Decreased Susceptibility of Neisseria gonorrhoeae to Fluoroquinolones -- Ohio and Hawaii, 1992-1994

Until 1992, virtually all strains of N. gonorrhoeae tested were susceptible to fluoroquinolones, including ciprofloxacin (minimal inhibitory concentrations {MICs} of less than or equal to 0.06 ug/mL) (1). However, gonococcal strains with decreased susceptibilities to ciprofloxacin (MICs of 0.13-0.25 ug/mL) have been isolated sporadically from patients in the United States through the Gonococcal Isolate Surveillance Project (GISP), which measures antimicrobial susceptibilities of urethral isolates from men each month (2). This report describes findings from Ohio and Hawaii that suggest the emergence of fluoroquinolone resistance in N. gonorrhoeae.

Ohio. From January 1992 through June 1993, 450 isolates of N. gonorrhoeae in the GISP sample were tested; 25 (5.6%) had decreased susceptibilities to ciprofloxacin. When tested at CDC, these isolates had MICs of 0.13-0.25 ug/mL of ciprofloxacin. Expanded screening of all isolates from men at one sexually transmitted disease (STD) clinic during November-December 1993 identified 17 (13.7%) of 124 isolates with MICs of 0.13-0.25 ug/mL of ciprofloxacin. Infections caused by strains with these MICs apparently were not linked to recent travel outside the United States by the patients or their sex partners and may have been transmitted locally. All patients were treated with ceftriaxone and doxycycline.

Hawaii. From May 1993 through February 1994, gonococcal strains exhibiting MICs of 2.0 ug/mL of ciprofloxacin were isolated from three patients in Hawaii. These strains were detected during an evaluation of antimicrobial resistance in 37 penicillinase- producing N. gonorrhoeae isolates. All three infected persons had traveled to or had had sex partners who had recently traveled to Southeast Asia. The three patients were treated with ceftriaxone and doxycycline.

Analysis of findings. Agar dilution and disk-diffusion susceptibilities to ciprofloxacin and ofloxacin of the isolates from Ohio and Hawaii were determined as recommended by the National Committee for Clinical Laboratory Standards (Table_1) (1,3). Disk-diffusion susceptibility testing of isolates from Ohio produced zone diameters similar to those of susceptible strains (i.e., greater than or equal to 36 mm and greater than or equal to 31 mm for ciprofloxacin and ofloxacin, respectively) (3). Inhibition zone diameters for strains from Hawaii were smaller. All isolates were susceptible to ceftriaxone and cefixime.

Reported by: R Ohye, MS, H Higa, R Vogt, MD, State Epidemiologist, State of Hawaii Dept of Health. JA Washington, MD, L Doyle, Cleveland Clinic Foundation; D Sayers, TJ Halpin, MD, State Epidemiologist, Ohio Dept of Health. Molecular Epidemiology and Pathogenesis Br, Div of Sexually Transmitted Diseases Laboratory Research, Office of the Director, National Center for Infectious Diseases; Epidemiology Research Br and Surveillance and Information Systems Br, Div of Sexually Transmitted Diseases and HIV Prevention, National Center for Prevention Svcs, CDC.

Editorial Note

Editorial Note: The reports from Ohio and Hawaii suggest that the epidemiology of gonorrhea caused by strains with decreased susceptibility to fluoroquinolones may be changing. The Ohio report is the first that describes the repeated isolation of strains with this resistance phenotype in a community in the United States and indicates that, in that community, these strains may have become endemic. The Hawaii report documents MICs higher than those previously reported in the United States; strains with similar MICs have been reported in Thailand and Australia (4,5). As a result of these findings, Ohio and Hawaii have expanded surveillance efforts to detect gonococcal strains with decreased susceptibilities to fluoroquinolones.

Gonococcal organisms with decreased in vitro susceptibilities to ciprofloxacin have decreased susceptibilities to all fluoroquinolones, including ofloxacin, enoxacin, lomefloxacin, and norfloxacin (6). However, pharmacokinetics, as well as susceptibilities, must be considered in evaluating the potential for treatment failure. Reported treatment failures have resulted from decreased susceptibility of the infecting strain to enoxacin and norfloxacin (7,8) and have occurred after treatment with ciprofloxacin (500 mg) (5).

Although the MICs of strains from Ohio exceed the National Committee for Clinical Laboratory Standards criterion for susceptibility to ciprofloxacin, serum levels achieved with the recommended dose of this agent suggest that these strains should respond to therapy (9). However, no treatment efficacy data are available to confirm this interpretation. In contrast, strains that have MICs of 2.0 ug/mL ciprofloxacin may not respond to therapy with the recommended dose of ciprofloxacin (or other fluoroquinolones) (5).

Because treatment failure can occur following any antimicrobial regimen, patients treated for gonorrhea should be advised to return for reevaluation if symptoms persist. Reevaluated patients who have a gonococcal infection within 2 weeks after treatment should be interviewed regarding possible reinfection, and a specimen should be collected for culture and susceptibility testing (1,3). If susceptibility testing cannot be performed locally, isolates should be forwarded to a reference laboratory for testing. Thus, local laboratories that routinely use nonculture tests for the diagnosis of gonorrhea should maintain the ability to isolate N. gonorrhoeae to facilitate susceptibility testing of posttreatment isolates.

Antimicrobial resistance in N. gonorrhoeae is an increasing and costly public health problem. Because of increasing resistance to inexpensive therapeutic antimicrobial agents (e.g., penicillin and tetracycline), in 1989 CDC recommended alternative but more costly regimens, including fluoroquinolones, for the treatment of gonorrhea (10). The findings in these reports of N. gonorrhoeae strains with decreased susceptibilities to fluoroquinolones do not justify changes at this time in recommendations for the routine treatment of gonorrhea in the United States. However, because infections with N. gonorrhoeae strains with MICs of 1.0-2.0 ug/mL of ciprofloxacin have been acquired in Southeast Asia and Australia (4,5), clinicians treating persons believed to have been infected in these areas should consider using other antimicrobials.

Clinics using fluoroquinolones to treat gonorrhea should monitor the susceptibilities of gonococcal isolates to these agents. CDC will continue to monitor the susceptibilities of N. gonorrhoeae strains to fluoroquinolones and other antimicrobial agents through GISP and other surveillance systems and is reassessing the appropriateness of fluoroquinolones in gonorrhea therapy in the United States.

References

1. National Committee for Clinical Laboratory Standards. Methods

for dilution antimicrobial susceptibility tests for bacteria that grow aerobically -- third edition; approved standard. Villanova, Pennsylvania: National Committee for Clinical Laboratory Standards, 1993; NCCLS document no. M7-A3 (vol 13, no. 25).

2. Gorwitz RJ, Nakashima AK, Moran JS, Knapp JS, The Gonococcal Isolate Surveillance Project Study Group. Sentinel surveillance for antimicrobial resistance in Neisseria gonorrhoeae -- United States, 1988-1991. MMWR 1993;42(no. SS-3):29-39.

3. National Committee for Clinical Laboratory Standards. Performance standards for anti- microbial disk susceptibility tests -- 5th edition; approved standard. Villanova, Pennsylvania: National Committee for Clinical Laboratory Standards, 1993; NCCLS document no M2-A5 (vol 13, no. 24).

4. Clendennen TE, Echeverria P, Saengeur PS, Kees ES, Boslego JW, Wignall FS. Antibiotic susceptibility survey of Neisseria gonorrhoeae in Thailand. Antimicrob Agents Chemother 1992;36:1682- 7.

5. Tapsall JW, Lovett R, Munro R. Failure of 500 mg ciprofloxacin therapy in male urethral gonorrhea. Med J Aust 1992;156:143.

6. Barry AL, Jones RN. Cross-resistance among cinoxacin, ciprofloxacin, DJ-6783, enoxacin, nalidixic acid, norfloxacin, and oxolinic acid after in vitro selection of resistant populations. Antimicrob Agents Chemother 1984;25:775-7.

7. Van der Willigen AH, van der Hoek JCS, Wagenvoort JHT. Comparative double-blind study of 200- and 400-mg enoxacin given orally in the treatment of acute uncomplicated urethral gonorrhea in males. Antimicrob Agents Chemother 1987;31:535-8.

8. Bogaerts J, Tello WM, Akingeneye J, Mudantabana V, van Dyck E. Effectiveness of norfloxacin and ofloxacin for treatment of gonorrhoea and decrease of in vitro susceptibility to quinolones over time in Rwanda. Genitourin Med 1993;69:196-200.

9. Tartaglione TA, Russo ME. Pharmacology of drugs used in venereology. In: Holmes KK, M¦rdh P-A, Sparling PF, Wiesner PJ, eds. Sexually transmitted diseases. 2nd ed. New York: McGraw-Hill Information Services Company, 1990:993-1019. 10. CDC. 1989 Sexually transmitted diseases treatment guidelines. MMWR 1989;38 (no. SS-8).

TABLE 1. Agar dilution and disk-diffusion susceptibilities to ciprofloxacin and ofloxacin
of strains of Neisseria gonorrhoeae with decreased susceptibilities to ciprofloxacin --
Ohio and Hawaii
=================================================================================================
                               MIC * range     Zone diameters
Source           Agent          (ug/mL) +          (mm) +&
-------------------------------------------------------------
Ohio         Ciprofloxacin      0.13-0.25           31-39
               Ofloxacin        0.13-0.50           28-35

Hawaii       Ciprofloxacin         2.0              22-24
               Ofloxacin           2.0              18-20
-------------------------------------------------------------
* Minimal inhibitory concentration.
+ Susceptibility testing performed on GC II agar base supplemented with 1% IsoVitaleX according
  to the methods recommended by the National Committee for Clinical Laboratory Standards
  (1,3).
& Ciprofloxacin and ofloxacin disks, each 5 ug mass.
=================================================================================================

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