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Oral fosfomycin versus ciprofloxacin in women with E.coli febrile urinary tract infection, a double-blind placebo-controlled randomized controlled non-inferiority trial (FORECAST).

ABSTRACT: BACKGROUND:Febrile Urinary Tract Infection (FUTI) is frequently treated initially with intravenous antibiotics, followed by oral antibiotics guided by clinical response and bacterial susceptibility patterns. Due to increasing infection rates with multiresistant Enterobacteriaceae, antibiotic options for stepdown treatment decline and patients more frequently require continued intravenous antibiotic treatment for FUTI. Fosfomycin is an antibiotic with high bactericidal activity against Escherichia coli and current resistance rates are low in most countries. Oral Fosfomycin-Trometamol 3000?mg (FT) reaches appropriate antibiotic concentrations in urine and blood and is considered safe. As such, it is a potential alternative for stepdown treatment. METHODS:The FORECAST study (Fosfomycin Randomized controlled trial for E.coli urinary tract infections as Alternative Stepdown Treatment) is a randomized, double-blind, double-dummy, non-inferiority trial in which 240 patients will be randomly allocated to a stepdown treatment with FT or ciprofloxacin (standard of care) for FUTI, caused by Escherichia coli with in vitro susceptibility to both antibiotics. The study population consists of consenting female patients (?18?years) with community acquired E. coli FUTI. After intravenous antibiotic treatment during at least 48 (but less than 120) hours, and if eligibility criteria for iv-oral switch are met, patients receive either FT (3?g every 24?h) or ciprofloxacin (500?mg every 12?h) for a total antibiotic duration of 10?days. The primary endpoint is clinical cure (resolution of symptoms) 6-10?days post-treatment. Secondary endpoints are microbiological cure 6-10?days post-treatment, clinical cure, mortality, ICU admittance, relapse, reinfection, readmission, additional antibiotic use for UTI, early study discontinuation, adverse events, days of hospitalization and days of absenteeism within 30-35?days post-treatment. The sample size is based on achieving non-inferiority on the primary endpoint, applying a non-inferiority margin of 10%, a two-sided p-value of

SUBMITTER: Ten Doesschate T

PROVIDER: S-EPMC6280543 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Oral fosfomycin versus ciprofloxacin in women with E.coli febrile urinary tract infection, a double-blind placebo-controlled randomized controlled non-inferiority trial (FORECAST).

Ten Doesschate Thijs T van Mens Suzan P SP van Nieuwkoop Cees C Geerlings Suzanne E SE Hoepelman Andy I M AIM Bonten Marc J M MJM

BMC infectious diseases 20181205 1

<h4>Background</h4>Febrile Urinary Tract Infection (FUTI) is frequently treated initially with intravenous antibiotics, followed by oral antibiotics guided by clinical response and bacterial susceptibility patterns. Due to increasing infection rates with multiresistant Enterobacteriaceae, antibiotic options for stepdown treatment decline and patients more frequently require continued intravenous antibiotic treatment for FUTI. Fosfomycin is an antibiotic with high bactericidal activity against Es ...[more]

PMID: 30518334

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Project description:BackgroundIn adults with febrile urinary tract infection (fUTI), data on optimal treatment duration in patients other than non-pregnant women without comorbidities are lacking.MethodsA randomized placebo-controlled, double-blind, non-inferiority trial among 35 primary care centers and 7 emergency departments of regional hospitals in the Netherlands. Women and men aged ≥ 18 years with a diagnosis of fUTI were randomly assigned to receive antibiotic treatment for 7 or 14 days (the second week being ciprofloxacin 500 mg or placebo orally twice daily). Patients indicated to receive antimicrobial treatment for at least 14 days were excluded from randomization. The primary endpoint was the clinical cure rate through the 10- to 18-day post-treatment visit with preset subgroup analysis including sex. Secondary endpoints were bacteriologic cure rate at 10-18 days post-treatment and clinical cure at 70-84 days post-treatment.ResultsOf 357 patients included, 200 were eligible for randomization; 97 patients were randomly assigned to 7 days and 103 patients to 14 days of treatment. Overall, short-term clinical cure occurred in 85 (90%) patients treated for 7 days and in 94 (95%) of those treated for 14 days (difference -4.5%; 90% CI, -10.7 to 1.7; P non-inferiority = 0.072, non-inferiority not confirmed). In women, clinical cure was 94% and 93% in those treated for 7 and 14 days, respectively (difference 0.9; 90% CI, -6.9 to 8.7, P non-inferiority = 0.011, non-inferiority confirmed) and, in men, this was 86% versus 98% (difference -11.2; 90% CI -20.6 to -1.8, P superiority = 0.025, inferiority confirmed). The bacteriologic cure rate was 93% versus 97% (difference -4.3%; 90% CI, -9.7 to 1.2, P non-inferiority = 0.041) and the long-term clinical cure rate was 92% versus 91% (difference 1.6%; 90% CI, -5.3 to 8.4; P non-inferiority = 0.005) for 7 days versus 14 days of treatment, respectively. In the subgroups of men and women, long-term clinical cure rates met the criteria for non-inferiority, indicating there was no difference in the need for antibiotic retreatment for UTI during 70-84 days follow-up post-treatment.ConclusionsWomen with fUTI can be treated successfully with antibiotics for 7 days. In men, 7 days of antibiotic treatment for fUTI is inferior to 14 days during short-term follow-up but it is non-inferior when looking at longer follow-up.Trial registrationThe study was registered at ClinicalTrials.gov [ NCT00809913 ; December 16, 2008] and trialregister.nl [ NTR1583 ; December 19, 2008].

Project description:Study questionCan treatment of the symptoms of uncomplicated urinary tract infection (UTI) with ibuprofen reduce the rate of antibiotic prescriptions without a significant increase in symptoms, recurrences, or complications?MethodsWomen aged 18-65 with typical symptoms of UTI and without risk factors or complications were recruited in 42 German general practices and randomly assigned to treatment with a single dose of fosfomycin 3 g (n=246; 243 analysed) or ibuprofen 3 × 400 mg (n=248; 241 analysed) for three days (and the respective placebo dummies in both groups). In both groups additional antibiotic treatment was subsequently prescribed as necessary for persistent, worsening, or recurrent symptoms. The primary endpoints were the number of all courses of antibiotic treatment on days 0-28 (for UTI or other conditions) and burden of symptoms on days 0-7. The symptom score included dysuria, frequency/urgency, and low abdominal pain.Study answer and limitationsThe 248 women in the ibuprofen group received significantly fewer course of antibiotics, had a significantly higher total burden of symptoms, and more had pyelonephritis. Four serious adverse events occurred that lead to hospital referrals; one of these was potentially related to the trial drug. Results have to be interpreted carefully as they might apply to women with mild to moderate symptoms rather than to all those with an uncomplicated UTI.What this paper addsTwo thirds of women with uncomplicated UTI treated symptomatically with ibuprofen recovered without any antibiotics. Initial symptomatic treatment is a possible approach to be discussed with women willing to avoid immediate antibiotics and to accept a somewhat higher burden of symptoms.Funding, competing interests, data sharingGerman Federal Ministry of Education and Research (BMBF) No 01KG1105. Patient level data are available from the corresponding author. Patient consent was not obtained but the data are anonymised and risk of identification is low.Trial registration No ClinicalTrialGov Identifier NCT01488955.

Project description:Oral fosfomycin is approved in Canada for the treatment of acute uncomplicated cystitis. Several studies have reported "off label" use of oral fosfomycin in the treatment of patients with complicated lower urinary tract infection (cLUTI). This review summarizes the available literature describing the use of oral fosfomycin in the treatment of patients with cLUTI. Collectively, these studies support the use of a regimen of 3 grams of oral fosfomycin administered once every 48 or 72 hours for a total of 3 doses for patients who have previously failed treatment with another agent, are infected with a multidrug-resistant (MDR) pathogen, or cannot tolerate first-line treatment due to intolerance or adverse effects. Additionally, a Phase 2/3 clinical trial, known as the ZEUS study, assessed the efficacy and safety of intravenous (IV) fosfomycin versus piperacillin-tazobactam in the treatment of patients with complicated upper urinary tract infection (cUUTI) or acute pyelonephritis (AP) including in patients with concomitant bacteremia. IV fosfomycin was reported to be noninferior to piperacillin-tazobactam in treating patients with cUUTI and AP; however, when outcomes were independently evaluated according to baseline diagnosis (i.e., cUUTI versus AP), IV fosfomycin was superior to piperacillin-tazobactam in the treatment of patients with cUUTI and demonstrated superior microbiological eradication rates, across all resistant phenotypes including extended-spectrum β-lactamase- (ESBL-) producing Escherichia coli and Klebsiella spp. and carbapenem-resistant (CRE), aminoglycoside-resistant, and MDR Gram-negative bacilli (primarily Enterobacterales). Based on the ZEUS study, IV fosfomycin dosed at 6 grams every 8 hours for 7 days (14 days in patients with concurrent bacteremia) appears to be a safe and effective therapeutic option in treating patients with upper urinary tract infections, particularly those with cUUTI caused by antimicrobial-resistant Enterobacterales.

Project description:Current guidelines on the management of urinary tract infection recommend treating febrile urinary tract infection or acute pyelonephritis with antimicrobials for at least 14 days. Few randomized trials showed the effectiveness of treatment durations of 5 to 7 days but this has only been studied in young previously healthy women.A randomized placebo-controlled double-blind multicenter non-inferiority trial in which 400 patients with community acquired febrile urinary tract infection will be randomly allocated to a short treatment arm (7 days of ciprofloxacin or 7 days of empirical beta-lactams +/- gentamicin intravenously with early switch to oral ciprofloxacin followed by 7 days of blinded placebo) or standard treatment arm (7 days of ciprofloxacin or 7 days of empirical beta-lactams +/- gentamicin intravenously with early switch to oral ciprofloxacin followed by 7 days of blinded ciprofloxacin). The study is performed in the Leiden region in which one university hospital, 6 general hospitals and 32 primary health care centers are clustered. Patients eligible for randomization are competent patients aged 18 years or above with a presumptive diagnosis of acute pyelonephritis as defined by the combination of fever, one or more symptoms of urinary tract infection and a positive urine nitrate test and/or the presence of leucocyturia. Exclusion criteria are known allergy to fluoroquinolones, female patients who are pregnant or lactating, polycystic kidney disease, permanent renal replacement therapy, kidney transplantation, isolation of ciprofloxacin-resistant causal uropathogen, renal abscess, underlying chronic bacterial prostatitis, metastatic infectious foci and inability to obtain follow-up. The primary endpoint is the clinical cure rate through the 10- to 18-day post-treatment visit. Secondary endpoints are the microbiological cure rate 10- to 18-day post-treatment, the 30- and 90-day overall mortality rate, the clinical cure rate 70- to 84-day post-treatment, relapse rate of UTI and adverse events or complications during 90 days of follow-up.This study aims to demonstrate that 7 days of antimicrobial treatment is non-inferior as compared with 14 days of treatment in patients with febrile urinary tract infection. In addition, it will generate insights into the side-effects of antimicrobial treatment in relation to its duration. The study population will also include men, the elderly and patients with significant co-morbidity. Reflecting daily practice of primary health care and emergency departments, the results of this study can be generalized to other locations.

Dataset Information

Oral fosfomycin versus ciprofloxacin in women with E.coli febrile urinary tract infection, a double-blind placebo-controlled randomized controlled non-inferiority trial (FORECAST).

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Oral fosfomycin versus ciprofloxacin in women with E.coli febrile urinary tract infection, a double-blind placebo-controlled randomized controlled non-inferiority trial (FORECAST).

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