The best treatment for urogenital infections with Chlamydia trachomatis (CT) is not clear. Accumulating evidence suggests that azithromycin is less efficacious than doxycycline, but no study has been sufficient to prompt a widespread change in practice or sexually transmitted disease (STD) treatment guidelines. Recently, Geisler and colleagues1 published the results of a randomized controlled trial (RCT) of azithromycin versus doxycycline for the treatment of urogenital CT infections among adolescents in youth correctional facilities. The efficacy of doxycycline was 100% and azithromycin 96.8%, but the confidence intervals around the 3.2% difference did not meet the study's prespecified threshold to establish the noninferiority of azithromycin. Most of the men included in the Geisler study were asymptomatic, and some evidence suggests that men with symptomatic urethritis have a poorer response to azithromycin. In a meta-analysis of trials that compared azithromycin with doxycycline for the treatment of urogenital chlamydial infection, Kong and colleagues2 estimated a 7% increased efficacy for doxycycline compared with azithromycin for the treatment of symptomatic urethral infection in men. Indeed, Geisler and colleagues found a similar, though nonsignificant, differential efficacy in a subanalysis of their study data: 10% (2 of 20) of men who reported painful urination failed azithromycin compared with 2% (2 of 82) of men who did not report painful urination (P = 0.17).
Three recent prospective studies have assessed azithromycin treatment failure among men with symptomatic chlamydial urethritis treated with single-dose azithromycin, 2 of which compared azithromycin with doxycycline. In 2011, Schwebke and colleagues3 reported the results of an RCT for the treatment of nongonococcal urethritis (NGU) with doxycycline plus or minus tinidazole versus azithromycin plus or minus tinidazole. In that study, azithromycin was significantly less effective than doxycycline for the treatment of urogenital CT infections in men (77% vs 95%, P = 0.01). In 2013, Manhart and colleagues4 reported the results of an RCT for the treatment of NGU, but found no significant difference between azithromycin and doxycycline (86% vs 90%, P = 0.56). Also, in 2013, Kissinger and colleagues5 reported the results of a prospective study that retested men 4 to 6 weeks after treatment for CT urethritis. They reported a 94% success rate with azithromycin treatment, but over half of the men with CT redetection reported sexual exposure in the interim between treatment and retesting. This result suggested that a high proportion of putative treatment failures in the other 2 studies could have been explained by reinfection from reexposure to a prior partner or from a new partner.
In an exemplary instance of scientific cooperation, the authors who conducted the 3 studies described above collaborated to reanalyze their data with harmonized methods to generate a more precise estimate of azithromycin treatment failure for the treatment of symptomatic urethritis in men who have sex with women (MSW).6 They were thus able to examine the degree to which reexposure, and likely reinfection, or detection of remnant chlamydial DNA due to early (<3 weeks) test-of-cure sampling accounted for redetection of CT in each of the studies and how differential classification of uncertain cases affected the results. The study found that, overall, 6.2% to 12.8% of urethral CT infections failed treatment. This is higher than the 5% threshold considered acceptable by the World Health Organization for a medication used to treat a sexually transmitted infection (STI).7
The analysis by Kissinger and colleagues raises a number of important questions. First, what causes azithromycin treatment failure? Antimicrobial resistance is one potential explanation, but macrolide resistance in human chlamydial strains has not been conclusively demonstrated.8 One report described an isolate with high-level resistance to azithromycin in vitro,9 but this was later shown to be due to heterotypic survival of the organism rather than true resistance.10 That is, some organisms survived in the presence of azithromycin and others did not, but there was no difference in the minimum inhibitory concentration to azithromycin between surviving and non-surviving strains. The same phenomenon was observed with 44 other CT isolates from patients whose infections were successfully treated with azithromycin, and thus, could not account for treatment failure. Antimicrobial susceptibility in CT is difficult to assess or monitor because in vitro testing does not correlate well with clinical persistence.11,12 Treatment failure of an infectious disease can be due to several other factors besides antimicrobial resistance, including inadequate tissue penetration of the antibiotic, subject variability in bioavailability, or inadequate concentration or duration of the antibiotic for the pathogen's level of susceptibility. Although the development of decreased susceptibility to azithromycin among CT remains a possibility, it is unlikely that antimicrobial resistance accounts for many treatment failures at present.
Redetection of CT after treatment can also result from reexposure, and disentangling treatment failure from reinfection is a perennial challenge for STI clinical researchers. Even with successful treatment, men with chlamydial urethritis are at substantial risk of reinfection. The findings of the Kissinger study provide a reminder of the importance of retesting to detect reinfection. Comprehensive treatment of a patient with chlamydial urethritis is not limited to a dose of azithromycin or a course of doxycycline, but must also include partner treatment and a plan for retesting in 3 months. In many, perhaps most, areas of the United States, health departments do not contact the sex partners of persons diagnosed with CT infection because there are insufficient resources to do so in the context of competing STD/human immunodeficiency virus disease control priorities. Thus, medical providers who diagnose chlamydia must address partner treatment, including through the use of expedited partner therapy where legal and available.
Has azithromycin treatment failure of chlamydial urethritis become more common over time? As Kissinger and colleagues6 point out, a meta-analysis from 2002 estimated the failure rate to be 3% and another in 2014 estimated it to be 6%.2 The current study finds a lower limit of treatment failure of 6.2% (95% confidence interval [CI], 3.2–9.2%). In the absence of consistent data with which to monitor chlamydia treatment failure over time, it is impossible to answer this question with certainty. However, almost all of the studies in the earlier meta-analysis used culture for detection of CT, and several studies in the latter meta-analysis used more sensitive molecular methods. Furthermore, rates of CT redetection observed in earlier studies are within the range of treatment failure reported by Kissinger and colleagues. The key study demonstrating the equivalence of azithromycin and doxycycline for the treatment of non-gonococcal urethritis was an RCT in 11 US STD Clinics published in 1995.14 Among men with chlamydial urethritis in that study, the microbiological cure rates were 83% for azithromycin (95% CI, 65–94%) and 90% (95% CI, 68–98%) for doxycycline. To us, this suggests that we are not identifying an emerging problem, but rather are more clearly recognizing the long-standing problem of azithromycin treatment failure.
What are the implications of the azithromycin treatment failure prevalence being higher than the World Health Organization 5% threshold? Although the 5% level does not have a specific clinical or epidemiological implication in and of itself, it does serve as a clear guideline to treating providers and to our field more broadly. In general, if we have the option of a treatment with greater efficacy at comparable or superior safety and cost it should be the preferred therapy. Patient adherence to therapy is another important aspect of treatment decisions. Azithromycin has the major advantage of being administered as a single dose, whereas doxycycline is given as a twice daily 7-day regimen. On this basis alone, many providers prefer azithromycin and question whether the efficacy of doxycycline observed in trials translates into effectiveness in practice. However, we do not know what level of adherence to doxycycline is necessary for effective treatment. Studies of chlamydial treatment with less frequent doxycycline dosing (eg, 200 mg on day 1 followed by 100 mg daily for 6–9 days) have shown high efficacy,13 and with a half-life of 18 hours, it is plausible that incomplete adherence to doxycycline could still achieve cure. Although practitioners tend to prefer single dose therapy for STIs, it is worth examining that preference closely when the adequacy of single dose therapy is in question. Many patients with chlamydia will not have difficulty adhering to doxycycline for a week. A reasonable treatment approach would be to use doxycycline preferentially, but use azithromycin when a patient's ability to adhere to treatment is in doubt.
The studies of focus in the Kissinger paper were conducted in MSW. This is important to note because men who have sex with men are at risk for rectal CT infection, for which retrospective data suggest azithromycin treatment is substantially less effective than doxycycline.15,16 These retrospective studies are inherently limited, and a prospective RCT is needed to definitively address this question. For MSW with chlamydial urethritis, however, the evidence is clear: about 6% to 13% will fail treatment with azithromycin, and this level is higher than the standard we generally accept for treatment of an STI.
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