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INFECTIONS IN DIABETES
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INFECTIONS IN THE COMPROMISED HOST
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INFECTIONS IN DIABETES Helene M. Calvet, MD, and Thomas T. Yoshikawa, MD
It is estimated that approximately 7% of the adult population in the United States, or 8 million adults, are affected by diabetes mellitus. Despite the progress in pharmaceutics with many new oral medications available to control diabetes, many diabetics continue to experience serious morbidities related to their disease. Infectious morbidities are common, with diabetics being susceptible to infection for a variety of reasons. Certain types of infections tend to be more common in diabetics than in others, and other infections may be more severe in diabetics than in nondiabetics. In this article, the immune defects leading to increased susceptibility to infections will be reviewed, followed by brief reviews of infections that are common in diabetics (Table 1). ALTERED HOST DEFENSES
Innate Cellular Immunity Several different immune deficits have been described in diabetics. Cell-mediated immunity seems to be most affected, with abnormalities of polymorphonuclear leukocytes (PMNLs), monocytes, and lymphocytes reported. Numerous researchers have studied PMNLs in the past, reporting abnormalities of adherence, chemotaxis, phagocytosis, oxidative burst, and intracellular killing. More recent studies confirm previous findings; Delamaire6 found significantly lower neutrophil chemotaxis among both Type I and I1 diabetics, and although there was an increased
From the Division of Infectious Diseases (HMC), and the Department of Internal Medicine (TTY), Charles Drew University of Medicine and Science and King-Drew Medical Center (HMC, W),Los Angeles, California
INFECTIOUS DISEASE CLINICS OF NORTH AMERICA VOLUME 15 * NUMBER 2 JUNE 2001
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Table 1. COMMON INFECTIONS IN DIABETICS Infections with Increased Incidence in Diabetics
Infections Predominantly (>50%) Occurring in Diabetics
Head and Neck Oral candidiasis Esophageal candidiasis Urinary Tract Bacteriuria and cystitis (women) Pyelonephritis Renal/perinephric abscess Skin/Soft TissudBone Surgical wound infection Foot infection Osteomyelitis Pulmonary Tuberculosis S. aureus pneumonia Gram-negative pneumonia Abdominal Emphysematous cholecystitis
Head and Neck Rhinocerebral mucormycosis Malignant otitis extema Urinary Tract Emphysematous cystitis Emphysematous pyelitis Emphysematous pyelonephritis Skin/Soft TissudBone Synergistic necrotizing cellulitis Foumier 's gangrene
~~
Salmonella enteritidis Campylobacferjejuni Listeriu monocytogenes
expression of certain adhesion molecules and evidence of spontaneous activation of PMNLs with increased free radical activation, the neutrophi1 response after stimulation was lower than in controls. Gallacher et all5 found a significant negative correlation between glycated hemoglobin levels and neutrophil bactericidal activity. The pathogenesis of these abnormalities is not entirely clear, but seems to be related to the degree and duration of hyperglycemia, and some abnormalities will correct with good glycemic control. Some researchers theorize that hyperglycemia or the presence of advanced glycation end products (AGES)leads to a state of low-level persistent activation in PMNLs, as evidenced by increased concentration of neutrophil elastase, increased activity of neutrophil alkaline phosphatase and luminol-dependent chemiluminescenceand an increased rate of neutrophil oxygen consumption among unstimulated PMNLs of diabetic patients.2, This hyperexcited state leads to spontaneous activation of the oxidative burst and release of myeloperoxidase, elastase, and other neutrophil granule components that can be detrimental in two ways: (1)may lead to a "burned-out" or tolerant PMNL that responds less vigorously when stimulated by an infectious pathogen, and (2) may initiate pathologic processes leading to vascular injury (Fig. 1). Other authors have pointed to the increased adhesion molecule expression in PMNLs also as being important in the pathogenesis of atherosclerotic disease, so it is possible that the immune dysregulation seen in diabetes not only predisposes to infectious complications, but also vascular complications.
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Normal PMNL
Diabetic milieu
v Oxidative burst Degranulation Free radical production Adhesion molecules
Activated Resting PMNL Chronic diabetic milieu
? Vascular Injury
a Risk of infection Intracellular killing
Figure 1. Theory of neutrophil dysfunction in diabetes. PMNL cyte.
=
Polyrnorphonuclear leuko-
A similar state of hyperexcitement leading to tolerance has been described in peripheral blood mononuclear cells (PBMCs), as we11.16 The resting levels of cytokines, that is, tumor necrosis factor (TNF) a, interleukin (IL) 6 and IL-8 are increased among diabetics, but upon stimulation, the cells produce less IL-1 and IL-6 than controls. Abnormalities in monocyte/macrophage chemotaxis and phagocytosis also have been reported. Adaptive Cellular and Humoral Immunity
Adaptive humoral immunity in diabetics appears to be normal with normal levels of immunoglobulins and normal response to vaccinations. Adaptive cellular immunity does appear to be affected, however, with decreased lymphocyte proliferative response to stimulants such as phytohemagglutinin and certain pathogens such as Staphylococcus aureus, but normal response to others, such as Candida a l b i ~ a n s .Abnormal ~ delayed-type hypersensitivity (DTH) also has been described in diabetics. Impact of Glucose Control on immune Defects
Fortunately, good glucose control appears to rectify some of these immune deficiencies, and several studies show that perioperative tight
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glucose control decreases the risk of postoperative wound infections. Zerr et al” found that the rate of deep sternal wound infections after cardiac surgery was four times higher in diabetics than in nondiabetics; review of risk factors showed that mean blood glucose concentration in the first two postoperative days was an independent predictor of deep wound infection. After institution of a protocol of postoperative continuous insulin infusion to maintain blood glucose less than 200mg/dL, there was a significant decrease in the number of deep wound infections among diabetics. Similarly, Rassias et alMfound that aggressive insulin therapy after cardiac bypass in diabetic patients improved the neutrophil phagocytic activity compared with controls receiving standard insulin therapy. Tight glucose control benefits not only cardiac surgery patients, but others, as well. Pomposelli et a143demonstrated that among diabetic patients undergoing a variety of elective surgeries, those with any blood glucose measurement over 220 mg/dL on postoperative day 1 had a rate of infection 2.7 times higher than those who maintained glucose levels lower than 220 mg/dL (p < 0.05). SPECIFIC INFECTIONS Head and Neck Infections
There are two serious head and neck infections to which diabetics are predisposed: rhinocerebral mucormycosis and malignant (or necrotizing) otitis externa. Both infections are rare but potentially life threatening. Diabetics are also predisposed to oral thrush-which is much more common but not serious-and occasionally may develop esophageal candidiasis. Approximately 50% to 75% of cases of rhinocerebral mucormycosis occur in diabetic patients.%,49 Ketoacidosis appears to be the most important predisposing factor, although it is present in only about 50% of the cases in diabetics. There are several possible explanations for the increased susceptibility to this infection among acidotic diabetics. Meyer hypothesized that the greater availability of iron for the pathogen at lower pH ranges is important?O whereas Gale found a lack of serum inhibitory activity against Rhizopus at lower pHI4 that was restored at neutral pH. Finally, a murine model showed that the pulmonary macrophages of diabetic mice were less likely to prevent the germination of Rhizopus, so hyperglycemia also may be an important factor?* A number of different pathogens may be seen in this condition, the most common being in the family Mucoraceae, including Rhizopus species, Absidia and Mucor species. The pathogenesis of the disease probably starts with inhalation of the fungus into the paranasal sinuses. Upon germination, the fungus may spread inferiorly to invade the palate, posteriorly to invade the sphenoid sinus and beyond into the cavernous sinus, laterally to involve the orbits, or superiorly to invade the brain. Initial symptoms and signs
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may include fever, headache, facial pain or swelling, ocular pain or periorbital swelling, or nasal stuffiness that may be accompanied by a discharge. A black eschar may be visible in the nasal mucosa or the palate of about 40% of which results from the ischemic necrosis of tissues after vascular invasion of the fungus. The invasion progresses rapidly and may lead to proptosis, ophthalmoplegia and visual loss caused by involvement of the orbit, other cranial nerve palsies caused by involvement of the cavernous sinus, or massive stroke caused by occlusion of the carotid artery. Early diagnosis and treatment is essential in this condition to limit invasion of the fungus and the accompanying morbidity and mortality. Aside from the physical findings, the diagnosis may be supported by radiologic studies, such as computed tomography (CT) or magnetic resonance imaging (MRI) that may show intracranial extension, mass in the orbit, thickening of the ocular muscles, or sinus involvement with bony erosion. Eschar or discharge seen on examination can be collected or scraped and examined with a potassium hydroxide preparation, which may reveal the characteristic broad, nonseptate hyphae with right angle branching. Initial therapy consists of rapid and wide surgical debridement, followed by high-dose amphotericin B therapy, 1 to 1.5 mg/kg/day. The newer lipid formulations of amphotericin allow for higher doses with lower systemic toxicity, and an accumulating body of clinical data suggests these agents are useful in the treatment of rhinocerebral mucormycosis.10,14,31,48,62 There is no role for azoles or flucytosine in this infection. Untreated, the disease is universally fatal, but aggressive surgery and long-term high dose amphotericin B therapy can lead to a mortality rate as low as 16.7%, as reported in one series.42The usefulness of other therapies, such as hyperbaric oxygen and granulocyte colony stimulating factor (G-CSF), remains to be determined.50 Invasive, or malignant, otitis extema is another infection that may be complicated by intracranial extension in diabetics. The vast majority (90%) of patients with this condition are and the risk for this condition is increased by poor glucose control, swimming, old age, use of a hearing aid, and possibly ear irrigation with nonsterile water.7 Pseudomonus ueruginosu is the most common isolate. The hallmarks of this infection include persistent external otitis with unrelenting ear pain, presence of extensive granulation tissue in the canal, clinical or radiologic evidence of erosion of the canal, and isolation of P. aerugiizosu from the external The usual path of spread of the organism leads it to the temporal bone by way of the cartilaginous junction of the canal, with involvement of the facial nerve at the stylomastoid foramen about 30% to 40% of the time? Other areas of involvement may include the temporomandibular joint, the mastoid air cells, the base of the skull (presenting with palsies of cranial nerves IX-XII), the sigmoid sinus or the meninges.49The mortality with extensive intracranial involvement may approach ? J O % . ~As in rhinocerebral mucormycosis, rapid diagnosis and treatment is essential. MRI with gadolinium is the radiologic examination of choice because of the ability to evaluate the extent of the soft-
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tissue and bone i n ~ o l v e m e n tCT . ~ ~scan is also useful, and radionuclide studies, such as technetium or gallium scans, may show evidence of temporal bone osteomyelitis sooner than MRI or CT.18 Management of this infection includes surgical debridement of necrotic tissue and deep tissue biopsy for culture to determine the susceptibility pattern of the organism, because long-term antimicrobial therapy is usually indicated. Empiric therapy with antipseudomonal antibiotics is indicated, and total duration of intravenous therapy should be 4 to 6 weeks. Some advocate following gallium scans and erythrocyte sedimentation rates (ESR) to document response,18because relapse caused by inadequate duration of therapy has occurred. Oral ciprofloxacin therapy may be appropriate for selected mild cases.17,47
Pulmonary Infections Diabetes alone does not appear to be an independent risk factor for acquiring respiratory tract infection^.^^ However, some have noted an increased frequency of certain respiratory pathogens among diabetics, such as Stuphylococcus uureus, gram-negative organisms and Mycobucterium tuberculosis, or an increased rate of morbidity or mortality among diabetics caused by other organisms such as Streptococcus pneumoniue, influenza virus, and LegioneZl~.~~ The increased rate of S. uureus and gram-negative bacterial pneumonias in diabetics is likely related to increased frequency of upper airway colonization with these pathogens. Diabetics are almost three times more likely to be nasopharyngeal carriSuch colonization puts them at ers of S. uureus than n~ndiabetics.~~ greater risk of developing S. uureus lower tract infections, especially with the ciliary impairment seen after an influenza infection. An increased rate of gram-negative upper airway colonization also is seen in diabetDiabetics are not thought to be more susceptible to S. pneumoniue lower respiratory tract infections, nor do they have a higher rate of colonization with the organism, but those who do develop pneumococcal pneumonia are more likely to become bacteremic and be hospitalized than nondiabetics20 Diabetics who are hospitalized with communityacquired pneumonia have a higher risk of death (odds ratio [OR] = 1.3) than nondiabetics." For these reasons, the American College of Physicians recommends that diabetics receive the pneumococcal vaccine and annual immunization with influenza vaccine.' An association between diabetes mellitus and pulmonary tuberculosis was noted in the literature in the 1930s, but as antituberculous medications and insulin therapy were introduced, the comorbidity became much more rare. In a retrospective study looking at hospital discharge records in California in 1991,37however, significant association between diabetes and active tuberculosis was found among Caucasians (OR = 1.31, 95% confidence intervals [95% CI] = 1.19, 1.45), Hispanics (OR = 2.95, 95% CI = 2.61, 3.33) and "other" race/ethnicity groups (OR = 2.55, 95% CI = 2.15, 3.01), but not among blacks (OR = 0.93,
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95% CI = 0.78, 1.09). The effect appeared to be much greater for those less than 25 years old, increasing the risk of active tuberculosis almost eight-fold. Among middle-aged Hispanics, the attributable risk of tuberculosis caused by diabetes mellitus equaled the attributable risk caused by human immunodeficiency virus (HIV) infection.37Other authors estimate the relative risk of developing active tuberculosis to be two to four times that of the general population?, 34 Because of the increased risk of developing active disease, the American Thoracic Society (ATS) recommends preventive chemotherapy be given to diabetics who have a tuberculin skin test positive at 10 or more millimeters and no evidence of active d i ~ e a s e . ~ Abdominal and Gastrointestinal infections
Emphysematous cholecystitis is an uncommon but serious biliary tract infection that occurs with increased frequency among diabetics. It is estimated that 35% of the cases occur in diabetics, and there is a male pred~minance.~~ The clinical presentation is not unlike that of uncomplicated cholecystitis, although occasionally crepitus may be present upon abdominal palpation.54Gallstones are present only 50% of the time, and the disease may be precipitated by gallbladder surgery in a patient with active biliary infecti0n.4~The infection often is polymicrobial, with gram-negative enteric bacilli and anaerobes involved. The emphysematous infection is diagnosed by radiographic demonstration of gas on plain films or by CT,” and frequently is complicated by gallbladder gangrene or perforation. The treatment of choice is rapid surgical removal of the gallbladder and broad-spectrum antimicrobial therapy. Mortality caused by this infection is substantially higher than that of uncomplicated cholecystitis, ranging 15% to 25% compared with less than 4 percent.29,49 Diabetics may have a predisposition to disease from enteric pathogens because diabetes often leads to gastrointestinal dysmotility syndromes (esophageal, gastric, colonic), and motility appears to be an important host defense against gastrointestinal infections. Two pathogens that have been reported with increased frequency among diabetics include SaZmoneZZa ente~itidis,5~ which is seen at a three-fold higher rate among diabetics, and Carnpylobacter, which is seen four times more commonly among diabetics?2 Diabetes is also a risk factor for infection with Listeria monocytogenes, a pathogen whose portal of entry is the gastrointestinal tract but usually presents with bacteremia or meningitis. Diabetics and other patients with underlying diseases or immunosuppression have a higher mortality rate from listeriosis than do healthy individual^.^^ Urinary Tract Infections
Studies have shown that community-dwelling female diabetics have a two- to three-fold higher prevalence of bacteriuria than nondiabetic
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but the same has not been shown for diabetic men. Diabetic cystopathy, with the resultant increased urine residual volumes and ureteral reflux, is a likely reason for this predisposition in women, but diabetic women with bacteriuria do not have higher glycosylated hemoglobin levels or greater incidence of diabetic complications than do nonbacteriuric diabetic women. Normally, asymptomatic bacteriuria is not an indication for antimicrobial therapy, but since diabetics are predisposed to upper tract involvement, the management of asymptomatic bacteriuria in diabetics is a source of debate. Several studies estimate that the prevalence of upper tract involvement in diabetic women with 36 and an autopsy study found a bacteriuria ranges from 43% to ~OYO,’~, four to five times higher rate of acute pyelonephritis among diabetics than in nondiabetics.& Upper tract involvement in diabetics may be asymptomatic. Because there is such a high rate of upper tract involvement among diabetic women, a longer course of antimicrobial therapy (7 to 14 days) is recommended for apparently uncomplicated lower tract infection^.'^, 55 Recurrence of bacteriuria is not uncommon, and is estimated to occur in up to 70% of women followed for almost 3 years.I3 Emphysematous cystitis is an extremely rare complication of lower tract infection that occurs predominantly in diabetics. This complication results from primary infection of the bladder, and occurs most commonly from Escherichiu coZi, but many other pathogens, including Enterubucter, Proteus, KZebsiella, and Cundidu also have been reported.39Patients with this complication are not as acutely ill as with emphysematous complications of the upper tract, and present with typical UTI-like symptoms, often accompanied by chronic abdominal pain. Unusual findings that suggest the diagnosis include gross hematuria and pneumaturia, and radiography demonstrating air in the bladder wall or l ~ m e n . 3 Unlike ~ other emphysematous complications, this cystitis often will respond to antimicrobials alone. Acute pyelonephritis is four to five times more common in diabetics, and the clinical presentation is the same as for nondiabetics, except that bilateral involvement is more common.8 Diabetics, however, are also at increased risk for complications of pyelonephritis, such as renal or perinephric abscess, emphysematous pyelonephritis, or renal papillary necrosis. Treatment of uncomplicated pyelonephritis in diabetic patients is no different than in nondiabetic patients, and improvement with decreasing temperature curve should be observed within 72 hours. If high fevers persist into the fourth or fifth day of appropriate antimicrobial therapy, then a search for renal abscess, perinephric abscess, or papillary necrosis should be initiated.58Renal or perinephric abscesses can be detected by ultrasonography, CT, or MRI scans. Whereas surgery is a mainstay of therapy for perinephric abscesses, renal abscesses, may respond to antimicrobials alone. Drainage of a renal abscess may be indicated if the abscess is large, there is persistent fever, or if the patient has lack of clinical response to antimicrobial therapy within 1 week?* Renal papillary necrosis is a rare complication of upper tract infection, but over half of the cases occur in diabetics. The diagnosis is suggested
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by flank and abdominal pain, persistent fever, or the development of renal insufficiency. The diagnostic method of choice is retrograde pyelography. Emphysematous pyelonephritis is a complication almost exclusively It results seen in diabetics, who account for 70% to 90% of the ~ases.3~ from a severe form of acute multifocal bacterial nephritis, and Esckerichiu coli is the most commonly isolated pathogen, followed by other enteric gram-negative bacilli, such as Enterobucter nerogenes, Klebsielh species, and Pvoteus species. Occasionally, Streptococcus species, and Cundida have been reported as causes.23,51 Women are twice as likely to develop emphysematous pyelonephritis as men, and obstruction is a common predisposing factor. In addition to the usual clinical findings seen in pyelonephritis, flank mass is present about 50% of the time and less frequently, crepitus is present over the flank or thigh. Gas in the kidney is demonstrated by plain films about 85% of the time? but because CT scanning helps to localize the gas to the renal parenchyma, perinephric space or renal collecting it is considered the diagnostic test of choice. If gas is found only in the renal collecting system, the disease is termed ”emphysematous pyelitis,” and medical therapy with relief of obstruction, if present, is usually sufficient. For cases in which the gas is seen in the renal parenchyma or in the perinephric space (emphysematous pyelonephritis), the mortality with medical therapy alone ranges 60% to 809’0~~; thus, nephrectomy is usually indicated, and reduces the mortality to about 20%:
Skin and Soft Tissue Infections Practitioners may have the belief that diabetics are predisposed to simple skin infections like folliculitis, furunculosis and subcutaneous abscesses, but no controlled studies have documented such an associat i ~ n Insulin-dependent .~~ diabetics do have a higher rate of carriage of S. uureus in the nares (34%) compared with diabetics using oral hypoglycemics (1lY0) or normal controls (loo/, to 15%)60; therefore, it is possible that insulin-dependent diabetics may be more likely to develop staphylococcal skin infections if predisposed. Diabetics are more predisffl and this predisposition probably posed to surgical wound infections,43* arises more from poor glucose control than from colonization of the nares. Many agree, however, that there are several complicated skin and soft tissue infections that occur more commonly in diabetics, especially synergistic necrotizing cellulitis and Fournier’s gangrene. Synergistic necrotizing cellulitis is actually a misnomer, since it represents a severe form of necrotizing fasciitis in which involvement of the underlying muscles is common and extensive. It is estimated that 75% of patients with this condition have diabetes.63Many patients may have an initial subacute course, but eventually progress and become acutely ill and ketoacidotic. Most commonly affected areas include the perineum and
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lower extremities, and the clinical presentation is one of severely painful soft tissues in which the skin has limited areas of necrosis with small ulcers draining a discolored, foul-smelling fluid; intervening areas of skin may appear normal. Air in the soft tissues is found about 25% of the time, and the infection is usually polymicrobial with most common isolates being gram-negative bacilli, anaerobic streptococci, and Bacteuoides. The infection is life threatening, and immediate wide surgical debridement is necessary, with accompanying broad-spectrum antibiotics. Despite appropriate therapy, however, there is still 60% mortality.63 It is unclear if diabetics experience necrotizing fasciitis more commonly than nondiabetics, but the microvascular complications they commonly have lead to chronic open wounds that can predispose to the Type 11, or mixed type, of necrotizing fasciitis. One area of involvement with necrotizing fasciitis that does seem to have a predilection for diabetics is the male genitalia, an infection termed Fournier 's gangrene. An estimated 40% to 60% of patients with Fournier 's gangrene have diabetes,4O but some may not have recognized diabetes before the diagn ~ s i s Predisposing .~~ genitourinary or colorectal pathologies are found in most cases, such as urethral strictures with extravasation of urine, urinary tract trauma caused by instrumentation, perianal fissure or abscess, or chronic disease or trauma of the perineal Patients normally present with scrota1 discomfort for several days, which progresses to erythema and edema, and eventually to skin necrosis. Depending on the initiating source, the infection may spread up the abdominal wall, or to the buttocks or thighs. Extensive debridement is indicated, but orchiectomy and penile amputation can usually be avoided because of the alternative blood supplies of the testes and The infection is usually polymicrobial, involving gram-negative bacilli, Clostridium species, aerobic and anaerobic streptococci, and Bacteroides. Despite appropriate therapy, mortality ranges 20% to 35%, and there has been no improvement in the mortality rates over the last 10 years? Foot infections
Diabetic foot infections are an extremely common problem. It is estimated that clinically apparent neuropathy is present in about 25% of diabetic^,^ and 35% to 40% of diabetics with foot ulcers will require an amputation within 3 years.26More than half of nontraumatic limb amputations occur in diabetics. A number of factors may predispose diabetics to developing foot infections: the friction from ill-fitting shoes leads to the formation of blisters and ulcers that are not detected because of neuropathy, or skin breakdown caused by dermatophyte infection or paronychia may allow entrance of pathogens. Unless a patient inspects his feet on a regular basis, these infections may develop and extend to deeper tissues without the patient's knowledge. Foot infections are generally stratified into mild or nonlimb-threatening infections and severe or limb-threatening infections. Patients pre-
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senting with foot infection should have a careful examination performed and radiography of the involved foot should be obtained to help stratify the infection. Mild infection is defined as superficial infection with less than 2 cm of cellulitis and no evidence of serious ischemia, systemic toxicity, or bone or joint involvement. Limb-threatening infection is defined as a full-thickness ulceration with greater than 2 cm of cellulitis, or evidence of serious ischemia, systemic toxicity, or bone or joint involvement. The presence of ischemia or systemic toxicity may be apparent on initial examination, but bone involvement could be more difficult to determine. Two simple clinical features are predictive of the presence of osteomyelitis: size and depth of the ulcer (ability to visualize or probe bone through the ulcer) and an ESR of over 70 mm/hr.26Ulcers that are larger than 2 cm2 in surface area or are deep are more likely to be associated with underlying bone and a positive “probeto-bone” test has a sensitivity, specificity, and positive predictive value Bone involvement for osteomyelitis of 6670, 85% and 89%, respe~tively.’~ may be seen on plain films, but abnormalities are often not evident until 10 to 20 days after infection, or when 40% to 70% of bone has been lost. 99mTc-diphosphonate scanning is more sensitive than plain radiography, but has poor specificity. The radiologic examinations of choice currently are the In-labeled leukocyte scan,”’ which has a sensitivity of 89% and a specificity of 78Y0,2~and MRI, with a sensitivity of 99% and specificity of 83%. MRI is also helpful in determining the extent of the soft tissue involvement. For mild infections, if the patient is reliable and has an appropriate support system at home, outpatient treatment can be pursued with an oral regimen targeting gram-positive flora, such as cephalexin, clindamycin, dicloxacillin, or amoxicillin-clavulanate.5 Rest of the involved area is essential, and patients should be re-examined in 24 to 48 hours to ensure proper response. If patients do not have the appropriate support network at home to allow rest, then inpatient treatment should be considered. For patients with open wounds on presentation, repeat radiography after 2 weeks of therapy should be considered to detect interval changes of occult 0steomyelitis.3~Antimicrobial therapy should be continued for 7 to 14 days (Fig. 2). Patients presenting with moderate to severe foot infection should be evaluated for the presence of osteomyelitis, which complicates 50% to 60% of these infections, and undergo debridement of devitalized areas or drainage of accumulated pus as soon as possible to maximize the chances of limb salvage. It is controversial whether patients with foot osteomyelitis who have no clear indications for surgery (necrosis, gangrene, abscesses) should be treated medically or with a combined medical-surgical approach. Medical therapy alone is reported to cure 53% to 87% of those with diabetic foot osteomyelitis, but long-term therapy (24 weeks) is usually necessary, as is longterm followup to detect recurrence. In patients with osteomyelitis of the phalanx or metatarsal head, limited amputation, such as a digit or ray resection, may be the most cost-effective approach since it preserves a weight bearing surface, will allow a shorter course of antimicrobials (2
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1 Diabetic Foot Ulcer with Infection I ModerateEevere Infection*
of osteomyelitis?
Local debridement and evaluation for osteomyelitis*
antimicrobials
Good home support? Yes
4
Yes
1 O u t p a y Rx 1 Improvement in 48 hrs? Yes
1
7 - 14 days antimicrobials
Repeat X-ray in 14 days to
NO
1
J
Evaluate need for surgery or revascularization I
4 Infected bone resected? No
4
6 - 8 weeks antimicrobials
antimicrobials
Yes
I
Figure 2. Management of diabetic foot infections. *See text for definition or more detail. IV = intravenous; Rx = treatment.
weeks), and leads to a high cure rate.2l A retrospective study of patients with foot osteomyelitis, 77 of whom received surgical intervention (debridement or local limited amputation) within 3 days of admission and 87 of whom did not, demonstrated that those receiving early surgical intervention had fewer above-the-ankle amputations (13% vs. 28%) and a shorter duration of hospitalization (9.6 days vs. 18.8 The decision to pursue surgical intervention in many cases needs to be individualized, taking into account the extent of the infection, the antimicrobial susceptibility profile of the pathogens, the patient’s vascular status, and the patient’s personal circumstances (i.e., ambulatory status, ability to comply with long-term antimicrobials). One advantage of surgery is to obtain deep tissue specimens or a specimen of bone for culture, which is helpful in directing appropriate antimicrobial coverage. Moderate to severe diabetic foot infections are often polymicrobial, and surface cultures yield many more pathogens than are found in surgically (or percutaneously) obtained specimens. Therefore, basing treatment decisions on superficial cultures often leads to overuse of antimicrobials that may lead to problems with drug toxicity and the emergence of multiresistant pathogens. Empiric coverage of severe diabetic foot infections should include agents active against S. aureus, Pseudomonas, entero-
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cocci, and anaerobes. Many different combinations of antibiotics are effective, and a recent review summarizes the available data on antimicrobial treatment of diabetic foot infection^.^^ References 1. ACE' Task Force on Adult Immunization. Immunizations for immunocompromised adults. In Guide for Adult Immunization. Philadelphia, ACP, 1994, p 49 2. Aleksandrovski YA: Molecular mechanisms of diabetic complications. Biochemistry (Moscow) 61:1249, 1998 3. American Thoracic Society: Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 161:S221, 2000 4. Bilton BD, Zibari GB, McMillan RW, et a1 Aggressive surgical management of necrotizing fasciitis serves to decrease mortality: A retrospective study. Am Surg 64.397, 1998 5. Caputo GM, Cavanagh PR, Ulbrecht JS, et al: Current concepts: Assessment and management of foot disease in patients with diabetes. N Engl J Med 331:854, 1994 6. Delamaire M, Maugendre D, Moreno M, et al: Impaired leucocyte function in diabetic patients. Diabetic Med 1429,1997 7. Deresinski S Infections in the diabetic patient: Strategies for the clinician. Infectious Disease Reports 1:1, 1995 8. Ellenbogen PH, Talner L B Uroradiology of diabetes mellitus. Urology 8:413, 1976 9. Evanoff GV, Thompson CS, Foley R, et al: Spectrum of gas within the kidney: Emphysematous pyelonephritis and emphysematous pyelitis. Am J Med 83:149, 1987 10. Fairley C, Sullivan TJ, Bartley P, et a1 Survival after rhino-orbital-cerebral mucormycosis in an immunocompetent patient. Ophthalmology 107555,2000 11. Fine M, Smith M, Carson C, et al: Prognosis and outcomes of patients with communityacquired pneumonia. JAMA 275:134, 1996 12. Forland M, Thomas V, Shelokov A: Urinary tract infections in patients with diabetes mellitus: Studies on antibody coating of bacteria. JAh4A 238:1924, 1977 13. Forland M, Thomas VL: The treatment of urinary tract infections in women with diabetes mellitus. Diabetes Care 8:499, 1985 14. Gale GR, Welch AM. Studies of opportunistic fungi. I. Inhibition of Rhizopus oryzae by human serum. Am J Med Sci 241:604, 1961 15. Gallacher S, Thomson G, Fraser WD, et al: Neutrophil bactericidal function in diabetes mellitus: Evidence for association with blood glucose control. Diabetic Med 12916, 1995 16. Geerlings SE, Hoepelman A Immune dysfunction in patients with diabetes mellitus. FEMS Immunology and Medical Microbiology 26: 259, 1999 17. Gehanno P: Ciprofloxacin in the treatment of malignant external otitis. Chemotherapy Suppl 1:35, 1994 18. Gleckman R, Al-Wawi M: A review of selective infections in the adult diabetic. Comp Ther 25: 109, 1999 19. Grayson ML, Gibbons GW, Balogh K, et al: Probing to bone in infected pedal ulcers. JAMA 27721, 1995 20. Hui KP, Chin NK, Chow K, et a 1 Prospective study of the aetiology of adult community acquired bacterial pneumonia needing hospitalization in Singapore. Singapore Med J 34329, 1993 21. Karchmer AW, Gibbons GW. Foot infections in diabetes: Evaluation and management. Curr Clin Top Infect Dis 141,1994 22. Kass EH: Asymptomatic infections of the urinary tract. Trans Assoc Am Physicians 69:56, 1956 23. Klein DE, Mahoney SA, Youngen R, et al: Renal emphysema. J Urol95:625, 1966 24. Koziel H, Koziel MJ: Pulmonary complications of diabetes mellitus: Pneumonia. Infect Dis Clin North Am 9:65, 1995 25. Lipsky BA Evidence-based antibiotic therapy of diabetic foot infections. FEMS Immunology and Medical Microbiology 26:267, 1999
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26. Lipsky BA: Osteomyelitis of the foot in diabetic patients. Clin Infect Dis 25:1318,1997 27. Lipsky BA, Pecoraro RE, Chen MS, et a1 Factors affecting staphylococcal colonization among NIDDM outpatients. Diabetes Care 10:483, 1987 28. Mackowiak PA, Martin RM, Jones SR, et al: Pharyngeal colonizationby gram-negative bacilli in aspiration-prone persons. Arch Intern Med 138:1244,1978 29. Mentzer RM Jr, Golden GT, Chandler JG, et a1 A comparative appraisal of emphysematous cholecystitis. Am J Surg 129:10, 1975 30. Meyer BR, Wormser G, Hirschan SZ, et al: Rhinocerebral mucormycosis: Premortem diagnosis and therapy. Arch Intern Med 139:557, 1979 31. Moses A, Rahav G, Barenholz Y, et al: Rhinocerebral mucormycosis treated with amphotericin B colloidal dispersion in three patients. Clin Infect Dis 2 32. Neal K, Slack R Diabetes mellitus, antisecretory drugs and other Campylobacter gastro-enteritis in adults: A case-control study. Epidemiology and Infection 119:307, 1997 33. Newman LG, Waller J, Palestro CJ, et a1 Unsuspected osteomyelitis in diabetic foot ulcers: Diagnosis and monitoring by leukocyte scanning with indium 111oxyquinoline. JAMA 266:1246, 1991 34. Nirmal J, Caputo G, Wietekamp M, et al: Primary care: Infections in patients with diabetes mellitus. N Engl J Med 341:1906, 1999 35. Olsof’ka JN, Carrillo EH, Spain DA, et a1 The continuing challenge of Foumier’s gangrene. Am Surg 65:1156,1999 36. Ooi BS, Chen BTM, Yu M Prevalence and site of bacteriuria in diabetes mellitus. Postgrad Med J 50:497,1974 37. Pablos-Mendez A, Blustein J, Knirsch C: The role of diabetes in the higher prevalence of tuberculosis among hispanics. Am J Public Health 87574, 1997 38. Patterson JE, Andriole VT: Bacterial urinary tract infections in diabetes. Infect Dis Clin North Am 995,1995 39. Patterson JE, Andriole VT: Bacterial urinary tract infections in diabetes. Infect Dis Clin North Am 11:735, 1997 40. Paty R, Smith AD Gangrene and Foumier’s gangrene. Urol Clin North Am 19:149, 1992 41. Penlaver FJ, Romero R, Fores R, et a1 Rhinocerebral mucormycosis following donor leukocyte infusion: Successful treatment with liposomal amphotericin B and surgical debridement. Bone Marrow Trans 22817, 1998 42. Peterson KL, Wang M, Canalis RF, et al: Rhinocerebral mucormycosis: Evolution of the disease and treatment options. Laryngoscope 107855,1997 43. Pomposelli J, Baxter J, Babineau T, et al: Early postoperative glucose control predicts infection rate in diabetic patients. JPEN 2277,1998 44. Rassias A, Marrin C, Arruda J, et a1 Insulin infusion improves neutrophil function in diabetic cardiac surgery patients. Anesth Analg 881011,1999 45. Robbins SL, Tucker AW Jr: The cause of death in diabetes: A report of 307 autopsied cases. N Engl J Med 231:865, 1944 46. Rubin J, Yu VL: Malignant external otitis: Insights into pathogenesis, clinical manifestations, diagnosis and therapy. Am J Med 85:391, 1988 47. Sade J, Lang R, Gosken S, et al: Ciprofloxacin treatment of malignant external otitis. Am J Med 87(Supp15A):1385,1989 48. Saltoglu N, Tasova Y, Zorludemir S, et a1 Rhinocerebral zygomycosis treated with liposomal amphotericin B and surgery. Mycoses 41:45, 1998 49. Sapico F, Bessman A Infections in the diabetic patient. Infect Dis Clin Pract 1:339,1995 50. Schmidt J, Poublon R: Rhinocerebral mycosis in immunocompromisedpatients: A case report and review of the literature. Rhinology 3690, 1998 51. Seidenfeld SM, Lemaistre CF, Setiawan H, et a1 Emphysematouspyelonephritis caused by Candida tropicalis. J Infect Dis 146569, 1982 52. Sentochnik DE: Deep soft tissue infections in diabetic patients. Infect Dis Clin North Am 953, 1995 53. Skogberg K, Syrjanen J, Jahkola M, et al: Clinical presentation and outcome of listeriosis in patients with and without immunosuppressive therapy. Clin Infect Dis 17143, 1992
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54. Smitherman KO, Peacock JE Jr: Infections emergencies in patients with diabetes mellitus. Med Clin North Am 79:53, 1995 55. Stamm WE, Hooton TM: Management of urinary tract infections in adults. N Engl J Med 329:1328, 1993 56. Tan JS, Friedman NM, Hazelton-Miller C, et a 1 Can aggressive treatment of diabetic foot infections reduce the need for above-ankle amputations. Clin Infect Dis 23:286, 1996 57. Telzak EE, Greenberg MS, Budnick LD, et al: Diabetes mellitus-a newly described risk factor for infection from Salmonella enteritidis. J Infect Dis 164538, 1991 58. Thorley JD, Jones SR, Sanford JP: Perinephric abscess. Medicine (Baltimore) 53:441, 1974 59. Tiemey MR, Baker AS: Infections of the head and neck in diabetes mellitus. Infect Dis Clin North Am 9:195, 1995 60. Tuazon C U Skin and skin structure infections in the patient at risk: Carrier state of Staphylococcus aureus. Am J Med 76:166, 1984 61. Waldorf AR, Ruderman N, Diamond RD: Specific susceptibility to mucormycosis in murine diabetes and bronchoalveolar macrophage defense against Rhizopus. J Clin Invest 74150, 1984 62. Walsh T, Hiemenz J, Seibel N, et al: Amphotericin B lipid complex for invasive fungal infections: Analysis of safety and efficacy in 556 cases. Clin Infect Dis 26:1383, 1998 63. Wheat LJ: Infection and diabetes mellitus. Diabetes Care 3:187, 1980 64. Zerr K, Fumary A, Grunkmeier G, et al: Glucose control lowers the risk of wound infection in diabetics after open heart operations. Ann Thorac Surg 63:356, 1997
Address reprint requests to Helene M. Calvet, MD Long Beach DHHS 2525 Grand Avenue Long Beach, CA 90815 e-mail: hecalvet8cdrewu.edu
INFECTIONS IN THE COMPROMISED HOST
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INFECTIONS IN DIABETES Helene M. Calvet, MD, and Thomas T. Yoshikawa, MD
It is estimated that approximately 7% of the adult population in the United States, or 8 million adults, are affected by diabetes mellitus. Despite the progress in pharmaceutics with many new oral medications available to control diabetes, many diabetics continue to experience serious morbidities related to their disease. Infectious morbidities are common, with diabetics being susceptible to infection for a variety of reasons. Certain types of infections tend to be more common in diabetics than in others, and other infections may be more severe in diabetics than in nondiabetics. In this article, the immune defects leading to increased susceptibility to infections will be reviewed, followed by brief reviews of infections that are common in diabetics (Table 1). ALTERED HOST DEFENSES
Innate Cellular Immunity Several different immune deficits have been described in diabetics. Cell-mediated immunity seems to be most affected, with abnormalities of polymorphonuclear leukocytes (PMNLs), monocytes, and lymphocytes reported. Numerous researchers have studied PMNLs in the past, reporting abnormalities of adherence, chemotaxis, phagocytosis, oxidative burst, and intracellular killing. More recent studies confirm previous findings; Delamaire6 found significantly lower neutrophil chemotaxis among both Type I and I1 diabetics, and although there was an increased
From the Division of Infectious Diseases (HMC), and the Department of Internal Medicine (TTY), Charles Drew University of Medicine and Science and King-Drew Medical Center (HMC, W),Los Angeles, California
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Table 1. COMMON INFECTIONS IN DIABETICS Infections with Increased Incidence in Diabetics
Infections Predominantly (>50%) Occurring in Diabetics
Head and Neck Oral candidiasis Esophageal candidiasis Urinary Tract Bacteriuria and cystitis (women) Pyelonephritis Renal/perinephric abscess Skin/Soft TissudBone Surgical wound infection Foot infection Osteomyelitis Pulmonary Tuberculosis S. aureus pneumonia Gram-negative pneumonia Abdominal Emphysematous cholecystitis
Head and Neck Rhinocerebral mucormycosis Malignant otitis extema Urinary Tract Emphysematous cystitis Emphysematous pyelitis Emphysematous pyelonephritis Skin/Soft TissudBone Synergistic necrotizing cellulitis Foumier 's gangrene
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Salmonella enteritidis Campylobacferjejuni Listeriu monocytogenes
expression of certain adhesion molecules and evidence of spontaneous activation of PMNLs with increased free radical activation, the neutrophi1 response after stimulation was lower than in controls. Gallacher et all5 found a significant negative correlation between glycated hemoglobin levels and neutrophil bactericidal activity. The pathogenesis of these abnormalities is not entirely clear, but seems to be related to the degree and duration of hyperglycemia, and some abnormalities will correct with good glycemic control. Some researchers theorize that hyperglycemia or the presence of advanced glycation end products (AGES)leads to a state of low-level persistent activation in PMNLs, as evidenced by increased concentration of neutrophil elastase, increased activity of neutrophil alkaline phosphatase and luminol-dependent chemiluminescenceand an increased rate of neutrophil oxygen consumption among unstimulated PMNLs of diabetic patients.2, This hyperexcited state leads to spontaneous activation of the oxidative burst and release of myeloperoxidase, elastase, and other neutrophil granule components that can be detrimental in two ways: (1)may lead to a "burned-out" or tolerant PMNL that responds less vigorously when stimulated by an infectious pathogen, and (2) may initiate pathologic processes leading to vascular injury (Fig. 1). Other authors have pointed to the increased adhesion molecule expression in PMNLs also as being important in the pathogenesis of atherosclerotic disease, so it is possible that the immune dysregulation seen in diabetes not only predisposes to infectious complications, but also vascular complications.
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Normal PMNL
Diabetic milieu
v Oxidative burst Degranulation Free radical production Adhesion molecules
Activated Resting PMNL Chronic diabetic milieu
? Vascular Injury
a Risk of infection Intracellular killing
Figure 1. Theory of neutrophil dysfunction in diabetes. PMNL cyte.
=
Polyrnorphonuclear leuko-
A similar state of hyperexcitement leading to tolerance has been described in peripheral blood mononuclear cells (PBMCs), as we11.16 The resting levels of cytokines, that is, tumor necrosis factor (TNF) a, interleukin (IL) 6 and IL-8 are increased among diabetics, but upon stimulation, the cells produce less IL-1 and IL-6 than controls. Abnormalities in monocyte/macrophage chemotaxis and phagocytosis also have been reported. Adaptive Cellular and Humoral Immunity
Adaptive humoral immunity in diabetics appears to be normal with normal levels of immunoglobulins and normal response to vaccinations. Adaptive cellular immunity does appear to be affected, however, with decreased lymphocyte proliferative response to stimulants such as phytohemagglutinin and certain pathogens such as Staphylococcus aureus, but normal response to others, such as Candida a l b i ~ a n s .Abnormal ~ delayed-type hypersensitivity (DTH) also has been described in diabetics. Impact of Glucose Control on immune Defects
Fortunately, good glucose control appears to rectify some of these immune deficiencies, and several studies show that perioperative tight
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glucose control decreases the risk of postoperative wound infections. Zerr et al” found that the rate of deep sternal wound infections after cardiac surgery was four times higher in diabetics than in nondiabetics; review of risk factors showed that mean blood glucose concentration in the first two postoperative days was an independent predictor of deep wound infection. After institution of a protocol of postoperative continuous insulin infusion to maintain blood glucose less than 200mg/dL, there was a significant decrease in the number of deep wound infections among diabetics. Similarly, Rassias et alMfound that aggressive insulin therapy after cardiac bypass in diabetic patients improved the neutrophil phagocytic activity compared with controls receiving standard insulin therapy. Tight glucose control benefits not only cardiac surgery patients, but others, as well. Pomposelli et a143demonstrated that among diabetic patients undergoing a variety of elective surgeries, those with any blood glucose measurement over 220 mg/dL on postoperative day 1 had a rate of infection 2.7 times higher than those who maintained glucose levels lower than 220 mg/dL (p < 0.05). SPECIFIC INFECTIONS Head and Neck Infections
There are two serious head and neck infections to which diabetics are predisposed: rhinocerebral mucormycosis and malignant (or necrotizing) otitis externa. Both infections are rare but potentially life threatening. Diabetics are also predisposed to oral thrush-which is much more common but not serious-and occasionally may develop esophageal candidiasis. Approximately 50% to 75% of cases of rhinocerebral mucormycosis occur in diabetic patients.%,49 Ketoacidosis appears to be the most important predisposing factor, although it is present in only about 50% of the cases in diabetics. There are several possible explanations for the increased susceptibility to this infection among acidotic diabetics. Meyer hypothesized that the greater availability of iron for the pathogen at lower pH ranges is important?O whereas Gale found a lack of serum inhibitory activity against Rhizopus at lower pHI4 that was restored at neutral pH. Finally, a murine model showed that the pulmonary macrophages of diabetic mice were less likely to prevent the germination of Rhizopus, so hyperglycemia also may be an important factor?* A number of different pathogens may be seen in this condition, the most common being in the family Mucoraceae, including Rhizopus species, Absidia and Mucor species. The pathogenesis of the disease probably starts with inhalation of the fungus into the paranasal sinuses. Upon germination, the fungus may spread inferiorly to invade the palate, posteriorly to invade the sphenoid sinus and beyond into the cavernous sinus, laterally to involve the orbits, or superiorly to invade the brain. Initial symptoms and signs
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may include fever, headache, facial pain or swelling, ocular pain or periorbital swelling, or nasal stuffiness that may be accompanied by a discharge. A black eschar may be visible in the nasal mucosa or the palate of about 40% of which results from the ischemic necrosis of tissues after vascular invasion of the fungus. The invasion progresses rapidly and may lead to proptosis, ophthalmoplegia and visual loss caused by involvement of the orbit, other cranial nerve palsies caused by involvement of the cavernous sinus, or massive stroke caused by occlusion of the carotid artery. Early diagnosis and treatment is essential in this condition to limit invasion of the fungus and the accompanying morbidity and mortality. Aside from the physical findings, the diagnosis may be supported by radiologic studies, such as computed tomography (CT) or magnetic resonance imaging (MRI) that may show intracranial extension, mass in the orbit, thickening of the ocular muscles, or sinus involvement with bony erosion. Eschar or discharge seen on examination can be collected or scraped and examined with a potassium hydroxide preparation, which may reveal the characteristic broad, nonseptate hyphae with right angle branching. Initial therapy consists of rapid and wide surgical debridement, followed by high-dose amphotericin B therapy, 1 to 1.5 mg/kg/day. The newer lipid formulations of amphotericin allow for higher doses with lower systemic toxicity, and an accumulating body of clinical data suggests these agents are useful in the treatment of rhinocerebral mucormycosis.10,14,31,48,62 There is no role for azoles or flucytosine in this infection. Untreated, the disease is universally fatal, but aggressive surgery and long-term high dose amphotericin B therapy can lead to a mortality rate as low as 16.7%, as reported in one series.42The usefulness of other therapies, such as hyperbaric oxygen and granulocyte colony stimulating factor (G-CSF), remains to be determined.50 Invasive, or malignant, otitis extema is another infection that may be complicated by intracranial extension in diabetics. The vast majority (90%) of patients with this condition are and the risk for this condition is increased by poor glucose control, swimming, old age, use of a hearing aid, and possibly ear irrigation with nonsterile water.7 Pseudomonus ueruginosu is the most common isolate. The hallmarks of this infection include persistent external otitis with unrelenting ear pain, presence of extensive granulation tissue in the canal, clinical or radiologic evidence of erosion of the canal, and isolation of P. aerugiizosu from the external The usual path of spread of the organism leads it to the temporal bone by way of the cartilaginous junction of the canal, with involvement of the facial nerve at the stylomastoid foramen about 30% to 40% of the time? Other areas of involvement may include the temporomandibular joint, the mastoid air cells, the base of the skull (presenting with palsies of cranial nerves IX-XII), the sigmoid sinus or the meninges.49The mortality with extensive intracranial involvement may approach ? J O % . ~As in rhinocerebral mucormycosis, rapid diagnosis and treatment is essential. MRI with gadolinium is the radiologic examination of choice because of the ability to evaluate the extent of the soft-
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tissue and bone i n ~ o l v e m e n tCT . ~ ~scan is also useful, and radionuclide studies, such as technetium or gallium scans, may show evidence of temporal bone osteomyelitis sooner than MRI or CT.18 Management of this infection includes surgical debridement of necrotic tissue and deep tissue biopsy for culture to determine the susceptibility pattern of the organism, because long-term antimicrobial therapy is usually indicated. Empiric therapy with antipseudomonal antibiotics is indicated, and total duration of intravenous therapy should be 4 to 6 weeks. Some advocate following gallium scans and erythrocyte sedimentation rates (ESR) to document response,18because relapse caused by inadequate duration of therapy has occurred. Oral ciprofloxacin therapy may be appropriate for selected mild cases.17,47
Pulmonary Infections Diabetes alone does not appear to be an independent risk factor for acquiring respiratory tract infection^.^^ However, some have noted an increased frequency of certain respiratory pathogens among diabetics, such as Stuphylococcus uureus, gram-negative organisms and Mycobucterium tuberculosis, or an increased rate of morbidity or mortality among diabetics caused by other organisms such as Streptococcus pneumoniue, influenza virus, and LegioneZl~.~~ The increased rate of S. uureus and gram-negative bacterial pneumonias in diabetics is likely related to increased frequency of upper airway colonization with these pathogens. Diabetics are almost three times more likely to be nasopharyngeal carriSuch colonization puts them at ers of S. uureus than n~ndiabetics.~~ greater risk of developing S. uureus lower tract infections, especially with the ciliary impairment seen after an influenza infection. An increased rate of gram-negative upper airway colonization also is seen in diabetDiabetics are not thought to be more susceptible to S. pneumoniue lower respiratory tract infections, nor do they have a higher rate of colonization with the organism, but those who do develop pneumococcal pneumonia are more likely to become bacteremic and be hospitalized than nondiabetics20 Diabetics who are hospitalized with communityacquired pneumonia have a higher risk of death (odds ratio [OR] = 1.3) than nondiabetics." For these reasons, the American College of Physicians recommends that diabetics receive the pneumococcal vaccine and annual immunization with influenza vaccine.' An association between diabetes mellitus and pulmonary tuberculosis was noted in the literature in the 1930s, but as antituberculous medications and insulin therapy were introduced, the comorbidity became much more rare. In a retrospective study looking at hospital discharge records in California in 1991,37however, significant association between diabetes and active tuberculosis was found among Caucasians (OR = 1.31, 95% confidence intervals [95% CI] = 1.19, 1.45), Hispanics (OR = 2.95, 95% CI = 2.61, 3.33) and "other" race/ethnicity groups (OR = 2.55, 95% CI = 2.15, 3.01), but not among blacks (OR = 0.93,
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95% CI = 0.78, 1.09). The effect appeared to be much greater for those less than 25 years old, increasing the risk of active tuberculosis almost eight-fold. Among middle-aged Hispanics, the attributable risk of tuberculosis caused by diabetes mellitus equaled the attributable risk caused by human immunodeficiency virus (HIV) infection.37Other authors estimate the relative risk of developing active tuberculosis to be two to four times that of the general population?, 34 Because of the increased risk of developing active disease, the American Thoracic Society (ATS) recommends preventive chemotherapy be given to diabetics who have a tuberculin skin test positive at 10 or more millimeters and no evidence of active d i ~ e a s e . ~ Abdominal and Gastrointestinal infections
Emphysematous cholecystitis is an uncommon but serious biliary tract infection that occurs with increased frequency among diabetics. It is estimated that 35% of the cases occur in diabetics, and there is a male pred~minance.~~ The clinical presentation is not unlike that of uncomplicated cholecystitis, although occasionally crepitus may be present upon abdominal palpation.54Gallstones are present only 50% of the time, and the disease may be precipitated by gallbladder surgery in a patient with active biliary infecti0n.4~The infection often is polymicrobial, with gram-negative enteric bacilli and anaerobes involved. The emphysematous infection is diagnosed by radiographic demonstration of gas on plain films or by CT,” and frequently is complicated by gallbladder gangrene or perforation. The treatment of choice is rapid surgical removal of the gallbladder and broad-spectrum antimicrobial therapy. Mortality caused by this infection is substantially higher than that of uncomplicated cholecystitis, ranging 15% to 25% compared with less than 4 percent.29,49 Diabetics may have a predisposition to disease from enteric pathogens because diabetes often leads to gastrointestinal dysmotility syndromes (esophageal, gastric, colonic), and motility appears to be an important host defense against gastrointestinal infections. Two pathogens that have been reported with increased frequency among diabetics include SaZmoneZZa ente~itidis,5~ which is seen at a three-fold higher rate among diabetics, and Carnpylobacter, which is seen four times more commonly among diabetics?2 Diabetes is also a risk factor for infection with Listeria monocytogenes, a pathogen whose portal of entry is the gastrointestinal tract but usually presents with bacteremia or meningitis. Diabetics and other patients with underlying diseases or immunosuppression have a higher mortality rate from listeriosis than do healthy individual^.^^ Urinary Tract Infections
Studies have shown that community-dwelling female diabetics have a two- to three-fold higher prevalence of bacteriuria than nondiabetic
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but the same has not been shown for diabetic men. Diabetic cystopathy, with the resultant increased urine residual volumes and ureteral reflux, is a likely reason for this predisposition in women, but diabetic women with bacteriuria do not have higher glycosylated hemoglobin levels or greater incidence of diabetic complications than do nonbacteriuric diabetic women. Normally, asymptomatic bacteriuria is not an indication for antimicrobial therapy, but since diabetics are predisposed to upper tract involvement, the management of asymptomatic bacteriuria in diabetics is a source of debate. Several studies estimate that the prevalence of upper tract involvement in diabetic women with 36 and an autopsy study found a bacteriuria ranges from 43% to ~OYO,’~, four to five times higher rate of acute pyelonephritis among diabetics than in nondiabetics.& Upper tract involvement in diabetics may be asymptomatic. Because there is such a high rate of upper tract involvement among diabetic women, a longer course of antimicrobial therapy (7 to 14 days) is recommended for apparently uncomplicated lower tract infection^.'^, 55 Recurrence of bacteriuria is not uncommon, and is estimated to occur in up to 70% of women followed for almost 3 years.I3 Emphysematous cystitis is an extremely rare complication of lower tract infection that occurs predominantly in diabetics. This complication results from primary infection of the bladder, and occurs most commonly from Escherichiu coZi, but many other pathogens, including Enterubucter, Proteus, KZebsiella, and Cundidu also have been reported.39Patients with this complication are not as acutely ill as with emphysematous complications of the upper tract, and present with typical UTI-like symptoms, often accompanied by chronic abdominal pain. Unusual findings that suggest the diagnosis include gross hematuria and pneumaturia, and radiography demonstrating air in the bladder wall or l ~ m e n . 3 Unlike ~ other emphysematous complications, this cystitis often will respond to antimicrobials alone. Acute pyelonephritis is four to five times more common in diabetics, and the clinical presentation is the same as for nondiabetics, except that bilateral involvement is more common.8 Diabetics, however, are also at increased risk for complications of pyelonephritis, such as renal or perinephric abscess, emphysematous pyelonephritis, or renal papillary necrosis. Treatment of uncomplicated pyelonephritis in diabetic patients is no different than in nondiabetic patients, and improvement with decreasing temperature curve should be observed within 72 hours. If high fevers persist into the fourth or fifth day of appropriate antimicrobial therapy, then a search for renal abscess, perinephric abscess, or papillary necrosis should be initiated.58Renal or perinephric abscesses can be detected by ultrasonography, CT, or MRI scans. Whereas surgery is a mainstay of therapy for perinephric abscesses, renal abscesses, may respond to antimicrobials alone. Drainage of a renal abscess may be indicated if the abscess is large, there is persistent fever, or if the patient has lack of clinical response to antimicrobial therapy within 1 week?* Renal papillary necrosis is a rare complication of upper tract infection, but over half of the cases occur in diabetics. The diagnosis is suggested
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by flank and abdominal pain, persistent fever, or the development of renal insufficiency. The diagnostic method of choice is retrograde pyelography. Emphysematous pyelonephritis is a complication almost exclusively It results seen in diabetics, who account for 70% to 90% of the ~ases.3~ from a severe form of acute multifocal bacterial nephritis, and Esckerichiu coli is the most commonly isolated pathogen, followed by other enteric gram-negative bacilli, such as Enterobucter nerogenes, Klebsielh species, and Pvoteus species. Occasionally, Streptococcus species, and Cundida have been reported as causes.23,51 Women are twice as likely to develop emphysematous pyelonephritis as men, and obstruction is a common predisposing factor. In addition to the usual clinical findings seen in pyelonephritis, flank mass is present about 50% of the time and less frequently, crepitus is present over the flank or thigh. Gas in the kidney is demonstrated by plain films about 85% of the time? but because CT scanning helps to localize the gas to the renal parenchyma, perinephric space or renal collecting it is considered the diagnostic test of choice. If gas is found only in the renal collecting system, the disease is termed ”emphysematous pyelitis,” and medical therapy with relief of obstruction, if present, is usually sufficient. For cases in which the gas is seen in the renal parenchyma or in the perinephric space (emphysematous pyelonephritis), the mortality with medical therapy alone ranges 60% to 809’0~~; thus, nephrectomy is usually indicated, and reduces the mortality to about 20%:
Skin and Soft Tissue Infections Practitioners may have the belief that diabetics are predisposed to simple skin infections like folliculitis, furunculosis and subcutaneous abscesses, but no controlled studies have documented such an associat i ~ n Insulin-dependent .~~ diabetics do have a higher rate of carriage of S. uureus in the nares (34%) compared with diabetics using oral hypoglycemics (1lY0) or normal controls (loo/, to 15%)60; therefore, it is possible that insulin-dependent diabetics may be more likely to develop staphylococcal skin infections if predisposed. Diabetics are more predisffl and this predisposition probably posed to surgical wound infections,43* arises more from poor glucose control than from colonization of the nares. Many agree, however, that there are several complicated skin and soft tissue infections that occur more commonly in diabetics, especially synergistic necrotizing cellulitis and Fournier’s gangrene. Synergistic necrotizing cellulitis is actually a misnomer, since it represents a severe form of necrotizing fasciitis in which involvement of the underlying muscles is common and extensive. It is estimated that 75% of patients with this condition have diabetes.63Many patients may have an initial subacute course, but eventually progress and become acutely ill and ketoacidotic. Most commonly affected areas include the perineum and
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lower extremities, and the clinical presentation is one of severely painful soft tissues in which the skin has limited areas of necrosis with small ulcers draining a discolored, foul-smelling fluid; intervening areas of skin may appear normal. Air in the soft tissues is found about 25% of the time, and the infection is usually polymicrobial with most common isolates being gram-negative bacilli, anaerobic streptococci, and Bacteuoides. The infection is life threatening, and immediate wide surgical debridement is necessary, with accompanying broad-spectrum antibiotics. Despite appropriate therapy, however, there is still 60% mortality.63 It is unclear if diabetics experience necrotizing fasciitis more commonly than nondiabetics, but the microvascular complications they commonly have lead to chronic open wounds that can predispose to the Type 11, or mixed type, of necrotizing fasciitis. One area of involvement with necrotizing fasciitis that does seem to have a predilection for diabetics is the male genitalia, an infection termed Fournier 's gangrene. An estimated 40% to 60% of patients with Fournier 's gangrene have diabetes,4O but some may not have recognized diabetes before the diagn ~ s i s Predisposing .~~ genitourinary or colorectal pathologies are found in most cases, such as urethral strictures with extravasation of urine, urinary tract trauma caused by instrumentation, perianal fissure or abscess, or chronic disease or trauma of the perineal Patients normally present with scrota1 discomfort for several days, which progresses to erythema and edema, and eventually to skin necrosis. Depending on the initiating source, the infection may spread up the abdominal wall, or to the buttocks or thighs. Extensive debridement is indicated, but orchiectomy and penile amputation can usually be avoided because of the alternative blood supplies of the testes and The infection is usually polymicrobial, involving gram-negative bacilli, Clostridium species, aerobic and anaerobic streptococci, and Bacteroides. Despite appropriate therapy, mortality ranges 20% to 35%, and there has been no improvement in the mortality rates over the last 10 years? Foot infections
Diabetic foot infections are an extremely common problem. It is estimated that clinically apparent neuropathy is present in about 25% of diabetic^,^ and 35% to 40% of diabetics with foot ulcers will require an amputation within 3 years.26More than half of nontraumatic limb amputations occur in diabetics. A number of factors may predispose diabetics to developing foot infections: the friction from ill-fitting shoes leads to the formation of blisters and ulcers that are not detected because of neuropathy, or skin breakdown caused by dermatophyte infection or paronychia may allow entrance of pathogens. Unless a patient inspects his feet on a regular basis, these infections may develop and extend to deeper tissues without the patient's knowledge. Foot infections are generally stratified into mild or nonlimb-threatening infections and severe or limb-threatening infections. Patients pre-
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senting with foot infection should have a careful examination performed and radiography of the involved foot should be obtained to help stratify the infection. Mild infection is defined as superficial infection with less than 2 cm of cellulitis and no evidence of serious ischemia, systemic toxicity, or bone or joint involvement. Limb-threatening infection is defined as a full-thickness ulceration with greater than 2 cm of cellulitis, or evidence of serious ischemia, systemic toxicity, or bone or joint involvement. The presence of ischemia or systemic toxicity may be apparent on initial examination, but bone involvement could be more difficult to determine. Two simple clinical features are predictive of the presence of osteomyelitis: size and depth of the ulcer (ability to visualize or probe bone through the ulcer) and an ESR of over 70 mm/hr.26Ulcers that are larger than 2 cm2 in surface area or are deep are more likely to be associated with underlying bone and a positive “probeto-bone” test has a sensitivity, specificity, and positive predictive value Bone involvement for osteomyelitis of 6670, 85% and 89%, respe~tively.’~ may be seen on plain films, but abnormalities are often not evident until 10 to 20 days after infection, or when 40% to 70% of bone has been lost. 99mTc-diphosphonate scanning is more sensitive than plain radiography, but has poor specificity. The radiologic examinations of choice currently are the In-labeled leukocyte scan,”’ which has a sensitivity of 89% and a specificity of 78Y0,2~and MRI, with a sensitivity of 99% and specificity of 83%. MRI is also helpful in determining the extent of the soft tissue involvement. For mild infections, if the patient is reliable and has an appropriate support system at home, outpatient treatment can be pursued with an oral regimen targeting gram-positive flora, such as cephalexin, clindamycin, dicloxacillin, or amoxicillin-clavulanate.5 Rest of the involved area is essential, and patients should be re-examined in 24 to 48 hours to ensure proper response. If patients do not have the appropriate support network at home to allow rest, then inpatient treatment should be considered. For patients with open wounds on presentation, repeat radiography after 2 weeks of therapy should be considered to detect interval changes of occult 0steomyelitis.3~Antimicrobial therapy should be continued for 7 to 14 days (Fig. 2). Patients presenting with moderate to severe foot infection should be evaluated for the presence of osteomyelitis, which complicates 50% to 60% of these infections, and undergo debridement of devitalized areas or drainage of accumulated pus as soon as possible to maximize the chances of limb salvage. It is controversial whether patients with foot osteomyelitis who have no clear indications for surgery (necrosis, gangrene, abscesses) should be treated medically or with a combined medical-surgical approach. Medical therapy alone is reported to cure 53% to 87% of those with diabetic foot osteomyelitis, but long-term therapy (24 weeks) is usually necessary, as is longterm followup to detect recurrence. In patients with osteomyelitis of the phalanx or metatarsal head, limited amputation, such as a digit or ray resection, may be the most cost-effective approach since it preserves a weight bearing surface, will allow a shorter course of antimicrobials (2
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1 Diabetic Foot Ulcer with Infection I ModerateEevere Infection*
of osteomyelitis?
Local debridement and evaluation for osteomyelitis*
antimicrobials
Good home support? Yes
4
Yes
1 O u t p a y Rx 1 Improvement in 48 hrs? Yes
1
7 - 14 days antimicrobials
Repeat X-ray in 14 days to
NO
1
J
Evaluate need for surgery or revascularization I
4 Infected bone resected? No
4
6 - 8 weeks antimicrobials
antimicrobials
Yes
I
Figure 2. Management of diabetic foot infections. *See text for definition or more detail. IV = intravenous; Rx = treatment.
weeks), and leads to a high cure rate.2l A retrospective study of patients with foot osteomyelitis, 77 of whom received surgical intervention (debridement or local limited amputation) within 3 days of admission and 87 of whom did not, demonstrated that those receiving early surgical intervention had fewer above-the-ankle amputations (13% vs. 28%) and a shorter duration of hospitalization (9.6 days vs. 18.8 The decision to pursue surgical intervention in many cases needs to be individualized, taking into account the extent of the infection, the antimicrobial susceptibility profile of the pathogens, the patient’s vascular status, and the patient’s personal circumstances (i.e., ambulatory status, ability to comply with long-term antimicrobials). One advantage of surgery is to obtain deep tissue specimens or a specimen of bone for culture, which is helpful in directing appropriate antimicrobial coverage. Moderate to severe diabetic foot infections are often polymicrobial, and surface cultures yield many more pathogens than are found in surgically (or percutaneously) obtained specimens. Therefore, basing treatment decisions on superficial cultures often leads to overuse of antimicrobials that may lead to problems with drug toxicity and the emergence of multiresistant pathogens. Empiric coverage of severe diabetic foot infections should include agents active against S. aureus, Pseudomonas, entero-
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cocci, and anaerobes. Many different combinations of antibiotics are effective, and a recent review summarizes the available data on antimicrobial treatment of diabetic foot infection^.^^ References 1. ACE' Task Force on Adult Immunization. Immunizations for immunocompromised adults. In Guide for Adult Immunization. Philadelphia, ACP, 1994, p 49 2. Aleksandrovski YA: Molecular mechanisms of diabetic complications. Biochemistry (Moscow) 61:1249, 1998 3. American Thoracic Society: Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 161:S221, 2000 4. Bilton BD, Zibari GB, McMillan RW, et a1 Aggressive surgical management of necrotizing fasciitis serves to decrease mortality: A retrospective study. Am Surg 64.397, 1998 5. Caputo GM, Cavanagh PR, Ulbrecht JS, et al: Current concepts: Assessment and management of foot disease in patients with diabetes. N Engl J Med 331:854, 1994 6. Delamaire M, Maugendre D, Moreno M, et al: Impaired leucocyte function in diabetic patients. Diabetic Med 1429,1997 7. Deresinski S Infections in the diabetic patient: Strategies for the clinician. Infectious Disease Reports 1:1, 1995 8. Ellenbogen PH, Talner L B Uroradiology of diabetes mellitus. Urology 8:413, 1976 9. Evanoff GV, Thompson CS, Foley R, et al: Spectrum of gas within the kidney: Emphysematous pyelonephritis and emphysematous pyelitis. Am J Med 83:149, 1987 10. Fairley C, Sullivan TJ, Bartley P, et a1 Survival after rhino-orbital-cerebral mucormycosis in an immunocompetent patient. Ophthalmology 107555,2000 11. Fine M, Smith M, Carson C, et al: Prognosis and outcomes of patients with communityacquired pneumonia. JAMA 275:134, 1996 12. Forland M, Thomas V, Shelokov A: Urinary tract infections in patients with diabetes mellitus: Studies on antibody coating of bacteria. JAh4A 238:1924, 1977 13. Forland M, Thomas VL: The treatment of urinary tract infections in women with diabetes mellitus. Diabetes Care 8:499, 1985 14. Gale GR, Welch AM. Studies of opportunistic fungi. I. Inhibition of Rhizopus oryzae by human serum. Am J Med Sci 241:604, 1961 15. Gallacher S, Thomson G, Fraser WD, et al: Neutrophil bactericidal function in diabetes mellitus: Evidence for association with blood glucose control. Diabetic Med 12916, 1995 16. Geerlings SE, Hoepelman A Immune dysfunction in patients with diabetes mellitus. FEMS Immunology and Medical Microbiology 26: 259, 1999 17. Gehanno P: Ciprofloxacin in the treatment of malignant external otitis. Chemotherapy Suppl 1:35, 1994 18. Gleckman R, Al-Wawi M: A review of selective infections in the adult diabetic. Comp Ther 25: 109, 1999 19. Grayson ML, Gibbons GW, Balogh K, et al: Probing to bone in infected pedal ulcers. JAMA 27721, 1995 20. Hui KP, Chin NK, Chow K, et a 1 Prospective study of the aetiology of adult community acquired bacterial pneumonia needing hospitalization in Singapore. Singapore Med J 34329, 1993 21. Karchmer AW, Gibbons GW. Foot infections in diabetes: Evaluation and management. Curr Clin Top Infect Dis 141,1994 22. Kass EH: Asymptomatic infections of the urinary tract. Trans Assoc Am Physicians 69:56, 1956 23. Klein DE, Mahoney SA, Youngen R, et al: Renal emphysema. J Urol95:625, 1966 24. Koziel H, Koziel MJ: Pulmonary complications of diabetes mellitus: Pneumonia. Infect Dis Clin North Am 9:65, 1995 25. Lipsky BA Evidence-based antibiotic therapy of diabetic foot infections. FEMS Immunology and Medical Microbiology 26:267, 1999
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