bacterial urinary tract infections in diabetes

URINARY TRACT INFECTIONS 0891-5520/97 $0.00 + .20

BACTERIAL URINARY TRACT INFECTIONS IN DIABETES

Jan Evans Patterson, MD, and Vincent T. Andriole, MD

EPIDEMIOLOGY

Urinary tract infection is a significant problem in patients with diabetes mellitus because of the multiple effects of this disease on the urinary tract and host immune system. Complicated urinary tract infections associated with diabetes include renal and perirenal abscess, the gas-forming infections, such as emphysematous pyelonephritis and emphysematous cystitis, fungal infections, xanthogranulomatous pyelonephritis, and renal papillary necrosis. Renal and perirenal abscess, fungal urinary tract infections, and xanthogranulomatous pyelonephritis are discussed elsewhere in this issue. The increased rate of bacteriuria in diabetic women and bacterial infections causing lower urinary tract infection, pyelonephritis, urinary tract emphysema, and renal papillary necrosis are discussed in this article.

Bacteriuria and urinary tract infections are more common in diabetic women compared with nondiabetic women. Although some early studies showed no difference between the frequency of urinary tract infections in patients with diabetes compared with controls,6°, 66,86 more recent studies have documented a twofold to threefold increase in this problem in diabetic women.22, 35,5y,y0 Kass et a1 documented a higher rate (16% to 19%) of bacteriuria in diabetic women compared with nondiabetic women (5% to 8%). Studies suggest no significant difference in the prevalence of bacteriuria in diabetic versus nondiabetic men. Diabetes mellitus is also a significant risk factor for nosocomial urinary tract infectionR, 65 Although the site of urinary tract infection in unselected populations usually shows an equal distribution between upper and lower tract

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From the Departments of Medicine (Infectious Diseases) and Pathology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas (JEP); and Depart- ment of Medicine (Infectious Diseases), Yale University School of Medicine, New Haven, Connecticut (VTA)

INFECTIOUS DISEASE CLINICS OF NORTH AMERICA

VOLUME 11 - NUMBER 3 * SEPTEMBER 1997 735

736 PAlTERSON & ANDRIOLE

localization:a,82 upper tract infection is more common in diabetes mellitus. Using bladder washout studies, Ooi et a1 showed that 63% of 24 diabetic women with bacteriuria had kidney infection.5y Forland et a1 used studies of antibody-coated bacteria to show that 43% of diabetic women with bacteriuria had renal parenchymal infection at initial testing, and by 7 weeks, 80% of these women had renal parenchymal infection.22 Further, an autopsy series documented a fourfold to fivefold higher rate of acute pyelonephritis in diabetics compared with nondiabetic patients.67 The urinary tract is a common source of bacteremia in diabetics compared with causes of bacteremia in nondiabetic patients, and for this reason, diabetics are more likely to receive inappropriate empiric therapy for community-acquired bacteremiaB When complicated upper urinary tract conditions occur, such as intrarenal abscess, urinary tract emphysema, perinephric abscess, papillary necrosis, and metastatic infection from the urinary tract, they are frequently seen in patients with diabetes me l l i t~s .~~ , y2

PATHOGENESIS

The chronic effects of diabetes mellitus on the genitourinary system include diabetic cystopathy, diabetic nephropathy, renal papillary necrosis, renal artery stenosis, and vas deferens calcification.6x Although factors such as age, degree of glycosuria, and instrumentation have been suspected as risk factors for the increased likelihood of upper tract involvement with urinary tract infection in diabetic women, studies have not confirmed these as major contributors.22, 66, ')' A variety of factors may contribute. The most important predisposing factor may be bladder dysfunction as a result of diabetic neuropathy and ~ystopathy.'~,

92 Diabetic cystopathy begins as decreased bladder sensation and decreased reflex detrusor activity caused by neuropathy affecting sympathetic and parasympathetic afferent fibers.68 Impaired bladder sensation results in bladder distention and increased residual urine volume. Long-term effects may eventu- ally be vesicoureteral reflux and recurrent upper urinary tract infection. A survey by Forland has documented a high prevalence of genitourinary structural abnormalities in a group of diabetic women:' whereas several studies have shown a low rate of significant structural abnormalities (4%) in unselected women with recurrent urinary tract infection.1','9, 23, 56 In the Forland study, 30% of the group of diabetic women had significant structural abnormalities, such as cystocoele, cystourethrocoele, or rectocele. Another contributing factor that has been suggested is recurrent ~ a g i n i t i s . ~ ~ Generalized vascular disease as a result of long-standing diabetes mellitus may also be important. Vascular complications, such as retinopathy, neuropathy, heart disease, peripheral vascular disease, and diabetes of more than 20 years' duration, have correlated with an increased incidence of urinary tract infection, whereas insulin dose and nephropathy have not?' Finally, although the degree of glycosuria has not been directly implicated in clinical studies, high levels of urinary glucose have been shown to impair phagocytic function of the leukocyte.y Other studies have also documented abnormal leukocyte function in diabete~.~, 7,12. 57 All of these factors likely contribute to explain the increased prevalence and severity of urinary tract infection in patients with diabetes.

24,

CLINICAL PRESENTATIONS

Uncomplicated Urinary Tract Infection

Bacteriuria is common in diabetic women and is often associated with upper tract infection, as discussed previously. Infection may be asymptomatic, even

BACTERIAL URINARY TRACT INFECTIONS IN DIABETES 737

with upper tract disea~e.5~. 90 Although data are limited: 21* 22* 96 many experts recommend treating asymptomatic bacteriuria in patients with diabetes when detected because of the frequency and severity of upper urinary tract infection associated with bacteriuria in these patients. Bacteriuria is difficult to eradicate, however, in patients with anatomic abnormalities of the bladder or perineum, such as cystocoele or rectocoele. In these patients, therapy should probably be reserved for symptomatic episodes?6 Because of the high rate of upper tract infection as indicated by the presence of antibody-coated bacteria, the short course 3-day regimen recommended for acute uncomplicated cystitis in nondiabetic women would not be recommended for cystitis in diabetic^.^^ Because of the concern about upper tract involvement, 7-day to 14-day oral antimicrobial regimens are recommended for uncomplicated infection in patients with diabetes.z1, 83 Recurrent infection in the urinary tract occurs often in these patients. A study by Forland et a1 in a group of Mexican-American diabetic women showed that 70% of patients had recurrence of the bacteriuria during a 34- month follow-up period.21 Most recurrences (75%) were reinfections with a different organism than the one causing the original infection. Two weeks of oral trimethoprim/sulfamethoxazole (TMP/SMX) antimicrobial therapy was as effective as 6 weeks of prolonged therapy for eradication of bacteriuria in these women. Similar results were found in a study using ampicillin or nitrofurantion in a general population of 142 women and 4 men with recurrent urinary tract infection that was not localized to the upper or lower tract.37 In men with upper tract disease, determined by antibody-coated bacteria, the superiority of 12 weeks versus 10 days of TMP/SMX and of 6 weeks versus 2 weeks of therapy in eradicating and preventing relapse of infection has been documented.21, ’’

The most common bacterial cause of urinary tract infection in patients with diabetes is still Escherichia coli; other enteric coliforms, such as Klebsiella pneurnoniae and Proteus rnirabilis, are also common. Klebsiella pneurnoniae, in particular, is more common in the diabetic person compared with the nondiabetic person in both the community-acquired and nosocomial infection^.^^ In addition, the diabetic patient is more likely to have an antibiotic-resistant pathogen causing a nosocomial urinary tract infection.51 Enterobacter sp, Enterococcus sp, and Pseu- domonas aeruginosa should be considered in diabetic patients who are hospitalized, have had recent urologic procedures, or have recurrent infection following antibiotic therapy. Enterobacter sp. infection, particularly Enterobacter aerogenes, has also been observed to be community-acquired in the diabetic patient?’ Enterococcus sp. and P. aeruginosa should also be considered in patients in the community who have received recent antimicrobials for urinary tract or other infections. Fungal infections are common in diabetic patients and are discussed in a separate article in this issue. Because of the frequency of upper tract disease, potential upper tract complications, and frequent recurrent infection, urinary tract infections in diabetes patients should be culture-documented as opposed to uncomplicated cystitis in nondiabetic young women. In addition, a follow-up urine culture after completion of antimicrobial therapy is recommended in most diabetic women to detect those in whom bacteriologic cure has not been achieved.

Trimethoprim/sulfamethoxazole (160 mg/800 mg) twice daily remains an excellent choice for first-line oral antimicrobial therapy of uncomplicated urinary tract infection in patients with diabetes. Resistance to TMP/SMX among coliforms is relatively low (so/, to 15%) in the United States, although it may be increasing.”, TMP/SMX should be used with caution in patients taking oral hypoglycemic agents because TMP/SMX can potentiate the hypoglycemic effect of these drugs.2, 33 This potentiation has usually occurred when larger doses of

738 PATTERSON & ANDRIOLE

TMP/SMX or parenteral TMP/SMX is used. The fluoroquinolones (ciprofloxacin, norfloxacin, ofloxacin, lomefloxacin, levofloxacin, or enoxacin) are also highly effective in treating urinary tract infections for diabetic and nondiabetic patients. Flouroquinolone resistance remains less than 5% in most areas of the United States but should be reserved as a second choice when possible, such as in a patient with allergy to TMP/SMX or a TMP/SMX-resistant organism, to avoid the widespread rapid selection of organisms resistant to fluoroquinolones. Ciprofloxacin is the oral drug of choice for a urinary tract infection caused by P. aeruginosa. The fluoroquinolones may be particularly effective in treating prostatitis because of excellent tissue penetration.

Now that approximately one third of bacteria causing uncomplicated urinary tract infection in the United States are resistant to amoxicillin and ampicillin and 15% to 20% are resistant to nitrofurantoin,5*, 83 the use of these agents for empiric therapy is limited.

Enterococcal superinfection of the urinary tract may occur in a patient treated with a fluoroquinolone or TMP/SMX because of the intrinsic resistance of the Enferococcus to these agents. Amoxicillin or ampicillin remain the oral drugs of choice for Enterococcus sp when the organisms are susceptible. In a patient allergic to penicillins, oral antibiotic alternatives include nitrofurantoin, tetracycline, or doxycycline. These regimens should be used for uncomplicated enterococcal infections only because the agents have limited activity against Enterococcus sp. Complicated enterococcal urinary tract infections do not likely respond to these alternatives, and intravenous therapy with ampicillin or vancomycin would be warranted.

Vancomycin-resistant enterococci, particularly vancomycin-resistant Entero- coccus faecium isolates, are increasing. lo These pathogens are usually resistant to penicillin, ampicillin, extended spectrum penicillins, fluoroquinolones, TMP/ SMX, erythromycin, tetracycline, and high levels of aminoglycosides. When these multiresistant organisms are isolated from the urine, it is important to determine whether they represent contamination, colonization, or infection. If infection is suspected, susceptibility to alternative agents should be determined. For noninvasive infections, nitrofurantoin or doxycycline are potential oral alternative therapies, as guided by susceptibility testing. Options for therapy of invasive infections are discussed in a subsequent section.

Studies of the role of suppressive therapy to prevent recurrence of bacteriuria in diabetic women are limited. Forland showed the effectiveness of a low- dose regimen of TMP/SMX (40 mg/200 mg) once daily at bedtime in preventing recurrent infection on suppression. Although emergence of TMP/SMX-resistant organisms did not occur, bacteriuria recurred in all patients at 7 weeks after antibiotic suppression was discontinued. Nitrofurantoin is an agent commonly used for suppression; however, recurrent infection with nitrofurantoin-resistant organisms may occur in diabetic women on nitrofurantoin suppression.*' Also, patients on nitrofurantoin chronically should be monitored for the well-known adverse effect of chronic pulmonary fibrosis and also for the rheumatologic syndrome that can occur in older women on this

Acute Pyelonephritis

Acute pyelonephritis occurs more commonly in patients with diabetes. One study has documented a rate of pyelonephritis as high as fivefold that of nondiabetic patient^.^^ This is likely related to the higher rate of bacteriuria and upper tract infection in these patients and local host factors in the kidney itself.


Pyelonephritis occurs as a result of ascending infection of the urinary tract, and therefore, E. coli and the other common gram-negative uropathogens, such as Klebsiella sp, Enterobacter, and Proteus sp, are the usual bacterial causes. This entity is more common in women, and bilateral involvement occurs more commonly in diabetic patients.l6 The clinical syndrome of acute pyelonephritis involves symptoms of ascending upper tract disease (fever and chills, nausea and vomiting, flank pain or tenderness), often seen in combination with symptoms of the initiating lower tract infection (dysuria, frequency, urgency). In patients with mild illness, lower tract symptoms may predominate with only mild flank pain.% Laboratory findings are nonspecific but usually are remarkable for leukocytosis with a shift to the left and pyuria. Because complications can occur, a urine culture is recommended in patients with suspected pyelonephritis so that therapy can be culture directed. Patients presenting with severe illness and toxicity (high fever, nausea and vomiting, inability to take oral medication, and hydration) or those with debilitating underlying conditions (uncontrolled diabetes mellitus, advanced age, immunosuppression) should be hospitalized. A blood culture should be obtained in those with severe illness; 15% to 20% of these will be 72 Any patient with a urinary tract abnormality, but particularly diabetic patients, are at risk for a focal, complicated form of pyelonephritis, which leads to intrarenal abscess. Because emphysematous pyelonephritis is a complication requiring early intervention that can occur in patients with diabetes in particular, a screening plain abdominal radiograph is recommended.18 (See below, Emphysematous Complications).

Complicated Urinary Tract Infection

Upper urinary tract infection can result in a number of severe complications in patients with diabetes (Tables 1 and 2). Based on sensitive renal imaging techniques now available, upper tract disease can be classified as intrarenal or perirenal pathology. The spectrum of intrarenal infection now includes pyelonephritis, acute focal bacterial nephritis, and acute multifocal bacterial nephritis and the long-recognized renal cortical abscess, renal corticomedullary abscess, and xanthogranulomatous pyelonephritis and perinephric abscess. In addition, emphysematous pyelonephritis and emphysematous cystitis are entities oc- curring almost exclusively in diabetics. Renal papillary necrosis is also highly associated with diabetes mellitus.

Table 1. PATHOGENESIS AND RISK OF UPPER TRACT INFECTION IN DIABETICS

Route of Risk in Diabetic Infection Infection Pathogen Patients

Acute pyelonephritis Ascending E. coli Fourfold increase6'

Renal corticomedullary abscess Ascending E. coli Twofold increases2

Renal carbuncle Hematogenous S. aureus Increased'

Klebsiella Proteus

Klebsiella Proteus

From Patterson JE, Andriole VT: Bacterial urinary tract infections in diabetes. Infect Dis Clin North Am 9:25, 1995


Table 2. DIABETICS AND COMPLICATED RENAL INFECTION

Complication % Diabetic Reference

Emphysematous pyelonephritis 72 74

Emphysematous cystitis 80 4 Emphysematous pyelitis 50 18

Perinephric abscess 36 87 Papillary necrosis 57 46 Metastatic infection 12 78

Adapted from Wheat LJ: Infection and diabetes mellitus. Diabetes Care 3:188-197, 1980; with per- mission.

The entities of intrarenal abscess, acute focal bacterial nephritis, acute multifocal bacterial nephritis, renal cortical abscess, renal corticomedullary abscess, xanthogranulomatous pyelonephritis, and perinephric abscess are discussed elsewhere in this issue. The complicated urinary tract infections highly associated with diabetes mellitus, including the emphysematous complications, such as emphysematous pyelonephritis and emphysematous cystitis, and renal papillary necrosis are discussed in this article. The general approach to the radiographic evaluation of upper tract urinary tract infection in diabetics is crucial in the early detection of complications and is also discussed here. The radiographic characteristics of individual entities of renal abscess are described elsewhere in this issue. The radiographic characteristics of the emphysematous complications are described in this article.

Radiologic Findings

Uncomplicated pyelonephritis in a nondiabetic patient does not routinely require radiographic imaging of the upper urinary tract."? In the diabetic patient, however, a high degree of suspicion should be maintained for complicated urinary tract infection. Evanoff et a1 have recommended a screening abdominal radiograph at a minimum in the diabetic patient with pyelonephritis to rule out renal emphysema.1s A screening ultrasound should also be considered early on in the diabetic patient to look for obstructive complications. In the diabetic (or nondiabetic) patient who has not responded to 72 hours of appropriate intravenous therapy for pyelonephritis, an imaging study of the upper tract should be performed to evaluate for complicated upper tract pathology. As a general rule, ultrasonography is recommended as the first radiographic study of choice in- stead of an excretory urogram, particularly in the diabetic patient,h4 for several reasons. The excretory urogram is limited in characterizing acute renal parenchymal infections,Q 64 and diabetic patients are at excessive risk for renal toxicity from urographic contrast agents caused by preexisting diabetic nephr~pathy.~~, hH, Although the renal damage caused by contrast agents is usually transient, it can be permanent in some patients. If renal insufficiency is present and suspected to be caused by obstruction or a postrenal etiologic agent, ultrasonography is also helpful. As a confirmatory or more detailed study, retrograde pyelography may be more helpful than the excretory ~ r o g r a m . ~ Ultrasonography has been compared directly with intravenous urography for detecting urinary tract abnormalities in the setting of acute infection in adults.", R' Both studies documented that ultrasonography, combined with the plain abdominal radiograph, was as accurate in detecting abnormalities as the intravenous pyelogram.


The excretory urogram may be indicated with the presence of certain risk factors in women with recurrent urinary tract infections. These include infection of the urinary tract in childhood, relapsing infection with the same microorganism, history of urinary calculi, infection with urea-splitting organisms (e.g., Proteus sp), neurologic bladder dysfunction, and previous genitourinary surgery.17, 42 If there is a high degree of suspicion for an acute renal calculus obstruction, the excretory urogram is also useful. Even with these indications, however, the study must be done with caution in the diabetic patient.zh Such patients selected for intravenous contrast studies should be hydrated with normal saline; however, overhydration may result in an unsatisfactory excretory urogram because of contrast dilution.

Thus, when an imaging study is needed to characterize renal infection or rule out upper tract infectious complications, ultrasonography is a rapid, relatively inexpensive initial screen for the detection of parenchymal lesions and obstructive uropathy.M For emergent renal imaging, ultrasonography is usually the study of choice. If there is a high degree of clinical suspicion for renal abscess, CT scanning should be pursued even if ultrasonography is unrevealing.

Computed tomography is also indicated if a renal mass is detected by ultrasound to allow further characterization. The CT scan is also a sensitive screening method and characterizes renal infection as focal or diffuse, detects the presence and location of air, and determines whether there is perinephric extension.zs, 3o MR imaging is also accurate in differentiating renal masses. Gado- linium-enhanced MR imaging is advantageous compared with contrast-enhanced CT when the renal function is abnormaL6' Contrast-enhanced MR imaging can classify large retroperitoneal masses as intrarenal or e~trarenal.~" MR imaging is not a screening method for a renal mass, however, but can achieve sensitivity comparable to CT scanning when contrast agents and fat suppression are used.40 A distinctive feature of the MR image compared with ultrasound and CT is that a renally excreted paramagnetic contrast agent may be used in combination to evaluate renal function at the same time the renal mass is characterized. In addition, magnetic resonance angiography offers the option of evaluating renal vasculature if needed.4"

Emphysematous Complications

Emphysematous pyelonephritis is a severe, necrotizing form of acute multifocal bacterial nephritis that results in the presence of gas within the renal parenchyma. Often, the infection, and consequently the gas, extends through the renal capsule and involves the kidney and the perinephric space as well. Emphysematous pyelonephritis is a relatively uncommon but distinctive entity first described 100 years 39 It is an important entity to consider in the diabetic patient because 70% to 90% of reported cases have occurred in diabetics.18, 74 The most common bacterial cause is E . coli, accounting for 60% of casesIR; other enteric gram-negative bacilli such as Enterobacter aerogenes, Klebsiella sp, and Profeus sp account for most of the other reported cases; however, Streptococcus sp38 and Candida sp have also been rep~rted.'~, yi The source of the gas formation remains obscure, but several explanations are feasi- ble. The Enterobacteriaceae can produce gas in vitro by mixed acid fermentation. Production of carbon dioxide, from fermentation caused by a high concentration of sugar in the urine, and tissue of infecting bacteria in vivo has been widely regarded as a likely mechanism. Another proposed mechanism is fermentation of products from necrotic tissue.74 Others have suggested that the major factors are rapid catabolism and impaired transport of end products at the inflammatory


site."4 Recent analyses of gas from such infections have documented the presence of carbon dioxide, hydrogen, nitrogen, and unknown gases.32, y4 Whatever the exact mechanism, the three critical conditions necessary for this renal emphysema seem to be: (1) presence of gas-forming bacteria, (2) high local tissue glucose level, and (3) impaired tissue p e r f u s i ~ n . ~ ~

A common clinical triad of predisposing factors is: diabetes mellitus, remote or recent kidney infection, and obstruction. The entity is more common in women than in men (2:l). Presenting symptoms are similar to patients with acute pyelonephritis or renal abscess, with fever, chills, and frequently nausea and vomiting. On physical examination, 50% have evidence of a flank mass; however, the absence of this finding is not helpful. The dramatic finding of crepitation over the thigh or flank in a diabetic patient is infrequent but when present should raise a high degree of suspicion for emphysematous pyelonephritis with extension into the perinephric space and retroperitoneum.'h Typical laboratory findings include hyperglycemia, elevated white blood cell count, and blood urea nitrogen or serum creatinine. The urinalysis virtually always shows pyuria in this entity. Although glycosuria will be present, it has been suggested that quantitative urine glucose is less than suggested by the level of serum glucose because of increased fermentati~n.~~ In the diabetic patient presenting with fever, abdominal or flank pain, and pyuria, a plain abdominal radiograph is warranted to screen for the presence of gas in the kidneys.

The plain abdominal radiograph detects renal emphysema in 85% of cases1x; likewise, the renal ultrasound usually detects this entity.68 The left kidney is affected as frequently as the right (Fig. 1). Bilateral involvement is infrequent but can occur. If gas is present, CT should be performed to better characterize its location, in particular, whether the gas is in the renal parenchyma or the collecting system (see later discussion). The localization of air as intrarenal, perinephric, or confined to the collecting system is crucial in determining therapy and prognosis, and CT is the study of choice.25 Radiographic findings are

Figure 1. Emphysematous pyelonephritis. Air is present throughout the interstitiurn and the perinephric space of the right kidney. (Courtesy of Dr. Michael F. Sarosdy, University of Texas Health Science Center at San Antonio).


classified in three sequential Initially, there is diffuse mottling of the renal parenchyma, with gas distributed radially along the renal pyramids. As the disease progresses, more severe necrosis and extensive gas formation is characterized by a crescent of gas in Gerota’s fascia, combined with mottling in the renal parenchyma. Finally, gas may erode through Gerota’s fascia into the retroperitoneum, indicating perinephric extension of the infection and necrosis. The renal histopathologic correlation is acutely inflamed interstitium, with multiple areas of microabscess and macroabscess formation.’8

Emphysematous pyelonephritis carries a poor prognosis with medical therapy alone. In cases in which the gas is confined to renal parenchyma, the mortality is 60% in patients treated with an antibiotic, with or without surgical drainage.’” 27, 47, 55, 71,80 If gas has extended into the perinephric space, the mortality is 80% with antibiotic therapy a10ne.I~~ 41, 47, 75, 85 Surgical removal of the involved kidney lowers mortality substantially; the mortality rate is 20% or less in patients who undergo nephrectomy.18, 27, 55

Emphysematous pyelitis (or pneumopyonephrosis) is a distinct entity from emphysematous pyelonephritis and describes the presence of gas localized to the renal collecting system. The pathogenesis and prognosis of this entity vary somewhat from emphysematous pyelonephritis.18, Fifty percent of patients have diabetes, but many do not and have frank obstruction of the collecting system.18 The left kidney is affected twice as often as the right, and bilateral involvement is rare.

The clinical manifestations are nonspecific and usually include fever, chills, nausea, vomiting, and abdominal pain. An elevated white blood cell count and pyuria are almost always present; azotemia and hyperglycemia occur in half of the patients.’* The most common bacterial cause is, again, E. coli. The radiograph demonstrates gas following the outline of the renal pelvis, and gas may also be seen in the ureters (Fig. 2).

The overall mortality of this entity is 20°/0.47 Intravenous antibiotics are

Figure 2. Emphysematous pyelitis. Abdominal radiograph demonstra- ting a staghorn calculus and emphysematous pyelitis (pneumopyonephrosis) in a diabetic. The infection and air in the collecting system subsequently spread to the perinephric space. (Courtesy of Dr. Kedar Chintipalli, University of Texas Health Science Center at San Antonio.)

744 PATTERSON &I ANDRIOLE

given, and this is sufficient therapy if there is no obstruction. If obstruction is present, the obstruction must be corrected in addition to administration of parenteral antimicrobials.

Emphysematous cystitis (or cystitis emphysematosa) is a rare disease associated with air in the urinary tract.4, 5, 28, 31 More common causes of air in the bladder are vesicocolic or vesicovaginal fistulae associated with infection or neoplasm at another site. Emphysematous cystitis, however, results from a primary infection of the bladder. Approximately 50% to 80% of the patients reported with this entity are diabetics.4, 5, 28 E. coli is usually the offending agent, but Enterobacfer aerogenes, Proteus sp, Klebsiella sp, S. aureus, Clostridium perfringens, Nocardia, and Candida have been described:, 5, ZR Typically, patients are not as acutely ill as with emphysematous pyelonephritis or pyelitis and present with lower urinary tract symptoms referable to the bladder such as frequency, urgency, and dysuria. Abdominal pain is often present and may be chronic. Characteristic clinical features that may suggest the diagnosis include gross hematuria and pneumaturia, although the latter is uncommon. The history of pneumaturia is usually solicited rather than volunteered. Pneumaturia is not usually associated with emphysematous pyelonephritis or pyelitis. The radiograph shows evidence of air in the bladder wall or lumen (Fig. 3). An air fluid level may be seen and irregular areas of lucency or intramural air The entity may have a "cobblestone" appearance, with a lucent line of air outlining the bladder Renal ultrasound may show diffuse thickening of

Figure 3. Abdominal radiograph showing air throughout the bladder wall in a case of emphysematous cystitis. (Courtesy of Drs. Barney Graham and David Gregory, Van- derbilt University Medical Center, Nashville, TN.)


the bladder wall and echogenicity; CT scanning should easily demonstrate gas in the bladder wall and extension into the lumen.68 Emphysematous cystitis should be differentiated from gas in the rectum, vaginal emphysema, pneu- matosis cystoides intestinalis, uterine gas gangrene, enterovesical fistula, and bladder lumen air caused by trauma, instrumentation, or urinary catheteriza- tion.6x Cystoscopy, if done, has been described to show diffuse blebs throughout the bladder mucosa.2R, 31 In general, systemic antimicrobials and relief of any complicating bladder outlet obstruction, if present, are adequate therapy.

Renal Papillary Necrosis

Overall, renal papillary necrosis is uncommon in diabetics. When a case of renal papillary necrosis is diagnosed, however, over half of patients are diabetic,43,46,52,68 and an autopsy series has documented that this entity is five times more prevalent in diabetic patients than in nondiabetic patients. Other causes of renal papillary necrosis are sickle cell disease, analgesic abuse, and obstruction.s2 Patients may present with flank pain, fever, chills, and abdominal pain. Most patients are acutely ill, but the disease may also progress and present slowly.s2,hX Urinary tract infection is virtually always a concurrent complication when renal papillary necrosis is documented in the patient with diabetesT6 Renal insufficiency or acute renal failure is a common complication. Renal papillary necrosis should be considered in the diabetic patient presenting with symptoms of pyelonephritis who does not respond well to antibiotic therapy or in whom renal insufficiency 52 The common uropathogens are the typical bacterial causes associated with this disease.

Renal papillary necrosis is a radiologic diagnosis that is confirmed by histology of voided medullary tissue or at autopsy. The characteristic radiographic appearance is the same, whether the cause is diabetes, sickle cell disease, analgesic abuse, or obstruction. The retrograde pyelogram is the preferred proce- dure because of frequent renal insufficiency in diabetic patients when excretory urography is performed. When the cause is not obstruction, findings are typically bilateral. Early signs of the disease include a dilated calyceal fornix, re- tracted or irregular papillary tip, and extension of contrast material into the parenchyrna.l6, 44, 4y Later, a club-shaped cavity in the medulla or papillae may be formed. A "ring sign" may be observed on the radiographic study when a separated papilla is surrounded by contrast medium.16 The papilla itself may slough into the renal pelvis or ureter, causing obstruction. The necrotic papilla may calcify in a ring pattern, which is unique to renal papillary necrosis.6x On ultrasonography, renal papillary necrosis may be distinguished from hydrone- phrosis by the narrow infundibula between the clubbed calyces and the renal pelvis6* The pathogenesis of this type of urinary tract infection in the diabetic patient is not well understood, but it is thought that infection and ischemia in the diabetic patient compromise the already marginal vascular supply to the papilla causing it to s l o ~ g h . ~ ~ , ~ ~ Because of the obstructive nature of this disease, recurrent infection is a problem.

Therapy Empiric antibiotic therapy of diabetic patients with complicated urinary

tract infections is similar to that of patients with acute pyelonephritis because the causative pathogens are usually the same. Enteric gram-negative bacilli, such as E. coli, Proteus sp, Klebsiella sp, and Enterobacter, are the usual bacterial causes. For these serious infections, Pseudomonas aeruginosa and Enterococcus sp may also


need to be considered as possible causes, particularly in the patient who has recurrent infections, a history of previous urinary infections caused by these pathogens, or has been on previous broad spectrum antimicrobials. Invasive staphylococcal infection is not uncommon in the infected diabetic patient and should be considered as an etiologic agent of urinary tract sepsis in the diabetic patient, particularly if the pathogenesis of the upper urinary tract infection is that of renal carbuncle. Although cefotaxime or cefipime may provide reasonable empiric coverage for methicillin-susceptible staphylococci, if Staphylococcus sp are isolated or suspected because of clinical presentation as suggested for renal carbuncle, coverage should include oxacillin, nafcillin, or vancomycin based on susceptibilities. If Enterobacter cloacae is isolated as an etiologic pathogen, an antibiotic that is stable to the Group 1 beta-lactamase found commonly in Enferobacter sp should be used, such as ciprofloxacin, cefipime, or the carbapen- ems (imipenem or meropenem) because of the potential for emergence of resistance to the broad-spectrum cephalosp~rins.~~

As with pyelonephritis, the timely initiation of appropriate therapy with parenteral agents and intravenous hydration is critical in the diabetic patient for recovery and for avoidance of potential complications. Oral outpatient therapy is not recommended in the initial therapy of diabetic patients with complicated urinary tract infections. Because of the severity of illness and potential for high morbidity and mortality with complicated upper urinary tract disease in the diabetic patient, hospitalization and initial parenteral antibiotic therapy is recommended. Surgical drainage and debridement or CT-guided drainage may also be required for some complications, as discussed under the individual entities. Parenteral therapy with an extended spectrum beta-lactam, such as cefotaxime, ceftriaxone, ceftazidime, cefipime, mezlocillin, or piperacillin, may be used empirically to cover the most common gram-negative pathogens. Alternative parenteral regimens include trimethoprim/sulfamethoxazole or ampicillin in combination with gentamicin. Intravenous trimethoprim/sulfamethoxazole can potentiate the hypoglycemic effect of oral sulfonylureas, and concurrent use of these agents should be avoided.z, 33 The fluoroquinolones may be used in a patient allergic to beta-lactam agents. If antipseudomonal coverage is required, ceftazidime, cefipime, piperacillin, ciprofloxacin, imipenem, or meropenem may be used, based on susceptibility patterns and other potential coinfecting organisms.

If the spectrum should extend to cover Enterococcus, ampicillin or vancomycin may be used in combination with a gram-negative agent as outlined previously, or piperacillin or mezlocillin may be used; imipenem or meropenem will cover Enterococcus faeculis but not Enterococcus fuecium. For invasive infections, potential parenteral options that must be guided by susceptibility testing include chloramphenicol ( + / - rifampin), doxycycline, or investigational agents such as quinupristin/dalfopristin (Synercid).’, h3 Emergence of high-level fluoroquinolone resistance has occurred with vancomycin-resistant enterococci using currently available fluoroquin~lones.~~ Investigational fluoroquinolones with improved gram-positive activity are soon to be released (clinafloxacin, trovafloxa- cin) and may show improved in vitro susceptibility and clinical use if the isolate is not already cross-resistant to the fluoroquinolones.

Intravenous therapy is recommended until fever and symptomatology re- solves; usually this occurs within 2 to 3 days of initiating appropriate therapy. An oral regimen with an agent that achieves high serum levels such as trimethoprim/sulfamethoxazole or the fluoroquinolones should be used based on antibiotic susceptibility studies to complete at least 14 days of antibiotic therapy. The total duration of therapy in complicated urinary tract infection should be based


on clinical and radiographic resolution of the abnormal finding. In addition, documentation of bacteriologic cure is also recommended using a follow-up urine culture. In the patient without resolution of fever and symptomatic im- provement after 72 hours of appropriate therapy, further evaluation should begin to rule out complicated urinary tract infection; this is particularly important in the diabetic patient.83, 92

SUMMARY

Diabetes mellitus has a number of long-term effects on the genitourinary system. These effects predispose to bacterial urinary tract infections in the patient with diabetes mellitus. Bacteriuria is more common in diabetic women than in nondiabetic women because of a combination of host and local risk factors. Upper tract infection complications are also more common in this group. Diabetic patients are at higher risk for intrarenal abscess, with a spectrum of disease ranging from acute focal bacterial pyelonephritis to renal corticomedullary abscess, to the renal carbuncle. A number of uncommon complicated urinary tract infection complications occur more frequently in diabetics, such as emphysematous pyelonephritis and emphysematous pyelitis. Because of the frequency and severity of urinary tract infection in diabetic patients, prompt diagnosis and early therapy is warranted. A plain abdominal radiograph is recommended as a minimum radiographic screening tool in the patient with diabetes presenting with systemic signs of urinary tract infection. Ultrasonogra- phy or further radiographic studies such as CT scanning may also be warranted, depending on the clinical picture, to identify upper urinary tract complications early for appropriate intervention.

References

1. Andriole VT: Renal carbuncle. Medical Grand Rounds 2:250, 1983 2. Baciewicz AM, Swafford WB Jr: Hypoglycemia induced by the interaction of chlor-

3. Bagdade JD, Root RK, Bulger RJ: Impaired leukocyte function in patients with poorly

4. Bailey H: Cystitis emphysematosa. Am J Roentgen01 86:850-862, 1961 5. Bos CJ: Cystitis emphysematosa. Radio1 Clin Biol41:499-503, 1972 6. Botalla MA, Baladimos MC, Bradley RF: Bacteriuria in diabetes mellitus. Diabetologia

7. Bybee JD, Rogers DE: The phagocytic activity of polymorphonuclear leukocytes obtained from patients with diabetes mellitus. J Lab Clin Med 64:1, 1964

8. Carton JA, Maradona JA, Nuno FJ, et al: Diabetes mellitus and bacteraemia: A comparative study between diabetic and nondiabetic patients. Eur J Med 1:281, 1992

9. Chernew I, Braude A L Depression of phagocytosis by solutes in concentrations found in the kidney and urine. J Clin Invest 41:1945, 1962

10. Clark NC, Cooksey RC, Hill BC, et al: Characterization of glycopeptide-resistant enterococci from US. hospitals. Antimicrob Agents Chemother 372311, 1993

11. Davidson AJ, Talner LB: Urographic and angiographic abnormalities in adult-onset acute bacterial nephritis. Radiology 106:249, 1973

12. Drachman RH, Root RK, Wood WB Jr: Studies on the effect of experimental nonketotic diabetes mellitus on antibacterial defenses: I. Demonstration of a defect in phagocytosis. J Exp Med 124:227, 1966

13. Dunn SR, Dewolf WC, Gonzalez R: Emphysematous pyelonephritis: Report of 3 cases treated by nephrectomy. J Urol 114:348-350, 1975

propamide and co-trimoxazole. Drug Intel1 Clin Pharm 18:309-310, 1984

controlled diabetes. Diabetes 23:9-15, 1974

7297-301, 1971


14. Ellenberg M: Diabetic neuropathy: Clinical aspects. Metabolism 25:1627-1655, 1976 15. Ellenberg M, Weber H The incipient asymptomatic diabetic bladder. Diabetes 15:524-

16. Ellenbogen PH, Talner LB: Uroradiology of diabetes mellitus. Urology 8:413419, 1976 17. Engel G, Schaeffer AJ, Grayhack JJ, et al: The role of excretory urography and cystos-

copy in the evaluation and management of women with recurrent urinary tract infection. J Urol 123:190-191, 1980

18. Evanoff GV, Thompson CS, Foley R, et al: Spectrum of gas within the kidney: Emphy- sematous pyelonephritis and emphysematous pyelitis. Am J Med 83:149-154, 1987

19. Fair WR, McClennan BL, Jost RG: Are excretory urograms necessary in evaluating women with urinary tract infection? J Urol 121:313-315, 1979

20. Fairley KF, Carson NE, Gutch RC, et al: Site of infection in acute urinary tract infection in general practice. Lancet 2:615-618, 1971

21. Forland M, Thomas VL The treatment of urinary tract infections in women with diabetes mellitus. Diabetes Care 8:499-506, 1985

22. Forland M, Thomas V, Shelokov A: Urinary tract infections in patients with diabetes mellitus: Studies on antibody coating of bacteria. JAMA 238:1924-1926, 1977

23. Fowler JE, Pulaski E T Excretory urography, cystography and cystoscopy in the evaluation of women with urinary tract infection. N Engl J Med 304:462465, 1981

24. Frimodt-Moller C: Diabetic cystopathy I-IV. Dan Med Bull 23:267-294, 1976 25. Goldman SM, Fishman E K Upper urinary tract infection: The current role of CT,

ultrasound, and MRI. Semin Ultrasound CT MR 12335-360, 1991 26. Harkonen S, Kjellstrand CM: Exacerbation of diabetic renal failure following intrave-

nous pyelography. Am J Med 63:939-946, 1977 27. Hawes S, Whigham T, Ehrmann S, et al: Emphysematous pyelonephritis. Infection in

Surgery 1:191-196, 1983 28. Hawtrey CE, Williams JJ, Schmidt JD: Cystitis emphysematosa. Urology 3:612-614,

1974 29. Heusser MF, Patterson JE, Kuritza AP, et al: Emergence of resistance to multiple beta-

lactams in Enterobacter cloacae during treatment for neonatal meningitis with cefotaxime. Pediatr Infect Dis J 9:509-512, 1990

30. Hoffman EP, Mindelzun RE, Anderson RU: Computed tomography in acute pyelonephritis associated with diabetes. Radiology 135:691, 1980

31. Holesh S Gas in the bladder: Cystitis emphysematosa. Clin Radiol 20234-236, 1969 32. Huang J, Chen K, Ruann M: Mixed acid fermentation of glucose as a mechanism of

emphysematous urinary tract infection. J Urol 146:148-151, 1991 33. Johnson JF, Dobmeier ME: Symptomatic hypoglycemia secondary to a glipizide-tri-

methoprim/sulfamethoxazole drug interaction. Drug Intel1 Clin Pharm 24:250-251, 1990

34. Johnson JR, Lyons MF 11, Pearce W, et al: Therapy for women hospitalized with acute pyelonephritis: A randomized trial of ampicillin versus trimethoprim-sulfamethoxazole for 14 days. J Infect Dis 163325-330, 1991

35. Kass EH: Asymptomatic infections of the urinary tract. Trans Assoc Am Physicians

36. Kelly HA, MacCallum WG: Pneumaturia. JAMA 31:375-381, 1898 37. Kincaid-Smith P, Fairley KF: Controlled trial comparing effect of two and six weeks’

38. Klein DE, Mahoney SA, Youngen R, et al: Renal emphysema. J Urol 95:625-629, 1966 39. Klein FA, Smith MJV, Vick CW 111, et a1 Emphysematous pyelonephritis: Diagnosis

40. Krestin GP: Magnetic resonance imaging of the kidneys: Current status. Magn Reson

41. Kumar D, Rao B R Case profile: Bilateral emphysematous pyelonephritis. Urology

42. Kumar R, Schreiber MH: The changing indications for excretory urography. JAMA

43. Lagergren C, Lindvall N: Renal papillary necrosis. Acta Radiol 192:1, 1960

525, 1966

69:56-63, 1956

treatment in recurrent urinary tract infection. Br Med J 2:145-146, 1969

and treatment. South Med J 79:4146, 1986

Q 10:2-21, 1994

20:96, 1982

254:403405, 1985


44. Lalli AF: Renal papillary necrosis. Am J Roentgenol Radium Ther Nucl Med 114:741-

45. Langston CS, Pfister RC: Renal emphysema. Am J Roentgenol 110:778-786, 1970 46. Lauler DP, Schreiner GE, David A: Renal medullary necrosis. Am J Med 29:132-156,

47. Lautin EM, Gordon PM, Friedman AC, et al: Emphysematous pyelonephritis: Optimal

48. Levy AH, Schwinger HN: Gas-containing perinephric abscess. Radiology 60:720-722,

49. Lindvall N: Renal papillary necrosis. Acta Radiol 192:1, 1960 50. Low DE: Quinupristin/dalfopristin: Spectrum of activity, pharmacokinetics, and initial

51. Lye WC, Chan RK, Lee EF, et a1 Urinary tract infections in patients with diabetes

52. Mandel EE: Renal medullary necrosis. Am J Med 13322-327, 1952 53. Mani S, Edberg SC, Patterson JE: Community-acquired Enterobacter bacteremia in a

patient with urosepsis. Clin Infect Dis 115:565-566, 1992 54. McNicholas MM, Griffin JF, Cantwell DF: Ultrasound of the pelvis and renal tract

combined with a plain film of abdomen in young women with urinary tract infection: Can it replace intravenous urography? A prospective study. Br J Radiol 64221-224, 1991

745, 1972

1960

diagnosis and treatment. Urol Radiol 1:93-96, 1979

1953

clinical experience. Microb Drug Res 1:223, 1995

mellitus. J Infect 24:169, 1992

55. Michaeli J, Mogle P, Perlberg S, et al: Emphysematous pyelonephritis. J Urol 131:203- 207. 1984

56. Mogensen P, Hansen LK Do intravenous urography and cystoscopy provide important information in otherwise healthy women with recurrent urinary tract infection? Br J Urol 55:261-263, 1983

57. Mowat AG, Baum J: Chemotaxis of polymorphonuclear leukocytes from patients with diabetes mellitus. N Engl J Med 284:621-627, 1971

58. Norrby SR: Short-term treatment of uncomplicated lower urinary tract infections in women. Rev Infect Dis 12458467, 1990

59. Ooi BS, Chen BTM, Yu M: Prevalence and site of bacteriuria in diabetes mellitus. Postgrad Med J 50:497499, 1974

60. OSullivan DJ, Fitzgerald MG, Meynell MJ, et al: Urinary tract infection: A comparative study in the diabetic and general populations. Br Med J 1:786-788, 1961

61. Patterson JE, Andriole VT: Bacterial urinary tract infections in diabetes. Infect Dis Clin North Am 1:25, 1995

62. Patterson JE, Andriole VT Renal and perirenal abscesses. Infect Dis Clin North Am 1:907, 1987

63. Patterson JE, Sweeney AH, Simms M, et al: An analysis of 110 serious enterococcal infections: Epidemiology, antibiotic susceptibility, and outcome. Medicine 74:191, 1995

64. Piccirillo M, Rigsby C, Rosenfield AT Contemporary imaging of renal inflammatory disease. Infect Dis Clin North Am 1:927, 1987

65. Platt R, Polk BF, Murdock B, et al: Risk factors for nosocomial urinary tract infection. Am J Epidemiol 124:977-985, 1986

66. Pometta D, Reese SB, Younger D, et al: Asymptomatic bacteriuria in diabetes mellitus. N Engl J Med 276:1118-1121, 1967

67. Robbins SL, Tucker AW: The cause of death in diabetes. N Engl J Med 2312365-868, 1944

68. Rodriguez-de-Velasquez A, Yoder IC, Velasquez PA, et al: Imaging the effects of diabetes in the genitourinary system. Radiographics 15:1051, 1995

69. Rominger MB, Kenney PJ, Morgan DE, et al: Gadolinium-enhanced MR imaging of renal masses. Radiographics 12:1097-1118, 1992

70. Ronald AR, Nicolle LE, Harding GK Standards of therapy for urinary tract infections in adults. Infection 20(Suppl 63):164-170, 1992

71. Rosenberg JW, Quader A, Brown JS: Renal emphysema. Urology 1:237-239, 1973 72. Rubin RH, Shapiro ED, Andriole VT, et al: Evaluation of new antiinfective drugs for

the treatment of urinary tract infection. Clin Infect Dis 15(suppl 1):216-227, 1992 73. Savin JA: Bacterial infections in diabetes mellitus. Br J Dermatol 91:481484, 1974


74. Schainuck LI, Fouty R, Cutler RE: Emphysematous pyelonephritis. Am J Med 44:134-

75. Schultz EH, Klorfein E H Emphysematous pyelonephritis. J Urol 87762-766, 1962 76. Seidenfeld SM, Lemaistre CF, Setiawan H, et al: Emphysematous pyelonephritis caused

77. Selroos 0, Edgren J: Lupus-like syndrome associated with pulmonary reaction to

78. Siroky MB, Moylan RA, Austen G Jr, et a1 Metastatic infection secondary to genitouri-

79. Smith JW, Jones SR, Reed WP, et al: Recurrent urinary tract infections in men:

80. Spagnola AM: Emphysematous pyelonephritis. Am J Med 64:840-844, 1978 81. Spencer J, Lindsell D, Mastorakou I: Ultrasonography compared with intravenous

urography in investigation of urinary tract infections in adults. BMJ 301:221-224, 1990 82. Stamey TA, Govan DE, Palmer JM: The localization and treatment of urinary tract

infections: The role of bacterial urine levels as opposed to serum levels. Medicine

83. Stamm WE, Hooton TM. Management of urinary tract infections in adults. N Engl J Med 329:1328-1334, 1993

84. Stamm WE, McKevitt M, Counts G W Acute renal infection in women: Treatment with trimethoprim-sulfamethoxazole or ampicillin for two or six weeks: A randomized trial. Ann Intern Med 106:341-345, 1987

85. Sun NC: Nonclostridial emphysematous nephritis, ureteritis, cystitis, and adrenalitis due to Escherichia coli. South Med J 61:400-403, 1968

86. Szucs S, Cserhati I, Csapo G, et a1 The relation between diabetes mellitus and infections of the urinary tract. Am J Med Sci 240186-191, 1960

87. Thorley JE, Jones SR, Sanford JP Perinephric abscess. Medicine 53:41, 1974 88. Turman AE, Rutherford C: Emphysematous pyelonephritis with perinephric gas. J

Urol 105:165-170, 1971 89. VanZee BE, Hoy WE, Talley TE, et al: Renal injury associated with intravenous

pyelography in nondiabetic and diabetic patients. Ann Intern Med 89:51-54, 1978 90. Vejlsgaard R Studies on urinary infection in diabetics: I. Bacteriuria in patients with

diabetes mellitus and in control subjects. Acta Med %and 179:173-189, 1966 91. Vejlsgaard R Studies on urinary infection in diabetes: 11. Significant bacteriuria in

relation to long-term diabetic manifestations. Acta Med Scand 179:183-188, 1966 92. Wheat LJ: Infection and diabetes mellitus. Diabetes Care 3:187-197, 1980 93. Williams DN, Knight AH, King H, et al: The microbial flora of the vagina and its

relationship to bacteriuria in diabetic and non-diabetic women. Br J Urol 47:453457, 1975

94. Yang W, Shen N: Gas-forming infection of the urinary tract: an investigation of fermentation as a mechanism. J Urol 143:960-964, 1990

95. Zabbo A, Montie JE, Popowniak KL, et al: Bilateral emphysematous pyelonephritis. Urology 25:293-296, 1985

96. Zhanel GG, Harding GKM, Guay DRP: Asymptomatic bacteriuria: Which patients should be treated? Arch Intern Med 150:1389-1396, 1990

139, 1968

by Candida tropicalis. J Infect Dis 146:569, 1982

nitrofurantoin: Report of three cases. Acta Med Scand 197:125-129, 1975

nary tract sepsis. Am J Med 61:351-360, 1977

Characteristics and response to therapy. AM Intern Med 91:544-548, 1979

44:1-36, 1965

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