This document discusses fungal infections in critically ill patients in the ICU. It notes that prolonged antibiotic use, acute illness, surgery, and poor nutrition can temporarily depress the immune system and allow fungal infections to develop. The most common invasive fungal infections in the ICU are candidiasis and aspergillosis. Candida infections, including Candida bloodstream infections, are discussed in detail, including changing epidemiology with more non-albicans Candida species, risk factors, symptoms, and challenges with diagnosis.
This document discusses fungal infections in critically ill patients in the ICU. It notes that prolonged antibiotic use, acute illness, surgery, and poor nutrition can temporarily depress the immune system and allow fungal infections to develop. The most common invasive fungal infections in the ICU are candidiasis and aspergillosis. Candida infections, including Candida bloodstream infections, are discussed in detail, including changing epidemiology with more non-albicans Candida species, risk factors, symptoms, and challenges with diagnosis.
This document discusses fungal infections in critically ill patients in the ICU. It notes that prolonged antibiotic use, acute illness, surgery, and poor nutrition can temporarily depress the immune system and allow fungal infections to develop. The most common invasive fungal infections in the ICU are candidiasis and aspergillosis. Candida infections, including Candida bloodstream infections, are discussed in detail, including changing epidemiology with more non-albicans Candida species, risk factors, symptoms, and challenges with diagnosis.
This document discusses fungal infections in critically ill patients in the ICU. It notes that prolonged antibiotic use, acute illness, surgery, and poor nutrition can temporarily depress the immune system and allow fungal infections to develop. The most common invasive fungal infections in the ICU are candidiasis and aspergillosis. Candida infections, including Candida bloodstream infections, are discussed in detail, including changing epidemiology with more non-albicans Candida species, risk factors, symptoms, and challenges with diagnosis.
Fungal infections occur not only in immunocompromised
patients (see chapter on The Immunocompromised Patient), but also in patients who are under critical care for various problems, e.g. acute infections, trauma or major surgery, and who have a normal immune defense mechanism to start with. Perhaps the most important cause of fungal overgrowth and any systemic or deep-seated fungal infection in these patients is the prolonged use of broad-spectrum antibiotics which alter the bacterial flora, and promote the growth of unusual resistant organisms and fungi. Acute or critical illnesses in the course of time also temporarily depress the immune mechanisms within the body to some extent. Thus patients with unresolved or persistent septic infections, or long- standing untreated foci of infection, e.g. undrained abscesses, show a decreased capacity to respond to immunological challenges. All major surgical procedures are also followed by a depressed immunological response; this is related to an increase in suppressor cells, a fall in T4 lymphocytes, and alterations in lymphokine production. These changes are however temporary, and are quickly reversed as recovery progresses. In the presence of complications, the postoperative changes noted above are protracted, and may well play a role in predisposing the patient to both bacterial and fungal infections. Finally, poor nutritional status further depresses the immune defense mechanisms. Thus a combination of various factors, varying in degree in each individual critically ill patient, form a background against which fungal infections can occasionally supervene. The environment too perhaps has some part to play, e.g. clear-cut nosocomial outbreaks of invasive aspergillosis have been described in critical care units, and these have been related to the marked increase in air-borne spores of Aspergillus fumigatus in these units. The important invasive fungal infections encountered in a critical care setting are candidiasis and aspergillus infections. Occasionally, infections with the mucor species are observed, particularly in diabetics or other severely immunocompromised patients. Other fungal infections are being increasingly recognized in the West; in our country, however, we are as yet blissfully unaware of their possible occurrence. CANDIDAL BLOODSTREAM INFECTIONS Epidemiology Candida represents the commonest form of invasive fungal disease 1 in most ICUs all over the world. It now accounts for 12% of all hospital-acquired bloodstream infections (BSIs). Though there was a major increase in candida BSI in the 1980s, the incidence of BSI has now stabilized or even declined in the West. The incidence of BSI with candida varies in different ICUs in our country. We have noted a definite increase in candidal BSI in our unit; perhaps this holds for many units in the large urban centers of India. An important epidemiological trend in many western centers is the shift in the distribution of candidal species responsible for BSI, Candida albicans being responsible for only half of all BSIs caused by yeast. Recent data from the Prospective Antifungal Therapy Alliance (PATH) database from 2004 to 2008 showed that the incidence of candidemia caused by the non-albicans candida species was higher (54.4%) than C. albicans (45.6%). The commonest non-albicans species that were isolated being C. glabrata, C. parapsilosis, C. tropicalis, C. krusei. 2 In our unit C. albicans is no longer the main isolate BSI; there is a slow but definite increase in isolates of C. tropicalis, C. glabrata, C. parapsilosis, C. krusei and also an occasional presence of other rare candida species. C. tropicalis now is the main bloodstream isolate Invasive Fungal Infections in the ICU C H A P T E R 47 13 561 Chapter 47 Invasive Fungal Infections in the ICU constituting 14% of all bloodstream yeast isolates. It is possible that the increasing incidence of non C. albicans species may be related to the extensive use of fluconazole not only as treatment but also as a prophylactic drug in patients in whom fungal infections are likely to occur. This epidemiological shift is obvious in the West but slowly making itself felt in our country as well has important implications for therapy, because of intrinsic resistance of C. glabrata and C. krusei to fluconazole. Figure 1 illustrates the distribution of yeasts isolated from blood cultures and resistance to fluconazole. A study on bloodstream fungal infection from the Sir Ganga Ram Hospital, New Delhi, India, 3 has also shown a significant increase in both candidemia and total antifungal use. There was increase in infections due to the non- albicans species and this was correlated to increasing use of fluconazole. The study also revealed the emergence and isolation of a novel species C. haemolunii with decreased susceptibility to both amphotericin B and azoles. The authors of this study have commented that decreased susceptibility to fluconazole, as well as the threat of emergence of cross- resistance to voriconazole against the background of high azole consumption, may limit the use of these agents as presumptive therapy for candida BSIs. A study by Chakrabarti A et al (presented as a poster at the ID Week San Diego, 2012) included 25 ICUs across India and found that the incidence of candidemia was 7.0/1,000 ICU admissions over a 6-month period. This study highlighted the distribution of candidia species in these patients, the most common being C. tropicalis and the emergence of uncommon species like C. haemulonii and C. rugosa, C. guilliermondii, C. pelliculosa and also of azole resistant C. albicans and C. tropicalis. Figure 2 shows the distribution of various candida species in this study. Fig. 1: Fluconazole resistance among yeast isolated from blood cultures (20102012) Fig 2 : Distribution of various candida species in candidemia patients Source: Candidemia in Intensive Care Units of India: a Six Months Interim Report on Active Surveillance. ID week 2012, San Diego. Poster Abstract Session: Clinical Mycology and Fungal Virulence October 18, 2012. 13 562 Section 13 Fever and Acute Infections in a Critical Care Setting Risk Factors for Invasive Candidiasis Specific to the ICU, several risk stratification schemes exist to identify patients at high risk for candidemia. A multicenter cohort study from Spain 4 involving 1,699 adult ICU patients identified surgery, multifocal colonization, TPN and severe sepsis to be a strong predictor of candidal infection. Another large cohort study from American and Brazilian ICUs identified the following features to predict invasive candidiasis. These factors were antibiotics, central venous catheter (CVC), TPN, dialysis, major surgery, pancreatitis, use of steroids and other immunosuppressive agents. 5 Both these studies in our opinion have omitted one major risk factor for invasive candidiasisduration of ICU stay. The longer the stay in the ICU, the greater the chance of the patient developing a fungal infection. What combination of risk factors stated above are more likely to cause invasive candidiasis is undetermined. The risk factors for invasive candidiasis are listed in Box 1. According to the Indian study by Chakrabarti et al. quoted earlier, central venous catheterization, urethral catheterization and mechanical ventilation were seen as significant risk factors associated with candidemia in the ICU. Box 2 shows the various risk factors linked with candidemia as found in this study. Proof of invasive candidiasis rests in a positive blood culture for candida. Unfortunately blood cultures are positive only in 5070% of patients with invasive candidiasis. It is important to note that a positive blood culture for candida should never be ignored as a possible contaminant and should prompt search for the source of infection. Biopsy of a specific lesions from a normally sterile site (e.g. lung, liver) demonstrating the histopathology of invasive candidiasis can give a definite diagnosis, but this is often not feasible in critically ill patients. Because of these difficulties in diagnosis, a non-culture based diagnosis test has been researched upon and recently approved by the Food and Drug Administration. This test is the 1-3-b-D-glucan test. 1-3-b-D-glucan is an important major component of the fungal cell wall and it can be detected from the blood and assayed in patients with invasive candidiasis. It has a sensitivity of 75100% and a specificity of 88100%. However, this is a broad spectrum assay that detects not just candida but also Aspergillus, Fusarium, Acremonium, Saccharomyces species. 6 The test therefore requires careful interpretation. In fact none of the currently available tests allow of a reliable diagnosis. Hence, in a febrile critically ill patient who is unresponsive to antibiotics and who has risk factors for invasive candidiasis, empiric treatment against candidal infection is justified. Clinical Features Pyrexia of unknown origin not responding to antibiotics therapy is the key presentation in most cases. Candidal infection can involve any organ system in invasive candidiasis. Liver and spleen involvement lead to hepatosplenomegaly. The kidney, lungs, brain may also be involved. Endophthalmitis is a rare but noteworthy feature in some patients. Treatment 7 Treatment should not await a confirmed culture. High risk cases presenting with fever and showing a sharp clinical deterioration should be promptly started on antifungal therapy. The CVC should as far as possible be removed. If absolutely necessary a new central line on the opposite side should be inserted. For non-neutropenic hemodynamically stable patients, fluconazole is the drug of choice unless there is a suspicion of a fluconazole resistant speciese.g. history of a recent azole exposure or a history of previous colonization by C. glabrata, C. krusei. If used empirically the drug is given IV in a dose of 800 mg/day, the dose being adjusted with reference to renal function. The drug is continued till the offending candida species has been identified. In neutropenic patients, or in hemodynamically unstable patients, or in ICUs where there is significant infection rate with fluconazole resistant species, an echinocandin is the drug of choice till species identification of the fungal isolate is made. The echinocandin generally used is caspofungin. Two other commercially available echinocandins are also available. These are micafungin and anidulafungin. Experience with Box 1: The risk factors for invasive candidiasis x Prolonged use of antibiotics x Corticosteroids, immunosuppressive therapy x Central venous catheterization x Prolonged ICU stay x Surgery x TPN x Diabetes, malignancy x Organ transplant x Dialysis x Pancreatitis x Multifocal colonization Box 2: Risk factors associated with candidemia in the ICU Risk factors No. of cases x CVL catheterization 218 x Urethral catheterization 201 x Invasive mechanical ventilation 169 x Drainage catheter 88 x Antibiotic therapy 63 x Dialysis 55 x Total parenteral nutrition 55 x Steroid therapy 61 Source: Candidemia in Intensive Care Units of India: a Six Months Interim Report on Active Surveillance. ID week 2012, San Diego. Poster Abstract Session: Clinical Mycology and Fungal Virulence October 18, 2012. 13 563 Chapter 47 Invasive Fungal Infections in the ICU the last two echinocandins is however limited. Lyophylized amphotericin can also be used if there is intolerance to or unavailability of an echinocandins. Voriconazole is an acceptable alternative but offers no advantage over fluconazole. It is to be recommended as step-drown oral therapy for selected cases of candidiasis due to C. krusei or voriconazole susceptible C. glabrata. If infection has been caused by C. parapsilosis, fluconazole is preferred as these fungi are less susceptible to echinocandins. The duration of therapy recommended is 14 days from the last positive cultures. If cultures remain negative treatment should continue for 710 days after the patient is afebrile. Treatment may at times needs to be longer depending on the degree and site involved. INVASIVE ASPERGILLOSIS Invasive aspergillosis is less commonly encountered than invasive candidiasis. Sinopulmonary infection is most often observed, though many organ systems can be involved. A. fumigatus, A. flavus and A. niger account for nearly all human disease. Though the disease may rarely be encountered in immunocompetent individuals, it is most frequently seen in immunocompromised or immunosuppressant patients in the ICU. The risk factors are T Prolonged neutropenia. T Corticosteroids and immunosuppressive therapy. T Solid organ transplant patients. T Hemopoietic stem cell transplant patients. T Advanced HIV with CD counts often below 100/cm. T Chronic granulomatous disease. The clinical features have been discussed in the chapter on The Immunocompromised patient. Demonstration of the aspergillus in biopsy samples is the gold standard for diagnosis. A positive aspergillus culture from the blood though uncommon is also confirmatory. A bronchoalveolar lavage (BAL) culture positive for aspergillus should lend strong suspicion for invasive pulmonary aspergillosis, if clinical features are compatible with the diagnosis. Computed tomography (CT) findings of the chest may suggest the diagnosiscavitations, nodules, wedge shaped pleural based shadows suggesting pulmonary infarcts, the halo sign, the crescent sign may be observed. The clinical and imaging features as also the value of the galactomannan test and the b glucan test have been commented upon in the chapter on The Immunocompromised Patient. Treatment 8 According to a multicenter randomized open label trial comparing amphotericin B to voriconazole as initial therapy for invasive aspergillosis, voriconazole was associated with increased survival (76% vs 58%). Voriconazole is therefore generally recommended as first line therapy. Before voriconazole, itraconazole was used intravenously against invasive aspergillosis with reasonable success. Voriconazole has now replaced itraconazole in treatment. Posaconazole is an additional extended triazole for treating refractory disease. The echinocandins (caspofungin) can be used as alternative therapy to voriconazole particularly in patients who cannot tolerate voriconazole or who are refractory to standard therapy. Many units use a combination of amphotericin B or amphotericin B lipid formulation and voriconazole in the treatment of severe invasive aspergillosis. There is however very little evidence for the increased efficacy and safety of this combination therapy. The final drugs recommended as salvage therapy for invasive aspergillosis are micafungin and anidulafungin, two new echinocandins. 8 The experience with micafungin or anidulafungin is limited. The drugs are best kept in reserve for salvage therapy. MUCORMYCOSIS Mucormycosis is a life threatening mold infection caused by fungi belonging to the older Mucorales. The organisms causing this mold infection include Rhizopus, Rhizomucor, Absidia and Mucor. These organisms almost always have a predilection for immunocompromised patients and present with a rapid onset angioinvasive disease. Risk factors include diabetes, acidosis, solid organ and bone marrow transplant recipients, use of immunosuppressant drugs, iron overload, deferoxamine treatment. Diabetes and in particular diabetic acidosis are major risk factors. Patients present with rhinocerebral disease that causes destruction of the nasal septum and paranasal sinuses; the disease then extends into and destroys the orbit and penetrates upward into the brain. Pulmonary mucormycosis is the typical presentation in post-transplant patients. Invasion of vessels with ischemic necrosis of the tissue is a typical feature of this fungal disease. Treatment 9 is with high dose amphotericin B 11.5 mg/kg per day or amphotericin B lipid preparation in doses of 57.5 mg/kg per day. Azoles and echinocandins are ineffective in mucormycosis. Urgent surgical treatment is always necessary to excise and debride involved tissue in rhinocerebral disease. Surgery may also be necessary in pulmonary mucormycosis. Early diagnosis is critical for survival. Diagnosis is made on clinical grounds and the presence of the fungus in scrapings of involved tissue, and of the fungus in the discharge from infected tissue. Delay in initiating treatment increases mortality. Posaconazole has been recently used as prophylaxis in severely immunocompromised patients. This drug has also occasionally been used as salvage therapy but is not a standard treatment for the disease. The efficacies of antifungal agents are listed in Table 1. Doses and dosing adjustment of commonly used antifungal agents are listed in Table 2. 13 564 Section 13 Fever and Acute Infections in a Critical Care Setting Table 2: Doses of commonly used antifungal agents Drug Dose Dose adjustment Invasive Candidiasis Amphotericin B 0.61 mg/kg/day, IV None, careful monitoring of renal and liver function Amphotericin B lipid formulation 35 mg/kg/day, IV None, careful monitoring of renal and liver function Fluconazole 400800 mg/day, IV or PO Renal insufficiency Voriconazole IV, 6 mg/kg every 12 hr for 2 doses followed by 34 mg/kg every 12 hr PO, <40 kg 100 mg every 12 hr; >40 kg 200 mg every 12 hr Hepatic dysfunction Echinocandins Caspofungin 70 mg loading dose followed by 50 mg/day, IV Hepatic dysfunction Micafungin 100 mg/kg Anidulafungin 200 mg loading dose followed by 100 mg/day, IV None Invasive Aspergillus Amphotericin B 11.5 mg/kg/day, IV As listed above Amphotericin B lipid formulation 5 mg/kg/day, IV As listed above Voriconazole As listed above As listed above Echinocandins As listed above As listed above Itraconazole IV, 200 mg every 12 hr for 4 doses followed by 200 mg/day PO, 200400 mg/day Multiple drug interaction, IV not recommended for CrCl <30 mL/min Mucormycosis Amphotericin B 11.5 mg/kg/day, IV As listed above Amphotericin B lipid formulation 5 mg/kg/day, IV As listed above Table 1: Efficacy of antifungal agents in fungal infections Amphotericin B or Amphotericin B lipid formulation Fluconazole Voriconazole Echinocandin C. Albicans + + + + C. Tropicales + + + + C. Glabrata + - - + C. Krusei + - + + C. Parapsilosis + + + +/- Aspergillus + - + + Cryptococcus + + + - Mucorales + - - - Fusarium - - + +/- Note: Aspergillus terreus is intrinsically resistant to amphotericin B. Aspergillus lentulus is intrinsically resistant to azoles. This is followed by a brief description on the role of amphotericin B in fungal infections. Amphotericin B For poor developing countries, the cheapest of all antifungal agents against invasive fungal infection is amphotericin B deoxycholate and it is therefore appropriate to add a few additional remarks on this drug. The drug has important side effects and in critically ill patients it is best to start with a test dose of 1 mg in adults (0.5 mg in children <30 kg) given over 1 hour. This is followed after 4 hours by a dose of 0.5 mg/kg administered over 34 hours. Even if the test dose produces Abbreviations: PO, by mouth; IV, intravenous; CrCl, creatinine clearance. 13 565 Chapter 47 Invasive Fungal Infections in the ICU a reaction, 10 mg is administered after 4 hours. The dose is increased by 1520 mg daily so that the dose of 0.51 mg/ kg is reached within 37 days. The drug is then continued daily till a total dose of at least 11.5 g is administered. In granulocytopenic patients empirically given amphotericin B should be continued till recovery from granulocytopenia ensues. Deep visceral infections may require a total dose of 23 g or even more. Amphotericin B should be given in a 5% dextrose solution. Electrolyte solutions should be avoided, as they cause precipitation of the amphotericin B suspension. Side effects are common; pyrexia with chills is the most frequent side effect observed. Intravenous hydrocortisone in a dose of 50 mg given at the time of infusion often controls a severe pyrexial reaction. Other important side effects include hypotension, nausea, thrombophlebitis, hypokalemia and renal dysfunction with a rise in the serum creatinine level. A significant rise in the latter warrants a temporary stoppage of the drug; it is restarted when the creatinine level drops. Permanent renal tubular damage may occur when large doses (34 g) of amphotericin B are used. Amphotericin B does not achieve significant concentration in the urine, CSF or peritoneal fluid. In cases of fungal meningitis, intrathecal administration of amphotericin B may be combined with intravenous therapy. The intrathecal dose is 0.51 mg dissolved in the CSF. The total dose should not exceed 15 mg. Arachnoiditis and motor or sensory disturbances may occur as complications. An Omaha reservoir is sometimes used for instillation of amphotericin B into the cerebral ventricles in patients with CNS fungal infection. The danger of introducing secondary bacterial infection is ever present with this mode of administration. Clinical Resistance to Amphotericin B Clinical resistance to amphotericin B is observed in severely immunocompromised patients, in patients with infected prosthetic valves or other foreign bodies, and in advanced visceral fungal infections involving the liver, spleen or kidneys. Hepatosplenic candidiasis is a clinically resistant infection which may prove resistant to even high doses of amphotericin B. The development of fever, abdominal pain, or liver cell dysfunction occurring in a patient recovering from granulocytopenia should raise suspicion of candidal infection within the abdomen. Investigations should include ultrasound, CT and, if necessary, MRI imaging of the abdominal organs. A combination of amphotericin B and flucytosine or fluconazole should be promptly started. Therapy may need to be continued for several months, and may yet be unsuccessful. Microbiological resistance to amphotericin B has been reported in C. albicans, C. tropicales, other candida species, as also against other fungiTrichosporon beigeli, Fusarium species, and Pseudallescheria boydii species. 10
In the West, Trichosporon beigelii, Fusarium species, and P. boydii species are increasingly recognized causes of systemic fungal infections. 10 A combination therapy of high doses of amphotericin B with flucytosine or fluconazole is recommended as initial treatment. If unsuccessful, fluconazole plus flucytosine is advised for systemic fungal infections due to polyene resistant fungi. 10 Systemic fungal infections originating from an infected foreign body, viz. an infected prosthetic valve, can never be controlled unless the foreign body is first removed. Fungal valvular endocarditis invariably necessitates removal of the valve. Further examples where removal of infected foreign bodies is mandatory include T Removal of central venous lines. T Removal of infected ventriculoperitoneal shunts in pati- ents with fungal infections of the CNS. T Removal of urinary catheters in patients with candidiasis involving the urinary tract. T Removal of a dialysis catheter in fungal peritonitis associated with peritoneal dialysis. It is not enough to use antifungal drugs in the treatment of systemic fungal infections in critically ill patients. As always, overall critical care is of vital importance. An assiduous search to determine why systemic fungal infection occurred, and whether the source of infection can be controlled or eradicated is of great importance. Flucytosine Flucytosine is an antifungal drug that has not been discussed earlier. It is effective both orally and on intravenous use and is active against candida species and cryptcoccus. It enters cerebrospinal fluid as also urine and peritoneal fluid and is particularly useful in fungal (especially cryptococcal) infections involving the meninges and/or the neuroaxis. It excretion is reduced in renal failure; the daily dose should therefore be adjusted in these patients. Its main disadvantage is the development of either primary or secondary drug resistance to a significant number of fungal isolates. There is also the danger of bone marrow suppression, particularly with use of toxic doses. The dose of flucytosine is 100 mg/ kg of bodyweight orally, divided in four equal doses every 6 hours. The dose for intravenous infusions is 50 mg/kg infused over 2040 minutes every 6 hours. If possible blood levels of the drug should be estimated and not allowed to go beyond 100120 g/dL. As has already been mentioned, combination therapy with amphotericin B and flucytosine is often used in relatively resistant fungal infection. The drugs when used together are synergistic, so that the dose of amphotericin may be reduced in patients who do not tolerate its full dose. In cryptococcal meningitis, a combination therapy of 0.30.6 mg/kg of amphotericin B and the usual dose of flucytosine is more effective in sterilizing the CSF and prevents relapse. Alternatively, IV amphotericin B (0.7 mg/kg per day) can be used for the first 2 weeks, followed by fluconazole or flucytosine orally. 13 566 Section 13 Fever and Acute Infections in a Critical Care Setting REFERENCES 1. Pfaller MA, Diekema DJ. Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev. 2007;20:133-63. 2. Horn DL, Neofytos D, Anaissie EJ, et al. Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis. 2009;48(12):1695-703. 3. Oberoi JK, Wattal C, Goel N, et al. Non-albicans candida species in blood stream infections in a tertiary care hospital at New Delhi, India. Indian J Med Res. 2012;136(6):997-1003. 4. Len C, Ruiz-Santana S, Saavedra P, et al. A bedside scoring system (candida score) for early antifungal treatment in nonneutropenic critically ill patients with Candida colonization. Crit Care Med. 2006;34(3):730-7. 5. Ostrosky-Zeichner L, Sable C, Sobel J, et al. Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting. Eur J Clin Microbiol Infect Dis. 2007;26(4):271-6. 6. Odabasi Z, Mattiuzzi G, Estey E, et al. Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis. 2004;39(2):199-205. 7. Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(5):503-35. 8. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(3):327-60. 9. Spellberg B, Walsh TJ, Kontoyiannis DP. Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis. 2009;48(12):1743-51. 10. Ostrosky-Zeichner L, Rex JH. Antifungal and antiviral therapy. In: Parrillo JE (Ed). Critical Care Medicine, 3rd edition. Philadelphia: Mosby Elsevier; 2008. pp. 1089-109.
Epidemiological Profile of Acute Typical Bacterial Pneumonia at The National Reference University Hospital Center of NDjamena Risk Factors and Antibiotic Resistance