[Are there alternatives to antimicrobial therapy and prophylaxis of uncomplicated urinary tract infections?]

The acute uncomplicated cystitis in women is one of the most frequently diagnosed bacterial infection. A clinically symptomatic urinary tract infection must be differentiated from the asymptomatic bacteriuria, which is not considered an infection but rather a colonization which should not be treated. For the antimicrobial therapy according to the European guidelines the old oral antibiotics (fosfomycin trometamol, nitrofurantoin, pivmecillinam) should be prescribed, against which E. coli is still susceptible in over 90%. With new therapeutic concepts not mainly the elimination of bacteria but rather the treatment of the inflammatory (over)reaction of the host is highlighted. To establish the significance of these therapeutic options as compared to the standard antibiotic therapy, the results of the ongoing and planned phase 3 studies need to be awaited. Thus reliable clinical measuring parameters for diagnostics and outcome are needed. The acute cystitis symptom score (ACSS) was developed and validated in Russian and Uzbec languages. Because of its high reliability, validity and predictive value it can be used not only in daily practice but also for clinical studies for the diagnosis of an acute uncomplicated cystitis in women.

[New aspects on diagnostics and therapy of uncomplicated cystitis]. / Neue Aspekte zur Diagnose und Therapie der unkomplizierten Zystitis.

BACKGROUND: Acute uncomplicated cystitis in women is one of the most frequently diagnosed bacterial infections. A clinically symptomatic urinary tract infection must be differentiated from asymptomatic bacteriuria, which is not considered an infection but more a colonization which as a rule should not be treated. Acute cystitis can also be caused by a low number of uropathogenic bacteria, especially Escherichia coli, which is often overlooked during routine bacteriological diagnostics. ANTIBIOTIC THERAPY: According to the guidelines the old oral antibiotics (e.g. fosfomycin tromethamine, nitrofurantoin and pivmecillinam) should be prescribed for antimicrobial therapy which are still effective against Escherichia coli in over 90% of cases. ALTERNATIVE THERAPY: With new therapeutic concepts the elimination of bacteria is no longer the main aim but treatment of the inflammatory (over) reaction of the host. To establish the significance of these therapeutic options as compared to the standard antibiotic therapy, the results of the ongoing and planned phase 3 studies need to be awaited. Thus, reliable clinical measurement parameters for diagnostics and outcome are needed. The acute cystitis symptom score (ACSS) has now also been developed and validated in the German language. Because of its high reliability, validity and predictive value it can be used not only in daily practice but also for clinical studies for the diagnosis of acute uncomplicated cystitis in women.

Prevention of recurrent urinary tract infections.

Urinary tract infections (UTI) are among the most frequent bacterial infections in the community and health care setting. Mostly young and, to some extent, postmenopausal women are affected by recurrent UTI (rUTI) defined as ≥3 UTI/year or ≥2 UTI/half year. In contrast, rUTI is rare in healthy men. On the other hand, rUTI are frequently found in female and male patients with complicating urological factors, e.g. urinary catheters, infection stones. Remediable predisposing factors in uncomplicated rUTI in women are rare. In complicated rUTI the success depends mainly on the possibility to eliminate or at leastimprove the complicating risk factors. Continuous antibiotic prophylaxis or postcoital prophylaxis, if there is close correlation with sexual intercourse, are most effective to prevent rUTI. Nitrofurantoin, trimethoprim (or cotrimoxazole), and fosfomycin trometamol are available as first-line drugs. Oral cephalosporins and quinolones should be restricted to specific indications. Antibiotic prophylaxis reduces the number of uropathogens in the gut and/or vaginal flora and reduces bacterial "fitness". Given the correct indication, the recurrence rate of rUTI can be reduced by about 90%. Due to possible adverse events and the concern of selecting resistant pathogens, according to the guidelines of the European Association of Urology antimicrobial prophylaxis should be considered only after counselling, behavioural modification and non-antimicrobial measures have been attempted. In postmenopausal patients vaginal substitution of oestriol should be started first. Oral or parenteral immunoprophylaxis is another option in patients with rUTI. Other possibilities with varying scientific evidence are prophylaxis with cranberry products, specific plant combinations or probiotics. The prophylaxis of catheter-associated UTI should employ strategies which result in a reduction of frequency and duration of catheter drainage of the urinary tract. The currently available catheter materials have only little influence on reducing catheter-associated rUTI.

Improved diagnostics of chronic inflammatory prostatitis.

AIM: Prostatitis is a prevalent condition that encompasses a large array of clinical symptoms with significant impacts on men's life. The diagnosis and treatment of this disorder presents numerous challenges for urologists, most notably, a lack of specific and effective diagnostic methods. METHODS: To improve the diagnostics the comparison of classic 4-glass test Meares and Stamey, 2-glass tests and 3-glass test was conducted in 177 men suspicious for chronic prostatitis. RESULTS: Four-glass test is uncomfortable both for patients and doctors, and leads to contamination of urine with prostatic secretion. Two-glass test is insufficiently effective too. Three-glass test (three urine specimens obtained from one continuous micturition stream) gives more adequate results and may be used for screening. CONCLUSION: Three-glass test as screening test with the option of an additional EPS investigation in those patients the final diagnosis of chronic prostatitis has to be confirmed is more convenient for patients and doctors than the standard M&S 4-glass test and "false-positive" (contaminated with EPS) midstream urine results are avoided thus improving discrimination of urethritis, cystitis and prostatitis. Therefore, we recommend the KE 3-glass test as a new standard for screening patients with signs and symptoms of chronic inflammatory prostatitis.

[Primary and secondary prevention of urinary tract infections]. / Primär- und Sekundärprävention von Harnwegsinfektionen.

Urinary tract infections (UTI) are among the most frequent bacterial infections in the community and health care setting. Mostly young and, to some extent, postmenopausal women are affected by recurrent UTI (rUTI) defined as ≥3 UTI/year. On the other hand rUTI are frequently found in patients with complicating urological factors, e.g. urinary catheters. Modifiable predisposing factors in uncomplicated rUTI in women are rare. Continuous antibiotic prophylaxis or postcoital prophylaxis, if there is close correlation with sexual intercourse, are most effective to prevent rUTI. Nitrofurantoin, trimethoprim (or cotrimoxazole), and fosfomycin trometamol are available as first-line drugs. Oral cephalosporins and quinolones should be restricted to specific indications. Antibiotic prophylaxis reduces the number of uropathogens in the gut and/or vaginal flora and reduces bacterial"fitness". Given the correct indication, the recurrence rate of rUTI can be reduced by about 90%. In postmenopausal patients vaginal substitution of oestriol should be started first. Oral or parenteral immunoprophylaxis is another option in patients with rUTI. Other possibilities with varying scientific evidence are prophylaxis with cranberries or probiotics. The prophylaxis of catheter-associated UTI or asymptomatic bacteriuria should employ strategies which result in a reduction of frequency and duration of catheter drainage of the urinary tract. The currently available catheter materials have only little influence on reducing catheter-associated rUTI.

[Uncomplicated urinary tract infection and treatment]. / Unkomplizierte Harnwegsinfektion - Leitlinienkonforme Behandlung.

Urinary tract infections (UTI) are frequent infections in the outpatient and hospital setting. With respect to treatment options, UTI can generally be stratified into uncomplicated and complicated / nosocomial infections. Uncomplicated UTI are represented by the acute uncomplicated cystitis and the uncomplicated pyelonephritis. They are mainly caused by E. coli. There are, however, also increasing resistance rates found in uncomplicated UTI, e. g., against aminopenicillins, cotrimoxazole and increasingly also fluoroquinolones. This development has called for a new evaluation of the treatment recommendations in uncomplicated UTI. As an empirical therapy for uncomplicated cystitis fosfomycin trometamol, nitrofurantoin or pivmecillinam are recommended as first-line agents. As the oral first line therapy for uncomplicated pyelonephritis fluroquinolones in high dosages are recommended. The frequent asymptomatic bacteriuria does not need to be treated, with only a few exceptions. Due to the increasing antibiotic resistance and the emergence of multiresistant uropathogens, empirical antibiotic treatment becomes more difficult. Therefore the results of susceptibility testing should be awaited whenever possible.

Do different susceptibility breakpoints affect the selection of antimicrobials for treatment of uncomplicated cystitis?

Because of increasing antibiotic resistance in Escherichia coli, the main uropathogen of uncomplicated urinary tract infections (UTIs), updated susceptibility data are vital in guiding the selection of first-line treatment agents. interpretation of these data depends on the breakpoints adopted, that may vary among different guidelines.In this study we report the minimum inhibitory concentrations (MICs) of eight antibiotics and compare antimicrobial susceptibility results obtained in 2315 E. coli strains recently collected during the ARESC survey using EUCAST and CLSI breakpoints. We have also evaluated the clinical impact of breakpoint discrepancies on the overall susceptibility patterns.Fosfomycin, nitrofurantoin and mecillinam showed the highest susceptibility rates in all countries (>92%) according to both CLSI and EUCAST criteria. Minor category shifts were observed for ciprofloxacin, amoxicillin-clavulanic acid, ampicillin and trimethoprim/sulfamethoxazole. A large number of strains classified as intermediate resistant to cefuroxime according to CLSI are included by the EUCAST in the susceptible category.In conclusion, fosfomycin, mecillinam, and nitrofurantoin have preserved their in vitro activity in all countries investigated, regardless of the criteria adopted. They continue to represent effective options for the empiric therapy of female patients with uncomplicated cystitis. The use of different interpretative criteria for E. coli responsible for UTIs therefore has no influence on the decision to be taken by the physicians managing the patients.

Chronic bacterial prostatitis (NIH type II): diagnosis, therapy and influence on the fertility status.

In only approximately 10% of men with symptoms of chronic prostatitis/chronic pelvic pain syndrome bacterial infection of the prostate can be demonstrated by the Meares and Stamey 4-glass or the pre- and post-prostate massage (PPM) two-glass test. Chronic bacterial prostatitis is mainly caused by Gram-negative uropathogens. The role of Gram-positives, atypicals and anaerobes is still debatable. For treatment, fluoroquinolones are considered the drugs of choice because of their favourable pharmacokinetic properties and their antimicrobial spectrum. As relapse and re-infection are a major problem in chronic bacterial prostatitis, only the results of studies with a follow up period of at least 6 months are meaningful. Analysing the concentrations of various fluoroquinolones in prostatic and seminal fluid as well as in prostatic tissue, it becomes, however, obvious that fluoroquinolones differ not only in plasma concentrations, but also in their penetration ability to these sites. Nevertheless, the concentrations at the site of infection of most fluoroquinolones with this indication should be sufficient for the treatment of chronic bacterial prostatitis caused by susceptible pathogens. On the other hand, male accessory gland infection has been linked to male infertility. However, there is still a lack of evidence showing that bacterial prostatitis would have a negative impact on sperm quality.

Antibiotics in urology: new essentials.

The bacterial spectrum and rates of antimicrobial resistance of uncomplicated community-acquired and complicated and nosocomially acquired urinary tract infections differ substantially. Significant variation exists from region to region and over time. On the other hand, antibiotics are widely used in urologic practice for the need of modern medicine; therefore, antibiotic substances are continuously evaluated for clinical usage. The use of antibiotics must keep up with continuous changes in antimicrobial resistance and be tailored to the needs of individual patients.

Serum and prostatic tissue concentrations of moxifloxacin in patients undergoing transurethral resection of the prostate.

The spectrum of pathogens causing chronic bacterial prostatitis comprises Gram-negative, Gram-positive and atypical microorganisms. Because of its broad spectrum of activity, the group 4 fluoroquinolone moxifloxacin might be a suitable antibiotic for treatment of bacterial prostatitis. The aim of this prospective study was to investigate the penetration of moxifloxacin into prostatic tissue in patients with benign prostatic hyperplasia. Patients received a single dose of moxifloxacin 400 mg in an 1 hour lasting infusion (250 ml) for perioperative prophylaxis before undergoing transurethral resection of the prostate (TURP). Serum concentrations were determined in all patients before infusion, at the end of infusion (time point 0), 0.5, 1 and 2 h after the end of infusion. Patients were randomized for tissue sampling either 0, 0.5, 1 or 2 h after the end of infusion. At beginning of TURP approximately 1 g of tissue was sampled for analysis. Concentrations of moxifloxacin in serum and tissue were determined by HPLC. 39 patients were evaluated. Median serum and prostatic tissue concentrations peaked at 0 h (4.94 mg/ L and 8.50 mg/ kg, respectively). The lowest concentrations were quantified at 2 h after the end of infusion (2.46 mg/ L and 3.88 mg/ kg, respectively). The prostatic tissue concentrations of moxifloxacin were approximately twice as high as in corresponding serum. At the end of infusion the tissue and serum concentrations seemed to be already equilibrated, as their ratios did not differ significantly during the time of investigation. After an intravenous infusion of 400 mg the serum and prostatic tissue concentrations of moxifloxacin were well above the MIC values of most important prostatic pathogens. The high tissue/ serum ratio and the extended antibacterial spectrum suggests active concentration in the prostate which may translate into increased efficacy compared to group 2 and 3 fluoroquinolones in the treatment of chronic bacterial prostatitis.

New drugs for Gram-positive uropathogens.

Complicated urinary tract infections (UTIs) are frequent nosocomial infections. The bacterial spectrum encompasses Gram-negative but also Gram-positive pathogens in up to 30-40%. The existing treatment for Gram-positive pathogens is not always optimal. Antimicrobials for the treatment of Gram-positive uropathogens comprise older agents, such as aminopenicillins with or without beta-lactamase inhibitors and vancomycin, as well as newer fluoroquinolones, such as levofloxacin or gatifloxacin. However, resistant bacteria such as vancomycin-resistant enterococci (VRE) or methicillin-resistant Staphylococcus aureus (MRSA) (except vancomycin-resistant) are generally also not susceptible to the fluoroquinolones. Therefore new agents need to be assessed in the treatment of UTI. Daptomycin and linezolid are new antimicrobial agents with good efficacy against Gram-positive uropathogens as shown by their minimal inhibitory concentrations. In a phase II study the urinary bactericidal activity of linezolid versus ciprofloxacin in volunteers showed comparable activity of both drugs against fluoroquinolone susceptible Gram-positive uropathogens, whereas linezolid was also as active against fluoroquinolone resistant ones. The pharmacokinetics and the mode of action of these two antibiotics are discussed together with some clinical data in the context of therapeutic use in patients with complicated UTIs.

Gatifloxacin 400 mg as a single shot or 200 mg once daily for 3 days is as effective as ciprofloxacin 250 mg twice daily for the treatment of patients with uncomplicated urinary tract infections.

The efficacy and safety of two oral dosing regimens of gatifloxacin compared with ciprofloxacin for the treatment of acute uncomplicated lower urinary tract infection was investigated in a double-blind, randomised study, in adult female patients who received either gatifloxacin (400 mg as a single shot or 3 days of 200 mg once daily) or ciprofloxacin (250 mg given twice daily for 3 days). Bacteriological and clinical responses were assessed 7-9 days after the end of treatment (EOT), and 4-6 weeks post-treatment (end of study, EOS). One thousand one hundred and two women were treated, 741 (248 in the gatifloxacin 400 mg group, 252 in the gatifloxacin 200 mg group, and 241 in the ciprofloxacin group) presented with bacteriological proof of infection and entered the efficacy analysis. The bacteriological response per patient at EOT in the three groups were 80% (177/220) [95% CI to ciprofloxacin -8.4%; 6.4%], 83% (184/222) [95% CI to ciprofloxacin -5.9%; 8.7%] and 81% (176/216), respectively. At the follow-up assessment they were slightly lower, 75% (167/224), 79% (169/213) and 79% (171/217), respectively. The clinical responses at EOT were 81% (197/243) [95% CI to ciprofloxacin -10.2%; 3.4%], 85% (213/250) [95% CI to ciprofloxacin -5.7%; 7.2%] and 85% (201/238), respectively. At EOS they were 82% (195/239), 88% (212/241) and 86% (200/233), respectively. The eradication rates for all initial pathogens at the EOT were 90.3% in the gatifloxacin 400 mg S.D. group, 90.6% in the gatifloxacin 200 mg group, and 88.3% in the ciprofloxacin group. All treatment groups showed a similar safety profile. The incidence of treatment-related adverse events was comparable, the majority of adverse events were of mild or moderate intensity and the medications were well tolerated. Both the administration of gatifloxacin 200 mg once daily for 3 days, and gatifloxacin 400 mg as a single shot were shown to be equivalent to ciprofloxacin 250 mg twice daily for 3 days for the treatment of acute uncomplicated lower urinary tract infections.

Rapid resolution of symptoms with ciprofloxacin therapy in 3859 hospitalised patients with urinary tract infection.

This post-marketing surveillance study including 3859 hospitalised patients with urinary tract infection (UTI) was conducted to evaluate the efficacy and tolerability of treatment with intravenous or orally administered ciprofloxacin. The most frequent initial doses of ciprofloxacin were a total daily dose of 400 mg intravenously and 500 mg orally. After 4 days of therapy, 75.6% of patients were asymptomatic and, 92.0% after 7 days. 93.9% of patients were rated as having improved or have been cured at the end of the observation period. Improvement and cure were independent of the severity of infection. The tolerability of the treatment was rated by physicians as good or very good for 96.9% of patients. Adverse events were reported in 3.5% of patients.

Gatifloxacin 200 mg or 400 mg once daily is as effective as ciprofloxacin 500 mg twice daily for the treatment of patients with acute pyelonephritis or complicated urinary tract infections.

The efficacy and safety of two oral dosing regimens of gatifloxacin were compared to ciprofloxacin in the treatment of complicated urinary tract infection in a randomised, double-blind multi-centre trial. One thousand one hundred and twenty-three adult patients with complicated urinary tract infection (70%) or pyelonephritis (30%) were initially enrolled, 1122 were treated. Of these, 824 were included in a modified ITT population: gatifloxacin 200 mg (274 patients) or 400 mg (280 patients) once daily or ciprofloxacin 500 mg twice daily for 5-14 days (269 patients). Bacteriological and clinical responses were assessed 7-9 days after the end of treatment (EOT) and 4-6 weeks post-treatment (end of study visit, EOS). The bacteriological response rates per patient at EOT in the gatifloxacin 400 mg, gatifloxacin 200 mg and ciprofloxacin groups were 77% (207/269), 78% (208/268) and 73% (190/259), respectively. At EOS they were slightly lower: 70% (184/262), 71% (176/248) and 69% (174/252), respectively. The clinical responses at EOT were 69% (190/277), 70% (190/273) and 65% (174/266). At EOS they were 71% (193/273), 70% (182/259) and 74% (190/258). The overall eradication rates of initial pathogens at EOT and EOS were 85.3% and 88.4% in the gatifloxacin 400 mg group; 84.1 and 90.1% in the gatifloxacin 200 mg group and 85.1 and 91.4% in the ciprofloxacin group. Both oral regimens of gatifloxacin were as effective as that of ciprofloxacin. All treatment groups showed a similar safety profile, nausea being the most frequently reported adverse event.

[Recurrent urinary tract infections should not be treated cavalierly. First verify the diagnosis!]. / Rezidivierende Harnwegsinfektionen nicht auf Verdacht behandeln. Sichern Sie erst die Diagnose!

Acute uncomplicated cystitis (AUC) and acute uncomplicated pyelonephritis (AUP) are two common urinary tract infections (UTI) in otherwise healthy young women. Both weaknesses of the mucosal barrier and specific factors of uropathogenic bacteria must be present before the bacteria can adhere to the urothelium and give rise to an infection. These circumstances are also of relevance in recurrent UTI. Antibiotic treatment of AUC and AUP is based on the guidelines of the Infectious Diseases Society of America (IDSA). For the prevention of recurrent UTI, antibiotics, functional foods, injections, probiotic agents and other measures are recommended with varying potential for success.

Spectrum and antibiotic resistance of uropathogens from hospitalized patients with urinary tract infections: 1994-2000.

During the period 1994-2000 all uropathogens cultured from urine of hospitalized urological patients were identified and susceptibility was tested against 11 antibacterials. Duplicated isolates were eliminated. There was no general trend of increased of resistance apart from E. coli to ciprofloxacin (10.4% in 2000). Vancomycin-resistant staphylococci or enterococci was not significant. The lowest overall rates of resistance were found with piperacillin/tazobactam followed by ciprofloxacin and trimethoprim/sulphamethoxazole. Ciprofloxacin was the best oral antibiotic for the empirical treatment of urinary tract infection (UTI) due to Gram-negative rods and ampicillin/sulbactam for the treatment of UTI with Gram-positive cocci.

Which fluoroquinolones are suitable for the treatment of urinary tract infections?

A number of fluoroquinolone agents are now available for clinical use and even more under development. Whether these compounds are equally effective and thus interchangeable in the treatment of urinary tract infection (UTI) has to be answered by comparing their antimicrobial activity against uropathogens, the pharmacokinetic and pharmacodynamic parameters and outcome of statistically meaningful clinical studies. Whereas almost all fluoroquinolones give equivalent results with short term therapy of acute uncomplicated cystitis in women, for patients with complicated UTI, only those compounds at the appropriate dosage regimen should be chosen for empiric therapy, which would exhibit sufficiently high urinary bactericidal activity against Gram-negative as well as Gram-positive uropathogens. When considering antibacterial activity, pharmacokinetic and pharmacodynamic properties as well as the results of the published clinical studies, a dosage of 500 mg ciprofloxacin twice daily, 500 mg levofloxacin once daily, or 400 mg gatifloxacin once daily may be comparable dosage regimens in the treatment of severe complicated UTI. In the case of ciprofloxacin (750 mg twice daily) and levofloxacin (500 mg twice daily), the dose could even be increased in UTI caused by less susceptible uropathogens, such as Pseudomonas aeruginosa.