Mini-Reviews in Medicinal Chemistry, 2008, 8, 000-000 1 1389-5575/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Current Anti-Infective Treatment of Bacterial Urinary Tract Infections Florian M.E. Wagenlehner 1,* , Christine Wagenlehner 3 , Kurt G. Naber 2 and W. Weidner 1 1 Department of Urology, Justus-Liebig-University, Giessen, Germany; 2 Technical University, Munich, Germany; 3 Department of Anesthesia, Evangelisches Krankenhaus, Giessen, Germany Abstract: Antibiotic resistance nowadays plays an important role in the treatment of uncomplicated and complicated uri- nary tract infections (UTIs). In uncomplicated UTI efforts are made to use antibiotic substances exclusively for this indi- cation. In complicated UTI substances with activity against bacteria harbouring common resistance mechanisms are inves- tigated. Additionally pharmacokinetic/ pharmacodynamic parameters are used to improve dosing strategies. Key Words: Urinary tract infections, uncomplicated UTI, complicated UTI, antibiotic resistance, pharmacokinetics, pharma- codynamics. 1. INTRODUCTION Urinary tract infections (UTIs) are among the most prevalent microbial diseases, and their financial burden on society is substantial. UTIs account for more than 100,000 hospital admissions annually, most often for pyelonephritis [1, 2], and they also account for at least 40% of all hospital- acquired infections which are in the majority of cases cathe- ter-associated [3-5]. 2. UNCOMPLICATED, COMMUNITY ACQUIRED UTI In uncomplicated UTI E. coli is the most common patho- gen, typically being isolated from over 80% of outpatients with acute uncomplicated cystitis across the various regions of the world [2, 6-8]. In clinical practice urine culture is usu- ally not performed in the setting of community acquired, uncomplicated cystitis. Antibiotic therapy therefore is mostly empiric and more or less based upon knowledge of national or international surveillance studies. The local resistance level of E. coli therefore determines the empiric antibiotic treatment. The range of pathogens associated with acute un- complicated pyelonephritis is similar to that seen in acute uncomplicated cystitis [9]. In a surveillance study of urinary E. coli isolates from outpatient women in the United States, collected during the year 2000, the rates of ampicillin and TMP/SMX susceptibil- ity (60% and 76%, respectively) were far lower than the in- cidence of susceptibility to ciprofloxacin (96%) [10, 11]. Similar findings were reported in the analysis of 16,745 E. coli isolates from female outpatients with UTI collected in the Pacific region of the United States in 2001 (ampicillin resistance: 38%; TMP/SMX resistance: 20%; ciprofloxacin resistance: 2%) [10, 11]. The ARESC Project, an international surveillance study involving 9 countries in Europe and Brasil, has monitored the antimicrobial susceptibility of uropathogens in the years *Address correspondence to this author at the Department of Urology, Justus-Liebig-University of Giessen, Rudolf-Buchheim-Str. 7, D-35385 Giessen, Germany; Tel: 49-641-99-44501; Fax: 49-641-99-44509; E-mail: Wagenlehner@AOL.com 2004 to 2006. The aim of the study was to rank the present usefulness of drugs employed in the therapy of this condition [12]. 1669 uropathogens including 1198 E. coli (71.8%; range 59-81% in the different Countries), 196 other Gram- negatives (11.7%) and 275 Gram-positives (16.5%) were collected. Resistance in E. coli was most common towards ampicillin (mean 59.2%; range 26-76%), cefuroxime (28%; 14-43%) and co-trimoxazole (26%; 14-38%). Ciprofloxacin resistance was 8% but the figures for Spain and Italy were substantially higher (14% and 20%). Fosfomycin, mecilli- nam and nitrofurantoin were the most active agents (98.8%, 94.9% and 94.4% of susceptible E. coli). The results of these studies show that antibiotic sub- stances classically used for the treatment of uncomplicated UTI, such as cotrimoxazole, fluoroquinolones or aminopeni- cillines, loose their effectiveness due to increasing resistance. Ideal substances are those with low resistance rates, exclu- sively used for this indication, such as fosfomycin trometh- amine, nitrofurantoin or pivmecillinam (Table 1). i. Fosfomycin Fosfomycin tromethamine is the oral applicable salt of fosfomycin. Fosfomycin (cis-(1R,2S)-epoxypropylphosphonic acid) is an oxirane antibiotic unrelated to other substances [13] and is produced as a secondary metabolite by Strepto- myces and Pseudomonas spp. (S)-2-Hydroxypropylphos- phonic acid epoxidase catalyzes the epoxide ring closure of (S)-2-Hydroxypropylphosphonic acid to form fosfomcyin in an iron-redox mechanism [14]. Interestingly hydroxypropyl- phosphonic acid epoxidase represents a new subfamily of non-haem mononuclear iron enzymes that respond to its sub- strates with a conformational change that protects the radi- cal-based intermediates formed during catalysis [15]. Fosfo- mycin is active against Gram-positive and Gram-negative bacteria, but shows decreased activity against M. morganii, P. vulgaris, P. aeruginosa and E. faecium. Despite many years of usage, fosfomycin continues to be characterized by a low incidence of E. coli resistant strains (1% to 3%) world- wide [16]. Fosfomycin trometamol has retained its activity against quinolone-resistant strains of E. coli and cross- resistance with other classes of antimicrobial agents is pres- ently not a problem [17]. It is less active against coagulase-