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Standards for Treatment and Control Regimens in Therapeutic Trials for Gonorrhea: Lessons From a "Failed" Trial.

Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a worldwide crisis that has begun to reignite interest in antibiotic development for gonorrhea treatment. However, the drug development pipeline for gonorrhea treatment remans sparse. Delafloxacin is a novel fluoroquinolone antibiotic that is active against N. gonorrhoeae, including strains with quinolone resistance and those with reduced susceptibility to cephalosporins. Its mechanism of action may be less likely to stimulate resistance, and its pharmacokinetics suggested likely efficacy in a single dose against uncomplicated gonorrhea. In this issue, Hook et al report the results of a phase 3, multicenter, randomized controlled trial (RCT) comparing delafloxacin in a single oral dose of 900 mg to ceftriaxone 250 mg intramuscularly in patients with uncomplicated gonorrhea, using a noninferiority design. Not many women could be enrolled, but otherwise the methodology, execution, and analyses are impeccable. The results are disappointing. For urogenital gonorrhea in men and women, the modified intention-to-treat analysis, which assumed treatment failure when patients failed to return for followup, found that infection was cured in only 194 (85.1%) of 228 patients treated with delafloxacin, compared with 91 (91.0%) of 100 given ceftriaxone. Although this difference is not statistically significant by traditional standards (P = 0.16), the 95% confidence interval of the non-inferiority margin was −13.8% to 1.36%. This lower bound exceeds the standard of −10% specified in the study design; therefore, delafloxacin was not noninferior to ceftriaxone. The cure rates in patients who returned for followup may be higher, because available data indicate that ceftriaxone remains substantially more effective than 91% for anogenital gonorrhea. Ancillary analyses raise other doubts about delafloxacin. Cure with delafloxacin was achieved in 175 (99.4%) of 176 urogenital infections caused by N. gonorrhoeae with delafloxacin minimum inhibitory concentration (MIC) no higher than 0.002 μg/mL. In contrast, for the 48 patients whose isolates had MICs 0.008 μg/mL or greater, only 17 (35%) were cured (P < 0.001). In addition, urethral infection was cured by delafloxacin in only 54 (70%) of 77 men who have sex with men (MSM), compared with 139 (92.7%) of 150 women and heterosexual men with cervical or urethral gonorrhea (P = 0.017). This outcome interacted with the susceptibility of N. gonorrhoeae to delafloxacin: 42% of urethral isolates from MSM had delafloxacin MICs 0.008 μg/mL or greater, compared with 11% of isolates from women and heterosexual men (P < 0.001). This is consistent with observations of reduced susceptibility of N. gonorrhoeae to penicillin in MSM going back to the 1970s and subsequently documented for all classes of antibiotics. Persistent rectal and pharyngeal infections were more common with delafloxacin than ceftriaxone, but there were too few infections for conclusive interpretation. Notwithstanding the disappointing results, this is an important study, and we congratulate the authors for publishing it. The study compared delafloxacin alone with ceftriaxone alone, without azithromycin or doxycycline cotreatment. That was the correct decision, as it was for another recent trial by some of the same investigators, comparing zoliflodacin with ceftriaxone. This is the preferred design for future studies of new treatments for gonorrhea. Combination treatment has been policy in the United States for over 3 decades and is likely to remain so in the near future. Therefore, from a regulatory standpoint, a case can be made to compare new drugs with the standard of care for routine treatment, currently ceftriaxone with azithromycin. However, we challenge that conclusion. Dual treatment was first implemented to treat coincident infection with Chlamydia trachomatis, present in 15% to 40% of persons with gonorrhea. We both had a hand in promoting 2 additional rationales: that cotherapy might improve treatment outcomes; and that it might reduce the potential for selection of AMR in N. gonorrhoeae. At the time, few if any gonorrhea treatment failures had been observed with dual therapy, and it was biologically plausible that giving 2 antibiotics with differing mechanisms of action would reduce the potential for resistance. This rationale has been cited in national