Treatment of Bacterial Urinary Tract Infections: Presence and Future

european urology 49 (2006) 235–244

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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 resistance 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 responsible 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 concentrations 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 insufficiency, 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 because of the lack of comparator for the treatment of UTI. 238 european urology 49 (2006) 235–244

The main drawback of current antibiotic therapies 2.1.3. Probiotics is the emergence and rapid increase of antibiotic The use of probiotics entails prophylaxis and resistance [10]. Since antibiotics have been intro- treatment of UTI and is mainly concentrated on duced into clinical medicine, antibiotic resistant Lactobacilli. Conflicting results have been observed bacteria have evolved [11]. Antibiotic resistance in clinical trials and animal studies mostly because mechanisms have recently been alluded to in the unspecific strains of Lactobacilli have been used. European Urology Update Series 2, 2004, page 125–135 Positive results have only been obtained using well [10]. The overall cause of increasing antibiotic characterized strains [17]. Application for prophy- resistance is selective pressure by antimicrobial laxis can be intravaginal or oral. For treatment substances in various environmental settings caus- probiotics were mainly installed into the bladder. ing antibiotic resistant bacterial clones, followed by Clinical studies using vaginally administered the distribution of such clones facilitated by modern Lactobacillus rhamnosis GR1 in combination with medico-social circumstances [10]. The development either L. reuteri B 54 or RC 14 resulted in reduced of new antimicrobial substances in the past has UTI recurrences. In one study of 52 women, UTI counterbalanced this trend. However we are cur- recurrences were reduced from an average of 6 per rently approaching a resistance level that might pose year to 1.6 with once weekly vaginal suppositories of a risk to loose effectiveness of antibiotic treatment in GR-1/B-54 [18]. the future. The epidemiology of antibiotic resistant A clinical randomized, placebo controlled study bacteria varies with type of infection, with medical of 64 women using daily oral intake of L. rhamnosus speciality, with region, and with time. GR-1 and L. reuteri RC-14 led to a significant reduction in uropathogens and yeast in the vagina [19]. It can 2.1.2. Vaccines possibly be concluded from such findings that UTI There are two different agents for immunisation might also be preventable by oral intake of specific 1 1 currently availabale. Uro-vaxom and Strovac . lactobacilli. Both preparations are recommended for patients Few studies have shown positive results in the with recurrent uncomplicated UTIs. treatment of UTI by probiotics. One such animal 1 Uro-vaxom is an orally administered bacterial study showed that after therapeutic application of extract consisting of immunostimulating compo- Lactobacillus murinus bladder counts of treated mice nents derived fom 18 uropathogenic E. coli strains were significantly lower although no significant [12]. A metaanalysis on five placebo controlled, differences were detected in P. mirabilis kidney double-blind studies comprising 601 women colonisation of treated and non-treated animals [20]. resulted in a pooled odds ratio of 2.28. UTIs per year were reduced from 1 to a rate of 0.15–0.82 [13]. In a multicenter, double-blind study 453 female 3. Future strategies in the treatment of 1 patients were enrolled and Uro-vaxom resulted in bacterial UTI a 34% reduction of UTIs in patients compared to placebo [14]. Therefore the oral immunotherapy The current research goals comprise the following with Uro-vaxom is effective in the prevention of targets: recurrent UTI. Nevertheless a metaanalysis showed that if antibiotic prophylaxis was compared with - known substances are improved in terms of higher placebo the reduction of recurrent UTIs was 81% bioavailability, longer half life, better PK/PD with antibiotics compared to placebo [15]. Unfortu- performance, other formulations (i.e. extended/ 1 nately there are no data comparing Uro-vaxom gastric release formulation; liposomal formula- with antibiotics in the prevention of recurrent UTI. tion). 1 Strovac is a whole cell bacterial extract derived - known substances are evaluated for other indica- from uropathogenic E. coli strains, P. mirabilis, M. tions (i.e. UTI). morganii, K. pneumoniae and E. faecalis. The prepara- - new derivatives of known substance classes are tion is administered intramuscularly also for pre- developed in order to enlarge the bacterial vention of recurrent UTI. In an prospective, spectrum, improve bioavailability, improve anti- comparing study 41 patients with recurrent uncom- microbial action (i.e. younger generation sub- plicated UTI were evaluated. The rate of reinfections stances). within 6 months was 41% in patients treated with - new substance classes which should have new 1 SulcoUrovac versus 96% in patients receiving molecular targets are developed. placebo [16]. Follow-up studies, however should be - new strategies to improve susceptibility of bac- carried out. teria are developed (i.e. efflux-pump inhibitors). european urology 49 (2006) 235–244 239

- new strategies to slow down the emergence of 3.3. Emerging vaccines antimicrobial resistance are developed. - alternative antimicrobial substances are under Vaccination theoretically is the best strategy to discovery (e.g. bacteriophages, bacteriophage prevent bacterial infections. There are however some enzymes). pitfalls in the vaccination against UTIs: Complicated - new compounds for vaccination in uncompli- UTIs show a highly heterogenous bacterial spectrum. cated, and possibly as well as in complicated In uncomplicated UTIs E. coli is the predominant UTI are developed. pathogen. However infections and recurrent infections are usually caused by a variety of E. coli strains. Bacteria exhibit an enormous repertoire of dif- All uropathogenic E. coli as a common feature ferent resistance mechanisms. Unspecific mechan- have a FimH-chaperone-adhesin on the tip of their isms such as reduced permeability or efflux alter the type 1 fimbriae. A FimH adhesion-based vaccine, tolerance to antibiotic substances less than specific which showed promising results in animal and in mechanisms, such as inactivation of the antibiotic vitro studies [24,25], so far could not enter larger for example. However the antibiotic spectrum tar- vaccination trials in humans. geted is much more extensive. On the other hand A somewhat different approach is made by using unspecific mechanisms can also be induced by non a vaginal vaccine containing 10 heat killed uro- antibiotic substances such as salicylates. Low-level pathogenic bacteria. A placebo-controlled phase II resistance can thus be confered and give bacteria a clinical trial was performed in 54 women. Women selection-advantage [10]. receiving immunisation experienced an infection in What parameters should be assessed for new 45%, whereas the placebo treated women experi- drugs to become included in the treatment of UTI? enced an infection in 89% [26]. Based on this result Although there are no exact quantitative prereque- vaginal mucosal vaccine seem to be effective. sites, the following qualities should be considered: P. mirabilis is a difficult to treat pathogen causing complicated UTIs especially in patients with per- - coverage of the respective bacterial spectrum manent catheters or stents. The urease produced by (uncomplicated versus complicated UTIs) this organism leads to stone formation and catheter - antimicrobial activity in urine in an acidic as well blockage. The primary surface antigen is the MR/P as alkaline environment fimbria is a good candidate for vaccination. In vitro - sufficient urinary excretion of the drug studies with a MrpH vaccine showed promising results [27]. 3.1. Emerging chemotherapeutics

Emerging compounds are discussed in Table 2 4. Prevention of emergence of antibiotic regarding the following parameters: Substance, class, resistance mode of action, bacterial spectrum, pharmacokinetics with emphasis on urinary excretion, opinion The most important draw-back in the treatment of about success. The target and mechanism of actions UTIs is the development of antimicrobial resistance. of future chemotherapeutic drugs are shown in Fig. 1. The prevention of emergence of resistance in human medicine entails several strategies: 3.2. Emerging novel strategies - decrease of antibiotic consumption Bacteriophage lytic enzymes are highly evolved - antibiotic cycling molecules produced by bacterial viruses to digest - new dosing strategies for antibiotics the bacterial cell wall for bacteriophage progeny - combination of two classes of antibiotics release [21]. These enzymes have been used success- fully in animal models to treat bacterial infections in All strategies not specifically designed for anti- blood and mucosal surfaces. Phages or their enzymes microbial therapy of UTI may have to be adjusted are very specific for the pathogen without disturbing accordingly. the normal flora. These novel antimicrobial strategies have shown very interesting in vitro results [22,23]. 4.1. Decrease of antibiotic consumption The further development might be promising, because this strategy involves highly conserved To lower antibiotic consumption in UTI three evolutionary mechanisms that have proven to be strategies are developed and are evidence based efficacious in nature over millions of years. by several good clinical studies: (i) asymptomatic 240 european urology 49 (2006) 235–244

Table 2 – Emerging compounds are discussed regarding substance-name, antibiotic class and characteristics (mode of action, bacterial spectrum, pharmacokinetics with emphasis on urinary excretion, opinion about success)

Antibiotic substance Antibiotic class Characteristics

Daptomycin (intravenous) Lipopetide-antibiotic Exerts its antibacterial activity by disrupting multiple aspects of the bacterial membrane function. Speciﬁc activity against Gram-positive pathogens including MRSA and VRE, not active against Gram-negative bacteria. Urinary excretion is 78%. Clinically relevant toxicities are limited to skeletal muscle effects, at higher dose levels, peripheral nerve effects. The high urinary excretion promises activity in UTI, however the large molecule might hinder distribution into urinary tract tissues. The speciﬁc Gram-positive activity restricts the substance to treatment of a relative small proportion of UTIs [32–37].

Tigecycline (intravenous) Glycylcyline Exerts its antibacterial activity by inhibiting protein synthesis. Good activity against Gram-positive pathogens including MRSA and VRE, and against E. coli, Klebsiella spp., Enterobacter spp. and C. freundii, including ESBL producing organisms. Less active against P. aeruginosa, Proteus spp., M. morganii and S. marcsecens because of efflux-mechanisms. Urinary excretion is approximately 14%. Side effects observed in general were mild. The substance covers an interesting bacterial spectrum for the treatment of UTI, although difficult to treat organisms, such a P. aeruginosa or Proteus spp. are more resistant because of efflux pump activity. The relatively low urinary excretion might be a potential drawback in the treatment of UTI [38].

Cefozopran (intravenous) Cephalosporin Strong activity against P. aeruginosa. Because of the speciﬁc activity against P. aeruginosa this compound is of potential interest for the treatment of complicated UTI [39].

Ceftobiprole (intravenous) Cephalosporin Anti-MRSA cephalosporin. Against Gram-negative bacteria comparable activity to group 3 and 4 cephalosporins. The spectrum of activity towards P. aeruginosa resembles that of ceftazidime. Limited activity against putative ESBL poducers but good activity against putative high-level AmpC producers. Urinary excretion is about 90%. Because of the wide range of activity against most uropathogens and the high urinary excretion, the substance is of potential interest in the treatment of UTI [40].

Doripenem (intravenous) Carbapenem Exerts activity against Gram-positive bacteria except MRSA and enterococci and Gram-negative bacteria including imipenem resistant P. aeruginosa. Urinary excretion is 75%. Doripenem is highly excreted in urine and shows excellent activity against P. aeruginosa. Therefore it is of potential interest for treatment of complicated UTI [41].

Not indicated b-lactamase inhibitors Novel b-lactamase inhibitors are under development for the potential treatment of UTI. Because of the increasing prevalence of ESBL-producing enterobacteria in UTIs, novel b-lactamase inhibitors might be promising.

Ciprofloxacin XR Fluoroquinolone Exerts identical antibacterial activity as ciprofloxacin targeting (extended release) (oral) predominantly Gram-negative pathogens with good activity against P. aeruginosa. Urinary excretion is 40%. Ciprofloxacin XR is a once daily formulation, overall comparable to twice daily ciprofloxacin [42–44].

Balofloxacin (oral) Fluoroquinolone Exerts good antibacterial activity against Gram-positive pathogens, but in comparison to other fluoroquinolones decreased activity against Gram-negative pathogens. Urinary excretion is 86%. Balofloxacin is in the treatment of UTI probably not superior to other fluoroquinolones [45]. european urology 49 (2006) 235–244 241

Table 2 (Continued ) Antibiotic substance Antibiotic class Characteristics

Garenoxacin Des-F(6)-quinolone Exerts good antibacterial activity against Gram positive pathogens. (oral and intravenous) Activity against Gram-negative pathogens is comparable to fluoroquinolones, such as ciprofloxacin or levofloxacin, activity against P. aeruginosa is poor. It seems that garenoxacin exerts also activity against fluoroquinolone resistant strains. The ability to induce resistance in vitro is apparently less than with fluoroquinolones such as levofloxacin. Urinary excretion is 30 to 40%. In view of the increasing quinolone resistance, substances of this class with decreased cross resistance and less susceptibility to resistance emergence are needed. Des-F(6)-quinolone derivatives like garenoxacin are promising substances for the treatment of UTI [46]. Not indicated Dihydrofolate Novel dihydrofolate reductase inhibitors are under discovery. The novel reductase inhibitors compounds are more active against Gram-positive pathogens. Because of the long lasting activity of trimethoprim, novel dihydrofolate reductase inhibitors are generally of interest in the treatment of UTI.

Not indicated MurA inhibitors Exert activity against Gram-positive and Gram-negative organisms to a variable degree. They target the bacterial enzyme MurA and thus inhibit cell wall synthesis. In view of the increasing antimicrobial resistance novel acting antibiotics are of interest for all kinds of bacterial infections [47]. Not indicated Bacterial efflux Exert activity in combination with other antimicrobials against bacterial pump inhibitors species that overexpress efflux pumps, such as P. aeruginosa. Efflux pump inhibitor agents have provided proof-of-principle of potentiation of other animicrobials both in vitro and in vivo. The initial practical application of improving activity against P. aeruginosa confirms that existing antibiotics can be potentiated by inhibition of efflux pumps, and suggests that efflux pump inhibitors may be a possible future treatment option that would address an unmet medical need. In addition efflux pumps contribute to a large extent to the emergence of resistance against different antibiotic classes. Efflux pump inhibitors can narrow the mutant selection window and thus slow down emergence of antibiotic resistance [48]. Not indicated Siderophore-b-lactam Novel strategy for the potential treatment of Gram-negative bacterial conjugates infections, including P. aeruginosa. Siderophore substances are covalently bound to aminopenicillins. Because of the bacterial spectrum covered, siderophore-b-lactam conjugation is a novel strategy of interest for the treatment of UTIs [49]. bacteriuria must not be treated in general (there are concentrations that require bacterial cells to obtain some exceptions), (ii) short-term therapy of uncom- two concurrent resistance mutations for growth. plicated UTI by suitable antimicrobial agents, and iii) That concentration has been called mutant preven- low dose prophylaxis in uncomplicated recurrent tion concentration (MPC) because no resistant bac- UTI, respectively development of effective vaccines. terial colony is recovered even when high numbers of bacterial cells are plated. Resistant mutants are 4.2. Antibiotic cycling selected exclusively within a vulnerable concentration range (mutant selection window) that extends For antibiotic cycling there are practically no reliable from the point where growth inhibition begins, studies available concerning treatment of UTI. There approximately by the minimal inhibitory concentra- is, however, a more or less general agreement that the tion, up to the mutant prevention concentration [28]. overuse of one group of antibiotics selecting for If the antibiotic dose given is high enough also to kill similar resistance genes should be avoided especially the mutant population, the selection of clinically in a hospital of institutional setting. Therefore good resistant mutants could be restricted [29]. A further guidelines recommend in general alternative sub- idea in this respect is to narrow the mutant selection stances as well, to allow antibiotic cycling. window by developing appropriate substances, for example those which lower the MPC, or those 4.3. Antibiotic dosing that lower these concentrations of other drugs (e.g. efflux pump inhibitors). Therefore drugs with the The key idea of the third strategy, however yet most favourable pharmacokinetic/pharmacody- clinically untested, is based on the use of antibiotic namic characteristics should be used as first-line 242 european urology 49 (2006) 235–244 agents in order to preserve the potential of a specific - The low dose antibiotic prophylaxis in recurrent drug class and, most importantly, to provide the UTIs is effective, however the emergence of patient with an optimally effective regimen. On the antibiotic resistant pathogens might be under- other hand the dosing of an antibiotic should be estimated, although the idea of antibiotic prophy- aimed high enough to reach the MPC. laxis is to use low dosages that do not fall within the mutant selection window and thus theoreti- 4.4. Combination of two classes of antibiotics cally should not cause emergence of resistance. - Vaccination will be an important issue in the For some organisms or in some infections it is future. The most experience has been made with difficult to find antibiotics that can be dosed high vaccines in recurrent uncomplicated cystitis, enough to prevent emergence of antibiotic resis- because a single species E. coli causes more than tance. A typical example is antibiotic treatment of M. 90% of episodes. Desirable would be more tuberculosis where combination therapy with two or attempts for vaccination in complicated UTIs, more antibiotic substances of different classes is especially with difficult to treat organisms like P. recommended. In order to become resistant against aeruginosa. two antibiotic substances, two concurrent mutations are required for bacterial growth, which has a The ongoing process in the treatment of infec- very low probability to occur [28]. Clinical studies in tious diseases is highly dynamic. The substantial UTIs however are very scarce. In one study combi- difference to non-infectious diseases is that the nation therapy with a macrolide and ciprofloxacin management of an infection in a single patient al- showed higher efficacy in eliminating uropathogens lways has an effect on the environment. Consider- than the single therapy with ciprofloxacin [30]. The ing this, the management of infectious diseases success of the macrolide in this study however was must be highly responsible. more attributed to the specific biofilm inhibiting effect of the macrolide [30]. References

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