european urology 49 (2006) 235–244 available at www.sciencedirect.com journal homepage: www.europeanurology.com Review - Infections Treatment of Bacterial Urinary Tract Infections: Presence and Future Florian M.E. Wagenlehner *, Kurt G. Naber Urologic Clinic, Hospital St. Elisabeth, Straubing, Germany Article info Abstract Article history: Bacterial urinary tract infections (UTIs) are frequent infections in the Accepted December 12, 2005 outpatient as well as in the nosocomial setting. The stratification into Published online ahead of uncomplicated and complicated UTIs has proven to be clinically useful. print on January 4, 2006 Bacterial virulence factors on the one side and the integrity of the host defense mechanisms on the other side determine the course of the Keywords: infection. In uncomplicated UTIs Escherichia coli is the leading organism, Urinary tract infections (UTI) whereas in complicated UTIs the bacterial spectrum is much broader Uncomplicated and including Gram-negative and Gram-positive and often multiresistant complicated UTI organisms. The therapy of uncomplicated UTIs is almost exclusively Antibiotic resistance of antibacterial, whereas in complicated UTIs the complicating factors uropathogens have to be treated as well. There are two predominant aims in the Antibiotic treatment antimicrobial treatment of both uncomplicated and complicated UTIs: New antiinfectives for (i) rapid and effective response to therapy and prevention of recurrence treatment of UTI of the individual patient treated; (ii) prevention of emergence of resis- tance to antimicrobial chemotherapy in the microbial environment. The main drawback of current antibiotic therapies is the emergence and rapid increase of antibiotic resistance. To combat this development several strategies can be followed. Decrease the amount of antibiotics administered, optimal dosing, prevention of infection and development of new antibiotic substances. The aim of this review is to highlight the current and to describe future treatment options for UTIs. # 2005 Elsevier B.V. All rights reserved. * Corresponding author. Urologic Clinic, Hospital St. Elisabeth, St. Elisabeth Str. 23, D-94315 Straubing, Germany. Tel. +49 9421 710 6702; Fax: +49 9421 710 1717. E-mail address: [email protected] (Florian M.E. Wagenlehner). 1. Background In the United States of America, UTIs are respon- sible for over 7 million physician visits annually, Urinary tract infections (UTIs) are among the most including more than 2 million visits for cystitis [1,2]. prevalent microbial diseases, and their financial Approximately 15% of all community-prescribed burden on society is substantial. antibiotics in the United States are dispensed for 0302-2838/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2005.12.017 236 european urology 49 (2006) 235–244 UTI, at an estimated annual cost of over $1 billion [3]. (ii) prevention of emergence of resistance to che- Furthermore, the direct and indirect costs associated motherapy in the microbial environment or at with community-acquired UTIs in the United States least prevention of further increase of resis- alone exceed an estimated $1.6 billion [2]. tance. UTIs account for more than 100,000 hospital admissions annually, most often for pyelonephritis 2.1. Current treatment and prophylaxis of UTI [1,2], and they also account for at least 40% of all hospital-acquired infections and are in the majority Two major strategies currently exist in the pharma- of cases catheter-associated [4–6]. Nosocomial bac- cological treatment and prophylaxis of UTIs: teriuria develops in up to 25% of patients requiring a urinary catheter for 7 days, with a daily risk of 5% (i) Antimicrobial chemotherapy and [6]. It has been estimated that an episode of (ii) Vaccines. nosocomial bacteriuria adds $500 to $1,000 [7,8] to the direct cost of acute-care hospitalization. In 2.1.1. Chemotherapy addition the pathogens are fully exposed to the The currently recommended chemotherapeutic nosocomial environment, including selective pres- classes and dosages of antiinfectives for the treat- sure by antibiotic or antiseptic substances. There- ment of bacterial UTI are listed in Table 1. The target fore nosocomial UTIs comprise perhaps the largest and mechanism of actions of chemotherapeutic institutional reservoir of nosocomial antibiotic- drugs is shown in Fig. 1. resistant pathogens [6]. Antimicrobial susceptibility levels are often Whereas community acquired UTIs are often gauged relative to what antibiotic concentration is uncomplicated, almost all nosocomial UTIs are achievable in the blood. However tissue levels in complicated infections. Complicated UTI is a very renal parenchyma, the deeper layer of the urinary heterogenous entity, with a common pattern of the bladder wall or in the prostate may be more relevant following complicating factors: in the treatment of UTI. Because these concentra- tions are difficult to assess in humans, urinary - anatomical, structural or functional alterations of concentrations or antimicrobial activity levels in the the urinary tract (e.g. stents, urine transport urine are frequently consulted to evaluate the disturbances, instrumentation of the urinary tract, activity of an antibiotic substance in the treatment stones, tumors, neurological disorders) of UTI [9]. The urinary excretion and the determina- - impaired renal function, by parenchymal dis- tion of the activity of a substance in urine is eases, or pre,-intra,-or post renal nephropathies therefore important to assess if a substance is (e.g. acute, chronic renal insufficiencies, heart suitable for treatment of UTI. The urinary excretion insufficiency) of fluoroquinolones for example differs widely - accompanying diseases, that impair the patients between substances. A high urinary excretion immune status (e.g. diabetes mellitus, liver insuf- ficiency, immunosuppression, cancer, AIDS, hypothermia). For antimicrobial chemotherapy the bacterial s- pectrum, it’s antimicrobial resistance patterns and the development of both over the time is critical for an effective chemotherapy. The prevalence of uropathogens is different comparing uncomplicated and complicated UTI. 2. Aims in the treatment of UTI There are two predominant aims in the treatment of both uncomplicated and complicated UTIs: Fig. 1 – Target and mechanism of actions of current and (i) rapid and effective response to therapy and future antibacterial substances [modified after [50]. DHFA – prevention of recurrence in the individual dihydrofolic acid; THFA – tetrahydrofolic acid; PABA – patient treated. para-amino-benzoic acid. european urology 49 (2006) 235–244 237 Table 1 – Groups and dosages of current chemotherapeutics for the treatment of UTI in adults Antibiotic groups Antimicrobial substance Daily dosage oral i.v./i.m. b-lactams Mecillinam Pivmecillinam 2 Â 200*–400* mg – Aminopenicillin + BLI Ampicillin/Sulbactam 2 Â 750 mg 3 Â 0.75–3 g Amoxicillin/Clavulanic acid 3 Â 625–1000 mg 3 Â 1.2–2.2 g Acylureidopenicillin + BLI Piperacillin/Tazobactam – 3 Â 2.5–4.5 g Cephalosporin Gr. 1 Cephalexin for prophylaxis only – Cephalosporin Gr. 2 Cefuroxime axetil 2 Â 250*–500 mg – Cefuroxime – 3 Â 0.75–1.5 g Cefotiam – 2–3 Â 1–2 g Cephalosporin Gr. 3 Cefpodoxim proxetile 2 Â 200 mg – Cefixime 1 Â 400 mg – Ceftibuten 1 Â 200*–400 mg – Cephalosporin Gr. 3a Cefotaxime – 2–3 Â 1–2 g Cetriaxone – 1 Â 1–2 g Cephalosporin Gr. 3b Ceftazidime – 2–3 Â 1–2 g Cephalosporin Gr. 4 Cefepime – 2 Â 2g Carbapenem Gr. 1 Ertapenem – 1 Â 1g Carbapenem Gr. 2 Imipenem – 3–4 Â 0.5–1 g Meropenem – 3 Â 0.5–1 g Fluoroquinolones Fluoroquinolone Gr. 1 Norfloxacin 2 Â 400* mg – Fluoroquinolone Gr. 2 Ciprofloxacin 2 Â 500–750 mg 2–3 Â 400 mg Fluoroquinolone Gr. 3 Levofloxacin 1–2 Â 500 mg 1–2 Â 500 mg Fluoroquinolone Gr. 4 Gatifloxacin 1 Â 400 mg 1 Â 400 mg Pyrimethamines Trimethoprim 2 Â 200 mg Trimethoprim + Sulfamethoxazole 2 Â 160 mg + 2 Â 800 mg Fosfomycines Fosfomycine Fosfomycin-trometamol 1 Â 3* g Nitrofuranes Nitrofurane Nitrofurantoin 3 Â 100* mg Aminoglycosides Aminoglycoside Gentamicin – 1 Â 5–7 mg/BW Tobramycin – 1 Â 5–7 mg/BW Amikacin – 1 Â 15 mg/BW Oxazolidinones Oxazolidinone Linezolid 2 Â 600 mg 2 Â 600 mg Glycopeptides Glycopeptide Vancomycin – 2 Â 1000 mg Teicoplanin – 1 Â 400 mg BLI – beta-lactamase inhibitor; Gr. – group according to PEG [31]; BW – body weight (kg); *recommended for uncomplicated UTI. (75%) can be observed with gatifloxacin (80%), substances at these days. The newer fluoroquinolone levofloxacin (84%), lomefloxacin (75%) and ofloxacin substances gemifloxacin and moxifloxacin both have (81%). An intermediate excretion rate (40–74%) is seen passed phase III UTI studies with the comparator with ciprofloxacin (43%), enoxacin (53%), fleroxacin agents ciprofloxacin, ofloxacin or levofloxacin with (67%), and a low excretion rate (<40%) is seen with generally unsatisfying results (data on file Bayer gemifloxacin (28%), moxifloxacin (20%), norfloxacin Healthcare, SmithKline Beecham). As a result of these (20%), pefloxacin (14%) and sparfloxacin (10%) [9]. studies the indication for the treatment of UTI in both Whereas most of the drugs with high or intermediate substances was not achieved up to date. Therefore excretion achieved the clinical indication for the both pharmacokinetic parameters, serum concen- treatment of UTI, of the drugs with low excretion only tration and urinary excretion are currently used to the older substance norfloxacin achieved this indica- evaluate if an antibiotic substance might be suitable tion, possibly