In the United States, an estimated 700,000-800,000 persons are infected with Neisseria gonorrhoeae each year.^1, 2 Since 1993, CDC has recommended use of fluoroquinolones (i.e., ciprofloxacin, ofloxacin, or levofloxacin) for gonorrhea treatment. Fluoroquinolone therapy is used frequently because it is an inexpensive, oral, and single-dose therapy. However, because of increased prevalence of fluoroquinolone-resistant N. gonorrhoeae (QRNG)* in Asia, the Pacific Islands (including Hawaii), and California, fluoroquinolones are no longer recommended for treating gonorrhea acquired in those locations.^3-5 This report describes increases in QRNG among men who have sex with men (MSM) in Massachusetts, New York City, and 30 sites surveyed by the Gonococcal Isolate Surveillance Project (GISP) during 2003. CDC recommends that clinicians no longer use fluoroquinolones as a first-line treatment for gonorrhea in MSM.

GISP

GISP is a CDC-sponsored sentinel surveillance system that monitors antimicrobial susceptibilities in N. gonorrhoeae through ongoing testing of approximately 5,000 male urethral gonococcal isolates obtained annually from patients at 30 sexually transmitted disease (STD) clinics in the United States. Preliminary data collected during January-September 2003 from all GISP sites indicate a QRNG prevalence of 4.2%, compared with 2.2% in 2002⁶ and 0.7% in 2001.⁶ Excluding Hawaii and California, preliminary 2003 QRNG prevalence was 0.9% in 2003, compared with 0.4% in 2002 and 0.02% in 2001; in addition, in 2003, QRNG prevalence was 4.9% among MSM and 0.4% among heterosexual men (Figure), compared with 1.8% among MSM and 0.2% among heterosexual men in 2002.

Massachusetts

During January-August 2003, the Massachusetts State Laboratory Institute performed antimicrobial susceptibility tests on 249 gonococcal isolates from 235 patients in clinical facilities throughout the state. QRNG accounted for 10.4% (26 of 249) of gonococcal isolates tested during this period, compared with 2.1% (10 of 486) in 2002 and zero (0 of 386) in 2001.

The 26 QRNG isolates in 2003 were obtained from 24 patients, of whom 22 were male and two were female partners of men identified with QRNG; seven (29%) were STD clinic patients. Of the 22 male QRNG patients, four (18%) reported having sex exclusively with women, one reported having sex with men and women, and 17 (77%) reported having sex exclusively with men. None of the patients with QRNG was identified as a result of treatment failure.

Medical records were reviewed for all 111 male gonorrhea patients who had diagnosis by culture at STD clinics in the state. Of these, seven (6.3%) had QRNG identified, with 11.1% (six of 54) QRNG prevalence among MSM and 1.8% (one of 55) among heterosexual men. A total of 14 female patients had gonorrhea diagnosed at STD clinics; none had QRNG.

Since 1987, the Massachusetts Department of Public Health has recommended use of ceftriaxone rather than fluoroquinolones for treatment of uncomplicated gonococcal infections. When local increases in QRNG were identified in late 2002, the health department issued a clinical advisory to health-care providers throughout the state, alerting them to the increase and advising that fluoroquinolones were not recommended for gonorrhea treatment unless antimicrobial susceptibility testing excluded fluoroquinolone resistance.** Beginning in June 2003, any health-care provider who reported a patient who had been treated with a fluoroquinolone was sent a notice recommending that a test of cure be performed unless susceptibility testing was performed initially to rule out QRNG.

New York City

During January-July 2003, antimicrobial susceptibility testing was performed on 643 gonococcal isolates from patients evaluated at the 10 STD clinics operated by the New York City Department of Health and Mental Hygiene's Bureau of Sexually Transmitted Disease Control. During this interval, antimicrobial resistance information was available from cultures performed on oropharyngeal and rectal specimens in all 10 clinics. Consequently, MSM probably are overrepresented among men who have culture-confirmed gonorrhea. In one clinic, cultures also were performed on urethral specimens. None of the clinics obtained endocervical specimens for culture. Most testing for gonorrhea was conducted by using nucleic acid amplification methods. QRNG accounted for 3.4% (22 of 643) of isolates tested during January-July 2003, compared with 0.3% (eight of 3,196) in 2002 and 0.1% (three of 3,144) in 2001.

Medical record reviews were performed at six of the STD clinics. During January-July 2003, a total of 394 gonococcal isolates from 369 patients at these six clinics were tested for antimicrobial susceptibility; QRNG was identified in 5% (18 of 369) of the patients. Seventeen (94%) of the 18 patients with QRNG were male, and 13 (77%) reported being MSM. QRNG prevalence among patients for whom sexual behavior was documented was 12.5% (14 of 112) among MSM, 1.6% (three of 183) among heterosexual men, and 2.4% (one of 42) among women.

Fourteen of the 17 patients with QRNG for whom gonorrhea treatment history was available had been treated with ceftriaxone. New York City STD clinic treatment protocols specify that gonorrhea be treated with ceftriaxone and that fluoroquinolones only be used if culture is performed so the patient can be recalled if QRNG is identified.

S. Ratelle, T. Bertrand and W. Dumas are with the Massachusetts Dept of Public Health. K. Macomber and D. Ganoczy are with the Michigan Dept of Community Health. J. Schillinger, S. Manning, J. Reddy and S. Blank are with the New York City Dept of Health and Mental Hygiene. S. Wang, H. Weinstock, J. Newhall, K. Workowski and S. Berman are with the Division of STD Prevention, National Center for HIV, STD, and TB Prevention, CDC.

Editorial Note

Fluoroquinolones are used frequently to treat gonorrhea in the United States because they are inexpensive and easy to administer and their continued use might decrease the use of cephalosporins and delay the development of cephalosporin resistance. However, local and national data suggest that the prevalence of QRNG among MSM infected with gonorrhea is close to or exceeds 5%. This level of resistance often is used as the level at which a therapeutic regimen should be changed;⁷ other factors, including prevalence of gonorrhea, availability of antimicrobial susceptibility data, and cost of various diagnostic and treatment options, might result in higher or lower thresholds for change. In the absence of antimicrobial susceptibility testing or tests of cure, fluoroquinolones should no longer be used to treat proven or suspected gonococcal infections in MSM in the United States. Health departments should notify clinicians about this new recommendation. Some local health departments have issued similar recommendations recently.

Fluoroquinolones also should not be used to treat patients whose gonorrhea was acquired in Asia, the Pacific Islands (including Hawaii), California, and other areas, such as England and Wales, with increased QRNG prevalence.^4, 8 For those infections acquired where QRNG is not endemic, before determining treatment, clinicians should obtain travel histories from patients and information on the sex of sex partners from male patients with proven or suspected gonorrhea. A list of places that should be included in a relevant travel history is available at www.cdc.gov/std/gisp.

For patients with gonorrhea who are MSM or who provide a history suggesting acquisition of infection in an area with high QRNG prevalence, CDC recommends ceftriaxone 125 mg intramuscularly or cefixime 400 mg orally (not currently available in the United States⁹); spectinomycin 2 g intramuscularly is an alternative. Spectinomycin may be used for urogenital and anorectal gonorrhea but is not sufficiently effective to treat pharyngeal gonorrhea.^4, 10 If Chlamydia trachomatis is not ruled out, each regimen should be followed with either azithromycin 1.0 g orally (single dose) or doxycycline 100 mg orally twice daily for 7 days to treat possible co-infection with chlamydia.

The limited availability of a recommended oral treatment regimen for gonorrhea poses practical problems for treating QRNG. Besides the fluoroquinolones, cefixime, whose manufacture was discontinued in 2002, is the only CDC-recommended oral agent for treating gonorrhea. Although Lupin, Ltd. (Baltimore, Maryland) received Food and Drug Administration approval to manufacture and market cefixime in February 2004, the 400-mg tablets to treat gonorrhea are not yet available; the suspension (100 mg/5 mL) is available. The health departments of California and Washington state have suggested alternative oral treatments (e.g., cefpodoxime 400 mg) that have not yet been evaluated adequately. CDC will provide additional information about the availability of cefixime and efficacy of other oral agents for treating gonorrhea as it becomes available (www.cdc.gov/std/treatment/cefixime.htm).

Clinicians must be vigilant in identifying treatment failures when fluoroquinolones are used, advise their patients about the importance of follow-up if symptoms persist, and be prepared to evaluate such cases by culture. In cases of persistent gonococcal infection after treatment with fluoroquinolones, antimicrobial susceptibility testing should be performed. Only culture of N. gonorrhoeae can be used to determine antimicrobial susceptibility. Health departments without the capacity to perform culture and antimicrobial susceptibility testing should develop those capabilities locally or partner with laboratories outside their jurisdictions. The antimicrobial susceptibility testing panel should, at a minimum, include a fluoroquinolone, ceftriaxone, spectinomycin, azithromycin, and any other drugs in local use for gonorrhea treatment. Arrangements for antimicrobial susceptibility testing can be made by contacting state and local health departments. Through their state and local health departments, clinicians and laboratorians should report treatment failures or resistant gonococcal isolates to CDC, telephone 404-639-2059.

Given the apparent low prevalence of QRNG among heterosexuals, a national change in treatment in that group is not recommended at this time. However, QRNG prevalence among heterosexuals is likely to increase over time and already might be high enough in some areas to warrant new local treatment recommendations. For example, increased prevalence of QRNG among heterosexuals has been identified in several counties in Michigan, where recommendations have been made to avoid using fluoroquinolones among all persons infected with gonorrhea. Because gonococcal infections, especially in women, frequently are asymptomatic, monitoring for symptomatic treatment failures alone does not provide a reliable indication of emerging antimicrobial resistance. Therefore, as part of effective gonorrhea-control programs, health departments should evaluate their current QRNG surveillance activities and consider plans to monitor for the presence of QRNG among heterosexual populations with gonorrhea. If prevalence increases nationally among heterosexuals, guidance from CDC will be forthcoming. Local and state treatment recommendations, technical information, surveillance data, references, and other links related to gonococcal resistance are available at www.cdc.gov/std/gisp.

References

1. Institute of Medicine, Division of Health Promotion and Disease Prevention. The hidden epidemic: confronting sexually transmitted diseases. Eng TR, Butler WT, eds. Washington, DC: National Academy Press, 1997.

2. Weinstock H, Berman S, Cates W. Sexually transmitted infections in American youth: incidence and prevalence estimates, 2000. Perspectives on Sexual and Reproductive Health 2004;36:6-10.

3. CDC. Fluoroquinolone-resistance in Neisseria gonorrhoeae in Hawaii, 1999 and decreased susceptibility to azithromycin in N. gonorrhoeae, Missouri, 1999. MMWR 2000;49:833-6.

4. CDC. Sexually transmitted diseases treatment guidelines 2002. MMWR 2002;51(No. RR-6).

5. CDC. Increases in fluoroquinolone-resistant Neisseria gonorrhoeae -- Hawaii and California, 2001. MMWR 2002;51:1041-4.

6. CDC. Sexually Transmitted Disease Surveillance 2002 Supplement: Gonococcal Isolate Surveillance Project (GISP) Annual Report 2002. Atlanta, Georgia: U.S. Department of Health and Human Services, CDC, 2003.

7. Tapsall J. Antimicrobial resistance in Neisseria gonorrhoeae. Geneva, Switzerland: World Health Organization, 2001; WHO/CDS/DRS/2001.3:16.

8. Fenton KA, Ison C, Johnson AP, et al. Ciprofloxacin resistance in Neisseria gonorrhoeae in England and Wales in 2002. Lancet 2003;361:1867-9.

9. CDC. Discontinuation of cefixime tablets -- United States. MMWR 2002;51:1052.

10. CDC. Oral alternatives to cefixime for the treatment of uncomplicated Neisseria gonorrhoeae urogenital infections. Available at www.cdc.gov/std/treatment/cefixime.htm.

* Defined by the National Committee on Clinical Laboratory Standards as N. gonorrhoeae resistant to ciprofloxacin (minimum inhibitory concentration [MIC] >1.0 µg/mL by agar dilution or disk diffusion zone size <27 mm) or ofloxacin (MIC >2.0 µg/mL or disk diffusion zone size <24 mm).

** Available at www.state.ma.us/dph/cdc/std/ca_gc.htm.