Infections in the Diabetic Patient

Infections in patients with diabetes mellitus are associated with considerable morbidity and mortality. Possible abnormalities in host defenses at several levels have been described in patients with diabetes (Table 1). The extent to which diabetes actually increases the risk of infections is still controversial because large controlled clinical studies are lacking. Nevertheless, certain infections occur predominantly in patients with diabetes while others may be more severe in this disease.

Uncommon Life-threatening Infections in Patients with Diabetes

Although rare, these infections are associated with high rates of mortality. An awareness of these syndromes is important for early diagnosis and expeditious medical and surgical intervention (Table 2).

Malignant otitis externa is a severe, sometimes indolent, necrotizing infection that can become destructive and life-threatening as it erodes through deeper structures. The causative agent is usually Pseudomonas aeruginosa although other pathogens have been described. Initial symptoms include severe pain and swelling of the ear canal and pinna with accompanying purulent drainage. A mass of granulation tissue can be seen on otoscopic examination in the majority of patients. Fever and leukocytosis are frequently absent. If untreated, infection spreads to involve the surrounding structures resulting in osteomyelitis of the temporal bone, progressive cranial neuropathies, meningitis, brain abscesses or dural sinus thromboses. Initial presentation may include 7th cranial nerve palsy, followed by involvement of cranial nerves 9 through 12. Cultures of the purulent discharge for pathogen identification and susceptibility testing are necessary to guide antibiotic therapy. Computerized tomography (CT) and/or magnetic resonance imaging are indicated to delineate the extent of infection. Surgical débridement may be required. Systemic antipseudomonal or other appropriate antibiotics are usually administered for 4 to 8 weeks. Antibiotic combinations (e.g. ß-lactam and aminoglycoside) have been used for severe disease. Monotherapy with ceftazidime or ciprofloxacin has been used and may be acceptable for milder cases.

Rhinocerebral mucormycosis is a rare, potentially rapidly fatal infection involving the nasal mucosa, palate, paranasal sinuses, and orbit. It is often associated with poor glucose control and diabetic ketoacidosis. Fungi of the order Mucorales are usually the causative pathogens. Facial pain with swelling is rapidly followed by proptosis, ophthalmoplegia, and loss of visual acuity. Vascular invasion and thrombosis cause a black necrotic eschar on the skin or palate which is indicative of the diagnosis. Management includes urgent surgical consultation for aggressive débridement and administration of parenteral amphotericin B.

Emphysematous cholecystitis is a severe form of acute cholecystitis characterized by gas production in and around the gallbladder wall. Clostridium spp. are often isolated from bile cultures in addition to other enteric flora. In contrast to acute cholecystitis, emphysematous cholecystitis occurs more commonly in males and is frequently associated with gangrene, perforation, and death. Symptoms, including fever and right upper quadrant pain, are initially similar to those of uncomplicated cholecystitis. Diagnosis involves the demonstration of gas within the lumen or walls of the gall bladder by ultrasound or CT scan. Prompt surgical intervention is necessary in addition to administering broad-spectrum antibiotics.

Emphysematous pyelonephritis is a severe form of renal infection with gas-forming organisms. Escherichia coli is usually found, although other gram-negative bacilli and Candida spp. have been implicated. Symptoms of fever and flank pain are similar to classic pyelonephritis. Blood and urine cultures usually identify the causative pathogen. Demonstration of gas in the renal parenchyma on plain X-ray films or a CT scan is diagnostic. Antibiotics are directed broadly against potential uropathogens until culture results are known. Surgical intervention may be required if medical therapy fails.

Necrotizing soft tissue infections can involve skin, subcutaneous tissue, fascia, and muscle. Necrotizing soft tissue infections often involve the perineum (Fournier's gangrene), abdominal wall, or lower extremities. The clinical presentation is usually acute with marked systemic toxicity. The affected areas may exhibit erythema, bullae, weeping ulcers, and/or necrosis. It is important to note that the skin overlying the affected area can initially appear normal. However, gentle palpation often reveals severe tenderness and crepitus. The diagnosis is usually suspected on clinical grounds. Radiologic studies demonstrate involvement of deeper structures or gas in tissues. Bacteremia occurs in a significant proportion of cases. Prompt surgical consultation for débridement is indicated in addition to broad-spectrum antibiotics pending culture results. Infections are often polymicrobial; monomicrobial infection is usually due to group A streptococci.

Uncommon Severe Infections in Patients with Diabetes

Endophthalmitis is an infection of the vitreal contents of the eye. Exogenous endophthalmitis is usually a complication of cataract surgery. It is caused predominantly by gram-positive organisms, including Staphylococcus aureus and Staphylococcus epidermidis, although other organisms may be encountered. Endogenous endophthalmitis is a result of secondary seeding from bacteremia caused by either gram-positive or gram-negative bacteria. A renal source is sometimes implicated, often with E. coli isolated from cultures. Presenting symptoms and physical signs include ocular pain with visual loss, lid edema, conjunctival irritation, and hypopyon. Immediate evaluation by an ophthalmologist is warranted 1) to differentiate endophthalmitis from other inflammatory conditions; 2) to obtain intravitreal cultures; 3) for the administration of intravitreal antibiotics; and 4) for other management as necessary, such as vitrectomy, topical antibiotics, and/or steroids. Systemic antibiotics, usually indicated, are necessary in endogenous disease resulting from bacteremia.

Common Infections in Patients with Diabetes (Table 3)

Foot ulcers and osteomyelitis. Diabetes is the leading cause of lower extremity amputation in the United States. Sensory and motor neuropathy results in unrecognized trauma and foot deformities which predispose the patient to ulcer formation. Furthermore, peripheral vascular disease may impede healing and antibiotic tissue penetration.

Appropriate shoes are important for patients with neuropathy. Shoes with cushioned soles may suffice in some. In patients with foot deformity molded shoes or those with extra depth may be necessary. Changing shoes and socks every 3 to 4 hours permits inspection of the feet and rotation of pressure points. Foot ulcers in patients with diabetes should be treated in consultation with someone trained in this area. Attempts at outpatient management of foot ulcers should only be considered when the ulcer is superficial, erythema minimal, there is no evidence of ischemia or systemic toxicity, and conditions for home care are favorable. Avoidance of weight-bearing is important and may even require padding of the affected area. Gauze dressings moistened with sterile saline and oral antibiotics are usually prescribed. The ulcer should be reassessed in 24 to 48 hours.

Infected foot ulcers may become limb- or life-threatening. These are usually deeper (even to bone) and may be associated with extensive cellulitis, lymphangitis, or systemic toxicity. Signs of inflammation may be blunted in immunocompromised patients. Initial management, after evaluation, includes medical stabilization (including glucose control), surgical inspection for emergent drainage or débridement as necessary, and empiric antibiotics. Such infections are typically polymicrobial and empiric therapy should cover staphylococci, streptococci, gram-negative bacilli and anaerobes, until culture results are available.

Pneumonia. Although the incidence of pulmonary infections in patients with diabetes does not appear to be increased, these infections are associated with significant morbidity and mortality. This may reflect coexisting medical conditions, structural pulmonary abnormalities, and altered pulmonary immune cell function. For example, infections due to Streptococcus pneumoniae, Haemophilus influenzae, Legionella spp., and influenza are often more severe and may require hospitalization more frequently than in nondiabetic patients. Furthermore, certain pathogens (S. aureus, gram-negative bacilli, Mycobacterium tuberculosis, and fungi) are more likely to cause pulmonary infections in patients with diabetes. The higher prevalence of some of these pathogens reflects an increase in upper airway colonization due to frequent hospitalizations and/or a higher risk of exposure. It is difficult to identify the causative pathogen on clinical data alone. Sputum cultures are necessary to guide antibiotic therapy. As with all infections in diabetic patients, data on the susceptibility pattern is especially important since antibiotic-resistant organisms are common. The radiographic picture may not be typical. Tuberculosis, for example, may present as lower lobe disease in patients with diabetes.

Staphylococcus aureus infections. Some studies suggest that patients with diabetes are more likely than nondiabetics to be colonized with S. aureus--a finding of uncertain significance even if true. It is unclear if diabetic patients with S. aureus bacteremia are at increased risk of complications (e.g. metastatic seeding). However, diabetic patients with a demonstrable primary focus of S. aureus infection (e.g. chronic foot ulcers) leading to intermittent bacteremia may be exposed to endocardial seeding. Therefore, some authors have recommended diabetic patients with S. aureus bacteremia be evaluated by echocardiography, especially if there is evidence of a chronically infected site elsewhere.

Group B streptococcal infections. Patients with diabetes are at a significantly increased risk of both community-acquired and nosocomial group B streptococcal infections. The most common clinical manifestations include skin, soft tissue, and bone infections; bacteremia with an undefined focus; pneumonia; and urosepsis. Patients usually respond to treatment with a systemic penicillin; however, relapse may occur. Therefore, careful followup and attention to treatment failure is warranted.

Mucocutaneous candidiasis. Colonization and infections with Candida spp. are generally believed to be more common in patients with diabetes. Intertrigo presents as weeping erythematous plaques and occurs in skin folds and interdigital spaces of fingers and toes. Overweight patients are particularly prone to this condition. Paronychia, an inflammatory infection affecting the proximal nail fold, results from trauma or frequent water exposure. It presents as a swollen, erythematous, tender area with occasional bacterial superinfection. In chronic paronychia the nail is usually thick, hard, and brownish with transverse indentations and should be differentiated from dermatophyte infections since treatment options differ. The former may be extremely painful and the nails perhaps not as friable. Nail scrapings may be necessary to differentiate between the two entities. Poorly controlled diabetes can also result in oral candidiasis, which presents as white mucosal plaques sometimes associated with a burning sensation. Extension to the esophagus should be suspected if dysphagia or odynophagia is present. Candidal vulvovaginitis also occurs more frequently in women with diabetes.

Urinary tract infections. Women with diabetes are predisposed to developing urinary tract infections (UTIs). Possible risks include neuropathic bladder, vascular disease, elevated urinary glucose levels, or use of invasive instrumentation. As in nondiabetic patients, enteric gram-negative bacilli are the most common sources of infection, although enterococci, staphylococci, or resistant gram-negative bacteria (e.g. Pseudomonas aeruginosa) can occur. These more resistant bacteria, as well as Candida spp. should be suspected after recent hospitalization or a urologic procedure. The majority of patients with Candida spp. UTIs will have an indwelling urinary catheter or a urinary obstruction. Because Candida spp., may contaminate voided specimens, differentiation between colonization and true infection is necessary. The presence of symptoms and a urinalysis with high counts of yeast colonies and white blood cells suggest infection. Catheter removal may be sufficient. However, in patients who may be at risk of ascending infection, treatment with amphotericin B bladder irrigation or fluconazole is indicated.

Upper UTIs, including intrarenal abscesses and pyelonephritis, occur 2 to 4 times more frequently in patients with diabetes. These infections can occur as a result of secondary seeding from bacteremia or may ascend via the ureters. Approximately 2 weeks of antibiotic therapy is probably appropriate for uncomplicated bacterial acute pyelonephritis. A variety of complications from upper tract disease (renal carbuncle, perinephric abscess, renal papillary necrosis) can occur in diabetic patients. These require prolonged, intensive antibiotic treatment and sometimes surgical exploration.

Many patients with diabetes progress to renal failure which may require hemodialysis, peritoneal dialysis, or renal transplantation. These treatment modalities expose the patient to specific risks of infection (Table 4).

General Care

It is important to consider the following points in selecting specific antibiotic therapy in patients with diabetes. Avoid or minimize use of nephrotoxic agents, if possible, because many diabetic patients will have some degree of underlying renal insufficiency. Ototoxic agents should be avoided if there is underlying diabetic retinopathy or sensory neuropathy. In these patients loss of hearing and/or balance may have a greater impact when there is concomitant decrease in visual acuity. Dosage adjustment of antimicrobials for renal insufficiency is often necessary in diabetic patients. Carefully monitor glucose levels when sulfonamides or chloramphenicol are administered because these antibiotics enhance the hypoglycemic action of some oral hypoglycemic agents. Finally, intramuscular antibiotics may be less reliably absorbed in patients with severe vascular disease and oral antibiotics may be less reliably absorbed in patients with gastroparesis.

Patients with diabetes are considered at high risk for influenza complications and should receive influenza vaccine yearly unless otherwise contraindicated. Because people with diabetes may be at greater risk of complicated pneumococcal disease, pneumococcal vaccine should be considered in this population. The risk of tuberculosis in patients with diabetes is 2- to 4-fold higher than the general population. Thus, patients should be screened for tuberculosis by a purified protein derivative (PPD) skin test (considered reactive at >=10 mm of induration in this population).

Conclusion

In general, delivering good medical care to patients with diabetes mellitus requires little more than the conscientious application of general medical principles appropriate to all patients. The clinician should be aware of the uncommon entities to which patients with diabetes may be especially prone and be able to identify or at least suspect these promptly. Also keep in mind the concepts that infections may present atypically in this population (e.g. tuberculosis), that signs of inflammation may be blunted, and that seemingly mild infections may progress rapidly with devastating consequences. Because optimal modalities of diagnosis and treatment of infections evolve rapidly, there should be a low threshold for calling on the expertise of specialists in relevant areas. Early, well-coordinated teamwork involving medical and surgical colleagues best serves the patients' interest.

Erika D'Agata, MD
Senior Research Fellow
Division of Infectious Diseases
Beth Israel Deaconess Medical Center and Harvard Medical School
Boston, Massachusetts

George Eliopoulos, MD
Associate Professor of Medicine
Division of Infectious Diseases
Beth Israel Deaconess Medical Center and Harvard Medical School
Boston, Massachusetts

Dr Eliopoulos has a research grant from Bayer Corporation.

Infections in the Diabetic Patient

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