Urinary tract infection occurs with increased frequency and severity in patients with diabetes mellitus. General host factors enhancing risk for urinary tract infection in diabetics include age, metabolic control, and long term complications. Treatment of asymptomatic bacteriuria in diabetic patients is not indicated. Early diagnosis and prompt intervention is recommended to limit morbidity of symptomatic infection.
Urinary tract infection occurs with increased frequency and severity in patients with diabetes mellitus. General host factors enhancing risk for urinary tract infection in diabetics include age, metabolic control, and long term complications. Treatment of asymptomatic bacteriuria in diabetic patients is not indicated. Early diagnosis and prompt intervention is recommended to limit morbidity of symptomatic infection.
Urinary tract infection occurs with increased frequency and severity in patients with diabetes mellitus. General host factors enhancing risk for urinary tract infection in diabetics include age, metabolic control, and long term complications. Treatment of asymptomatic bacteriuria in diabetic patients is not indicated. Early diagnosis and prompt intervention is recommended to limit morbidity of symptomatic infection.
ISSN 0301-0430 DOI 10.5414/CN107216 e-pub: December 20, 2011 Received March 10, 2011; accepted June 7, 2011
Correspondence to Prof. Dr. Reinhard Fnfstck Sophien- und Hufeland- Klinikum Weimar, Henry-van-de-Velde- Strae 2, 99425 Weimar, Germany innere1@ klinikum-weimar.de Key words diabetes mellitus urinary tract infection pyelonephritis anti- biotics Urinary tract infection in patients with diabetes mellitus Reinhard Fnfstck 1 , Lindsay E. Nicolle 2 , Markolf Hanefeld 3 and Kurt G. Naber 4 1 Department of Internal Medicine, Sophien- und Hufeland-Klinikum Weimar, Germany, 2 University of Manitoba and Health Sciences Centre, Winnipeg, Manitoba, Canada, 3 Center for clinical studies, GWT, Technical University Dresden, and 4 Technical University of Munich, Department of Urology, Munich, Germany Abstract. Urinary tract infection occurs with increased frequency and severity in pa- tients with diabetes mellitus. General host factors enhancing risk for urinary tract infec- tion in diabetics include age, metabolic con- trol, and long term complications, primarily diabetic nephropathy and cystopathy. Altera- tions in the innate immune system have been described and may also contribute. Treat- ment of asymptomatic bacteriuria in diabetic patients is not indicated. Early diagnosis and prompt intervention is recommended to limit morbidity of symptomatic infection. Clini- cal studies comparing management of uri- nary tract infection in persons with diabetes compared to those without as well as diabetic patients with good or poor glucose control will be necessary to improve care of urinary infection in persons with diabetes mellitus. Introduction Clinical observations suggest an asso- ciation between diabetes mellitus and an increased susceptibility to and severity of infections [1]. Metabolic abnormalities and long term complications including neuropa- thy and nephropathy are presumed to be de- terminants of increased infectious morbidity [2], but the specifc contributions of individ- ual variables are not well characterized. In addition, the heterogeneity of diabetic popu- lations compromises efforts to understand the associations of diabetes mellitus and infection. Urinary tract infection is one of the most common infections. It occurs with increased frequency and severity in diabetic populations, and is more likely to be asso- ciated with complications [3]. This review summarizes the current understanding of this important infection in diabetic patients. Urinary tract infection may present as asymptomatic bacteriuria, acute uncompli- cated urinary tract infection in women (acute cystitis or acute nonobstructive pyelonephri- tis), complicated urinary tract infection in men or women with underlying abnormali- ties of the genitourinary tract and, in men, acute or chronic bacterial prostatitis. Infec- tion is often recurrent, either as relapse when an organism persists within the genitourinary tract and recurs following treatment, or rein- fection with new organisms introduced into the genitourinary tract. Epidemiology Asymptomatic bacteriuria occurs in 8 26% of diabetic women, a prevalence estimated to be 2 3 times higher than nondiabetic women [4]. There is limited, if any, increased frequency of asymptomatic bacteriuria for diabetic men. In a cohort of over 6,000 patients with dia- betes mellitus enrolled into ten clinical trials of diabetes therapies, the incidence of urinary infection was 91.5/1,000 person-years for women and 28.2/1,000 for men; the cumula- tive risk over 6 months was 3.5% of women and 1.1% of men [5]. In the Dutch National Survey of General Practice, patients with Type 1 diabetes mellitus were 1.96 times more like- ly to experience urinary infection (95% con- fdence intervals (CI) 1.49 2.58), and with Type 2 diabetes 1.24 times more likely (95% CI 1.10 1.39) [6]. A case control study of pre-menopausal women enrolled in a Wash- ington health group reported diabetes was an independent risk factor for pyelonephritis, with an odds ratio of 4.1 (95% CI 1.6 10.9) [7]. Women 30 years or older with diabetes enrolled from ten Dutch primary care prac- tices experienced relapse and reinfection in 7.1% and 15.9%, respectively, compared Clinical Nephrology, Vol. 77 No. 1/2012 (40-48) Urinary tract infection in patients with diabetes mellitus 41 with 2.0% and 4.1% for women without diabetes [8]. In a Canadian report, diabetic women were 6 15 times more frequently hospitalized for acute pyelonephritis and dia- betic men 3.4 17 times [9], while a Danish study reported diabetics were 3.0 times more likely to be hospitalized with urinary tract infection [10]. A retrospective analysis of patients en- rolled in two clinical trials of urinary tract in- fection found that diabetes mellitus was one of four variables independently associated with a poor outcome (clinical or bacteriologi- cal failure or relapse) of therapy for acute py- elonephritis (OR 8.3; 95% CI 2.3 30.3) [11]. Other evidence supporting increased sever- ity of infection is an increased frequency of bacteremia, more prolonged duration of fever, and increased mortality (12.5% with diabetes and 2.5% without) in older patients with diabetes [12]. Over 90% of episodes of emphysematous pyelonephritis cases occur in persons with diabetes [13] and 67% of epi- sodes of emphysematous cystitis [14]. Thus, the evidence supporting an excess burden of urinary infection in persons with diabetes is compelling. Pathogenesis Host defense Urinary tract infection occurs when bac- teria or fungi colonizing the urethra and, in women, the vagina ascend into the bladder and kidney. Normal host defense mecha- nisms usually prevent entry to or persistence of bacteria within the urinary tract. Urine is a good nutrient source for most microorganisms. The growth rate of bacteria and fungi in urine is stimulated by glycos- uria [15]. Figure 1 demonstrates the growth kinetics of E. coli correlated with urinary glucose level in diabetic patients with an in- creased HbA1c-level. The clinical scenario where hyperglycosuria has the most immedi- ate relevance is in presentations of emphyse- matous cystitis or pyelonephritis, where high urine glucose levels provide a substrate for Enterobacteriaceae in the urine resulting in gas formation [13, 14]. Bacterial attachment to the uroepithe- lium is the necessary initiating event permit- ting bacterial persistence, and also stimulates early activation of the innate immune system. Figure 1. Growth of E.coli in urine with high glucose or high urea concentrations [16]. Growth rates of E.coli ATCC 25922 (American type culture collection; Rocheville, USA and E.coli DSM 7871 German col- lection of microorganisms and cell cultures; Braunschweig, Germany) were analyzed. Strains were incu- bated on MacConkey agar at 37 C. One colony forming unit of each strain was suspended in 2 ml of both sterilized urine samples, diluted to an concentration of 10 6 cfu/ml, and incubated at 37 C for 1 h. Cultures were then diluted with sterile urine to 10 3 cfu/ml at 0, 2 5 and 8 h. A 100 l and 50 l aliquot of these sus- pensions was inoculated onto MacConkey agar plates. Plates were incubated at 37 C for 18 h and colo- nies were counted. Fnfstck, Nicolle, Hanefeld and Naber 42 Type1 fmbriated (fmH) E. coli strains are the predominant phenotypic variant isolated from patients with urinary tract infection, and the presence of this adhesin is essential for estab- lishing acute cystitis. Geerlings and Hoepel- mann [16] demonstrated that E. coli express- ing Type 1 fmbriae have increased adherence to uroepithelial cells of women with diabetes mellitus compared to those without diabetes. Urinary Tamm Horsfall glycoprotein (THP) incorporates high-mannose and NeuAca2, 3Gal sequences which are ligands for both Type 1 and Type S fmbriated E. coli. Pak et al. [17] showed that THP binds type1 fmbriated E. coli in vitro and thus prevents E. coli from attaching to the membrane glycoproteins of the luminal surface of the uroepithelial cells (Uroplakin Ia and Ib). A reduction of urinary THP excretion which correlates with reduc- tion of renal mass is consistently observed in diabetic nephropathy [18, 19]. Glycation of THP in patients with diabetes or renal diseas- es also reduces the capacity of THP to inhibit bacterial adherence to human uroepithelium [20]. However, the clinical relevance of uri- nary THP excretion or glycation on urinary infection has not yet been described. Local urinary cytokines regulate host de- fence against urinary tract infections. Acti- vation of Toll-like receptors on uroepithelial cells promotes release of cytokines which, in turn, recruit and activate granulocytes, mac- rophages, monocytes and other immune reg- ulatory cells [21]. A potential risk factor for urinary tract infection is polymorphonuclear leukocyte dysfunction in a high-glucose state [22, 23]. Studies of neutrophil function in diabetic patients, however, report contradic- tory results [24, 25], and the incidence of uri- nary tract infection is not increased in other groups of patients with neutrophil defects or neutropenia [26]. Signifcantly lower urinary IL-8- and IL-6-concentrations are found in diabetic women compared with nondiabetic controls, and these lower levels correlate with lower urinary leukocyte counts [27]. On the other hand, Zozulinska et al. [28] found increased baseline levels of IL-8 in serum of patients with diabetes. Li et al. [29] observed that advanced glycation end products found in serum of diabetic subjects may inhibit the enzymatic and bactericidal activity of lyso- zyme, blocking bacterial agglutination and impairing killing activity of lactoferrin. Both actions are important in the frst line of de- fense against urinary tract infection. Thus, studies describe a number of alternations of the innate immune system in patients with diabetes, although the clinical relevance of these alterations remains uncertain. Diabetes complications General host factors associated with risk of infection in patients with diabetes include age, metabolic control, duration of diabe- tes mellitus, microvascular complications, urinary incontinence, and cerebrovascular disease or dementia [30]. While the specifc variables contributing to the increased inci- dence and severity of urinary tract infection in diabetic patients remain poorly characterized, most studies report that diabetic patients with long term complications are at greater risk [1, 2, 3]. However in the Epidemiology of Dia- betes Interventions and Complications study [31], the only risk factor associated with acute cystitis in premenopausal women with Type I diabetes was sexual activity, similar to non- diabetic women. This highlights the diffcul- ties in generalization given the heterogenicity of populations with diabetes mellitus. Over 50% of men and women with diabe- tes have bladder dysfunction which may impair voiding and facilitate infection [32, 33]. The presence of renal disease is an additional pre- dictor of urinary tract infection [34]. Urinary incontinence is consistently associated with urinary tract infection in diabetic women [35, 36], but this association is not likely causative. Diabetic cystopathy is an insidious problem attributable to autonomic nervous dysfunc- tion and characterized by a loss of sensation of bladder distension leading to decreased frequency of voiding and increased post-void residual urine volume. Bladder dysfunction oc- curs in 26 86% of diabetic women depending on age, extent of neuropathy and duration of diabetic disease [33]. The possibility that void- ing disorders are contributing to UTI should be considered in all diabetic patients. Microbiological aspects The most common uropathogen isolated from symptomatic or asymptomatic infection Urinary tract infection in patients with diabetes mellitus 43 is E. coli. Other bacteria, such as Proteus spp., Klebsiella spp., Enterobacter spp. and Entero- coccus spp. are isolated less frequently [4, 16]. Bacteria which cause acute, uncomplicated urinary infection in normal women express virulence determinants which may be found on chromosomal or extrachromosomal genes. For uropathogenic E. coli, these virulence factors include an array of toxins such as hemolysin, iron scavenging systems such as hydroxamate/ aerobactin, and adhesins such as mannose-re- sistant or mannose-sensitive hemagglutins or specifc O- or K-antigens [37]. E. coli isolated from the urine of diabetic patients with asymp- tomatic bacteriuria have a low frequency of ge- notypic virulence characteristics, an observa- tion consistent with nondiabetic patients with asymptomatic bacteriuria or complicated uri- nary infection [15, 38, 39]. For instance, genes determining production of hemolysins and colony necrotizing factor 1, typical virulence properties associated with acute symptomatic episodes of urinary tract infection, are less frequent [37]. Meiland et al. [40] also report- ed fmH genetic sequences of E. coli strains isolated from asymptomatic bacteriuria were similar for diabetic and non-diabetic women, although they did not describe strains isolated from symptomatic episodes. Hospital based microbiology surveys from Italy [41] and Greece [42] reported no differ- ences in bacterial spectrum or susceptibility of organisms isolated from the urine of dia- betic or nondiabetic patients. Colodner et al. [43], however, described a higher frequency of extended spectrum beta-lactamase (ESBL) producing E. coli and Klebsiella pneumoniae in non- hospitalized Israeli diabetic compared with non diabetic patients. Similar results were found by Rodriguez-Bano et al. [44] in Spanish patients with community acquired ESBL urinary infection. However, neither study reported whether diabetes was an in- dependent risk factor for increased resistance once age, prior antimicrobial treatment, or urologic abnormalities were considered. Diagnosis Clinical Diabetic patients generally present with symptoms similar to nondiabetic patients. These are frequency, urgency, dysuria, or su- prapubic discomfort for lower tract infection, and costovertebral angle pain or tenderness, often with fever, for upper tract infection. Clinical signs may be altered in some patients with peripheral or autonomic neuropathy. Pa- tients with diabetes are more likely to have more severe presentations of pyelonephritis including fever, bacteremia, and bilateral renal involvement [12]. Less frequent presentations of urinary infection which occur most often in patients with diabetes include emphyse- matous cystitis or pyelonephritis, ureteral ob- struction secondary to papillary necrosis, and renal or perinephric abscesses. Rarely, acute renal failure complicating pyelonephritis has been reported, and most cases described are patients with diabetes. Symptomatic urinary tract infection in diabetes mellitus may be complicated by hypo- or hyperglycemia, hyperosmolar de- hydration, or ketoacidosis which may further impair the host response to infection. Early diagnosis and treatment of symptomatic in- fection and metabolic abnormalities is im- portant to limit morbidity. Laboratory A urine specimen for culture should be obtained prior to initiating antimicrobial therapy for every diabetic patient present- ing with pyelonephritis or complicated uri- nary tract infection. Women with symptoms consistent with acute cystitis and who do not have diabetic nephropathy or other long term complications, particularly if they have a prior history of recurrent acute cystitis, do not usually require a urine culture. However, these women should also have a urine speci- men for culture if this is a recurrent episode within one month of treatment, if empiric therapy has failed, or if there has been recent antimicrobial treatment so resistant organ- isms are more likely. A diagnosis of bacteriuria is made when 10 5 cfu/ml of an organism is isolated from a voided urine specimen. For diabetic wom- en with good metabolic control and without long term complications who present with acute uncomplicated cystitis, quantitative counts < 10 5 cfu/ml are isolated from 20 to 25% of premenopausal women and about Fnfstck, Nicolle, Hanefeld and Naber 44 10% of postmenopausal women. Only 5% of patients with acute pyelonephritis have lower quantitative counts isolated. Isolation of lower quantitative counts is presumed to result from impaired renal concentrating ability or diuresis which limits the dwell time of urine in the bladder. Pyuria is a universal accompaniment of symptomatic urinary tract infection. It is also present in 70% of diabetic women with asymptomatic bacteriuria [4]. Pyuria may also be caused by vaginal, bladder or renal conditions other than urinary tract infection. Thus, the presence of pyuria, by itself, is not useful for diagnosis of urinary tract infection or to differentiate asymptomatic and symp- tomatic infection. The absence of pyuria, however, is useful to exclude urinary tract infection in patients with questionable symp- toms. Diagnostic imaging The increased frequency of serious com- plications of urinary tract infection in pa- tients with diabetes requires a low threshold for obtaining diagnostic imaging [3, 45]. Diabetic patients who present with severe systemic manifestations of disease, includ- ing severe sepsis or septic shock, all men, patients who do not respond following 48 72 h of appropriate antimicrobial therapy, or who experience early symptomatic relapse following discontinuation of antimicrobial therapy should have diagnostic imaging per- formed promptly to identify underlying ab- normalities which may require intervention. Ultrasound and intravenous urography were previously the most common imaging studies used. Ultrasound scanning is safer, less costly, and easier to perform. These methods allowed detection of calculi, ob- struction, and incomplete bladder emptying. Computerized tomography (CT) is now ac- cepted as the most sensitive imaging modal- ity for diagnosis and follow-up of abnor- malities potentially associated with urinary tract infections [46]. An enhanced CT scan is preferred, but contrast media should be used with caution in patients with diabetes mel- litus or with renal disease, given the risk for contrast media induced renal failure. It has been recommended that metformin be dis- continued on the day of contrast injection if the glomerular fltration rate (GFR) is < 60 ml/min/1.73 m 2 , and restarted two days later, providing the GFR has not signifcantly dete- riorated [47]. Nuclear medicine has a limited role in the evaluation of urinary infections in adults, and is used primarily for the assess- ment of renal function. Magnetic resonance imaging (MRI) has a limited but increasing role. It is particularly useful for patients with allergy to iodinated contrast media, but is not as reliable as a CT scan for identifying gas or stones in the genitourinary tract. Treatment strategies Treatment of urinary tract infection in patients with diabetes is generally similar to non-diabetic patients [48]. Key factors to consider include whether the patient is asymptomatic or symptomatic, whether in- fection is localized to the bladder or kidney, and renal function. For diabetic patients, the severity of metabolic alterations character- ized by hyper- or hypoglycemia, increas- ing signs of insulin resistance, the level of HbA1c, and glycosuria must also be consid- ered. Asymptomatic bacteriuria There are no short or long term benefts for treatment of asymptomatic bacteriuria in women with diabetes mellitus [49, 50]. Treat- ment of asymptomatic bacteriuria in stable di- abetic patients does not reduce the frequency of subsequent symptomatic episodes of cysti- tis or pyelonephritis or hospitalization for uri- nary tract infection. Asymptomatic bacteriuria by itself is not associated with an increased rate of progression to renal impairment or other long term complications in patients with diabetes [50]. Thus, screening for and treat- ment of asymptomatic bacteriuria in diabetic patients is not indicated [51]. Symptomatic infection Acute cystitis in women with good glucose control and without long term complications should be managed as uncomplicated urinary Urinary tract infection in patients with diabetes mellitus 45 infection, usually with short term antimicrobial therapy (Table 1) [52, 53]. Patients with pyelo- nephritis and mild or moderately severe pre- sentations can usually be successfully treated with oral therapy (Table 2) [52, 53]. However, patients with pyelonephritis and severe system- ic symptoms including nausea and vomiting or hemodynamic instability should be hospital- ized for initial parenteral antibiotic therapy. Patients with gastric emptying impairment will also usually require parenteral therapy. Parenteral antimicrobial therapy is modifed to an oral regimen once patients can tolerate oral therapy, the clinical status of the patient has improved, and urine culture results are avail- able. If infection is associated with complica- tions such as renal or perinephric abscesses or emphysematous pyelonephritis, prompt inter- vention with a combined surgical and medical approach is often required. Antimicrobial selection The choice of initial empiric antimicrobi- al therapy should consider current treatment guidelines, the patients metabolic status and tolerance, the clinical presentation, and known or suspected local or institutional sus- ceptibility of uropathogens (Tables 1, 2) [3, 52, 53]. Broad spectrum cephalosporins and fuoroquinolones are the drugs of choice for pyelonephritis. However, alternate regimens such as the carbapenems meropenem, er- tapenem or doripenem or beta lactam/beta lactamase inhibitors such as piperacillin/ tazobactam or ampicillin/sulbactam may be appropriate if antimicrobial resistance is a concern. For patients who present with se- vere sepsis or septic shock, broad spectrum antimicrobial therapy to provide maximal coverage for resistant organisms should be initiated pending urine culture results. Possible drug interactions between antimi- crobials and antidiabetic or antihypertensive drugs must be considered (Table 3). Antimi- crobials may impair glucose homeostasis and lipid metabolism [54, 55]. Antimicrobials with nephrotoxic side effects, e.g. aminoglycosides, should be used with caution in patients with renal insuffciency. Patients with diminished renal function are also susceptible to the neph- rotoxic effects of drug combinations such as cephalosporins given with furosemide or ethac- rynic acid. Some antibiotics cause elevation of the serum creatinine by mechanisms other than nephrotoxicity. For instance, trimethoprim can inhibit tubular secretion of creatinine. Tetracy- cline has an antianabolic effect in renal failure and is best avoided, but doxycycline may be used if there is a clear indication, such as ure- thritis. Nitrofurantoin should be avoided in re- nal failure as drug metabolites accumulate and may cause peripheral neuropathy [56]. While no other antimicrobials are specifcally contra- indicated in renal insuffciency, dosage adjust- ments appropriate to the level of renal impair- ment are usually necessary. Table 1. Recommendations for antimicrobial therapy in uncomplicated cysti- tis in patients with diabetes mellitus [48, 52, 53]. Antimicrobial Regimen Duration First line Fosfomycin trometamol 3,000 mg single dose Nitrofurantoin 50 100 mg orally 3 4 times a day 5 days Nitrofurantoin mono hydrate/ macrocrystals 100 mg twice a day 5 days TMP-SMX* 800/160 mg orally every 12 h 3 days Trimethoprim 200 mg every 12 h 5 days Alternatives Ciprofoxacin 250 500 mg orally every 12 h 3 days Levofoxacin 250 500 mg every 12 h 3 days Norfoxacin 400 mg orally every 12 h 3 days Ofoxacin 200 mg orally every 12 h 3 days Cephelexin 500 mg 4 times daily 7 days Cefuroxime axetil 500 mg twice daily 7 days Cefpodoxime proxetil 100 mg orally every 12 h 3 days Cefxime 400 mg daily *trimethoprim/sulfamethoxazole. Table 2. Preferred regimens for antimicrobial therapy for uncomplicated py- elonephritis with diabetes mellitus [52, 53]. Antimicrobial Regimen Intravenous administration Cefotaxime 1g q8h Ceftriaxone 1 2 g daily Ciprofoxacin 400 mg twice a day Levofoxacin 500 750 mg once a day Gentamicin or tobramycin with ampicillin 3 5 mg/kg once a day 2 g IV q6h Oral administration Levofoxacin 250 500 mg once a day Ciprofoxacin 500 mg twice a day Cefpodoxime proxetil 200 mg twice a day Amoxicillin/clavullanic acid 1/0.2 2/0.2 g 3 times a day TMP-SMX * 160/800 mg twice a day *if isolate susceptible. Fnfstck, Nicolle, Hanefeld and Naber 46 Recurrent infection The management of recurrent urinary tract infection is similar for diabetic and non- diabetic patients. Recurrent infection in young women without long term complications of diabetes is managed as acute uncomplicated cystitis, including antimicrobial therapy giv- en as long term low dose or post intercourse prophylaxis for women with very frequent re- currences [53]. Management of recurrent in- fection in individuals with complex urologic abnormalities or renal failure is more prob- lematic. For patients with complicated infec- tion prophylactic antimicrobial therapy is not recommended as this does not decrease the frequency of symptomatic urinary tract infec- tion and leads to recurrent infection with more resistant organisms. It is essential to identify and correct any known urologic abnormali- ties and to optimize voiding, including use of intermittent catheterization where appropri- ate. For some patients with renal impairment or men with prostate infection, bacteria may persist within the nonfunctioning kidney or prostate despite prolonged courses of anti- microbial therapy. In selected patients with recurrent symptomatic infection and abnor- malities which cannot be corrected, prolonged suppressive therapy may be necessary. Conclusions Asymptomatic bacteriuria and symptom- atic urinary tract infection are more common in patients with diabetes mellitus. Symptom- atic infection is associated with an increased severity and frequency of complications. The underlying mechanisms determining the increased risk and severity of infection are not fully described, but alterations in specifc components of the host response, metabolic abnormalities, and long term complications of diabetes likely all contribute. The hetero- genicity of diabetic populations complicates efforts to identify specifc determinants of increased morbidity. To better defne man- agement strategies and prognosis, diagnostic evaluation and therapeutic outcome should be stratifed by age, sex, the site of urinary tract infection, underlying renal or bladder impairment, and the metabolic status of the patient. Controlled clinical trials of therapy comparing patients with and without diabe- tes mellitus, or diabetic patients stratifed by adequacy of control and complications will be necessary to improve management of this common and important problem. References [1] Joshi N, Caputo GM, Weitekamp MR, Karchmer AW. Infections in patients with diabetes mellitus. N Engl J Med. 1999; 341: 1906-1912. doi:10.1056/NEJM199912163412507 PubMed [2] McMahon MM, Bistrian BR. Host defenses and susceptibility to infection in patients with diabetes mellitus. Infect Dis Clin North Am. 1995; 9: 1-9. PubMed [3] Nicolle LE. Urinary tract infection in diabetes. Curr Opin Infect Dis. 2005; 18: 49-53. doi : 10. 1097/ 00001432-200502000-00009 PubMed Table 3. Potential metabolic side effects of antimicrobial drugs on glucose level in diabetic patients. Antimicrobial substances Effects on glucose level Antimicrobial sustances Effects on glucose level Fluoroquinolones Penicillins Ciproloxacin Ampicillin Levofoxacin Amoxicillin Gatifoxacin Sulbactam/ ampicillin
Norfoxacin none Aminoglycosides Tazobactam none Gentamicin none Cephalosporins Tobramycin none Cefazolin none Amikacin none Cefuroxime none Contrimoxazole Cefotaxime none Nitrofurantoin none Ceftazidime Antifungal drugs none Cefxime none Carbapenems Imipenem none Meropenem none Ertapenem none Urinary tract infection in patients with diabetes mellitus 47 [4] Zhanel GG, Harding GK, Nicolle LE. Asymptom- atic bacteriuria in patients with diabetes mellitus. Rev Infect Dis. 1991; 13: 150-154. doi:10.1093/ clinids/12.5.150 PubMed [5] Hammar N, Farahmand B, Gran M, Joelson S, Andersson SW. Incidence of urinary tract infec- tion in patients with type 2 diabetes. Experience from adverse event reporting in clinical trials. Pharmacoepidemiol Drug Saf. 2010; 19: 1287- 1292. doi:10.1002/pds.2043 PubMed [6] Muller LM, Gorter KJ, Hak E, Goudzwaard WL, Schellevis FG, Hoepelman AI, Rutten GE. In- creased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clin Infect Dis. 2005; 41: 281-288. doi:10.1086/431587 PubMed [7] Scholes D, Hooton TM, Roberts PL, Gupta K, Stapleton AE, Stamm WE. Risk factors associated with acute pyelonephritis in healthy women. Ann Intern Med. 2005; 142: 20-27. PubMed [8] Gorter KJ, Hak E, Zuithoff NP, Hoepelman AIM, Rutten GEHM. Risk of recurrent acute lower uri- nary tract infections and prescription pattern of antibiotics in women with and without diabetes in primary care. Fam Pract. 2010; 27: 379-385. doi:10.1093/fampra/cmq026 PubMed [9] Nicolle LE, Friesen D, Harding GKM, Roos LL. Hospitalization for acute pyelonephritis in Mani- toba, Canada, during the period from 1989 to 1992; impact of diabetes, pregnancy, and aborigi- nal origin. Clin Infect Dis. 1996; 22: 1051-1056. doi:10.1093/clinids/22.6.1051 PubMed [10] Benfeld T, Jensen JS, Nordestgaard BG. Infu- ence of diabetes and hyperglycaemia on infec- tious disease hospitalisation and outcome. Diabe- tologia. 2007; 50: 549-554. doi:10.1007/ s00125-006-0570-3 PubMed [11] Pertel PE, Haverstock D. Risk factors for a poor outcome after therapy for acute pyelonephritis. BJU Int. 2006; 98: 141-147. doi:10.1111/j.1464-410X.2006.06222.x PubMed [12] Kofteridis DP, Papadimitraki E, Mantadakis E, Maraki S, Papadakis JA, Tzifa G, Samonis G. Ef- fect of diabetes mellitus on the clinical and micro- biologic features of hospitalized elderly patients with acute pyelonephritis. J Am Geriatr Soc. 2009; 57: 2175-2128. doi:10.1111/j.1532-5415.2009.02550.x [13] Soo Park B, Lee SJ, Wha Kim Y, Sik Huh J, Il Kim J, Chang SG. Outcome of nephrectomy and kid- ney-preserving procedures for the treatment of emphysematous pyelonephritis. Scand J Urol Nephrol. 2006; 40: 332-338. doi:10.1080/00365590600794902 PubMed [14] Thomas AA, Lane BR, Thomas AZ, Remer EM, Campbell SC, Shoskes DA. Emphysematous cys- titis: a review of 135 cases. BJU Int. 2007; 100: 17-20. doi:10.1111/j.1464-410X.2007.06930.x PubMed [15] Werner T. Geno- und phnotypische Charakter- isierung von E.coli bei Patienten mit Diabetes mellitus Typ 2 und einer asymptomatischen Bak- teriurie und Patienten nach Nierentransplantation. Promotionsschrift (Theses to M.D.-Qualifying), University of Jena: 2008. [16] Geerlings SE, Meiland R, van Lith EC, Brouwer EC, Gaastra W, Hoepelman AIE. Adherence of type 1-fmbriated Escherichia coli to uroepithelial cells: more in diabetic women than in control sub- jects. Diabetes Care. 2002; 25: 1405-1409. doi:10.2337/diacare.25.8.1405 PubMed [17] Pak J, Pu Y, Zhang ZT, Hasty DL, Wu XR. Tamm- Horsfall protein binds to type 1 fmbriated Esch- erichia coli and prevents E. coli from binding to uroplakin Ia and Ib receptors. J Biol Chem. 2001; 276: 9924-9930. doi:10.1074/jbc.M008610200 PubMed [18] Torffvit O, Agardh CD. Urinary excretion rate of NC1 and Tamm-Horsfall protein in the microal- buminuric type I diabetic patient. J Diabetes Complications. 1994; 8: 77-83. doi:10.1016/1056- 8727(94)90055-8 PubMed [19] Below AA, Chakraborty J, Khuder SH, Haselhuhn GD. Evaluation of urinary Tamm-Horsfall protein in post-menopausal diabetic women. J Diabetes Complications. 1999; 13: 204-210. doi:10.1016/ S1056-8727(99)00046-X PubMed [20] Serafni-Cessi F, Malagolini N, Cavallone D. Tamm-Horsfall glycoprotein: biology and clinical relevance. Am J Kidney Dis. 2003; 42: 658-676. doi:10.1016/S0272-6386(03)00829-1 PubMed [21] Fnfstck R, Franke S, Hellberg M, Ott U, Knfel B, Straube E, Sommer M, Hacker J. Secretion of cytokines by uroepithelial cells stimulated by Escherichia coli and Citrobacter spp. Int J Antimi- crob Agents. 2001; 17: 253-258. doi:10.1016/ S0924-8579(01)00301-6 PubMed [22] Delamaire M, Maugendre D, Moreno M, Le Goff MC, Allannic H, Genetet B. Impaired leucocyte functions in diabetic patients. Diabet Med. 1997; 14: 29-34. doi:10.1002/(SICI)1096- 9136(199701)14:1 < 29::AID-DIA300 > 3.0.CO;2-V PubMed [23] Muchov J, Liptkov A, Orszghov Z, Gara- iov I, Tison P, Crsky J, Durackov Z. Antioxi- dant systems in polymorphonuclear leucocytes of Type 2 diabetes mellitus. Diabet Med. 1999; 16: 74-78. doi:10.1046/j.1464-5491.1999.00015.x PubMed [24] nnn double of Nr. 22!Delamaire M, Maugendre D, Moreno M, Le Goff MC, Allannic H, Genetet B. Impaired leucocyte functions in diabetic patients. Diabet Med. 1997; 14: 29-34. doi:10.1002/ (SICI)1096-9136(199701)14:1 < 29::AID- DIA300 > 3.0.CO;2-V PubMed [25] Balasoiu D, van Kessel KC, van Kats-Renaud HJ, Collet TJ, Hoepelman AI. Granulocyte function in women with diabetes and asymptomatic bacteri- uria. Diabetes Care. 1997; 20: 392-395. doi:10.2337/diacare.20.3.392 PubMed [26] Wang QN, Qiu ZD. Infection in acute leukemia: an analysis of 433 episodes. Rev Infect Dis. 1989; 11 (Suppl 7): S1613-S1620. doi:10.1093/cli- nids/11.Supplement_7.S1613 PubMed [27] Geerlings SE, Brouwer EC, Van Kessel KC, Gaas- tra W, Stolk RP, Hoepelman AIE. Cytokine secre- tion is impaired in women with diabetes mellitus. Eur J Clin Invest. 2000; 30: 995-1001. doi:10.1046/j.1365-2362.2000.00745.x PubMed [28] Zozuliska D, Majchrzak A, Sobieska M, Wiktoro- wicz K, Wierusz-Wysocka B. Serum interleukin-8 level is increased in diabetic patients. Diabetolo- gia. 1999; 42: 117-118. doi:10.1007/ s001250051124 PubMed [29] Li YM, Tan AX, Vlassara H. Antibacterial activity of lysozyme and lactoferrin is inhibited by bind- ing of advanced glycation-modifed proteins to a conserved motif. Nat Med. 1995; 1: 1057-1061. doi:10.1038/nm1095-1057 PubMed [30] Brown JS, Wessells H, Chancellor MB, Howards SS, Stamm WE, Stapleton AE, Steers WD, Van Den Eeden SK, McVary KT. Urologic complica- tions of diabetes. Diabetes Care. 2005; 28: 177- 185. doi:10.2337/diacare.28.1.177 PubMed [31] Czaja CA, Rutledge BN, Cleary PA, Chan K, Sta- pleton AE, Stamm WE; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Urinary tract infections in women with type 1 diabetes mellitus: survey of female partici- pants in the epidemiology of diabetes interven- Fnfstck, Nicolle, Hanefeld and Naber 48 tions and complications study cohort. J Urol. 2009; 181: 1129-1134., discussion 1134-1135. doi:10.1016/j.juro.2008.11.021 PubMed [32] Kaplan SA, Te AE, Blaivas JG, McGuire EJ. Uro- dynamic fndings in patients with diabetic cys- topathy. J Urol. 1995; 153: 342-344. doi : 10. 1097/ 00005392-199502000-00013 PubMed [33] Frimodt-Mller C. Diabetic cystopathy: epidemi- ology and related disorders. Ann Intern Med. 1980; 92: 318-321. PubMed [34] Stein G, Eichhorn T, Fnfstck R. Urinary tract infections in patients with renal insuffciency. Nieren- Hochdruckkr. 2007; 36: 288291. [35] Phelan S, Kanaya AM, Subak LL, Hogan PE, Es- peland MA, Wing RR, Burgio KL, Dilillo V, Gorin AA, West DS, Brown JS; Action for Health in Dia- betes (Look AHEAD) Research Group. Preva- lence and risk factors for urinary incontinence in overweight and obese diabetic women: action for health in diabetes (look ahead) study. Diabetes Care. 2009; 32: 1391-1397. doi:10.2337/dc09- 0516 PubMed [36] Sarma AV, Kanaya A, Nyberg LM, Kusek JW, Vit- tinghoff E, Rutledge B, Cleary PA, Gatcomb P, Brown JS; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Risk factors for urinary incontinence among women with type 1 diabetes: fndings from the epidemiology of dia- betes interventions and complications study. Urology. 2009; 73: 1203-1209. doi:10.1016/j. urology.2008.11.009 PubMed [37] Fnfstck R, Tschpe H, Stein G, Vollandt R, Schneider S. Virulence of Escherichia coli strains in relation to their hemolysin formation, mannose- resistant hemagglutination, hydroxamate produc- tion, K 1-antigen and the plasmid profle in pa- tients with chronic pyelonephritis. Clin Nephrol. 1989; 32: 178-184. PubMed [38] Oelschlger T, Fnfstck R. Rezidivierende Harn- wegsinfektionen der Frau. Urologea. 2006; 45: 412-420. doi:10.1007/s00120-006-1020-z [39] Dalal S, Nicolle L, Marrs CF, Zhang L, Harding G, Foxman B. Long-term Escherichia coli asymp- tomatic bacteriuria among women with diabetes mellitus. Clin Infect Dis. 2009; 49: 491-497. doi:10.1086/600883 PubMed [40] Meiland R. Geerlings, Langermann S. Fim CH antiserum inhibits the adherence of Escherichia coli to cells collected by voided urine specimens of diabetic women. J Urol. 2004; 171: 1589-1593. PubMed doi:10.1097/01.ju.0000118402.01034.fb [41] Bonadio M, Costarelli S, Morelli G, Tartaglia T. The infuence of diabetes mellitus on the spectrum of uropathogens and the antimicrobial resistance in elderly adult patients with urinary tract infec- tion. BMC Infect Dis. 2006; 6: 54-61. doi:10.1186/1471-2334-6-54 PubMed [42] Papazafropoulou A, Daniil I, Sotiropoulos A, Petropoulou D, Konstantopoulou S, Peppas T, Pappas S. Urinary tract infection, uropathogens and antimicrobial resistance in diabetic and non- diabetic patients. Diabetes Res Clin Pract. 2009; 85: e12-e13. doi:10.1016/j.diabres.2009.04.020 PubMed [43] Colodner R, Rock W, Chazan B, Keller N, Guy N, Sakran W, Raz R. Risk factors for the develop- ment of extended-spectrum beta-lactamase-pro- ducing bacteria in nonhospitalized patients. Eur J Clin Microbiol Infect Dis. 2004; 23: 163-167. doi:10.1007/s10096-003-1084-2 PubMed [44] Rodrguez-Bao J, Navarro MD, Romero L, Mar- tnez-Martnez L, Muniain MA, Perea EJ, Prez- Cano R, Pascual A. Epidemiology and clinical features of infections caused by extended-spec- trum beta-lactamase-producing Escherichia coli in nonhospitalized patients. J Clin Microbiol. 2004; 42: 1089-1094. doi:10.1128/ JCM.42.3.1089-1094.2004 PubMed [45] Goswami R, Bal CS, Tejaswi S, Punjabi GV, Kapil A, Kochupillai N. Prevalence of urinary tract in- fection and renal scars in patients with diabetes mellitus. Diabetes Res Clin Pract. 2001; 53: 181- 186. doi:10.1016/S0168-8227(01)00255-8 PubMed [46] Demertzis J, Menias CO. State of the art: imaging of renal infections. Emerg Radiol. 2007; 14: 13- 22. doi:10.1007/s10140-007-0591-3 PubMed [47] van Dijk Azn R, Wetzels JF, ten Dam MA, Aarts NJ, Schimmelpenninck-Scheiffers ML, Freericks MP, Said SA, Geenen RW, Stuurman A, van Everdingen JJ. Guideline Precautionary mea- sures for contrast media containing iodine. Ned Tijdschr Geneeskd. 2008; 152: 742-746. PubMed [48] Meiland R, Geerlings SE, Hoepelman AI. Man- agement of bacterial urinary tract infections in adult patients with diabetes mellitus. Drugs. 2002; 62: 1859-1868. doi:10.2165/00003495- 200262130-00003 PubMed [49] Harding GKM, Zhanel GG, Nicolle LE, Cheang M; Manitoba Diabetes Urinary Tract Infection Study Group. Antimicrobial treatment in diabetic women with asymptomatic bacteriuria. N Engl J Med. 2002; 347: 1576-1583. doi:10.1056/NEJ- Moa021042 PubMed [50] Meiland R, Geerlings SE, Stolk RP, Netten PM, Schneeberger PM, Hoepelman AIM. Asymptom- atic bacteriuria in women with diabetes mellitus: effect on renal function after 6 years of follow-up. Arch Intern Med. 2006; 166: 2222-2227. doi:10.1001/archinte.166.20.2222 PubMed [51] Nicolle LE, Bradley S, Colgan R, Rice JC, Schaef- fer A, Hooton TM. IDSA guideline for the diagno- sis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis. 2005; 40: 643-654. PubMed doi:10.1086/427507 [52] Gupta K, Hooton TM, Naber KG et al. Interna- tional clinical practice guidelines for the treat- ment of acute uncomplicated cystitis and pyelone- phritis in women: A 2010 Update of the IDSA and ESCMID guidelines. Clin Infect Dis. 2011. in press. PubMed doi:10.1093/cid/cir102 [53] Nicolle LE. Uncomplicated urinary tract infection in adults including uncomplicated pyelonephritis. Urol Clin North Am. 2008; 35: 1-12. doi:10.1016/j. ucl.2007.09.004 PubMed [54] Chan JC, Cockram CS, Critchley JA. Drug-in- duced disorders of glucose metabolism. Mecha- nisms and management. Drug Saf. 1996; 15: 135- 157. doi:10.2165/00002018-199615020-00005 PubMed [55] Strevel EL, Kuper A, Gold WL. Severe and pro- tracted hypoglycaemia associated with co-trimox- azole use. Lancet Infect Dis. 2006; 6: 178-182. doi:10.1016/S1473-3099(06)70414-5 PubMed [56] Munar MY, Singh H. Drug dosing adjustments in patients with chronic kidney disease. Am Fam Physician. 2007; 75: 1487-1496. PubMed