AFTER THE SPREAD OF PENICILLIN- and tetracycline-resistant strains in the early 1990s, ciprofloxacin has been widely used as first-line therapy for gonorrhea. Recently, some European countries have reported an increase of Neisseria gonorrhoeae (NG) ciprofloxacin resistance.1–3 In the United States, fluoroquinolones are no longer recommended for gonorrhea acquired in Hawaii and in California, but also for gonococcal infections occurring in male patients who have sex with men.4
In France, NG antimicrobial susceptibility has been monitored through a sentinel laboratory network, RENAGO, since 1986. An average of 230 laboratories (82% private and 18% laboratories attached to a hospital) located in all regions of France (except Corsica) participate each year. NG ciprofloxacin resistance, which was low until 2000,5 has recently sharply increased.
The RENAGO network has been previously described.5 Briefly, participating laboratories send each isolated NG strain to the National Reference Centre for Neisseria gonorrhoeae (Institut Alfred Fournier, Paris, France), where the minimum inhibitory concentration (MIC) is determined. The reference agar plate dilution technique was used until 20006 and by the E-test method after (AB Biodisk, Solna, Sweden; AES Laboratories, France). Since 1989, NG ciprofloxacin susceptibility has been monitored.
The criteria to define resistance are those recommended by the U.S. Committee on Clinical Laboratory Standards (NCCLS) for aerobic bacteria.7 Isolates with ciprofloxacin MIC ≥1 mg/L were classified as resistant to ciprofloxacin and those with MICs of 0.125 to 0.5 mg/L as exhibiting an intermediate resistance to ciprofloxacin.
For each strain, the age, sex, anatomic site, and country of acquisition were collected for each patient.
A random selection of ciprofloxacin resistant strains isolated during the years 2002–2003 were sent to the Department of Medical Microbiology, Imperial College London. NG strains were genotyped using the sequence-based technique of NG-MAST in which 2 highly polymorphic antigen-encoding loci por and tbpB are sequenced and a 2-locus allelic profile are assigned as sequence type8 through the NG-MAST web site (www.ng-mast.net).
To assess change over time in NG antibiotic-resistance patterns, microbiologic data are presented according to 4 study periods: 1989–1992, 1993–1997, 1998–2000, and 2001–2003.
From 1989 to 2003, 1921 NG strains were available for ciprofloxacin susceptibility testing. NG intermediate resistance to ciprofloxacin accounted for 0.25% (n = 1) of the tested isolates in 1989–1992. Resistance to ciprofloxacin was detected for the first time in 1997. The percentage of isolates with intermediate resistance or resistant to ciprofloxacin was equal at 1.8% (n = 9) in 1993–1997 and 5.2% (n = 29) in 1998–2000. This proportion significantly increased (chi-squared for trend; P value < 10−5) during the latest study period 2001–2003, to reach 14.8% corresponding to 70 NG isolates. Of them, 24 (5.1%) presented intermediate resistance to ciprofloxacin and 46 (9.7%) were resistant (Fig. 1).
High-level resistance (i.e., ciprofloxacin MIC ≥4 mg/L) appeared for the first time in 2003 when 18 strains with MIC values ranging from 4 mg/L to 32 mg/L were isolated.
The laboratories that sent the NG-resistant strains were located in 9 regions of France. Epidemiologic data on the 70 patients with NG strains resistant to ciprofloxacin indicated a sex ratio male to female of 22 (67 males/3 females). The mean age of patients was 34 years (range, 12–67 years). Among the men, 8 (11.2%) had rectal and 5 (7.1%) pharyngeal gonorrhea. Country of acquisition was recorded for 20 patients. Of them, 12 were infected through sexual contact in France and 8 abroad (4 in Asia, 2 in Africa, and 2 in Europe).
Patients with NG strains resistant to ciprofloxacin did not differ from those with susceptible strains with regard to sex, area of residence (Paris area vs. other French regions), type of laboratory (private/public), or anatomic site of the specimen. However, ciprofloxacin-resistant strains were significantly (chi-square; P value < 10−4) more often resistant to penicillin (30% vs. 7%) and to tetracycline (66% vs. 30%) than the susceptible ones.
Among the 70 ciprofloxacin-resistant strains isolated during 2001–2003, 40 (56%) were genotyped using the NG-MAST technique. These strains had been recovered from the male urethra (n = 32), the male rectum (n = 5), and the female cervix (n = 3) and were isolated in laboratories located in 9 regions of France. Among these 40 NG isolates, 26 different por alleles and 13 different tbpB defined 33 specific sequence types. A cluster included 6 strains (4 male urethral, one cervix female, one male rectal) isolated in 4 regions of France. There was also one cluster of 2 male urethral strains isolated in the same sexually transmitted infection clinic in Paris and one cluster of 2 male urethral strains from 2 different regions. The sequence type for the 30 remaining strains was unique to one isolate.
From 1998 to 2003, NG resistance to ciprofloxacin sharply increased in France from 5.2% to 14.8%. Furthermore, ciprofloxacin-resistant NG strains isolated during 2003 showed high levels of resistance with MIC values of 4 mg/L or greater. Epidemiologic patterns of ciprofloxacin-resistant strains were not significantly different from the patterns of susceptible ones. In particular, NG-resistant strains were not only located in the Paris area. The genotyping study among 40 resistant strains found 3 clusters, one of presented 6 strains disseminated in 4 regions of France. A high level of diversity in the typed ciprofloxacin-resistant isolates was detected in that 75% of the isolates had a unique ST and only 3 clusters had the same ST. It would appear that there are several different ciprofloxacin-resistant isolates being introduced in France.
Although RENAGO is a sentinel surveillance network, the NG ciprofloxacin-resistant patterns observed in this network probably reflect the NG ciprofloxacin resistance in France because this network covers all regions. Participating laboratories account for 5.6% of all laboratories and belong to both the private and public health sector.
The epidemiologic data and the results of genotyping suggest that different ciprofloxacin-resistant NG strains are geographically disseminated in France. These strains are not affecting a specific population group.
There are no gonorrhea treatment guidelines in France, but 250 to 500 mg ciprofloxacin as a single dose is widely prescribed for gonorrhea. A public health alert was made following the increase of ciprofloxacin resistance, and an expert group has been appointed by the Ministry of Health to make new recommendations regarding discontinuing the use of ciprofloxacin to treat gonorrhea.
In addition, because NG ciprofloxacin resistance has been documented in several European countries1–3 and sexually transmitted infections disseminate vary widely through Europe as confirmed by the recent rectal lymphogranuloma venereum outbreak,9 European recommendations for treatment of gonorrhea are becoming increasingly necessary.
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9. Center for Disease Control and Prevention. Lymphogranuloma venereum among men having sex with men—Netherlands, 2003–2004. MMWR Morb Mortal Wkly Rep 2004; 53:985–988.