CLINICAL DIABETES
VOL. 18 NO. 3 Summer 2000


FEATURE ARTICLE


Infectious Emergencies in Patients With Diabetes


Douglas S. Paauw, MD, FACP


IN BRIEF

Several infectious diseases are strongly associated with diabetes, whereas others are more complicated or severe in the presence of diabetes. This article reviews the infectious diseases unique to or more complicated in patients with diabetes and offers therapy recommendations for each.

Patients with diabetes appear to be at greater risk for a number of different kinds of infections. Good data delineating the risk of specific infections are lacking. Conflicting data exist on carriage rates of Staphylococcus aureus and risk of specific staphylococcal infections.1-3 This article will cover several serious infections that are strongly associated with diabetes.

SOFT TISSUE INFECTIONS
Pyomyositis
Pyomyositis is a bacterial infection of the skeletal muscle. The clinical features include fever, localized muscle pain, and swelling of the involved muscles.4,5 The largest reported series of pyomyositis in the United States involved 84 patients, 15% of whom had diabetes.6 Numerous case reports of pyomyositis have involved patients with diabetes.7-10 Almost all cases (90%) of pyomyositis are due to S. aureus.

The most useful diagnostic modality for pyomyositis is computed tomography (CT) or magnetic resonance imaging (MRI) scanning.11-13 MRI is extremely helpful in delineating the extent of muscle involvement. CT- or MRI-guided muscle biopsy or open biopsy of the affected muscle is the definitive diagnostic test. The disease with the most similar presentation to pyomyositis in the differential diagnosis of the acutely swollen painful leg in patients with diabetes is diabetic muscle infarction.14,15 The MRI appearance can be similar to that of pyomyositis. Biopsy is the definitive test to distinguish between these two diseases.

Therapy for pyomyositis is with intravenous antibiotics with good S. aureus coverage. Nafcillin or a first-generation cephalosporin is usually the best choice. In areas of high prevalence of methicillin-resistant S. aureus, the use of vancomycin empirically is appropriate until cultures and sensitivities return. The outcome is usually good with minimal long-term sequelae.5

Necrotizing Fasciitis
Necrotizing fasciitis is a deep infection of the subcutaneous tissue that results in destruction of fascia and fat. It has a very high mortality rate. Patients with diabetes make up 2030% of patients in case series on necrotizing fasciitis.12,16-18

Type I necrotizing fasciitis is more common in patients with diabetes and is usually due to a mixed aerobic and anaerobic infection. Common organisms include S. aureus, Group A streptococci, Escherichia coli, and a variety of anaerobic organisms. The portal of entry is usually on a foot scrape or ulcer. Rapid extension can occur along the fascia into the leg.

A typical feature of early necrotizing fasciitis is pain far out of proportion to the clinical findings on examination. This is because the inflammation is deep and rarely involves the overlying skin early in the course of the disease. The involved area is usually tender to palpation. Patients often exhibit signs of systemic toxicity including fever, tachycardia, and hypotension. Late-appearing physical findings include bullae formation in the skin, gangrene, ulcerations, and skin discoloration. Crepitance due to underlying gas formation is present in about half of patients and is seen late in the course. It may be more common in patients with diabetes. In one series, gas was visualized on X-ray in 17 of 21 patients with diabetes.19 Lab tests usually show an elevated white blood count with a left shift. Creatinine phosphokinase levels are often elevated.

Definitive diagnosis is made by surgical exploration. CT or MRI scanning are most useful in cases where the clinical suspicion is modest. Absence of deeper tissue involvement confirmed by the MRI or CT is helpful in cases where the clinical likelihood of necrotizing fasciitis is relatively low. If the clinical suspicion is high, then surgical exploration has a dual role, both diagnostically and therapeutically.

Therapy for necrotizing fasciitis consists of aggressive surgical exploration and debridement of nonviable tissue. Antibiotic therapy should be based on surgical gram stain and culture results. Empiric therapy before surgery should include clindamycin plus a broad-spectrum penicillin plus a B lactamase inhibitor such as piperacillin-sulbactam. In penicillin-allergic patients, a fluoroquinolone can be added to clindamycin (Cleocin). Animal studies have shown superiority of clindamycin over penicillin for treatment of Group A streptococcal fasciitis.20

Malignant External Otitis
Malignant external otitis, also called invasive external otitis, is a disease that occurs almost exclusively in patients with diabetes.21 Over 90% of reported cases of malignant external otitis have occurred in patients with diabetes as an underlying risk factor.22,23 Most cases of malignant external otitis occur in patients with type 2 diabetes. Diabetic microangiopathy is one possible explanation for the preponderance of this disease in elderly patients with type 2 diabetes.23 Another recognized risk factor is irrigation of the external auditory canal with nonsterile water (tap water).21,22,24

Otalgia is the most common clinical feature of malignant external otitis, occurring in more than 90% of patients.22,25 The pain is described as lancinating and throbbing, does not respond to routine analgesics, and is worse at night. Tenderness and swelling in the periauricular area is common. Most patients will develop purulent otorrhea during the course of their disease. Granulation tissue is usually present in the ear canal. Frequently, the ear canal can become occluded, blocking visualization of the tympanic membrane and leading to mild conductive hearing loss.

Because the early features are similar to simple external otitis, the diagnosis is often delayed for several months. Cranial nerve dysfunction occurs in about one-third of patients, almost always involving the seventh cranial nerve.26 When cranial nerve dysfunction occurs, the patient has usually had symptoms of malignant external otitis for months.

Diagnosis is made based on history and physical exam findings supported by radiological studies. CT and MRI scanning are useful in establishing osteomyelitis underlying malignant external otitis. MRI scanning is more sensitive at picking up soft tissue abnormalities.27 CT and MRI scanning are not helpful in following disease progression or healing because abnormalities may persist despite clinical improvement. CT scans can fail to show abnormalities early in the course of the disease. Gallium-67 scans are very sensitive and can show abnormalities early in the course of the disease.28 Gallium uptake returns to normal quickly when infection is cleared, so there is a role for using these scans to follow resolution. Technetium bone scans are sensitive for the presence of osteomyelitis of the skull base and can be positive before this is picked up by a CT or MRI scan.29 The bone scan can remain positive for months after infection has cleared, so follow-up bone scans are not helpful to evaluate for resolution.

Therapy is directed at pseudomonas aeruginosa, the most commonly involved organism. Culture of ear debris and granulation tissue is important to make sure long-term antibiotic therapy is directed at the correct organism and to ascertain drug susceptibilities. Traditionally, therapy has been with an antipseudomonal penicillin and an aminoglycoside for 4–6 weeks. Ceftazidime (Fortaz), an antipseudomonal third-generation cephalosporin has been reported to be an effective single-drug therapy.30 Lang and associates studied 23 consecutive patients with malignant external otitis.31 All received local surgical debridement and 1.5–2.25 g of oral ciprofloxacin (Cipro) for a total of 6 weeks. A cure was achieved in 21 patients (91%). Mortality from malignant external otitis is 10–20% and is highest if cranial nerve involvement is present.22,26

URINARY TRACT INFECTIONS
Acute Pyelonephritis

Acute pyelonephritis is a more common disease in patients with diabetes than in nondiabetic patients.32 Patients with diabetes are more likely to have bacteruria, and recurrent urinary tract infections are more common in these patients.33 Patients with diabetes should not receive short-course (3-day) cystitis therapy because asymptomatic upper tract disease may be more common with diabetes.

The frequency of organisms causing urinary tract infection in patients with diabetes is slightly different than in patients without diabetes. E. coli is the most common organism in both groups, but klebsiella and gram-positive cocci are more common in community-acquired urinary tract infections in patients with diabetes.34

Current recommendations are to treat for a full 7-day course for cystitis in patients with diabetes.35 Patients with pyelonephritis who are vomiting, hypovolemic, or have uncontrolled blood glucose levels should be admitted for intravenous antibiotics and control of blood glucose with an insulin drip.

Renal Emphysema
Two distinct clinical entities, emphysematous pyelonephritis and emphysematous pyelitis, can cause gas to occur in the kidney. Both are strongly associated with the presence of underlying diabetes. More than 90% of cases of emphysematous pyelonephritis occur in patients with diabetes, whereas diabetes is present in half of the cases of emphysematous pyelitis.36 Both infections are extremely serious with high mortality rates.

Emphysematous pyelonephritis is a necrotizing gas-producing infection of the renal parenchyma, which can extend into the perinephric tissue. The infection is usually caused by gram-negative rods, with E. coli being the most common organism.36 The clinical symptoms of emphysematous pyelonephritis are indistinguishable from nonemphysematous pyelonephritis: fever, chills, nausea, vomiting, and flank pain. Two distinguishing clinical features are a palpable mass in ~50% of cases and, rarely, the presence of crepitus in the flank.37 Mortality rates are highest in patients who present with renal insufficiency and thrombocytopenia.38

Because the diagnosis of emphysematous pyelonephritis is difficult based on clinical symptoms, many authors recommend obtaining an abdominal plain film including kidneys, ureter, and bladder on all patients with diabetes who present with symptoms of pyelonephritis.32,36,39,40 The plain X-ray film detects gas in the kidney in 85% of cases.36 CT scans are more sensitive and are useful in confirming the location of the gas collection and in evaluating extension into surrounding structures.

Therapy for emphysematous pyelonephritis includes antibiotic therapy and some form of surgical drainage. Mortality rates for antibiotic therapy alone are between 70 and 80%.36,39-41 Mortality rates drop to 20–30% if patients have an incision and drainage procedure or a nephrectomy.36,39–42 A promising less-invasive treatment option is use of CT-guided percutaneous drainage. In a recent study of 25 patients treated with percutaneous drainage of emphysematous pyelonephritis, 92% were successfully treated, with preservation of renal function in 80%.43

Emphysematous pyelitis is characterized by gas occurring solely in the renal collecting system. Patients have similar clinical symptoms to patients with noncomplicated pyelonephritis: fever, nausea, vomiting, and abdominal pain. Emphysematous pyelitis is strongly associated with underlying obstruction of the urinary tract. On a plain radiograph, gas outlines the renal pelvis. In contrast to emphysematous pyelonephritis, antibiotics alone can be successful if no obstruction is present. If obstruction is present, it must be corrected for successful therapy to take place.

MISCELLANEOUS INFECTIONS
Rhinocerebral Mucormycosis

Rhinocerebral mucormycosis is an extremely rare fungal infection seen in patients with type 1 diabetes (~50% of cases of mucormycosis),44 usually in the setting of ketoacidosis.45 Rhinocerebral mucormycosis has been reported to occur in patients with new-onset diabetic ketoacidosis.

The infection usually begins in the rhino-orbital region and extends to the brain via the paranasal sinuses and cribriform plate or retro-orbitally. Early clinical manifestations include ocular pain, headache, and nasal stuffiness. Physical findings of this disease include periorbital swelling, proptosis, and dark necrotic lesions of the palate and nasal mucosa.

Cavernous sinus thrombosis is a common complication of rhinocerebral mucormycosis, and patients present with severe headache, ophthalmoplegia, visual loss, and corneal anesthesia. Occasionally paralysis of the seventh nerve may occur. Internal carotid artery thrombosis is another severe complication of rhinocerebral mucormycosis, occurring in about one-third of cases.46,47 Patients who present with hemiplegia due to carotid artery thrombosis are at highest risk for death.48

Diagnosis is made through evaluation of biopsy specimens. Deep biopsies are necessary to see the fungus. Superficial scrapings may only show necrotic tissue. Culture results are frequently negative in patients with mucormycosis. In one series, only 15% of patients with mucormycosis had a positive culture result.49 CT and MRI scanning are useful to assess the extent of disease involvement.

Aggressive therapy with amphotericin B and surgical debridement are crucial for survival. Amphotericin B in doses of 1–1.5 mg/kg/day to a dose of 2–3 g is recommended. More recently, liposomal amphotericin B has been used successfully.50,51 In some cases, both intravenous and intrathecal amphotericin B is given.

Surgical debridement of necrotic tissue is a critical part of the therapeutic plan for patients with rhinocerebral mucormycosis. Endoscopic sinus surgery has recently been successfully used in the management of rhinocerebral mucormycosis.52 This development may allow for a more limited surgical approach. Aggressive control of blood glucose levels and treatment of ketoacidosis is also critical in controlling the infection.

Emphysematous Cholecystitis
Emphysematous cholecystitis is a rare variant of acute cholecystitis. When it does occur, diabetes is frequently a risk factor. In the largest reported review series, diabetes was present in 38% of the patients. In a recently published smaller series, 55% of the patients with emphysematous cholecystitis had diabetes.53

This infection is characterized by the presence of gas in the gall bladder lumen, gall bladder wall, or pericholecystic tissues. The mortality rate is much higher for patients with emphysematous cholecystitis than for acute nonemphysematous cholecystitis. In patients less than 60 years old, 15% with emphysematous cholecystitis die compared with a mortality rate of 1.4% in patients with acute nonemphysematous cholecystitis.54 Patients with emphysematous cholecystitis are at greater risk for gall bladder necrosis and perforation. The most common organisms isolated from patients were Clostridial species (46%), with Clostridia welchii the most common, and E. coli (33%).54

Diagnosis is made by radiological imaging. The abdominal radiograph is usually abnormal but can be normal in patients with emphysematous cholecystitis.55 Ultrasound can pick up emphysematous cholecystitis but can miss it as well. False negatives occur because the gas in the gall bladder makes it hard to visualize. CT scan is probably the most sensitive radiological test for emphysematous cholecystitis. Most cases will be picked up by plain radiograph or suggested by ultrasound.

Treatment is cholecystectomy. Laparoscopic cholecystectomy has been a successful form of treatment.56 Antibiotic therapy should include anaerobe coverage and good gram-negative coverage. Penicillin drugs with beta.gif (968 bytes)-lactamase inhibitors (Zosyn‚ Timentin‚ or Unasyn) would be effective choices.


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Douglas S. Paauw, MD, FACP, is an associate professor in the Department of Medicine at the University of Washington School of Medicine in Seattle.


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