Vous êtes sur la page 1sur 9


2012 Dustri-Verlag Dr. K. Feistle

ISSN 0301-0430
DOI 10.5414/CN107216
e-pub: December 20, 2011
March 10, 2011;
June 7, 2011

Correspondence to
Prof. Dr. Reinhard
Sophien- und Hufeland-
Klinikum Weimar,
Strae 2, 99425
Weimar, Germany
Key words
diabetes mellitus
urinary tract infection
pyelonephritis anti-
Urinary tract infection in patients with diabetes
Reinhard Fnfstck
, Lindsay E. Nicolle
, Markolf Hanefeld
and Kurt G. Naber
Department of Internal Medicine, Sophien- und Hufeland-Klinikum Weimar,
University of Manitoba and Health Sciences Centre, Winnipeg,
Manitoba, Canada,
Center for clinical studies, GWT, Technical University Dresden,
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.
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.
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
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
cfu/ml, and incubated at 37 C for 1 h. Cultures
were then diluted with sterile urine to 10
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.
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.
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
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
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-
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
, 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-
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
mono hydrate/
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
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
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
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.
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.
[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.
[3] Nicolle LE. Urinary tract infection in diabetes.
Curr Opin Infect Dis. 2005; 18: 49-53.
doi : 10. 1097/ 00001432-200502000-00009
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/

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
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
[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.
[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
[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
[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
[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
[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
[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
[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
[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