A RESURGENCE OF BACTERIAL sexually transmitted infections (STIs) has been documented recently in several industrialized countries following a decline in the incidence of these infections in the 1980s and early 1990s.1,2 In Israel, a sharp increase in the incidence of gonorrhea was observed starting in 1998,3 accompanied by a high rate of ciprofloxacin resistance.4 In an investigation conducted among a cohort of patients with gonorrhea, almost one half of the individuals admitted contracting the infection from a sex worker. In two thirds of the cases, oral sex (fellatio) was the most probable route of acquiring the disease. Because there is a general misperception that STIs cannot be transmitted by oral sex, these individuals either engaged in unprotected oral sex solely or had unprotected oral sex followed by protected vaginal intercourse.5 A similar observation was reported from Japan, where cases of gonococcal urethritis acquired by oral sex with new, expanding types of sex workers who offer only nonvaginal, usually unprotected sex, began to appear in the 1990s.6 The proportion of cases of gonococcal urethritis acquired by fellatio in the present outbreak is markedly higher than that reported previously: a retrospective review of cases of male gonococcal urethritis at a USAF clinic in the Philippines in 1980 revealed 46 cases of probable oral to genital transfer of Neisseria gonorrhoeae among more than 2600 cases of gonococcal urethritis.7 It is difficult to tell whether this difference in the rate of fellatio-associated gonococcal urethritis is explained by changing sexual habits or by geographical differences in sexual practices.
Sex workers constitute a well-recognized high-risk group for dissemination of STIs. In some areas, like Africa and the Far East, commercial sex has also been an important factor in the spread of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. Strategies to rapidly lower STI occurrence consist of either treating general population groups or more selective presumptive treatment of core groups with high rates of STIs.6 It has been suggested that interventions focusing on core groups are potentially more rewarding and cost-effective in reducing community prevalence of STIs than the general-population approach.8
Our initial finding of the important role of oral sex in the spread of gonorrhea in Tel Aviv, Israel, prompted the investigation of the prevalence of pharyngeal gonorrhea among sex workers, which was coupled with mass treatment of this core group considered to be the main contributor to the outbreak.
Recruitment of Women
Female sex workers practicing in brothels in Tel Aviv were approached by teams consisting each of a physician and a nurse; the women were offered to be screened for STIs and to receive presumptive treatment with azithromycin. Brothels from different parts of the city were visited, usually during daytime. Pamphlets containing information on safe sex and condom use, written in Hebrew and Russian, were distributed. Each such brothel harbors between 3 and 15 women and is supervised by its owner or an assistant. No incentives other than the services themselves were used to encourage participation. Just a few women refused to give samples or to receive treatment.
Each woman who agreed to participate was asked to complete a self-administered standardized questionnaire to collect information regarding demographics, working conditions, sexual history, and current symptoms. From each participant, a blood sample was obtained by venipuncture, the throat was swabbed, and a urine sample was collected. The throat swabs were transported in charcoal transport medium and were streaked within a few hours onto New York City agar (Hy Laboratories, Ltd., Rehovot, Israel). Urine samples were stored in a cold box and transported daily to the laboratory, where they were frozen at −70 °C. Samples were analyzed for N gonorrhoeae and Chlamydia trachomatis using polymerase chain reaction (Roche Amplicor; Roche Diagnostics Corporation, Basel, Switzerland). Serum was tested for HIV, quantitative VDRL, FTA, and TPHA. The identity of gonococcal isolates was confirmed with the API-NH system for the identification of Neisseria and Haemophilus (bioMerieux, Lyon, France). Susceptibility of N gonorrhoeae to antimicrobial agents was tested using the Etest method (AB Biodisk, Solna, Sweden), as specified in the product’s package insert provided by the manufacturer. The agents tested included penicillin, ciprofloxacin, ceftriaxone, and azithromycin.
All participants were given presumptive treatment with a single 2-g dose of azithromycin under direct observation. Women with positive throat cultures for N gonorrhoeae were traced a week later and were recultured.
Three hundred one female sex workers practicing in brothels were surveyed during May to November 2001. Throat cultures were positive for N gonorrhoeae in 27 (9%) of the women, whereas urine PCR was positive for the same organism in 3% of the cases. The mean age of individuals with gonococcal pharyngitis was 23 years (range, 18–32 years). Twenty-three (85%) were born in the former USSR, and 3 (11%) were Israeli born. The mean number of clients per day was 7. Regular condom use in vaginal sex was reported by 88% of the participants, and 60% answered that they used condoms regularly in oral sex (P = 0.02). Women with pharyngeal gonorrhea reported use of condom for vaginal and oral sex less often than female sex workers with negative throat gonococcal cultures, but the difference was not statistically significant. Four women with pharyngeal gonorrhea (15%) reported a recent sore throat, but none had frank signs of acute pharyngitis. Twenty-two women could be traced a week later for repeat throat culture: 2 of the recultured individuals grew again N gonorrhoeae, 1 of whom refused presumptive treatment on the first visit. Thus, the eradication of N gonorrhoeae from the throat was documented in 20 out of 21 (95.4%) sex workers who were treated with azithromycin (95% confidence interval, 76.2%–99.9%).
The antimicrobial susceptibilities of the 27 throat isolates were as follows: all were susceptible to ceftriaxone (MIC ≤0.016 μg/ml); MIC of azithromycin was ≤0.5 μg/ml; 37% of the isolates were resistant to ciprofloxacin (MIC ≥1 μg/ml), and 85% were nonsusceptible to penicillin (MIC ≥0.12 μg/ml). The MICs of azithromycin for the pre- and posttreatment isolates of the woman whom remained culture positive after treatment were 0.5 μg/ml.
We have documented an unusually high rate of pharyngeal gonorrhea among sex workers practicing in Tel Aviv brothels. The demographics of these women were similar to those of the whole group surveyed: the majority were trafficked women from the former USSR (mostly Russia, Ukraine, and Moldova) who did not practice prostitution in their countries of origin.
Studies on the prevalence of gonorrhea among sex workers usually do not include sampling of the pharyngeal site, and data on pharyngeal carriage of gonococci in this population are scarce. In the early 1980s, gonococci were isolated from the pharynx in 2.2% of 903 prostitutes in the Republic of the Philippines.7 The issue was more thoroughly investigated by Wong et al.9–13 from Singapore. These authors have documented a correlation between increased condom use for vaginal sex with decrease in cervical gonorrhea and a concomitant increase of unprotected oral sex and pharyngeal gonorrhea. In the early 1990s, the prevalence of pharyngeal gonorrhea among sex workers in Singapore was 0.69%.9 Toward the end of the decade, gonococci were isolated from the throat of 5.2% sex workers, whereas cervical cultures were positive in 2.5% of the participants.11 The implementation of a condom promotion program among sex workers that included oral sex led to a reduction in the prevalence of pharyngeal gonorrhea.12,13
Our findings are in accordance with previous reports suggesting that pharyngeal gonorrhea is most often asymptomatic: in one study, 79% of the patients denied any upper respiratory symptoms, whereas 15% reported a sore throat and 5% had purulent tonsillitis.14 Another study found that symptoms of pharyngitis correlated with fellatio but not with gonococcal pharyngeal infection.15 The asymptomatic nature of the pharyngeal infection probably contributes to the role of this reservoir in the dissemination of infection among contacts: asymptomatic women do not seek treatment, continue to carry the organism and to infect others. Although gonococcal cervicitis is also often asymptomatic, its impact on the transmission of the infection was less important in the present outbreak because significantly more sex worker insisted on condom use with vaginal than with oral sex. The same pattern was documented by the study from Singapore,11 where the higher prevalence of pharyngeal gonorrhea compared with that of cervical infection reflected a lower rate of consistent condom use in oral sex compared to vaginal sex (70.4% versus 96.8%).
A sharp rise in oral sex was documented among sex workers in Singapore, from 27.1% in 1992 to 81.7% in 1997.11 It has been suggested that the rise could have been related, at least partially, to clients’ demands for unprotected alternatives, after the successful implementation of a condom promotion program for vaginal sex.16 In Japan, a substantial change has occurred since the 1980s in the sex industry, which became dominated by a new type of sex worker who offered manual stimulation, cunnilingus, and fellatio, but not vaginal intercourse; they used condoms significantly less often than “vaginal sex workers.”6 Although our investigation was not designed to document changes in sexual behavior among commercial sex consumers, a substantial number of our patients with gonorrhea reported unprotected fellacio as the only service obtained from sex workers. Because adolescents and adults may erroneously view oral sex as a risk-free behavior and engage in it with no use of barrier protection,6,17 the contribution of oral sex to gonorrhea transmission may be more important than that of other forms of intercourse despite the lower transmissibility of gonorrhea with the former. In view of the increasing popularity of oral sex, safe sex educators should stress the role of this practice in transmitting STIs and should place more emphasis on the need for consistent condom use with oral sex. Studies on the prevalence of gonorrhea among sex workers and other high-risk groups should also include sampling of the pharynx. This potential reservoir of N gonorrhoeae should also be taken in account when studying patterns and efficacy of condom use.
We chose to use azithromycin for the presumptive therapy because of its activity against the most common bacterial pathogens causing STI and for its convenient dosing (single oral administration). Single 1-g dose of azithromycin is the regimen of choice for chlamydial infection18; the drug has also been shown to be effective against gonorrhea, although there is no unanimity regarding the optimal dosing. In a single-blind comparative study, azithromycin, 1 g, was as efficacious as ciprofloxacin, 500 mg (96% and 92.1% cure rate, respectively).19 Similar results were reported from South Africa20 and by authors from the United Kingdom.21,22 However, reduced susceptibility of N gonorrhoeae to azithromycin is being increasingly reported from various parts of the globe,23–26 and failure of treatment with a 1-g regimen for apparently in vitro susceptible isolates was also described.27,28 In order to improve eradication rates and to delay the development of resistance, a regimen of 2 g azithromycin for gonorrhea has been suggested.29,30 In a large multicenter randomized trial, azithromycin 2 g was as effective as 250 mg ceftriaxone in the treatment of uncomplicated gonorrhea in both men and women (99% and 98% eradication rate, respectively). Azithromycin administration was associated, however, with a relatively high frequency of gastrointestinal side effects, which occurred in 35% of the patients; 10% of the symptomatic patients had moderate symptoms, and 3% had severe symptoms.30 Some of our patients also reported nausea and vomiting; we could not obtain precise numbers regarding side effects because only a minority of the women were followed after treatment. Nevertheless, the gastrointestinal manifestations did not seem to have any impact on treatment outcome (the only patient that failed to respond did not report side effects).
The existing information on the efficacy of azithromycin in eradicating gonococci from the throat is very limited. In their multicenter trial, Handsfield el al.30 included 34 patients with pharyngeal gonorrhea, 19 of whom received a single 2-g dose of azithromycin, and the other 15 were treated with ceftriaxone 250 mg intramuscularly. Eradication of N gonorrhoeae was achieved in all patients. The investigators have concluded, however, that the routine use of this regimen was likely to be limited by the cost of azithromycin and the high frequency of gastrointestinal intolerance. In a earlier open study, a single 1-g dose of azithromycin eradicated the pathogen from the throat of 2/2 patients.22
New efficacious single-dose oral agents for the treatment of uncomplicated gonorrhea are highly needed: cefixime is no longer available on the market,31 and fluoroquinolone resistance is spreading worldwide.32 Cefpodoxime proxetil 200 mg is less active against N gonorrhoeae in vitro than cefixime and also does not quite meet the minimum efficacy criteria, with cure rates of 96.5% for urogenital and rectal infection; efficacy in treating pharyngeal infection (79%) is also unsatisfactory. Cefpodoxime 400 mg has not been well studied.33 Azithromycin is the only available drug that fulfills the desired criteria, coupled with an excellent efficacy against Chlamydia infections, although the decreasing susceptibility is a subject of concern. Although side effects with the 2-g dosing are common, they are most often mild to moderate and should not have practical repercussions when dealing with a single-dose regimen.
1. Van Duynhoven YT. The epidemiology of Neisseria gonorrhoeae
in Europe. Microbes Infect 1999; 1:455–464.
2. Nicoll A, Hamers FF. Are trends in HIV, gonorrhoea, and syphilis worsening in western Europe? BMJ 2002; 324:1324–1327.
3. Green MS, Anis E, Gandacu D, et al. The fall and rise of gonorrhoea incidence in Israel: an international phenomenon? Sex Transm Infect 2003; 79:116–118.
4. Dan M, Poch F, Sheinberg B. High prevalence of high-level ciprofloxacin resistance in Neisseria gonorrhoeae
in central Israel: correlation with response to therapy. Antimicrob Agents Chemother 2002; 46:1671–1673.
5. Dan M, Srugo I, Poch F, et al. Demographic characteristics and prevalence of STIs among immigrant sex workers in Tel Aviv, Israel. 5th
European Congress of Chemotherapy and Infection, Rhodes, Greece, October 2003
6. Kimoto K, Hayashi M, Okuni T, et al. Changing patterns in the sex industry and in sexually transmitted diseases among commercial sex workers in Osaka, Japan. Sex Transm Dis 2002; 29:79–82.
7. Tice AW, Rodriquez Vl. Pharyngeal gonorrhea. JAMA 1981; 246:2717–2719.
8. Steen R, Vuylsteke B, DeCoito T, et al. Evidence of declining STD prevalence in a South African mining community following a core-group intervention. Sex Transm Dis 2000; 27:1–8.
9. Department of STD Control. Annual Report 1992. Singapore: Department of STD Control, 1992.
10. Wong ML, Chan RKW, Koh D, et al. Increase in oral sex and pharyngeal gonorrhea: an unintended effect of a successful condom promotion program for vaginal sex. AIDS 1999; 13:1981–1982.
11. Wong ML, Chan RK. A prospective study of pharyngeal gonorrhoea and inconsistent condom use for oral sex among female brothel-based sex workers in Singapore. Int J STD AIDS 1999; 10:595–599.
12. Wong ML, Chan RKW, Koh D. Promoting condoms for oral sex: the impact on pharyngeal gonorrhea among female brothel-based sex workers. Sex Transm Dis 2002; 29:311–318.
13. Wong ML, Chan R, Koh D. Long-term effects of condom promotion programmes for vaginal and oral sex on sexually transmitted infections among sex workers in Singapore. AIDS 2004; 18:1195–1199.
14. Bro-Jorgensen A, Jensen T. Gonococcal pharyngeal infections: report of 110 cases. Br J Vener Dis 1973; 49:491–439.
15. Wiesner PJ, Tronca E, Bonin P, et al. Clinical spectrum of pharyngeal gonococcal infection. N Engl J Med 1973; 288:181–185.
16. Wong ML, Chan RKW, Koh D. A sustainable behavioral intervention to increase condom use and reduce gonorrhea among sex workers in Singapore: 2-year follow-up. Prev Med 1998; 27:891–900.
17. Remez L. Oral sex among adolescents: is it sex or is it abstinence? Fam Plan Perspect 2000; 32:298–304.
18. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002; 51:32–36.
19. Gruber F, Brajac I, Jonjic A, et al. Comparative trial of azithromycin and ciprofloxacin in the treatment of gonorrhea. J Chemother 1997; 9:263–266.
20. Rustomjee R, Kharsany AB, Connolly CA, et al. A randomized controlled trial of azithromycin versus doxycycline/ciprofloxacin for the syndromic management of sexually transmitted infections in a resource-poor setting. J Antimicrob Chemother 2002; 49:875–878.
21. Habib AR, Fernando R. Efficacy of azithromycin 1g single dose in the management of uncomplicated gonorrhoea. Int J STD AIDS 2004; 15:240–242.
22. Waugh MA. Open study of safety and efficacy of a single oral dose of azithromycin for the treatment of uncomplicated gonorrhea in men and women. J Antimicrob Chemother 1993; 31(suppl E):193–198.
23. Dillon J-AR, Li H, Sealy J, et al. Antimicrobial susceptibility of Neisseria gonorrhoeae
isolates from three Caribbean countries: Trinidad, Guyana, and St. Vincent Sex Transm Dis 2001; 28:508–514.
24. Sosa J, Ramirez-Arcos S, Ruben M, et al. High percentages of resistance to tetracycline and penicillin and reduced susceptibility to azithromycin characterize the majority of strain types of Neisseria gonorrhoeae
isolates in Cuba, 1995–1998. Sex Transm Dis 2003; 30:443–448.
25. Arreaza L, Vazquez F, Alcala B, et al. Emergence of gonococcal strains with resistance to azithromycin in Spain. J Antimicrob Chemother 2003; 51:190–191.
26. McLean CA, Wang SA, Hoff GL, et al. The emergence of Neisseria gonorrhoeae
with decreased susceptibility to azithromycin in Kansas City, Missouri, 1999 to 2000. Sex Transm Dis 2004; 31:73–78.
27. Tapsall JW, Shultz TR, Limnios EA, et al. Failure of azithromycin therapy in gonorrhea and discorrelation with laboratory test parameters. Sex Transm Dis 1998; 25:505–508.
28. Young H, Moyes A, McMillan A. Azithromycin and erythromycin resistant Neisseria gonorrhoeae
following treatment with azithromycin. Int J STD AIDS 1997; 8:299–302.
29. Waugh MA. Azithromycin in gonorrhea. Int J STD AIDS 1996; 7(suppl 1):2–4.
30. Handsfield HH, Dalu ZA, Martin DH, et al. Multicenter trial of single-dose azithromycin versus ceftriaxone in the treatment of uncomplicated gonorrhea: Azithromycin Gonorrhea Study Group. Sex Transm Dis 1994; 21:107–111.
31. Centers for Disease Control and Prevention. Notice to readers: discontinuation of cefixime tablets: United States. MMWR Morb Mortal Wkly Rep 2002; 51:1052.
32. Dan M. The use of fluoroquinolones in gonorrhea: the increasing problem of resistance. Expert Opin Pharmacother 2004; 5:829–854.
33. Centers for Disease Control and Prevention. Oral alternatives to cefixime for the treatment of uncomplicated Neisseria gonorrhoeae
urogenital infections. Available at: http://www.cdc.gov/std/treatment/cefixime.htm
. Accessed April 30, 2004.