Cephalosporins

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.

PurposeWe assessed the effectiveness and safety of cefiderocol in patients with Gram-negative bacterial infections, excluding Acinetobacter spp., in the early access programme (EAP) in Spain.MethodsThe retrospective, multicentre PERSEUS study (2018-2022) enrolled hospitalised patients with serious Gram-negative infections, except Acinetobacter spp., who received first-time cefiderocol for ≥ 72 h following requests through the EAP. Clinical cure at end of treatment, all-cause mortality at Day 28, cefiderocol use, and adverse drug reactions (ADRs) were the key outcomes.ResultsOverall, 261 patients were eligible for analysis. Median (interquartile range) age was 61 (49-68) years, 202 (77.4%) were male and 165 (63.2%) were in the intensive care unit. The most frequent diagnoses were respiratory tract infection (47.9%), intra-abdominal infection (14.6%), and urinary tract infection (14.6%). The median (IQR) duration of cefiderocol treatment was 10 (7-14) days. Overall, the clinical cure rate was 80.5% (210/261) and the 28-day mortality rate was 21.5% (56/261). In patients with Pseudomonas aeruginosa infection (66.7% [n = 174], including 73 [42%] with metallo-β-lactamases), the clinical cure rate was 84.5% (147/174) and the 28-day mortality was 17.2% (30/174). Logistic regression analysis showed that prior antibiotic treatment for > 7 days (OR 0.19, 95% CI 0.05-0.56) and mechanical ventilation (OR 0.32, 95% CI 0.15-0.67) were independent negative predictive factors for clinical cure. ADRs occurred in seven patients, six events resolved, and one was fatal (toxic epidermal necrolysis).ConclusionsCefiderocol is a valuable option in the treatment of serious Gram-negative bacterial infections, particularly for those caused by P. aeruginosa.ClinicaltrialsGOV: NCT05789199 (Registration date: 16 February 2023).

PurposeThis subgroup analysis of the PERSEUS study aimed to describe the effectiveness of cefiderocol treatment in the early access programme in Spain in patients infected by Stenotrophomonas maltophilia, Burkholderia cepacia complex (Bcc) or Achromobacter species.MethodsIn the retrospective, observational, multicentre PERSEUS study in Spain, the effectiveness and safety of cefiderocol treatment administered for at least 72 h up to 28 days in patients infected by Gram-negative bacteria, except Acinetobacter spp., in the early access programme was investigated. Patient demographics and baseline clinical characteristics, cefiderocol use, clinical cure at end of treatment, all-cause mortality at Day 28 were the main outcomes.ResultsA total of 20 patients had S. maltophilia infections, and 14 patients had other rare glucose non-fermenters (Bcc 8, Achromobacter spp. 5, Ralstonia mannitolilytica 1). The median (interquartile range [IQR]) age was 60.5 (48.0-65.5) years and 49.5 (33.0-59.0) years for patients with S. maltophilia and other rare non-fermenters, respectively. The majority of patients had respiratory tract infections (S. maltophilia 55%; other rare non-fermenters 71.4%), and median (IQR) duration of cefiderocol treatment was 10.0 (6.5-13.5) days and 8.0 (6-14) days, respectively. Clinical cure rates were 70%, 62.5% and 80.0% for patients with S. maltophilia, Bcc and Achromobacter spp., respectively. Corresponding 28-day all-cause mortality rates were 30.0%, 37.5% and 40.0%, respectively. One patient with R. mannitolilytica had clinical cure and survived to Day 28.ConclusionsCefiderocol is an important addition to the limited treatment options for patients infected by these rare glucose non-fermenting Gram-negative bacteria.Trial registrationClinicalTrials.gov: NCT05789199 (Registration date: 16 February 2023).