Abstract: We selected 14 studies ( 2715 participants: 2147 (79.08%) men and 568 (20.92%) women). The studies were conducted mainly at STD clinics. Sample sizes ranged from 71 to 606 participants; follow-up was 29.7 days on average. For the comparison: azithromycin single dose versus doxycycline once or twice daily for 7 days, in men treated for CT, the risk of microbiological failure was higher in the azithromycin group (RR 2.45, 95% CI 1.36 to 4.41; participants = 821; studies = 9; moderate-quality evidence), but regarding clinical failure, the results showed that the effect is uncertain (RR 0.94, 95% CI 0.43 to 2,05; I² = 55%; participants = 525; studies = 3; low-quality evidence). Regarding adverse events (AE) in men there could be little or no difference between the antibiotics (RR 0.83, 95% CI 0.67 to 1.02; participants = 1424; studies = 6; low-quality evidence). About women treated for CT, the effect on microbiological failure was uncertain (RR = 1.71, 95% CI 0.48 to 6.16; participants = 338; studies = 5; very low-quality evidence). There were no studies assessing clinical failure or adverse events in women, however, we found that azithromycin probably has fewer adverse events in both genders (RR 0.83, 95% CI 0.71 to 0.98; I² = 0%; participants = 2261; studies = 9; moderate-quality evidence). For the second comparison: doxycycline compared to ofloxacin, for men treated for CT the effect on microbiological failure was uncertain (RR 8.53, 95% CI 0.43 to 167.38, I² not applicable; participants = 80; studies = 2; very low-quality evidence), as also it was on clinical failure (RR 0.85, 95% CI 0.28 to 2.62; participants = 36; studies = 1; very low-quality evidence). The effect of in women on clinical failure was uncertain (RR 0.94, 95% CI 0.39 to 2.25; I² = 39%; participants = 127; studies = 2; very low-quality evidence).Regarding adverse events, the effect in both men and women was uncertain (RR 1.02 95% CI 0.66 to 1.55; participants = 339 studies = 3; very low-quality evidence). The effect on microbiological failure in women and in men and women together was not estimable. The most frequently AE reported were not serious and of gastrointestinal origin.No studies assessed antimicrobial resistance or reinfection in either comparison. In men, regimens with azithromycin are probably less effective than doxycycline for microbiological failure, however, there might be little or no difference for clinical failure. For women, we are uncertain whether azithromycin compared to doxycycline increases the risk of microbiological failure. Azithromycin probably slightly reduces adverse events compared to doxycycline in men and women together but may have little difference in men alone. We are uncertain whether doxycycline compared to ofloxacin reduces microbiological failure in men or women alone, or men and women together, nor if it reduces clinical failure or adverse events in men or women. Based on the fact that women suffer mainly asymptomatic infections, and in order to test the effectiveness and safety of the current recommendations (azithromycin, doxycycline and ofloxacin), for CT infection, especially in low and middle income countries, future RCTs should be designed and conducted to include a large enough sample size of women, and with low risk of bias. It is also important that future RCTs include adherence, CT resistance to antibiotic regimens, and risk of reinfection as outcomes to be measured. In addition, it is important to conduct a network meta-analysis in order to evaluate all those studies that included in one arm only the current antibiotic treatments for CT infection that are recommended by the updated clinical practice guidelines.

Plain-language summary: We selected 14 studies with a total of 2715 men and non-pregnant women with CT infection, who had been treated with any antibiotic recommended by clinical guidelines (2147 (79.08%) men and 568 (20.92%) women). Women showed no symptoms or had uterine cervicitis, and men had non-gonococcal urethritis (an inflammation of the urethra not caused by gonorrhoeal infection). All of the participants had a positive test for CT. The studies lasted from 7 to 84 days after the end of treatment, with an average of 28 days. Most of the studies took place in sexually transmitted disease clinics in the USA. Studies compared the antibiotics doxycycline with azithromycin, and doxycycline with ofloxacin. One study reported funding from academic grants, another four studies declared having received sponsorship or grants from pharmaceutical companies. The other studies declared that they were self-funded or did not mention funding at all. We developed meta-analysis (a way of combining the results of studies), for two comparisons: azithromycin 1 g single dose versus doxycycline 100 mg twice a day for seven days, and doxycycline 100 mg twice a day for seven days versus ofloxacin 300 mg to 400 mg once daily or twice daily for seven days. We found that microbiological failure was less likely in men treated with doxycycline than men given azithromycin, and there were fewer adverse events (side effects) in men and women with azithromycin. There were no differences in clinical failure for women or men in doxycycline versus azithromycin nor in doxycycline versus ofloxacin. This means that with current available evidence, doxycycline would be the first option for treatment in men with urethritis. For non-pregnant women with CT infections there are no advantages with any of the included antibiotics. However, clinicians could consider single-dose azithromycin as an option, because it caused fewer adverse events. The included studies used poor methods that could mean that their results were biased (incorrectly favouring one drug instead of the other). This means we thought that the evidence they provided for microbiological failure in men, and for adverse events in men and women when azithromycin was compared with doxycycline was moderate quality, and for all the outcomes when doxycycline was compared with ofloxacin, we thought it was very low quality.