Dataset Information

Evaluation of three-dose fosfomycin tromethamine in the treatment of patients with urinary tract infections: an uncontrolled, open-label, multicentre study.

ABSTRACT:

Objective

To evaluate the clinical and microbiological efficacy and safety of three doses of 3 g fosfomycin tromethamine administered orally to treat lower urinary tract infections.

Design and participants

This prospective, uncontrolled, open-label study was conducted in 12 medical centres in China, between January and December 2011. According to the diagnosis criteria of Chinese Guidelines on Urological Infections, patients (18-70 years) with acute uncomplicated cystitis, recurrent lower urinary tract infection or complicated lower urinary tract infection received three doses of 3 g fosfomycin tromethamine orally, at days 1, 3 and 5.

Primary and secondary outcome measures

Efficacy endpoints (clinical efficacy, microbiological efficacy and overall efficacy) were evaluated on day 15. Clinical symptoms, physical signs, urinalysis, liver and kidney function, patient records and evaluation of adverse events (AEs) and serious AEs up to day 15 were evaluated for analysis of safety.

Results

361 patients were included in the full analysis set, 356 in the safety analysis set and 335 in the per-protocol set (PPS). In the PPS, the clinical efficacy rates at day 15 for acute uncomplicated cystitis, recurrent lower urinary tract infection and complicated lower urinary tract infection were 94.71% (179/189), 77.22% (61/79) and 62.69% (42/67), respectively. The microbiological efficacy rates (day 15) were 97.65% (83/85), 94.44% (34/36) and 83.87% (26/31), respectively. The overall efficacy rates (day 15) were 95.29% (81/85), 77.78% (28/36) and 64.52% (20/31), respectively. 20/356 (5.6%) patients reported drug-related AEs, the most common being diarrhoea. No serious drug-related AEs were reported.

Conclusions

This fosfomycin tromethamine dosing regimen showed clinical and microbiological efficacy with some AEs and good tolerability in patients with acute uncomplicated cystitis, recurrent lower urinary tract infection and complicated lower urinary tract infection.

SUBMITTER: Qiao LD

PROVIDER: S-EPMC3855495 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Publications

Evaluation of three-dose fosfomycin tromethamine in the treatment of patients with urinary tract infections: an uncontrolled, open-label, multicentre study.

Qiao Lu-Dong LD Zheng Bo B Chen Shan S Yang Yong Y Zhang Kai K Guo Hong-Feng HF Yang Bo B Niu Yuan-Jie YJ Wang Yi Y Shi Ben-Kang BK Yang Wei-Min WM Zhao Xiao-Kun XK Gao Xiao-Feng XF Chen Ming M

BMJ open 20131204 12

<h4>Objective</h4>To evaluate the clinical and microbiological efficacy and safety of three doses of 3 g fosfomycin tromethamine administered orally to treat lower urinary tract infections.<h4>Design and participants</h4>This prospective, uncontrolled, open-label study was conducted in 12 medical centres in China, between January and December 2011. According to the diagnosis criteria of Chinese Guidelines on Urological Infections, patients (18-70 years) with acute uncomplicated cystitis, recurre ...[more]

PMID: 24309172

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Project description:BackgroundRepeated symptomatic urinary tract infections (UTIs) affect 25% of people who use clean intermittent self-catheterisation (CISC) to empty their bladder. We aimed to determine the benefits, harms, and cost-effectiveness of continuous low-dose antibiotic prophylaxis for prevention of recurrent UTIs in adult users of CISC.MethodsIn this randomised, open-label, superiority trial, we enrolled participants from 51 UK National Health Service organisations. These participants were community-dwelling (as opposed to hospital inpatient) users of CISC with recurrent UTIs. We randomly allocated participants (1:1) to receive either antibiotic prophylaxis once daily (prophylaxis group) or no prophylaxis (control group) for 12 months by use of an internet-based system with permuted blocks of variable length. Trial and laboratory staff who assessed outcomes were masked to allocation but participants were aware of their treatment group. The primary outcome was the incidence of symptomatic, antibiotic-treated UTIs over 12 months. Participants who completed at least 6 months of follow-up were assumed to provide a reliable estimate of UTI incidence and were included in the analysis of the primary outcome. Change in antimicrobial resistance of urinary and faecal bacteria was monitored as a secondary outcome. The AnTIC trial is registered at ISRCTN, number 67145101; and EudraCT, number 2013-002556-32.FindingsBetween Nov 25, 2013, and Jan 29, 2016, we screened 1743 adult users of CISC for eligibility, of whom 404 (23%) participants were enrolled between Nov 26, 2013, and Jan 31, 2016. Of these 404 participants, 203 (50%) were allocated to receive prophylaxis and 201 (50%) to receive no prophylaxis. 1339 participants were excluded before randomisation. The primary analysis included 181 (89%) adults allocated to the prophylaxis group and 180 (90%) adults in the no prophylaxis (control) group. 22 participants in the prophylaxis group and 21 participants in the control group were not included in the primary analysis because they were missing follow-up data before 6 months. The incidence of symptomatic antibiotic-treated UTIs over 12 months was 1·3 cases per person-year (95% CI 1·1-1·6) in the prophylaxis group and 2·6 (2·3-2·9) in the control group, giving an incidence rate ratio of 0·52 (0·44-0·61; p<0·0001), indicating a 48% reduction in UTI frequency after treatment with prophylaxis. Use of prophylaxis was well tolerated: we recorded 22 minor adverse events in the prophylaxis group related to antibiotic prophylaxis during the study, predominantly gastrointestinal disturbance (six participants), skin rash (six participants), and candidal infection (four participants). However, resistance against the antibiotics used for UTI treatment was more frequent in urinary isolates from the prophylaxis group than in those from the control group at 9-12 months of trial participation (nitrofurantoin 12 [24%] of 51 participants from the prophylaxis group vs six [9%] of 64 participants from the control group with at least one isolate; p=0·038), trimethoprim (34 [67%] of 51 vs 21 [33%] of 64; p=0·0003), and co-trimoxazole (26 [53%] of 49 vs 15 [24%] of 62; p=0·002).InterpretationContinuous antibiotic prophylaxis is effective in reducing UTI frequency in CISC users with recurrent UTIs, and it is well tolerated in these individuals. However, increased resistance of urinary bacteria is a concern that requires surveillance if prophylaxis is started.FundingUK National Institute for Health Research.

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:BackgroundBladder and urinary tract cancers account for approximately 21,000 new diagnoses and 5,000 deaths annually in the UK. Approximately 90% are transitional cell carcinomas where advanced disease is treated with platinum based chemotherapy and PD-1/PD-L1 directed immunotherapy. Urinary tract squamous cell carcinoma (UTSCC) accounts for about 5% of urinary tract cancers overall making this a rare disease. We have yet to establish definitive systemic treatment options for advanced UTSCC. Preliminary translational data, from UTSCC patient tumour samples, indicate high PD-L1 expression and tumour infiltrating lymphocytes in a proportion of cases. Both of these features are associated with differential gene expression consistent with a tumour/immune microenvironment predicted to be susceptible to immune checkpoint directed immunotherapy which we will evaluate in the AURORA trial.MethodsAURORA is a single arm, open-label, multicentre,UK phase II clinical trial. 33 patients will be recruited from UK secondary care sites. Patients with UTSCC, suitable for treatment with palliative intent, will receive atezolizumab PD-L1 directed immunotherapy (IV infusion, 1680 mg, every 28 days) for one year if tolerated. Response assessment, by cross sectional imaging will occur every 12 weeks. AURORA uses a Simon's 2-stage optimal design with best overall objective response rate (ORR, by RECIST v1.1) at a minimum of 12 weeks from commencing treatment as the primary endpoint. Secondary endpoints will include overall survival, progression-free survival, duration of response, magnitude of response using waterfall plots of target lesion measurements, quality of life using the EORTC QLQ-C30 tool, safety and tolerability (CTCAE v5) and evaluation of potential biomarkers of treatment response including PD-L1 expression. Archival tumour samples and blood samples will be collected for translational analyses.DiscussionIf this trial shows atezolizumab to be safe and effective it may lead to a future late phase randomised controlled trial in UTSCC. Ultimately, we hope to provide a new option for treatment for such patients.Trial registrationsEudraCT Number: 2021-001995-32 (issued 8th September 2021); ISRCTN83474167 (registered 11 May 2022); NCT05038657 (issued 9th September 2021).

Project description:ImportanceThe consumption of broad-spectrum drugs has increased as a consequence of the spread of multidrug-resistant (MDR) Escherichia coli. Finding alternatives for these infections is critical, for which some neglected drugs may be an option.ObjectiveTo determine whether fosfomycin is noninferior to ceftriaxone or meropenem in the targeted treatment of bacteremic urinary tract infections (bUTIs) due to MDR E coli.Design, setting, and participantsThis multicenter, randomized, pragmatic, open clinical trial was conducted at 22 Spanish hospitals from June 2014 to December 2018. Eligible participants were adult patients with bacteremic urinary tract infections due to MDR E coli; 161 of 1578 screened patients were randomized and followed up for 60 days. Data were analyzed in May 2021.InterventionsPatients were randomized 1 to 1 to receive intravenous fosfomycin disodium at 4 g every 6 hours (70 participants) or a comparator (ceftriaxone or meropenem if resistant; 73 participants) with the option to switch to oral fosfomycin trometamol for the fosfomycin group or an active oral drug or parenteral ertapenem for the comparator group after 4 days.Main outcomes and measuresThe primary outcome was clinical and microbiological cure (CMC) 5 to 7 days after finalization of treatment; a noninferiority margin of 7% was considered.ResultsAmong 143 patients in the modified intention-to-treat population (median [IQR] age, 72 [62-81] years; 73 [51.0%] women), 48 of 70 patients (68.6%) treated with fosfomycin and 57 of 73 patients (78.1%) treated with comparators reached CMC (risk difference, -9.4 percentage points; 1-sided 95% CI, -21.5 to ∞ percentage points; P = .10). While clinical or microbiological failure occurred among 10 patients (14.3%) treated with fosfomycin and 14 patients (19.7%) treated with comparators (risk difference, -5.4 percentage points; 1-sided 95% CI, -∞ to 4.9; percentage points; P = .19), an increased rate of adverse event-related discontinuations occurred with fosfomycin vs comparators (6 discontinuations [8.5%] vs 0 discontinuations; P = .006). In an exploratory analysis among a subset of 38 patients who underwent rectal colonization studies, patients treated with fosfomycin acquired a new ceftriaxone-resistant or meropenem-resistant gram-negative bacteria at a decreased rate compared with patients treated with comparators (0 of 21 patients vs 4 of 17 patients [23.5%]; 1-sided P = .01).Conclusions and relevanceThis study found that fosfomycin did not demonstrate noninferiority to comparators as targeted treatment of bUTI from MDR E coli; this was due to an increased rate of adverse event-related discontinuations. This finding suggests that fosfomycin may be considered for selected patients with these infections.Trial registrationClinicalTrials.gov Identifier: NCT02142751.

Dataset Information

Evaluation of three-dose fosfomycin tromethamine in the treatment of patients with urinary tract infections: an uncontrolled, open-label, multicentre study.

Objective

Design and participants

Primary and secondary outcome measures

Results

Conclusions

Publications

Evaluation of three-dose fosfomycin tromethamine in the treatment of patients with urinary tract infections: an uncontrolled, open-label, multicentre study.

Similar Datasets

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