HIV negative, who do not have cavities on the chest radiograph, and who have negative sputum AFB smears at completion of the initial phase of treatment may be treated with once weekly INH and rifapentine in the continuation phase for 4 months. If the culture of the sputum obtained at 2 months is positive, observational data and expert opinion suggest that the continuation phase of once weekly INH and rifapentine should be 7 months (4). 5.2.2. Nine-month regimen. If PZA cannot be included in the initial regimen, or if the isolate is determined to be resistant to PZA (an unusual circumstance, except for Mycobacterium bovis and M. bovis var. BCG), a regimen consisting of INH, RIF, and EMB should be given for the initial 2 months (Regimen 4) followed by INH and RIF for 7 months given either daily or twice weekly (Regimens 4a and 4b). 5.2.3. Alternative regimens. In some cases, either because of intolerance or drug resistance, the above-described regimens cannot be used. In these instances, an alternative regimen may be required. In a retrospective analysis of the combined results of clinical trials conducted by the BMRC it was concluded that, in the presence of initial resistance to INH, if a four-drug regimen containing RIF and PZA was used in the initial phase and RIF was used throughout a 4-month continuation phase there were no treatment failures and 7% relapses compared with 4% relapses among patients with fully susceptible strains (3). Data from a Hong Kong BMRC study suggests that in the presence of INH resistance results are better when PZA is used throughout (5). On the basis of these data, when INH cannot be used or the organisms are resistant to INH, a 6-month regimen of RIF, PZA, and EMB is nearly as efcacious as an INH-containing regimen (Rating BI) (3). Alternatively, RIF and EMB for 12 months may be used, preferably with PZA during at least the initial 2 months (Rating BII) (5, 6). If RIF is not used, INH and EMB should be given for a minimum of 1218 months with PZA during at least the initial 2 months (Rating CI) (5, 7). Levooxacin, moxioxacin, or gatioxacin may be useful in alternative regimens, but the potential role of a uoroquinolone and optimal length of therapy have not been dened (8, 9). In situations in which several of the rst-line agents cannot be used because of intolerance, regimens based on the principles described for treating multiple drug-resistant tuberculosis (Section 9.3: Management of Tuberculosis Caused by Drug-resistant Organisms) should be used.
5.3. Deciding to Initiate Treatment
The decision to initiate combination chemotherapy for tuberculosis should be based on epidemiologic information, clinical and radiographic features of the patient, and the results of the initial series of AFB smears (preferably three) and, subsequently, cultures for mycobacteria. Rapid amplication tests, if used, can also conrm the diagnosis of tuberculosis more quickly than cultures. On the basis of this information, the likelihood that a given patient has tuberculosis can be estimated. For example, a patient who has emigrated recently from a high-incidence country, has a history of cough and weight loss, and has characteristic ndings on chest radiograph should be considered highly likely to have tuberculosis. In such situations combination drug therapy should be initiated, even before AFB smear and mycobacterial culture results are known. Empirical treatment with a four-drug regimen should be initiated promptly when a patient is seriously ill with a disorder that is thought possibly to be tuberculosis.
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Initiation of treatment should not be delayed because of negative AFB smears for patients in whom tuberculosis is suspected and who have a life-threatening condition. Disseminated (miliary) tuberculosis, for example, is often associated with negative sputum AFB smears. Likewise, for a patient with suspected tuberculosis and a high risk of transmitting M. tuberculosis if, in fact, she or he had the disease, combination chemotherapy should be initiated in advance of microbiological conrmation of the diagnosis to minimize potential transmission. A positive AFB smear provides strong inferential evidence for the diagnosis of tuberculosis. If the diagnosis is conrmed by isolation of M. tuberculosis or a positive nucleic acid amplication test, or is strongly inferred from clinical or radiographic improvement consistent with a response to treatment, the regimen can be continued to complete a standard course of therapy (Figure 1). A PPD-tuberculin skin test may be done at the time of initial evaluation, but a negative test does not exclude the diagnosis of active tuberculosis. However, a positive skin test supports the diagnosis of culture-negative pulmonary tuberculosis or, in persons with stable abnormal chest radiographs consistent with inactive tuberculosis, a diagnosis of latent tuberculosis infection (see below). If the cultures are negative, the PPD-tuberculin skin test is positive (5 mm or greater induration), and there is no response to treatment, the options are as follows: (1 ) stop treatment if RIF and PZA have been given for at least 2 months; (2 ) continue treatment with RIF, with or without INH, for a total of 4 months; or (3 ) continue treatment with INH for a total of 9 months (10). All three of these options provide adequate therapy for persons with prior tuberculosis once active disease has been excluded. If clinical suspicion for active tuberculosis is low, the options are to begin treatment with combination chemotherapy or to defer treatment until additional data have been obtained to clarify the situation (usually within 2 months) (Figure 2, top). Even when the suspicion of active tuberculosis is low, treatment for latent tuberculosis infection with a single drug should not be initiated until active tuberculosis has been excluded. In low-suspicion patients not initially treated, if cultures remain negative, the PPD-tuberculin skin test is positive (5 mm or greater induration), and the chest radiograph is unchanged after 2 months, there are three treatment options (Figure 2, top) (10). The preferred options are INH for 9 months or RIF, with or without INH, for 4 months. RIF and PZA for a total of 2 months can be used for patients not likely to complete a longer regimen and who can be monitored closely. However, this last regimen has been associated with an increased risk of hepatotoxicity and should be used only in the limited circumstances described (11, 12). An advantage of the early use of combination chemotherapy is that, once active disease is excluded by negative cultures and lack of clinical or radiographic response to treatment, the patient will have completed 2 months of combination treatment that can be applied to the total duration of treatment recommended for latent tuberculosis infection (Figure 2, bottom).
5.4. Baseline and Follow-up Evaluations
Patients suspected of having tuberculosis should have appropriate specimens collected for microscopic examination and mycobacterial culture. When the lung is the site of disease, three sputum specimens should be obtained 824 hours apart. In patients who are not producing sputum spontaneously, induction of sputum using aerosolized hypertonic saline or bronchoscopy (performed under appropriate infection control procedures) may be necessary to obtain specimens. Susceptibility testing for INH, RIF, and EMB should be performed on an initial positive culture, regardless of the source. Second-line drug susceptibility testing should be done only in reference laboratories and be
limited to specimens from patients who have had prior therapy, have been in contact of a patient with known drug resistance, have demonstrated resistance to rifampin or two other rst-line drugs, or who have positive cultures after more than 3 months of treatment. At the time treatment is initiated, in addition to the microbiologic examinations, it is recommended that all patients with tuberculosis have counseling and testing for HIV infection (13). Patients with epidemiologic factors suggesting a risk for hepatitis B or C, for example, injection drug use, birth in Asia or Africa, or HIV infection, should have serologic tests for these viruses (14, 15). HIV-infected patients should also undergo CD4 lymphocyte count measurement. Measurements of AST, bilirubin, alkaline phosphatase, and serum creatinine and a platelet count should be obtained for all adults. Testing of visual acuity (Snellen chart) and color vision (Ishihara tests) should be performed when EMB is to be used. During treatment of patients with pulmonary tuberculosis, at a minimum, a sputum specimen for AFB smear and culture should be obtained at monthly intervals until two consecutive specimens are negative on culture. As described subsequently, important decisions concerning the continuation-phase regimen hinge on the microbiological status at the end of the initial phase of treatment, thus, obtaining sputum specimens at this juncture is critical, if sputum conversion to negative has not already been documented. For patients who had positive AFB smears at the time of diagnosis, follow-up smears may be obtained at more frequent intervals (e.g., every 2 weeks until two consecutive specimens are negative) to provide an early assessment of the response to treatment, especially for patients in situations in which the risk of transmission is high. On occasion, AFB-positive sputa are culture negative; this occurs most frequently among patients with far advanced cavitary tuberculosis after the rst months of treatment. It is thought that these organisms are dead and that their presence is not a sign of treatment failure, even if noted later in treatment. However, repeat cultures should be obtained to conrm that the earlier culture result was correct and not a false negative. Drug susceptibility tests should be repeated on isolates from patients who have positive cultures after 3 months of treatment. As described in Section 9.2 (Treatment Failure), patients who have positive cultures after 4 months of treatment should be considered as having failed treatment and managed accordingly. For patients with extrapulmonary tuberculosis the frequency and kinds of evaluations will depend on the sites involved and the ease with which specimens can be obtained. In addition to the microbiological evaluations, it is essential that patients have clinical evaluations at least monthly to identify possible adverse effects of the antituberculosis medications and to assess adherence. For patients with positive cultures at diagnosis, a repeat chest radiograph at completion of 2 months of treatment may be useful but is not essential. A chest radiograph at completion of therapy provides a baseline against which subsequent examinations can be compared, but, as with the 2-month examination, it is not essential. When the initial sputum cultures are negative, a presumptive diagnosis can be made if radiographic improvement is noted, generally by the time 2 months of treatment has been completed. Thus, in patients with negative initial cultures, a chest radiograph is necessary after 2 months of treatment and a radiograph at completion of treatment is desirable. Generally, follow-up after completion of therapy is not necessary. As a routine, it is not necessary to monitor liver or renal function or platelet count for patients being treated with rstline drugs unless there were abnormalities at baseline or there are clinical reasons to obtain the measurements. Patients who
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have stable abnormalities of hepatic or renal function at baseline should have repeat measurements early in the course of treatment, then less frequently to ensure that there has not been worsening. Patients receiving EMB should be questioned regarding visual disturbances at monthly intervals; monthly repeat testing of visual acuity and color vision is recommended for patients receiving an EMB dose exceeding 1520 mg/kg (the recommended range) and for patients receiving the drug for more than 2 months. Monitoring tests for the individual second-line drugs are listed in Section 3 (Drugs in Current Use).
5.5. Identification and Management of Patients at Increased Risk of Relapse
PATIENTS AT INCREASED RISK OF RELAPSE Patients who have cavitation on initial chest radiograph and who have a positive culture at completion of 2 months of therapy are at substantially increased risk of relapse. For these patients it is recommended that the continuation phase of treatment be prolonged to 7 months, making a total treatment period of 9 months.
approximately a 56% rate of relapse (Table 11) (17). This rate of adverse outcomes is not deemed to be sufcient to recommend prolongation of the continuation phase; however, patients with one or the other of these risk factors should be monitored more closely and consideration given to lengthening treatment if there are suggestions of a poor response. Additional factors to be considered in deciding to prolong treatment in patients with either cavitation or a positive culture at 2 months (but not both) might include being more than 10% underweight at diagnosis, having HIV infection, or having extensive involvement on chest radiograph. Patients with noncavitary pulmonary tuberculosis and a negative AFB smear at 2 months who are started on the once weekly rifapentineINH continuation phase and are subsequently found to be culture positive at 2 months should have treatment extended by an additional 3 months for a total of 9 months.
5.6. Definition of Completion of Therapy
The result of a sputum culture at the conclusion of the initial phase of treatment (2 months) has been shown to correlate with the likelihood of relapse after completion of treatment for pulmonary tuberculosis. In seven clinical trials performed by the BMRC, the regimens that had the highest proportion of patients with a positive sputum culture at 2 months after treatment was initiated were associated with a higher likelihood of relapse within 2 years (16). Of greater relevance to the current recommendations, data from USPHS Trial 22 comparing once weekly rifapentine and INH with twice weekly RIF and INH, showed an increased rate of relapse in patients who had a positive culture at 2 months in both study arms (17). Cavitation on the initial chest radiograph was also an independent risk factor for relapse. In patients in the control arm (twice weekly INHRIF) the presence of both cavitation and a positive culture at completion of 2 months of therapy was associated with a 21% rate of relapse, compared with 2% for patients who had neither risk factor (Table 11). Similar ndings were reported in a retrospective analysis of data from BMRC trials (16) and from a USPHS trial conducted in Poland (18). The most effective means of decreasing the likelihood of relapse for patients at increased risk has not yet been determined by clinical trials. However, in a controlled trial of treatment for silicotuberculosis in Hong Kong, prolongation of the continuation phase from 4 to 6 months decreased the rate of relapse from 22 to 7% (p 0.025) (19). Also in studies from Hong Kong, it was found that increasing the duration of PZA beyond the 2-month initial phase did not improve the efcacy of RIFcontaining regimens (20). It has been reported that for patients at high risk of relapse, prolongation of the once weekly INH rifapentine continuation phase from 4 to 7 months resulted in signicantly better results compared with patients in an earlier trial (4). In view of this evidence and on the basis of expert opinion, it is recommended that treatment for patients who have cavitation noted on the initial chest radiograph and who have positive cultures at completion of 2 months of therapy should be extended with INH and RIF for an additional 3 months for a total of 9 months (Rating AIII). In USPHS Study 22 patients treated with INH and RIF twice weekly in the continuation phase who had either cavitation on the initial chest radiograph or a positive culture at 2 months had
Treatment for a dened duration without accounting for the number of doses taken can result in undertreatment. Therefore, the determination of whether or not treatment has been completed is based on the total number of doses takennot solely on the duration of therapy (Table 2). For example, the 6-month daily (given 7 days/week) regimen should consist of at least 182 doses of INH and RIF, and 56 doses of PZA. If the drugs are administered by DOT at 5 days/week, the minimum number of doses is 130. A similar reduction in the target number of doses for 5-day-a-week administration applies to any of the regimens with a daily component. In some cases, either because of drug toxicity or nonadherence to the regimen, the specied number of doses cannot be administered within the targeted time period. In such cases, it is recommended that all of the specied number of doses for the initial phase be delivered within 3 months and those for the 4-month continuation phase be delivered within 6 months, so that the 6-month regimen should be completed within 9 months. If these targets are not met the patient must be considered to have interrupted therapy and be managed as described below.
5.7. Interruptions in Therapy
Interruptions in therapy are common in the treatment of tuberculosis. When interruptions occur, the person responsible for supervision must decide whether to restart a complete course of treatment or simply to continue as intended originally. This decision depends in part on whether the interruption occurred during the initial or the continuation phase of therapy. In general, the earlier the break in therapy and the longer its duration, the more serious the effect and the greater the need to restart the treatment from the beginning. Continuous treatment is more important in the initial phase of therapy, when there is the highest bacillary population and the chance of developing drug resistance is greatest. During the continuation phase, the number of bacilli is much smaller and the goal of therapy is to kill the persisting organisms. The duration of the interruption and the bacteriological status of the patient before and after the interruption are also important considerations. There is no evidence on which to base detailed recommendations for managing interruptions in treatment, and no recommendations will cover all of the situations that may arise. The following approach (summarized in Figure 5), modied from the New York City Bureau of Tuberculosis Control Clinical Policies and Protocols (21), is presented as an example. If the interruption occurs during the initial phase of treatment and the lapse is 14 days or more in duration, treatment should be restarted from the beginning. However, if the lapse is less than 14 days, the treatment regimen should be continued. In either instance the total number of doses targeted for the initial phase should be
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Figure 5. Management of treatment interruptions. *Patients who were initially AFB smearpositive should receive additional therapy. Recheck smears and cultures (if positive, check drug susceptibility results). Start DOT if not already being used. If repeat culture is positive, restart four-drug regimen while waiting for drug susceptibility results. If repeat culture is negative, continue therapy to complete regimen within 9 months of original start date. If repeat culture is positive, continue fourdrug regimen while waiting for drug susceptibility results. If repeat culture is negative, consider stopping therapy if patient has received a total of 9 months of therapy.
given. If the interruption in treatment occurs during the continuation phase after the patient has received more than 80% of the planned total continuation phase doses given by DOT, further treatment may not be necessary if the patients sputum was AFB smear negative on initial presentation. However, for patients who were smear positive initially, continued treatment to complete the planned total number of doses is warranted. If the patient has received less than 80% of the planned total doses and the lapse is 3 months or more in duration, treatment should be restarted from the beginning. If the lapse is less than 3 months in duration, treatment should be continued to complete a full course. At the time the patient is returned to treatment sputum cultures should be obtained and repeat drug susceptibility testing performed. If the cultures are still positive, the treatment regimen should be restarted. If sputum cultures are negative the patient could be treated as having culture-negative tuberculosis and given an additional 4 months of combination chemotherapy. Regardless of the timing and duration of the interruption, DOT should be used. If the patient was already being managed with DOT, additional measures will be necessary to ensure completion of therapy. Consultation with an expert is recommended to assist in managing treatment interruptions.
References
1. Gross PA, Barrett TL, Dellinger EP, Krause PJ, Martone WJ, McGowan JE Jr, Sweet RL, Wenzel RP. Purpose of quality standards for infectious diseases. Clin Infect Dis 1994;18:421. 2. Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2001. Atlanta, GA: US Department of Health and Human Services; 2002. www.cdc.gov/nchstp/tb/ 3. Mitchison DA, Nunn AJ. Inuence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1986;133:423430. 4. Bock NN, Sterling TR, Hamilton CD, Pachucki C, Wang YC, Conwell DS, Mosher A, Samuels M, Vernon A; The Tuberculosis Trials Consortium, Centers for Disease Control and Prevention, Atlanta, Georgia. A prospective, randomized, double-blind study of the tolerability of rifapentine 600, 900, and 1,200 mg plus isoniazid in the continuation phase of tuberculosis treatment. Am J Respir Crit Care Med 2002; 165:15261530. 5. Hong Kong Chest Service/British Medical Research Council. Five-year follow-up of a controlled trial of ve 6-month regimens of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1987;136:1339 1342. 6. Zierski M. Prospects of retreatment of chronic resistant pulmonary tuberculosis: a critical review. Lung 1977;154:91. 7. Bobrowitz ID. Ethambutolisoniazid vs streptomycinethambutoliso-
8. 9. 10.
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niazid in original treatment of cavitary tuberculosis. Am Rev Respir Dis 1974;109:548553. Gillespie SH, Kennedy N. Fluoroquinolones: a new treatment for tuberculosis? Int J Tuberc Lung Dis 1998;2:265271. Alangaden GJ, Lerner SA. The clinical use of uoroquinolones for the treatment of mycobacterial diseases. Clin Infect Dis 1997;1:89. Centers for Disease Control and Prevention. Core curriculum on tuberculosis: what the clinician should know, 4th edition. Atlanta, GA: US Department of Health and Human Services; 2000. www.cdc.gov/ nchstp/tb/ Centers for Disease Control and Prevention. Update: Fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/ CDC recommendationsUnited States, 2001. MMWR Morb Mortal Wkly Rep 2001;50:733735. www.cdc.gov/nchstp/tb/ Jasmer RM, Saukkonen JJ, Blumberg HM, Daley CL, Bernardo J, Vittinghoff E, King MD, Kawamura LM, Hopewell PC. Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multucenter clinical trial. Short-Course Rifampin and Pyrazinamide for Tuberculosis Infection (SCRIPT) Study Investigators. Ann Intern Med 2002;137:640647. American Thoracic Society/Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221S247. www.cdc.gov/ nchstp/tb/ Centers for Disease Control and Prevention. Recommendations for prevention of hepatitis C virus (HCV) infection and HCV chronic disease. MMWR 1998;47(RR-19):139. www.cdc.gov/mmwr/PDF/rr/rr4719.pdf Margolis HS, Alter MJ, Hadler SC. Hepatitis B: evolving epidemiology and implications for control. Semin Liver Dis 1991;11:8492. Mitchison DA. Assessment of new sterilizing drugs for treating pulmonary tuberculosis by culture at 2 months. Am Rev Respir Dis 1993;147: 10621063. Tuberculosis Trials Consortium. Rifapentine and isoniazid once a week versus rifampin and isoniazid twice a week for treatment of drugsusceptible pulmonary tuberculosis: a randomized clinical trial. Lancet 360:528534. Zierski M, Bek E, Long MW, Snider DE Jr. Short-course (6-month) cooperative tuberculosis study in Poland: results 30 months after completion of treatment. Am Rev Respir Dis 1981;124:249251. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. A controlled clinical comparison of 6 and 8 months of antituberculosis chemotherapy in the treatment of patients with silicotuberculosis in Hong Kong. Am Rev Respir Dis 1991;143: 262267. Hong Kong Chest Service/British Medical Research Council. Controlled trial of 2, 4, and 6 months of pyrazinamide in 6-month, three-timesweekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin, and pyrazinamide. Am Rev Respir Dis 1991;143:700706. Bureau of Tuberculosis Control. Clinical policies and protocols, 3rd edition. New York: Bureau of Tuberculosis Control, New York City Department of Health; 1999. p. 5557.
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6. PRACTICAL ASPECTS OF TREATMENT

6.1. Drug Administration
The rst-line antituberculosis medications should be administered together as single dose rather than in divided doses. A single dose leads to higher, and potentially more effective, peak serum concentrations. Administering a single daily dose also facilitates using DOT. Ingestion with food delays or moderately decreases the absorption of antituberculosis drugs (1). However, given the wide therapeutic margin of the rst-line agents, the effects of food are of little clinical signicance. Thus, if patients have epigastric distress or nausea with the rst-line drugs, dosing with food is recommended. Administration with food is preferable to splitting a dose or changing to a second-line drug. The absorption of INH can be substantially decreased when the drug is ingested with glucose or lactose. Because of this effect, the commercial preparation of INH elixir uses sorbitol for avor, rather than glucose or lactose. However, sorbitol can cause diarrhea, limiting the acceptability of the commercial INH elixir. Administration of crushed INH tablets in a food with relatively low concentrations of glucose, such as applesauce, has not been formally evaluated, but has been used successfully by many providers. Antacids have minimal effects on the absorption of the rst line antituberculosis drugs. With the exception of uoroquinolones, there is little information regarding the effect of food and antacids on the second line antituberculosis drugs. In the absence of data, it is preferable to administer the drugs on an empty stomach if they are tolerated. However, antacids and other medications containing divalent cations markedly decrease the absorption of the uoroquinolones, an interaction that has been associated with failure of antibiotic therapy (2, 3). Therefore, it is critical that any uoroquinolone not be administered within 2 hours of a dose of antacids, the chewable tablet form of didanosine, sucralfate, iron, magnesium, calcium, zinc, or vitamins or dietary supplements (e.g., Ensure, Sustical) containing a signicant amount of these cations. Parenteral therapy is indicated for severely ill patients who cannot take oral therapy and may be useful for the uncommon patient for whom poor absorption has been documented. Preparations of INH, RIF, the aminoglycosides, capreomycin, and most uoroquinolones are available for intravenous administration.
6.2. Fixed-Dose Combination Preparations
DOT is given daily and when DOT is not possible. Moreover, they are strongly recommended in international recommendations of the WHO and IUATLD. The theoretical advantage of reducing the risk of inadvertent monotherapy, the ease of administration, and the potential for reducing medication errors make them preferable to individual medications in many instances. When prescribing a xed-dose combination preparation, care must be taken because of the similarity of the trade names of RIF (Rifadin) and the xed-dose combinations (Rifamate, Rifater).
6.3. Management of Common Adverse Effects
There are two xed-dose combination preparations currently available for use in the United States, a combination of INH and RIF (Rifamate) and a combination of INH, RIF, and PZA (Rifater) (see Section 3: Drugs in Current Use). (A four-drug combination of INH, RIF, EMB, and PZA is available in some countries.) Two tablets of Rifamate provide conventional daily doses of both INH (300 mg) and RIF (600 mg). The Rifater tablet that is available in the United States contains INH (50 mg), RIF (120 mg), and PZA (300 mg). Six tablets of Rifater would provide INH (300 mg) RIF (720 mg), and PZA (1,800 mg). The RIF dose is higher than is used typically in the United States because the RIF is less bioavailable in this formulation. These xed-dose combinations have been formulated for use in daily therapy, although some programs use Rifamate plus INH tablets for twice weekly treatment. It should be noted that the dose of PZA in Rifater is such that additional PZA tablets will be required to provide an adequate dose for persons weighing more that 90 kg. Although there is no evidence indicating that xed-dose combination medications are superior to individual drugs, expert opinion suggests that these formulations should be used when
As is true with all medications, combination chemotherapy for tuberculosis is associated with a predictable incidence of adverse effects, some mild, some serious. A comprehensive list of reported adverse reactions and their frequency is described in Section 3 (Drugs in Current Use). Mild adverse effects can generally be managed with symptomatic therapy, whereas with more severe effects the offending drug or drugs must be discontinued. Although it is important to be attuned to the potential for adverse effects it is at least equally important that rst-line drugs not be stopped without adequate justication. The following is a summary, based largely on clinical experience and expert opinion, of the approaches that should be taken in managing the common adverse effects of tuberculosis treatment. Proper management of more serious adverse reactions often requires expert consultation. 6.3.1. Gastrointestinal upset: nausea, vomiting, poor appetite, abdominal pain. Gastrointestinal reactions are common, particularly in the rst few weeks of therapy. Many of the antituberculosis drugs can cause gastrointestinal upset (4). In the presence of gastrointestinal symptoms serum AST and bilirubin should be measured. If the AST level is less than three times the upper limit of normal, the symptoms are assumed not to be due to hepatic toxicity. However, if the AST level is three or more times the upper limit of normal the symptoms should be assumed to represent hepatic toxicity, and the patient should be evaluated as described below. The initial approach to gastrointestinal intolerance, not associated with hepatic toxicity, is to change the hour of drug administration and/or to administer the drugs with food. If patients are taking daily DOT, the timing of the drug administration should be altered, preferably to be closer to mealtime. Alternatively, food can be taken at the time of DOT administration. (In many programs food is offered as an incentive with DOT.) Patients receiving self-administered therapy can take the medications at bedtime. If gastrointestinal intolerance persists it may be best for all medications to be taken with meals. 6.3.2. Rash. All drugs used in treating tuberculosis can cause a rash. The response to a patient with a rash depends on its severity. The rash may be minor, affecting a limited area or being predominantly manifested as itching, in which case antihistamines should be given for symptomatic relief, but all antituberculosis medications can be continued. A petechial rash may suggest thrombocytopenia in patients taking RIF (5). The platelet count should be checked and, if low, RIF hypersensitivity should be presumed to be the cause. RIF should be stopped and the platelet count monitored until it returns to baseline; RIF should not be restarted. If there is a generalized erythematous rash, especially if it is associated with fever and/or mucous membrane involvement, all drugs should be stopped immediately. If the patient has severe tuberculosis, three new drugs (e.g., an aminoglycoside and two oral agents) should be started. When the rash is substantially improved the medications can be restarted one by one, at intervals of 23 days. RIF should be
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restarted rst (because it is the least likely to cause rash, and it is the most important agent), followed by INH, and then EMB or PZA. If the rash recurs the last drug added should be stopped. If no rash appears after the rst three drugs have been restarted, the fourth drug should not be restarted unless the rash was relatively mild and the fourth drug is considered essential for therapy. 6.3.3. Drug fever. Recurrence of fever in a patient who has been receiving therapy for several weeks should suggest drug fever, especially if the patient is showing microbiological and radiographic improvement. It should be noted, however, that fever from tuberculosis may persist for as long as 2 months after therapy has been initiated (6). Fever may also be a manifestation of a paradoxical reaction, especially in patients with HIV infection (see Section 8.1: HIV Infection) (7). The clinical hallmark of drug fever is that the patient looks and feels well despite having a high fever (often greater than 39 C). There is no specic pattern to the fever. Eosinophilia may or may not be present. The rst step in management of a possible drug fever is to ensure that there is no superinfection or worsening of tuberculosis. If these potential causes are excluded all drugs should be stopped. Drug-related fever usually will resolve within 24 hours. Patients with severe tuberculosis should be given at least three new drugs in the interim. Once the fever has resolved, the same protocol as described above for restarting drugs in the presence of a rash should be followed. 6.3.4. Hepatitis. (Management of patients with baseline abnormal liver function is described in Section 8.8: Hepatic Disease.) Three of the rst-line antituberculosis drugs, INH, RIF, and PZA, can cause drug-induced liver injury (AST level three or more times the upper limit of normal in the presence of symptoms, or ve or more times the upper limit of normal in the absence of symptoms) (8). If the AST level is less than 5 times the upper limit of normal, toxicity can be considered mild, an AST level 510 times normal denes moderate toxicity, and an AST level greater than 10 times normal (i.e., greater than 500 IU) is severe (9). In addition to AST elevation, occasionally there are disproportionate increases in bilirubin and alkaline phosphatase. This pattern is more consistent with rifampin hepatotoxicity It is important to note that an asymptomatic increase in AST concentration occurs in nearly 20% of patients treated with the standard four-drug regimen (10). In the absence of symptoms therapy should not be altered because of modest asymptomatic elevations of AST, but the frequency of clinical and laboratory monitoring should be increased. In most patients, asymptomatic aminotransferase elevations resolve spontaneously. However, if AST levels are more than ve times the upper limit of normal (with or without symptoms) or more than three times normal in the presence of symptoms, hepatotoxic drugs should be stopped immediately and the patient evaluated carefully. Similarly, a signicant increase in bilirubin and/or alkaline phosphatase is cause for a prompt evaluation. Serologic testing for hepatitis A, B, and C should be performed and the patient questioned carefully regarding symptoms suggestive of biliary tract disease and exposures to other potential hepatotoxins, particularly alcohol and hepatotoxic medications. Drug-induced hepatitis is usually a diagnosis of exclusion but in view of the frequency with which other possible causes are present in any given patient, determining the cause may be difcult. Because the schedule for restarting antituberculosis medications is slower with hepatitis than for rash or drug fever it is generally prudent to give at least three nonhepatotoxic antituberculosis drugs until the specic cause of hepatotoxicity can be determined and an appropriate longer term regimen begun. The suspect antituberculosis medications should be restarted one at
a time after the AST concentration returns to less than two times the upper limit of normal. (In patients with elevated baseline AST from preexisting liver disease, drugs should be restarted when the AST returns to near baseline levels.) Because RIF is much less likely to cause hepatotoxicity than is INH or PZA (Table 10) (10) and is the most effective agent, it should be restarted rst. If there is no increase in AST after about 1 week, INH may be restarted. PZA can be started 1 week after INH if AST does not increase. If symptoms recur or AST increases the last drug added should be stopped. If RIF and INH are tolerated, and hepatitis was severe, PZA should be assumed to be responsible and should be discontinued. In this last circumstance, depending on the number of doses of PZA taken, severity of disease, and bacteriological status, therapy might be extended to 9 months.
6.4. Serum Drug Concentration Measurements
The rst-line drugs (INH, RIF, PZA, and EMB) have relatively predictable pharmacokinetics (11, 12) and are highly efcacious when given in standard doses as DOT (13, 14). Rarely, patients may have poor absorption or altered metabolism of the rstline drugs, resulting in failure of therapy (15, 16) Second-line agents have a much narrower therapeutic window (the range of concentrations having reliable activity against M. tuberculosis but rarely causing toxicity) than the rst-line drugs, and the consequences of treatment failure of drug-resistant tuberculosis may be difcult to manage. These considerations suggest several clinical situations in which therapeutic drug monitoring may be helpful: (1 ) patients with treatment failure that is not explained by nonadherence or drug resistance, (2 ) persons with medical conditions that may result in abnormal pharmacokinetics of the rst-line drugs, and (3 ) the management of multidrug-resistant tuberculosis with second-line drugs. Be aware, however, that there are many uncertainties about the use of therapeutic drug monitoring in tuberculosis treatment. An important limitation is the lack of sufcient data to formulate clinically validated therapeutic ranges for antituberculosis agents. One response to the lack of clinically derived therapeutic ranges for the rifamycins is to use the distribution of concentrations achieved in healthy volunteers as the therapeutic range. However, in practice this approach has been quite problematic. For example, serum concentrations of the rst-line drugs among HIV-infected patients with active tuberculosis are frequently lower than those in healthy volunteers (17, 18), but HIV-related tuberculosis responds well to standard tuberculosis treatment regimens (19, 20). The disadvantages of therapeutic drug monitoring are as follows: (1 ) the time necessary, from both patients and providers, to obtain and ship blood samples, and (2 ) the relatively high cost of measuring serum drug concentrations. Until more data are available, it seems prudent to restrict therapeutic drug monitoring for the rst-line drugs to patients who are having an inadequate response to DOT (that is not due to nonadherence or drug resistance) or evidence of severe gastrointestinal or metabolic abnormalities. Examples of such circumstances include severe gastroparesis, short-bowel syndrome, chronic diarrhea with malabsorption, and renal insufciency. As described above, patients with HIV-related tuberculosis may have an increased incidence of malabsorption of antituberculosis drugs (although some studies have contrary ndings) (21, 22). Even if true, this tendency for lower drug concentrations among patients with HIV-related tuberculosis is not sufcient to warrant routine therapeutic drug monitoring in this population.
638 References
7. DRUG INTERACTIONS
7.1. Interactions Affecting Antituberculosis Drugs
1. Burman W, Gallicano K, Peloquin C. Therapeutic implications of drug interactions in the treatment of HIV-related tuberculosis. Clin Infect Dis 1999;28:419430. 2. Sahai J, Gallicano K, Oliveras L, Khaliq S, Hawley-Foss N, Garber G. Cations in didanosine tablet reduce ciprooxacin bioavailability. Clin Pharmacol Ther 1993;53:292297. 3. Lomaestro BM, Bailie GR. Effect of multiple staggered doses of calcium on the bioavailability of ciprooxacin. Ann Pharmacother 1993;27: 13251328. 4. Centers for Disease Control and Prevention. Core curriculum on tuberculosis: what the clinician should know, 4th edition. Atlanta, GA: US Department of Health and Human Services; 2000. www.cdc.gov/ nchstp/tb/ 5. Mehta YS, Jijina FF, Badakere SS, Pathare AV, Mohanty D. Rifampininduced immune thrombocytopenia. Tuberc Lung Dis 1996;77:558 562. 6. Kiblawi SS, Jay SJ, Stonehill RB, Norton J. Fever response of patients on therapy for pulmonary tuberculosis. Am Rev Respir Dis 1981;123: 2024. 7. Chien JW, Johnson JL. Paradoxical reactions in HIV and pulmonary TB. Chest 1998;114:933936. 8. Ormerod LP. Hepatotoxicity of antituberculosis drugs. Thorax 1996;51: 111113. 9. World Health Organization Collaborating Center for International Drug Monitoring. Adverse drug reaction terminology (ART), 1979. http:// www.WHO-UMC.org (or e-mail: [email protected]) 10. Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin: a meta-analysis. Chest 1991;99:465471. 11. Acocella G, Nonis A, Perna G, Patane E, Gialdroni-Grassi G, Grassi C. Comparative bioavailability of isoniazid, rifampin, and pyrazinamide administered in free combination and in a xed triple formulation designed for daily use in antituberculosis chemotherapy. Am Rev Respir Dis 1988;138:886890. 12. Peloquin CA, Vernon A, Burman W, Benator D. Pharmacokinetics of rifapentine, rifampin, and isoniazid in TB patients [abstract]. Am J Respir Crit Care Med 1999;159:A16. 13. Cohn DL, Catlin BJ, Peterson KL, Judson FN, Sbarbaro JA. A 62-dose, 6-month therapy for pulmonary and extrapulmonary tuberculosis: a twice-weekly, directly observed, and cost-effective regimen. Ann Intern Med 1990;112:407415. 14. Hong Kong Chest Service/British Medical Research Council. Controlled trial of 4 three-times-weekly regimens and a daily regimen all given for 6 months for pulmonary tuberculosis. Second report. The results up to 24 months. Tubercle 1982;63:8998. 15. Kimerling ME, Phillips P, Patterson P, Hall M, Robinson CA, Dunlap NE. Low serum antimycobacterial drug levels in non-HIV-infected tuberculosis patients. Chest 1998;113:11781183. 16. Berning SE, Huitt GA, Iseman MD, Peloquin CA. Malabsorption of antituberculosis medications by a patient with AIDS [letter]. N Engl J Med 1992;327:18171818. 17. Sahai J, Gallicano K, Swick L, Tailor S, Garber G, Seguin I, Oliveras L, Walker S, Rachlis A, Cameron DW. Reduced plasma concentrations of antituberculous drugs in patients with HIV infection. Ann Intern Med 1997;127:289293. 18. Peloquin CA, Nitta AT, Burman WJ, Brudney KF, Miranda-Massari JR, McGuinness ME, Berning SE, Gerena GT. Low antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother 1996;30:919 925. 19. Chaisson RE, Clermont HC, Holt EA, Cantave M, Johnson MP, Atkinson J, Davis H, Boulos R, Quinn TC, Halsey NA. Six-month supervised intermittent tuberculosis therapy in Haitian patients with and without HIV infection. Am J Respir Crit Care Med 1996;154:10341038. 20. El-Sadr W, Perlman DC, Matts JP, Nelson ET, Cohn DL, Salomon N, Olibrice M, Medard F, Chirgwin KD, Mildvan D, et al. Evaluation of an intensive intermittent-induction regimen and short course duration of treatment for HIV-related pulmonary tuberculosis. Clin Infect Dis 1998;26:11481158. 21. Choudri SH, Hawken M, Gathau S, Minyiri GO, Watkins W, Sahai J, Sitar DS, Aoki FY, Long R. Pharmacokinetics of antimycobacterial drugs in patients with tuberculosis, AIDS, and diarrhea. Clin Infect Dis 1997;25:104111. 22. Taylor J, Smith PJ. Does AIDS impair the absorption of antituberculosis agents? Int J Tuberc Lung Dis 1998;2:670675.
Drugdrug interactions can result in changes in the concentrations of one or both of the drugs involved. In the case of the antituberculosis drugs, there are relatively few interactions that substantially change the concentrations of the antituberculosis drugs; much more often the antituberculosis drugs cause clinically relevant changes in the concentrations of other drugs. The exceptions to this general rule are rifabutin and the uoroquinolones. Rifabutin is partially metabolized by cytochrome P450 (CYP) 3A. Inhibitors of CYP3A increase serum concentrations of rifabutin and one of its metabolites (25-O-desacetyl-rifabutin), sometimes to toxic levels. For example, administration of ritonavir, a potent CYP3A inhibitor, with the standard daily dose of rifabutin (300 mg) increases the serum concentrations of rifabutin (4-fold increase) and 25-O-desacetyl-rifabutin (35-fold increase) (1) and is associated with increased rates of leukopenia, arthralgias, skin discoloration, and uveitis (2), all recognized to be toxic effects of rifabutin or one of its metabolites (3, 4). Conversely, administering rifabutin with a CYP3A inducer decreases its concentrations, perhaps to ineffective levels. For example, efavirenz, a potent antiretroviral drug, decreases rifabutin serum concentrations by approximately one-third (5). Recommendations for making dose adjustments of rifabutin when it is given with commonly used CYP3A inhibitors and inducers are available (6, 7). However, the complexity of these interactions and the rapidly changing nature of antiretroviral therapy strongly suggest that the management of cases of HIVrelated tuberculosis should involve a physician with experience in this eld. Absorption of the uoroquinolones is markedly decreased by ingestion with medications containing divalent cations (calcium, iron, zinc), including antacids (8, 9); supplements or vitamins containing calcium, iron or zinc (10), sucralfate (11); and the chewable tablet formulation of didanosine (12). These drug interactions can be avoided by assuring that medications containing divalent cations are ingested at least 2 hours apart from doses of uoroquinolones (13).
7.2. Effects of Antituberculosis Drugs on Other Drugs
7.2.1. Drug interactions due to rifamycins. The drugs used to treat tuberculosis affect the metabolism of many other drugs, and can result in a lack of efcacy (interactions with the rifamycins) or toxicity (interactions with isoniazid and the uoroquinolones). Most of the clinically relevant drugdrug interactions involving the antituberculosis drugs are due to the effect of the rifamycins (rifampin, rifabutin, and rifapentine) on the metabolism of other drugs. All of the rifamycins are inducers of a variety of metabolic pathways, particularly those involving the various isozymes of the cytochrome P450 system (1418). By inducing the activity of metabolic enzymes, rifamycin therapy results in a decrease in the serum concentrations of many drugs, sometimes to levels that are subtherapeutic. The rifamycins differ substantially in their potency as enzyme inducers; rifampin is the most potent, rifapentine is intermediate, and rifabutin is the least potent enzyme inducer (19). The well-described, clinically relevant drugdrug interactions involving the rifamycins are presented in Table 12 (1, 5, 15, 2088). However, it is important to note that many possible interactions involving the rifamycins have not been investigated fully and additional clinically relevant interactions undoubtedly will be described. Therefore, it is important to check all concomitant medications for possible, as well as conrmed, drugdrug interactions with rifamycins.
American Thoracic Society Documents TABLE 12. CLINICALLY SIGNIFICANT DRUGDRUG INTERACTIONS INVOLVING THE RIFAMYCINS*
Drug Class Antiinfectives Drugs Whose Concentrations Are Substantially Decreased by Rifamycins (References) HIV-1 protease inhibitors (saquinavir, indinavir, nelfinavir, amprenavir, ritonavir, lopinavir/ ritonavir) (1, 2025) Nonnucleoside reverse transcriptase inhibitors Delavirdine (26, 27) Nevirapine (28) Efavirenz (29) Macrolide antibiotics (clarithromycin, erythromycin) (3032) Doxycycline (33) Azole antifungal agents (ketoconazole, itraconazole, voriconazole) (3438) Atovaquone (39) Chloramphenicol (40) Mefloquine (41) Hormone therapy Ethinylestradiol, norethindrone (4244) Tamoxifen (45) Levothyroxine (46, 47) Narcotics Anticoagulants Methadone (48, 49) Warfarin (50) Comments
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Can be used with ribabutin. Ritonavir, 400600 mg twice-daily, probably can be used with rifampin. The combination of saquinavir and ritonavir can also be used with rifampin. Delavirdine should not be used with any rifamycin. Doses of nevirapine (28) and efavirenz (29) need to be increased if given with rifampin, no dose increase needed if given with rifabutin (5) Azithromycin has no significant interaction with rifamycins May require use of a drug other than doxycycline Itraconazole ketoconazole, and voriconazole concentrations may be subtherapeutic with any of the rifamycins. Fluconazole can be used with rifamycins, but the dose of fluconazole may have to be increased Consider alternate form of Pneumocystis carinii treatment or prophylaxis Consider an alternative antibiotic Consider alternate form of malaria prophylaxis Women of reproductive potential on oral contraceptives should be advised to add a barrier method of contraception when taking a rifamycin May require alternate therapy or use of a nonrifamycin-containing regimen Monitoring of serum TSH recommended; may require increased dose of levothyroxine Rifampin and rifapentine use may require methadone dose increase; rifabutin infrequently causes methadone withdrawal Monitor prothrombin time; may require two- to threefold dose increase Rifabutin may allow concomitant use of cyclosporine and a rifamycin; monitoring of cyclosporine serum concentrations may assist with dosing Monitor clinically; may require two- to threefold increase in corticosteroid dose (58) Therapeutic drug monitoring recommended; may require anticonvulsant dose increase Clinical monitoring recommended; may require change to an alternate cardiovascular agent Clinical monitoring recommended; may require dose increase or change to an alternate cardiovascular drug Monitor clinically; may require a dose increase or use of an alternate cardiovascular drug Therapeutic drug monitoring recommended; may require digoxin or digitoxin dose increase Therapeutic drug monitoring recommended; may require quinidine dose increase Clinical monitoring recommended; may require change to an alternate cardiovascular drug Therapeutic drug monitoring recommended; may require theophylline dose increase Monitor blood glucose; may require dose increase or change to an alternate hypoglycemic drug Monitor hypolipidemic effect; may require use of an alternate hypolipidemic drug Therapeutic drug monitoring recommended; may require dose increase or change to alternate psychotropic drug Monitor clinically; may require a dose increase or use of an alternate psychotropic drug Monitor clinically; may require a dose increase or use of an alternate psychotropic drug
Immunosuppressive agents Cyclosporine, tacrolimus (5153) Corticosteroids (5457) Anticonvulsants Cardiovascular agents Phenytoin (59), lamotrigine (60) Verapamil (61), nifedipine (62, 63), diltiazem (a similar interaction is also predicted for felodipine and nisoldipine) Propranolol (64), metoporol (65) Enalapril (66), losartan (67) Digoxin (among patients with renal insufficiency) (68), digitoxin (69) Quinidine (70, 71) Mexilitine (72), tocainide (73), propafenone (15) Bronchodilators Theophylline (74)
Sulfonylurea hypoglycemics Tolbutamide, chlorpropamide, glyburide, glimepiride, repaglinide (7579) Hypolipidemics Psychotropic drugs Simvastatin (80), fluvastatin (81) Nortriptyline (82) Haloperidol (83), quetiapine (84) Benzodiazepines (e.g., diazepam [85], triazolam [86]), zolpidem (87), buspirone (88) * For reference citations, refer to Section 7.2.
Some of these drugdrug interactions can be managed with close clinical or laboratory monitoring and dose increases of the medication(s) affected by the rifamycins (Table 12). In other cases, the magnitude of the decrease in concentrations of a concomitant medication may be such that serum concentrations
cannot be restored by a dose increase. If the dose of a medication is increased to compensate for the effect of a rifamycin, it is critical to remember that the dose of this drug will probably need to be decreased within the 2 weeks after the rifamycin is discontinued and its inductive effect resolves.
640
aluminum hydroxide and calcium carbonate antacids on the bioavailability of ciprooxacin. Antimicrob Agents Chemother 1992;36:830 832. Polk RE, Healy DP, Sahai J, Drwal L, Racht E. Effect of ferrous sulfate and multivitamins with zinc on absorption of ciprooxacin in normal volunteers. Antimicrob Agents Chemother 1989;33:18411844. Lehto P, Kivisto KT. Effect of sucralfate on absorption of noroxacin and ooxacin. Antimicrob Agents Chemother 1994;38:248251. Sahai J, Gallicano K, Oliveras L, Khaliq S, Hawley-Foss N, Garber G. Cations in didanosine tablet reduce ciprooxacin bioavailability. Clin Pharmacol Ther 1993;53:292297. Lomaestro BM, Bailie GR. Effect of multiple staggered doses of calcium on the bioavailability of ciprooxacin. Ann Pharmacother 1993;27: 13251328. Gharaibeh MN, Gillen LP, Osborne B, Schwartz JI, Waldman SA. Effect of multiple doses of rifampin on the [14C N-methyl] erythromycin breath test in healthy male volunteers. J Clin Pharmacol 1998;38: 492495. Dilger K, Greiner B, Fromm MF, Hofmann U, Kroemer HK, Eichelbaum M. Consequences of rifampicin treatment on propafenone disposition in extensive and poor metabolizers of CYP2D6. Pharmacogenetics 1999;9:551559. Bachmann KA, Jauregui L. Use of single sample clearance estimates of cytochrome P450 substrates to characterize human hepatic CYP status in vivo. Xenobiotica 1993;23:307315. Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determination of codeine induction by rifampin: the impact on codeines respiratory, psychomotor and meiotic effects. J Pharmacol Exp Ther 1997;281: 330336. Greiner B, Eichelbaum M, Fritz P, Kreichgauer HP, von Richter O, Zundler J, Kroemer HK. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest 1999;104:147153. Li AP, Reith MK, Rasmussen A, Gorski JC, Hall SD, Xu L, Kaminski DL, Cheng LK. Primary human hepatocytes as a tool for the evaluation of structureactivity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine, and rifabutin. Chem Biol Interact 1997;107:1730. Indinavir Pharmacokinetic Study Group. Indinavir (MK 639) drug interactions studies. In: XIth International Conference on AIDS, Vancouver, Canada, 1996. p. 18. Kerr B, Lee C, Yuen G, Anderson R, Daniels R, Greitenberger H, Liang B-H, Quart B, Shetry B, Wu F. Overview of in-vitro and in-vivo drug interaction studies of nelnavir mesylate, a new HIV-1 protease inhibitor. In: Program and abstracts of the 4th Conference on Retroviruses and Opportunistic Infections, January 2226. Washington, DC: Foundation for Retrovirology and Human Health; 1997. p. 133. Kerr BM, Daniels R, Clendeninn N. Pharmacokinetic interaction of nelnavir with half-dose rifabutin [abstract]. Can J Infect Dis 1999;10 (Suppl B):21B. Moyle GJ, Buss NE, Goggin T, Snell P, Higgs C, Hawkins DA. Interaction between saquinavir soft-gel and rifabutin in patients infected with HIV. Br J Clin Pharmacol 2002;54:178182. Moreno S, Podzamczer D, Blazquez R, Tribarren JA, Ferror B, Reparez J, Pena JM, Cabrero E, Usan L. Treatment of tuberculosis in HIVinfected patients: safety and antiretroviral efcacy of the concomitant use of ritonavir and rifampin. In: XIIIth International AIDS Conference, July 914, Durban, South Africa, 2000. 2:49. Polk RE, Brophy DF, Israel DS, Patron R, Sadler BM, Chittick GE, Symonds WT, Lou Y, Kristoff D, Stein DS. Pharmacokinetic interaction between amprenavir and rifabutin or rifampin in healthy males. Antimicrob Agents Chemother 2001;45:502508. Borin MT, Chambers JH, Carel BJ, Gagnon S, Freimuth WW. Pharmacokinetic study of the interaction between rifampin and delavirdine mesylate. Clin Pharmacol Ther 1997;61:544553. Borin MT, Chambers JH, Carel BJ, Freimuth WW, Aksentijevich S, Piergies AA. Pharmacokinetic study of the interaction between rifabutin and delavirdine mesylate in HIV-1 infected patients. Antiviral Res 1997;35:5363. Robinson P, Lamsom M, Gigliotti M, Myers M. Pharmacokinetic interaction between nevirapine and rifampin. Geneva, Switzerland: International Conference on AIDS; 1998. p. 1115. Benedek IH, Joshi A, Flake WD, White SJ, Stevenson D, Bawerjee G, Kornhauser DM. Pharmacokinetic interaction between efavirenz and rifampin in healthy volunteers. Geneva, Switzerland: 12th World AIDS Conference; 1998. p. 829. Hafner R, Bethel J, Power M, Landry B, Banach M, Mole L, Standiford HC, Follansbee S, Kumar P, Raasch R, et al. Tolerance and pharmacokinetic interactions of rifabutin and clarithromycin in human immuno-
In some situations, rifabutin can sometimes be used in place of rifampin, if there is an unacceptable drugdrug interaction between rifampin and another drug, such as cyclosporine (51) and most of the HIV-1 protease inhibitors (89). All the rifamycins may cause unacceptable decreases in the serum concentrations of certain drugs, such as delavirdine (26, 27, 90), ketoconazole and itraconazole (34, 91). 7.2.2. Drug interactions due to isoniazid. Isoniazid is a relatively potent inhibitor of several cytochrome P450 isozymes (CYP2C9, CYP2C19, and CYP2E1) (92), but has minimal effect on CYP3A (20). As an inhibitor, isoniazid can increase concentrations of some drugs to the point of toxicity. The clearest examples of toxicity due to the inhibitory activity of isoniazid are the anticonvulsants, phenytoin (93, 94) and carbamazepine (95, 96). Isoniazid also increases concentrations of benzodiazepines metabolized by oxidation, such as diazepam (85) and triazolam (97), but not those metabolized by conjugation, such as oxazepam (97). It is worth noting that rifampin has the opposite effect on the serum concentrations of many of these drugs. The available data demonstrate that the inductive effect of rifampin outweighs the inhibitory effect of isoniazid, so that the overall effect of combined therapy with rifampin and isoniazid is a decrease in the concentrations of drugs such as phenytoin (59) and diazepam (85). Isoniazid may increase toxicity of other drugsacetaminophen (98), valproate (99), serotonergic antidepressants (100), disulram (101), warfarin (102), and theophylline (103)but these potential interactions have not been well studied. 7.2.3. Drug interactions due to uoroquinolones. Ciprooxacin (104) inhibits the metabolism of theophylline and can cause clinical theophylline toxicity (105). However, levooxacin (106), gatioxacin (107), and moxioxacin (108) do not affect theophylline metabolism.
References
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adrenal crisis in addisonian patients receiving corticosteroid replacement therapy. J Clin Endocrinol Metab 1984;59:12041206. Perucca E, Grimaldi R, Frigo GM, Sardi A, Monig H, Ohnhaus EE. Comparative effects of rifabutin and rifampicin on hepatic microsomal enzyme activity in normal subjects. Eur J Clin Pharmacol 1988;34:595599. Lin FL. Rifampin-induced deterioration in steroid-dependent asthma. J Allergy Clin Immunol 1996;98:1125. Carrie F, Roblot P, Bouquet S, Delon A, Roblot F, Becq-Giraudon B. Rifampin-induced nonresponsiveness of giant cell arteritis to prednisone treatment. Arch Intern Med 1994;154:15211524. McAllister WA, Thompson PJ, Al-Habet SM, Rogers HJ. Rifampicin reduces effectiveness and bioavailability of prednisolone. Br Med J (Clin Res Ed) 1983;286:923925. Kay L, Kampmann JP, Svendsen TL, Vergman B, Hansen JE, Skovsted L, Kristensen M. Inuence of rifampin and isoniazid on the kinetics of phenytoin. Br J Clin Pharmacol 1985;20:323326. Ebert U, Thong NQ, Oertel R, Kirch W. Effects of rifampicin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. Eur J Clin Pharmacol 2000;56:299304. Barbarash RA, Bauman JL, Fischer JH, Kondos GT, Batenhorst RL. Near-total reduction in verapamil bioavailability by rifampin: electrocardiographic correlates. Chest 1988;94:954959. Holtbecker N, Fromm MF, Kroemer HK, Ohnhaus EE, Heidemann H. The nifedipinerifampin interaction: evidence for induction of gut wall metabolism [see comments]. Drug Metab Dispos 1996;24:1121 1123. Yoshimoto H, Takahashi M, Saima S. [Inuence of rifampicin on antihypertensive effects of dihydropiridine calcium-channel blockers in four elderly patients]. Nippon Ronen Igakkai Zasshi 1996;33:692696. Herman RJ, Nakamura K, Wilkinson GR, Wood AJ. Induction of propranolol metabolism by rifampicin. Br J Clin Pharmacol 1983;16:565 569. Bennett PN, John VA, Whitmarsh VB. Effect of rifampicin on metoprolol and antipyrine kinetics. Br J Clin Pharmacol 1982;13:387391. Kandiah D, Penny WJ, Fraser AG, Lewis MJ. A possible drug interaction between rifampicin and enalapril. Eur J Clin Pharmacol 1988;35:431432. Williamson KM, Patterson JH, McQueen RH, Adams KF Jr, Pieper JA. Effects of erythromycin or rifampin on losartan pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 1998;63:316323. Gault H, Longerich L, Dawe M, Fine A. Digoxinrifampin interaction. Clin Pharmacol Ther 1984;35:750754. Poor DM, Self TH, Davis HL. Interaction of rifampin and digitoxin. Arch Intern Med 1983;143:599. Damkier P, Hansen LL, Brosen K. Rifampicin treatment greatly increases the apparent oral clearance of quinidine. Pharmacol Toxicol 1999;85:257262. Ahmad D, Mathur P, Ahuja S, Henderson R, Carruthers G. Rifampicin quinidine interaction. Br J Dis Chest 1979;73:409411. Pentikainen PJ, Koivula IH, Hiltunen HA. Effect of rifampicin treatment on the kinetics of mexiletine. Eur J Clin Pharmacol 1982;23:261 266. Rice TL, Patterson JH, Celestin C, Foster JR, Powell JR. Inuence of rifampin on tocainide pharmacokinetics in humans. Clin Pharm 1989;8:200205. Gillum JG, Sesler JM, Bruzzese VL, Israel DS, Polk RE. Induction of theophylline clearance by rifampin and rifabutin in healthy male volunteers. Antimicrob Agents Chemother 1996;40:18661869. Self TH, Morris T. Interaction of rifampin and chlorpropamide. Chest 1980;77:800801. Zilly W, Breimer DD, Richter E. Induction of drug metabolism in man after rifampicin treatment measured by increased hexobarbital and tolbutamide clearance. Eur J Clin Pharmacol 1975;9:219227. Surekha V, Peter JV, Jeyaseelan L, Cherian AM. Drug interaction: rifampicin and glibenclamide. Natl Med J India 1997;10:1112. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ, Kivisto KT. Rifampin decreases the plasma concentrations and effects of repaglinide. Clin Pharmacol Ther 2000;68:495500. Niemi M, Kivisto KT, Backman JT, Neuvonen PJ. Effect of rifampicin on the pharmacokinetics and pharmacodynamics of glimepiride. Br J Clin Pharmacol 2000;50:591595. Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ. Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 2000;68:592597. Scripture CD, Pieper JA. Clinical pharmacokinetics of uvastatin. Clin Pharmacokinet 2001;40:263281.
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82. Self T, Corley CR, Nabhan S, Abell T. Case report: interaction of rifampin and nortriptyline. Am J Med Sci 1996;311:8081. 83. Kim YH, Cha IJ, Shim JC, Shin JG, Yoon YR, Kim YK, Kim JI, Park GH, Jang IJ, Woo JI, et al. Effect of rifampin on the plasma concentration and the clinical effect of haloperidol concomitantly administered to schizophrenic patients. J Clin Psychopharmacol 1996; 16:247252. 84. Misra LK, Erpenbach JE, Hamlyn H, Fuller WC. Quetiapine: a new atypical antipsychotic. S D J Med 1998;51:189193. 85. Ochs HR, Greenblatt DJ, Roberts GM, Dengler HJ. Diazepam interaction with antituberculosis drugs. Clin Pharmacol Ther 1981;29:671 678. 86. Yuan R, Flockhart DA, Balian JD. Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug interactions with alprazolam, midazolam, and triazolam. J Clin Pharmacol 1999;39:1109 1125. 87. Villikka K, Kivisto KT, Luurila H, Neuvonen PJ. Rifampin reduces plasma concentrations and effects of zolpidem. Clin Pharmacol Ther 1997;62:629634. 88. Kivisto KT, Lamberg TS, Neuvonen PJ. Interactions of buspirone with itraconazole and rifampicin: effects on the pharmacokinetics of the active 1-(2-pyrimidinyl)-piperazine metabolite of buspirone. Pharmacol Toxicol 1999;84:9497. 89. Narita M, Stambaugh JJ, Hollender ES, Jones D, Pitchenik AE, Ashkin D. Use of rifabutin with protease inhibitors for human immunodeciency virus-infected patients with tuberculosis. Clin Infect Dis 2000; 30:779783. 90. Cox SR, Herman BD, Batta DH, Carel BJ, Carberry PA. Delavirdine and rifabutin: pharmacokinetic evaluation in HIV-1 patients with concentration-targeting of delavirdine. In: 5th Conference on Retroviruses and Opportunistic Infections, February 15, Chicago, IL, 1998. p. 144. 91. Smith JA, Hardin TC, Patterson TF, Rinaldi MG, Graybill JR. Rifabutin decreases itraconazole plasma levels in patients with HIV-infection. In: 2nd National Conference on Human Retroviruses, January 29 February 2, Washington, DC, 1995. p. 126. 92. Self TH, Chrisman CR, Baciewicz AM, Bronze MS. Isoniazid drug and food interactions. Am J Med Sci 1999;317:304311. 93. Kutt H, Brennan R, Dehajia H, Verebely K. Dephenylhydantoin intoxiciation: a complication of isoniazid therapy. Am Rev Respir Dis 1970;101:377383. 94. Miller RR, Porter J, Greenblatt DJ. Clinical importance of the interaction of phenytoin and isoniazid: a report from the Boston Collaborative Drug Surveillance Program. Chest 1979;75:356358. 95. Block SH. Carbamazepineisoniazid interaction. Pediatrics 1982;69: 494495. 96. Valsalan VC, Cooper GL. Carbamazepine intoxication caused by interaction with isoniazid. BMJ 1982;285:261262. 97. Ochs HR, Greenblatt DJ, Knuchel M. Differential effect of isoniazid on triazolam oxidation and oxazepam conjugation. Br J Clin Pharmacol 1983;16:743746. 98. Murphy R, Swartz R, Watkins PB. Severe acetaminophen toxicity in a patient receiving isoniazid. Ann Intern Med 1990;113:799800. 99. Jonville AP, Gauchez AS, Autret E, Billard C, Barbier P, Nsabiyumva F, Breteau M. Interaction between isoniazid and valproate: a case of valproate overdosage [letter]. Eur J Clin Pharmacol 1991;40:197198. 100. Judd FK, Mijch AM, Cockram A, Norman TR. Isoniazid and antidepressants: is there cause for concern? Int Clin Psychopharmacol 1994;9: 123125. 101. Whittington HG, Grey L. Possible interaction between disulram and isoniazid. Am J Psychiatry 1969;125:17251729. 102. Rosenthal AR, Self TH, Baker ED, Linden RA. Interaction of isoniazid and warfarin. JAMA 1977;238:2177. 103. Torrent J, Izquierdo I, Cabezas R, Jane F. Theophyllineisoniazid interaction. DICP 1989;23:143145. 104. Robson RA, Begg EJ, Atkinson HC, Saunders DA, Frampton CM. Comparative effects of ciprooxacin and lomeoxacin on the oxidative metabolism of theophylline. Br J Clin Pharmacol 1990;29:491 493. 105. Raoof S, Wollschlager C, Khan FA. Ciprooxacin increases serum levels of theophylline. Am J Med 1987;82:115118. 106. Gisclon LG, Curtin CR, Fowler CL, Williams RR, Hafkin B, Natarajan J. Absence of a pharmacokinetic interaction between intravenous theophylline and orally administered levooxacin. J Clin Pharmacol 1997;37:744750. 107. Niki Y, Hashiguchi K, Miyashita N, Nakajima M, Matsushima T. Inu-
8. TREATMENT IN SPECIAL SITUATIONS

8.1. HIV Infection
TUBERCULOSIS AND HIV INFECTION The treatment of tuberculosis in persons with HIV infection is essentially the same as for patients without HIV infection. There are two important exceptions to this generalization: (1 ) Once weekly INHrifapentine in the continuation phase should not be used in any HIV-infected patient; and (2 ) twice weekly INHRIF or rifabutin should not be used for patients with CD4 lymphocyte counts less than 100/ l. Providers must be alert to the potential for interactions among many of the antiretroviral drugs and the rifamycins. Paradoxical reactions that mimic worsening of tuberculosis are more common in patients with HIV infection and may complicate therapy.
Treatment of tuberculosis in patients with HIV infection follows the same principles as treatment of HIV-uninfected patients. However, there are several important differences between patients with and without HIV infection. These differences include the potential for drug interactions, especially between the rifamycins and antiretroviral agents, paradoxical reactions that may be interpreted as clinical worsening, and the potential for the development of acquired resistance to rifamycins when treated with highly intermittent therapy. 8.1.1. Clinical trials of treatment for tuberculosis in HIV-infected patients. There have been seven prospective studies of 6month regimens for the treatment of pulmonary tuberculosis in patients with HIV infection for which recurrence data were reported. Four of the studies were randomized, controlled trials (14), and three were observational in nature (5, 6). These studies differed somewhat in design, patient population, eligibility criteria, frequency of dosing, treatment supervision, and outcome denitions; therefore, it is difcult to provide meaningful crossstudy comparisons. All of the studies reported a good early clinical response to therapy and the time required for sputum culture conversion from positive to negative and treatment failure rates were similar to these indices of treatment efcacy in patients without HIV infection. Recurrence rates have varied among studies, with most reporting rates of 5% or less (2, 3, 5, 6). In one study from the Democratic Republic of Congo (formerly Zaire), in which the recurrence rate in the 6-month arm was 9% compared with 3% in the 12-month arm, nonadherence in the continuation phase and/or exogenous reinfection may have contributed to the higher recurrence rate (1). In a randomized trial of once weekly INHrifapentine versus twice weekly INHRIF in the continuation phase of therapy, 5 of 30 (17%) HIV-infected patients receiving treatment in the once weekly arm relapsed compared with 3 of 31 (10%) patients in the twice weekly INHRIF arm (4). Four of the ve relapsed patients in the once weekly group had resistance to rifampin alone compared with none in the standard treatment arm. Because of the small sample size in the standard treatment arm, it is difcult to interpret the relapse rate of 10%. In an observational study of twice weekly INHrifabutin among HIV-infected tuberculosis patients also receiving antiretroviral therapy, 7 of 156 patients failed treatment or relapsed (7). Although the life table rate of failure/relapse was low (4.6%), M. tuberculosis isolated from all ve of these patients was resis-
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tant to RIF alone. The phenomenon of acquired rifampin monoresistance was also seen in a trial of largely twice weekly INHRIF therapy, albeit at a lower rate (3). In all of these studies, acquired RIF resistance occurred only among patients with CD4 cell counts 100 cells/ l. Acquired rifampin resistance has not been seen in trials where RIF was given daily. A consistent nding in the treatment studies has been a high mortality rate among HIV-seropositive patients. In most studies the cause of death is difcult to ascertain. Early mortality may be related to advanced tuberculosis, but deaths during the continuation phase of therapy are usually due to other AIDS-related conditions. Mortality during treatment among HIV-infected patients with tuberculosis has been associated with advanced HIV disease (1, 3, 6, 8). However, the use of effective antiretroviral therapy during the treatment of tuberculosis in persons with HIV infection may improve treatment outcomes and, thus, is recommended, as described subsequently (9). A major concern in treating tuberculosis in the setting of HIV infection is the interaction of RIF with antiretroviral agents (see Section 7: Drug Interactions, and Table 12). As described previously, rifabutin is highly active against M. tuberculosis but has less of an effect in inducing hepatic microsomal enzymes than RIF. Data from clinical trials suggest that rifabutin and RIF-based regimens are equally efcacious. Gonzalez-Montaner and colleagues (10) reported the rst randomized clinical trial comparing rifabutin (150 and 300 mg) with RIF in a 6-month regimen in persons without HIV infection. The outcomes were highly favorable in both groups and there were few adverse reactions. Investigators from South Africa reported a randomized, open-label trial comparing rifabutin with RIF in a standard fourdrug regimen administered with DOT (11). Although patients did not have HIV testing performed, the HIV seroprevalence was reportedly low at the time of the study. In the continuation phase, the medications were given twice weekly. By 2 months after treatment was begun, 88% of the patients in the RIF arm and 92% of those given rifabutin had negative sputum cultures. The relapse rate was 3.8% in the RIF group versus 5.1% in the rifabutin group (p NS). Only one study examining the effectiveness of rifabutin included HIV-infected patients (12). A single blind randomized study of 50 HIV-infected patients in Uganda compared a fully supervised regimen of RIF versus rifabutin together with INH, EMB, and PZA. Time to sputum conversion was similar between groups when controlling for baseline characteristics. Relapse data were not available. Investigators in Uganda have reported a higher mortality rate among HIV-infected patients treated with regimens that did not contain RIF. Wallis and associates (13) reported that a nonRIF-containing regimen was associated with shortened survival compared with an RIF-based regimen. In addition to the higher mortality associated with non-RIF-based regimens, other studies have demonstrated unacceptably high recurrence rates in the setting of HIV infection (14, 15). Thus, every effort should be made to use a rifamycin-based regimen for the entire course of therapy in persons with HIV infection. 8.1.2. Treatment recommendations. Recommendations for the treatment of tuberculosis in HIV-infected adults are, with two exceptions, identical to those for HIV-uninfected adults: a 6month regimen consisting of an initial phase of INH, RIF, PZA, and EMB given for 2 months followed by INH and RIF for 4 months when the disease is caused by organisms that are known or presumed to be susceptible to the rst-line agents. This regimen may be given by daily or intermittent administration as listed in Table 1 and described in Section 5.2 (Recommended Regimens). However, on the basis of data showing an increased
frequency of rifamycin resistance among patients having CD4 cell counts 100/ l, it is recommended that patients with advanced HIV disease be treated with daily or three times weekly therapy in the continuation phase (Rating AIII) (16). Twice weekly drug administration in the continuation phase should not be used in patients with CD4 cell counts 100/ l. Twice weekly therapy may be considered in patients with less advanced immunosuppression (CD4 cell counts 100/ l). Once weekly administration of INHrifapentine in the continuation phase should not be used in any patient with HIV infection. Six months should be considered the minimum duration of treatment for adults, even for patients with culture-negative tuberculosis. If there is evidence of a slow or suboptimal response (e.g., cultures are still positive after 2 months of therapy), prolongation of the continuation phase to 7 months (a total of 9 months treatment) should be strongly considered. DOT and other adherence-promoting strategies should be used in all patients with HIV-related tuberculosis. Although there are no data on which to base recommendations, the American Academy of Pediatrics recommends that for HIV-infected children the minimum duration of therapy be 9 months (17). All patients with tuberculosis should be advised to undergo voluntary counseling and HIV testing. Efforts should be made to engage all patients with a new diagnosis of HIV infection in HIV care during their treatment for tuberculosis. Ideally, patients should be managed by physicians who are expert in the treatment of tuberculosis/HIV coinfection. If the HIV care provider and tuberculosis care provider are not the same person, communication between them is essential and should occur frequently throughout the course of treatment. 8.1.3. Safety and tolerability. The frequency of antituberculosis drug-related toxicity in patients with HIV infection has varied from study to study. In a retrospective study from San Francisco, 18% of HIV-seropositive patients with tuberculosis had a change of regimen because of adverse drug reactions (18). RIF was the drug implicated most commonly, producing an adverse reaction in 12% of the patients. In the Democratic Republic of Congo, 11% of the seropositive patients developed a rash but in none was the treatment interrupted (1). Paresthesia developed in 21% of the cases, suggesting the need for pyridoxine when treating tuberculosis in persons with HIV infection. Other investigators have reported low rates of signicant adverse reactions (3, 5, 6, 19). In the three times weekly regimen studied in Haiti, there were no differences in adverse events between HIV-infected and uninfected patients (6). In HIV-infected patients it is often difcult to distinguish an adverse reaction to antituberculosis drugs from the effects of associated conditions or reactions to any of the many medications that are often being taken concurrently. Because of the difculties in diagnosing a drug reaction and in determining the responsible agent, the rst-line antituberculosis drugs (especially INH or RIF) should not be stopped permanently without strong evidence that the antituberculosis drug was the cause of the reaction. In such situations consultation with an expert in treating tuberculosis in persons with HIV infection is recommended. In a study reported by Ungo and associates (20), it was demonstrated that the relative risk of developing drug-induced hepatoxicity in tuberculosis patients with hepatitis C virus or HIV infection was 5- and 4-fold, respectively, compared with a 14-fold relative risk in patients with both hepatitis C virus and HIV infections. This nding was not conrmed in a study from Baltimore, in which rates of transaminase elevation were not greater in patients with HIV and hepatitis C virus who were given INH (21). Current IDSA and USPHS guidelines recommend screening all HIV-infected patients for hepatitis C virus (22). Until more data are available it is probably prudent to provide more frequent clinical and
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laboratory monitoring, as described for patients with preexisting liver disease, for patients with HIV infection or hepatitis C virus infection who are being treated for tuberculosis. 8.1.4. Concurrent administration of antiretroviral agents and rifamycins. Most patients with tuberculosis have relatively advanced HIV disease and, thus, antiretroviral therapy is indicated (23). Antiretroviral therapy should not be withheld simply because the patient is being treated for tuberculosis, if it is otherwise indicated. Nevertheless, it is not advisable to begin both antiretroviral therapy and combination chemotherapy for tuberculosis at nearly the same time. So doing may involve as many as eight new drugs with interactions and overlapping toxicities that would be difcult to evaluate. Although there are few data on which to base recommendations, expert opinion suggests that treatment for tuberculosis should be initiated rst. Although antiretroviral therapy has a dramatic effect in decreasing progression of HIV disease (decreasing CD4 cell counts, new opportunistic infections, or death) among patients with HIV-related tuberculosis, the use of antiretroviral therapy in the setting of tuberculosis therapy is complex. In those patients not already receiving antiretroviral therapy, early initiation of antiretroviral therapy may decrease HIV disease progression, but is also associated with a high incidence of side effects and paradoxical reactions, some severe enough to warrant discontinuation of both antiretroviral and antituberculosis drugs (9). In addition, starting so many new medications in a short time period may present a tremendous adherence challenge for patients adjusting to the diagnoses of both tuberculosis and AIDS. Delaying the initiation of antiretroviral therapy until 48 weeks after starting antituberculosis therapy has the potential advantages of being better able to ascribe a specic cause for a drug side effect, decreasing the severity of paradoxical reactions, and decreasing the adherence difculties for the patient. Until there have been controlled studies evaluating the optimal time for starting antiretroviral therapy in patients with HIV infection and tuberculosis, this decision should be individualized, based on the patients initial response to treatment for tuberculosis, occurrence of side effects, and ready availability of multidrug antiretroviral therapy. For patients with CD4 cell counts 350 cells/ l, the antiretroviral regimen could be initiated at any time after tuberculosis treatment was begun, based on current recommendations (23). For patients who are already receiving an antiretroviral regimen, treatment should generally be continued, although the regimen may need to be modied on the basis of the risk of drugdrug interactions, as described in Section 7 (Drug Interactions). Even though drug interactions are common, a rifamycin should not be excluded from the tuberculosis treatment regimen for fear of interactions with some antiretroviral agents. The exclusion of a rifamycin from the treatment regimen is likely to delay sputum conversion, will prolong the duration of therapy, and possibly result in a poorer outcome (24). As noted in Section 7 (Drug Interactions), rifabutin has fewer interactions than RIF and should be used if these categories of antiretroviral agents are being administered. The categories of antiretroviral agents available currently are nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). The NRTIs and NtRTIs do not have clinically signicant drug interactions with the standard antituberculosis medications; thus, drugs in these categories can be used together with rifamycins without any dose adjustment being necessary. However, the PIs and NNRTIs, depending on the specic drug, may either inhibit or induce cytochrome P450 isoenzymes (CYP450). Thus, these drugs may alter the serum concentration of rifabutin, as de-
scribed in Section 7.1 (Interactions Affecting Antituberculosis Drugs). When rifabutin is combined with antiretroviral agents, its dose and the dose of the antiretroviral agents may require adjustment. A report described the successful use of rifabutin with an antiretroviral regimen containing PIs (25). All 25 patients became culture negative by 2 months and no relapses were reported after a median follow-up of 13 months. Moreover, the circulating HIV RNA levels decreased signicantly, with 20 of 25 patients achieving viral loads of less than 500 copies/ml. Thus, it appears that both tuberculosis and HIV can be treated successfully with concurrent use of a rifabutin-based regimen and potent combinations of antiretroviral agents. Previous guidelines from the CDC specically stated that RIF was contraindicated in patients who were taking any PI or NNRTI (26). However, new data indicate that RIF can be used for the treatment of tuberculosis with certain combinations of antiretroviral agents (27, 28). As recommended by the CDC (27), rifampin can be used with a regimen of efavirenz and two NRTIs, with ritonavir and one or more NRTIs, with ritonavir and saquinavir (either hard-gel or soft-gel capsule), and with a triple nucleoside regimen. As new antiretroviral agents and more pharmacokinetic data become available, these recommendations are likely to be modied. Because these recommendations are frequently revised, obtaining the most up-to-date information from the CDC website, http://www.cdc.gov/nchstp/tb/, is advised. Updated information on antiretroviral drugs and drug interactions, compiled by Medscape, can be found at http://www. medscape.com/updates/quickguide. When starting NNRTIs or PIs for tuberculosis patients receiving RIF, a 2-week washout period is generally recommended between the last dose of RIF and the rst dose of PIs or NNRTIs to allow for reduction of the enzyme-inducing activity of RIF. During this time, rifabutin may be started to ensure that the tuberculosis treatment regimen is adequate. For patients already receiving antiretroviral agents at the time treatment for tuberculosis is begun, an assessment of the antiretroviral regimen should be undertaken and, if necessary, changes made to ensure optimum treatment of the HIV infection during tuberculosis therapy. Conversely, the determination of whether to use RIF and the dose of the rifamycin must take into account the antiretroviral regimen. 8.1.5. Paradoxical reaction. On occasion, patients have a temporary exacerbation of symptoms, signs, or radiographic manifestations of tuberculosis (paradoxical reaction) after beginning antituberculosis treatment. Worsening of this sort occurs in patients without HIV infection, especially with lymphadenitis, but it is more common among HIV-infected patients. These reactions presumably develop as a consequence of reconstitution of immune responsiveness brought about by antiretroviral therapy or, perhaps, by treatment of the tuberculosis itself. Narita and colleagues (29) reported that among HIV-infected patients who were taking antiretroviral agents, 36% developed paradoxical worsening after beginning treatment for tuberculosis compared with 7% of those who were not taking antiretroviral drugs. In contrast, Wendel and colleagues (30) reported that only 7% of HIV-infected patients with tuberculosis developed paradoxical worsening and the reactions were not associated with antiretroviral therapy. Signs of a paradoxical reaction may include high fevers, increase in size and inammation of involved lymph nodes, new lymphadenopathy, expanding central nervous system lesions, worsening of pulmonary parenchymal inltrations, and increasing pleural effusions. Such ndings should be attributed to a paradoxical reaction only after a thorough evaluation has excluded other possible causes, especially tuberculosis treatment failure.
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Kaboto M, Mukadi Y, Pauwels P, Ryder RW, Prignot J, et al. Increased mortality and tuberculosis treatment failure rate among human immunodeciency virus (HIV) seropositive compared with HIV seronegative patients with pulmonary tuberculosis in Kinshasa, Zaire. Am Rev Respir Dis 1991;144:750755. Centers for Disease Control and Prevention. Acquired rifamycin resistance in persons with advanced HIV disease being treated for active tuberculosis with intermittent rifamycin-based regimens. MMWR Morb Mortal Wkly Rep 2002;51:214215. www.cdc.gov/nchstp/tb/ American Academy of Pediatrics. Tuberculosis. In: Pickering LJ, editor. Red book report of the Committee on Infectious Diseases, 25th edition. Elk Grove Village, IL: American Academy of Pediatrics; 2000. p. 593613. Small PM, Schecter GF, Goodman PC, Sande MA, Chaisson RE, Hopewell PC. Treatment of tuberculosis in patients with advanced human immunodeciency virus infection. N Engl J Med 1991;324:289294. Jones BE, Otaya M, Antoniskis D, Sian S, Wang F, Mercado A, Davidson PT, Barnes PF. A prospective evaluation of antituberculosis therapy in patients with human immunodeciency virus infection. Am J Respir Crit Care Med 1994;150:14991502. Ungo JR, Jones D, Ashkin D, Hollender ES, Bernstein D, Albanese AP, Pitchenik AE. Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeciency virus. Am J Respir Crit Care Med 1998;157:18711876. Sadaphal P, Astemborski J Graham NM, Sheely L, BondsM, Madison A, Vlahov D, Thomas DL, Sterling TR. Isoniazid preventive therapy, hepatitis C virus infection, and hepatotoxicity among injection drug users infected with Mycobacterium tuberculosis Clin Infect Dis 2001;33: 16871691. United States Public Health Service (USPHS), Infectious Diseases Society of America (IDSA). USPHS/IDSA guidelines for the prevention of opportunistic infections in persons with human immunodeciency virus. November 28, 2001. www.hivatis.org/guidelines/other/OIs/ OIGNov27.pdf Yeni PG, Hammer SM, Carpenter CCJ, Cooper DA, Fischl MA, Gatell JM, Gazzard BG, Hirsch MS, Jacobsen DM, Katzenstein DA, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS SocietyUSA panel. JAMA 2002;288:222235. Okwera A, Whalen C, Byekwaso F, Vjecha J, Johnson J, Huebner R, Mugerwa R, Ellner J. Randomized trial of thiacetazone and rifampicincontaining regimens for pulmonary tuberculosis in HIV infected Ugandans. Makere UniversityCase Western Reserve University Research Collaboration. Lancet 1994;344:13231328. Narita M, Stambaugh JJ, Hollender ES, Jones D, Pitchenik AE, Ashkin D. Use of rifabutin with protease inhibitors for human immunodeciency virus-infected patients with tuberculosis. Clin Infect Dis 2000;30: 779783. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeciency virus: principles of therapy and revised recommendations. MMWR Morb Mortal Wkly Rep 1998;47:158. www.cdc.gov/nchstp/tb/ Centers for Disease Control and Prevention. Updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR 2000;49: 185200. www.cdc.gov/nchstp/tb/ Burman WJ, Jones BE. Treament of HIV-related tuberculosis in the era of effective antiretroviral therapy. Am J Respir Crit Care Med 2001;164:712. Narita M, Ashkin D, Hollender ES, Pitchenik AE. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 1998;158:157161. Wendel KA, Alwood KS, Gachuhi R, Chaisson RE, Bishai WR, Sterling TR. Paradoxical worsening of tuberculosis in HIV-infected persons. Chest 2001;120:193197.
A paradoxical reaction that is not severe should be treated symptomatically without a change in antituberculosis or antiretroviral therapy. Although approaches to the management of severe reactions, such as high fever, airway compromise from enlarging lymph nodes, enlarging serosal uid collections, and sepsis syndrome, have not been studied, expert opinion suggests that prednisone or methylprednisolone be started at a dose of about 1 mg/kg and gradually reduced after 1 to 2 weeks.
References
1. Perriens JH, St. Louis ME, Mukadi YB, Brown C, Prignot J, Pouthier F, Portaels F, Willame JC, Mandala JK, Kaboto M, et al. Pulmonary tuberculosis in HIV-infected patients in Zaire: a controlled trial of treatment for either 6 or 12 months. N Engl J Med 1995;332:779784. 2. Kennedy N, Berger L, Curram J, Fox R, Gutmann J, Kisyombe GM, Ngowi FI, Ramsay ARC, Saruni AOS, Sam N, Tillotson G, Uiso LO, Yates M, Gillespie SH. Randomized controlled trial of a drug regimen that includes ciprooxacin for the treatment of pulmonary tuberculosis. Clin Infect Dis 1996;22:827833. 3. El-Sadr WM, Perlman DC, Matts JP, Nelson ET, Cohn DL, Salomon N, Olibrice M, Medard F, Chirgwin KD, Mildvan D, et al. Evaluation of an intensive intermittent-induction regimen and duration of shortcourse treatment for human immunodeciency virus-related pulmonary tuberculosis. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) and the AIDS Clinical Trials Group (ACTG). Clin Infect Dis 1998;26:11481158. 4. Vernon, A, Burman W, Benator D, Khan A, Bozeman L. Acquired rifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Tuberculosis Trials Consortium. Lancet 1999;353:18431847. 5. Kassim S, Sassan-Morokro M, Ackah A, Abouya LY, Digbeu H, Yesso G, Coulibaly IM, Coulibaly D, Whitaker PJ, Doorly R, et al. Two year follow-up of persons with HIV-1 and HIV-2 associated pulmonary tuberculosis treated with short course chemotherapy in West Africa. AIDS 1995;9:11851191. 6. Chaisson RE, Clermont HC, Holt EA, Clermont HC, Holt EA, Cantave M, Johnson MP, Atkinson J, Davis H, Boulos R, et al., JHU-CDS Research Team. Six-months supervised intermittent tuberculosis therapy in Haitian patients with and without HIV infection. Am J Respir Crit Care Med 1996;154:10341038. 7. Centers for Disease Control and Prevention. Notice to readers: acquired rifamycin resistance in persons with advanced HIV disease being treated for active tuberculosis with intermittent rifamycin-based regimens. MMWR Morb Mortal Wkly Rep 2002;51:214215. www.cdc.gov/ nchstp/tb/ 8. Murray J, Sonnenberg P, Shearer SC, Godfrey-Faussett P. Human immunodeciency virus and the outcome of treatment for new and recurrent pulmonary tuberculosis in African patients. Am J Respir Crit Care Med 1999;159:733740. 9. Dean GL, Edwards SG, Ives NJ, Matthews G, Fox EF, Navaratne L, Fisher M, Taylor GP, Miller R, Taylor CB, et al. Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy. AIDS 2002;16:7583. 10. Gonzalez-Montaner LJ, Natal S, Yonchaiyud P, Olliaro P. Rifabutin for the treatment of newly-diagnosed pulmonary tuberculosis: a multinational, randomized, comparative study versus rifampicin. Tuber Lung Dis 1994;75:341347. 11. McGregor MM, Olliaro P, Womarans L, Mabuza B, Bredell M, Felten MK, Fourie PB. Efcacy and safety of rifabutin in the treatment of patients with newly diagnosed pulmonary tuberculosis. Am J Respir Crit Care Med 1996;154:14621467. 12. Schwander S, Rusch-Gerdes S, Mateega A, Lutalo T, Tugume S, Kityo C, Rubaramira R, Mugyenyi P, Okwera A, Mugerwa R. A pilot study of antituberculosis combinations comparing rifabutin in the treatment of patients with newly diagnosed pulmonary tuberculosis. Tuber Lung Dis 1995;76:210218. 13. Wallis RS, Helfand MS, Whalen CC, Johnson JL, Mugerwa RD, Vjecha M, Okwera A, Ellner JJ. Immune activation, allergic drug toxicity and mortality in HIVpositive tuberculosis. Tuber Lung Dis 1996;77:516 523. 14. Hawken M, Nunn P, Gathua S, Brindle R, Godfrey-Faussett P, Githui W, Odhiambo J, Batchelor B, Gilks C, Morris J, et al. Increased recurrence of tuberculosis in HIV-1-infected patients in Kenya. Lancet 1993;342:332338. 15. Perriens JH, Colebunders RL, Karahunga C, Willame J-C, Jeugmans J,
16.
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30.
8.2. Children and Adolescents
Children most commonly develop tuberculosis as a complication of the initial infection with M. tuberculosis (primary tuberculosis). Radiographically, primary tuberculosis is characterized by intrathoracic adenopathy, mid- and lower lung zone inltrates, and the absence of cavitation. However, children, occasionally, and adolescents, more frequently, develop adult-type tuberculosis (upper lobe inltration and cavitation associated with sputum production). The lesions of primary tuberculosis have a smaller
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number of M. tuberculosis organisms than those of adult-type pulmonary tuberculosis; thus, treatment failure, relapse, and development of secondary resistance are rare phenomena among children. Because it is more difcult to isolate M. tuberculosis from a child with pulmonary tuberculosis than from an adult, it is frequently necessary to rely on the results of culture and susceptibility tests of specimens from the person presumed to be the source of the infection in the child to guide the choice of drugs for the child. In children in whom drug resistance is suspected or for whom no source case isolate is available, attempts to isolate organisms via three early morning gastric aspirations (optimally during hospitalization), bronchoalveolar lavage, or tissue biopsy must be considered. Because tuberculosis in infants and children younger than 4 years of age is more likely to disseminate, treatment should be started as soon as the diagnosis is suspected. Asymptomatic children with a positive PPD-tuberculin skin test and an abnormal chest radiograph (atelectasis, parenchymal inltrate, or hilar adenopathy) should receive combination chemotherapy, usually with INH, RIF, and PZA as initial therapy. Several controlled and observational trials of 6-month therapy in children with pulmonary tuberculosis caused by organisms known or presumed to be susceptible to the rst-line drugs have been published (19). Six months of therapy with INH and RIF has been shown to be effective for hilar adenopathy and pulmonary disease caused by drug-susceptible organisms (5, 6). However, most studies used 6 months of daily treatment with INH and RIF, supplemented during the rst 2 weeks to 2 months with PZA. This three-drug combination has a success rate of greater than 95% and a rate of adverse effects of less than 2%. Two studies used twice or three times weekly therapy from the beginning with good results (1, 7). Many experts prefer to treat children with three (rather than four) drugs in the initial phase because the bacillary population is low, because many infants and children cannot tolerate the pill burden required with four oral drugs, and because of the difculty in performing visual acuity tests in young children who are being treated with EMB. In children suspected or known to have been infected with an M. tuberculosis strain that is fully susceptible, the initial phase should consist of INH, RIF, and PZA. If the susceptibility of the presumed infecting strain is not known and the likelihood of failure is low (primary tuberculosis), some experts prefer to use three drugs. However, children and adolescents with adult-type pulmonary tuberculosis, as dened above, should be treated with the four-drug initial phase regimen, unless the infecting strain is known to be susceptible (10). When epidemiologic circumstances (Table 6) suggest an increased risk of drug-resistant organisms being present, EMB can be used safely in a dose of about 1520 mg/kg per day, even in children too young for routine eye testing. Older children should have monthly evaluations of visual acuity and color discrimination while taking EMB. SM, kanamycin, or amikacin can be used as the fourth drug, when necessary. The usual doses for daily and twice weekly treatment in children are listed in Section 3 (Drugs in Current Use) and shown in Table 3. Three times weekly therapy is not recommended for children. Pyridoxine is recommended for infants, children, and adolescents who are being treated with INH and who have nutritional deciencies, symptomatic HIV infection, or who are breastfeeding. DOT should be used for all children with tuberculosis. The lack of pediatric dosage forms of most antituberculosis medications necessitates using crushed pills and suspensions. Even when drugs are given under DOT, tolerance of the medications must
be monitored closely. Parents should not be relied on to supervise DOT. Because of the difculties in isolating M. tuberculosis from children, bacteriological examinations are less useful in evaluating the response to treatment and clinical and radiographic examinations are of relatively greater importance. However, hilar adenopathy and resultant atelectasis may require 23 years to resolve. Thus, a persisting abnormality on chest radiographs is not necessarily a criterion for extending continuing therapy. Recognition of treatment failure or relapse in a child is subject to the same difculties as making a diagnosis. Thus, clinical and radiographic worsening may not be accompanied by positive AFB smears or mycobacterial cultures. A decision to modify the drug regimen should not be made lightly, but often must be made on clinical grounds only. In general, extrapulmonary tuberculosis in children can be treated with the same regimens as pulmonary disease. Exceptions may be disseminated disease, and meningitis, for which there are inadequate data to support 6-month therapy. A fourth drug is recommended in the initial phase when there is disseminated tuberculosis. The recommended duration is 912 months. The optimal treatment of pulmonary tuberculosis in children and adolescents with HIV infection is unknown. The American Academy of Pediatrics recommends that initial therapy should always include at least three drugs (INH and RIF, plus PZA for the rst 2 months), and the total duration of therapy should be at least 9 months (11).
References
1. Te Water Naude JM, Donald PR, Hussey GD, Kibel MA, Louw A, Perkins DR, Schaaf HS. Twice weekly vs. daily chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 2000;19:405410. 2. Tsakalidis D, Pratsidou P, Hitoglou-Makedou A, Tzouvelekis G, Sofroniadis I. Intensive short course chemotherapy for treatment of Greek children with tuberculosis. Pediatr Infect Dis J 1992;11:10361042. 3. Kumar L, Dhand R, Singhi PO, Rao KL, Katariya S. A randomized trial of fully intermittent vs. daily followed by intermittent short course chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990;9: 802806. 4. Biddulph J. Short course chemotherapy for childhood tuberculosis. Pediatr Infect Dis J 1990;9:794801. 5. Reis FJC, Bedran MBM, Moura JAR, Assis I, Rodrigues ME. Six-month isoniazid-rifampin treatment for pulmonary tuberculosis in children. Am Rev Respir Dis 1990;142:996999. 6. Jacobs RF, Abernathy RS. The treatment of tuberculosis in children. Pediatr Infect Dis J 1985;4:513517. 7. Varudkar B. Short course chemotherapy for tuberculosis in children. Indian J Pediatr 1985;52:593597. 8. Ibanez Quevedo S, Ross Bravo G. Quimioterapia abreviada de 6 meses en tuberculosis pulmonar infantil. Rev Chil Pediatr 1980;51:249252. 9. Al-Dossary FS, Ong LT, Correa AG, Starke JR. Treatment of childhood tuberculosis using a 6-month, directly observed regimen with only 2 weeks of daily therapy. Pediatr Infect Dis J 2002;21:9197. 10. Trebucq A. Should ethambutol be recommended for routine treatment of tuberculosis in children? A review of the literature. Int J Tuberc Lung Dis 1997;1:1215. 11. American Academy of Pediatrics. Tuberculosis. In: Pickering LJ, editor. Red book report of the Committee on Infectious Diseases, 25th edition. Elk Grove Village, IL: American Academy of Pediatrics; 2000. p. 593613.
8.3. Extrapulmonary Tuberculosis
Tuberculosis can involve virtually any organ or tissue in the body. Nonpulmonary sites tend to be more common among children and persons with impaired immunity. To establish the diagnosis of extrapulmonary tuberculosis, appropriate specimens including pleural uid; pericardial or peritoneal uid; pleural, pericardial, and peritoneal biopsy specimens; lymph node tissue; and bone marrow, bone, blood, urine, brain, or cerebrospinal uid should be obtained for AFB staining, mycobacterial
American Thoracic Society Documents TABLE 13. EVIDENCED-BASED* GUIDELINES FOR THE TREATMENT OF EXTRAPULMONARY TUBERCULOSIS AND ADJUNCTIVE USE OF CORTICOSTEROIDS
Site Lymph node Bone and joint Pleural disease Pericarditis CNS tuberculosis including meningitis Disseminated disease Genitourinary Peritoneal Length of Therapy (mo) 6 69 6 6 912 6 6 6 Rating (Duration) AI AI AII AII BII AII AII AII Corticosteroids Not recommended Not recommended Not recommended Strongly recommended Strongly recommended Not recommended Not recommended Not recommended Rating (Corticosteroids) DIII DIII DI AI AI DIII DIII DIII
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* For rating system, see Table 1. Duration of therapy for extrapulmonary tuberculosis caused by drug-resistant organisms is not known. Corticosteroid preparations vary among studies. See Section 8.3 for specific recommendations.
culture, and drug susceptibility testing (1). Tissue specimens should also be examined microscopically, after routine and AFB staining, but the absence of AFB and of granulomas or even failure to culture M. tuberculosis does not exclude the diagnosis of tuberculosis. Bacteriological evaluation of the response to treatment in extrapulmonary tuberculosis is often limited by the difculty in obtaining follow-up specimens. Thus, response often must be judged on the basis of clinical and radiographic ndings. The basic principles that underlie the treatment of pulmonary tuberculosis also apply to extrapulmonary forms of the disease. Although many fewer treatment studies have examined treatment of extrapulmonary tuberculosis, compared with pulmonary disease, increasing evidence, including some randomized controlled trials, suggests that 6- to 9-month regimens that include INH and RIF are effective (216). Therefore, among patients with extrapulmonary tuberculosis, a 6- to 9-month regimen (2 months of INH, RIF, PZA, and EMB followed by 47 months of INH and RIF) is recommended as initial therapy unless the organisms are known or strongly suspected of being resistant to the rst-line drugs. If PZA cannot be used in the initial phase, the continuation phase must be increased to 7 months, as described for pulmonary tuberculosis. The exception to the recommendation for a 6- to 9-month regimen is tuberculous meningitis, for which the optimal length of therapy has not been established, but some experts recommend 912 months. Although in extrapulmonary tuberculosis there have not been controlled trials of the various patterns of intermittent drug administration listed in Table 2, expert opinion suggests that all could be used, with the exception of INHrifapentine once weekly in the continuation phase. Given the lack of experience with this regimen, it is not recommended currently for treating extrapulmonary tuberculosis. Corticosteroid treatment is a useful adjunct in treating some forms of extrapulmonary tuberculosis, specically meningitis and pericarditis caused by drug-susceptible organisms. Evidencebased recommendations on the duration of treatment for extrapulmonary tuberculosis and the use of corticosteriods are shown in Table 13. 8.3.1. Lymph node tuberculosis. A 6-month regimen as described in Section 5 (Recommended Treatment Regimens) and Table 2 is recommended for initial treatment of all patients with tuberculous lymphadenitis caused by drug-susceptible organisms (26). Affected lymph nodes may enlarge while patients are receiving appropriate therapy or after the end of treatment without any evidence of bacteriological relapse (3, 5, 17, 18). On
occasion, new nodes can appear during or after treatment as well. Therapeutic lymph node excision is not indicated except in unusual circumstances. For large lymph nodes that are uctuant and appear to be about to drain spontaneously, aspiration or incision and drainage appears to be benecial, although this approach has not been examined systematically (Rating BIII). It should be noted that the majority of cases of lymphatic mycobacterial disease in children in the United States are caused by nontuberculous mycobacteria. 8.3.2. Bone and joint tuberculosis. Several studies have examined treatment of bone and joint tuberculosis and have shown that 6- to 9-month regimens containing RIF are at least as effective as 18-month regimens that do not contain RIF (1315) Because of the difculties in assessing response, however, some experts tend to favor the 9-month duration. A randomized trial performed primarily among ambulatory patients by the Medical Research Council Working Party on Tuberculosis of the Spine (13) demonstrated no additional benet of surgical debridement or radical operation (resection of the spinal focus and bone grafting) in combination with chemotherapy compared with chemotherapy alone. Myelopathy with or without functional impairment most often responds to chemotherapy. In two Medical Research Council studies conducted in Korea, 24 of 30 patients in one study (14) and 74 of 85 patients in an earlier study (19) had complete resolution of myelopathy or complete functional recovery when treated medically. In some circumstances, however, surgery appears to be benecial and may be indicated. Such situations include failure to respond to chemotherapy with evidence of ongoing infection, the relief of cord compression in patients with persistence or recurrence of neurologic decits, or instability of the spine. 8.3.3. Pericardial tuberculosis. For patients with pericardial tuberculosis, a 6-month regimen is recommended. Corticosteroids are recommended as adjunctive therapy for tuberculous pericarditis during the rst 11 weeks of antituberculosis therapy. In a randomized, double-blind, controlled trial, patients in the later effusiveconstrictive phase who received prednisolone had a signicantly more rapid clinical resolution compared with patients given placebo. Prednisolone-treated patients also had a lower mortality (2 of 53 [4%] versus 7 of 61 [11%]) and needed pericardiectomy less frequently (11 of 53 [21%] versus 18 of 61 [30%]), but the differences did not reach statistical signicance (8). Prednisolone did not reduce the risk of constrictive pericarditis. In a second prospective, double-blind, randomized trial of adjunctive prednisolone therapy involving patients with effusive pericarditis (i.e., more acute disease), prednisolone reduced the
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need for repeated pericardiocentesis (7 of 76 [9%] versus 17 of 74 [23%]; p 0.05) and was associated with a signicantly lower mortality (2 of 76 [3%] died among those who received prednisolone compared with 10 of 74 [14%] among those not given prednisolone; p 0.05) (9). As before, there was no statistically signicant impact on progression to constriction or in the need for pericardiectomy. An additional small randomized trial by Hakim and associates (20) performed in HIV-infected patients with tuberculous pericarditis also demonstrated that prednisolone therapy was associated with a reduced risk of mortality. On the basis of these studies, it is recommended that daily adjunctive prednisolone or prednisone treatment be given to adults and children with tuberculous pericarditis. For adults the prednisone dose is 60 mg/day (or the equivalent dose of prednisolone) given for 4 weeks, followed by 30 mg/day for 4 weeks, 15 mg/day for 2 weeks, and nally 5 mg/day for week 11 (the nal week). Children should be treated with doses proportionate to their weight, beginning with about 1 mg/kg body weight and decreasing the dose as described for adults. 8.3.4. Pleural tuberculosis. A 6-month regimen is also recommended for treating pleural tuberculosis. A number of studies have examined the role of corticosteroid therapy for tuberculous pleural effusions (21), but only two have been prospective, double blind, and randomized (7, 22). In both of these studies, prednisone (or prednisolone) administration did not reduce the development of residual pleural thickening. Lee and associates (22) found that patients with pleural tuberculosis who received prednisone had a signicantly more rapid resolution of symptoms such as fever, chest pain, and dyspnea than patients given placebo. Patients who received prednisone had a more rapid radiographic resolution of the effusions. In the study by Wyser and colleagues (7), all patients had complete drainage of the effusion performed at the time of the diagnostic procedure; patients were then allocated at random to receive adjunctive oral prednisone or placebo for 6 weeks. The complete drainage led to a rapid resolution of symptoms, and the added benet of corticosteroids on symptoms was minimal. Tuberculous empyema, a chronic, active infection of the pleural space containing a large number of tubercle bacilli, usually occurs when a cavity ruptures into the pleural space. Treatment consists of drainage (often requiring a surgical procedure) and antituberculous chemotherapy. Surgery, when needed, should be undertaken by experienced thoracic surgeons (23). The optimum duration of treatment for this unusual form of tuberculosis has not been established. 8.3.5. Tuberculous meningitis. Before the advent of effective antituberculosis chemotherapy, tuberculous meningitis was uniformly fatal. Tuberculous meningitis remains a potentially devastating disease that is associated with a high morbidity and mortality, despite prompt initiation of adequate chemotherapy (2429). HIV-infected patients appear to be at increased risk for developing tuberculous meningitis but the clinical features and outcomes of the disease are similar to those in patients without HIV infection (2426, 29). Patients presenting with more severe neurologic impairment such as drowsiness, obtundation, or coma have a greater risk of neurologic sequelae and a higher mortality. Chemotherapy should be initiated with INH, RIF, PZA, and EMB in an initial 2-month phase. INH and RIF, as well as the aminoglycosides, capreomycin, and the uoroquinolones are available in parenteral forms for patients with altered mental status who may not be able to take oral medications. After 2 months of four-drug therapy for meningitis caused by susceptible strains, PZA and EMB may be discontinued, and INH and RIF continued for an additional 710 months, although
the optimal duration of chemotherapy is not dened, and there are no data from randomized, controlled trials to serve as the basis of recommendations. Repeated lumbar punctures should be considered to monitor changes in CSF cell count, glucose, and protein, especially in the early course of therapy. Differences in regimens among patient groups and in the use of corticosteroid therapy have made meta-analysis of published treatment trials impossible (30). Some authors have advocated longer courses of therapy, up to 2 years (28, 31), whereas others have suggested that short-course RIF-based regimens for 6 to 9 months may be adequate therapy (10, 32, 33). It has been reported that some patients being treated for tuberculous meningitis develop tuberculomas during therapy, perhaps as a form of paradoxical reaction; however, this does not necessarily indicate treatment failure. A number of investigators have examined the role of adjunctive corticosteroid therapy in the treatment of tuberculous meningitis (21, 3441), but many of these are limited by small sample size or use of a regimen that did not include RIF. There are no large, prospective, randomized, controlled trials of adjunctive corticosteroid use for tuberculous meningitis in which an RIF-based regimen has been used. Six of eight controlled trials noted a benet of corticosteroid therapy in terms of survival, frequency of sequelae, or both. In the study conducted by Girgis and coworkers (34), the greatest benet was for patients with Stage II disease (lethargic) on presentation (4 of 27 [15%] of those who received dexamethasone died versus 14 of 35 [40%] in the control group; p 0.02). For patients presenting with coma (Stage III), there was no signicant difference in survival between those who received dexamethasone and control patients (28 of 44 [64%] mortality for the dexamethasone group versus 35 of 46 [76%] for control subjects). However, the small sample size may have precluded nding an effect. Likewise, there were too few patients with Stage I disease (alert) on entry to determine the effectiveness of dexamethasone for this less severely ill group. On the basis of the available data, albeit limited, adjunctive corticosteroid therapy with dexamethasone is recommended for all patients, particularly those with a decreased level of consciousness, with tuberculous meningitis. The recommended regimen is dexamethasone in an initial dose of 8 mg/day for children weighing less than 25 kg and 12 mg/day for children weighing 25 kg or more and for adults. The initial dose is given for 3 weeks and then decreased gradually during the following 3 weeks. 8.3.6. Disseminated tuberculosis. A 6-month regimen is recommended for tuberculosis at multiple sites and for miliary tuberculosis, although there are limited data from controlled clinical trials addressing this issue. (The AAP recommends 9 months of treatment for children with disseminated tuberculosis.) Expert opinion suggests that corticosteroid therapy may be useful for treating respiratory failure caused by disseminated tuberculosis but there are no data to support its use. 8.3.7. Genitourinary tuberculosis. Renal tuberculosis is treated primarily with medical therapy (12, 4246), and a 6month regimen is recommended. If ureteral obstruction occurs, procedures to relieve the obstruction are indicated. In cases of hydronephrosis and progressive renal insufciency due to obstruction, renal drainage by stenting or nephrostomy is recommended (42). The use of corticosteriods in addition to stenting for the treatment of ureteric stenosis is discussed in the urologic literature but the efcacy of steroids in this setting is unclear. Nephrectomy is not usually indicated for the treatment of uncomplicated renal tuberculosis but should be considered when there is a nonfunctioning or poorly functioning kidney, particu-
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Controlled trial of short-course regimens of chemotherapy in the ambulatory treatment of spinal tuberculosis: results at three years of a study in Korea. J Bone Joint Surg Br 1993;75:240248. Medical Research Council Working Party on Tuberculosis of the Spine. A controlled trial of six-month and nine-month regimens of chemotherapy in patients undergoing radical surgery for tuberculosis of the spine in Hong Kong. Tubercle 1986;67:243259. British Thoracic Society Research Committee. Short course chemotherapy for tuberculosis of lymph nodes: a controlled trial. BMJ 1985;290: 11061108. Campbell IA, Dyson AJ. Lymph node tuberculosis: a comparison of various methods of treatment. Tubercle 1977;58:171179. Campbell IA, Dyson AJ. Lymph node tuberculosis: a comparison of treatments 18 months after completion of chemotherapy. Tubercle 1979;60:9598. Pattison PRM. Potts paraplegia: an account of the treatment of 89 consecutive patients. Paraplegia 1986;24:7791. Hakim JG, Ternouth I, Mushangi E, Siziya S, Robertson V, Malin A. Double blind randomised placebo controlled trial of adjunctive prednisolone in the treatment of effusive tuberculous pericarditis in HIV seropositive patients. Heart 2000;84:183188. Dooley DP, Carpenter JL, Rademacher S. Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin Infect Dis 1997;25:872877. Lee CH, Wang WJ, Lan RS, Tsai YH, Chiang YC. Corticosteroids in the treatment of tuberculous pleurisy: a double-blind, placebo controlled, randomized study. Chest 1988;94:12561259. Sahn SA, Iseman MD. Tuberculous empyema. Semin Respir Infect 1999;14:8287. Dube MP, Holtom PD, Larsen RA. Tuberculous meningitis in patients with and without human immunodeciency virus infection. Am J Med 1992;93:520524. Berenguer J, Moreno S, Laguna F, Vicente T, Adrados M, Ortega A, Gonzalez-LaHoz J, Bouza E. Tuberculous meningitis in patients infected with the human immunodeciency virus. N Engl J Med 1992;326: 668672. Porkert MT, Sotir M, Moore PP, Blumberg HM. Tuberculous meningitis at a large inner-city medical center. Am J Med Sci 1997;313:325331. Yechoor VK, Shandera WX, Rodriguez P, Cate TR. Tuberculous meningitis among adults with and without HIV infection: experience in an urban public hospital. Arch Intern Med 1996;156:17101716. Girgis NI, Sultan Y, Farid Z, Mansour MM, Erian MW, Hanna LS, Mateczun AJ. Tuberculosis meningitis, Abbassia Fever Hospital-Naval Medical Research Unit No. 3: Cairo, Egypt, from 1976 to 1996. J Trop Med Hyg 1998;58:2834. Karstaedt AS, Valtchanova S, Barriere R, Crewe-Brown HH. Tuberculous meningitis in South African urban adults. Q J Med 1988;91:743 747. Thwaites G, Chau TTH, Mai NTH, Brobniewski F, McAdam K, Farrar J. Tuberculous meningitis. J Neurol Neurosurg Psychiatry 2000;68:289 299. Goel A, Pandya S, Satoskar A. Whither short-course chemotherapy for tuberculous meningitis? Neurosurgery 1990;27:418421. Jacobs RF, Sunakorn P, Chotpitayasunonah T, Pope S, Kelleher K. Intensive short course chemotherapy for tuberculous meningitis. Pediatr Infect Dis J 1992;11:194198. Phuapradit P, Vejjajiva A. Treatment tuberculous meningitis: role of short-course chemotherapy. Q J Med 1987;62:249258. Girgis NI, Farid Z, Kilpatrick ME, Sultan Y, Mikhail IA. Dexamethasone adjunctive treatment for tuberculous meningitis. Pediatr Infect Dis J 1991;10:179183. Girgis NI, Farid Z, Hanna LS, Yassin MW, Wallace CK. The use of dexamethasone in preventing ocular complications in tuberculous meningitis. Trans R Soc Trop Med Hyg 1983;77:658659. Kumarvelu S, Prasad K, Khosla A, Behari M, Ahuja GK. Randomized controlled trial of dexamethasone in tuberculous meningitis. Tuber Lung Dis 1994;75:203207. Lepper MH, Spies HW. The present status of the treatment of tuberculosis of the central nervous system. Ann N Y Acad Sci 1963;106:106123. Escobar JA, Belsey MA, Duenas A, Medinea P. Mortality from tuberculous meningitis reduced by steroid therapy. Pediatrics 1975;56:1050 1055. OToole RD, Thornton GF, Mukherjee MK, Nath RL. Dexamethasone in tuberculous meningitis: relationship of cerebrospinal uid effects to therapeutic efcacy. Ann Intern Med 1969;70:3948. Ashby M, Grant H. Tuberculous meningitis treatment with cortisone. Lancet 1955;1:6566.
larly if hypertension or continuous ank pain is present. Tuberculosis of either the female or male genital tract responds well to standard chemotherapy, and surgery is needed only for residual large tubo-ovarian abscesses. A positive urine culture for M. tuberculosis occurs relatively commonly as an incidental nding among patients with pulmonary or disseminated disease, especially those with HIV infection. The positive culture may occur in the absence of any abnormalities on urinalysis and does not necessarily represent genitourinary tract involvement. 8.3.8. Abdominal tuberculosis. A 6-month regimen is recommended for patients with peritoneal or intestinal tuberculosis (47, 48). There are insufcient data to recommend adjunctive corticosteroid therapy in the treatment of tuberculous peritonitis (21). In a small study of peritoneal tuberculosis alternate patients received adjunctive corticosteroid therapy for 4 months (total of 23 steroid recipients) (49). Fibrotic complications were noted in 4 of 24 in the control group and in none of those in the steroid group (23 patients), but the difference was not statistically signicant. 8.3.9. Other sites of involvement. As noted above, tuberculosis can involve any organ or tissue. In treating tuberculosis in sites other than those mentioned, the basic principles of therapy apply, but experts should be consulted for specic advice concerning individual patients.
References
1. American Thoracic Society, Centers for Disease Control and Prevention. Diagnostic standards and classication of tuberculosis in adults and children. Am J Respir Crit Care Med 2000;161:13761395. www.thoracic.org/adobe/statements/tbadult1-20.pdf. 2. Yuen APW, Wong SHW, Tam CM, Chan SL, Wei WI, Lau SK. Prospective randomized study of the thrice weekly six-month and nine-month chemotherapy for cervical tuberculous lymphadenopathy. Otolaryngol Head Neck Surg 1997;116:189192. 3. British Thoracic Society Research Committee. Six-months versus ninemonths chemotherapy for tuberculosis of lymph nodes: preliminary results. Respir Med 1992;86:1519. 4. Jawahar MS, Sivasubramanian S, Vijayan VK, Ramakrishnan CV, Paramasivan CN, Selvakumar V, Paul S. Short course chemotherapy for tuberculous lymphadenitis in children. BMJ 1990;301:359362. 5. Campbell IA, Ormerod LP, Friend PA, Jenkins R, Prescott J. Six months versus nine months chemotherapy for tuberculosis of lymph nodes: nal results. Respir Med 1993;87:621623. 6. Cheung WL, Siu KF, Ng A. Six-month combination chemotherapy for cervical tuberculous lymphadenitis. J R Coll Surg Edinb 1992;35:293 295. 7. Wyser C, Walzl G, Smedema JP, Swart F, van Schalkwyk M, van de Wal BW. Corticosteroids in the treatment of tuberculous pleurisy: a doubleblind, placebo-controlled, randomized study. Chest 1996;110:333338. 8. Strang JI, Kakaza HH, Gibson DG, Girling DJ, Nunn AJ, Fox W. Controlled trial of prednisolone as adjuvant in treatment of tuberculous constrictive pericarditis in Transkei. Lancet 1987;2:14181422. 9. Strang JI, Kakaza HH, Gibson DG, Allen BW, Mitchison DA, Evans DJ, Girling DJ, Nunn AJ, Fox W. Controlled clinical trial of complete open surgical drainage and of prednisolone in treatment of tuberculous pericardial effusion in Transkei. Lancet 1988;2:759764. 10. Donald PR, Schoeman JF, Van Zyl LE, De Villiers JN, Pretorius M, Springer P. Intensive short course chemotherapy in the management of tuberculous meningitis. Int J Tuberc Lung Dis 1998;2:704711. 11. Rajeswari R, Balasubramanian R, Venkatesan P, Sivasubramanian S, Soundarapandian S, Shanmugasundaram TK, Prabhakar R. Shortcourse chemotherapy in the treatment of Potts paraplegia: report on ve year follow-up. Int J Tuberc Lung Dis 1997;1:152158. 12. Dutt KA. Short-course chemotherapy for extrapulmonary tuberculosis: nine years experience. Ann Intern Med 1986;401:712. 13. Medical Research Council Working Party on Tuberculosis of the Spine. Five-year assessment of controlled trials of short-course chemotherapy regimens of 6, 9 or 18 months duration for spinal tuberculosis in patients ambulatory from the start or undergoing radical surgery. Int Orthop 1999;23:7381. 14. Medical Research Council Working Party on Tuberculosis of the Spine.
15.
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26. 27.
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31. 32.
33. 34.
35.
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37. 38.
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41. Voljavec BF, Corpe RF. The inuence of corticosteriod hormones in the treatment of tuberculous meningitis in Negroes. Am Rev Respir Dis 1960;81:539545. 42. Carl P, Stark L. Indications for surgical management of genitourinary tuberculosis. World J Surg 1997;21:505510. 43. Skutil V, Varsa J, Obsitnik M. Six-month chemotherapy for urogenital tuberculosis. Eur Urol 1985;11:170176. 44. Gow JG. Genitourinary tuberculosis: a study of the disease in one unit over a period of 24 years. Ann R Coll Surg Engl 1971;49:5070. 45. Christensen WI. Genitourinary tuberculosis: review of 102 cases. Medicine (Baltimore) 1974;53:377390. 46. Simon HB, Weinstein AJ, Pasternak MS, Swartz MN, Kunz LJ. Genitourinary tuberculosis: clinical features in a general hospital population. Am J Med 1977;63:410420. 47. Bastani B, Shariatzadeh MR, Dehdashti F. Tuberculous peritonitis: report of 30 cases and review of the literature. Q J Med 1985;56:549557. 48. Demir K, Okten A, Kaymakoglu S, Dincer D, Besisik F, Cevikbas U, Ozdil S, Bostas G, Mungan Z, Cakaloglu Y. Tuberculous peritonitis: reports of 26 cases, detailing diagnostic and therapeutic problems. Eur J Gastroenterol Hepatol 2001;13:581585. 49. Singh MM, Bhargava AN, Jain KP. Tuberculous peritonitis: an evaluation of pathogenetic mechanisms, diagnostic procedures and therapeutic measures. N Engl J Med 1969;281:10911094.
negative cultures. There are several potential explanations for this occurrence, including the possibilities that the acid-fast organisms are nontuberculous and difcult to culture, that they are nonviable tubercle bacilli, and that they are the result of laboratory error. The approach taken in such cases should be individualized, on the basis of clinical and radiographic ndings. If suspicion of tuberculosis is high and the patient has positive AFB smears, even with negative cultures, he/she should be treated as if the culture is positive, using one of the recommended regimens.
References
1. Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2000. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, August 2001. www.cdc.gov/nchstp/tb/ 2. Dutt AK, Moers D, Stead WW. Smear- and culture-negative pulmonary tuberculosis: four-month short-course chemotherapy. Am Rev Respir Dis 1989;139:867870.
8.4. Culture-negative Pulmonary Tuberculosis in Adults
8.5. Radiographic Evidence of Prior Tuberculosis: Inactive Tuberculosis
Failure to isolate M. tuberculosis from appropriately collected specimens in persons who, because of clinical or radiographic ndings, are suspected of having pulmonary tuberculosis does not exclude a diagnosis of active tuberculosis. For the United States as a whole, about 17% of the reported new cases of pulmonary tuberculosis have negative cultures (1). Low bacillary populations, temporal variations in the number of bacilli being expelled, and errors in specimen processing all may result in failure to isolate organisms from patients who have active tuberculosis. It should be emphasized that alternative diagnoses must be considered carefully and appropriate diagnostic studies undertaken in patients who have what appears to be culture-negative tuberculosis. At a minimum, patients suspected of having pulmonary tuberculosis should have three sputum specimens (using sputum induction with hypertonic saline if necessary) for AFB smears and cultures for mycobacteria as part of the diagnostic evaluation. Depending on the clinical features and differential diagnosis, other diagnostic testing, such as bronchoscopy with bronchoalveolar lavage and biopsy, should be considered before making a presumptive diagnosis of culture-negative tuberculosis. Patients who, on the basis of careful clinical and radiographic evaluation, are thought to have pulmonary tuberculosis should have treatment initiated with INH, RIF, PZA, and EMB even when the initial sputum smears are negative. If M. tuberculosis is isolated in culture, treatment for active disease should be continued. Patients who have negative cultures but who still are presumed to have pulmonary tuberculosis should have a thorough follow-up clinical and radiographic evaluation at the time 2 months of therapy has been completed to determine whether there has been a response that can be attributed to antituberculosis treatment. If there is either clinical or radiographic improvement and no other etiology is identied, treatment should be continued for active tuberculosis. A 4-month, INH and RIF regimen for culture-negative tuberculosis has been demonstrated to be successful with only 1.2% relapses during an average follow-up of 44 months (2). However, because the results of cultures may not be known for 38 weeks and because of the possibility of drug resistance, initiation of two-drug therapy with INH and RIF alone is not recommended, but the continuation phase can be shortened to 2 months using INH and RIF (Figure 2). On occasion, patients who are being evaluated for pulmonary tuberculosis will be found to have positive AFB smears but
Persons with a positive tuberculin PPD skin test who have radiographic ndings consistent with prior pulmonary tuberculosis (ATS/CDC Class 4) (1) and who have not been treated are at increased risk for the subsequent development of active tuberculosis (24). The radiographic ndings that constitute evidence of prior tuberculosis are apical bronodular inltrations, often with volume loss. Case rates among such persons in one study were about 2.5 times those of persons infected with M. tuberculosis who did not have chest radiographic abnormalities (2). Persons with radiographic ndings of healed primary tuberculosis (e.g., calcied solitary pulmonary nodules, calcied hilar lymph nodes, and pleural thickening) are not at increased risk for tuberculosis compared with other persons with latent tuberculosis infection. Patients should not be classied as having radiographic evidence of prior tuberculosis if another disease is found to account for the radiographic ndings. The activity of tuberculosis cannot be determined from a single chest radiograph, and unless there are previous radiographs showing that the abnormality has not changed, it is recommended that sputum examination, using sputum induction if necessary, be performed to assess the possibility of active tuberculosis. Once active tuberculosis has been excluded by sputum culture, these persons are high-priority candidates for treatment of latent tuberculosis infection (5). The optimum treatment for patients with latent tuberculosis infection and abnormal chest radiographs consistent with prior tuberculosis has been examined in several studies. A placebocontrolled trial conducted by the IUATLD (2) compared the efcacy of 3, 6, and 12 months of INH in preventing active tuberculosis for persons with latent tuberculosis infection who had chest radiographs showing brotic lesions consistent with inactive tuberculosis. Among those receiving INH for at least 6 months, the incidence of tuberculosis was signicantly reduced compared with those given placebo. In patients with brotic lesions greater than 2 cm in diameter INH given for 12 months was signicantly better than 6 months (89 versus 67% reduction). A reanalysis of data from a community-based study of persons with abnormal radiographs felt to represent inactive tuberculosis showed that the efcacy of INH decreased signicantly if less than 9 months of the drug was taken, but that further protection was not conferred if the duration was extended from 9 to 12 months (6). On the basis of these data, guidelines for treatment of latent tuberculosis infection recommend 9 months of INH for persons with abnormal chest radiographs consistent with prior
American Thoracic Society Documents TABLE 14. SUMMARY OF EVIDENCE* FOR TREATMENT OF PERSONS WITH RADIOGRAPHIC EVIDENCE OF PRIOR TUBERCULOSIS AND NEGATIVE SPUTUM CULTURES NOT TREATED PREVIOUSLY
Rating/Evidence Treatment Regimen INH for 9 mo RIF with or without INH for 4 mo RIF and PZA for 2 mo Definition of abbreviations: INH isoniazid; PZA * For rating system, see Table 1. HIV Negative AII BII CIII pyrazinamide; RIF HIV Positive AII BIII BI rifampin.
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CDC recommendations. MMWR Morb Mortal Wkly Rep 2001;50:733 735. www.cdc.gov/nchstp/tb/ 9. Jasmer RM, Saukkonen JJ, Blumberg HM, Daley CL, Bernardo J, Vittinghoff E, King MD, Kawamura LM, Hopewell PC. Short course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial. Ann Intern Med 2002;137:640647.
8.6. Pregnancy and Breastfeeding
tuberculosis (5). Additional treatment regimens are RIF (with or without INH) for 4 months, and RIF and PZA for 2 months (for persons who are unlikely to complete a longer course and who can be monitored carefully) (5) (Table 14). A study comparing the cost-effectiveness of INH and RIF with INH alone in treating this category of patient showed that 4 months of INH and RIF was cost saving compared with INH alone, and the cost savings increased as the prevalence of infection with strains resistant to INH increased (7). Instances of severe and fatal liver disease have been reported in patients taking RIF and PZA for treatment of latent tuberculosis infection (8). In addition, the frequency of hepatotoxicity has been shown to be greater with RIFPZA than with INH alone (7.7% Grade 3 or 4 hepatotoxicity with RIFPZA compared with 1% for INH; p 0.001) (9). In view of these data, the regimen should be used with caution and with careful monitoring, measuring serum AST and bilirubin at baseline and after 2, 4, and 6 weeks of treatment. RIFPZA is not recommended for patients with underlying liver disease or a history of alcoholism, or for those who have had hepatotoxicity from INH. The regimen should be reserved for patients who are not likely to complete a longer course of treatment and who can be monitored carefully.
References
1. American Thoracic Society, Centers for Disease Control and Prevention. Diagnostic standards and classication of tuberculosis in adults and children. Am J Respir Crit Care Med 2000;161:13761395. www.cdc. gov/nchstp/tb/ 2. International Union Against Tuberculosis Committee on Prophylaxis. The efcacy of varying durations of isoniazid preventive therapy for tuberculosis: ve years of follow-up in the IUAT Trial. Bull World Health Organ 1982;60:555564. 3. Grzybowski S, Fishaut H, Rowe J, Brown A. Tuberculosis among patients with various radiologic abnormalities, followed by chest clinic service. Am Rev Respir Dis 1972;104:605608. 4. Comstock GW, Woolpert SF. Preventive treatment of untreated, nonactive tuberculosis in an Eskimo population. Arch Environ Health 1972;25:333337. 5. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221S247. www.cdc.gov/ nchstp/tb/ 6. Comstock GW. How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults? Int J Tuberc Lung Dis 1999;3: 847850. 7. Jasmer RM, Snyder DC, Chin DP, Hopewell PC, Cuthbert SC, Paz EA, Daley CL. Twelve months of isoniazid compared with four months of isoniazid and rifampin for persons with radiographic evidence of previous tuberculosis: an outcome and cost-effectiveness analysis. Am J Respir Crit Care Med 2000;162:16481652. 8. Centers for Disease Control and Prevention. Update: fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/
Untreated tuberculosis represents a far greater hazard to a pregnant woman and her fetus than does treatment of the disease. Infants born to women with untreated tuberculosis may be of lower birth weight than those born to women without tuberculosis and, rarely, the infant may acquire congenital tuberculosis (13). Thus, treatment of a pregnant woman with suspected tuberculosis should be started if the probability of tuberculosis is moderate to high. The initial treatment regimen should consist of INH, RIF, and EMB. SM should not be substituted for EMB. Although PZA is recommended for routine use in pregnant women by the WHO (4) and the IUATLD (5), the drug has not been recommended for general use in pregnant women in the United States because of insufcient data to determine safety. However, some public health jurisdictions in the United States have used PZA in pregnant women without reported adverse events (1). If PZA is not included in the initial treatment regimen, the minimum duration of therapy is 9 months. Pyridoxine, 25 mg/day, should be given to pregnant women who are receiving INH. INH, RIF, and EMB cross the placenta, but none has been shown to have teratogenic effects (6). SM, the only antituberculosis drug documented to have harmful effects on the human fetus, interferes with development of the ear and may cause congenital deafness. In 40 pregnancies among women being treated with SM, 17% of the babies had eighth nerve damage with decits ranging from mild hearing loss to bilateral deafness (6, 7). Kanamycin, amikacin, and capreomycin presumably share this toxic potential; however, there is little specic information on the fetal effects of these three drugs. PAS was used commonly with INH in the past and there was no indication of teratogenicity among babies whose mothers had received these two drugs (2). There are not enough data to determine the risk of cycloserine or ethionamide, although one report described nonspecic teratogenic effects attributed to ethionamide (8). The uoroquinolones have been associated with arthropathies in young animals; therefore, they should be avoided if possible in pregnant women (6). In general, administration of antituberculosis drugs is not an indication for termination of pregnancy (2). However, in women who are being treated for drug-resistant tuberculosis, counseling concerning the risk to the fetus should be provided because of the known and unknown risks of the second-line agents. Breastfeeding should not be discouraged for women being treated with rst-line agents, because the small concentrations of these drugs in breast milk do not produce toxic effects in the nursing infant (9). Conversely, drugs in breast milk should not be considered to serve as effective treatment for active tuberculosis or latent tuberculosis infection in a nursing infant. Supplementary pyridoxine is recommended both for the nursing mother and her infant even if the infant is not receiving INH. The administration of the uoroquinolones during breastfeeding is not recommended, although, as of 1998, there have been no reported cases of adverse reactions in infants breast fed by women taking these drugs (6).
References
1. Davidson PT. Managing tuberculosis during pregnancy. Lancet 1995;346: 199200. 2. Snider DE, Layde PM, Johnson MW, Lyle MA. Treatment of tuberculosis during pregnancy. Am Rev Respir Dis 1980;122:6579.
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3. Jana N, Vasishta K, Jindal SK, Khunnu B, Ghosh K. Perinatal outcome in pregnancies complicated by pulmonary tuberculosis. Int J Gynaecol Obstet 1994;44:119124. 4. World Health Organization. Treatment of tuberculosis: guidelines for national programmes, 2nd edition. WHO/TB/97.220. Geneva, Switzerland: World Health Organization; 1997. www.who.int/gtb/publications/ ttgnp/PDF/tb97_220.pdf 5. Enarson DA, Rieder HL, Arnodottir T, Trebucq A. Tuberculosis guide for low income countries, 4th edition. Paris: International Union against Tuberculosis and Lung Diseases; 1996. 6. Briggs GG, Freeman RK, Yaffe SJ, editors. Drugs in pregnancy and lactation, 5th edition. Baltimore, MD: Williams & Wilkins; 1998. 7. Varpela E, Hietalalahti J, Aro M. Streptomycin and dihidrostreptomycin during pregnancy and their effect on the childs inner ear. Scand J Respir Dis 1969;50:101109. 8. Potworowska M, Sianozecko E, Szuodowica R. Ethionamide treatment and pregnancy. Pol Med J 1966;5:11531158. 9. Snider DE, Powell KE. Should women taking antituberculosis drugs breast-feed? Arch Intern Med 1984;144:589590.
8.7. Renal Insufficiency and End-stage Renal Disease
Renal insufciency complicates the management of tuberculosis because some antituberculosis medications are cleared by the kidneys. Management may be further complicated by the removal of some antituberculosis agents via hemodialysis. Thus, some alteration in dosing antituberculosis medications is commonly necessary in patients with renal insufciency and endstage renal disease (ESRD) receiving hemodialysis (Table 15). Decreasing the dose of selected antituberculosis drugs may not be the best method of treating tuberculosis because, although toxicity may be avoided, the peak serum concentrations may be too low. Therefore, instead of decreasing the dose of the antituberculosis agent, increasing the dosing interval is recommended (1). The general approach described in Table 15 involves either estimating or measuring creatinine clearance. Administration of drugs that are cleared by the kidneys to patients having a creatinine clearance of less than 30 ml/minute and those receiving hemodialysis are managed in the same manner, with an increase in dosing interval (C. Peloquin, personal communication). There are insufcient data to guide dosing recommendations for patients having a reduced creatinine clearance but not less than 30 ml/minute. In such patients standard doses should
be used, but measurement of serum concentrations should be considered to avoid toxicity. RIF and INH are metabolized by the liver, so conventional dosing may be used in the setting of renal insufciency (15). PZA is also metabolized by the liver but its metabolites (pyrazinoic acid and 5-hydroxy-pyrazinoic acid) may accumulate in patients with renal insufciency (3, 6). EMB is about 80% cleared by the kidneys and may accumulate in patients with renal insufciency (7). A longer interval between doses with three times a week administration is recommended for PZA and EMB (3, 7). INH, EMB, and PZA (as well as its metabolites) are cleared by hemodialysis to some degree, but only PZA and presumably its metabolites are dialyzed to a signicant degree (3). RIF is not cleared by hemodialysis because of its high molecular weight, wide distribution into tissues, high degree of protein binding, and rapid hepatic metabolism (3). Therefore, supplemental dosing is not necessary for INH, RIF, or EMB. If PZA is given after hemodialysis, supplemental dosing is not required. In general, antituberculosis drugs should be given after hemodialysis to avoid any loss of the drugs during hemodialysis, and to facilitate DOT. Doses of streptomycin, kanamycin, amikacin, and capreomycin must be adjusted in patients with renal failure because the kidneys excrete essentially all of these drugs. Approximately 40% of the dose is removed with hemodialysis when these drugs are given just before hemodialysis (8). Far less drug is likely to be removed once the drugs have had time to distribute throughout the body, and some accumulation of the drugs should be anticipated. As with EMB and PZA, the dosing interval should be increased. In general, the dose should not be reduced because the drugs exhibit concentration-dependent bactericidal action (9), and smaller doses may reduce drug efcacy. Ethionamide is not cleared by the kidneys, nor is the drug removed with hemodialysis, so no dose adjustment is necessary (10). PAS is modestly cleared by hemodialysis (6.3%) but its metabolite, acetyl-PAS, is substantially removed by hemodialysis; twice daily dosing (4 g) should be adequate if the granule formulation is used (Jacobus Pharmaceuticals) (10). Cycloserine is excreted primarily by the kidney, and is cleared by hemodialysis (56%). Thus, an increase in the dosing interval is necessary to avoid
TABLE 15. DOSING RECOMMENDATIONS FOR ADULT PATIENTS WITH REDUCED RENAL FUNCTION AND FOR ADULT PATIENTS RECEIVING HEMODIALYSIS
Drug Isoniazid Rifampin Pyrazinamide Ethambutol Levofloxacin Cycloserine Ethionamide p-Aminosalicylic acid Streptomycin Capreomycin Kanamycin Amikacin Change in Frequency? No change No change Yes Yes Yes Yes No change No change Yes Yes Yes Yes Recommended Dose and Frequency for Patients with Creatinine Clearance 30 ml/min or for Patients Receiving Hemodialysis 300 mg once daily, or 900 mg three times per week 600 mg once daily, or 600 mg three times per week 2535 mg/kg per dose three times per week (not daily) 1525 mg/kg per dose three times per week (not daily) 7501,000 mg per dose three times per week (not daily) 250 mg once daily, or 500 mg/dose three times per week* 250500 mg/dose daily 4 g/dose, twice daily 1215 mg/kg/dose two or three times per week (not daily) 1215 mg/kg/dose two or three times per week (not daily) 1215 mg/kg/dose two or three times per week (not daily) 1215 mg/kg/dose two or three times per week (not daily)
Standard doses are given unless there is intolerance. The medications should be given after hemodialysis on the day of hemodialysis. Monitoring of serum drug concentrations should be considered to ensure adequate drug absorption, without excessive accumulation, and to assist in avoiding toxicity. Data currently are not available for patients receiving peritoneal dialysis. Until data become available, begin with doses recommended for patients receiving hemodialysis and verify adequacy of dosing, using serum concentration monitoring. * The appropriateness of 250-mg daily doses has not been established. There should be careful monitoring for evidence of neurotoxicity (see Section 3).
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accumulation between hemodialysis sessions, and the drug should be given after hemodialysis to avoid underdosing (10). The uoroquinolones undergo some degree of renal clearance that varies from drug to drug. For example, levooxacin undergoes greater renal clearance than moxioxacin (11). It should be noted that the uoroquinolone dosing recommendations for end-stage renal disease provided by the manufacturers were developed for treating pyogenic bacterial infections. These recommendations may not be applicable to the treatment of tuberculosis in patients with end-stage renal disease. As noted above, administration of all antituberculosis drugs immediately after hemodialysis will facilitate DOT (three times per week) and avoid premature removal of the drugs (2). It is important to monitor serum drug concentrations in persons with renal insufciency who are taking cycloserine, EMB, or any of the injectable agents to minimize dose-related toxicity, while providing effective doses. Clinicians also should be aware that patients with end-stage renal disease may have additional clinical conditions, such as diabetes mellitus with gastroparesis, that may affect the absorption of the antituberculosis drugs, or they may be taking concurrent medications that interact with these drugs. Under these circumstances a careful clinical and pharmacologic assessment is necessary, and, in selected cases, serum drug concentration measurements may be used to assist in determining the optimum dose of the antituberculosis drugs (9). Finally, data currently do not exist for patients receiving peritoneal dialysis. Because the drug removal mechanisms differ between hemodialysis and peritoneal dialysis, it cannot be assumed that all of the recommendations in Table 15 will apply to peritoneal dialysis. Such patients may require close monitoring, including measurements of the serum concentrations of the antituberculosis drugs.
References
1. Peloquin CA. Antituberculosis drugs: pharmacokinetics. In: Heifets L, editor. Drug susceptibility in the chemotherapy of mycobacterial infections. Boca Raton, FL: CRC Press; 1991. p 5988. 2. Ellard GA. Chemotherapy of tuberculosis for patients with renal impairment. Nephron 1993;64:169181. 3. Malone RS, Fish DN, Spiegel DM, Childs JM, Peloquin CA. The effect of hemodialysis on isoniazid, rifampin, pyrazinamide, and ethambutol. Am J Respir Crit Care Med 1999;159:15801584. 4. Bowersox DW, Winterbauer RH, Stewart GL, Orme B, Barron E. Isoniazid dosage in patients with renal failure. N Engl J Med 1973;289:8487. 5. Acocella G. Clinical pharmacokinetics of rifampicin. Clin Pharmacol 1978;13:108127. 6. Ellard GA. Absorption, metabolism, and excretion of pyrazinamide in man. Tubercle 1969;50:144158. 7. Strauss I, Erhardt F. Ethambutol absorption, excretion and dosage in patients with renal tuberculosis. Chemotherapy 1970;15:148157. 8. Matzke GR, Halstenson CE, Keane WF. Hemodialysis elimination rates and clearance of gentamicin and tobramycin. Antimicrob Agents Chemother 1984;25:128130. 9. Peloquin CA. Using therapeutic drug monitoring to dose the antimycobacterial drugs. Clin Chest Med 1997;18:7987. 10. Malone RS, Fish DN, Spiegel DM, Childs JM, Peloquin CA. The effect of hemodialysis on cycloserine, ethionamide, para-aminosalicylate, and clofazimine. Chest 1999;116:984990. 11. Fish DN, Chow AT. The clinical pharmacokinetics of levooxacin. Clin Pharmacokinet 1997;32:101119.
clinicians may consider regimens with fewer potentially hepatotoxic agents in patients with advanced or unstable liver disease, and expert consultation is advisable in treating such patients. It should be noted that tuberculosis itself may involve the liver, causing abnormal liver function; thus, not all abnormalities in liver function tests noted at baseline should be attributed to causes other than tuberculosis. The hepatic abnormalities caused by tuberculosis will improve with effective treatment. Possible treatment regimens in the setting of liver disease include the following. 8.8.1. Treatment without INH. As described in Section 5.2 (Alternative Regimens), analysis of data from several studies conducted by the BMRC in patients with smear-positive pulmonary tuberculosis demonstrated high levels of efcacy with 6month regimens despite in vitro resistance to INH so long as the initial phase contained four drugs and RIF was used throughout the 6 months (1). Subsequent studies by the Hong Kong Chest Service and the BMRC suggested that results were improved when PZA was used throughout the 6 months (2). Thus, it is reasonable to employ an initial phase regimen of RIF, PZA, and EMB followed by a continuation phase of RIF, EMB, and PZA (Rating BII). Although this regimen has two potentially hepatotoxic medications, it has the advantage of retaining the 6-month duration. 8.8.2. Treatment without PZA. Although the frequency of PZA-induced hepatitis is slightly less than occurs with INH or RIF, the liver injury induced by this drug may be severe and prolonged (3). Therefore, one might elect to employ a regimen with an initial phase of INH, RIF, and EMB for 2 months followed by a continuation phase of INH and RIF for 7 months, for a total of 9 months (Table 2, Regimen 4). 8.8.3. Regimens with only one potentially hepatotoxic drug. For patients with advanced liver disease, a regimen with only one potential hepatotoxic drug might be selected. Generally, RIF should be retained. Additional agents in such regimens could include EMB, a uoroquinolone, cycloserine, and injectable agents. The duration of treatment with such regimens should be 1218 months, depending on the extent of the disease and the response (Rating CIII). Consultation is advised in such situations. 8.8.4. Regimens with no potentially hepatotoxic drugs. In the setting of severe unstable liver disease, a regimen with no hepatotoxic agents might be necessary. Such a regimen might include SM, EMB, a uoroquinolone, and another second-line oral drug. There are no data that provide guidance as to the choice of agents or the duration of treatment or that indicate the effectiveness of such a regimen. Expert opinion suggests that a regimen of this sort should be given for 1824 months (Rating CIII). Consultation should always be obtained before embarking on such a treatment plan.
References
1. Mitchison DA, Nunn AJ. Inuence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1986;133:423430. 2. Hong Kong Chest Service, British Medical Research Council. Five-year follow-up of a controlled trial of ve 6-month regimens of chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis 1987;136:13391342. 3. United States Public Health Service. Hepatic toxicity of pyrazinamide used with isoniazid in tuberculous patients. United States Public Health Service Tuberculosis Therapy Trial. Am Rev Respir Dis 1959;80:371 387.
8.8. Hepatic Disease
The treatment of tuberculosis in patients with unstable or advanced liver disease is problematic for several reasons. First, the likelihood of drug-induced hepatitis may be greater. Second, the implications of drug-induced hepatitis for patients with marginal hepatic reserve are potentially serious, even life-threatening. Finally, uctuations in the biochemical indicators of liver function (with/without symptoms) related to the preexisting liver disease confound monitoring for drug-induced hepatitis. Thus,
8.9. Other Associated Disorders
Tuberculosis commonly occurs in association with other diseases or conditions. An associated disorder may alter immune responsiveness, thereby causing a predisposition to tuberculosis, or sim-
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ply may be a disorder that occurs frequently in the same social and cultural milieu as tuberculosis. Examples of the former class of disorders include HIV infection, hematologic or reticuloendothelial malignancies, immunosuppressive therapy, chronic renal failure, poorly controlled, insulin-dependent diabetes mellitus, and malnutrition. Silicosis, by impairing pulmonary macrophage function, is a unique example of local immune dysfunction. The latter group of disorders includes chronic alcoholism and its secondary effects, other substance abuse, and psychiatric illnesses, among others. All of these conditions may inuence the organization, supervision, and outcome of therapy (discussed in Section 2: Organization and Supervision of Treatment). The response of immunocompromised patients to treatment may not be as good as would be expected in a person with normal immunity, although in patients with HIV infection the response to treatment is not impaired Nevertheless, therapeutic decisions for the immunocompromised host should be more individualized, taking into account the severity of tuberculosis and the response to treatment. When possible, steps should be taken to correct the immune deciency. In patients with silicotuberculosis there are data demonstrating that the rate of cure is improved if the continuation phase is extended for at least 2 months (1, 2).
References
1. Hong Kong Chest Service, Tuberculosis Research Centre, Madras/British Medical Research Council. A control trial of 6 and 8 months of antituberculosis chemotherapy in the treatment of patients with silicotuberculosis in Hong Kong. Am Rev Respir Dis 1991;143:262267. 2. Lin T-P, Suo J, Lee C-N, Lee J-J, Yang S-P. Short course chemotherapy of pulmonary tuberculosis in pneumoconiotic patients. Am Rev Respir Dis 1987;136:808810.
9. MANAGEMENT OF RELAPSE, TREATMENT FAILURE, AND DRUG RESISTANCE

9.1. Relapse
MICROBIOLOGICAL CONFIRMATION OF RELAPSE SHOULD BE PURSUED VIGOROUSLY Relapses may occur with either drug-resistant or drug-susceptible strains of M. tuberculosis. To conrm that a true relapse has occurred and to obtain drug susceptibility tests, microbiological conrmation of relapse should be pursued vigorously.
However, in patients who received self-administered therapy or a nonrifamycin regimen and who have a relapse, the risk of acquired drug resistance is substantial. In addition, if initial drug susceptibility testing was not performed and the patient fails or relapses with a rifamycin-containing regimen given by DOT, there is a high likelihood that the organisms were resistant from the outset. Among patients who received self-administered therapy, the risk of erratic drug administration leading to relapse with resistant organisms is greater. In view of these considerations, the selection of empirical treatment regimens for patients with relapses should be based on the prior treatment scheme. For patients with tuberculosis that was caused by drug-susceptible organisms, who were treated by DOT, and who have relapses, retreatment using the standard four-drug initial phase regimen may be appropriate, at least until the results of susceptibility tests are known. For patients who did not receive DOT or are known to have had irregular treatment in the past, it is prudent to infer a higher risk of acquired drug resistance and begin an expanded regimen (see below). The expanded regimen is indicated especially in patients with impaired immunity, limited respiratory reserve, central nervous system involvement, or other life-threatening circumstances, that is, cases in which treatment with an inadequate regimen could have severe consequences. For the relatively few patients in whom epidemiologic circumstances provide a strong suspicion of exogenous reinfection as the cause of apparent relapse, the choice of a regimen is inuenced by the drug susceptibility pattern of the presumed source case. If the presumed source case is known to have tuberculosis caused by drug-susceptible organisms, resumption of a standard four-drug initial phase may be indicated. However, if the likely source case is known to have drug-resistant organisms, an empirically expanded regimen based on the resistance prole of the putative source case may be suitable. There are no clinical trials to guide the choice of agents to include in expanded empirical regimens for presumed drug resistance; however, expert opinion indicates that such regimens should generally employ INH, RIF, and PZA plus an additional three agents, based on the probability of in vitro susceptibility. Usual agents would include EMB, a uoroquinolone, and an injectable agent such as SM (if not used previously, and the initial isolate was susceptible) amikacin, kanamycin or capreomycin, with or without other drugs.
9.2. Treatment Failure
Relapse refers to the circumstance in which a patient becomes and remains culture-negative while receiving antituberculosis drugs but, at some point after completion of therapy, either becomes culture-positive again or experiences clinical or radiographic deterioration consistent with active tuberculosis. In such patients vigorous efforts should be made to establish a diagnosis and to obtain microbiological conrmation of the relapse to enable testing for drug resistance. True relapses are due to failure of chemotherapy to sterilize the host tissues, thereby enabling endogenous recrudescence of the original infection. In some hyperendemic settings, however, exogenous reinfection with a new strain of M. tuberculosis may be responsible for the apparent relapse (1). Patients who are most likely to have true relapses are those with extensive tuberculosis whose sputum cultures remain positive after 2 months of chemotherapy (24). Most patients relapse within the rst 612 months after completion of therapy. In nearly all patients with tuberculosis caused by drug-susceptible organisms who were treated with rifamycin-containing regimens using DOT, relapses occur with susceptible organisms (5, 6).
NEVER ADD A SINGLE DRUG TO A FAILING REGIMEN Treatment failure is dened by continued or recurrent positive cultures after 4 months of treatment in patients in whom medication ingestion was assured. Patients with treatment failure should be assumed, until proven otherwise, to have drug-resistant organisms and be treated with multiple agents that they have not received before. A single drug should never be added to a failing regimen. So doing risks development of resistance to the new drug, further complicating management.
Treatment failure is dened as continued or recurrently positive cultures in a patient receiving appropriate chemotherapy. Among patients with drug-susceptible pulmonary tuberculosis, even with extensive lung cavitation, 9095% will be culturenegative after 3 months of treatment with a regimen that contains INH and RIF. During this time the vast majority of patients show clinical improvement, including defervescence, reduced
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cough, and weight gain. Thus, patients with persistently positive cultures after 3 months of chemotherapy, with or without ongoing symptoms, should be evaluated carefully to attempt to identify the cause of the delayed response. Patients whose sputum cultures remain positive after 4 months of treatment are considered to have failed treatment. There are multiple potential reasons for treatment failure. If the patient is not receiving DOT, the most likely explanation for persistently positive cultures is nonadherence to the drug regimen. Among patients receiving DOT, cryptic nonadherence (spitting out or deliberately regurgitating pills) or failure of the health care system to reliably deliver the drugs may be the cause. Other potential reasons include unrecognized drug resistance (Was initial drug-susceptibility testing done? Was it reported accurately?), malabsorption (prior resectional surgery of the stomach or small intestine, taking tuberculosis medication with antacids or other drugs/substances that might bind or interfere with drug absorption (see Section 6.1: Drug Administration and Section 7.1: Interactions Affecting Antituberculosis Drugs), or simply an extreme biologic variation (For unclear reasons, rare normal patients may experience very protracted disease including persistently positive cultures or prolonged symptoms in the face of chemotherapy that would be expected to be effective). Laboratory error should also be considered as a possible reason for a positive culture in a patient who is doing well. Recent reports document cross contamination or mislabeling of specimens as a source for some of these unexpectedly positive cultures (7, 8). Clinicians should be alert, as well, to the possibility of transient clinical or radiographic worsening (paradoxical reactions), despite appropriate therapy that would eventually result in cure. Examples of this include ongoing inammation at sites of lymphadenitis, worsened abnormalities on chest radiographs after several months of treatment, or the new appearance of pleural effusions during therapy for pulmonary tuberculosis (911). Such paradoxical worsening during treatment occurs more commonly but not exclusively in persons with HIV infection (1214) (see Section 8.1: HIV Infection). For patients who meet criteria for treatment failure, the possible reasons listed above should be addressed promptly. If clinicians are not familiar with the management of drug-resistant tuberculosis, prompt referral to, or consultation with a specialty center is indicated. If treatment failure is presumed to be due to drug resistance and the patient does not have severe tuberculosis, one may either initiate an empirical retreatment regimen or wait for drug susceptibility results from a recent isolate. If the patient is seriously ill or has a positive sputum AFB smear, an empirical regimen that would be anticipated to be effective should be started immediately and continued until susceptibility tests are available to guide therapy. For patients who have failed treatment, mycobacterial isolates should be sent promptly to a reference laboratory for susceptibility testing for both rst- and second-line drugs. A fundamental principle in managing patients who have failed treatment is that a single new drug should never be added to a failing regimen; so doing may lead to acquired resistance to the added drug. In such cases, it is generally prudent to add at least three new drugs to which susceptibility could logically be inferred to lessen the probability of further acquired resistance. As noted previously there are no clinical trials to guide the choice of an empirical regimen; however, expert opinion indicates that empirical retreatment regimens might include a uoroquinolone such as levooxacin, an injectable agent such as SM (if not used previously and the isolate was susceptible initially), amikacin, kanamycin, or capreomycin, and an oral agent such as PAS, cycloserine, or ethionamide (Rating AIII).
When drug susceptibility results are available, the regimen should be adjusted according to the results.
9.3. Management of Tuberculosis Caused by Drug-resistant Organisms
REQUEST CONSULTATION Treatment of tuberculosis caused by drug-resistant organisms should be done by or in close consultation with an expert in the management of these difcult situations. Second-line regimens often represent the patients last best hope for being cured. Inappropriate management can, thus, have life-threatening consequences.
Tubercle bacilli are continually undergoing spontaneous mutations that create resistance to individual antituberculosis drugs. However, the frequency of these single mutations is sufciently low that with appropriate combination chemotherapy that is reliably ingested, clinically signicant resistance will not develop (see Section 4.1: Combination Chemotherapy) (15). Most commonly the development of acquired drug resistance occurs when there is a large bacillary population, such as in pulmonary cavities, when an inadequate drug regimen is prescribed (inappropriate drugs, insufcient dosage) or when there is a combined failure of both the patient and the provider to ensure that an adequate regimen is taken (16). Rarely, malabsorption of one or more antituberculosis drugs may account for acquired resistance. Drug resistance is much more likely to occur in cavitary pulmonary tuberculosis because of the immense number of rapidly multiplying bacilli in the cavity(ies) (17). During extended or repeated treatment, resistance to multiple agents may evolve. Patients with acquired drug resistance may transmit their strains to others who, if they develop tuberculosis, will have primary drug resistance. Drug resistance in a patient with newly diagnosed tuberculosis may be suspected on the basis of historical (previous treatment) or epidemiologic information (contact with a known drugresistant case or coming from a region in which drug resistance is common) (18, 19). In such situations it is prudent to employ an empirically expanded regimen, as described previously, especially if the patient is seriously ill (Table 16). Drug resistance can be proven only by drug-susceptibility testing performed in a competent laboratory (Table 17). The steps taken when resistance is shown to be present are of critical importance. Patients harboring strains of M. tuberculosis resistant to both INH and RIF (MDR) are at high risk for treatment failure and further acquired resistance; they must be referred immediately to a specialist or consultation obtained from specialized treatment centers. Patients with strains resistant to RIF alone have a better prognosis than MDR cases, but also are at increased risk for failure and additional resistance. Thus, their management should also be subject to special scrutiny. Denitive randomized or controlled studies have not been performed among patients with the various patterns of drug resistance. In the absence of ideal evidence, practices in the treatment of patients are based on a mixture of general principles, extrapolations and expert opinion. The WHO and IUATLD have formulated standard algorithmic regimens for the management of treatment failure or chronic cases, largely based on the principles listed below, as well as on expert opinion (20, 21). This approach is best suited to regions without in vitro susceptibility testing capacity and access to the full array of retreatment medications, but it is not appropriate for industrialized nations with more ample resources (22, 23). Guidelines for management of patients with tuberculosis
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TABLE 16. POTENTIAL REGIMENS FOR THE MANAGEMENT OF PATIENTS WITH DRUG-RESISTANT PULMONARY TUBERCULOSIS
Pattern of Drug Resistance INH ( SM) Suggested Regimen RIF, PZA, EMB (a FQN may strengthen the regimen for patients with extensive disease) Duration of Treatment (mo) 6 Comments In BMRC trials, 6-mo regimens have yielded 95% success rates despite resistance to INH if four drugs were used in the initial phase and RIF plus EMB or SM was used throughout.* Additional studies suggested that results were best if PZA was also used throughout the 6 mo (Rating BII). Fluoroquinolones were not employed in BMRC studies, but may strengthen the regimen for patients with more extensive disease (Rating BIII). INH should be stopped in cases of INH resistance (see text for additional discussion) In such cases, extended treatment is needed to lessen the risk of relapse. In cases with extensive disease, the use of an additional agent (alternative agents) may be prudent to lessen the risk of failure and additional acquired drug resistance. Resectional surgery may be appropriate (see text) Use of the first-line agents to which there is susceptibility. Add two or more alternative agents in case of extensive disease. Surgery should be considered (see text) Daily and three times weekly regimens of INH, PZA, and SM given for 9 mo were effective in a BMRC trial (Rating BI). However, extended use of an injectable agent may not be feasible. It is not known if EMB would be as effective as SM in these regimens. An all-oral regimen for 12 mo should be effective (Rating BIII). But for more extensive disease and/or to shorten duration, an injectable agent may be added in the initial 2 mo of therapy (Rating BIII)
INH and RIF (
SM)
FQN, PZA, EMB, IA, agent
alternative
1824
INH, RIF ( SM), and EMB or PZA RIF
FQN (EMB or PZA if active), IA, and two alternative agents INH, PZA, EMB (a FQN may strengthen the regimen for patients with more extensive disease)
24
912
Definition of abbreviations: BMRC British Medical Research Council; EMB ethambutol; FQN fluoroquinolone; IA injectable agent; INH isoniazid; PZA pyrazinamide; RIF rifampin; SM streptomycin. FQN Fluoroquinolone; most experience involves ofloxacin, levofloxacin, or ciprofloxacin. IA Injectable agent; may include aminoglycosides (streptomycin, amikacin, or kanamycin) or the polypeptide capreomycin. Alternative agents Ethionamide, cycloserine, p-aminosalicylic acid, clarithromycin, amoxicillin/clavulanate, linezolid. * Mitchison DA, Nunn AJ. Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1986;133:423430. Hong Kong Chest Service, British Medical Research Council. Five-year follow-up of a controlled trial of five, 6 month regimens of chemotherapy for tuberculosis. Am Rev Respir Dis 1987;136:13391342. Hong Kong Chest Service, British Medical Research Council. Controlled trial of 6-month and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. Am Rev Respir Dis 1977;115:727735.
TABLE 17. RECOMMENDED DRUG CONCENTRATIONS* FOR SUSCEPTIBILITY TESTING

Proportion Method Drug First-line drugs Isoniazid Isoniazid (high) Rifampin Ethambutol Pyrazinamide Second-line drugs Streptomycin Streptomycin (high) Ethambutol (high) Capreomycin Ethionamide Kanamycin# Ofloxacin p-Aminosalicylic acid Rifabutin** 7H10 agar 0.2 1.0 1.0 5.0 NR 2.0 10.0 10.0 10.0 5.0 5.0 2.0 2.0 0.5 7H11 agar 0.2 1.0 1.0 7.5 NR 2.0 10.0 10.0 10.0 10.0 6.0 2.0 8.0 0.5 Radiometric (BACTEC) 0.1 0.4 2.0 2.5 100.0 2.0 6.0 7.5 Broth-based Systems ESP Myco 0.1 0.4 1.0 5.0 MGIT 0.1 0.4 1.0 5.0 100.0 1.0 4.0 7.5 BacT/ALERT MB 0.09 0.4 0.9 2.3 200.0 0.9
Definition of abbreviations: ESP Myco ESP (Extra Sensing Power) Culture System II; BacT/ALERT MB BacT/ALERT MB susceptibility kit; MGIT mycobacterial growth indicator tube; NR not recommended. Adapted from the following: (1) Woods GL. Clin Infect Dis 2000;31:12091215; (2) National Committee for Clinical Laboratory Standards (NCCLS). Susceptibility testing of mycobacteria, Nocardia, and other aerobic actinomycetes, 2nd edition. Tentative standard M24-T2. Wayne, PA: National Committee for Clinical Laboratory Standards; 2000. www.nccls.org/microbiology.htm * Concentration in micrograms per milliliter. BacT/ALERT MB is not currently FDA approved for susceptibility tests. Critical concentration of the drug in this medium. Rifampin is the class agent for rifapentene. Isolates of M. tuberculosis that are resistant to rifampin or resistant to any two primary drugs should be tested for susceptibility to the secondary drugs. In addition, NCCLS recommends a higher concentration of ethambutol (i.e., 10 g/ml in both 7H10 and 7H11 agar) should be tested. # Kanamycin is the class agent for amkicacin. ** Some investigators also test a higher concentration (usually 1.0 or 2.0 g/ml) of rifabutin.
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caused by drug-resistant organisms are based on the following guidelines, all of which are rated A III: A single new drug should never be added to a failing regimen. When initiating or revising therapy, always attempt to employ at least three previously unused drugs to which there is in vitro susceptibility. One of these should be an injectable agent. Do not limit the regimen to three agents if other previously unused drugs that are likely to be active are available. In patients with MDR organisms in whom there is resistance to rst-line agents in addition to INH and RIF, regimens employing four to six medications appear to be associated with better results (2426). Patients should receive either hospital-based or domiciliary DOT. The implications of treatment failure and further acquired resistance are such that these cases should receive highest priority for DOT. Intermittent therapy should not be used in treating tuberculosis caused by drug-resistant organisms, except perhaps for injectable agents after an initial period (usually 23 months) of daily therapy. The use of drugs to which there is demonstrated in vitro resistance is not encouraged because there is little or no efcacy of these drugs (assuming the test results are accurate), and usually, alternative medications are available. However, the clinical signicance and effectiveness of the use of INH in the setting of low-level INH resistance is unclear (see Section 9.5). It should be noted that the use of INH was associated with better survival rates in patients with the strain-W variety of MDR M. tuberculosis that was susceptible to higher concentrations of INH (27). Resistance to RIF is associated in nearly all instances with cross-resistance to rifabutin and rifapentine (28). Rare strains with RIF resistance retain susceptibility to rifabutin; this is associated with uncommon mutations of the RNApolymerase locus in the bacillus (29). However, unless in vitro susceptibility to rifabutin is demonstrated, this agent should not be employed in cases with RIF resistance. Crossresistance between RIF and rifapentine appears almost universal (28). There is no cross-resistance between SM and the other injectable agents: amikacin, kanamycin, and capreomycin (although resistance to all may occur as independent events); however, cross-resistance between amikacin and kanamycin is universal (24). Simultaneous use of two injectable agents is not recommended due to the absence of proof of efcacy and potential amplication of drug toxicity. Determination of resistance to PZA is technically problematic and, thus, is not made in many laboratories. However, resistance to PZA is uncommon in the absence of resistance to other rst-line drugs (30). If monoresistance to PZA is observed, consideration must be given to the possibility that the etiologic agent is M. bovis, not M. tuberculosis (M. bovis is genotypically resistant to PZA and is not distinguished from M. tuberculosis by nucleic acid hybridization probe assays that are commonly used for identication). Table 16 contains regimens suggested for use in patients with various patterns of drug-resistant tuberculosis.
9.4 Role of Surgery in MDR Tuberculosis
drug resistance (on average, having resistance to more than 5 drugs) appeared to benet from the resection of cavitary or badly damaged lung tissue when compared with historical controls (31). In contrast, other clinicians have reported patients with drug resistance having similar cure rates without surgery (25, 32). The disparity in these reports may be due to longstanding disease with extensive brosis in the former group. If surgery is to be done, it should be performed by an experienced surgeon after the patient has received several months of intensive chemotherapy. Even with successful resection, 1224 additional months of chemotherapy, using drugs to which there is demonstrated susceptibility, should be given.
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The role of resectional surgery in the management of patients with extensive pulmonary MDR tuberculosis has not been established in randomized studies. In one series, patients with severe
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19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30. 31.
32.
on Anti-Tuberculosis Drug Resistance Surveillance. N Engl J Med 2001;344:12941303. Dye C, Espinal MA, Watt CJ, Mbiaga C, Williams BG. Worldwide incidence of multidrug-resistant tuberculosis. J Infect Dis 2002;185: 11971202. World Health Organization. Treatment of tuberculosis: guidelines for national programmes. Geneva: World Health Organization; 1996. WHO/TB/96.199. www.who.int/gtb/publications Enarson DA, Rieder HL, Arnadottir T, Trebucq A. Management of tuberculosis: a guide for low income countries. International Union against Tuberculosis and Lung Disease. 2000; 5th edition. www.iuatld. org/assets/images/Management-of-TB Espinal MA, Kim SJ, Suarez PG, Kam KM, Khomenko AG, Migliori GB, Baez J, Kochi A, Dye C, Raviglione MC. Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcome in six countries. JAMA 2000;283:25372545. Garca-Garca M, Ponce-de-Leon A, Jimenez-Corona ME, JimenezCorona A, Palacios-Martinez M, Balandrano-Campos S, FerreyraReyes L, Juarez-Sandino L, Sifuentes-Osornio J, Olivera-Diaz H, et al. Clinical consequences and transmissibility of drug-resistant tuberculosis in southern Mexico. Arch Intern Med 2000;160:630636. Goble M, Iseman MD, Madsen LA, Waite D, Ackerson L, Horsburgh CR Jr. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993;328:527532. Park SK, Kim CT, Song SD. Outcome of chemotherapy in 107 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. Int J Tuberc Lung Dis 1998;2:877884. Geerligs WA, van Altena R, de Lange WCM, van Soolingen D, van der Werf TS. Multidrug-resistant tuberculosis: long-term treatment outcome in the Netherlands. Int J Tuberc Lung Dis 2000;4:758764. Frieden TR, Sherman LF, Maw KL, Fujiwara PI, Crawford JT, Nivin B, Sharp V, Hewlett D Jr, Brudney K, Alland D, et al. A multi-institutional outbreak of highly drug-resistant tuberculosis: epidemiology and clinical outcomes. JAMA 1996;276:12291235. Moghazeh SL, Pan X, Arain T, Stover CK, Musser JM, Kreiswirth BN. Comparative antimicrobial activities of rifampin, rifapentine, and KRM-1648 against a collection of rifampin-resistant Mycobacterium tuberculosis isolates with known rpoB mutations. Antimicrob Agents Chemother 1996;40:26552657. Bodmer T, Zurcher G, Imboden I, Telenti A. Molecular basis of rifabutin susceptibility in rifampicin-resistant M. tuberculosis. J Antimicrob Chemother 1995;35:345348. Moore M, Onorato IM, McCray E, Castro KG. Trends in drug-resistant tuberculosis in the United States, 19931996. JAMA 1997;278:833837. Pomerantz BJ, Cleveland JC Jr, Olson HK, Pomerantz M. Pulmonary resection for multi-drug resistant tuberculosis. J Thorac Cardiovasc Surg 2001;121:448453 Farmer PE, Bayona J, Shin S, Becerra M, et al. Preliminary results of community-based MDRTB treatment in Lima, Peru. Int J Tuberc Lung Dis 1998;2(11 Suppl. 2):S371.
9.5. Laboratory Considerations in Determining Drug Resistance
by the physician. As noted previously, susceptibility testing should be repeated if the patient still has a positive culture result after 3 months of therapy or again develops positive cultures after a period of negative cultures (2). Antimicrobial susceptibility testing should be performed using a standard methodology, such as that recommended by the National Committee for Clinical Laboratory Standards (3). The second edition of a tentative standard (M24-T2) for susceptibility testing of mycobacteria was published by the National Committee for Clinical Laboratory Standards in 2000 (3). Susceptibility of M. tuberculosis is determined by evaluating the ability of an isolate to grow on agar or in broth containing a single critical concentration of a drug (2). The agar proportion method has been proposed as the reference method for all antituberculosis drugs except pyrazinamide, in which case the BACTEC broth-based methodology is the reference method (3). With the agar proportion method, resistance is dened as growth on the drug-containing plate that is more than 1% of the growth on the nondrug-containing plate (4). Because the agar method requires up to 6 weeks to yield results, it is recommended that initial susceptibility testing of M. tuberculosis isolates to rstline antituberculosis drugs be performed using more rapid brothbased methods (e.g., BACTEC and others). The goal, as stated by CDC, is to have culture and susceptibility results (to rstline drugs) available within 28 days of receipt of a clinical specimen (5). The critical concentrations recommended by the National Committee for Clinical Laboratory Standards for agar proportion method and equivalent concentrations for brothbased testing methods are shown in Table 17 (2,3). The National Committee for Clinical Laboratory Standards recommends that susceptibility testing be performed for INH (two concentrations) and RIF and EMB (one concentration each) using a broth-based method on all initial M. tuberculosis isolates. Pyrazinamide testing may be done if there is a sufciently high prevalence of PZA resistance. It is also recommended that the full panel of drugs (including second-line drugs) be tested when there is resistance to RIF alone or to two or more drugs. Testing of second-line drugs is performed using the agar proportion method, generally by public health laboratories. Secondary antituberculous drugs used for testing are capreomycin, ethionamide, kanamycin (which also predicts amikacin susceptibility), ooxacin (used to assess uoroquinolone activity), PAS, rifabutin, and SM (3). For second-line drug testing, a second concentration of EMB is also recommended. Susceptibility testing for cycloserine is not recommended because of the technical problems associated with the test.
References
1. American Thoracic Society and Centers for Disease Control and Prevention. Diagnostic standards and classication of tuberculosis in adults and children. Am J Respir Crit Care Med 2000;161:13761395. 2. Woods GL. Susceptibility testing for mycobacteria. Clin Infect Dis 2000; 31:12091215. 3. National Committee for Clinical Laboratory Standards (NCCLS). Susceptibility testing of mycobacteria, Nocardia, and other aerobic actinomycetes. 2nd ed. Tentative standard M24T2. Wayne, PA: National Committee for Clinical Laboratory Standards; 2000. www.nccls.org/ microbiology.htm 4. Kent PT, Kubica GP. Antituberculosis chemotherapy and drug susceptibility testing. In: Kent PT, Kubica GP. Public health mycobacteriology: a guide for the level III laboratory. Atlanta: Centers for Disease Control and Prevention; 1985. p. 159184. 5. Tenover FC, Crawford JT, Huebner RE, Geiter LJ, Horsburgh CR Jr, Good RC. The resurgence of tuberculosis: is your laboratory ready? J Clin Microbiol 1993;31:767770.
OBTAINING DRUG SUSCEPTIBILITY TESTS Drug susceptibility testing for INH, RIF and EMB should be performed on an initial isolate of M. tuberculosis from all patients. Susceptibility testing for rst-line and second line drugs should be performed for all patients with possible treatment failure or relapse. Most public health laboratories will perform initial susceptibility tests without a specic request, but this may not be true for private laboratories. Testing for susceptibility to the second-line drugs should be performed only in reference laboratories.
Susceptibility testing of M. tuberculosis is critical for appropriate patient management and should be performed on an initial isolate from all patients from whom M. tuberculosis is recovered (1). Public health laboratories routinely will perform susceptibility testing on initial isolates but, often, private laboratories do not perform such testing unless specically requested to do so
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10. TREATMENT OF TUBERCULOSIS IN LOW-INCOME COUNTRIES: RECOMMENDATIONS AND GUIDELINES OF THE WHO AND THE IUATLD
This brief summary of the differences between the recommendations for treatment of tuberculosis in high-income, low-incidence countries and low-income, high incidence countries is presented to provide an international context for the ATS/CDC/IDSA guidelines. As tuberculosis in low-incidence countries, such as the United States, becomes more and more a reection of the situation in high-incidence countries, it is important that health care providers in low-incidence countries have an understanding of the differences in the approaches used and the reasons for these differences so as to be better equipped to treat the increasing proportion of patients from high-incidence countries (1). As noted at the outset of this document, the ATS/CDC/IDSA recommendations cannot be assumed to be applicable under all epidemiologic and economic circumstances. The incidence of tuberculosis and the resources with which to confront it to an important extent determine the approaches used. A number of differences exist between these new ATS/CDC/ IDSA recommendations, and the current tuberculosis treatment recommendations of WHO (2) and IUATLD (3), the two major sets of international guidelines. Rather than being recommendations per se, the IUATLD document presents a distillation of IUATLD practice, validated in the eld. The WHO and the IUATLD documents target, in general, countries in which mycobacterial culture and susceptibility testing and radiographic examinations are not widely available. These organizations recommend a tuberculosis control strategy called DOTS (Directly Observed Treatment, Short-Course) in which direct observation of therapy (DOT in the current statement) is only one of ve key elements (4). The boxed insert lists the elements of DOTS strategy.
FIVE COMPONENTS OF DOTS Government commitment to sustained TB control activities. Case detection by sputum smear microscopy among symptomatic patients self-reporting to health services. Standardized treatment regimen of 68 months for at least all conrmed sputum smear positive cases, with directly observed treatment (DOT) for at least the initial 2 months. A regular, uninterrupted supply of all essential antituberculosis drugs. A standardized recording and reporting system that allows assessment of treatment results for each patient and of the TB control program overall.
mended because of cost, limited applicability and lack of facilities. However, susceptibility testing is recommended by the WHO for patients who fail (sputum smearpositive in month 5 of treatment or later during the course of treatment) the initial treatment regimen, and for those who fail a supervised retreatment regimen. Regarding follow-up, it is recommended by the WHO and the IUATLD that patients who have initial positive smears have repeat smears examined at 2 months, 5 months, and at completion of treatment (either 6 or 8 months). The IUATLD recommends that for patients who have positive smears at 2 months, the initial phase should be extended for 1 month.
10.2. Use of Chest Radiographs in Diagnosis and Follow-up of Patients Being Treated
In many parts of the world radiographs are not readily available. Moreover, because the highest priority for treatment is the highly infectious sputum smearpositive patient, there is concern that treatment based on radiographic ndings alone is an inefcient use of resources. Thus, chest radiography is recommended by both the WHO and the IUATLD only for patients with negative sputum smears and is not recommended at all for follow-up.
10.3. Initial Treatment Regimens
Selected important differences among the recommendations are summarized below. Some of the differences arise from variations in strategies, based on availability of resources, whereas others, such as the use of twice weekly regimens, arise from different interpretations of common elements, for example, whether DOT is used throughout the entire course of therapy or is limited to the initial phase.
10.1. Microbiological Tests for Diagnosis and Evaluation of Response
The WHO recommends a single initial phase of daily INH, RIF, PZA, and EMB (or SM) for 2 months followed by a continuation phase of either daily or three times a week INH and RIF, all given by DOT, for 4 months or daily INH and EMB for 6 months (self-administered). The WHO specically discourages programs from using twice weekly regimens, the reason being that there is a lesser margin of safety if a dose or doses are missed. The IUATLD recommends a 2-month initial phase of INH, RIF, PZA, and EMB given by DOT, followed by a 6-month continuation phase of daily INH and thiacetazone, self-administered. For patients with HIV infection the IUATLD recommends EMB in place of thiaocetazone. The IUATLD also recommends a 12-month regimen with a 2-month initial phase of INH, SM, and thioacetazone given daily and a 10-month continuation phase of daily INH and thioacetazone. This regimen is intended to be used for patients who have negative smears or when the 8-month regimen is not available. The rationale for the 8-month regimen recommendation is that it is felt that RIF should always be given by DOT; yet, many programs cannot afford to provide the supervision required by DOT for the full 6 months of treatment. The 8-month regimen is less efcacious in patients with drug-susceptible tuberculosis, but use of this regimen will likely preserve RIF for use in retreatment regimens. In addition to the issue of supervision, the 8-month regimens continuation phase of INH and EMB costs about 27% less than a 4-month continuation phase of daily INH and RIF.
10.4. Approach to Previously Treated Patients
The WHO and the IUATLD recommend diagnosis and classication of cases and assessment of response based on sputum AFB smears. The AFB smear is emphasized because access to reliable culture facilities is limited in many countries. In addition, the AFB smear identies patients who are most likely to transmit the organism. Susceptibility testing for new patients is not recom-
The WHO and the IUATLD recommend a standardized regimen for patients who have relapsed, had interrupted treatment, or have failed treatment. (The approach to this last group of patients is currently under discussion at the WHO.) The regimen consists of an initial phase of INH, RIF, PZA, EMB, and SM given daily for 2 months and then 1 month of daily INH, RIF, PZA, and EMB. The continuation phase consists of 5 months of daily INH, RIF, and EMB. Patients who have failed supervised retreatment are considered chronic cases and are highly likely to have tuberculosis caused by MDR organisms. Susceptibility testing and a tailored regimen using second-line drugs based on the test results are
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 167 2003 References
1. Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2001. Atlanta, GA: United States Department of Health and Human Services; 2002. www.cdc.gov/nchstp/tb/ 2. World Health Organization. Treatment of tuberculosis: guidelines for national programmes, 2nd edition. WHO/TB/97.220. Geneva, Switzerland: World Health Organization; 1997. 3. International Union against Tuberculosis and Lung Disease. Management of tuberculosis: a guide for low income countries, 5th edition. 2000. www.iuatld.org 4. World Health Organization. What is DOTS? A guide to understanding the WHO-recommended TB control strategy known as DOTS. WHO/ CDS/CPC/TB/99.270. Geneva, Switzerland: World Health Organization; 1999. www.who.int/gtb/dots 5. World Health Organization. An Expanded DOTS framework for effective tuberculosis control. WHO/CDS/TB/2002.297. Geneva, Switzerland: World Health Organization; 2002. www.who.int/gtb/dots 6. Farmer P. DOTS and DOTS-plus: not the only answer. Ann N Y Acad Sci 2001;953:16584. 7. Mitnick C, Bayona J, Palacios E, Shin S, Furin J, Alcantara F, Sanchez E, Barria M, Beerra M, Fawzi MC, Kapiga S, Neuberg D, Maguire JH, Kim JY, Tanner P. Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med 2003;348:119128.
recommended by the WHO, if testing and second-line drugs are available. The IUATLD recommendations do not address the issue (5). The issue of chronic cases is an area of considerable controversy (6). In countries with sufcient resources, such as the United States, individualized retreatment regimens, based on drug susceptibility patterns, as described in Section 9 (Management of Relapse, Treatment Failure, and Drug Resistance), are recommended. However, in countries without the capacity to obtain susceptibility tests, individualized regimens cannot be prescribed. Nevertheless, at least one group has demonstrated that in a high-incidence, low-income country (Peru) treatment with individualized regimens is feasible and effective (7).
10.5. Monitoring of Outcomes of Therapy
Both the WHO and the IUATLD recommend a formal system for monitoring outcomes of treatment that classies all cases into one of six categories (cured, completed without proof of cure, failed, died, defaulted, or transferred out). The assessment of cure is based on clinical response and on sputum AFB smear (or culture when available) at completion of treatment. The analysis of these outcomes is by temporal cohorts and enables identication of programmatic shortcomings.
10.6. Recommended Doses of Antituberculosis Drugs
11. RESEARCH AGENDA FOR TUBERCULOSIS TREATMENT

11.1. New Antituberculosis Drugs
The WHO recommends 10 mg/kg as the dose for three times weekly INH, whereas the ATS/CDC/IDSA recommend 15 mg/ kg (Table 3). There is no difference in the daily doses recommended for adults (5 mg/kg per day to a maximum of 300 mg/ day), but the ATS/CDC/IDSA recommend a higher dose for children (1015 mg/kg per day), based primarily on the expert opinion of pediatricians. The IUATLD recommendations are based on the number of pills required for three weight ranges resulting in a dose of about 5 mg/kg up to 300 mg/day. The clinical trials of the BMRC that established the efcacy of three times weekly regimens all used an INH dose of 15 mg/kg. The 10-mg/kg INH dose for thrice-weekly regimens was extrapolated by the WHO and the IUATLD (with assistance from global experts), and was chosen to maintain the weekly amount of INH approximately equal to that of the daily or twice weekly regimens.
10.7. Drugs/Preparations Not Available in the United States
Thioacetazone, which formerly was commonly used, is still available in most parts of the world, but is used less frequently. However, thioacetazone remains listed as an essential rstline drug by the WHO and is a component of the recommended IUATLD rst-line regimen. Combination preparations not available in the United States but listed by the WHO include the following: INH (150 mg) and EMB (400 mg); INH (100 mg) and thioacetazone (50 mg); and INH (75 mg), RIF (150 mg), PZA (400 mg), and EMB (275 mg). The IUATLD recommends using only combination preparations of INH and RIF, INH and thiacetazone.
10.8. Treating Pregnant Women
Both the WHO and the IUATLD include PZA in the regimen for treating pregnant women, in the absence of data indicating that there are adverse consequences.
10.9. Management of Common Adverse Reactions
Neither baseline nor follow-up testing is recommended by the WHO and the IUATLD. It is recommended that patients be taught to recognize the symptoms associated with drug toxicity and to report them promptly.
New antituberculosis drugs are needed for three reasons: to shorten or otherwise simplify treatment of tuberculosis caused by drug-susceptible organisms, to improve the treatment of patients with MDR tuberculosis, and to provide more effective and efcient treatment of latent tuberculosis infection (LTBI) (1). Although treatment regimens for drug-susceptible tuberculosis are effective, they must be administered for a minimum of 6 months to achieve optimal results. Nonadherence to this relatively lengthy course of treatment remains a major problem. To address the problem of nonadherence, DOT (as a component of the DOTS strategy) is recommended as a standard of care worldwide. However, the administrative and nancial burden of providing DOT for all patients is considerable. Thus, new drugs that would permit signicant shortening of treatment are urgently needed, as are drugs that could enable effective treatment to be given at dosing intervals of 1 week or more. Rates of multidrug-resistant tuberculosis are alarmingly high in several countries (2), and even in countries, such as the United States, where the rates are low and decreasing, the occasional case presents an often extremely difcult treatment problem (see Section 9: Management of Relapse, Treatment Failure, and Drug Resistance). Current treatment regimens for drug-resistant tuberculosis utilize drugs that are less effective, more toxic, and more expensive than those used for standard treatment. Moreover, these treatment regimens often have to be given for 1824 months. Although new drugs that are effective against resistant organisms would alone not solve the problem of drug resistance, their judicious use would greatly improve the treatment for many patients. Finally, the United States and several other low-incidence countries have embarked on plans to eliminate tuberculosis. An important component of an elimination strategy is the identication and treatment of persons with LTBI who are at high risk of developing tuberculosis (3). In the United States the most commonly used LTBI treatment regimen is INH given for 9 months; however, poor adherence to this regimen imposes a major limitation on its effectiveness. A shorter LTBI treatment regimen with RIF and PZA appears to be effective, but reports have indicated that toxicity may be unacceptably high (4). Thus, new drugs to provide for safe and effective short-course LTBI treatment are a major need. No truly novel compounds that are likely to have a signicant impact on tuberculosis treatment are presently available for clini-
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cal study. However, further work to optimize the effectiveness of once weekly rifapentine regimens and investigate the role of newer uoroquinolones in the treatment of drug-susceptible tuberculosis is warranted. As noted above, once weekly rifapentineINH is recommended only in the continuation phase for HIV-negative patients with noncavitary pulmonary tuberculosis who have negative sputum smears at completion of 2 months of treatment. Two approaches to improve intermittent rifapentine regimens have been suggested by experimental studies: increasing the rifapentine dosage (5), and adding moxioxacin as a companion drug to provide better protection against the development of drug resistance and enhance the sterilizing activity of the regimen (6). Other data from a clinical trial of ooxacin suggest that uoroquinolones have the potential to signicantly shorten treatment (7). Of the newer uoroquinolones with more potent activity against M. tuberculosis, moxioxacin appears to be the most promising. Other compounds that might become available for clinical evaluation in the future include the nitroimidazopyrans that are chemically related to metronidazole, for which activity against dormant M. tuberculosis has been suggested; oxazolidinones such as linezolid; and drugs that target isocitrate lyase, an enzyme that may be necessary for the establishment of latent tuberculosis infection (8). The nitroimidazopyran compound PA-824 has bactericidal activity comparable to that of INH and appears to act as well on bacilli maintained in an anaerobic environment (9). However, additional preclinical evaluation of PA-824 is needed before clinical studies could begin. Although linezolid, a drug that is marketed for the treatment of selected acute bacterial infections, does have demonstrated activity against M. tuberculosis, other compounds in that class may be more suited for the treatment of tuberculosis (10).
11.2. Other Interventions to Improve the Efficacy of Treatment
A number of other approaches have been suggested that might lead to improved treatment outcome, including alternative drug delivery systems and a variety of methods of immunomodulation and immunotherapy. Experimental studies have demonstrated that effective serum concentrations of INH and PZA can be provided through incorporation of drug into slow-release, biodegradable polymers that are implanted subcutaneously (11). However, there has been little apparent commercial interest in pursuing this approach. Liposomal encapsulation of antituberculosis drugs has been suggested as an approach to direct drug to the proposed site of infection (i.e., the macrophage) providing for more effective and better tolerated therapy, as well as for more widely spaced treatment. Similarly, incorporation of drug into inhalable microparticles may reduce dose requirements, minimize toxicity, and deliver drug to infected alveolar macrophages. Although experimental studies have suggested that these approaches might be effective, little clinical work has been done in these areas (11, 12). Because of possible detrimental effects of the cytokine, tumor necrosis factor- , in HIV-associated tuberculosis, there has been some interest in the use of drugs, such as thalidomide and pentoxifylline, that block tumor necrosis factor- production. Studies have shown that administration of thalidomide improves weight gain in both HIVpositive and HIV-negative tuberculosis patients (13). Pentoxifylline has been associated with reductions in circulating HIV viral load in patients with tuberculosis (14). However, the potential side effects of these drugs may outweigh possible benets. A more promising intervention is the administration of protective cytokines, such as aerosolized interferon- and subcutaneous interleukin-2, that have shown activity as adjuncts to chemotherapy in patients with multidrug-resistant
tuberculosis (15, 16). Another method of immunomodulation, the use of heat-killed preparations of M. vaccae as a therapeutic vaccine, has not shown clinically signicant benets when carefully evaluated in randomized clinical trials (17). Nonetheless, there continues to be interest in this approach, especially for patients with advanced drug-resistant tuberculosis. Other vaccines that have been shown to lead to expression of protective cytokines have shown more promise in experimental studies (18). Finally, a study suggested that the administration of Vitamin A and zinc to patients with pulmonary tuberculosis is associated with an increased rate of sputum conversion and improvement in chest radiographs (19). Further assessment of nutritional supplements in tuberculosis treatment may be indicated. 11.2.1. Better methods to identify and manage high- and lowrisk patients As noted above, sputum culture positivity at 2 months appears to be a marker for an increased risk of relapse for patients with pulmonary tuberculosis. Surrogate markers that could be measured earlier in therapy and have a greater sensitivity and specicity for a poor outcome could better select high risk patients for more intensive or longer therapy, thus minimizing the likelihood of relapse. Studies of several molecular markers in the sputum have shown promise and deserve further evaluation (20). Conversely, markers that reliably identify patients at lower risk of an adverse treatment outcome would be helpful to select patients for less intense or shorter treatment. Whether or not low-risk patients can be treated with shorter regimens using currently available drugs is a topic of considerable importance. 11.2.2. Health services research to facilitate treatment administration and improve treatment outcome Although DOT (as a component of DOTS) is widely advocated as a universal standard of care for tuberculosis treatment, many tuberculosis control programs do not have the resources to provide DOT for all patients. Moreover, some programs have achieved excellent results by targeting DOT to patients known or suspected of being at increased risk for nonadherence. Further evaluation of alternatives to universal DOT is needed. Finally, although limited work has been done in the area of behavioral studies of tuberculosis patients and providers, an ambitious research agenda established in the mid-1990s has not been implemented and should be revisited (21).
References
1. OBrien RJ, Nunn PP. The need for new drugs against tuberculosis: obstacles, opportunities, and next steps. Am J Respir Crit Care Med 2001;163:10551058. 2. Espinal MA, Laszlo A, Simonsen L, Boulahbal F, Kim SJ, Reniero A, Hoffner S, Rieder HL, Binkin N, Dye C, Williams R, Raviglione MC. Global trends in resistance to antituberculosis drugs. World Health Organization-International Union against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance. N Engl J Med 2001;344:1294303. 3. American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221S247. www.cdc.gov. nchstp.tb/ 4. Centers for Disease Control and Prevention. Update: fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/ CDC recommendations. MMWR 2001;50:733735. http://www.cdc.gov/ mmwr/PDF/wk/mm5034.pdf 5. Daniel N, Lounis N, Ji B, OBrien RJ, Vernon A, Geiter LJ, Szpytma M, Truffot-Pernot C, Hejblum G, Grosset J. Antituberculosis activity of once-weekly rifapentine-containing regimens in mice: long-term effectiveness with 6- and 8-month treatment regimens. Am J Respir Crit Care Med 2000;161:15721577. 6. Lounis N, Bentoucha A, Truffot-Pernot C, Ji B, OBrien RJ, Vernon A, Roscigno G, Grosset J. Effectiveness of once-weekly rifapentine and
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20. Desjardin LE, Perkins MD, Wolski K, Haun S, Teixeira L, Chen Y, Johnson JL, Ellner JJ, Dietze R, Bates J, et al. Measurement of sputum Mycobacterium tuberculosis messenger RNA as a surrogate for response to chemotherapy. Am J Respir Crit Care Med 1999;160:203210. 21. Centers for Disease Control and Prevention. Improving tuberculosis treatment and control: an agenda for behavioral, social, and health services research. In: Proceedings of tuberculosis and behavior: national workshop on research for the 21st century, Bethesda, MD, August 2830, 1994. Atlanta, GA: Centers for Disease Control and Prevention; 1995.
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Committee
This document was written by a joint committee of the American Thoracic Society (ATS), the Infectious Diseases Society of America (IDSA), and the Centers for Disease Control and Prevention (CDC). The committee members are as follows*: Henry M. Blumberg, M.D., Co-chair, IDSA William J. Burman, M.D. Richard E. Chaisson, M.D. Charles L. Daley, M.D. Sue C. Etkind, B.S.N., M.S. Lloyd N. Friedman, M.D. Paula Fujiwara, M.D., M.P.H. Malgosia Grzemska, M.D. Philip C. Hopewell, M.D., Co-chair, ATS Michael D. Iseman, M.D. Robert M. Jasmer, M.D. Venkatarama R. Koppaka, M.D., Ph.D. Richard I. Menzies, M.D. Richard J. OBrien, M.D., Co-chair, CDC Randall R. Reves, M.D. Lee B. Reichman, M.D., M.P.H. Patricia M. Simone, M.D. Jeffrey R. Starke, M.D. Andrew A. Vernon, M.D., M.H.S. *Charles Peloquin, Pharm.D., also made substantial contributions to the document.
Acknowledgment : The Committee thanks Elisha Malanga of the American Thoracic Society for excellent administrative support. The Committee also thanks the members of an ad hoc rerview panel convened by the Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, for their thorough review and helpful comments. The members of this panel were as follows: Noami Bock, M.D., James Burns, M.D., Mike Holcombe, M.P.P.A., James Lamberti, M.D., Evelyn Lancaster, R.N., Kathleen Moser, M.D., M.P.H., James McDaniel, M.D., F.A.C.P., Sonal Munsiff, M.D., Margaret Oxtoby, M.D., Carol Pozsik, R.N., M.P.H., Susan Ray, M.D., Jon Tillinghast, M.D., M.P.H., Victor Tomlinson, Jr., M.D., and Charles Wallace, Ph.D.

Treatment of Tuberculosis

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American Thoracic Society Documents

. . 650 . . 650 . . 651 . . 652 . . 653 . . 653

. . . . 654 . . . . 654 . . . . 655 . . . . 657 . . . . 658

. . . . 634 . . . . 634 . . . . 634 . . . . . . . . . . . . . 636 . 636 . 636 . 637

INH/RIF Three times weekly for 54 doses (18 wk)

273195 (39 wk) 118102 (39 wk)

TABLE 3. DOSES* OF ANTITUBERCULOSIS DRUGS FOR ADULTS AND CHILDREN

Adults (max.) Children (max.)

15 mg/kg (900 mg)

Adults (max.) Children (max.)

10 mg/kg (600 mg) 1020 mg/kg (600 mg)

Tablet (150 mg, film coated)

Tablet (500 mg, scored) Tablet (100 mg; 400 mg)

Capsule (250 mg)

Tablet (250 mg)

Adults (max.) Children

5 mg/kg (300 mg) Appropriate dosing for children is unknown

Aqueous solution (1-g vials) for intravenous or intramuscular administration

Adults (max.) Children (max.)

There are no data to support intermittent administration

There are no data to support intermittent administration

There are no data to support intermittent administration

There are no data to support intermittent administration

There are no data to support intermittent administration

There are no data to support intermittent administration

There are no data to support intermittent administration

American Thoracic Society Documents

American Thoracic Society Documents

American Thoracic Society Documents

1. INTRODUCTION AND BACKGROUND

2. ORGANIZATION AND SUPERVISION OF TREATMENT

American Thoracic Society Documents

2.1. Role of the Health Department

2.2. Promoting Adherence

TABLE 8. POSSIBLE COMPONENTS OF A MULTIFACETED, PATIENT-CENTERED TREATMENT STRATEGY

American Thoracic Society Documents

Figure 4. Example of flow chart for patient monitoring.

3. DRUGS IN CURRENT USE

TABLE 9. ANTITUBERCULOSIS DRUGS CURRENTLY IN USE IN THE UNITED STATES

American Thoracic Society Documents

American Thoracic Society Documents

American Thoracic Society Documents

American Thoracic Society Documents

79. 80. 81. 82. 83.

84. 85. 86. 87. 88. 89. 90.

93. 94. 95. 96. 97. 98.

123. 124. 125. 126. 127. 128. 129.

99. 100. 101. 102.

103. 104. 105. 106. 107.

131. 132. 133. 134. 135. 136.

American Thoracic Society Documents

4. PRINCIPLES OF ANTITUBERCULOSIS CHEMOTHERAPY

4.1. Combination Chemotherapy

American Thoracic Society Documents

5. RECOMMENDED TREATMENT REGIMENS

American Thoracic Society Documents

American Thoracic Society Documents

6. PRACTICAL ASPECTS OF TREATMENT

American Thoracic Society Documents

American Thoracic Society Documents