Advances in Urological Infections Urinary Tract Infections

12:29 pm
Page 115
Urinary Tract Infections
Advances in Urological Infections
a report by
F l o r i a n M E W a g e n l e h n e r , 1 W W e i d n e r 1 and K u r t G N a b e r 2
1. Urology and Paediatric Urology Clinic, Justus-Liebig University, Giessen; 2. Technical University, Munich
Urinary tract infections (UTIs) are one of the most common reasons for
of drugs employed in the therapy of this condition.10 Susceptibility of
adults to seek medical and, specifically, urological consultations and are
E. coli was least common towards ampicillin (mean 48%; range
also among the most frequently occurring nosocomial infections.1–4 In
28–63%), followed by co-trimoxazole (71%; range 55–88%),
urology, nosocomial UTIs are almost exclusively complicated UTIs, i.e.
cefuroxime (83%; range 73–93%) and ciprofloxacin (92%; range
UTIs associated with structural or functional abnormalities of the urinary
86–98%). Fosfomycin, mecillinam and nitrofurantoin were the agents
tract, with a broad spectrum of aetiological pathogens.5 Empirical
with the highest susceptibility rates (98, 96 and 95%, respectively) in
antimicrobial therapy in urology has to be instigated when urosepsis is
all countries investigated.
pending or the general condition is deteriorating and likely to be
improved significantly by the immediate introduction of antimicrobials.6
Complicated Urinary Tract Infections
For rational empirical therapy it is necessary to consider the bacterial
The bacterial spectrum of complicated nosocomial UTIs is much more
spectrum and the local antibiotic susceptibility of the uropathogens.
heterogenous than that of uncomplicated UTIs and comprises a wide
range of Gram-negative and Gram-positive species.
The prostatitis syndrome is one of the most common entities encountered
in urological practice. Classification of the prostatitis syndrome is based on
In the SENTRY antimicrobial surveillance programme in 2000, the
the clinical presentation of the patient, the presence or absence of white
bacterial spectrum of hospitalised urological patients in North America
blood cells in the expressed prostatic secretion (EPS) and the presence or
consisted of 47% E. coli, 13% Enterococcus spp., 11% Klebsiella spp.,
absence of bacteria in the EPS.7 Chronic bacterial prostatitis is usually
8% Pseudomonas spp., 5% Proteus mirabilis, 4% Enterobacter spp.
detected in fewer than 10% of patients with characteristic symptoms of
and 3% Citrobacter spp. (less frequently isolated species not
the chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).
mentioned).11 In E. coli, antibiotic resistance to ampicillin was 37%, to
ciprofloxacin 4% and to trimethoprim/sulfamethoxazole 23%. In
Epididymitis is classified as an acute or chronic process. Chronic
P. aeruginosa, resistance to ciprofloxacin was 29%. Vancomycin
inflammation with induration develops in about 15% of patients
resistance in Enterococcus spp. was 7%. The presence of extended-
following an episode of acute epididymitis. Epididymitis with sexually
spectrum β-lactamase in E. coli was 4%, and in Klebsiella spp. 19%.
transmitted pathogens is common among individuals who have high-risk
sexual behaviours. In middle-aged and older men, epididymitis is usually
Therapy of Uncomplicated Urinary Tract Infections
due to the same organisms as those that cause UTIs and is presumably a
The results of studies performed in the field of uncomplicated UTIs
direct extension from the urinary tract.
show that antibiotic substances classically used for the treatment of
uncomplicated UTIs, such as cotrimoxazole, fluoroquinolones or
Bacterial Spectrum and Antimicrobial Resistance in
Urinary Tract Infections
Uncomplicated Urinary Tract Infections
In uncomplicated UTIs, Escherichia coli is the most common pathogen,
typically being isolated from over 80% of outpatients with acute
uncomplicated cystitis across the various regions of the world.8
Staphylococcus saprophyticus accounts for 5–15% of these infections
and is especially prevalent in younger women with cystitis. Causative
Florian ME Wagenlehner is a Consultant Urologist in the
Urology and Paediatric Urology Clinic at Justus Liebig
University in Giessen. He is a member of the European
Association of Clinical Microbiology and Infectious Diseases
(ESCMID) and the European Association of Urology (EAU),
and a member of the working group of the European Society
for Infections in Urology (ESIU) guideline section. He received
his MD from the Technical University in Munich in 1996.
E: [email protected]
pathogens in the remaining 5–10% of cases include aerobic Gramnegative rods, such as Klebsiella and Proteus spp., and enterococci.
The range of pathogens associated with acute uncomplicated
pyelonephritis is similar to that seen in acute uncomplicated cystitis.9
The Clinical Aspects and Antimicrobial Resistance Epidemiology in
Females with Cystitis (ARESC) Project, an international surveillance
study involving nine countries in Europe and Brazil, has monitored the
antimicrobial susceptibility of uropathogens over the period
Kurt G Naber is an Associate Professor of Urology at the
Technical University of Munich. Previously, he was Head of
the Urological Clinic at St Elisabeth Hospital in Straubing.
He is President of the International Society of Chemotherapy
(ISC) for Infection and Cancer. Dr Naber is the author of
more than 540 scientific articles and serves on the Editorial
Board of several journals. He is a member of numerous
societies, including the German, European and American
Urological Associations, and infectious diseases societies.
His research interests include urological infections, especially the microbiology and
pharmacokinetics of antimicrobials for treatment of urinary tract infections and prostatitis.
2004–2006. The aim of the study was to rank the current usefulness
12:29 pm
Page 116
Urinary Tract Infections
aminopenicillines, are losing their effectiveness due to increasing
Klebsiella spp., Enterobacter spp., enterococci and staphylococci.
resistance.10,12 Ideal substances are those with low resistance rates that
Numbers of extended-spectrum β-lactamase-producing E. coli and
are exclusively used for this indication, such as fosfomycin
K. pneumoniae rapidly increase and may cause significant clinical
tromethamine, nitrofurantoin or pivmecillinam.
problems in the treatment of UTIs.21,22 Antibiotic substances with novel
modes of action that are effective against Gram-negative pathogens are
scarce. Older, established substances such as polymyxins or temocillin
Fosfomycin tromethamine is the oral applicable salt of fosfomycin.
regain interest in situations where multiple-antibiotic-resistant
Fosfomycin (cis-(1R,2S)-epoxypropylphosphonic acid) is an oxirane
pathogens appear. On the other hand, carbapenems still retained their
antibiotic unrelated to other substances13 and is produced as a
activity in most of the uropathogens. Carbapenems are therefore
secondary metabolite by Streptomyces and Pseudomonas spp.
currently widely developed for the treatment of complicated UTIs.
Fosfomycin is active against Gram-positive and Gram-negative
bacteria, but shows decreased activity against Morganella morganii,
P. vulgaris, P. aeruginosa, E. faecium and coagulase-negative
Until now, carbapenems have been available only intravenuously, with
staphylococci. Despite many years of usage, fosfomycin continues to
the exception of faropenem, which is licensed in Japan. Ertapenem is
be characterised by a low incidence of E. coli-resistant strains (1–3%)
the sole representative of the first group of carbapenems; imipenem
worldwide.14 Fosfomycin tromethamine has retained its activity against
and meropenem are the representatives of the second group, and are
quinolone-resistant strains of E. coli, and cross-resistance with other
classes of antimicrobial agents is currently not a problem.15
Ideal substances are those with low
Nitrofurantoin belongs to the nitroheterocyclic compounds. The
nitrogroup coupled onto the heterocyclic furan ring represents the
proper site of effect. The nitrogroup is inactive and has to be activated
by microbial nitroreductases after penetration into the microbial cell.16
resistance rates that are exclusively
used for this indication, such as
fosfomycin tromethamine,
nitrofurantoin or pivmecillinam.
antibacterial activity is generally weak, but in the urine its activity
against E. coli and some other enterobacteria such as Klebsiella spp.
and Enterobacter spp. is sufficient for the treatment of uncomplicated
currently licensed in Europe. Carbapenems are active against
UTsI. It has no activity against Proteus spp. or P. aeruginosa. Low levels
Gram-positive and Gram-negative pathogens, as well as anaerobic
of resistance to nitrofurantoin among uropathogens (e.g. E. coli <2%)
pathogens. Carbapenems maintain antibacterial efficacy against the
have revived interest in this agent.
vast majority of β-lactamase-producing organisms. This stability against
In a multicentre clinical trial, single-dose fosfomycin tromethamine 3g
and its unique juxtaposition to the β-lactam carbonyl group.23 The
stability encompasses extended-spectrum β-lactamases and AmpC
serine β-lactamases is due to the trans-1-hydroxyethyl substituent
monohydrate/macrocrystal 100mg for the treatment of acute
β-lactamases; however, it does not extend to metallo-β-lactamases.
uncomplicated lower UTIs in 749 female patients.17 Bacteriological
cure rates at one week post-treatment were 87 and 81% for
The group one parenteral carbapenem ertapenem has good Gram-
fosfomycin and nitrofurantoin, respectively. The clinical success rate
negative activity, excluding against P. aeruginosa. However, it is not
(cure and improvement) was higher than 80% in both treatment
active against methicillin-resistant S. aureus (MRSA) and enterococci.
groups. Therefore, bacteriological and clinical cure rates were
The group two parenteral carbapenems imipenem and meropenem are
comparable in both treatment groups.17
active against many Gram-negative organisms, including P. aeruginosa,
as well as Gram-positive uropathogens, excluding MRSA, E. faecium
and vancomycin-resistant enterococci (VRE). Imipenem is hydrolysed by
Pivmecillinam is a unique β-lactam antimicrobial that has been used for
the renal dihydropeptidase I and is therefore combined with the specific
the treatment of acute uncomplicated UTIs for more than 20 years.
inhibitor cilastatin.
Pivmecillinam is the prodrug (ester) of mecillinam, with specific and high
activity against Gram-negative organisms such as E. coli and other
Chronic Bacterial Prostatitis
enterobacteriaceae. Mecillinam is an amidine derivative of the penicillin
Chronic bacterial proastatitis (CBP) often presents as the source of
group. Pivmecillinam is also well absorbed orally.18 The level of resistance
acute recurrent UTIs and/or recurrent acute bacterial prostatitis.
has remained low: it is estimated that fewer than 2% of E. coli
Patients presenting with prostatic complaints should have a prostatic
community isolates are resistant to mecillinam.19 A comparative study
localisation test. 24 Increased numbers of neutrophils (over 10
(pivmecillinam versus norfloxacin) has shown similar outcomes with seven
neutrophils/high-power field) in the EPS indicate prostatitis.25,26 In
days of pivmecillinam 200mg twice daily (BID) or three days of norfloxacin
patients for whom an EPS cannot be obtained, increased numbers of
400mg BID, with bacteriological outcomes pooled from two studies.20
neutrophils in the urine after prostatic massage (VB3) is an indication
of prostatitis if first voided urine (VB1) and midstream urine (VB2) do
Therapy of Complicated Urinary Tract Infections
not contain these cells. Additionally, bacterial pathogens are present in
In most studies of complicated UTIs, increasing rates of antibiotic
the EPS or VB3 in larger numbers – usually with a 10-fold higher
resistance were found with specific species such as E. coli, P. aeruginosa,
concentration than in VB1 and VB2.25,26 A simpler screening test to
4:07 pm
Page 117
Advances in Urological Infections
assess inflammation/infection is the two-glass pre- and post-massage
cases of suspected sexually transmitted pathogens, a therapeutic
test (PPMT). The PPMT has good concordance with the four-glass test
regimen that covers both of these pathogens is mandatory.
for the initial evaluation.27 The PPMT is therefore a reasonable
alternative when EPS cannot be obtained or when microbiological
Antibiotic resistance in N. gonorrhoeae has increased dramatically over
assistance is not available, because EPS – due to its usually small
the last few years. The World Health Organization (WHO) surveillance of
volume – has to be processed and plated immediately.
antibiotic resistance in N. gonorrhoeae in the Western Pacific Region,
carried out in 2005, revealed up to 100% resistance to penicillins and
Antibiotic treatment is warranted only if CBP has been detected
quinolones and up to 80% resistance to tetracyclines in some countries.28
in a suitable localisation study; the treatment period is approximately four
Penicillin- and fluoroquinolone-resistant strains have already reached
weeks. The agents of choice are the fluoroquinolones because
western countries. The Centers for Disease Control and Prevention (CDC)
of their excellent pharmacokinetic properties within the prostate.
has adapted to this resistance trend and now recommends ceftriaxone at
Prostatitis due to P. aeruginosa or enterococci often fails to respond to
a rather low single intramuscular dose of 125mg for treatment of acute
treatment. Increasing fluoroquinolone resistance among enterobacteria
urethritis and 250mg for the treatment of epididymitis as the first-line
also leads to increasing treatment failure. In the case of CBP due to
agent for the treatment of acute urethritis and epididymitis caused by N.
fluoroquinolone-resistant strains, prolonged treatment with cotrimoxazole
gonorrhoeae.29 Additional treatment of non-gonococcal agents is also
for two to three months is recommended for susceptible pathogens.
recommended; here, a tetracycline agent can be used.29
Urethritis and Epididymitis
The microbiological diagnosis of acute infectious urethritis and
Antibiotic resistance is an increasing problem in all urological
acute epididymitis must be made as specifically as possible. A
infections. Both uncomplicated and complicated, and especially
urethral Gram stain, urine culture and other studies, such as
nosocomial, uropathogens may exhibit resistance to multiple antibiotics
amplification techniques, for the identification of N. gonorrhoeae and
and pose problems for empirical therapy. In particular, N. gonorrhoeae
C. trachomatis should be obtained for all patients.
with high resistance rates against various antibiotics has been seen
much more frequently in the last few years in sexually transmitted
In both infections antimicrobial agents should be chosen for initial
diseases such as urethritis and epididymitis. In order to choose the right
empirical treatment based on the probability of the aetiological agent.
antibiotic for empirical therapy it is necessary to consider the bacterial
Acute infectious urethritis is almost always a sexually transmitted disease
spectrum and the local antibiotic susceptibility of the uropathogens. To
caused by N. gonorrhoeae and/or C. trachomatis. In acute epididymitis,
combat the development of antibiotic resistance, a basic understanding
sexually transmitted pathogens and pathogens causing complicated UTIs
of antibiotic action and resistance mechanisms is helpful. The rate of
are aetiological agents. Young sexually active men with acute
antibiotic resistance will possibly continue to increase. Strategies to
epididymitis are at risk of C. trachomatis or N. gonorrhoeae, while older
combat this trend, such as antibiotic policies, will need to be developed
men more frequently harbour pathogens seen in complicated UTIs. In
and incorporated into urological praxis. ■
Bouza E, San Juan R, Munoz P, et al., A European perspective
on nosocomial urinary tract infections I. Report on the
microbiology workload, etiology and antimicrobial susceptibility
(ESGNI-003 study). European Study Group on Nosocomial
Infections, Clin Microbiol Infect, 2001;7(10):523–31.
2. Foxman B, Epidemiology of urinary tract infections: incidence,
morbidity, and economic costs, Am J Med, 2002;113(Suppl 1A):
3. Maki DG, Tambyah PA, Engineering out the risk for infection
with urinary catheters, Emerg Infect Dis, 2001;7(2):342–7.
4. Ruden H, Gastmeier P, Daschner FD, Schumacher M,
Nosocomial and community-acquired infections in Germany.
Summary of the results of the First National Prevalence Study
(NIDEP), Infection, 1997;25(4):199–202.
5. Wagenlehner FM, Niemetz A, Dalhoff A, Naber KG, Spectrum
and antibiotic resistance of uropathogens from hospitalized
patients with urinary tract infections: 1994–2000, Int J
Antimicrob Agents, 2002;19(6):557–64.
6. Elhanan G, Sarhat M, Raz R, Empiric antibiotic treatment and
the misuse of culture results and antibiotic sensitivities in
patients with community-acquired bacteraemia due to urinary
tract infection, J Infect, 1997;35(3):283–8.
7. Schaeffer AJ, Prostatitis: US perspective, Int J Antimicrob Agents,
1999;11(3-4):205–11, discussion 213–16.
8. Gupta K, Hooton TM, Stamm WE, Increasing antimicrobial
resistance and the management of uncomplicated communityacquired urinary tract infections, Ann Intern Med, 2001;135(1):
9. Talan DA, Stamm WE, Hooton TM, et al., Comparison of
ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14
days) for acute uncomplicated pyelonephritis pyelonephritis in
women: a randomized trial, JAMA, 2000;283(12):1583–90.
10. Naber KG, Schito GC, Botto H, et al., Surveillance study in
Europe and Brazil on clinical aspects and antimicrobial resistance
epidemiology in females with cystitis (ARESC): Implications for
empiric therapy, Eur Urol, 2008; in press.
Gordon KA, Jones RN, Susceptibility patterns of orally
administered antimicrobials among urinary tract infection
pathogens from hospitalized patients in North America:
comparison report to Europe and Latin America. Results from
the SENTRY Antimicrobial Surveillance Program (2000), Diagn
Microbiol Infect Dis, 2003;45(4):295–301.
Kahlmeter G, Prevalence and antimicrobial susceptibility of
pathogens in uncomplicated cystitis in Europe. The ECO.SENS
study, Int J Antimicrob Agents, 2003;22(Suppl. 2):49–52.
McLuskey K, Cameron S, Hammerschmidt F, Hunter WN,
Structure and reactivity of hydroxypropylphosphonic acid
epoxidase in fosfomycin biosynthesis by a cation- and flavindependent mechanism, Proc Natl Acad Sci U S A, 2005;102(40):
Schito GC, Why fosfomycin trometamol as first line therapy
for uncomplicated UTI?, Int J Antimicrob Agents, 2003;22
(Suppl. 2):79–83.
Ungheri D, Albini E, Belluco G, In-vitro susceptibility of
quinolone-resistant clinical isolates of Escherichia coli to
fosfomycin trometamol, J Chemother, 2002;14(3):237–40.
Hof H, Antimicrobial therapy with nitroheterocyclic compounds,
for example, metronidazole and nitrofurantoin, Immun Infekt,
Stein GE, Comparison of single-dose fosfomycin and a 7-day
course of nitrofurantoin in female patients with uncomplicated
urinary tract infection, Clin Ther, 1999;21(11):1864–72.
Lancini G, Parenti F, Antibiotics, an integrated view, New York,
Heidelberg, Berlin: Springer-Verlag, 1982.
Graninger W, Pivmecillinam—therapy of choice for lower urinary
tract infection, Int J Antimicrob Agent, 2003;22
(Suppl. 2):73–8.
20. Nicolle LE, Pivmecillinam in the treatment of urinary tract
infections, J Antimicrob Chemother, 2000;46(Suppl. 1):35–9,
discussion 63–5.
21. Livermore DM, Woodford N, The beta-lactamase threat in
Enterobacteriaceae, Pseudomonas and Acinetobacter, Trends
Microbiol, 2006;14(9):413–20.
22. Ena J, Arjona F, Martinez-Peinado C, et al., Epidemiology of
urinary tract infections caused by extended-spectrum betalactamase-producing Escherichia coli, Urology, 2006;68(6):
23. Hammond ML, Ertapenem: a Group 1 carbapenem with distinct
antibacterial and pharmacological properties, J Antimicrob
Chemother, 2004;53(Suppl. 2):ii7–9.
24. Meares EM, Stamey TA, Bacteriologic localization patterns
in bacterial prostatitis and urethritis, Invest Urol, 1968;5(5):
25. Krieger JN, McGonagle LA, Diagnostic considerations and
interpretation of microbiological findings for evaluation of
chronic prostatitis, J Clin Microbiol, 1989;27(10):2240–44.
26. Andreu A, Stapleton AE, Fennell C, et al., Urovirulence
determinants in Escherichia coli strains causing prostatitis,
J Infect Dis, 1997;176(2):464–9.
27. Nickel JC, Shoskes D, Wang Y, et al., How does the premassage and post-massage 2-glass test compare to the MearesStamey 4-glass test in men with chronic prostatitis/chronic pelvic
pain syndrome?, J Urol, 2006;176(1):119–24.
28. Surveillance of antibiotic resistance in Neisseria gonorrhoeae in
the WHO Western Pacific Region, 2005, Commun Dis Intell,
29. Department of Health and Human Services, Centers for Disease
Control and Prevention. Available at: