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A single oral dose of the investigational antibiotic zoliflodacin performs as well as intramuscular ceftriaxone (Rocephin, Hoffman-LaRoche) for treatment of uncomplicated urogenital and rectal gonococcal infections, a multicenter phase 2 trial suggests.
“N [Neisseria] gonorrhoeae has developed resistance to every class of antibiotic recommended for treatment, which now includes cephalosporins and macrolides. Reports of multidrug-resistant N gonorrhoeae and the possibility of untreatable gonorrhea underscore the need for the development of new antimicrobial agents,” Stephanie N. Taylor, MD, and coinvestigators note.
“This phase 2 trial creates equipoise for larger, more definitive studies of zoliflodacin,” they write.
Trial results were published online November 7 in the New England Journal of Medicine.
Taylor, from the Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, and coinvestigators enrolled men and women who had signs or symptoms of uncomplicated urogenital gonorrhea or untreated urogenital gonorrhea or who had recently had sexual contact with an infected person.
The trial randomly assigned patients to receive a single oral 2-g dose (72 patients) or 3-g dose (67 patients) of zoliflodacin (Entasis Therapeutics), a first-in-class inhibitor of DNA biosynthesis, and 41 patients to receive a single 500-mg intramuscular dose of ceftriaxone on an open-label basis. Microbiologic cure was assessed with culture a mean of 6 days later.
Among evaluable patients in the intention-to-treat population, the rate of microbiologic cure at urogenital sites was 96% for those who received 2 g of zoliflodacin, 96% for those who received 3 g of zoliflodacin, and 100% for those who received ceftriaxone. Confidence intervals were overlapping.
All three regimens cured 100% of rectal infections, which were seen in small numbers of patients.
However, the rate of cure of pharyngeal infections, also uncommon, was 50% with 2 g of zoliflodacin and 82% with 3 g of zoliflodacin, compared with 100% with ceftriaxone.
“[I]t has been speculated that poor drug penetration into pharyngeal tissue may be responsible for most pharyngeal treatment failures rather than reinfection or resistant organisms,” the authors explain.
Findings were essentially the same in per-protocol analyses.
At safety visits conducted about a month after treatment, 24 adverse events were reported in the group given 2 g of zoliflodacin, 37 in the group given 3 g of zoliflodacin, and 23 in the group given ceftriaxone. Twenty-one patients experienced adverse events that were deemed to be related to zoliflodacin. These events were predominantly gastrointestinal and were self-limiting.
Single-drug regimens were used in the trial to facilitate comparison, according to the investigators. “However, current US and European guidelines recommend dual therapy for gonorrhea — theoretically, to slow the development of antimicrobial resistance and to treat concomitant chlamydial infection,” they note. “Should the development of zoliflodacin for gonorrhea therapy be pursued, its use in combination with another active agent would probably be the goal.”
New Antibiotics Needed as Treatment Options Dwindle
In a related editorial, Susan Blank, MD, MPH, from the Division of Disease Control, New York City Department of Health and Mental Hygiene, and the Centers for Disease Control and Prevention, and Demetre C. Daskalakis, MD, MPH, from the Division of Disease Control, New York City Department of Health and Mental Hygiene, agree that new antibiotics are needed at a time when gonorrhea infections are on the rise and treatment options are dwindling.
“Given the challenges in clinical follow-up in this patient population, the single-dose regimen is promising,” they write. “Though the study was small, the efficacy shown is encouraging, and zoliflodacin has the potential to be an effective antibiotic for treating gonorrhea, though the limited activity observed in key anatomical sites of infection such as the pharynx will need to be better defined….
“With more dedicated research on sexually transmitted infections to advance biomedical innovation and develop better diagnostics, therapeutics, and even vaccines, we may be able to avoid the advent of gonorrhea that is either treatable only with expensive intravenous or intramuscular agents or entirely untreatable,” the editorialists add.
Dr Taylor received grants from the National Institutes of Health during the conduct of the study, as well as grants from Melinta, Becton-Dickinson, Roche Molecular, Hologic, and Beckman Coulter and grants and personal fees from GlaxoSmithKline outside the study. Several coauthors report various financial relationships with Activbiotics, AstraZeneca (the parent company of Entasis), Becton-Dickinson, Cepheid, Gilead, GlaxoSmithKline, Hologic, Melinta Therapeutics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Roche Molecular, and Warner-Chlicott. Dr Blank and Dr Daskalakis have disclosed no relevant financial relationships.
N Engl J Med. 2018;379:1795-1787, 1835-1845.
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