STD Quarterly

Treatment alert for sexually transmitted diseases: Check use of azithromycin for early syphilis  

Reports note azithromycin treatment failures in syphilis infections

Clinicians who opt to use azithromycin for treatment of early syphilis should review recently published research that indicates that at least 10% of syphilis samples from patients at sexually transmitted disease (STD) clinics in four cities had a strain resistant to the antibiotic.1

Penicillin G is the preferred drug for treatment of all stages of syphilis, according to the Atlanta-based Centers for Disease Control and Prevention (CDC).2 The recommended dosage for the drug, 2.4 million units, must be given intramuscularly.2 The injections are more painful than regular shots because a large amount of the antibiotic must be forced into the muscle.3 Some disease-control programs have been using azithromycin as a single oral regimen as an alternate approach to simplify treatment of early syphilis patients and their sexual contacts.4

Antibiotic resistance is a concern to public health officials because syphilis has been on the increase in the United States since 2000. Between 2001 and 2002, the overall rate of syphilis increased 9.1%, from 2.2 cases to 2.4 cases per 100,000 population, the highest rate since 1999, according to CDC statistics.5

Check the data

The new report on azithromycin treatment failures was initiated by a separate inquiry into syphilis cases, says Sheila Lukehart, PhD, research professor of infectious diseases at the University of Washington in Seattle. In working with other researchers, she learned of apparent clinical treatment failures following treatment of syphilis with azithromycin in cases reported to the San Francisco Department of Public Health.4

First alerted of an azithromycin failure in the treatment of primary syphilis in one patient in April 2003, San Francisco health officials began collecting case information, with a total of eight apparent treatment failures recorded.4 All of the patients were male and self-reported as homosexual. Median patient age was 34 years. Seven patients were non-Hispanic whites, and one was Asian American. Five patients were positive for HIV.4

"I recalled that there was a single documented macrolide-resistant strain of Treponema pallidum that was isolated in the 1970s,"6 recalls Lukehart. "So I suggested that we look for a similar gene mutation in strains from some of the patients with suspected azithromycin treatment failure."

The new report confirms resistance to azithromycin and identifies a mutation in the 23S rRNA genes of Treponema pallidum.1 The mutation also was found in samples collected in Baltimore, Seattle, and Dublin, Ireland. Frequency of the mutation varied among the sites; 88% of the Dublin samples contained the mutation, while in San Francisco, 37% were found with the mutation.

The next step in research is to examine the geographical distribution of strains containing the mutation throughout the United States and the world, says Lukehart. It is expected that the mutation will be found in many geographical regions, but it may well be absent in others, she observes.

Research eyes drug

Results from a Phase III equivalence trial of azithromycin vs. benzathine penicillin for the treatment of early syphilis may shed further light on the subject, says Edward Hook, III, MD, professor of medicine at the University of Alabama at Birmingham. The Bethesda, MD-based National Institute of Allergy and Infectious Diseases funded the research. The purpose of the study is to determine if azithromycin (2.0 g administered orally as a single dose), is as effective for syphilis therapy as the usual penicillin treatment (benzathine G penicillin, 2.4 million units).

A pilot study, conducted by a research team led by Hook, indicated that oral therapy with 2.0 g azithromycin as a single dose or as two doses one week apart would serve as an effective alternative to therapy with benzathine penicillin G.7 The pilot study treated almost 50 patients; the phase III trial has 320 patients enrolled, he notes.

A data safety review board looked at interim results of the Phase III trial in January 2003, and gave researchers no indications to stop the study, says Hook.

"I think the bottom line is that preliminary data suggest that azithromycin may have a promising role," he comments. "However, there is a well-described resistance mutation in some Treponema pallidum isolates and in some instances, that mutation appears to be related to treatment failure."

What is your approach when it comes to treating syphilis? In the primary stage of infection, patients may present with a single or multiple sores, known as chancres. Sores normally occur on the external genitals, vagina, anus, or in the rectum, but also can be found on the lips and in the mouth. Transmission of the organism occurs during vaginal, anal, or oral sex.8

According to the CDC, the time between infection with syphilis and the start of the first symptom can range from 10 to 90 days, with an average of 21 days. Chancres will be painless and will be firm, round, and small in appearance. Chancres normally last three to six weeks. If adequate treatment is not administered, syphilis will progress to a secondary stage, marked by a skin rash and mucous membrane lesions.8

"Clearly, penicillin remains the drug of choice for treating syphilis," says Hook. "Azithromycin may have a role; however, it would be inappropriate to treat a patient with azithromycin unless careful follow-up can be ensured."


1. Lukehart SA, Godornes C, Molini BJ, et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med 2004; 351:154-158.

2. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR 2002: 51(No. RR-6): Accessed at

3. Associated Press. Antibiotic-resistant strain of syphilis is spreading. USA Today. July 7, 2004. Accessed at:

4. Centers for Disease Control and Prevention. Brief report: Azithromycin treatment failures in syphilis infections — San Francisco, California, 2002-2003. MMWR 2004; 53:197-198.

5. Centers for Disease Control and Prevention. Primary and secondary syphilis — United States, 2002. MMWR 2003; 52:1,117-1,120.

6. Stapleton JT, Stamm LV, Bassford PJ. Potential for development of antibiotic resistance in pathogenic treponemes. Rev Infect Dis 1985; 7(suppl 2):S314-S317.

7. Hook EW 3rd, Martin DH, Stephens J, et al. A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis. Sex Transm Dis 2002; 29:486-490.

8. Centers for Disease Control and Prevention. Syphilis. Accessed at: