Uncomplicated Lower Urinary Tract Infections Research Articles

Betalactamasas de espectro extendido en las infecciones del tracto urinario causadas por enterobacterias: aproximación a su conocimiento y pautas de actuación

ContextBeta-lactamases are bacterial enzymes that protect microorganisms from the lethal effects of β-lactam antibiotics. The production of beta-lactamases is the most important mechanism of resistance to these antibiotics, especially in Gram-negative bacteria. ObjectiveReview the magnitude of the problem of extended-spectrum beta-lactamases (ESBL) in the urological setting and present the fundamental action guidelines on the issue, the main risk factors and the prevention strategies. Acquisition of evidenceA structured search strategy for patient, problem, intervention, comparison and result was conducted in the PubMed-Medline database to identify the most relevant studies related to the management of patients with urinary tract infection by ESBL-producing microorganisms. We also present a caseload analysis of our center on this issue. Summary of the evidenceESBL are found in Enterobacteria, mainly Klebsiella sp. and Escherichia coli and are characterized by their hydrolytic ability compared with beta-lactam antibiotics, which entails resistance to penicillin, cephalosporin and aztreonam. They are also associated with resistance to other antibiotics. There is a high risk of infection and colonization by ESBL producers in patients with prolonged hospital stays or who required invasive devices. The prior use of antibiotics and stays in residential care are also risk factors. Prevention programs should focus on preventing nosocomial infection. It is essential that a restrictive policy on the use of antibiotics be implemented. The therapy of choice for severe infections is focused on carbapenems, although their indiscriminate use should be avoided. In uncomplicated lower urinary tract infections, fosfomycin and nitrofurantoin are the best treatment alternatives. ConclusionESBL-producing strains constitute a true global health problem. Prevention strategies should focus on nosocomial infection. We should not forget, however, that the appearance of these pathogens in community-acquired infections is increasingly frequent. Therapeutic decisions should be based on an understanding of the local distribution of microorganisms and their resistance patterns.

Fosfomycin Trometamol: A Review of Its Use as a Single-Dose Oral Treatment for Patients with Acute Lower Urinary Tract Infections and Pregnant Women with Asymptomatic Bacteriuria

Fosfomycin trometamol (fosfomycin tromethamine) [Monuril(®), Monurol(®), Monural(®)] is approved in numerous countries worldwide, mainly for the treatment of uncomplicated urinary tract infections (UTIs). Fosfomycin has good in vitro activity against common uropathogens, such as Escherichia coli (including extended-spectrum β-lactamase-producing E. coli), Proteus mirabilis, Klebsiella pneumoniae and Staphylococcus saprophyticus, and the susceptibility of uropathogens to fosfomycin has remained relatively stable over time. A single oral dose of fosfomycin trometamol 3g (the approved dosage) achieves high concentrations in urine. Results of recent randomized trials indicate that single-dose fosfomycin trometamol had similar clinical and/or bacteriological efficacy to 3- to 7-day regimens of ciprofloxacin, norfloxacin, cotrimoxazole or nitrofurantoin in women with uncomplicated lower UTIs. In addition, single-dose fosfomycin trometamol had similar bacteriological efficacy to a 5-day course of cefuroxime axetil or a 7-day course of amoxicillin/clavulanic acid in pregnant women with asymptomatic bacteriuria, and similar clinical and/or bacteriological efficacy to a 5-day course of cefuroxime axetil or amoxicillin/clavulanic acid or a 3-day course of ceftibuten in pregnant women with a lower UTI. Single-dose fosfomycin trometamol was generally well tolerated, with gastrointestinal adverse events (e.g. diarrhoea, nausea) reported most commonly. In conclusion, single-dose fosfomycin trometamol is an important option for the first-line empirical treatment of uncomplicated lower UTIs.

Non-antibiotic herbal therapy of uncomplicated lower urinary tract infection in women - a pilot study

Non-antibiotic herbal therapy of uncomplicated lower urinary tract infection in women - a pilot study

Trimethoprim and a case of lower urinary tract infection

This article discusses the use of trimethoprim in the treatment of uncomplicated lower urinary tract infections (LUTI) in adult women. It takes the form of a case study and will explore the pharmacological dynamics of the drug, as well as comparing it to others also used in the treatment of LUTI. Trimethoprim is considered the gold standard for treatment and the three-day course has become the usual recommended treatment for non-complex LUTIs and for empirical treatment of cystitis with a 90% eradication rate (Salvatore et al, 2001; Scottish Intercolleguiate Guidance Network, 2006). This article describes the presenting symptoms, possible differentials, treatment, and rationale for the treatment chosen.

Mecillinam resistance and outcome of pivmecillinam treatment in uncomplicated lower urinary tract infection in women.

Pivmecillinam (PIV) is a first-line antimicrobial for treatment of lower urinary tract infection in women (LUTIW). Mecillinam, the active substance of PIV, is bactericidal mainly against gram-negative uropathogens, whereas gram-positive species are considered intrinsically resistant. However, successful treatment of LUTIW caused by Staphylococcus saprophyticus has been reported, but more rarely for other gram-positive species. The aim of this study was to compare clinical and bacteriological outcome of PIV vs placebo treatment among uropathogens with special focus on mecillinam-resistant isolates. We analysed data from a prospective, multicentre, placebo-controlled, primary health care, therapy study performed in Sweden in 1995–1998 that included 1143 women with symptoms suggestive of LUTIW. Urine cultures were collected and symptoms registered at inclusion and at follow-up visits. Overall, the efficacy of PIV was superior to that of placebo. Clinical and bacteriological outcomes of PIV treatment were similar for S. saprophyticus, Escherichia coli as for most other uropathogens irrespective of their susceptibility to mecillinam. However, the occurrence of enterococci increased nearly fivefold shortly post PIV treatment, although with mild symptoms and a high spontaneous eradication. As susceptibility to mecillinam in vitro did not predict bacteriological and clinical outcome of PIV treatment, we suggest that the present breakpoints for mecillinam should be revised.

Randomized comparative study for the assessment of a new therapeutic schedule of fosfomycin trometamol in postmenopausal women with uncomplicated lower urinary tract infection

ObjectivesTo compare two therapeutic regimes in terms of bacterial eradication of post-menopausal with uncomplicated acute cystitis who complete antibiotic treatment. Materials and methodsA multicenter, randomized, prospective and controlled study between two short antibiotic regimes: fosfomycin trometamol (FMT) 3g, 2 doses separated by 72h and ciprofloxacin 250mg every 12h for 3 days. A total of 118 post-menopausal women were enrolled in the study. They underwent an initial urine culture to know the responsible microorganism and susceptibility to treatment. This was repeated 5–7 days and 4 weeks after the treatment to evaluate bacterial eradication. Clinical symptoms and treatment safety were also evaluated. ResultsThere were microbiological data at the onset of the treatment in 82 women (69.49%). Of these, 27 did not have positive culture at the first visit (30.51%), 76 (64.41%) fulfilled all the protocol requirements and adverse effects from the treatment were collected in 113 (95.76%) of the patients enrolled in the study. The germs isolated most frequently were Escherichia coli (E. coli) (76.83%), Klebsiella pneumoniae (K. pneumoniae) (7.32%), Proteus mirabilis (P. mirabilis) (4.89%) and Enterococo sp. (3.66%). In terms of efficacy, no differences were detected in the proportion of patients who achieved bacterial eradication between the two study arms: 62.16% of the patients who received FMT and 58.97% of those treated with ciprofloxacin (Chi-square, p=0.78). The proportion of patients who achieved clinical cure was also similar (86.49% for FMT and 82.05% for ciprofloxacin; square, p=0.59). These results indicate similar efficacy of both antibiotics in the treatment of uncomplicated lower tract urinary infection in post-menopausal women. In regards to safety data, the proportion of global adverse effects associated to the treatments was 3.45% for FMT and 9.09% for ciprofloxacin. Treatment compliance was 100% for FMT and 83.64% for ciprofloxacin. ConclusionsThe FMT administered at a dose of 3g every 72h (2 total doses) and ciprofloxacin at a dose of 250mg every 12h during 3 days (6 total doses) have a comparable efficacy profile in lower tract urinary infection in post-menopausal women who adequately comply with the treatment, also having comparable safety. The FMT has a better antimicrobial susceptibility profile and better rate of treatment compliance.

Upoštevanje Smernic Za Zdravljenje Nezapletene Okužbe Spodnjih Sečil V Dežurni Ambulanti Osnovnega Zdravstva / Adherence to Guidelines for the Treatment of Uncomplicated Lower Urinary Tract Infections in the Primary Care Emergency Department

Background: Doctors working in emergency departments on the primary care level often face patients with signs of uncomplicated lower urinary tract infections. The aim of this study was to determine the adherence to guidelines in the management of such patients in emergency units.Methods: This was a prospective study that took place from February 1st to July 30th 2011. The emergency departments of all primary health centres in Slovenia (N = 60) were invited. Invitation was accepted by 14 (23.3%) of them. In the sample, 10 consecutive women (including home visits and telephone consultations) in every emergency department were included. A total of 139 patients (23.2%) participated in the study. We collected data with a questionnaire, which was filled in by the doctor on duty for each patient individually.Results: The final sample included 117 women (84.2%), aged 20-64 years. Physicians in the emergency department prescribed therapy according to the guidelines for the treatment of an uncomplicated urinary tract infection in one quarter of the patients. The first choice antibiotic was prescribed to most patients, however the duration of treatment exceeded the recommendation. No clear pattern of factors that influenced physicians’ decision to treat patients according to the guidelines was detected.

Can we improve adherence to guidelines for the treatment of lower urinary tract infection? A simple, multifaceted intervention in out-of-hours services

To improve antimicrobial prescribing behaviour of general practitioners in large-scale out-of-hours services for uncomplicated lower urinary tract infection (LUTI) in females aged 20-80 years, which is regarded as one of the most prevalent bacterial infections in primary care. A quasi-experimental design was used in two regional large-scale out-of-hours services. A simple, multifaceted intervention was offered in a 16 week period in one region (the intervention region). During the two washout periods, at 5 and 17 months, we observed diagnoses and prescriptions. The main outcome measure was the share of appropriate and inappropriate prescriptions. The proportion of patients with LUTI ranged from 1.0% to 2.1%. The relative proportion of appropriate prescriptions in the intervention region increased from 26.9% to 69.4%, but decreased afterwards to 40.8%. A simple, multifaceted intervention for treatment of LUTI during out-of-hours care may improve the quality of antimicrobial prescribing, although the improvement may not be sustained in the longer term.

Antimicrobial agents for treating uncomplicated urinary tract infection in women

Acute uncomplicated lower urinary tract infection (UTI) is one of the most common problems for which young women seek medical attention. To compare the efficacy, resistance development and safety of different antimicrobial treatments for acute uncomplicated lower UTI. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Renal Group's Specialised Register, MEDLINE, EMBASE and bibliographies of included studies. Randomised controlled trials (RCTs) comparing different classes of antimicrobials for acute uncomplicated UTI in women were included. The outcomes of interest were symptomatic and bacteriological cure at short and long-term follow-up, resistance development, number of days to symptom resolution, days of work loss, adverse events and complications. Two authors independently extracted the data and assessed study quality. Statistical analyses were performed using the random effects model and the results expressed as risk ratios (RR) with 95% confidence intervals (CI). Trimethoprim-sulfamethoxazole (TMP-SMX) was as effective as fluoroquinolones in achieving short-term (RR 1.00, 95% CI 0.97 to 1.03) and long-term (RR 0.99, 95% CI 0.94 to 1.05) symptomatic cure. Beta-lactam drugs were as effective as TMP-SMX for short-term (RR 0.95' 95% CI 0.81 to 1.12) and long-term (RR 1.06' 95% CI 0.93 to 1.21) symptomatic cure. Short-term cure for nitrofurantoin was similar to that of TMP-SMX (RR 0.99' 95% CI 0.95 to 1.04) as was long-term symptomatic cure (RR 1.01' 95% CI 0.94 to 1.09).Fluoroquinolones were more effective than beta-lactams (RR 1.22, 95% CI 1.13 to 1.31) for short-term bacteriological cure. Rashes were more frequent in patients treated with TMP-SMX than with nitrofurantoin or fluoroquinolones and in patients treated with beta-lactam drugs compared to fluoroquinolones. Minimal data were available on the emergence of resistant strains during or after antimicrobial treatment. No differences were observed between the classes of antimicrobials included in this review for the symptomatic cure of acute uncomplicated UTI. Fluoroquinolones proved more effective than beta-lactams for the short-term bacteriological outcome, probably with little clinical significance. Individualised treatment should take into consideration the predictable susceptibility of urinary pathogens in local areas, possible adverse events and resistance development, and patient preference.

Etiología y sensibilidad de los uropatógenos identificados en infecciones urinarias bajas no complicadas de la mujer (Estudio ARESC): implicaciones en la terapia empírica

Background and objective To determine the etiology and susceptibility of uropathogens identified in women with uncomplicated lower urinary tract infections (UTI). Patients and methods In a multicenter study (ARESC) in 9 Spanish hospitals, 803 female patients with uncomplicated cystitis were consecutively enrolled and evaluated to identify the uropathogens and their susceptibility to 9 antimicrobials. Results Of 803 patients with uncomplicated cystitis, 784 patients were included. A positive urine culture was found in 87.7% of the samples. Of the 650 pathogens isolated, Escherichia coli (E. coli) was the most frequent (79.2%) followed by Staphylococcus saprophyticus (4.4%), Proteus mirabilis (4.3%), Enterococcus faecalis (3.2%) and Klebsiella pneumoniae (2.3%). E. coli showed a high rate of susceptibility to phosphomycin (97.2%), nitrofurantoin (94.1%) and somewhat lower to ciprofloxacin (88.1%). Fluorquinolone resistance rates were higher among postmenopausal women (17 versus 10%). E. coli was highly resistant to ampicillin (65%) and cotrimoxazole (34%) and 25% of the strains were resistant to amoxicillin/clavulanalic acid and cefuroxime. Conclusions In Spain, E. coli shows high resistance rates to widely used antimicrobial antibiotics. Phosphomycin and nitrofurantoin have a high in vitro activity. Taking into account practical aspects such as convenience (only one dose), and the influence of the amount of fluorquinolone use on enterobacteriaceae and other microorganisms resistance levels, phosphomycin trometamol represents the option of first choice for the empirical treatment of uncomplicated cystitis in women.

A randomized comparative study of single-dose fosfomycin and 5-day ciprofloxacin in female patients with uncomplicated lower urinary tract infections

Uncomplicated lower urinary tract infections (UTIs) are the most frequent infections in females. Increased resistance rates against commonly used antibiotics have led to the use of novel antimicrobials. The aim of the present study was to evaluate the bacteriological and clinical effects of single-dose fosfomycin trometamol (FMT) and 5-day ciprofloxacin in females with uncomplicated UTIs. In this randomized comparative study, 260 female patients between 18 and 65years of age enrolled, of whom 142 completed the study. The most frequently isolated bacterial pathogen in the urine cultures of patients were Escherichia coli (82.3%) and Enterobacter spp. (8.4%). FMT sensitivity was 94% and ciprofloxacin sensitivity was 59% in Escherichia coli; in comparison, FMT sensitivity was 75% and ciprofloxacin sensitivity was 50% in Enterobacter spp. The MIC90 for FMT was 4μg/ml. Of the 142 patients, 77 were treated with FMT and 65 were treated with ciprofloxacin. The clinical remission rate was 83% in the FMT group and 81% in the ciprofloxacin group; the bacterial eradication rate was 83% in the FMT group and 78% in the ciprofloxacin group, and there was no significant difference between the two study groups. In conclusion, a single dose of FMT (at 3g) was as effective as ciprofloxacin, at 500mg twice a day for 5days, in the treatment of uncomplicated lower UTIs. It was concluded that the use of FMT as a first-line treatment in the empirical treatment of uncomplicated UTIs might have a positive impact on the problem of resistance to other antibiotics.

Macrodantin in the treatment of urinary tract infections

Nitrofurantoin is a long-established and proven antibacterial agent used for the treatment and prophylaxis of uncomplicated lower urinary tract infections caused by the most common uropathogens. Macrodantin is a macrocrystalline formulation of nitrofurantoin. The macrocrystalline formulation retards the absorption of the drug from the alimentary tract. Studies (e.g. Kalowski et al, 1974) have shown that it has the same high cure rates and low resistance profile as generic nitrofurantoin but with the additional benefits of reduced gastrointestinal side-effects and potential increased patient compliance.

Persistent Extended-Spectrum β-Lactamase Urinary Tract Infection

To the Editor: Uncomplicated urinary tract infections (UTIs) in otherwise healthy adults are usually treated empirically because the causative microbe is highly predictable: 80%–90% are caused by Escherichia coli. In addition, short courses of therapy (1 day or 3 days) are usually completed before laboratory results become available. In the past decade, reports of community-acquired, extended-spectrum β-lactamase (ESBL)–producing E. coli isolates have increased worldwide, but they are still uncommon in the United States (1), where reported cases are generally associated with hospitals. An early report of true community-acquired ESBL-producing E. coli infections in the United States was published in 2007 (2). We report a case of community-acquired lower UTI caused by ESBL-producing and multidrug resistant E. coli in an otherwise healthy college-aged woman who had no hospital exposure. Despite proper treatment, her infection persisted subclinically and symptoms recurred 2 months later.

Recurrent Urinary Tract Infection (UTI) in Women

Abstract Recurrent lower urinary tract infections (UTIs) are usually defined as two or more episodes of such infection occurring in the preceding 12 months. In most cases, such infections are the result of sexual habits and hygiene (e.g., women who are sexually active, especially those using diaphragms and/or spermatocides). A clean-catch or catheterized specimen for culture typically reveals greater than 100,000 organisms per milliliter of urine. The typical infecting organism is Escherichia coli. The route of infection is ascending from the perianal area and vagina via the urethra and into the bladder. However, in uncomplicated lower UTIs, there is complete clearing of bacteriuria and hematuria with appropriate antimicrobial therapy. In some cases, single-dose antimicrobial therapy after intercourse or at the onset of irritative voiding symptoms is adequate to control frequent recurrences of cystitis. Uncomplicated recurrent lower UTIs in women must be differentiated from “reinfection,” which may indicate causes such as a vesicovaginal or vesicoenteric fistula or a paravesical abscess with fistula to the bladder. Furthermore, “bacterial persistence” is defined as an infection with the same organism, typically from a site within the urinary tract, after the bacteriuria has resolved for at least several days and antimicrobial therapy has ceased. Causes of bacterial persistence include calculi, foreign bodies, urethral or bladder diverticula, infected urachal cyst, and postoperative changes such as a remaining ureteral stump that retains urine and results in stasis. In such patients with frequent recurrences and reinfections with the same bacteria, imaging is indicated to detect a treatable condition and monitor its progress. Compromised immunity needs attention to avoid longstanding morbidity. Vaccine developed will lead more prevention in future.

Managing lower UTI in adults in the community

Urinary tract infections (UTI) are more common in women than in men. They are one of the most common bacterial infections managed by general practitioners and within the community. About 50% of women will be treated for a symptomatic UTI in their lifetime. The judicial use of antibiotics in the treatment of UTIs is important to prevent resistance to commonly used antibiotics. Patient education regarding the proper use of antibiotics and preventative measures is important in preventing recurrent and resistant infections. This article will discuss the diagnosis, treatment and education of women with acute, uncomplicated lower UTI.

Cystites aiguës

The management of uncomplicated lower urinary tract infections (UTI) implicate to look for risk factors and complications. Bacterial or radiological exams are not recommanded and short course of antibiotic is effective for treating uncomplicated UTI. Complicated UTI needs clinical, bacteriological and radiological exams, longer treatments are recommanded. Recurrent UTI definition is precised in these guidelines.

Nitrofurantoin Neuropathy

Nitrofurantoin is a widely prescribed antibiotic used to treat uncomplicated lower urinary tract infections. Unknown in the obstetric and gynecologic literature is the complication of peripheral neuropathy as an adverse effect. We describe a patient who developed a severe sensory neuropathy after taking nitrofurantoin intermittently and then continuously over a 7-year period. She recovered almost completely after its discontinuation. Peripheral neuropathy is a rare and potentially reversible adverse effect, unreported in the obstetric and gynecologic literature, and commonly unrecognized by physicians who prescribe it.

Clinical and bacteriological outcome of different doses and duration of pivmecillinam compared with placebo therapy of uncomplicated lower urinary tract infection in women: The LUTIW project

Objective. To analyse associations between symptoms and bacteriuria in uncomplicated lower urinary tract infection in women (LUTIW) and to evaluate outcome of therapy with three different regimens of pivmecillinam or placebo. Design. Prospective, multicentre, randomized, double-blind, and placebo-controlled therapy study. Symptoms registered at inclusion, during therapy and at follow-up visits after 8–10 and 35–49 days. Significant bacteriuria defined according to current European guidelines. Setting. A total of 18 primary healthcare centres in northern Sweden. Subjects. Women aged 18 years and above with symptoms of urgency, dysuria, supra pubic or loin pain. Main outcome measures. Symptoms and bacteriuria at inclusion and course of symptoms, bacteriuria, and their combinations during and post-therapy. Results. At inclusion, no associations or significant differences were found between symptom scores and bacteriuria, bacterial counts, or species. The 884 patients (77%) with significant bacteriuria were followed up. All pivmecillinam therapies were superior to placebo (p < 0.001). From day six until first follow-up, the mean values of all symptoms were higher and the bacteriological cure was lower at first follow-up in the three days (84%) compared with the seven days regimens (93–94%, p < 0.001). At final follow-up clinical cure was similar in all pivmecillinam regimens (65–72%) as was bacteriological cure (83–89%). Pivmecillinam had few low to mild adverse reactions, comparable to placebo. Conclusions. Symptoms are not conclusive for diagnosis of LUTIW. Pivmecillinam therapies are superior to placebo and seven days regimens are more efficient than three days. Pivmecillinam 200 mg×2×7 days is recommended as a first-line therapy for LUTIW.

Fosfomicina trometamol. Dosis múltiples como pauta larga en el tratamiento de las infecciones urinarias bajas

A short antibiotic regimen is recommended for the treatment of uncomplicated lower urinary tract infection. Nevertheless, the treatment to follow in other situations is not so clearly defined. When the person affected by lower urinary tract infection is not a young woman, it is recommended to treat at least 7 days, and quinolones or cotrimoxazole are the antibiotics most often used. However, because of the frequency of drug resistance in this type if infection, it is advisable to apply antibiotics with lower rates of resistance, such as fosfomycin trometamol, for longer treatment periods than the often-used single dose. Using the data on urinary elimination of fosfomycin after a single dose obtained in a prior study in healthy volunteers, we simulated the urinary concentrations of this antibiotic following administration of two doses. In addition, we calculated the interval of administration required to achieve urinary concentrations greater than 16 mg/L, the critical concentration of sensitivity for Escherichia coli, one of the most commonly implicated microorganisms in these infections. Fosfomycin concentrations in urine persisted above the defined cut-off for 161 hours after administration of two 3-g doses of fosfomycin trometamol, 72 hours apart. This implied an efficacy time of 66% in a period of 7 days. From the pharmacokinetic viewpoint, the optimum dosage of fosfomycin trometamol to achieve appropriate urinary concentrations along 7 days is administration of two 3-g doses, 72 hours apart.

Antibiothérapie des infections urinaires basses: bases cliniques, microbiologiques et pharmacologiques

While uncomplicated lower urinary tract infection (UTI) in young women is a common and very frequent disorder, change and progress in the infection’s management, choice of antimicrobial agents and whether or not it is necessary to perform urine cultures and antibiotic susceptibility testing, are not precluded. Among the factors supporting use of urine cultures, the increasing emergence of antibiotic-resistant bacteria may theoretically pose an argument for use of this test. And yet, epidemiological studies on urinary tract infections have investigated the predominant uropathogens and their antibiotic sensitivity: the results for several years of data show the stable incidence of Escherichia coli, Proteus mirabilis, Klebsiella spp or Staphylococcus saprophyticus; the investigations’ results also demonstrate low resistance rates to the most frequently used antimicrobial agents, with the exception of beta-lactams, represented mainly by aminopenicillins. The availability of several new classes of antibiotics and the development of antibiomicrobial agents specific to urinary infections are factors allowing empirical treatment of uncomplicated lower UTIs. In this case, the use of urine culture to diagnose urinary tract infections is called into question, the clinical presentation and use of urine dip-sticks being adequate. Finally, the change in therapeutic strategy towards shorter treatment regimens with an optimum 3-day course of therapy, is manifested by treatment with fluoroquinolones, which are broad-spectrum antimicrobial agents that are mainly excreted in the urine. This latter pharmacokinetic parameter makes it possible to ensure bacterial eradication when high doses (cause of poor safety profile) of the selected compound are not necessary, when this compound is weakly bound to plasma proteins, undergoes little metabolism and maintains high urinary concentrations of the product in unchanged form that persist after the end of treatment.