Nitrofurantoin

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; pInterpretationContinuous 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.

Antibiotic resistance increasingly limits the success of antibiotic treatments, and physicians require new ways to achieve efficient treatment despite resistance. Resistance mechanisms against a specific antibiotic class frequently confer increased susceptibility to other antibiotic classes, a phenomenon designated collateral sensitivity (CS). An informed switch of antibiotic may thus enable the efficient treatment of resistant strains. CS occurs in many pathogens, but the mechanisms that generate hypersusceptibility are largely unknown. We identified several molecular mechanisms of CS against the antibiotic nitrofurantoin (NIT). Mutants that are resistant against tigecycline (tetracycline), mecillinam (β-lactam), and protamine (antimicrobial peptide) all show CS against NIT. Their hypersusceptibility is explained by the overexpression of nitroreductase enzymes combined with increased drug uptake rates, or increased drug toxicity. Increased toxicity occurs through interference of the native drug-response system for NIT, the SOS response, with growth. A mechanistic understanding of CS will help to develop drug switches that combat resistance.

Background & aimsNo multi-national prospective study of drug-induced liver injury (DILI) has originated in Europe. The design of a prospective European DILI registry, clinical features and short-term outcomes of the cases and controls is reported.MethodsPatients with suspected DILI were prospectively enrolled in the United Kingdom, Spain, Germany, Switzerland, Portugal and Iceland, 2016-2021. DILI cases or non-DILI acute liver injury controls following causality assessment were enrolled.ResultsOf 446 adjudicated patients, 246 DILI patients and 100 had acute liver injury due to other aetiologies, mostly autoimmune hepatitis (n = 42) and viral hepatitis (n = 34). DILI patients (mean age 56 years), 57% women, 60% with jaundice and 3.6% had pre-existing liver disease. DILI cases and non-DILI acute liver injury controls had similar demographics, clinical features and outcomes. A single agent was implicated in 199 (81%) DILI cases. Amoxicillin-clavulanate, flucloxacillin, atorvastatin, nivolumab/ipilimumab, infliximab and nitrofurantoin were the most commonly implicated drugs. Multiple conventional medications were implicated in 37 (15%) and 18 cases were caused by herbal and dietary supplements. The most common single causative drug classes were antibacterials (40%) and antineoplastic/immunomodulating agents (27%). Overall, 13 (5.3%) had drug-induced autoimmune-like hepatitis due to nitrofurantoin, methyldopa, infliximab, methylprednisolone and minocycline. Only six (2.4%) DILI patients died (50% had liver-related death), and another six received liver transplantation.ConclusionsIn this first multi-national European prospective DILI Registry study, antibacterials were the most commonly implicated medications, whereas antineoplastic and immunomodulating agents accounted for higher proportion of DILI than previously described. This European initiative provides an important opportunity to advance the study on DILI.

BackgroundUncomplicated urinary tract infections (uUTIs) can cause distressing symptoms seriously impacting daily activities. Early symptom relief during treatment, though fundamental to patients, is often overlooked in clinical trials. Gepotidacin, a new antibacterial agent, was noninferior to the first-line treatment nitrofurantoin in two randomized controlled trials (EAGLE-2 [NCT04020341] and EAGLE-3 [NCT04187144]). The current analysis utilized pooled data from these two trials to evaluate symptom responses during and after treatment in participants with uUTI.MethodsParticipants were aged ≥12 years with at least two uUTI symptoms, urinary nitrite and/or pyuria, and no complicating factors. Participants were randomized 1:1 to oral gepotidacin (1500 mg) or nitrofurantoin (100 mg), both taken twice daily for 5 days. At baseline (Day 1), on-therapy (OT; Days 2-4), and test-of-cure (TOC; Days 10-13) visits, urinary symptoms were assessed (0-3; none-severe) from which a total score (0-12) was derived.ResultsOverall, 3136 participants were randomized (1572 gepotidacin, 1564 nitrofurantoin). Mean (median) baseline symptom scores for gepotidacin and nitrofurantoin arms were 7.1 (7.0) and 7.2 (7.0), respectively; at OT, this decreased to 3.6 (3.0) for both arms. At the OT visit, >80% of participants had clinical improvement/resolution. Among those with baseline symptoms affecting everyday activities (moderate or severe), 53.2% (728/1369) assigned gepotidacin and 53.6% (738/1377) assigned nitrofurantoin reported at OT that symptoms no longer affected everyday activities (mild or absent); at TOC, these percentages were 93.8% (1232/1313) and 93.3% (1254/1344), respectively.ConclusionsGepotidacin and nitrofurantoin provide meaningful and similar early relief from uUTI symptoms.