Sentinel Surveillance for Antimicrobial Resistance in Neisseria gonorrhoeae -- United States, 1988-1991

Rachel J. Gorwitz, M.P.H. Allyn K. Nakashima, M.D. John S. Moran, M.D. Division of Sexually Transmitted Diseases/HIV Prevention National Center for Prevention Services Joan S. Knapp, Ph.D. Division of Sexually Transmitted Diseases Laboratory Research National Center for Infectious Diseases The Gonococcal Isolate Surveillance Project Study Group *

Abstract

Problem/Condition: The prevalence of antimicrobial resistance in Neisseria gonorrhoeae in the United States has been increasing since the mid-1970s.

Description of System: The Gonococcal Isolate Surveillance Project (GISP) was established in 1986 to monitor trends of antimicrobial resistance in N. gonorrhoeae. GISP is a sentinel surveillance system consisting of 26 publicly funded sexually transmitted disease clinics and five regional laboratories. At each clinic, urethral isolates are obtained from the first 20 men diagnosed with gonorrhea each month; these isolates are shipped to one of the regional laboratories, where the susceptibilities of the organisms to a panel of antibiotics are determined.

Reporting Period Covered: This report describes the results of surveillance for antimicrobial resistance in N. gonorrhoeae from January 1991 through December 1991. These results are compared with data obtained from January 1988 through December 1990.

Results and Interpretation: In the 1991 GISP sample, 32.4% of isolates were resistant to penicillin or tetracycline. The proportions of isolates with high-level, plasmid-mediated resistance to penicillin, tetracycline, or both drugs have increased significantly (p less than 0.001) in the GISP sample during 1988-1991. No documented clinical treatment failures have been related to decreased susceptibility of N. gonorrhoeae to either ceftriaxone or ciprofloxacin, which belong to the classes of antibiotics currently recommended for gonococcal therapy.

Action Taken: Because of the demonstrated ability of N. gonorrhoeae to develop resistance to antimicrobial agents, surveillance to guide therapy recommendations will be continued.

INTRODUCTION

Although the overall reported incidence of gonorrhea has been decreasing since the mid-1970s in the United States, antimicrobial resistance in Neisseria gonorrhoeae has been increasing during the same period (1). Antimicrobial resistance in N. gonorrhoeae can be mediated by plasmid or chromosomal mechanisms and may occur to a single antimicrobial agent or to multiple agents (2). Strains with plasmid-mediated resistance include penicillinase-producing N. gonorrhoeae (PPNG), which produces a penicillin-cleaving b-lactamase. This enzyme makes PPNG strains resistant to all penicillins and first-generation cephalosporins but does not affect their susceptibility to second- and third-generation cephalosporins. Strains with plasmid-mediated resistance to tetracyclines are termed tetracycline-resistant N. gonorrhoeae (TRNG). Tetracycline resistance in these strains is due to the presence of the TetM determinant (3). Gonococcal isolates with both the beta-lactamase and tetracycline-resistance plasmids are termed PPNG/TRNG. Chromosomally mediated resistance occurs as a result of one or more mutations in the gonococcal genome, which may result in a variety of phenotypic expressions, such as altered membrane permeability (3).

Although PPNG isolates can be identified by simple, inexpensive, standardized tests for b-lactamase, the methods required to identify plasmid-mediated tetracycline resistance or chromosomally mediated resistance are more complex, expensive, and difficult to standardize. Many public health laboratories do not have adequate resources to perform these tests. Furthermore, for antimicrobial resistance testing results to be comparable within or between various laboratories, intra- and inter-laboratory standardization of testing methods must be established and maintained. The Gonococcal Isolate Surveillance Project (GISP) was created to address these issues. The recent conversion of some public health laboratories to non-culture-based methods of testing for gonorrhea, which reduces the number of isolates available for susceptibility testing, increases the importance of having a national system in place to monitor trends in gonococcal antimicrobial resistance.

GISP is a national sentinel surveillance system that was established in 1986 to estimate prevalence and to monitor trends of antimicrobial resistance in N. gonorrhoeae. Beginning in 1991, CDC stopped collecting antimicrobial resistance data detected through systems other than GISP. Beta-lactamase testing for PPNG, which accounted for most of the antimicrobial resistance in gonorrhea previously reported to the CDC by state and local health departments, has been discontinued in many areas because penicillins are no longer recommended therapy for gonorrhea. GISP is currently the only national surveillance system for monitoring gonococcal antimicrobial resistance. Results from GISP have been used to guide CDC in recommending treatment for gonorrhea (4). This report describes the results of surveillance for antimicrobial resistance in N. gonorrhoeae from January 1991 through December 1991; these results are compared with data obtained from January 1988 through December 1990.

METHODS GISP Data Collection Procedures

The GISP system currently includes 26 publicly funded sexually transmitted disease (STD) clinics ** and five regional laboratories (Figure 1). At the clinics, gonococcal isolates and demographic and clinical data on the corresponding patients are collected. Urethral specimens are collected from the first 20 men diagnosed with gonorrhea each month. The specimens are subcultured to obtain a pure culture, frozen, and shipped to one of the regional laboratories. Demographic and clinical information, abstracted from medical records, is sent directly from the clinics to CDC for analysis. At the regional laboratories, isolate susceptibilities to a panel of antibiotics are determined by the agar dilution technique (5), and b-lactamase testing is performed. Regional laboratories send results of susceptibility testing and a sample of resistant isolates to CDC for confirmation, further testing, and analysis.

Susceptibility and Resistance Definitions

Definitions of antimicrobial susceptibility and resistance are based on criteria established by the National Committee for Clinical Laboratory Standards (NCCLS) (Table 1) (6-9). Isolates having a minimum inhibitory concentration (MIC) of greater than or equal to 2 ug of penicillin or tetracycline/mL or greater than or equal to 128 ug of spectinomycin/mL are defined as being resistant to the corresponding agent. More than 15% of persons infected with a strain defined as resistant by these criteria would be expected not to respond to therapy with the corresponding agent (7). Clinical treatment failures related to decreased susceptibility of N. gonorrhoeae to ceftriaxone or ciprofloxacin have not yet been reported in the United States; however, the NCCLS has established susceptible criteria for these agents. Isolates having an MIC of less than or equal to 0.25 ug of ceftriaxone/mL or less than or equal to 0.06 ug of ciprofloxacin/mL are defined as being susceptible to these agents. The clinical importance of isolates with MICs higher than those defining the susceptible criteria for ceftriaxone and ciprofloxacin is not known.

For analyses described in this paper, six mutually exclusive categories of resistance have been defined for plasmid- and chromosomally mediated resistance to penicillin and tetracycline (Table 2). Isolates are defined as PPNG if they are b-lactamase-positive. Isolates are defined as TRNG if they have a tetracycline MIC of greater than or equal to 16 ug/mL. Isolates that are both b-lactamase-positive and have a tetracycline MIC of greater than or equal to 16 ug/mL are defined as PPNG/TRNG. Isolates with plasmid-mediated resistance typically have MICs much higher than those of isolates with chromosomally mediated resistance. Therefore, in grouping isolates into plasmid- and chromosomally mediated resistance categories, a hierarchical classification system is used; among isolates that are resistant to penicillin or tetracycline according to NCCLS criteria, those that do not have plasmid-mediated resistance to either of these drugs according to the above definitions are considered to have chromosomally mediated resistance.

Statistical Tests

Descriptive statistics were performed on the 1991 GISP data. Extended Mantel-Haenszel chi square test for trend statistics with p values were calculated to identify statistically significant trends in levels of the various types of resistance during the 4-year period 1988-1991.

RESULTS

Susceptibility data were collected for 5,238 gonococcal isolates in 1991. As in previous years, the demographic composition of the 1991 GISP sample was similar to that of all reported gonorrhea episodes in males in the United States (Table 3) (10). The percentage distribution of reported gonorrhea episodes among the various racial/ethnic categories is presented to illustrate that the GISP sample is similar in demographic composition to all reported gonorrhea episodes in males nationwide. Differences in gonorrhea incidence among racial/ethnic groups may reflect social, economic, behavioral, or other risk factors, rather than race/ethnicity directly.

The majority (73.9%) of gonorrhea episodes in the GISP sample were diagnosed in non-Hispanic black men, with 12.7% and 9.4% of episodes being diagnosed in Hispanic and non-Hispanic white men, respectively. Because of the selection of some sentinel STD clinic sites located in areas with large Hispanic populations, Hispanic men are overrepresented in GISP compared with the national sample. The mean age of men in the GISP sample was 26.9 years (range: 13-78 years). Of the 4,700 men in the GISP sample for whom sexual orientation data were available, 4.7% reported a history of same-sex sexual activity, and 95.3% reported only heterosexual activity.

Of the isolates in the 1991 GISP sample, 32.4% were found to be resistant to penicillin or tetracycline. Eleven percent of the isolates were classified as PPNG, 5.7% were classified as TRNG, and 2.1% were classified as PPNG/TRNG. Chromosomal resistance to tetracycline alone was identified in 7.2% of the 1991 isolates, and chromosomal resistance to both penicillin and tetracycline *** and to penicillin alone was identified in 4.6% and 1.8% of the isolates, respectively (Figure 2).

From 1988 through 1991, the proportion of GISP isolates with various types of plasmid-mediated resistance (PPNG, TRNG, PPNG/TRNG) increased significantly (p less than .001) (Figure 3). The proportion of GISP isolates classified as PPNG more than doubled, from 3.2% in 1988 to 7.4% in 1989, and continued to increase in 1990 and 1991. The proportion of GISP isolates classified as PPNG/TRNG increased from 0.3% in 1988 to 2.1% in 1991. The proportion of GISP isolates classified as TRNG also increased substantially from 1988 through 1991, although this proportion was slightly smaller in 1991 than in 1990.

The proportion of isolates in the GISP sample having chromosomally mediated resistance to penicillin also increased significantly (p less than .001) from 0.5% in 1988 to 1.8% in 1991 (Figure 4). The proportion of isolates with chromosomally mediated resistance to tetracycline decreased significantly (p less than

001) from 14.8% in 1988 to 7.2% in 1991, with the largest decrease occurring during the period 1988-1989. For the 4-year period 1988- 1991, the proportion of GISP isolates having chromosomally mediated resistance to both penicillin and tetracycline did not increase significantly. However, this proportion did increase from 3.1% in 1990 to 4.6% in 1991, the second consecutive year showing an increase.

No isolates in the 1991 GISP sample were found to be resistant to spectinomycin. Both the 1988 and 1990 GISP samples contained one spectinomycin-resistant isolate, whereas four spectinomycin-resistant isolates were found in the 1989 sample.

In 1991, four isolates (three from West Palm Beach and one from New Orleans) were reported to have MICs higher than the current NCCLS criterion for susceptibility to ceftriaxone (0.25 ug/mL). Following initial testing at a regional laboratory, the three West Palm Beach isolates were reported to have ceftriaxone MICs of 0.5 ug/mL. Susceptibilities of two of these three isolates were retested at CDC, where ceftriaxone MICs of 0.004 ug/mL were obtained. Susceptibilities of the New Orleans isolate, which was reported by the regional laboratory as having a ceftriaxone MIC of 1.0 ug/mL, were also retested at CDC, and a ceftriaxone MIC of 0.004 ug/mL was obtained. Each of the four patients from whom these gonococcal strains were isolated was treated with 250 mg of ceftriaxone intramuscularly, plus a 1-week regimen of orally administered doxycycline; all were reported to have responded to therapy. (One of these patients returned to the clinic approximately 1 month following initial therapy and was again diagnosed with and treated for gonorrhea, but this patient's history indicates that he was probably reinfected by an untreated partner). In the 1990 sample, two isolates (both from Atlanta) were reported by the regional laboratory to have ceftriaxone MICs of 0.5 ug/mL. When the susceptibilities of these isolates were retested at CDC, ceftriaxone MICs of 0.015 and 0.008 ug/mL were obtained. One of the two patients from whom these specimens were isolated was successfully treated with 250 mg of ceftriaxone intramuscularly, plus a 1-week regimen of orally administered doxycycline. The other patient was treated with 3 g of orally administered ampicillin, followed by doxycycline. In the 1988 and 1989 GISP samples, no isolates were reported to have MICs higher than the susceptibility criterion for ceftriaxone.

In 1991, 17 isolates were reported to have MICs higher than the NCCLS criterion for susceptibility to ciprofloxacin (0.06 ug/mL). Four of these isolates were submitted from Honolulu; the remaining isolates were submitted from San Antonio (three isolates); Anchorage, Cleveland, and San Diego (two isolates each); and Albuquerque, Boston, Cincinnati, and San Francisco (one isolate each). Ciprofloxacin MICs of 12 of these isolates were retested at CDC, and results within one dilution of the original reported value were obtained for seven of the isolates. Results two dilutions below the original reported value were obtained for an additional two isolates. The highest reported ciprofloxacin MIC in 1991 was 0.5 ug/mL, which was reported for one isolate from Honolulu and one from Boston. The ciprofloxacin MIC of the Honolulu isolate was confirmed by retesting at CDC, where an MIC of 1.0 ug of ciprofloxacin/mL was obtained. The patients infected with gonococcal strains reported to have ciprofloxacin MICs greater than 0.06 ug/mL were all treated with therapies other than ciprofloxacin or other fluoroquinolones. Information on ciprofloxacin susceptibility was available for only 1,709 of the isolates collected in 1990. Of these isolates, seven were reported to have MICs greater than 0.06 ug ciprofloxacin/mL, with the highest reported ciprofloxacin MIC being 0.25 ug/mL. Ciprofloxacin MICs of four of these isolates were retested at CDC, and results within one dilution of the reported value were obtained.

The distribution of ceftriaxone MICs, as observed in the 1991 GISP sample, shifts to the right (i.e., higher) for gonococcal isolates having chromosomal resistance to both penicillin and tetracycline, compared with isolates having no resistance to penicillin or tetracycline (Figure 5). The same is true for ciprofloxacin MICs, although the difference is less dramatic (Figure 6). ****

DISCUSSION

The GISP system is intended to provide early warning of increased prevalence of gonococcal antimicrobial resistance or the emergence or introduction of new resistance types in the United States. Because many of the GISP sentinel sites have previously been recognized as "ports-of-import" for resistant strains of N. gonorrhoeae, GISP provides a mechanism to monitor the importation of resistant strains. GISP is also useful for monitoring the direction(s) and rate of spread of strains with different types of resistance. The GISP sample is not, however, a random sample of gonococcal infections in the United States and hence may not be entirely representative of all such infections. Furthermore, if gonococcal strains with clinically important resistance to ceftriaxone or ciprofloxacin appear in this country, they will probably not be detected initially by GISP, because the sample represents only a small proportion (approximately 1.0%) of reported gonococcal infections in the United States. However, we anticipate that these resistant strains will become prevalent in a sentinel site soon enough to allow timely revisions of treatment recommendations for gonorrhea.

Proportions of gonococcal infections caused by isolates having plasmid-mediated resistance to penicillin (PPNG), tetracycline (TRNG), or both of these drugs (PPNG/TRNG) have increased substantially from 1988 through 1991. Although the proportion of gonococcal infections caused by TRNG isolates did not increase in 1991, TRNG isolates still accounted for 5.7% of gonococcal infections in the GISP system in 1991. Strains having plasmid-mediated resistance to penicillin or tetracycline typically have MICs much higher than the minimum criteria for resistance. For this reason, a large proportion of persons infected with plasmid-mediated resistant isolates are likely not to respond to therapy with the corresponding agent. Therefore, penicillin, ampicillin, amoxicillin, and tetracyclines are no longer recommended as therapy for gonorrhea.

Surveillance for gonococcal strains possessing chromosomally mediated resistance to both penicillin and tetracycline is important because these strains tend to have higher MICs of ceftriaxone and ciprofloxacin, which belong to the classes of antibiotics currently recommended for gonococcal therapy, than do other gonococcal strains (Figures 5 and 6). If clinical resistance to third-generation cephalosporins (such as ceftriaxone), quinolones (such as ciprofloxacin), or related agents develops in N. gonorrhoeae, it could emerge first among these strains.

In the United States, no documented clinical treatment failures have been related to reduced gonococcal susceptibility to either ceftriaxone or ciprofloxacin. Although a few isolates in the 1991 GISP sample were reported to have MICs higher than the NCCLS criteria for susceptibility to these drugs, no clinical treatment failures have been associated with these isolates. Since, among the isolates that were available for retesting at CDC, none of the reported high ceftriaxone MICs could be confirmed, the original reported values may have been incorrect. Alternatively, although we believe that MICs are generally stable, the reported values may have been accurate, but these isolates may have lost their resistance to ceftriaxone upon subculture. Beginning in 1992, regional laboratories were requested to retest and confirm all ceftriaxone MICs greater than 0.25 ug/mL and ciprofloxacin MICs greater than 0.06 ug/mL.

Test-of-cure cultures for gonorrhea should not be encouraged as a routine, because currently recommended therapies are highly effective. However, STD program staff are encouraged to conduct thorough epidemiologic investigations of patients who appear not to respond to therapy with recommended treatment regimens, in order to determine whether failure may be due to a resistant strain and to identify possible sources of reinfection. Isolates from these patients and their sex partners should be preserved and referred to the state laboratory and CDC for confirmation by standardized antimicrobial susceptibility test procedures.

Many states, concerned that the GISP system cannot provide adequate information for local therapy decisions, have considered establishing state surveillance systems to monitor antimicrobial susceptibility. Ideally, state laboratories should work toward providing antimicrobial susceptibility testing, using NCCLS-approved methods, for antimicrobials used locally to treat gonorrhea. However, the resources and labor required to establish and maintain a surveillance system similar to GISP are considerable; many states may lack an infrastructure that could support collection and analysis of these data. STD program staff should consider these factors before allocating program resources to such an endeavor.

References

1. Whittington WL, Knapp JS. Trends in antimicrobial resistance in Neisseria gonorrhoeae in the United States. Sex Transm Dis 1988;15:202-10.

2. Easmon CSF. Gonococcal resistance to antibiotics. J Antimicrob Chemother 1985;16:409-17.

3. Johnson SR, Morse SA. Antibiotic resistance in Neisseria gonorrhoeae: genetics and mechanisms of resistance. Sex Transm Dis 1988;15:217-24.

4. CDC. Sexually transmitted diseases treatment guidelines. MMWR 1989;38:(S-8):9-24.

5. National Committee for Laboratory Standards. Approved Standard M7-A2. Methods for dilution antimicrobial tests for bacteria that grow aerobically. 2nd ed. (ISSN 0273-3099). NCCLS, Villanova, PA: 1990.

6. Jones RN, Gavan TL, Thornsberry C, et al. Standardization of disk diffution and agar dilution susceptibility tests for Neisseria gonorrhoeae: interpretive criteria and quality control guidelines for ceftriaxone, penicillin, spectinomycin, and tetracycline. J Clin Microbiol 1989;27:2758-66.

7. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing; fourth information supplement. NCCLS Document M100-S4 (ISBN 1-56238-172-5). NCCLS, Villanova, PA: 1992.

8. Jaffe HW, Biddle JW, Thornsberry C, et al. National gonorrhea therapy monitoring study: in vitro antibiotic susceptibility and its correlation with treatment results. N Engl J Med 1976;295:5-9.

9. Fuchs PC, Barry AL, Baker C, Murray PR, Washington JA. Proposed interpretive criteria and quality control for testing in vitro susceptibility of Neisseria gonorrhoeae to ciprofloxacin. J Clin Microbiol 1991;29:2111-4. 

10. CDC. Sexually transmitted disease surveillance, 1991. U.S. Department of Health and Human Services, Public Health Service. Atlanta: Centers for Disease Control, 1992.

* King K. Holmes, M.D., Ph.D., and Judith A. Hale, M.S., University of Washington School of Medicine; Edward W. Hook, III, M.D., and Kim R. Smith, University of Alabama at Birmingham School of Medicine; Franklyn N. Judson, M.D., and Josephine M. Ehret, Division of Disease Control, Denver Public Health Department and University of Colorado; Sumner E. Thompson, M.D., M.P.H., and James G. Thomas, Emory University School of Medicine; John A. Washington, M.D., and Laura J. Doyle, Cleveland Clinic Foundation. 

** Since January 1988, six clinics have joined the GISP system, and one clinic has discontinued participation. Data from the Minneapolis clinic, which joined the system in September 1992, are not included in this report. 

*** Isolates in this category are sometimes referred to by the acronym CMRNG, for chromosomally mediated resistant Neisseria gonorrhoeae. 

**** The distributions of ceftriaxone and ciprofloxacin MICs for isolates with plasmid-mediated resistance to penicillin or tetracycline resembled the distributions for nonresistant isolates, although the distributions for isolates having chromosomal resistance to either penicillin or tetracycline alone were intermediate between those of nonresistant isolates and isolates with chromosomal resistance to both drugs.

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