New Schemes for Gonorrhea and Syphilis Treatment
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.
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
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:
- 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.
- It takes longer to provide a cure than ceftriaxone does.
- 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
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.
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
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
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
- 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
- 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.
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.
- 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
- 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.
- 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.
- 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.
- 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.