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Diversit and Comple it of Urinar Tract Infection in Diabetes Mellitus

Lukman M. Hakeem, Diptendu N. Bhattacharyya, Cyril Lafong, Khalid S. Janjua, Jonathan T. Serhan and Ian W. Campbell Posted: 08/19/2009; British Journal of Diabetes and Vascular Disease. 2009;9(3):119-125. 2009 Sage Publications, Inc.

Abstract and Introduction

Abstract

Urinary tract infections (UTIs) are a common burden in patients with diabetes mellitus. Cystitis, ascending infections leading to pyelonephritis, emphysematous complications and renal and perinephric abscesses are well recognised in this group of patients especially if glycaemic control is poor. Despite the clinical significance of UTI in diabetes, it is inadequately understood and management regimens are mostly not evidence based. Anticipation of potential complications and earlier interventions are vital to reduce serious adverse outcomes. Herein we discuss the aetiology, pathogenesis and management of UTI and its local and more remote complications.
Introduction

Diabetes mellitus is the most common endocrine disease and is associated with organ complications due to microvascular and macrovascular disease. People with diabetes also suffer from simple and complicated infections, although the association between diabetes mellitus and increased susceptibility to infection has been questioned.[1,2] Nevertheless many specific infections are commoner in diabetes and some occur almost exclusively in diabetic subjects. Others may occur with increased severity and may be associated with greater risk of complications.[3] UTIs fall into both these categories i.e. exclusive and more severe. Asymptomatic bacteriuria, acute pyelonephritis and complications of UTI are reported to be more common in patients with diabetes. Despite the clinical and economic significance, there is a paucity of research. Much has to be learned about the natural history of infection during the antimicrobial era.[4] Anatomical Spectrum of Infection UTIs invariably enter via the ascending route. Asymptomatic bacteriuria has been reported to be commoner in women with diabetes, although data are less convincing for men.[4,5] Many studies have also shown that bacteriuria in diabetic women involves the upper urinary tract more frequently.[6,7] However most authors believe that asymptomatic bacteriuria in patients with diabetes does not lead to complications and therefore screening and treatment is not warranted, except perhaps in pregnant women.[8-10] Acute pyelonephritis is a common presentation of UTI in diabetes. In one study by Nicolle et al.[11] diabetes increased the probability of acute pyelonephritis requiring hospital admission by 20 30-fold in those under 44 years of age and by three to five-fold in men and women aged 45 years and over. Not only do patients with diabetes have an increased incidence of acute pyelonephritis compared with non-diabetic controls, but bilateral pyelonephritis is also commoner and predisposes to more severe infection of the upper urinary tract with substantially greater complications. Bacteraemia is four times more likely to occur from UTIs in patients with diabetes than in non-diabetic controls. Acute renal failure is twice as likely to develop in bacteraemic patients.[4,12] This may be related to the additional presence of diabetic nephropathy. Metastatic Gram-negative infections are also commonly reported. Endophthalmitis, osteomyelitis, particularly of the vertebrae, septic arthritis, abscesses and bacteraemic Gram-negative pneumonia are the commonest metastatic complications arising from UTI.[13-15] Figures 1a and 1b illustrate a case of Gram-negative pneumonia as a complication of urinary sepsis in diabetes. The primary burden of acute pyelonephritis, however, occurs within the kidney itself with the commonest complications being acute papillary necrosis, emphysematous pyelonephritis and renal abscesses.[4,16,17]

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Figure 1. (a) Chest X-ray (CXR) showing bilateral extensive consolidation in a 47-year-old woman with type 1 diabetes presenting with right-sided pyelonephritis. Admission CXR showed clear lung fields. Blood cultures and mid-stream urine isolated E. coli. Despite receiving piperacillin/tazobactam 4.5 g three times daily the patient deteriorated 3 days after admission when E. coli pneumonia due to metastatic spread of organisms was diagnosed. Gentamicin was added to the antibiotic regime and the patient improved after a brief period in the intensive care unit (b) CT scan showing bilateral consolidation and pleural effusion more marked on the left side Emphysematous pyelonephritis is a gas-forming infection of the renal parenchyma, perinephric tissues, and collecting system. It is almost exclusively an infection of diabetic patients and carries a grave prognosis. Papillary necrosis complicates 21% of cases.[18,19] Intra-renal and perinephric abscesses are a collection of suppurative material that can pose a great diagnostic challenge, as the presentation is often insidious (figure 2). In one series of patients with perinephric abscess, 36% had diabetes.[20] Pathogenesis There are several reasons for an increased frequency of UTIs in diabetic patients. Several aspects of immunity are altered in patients with diabetes. Polymorphonuclear leukocyte function is depressed, particularly when acidosis is present. Leukocyte adherence, chemotaxis, and phagocytosis may be affected.[21-23] Antioxidant systems involved in bactericidal activity may also be impaired.[24] A lower urinary concentration of cytokines (IL8 and IL6) has been shown to correlate with a lower urinary leukocyte cell count in diabetic patients, which may contribute to the increased incidence of UTIs in this patient group.[25,26] Other factors may also be involved. Poor glycaemic control, and the resulting hyperglycaemia, by itself does not predict increased bacterial rates of multiplication and has not always been shown to be a major determinant of either the incidence of bacteriuria or its subsequent complications.[27-29] Increased adherence E. coli expressing type-1 fimbriae (a virulence factor) to uroepithelial cells of diabetic women may play an important role in the pathogenesis of UTI, especially if diabetes is poorly controlled.[30] Tamm Horsfall protein, which traps type 1 fimbriated E. coli in uromucoid present on epithelial cells, acts as an important defence mechanism as it prevents adherence and cell entry of pathogens. This protein is significantly reduced in some patients with diabetes.[31,32] Micturation abnormalities secondary to diabetic neuropathy occur in 10 40% of patients with longstanding diabetes resulting in increased residual urine. This presumably accounts for some of the increased morbidity and increased susceptibility to infection.[33] Emphysematous complications in renal tissue are likely to be due to the presence of organisms that rapidly ferment glucose and produce carbon dioxide. Impaired transport of metabolic end products either due to impaired tissue perfusion or
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some other factor in diabetes may also contribute.[16,34] Pathogenesis of acute papillary necrosis is not well understood. It is presumed to be due to a marginal change in vascular supply, which is further stressed by infection leading to infarction and sloughing of papillae.[17] Renal cortical abscess results from haematogenous spread of bacteria from a primary extrarenal focus of infection. In contrast, renal corticomedullary abscess develops as an ascending infection. Severe renal parenchymal involvement in combination with corticomedullary abscess is more likely to extend to the renal capsule and perforate, thus forming a perinephric abscesses (figure 2).

Figure 2. Contrast enhanced CT of abdomen showing large right-sided perinephric collection containing fluid and gas in a 70-year-old woman with type 2 diabetes and a history of renal calculi admitted with right renal angle tenderness and fever, 2 weeks after lithotripsy and ureteric stenting. The patient had been commenced on ciprofloxacin 500 mg twice daily when she had developed fever after the procedure. Mid-stream urine isolated enterococci. The patient was commenced on piperacillin/tazobactam 4.5 g three times and transferred to the urologist where she underwent ultrasound guided percutaneous drainage of the abscess Microbiological Spectrum of Infection UTIs in patients with diabetes are due to the same urinary pathogens as those found in the general population, with the majority of ascending infections being caused by E.coli. Other uropathogens found in patients with diabetes include Proteus spp., Enterobacter spp. and Enterococcus faecalis. Klebsiella pneumoniae and group B streptococci are also more common in patients with diabetes.[35,36] Staph lococcus aureus accounts for infections caused by haematogenous spread. About 50 75% of emphysematous pyelonephritis cases are caused by E.coli [19,37] and most of the rest are caused by other Gram-negative organisms.[3] Diabetes is a common predisposing factor for UTIs caused by fungi, particularly Candida species (C. albicans, C. glabrata,
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C. tropicalis). Around 5% of patients with candiduria will have two or more species simultaneously. The extent of involvement ranges from inconsequential lower urinary tract colonisation to clinical cystitis, emphysematous cystitis, pyelonephritis, and renal and perinephric abscess.[38-40] Upper urinary tract fungal infection only rarely becomes involved as ascending infection and even in these cases the presence of urinary tract obstruction, instrumentation, urethral stents, nephrostomy tubes and reflux may contribute. The majority of cases of renal candidiasis occur as a consequence of haematogenous seeding of renal parenchyma and not as a result of ascending spread. Clinical Features and Investigations Clinical features of UTI in patients with diabetes are essentially the same as in people without diabetes. Occasionally the fever may be less apparent, particularly in individuals with diabetic metabolic decompensation. Haematuria or flank pain secondary to sloughing papillae may be noted in patients with papillary necrosis. Occasionally patients may experience pneumaturia if gas has been produced within the urinary tract, or rarely gas in tissues may be palpated in flank or groin. The investigation of possible UTIs in patients with diabetes requires urinalysis and urine culture, by catheterisation if necessary, prior to initiation of antimicrobial treatment. A blood culture should be routine in patients with presumed pyelonephritis. Due to increased incidence of local complications imaging is essential in patients with diabetes and acute pyelonephritis. An abdominal X-ray may help exclude renal emphysema. Ultrasound or CT should be considered for all septic patients. Although intravenous and retrograde pyelograms, ultrasonography and nuclear imaging techniques all have played a role, CT scanning has become the preferred modality.[41-43] Helical CT scan provides an excellent view of the organs and can identify inflamed renal parenchyma, exclude obstruction and identify renal calculi. Contrast enables a more accurate recognition of acutely inflamed renal tissue and identifies air or pus in tissue with increased sensitivity and specificity. It also characterises renal infection as focal or diffuse. However, the use of radio-contrast may lead to concerns in patients with diabetes due to risks of transient or occasionally permanent loss of renal function. Extra care should be exercised in type 2 diabetic patients on metformin receiving contrast media, due to risks of lactic acidosis consequent to reduced clearance of the drug. According to the Royal College of Radiologists no special precaution is needed if the serum creatinine is normal, and low volume contrast agent is to be administered. If more than 100 ml of contrast agent or an intra-arterial route is to be used, metformin should be withheld for 48 h after the procedure. If serum creatinine is raised, the need for contrast should be assessed and if it is deemed necessary, metformin should be withheld for 48 h before and after the contrast study. However, with careful fluid management, most patients with diabetes would be able to tolerate low ionic contrast media.[4,41 43] Management In most prospective studies patients with diabetes are characterised as having 'complicated infections'. However, categorising all patients with diabetes into this group trivialises the concept. A 'complicated' UTI diagnosis should be reserved for diabetic patients who also have metabolic/systemic disease such as ketoacidosis, hyperosmolar state, renal impairment or structural abnormalities such as neurogenic bladder, renal perinephric abscess, papillary necrosis, renal/bladder emphysema, renal calculi, obstruction and urethral catheterisation. UTI in pregnancy and patients who relapse after therapy due to microbial persistence in renal or prostatic parenchyma also fall into this category.[4,44] Those diabetic subjects with more remote or metastatic infections such as pneumonia (see figure 1) are also in this category. Initial management consists of hydration usually with intravenous fluids for which the patient is hospitalised, and intravenous antibiotics, in addition to aggressive control of hyperglycaemia. Antibiotics that could be used for UTIs and complications are shown in table 1. Treatment protocols should avoid nephrotoxic antimicrobial agents whenever possible. Otherwise treatment regimens selected for patients with acute cystitis and pyelonephritis in patients without diabetes are appropriate for patients with diabetes. However, most authors prefer antimicrobial agents which achieve high levels not only in the urine but also in the renal tract tissues, such as fluoroquinolones, trimethoprim-sulphamethoxazole (TMPSMX) and amoxycillinclavulanic acid.[25,45] This may hold especially true given the data indicating invasion of E.coli into the bladder cells.[46] In this country, however, trimethoprim is commonly used as a single agent treatment for UTIs instead of TMP-SMX. Few therapeutic trials have specifically been performed with diabetic patients. Due to frequent upper urinary tract involvement and
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possible serious complications many experts recommend a 7 14-day oral antimicrobial regimen for bacterial cystitis in diabetic patients, instead of the usually recommended 3-day course.[25,45,47] The standard duration of therapy for uncomplicated pyelonephritis in both diabetic and non-diabetic patients is 14 days.[30,45,48] However, studies have shown a 7-day course of oral ciprofloxacin to be adequate and effective for uncomplicated pyelonephritis.[49] Vigilance for complications must occur throughout the care of an acutely ill patient with UTI. As these complications are common in patients with diabetes, their anticipation can lead to earlier interventions and fewer serious adverse outcomes.
Table 1. Causative organisms and treatment of urinar tract infection in patients with diabetes

Infection

Common Organisms

Antimicrobial Therap

Further Management and Comments Early surgical intervention in emphysematous infection Consider ESBL if no clinical improvement

Acute bacterial cystitis

E. coli, Proteus species

Trimethoprim 200 mg 2x Ciprofloxacin 500 mg 2x 7 14-day course

Acute pyelonephritis

E. coli, Proteus species

Ciprofloxacin 500 mg/400 mg 2x or third Emphysematous generation cephalosporins or infection should be piperacillin/tazobactam 4.5 g3x 7 14-day course considered If ESBL suspected meropenem 500 mg/1 g3x As above Emergency nephrectomy often required Surgical drainage

Emphysematous E. coli, K. pneumoniae pyelonephritis Perinephric and intra-renal abscess E. coli and other Gramnegative bacilli (associated with pyelonephritis) S. aureus (associated with bacteraemia)

As above but consider adding flucloxacillin 1 g/2 g i.v. if S. aureus suspected

Fungal cystitis

Candida species Fluconazole 100 mg2x 7 14 days (C. albicans, C. glabrata, C. (Amphotericin B bladder irrigation or single dose tropicalis) i.v. amphotericin)

Removal of urinary catheter

Fungal pyelonephritis and abscesses

Candida species Fluconazole 6 mg/kg/day prolonged therapy (2 6 Surgical drainage (C. albicans, C. glabrata, C. weeks ) or i.v. amphotericin Removal of stents and tropicalis) relieve obstruction if any

Ke : ESBL = extended spectrum beta-lactamase; i.v. = intravenous

There are increased concerns about emergence of resistant organisms in patients being treated for recurrent UTIs. Since UTIs are common in diabetes this becomes a major concern in this group of patients. Prominent among such infections are organisms producing ESBLs which have the ability to hydrolyse oxyimino-cephalosporins and monobactams. Enterobacteriaceae, especially Klebsiella spp. producing ESBLs such as SHV and TEM type enzymes, have been established since the 1980s as a major cause of hospital-acquired infections. However, more recently, enterobacteriaceae (mostly E. coli) producing novel ESBLs, the CTX-M enzymes, have been identified predominantly from the community as a cause of UTIs.[50] Resistance to other classes of antibiotics, especially the fluoroquinolones and aminoglycosides, is often associated with ESBL-producing organisms. Therefore the choice of antibiotics that could be used becomes severely restricted and may lead to increased prescription of more broad-spectrum and expensive drugs such as the carbapenems.[51] A heightened awareness of these organisms by clinicians and enhanced testing by laboratories, including molecular surveillance studies, is required to reduce treatment failures, to limit their introduction into hospitals and to
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prevent the spread of these emerging pathogens within the community.

Figure 3. Repeat CT scan of abdomen with contrast showing marked improvement of the perinephric abscess with reduction in size of the collection 2 weeks after percutaneous drainage. Abscess fluid showed an isolation of Enterococcus faecalis, group G streptococci and Bacteroides species. The patient continued with the antibiotic regime Upper UTIs and disseminated infections due to fungi require systemic therapy. The appropriate treatment of candida infection confined to the bladder remains controversial.[40] Distinguishing such infections from colonisation is often difficult. The presence of symptoms or pyuria suggests infection. Spontaneous resolution of funguria occurs in many cases.[52,53] Removal of an indwelling catheter, if one is present, is recommended as the initial intervention. The treatment options include bladder irrigation with amphotericin B,[54] a single dose of intravenous amphotericin B,[55] or oral fluconazole.[56] Currently fluconazole is the preferred drug of choice because of its ease of administration and relative absence of toxicity. Surgical management may be necessary in patients with renal emphysema and suppurating renal or perinephric abscesses. Obstruction should be sought and treated appropriately. The traditional treatment of emphysematous pyelonephritis is nephrectomy of the affected kidney. Surgery has been reported to lower the mortality from 80% in patients treated with antimicrobial treatment alone, to 20%.[47] Increasing numbers of cases are reported of successful antibiotic therapy combined with radiographically guided percutaneous drainage in cases where infection is localised.[57,58] Therefore initial conservative management with CT-guided drainage should usually be attempted with sequential studies to ensure that infection is controlled, air, if present, is evacuated and the patient is adequately responding.[4] Figures 2 4 illustrate a case for which a perinephric abscess was successfully treated with percutaneous drainage. Total nephrectomy is considered for patients whose condition does not improve clinically or in whom gas spreads despite non-surgical treatment.

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Figure 4. Repeat CT scan 3 months later showing marked improvement with significantly smaller residual collection around the right kidney which was thought to represent a haematoma. The patient completed a total 4-week course of antibiotics and made a good recovery Many UTIs in patients with recurrent bacteriuria can be prevented through strategies which include complete emptying of the bladder during voiding, antimicrobial prophylaxis, less use of spermicides, and optimal catheter care.[59] These are important points to consider in patients with diabetes, and this advice should be provided to all patients during diabetic education programmes and particularly after an initial episode of UTI. In conclusion, patients with diabetes have a higher incidence of both asymptomatic bacteriuria and symptomatic UTIs, which often lead to complications both local and remote as illustrated in the two case histories presented. Management regimens for the most part are not evidence based. Despite the clinical and economic significance research interest on this subject has been inadequate and therapeutic trials enrolling patients with diabetes are necessary to define the best therapeutic options, antimicrobial agents and optimal treatment duration. Clinicians should respond proactively to give optimal treatment to reduce morbidity and mortality in diabetic patients with UTIs. Ke Messages UTI is more common in patients with diabetes UTIs have potential diverse and complex complications A wide range of causative organisms may be involved Radiology is important in the diagnosis of complications Medical and surgical treatments can reduce morbidity and mortality
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Acknowledgments We would like to thank Nancy Steele and Jackie Wallace for the excellent secretarial work and Grace Thompson for all the help provided in completing this manuscript. Abbreviation Notes CT = computed tomography; CTX-M = cefotaxime-M type; E. coli = Escherichia coli; ESBL = extended spectrum betalactamase; IL = interleukin; SHV = sulphhydryl variable; TEM = Temoniera; UTI = urinary tract infection Correspondence to: Dr Lukman M Hakeem Department of Infectious Diseases, Victoria Hospital, Hayfield Road, Kirkcaldy, Fife, KY2 5AH, UK Tel: +44 (0)1592 643355 Ext 1834; Fax: +44 (0)1592 648037 E-mail: lukman.hakeem@faht.scot.nhs.uk British Journal of Diabetes and Vascular Disease. 2009;9(3):119-125. 2009 Sage Publications, Inc.

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