Adolescents 15 to 19 years of age have the highest prevalence of Chlamydia trachomatis of any age group, reaching 28.3% among detained youth.1,2 The most recent guidelines from the Centers for Disease Control and Prevention published in December of 2010 stated that single-dose azithromycin or doxycycline twice daily for 1 week remains the recommended treatment for uncomplicated chlamydial infections.3 A meta-analysis comparing azithromycin and doxycycline for the treatment of chlamydia infections found that cure rates were 97% (95% confidence interval [CI], 95.1%–97.6%) for azithromycin and 98% (95% CI, 96.5%–98.8%) for doxycycline.4 More recent studies suggested the cure rate may be decreasing.5–7 The effectiveness of azithromycin reported in a comparable study among a cohort of adolescent and young adults in an outpatient clinic was 92.2% (95% CI, 88.6%–94.9%).5 Efficacy of azithromycin cited in studies with symptomatic men ranges from 77.4% to 86.8%.7,8 This study was conducted to determine azithromycin treatment failure among adolescents with uncomplicated, urogenital C. trachomatis infection and to examine those whose infection persisted. The setting was a juvenile detention center (JDC), where treatment was directly observed and reinfection was unlikely; therefore, all treatment failures identified would likely indicate failure of antibiotics to treat the infection.
We conducted a prospective study in a large urban JDC in the southwest region of the United States. The Institutional review boards from The University of Texas Health Science Center at Houston and the JDC approved this project. During incarceration, detainees have little to no opportunity for sexual activity with other youth or adults in our facility. Male and female youth are strictly segregated in individual rooms with close observation by 2 or more juvenile supervision officers. A national survey conducted among detained youth found that staff sexual activity in JDCs is rare (<3%) and sexual activity in postadjudication facilities is decreasing (<10%).9 All detained youth at the JDC, as part of mandated screening, submitted first-catch urine specimens for gonorrhea and chlamydia testing upon arrival. The specimens were tested using the Gen-Probe Aptima Combo 2 assay (Gen-Probe Inc, San Diego, CA), with a reported sensitivity of 96.1% and a specificity of 98% for detection of chlamydia.10,11 Participants submitted a second first-catch urine specimen for the test of cure (TOC), 3 weeks after observed treatment with 1 g of azithromycin given orally. The Gen-Probe Aptima Chlamydia assay (sensitivity 96% [men], 94.3% [women]; specificity 97.2% [men], 98% [women]) was used for the TOC.12 Treatment failure was defined as a positive TOC result after administration of azithromycin. The Department of Health and Human Services ran the tests in batches, so that approximately 1 week elapsed between testing and notification of results. Study participants were detainees with positive urine nucleic acid amplification test results for C. trachomatis. We recruited participants after they received their results and treatment for chlamydia. Exclusion criteria included vomiting after azithromycin, coinfection with gonorrhea, treatment for pelvic inflammatory disease or epididymitis/orchitis before the TOC, or inability to take azithromycin due to an allergy or medication interaction. With a type 1 error of 0.05 and a power of 80%, we required a minimum of 127 participants for the study. After we obtained written informed assent, patients completed an enrollment questionnaire and received 1 g of azithromycin by mouth; the azithromycin was given with food under direct observation by the medical staff. The enrollment questionnaire screened each participant for symptomatic infections. Each patient returned to the medical clinic in 1 to 2 days and completed a follow-up questionnaire assessing symptoms of infection and medication tolerance. The participants then provided urine samples 3 weeks later for the chlamydia TOC and returned to the medical clinic for TOC results and a final questionnaire. Those with treatment failure submitted another urine sample to confirm the treatment failure and then received doxycycline 100 mg twice a day by mouth for 7 days. When possible, a final TOC was sent 3 weeks after doxycycline. The study’s primary outcomes were the incidence of azithromycin treatment failure defined by a positive TOC result and symptomatic infection at 4 weeks. In addition, descriptive statistics on the incidence of adverse effects of azithromycin administration (abdominal pain and/or nausea) are described. Fisher exact CIs were calculated in our study. STATA (Version 11.1; STATAcorp LP, College Station, TX) was used for all statistical analyses.
Between May 2012 and July 2013, 219 juvenile detainees tested positive for chlamydia. After eliminating 34 patients due to exclusion criteria, we enrolled 185 patients (Fig. 1). One hundred twenty-eight youth submitted a TOC (Table 1) an average of 29 days after azithromycin administration (range, 14–136 days, SD = 22 days). Five patients inadvertently submitted a TOC before 3 weeks; all were negative. Patients lost to follow-up (n = 48; 26%) were similar to the study population, except for sex (50% female). Five (3.9%; 95% CI, 1.2%–8.9%) male patients experienced treatment failure after administration of azithromycin. When stratified by sex, azithromycin efficacy was 95% (95% CI, 88.6%–98.3%) among male participants and 100% (95% CI, 88%–100%) among female participants. At baseline, the percentage of patients reporting any symptoms was similar between groups (20% treatment failure vs. 28% without treatment failure, P = 0.53). However, at 4 weeks, patients experiencing treatment failure were more likely to complain of symptoms (60%) compared with patients without treatment failure (1.3%; P < 0.01). Two patients complained of testicular pain (1 met the criteria for epididymitis) and 1 complained of continued abdominal pain at follow-up. All 5 patients with treatment failure were treated with doxycycline for 7 days. Three had a negative TOC result 3 weeks after completion of doxycycline; 2 were released before this reassessment. Of note, 47 (35%) patients in the cohort complained of abdominal pain with administration of azithromycin.
Among detained youth in a large urban JDC with uncomplicated urogenital C. trachomatis, the efficacy of azithromycin was overall 96.1% (95% CI, 91.1%–98.8%). The efficacy is slightly lower than 97%, as reported by Lau and Qureshi,4 but higher than more recent studies where the efficacy of azithromycin ranges from 77% to 92.2%4,7,8; however, our CI overlaps with the most comparable study. We found that experiencing symptoms at 4 weeks after treatment with azithromycin was a significant predictor of treatment failure. This is in keeping with a recent study reporting 75% of patients complaining of symptoms at the time of reattendance.13 Our results suggest that providers should counsel patients to return to clinic if they have persistent or new onset symptoms 3 to 4 weeks after treatment. The recent literature citing increased treatment failures with azithromycin among rectal and urogenital chlamydia infections may cause providers to question the use of azithromycin over doxycycline, especially as doxycycline continues to remain effective.7,14–17 Treatment failures not only impact the individual but may have a significant impact on the screening coverage and time required to achieve target reductions in chlamydia prevalence.18 As research continues with randomized control trials and research regarding the biologic mechanisms of treatment failures, azithromycin should remain first-line treatment for C. trachomatis in adolescent patients given improved adherence with single-dose therapy.17,19,20
A major strength of our study was our ability to follow up patients prospectively who had little opportunity for a sexual encounter before their TOC. The authors of previous studies relied on patient report of condom use and/or abstinence to account for cases of reinfection.5,7,8,21 Other strengths of our study include our ability to provide directly observed therapy. We performed TOCs at an average of 4 weeks to decrease the likelihood of residual chlamydia rRNA as the estimated clearance occurs at day 17 (rRNA was detectable in 21% of women 14 days after treatment for chlamydia).22 One study citing azithromycin efficacy of 77.4% sent TOCs at 2 weeks after treatment.7 The major limitation of our study is the inability to genotype the specimens to ensure treatment failure. Genotyping was not available in our laboratory. Another limitation of the study is lack of inquiry about interim sexual contact to exclude reinfection, but this is highly unlikely given private rooms, close monitoring, and sex separation. In addition, our participants were mostly asymptomatic adolescents; symptomatic patients may have a different failure rate. Finally, we used urine samples to test for chlamydia infections in young men and women. Because vaginal swabs have a higher sensitivity and specificity compared with urine samples in women, we may have underestimated the number of chlamydia infections and subsequent treatment failures in women.10 One important additional finding of the study was the high report of abdominal pain (35%) with administration of azithromycin. Four percent of our participants vomited. Our results suggest that physicians should recommend that patients take medication with food and warn of associated abdominal pain and potential vomiting necessitating additional medication. Our findings support previous studies identifying definite treatment failures with the use of azithromycin in treatment of uncomplicated C. trachomatis; however, azithromycin remained effective in our population. Further research studying the etiology of azithromycin treatment failure and its risk factors in other patient populations is needed to confirm our findings.
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