Effect on the 24-hour diurnal curve of intraocular pressure of a fixed ratio combination of timolol 0.5% and pilocarpine 2% in patients with COAG not controlled on timolol 0.5%.

Eight patients with chronic open-angle glaucoma who had an intraocular pressure greater than 24 mm Hg at some time during the day while taking timolol 0.5% twice daily were given the fixed ratio combination of timolol 0.5% with pilocarpine 2% (TP2) twice daily. By comparing full 24-hour diurnal curves on timolol with those on TP2 it was possible to show that all patients except one (at a single timepoint) had an IOP less than 22 mm Hg when changed to TP2. The mean IOPs, the area under the diurnal pressure curve, and the diurnal variation were all significantly lower on TP2 twice daily than on timolol 0.5% twice daily

Designing a pathogen-focused study to address the high unmet medical need represented by carbapenem-resistant gram-negative pathogens \u2013 the international, multicenter, randomized, open-label, phase 3 credible-cr study

Carbapenem-resistant (CR) Gram-negative infections, including those caused by Enterobacteriaceae and the non-fermenters, represent the greatest unmet need for new effective treatments. The clinical development of new antibiotics for the treatment of CR infections is challenging and should focus on the individual pathogens irrespective of the infection site. However, the drug approval pathway is generally infection-site specific and rarely includes such drug-resistant pathogens. To overcome this limitation, a streamlined clinical development program may include a pathogen-focused clinical study, such as the CREDIBLE-CR study, to meet the expectations of some health authorities (ie, the European Medicines Agency [EMA]) and the medical community. Cefiderocol is a novel siderophore cephalosporin designed to target CR pathogens, including CR strains of Enterobacteriaceae (CRE), Pseudomonas aeruginosa, Acinetobacter baumannii, and also Stenotrophomonas maltophilia, which is intrinsically CR. The CREDIBLE-CR study was planned to evaluate cefiderocol in patients with CR Gram-negative infections regardless of species or infection-site source. Rapid diagnostic testing and/or selective media were provided to facilitate detection of CR pathogens to rapidly enroll patients with nosocomial pneumonia, bloodstream infection/sepsis, or complicated urinary tract infection. Patients were randomized 2:1 to receive cefiderocol or best available therapy. There were no pre-specified statistical hypotheses for this study, as the sample size was driven by enrollment feasibility and not based on statistical power calculations. The objective of the CREDIBLE-CR study was to provide descriptive evidence of the efficacy and safety of cefiderocol for the target population of patients with CR infections, including the non-fermenters. The CREDIBLE-CR study is currently the largest pathogen-focused, randomized, open-label, prospective, Phase 3 clinical study to investigate a new antibiotic in patients with CR Gram-negative infections. Here we describe the design of this pathogen-focused study and steps taken to aid patient enrollment into the study within an evolving regulatory environment