Azithromycin resistant syphilis found in HIV-positive gay men

A strain of syphilis has emerged which is resistant to the oral antibiotic, azithromycin, according to a report in the July 8^th edition of the New England Journal of Medicine. The investigators note that many of the cases of resistant syphilis involve HIV-positive gay men and postulate that the mutant strain of syphilis may have been introduced, and rapidly spread around sexual networks.

Since it was first developed in the 1940s penicillin has been the first-line treatment for syphilis. A single injection of penicillin G benzathine, which remains active for weeks, is sufficient to cure early syphilis in nearly all cases, and there have been no case reports of penicillin resistant syphilis.

Since the 1990s the oral antibiotic azithromycin has been used by some doctors to treat syphilis. The advantages of the drug include its dosing – it is taken in a single oral 2g dose, its long half-life and also its activity against other sexually transmitted infections, particularly chlamydia.

However, there is evidence that the Street 14 strain of syphilis has become resistant to azithromycin. The investigators report that, in July 2003, a 33 year old, HIV-positive gay man attended a hospital emergency department in San Francisco for treatment for a non-tender ulcer on his penis. He was treated with a 2g oral dose of azithromycin immediately and a self administered 1g dose of the drug the following day. He subsequently attended a sexual health clinic where primary syphilis was diagnosed. Doctors were confident that he had already received appropriate treatment, however the individual returned three days later as the chancre was still present on his penis. Test results for syphilis were positive and azithromycin failure was diagnosed. He was subsequently treated with a 2.4mU intramuscular injection of penicillin G benzathine. Two weeks later the chancre had resolved, and a follow-up syphilis test three months later was non-reactive.

Investigators subsequently sequenced two samples obtained from two other male patients in San Francisco with azithromycin resistant syphilis. Both samples involved Street 14 strains of syphilis which had developed resistance to azithromycin.

A total of 114 samples were then obtained by swabbing primary or moist secondary syphilis lesions from patients attending sexual health clinics in San Francisco, Baltimore, Seattle, and Dublin. In addition, strains of syphilis isolated from laboratory studies involving rabbits were also analysed. The investigators wished to see how widespread azithromycin resistant strains of syphilis were and to identify risk factors.

The mutant Street 14 strain of syphilis was present in 88% of the samples from Dublin, 22% of the San Francisco samples, 13% of the Seattle samples, and 11% of the Baltimore samples.

In San Francisco prevalence of the resistant strain increased from 4% in 2002 to 37% in 2003.

A review of 18 historical samples of syphilis obtained between 1912 and 1987 confirmed that only the Street 14 strain of the bacteria had the mutation able to confer resistance to azithromycin.

Subsequent laboratory studies involving rabbits confirmed that the Street 14 strain had resistance to both azithromycin and erythromycin.

”The drug of choice for the treatment of syphilis is penicillin” write the investigators, “and to date there have been no documented cases of penicillin resistance in [syphilis] strains.” However, penicillin injections are uncomfortable and azithromycin, which is easy to take and has few side-effects has been considered as an alternative treatment.

Syphilis has reemerged recently in the UK, some European countries and in the US. Many of the cases involve HIV-positive gay men who met their sexual partners anonymously. The increase in prevalence in azithromycin resistant syphilis in San Francisco between 2002 and 2003 suggests to the investigators that “a mutated strain has either recently been introduced into a sexual network or has been selected for among people who engage in high risk-behaviours.” The high prevalence of samples from Dublin containing the mutant resistant strain suggests “the introduction of the mutant strain that spread rapidly within a defined sexual network.”

Wide-spread use of azithromycin by HIV-positive gay men, either as treatment for other sexually transmitted infections, or as prophylaxis for opportunistic infections could have “selected strains of [syphilis] that contain this mutation.”

However, the investigators add that not a single case of azithromycin resistance has been found in a large clinical trial in the US and Madagascar which is investigating the use of the drug as a therapy for syphilis. They note, however, that HIV-positive patients are excluded from this study and that there is a wide geographical spread of syphilis strains.

The investigators conclude that the use of azithromycin as treatment for syphilis should be avoided in regions where resistance to the drug is high. Patients treated with azithromycin should be closely followed and recommended to return to hospital if symptoms persist.