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Clinical Updates

New Schemes for Gonorrhea and Syphilis Treatment

Michel Janier, Michel Develoux

Wednesday, September 06, 2006

Gonorrhea and syphilis are common sexually transmitted diseases (STDs) that share many characteristics. Both are bacterial diseases with a long history throughout the centuries, both can be easily treated by single-dose antibiotics, both are good epidemiologic markers of recent high-risk sexual activity, and both have reappeared, commonly affecting homosexual males, after near eradication from developed countries in the mid-1980s.

There is nevertheless a major difference between these two infections: Neisseria gonorrhoeae (NG) has rapidly developed resistances to antibiotics (penicillin, tetracyclines, and now fluoroquinolones) over time, whereas Treponema pallidum remains highly sensitive to penicillin G after 60 years of use.

Gonorrhea Treatment

Most national guidelines from Europe and North America recommend single-dose ceftriaxone intramuscularly (125-500 mg) as the first choice for treating non-complicated gonorrhea (genital, anal, and oral) in females and males.

Ceftriaxone has very low MIC (minimal inhibitory concentration) against penicillinase- or non-penicillinase-producing NG (PPNG), and has been thoroughly studied in pharyngeal gonorrhea. It is highly active, is easy to administer (one dose), has very few adverse effects, and can be given safely to almost anyone (adults, children, pregnant women), even those with coagulation abnormalities (intravenous or subcutaneous administrations are possible). The only contraindication is a history of beta-lactam antibiotic anaphylaxis.

Two negative aspects are its cost (although comparable to most of the other treatments) and the necessity of an injection. Cefixime has the advantage of an easy oral administration but has several disadvantages compared with ceftriaxone:

  1. It has been less thoroughly studied in pharyngeal gonorrhea and thus is not recommended by most of the specialists for use in females and men who have sex with men (MSMs) because of the high rate of pharyngeal NG carriage.
  2. It takes longer to provide a cure than ceftriaxone does.
  3. There are major concerns about the emergence of NG isolates with reduced susceptibility to third-generation cephalosporins in Asia, with rising MIC 90 (x 4 for ceftriaxone and x 16 for cefixime) occurring in the last few years, and already some (rare) clinical failures with cefixime when MIC is higher than 0.125 µg/ml.1

Fluoroquinolones were frequently given in developed countries as an alternative to cephalosporins due to the possibility of an oral administration in one dose and good efficacy, although ciprofloxacin (the most widely used within this class) was not a good choice for treating pharyngeal gonorrhea. Highly resistant strains of NG to fluoroquinolones emerged in Asia more than 10 years ago due to their wide use and have now invaded most European countries (40% of the strains in France, 60% in Austria).2 Fluoroquinolones should not be used any more in most European and North American countries. They still can be useful in Africa, where the selection pressure by fluoroquinolones has been low until now.

Given the high rate of bacterial resistance to many antibiotics and the concern about rising MIC to cephalosporins, a culture for identifying NG and performing an antibiotic sensitivity test is mandatory before therapy. Testing to confirm the cure is not necessary when the patient is clinically cured, unless the NG strain is resistant to the antibiotic concerned. If ceftriaxone is not used, pharyngeal culture before and after therapy must also be performed in women and MSMs.

Syphilis Treatment

Benzathine benzyl penicillin G (BBP) has been used for several decades both in early syphilis (one 2.4 million unit intramuscular injection) and in late syphilis (three weekly doses) with a very high rate of success: Clinical failures are extraordinarily rare, although serological failure (a more than four-fold decrease of non-treponemal test - VDRL or RPR - titers after 6-12 months) is not rare.

BBP remains very active after many years of use, is easy to administer, poses no problems with compliance, and has a very low cost. Severe anaphylaxis is rare (1/100,000 doses), and desensitization is possible in patients with a history of penicillin allergy. The only pitfall is the route of administration: The injection must be intramuscular and is thus painful and contraindicated in cases of coagulation disorder. Oral beta-lactam antibiotics and third-generation cephalosporins compare unfavorably to BBP in terms of cost, compliance, and ease of administration.

In HIV-positive patients, most guidelines recommend the same therapeutic patterns as in HIV-negative ones, although some authors advocate cerebrospinal fluid assessment in late syphilis or latent syphilis of unknown duration in the latter group.

Azithromycin could have been a good candidate as an alternative treatment of syphilis: It's easy to administer in a single 2 g oral dose, and preliminary studies showed a good clinical and serological response. Two African studies were recently published:

  1. The first (2000-2003) involved 328 patients randomized between a single 2 g oral dose of azithromycin and BBP 2.4 MU intramuscularly. Most had latent syphilis of unknown duration, 50% being HIV-positive (Tanzania).3
  2. The second was a secondary analysis of the Rakaï trial (1994-1998, Uganda) comparing three arms: a single
    1 g oral dose of azithromycin, BBP, and both.4

These studies led to the same conclusion of a similar rate of serological failure between the groups of azithromycin and BBP. However, the results must be considered with caution because several cases of obvious clinical failure have been observed in the United States and Europe in primary and even in incubating syphilis; Treponema palllidum had rapidly acquired resistance to macrolides by mutations in the 23S RNA gene.5 This phenomenon has been observed in several US cities, Ireland, and Russia.

The International Union against Sexually Transmitted Infections (IUSTI) and the U.S. Centers for Disease Control and Prevention (CDC) recommend against using azithromycin because of the exponential appearance of resistance to macrolides (up to 90% of strains in some settings). Azithromycin could still be useful in mass treatment of syphilis, chancroid, and chlamydia in countries with limited resources, given that the resistance rate is low (which is difficult to ascertain), but for how long? The good response to azithromycin in Africa may be only fleeting.

Conclusions

After a historical nadir in the mid-1980s, gonorrhea and syphilis are increasing rapidly. Despite several recent publications, the scheme for syphilis has not yet changed. With their potential to spread HIV, gonorrhea and syphilis are a major threat. Now more than ever, prompt treatment is mandatory - with the hope that antibiotic resistance will not appear soon.

References

  1. Tanaka M, Nakayama H, Tunoe T et al. A remarkable reduction in the susceptibility of Neisseria gonorrhoeae isolates to cephems and the selection of antibiotic regimens for the single-dose treatment of gonococcal infection in Japan. J Infect Chemother. 2002 Mar;8(1):81-6.
  2. Uthman A, Heller-Vitouch C, Stary A et al. High-frequency of quinolone-resistant Neisseria gonorrhoeae in Austria with a common pattern of triple mutations in GyrA and ParC genes. Sex Transm Dis. 2004 Oct;31(10):616-8.
  3. Riedner G, Rusizoka M, Todd J et al. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Eng J Med. 2005 Sep 22;353(12):1236-4.
  4. Kiddugavu M, Kiwanuka N, Wawer MJ et al. Effectiveness of syphilis treatment using azithromycin and/or benzathine in Rakai, Uganda. Sex Transm Dis. 2005 Jan;32(1):1-6.
  5. Lukehart SA, Godornes C, Molini BJ et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Eng J Med. 2004 Jul 8;351(2):154-8.
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