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Gepotidacin, a first-in-class, bactericidal, triazaacenaphthylene antibacterial that inhibits bacterial DNA replication, was shown to be efficacious and well tolerated in the treatment of uncomplicated urinary tract infections. We evaluated the efficacy and safety of gepotidacin for the treatment of uncomplicated urogenital gonorrhoea. EAGLE-1 (NCT04010539) was a phase 3, open-label, sponsor-blinded, multicentre, non-inferiority study evaluating oral gepotidacin (two 3000 mg doses administered 10–12 h apart) compared with 500 mg intramuscular ceftriaxone plus 1 g oral azithromycin for the treatment of gonorrhoea. Eligible participants were aged 12 years and older, had a bodyweight over 45 kg, and had suspected uncomplicated urogenital gonorrhoea (including mucopurulent discharge), a positive laboratory test for Neisseria gonorrhoeae, or both. Participants were randomly allocated in a 1:1 ratio to each treatment group, stratified by sex (original urogenital anatomy at birth) and sexual orientation (men who have sex with men [MSM], men who have sex with women [MSW], and female) in combination, and age group (age <18 years, ≥18 to 65 years, or >65 years). The primary efficacy endpoint was microbiological success, defined as culture-confirmed bacterial eradication of N gonorrhoeae from the urogenital body site at test-of-cure (days 4–8). The non-inferiority margin was prespecified at –10%. The primary outcome was assessed in the microbiological intention-to-treat (micro-ITT) population, all participants randomly allocated to a study treatment who received at least one dose of their study treatment and had confirmed ceftriaxone-susceptible N gonorrhoeae isolated from the baseline culture of their urogenital specimen. The safety population comprised all participants who received one or more doses of any study treatment. Between Oct 21, 2019, and Oct 10, 2023, 628 participants were randomly allocated (314 allocated to each treatment group). Overall, 39 (6%) of 628 participants discontinued the study prematurely (20 in the gepotidacin group and 19 in the ceftriaxone plus azithromycin group), with the primary reason being lost to follow-up. The micro-ITT population included 406 participants (202 in the gepotidacin group and 204 in the ceftriaxone plus azithromycin group). Most participants in the micro-ITT population were male (372 [92%] vs 34 [8%] female), and there was a higher percentage of participants who were MSM (290 [71%]) compared with participants who were MSW (82 [20%]). Participants were predominantly White (299 [74%]) or Black or African American (61 [15%]), with 70 (17%) identifying as Hispanic or Latino. Results of the primary analysis of microbiological response at test-of-cure demonstrated microbiological success rates of 92·6% (187 of 202 [95% CI 88·0 to 95·8]) in the gepotidacin group and 91·2% (186 of 204 [86·4 to 94·7]) in the ceftriaxone plus azithromycin group (adjusted treatment difference –0·1% [95% CI –5·6 to 5·5]). Gepotidacin was non-inferior to ceftriaxone plus azithromycin. No bacterial persistence of urogenital N gonorrhoeae was observed at test-of-cure for either group. The gepotidacin group had higher rates of adverse events and drug-related adverse events, mainly due to gastrointestinal adverse events, and almost all were mild or moderate. No treatment-related severe or serious adverse events occurred in either group. Gepotidacin demonstrated non-inferiority to ceftriaxone plus azithromycin for urogenital N gonorrhoeae, with no new safety concerns, offering a novel oral treatment option for uncomplicated urogenital gonorrhoea. GSK and federal funds from the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority.

Glutamate excitotoxicity might contribute to the pathophysiology of amyotrophic lateral sclerosis. In animal models, decreased excitatory aminoacid transporter 2 (EAAT2) overexpression delays disease onset and prolongs survival, and ceftriaxone increases EAAT2 activity. We aimed to assess the safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis in a combined phase 1, 2, and 3 clinical trial. This three-stage randomised, double-blind, placebo-controlled study was done at 59 clinical sites in the USA and Canada between Sept 4, 2006, and July 30, 2012. Eligible adult patients had amyotrophic lateral sclerosis, a vital capacity of more than 60% of that predicted for age and height, and symptom duration of less than 3 years. In stages 1 (pharmacokinetics) and 2 (safety), participants were randomly allocated (2:1) to ceftriaxone (2 g or 4 g per day) or placebo. In stage 3 (efficacy), participants assigned to ceftriaxone in stage 2 received 4 g ceftriaxone, participants assigned to placebo in stage 2 received placebo, and new participants were randomly assigned (2:1) to 4 g ceftriaxone or placebo. Participants, family members, and site staff were masked to treatment assignment. Randomisation was done by a computerised randomisation sequence with permuted blocks of 3. Participants received 2 g ceftriaxone or placebo twice daily through a central venous catheter administered at home by a trained caregiver. To minimise biliary side-effects, participants assigned to ceftriaxone also received 300 mg ursodeoxycholic acid twice daily and those assigned to placebo received matched placebo capsules. The coprimary efficacy outcomes were survival and functional decline, measured as the slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00349622. Stage 3 included 66 participants from stages 1 and 2 and 448 new participants. In total, 340 participants were randomly allocated to ceftriaxone and 173 to placebo. During stages 1 and 2, mean ALSFRS-R declined more slowly in participants who received 4 g ceftriaxone than in those on placebo (difference 0·51 units per month, 95% CI 0·02 to 1·00; p=0·0416), but in stage 3 functional decline between the treatment groups did not differ (0·09, −0·06 to 0·24; p=0·2370). No significant differences in survival between the groups were recorded in stage 3 (HR 0·90, 95% CI 0·71 to 1·15; p=0·4146). Gastrointestinal adverse events and hepatobiliary adverse events were more common in the ceftriaxone group than in the placebo group (gastrointestinal, 245 of 340 [72%] ceftriaxone vs 97 of 173 [56%] placebo, p=0·0004; hepatobiliary, 211 [62%] vs 19 [11%], p<0·0001). Significantly more participants who received ceftriaxone had serious hepatobiliary serious adverse events (41 participants [12%]) than did those who received placebo (0 participants). Despite promising stage 2 data, stage 3 of this trial of ceftriaxone in amyotrophic lateral sclerosis did not show clinical efficacy. The adaptive design allowed for seamless transition from one phase to another, and central venous catheter use in the home setting was shown to be feasible. National Institute of Neurological Disorders and Stroke.

Ceftriaxone increases expression of the astrocytic glutamate transporter, EAAT2, which might protect from glutamate-mediated excitotoxicity. A trial using a novel three stage nonstop design, incorporating Phases I-III, tested ceftriaxone in ALS. Stage 1 determined the cerebrospinal fluid pharmacokinetics of ceftriaxone in subjects with ALS. Stage 2 evaluated safety and tolerability for 20-weeks. Analysis of the pharmacokinetics, tolerability, and safety was used to determine the ceftriaxone dosage for Stage 3 efficacy testing. In Stage 1, 66 subjects at ten clinical sites were enrolled and randomized equally into three study groups receiving intravenous placebo, ceftriaxone 2 grams daily or ceftriaxone 4 grams daily divided BID. Participants provided serum and cerebrospinal fluid for pharmacokinetic analysis on study day 7. Participants continued their assigned treatment in Stage 2. The Data and Safety Monitoring Board (DSMB) reviewed the data after the last participants completed 20 weeks on study drug. Stage 1 analysis revealed linear pharmacokinetics, and CSF trough levels for both dosage levels exceeding the pre-specified target trough level of 1 µM (0.55 µg/mL). Tolerability (Stages 1 and 2) results showed that ceftriaxone at dosages up to 4 grams/day was well tolerated at 20 weeks. Biliary adverse events were more common with ceftriaxone but not dose-dependent and improved with ursodeoxycholic (ursodiol) therapy. The goals of Stages 1 and 2 of the ceftriaxone trial were successfully achieved. Based on the pre-specified decision rules, the DSMB recommended the use of ceftriaxone 4 g/d (divided BID) for Stage 3, which recently closed. ClinicalTrials.gov NCT00349622.

Outpatient parenteral antimicrobial therapy in children is common despite no evidence of its efficacy or safety from clinical trials. We aimed to compare the efficacy and safety of intravenous antibiotic therapy at home with that of standard treatment in hospital for children with moderate to severe cellulitis. The Cellulitis at Home or Inpatient in Children from the Emergency Department (CHOICE) trial was a randomised, controlled, non-inferiority trial in children aged 6 months to 18 years who presented to the emergency department at The Royal Children's Hospital (Melbourne, VIC, Australia) with uncomplicated moderate to severe cellulitis. Participants were randomly assigned to receive either intravenous ceftriaxone (50 mg/kg once daily) at home or intravenous flucloxacillin (50 mg/kg every 6 h) in hospital with web-based randomisation, stratified by age and periorbital cellulitis. The primary outcome was treatment failure, which was defined as no clinical improvement or occurrence of an adverse event, resulting in a change in empiric antibiotics within 48 h of the first dose. Secondary outcomes included adverse events and acquisition of antibiotic-resistant bacteria. Outcomes were assessed in all randomised participants with outcome data (intention-to-treat population) and in all individuals who received treatment as allocated and did not have any major protocol violations (per-protocol population). For home treatment to be non-inferior to hospital treatment, the difference between groups in the proportion of children with treatment failure in the intention-to-treat population had to be less than 15%. This trial is registered with ClinicalTrials.gov, number NCT02334124. Between Jan 9, 2015, and June 15, 2017, we screened 1135 children for eligibility, of whom 190 were randomly assigned to receive ceftriaxone at home (n=95) or flucloxacillin in hospital (n=95). The intention-to-treat analysis comprised 188 children (93 in the home group and 95 in the hospital group) because two children in the home group were found to be ineligible after randomisation and were excluded. Treatment failure occurred in two (2%) children in the home group and in seven (7%) children in the hospital group (risk difference −5·2%, 95% CI −11·3 to 0·8, p=0·088). In the per-protocol analysis, treatment failure occurred in one (1%) of 89 children in the home group and in seven (8%) of 91 children in the hospital group (−6·5%, −12·4 to −0·7). Fewer children treated at home than in hospital had an adverse event (two [2%] vs ten [11%]; p=0·048). There was no difference between groups in rates of nasal acquisition of meticillin-resistant Staphylococcus aureus or gastrointestinal acquisition of extended-spectrum β-lactamase-producing bacteria or Clostridium difficile after 3 months. Home treatment with intravenous ceftriaxone is not inferior to treatment in hospital with intravenous flucloxacillin for children with cellulitis. The standard of care for the intravenous treatment of uncomplicated cellulitis in children should be home or outpatient care when feasible. The Royal Children's Hospital Foundation and Murdoch Children's Research Institute.

Ceftriaxone with or without a macrolide antibiotic is a recommended treatment for patients with community-acquired pneumonia requiring hospital admission and intravenous antibiotic treatment. We aimed to assess the efficacy and safety of ceftaroline fosamil compared with ceftriaxone in the treatment of Asian patients admitted to hospital with community-acquired pneumonia. In this international, randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial, adult Asian patients with Pneumonia Outcomes Research Team (PORT) risk class III–IV acute community-acquired pneumonia were randomly assigned (1:1) to receive intravenous ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (2 g every 24 h) for 5–7 days. Patients were randomly assigned via centralised telephone and web-based system; patients and treating clinicians were masked to treatment allocation. Investigators who did study assessments remained masked to treatment allocation until completion of the study. The primary endpoint was clinical cure at the test-of-cure visit (8–15 days after last dose of study drug) in the clinically evaluable population. Non-inferiority of ceftaroline fosamil was defined as a lower limit of the two-sided 95% CI for the difference in the proportion of patients clinically cured of −10% or higher; if non-inferiority was achieved, superiority was to be concluded if the lower limit of the 95% CI was greater than 0%. This trial is registered with ClinicalTrials.gov, number NCT01371838. Between Dec 13, 2011, and April 26, 2013, 847 patients were enrolled at 64 centres in China, India, South Korea, Taiwan, and Vietnam, of whom 771 were randomly assigned and 764 received study treatment. In the clinically evaluable population (n=498) 217 (84%) of 258 patients in the ceftaroline fosamil group and 178 (74%) of 240 patients in the ceftriaxone group were clinically cured at the test-of-cure visit (difference 9·9%, 95% CI 2·8–17·1). The superiority of ceftaroline fosamil was consistent across all preplanned patient subgroup analyses (split by age 65 years, age 75 years, sex, PORT risk class, and previous antibiotic use) apart from patients younger than 65 years. The frequency of adverse events was similar between treatment groups and the safety results for ceftaroline fosamil were consistent with the cephalosporin class and previous clinical trial data. Ceftaroline fosamil 600 mg given every 12 h was superior to ceftriaxone 2 g given every 24 h for the treatment of Asian patients with PORT III–IV community-acquired pneumonia. These data suggest that ceftaroline fosamil should be regarded as an alternative to ceftriaxone in empirical treatment regimens for this patient population. AstraZeneca.

Background. Ceftaroline, the active form of ceftaroline fosamil, is a broad-spectrum cephalosporin with bactericidal activity against pathogens causing community-acquired pneumonia (CAP), including Streptococcus pneumoniae. Ceftaroline was evaluated for the treatment of CAP in 2 randomized, double-blind, multicenter trials: Ceftaroline Community Acquired Pneumonia Trial versus Ceftriaxone in Hospitalized Patients (FOCUS) 1 and FOCUS 2. Methods. Patients hospitalized (but not admitted to an intensive care unit) with Pneumonia Outcomes Research Team risk class III or IV CAP requiring intravenous therapy were randomized to ceftaroline 600 mg every 12 h or ceftriaxone 1 g every 24 h for 5–7 days. Patients in FOCUS 1 received 2 doses of oral clarithromycin 500 mg every 12 h on day 1. Results. In the individual trials, clinical cure rates in the clinically evaluable (CE) population for ceftaroline versus ceftriaxone were as follows: FOCUS 1, 86.6% vs 78.2% (difference, 8.4%; 95% confidence interval [CI], 1.4%–15.4%); FOCUS 2, 82.1% vs 77.2% (difference, 4.9%; 95% CI, −2.5% to 12.5%). In the integrated analysis, 614 patients received ceftaroline and 614 received ceftriaxone. Of the CE patients treated with ceftaroline, 84.3% achieved clinical cure, compared with 77.7% of ceftriaxone-treated patients (difference, 6.7%; 95% CI, 1.6%–11.8%). Clinical cure rates in the modified intent-to-treat efficacy population were 82.6% versus 76.6% for ceftaroline and ceftriaxone (difference, 6.0%; 95% CI, 1.4%–10.7%). Ceftaroline and ceftriaxone were well tolerated; rates of adverse events, serious adverse events, deaths, and premature discontinuations caused by an adverse event were similar in both treatment arms. Conclusions. Ceftaroline was noninferior to ceftriaxone in the individual trials. In this integrated analysis, clinical cure rates for the ceftaroline group were numerically higher than those for the ceftriaxone group. Ceftaroline was well tolerated, with a safety profile similar to that of ceftriaxone.

Bacterial meningitis is associated with high morbidity and mortality. This randomized, double-blind study in Malawi involving 465 patients with acute meningitis, 90% of whom were HIV-positive, showed no significant difference in morbidity or mortality among patients treated with intravenous versus intramuscular ceftriaxone or among those who did or did not receive corticosteroids. This study showed no significant difference in morbidity or mortality among patients treated with intravenous versus intramuscular ceftriaxone or among those who did or did not receive corticosteroids. Bacterial meningitis ranks 10th as a cause of death from infectious diseases worldwide 1 and is common in the developing world. 2 Its incidence in Malawi, where most adult medical inpatients have advanced human immunodeficiency virus (HIV) infection, is 50 per 100,000 adult person-years, 3 more than 10 times the incidence seen in industrialized countries. 4 Streptococcus pneumoniae is the most common causative organism, with a mortality of 65% 5 as compared with 26 to 34% 6 , 7 in industrialized countries before the introduction of adjuvant therapy with corticosteroids. The host inflammatory response in bacterial meningitis contributes to neuronal injury 8 and can be modulated by corticosteroids. . . .

Objective. We sought to compare daptomycin with ceftriaxone for the treatment of patients with community-acquired pneumonia (CAP). Methods. Two phase-3 randomized, double-blind trials that enrolled adult patients hospitalized with CAP were conducted. Patients received intravenous daptomycin (4 mg/kg) or ceftriaxone (2 g) once daily for 5–14 days. Aztreonam could be added for patients with gram-negative infections. Clinical responses at the test-of-cure visit among patients in the intent-to-treat and clinically evaluable populations were the primary efficacy end points. Results. After combining data from the trials, the intent-to-treat population included 413 daptomycin-treated patients and 421 ceftriaxone-treated patients, and the clinically evaluable population included 369 daptomycin-treated patients and 371 ceftriaxone-treated patients. In the intent-to-treat population, the clinical cure rate among daptomycin-treated patients with CAP was 70.9%, compared with 77.4% among ceftriaxone-treated patients (95% confidence interval for the difference between cure rates, −12.4% to −0.6%). In the clinically evaluable population, the clinical cure rate was lower among daptomycin-treated patients (79.4%) than among ceftriaxone-treated patients (87.9%; 95% confidence interval for the difference between cure rates, −13.8% to −3.2%). A posthoc analysis revealed that, among those who had received up to 24 h of prior effective therapy, cure rates were similar among daptomycin-treated (90.7%) and ceftriaxone-treated patients (88.0%; 95% confidence interval for the difference between cure rates, −6.1% to 11.5%). Conclusions. Daptomycin is not effective for the treatment of CAP, including infections caused by Streptococcus pneumoniae and Staphylococcus aureus. The observation that as little as 24 h of prior effective therapy may impact clinical outcome suggests that trials to evaluate CAP treatment may need to exclude patients who have received any potentially effective therapy before enrollment.

In randomized, double-blind trials, there was no significant difference in the health-related quality of life. Antibiotic treatment is highly effective for the acute and late septic manifestations of Lyme disease, which is caused by the tick-borne bacterium Borrelia burgdorferi . 1 However, some patients have persistent fatigue, myalgias, arthralgias without arthritis, dysesthesias or paresthesias, or mood and memory disturbances after the standard courses of antibiotics. 2 , 3 Persistent symptoms have been reported both in patients who are seropositive for antibodies against B. burgdorferi and in patients who are seronegative. Although the cause of persistent symptoms has not been determined, their temporal association with B. burgdorferi infection has led some physicians to treat patients with prolonged courses of . . .

Background Pneumonia is the most common infection after out-of-hospital cardiac arrest (OHCA) occurring in up to 65% of patients who remain comatose after return of spontaneous circulation. Preventing infection after OHCA may (1) reduce exposure to broad-spectrum antibiotics, (2) prevent hemodynamic derangements due to local and systemic inflammation, and (3) prevent infection-associated morbidity and mortality. Methods The ceftriaxone to PRevent pneumOnia and inflammaTion aftEr Cardiac arrest (PROTECT) trial is a randomized, placebo-controlled, single-center, quadruple-blind (patient, treatment team, research team, outcome assessors), non-commercial, superiority trial to be conducted at Maine Medical Center in Portland, Maine, USA. Ceftriaxone 2 g intravenously every 12 h for 3 days will be compared with matching placebo. The primary efficacy outcome is incidence of early-onset pneumonia occurring < 4 days after mechanical ventilation initiation. Concurrently, T cell-mediated inflammation bacterial resistomes will be examined. Safety outcomes include incidence of type-one immediate-type hypersensitivity reactions, gallbladder injury, and C lostridioides difficile -associated diarrhea. The trial will enroll 120 subjects over approximately 3 to 4 years. Discussion The PROTECT trial is novel in its (1) inclusion of OHCA survivors regardless of initial heart rhythm, (2) use of a low-risk antibiotic available in the USA that has not previously been tested after OHCA, (3) inclusion of anti-inflammatory effects of ceftriaxone as a novel mechanism for improved clinical outcomes, and (4) complete metagenomic assessment of bacterial resistomes pre- and post-ceftriaxone prophylaxis. The long-term goal is to develop a definitive phase III trial powered for mortality or functional outcome. Trial registration ClinicalTrials.gov NCT04999592 . Registered on August 10, 2021.