Azithromycin has been widely used for many years as first-line therapy for chlamydial infection (or as equal first-line with doxycycline). However, there are now several reasons to reconsider its position.

Firstly, although earlier trials showed azithromycin to have cure rates which were high and equivalent to those of doxycycline, more recent studies have found it to have lower, and inadequate, levels of success in women with cervical infection, men with urethral infection, and for rectal infection in both men and women.

Secondly, the increasing recognition of the importance of Mycoplasma genitalium as a pathogen, especially as an important cause of urethritis in men. In the absence of a readily available test for M. genitalium, men with non-gonococcal urethritis are often treated with a single dose of azithromycin, which is known to be a less effective treatment for M. genitalium than is doxycycline. As a result many such men have persistent symptoms following such treatment, requiring repeat visits and further antibiotic therapy. Their sexual partners may also require further treatment. Additionally, there is evidence that single-dose azithromycin therapy (as against longer courses) can induce resistance in M. genitalium.

Thirdly, the widespread use of azithromycin is probably leading to increasing resistance to this agent in other infections where it has a place; especially in gonorrhoea where it is now widely recommended as an adjunct to ceftriaxone in the belief that this will reduce the likelihood of resistance to ceftriaxone developing, but also in the treatment of syphilis where azithromycin has a role as a second-line agent e.g. in cases of allergy to penicillins.