Urinary Tract Infections (UTI) in Diabetes Mellitus
Predisposition to urinary tract infections (UTIs) in diabetes mellitus results from several factors. Susceptibility increases with longer duration and greater severity of diabetes.  High urine glucose content and defective host immune factors predispose to infection. Hyperglycemia causes neutrophil dysfunction by increasing intracellular calcium levels and interfering with actin and, thus, diapedesis and phagocytosis. Vaginal candidiasis and vascular disease also play a role in recurrent infections.
Recently, the use of SGLT2 inhibitors, such as dapagliflozin, has produced concern about an increased risk of urinary tract infections in recipients of these medications. Levels of urinary glucose increased with greater doses of the medication; however, the incidence of urinary tract infections did not. Nonetheless, such patients do appear to be at a 3- to 5-fold increased risk of genital infections. [2, 3]
Over time, patients with diabetes may develop cystopathy, nephropathy, and renal papillary necrosis, complications that predispose them to UTIs. Long-term effects of diabetic cystopathy include vesicourethral reflux and recurrent UTIs. In addition, as many as 30% of women with diabetes have some degree of cystocele, cystourethrocele, or rectocele. All of these may contribute to the frequency and severity of UTIs in female diabetics.
Complicated UTIs in patients who have diabetes include renal and perirenal abscess, emphysematous pyelonephritis, emphysematous cystitis, fungal infections, xanthogranulomatous pyelonephritis, and papillary necrosis. The current article focuses on emphysematous UTIs, with which diabetes is closely associated.
Diabetes mellitus and obstruction of the urinary tract are the predominant risk factors for developing emphysematous UTIs. The exact mechanism for developing these distinctive infections is not well known. It appears that associated vascular thrombosis of the kidney produces a more fulminant infection because of necrosis and hemorrhagic infarction.  Emphysematous pyelonephritis carries a mortality rate of up to 80%. Ninety percent of cases are associated with diabetes mellitus. There is a significant rate of associated urinary tract obstruction. 
Upper tract emphysematous UTIs are divided into pyelonephritis and pyelitis. Emphysematous cystitis also occurs. Emphysematous infection can involve one or all 3 of these processes. Emphysematous pyelonephritis is necrotizing infection of the body of the kidney that may spread to the pararenal areas. Emphysematous pyelitis is limited to the collecting system and emphysematous cystitis to the bladder.
The organisms involved most commonly are Escherichia coli, Klebsiella pneumoniae, and Candida. 
Emphysematous upper tract infections may be classified into 4 prognostic categories based on CT scan appearance. These range from gas that is isolated to the collecting system (class I ) to the appearance of gas that is limited to the body of the kidney (class 2) to extension of the gas or abscess to the perinephric space or to adjacent tissue (class 3A and class 3B, respectively). Class 4 denotes involvement of both kidneys.
For more information on this topic, see the Medscape Reference article Urinary Tract Infections in Females.
Emphysematous pyelonephritis is a severe, necrotizing form of multifocal bacterial nephritis with gas formation within the renal parenchyma. From 70-90% of cases develop in patients with diabetes. Sixty percent of infections are secondary to E coli. Enterobacter aerogenes and Klebsiella, Proteus, Streptococcus, and Candida species also may play a role.
Three factors must be present for the development of renal emphysema—excess tissue glucose, impaired tissue perfusion, and a gas-producing bacterium. The gas may result from fermentation of necrotic tissue or from mixed acid fermentation by Enterobacteriaceae. Predisposing factors include diabetes mellitus, remote or recent kidney infection, and obstruction.
Patients with renal emphysema may present with fever, chills, and nausea or vomiting. Half of patients have evidence of a flank mass on examination. Rarely, patients have crepitus over the thigh or flank.
Laboratory findings include leukocytosis, hyperglycemia, pyuria, and an elevated blood urea nitrogen (BUN) and creatinine. A plain film of the abdomen may reveal gas in the kidneys in 85% of infections. Renal ultrasonography may also help establish the diagnosis. If gas is visualized, then a CT scan should be performed to reveal if the gas is in the parenchyma (emphysematous pyelonephritis) or the collecting system (emphysematous pyelitis).
The mortality rate is 60% in cases in which the gas is localized to the renal parenchyma, regardless of treatment. The mortality rate is 80% if the gas has spread in the perinephric space and the patient is treated with antibiotics alone.
Emphysematous pyelitis is defined as the presence of gas localized to the renal collecting system. Emphysematous cystitis is defined as air in the urinary tract. More than 50% of these patients have diabetes. Obstruction of the collecting system generally is the rule in emphysematous pyelitis. The left kidney is involved twice as often as the right in emphysematous pyelitis. The most common infectious etiology is E coli, but other gram-negative organisms, S aureus, Clostridium perfringens, and Candida species also may be responsible.
Patients with emphysematous pyelitis most commonly present with fever, chills, nausea and vomiting, and abdominal pain. Patients with emphysematous cystitis most commonly present with urinary frequency, urgency, and dysuria. Abdominal pain also may be present. Gross hematuria and pneumaturia are occasionally present.
Leukocytosis and pyuria are observed in most patients. In half of the patients, azotemia and hyperglycemia are present. Abdominal films may reveal gas outlining the renal pelvis and in the ureters. Abdominal films may reveal air in the bladder wall or lumen. Renal ultrasonography may reveal diffuse thickening of the bladder wall and echogenicity. CT scans may reveal gas in the bladder wall with extension into the lumen. Cystoscopy may reveal blebs in the bladder mucosa.
Antibiotics and relief of obstruction usually are sufficient. The mortality rate is 20%.
Emphysematous cystitis (cystitis emphysematosa) involves gas that is localized to the bladder secondary to a bladder infection. Gas in the bladder is more frequently related to a fistula between the bladder and the colon or vagina than to a gas-producing infection. As many as 80% of patients with emphysematous cystitis are diabetic.
Patient presentation is similar to that for pyelonephritis. Plain radiographs may demonstrate gas in the bladder wall or lumen, an air-fluid level in the bladder, or a cobblestone appearance to the bladder wall. CT scan is the study of choice to help localize the gas to the proper organ. Treatment involves intravenous antibiotics and relief of any outlet obstruction. This condition is not as life-threatening as emphysematous pyelonephritis or pyelitis.
In the patient with an emphysematous UTI, coverage for unusual or multiple antibiotic–resistant organisms (eg, Pseudomonas aeruginosa, extended spectrum beta-lactamase [ESBL]–producing Enterobacteriaceae) must be considered. Patients with diabetes are at greater risk for complications from aminoglycosides. An infectious disease consultation may be helpful in selecting the appropriate antimicrobial agent.
Urologic consultation is essential in patients with UTIs complicated by obstruction, renal cysts, perinephric abscess, renal carbuncle, or unknown renal masses. Other consultations depend on the patient’s underlying state of health and may include an endocrinologist, as well as an obstetrician, gynecologist, endocrinologist, nephrologist, neurologist, or neurosurgeon.
Cases that do not have evidence for abscess formation and/or obstruction and are limited to the collecting system (uncomplicated pyelitis) often can be successfully treated with intravenous antibiotics alone.
Pyelitis that has associated obstruction and/or abscess and emphysematous pyelonephritis that is limited to the body of the kidney is best managed with percutaneous catheter drainage and surgery if obstruction is present.
When infection has spread beyond the body of the kidney (class and class B), nephrectomy is usually indicated. If the patient is hemodynamically stable and without acute renal failure, decreased level of consciousness, and thrombocytopenia, it is reasonable to try percutaneous catheter drainage and intravenous antibiotics.
When the infectious process involves both kidneys (class 4) or there only one kidney present, nephrectomy-sparing approaches should be considered. 
Medical therapy with vigorous bladder irrigation if blood clots are present is usually adequate for treatment of emphysematous cystitis. However, 10% of cases require a combination of medical and surgical therapy that ranges from debridement to partial and, rarely, total cystectomy. 
Coverage of ESBL-producing organisms must be strongly considered in the initial empiric choice of antibiotics. Risk factors for infections with ESBL-producing gram-negative organisms include diabetes mellitus; recent travel to Asia, the Middle East, or Africa; male gender; residence in a nursing home; previous hospitalization; surgical or urological procedures; chronic renal failure; and freshwater swimming. The recent use of fluoroquinolones, especially as prophylaxis for transrectal biopsies, is becoming a major risk factor for ESBL-producing Enterobacteriaceae. [9, 10, 11]
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Tukenmez Tigen E, Tandogdu Z, Ergonul O, Altinkanat G, Gunaydin B, Ozgen M, et al. Outcomes of fecal carriage of extended-spectrum β-lactamase after transrectal ultrasound-guided biopsy of the prostate. Urology. 2014 Nov. 84 (5):1008-15. [Medline].
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John L Brusch, MD, FACP Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London
Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.
Urinary Tract Infections (UTI) in Diabetes Mellitus
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