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Reply to Yang et al.

TO THE EDITOR—We thank Yang and colleagues for their reflections on our article [1]. An a priori power calculation was not performed, because this study was not meant to be a noninferiority trial. Our study was a retrospective study and subject to biases inherent to such analysis, even though the sample size was large and subjects were followed for long periods of time. An a posteriori power estimation at the .05 significance level for various hazard ratios (HRs) for benzathine penicillin G (BPG) dosing suggested that, with 80% power, we would have been able to detect a statistically significant difference in dosing for HRs <0.74 and >1.36. Yang and colleagues also raise concern about within-subject response correlation due to our use of multiple episodes contributed by the same individual. It was not clear that any correlation existed; regardless, our models treated these outcomes as clustered by using frailty Cox proportional hazards models. Beyond this, sensitivity analyses excluded any subsequent episode treatments and found no difference in parameter estimates; results are detailed in Supplementary Table 1 [1]. We examined and discussed in the article the point raised regarding the effect of the use of intercurrent antibiotics (with activity against Treponema pallidum). One hundred twelve of the 478 included cases (23%) received 1 or more courses of antibiotics that had activity against T. pallidum between the start of their syphilis treatment and when treatment response was assessed. Azithromycin use was the most frequent (49 reported instances), followed by doxycycline (35 reported instances), amoxicillin-based regimens (33 instances), ceftriaxone (23 instances), oral penicillin (8 instances), and erythromycin (1 instance). As described in Supplementary Table 3 [1], after adjusting for intercurrent antibiotics, treatment response was similar among those who received 1 or more doses of BPG and resulted in minimal modification of the effect size. These results indicated that intercurrent antibiotic use had no appreciable effect on the primary endpoint. The difference in definitions is a likely reason for the different observations between our study and those of Yang et al [1, 2]. In our study, response to treatment was similar in those receiving 1 or >1 dose of BPG [1], whereas Yang et al observed that the use of single-dose BPG resulted in more failures [2]. Yang et al considered treatment to have failed if subjects exhibited a 4-fold decline in nontreponemal (NTr) titer followed by a 4-fold increase [2]. By this definition, subjects may have inadvertently been considered to have failed treatment when they were in fact reinfected. We defined treatment failure as a failure to achieve a 4-fold decline in NTr titer [1]. A majority of our patients (63%) had an intervening negative NTr test before the increase in NTr titers was noted, pointing to reinfection rather than relapse as the cause for the increase in NTr titers. When similar definitions are utilized, the observations from the 2 studies are similar: 88.1% receiving 1 dose of BPG and 86.0% receiving 3 doses of BPG exhibited response [2]. We agree that prospective randomized studies are needed to answer this question conclusively.