The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

Review Article

Primary Care I NFECTIONS IN P ATIENTS WITH D IABETES M ELLITUS

patients with diabetes; Table 2 summarizes their treatment, and Table 3 summarizes the various aspects of foot infections.
Respiratory Tract Infections

ONTRARY to common belief, the association between diabetes mellitus and increased susceptibility to infection in general is not supported by strong evidence.1,2 However, many specific infections are more common in diabetic patients, and some occur almost exclusively in them. Other infections occur with increased severity and are associated with an increased risk of complications in patients with diabetes. Several aspects of immunity are altered in patients with diabetes. Polymorphonuclear leukocyte function is depressed, particularly when acidosis is also present. Leukocyte adherence, chemotaxis, and phagocytosis may be affected.3-5 Antioxidant systems involved in bactericidal activity may also be impaired.6 The clinical data on humoral immunity are limited, but responses to vaccines appear to be normal. Cutaneous responses to antigen challenges and measures of T-cell function may be depressed. Although these in vitro findings have not yet been fully confirmed in clinical studies, there is evidence that improving glycemic control in patients improves immune function. For example, the efficiency of intracellular killing of microorganisms may improve with better glycemic control.5 Among diabetic patients undergoing heart surgery, those given insulin infusions have better neutrophil function than those given intermittent insulin therapy.7 Blood glucose levels should be closely controlled in diabetic patients with infections.8
COMMON INFECTIONS IN PATIENTS WITH DIABETES

It remains uncertain whether diabetes is an independent risk factor for an increased incidence or severity of common upper or lower respiratory tract infections.9,10 In the largest meta-analysis of community-acquired pneumonia to date, the odds ratio for death associated with diabetes was only 1.3 (95 percent confidence interval, 1.1 to 1.5).11 A retrospective cohort study did not identify diabetes as a significant independent risk factor for death at 30 days in elderly patients with pneumonia.12 However, two patterns of susceptibility to pneumonia in patients with diabetes have been noted.9 Infections caused by certain microorganisms (Staphylococcus aureus, gramnegative organisms, and Mycobacterium tuberculosis) occur with increased frequency. Infections due to other microorganisms (Streptococcus pneumoniae and influenzavirus) are associated with increased mortality and morbidity. Diabetes is a risk factor for bacteremia in patients with pneumococcal pneumonia and is associated with increased mortality.13,14 Diabetic patients have a normal response to pneumococcal vaccination, and vaccination is a cost-effective preventive strategy. There is increased mortality and an increased incidence of bacterial pneumonia and ketoacidosis among diabetic patients during epidemics of influenza pneumonia.9 Reduced pulmonary ciliary clearance in patients with influenza, combined with the high incidence of nasal carriage of Staph. aureus among diabetic patients, leads to an increased incidence of staphylococcal pneumonia. Guidelines recommend influenza and pneumococcal vaccines for all patients with diabetes.15
Urinary Tract Infections

Table 1 summarizes the clinical features, diagnosis, and causative organisms of common infections in
From Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pa. (N.J., G.M.C., M.R.W.); and Harvard Medical School, Beth Israel Deaconess Medical Center, Boston (A.W.K.). Address reprint requests to Dr. Joshi at Pennsylvania State University College of Medicine, Suite UPC 4100, Milton S. Hershey Medical Center, P.O. Box 850, MC-HU15, Hershey, PA 17033. 1999, Massachusetts Medical Society.

Several controlled studies have demonstrated a higher incidence of bacteriuria (by a factor of two to four) in diabetic women than in nondiabetic women.16-18 Whether this increase is due to the increased use of urinary tract catheters in these women or to diabetes itself is debated.19 Diabetes may also predispose patients to more severe infections of the upper urinary tract; the upper tract is involved in up to 80 percent of urinary tract infections in diabetic patients.20 Complications also occur more frequently in diabetic patients than in nondiabetic patients with established urinary tract infections.1 The clinical presentation of acute pyelonephritis in diabetic patients is similar to that in nondiabetic

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PRIMA RY CA R E

TABLE 1. CLINICAL FEATURES, DIAGNOSIS, AND CAUSATIVE ORGANISMS OF SELECTED INFECTIONS IN PATIENTS WITH DIABETES.
INFECTION CLINICAL FEATURES DIAGNOSTIC PROCEDURE* ORGANISMS COMMENTS

Respiratory tract Community-acquired pneumonia

Cough, fever

Chest radiography

Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, other gram-negative bacilli, atypical pathogens Escherichia coli, proteus species E. coli, proteus species E. coli, other gram-negative bacilli E. coli, other gram-negative bacilli Candida species Gram-negative bacilli, anaerobes (type I), or group A streptococci (type II) Pseudomonas aeruginosa Mucor and rhizopus species

Pneumococcal infection carries a higher risk of death in diabetic than in nondiabetic patients Bacteriuria more common in diabetic than in nondiabetic women Emphysematous infection should be considered Emergency nephrectomy often required Surgical drainage usually required Difficult to distinguish colonization from infection High mortality; emergency surgery required Prompt otolaryngologic consultation recommended Strong association with ketoacidosis; emergency surgery required High mortality; gallstones in 50%; emergency cholecystectomy required

Urinary tract Acute bacterial cystitis Acute pyelonephritis Emphysematous pyelonephritis Perinephric abscess Fungal cystitis Soft tissue Necrotizing fasciitis Other Invasive otitis externa Rhinocerebral mucormycosis Abdomen Emphysematous cholecystitis

Increased urinary frequency, dysuria, suprapubic pain Fever, flank pain Fever, flank pain, poor response to antibiotics Fever, flank pain, poor response to antibiotics Same as for acute bacterial cystitis Local pain, redness, crepitus, bullous skin lesions Ear pain, otorrhea, hearing loss, cellulitis Facial or ocular pain, fever, lethargy, black nasal eschar Fever, right-upper-quadrant abdominal pain, systemic toxicity

Urine culture Urine culture Radiography or CT scanning Ultrasonography or CT scanning Urine culture Radiography or CT scanning Clinical examination, magnetic resonance imaging Clinical examination, magnetic resonance imaging, pathological findings Radiography

Gram-negative bacilli, anaerobes

*CT denotes computed tomography. Foot infections are described in detail in Table 3.

patients, except that bilateral infection is more common in patients with diabetes.21 Plain abdominal radiography may document emphysematous infection.22 Treatment includes hydration and parenteral antibiotics (Table 2). A poor response to antibiotic therapy suggests complications, which may include papillary necrosis or perinephric abscess.1 Symptoms of papillary necrosis include flank and abdominal pain, accompanied by fever.23,24 The diagnosis is established by retrograde pyelography.25 In one series of patients with perinephric abscess, 36 percent had diabetes.26 Most cases (80 percent) occur as a complication of ascending urinary tract infection and are therefore caused by Escherichia coli or proteus species. Hematogenous infection, most commonly caused by Staph. aureus, accounts for the remainder of the cases. Although localizing clinical findings such as a flank or abdominal mass are highly suggestive, they are present in less than 25 percent of cases. Thorley et al.27 noted that fever that persisted for more than four days after the initiation of antibiotic therapy was the most useful factor in differentiating perinephric abscess from uncomplicated pyelonephritis. The diagnosis is established by ultrasonography or computed tomo-

graphic (CT) scan. Surgical drainage and systemic antibiotics are the mainstays of therapy.1 Diabetes is a common predisposing factor for urinary tract infections caused by fungi, particularly candida species. The extent of involvement ranges from inconsequential lower urinary tract colonization to clinical cystitis, emphysematous cystitis,28 pyelonephritis, and renal or perinephric abscess.29,30 Whereas upper urinary tract and disseminated infections require systemic therapy, the appropriate treatment of candida infection confined to the bladder remains controversial.30 Distinguishing such infection from colonization may be difficult. The presence of symptoms or pyuria suggests infection. Spontaneous resolution of funguria occurs in many cases.31,32 Removal of an indwelling catheter, if one is present, is recommended as the initial intervention. The treatment options include bladder irrigation with amphotericin B,33 a single dose of intravenous amphotericin B,34 or oral fluconazole.35 In one study, the rate of eradication seven days after therapy was higher in patients who received oral fluconazole for four days or single-dose intravenous amphotericin B than in those who underwent bladder irrigation with amphotericin B for
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TABLE 2. TREATMENT
INFECTION

OF

SELECTED INFECTIONS

IN

PATIENTS

WITH

DIABETES.
OTHER TREATMENT

EMPIRICAL ANTIMICROBIAL THERAPY

Respiratory tract Community-acquired pneumonia (outpatient) Community-acquired pneumonia (hospitalized patient)

Macrolide (e.g., erythromycin, 500 Doxycycline, 100 mg orally twice mg orally every 6 hr, or azithromydaily cin, 500 mg orally on day 1, then 250 mg per day on days 25) Cefuroxime, 0.75 g intravenously Levofloxacin, 500 mg intraveevery 6 hr, or ceftriaxone, 12 g nously every 24 hr, or doxyintravenously per day; consider cycline, 100 mg intravenously adding erythromycin, 0.51.0 g every 12 hr intravenously every 6 hr (or azithromycin, 500 mg intravenously per day, or doxycycline, 100 mg intravenously every 12 hr) Trimethoprimsulfamethoxazole, double strength, 1 pill twice daily Fluoroquinolones (e.g., ciprofloxacin, 250 mg twice daily, or ofloxacin, 200 mg twice daily) Fluoroquinolones (e.g., ciprofloxaAmpicillin, 2 g intravenously every cin, 400 mg intravenously every 6 hr, plus gentamicin, 5 mg/kg 12 hr, or ofloxacin, 400 mg intraevery 24 hr, or ceftriaxone, 2 g venously every 12 hr) intravenously per day, or piperacillin, 3 g intravenously every 6 hr

Urinary tract Acute bacterial cystitis Acute pyelonephritis

Early surgical intervention in emphysematous infection

Perinephric abscess Associated with staphylococcal bacteremia Associated with pyelonephritis Fungal cystitis

Nafcillin, 2 g intravenously every 4 hr Cefazolin, 2 g intravenously every 8 hr, or vancomycin, 15 mg/kg intravenously every 6 hr Same as for acute pyelonephritis Fluconazole, 200 mg orally on day 1, Amphotericin B bladder irrigation then 100 mg per day for 4 days (50 mg per liter of sterile water at 40 ml/hr for 2448 hr), or single dose of intravenous amphotericin B, 0.3 mg/kg Penicillin G, 24 million U intravenously per day, plus clindamycin, 900 mg intravenously every 8 hr, and gentamicin, 5 mg/kg intravenously per day Ciprofloxacin, 400 mg intravenously every 12 hr, and topical antipseudomonal or acetic acid drops Amphotericin B, target dose, 1.01.5 mg/kg intravenously per day Total dose, 2.53.0 g Ampicillinsulbactam, 3 g intravenously every 6 hr Ceftriaxone, 2 g intravenously every 24 hr, plus clindamycin, 900 mg intravenously every 8 hr Ceftazidime, 2 g intravenously every 8 hr, or imipenem, 500 mg intravenously every 6 hr

Surgical drainage

Removal of urinary catheter

Soft tissue Necrotizing fasciitis

Prompt surgical dbridement

Other Invasive otitis externa Rhinocerebral mucormycosis Abdomen Emphysematous cholecystitis

Surgical dbridement Surgical dbridement; aggressive treatment of ketoacidosis (if present)

Ampicillin, 2 g intravenously every 6 hr, plus gentamicin, 5 mg/kg every 24 hr, plus clindamycin, 900 mg intravenously every 8 hr (or metronidazole, loading dose of 15 mg/kg intravenously, followed by 7.5 mg/kg intravenously every 6 hr), or ceftriaxone, 2 g intravenously every 24 hr plus clindamycin (or metronidazole)

Emergency cholecystectomy required

*All doses are for patients with normal renal and hepatic function. The initial intravenous regimen may be changed to an oral regimen as soon as the patients clinical condition allows, unless the underlying infection requires prolonged parenteral therapy (e.g., staphylococcal bacteremia). Foot infections are described in detail in Table 3.

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PR IMA RY CA R E

TABLE 3. FOOT INFECTIONS

IN

PATIENTS

WITH

DIABETES.
INITIAL MANAGEMENT

DIAGNOSTIC PROCEDURE

CAUSATIVE ORGANISMS

Mild, nonlimbthreatening

Shallow ulcer; less than 2 cm cellulitis; Plain radiography, no evidence of fasciitis, abscess, possibly culture* or osteomyelitis; no evidence of ischemia; good metabolic control Deep ulcer; more than 2 cm cellulitis; suspected deep infection; ischemia; poor metabolic control

Primarily aerobic grampositive cocci (e.g., Staphylococcus aureus, streptococci)

Limb-threatening

Plain radiography; deep Polymicrobial: aerobic cultures; probe to gram-positive cocci, bone test strict anaerobes (e.g., Bacteroides fragilis), and gram-negative bacilli (e.g., Escherichia coli)

Oral antibiotics; wound care; outpatient management if there is good home support Immediate hospitalization and surgical consultation; broadspectrum intravenous antibiotics; wound care

*Since gram-positive cocci are the anticipated pathogens, cultures are not clearly required in each case. Recommended oral antibiotics include cephalexin, clindamycin, and amoxicillinclavulanate. Wound care includes sharp dbridement of devitalized tissue and callus, sterile dressings, and relief of pressure at the ulcer. The ability to touch bone when the wound is gently probed with a sterile surgical probe is predictive of underlying osteomyelitis. Recommended intravenous antibiotics include a beta-lactam plus a beta-lactamase inhibitor (e.g., ampicillinsulbactam) or clindamycin plus a gram-negative drug (e.g., a third-generation cephalosporin, a fluoroquinolone, or aztreonam). Vancomycin plus imipenemcilastatin is recommended for life-threatening infections.

three days.35 In another study, patients receiving amphotericin B bladder irrigation had higher rates of eradication two days after the beginning of therapy than those receiving oral fluconazole, but the cure rates in the two groups were similar one month after the beginning of therapy.36 Currently, fluconazole is the preferred drug because of its ease of administration and relative absence of toxicity (Table 2).
Soft-Tissue Infections

Foot infections are the most common soft-tissue infections in patients with diabetes (Table 3). Potential complications include osteomyelitis, amputation, and death. Surgical dbridement of all devitalized tissue is essential, and a multidisciplinary approach to the treatment of foot infection is recommended.37 Among nonpedal soft-tissue infections, necrotizing fasciitis is the most important.38-41 The associated mortality is approximately 40 percent. The infection starts in the subcutaneous space and spreads along fascial planes. The most common locations are the arms and legs and the abdominal wall. Necrotizing fasciitis has been classified as type I (infection caused by a combination of anaerobic and one or more facultative aerobic organisms) or type II (caused by group A streptococci, with or without staphylococci). It is clinically more useful to classify them as monomicrobial infections caused by streptococci (10 percent of cases) or polymicrobial infections caused by facultative gram-negative bacilli such as E. coli and strict anaerobes such as Bacteroides fragilis or clostridium species (90 percent of cases). The degree of pain typically is disproportionate to the severity of the findings on physical examination, such as erythema, swelling, and tenderness.38 Marked systemic toxicity is present. Later, more definitive skin

changes appear in the form of bullous lesions accompanied by localized anesthesia as a result of the occlusion of cutaneous arterioles. A cutaneous wound or eschar is often noted. Crepitus is a useful finding but is noted in only about half of cases. Soft-tissue gas may be detected more frequently by plain radiography than by clinical examination. In one study, gas was identified radiographically in 17 of 21 diabetic patients with necrotizing fasciitis.42 Fourniers gangrene is a form of necrotizing fasciitis involving the male genitalia.43 The infection usually involves the scrotum but may extend to the penis, perineum, and abdominal wall, and scrotal gangrene can occur rapidly. Emergency evaluation and treatment of necrotizing fasciitis are imperative. Broad-spectrum intravenous antibiotics are required (Table 2). Both Stevens et al.44 and Eagle45 noted a decreased efficacy of penicillin, due to the slower growth rate of the organism at a high inoculum, in laboratory animals with severe streptococcal infection. Clindamycin is more effective than penicillin in vitro.44 Because of the possibility of clindamycin resistance and the potentially life-threatening nature of this infection, a combination of penicillin and clindamycin is recommended, with the addition of gentamicin, pending the results of cultures. Prompt, aggressive surgical dbridement is crucial in decreasing mortality.
INFECTIONS OCCURRING PRINCIPALLY IN PATIENTS WITH DIABETES
Invasive Otitis Externa

Invasive (malignant) otitis externa is an uncommon but potentially life-threatening infection of the external auditory canal and skull.46,47 Pseudomonas aeruginosa is the causative organism in the vast majority of cases. Unrelenting pain, otorrhea, and hearing
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loss without fever are the characteristic symptoms. The diagnosis is often delayed for six to eight weeks if these symptoms are mistakenly attributed to typical, noninvasive otitis externa. There is intense cellulitis and edema of the auditory canal with formation of polypoid granulation tissue. Extension of the infection may result in cranial osteomyelitis and intracranial involvement.47 Early consultation with an otolaryngologist will facilitate the clinical diagnosis, the dbridement of necrotic tissue, and acquisition of deep tissue samples for Grams staining and culture. Tissue biopsy to rule out epidermal carcinoma is recommended. Magnetic resonance imaging with gadolinium is the most useful method for documenting the initial extent of soft-tissue involvement (including dural inflammation) and bone involvement. Gallium-67 single-photon-emission CT has also been reported to be useful both for early diagnosis and for follow-up during treatment.48,49 Treatment includes repeated dbridement of the ear, application of topical antipseudomonal or acetic acid drops, and use of systemic antibiotic therapy against Pseud. aeruginosa for four to six weeks (Table 2).
Rhinocerebral Mucormycosis

Emphysematous Infections
Cholecystitis

The intraabdominal infection characteristically associated with diabetes is emphysematous cholecystitis, an uncommon, gas-producing, virulent infection of the gallbladder. Approximately 35 percent of cases occur in patients with diabetes.54,55 Emphysematous cholecystitis may be clinically similar to acute cholecystitis, but the proportion of male patients is higher, gangrene of the gallbladder and perforation are more frequent, and the overall mortality is substantially higher (15 percent vs. less than 4 percent) than in patients with acute cholecystitis.55 Gallstones are present in only 50 percent of patients with emphysematous cholecystitis. The patients have pain in the right upper quadrant of the abdomen, nausea, vomiting, and fever. Although clinical signs of peritonitis are often absent, crepitus on abdominal palpation may be present and is an ominous sign.25 The diagnosis is established by radiographic demonstration of gas on plain films or by abdominal CT scanning.55,56 Polymicrobial infection with gram-negative bacilli and anaerobes is most common. Prompt cholecystectomy, in addition to broad-spectrum antibiotic therapy, is imperative (Table 2).
Pyelonephritis and Cystitis

Approximately 50 percent of cases of rhinocerebral mucormycosis occur in diabetic patients. Ketoacidosis is the most important risk factor; in vitro studies have documented a lack of inhibitory activity of serum from patients with diabetic ketoacidosis against Rhizopus oryzae that is restored on correction of acidosis.50 Early manifestations include facial or ocular pain and nasal stuffiness, with or without discharge.51 Later, proptosis, chemosis, and necrotic lesions on the palate or nasal mucosa occur. A black necrotic eschar on the nasal turbinates may be an important clue to the diagnosis.52 Generalized headache, fever, and lethargy may be present. Ophthalmoplegia or visual loss from cranial-nerve involvement may accompany cavernous sinus thrombosis. Thrombosis of the carotid artery or jugular vein may cause hemiparesis. The diagnosis is established by biopsy and culture of necrotic tissue from the nasal passages or the palate. Direct sampling from the sinuses may be necessary. The histologic finding of broad, nonseptate, haphazardly branching hyphae invading tissue confirms the diagnosis; cultures are often negative. Magnetic resonance imaging is preferred to define involvement of the sinuses, orbit, cavernous sinus, and central nervous system. Surgical dbridement of infected tissue and drainage of infected sinuses are key elements in achieving a cure. Control of diabetes and institution of amphotericin B are crucial adjunctive therapies. Imidazole antifungal drugs (fluconazole and itraconazole) cannot be recommended as first-line therapy.53
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Emphysematous pyelonephritis is a gas-forming infection of the renal parenchyma, perinephric tissues, and collecting system. Over 90 percent of cases occur in diabetic patients.25 Papillary necrosis complicates 21 percent of cases.23 Between 50 percent and 75 percent of cases are caused by E. coli,23,24 and most of the rest are caused by other gram-negative bacilli. Patients with emphysematous pyelonephritis usually present with a fever of rapid onset, chills, flank pain, nausea, and vomiting, occasionally accompanied by an abdominal mass. Failure of fever to resolve after three or four days of treatment of a urinary tract infection in a diabetic patient should arouse concern about the possibility of this uncommon complication.1 The diagnosis is made by demonstrating gas within the kidney tissue. Abdominal CT scanning is best for this purpose, since plain radiographs show gas in only about one third of patients.23 Initial treatment consists of vigorous hydration and intravenous antibiotics, in addition to aggressive control of hyperglycemia. Most cases require additional surgical intervention. Obstruction should be sought and treated appropriately. Total nephrectomy is considered for patients whose condition does not improve clinically or in whom gas spreads despite nonsurgical treatment. Radiographically guided percutaneous drainage has been reported to be successful in cases in which infection is localized.57 The presence of emphysematous cystitis, an uncommon sequela of lower urinary tract infections, is suggested by pneumaturia. Plain radiographs of the pelvis confirm the diagnosis.

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MICROORGANISMS STRONGLY ASSOCIATED WITH INFECTIONS IN PATIENTS WITH DIABETES

Patients with diabetes seem to be at particularly high risk for infection with certain microorganisms. For example, in a group of nonpregnant adults with group B streptococcal bacteremia, the prevalence of diabetes was found to be 27.5 percent.58 A disproportionately high incidence (30 to 60 percent) of diabetes has been reported in several series of patients with klebsiella infections, including bacteremia,59 liver abscess,60 endophthalmitis,61 and thyroid abscess.62 Diabetes has been identified as a risk factor for infection with Salmonella enteritidis.63 In several studies in the first half of the 20th century, the incidence of tuberculosis among persons with diabetes was found to be three or four times as high as in the general population.64,65 More recently, in an immigrant Asian community in England, lung cavitation was found to be more common among diabetic than nondiabetic persons.66 Although Staph. aureus infections have been noted to be more common among patients with diabetes, a recent careful review concluded that currently available data do not allow an estimation of the proportional risk of such infection among diabetic patients.67 A study of bacteremia caused by Staph. aureus found no difference in mortality between diabetic and nondiabetic patients.68 Other infections that occur with increased frequency in patients with diabetes include mucocutaneous candida infections such as oropharyngeal candidiasis, candidal vulvovaginitis, and cutaneous candidiasis in the intertriginous areas of obese diabetic patients.69
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1. Wheat LJ. Infection and diabetes mellitus. Diabetes Care 1980;3:187-97. 2. Thornton GF. Infections and diabetes. Med Clin North Am 1971;55: 931-8. 3. Valerius NH, Eff C, Hansen NE, et al. Neutrophil and lymphocyte function in patients with diabetes mellitus. Acta Med Scand 1982;211:463-7. 4. Delamaire M, Maugendre D, Moreno M, Le Goff MC, Allannic H, Genetet B. Impaired leucocyte functions in diabetic patients. Diabet Med 1997;14:29-34. 5. Gallacher SJ, Thomson G, Fraser WD, Fisher BM, Gemmell CG, MacCuish AC. Neutrophil bactericidal function in diabetes mellitus: evidence for association with blood glucose control. Diabet Med 1995;12:916-20. 6. Muchova J, Liptakova A, Orszaghova Z, et al. Antioxidant systems in polymorphonuclear leucocytes of type 2 diabetes mellitus. Diabet Med 1999;16:74-8. 7. Rassias AJ, Marrin CA, Arruda J, Whalen PK, Beach M, Yeager MP. Insulin infusion improves neutrophil function in diabetic cardiac surgery patients. Anesth Analg 1999;88:1011-6. 8. McMahon MM, Bistrian BR. Host defenses and susceptibility to infection in patients with diabetes mellitus. Infect Dis Clin North Am 1995;9:1-9. 9. Koziel H, Koziel MJ. Pulmonary complications of diabetes mellitus: pneumonia. Infect Dis Clin North Am 1995;9:65-96. 10. Woodhead MA, Macfarlane JT, McCracken JS, Rose DH, Finch RG. Prospective study of the aetiology and outcome of pneumonia in the community. Lancet 1987;1:671-4. 11. Fine MJ, Smith MA, Carson CA, et al. Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis. JAMA 1996; 275:134-41. 12. Houston MS, Silverstein MD, Suman VJ. Risk factors for 30-day mortality in elderly patients with lower respiratory tract infection: communitybased study. Arch Intern Med 1997;157:2190-5.

13. Marrie TJ. Bacteraemic pneumococcal pneumonia: a continuously evolving disease. J Infect 1992;24:247-55. 14. Bouter KP, Diepersloot RJ, van Romunde LK, et al. Effect of epidemic influenza on ketoacidosis, pneumonia and death in diabetes mellitus: a hospital register survey of 19761979 in the Netherlands. Diabetes Res Clin Pract 1991;12:61-8. 15. American College of Physicians Task Force on Adult Immunization. Guide for adult immunization. 2nd ed. Philadelphia: American College of Physicians, 1990. 16. Kass EH. Bacteriuria and the diagnosis of infections of the urinary tract: with observations on the use of methionine as a urinary antiseptic. Arch Intern Med 1957;100:709-14. 17. Hansen R. Bacteriuria in diabetic and non-diabetic out-patients. Acta Med Scand 1964;176:721-30. 18. Vejlsgaard R. Studies on urinary tract infection in diabetes. I. Bacteriuria in patients with diabetes mellitus and in control subjects. Acta Med Scand 1966;179:173-82. 19. Pometta D, Rees SB, Younger D, Kass EH. Asymptomatic bacteriuria in diabetes mellitus. N Engl J Med 1967;276:1118-21. 20. Forland M, Thomas V, Shelokov A. Urinary tract infections in patients with diabetes mellitus: studies on antibody coating of bacteria. JAMA 1977;238:1924-6. 21. Ellenbogen PH, Talner LB. Uroradiology of diabetes mellitus. Urology 1976;8:413-9. 22. Evanoff GV, Thompson CS, Foley R, Weinman EJ. Spectrum of gas within the kidney: emphysematous pyelonephritis and emphysematous pyelitis. Am J Med 1987;83:149-54. 23. Michaeli J, Mogle P, Perlberg S, Heiman S, Caine M. Emphysematous pyelonephritis. J Urol 1984;131:203-8. 24. Schainuck LI, Fouty R, Cutler RE. Emphysematous pyelonephritis: a new case and review of previous observations. Am J Med 1968;44:134-9. 25. Smitherman KO, Peacock JE Jr. Infectious emergencies in patients with diabetes mellitus. Med Clin North Am 1995;79:53-77. 26. Edelstein H, McCabe RE. Perinephric abscess: modern diagnosis and treatment in 47 cases. Medicine (Baltimore) 1988;67:118-31. 27. Thorley JD, Jones SR, Sanford JP. Perinephric abscess. Medicine (Baltimore) 1974;53:441-51. 28. Singh CR, Lytle WF Jr. Cystitis emphysematosa caused by Candida albicans. J Urol 1983;130:1171-3. 29. High KP, Quagliarello VJ. Yeast perinephric abscess: report of a case and review. Clin Infect Dis 1992;15:128-33. 30. Fisher JF, Newman CL, Sobel JD. Yeast in the urine: solutions for a budding problem. Clin Infect Dis 1995;20:183-9. 31. Wong-Beringer A, Jacobs RA, Guglielmo J. Treatment of funguria. JAMA 1992;20:2780-5. 32. Frye KR, Donovan JM, Drach GW. Torulopsis glabrata urinary infections: a review. J Urol 1988;139:1245-9. 33. Wise GJ, Kozinn PJ, Goldberg P. Amphotericin B as a urologic irrigant in the management of noninvasive candiduria. J Urol 1982;128:82-4. 34. Fisher JF, Hicks BC, Dipiro JT, Venable J, Fincher RM. Efficacy of a single intravenous dose of amphotericin B in urinary tract infections caused by Candida. J Infect Dis 1987;156:685-7. 35. Leu HS, Huang CT. Clearance of funguria with short-course antifungal regimens: a prospective, randomized, controlled study. Clin Infect Dis 1995;20:1152-7. 36. Jacobs LG, Skidmore EA, Freeman K, Lipschultz D, Fox N. Oral fluconazole compared with bladder irrigation with amphotericin B for treatment of fungal urinary tract infections in elderly patients. Clin Infect Dis 1996;22:30-5. 37. Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW. Assessment and management of foot disease in patients with diabetes. N Engl J Med 1994;331:854-60. 38. Sentochnik DE. Deep soft-tissue infections in diabetic patients. Infect Dis Clin North Am 1995;9:53-64. 39. Pessa ME, Howard RJ. Necrotizing fasciitis. Surg Gynecol Obstet 1985;161:359-61. 40. Gozal D, Ziser A, Shupak A, Ariel A, Melamed Y. Necrotizing fasciitis. Arch Surg 1986;121:233-5. 41. Ahrenholz DA. Necrotizing soft-tissue infections. Surg Clin North Am 1988;68:199-214. 42. Canoso JJ, Barza M. Soft tissue infections. Rheum Dis Clin North Am 1993;19:293-309. 43. Laucks SS II. Fourniers gangrene. Surg Clin North Am 1994;74: 1339-52. 44. Stevens DL, Gibbons AE, Bergstrom R, Winn V. The Eagle effect revisited: efficacy of clindamycin, erythromycin, and penicillin in the treatment of streptococcal myositis. J Infect Dis 1988;158:23-8. 45. Eagle H. Experimental approach to the problem of treatment failure with penicillin. I. Group A streptococcal infection in mice. Am J Med 1952;13:389-99.

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