Questioning Azithromycin for Chlamydial Infection

Single dose azithromycin, 1.0 g, or doxycycline, 100 mg twice daily for 7 days, are recommended as equal treatments of choice for uncomplicated chlamydial infection, and for syndromes associated with Chlamydia trachomatis, such as nongonococcal urethritis (NGU) and mucopurulent cervicitis (MPC) in young women.¹ However, a recent publication challenges the efficacy of azithromycin against chlamydial infection. Schwebke et al. conducted a multicenter randomized controlled trial (RCT) of the treatment of NGU in relation to Mycoplasma genitalium and Trichomonas vaginalis.² Men with symptomatic NGU (N = 305) attending sexually transmitted disease (STD) clinics in 4 cities in the southeastern United States were randomized to treatment with the recommended regimens of azithromycin or doxycycline, with or without tinidazole in a single dose of 2.0 g. All 4 regimens had similar clinical efficacy. Tinidazole eradicated T. vaginalis but made no difference in clinical resolution of urethritis, and M. genitalium was better eradicated by azithromycin than doxycycline, although neither drug was highly effective (67% vs 31%). The study also found that C. trachomatis was eradicated in only 41 (77%) of 53 men given azithromycin, compared with 55 (95%) of 58 patients treated with doxycycline (P = 0.011).

The study was well designed and conducted. Randomization was successful, with no important demographic, behavioral, or clinical differences between the treatment groups. Nucleic acid amplification testing (NAAT) by transcription medicated amplification (TMA) (Aptima®, Gen-Probe, Inc) was used to detect C. trachomatis, with follow-up at 15 to 19 and 35 to 45 days. Earlier research suggested that the first of these intervals might have risked false positive NAAT results due to persistent RNA without viable C. trachomatis.³ However, Renault et al. recently reported negative TMA results by 14 days in 48 (79%) of 61 infected women treated with azithromycin, and linear regression predicted 100% negative results at 17 days, with a 95% confidence interval of 16 to 18 days.⁴ Thus, probably the results of Schwebke et al. at the first follow-up visit, and certainly those at 35 to 45 days, were valid. More patients treated with azithromycin were lost to follow-up (31%) than those randomized to doxycycline (18%),² but the difference in number of patients followed in the two groups (N = 21) is unlikely to have materially influenced the results. Considering all aspects of study design, methodology, and follow-up, the difference in chlamydia eradication between azithromycin and doxycycline appears to be valid.

Other data in support of azithromycin against uncomplicated chlamydial infection appear strong. Most important, a meta-analysis of 12 studies calculated the efficacy of azithromycin to be 97%, compared with 98% for doxycycline.⁵ Nevertheless, there are reasons other than the new study² to question the reliability of azithromycin therapy. Three of the studies in the meta-analysis reported azithromycin cure rates of 81% to 92%, versus 99% to 100% for doxycycline.^6–8 Only one study suggested azithromycin to be superior, but the sample size was small; the observed cure rates were 88% for doxycycline (23 of 26 patients) and 95% for azithromycin (42 of 44).⁹ An RCT in pregnant women found azithromycin to cure a disappointing 35 (64%) of 55 women, not statistically better than amoxicillin (32 of 55 patients, 58%),¹⁰ although a later meta-analysis suggested ≥90% efficacy for azithromycin during pregnancy.¹¹ More recently, azithromycin cured only 59 (87%) of 68 men with asymptomatic rectal infection.¹²

Most of the published work is based on isolation of C. trachomatis in tissue culture, now known to be insensitive compared with NAAT,¹³ raising the possibility that chlamydia eradication may have been overestimated for both regimens.¹⁴ In studies of expedited partner therapy, treatment with either regimen has been associated with 8% to 12% rates of persistent infection by NAAT.^15,16 Similarly, in a recent cohort study that also used NAAT, 25 (7.9%) of 318 recurrent chlamydial infections in teen girls following treatment with azithromycin resulted from probable or possible treatment failure and could not be attributed to reinfection.¹⁷

It is important to not overreact to a single study, and it would be premature to formally modify management recommendations at this time. In all science, unexpected outcomes with far-reaching implications raise the bar for validation. However well done, the new RCT² had a modest sample size of men infected with C. trachomatis who attended inner-city STD clinics in the southeast. The results are not necessarily applicable to other population groups, to women, or to asymptomatic chlamydial infection; the difference in follow-up rates between the treatment arms remains a concern; and the study was not designed primarily to assess efficacy against chlamydia. Still, combined with other doubts about the efficacy of azithromycin, the results give pause, and suggest the time has come to reassess the roles of azithromycin and doxycycline in the management of uncomplicated chlamydial infections. Horner made the same recommendation several years ago,¹⁴ stimulated by the high frequency of apparent late treatment failures with both doxycycline and azithromycin in studies of expedited partner therapy.^15,16 Horner based the case primarily on the pathogenesis of chlamydial infection and the tenuous relationship between antimicrobial susceptibility of C. trachomatis, as traditionally measured, and treatment outcome.¹⁴

RCTs of chlamydia treatment would be ideal and should include prolonged follow-up of treated patients—eg, 3 months, perhaps even longer—with methods designed to assure excellent follow-up and perhaps with isolation of C. trachomatis in addition to NAAT.^4,14 In the meantime, observational research, such as systematic follow-up of patients treated routinely with azithromycin or doxycycline, could provide useful data quite rapidly. Additional research on antimicrobial susceptibility of C. trachomatis may be indicated.¹⁴ Other studies could investigate novel regimens, such as higher doses of azithromycin, repeating azithromycin after 5 to 7 days, or the efficacy and tolerance of dual therapy with azithromycin and doxycycline. (Although both drugs risk gastrointestinal intolerance, they do so through different biologic mechanisms and have different timing. Dual therapy might be as well tolerated as either drug alone.)

Such studies will take time, and sometimes those responsible for the public's health need to make recommendations with incomplete data. Some interim approaches might be considered. (1) Perhaps doxycycline should be considered the treatment of choice for selected patients, such as those with laboratory-confirmed infection who are likely to comply with 7 days treatment (recognizing that judging compliance is imprecise). (2) When azithromycin is used, there might be a role for test of cure, which can be accomplished by NAAT on urine or self-collected vaginal swabs ≥3 weeks after treatment.⁴ (3) Azithromycin probably remains acceptable for routine treatment of persons with presumptive but unconfirmed chlamydial infection, ie, for NGU, MPC, partner therapy, and supplemental treatment for gonorrhea. Typically C. trachomatis is found in 10% to 40% of such persons, so that treatment failure rates should remain acceptable. For example, among 100 men with NGU, of whom perhaps 30 or 40 will have chlamydia, only 3 to 6 excess treatment failures might be expected (depending on actual therapeutic efficacy) if azithromycin were employed instead of doxycycline. Test of cure can be advised if diagnostic testing is positive for C. trachomatis. (4) Rescreening after 3 to 6 months should be reemphasized for all patients with confirmed chlamydial infection,^1,14–17 regardless of the regimen used and whether the patient is tested for cure.

From a population perspective, does any of this matter very much? Even if azithromycin is less effective than previously believed, wide implementation of these suggestions might have modest impact on overall morbidity and prevention of chlamydial infection. It is plausible that the advantages of single-dose therapy would continue to dictate routine use at a cure rate of 90% or lower—itself a potentially important research topic. Nevertheless, the personal health benefits of doxycycline or test of cure might be substantial for many patients while we await confirmatory studies.