Clinical Pearls & Morning Reports
Zoliflodacin is an investigational spiropyrimidinetrione antimicrobial agent that has received “qualified infectious disease product” and subsequent “fast track” designations from the Food and Drug Administration for development solely as an oral treatment for gonococcal infections. Taylor et al. conducted a multicenter, randomized, open-label, phase 2 trial, that compared the efficacy and safety of a single dose of 2 g or 3 g of oral zoliflodacin with 500 mg of intramuscular ceftriaxone for the treatment of uncomplicated urogenital gonorrhea. Read the latest NEJM Original Article here.
Q: Is the incidence of gonorrhea in the United States increasing?
A: The incidence of gonorrhea in the United States increased by 67% from 2013 through 2017. 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. Unfortunately, no highly reliable, orally administered, and affordable alternative antimicrobial agents with minimal side effects are currently available.
Q: What is the mechanism of action of zoliflodacin?
A: The mechanism of action of zoliflodacin differs from currently available therapies in that it inhibits microbial biosynthesis by arresting the cleaved covalent gyrase complex and the formation of fused circular DNA required for biosynthesis. Zoliflodacin is also active against Chlamydia trachomatis, Chlamydophila pneumonia, Mycoplasma genitalium, and ureaplasma species.
A: In the trial by Taylor et al., the primary efficacy measure (microbiologic cure) was the proportion of participants with urogenital infection who had conversion from a positive baseline N. gonorrhoeae culture to a negative culture at the test-of-cure visit. Zoliflodacin was effective in treating gonococcal urogenital and rectal infections. Urogenital infections were cured in 55 of 57 participants (96%) in the group that received 2 g of zoliflodacin, 54 of 56 participants (96%) in the group that received 3 g of zoliflodacin, and 28 of 28 participants (100%) in the group that received 500 mg of ceftriaxone. All rectal infections in all groups were cured. The efficacy of zoliflodacin was lower among participants with pharyngeal infections than among those with urogenital and rectal infections. Pharyngeal gonorrhea was cured in 4 of 8 patients (50%) in the group that received 2 g of zoliflodacin and 9 of 11 patients (82%) in the group that received 3 g of zoliflodacin. All four pharyngeal infections in the ceftriaxone group were cured. A total of 21 participants reported adverse events that investigators assessed as being related to zoliflodacin; most such events were gastrointestinal and self-limiting.
A: Microbiologic cure was defined on the basis of negative gonococcal cultures instead of nucleic acid amplification tests (NAATs). Regulatory agencies have preferred culture over NAAT for the assessment of cure because of the concern that residual nucleic acids from dead organisms may remain after successful therapy. Therefore, an NAAT obtained at a test-of-cure visit may result in false positive results and an inability to determine microbiologic cure.