Wagerlehner.qxp 13/10/08 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 © TOUCH BRIEFINGS 2008 115 Wagerlehner.qxp 13/10/08 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 Fosfomycin 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, Carbapenems 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 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 Nitrofurantoin interferes with carbohydrate metabolism. Its 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 was stability encompasses extended-spectrum β-lactamases and AmpC serine β-lactamases is due to the trans-1-hydroxyethyl substituent compared with a seven-day course of nitrofurantoin 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 Pivmecillinam 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 116 EUROPEAN UROLOGICAL REVIEW Wagerlehner.qxp 8/10/08 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 Conclusion 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. ■ 1. 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. 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