TO CONTROL THE SPREAD of sexually transmitted infections (STIs), compulsory notification for cases of syphilis, gonorrhea, chancroid, and lymphogranuloma venereum was established in France by a law in 1942. These STIs could be diagnosed and treated free of charge in the 200 public STI clinics located all over the country. However, less than 20% of patients with STI were treated in these clinics, whereas most of them sought care from private physicians. Because 90% of mandatory notification of STI came from public STI clinics, it was estimated that less than 10% of syphilis and gonorrhea were really notified. 1
To supply the mandatory notification and to improve epidemiologic surveillance on STI, several sentinel surveillance systems were set up by the Institut de Veille Sanitaire (InVS): gonorrhea surveillance (RENAGO) in 1986, chlamydia infections surveillance in 1989, and syphilis surveillance in 2000.
Because of the diversity of health professionals and STI care units involved, a laboratory-based surveillance was preferred to monitor epidemiologic trends in gonorrhea and to assess antimicrobial susceptibility in Neisseria gonorrhoeae (NG), which was already a concern for penicillin in the 1980s. 2 In 1986, private laboratories located in all 22 French regions were invited to participate to the RENAGO sentinel surveillance system on a voluntary basis. As NG incidence fell dramatically in the early 1990s, the network was expanded in 1992 to additional laboratories, including laboratories attached to STI clinics. Because the number of participating laboratories was different every year, trends in gonorrhea incidence were monitored using the average number of reported NG per active laboratory per year. After identification by routine method in the reporting laboratory, all NG strains were sent to the National Reference Center for Neisseria gonorrhoeae, Institut Alfred Fournier, Paris, where NG strain susceptibility to 6 antibiotics was tested.
This article presents the epidemiologic and microbiologic data collected by RENAGO between 1986 and 2000.
Every month, laboratories participating in RENAGO reported to the InVS the number of positive NG isolates as well as the total number of samples processed. An active laboratory was defined as a laboratory sending more than 6 monthly forms per year, whether NG strains were isolated or not. To evaluate the distribution of participating laboratories, these laboratories were rank-ordered by number of NG isolated by year. For each sample, the following data were collected: age, sex, anatomic site, and symptoms. After 1991, coinfection with another STI during the same visit and country of contamination was also reported. Sexual orientation of the patient was not reported. For monitoring annual trends, we computed the number of NG isolated per laboratory per year (NG/lab/year).
Collection of Strains
Each strain isolated by the participating laboratories was sent to the National Reference Center for Neisseria gonorrhoeae on Amies semisolid gel medium with charcoal (TGV AER Biorad) where they were cultured on GC agar with 5% defibrinated horse cooked blood supplemented with 1% Polyvitex, (BioMerieux) for 24 hours at 36°C in 10% CO2.
After identification of the NG strains by carbohydrate degradation tests, the minimum inhibitory concentration (MIC) was determined by means of the reference agar-plate dilution technique recommended by the French Society of Microbiology. 3 The strains were cultured several times in nonselective media: GC agar with 5% defibrinated horse cooked blood supplemented with 1% Polyvitex (BioMerieux) without added antibiotics. The colonies were scrapped and suspensions of 108 CFU/mL (0.5 Mc Farland) were performed in tryptic soy broth (Oxoid, Basingstoke, U.K). The suspension was applied to antibiotic-containing media with a multipoint inoculator (104 CFU per point). The plates were incubated for 24 hours at 35° to 37°C in a 10% CO2 atm and the results were read.
MICs were defined at the lowest antibiotic concentration that inhibited bacterial growth. The antimicrobial agents tested were: penicillin G (Diamant), tetracycline (Roussel-Uclaf), thiamphenicol (Sigma), spectinomycin (Sigma), and since 1989, ciprofloxacin (Bayer) and ceftriaxone (Sigma).
Three control/reference strains fully susceptible to all tested antibiotics (ATCC 27628, ATCC 27632, and ATCC 27633) were included in each run of tests for quality control. MICs were performed once or twice a year at the National Reference Center for Neisseria gonorrhoeae.
β-Lactamase production was assessed by the chromogenic cephalosporin test.
To compare our results with other international studies, the criteria for resistance recommended by the U.S. Committee on Clinical Laboratory Standards for aerobic bacteria (NCCLS) 4 were used. Because the procedure and the culture media used in France are different of those used by the NCCLS, we compared in 3 different series the MIC obtained with the 3 reference strains used in the RENAGO surveillance system and the NCCLS-recommended reference strain ATCC 49226 in both culture media (GC agar with 5% defibrinated horse cooked blood supplemented with 1% Polyvitex and GC II supplemented with 1% isovitalex), respectively, recommended by the French Society of Microbiology and the NCCLS. MICs obtained with the ATCC 49226 were in the acceptable quality control ranges on both media. MICs results obtained with the RENAGO surveillance system reference strains and the ATCC 49226 one differed by no more than 1 dilution for all antibiotics, except for tetracycline for which MIC values difference between both media was less or equal to 2.
Six categories of chromosomal and plasmid resistance to penicillin and tetracycline were considered:
1. PPNG: β lactamase-positive with tetracycline MIC <16 mg/L
2. Plasmid-mediated tetracycline resistant NG (TRNG): β lactamase-negative with MIC tetracycline ≥16 mg/L
3. PP/TRNG: β lactamase-positive with tetracycline MIC ≥16 mg/L
4. Chromosomally mediated penicillin-resistant NG (PenR): β lactamase-negative with penicillin MIC ≥2 mg/L and tetracycline MIC <2 mg/L
5. Chromosomally mediated tetracycline-resistant NG (TetR): β lactamase-negative with MIC penicillin <2 mg/L and tetracycline MIC of 2 to 8 mg/L
6. Chromosomally mediated to both penicillin and tetracycline (CMRNG): β lactamase-negative with MIC penicillin ≥2 mg/L and tetracycline MIC of 2 to 8 mg/L
Isolates with ciprofloxacin MIC ≥1 mg/L were classified as resistant to ciprofloxacin and isolates with MICs of 0.125 to 0.5 mg/L were interpreted as exhibiting decreased susceptibility to ciprofloxacin. Concerning ceftriaxone, isolates with MIC ≥0.5 mg/L were defined as having decreased sensibility to this drug. Isolates with spectinomycin MIC ≥128 mg/L were defined as resistant to this agent. Isolates with thiamphenicol MIC >4 mg/L and MIC ≤16 mg/L were classified with decreased susceptibility and thiamphenicol MIC >16 mg/L were defined as resistant according to the French Society of Microbiology.
Epidemiologic data and microbiologic data could not be linked because of the absence of unique identification, except for rectal strains isolated during the last study period.
The proportion of laboratories that contributed 50% and 100% of all isolates as well as the proportion who did not report any isolate and trends in gonorrhea incidence are presented annually. To assess changes over time in NG antibiotic-resistance patterns, microbiologic data are presented according to 3 study periods: 1986 to 1992, 1993 to 1997, and 1998 to 2000. The third study period concerns the last 3 years of the study when changes in trends in NG incidence were observed. The cutoff point between the first 2 periods is in relation with the inclusion of additional laboratories in the network from 1993 onward.
Data were analyzed using SAS software version 8.2. Chi-square was used to assess differences in proportion and the chi-squared trend to assess changes over time.
From 1986 to 2000, 353 laboratories participated and reported at least 1 case of NG. The median participating time for all laboratories was 8 years (range, 1–15 years) and 41 laboratories (17.6%) reported cases during the entire 15-year period. Until 1992, the mean number of participating laboratories per year was 94 (range, 82–128); 88% of these laboratories were private laboratories and 12% were laboratories attached to hospitals. From 1993, after a recruitment campaign, the average number of participating laboratory increased to 230 (range, 212–250) and the proportion of private laboratories slightly decreased to 82%. The RENAGO laboratories accounted for 2.3% of the 4100 laboratories performing microbiology in France until 1992 and for 5.6% thereafter. The Paris area accounted for 20% of the overall participating laboratories, a proportion close to that observed in France for all laboratories of microbiology where 18.5% of the laboratories are located in the Paris area. The percentage of laboratories having reported at least 1 case varies widely according to the year of the study. The total number of NG cases was isolated by 89% of the participating laboratories in 1986 but only by 25% of the participating laboratories in 1997. Half of the NG-isolated cases by year were reported by 3% to 16% of the participating laboratories (Fig. 1).
The number of NG isolated per year per laboratory declined steadily from 10.6 in 1986 to a low of 0.6 in 1997 and then reached 1.9 in 2000. A similar overall trend was observed when only taking into account the 41 laboratories participating during the 15-year study period. Seasonal variations were observed. A third of the all NG strains isolated in any year occurred during 3 months, from August to October (data not shown).
Gonorrhea increase observed in 1998 to 2000 concerned only men. The average number of NG isolates per year per laboratory increased from 0.6 in 1997 to 1.8 in 2000 in men, whereas it remained at 0.1 in women during the same period (Fig. 2). This increase was observed in all 22 administrative French regions, and the proportion of laboratories reporting at least 1 case doubled from 25% in 1997% to 52% in 2000. Nevertheless, this increase was greater in the Paris area than in other regions of France. The average number of a NG isolated per laboratory per year increased from 1.3 in 1997 to 4.6 in 2000 in the Paris area laboratories and from 0.5 to 1.2 in laboratories from other regions.
During 15 years, 5182 NG strains were isolated in RENAGO laboratories. There were 4071 (78.6%) strains isolated in men and 1048 (20.2%) strains isolated in women (overall male to female ratio: 3.9). The M/F sex ratio increased from 2.8 in 1986 to 1992 to 10.8 in 1998 to 2000 (P <0.001). The median age was 30 years for men and 26 years for women. Rectal isolates accounted for 2.7% (n = 138) of all strains and occurred mostly (98%) in men. The proportion of rectal strains isolated in men increased from 0.6% in 1986 to 1992 to 9.2% in 1998 to 2000 (P <0.001) in all participating laboratories (Table 1) and from 0.3% in 1986 to 1992 to 2.6% (P = 0.001) in the 41 laboratories that reported cases throughout the overall study period.
Among 2,100 men and 323 women, 174 (8.2%) and 42 (13%), respectively, were coinfected with another STI. HIV infection was notified for 67 of these coinfected male patients but in none of the coinfected women. From 1991 to 2000, among 126 men with rectal gonorrhea, one fourth (n = 31) had a coinfection, including HIV infection (n = 23), syphilis (n = 5), and chlamydiae (n = 3)
Information about the place of infection was known for 3113 (60%) patients; 2364 (76%) reported having been infected in France and 749 (24%) abroad. Among those, the country of infection was reported for 83 (11%) of these 749 patients. The main area of contamination was North and Sub-Saharan Africa (67%), whereas less than 5% of abroad acquired strains came from Asia.
Among the 5182 strains isolated by all participating laboratories, 3576 (69%) were sent to the National Reference Center of Neisseria gonorrhoeae and 2109 (59%) were available for culture and then tested for antibiotic susceptibility. The proportion of strains sensible to all 6 tested antibiotics decreased significantly from 85% in 1986 to 1992 to 48% in 1993 to 1997 and to 65% in 1998 to 2000 (P <0.001).
Susceptibility to Penicillin and Tetracycline
The percentage of isolates with any type of resistance to penicillin or tetracycline increased from 11.9% in 1986 to 1992 to 50.6% in 1993 to 1997 and then decreased to 31.3% in 1998 to 2000 (Table 2). Until 1992, resistance to penicillin was higher than to tetracycline. Since 1993, NG resistance to tetracycline was the most common resistance observed in France reaching 27.4% in 1998 to 2000. PPNG strains remained below 10% (6.9% in 1986–2000 and 3.4% in 1998–2000), except for the period 1993 to 1997. The percentage of isolates with chromosomally mediated resistance to both penicillin and tetracycline (CMRNG) remained below or equal to 5% except in 1993 to 1997, when CMRNG strains accounted for 16% of the overall isolates.
Susceptibility to Ciprofloxacin
Resistance to ciprofloxacin was detected for the first time in 1997 in the Paris area, and then increased sharply thereafter and reached 5.2% (n = 29) of the isolates in 1998 to 2000 (Fig. 3). In 1993 to 1997, 2 strains (0.41%) had a ciprofloxacin MIC to 1 mg/L. In 1998 to 2000, 11 strains (1.9%) had a ciprofloxacin MIC to 1 to 2 mg/L.
Among the 29 resistant strains in 1998 to 2000, 18 had a reduced susceptibility to ciprofloxacin (CIP-reduced) and 11 were resistant to ciprofloxacin (QRNG) Furthermore, 23 strains (79%) exhibited plasmid or chromosomic resistance to penicillin or tetracycline. All the strains resistant to ciprofloxacin were acquired in France and were mostly isolated in the Paris area laboratories. Among these 29 strains, 2 (6.8%) were rectal strains.
Susceptibility to Ceftriaxone, Spectinomycin, and Thiamphenicol
The proportion of strains with reduced susceptibility to thiamphenicol has increased from 6% in 1986 to 1992 to 18.5% in 1998 to 2000. One strain resistant to thiamphenicol (MIC = 25 mg/L) was isolated in a Paris laboratory in 2000. This strain was also PP/TRNG and was susceptible to ciprofloxacin.
No resistant strain to ceftriaxone or spectinomycin was observed throughout the whole study period.
Resistance Among Rectal Strains
Among the 80 rectal strains isolated from 1998 to 2000, 60 (75%) were available for antimicrobial testing. The microbial susceptibility profile of these rectal strains was comparable to the 487 strains isolated from other anatomic sites during the same period. No difference in penicillin, tetracycline, and ciprofloxacin susceptibility was observed.
Epidemiologic and microbiologic data collected between 1986 and 2000 in the RENAGO surveillance system provide critical information about epidemiologic trends in gonorrhea and the evolution of antimicrobial drug-resistance patterns in NG in France.
Because RENAGO is a sentinel network, the participating laboratories might not be representative of all laboratories in France. Two national surveys in 1991 5 and 1996 6 performed on a national random sample of laboratories indicated that the number of NG isolated in RENAGO laboratories was slightly greater than those observed in other laboratories. However, the gonorrhea incidence trends observed in these 2 national studies were comparable to those observed in the RENAGO surveillance system during the same period. Because RENAGO is a sentinel surveillance system, it cannot provide a national gonorrhea incidence. Nevertheless, RENAGO was able to timely detect the increase in gonorrhea incidence trends in 1998, 7 which occurred after a continuing decrease in gonorrhea from 1986 to 1997. The early 1990s’ declining incidence of gonorrhea has previously been reported in France 5,8 and was probably the result of AIDS prevention campaigns.
Since 1997, an increase in gonorrhea was observed every year in RENAGO, whereas the number of participating laboratories remained stable. This increase affected mostly men living in the Paris area. Increasing gonorrhea observed in RENAGO was consistent with trends observed in other STI surveillance systems in France. The “Réseau Sentinelle,” a sentinel surveillance network of general practitioners, reported a rise in the incidence of adult male urethritis from 180 per 100,000 in 1996 to 270 per 100,000 in 1998. 9 The annual incidence was higher in the Paris area than outside Paris. An increase in NG infections was also observed in public STI clinics between 1997 and 1999, particularly in large cities like Paris (+64% in 1997 and +64% in 1998) and Marseille (+65% in 1998, +50% in 1999). 10 Trends in gonorrhea incidence observed in France were consistent with those observed in other European countries and in the United States. 11–14 An increased gonorrhea incidence was reported in numerous western countries, 15–18 especially among homosexual men. 19,20 In the RENAGO surveillance system, sexual orientation is not reported. However, the increased proportion of anal gonorrhea in men, a surrogate marker for male homosexual intercourse, showed that this increase of NG incidence in 1998 to 2000 was particularly of concern among homosexual men. Some clinical reports in France have already reported an increase in gonorrhea and syphilis in homosexual men since 1998. 21,22 The rising NG infections observed in homosexual men through sentinel surveillance systems suggest relapses to risky sexual behaviors. Behavioral surveillance, among gay magazine readers in France, showed an increase in unsafe sexual practices between 1997 and 2000. The proportion of men who had at least 1 incidence of unprotected anal intercourse with a casual partner rose from 17% to 25% in the Paris area and from 16% to 21% in other French regions. These risky behaviors concerned primarily young gay men, HIV-positive men, and men living in the Paris area. 23 Because STIs are associated with an increased risk of acquiring HIV infection, 24 RENAGO results highlight the need for strengthening HIV prevention and for integrating HIV and other STI prevention and care.
The changing patterns of antimicrobial resistance of NG have been reported since the introduction of the first antibiotic agent. 25 In the RENAGO surveillance system, the proportion of fully sensitive strains significantly decreased from 85% in 1986 to 1992 to 48% in 1993 to 1997 and then increased to 65% in 1998 to 2000. This result illustrates the necessity of monitoring NG susceptibility to antibiotics to help clinicians in their treatment choice. 26
The first PPNG strain was isolated in France in 1979. 27 PPGN strains have regularly increased ever since. The proportion of PPNG strains rose from 4.2% in 1985 to 15.8% in 1987 in an STI clinic in Paris. 28 Penicillin was not recommended as first-line treatment for NG infections in France as of the early 1990s. After a peak in 1994 to 1997, the proportion of PPNG strains decreased and remained below 10% in 1998 to 2000. Although PPNG prevalence declined over time in France, resistance to tetracycline remained at a high level in 1998 to 2000. The different patterns of resistance against these 2 antibiotics had been previously described in the United States 29 and could be explained by the recommended use of tetracycline for treating infections as chlamydiae and NG dual infections. In comparison with the other study periods, the proportion of chromosomally mediated to both penicillin and tetracycline strains was very high in 1993 to 1997 and especially during the years 1996 and 1997. The number of NG strains isolated during these years was small and all cases were reported by one fourth of the participating laboratories. Furthermore, laboratories that reported cases were mainly hospitals and STI laboratories. A possible bias inpatient recruitment during these years could explain this high proportion of chromosomally mediated resistance to both penicillin and tetracycline strains.
No resistant strains to ceftriaxone have been isolated in the RENAGO surveillance like in many countries. 30
Resistance to ciprofloxacin, which first appeared in the RENAGO surveillance system in a strain isolated in the Paris area in 1997, has increased regularly every year to reach 2% in 1998 to 2000. The proportion of ciprofloxacin resistance in the RENAGO surveillance system is consistent with those observed in the United Kingdom, (1.8%), 31 in The Netherlands, (2.2%), 32 or in the United States (0.7%) 33 and remained much lower than those observed in China (34.2%) 34 or in Japan (24.4%). 35 The increased proportion of ciprofloxacin resistance during the last study period needs to be carefully monitored, particularly in France where single-dose treatments are widely used.
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