Question

What is the optimal treatment duration of antimicrobial treatment of pyelonephritis, febrile urinary tract infection or urosepsis?

Recommendation

Women with acute uncomplicated pyelonephritis should be treated for 7 days when treated with ciprofloxacin.

 

Women with acute uncomplicated pyelonephritis should be treated for 10-14 days when treated with TMP-SMX or a beta-lactam.

 

Women with acute complicated pyelonephritis or other complicated UTIs should be treated for 10-14 days.

 

Men with complicated UTIs should be treated for 14 days.

Introduction

This guideline does not include individual introductions to each module. A general introduction can be found in the attachments under the heading 'related'.

Conclusions

 

Level 3 

A 5-day course of therapy with levofloxacin, administered at a dose of 750 mg once daily, is noninferior to a 10-day course of therapy with ciprofloxacin for the treatment of acute pyelonephritis or complicated UTI in women [(19) A2; (20) A2].

 

 

Level 2

Levofloxacin 250 mg once daily for 7-10 days, ciprofloxacin 500 mg twice daily for 10 days and lomefloxacin 400 mg once daily for 14 days result in similar clinical and bacteriological cure rates of 93-94% [(21) B].

Ciprofloxacin 7 and 14 days in women with acute uncomplicated and complicated (n=4) pyelonephritis showed similar cure rates [(18) A2].

 

 

Level 2 

A 7-day ciprofloxacin regimen is associated with greater bacteriologic and clinical cure rates than a 14-day TMP-SMX regimen in the treatment of acute uncomplicated pyelonephritis in women, especially in patients infected with TMP-SMX resistant strains [(17) /id} A2] and in young women (aged ≤ 20 years) [(22) B].

 

Level 3 

An increased chance of treatment failure is present in non-pregnant women when the treatment lasts less than 10 days, independent of the drug administered [(22) B].

 

Level 2 

No difference was found in clinical or microbiological cure rate in men with community-acquired febrile UTI after treatment of ciprofloxacin 500 mg twice daily for 2 or 4 weeks [(23) B].

 

 

 

Level 2

The bacteriological cure rate was significantly higher in adult men and women with febrile UTI who were treated with a 14-day course norfloxacin 400 mg twice daily compared to cefadroxil 1g twice daily [(24) B].

After initial intravenous treatment with cefuroxime, the clinical and bacteriological cure rates were higher in patients with a febrile UTI treated with norfloxacin (2 x 400 mg) (42% men) compared to treatment with ceftibuten 2x 200 mg for 10 days [(25) B].

Literature summary

Optimal treatment duration in women

Traditionally, the standard antimicrobial treatment duration of acute pyelonephritis in women was 6 weeks until 1987 when Stamm et al. showed that a 2-week regimen is equally effective (15). Since then, based on additional trials, current guidelines advocate a standard duration of about 2 weeks, whereas in special groups this can be limited to 5-7 days when using oral fluoroquinolones (3). These trials have already been reviewed (3), (16) and will be briefly discussed.

Talan et al. clearly demonstrated that a 7-day course of ciprofloxacin is sufficient in young, healthy women with acute pyelonephritis (17). This double-blind, multicenter randomized controlled trial (RCT) compared a 7-day regimen of oral ciprofloxacin 500 mg twice daily (n=128 included in the analysis) with a 14-day regimen of TMP-SMX 160/800mg twice daily (n=127 included in the analysis)for treatment of otherwise healthy women with mild to moderate pyelonephritis. Ciprofloxacin therapy had significantly higher microbiological (99% vs. 89%, respectively) and clinical (96% vs. 83%, respectively) cure rates (95% CI for difference, 0.04-0.16; P=0.004) compared to the TMP-SMX regimen, but this was mainly explained by differences in baseline resistance. Bacteremia (all E. coli) was present in 5.5% of the patients. The median age in this study was 24 (range 18-58) years and all patients had uncomplicated acute pyelonephritis.

The results of another trial showed similar efficacy between 7 and 14 days ciprofloxacin in women with acute uncomplicated and complicated (diabetes and/or known structural or functional abnormalities of the urinary tract) pyelonephritis. However, only 4 women with a complicated pyelonephritis were included. Among 156 women [median age 43 (range 18-89) years], 27% with bacteremia] cure rates for the 7-day regimen (n=73) and for the 14-day regimen (n=83) were 97.3% and 96.4%, respectively (18).

Additional evidence for a one-week regimen of fluoroquinolones as an effective and safe treatment for healthy young women was provided by another study (19), (20). These articles describe one double-blind, randomized multicenter trial, which included both men and women with complicated UTI (without fever) and acute pyelonephritis (mean age 39 years). A total of 1109 subjects (39% men, 61% women) were enrolled; 619 with confirmed diagnosis of acute pyelonephritis or complicated UTI. Subjects received either levofloxacin 750 mg intravenously or orally once daily for 5 days or ciprofloxacin 400 mg intravenously and/or ciprofloxacin 500 mg orally twice daily for 10 days. At end of therapy, eradication rates in the modified intent-to-treat population were 79.8% for levofloxacin and 77.5% for ciprofloxacin-treated subjects (95% CI, -8.8% to 4.1%). In the microbiologically evaluable population, eradication rates were 88.3% for levofloxacin and 86.7% for ciprofloxacin-treated subjects (95% CI, -7.4% to 4.2%). However, it is not possible to draw conclusions about men from this study, because most men did have a UTI without fever. Subgroup analysis of predominantly women with acute pyelonephritis (19) lend additional support that an oral 5-day regimen of once-daily levofloxacin 750 mg or a 10-day regimen of ciprofloxacin twice daily is effective for mild to moderate pyelonephritis, even in those with bacteremia or complicating factors like obstruction or the presence of a urinary catheter.

The finding that a one-week regimen of fluoroquinolones is both efficacious and safe for treatment of mild to moderate acute pyelonephritis was further supported by a randomized controlled open label study (majority of patients were female) demonstrating similar outcomes (clinical and bacteriological cure rate of 93-94%) when comparing levofloxacin 250 mg once daily for 7-10 days (n=89), ciprofloxacin 500 mg twice daily for 10 days (n=58) and lomefloxacin 400 mg once daily for 14 days (n=39). The mean age in this study was 41 years. The authors noted that in severe invasive infections, such a low dose of levofloxacin may result in marginal tissue and blood concentrations (21).

A population-based cohort of 1084 non-pregnant women (18-65 years) with acute pyelonephritis in an ambulatory care setting showed that, independent of the drug administered (either a fluoroquinolone or TMP-SMX), an increased chance of treatment failure was present whenever the treatment lasted less than 10 days. Furthermore, treatment outcomes were affected by the subject’s age. At age 20 years, treatment with a fluoroquinolone resulted in a reduced probability of treatment failure compared with TMP-SMX (OR, 0.56; 95% CI, 0.33-0.97). At age 60 years, there was no difference in the probability of treatment failure (OR, 1.61; 95% CI, 0.82-3.16) (22).

 

Optimal treatment duration in men

There is an apparent lack of studies on optimal treatment duration of acute pyelonephritis or febrile UTI in men. We found only one study directly comparing different treatment durations in men (23). In this open, prospective and randomized trial, 72 men with community-acquired febrile UTI (without a chronic indwelling catheter) were treated with ciprofloxacin 500 mg twice daily for two or four weeks. All responded successfully with resolution of fever and symptoms. There was no significant difference in bacteriological cure rate 2 weeks post-treatment between patients treated for 2 or 4 weeks (89% vs. 97%, 95% CI for difference in proportions –3% to 19%), nor after 1 year (59% versus 76%, 95% CI –5% to 39%). The cumulative clinical cure rate after 1 year was 72% and 82%, respectively (95% CI –10% to 30%). Recurrences after 1 year comprised asymptomatic bacteriuria (ASB) (48%), symptomatic lower UTI (23%) and another episode of febrile UTI (29%). A tendency towards more recurrences in the 2-week group could be attributed to a larger proportion of men with urological lesions requiring surgical interventions (26% vs. 12%) in that group. The results should be interpreted with some caution given the wide confidence interval for the differences in cure rate; however, this study suggests a 2-week course of ciprofloxacin 500 mg twice daily may be an adequate treatment for febrile UTI in men.

Another Swedish study provided additional support for a 2-week regimen of oral fluoroquinolones in men (24). In this randomized, double-blind trial, adult men and women with a presumptive diagnosis of acute pyelonephritis (defined as febrile UTI) were randomly assigned to receive a 14-day course of oral treatment with either norfloxacin 400 mg twice daily or cefadroxil 1g twice daily. Of 197 patients enrolled, 16 (29.5%) men were treated with norfloxacin and 12 (21.1%) with cefadroxil. In this subgroup, a 14-day regimen of norfloxacin was highly effective, regardless the presence of bacteremia or complicating factors such as diabetes mellitus or urinary tract abnormalities, with significantly higher bacteriological cure rate than with cefadroxil, both at 3-10 days (100% vs. 73%, respectively) and up to 2 months after cessation of treatment (88% vs. 75%, respectively).

The same results in men were obtained from a third Swedish trial which used step-down treatment; initial intravenous treatment with cefuroxime was followed by either norfloxacin 400 mg twice daily (n=83, 42% men) or ceftibuten 200 mg twice daily (n=85) for 10 days (25). The clinical and bacteriological cure rates were 96% and 89% for the norfloxacin group versus 89% and 75% for the ceftibuten group.

Search and select

Databases were Pubmed and the Cochrane Library.

Keywords: [urinary tract infection OR urosepsis OR pyelonephritis] AND treatment duration

Limits: English, adults, humans, clinical trials, guideline, meta-analysis, RCT, review, last 25 years.Pubmed: 245 results, all titles screened, all abstracts screened, 20 articles included.

 

Cochrane Library: no results.

 

Articles about antimicrobial agents which are not available in the Netherlands, or on the treatment of uncomplicated UTIs, were excluded.

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Evidence tables

This guideline does not include evidence tables.

Considerations

There are no published studies on the efficacy of amoxicillin, co-amoxicilav or TMP-SMX less than 14 days for the treatment of acute pyelonephritis. Therefore, when these agents are used for the treatment of acute pyelonephritis, the standard treatment duration should be 14 days according to Stamm et al. (15).

It should be emphasized that the above-mentioned conclusions on treatment durations less than 14 days are based upon studies that almost exclusively included young (≤ 50 years or premenopausal) women without any comorbidities. Thus, in patients with complicated disease, those with comorbidities, the elderly and in men, the standard duration of therapy remains 14 days.

A prospective observational cohort study from the Netherlands, including consecutive non-pregnant adults with febrile UTI study visiting primary health care centers (PHCs) and emergency departments (EDs), in which the treatment duration was determined by the treating physician, with a mean treatment duration of 10-14 days, supported this treatment duration (26). Median age was 63 [IQR 42-77] years, 34% was male and 58% had comorbidity, all characteristics were comparable between both groups. Bacteremia was present in 10% of the outpatients and 27% of the inpatients. During follow-up, 8 (5%) of PHC group were hospitalized because of suspected deteriorating sepsis, progressive illness or persistent symptoms; none of them required ICU admission nor were there any attributable deaths. Clinical cure rates at 30 days were high in both groups (90% in PHC and 89% in the ED group, respectively) and persistent at least until 3 months follow-up. Thus, the outcome of this group of patients treated with oral ciprofloxacin on an outpatient basis suggests that selected adults with febrile UTI can be safely treated at home using a 10-14 day regimen of oral fluoroquinolones, including men, the elderly, and patients with comorbidity or bacteremia.

Currently, there is an ongoing trial among elderly and more complicated cases with pyelonephritis that compares 7 and 14 days of ciprofloxacin (27). The data of this trial are expected in 2013.

Since levofloxacin and other fluoroquinolones are also active against gram-positive micro-organisms, and are therefore unnecessarily broad, the Guideline committee is of the opinion that only ciprofloxacin can be recommended for the treatment of a UTI.

Finally, the results of the mentioned RCTs with fluoroquinolones (17), (21), (19), (20), (18) are in contrast with those of Carrie et al. (22), which showed that failure rate was increased when treatment duration was shorter than 10 days. However, because this study (which evaluates healthcare claims) has a lower level of evidence than the RCTs, the Guideline committee has decided to follow the recommendations of the IDSA guideline (3) and will recommend a treatment duration of 7 days for ciprofloxacin, and 10-14 days for TMP-SMX or beta-lactams.

Authorization date and validity

Last review : 01-03-2013

Last authorization : 01-03-2013

This guideline was developed and approved by representatives of the professional medical societies, mentioned in the introduction and methods sections and therefore represents the current professional standard in 2013. The guideline contains general recommendations. It is possible that, in individual cases, these recommendations do not apply. Applicability of the guideline in clinical practice resorts to the responsibility of every individual practitioner. Facts or circumstances may occur, in which deviation of the guideline is justified, in order to provide optimal quality of care for the patient.

Initiative and authorization

Initiative : Stichting Werkgroep Antibioticabeleid

Authorized by:
  • Nederlandse Huisartsen Genootschap
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging voor Medische microbiologie
  • Nederlandse Vereniging voor Obstetrie en Gynaecologie
  • Nederlandse Vereniging voor Urologie

General details

Development of this guideline was supported and financed by the SKMS (Kwaliteitsgelden Medisch Specialisten).

Scope and target group

The objective of these guidelines is to update clinicians with regard to important advances and controversies in the antibiotic treatment of patients with complicated urinary tract infections (UTIs).

 

The guidelines described here cover the empirical antimicrobial therapy of adult patients (for this guideline 12 years or older) with a complicated UTI admitted to a hospital (emergency room or ward) in the Netherlands. Uncomplicated UTIs are treated predominantly by the general practitioner. For the relevant guidelines, see the recently updated Standard for Urinary Tract Infections of the Dutch Society of General Practitioners (NHG). We have tried to adhere to this standard insofar as possible. Urethritis and epididymitis are not included in this guideline.

The Guidelines give a general therapy advice for all UTI with systemic symptoms because, at first presentation of a patient, it is not always possible to differentiate between an acute prostatitis, pyelonephritis or urosepsis. In addition, this differentiation has no consequences for the choice of empirical antimicrobial therapy. Apart from these general guidelines, we give specific advice for certain groups of patients separately.

Samenstelling werkgroep

Preparation of the guideline text was carried out by a multidisciplinary committee consisting of experts, delegated from the professional societies for infectious diseases (VIZ), medical microbiology (NVMM), hospital pharmacists (NVZA), urology (NVU), gynaecology (NVO), nephrology (NFN) and general practice (NHG). After consultation with the members of these professional societies, the definitive guideline was drawn up by the delegates and approved by the board of SWAB.

 

  • Dr. S.E. Geerlings (coordinator, SWAB), Internal Medicine/Infectious Diseases specialist, Department of Internal Medicine, Division of Infectious Diseases, Academic Medical Center, Amsterdam
  • Dr. C. van Nieuwkoop (VIZ, NIV), Internal Medicine, Emergency Medicine and Infectious Diseases specialist, Department of Internal Medicine, Hagaziekenhuis, the Hague
  • E. van Haarst (NVU), Urologist, Department of Urology, St. Lucas Andreas Hospital, Amsterdam
  • Dr. M. van Buren (NFN), Internal Medicine and Nephrology specialist, Department of Internal Medicine, Hagaziekenhuis, the Hague
  • Dr. B.J. Knottnerus (NHG), General Practitioner, Department General Practice, Academic Medical Center, Amsterdam
  • Dr. E. E. Stobberingh (NVMM), Medical microbiologist, Lab Medical Microbiology, Maastricht Univerisity Medical Center, Maastricht
  • Prof. dr. C.J. de Groot (NVOG), Gynaecologist, Department of Obstetrics and Gynaecology, Vrije Universiteit Medical Center, Amsterdam
  • Prof. dr. J.M. Prins (SWAB), Internal Medicine/Infectious Diseases specialist, Department of Internal Medicine, Division of Infectious Diseases, Academic Medical Center, Amsterdam

 

The Guideline committee would also like to thank Frederique Bemelman (nephrologist) for her comments on the chapter about renal transplantation and Albert Vollaard (infectious disease specialist) for his comments on the subchapter about methenamine.

Declaration of interest

The SWAB employs strict guidelines with regard to potential conflicts of interests as described in the SWAB Format for Guideline Development (www.swab.nl). Members of the preparatory committee reported the following potential conflicts of interest:

 

SE Geerlings: for the RCTs mentioned in the reference numbers 84 en 168 (Beerepoot et al.): Ref 84: Cranberry capsules and placebo capsules for this trial were delivered by Springfield Nutraceuticals, Oud Beijerland, The Netherlands. Ref 168: Chr Hansen A/S, Denmark has the patents for Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 and donated the placebo capsules for this trial.

E v Haarst: has received speaker fees on a national urological symposium from GlaxoSmithKline, the manufacturer of amoxicillin-clavulanic acid.

Other authors: no potential conflicts of interest declared.

Patient involvement

This guideline does not include patient involvement.

Method of development

Evidence based

Implementation

This guideline does not include an implementation strategy.

Methods and proces

This guideline was drawn up according to the recommendations for evidence-based development of guidelines (6), (Evidence-Based Richtlijn-Ontwikkeling (EBRO) and Appraisal of Guidelines Research and Evaluation (AGREE), www.agreecollaboration.org). The guidelines are derived from a review of literature based on the 9 key questions concerning the treatment of UTI. Studies were assigned a degree of evidential value according to the handbook of the Dutch Institute for Healthcare Improvement (Centraal Begeleidingsorgaan/Kwaliteitsinstituut voor de gezondheidszorg, CBO) (CBO. Evidence-based Richtlijnontwikkeling, handleiding voor werkgroepleden. Utrecht: CBO; 2007). Conclusions were drawn, completed with the specific level of evidence, according to the grading system adopted by SWAB (Table 1 and 2). The only exception concerns Nethmap, an annual report from which the resistance surveillance data were used. The Guideline committee cannot give Nethmap a level of evidence and decided to use an asterix (*), but is of the opinion that the results can be given substantial weight, since the surveillance data described in Nethmap cover 30% of the Dutch population. Subsequently, specific recommendations were formulated.

In order to develop recommendations for the optimal treatment of UTI, the literature was searched for the key questions. For each question a literature search was performed in the PubMed database (January 1966 to January 2012) as well as in the Cochrane Register of Controlled Trials (CENTRAL). For resistance surveillance data NethMap 2011 was used, and for the interpretation of susceptibility test results, in addition, reports of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were used. When scientific verification could not be found, the guideline text was formulated on the basis of the opinions and experiences of the members of the Guideline committee.

Search strategy

Searches are available upon request. Please contact the Richtlijnendatabase.