Objectives: Novel antimicrobials for treatment of gonorrhoea are imperative. The first-in-class spiropyrimidinetrione zoliflodacin is promising and currently in an international Phase 3 randomized controlled clinical trial (RCT) for treatment of uncomplicated gonorrhoea. We evaluated the in vitro activity of and the genetic conservation of the target (GyrB) and other potential zoliflodacin resistance determinants among 1209 consecutive clinical Neisseria gonorrhoeae isolates obtained from 25 EU/European Economic Area (EEA) countries in 2018 and compared the activity of zoliflodacin with that of therapeutic antimicrobials currently used.
Methods: MICs of zoliflodacin, ceftriaxone, cefixime, azithromycin and ciprofloxacin were determined using an agar dilution technique for zoliflodacin or using MIC gradient strip tests or an agar dilution technique for the other antimicrobials. Genome sequences were available for 96.1% of isolates.
Results: Zoliflodacin modal MIC, MIC50, MIC90 and MIC range were 0.125, 0.125, 0.125 and ≤0.004-0.5 mg/L, respectively. The resistance was 49.9%, 6.7%, 1.6% and 0.2% to ciprofloxacin, azithromycin, cefixime and ceftriaxone, respectively. Zoliflodacin did not show any cross-resistance to other tested antimicrobials. GyrB was highly conserved and no zoliflodacin gyrB resistance mutations were found. No fluoroquinolone target GyrA or ParC resistance mutations or mutations causing overexpression of the MtrCDE efflux pump substantially affected the MICs of zoliflodacin.
Conclusions: The in vitro susceptibility to zoliflodacin was high and the zoliflodacin target GyrB was conserved among EU/EEA gonococcal isolates in 2018. This study supports further clinical development of zoliflodacin. However, additional zoliflodacin data regarding particularly the treatment of pharyngeal gonorrhoea, pharmacokinetics/pharmacodynamics and resistance selection, including suppression, would be valuable.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1093/jac/dkab024 | DOI Listing |
BMC Glob Public Health
September 2024
Global Antibiotic Research & Development Partnership, Geneva, Switzerland.
New, first-in-class oral antibiotics like zoliflodacin, developed in a public-private partnership, require an optimal introduction strategy while ensuring antibiotic stewardship. Zoliflodacin, given as a single dose for uncomplicated urogenital gonorrhoea, recently demonstrated non-inferiority to ceftriaxone plus azithromycin and safety in a phase 3 randomised controlled trial. Following regulatory approval, zoliflodacin could improve sexually transmitted infection (STI) management and help address the threat of untreatable gonorrhoea, as levels of resistance to current first-line treatments increase.
View Article and Find Full Text PDFInt J Mol Sci
October 2024
Medicines Discovery Institute, Cardiff University, Cardiff CF10 3AT, UK.
One of the challenges for experimental structural biology in the 21st century is to see chemical reactions happen. () DNA gyrase is a type IIA topoisomerase that can create temporary double-stranded DNA breaks to regulate DNA topology. Drugs, such as gepotidacin, zoliflodacin and the quinolone moxifloxacin, can stabilize these normally transient DNA strand breaks and kill bacteria.
View Article and Find Full Text PDFExpert Rev Anti Infect Ther
September 2024
Department of Pediatrics, Division of Infectious Diseases, State University of New York Downstate Health Sciences University, Brooklyn, NY, USA.
Introduction: The rise in antibiotic resistance to poses a substantial threat to effective gonorrhea treatment. Historical progression of resistance from sulfonamides to the more recent declines in efficacy of fluoroquinolones and susceptibilities of ceftriaxone highlight the urgent need for novel therapeutic approaches, necessitating the examination of alternative and new antibiotics.
Areas Covered: This review examines the potential of repurposing older antibiotics for gonorrhea treatment with a focus on their efficacy and limitations.
Int J STD AIDS
November 2024
STI Unit, Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
ACS Infect Dis
August 2024
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!