Polyketides

BackgroundDevelopment of new treatments for gonorrhoea is a global public health priority. We aimed to evaluate the efficacy and safety of zoliflodacin versus ceftriaxone plus azithromycin in patients with uncomplicated urogenital gonorrhoea.MethodsIn this phase 3, multinational, randomised, controlled, open-label, non-inferiority clinical trial, participants aged 12 years and older with clinical suspicion of uncomplicated urogenital gonorrhoea were eligible for inclusion. The trial was done in 17 outpatient clinics in Belgium, the Netherlands, South Africa, Thailand, and the USA. Participating countries with high disease prevalence were identified for participation in the study. Sites selected for participation were led by principal investigators with research experience, who were knowledgeable in HIV or sexually transmitted infections and treatment. Feasibility questionnaires and prestudy visits assessed sexually transmitted infection case management guidelines, clinical services, and resources (ie, facility, staff, proposed composition of the study team, standard sexually transmitted infection services offered at the site, assessment of laboratory capacity, research experience and ethical review of clinical trials). Eligible participants were randomly assigned (2:1) to receive a single dose of zoliflodacin 3 g (oral) or ceftriaxone 500 mg (intramuscular) plus azithromycin 1 g (oral). Treatment assignment was known to the participants and their treating clinicians; however, microbiology laboratory staff were masked and the sponsor's central study team were masked until after database lock. The primary endpoint was the proportion of patients with microbiological cure (eradication of Neisseria gonorrhoeae, determined by urethral or endocervical culture) at test of cure (TOC; day 6 ± 2) in the microbiological intention-to-treat population. The primary efficacy analysis declared non-inferiority if the upper bound of the two-sided 95% CI for the treatment difference (comparator minus zoliflodacin) fell below the 12% non-inferiority margin. The trial is registered with ClinicalTrials.gov, NCT03959527, and EudraCT, 2019-000990-22.FindingsBetween Nov 6, 2019, and March 16, 2023, 1011 patients were screened. 81 patients did not meet screening criteria and 930 participants were randomly assigned to zoliflodacin (n=621) or comparator (n=309). The mean participant age was 29·7 years (SD 9·4). 815 (88%) of 930 participants were assigned male at birth and 115 (12%) participants were assigned female at birth. 514 (55%) of 930 participants were Black or African American, 285 (31%) were Asian, and 113 (12%) were White. Microbiological cure rates at TOC in the microbiological intention-to-treat (urogenital) population (primary efficacy endpoint) were 460 (90·9%, 95% CI 88·1-93·3) of 506 participants for zoliflodacin and 229 (96·2%, 92·9-98·3) of 238 participants for comparator. The estimated difference between groups was 5·3% (95% CI 1·4-8·6) and the upper confidence interval limit was within the prespecified non-inferiority margin of less than 12%. Zoliflodacin was generally well tolerated and adverse events were similar between treatment groups. The most frequently reported treatment-emergent adverse events included headache (61 [10%] of 619 patients), neutropenia (42 [7%]), and leukopenia (24 [4%]) in the zoliflodacin group and injection site pain (38 [12%] of 308 patients), neutropenia (24 [8%]), and diarrhoea (22 [7%]) in the comparator group. The majority of adverse events were mild or moderate in severity. No serious adverse events were reported.InterpretationZoliflodacin was non-inferior to ceftriaxone plus azithromycin for the treatment of uncomplicated urogenital gonorrhoea and had a similar safety profile. These data suggest a potential role for zoliflodacin as an effective oral treatment option for uncomplicated urogenital gonorrhoea.FundingGerman Federal Ministry of Research, Technology and Space, UK Department of Health and Social Care as part of the Global Antimicrobial Resistance Innovation Fund, Japan Ministry of Health, Labour and Welfare, Netherlands Ministry of Health, Welfare and Sport and Directorate-General for International Cooperation, Switzerland Federal Office of Public Health, and the Canton of Geneva, Switzerland.

First identified in 2009, Candidozyma auris (formerly Candida auris) is an emerging multidrug-resistant fungus that can cause invasive infections with a crude mortality rate ranging from 30 to 60%. Currently, 30-50% of C. auris isolates are intrinsically resistant to amphotericin B. In this study, we characterized a clinical case of acquired amphotericin B resistance using whole-genome sequencing, a large-scale phenotypic screen, comprehensive sterol profiling, and genotypic reversion using CRISPR. Data obtained in this study provide evidence that a deletion resulting in a frameshift in ERG3 significantly contributes to the observed resistant phenotype, and a nonsense mutation in ERG4 may more modestly contribute to resistance. Characterization of this isolate also revealed that a fitness cost is associated with the abrogation of ergosterol production and its replacement with other late-stage sterols. This article presents a clinical case description of amphotericin B resistance from a frameshift mutation in ERG3 in C. auris and marks an advancement in the understanding of antifungal resistance in this fungal pathogen.

BackgroundMass administration of azithromycin to children 1 to 59 months of age has been shown to reduce mortality among infants and children in this age group in some areas of sub-Saharan Africa. The largest effects have appeared to be among infants younger than 12 months of age, within 3 months after treatment; this observation motivated the design of the current trial.MethodsIn this trial, we randomly assigned villages in Mali, West Africa, in a 3:4:2 ratio to receive distributions of placebo, azithromycin two times a year, or azithromycin four times a year. Infants 1 to 11 months of age received, in doses of 20 mg per kilogram of body weight, placebo every 3 months (control group); azithromycin at two quarterly visits from January through June and placebo at two quarterly visits from July through December (twice-yearly azithromycin group); or azithromycin every 3 months (quarterly azithromycin group). The primary outcome was death within 3 months after eligibility had been confirmed, analyzed in the intention-to-treat population.ResultsFrom December 2020 through December 2022, a total of 1151 villages were enrolled in the trial; 386 villages were randomly assigned to the control group, 511 to the twice-yearly azithromycin group, and 254 to the quarterly azithromycin group. Among all the villages, 149,090 infants received at least one dose of placebo or azithromycin, with a total of 82,600 person-years of follow-up; 968 deaths were recorded. Mortality was 11.9 deaths per 1000 person-years at risk in the control group, 11.8 deaths per 1000 person-years in the twice-yearly azithromycin group (incidence rate ratio, 1.00; 95% confidence interval [CI], 0.83 to 1.19), and 11.3 deaths per 1000 person-years in the quarterly azithromycin group (incidence rate ratio, 0.93; 95% CI, 0.75 to 1.15). Adverse events were rare, and the percentages of infants with adverse events were similar in the three groups. Mortality among untreated children 12 to 59 months of age was similar across groups.ConclusionsMass administration of azithromycin in Mali, limited to infants 1 to 11 months of age, did not result in lower infant or child mortality than placebo, regardless of whether azithromycin was delivered twice yearly or quarterly. (Funded by the Gates Foundation; LAKANA ClinicalTrials.gov number, NCT04424511.).