Chlamydia trachomatis infection is the most common sexually transmitted infection (STI) internationally, with the greatest burden of disease in young sexually active adults, and it is associated with pelvic inflammatory disease, chronic pelvic pain, infertility and pregnancy complications.[[1]] The purpose of this review is to inform prescribing practice for the management of female urogenital and anorectal chlamydia. Of note, where we refer to “male” or “female”, we refer to cisgender men and women; management of transgender and non-binary people should be anatomy-based. However, we recognise that transgender people also identify as male or female, and that gender identity is distinct from genital anatomy.

Internationally, treatment guidelines for urogenital infections of C. trachomatis recommend 1 gram (g) of azithromycin orally as a single dose, or 100 milligrams (mg) of doxycycline orally twice daily for seven days.[[1]] However, doxycycline is recommended over azithromycin for known anorectal infections due to increased microbial susceptibility.[[1]] Doxycycline is also available in a 200mg slow-release tablet which enables daily dosing, reduces side effects and provides comparable efficacy;[[2]] however, this formulation is not yet approved for sale in New Zealand. A recent meta-analysis[[3]] reported 68% (95% CI, 57% to 80%) of females with urogenital infections of C. trachomatis were also diagnosed with concurrent rectal infection. In addition, a lack of association between rectal C. trachomatis and anal intercourse was also reported. Therefore, it is possible that females who do not present with a history of anal intercourse could in fact unknowingly harbour anorectal infection of C. trachomatis that could provide a source for reinfection of the genitourinary tract.[[4]]

Azithromycin is a macrolide antibiotic with 40% oral bioavailability and a half-life of 68 hours following oral administration.[[5]] However, azithromycin has been associated with QT prolongation and is classified as a Category B1 medicine.[[5]] A member of the tetracycline family, doxycycline has 95% oral bioavailability, with a half-life of approximately 20 hours. Doxycycline is classified as a Category D medicine.[[5]]

In a small prospective cohort study conducted in a sexual health clinic, 50 females aged 16 years or older collected daily vaginal and rectal specimens for up to eight weeks to determine time to clearance for a C. trachomatis infection.[[6]] Participants were treated as per local guidelines with either azithromycin or doxycycline. The authors reported that the time to clearance for both rectal and vaginal infections was similar (seven and eight days, respectively), and that all participants with rectal C. trachomatis infections were cured when treated with a single dose of azithromycin.[[6]] However, there were limitations to this study, including small sample size, and only 13 females tested positive for either rectal or vaginal C. trachomatis in the cohort. Nine participants tested positive for concurrent vaginal and rectal infection, and only two participants were treated with doxycycline.[[6]]

An observational study of 416 females aged 18 years or older with confirmed C. trachomatis infections reported 341 had concurrent rectal infections.[[7]] Vaginal and rectal nucleic acid amplification tests (NAAT) were conducted at diagnosis then weekly for four weeks following treatment. All females were treated as per guidelines with azithromycin or doxycycline. Single dose azithromycin (1g orally) had an efficacy of 94% (95% CI, 90–96%) for urogenital infections, and 79% (95% CI, 73–84%) for rectal infections.[[7]] The authors reported that cure rates after treatment with doxycycline, were 96% (95% CI, 91–98%) for urogenital infection, and 96% (95% CI, 91–98%) for rectal infection. This study indicates that for urogenital infections, efficacy of azithromycin is similar to doxycycline, however, for undetected rectal infections females would be 6 (95% CI, 2 to 14) times more likely not to receive adequate treatment if azithromycin was prescribed. The authors recommend that in the absence of rectal testing and no presenting history of anal intercourse, doxycycline should be offered as first line for the management of urogenital infections of C. trachomatis in females.

Two recent systematic reviews and meta-analyses using Cochrane methodology examined the most effective treatment for urogenital and rectal C. trachomatis infections.[[8,9]] Páez-Canro et al.[[8]] included 14 studies with a total of 2,147 participants, of which 568 were females aged between 17–60 years. Five studies were included in the meta-analysis that investigated microbiological failure in non-pregnant females; the authors reported that overall, there was insufficient evidence to determine whether doxycycline or azithromycin was the more effective treatment for urogenital C. trachomatis infections (RR 1.71, 95% CI, 0.48 to 6.16). Nine studies, including both males and females, reported adverse effects, with azithromycin having significantly less adverse effects (17%) compared with doxycycline (RR 0.83, 95% CI, 0.71 to 0.98). Reported adverse effects were gastrointestinal in nature (nausea, vomiting, abdominal pain). Chen et al.[[9]] reported a 27% increase in risk of microbial failure with azithromycin in rectal C. trachomatis infections (RR 1.27, 95% CI, 1.20, 1.35). Subgroup analyses reported doxycycline consistently provided greater chance of microbial cure irrespective of gender, study design or country where the study was conducted.

There are multiple factors that need to be considered before prescribing treatment to females who have tested positive for C. trachomatis. Overall, the literature does not provide a clear answer as to whether azithromycin or doxycycline is the best treatment option for individuals. Research is lacking and overwhelmingly focused on infections in males. Peuchant et al.[[10]] are currently conducting a randomised multi-centre study to determine whether azithromycin or doxycycline is more effective at treating anorectal infections with C. trachomatis in females, when assessed 6 weeks after antibiotic treatment. Until further research is undertaken, and the results of this study are reported, in the absence of a negative rectal swab it may be preferable to prescribe doxycycline as first choice for treatment of C. trachomatis infections. This recommendation assumes the high likelihood of concurrent rectal infection. If doxycycline is contraindicated or the patient indicates that they will not complete their antibiotic course, azithromycin is likely the second most-effective drug. Kong et al.[[11]] state that it is likely that higher doses improve treatment efficacy by increasing the overall area under the curve (AUC), and considering this finding, a higher stat dose of azithromycin is something that could be explored in the future. In New Zealand, doxycycline is now recommended as a first line treatment for chlamydia by the New Zealand Sexual Health Society.[[12]] Anal chlamydia is ideally tested for using a proctoscope, and specialist advice should be sought if the person has anal symptoms or refer to the anorectal syndromes’ guideline.[[13]] Of note, doxycycline can also be considered for pharyngeal chlamydia. Clinicians should be encouraged to test for chlamydia (or any STIs) based on the type of sex people have.

In summary, C. trachomatis is a sexually transmitted infection that can impact female fertility. The burden of disease from C. trachomatis is highest in females aged between 15 and 19 years old. A considerable proportion of females may have concurrent rectal C. trachomatis infection, regardless of their sexual practices. Doxycycline offers greater efficacy over azithromycin for anorectal infection and comparable efficacy for urogenital infection.

Chlamydia trachomatis infection is the most common sexually transmitted infection (STI) internationally, with the greatest burden of disease in young sexually active adults, and it is associated with pelvic inflammatory disease, chronic pelvic pain, infertility and pregnancy complications.[[1]] The purpose of this review is to inform prescribing practice for the management of female urogenital and anorectal chlamydia. Of note, where we refer to “male” or “female”, we refer to cisgender men and women; management of transgender and non-binary people should be anatomy-based. However, we recognise that transgender people also identify as male or female, and that gender identity is distinct from genital anatomy.

Internationally, treatment guidelines for urogenital infections of C. trachomatis recommend 1 gram (g) of azithromycin orally as a single dose, or 100 milligrams (mg) of doxycycline orally twice daily for seven days.[[1]] However, doxycycline is recommended over azithromycin for known anorectal infections due to increased microbial susceptibility.[[1]] Doxycycline is also available in a 200mg slow-release tablet which enables daily dosing, reduces side effects and provides comparable efficacy;[[2]] however, this formulation is not yet approved for sale in New Zealand. A recent meta-analysis[[3]] reported 68% (95% CI, 57% to 80%) of females with urogenital infections of C. trachomatis were also diagnosed with concurrent rectal infection. In addition, a lack of association between rectal C. trachomatis and anal intercourse was also reported. Therefore, it is possible that females who do not present with a history of anal intercourse could in fact unknowingly harbour anorectal infection of C. trachomatis that could provide a source for reinfection of the genitourinary tract.[[4]]

Azithromycin is a macrolide antibiotic with 40% oral bioavailability and a half-life of 68 hours following oral administration.[[5]] However, azithromycin has been associated with QT prolongation and is classified as a Category B1 medicine.[[5]] A member of the tetracycline family, doxycycline has 95% oral bioavailability, with a half-life of approximately 20 hours. Doxycycline is classified as a Category D medicine.[[5]]

In a small prospective cohort study conducted in a sexual health clinic, 50 females aged 16 years or older collected daily vaginal and rectal specimens for up to eight weeks to determine time to clearance for a C. trachomatis infection.[[6]] Participants were treated as per local guidelines with either azithromycin or doxycycline. The authors reported that the time to clearance for both rectal and vaginal infections was similar (seven and eight days, respectively), and that all participants with rectal C. trachomatis infections were cured when treated with a single dose of azithromycin.[[6]] However, there were limitations to this study, including small sample size, and only 13 females tested positive for either rectal or vaginal C. trachomatis in the cohort. Nine participants tested positive for concurrent vaginal and rectal infection, and only two participants were treated with doxycycline.[[6]]

An observational study of 416 females aged 18 years or older with confirmed C. trachomatis infections reported 341 had concurrent rectal infections.[[7]] Vaginal and rectal nucleic acid amplification tests (NAAT) were conducted at diagnosis then weekly for four weeks following treatment. All females were treated as per guidelines with azithromycin or doxycycline. Single dose azithromycin (1g orally) had an efficacy of 94% (95% CI, 90–96%) for urogenital infections, and 79% (95% CI, 73–84%) for rectal infections.[[7]] The authors reported that cure rates after treatment with doxycycline, were 96% (95% CI, 91–98%) for urogenital infection, and 96% (95% CI, 91–98%) for rectal infection. This study indicates that for urogenital infections, efficacy of azithromycin is similar to doxycycline, however, for undetected rectal infections females would be 6 (95% CI, 2 to 14) times more likely not to receive adequate treatment if azithromycin was prescribed. The authors recommend that in the absence of rectal testing and no presenting history of anal intercourse, doxycycline should be offered as first line for the management of urogenital infections of C. trachomatis in females.

Two recent systematic reviews and meta-analyses using Cochrane methodology examined the most effective treatment for urogenital and rectal C. trachomatis infections.[[8,9]] Páez-Canro et al.[[8]] included 14 studies with a total of 2,147 participants, of which 568 were females aged between 17–60 years. Five studies were included in the meta-analysis that investigated microbiological failure in non-pregnant females; the authors reported that overall, there was insufficient evidence to determine whether doxycycline or azithromycin was the more effective treatment for urogenital C. trachomatis infections (RR 1.71, 95% CI, 0.48 to 6.16). Nine studies, including both males and females, reported adverse effects, with azithromycin having significantly less adverse effects (17%) compared with doxycycline (RR 0.83, 95% CI, 0.71 to 0.98). Reported adverse effects were gastrointestinal in nature (nausea, vomiting, abdominal pain). Chen et al.[[9]] reported a 27% increase in risk of microbial failure with azithromycin in rectal C. trachomatis infections (RR 1.27, 95% CI, 1.20, 1.35). Subgroup analyses reported doxycycline consistently provided greater chance of microbial cure irrespective of gender, study design or country where the study was conducted.

There are multiple factors that need to be considered before prescribing treatment to females who have tested positive for C. trachomatis. Overall, the literature does not provide a clear answer as to whether azithromycin or doxycycline is the best treatment option for individuals. Research is lacking and overwhelmingly focused on infections in males. Peuchant et al.[[10]] are currently conducting a randomised multi-centre study to determine whether azithromycin or doxycycline is more effective at treating anorectal infections with C. trachomatis in females, when assessed 6 weeks after antibiotic treatment. Until further research is undertaken, and the results of this study are reported, in the absence of a negative rectal swab it may be preferable to prescribe doxycycline as first choice for treatment of C. trachomatis infections. This recommendation assumes the high likelihood of concurrent rectal infection. If doxycycline is contraindicated or the patient indicates that they will not complete their antibiotic course, azithromycin is likely the second most-effective drug. Kong et al.[[11]] state that it is likely that higher doses improve treatment efficacy by increasing the overall area under the curve (AUC), and considering this finding, a higher stat dose of azithromycin is something that could be explored in the future. In New Zealand, doxycycline is now recommended as a first line treatment for chlamydia by the New Zealand Sexual Health Society.[[12]] Anal chlamydia is ideally tested for using a proctoscope, and specialist advice should be sought if the person has anal symptoms or refer to the anorectal syndromes’ guideline.[[13]] Of note, doxycycline can also be considered for pharyngeal chlamydia. Clinicians should be encouraged to test for chlamydia (or any STIs) based on the type of sex people have.

In summary, C. trachomatis is a sexually transmitted infection that can impact female fertility. The burden of disease from C. trachomatis is highest in females aged between 15 and 19 years old. A considerable proportion of females may have concurrent rectal C. trachomatis infection, regardless of their sexual practices. Doxycycline offers greater efficacy over azithromycin for anorectal infection and comparable efficacy for urogenital infection.