Is the current treatment of urogental and anorectal chlamydia infection appropriate?

© 2017 Dr Fabian KongChlamydia trachomatis is the most common bacterial sexually transmitted infection worldwide. In Australia, the community prevalence of urogenital chlamydia among women and men aged <30 years is 5.0% (95%CI: 3.1%,6.9%) and 3.9% (95%CI: 2.7%,5.1%), respectively. Among MSM, the prevalence of rectal, urethral and pharyngeal chlamydia is 5.6%, 1.1% and 0.5%, respectively. If left untreated, infections increase the risk of infertility in women and epididymo-orchitis in men and proctitis among both sexes. Research has shown that rectal infections may contribute to the transmission and acquisition of HIV. Therefore, efficacious treatments are essential to reduce chlamydia associated morbidity and break ongoing transmission of infection. The recommended treatments for uncomplicated chlamydia infections are either a single 1g dose of azithromycin or seven days of doxycycline (100mg twice a day). For urogenital infections, meta-analysis data from RCTs (Chapter 2) reported an efficacy of 97.4% (95%CI: 96.2%,98.7%) and 94.3% (95%CI: 91.8%,96.8%) for doxycycline and azithromycin, respectively (efficacy difference, 2.6%; 95%CI: 0.5%,4.7%, p=0.4). These data show that although the efficacy of azithromycin appears to have decreased over the last 10 years, the 95%CI show that it still fulfils the WHO threshold for an effective antibiotic of 95% and therefore remains an appropriate treatment for urogenital infections. For the treatment of rectal infections, a meta-analysis (Chapter 3) reported a pooled efficacy of >99% (95%CI: 98.6%,100%) for doxycycline and 82.9% (95%CI: 76.0%, 89.8%) for azithromycin (efficacy difference, 19.9%: 95%CI: 11.4%,28.3%, p=0.1). The efficacy for azithromycin was lower than the 95% efficacy recommended by the WHO suggesting it is not an appropriate treatment. However, this is based on poor quality observational data only. Therefore, RCTs comparing 1g azithromycin and seven days doxycycline for treating rectal chlamydia infections are urgently required. Findings from the research presented in this thesis suggest that high pre-treatment organism load (Chapter 4) is associated with repeat rectal infection. When further discriminated by multilocus sequence typing (MLST) and sexual behaviour data, cases classified as ‘treatment failures’ were associated with increased load (OR:1.9;95%CI: 1.4,2.6 for each additional log load). Cases of reinfection were also associated with increased load (OR:1.6;95%CI: 1.2, 2.2 for each additional log load) and >2 partners during the past three months (OR:3.5;95%CI: 1.2,10.9). The estimated treatment efficacy for 1g azithromycin was 83.6% (95%CI: 77.2%, 88.8%). As high organism load infections were associated with treatment failure, it is possible that higher extended doses of azithromycin could improve treatment outcomes. A review of the pharmacokinetics of azithromycin (Chapter 5) provided evidence that total drug absorption was more dependent on total dose rather than the duration of treatment. Further, short courses (< 3 days) with a higher first dose (‘front-end loading dose’, e.g. 1g) may be an optimal regimen when considering treatment in symptomatic patients with non-LGV Chlamydia trachomatis who may have a higher organism load and for drug tolerability. Lastly findings from this thesis (Chapter 6) also indicated that, following a 1g dose of azithromycin, rectal concentrations of azithromycin were rapidly attained (within two hours) with peak concentrations (median 133mcg/g) occurring after 24 hours and remained above the minimum inhibitory concentration for chlamydia of 0.125mcg/mL for at least 14 days. Inadequate tissue concentration is therefore unlikely a major contributor to rectal chlamydia treatment failure; however, factors affecting absorption (pH and diarrhoea) or drug depletion (douching and water-based lubricants) could be more important determinants. In conclusion, the current treatments for urogenital chlamydia infections remain appropriate but, with an observed decrease in azithromycin’s efficacy over the past decade, ongoing monitoring of its effectiveness should occur over the coming years. In contrast, although observational data raise the possibility that azithromycin may not represent the optimal treatment for rectal infections, the presence of high concentrations in rectal tissue following a 1g dose suggest that we shouldn’t disregard this treatment until we have robust RCT evidence of its efficacy. Further, available pharmacokinetic data suggest that azithromycin dosing could be optimised. Such information will help bring some consensus to rectal treatment guidelines both on national and international levels