Emerging Antimicrobial Resistance in Neisseria gonorrhoeae: Urgent Need to Strengthen Prevention Strategies

Neisseria gonorrhoeae infection can cause cervicitis, urethritis, proctitis, pelvic inflammatory disease with long-term sequelae (infertility, ectopic pregnancy, chronic pelvic pain), adverse outcomes of pregnancy, and increased susceptibility to and transmission of HIV infection (1, 2). Neisseria gonorrhoeae infection is the second most common notifiable disease in the United States, with 358366 cases reported in 2006 (3). However, reported cases probably represent an underestimate of the actual disease burden because of underdiagnosis and underreporting; it is estimated that there were approximately 718000 incident gonorrhea cases in 2000 (4). After national implementation of gonorrhea control activities in the 1970s, the incidence of gonorrhea in the United States declined markedly, with a 74% reduction in rates from 1975 to 1997. Although rates have remained relatively stable over the past decade, in 2006 the national gonorrhea case rate (120.9 cases per 100000 population) increased for the second consecutive year, particularly in the western United States (3, 5). Rates of gonorrhea remain high in the South and among African Americans, adolescents, young adults, and men who have sex with men. Recent reports have also documented high rates of gonorrhea among HIV-infected men who have sex with men (3). Because of increased infection rates, high burden of disease, and the reproductive and economic implications of gonorrhea infection, prevention and control of gonorrhea is an important public health concern (6, 7). As current therapeutic options become more limited, we describe the emergent challenges to maintaining antimicrobial effectiveness and a comprehensive approach to gonorrhea control. Historical Perspective on Antimicrobial Resistance An essential element in gonorrhea control is the availability and provision of appropriate, effective antimicrobial therapy. Effective treatment not only eradicates infection in the affected individual and prevents the development of complications, it also has an important public health benefit of shortening the duration of infection, thus decreasing transmission and eliminating reservoirs of infection. However, over the past 60 years N. gonorrhoeae has developed resistance to multiple classes of antimicrobials (Appendix Figure). Sulfanilamides were used for gonococcal treatment after their introduction in 1936, but their efficacy was short-lived because of the rapid emergence of resistance by 1945 (8). Penicillin became the recommended antimicrobial regimen for the next 40 years. The progressive decline in susceptibilityinitially associated with chromosomally mediated resistance (exhibited by a stepwise increase in resistance) and later by the acquisition and spread of plasmids containing genes for penicillinase productionrequired serial increases in the recommended dose of intramuscular procaine penicillin (with probenecid) from 50000 units in 1945 to 4.8 million units by the early 1970s (9). In 1985, because of emerging penicillin resistance, ceftriaxone became a recommended regimen for the treatment of uncomplicated gonococcal infections (10). At the same time, tetracycline resistance (both plasmid and chromosomally mediated) was spreading to the extent that tetracycline was no longer a viable treatment option. By 1989, resistance to penicillin was sufficiently widespread that penicillin was no longer effective. Ceftriaxone then became the recommended regimen for gonorrhea therapy, with ciprofloxacin as an alternative treatment option (11). By 1993, on the basis of data regarding high efficacy, safety, and convenience as single-dose therapies, oral fluoroquinolones (ciprofloxacin, ofloxacin) were recommended as oral regimens for gonorrhea treatment, as was the oral third-generation cephalosporin cefixime (12). Appendix Figure. Historical perspective on antimicrobial resistance in the United States. QRNG = quinolone-resistant Neisseria gonorrhoeae; MSM = men who have sex with men. In 1986, concerns about emerging gonococcal antimicrobial resistance lead to the development of the Gonococcal Isolate Surveillance Project (GISP), a national sentinel surveillance system that monitors antimicrobial susceptibility in the United States. Each year, approximately 6000 urethral gonococcal isolates from men attending 25 to 30 sexually transmitted disease (STD) clinics throughout the country are collected and analyzed to provide national data that help guide treatment recommendations. The GISP findings of notable importance include the continued high prevalence of penicillin and tetracycline resistance, which has remained greater than 15%; the increasing prevalence of isolates with decreased susceptibility to macrolides; the appearance of a limited number of multidrug-resistant isolates with decreased susceptibility to cefixime (3); and most important, the dramatic spread of quinolone-resistant N. gonorrhoeae. Based in part on data from GISP, the emergence of quinolone-resistant N. gonorrhoeae was first identified in Hawaii in 1991, at about same time that it was recognized as a problem in Asia (13). Thereafter, sporadic occurrences of quinolone-resistant N. gonorrhoeae were noted in the United States throughout the 1990s. By 2000, quinolone-resistant N. gonorrhoeae was increasingly observed in persons who became infected in Asia, the Pacific Islands (including Hawaii), or California. As a result, fluoroquinolones were no longer recommended for treating gonorrhea acquired in those locales (14, 15). Over the next several years, GISP identified increased rates of quinolone-resistant N. gonorrhoeae among men who have sex with men. This finding prompted an advisory in 2004 that fluoroquinolones were no longer recommended for treating gonorrhea in men who have sex with men, regardless of locale (16). Most recently, data from GISP indicate that quinolone-resistant N. gonorrhoeae is widely dispersed in the United States and that in 2006 the infection accounted for 39% of gonococcal isolates in men who have sex with men and 7% in heterosexual men. On the basis of these cumulative data, the Centers for Disease Control and Prevention (CDC) announced that fluoroquinolones are no longer recommended for treating gonococcal infections and associated conditions, such as pelvic inflammatory disease or epididymitis, in any population in the United States (17). The antimicrobial resistance data from GISP have provided a rational basis for recommended gonococcal treatment regimens. However, data from this sentinel surveillance system have limitations. The GISP data may not be representative of the total population with gonorrhea in the United States, because the current national surveillance system oversamples West Coast locations (where new resistant strains have been first detected), evaluates only male urethral isolates obtained from STD clinics, and samples only a minority of reported gonococcal infections. Dramatic differences in quinolone-resistant N. gonorrhoeae prevalence by geographic location and sexual orientation illustrate the challenge of achieving accurate representation (18). The rapid spread throughout the United States of quinolone-resistant N. gonorrhoeae in heterosexual men, as well as among men who have sex with men, makes defining remaining pockets of continued susceptibility of N. gonorrhoeae problematic. These limitations highlight the difficulty of defining an appropriate sentinel population and a frequency of sampling with sufficient representation to assure susceptibility in a particular locale. Thus, there is a need to monitor antimicrobial resistance at the local level, which would provide a more in-depth understanding of resistance trends and contribute to decisions that affect treatment recommendations in various locations (19, 20). Evolution of Criteria for Gonorrhea Treatment Recommendations The epidemiology of antimicrobial resistance guides decisions about gonococcal treatment recommendations. As discussed, data from GISP are critical when evaluated along with other relevant data, such as those provided by the Gonococcal Antimicrobial Surveillance Program of the Western Pacific Regional Office of the World Health Organization (WHO) in Southeast Asia and the Pacific region. The CDC and the WHO have recommended a change in the treatment regimen when the prevalence of antimicrobial resistance exceeds 5% for a specific antibiotic, while taking into account the prevalence of gonorrhea in the community, the cost of diagnostic and treatment regimens, and the availability of antimicrobial susceptibility data (2123). An accepted definition of gonococcal treatment efficacy requires a cure rate of over 95% with a lower bound of the 95% CI of at least 90% (24). At the time this criterion was proposed, many antimicrobial regimens met this standard, but in an attempt to reduce the risk for therapeutic failure and development of antimicrobial resistance, more stringent criteria were proposed by Moran and colleagues (25). Their criteria specified that efficacy exceed 95% in summed clinical trials, but required that the lower bound of the 95% CI also be at least 95%. In addition to efficacy data, decisions regarding treatment recommendations involve consideration of other factors. These include administration of at least twice the minimum dose to ensure therapeutic reserve, documentation that susceptibility is not lower among organisms recovered after treatment, and evidence that the serum or plasma concentration with the recommended dose is at least 4 times the minimum inhibitory concentration required to inhibit 90% of strains (MIC90) for 10 hours after the concentration peak (25). These stringent clinical efficacy criteria (95% efficacy with 95% CI) were used to determine the gonorrhea treatment regimens recommended in the CDC STD Treatment Guidelines since 1993. However, it was recently suggested that these criteria be modified, given the propensity of N. gonorrhoeae to develo