The fluoroquinolones ciprofloxacin and ofloxacin are among the antimicrobials recommended for treating uncomplicated gonorrhea (1). Fluoroquinolone-resistant strains of Neisseria gonorrhoeae have been identified frequently during the 1990s in the Far East (2). In the United States, fluoroquinolone-resistant N. gonorrhoeae has been reported sporadically; resistance associated with clinical treatment failure has been reported previously in only one person, who probably acquired the infection in the Philippines (3-5). This report describes the results of an investigation in 1997 of two cases of gonococcal infection in the United States with strains with a higher level of fluoroquinolone resistance than reported previously; clinical treatment failure occurred in one case.

CASE REPORTS

Patient 1

On July 14, a 24-year-old man sought care at the San Diego County Public Health Sexually Transmitted Diseases (STD) clinic following a 2-day history of purulent urethral discharge. Four days before onset of symptoms, he had had vaginal intercourse with a commercial sex worker in San Diego. He reported no other recent sex partners or travel outside the United States.

Gram-negative intracellular diplococci were identified in the urethral discharge. The culture grew N. gonorrhoeae and was sent for antimicrobial susceptibility testing as part of the national Gonococcal Isolate Surveillance Project (GISP). He received a single dose of 400 mg ofloxacin orally and began taking 100 mg doxycycline orally twice a day for 10 days for possible chlamydial co-infection.

The patient's urethral discharge persisted, and on July 17 he sought care from his primary-care physician. Repeat urethral culture grew N. gonorrhoeae; this isolate was not available for further testing. The patient was treated with 500 mg ceftriaxone intramuscularly, and his symptoms resolved. The clinical treatment failure was not reported to the health department.

Patient 2

On July 17, a 22-year-old man sought care at the San Diego County Public Health STD clinic following a 2-day history of purulent urethral discharge. He reported having had multiple female sex partners. Two weeks before gonorrhea was diagnosed, he had had one sexual contact with a woman from the United States whom he met at a nightclub frequented by U.S. military personnel in Tijuana, Mexico. He also reported having had a steady sex partner for 7 months. He had traveled to Asia in October 1996.

Gram-negative intracellular diplococci were identified in his urethral discharge. The culture grew N. gonorrhoeae and was sent to the GISP laboratory for susceptibility testing. The patient received a single dose of 400 mg ofloxacin orally and began taking 100 mg doxycycline orally twice a day for 10 days. His symptoms resolved without further treatment.

His steady sex partner was tested for gonorrhea; an endocervical culture was negative. The same regimen of ofloxacin and doxycycline was prescribed, which she reported completing. She reported no other recent sex partners or travel to Asia. The sex partner from the nightclub could not be located for follow-up.

FOLLOW-UP INVESTIGATION

On October 17, 1997, the STD Program of the San Diego Department of Health was notified by the GISP laboratory that the N. gonorrhoeae isolates from patients 1 and 2 were resistant to ciprofloxacin and ofloxacin (minimum inhibitory concentration {MIC} 16 ug/mL for both antibiotics). The isolates also were resistant to tetracycline (MIC 2.0 ug/mL) but sensitive to ceftriaxone (MIC 0.008 ug/mL) (6-8).

On October 28, patient 1 was reexamined, and a repeat urethral culture was negative. He reported two female partners since July; endocervical cultures from both were negative. One of the partners reported another male partner; his urethral culture was negative. None of these contacts reported other sex partners or travel to Asia.

On October 29, patient 2 and his steady partner were re-examined; repeat urethral and endocervical cultures were negative. The patient's symptoms had not recurred since his initial treatment in July. The patient and his partner reported having had no other sex partners since July.

Isolates from patients 1 and 2 belonged to the same auxotype/serovar class, PA/IB-3 (proline- and arginine-requiring), and had identical antimicrobial susceptibility profiles, suggesting that they were the same strain. Molecular studies indicated that the isolates had identical mutations in the genes encoding DNA gyrase (gyrA) and topo-isomerase IV (parC), mutations associated with fluoroquinolone resistance. No other fluoroquinolone-resistant N. gonorrhoeae isolates have been identified in San Diego County, neighboring Orange County, and the city of Long Beach. Gonococcal isolates from Tijuana have been requested for antimicrobial susceptibility testing.

In October 1997, a survey of 79 providers who treat patients in the high-risk STD area of San Diego County indicated that 80% used ceftriaxone or cefixime and 20% used ofloxacin or ciprofloxacin to treat gonorrhea. None reported treatment failures. Local military health-care facilities also treat gonorrhea with ceftriaxone.

Reported by: T Brazell, MD, C Peter, PhD, M Ginsberg, MD, Community Health Svcs, Health and Human Svcs Agency, San Diego County Dept of Health, San Diego; J Montes, G Bolan, MD, STD Control Br, S Waterman, MD, State Epidemiologist, California Dept of Health Svcs. J Ehret, MS, FN Judson, MD, Denver Dept of Health, Denver, Colorado. Bacterial Sexually Transmitted Diseases Br, Div of AIDS, STD, and TB Laboratory Research, National Center for Infectious Diseases; Epidemiology and Surveillance Br, Div of STD Prevention, National Center for HIV, STD, and TB Prevention; Div of Applied Public Health Training (proposed), Epidemiology Program Office; and an EIS Officer, CDC.

Editorial Note

Editorial Note: Fluoroquinolones and cephalosporins became the recommended therapies for gonorrhea following the appearance of penicillin- and tetracycline-resistant N. gonorrhoeae during the 1980s and early 1990s (1,2). Fluoroquinolone-resistant N. gonorrhoeae (ciprofloxacin MIC greater than or equal to 1.0 ug/mL or ofloxacin MIC greater than or equal to 2.0 ug/mL) (6,8) emerged during the 1990s and became well-established in several areas (e.g., Hong Kong, Japan, and the Philippines) (2). During the same period in the United States, N. gonorrhoeae with decreased susceptibility to ciprofloxacin (MIC 0.125-0.5 ug/mL) became endemic in at least one area and occurred sporadically in other areas (3-5). Among the 26 clinics participating in GISP, the overall prevalence of N. gonorrhoeae with decreased susceptibility to ciprofloxacin was 0.3% in 1991 (5) and 0.4% in January-June 1997 (CDC, unpublished data). The isolates from the two patients described in this report had the highest level of fluoroquinolone resistance ever reported in the United States.

Failure of infection to respond to single-dose therapy with 500 mg of ciprofloxacin has been reported with strains of N. gonorrhoeae with MICs greater than or equal to 1.0 ug/mL (2), but data are limited. In one trial, treatment with 500 mg ciprofloxacin failed to cure 45% of patients who had infections caused by N. gonorrhoeae with ciprofloxacin MICs greater than or equal to 4.0 ug/mL (9). In San Diego, doxycycline probably was the effective component of therapy because the isolates had tetracycline MICs at the low end of the resistance range (greater than or equal to 2.0 ug/mL) (6,8).

Identifying the sources of fluoroquinolone-resistant strains of N. gonorrhoeae found in the United States has been difficult, but some infections have been linked to importation from Southeast Asia and contact with commercial sex workers (3). In San Diego, both patients had anonymous sex contacts, but no international link was found. Military personnel travel frequently to Asia and are a potential source of imported strains of antimicrobial-resistant N. gonorrhoeae. However, the military treatment regimen decreases the likelihood of spread of fluoroquinolone-resistant strains.

Although the two San Diego isolates were the same strain, no epidemiologic link between the two patients could be identified. Despite enhanced surveillance, no additional cases of fluoroquinolone-resistant N. gonorrhoeae have been detected in San Diego. The spread of fluoroquinolone-resistant N. gonorrhoeae locally may be limited by the frequent use of cephalosporins for treating gonorrhea.

Because fluoroquinolone-resistant N. gonorrhoeae is rare in the United States, CDC recommends fluoroquinolones to treat gonococcal infections (1). However, ceftriaxone, cefixime, or spectinomycin should be used if the infection was acquired in Asia. In some areas (e.g., Cleveland, Ohio) where strains with decreased susceptibility to fluoroquinolones are endemic, fluoroquinolones should not be used to treat gonorrhea because these strains may represent a pool from which fluoroquinolone-resistant strains may emerge (3,5). Clinicians should obtain a culture and request susceptibility testing for any patient with apparent treatment failure after recommended therapy and report these cases promptly to the local health department.

This investigation underscores the importance of timely surveillance for antibiotic-resistant N. gonorrhoeae. As clinical laboratories increasingly use nonculture methods for the diagnosis of gonorrhea, the importance of maintaining N. gonorrhoeae culture capability and the ability to measure antimicrobial susceptibility in public health laboratories increases. Laboratories serving patients with gonococcal infections should maintain culture capability to evaluate patients with apparent treatment failure. Laboratories should report any isolates meeting proposed National Committee for Clinical Laboratory Standards criteria for resistance to ciprofloxacin (MIC greater than or equal to 1.0 ug/mL; zone inhibition diameter {5 ug disk} less than or equal to 27 mm) or ofloxacin (MIC greater than or equal to 2.0 ug/mL; zone inhibition diameter {5 ug disk} less than or equal to 24 mm) to their state public health laboratory (6,8). CDC laboratories will confirm resistant isolates.

References

1. CDC. 1998 Guidelines for treatment of sexually transmitted diseases. MMWR 1998;47(no. RR-1).

2. Knapp JS, Fox KK, Trees DL, Whittington WL. Fluoroquinolone resistance in Neisseria gonorrhoeae. Emerging Infectious Diseases 1997;3:33-9.

3. CDC. Fluoroquinolone resistance in Neisseria gonorrhoeae -- Colorado and Washington, 1995. MMWR 1995;44:761-4.

4. CDC. Decreased susceptibility of Neisseria gonorrhoeae to fluoroquinolones -- Ohio and Hawaii, 1992-1993. MMWR 1994;43:325-7.

5. Fox KK, Knapp JS, Holmes KK, Hook EW III, et al. Antimicrobial resistance in Neisseria gonorrhoeae in the United States, 1988-1994: the emergence of decreased susceptibility to the fluoroquinolones. J Infect Dis 1997;175:1396-403.

6. Knapp JS, Hale JA, Neal SW, Wintersheid K, Rice RJ, Whittington WL. Proposed criteria for interpretation of susceptibilities of strains of Neisseria gonorrhoeae to ciprofloxacin, ofloxacin, enoxacin, lomefloxacin, and norfloxacin. Antimicrob Agents Chemother 1995;39:2442-5.

7. National Committee for Clinical Laboratory Standards. Approved standard M7-A3: methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Villanova, Pennsylvania: National Committee for Clinical Laboratory Standards, 1993.

8. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing. M100-S8. Wayne, Pennsylvania: National Committee for Clinical Laboratory Standards, 1998.

9. Aplasca MR, Pato-Mesola V, Klausner J, Tuazon C, et al. High rates of failure after treatment with ciprofloxacin -- are fluoroquinolones no longer useful for gonorrhea treatment? {Abstract} In: Abstracts of the 4th International Congress on AIDS in Asia and the Pacific; October 1997; Manila, Philippines.

   
   

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