Cephalosporin-resistant Neisseria gonorrhoeae public health response plan

Gonorrhea is the second most commonly reported notifiable disease in the United States, with 309,341 cases reported in 2010. Although the national gonorrhea rate decreased 21.7% during 2000-2010, from 128.7 to 100.8 cases/100,000 population, future progress in gonorrhea control and prevention is threatened by resistance to an increasing number of antimicrobial agents and limited remaining treatment options. Over the years, Neisseria gonorrhoeae has readily acquired resistance to a broad spectrum of antimicrobial agents traditionally used for the treatment of gonococcal infections. In the United States, the antimicrobial susceptibility patterns of N. gonorrhoeae have been closely monitored since 1986 through the Gonococcal Isolate Surveillance Project (GISP), and the information has been used to update treatment recommendations. In 2010, 27.2% of all GISP isolates were resistant to penicillin, tetracycline, ciprofloxacin, or some combination of those antimicrobials and 6.9% of isolates were resistant to all three antimicrobials. Penicillin, tetracycline, and fluoroquinolone antimicrobials are no longer recommended as appropriate treatment for gonorrhea in the United States. Currently, the Centers for Disease Control and Prevention (CDC) recommends dual therapy with ceftriaxone (an injectable cephalosporin) 250 mg intramuscularly as a single dose plus either azithromycin 1 gram orally as a single dose or doxycycline 100 mg orally twice a day for 7 days as the most effective treatment for uncomplicated gonorrhea . For patients allergic to cephalosporins, azithromycin 2 grams orally as a single dose is the only alternative treatment option available; however, the use of monotherapy with azithromycin should be extremely judicious due to concerns about possible rapid emergence of azithromycin resistance. Other potential treatment options for gonorrhea are either not available in the United States, do not meet clinical effectiveness criteria for recommended treatment, or have not been adequately studied. Therefore, the emergence and spread of cephalosporin-resistant N. gonorrhoeae (Ceph-R NG) would severely limit treatment options for gonorrhea in the United States. The emergence of Ceph-R NG in the United States could occur either through the importation of Ceph-R NG from other countries, through genetic transformations by obtaining genetic material from other organisms, or through domestic drug selection pressures in the United States. While mutations through drug selection pressures generally take time, the more rapid introduction of antimicrobial-resistant N. gonorrhoeae strains to the United States through the importation of resistant strains, followed by subsequent transmission of resistant strains through local sexual networks has always been a concern. In the last decade, N. gonorrhoeae strains with decreased susceptibility to cephalosporins have been reported with increasing frequency from countries in Asia and the Pacific region, as well as from Europe, Canada, and the United States. Cefixime treatment failures were first reported from Japan in 2003 and have subsequently been reported from Norway, the United Kingdom, Austria, and France. More recently, and of great concern, a gonococcal isolate with high-level ceftriaxone resistance was identified in a Japanese woman with pharyngeal infection and apparent ceftriaxone treatment failure in 2009. Gonococcal isolates with high-level ceftriaxone resistance have subsequently been identified in men with urogenital infections in France and in Spain. While confirmed cephalosporin treatment failures have not yet been identified in the United States, GISP has detected recent increases in minimum inhibitory concentrations (MICs) for cephalosporins among gonococcal isolates in the United States. From 2006 to the first six months of 2011, the proportion of GISP isolates with an elevated cefixime MIC (MIC \ue2\u2030\ua50.25 _g/ml) increased from 0.1% to 1.7%, and the proportion with an elevated ceftriaxone MIC (MIC \ue2\u2030\ua50.125 _g/ml) increased from 0.05% to 0.5% [19]. These increases were most notable in the western United States and among MSM. In the West, the proportion of isolates with an elevated cefixime MIC increased from 0.2% to 3.6% and the proportion with an elevated ceftriaxone MIC increased from 0.04% to 1.9%. Among MSM, the proportion with an elevated cefixime MIC increased from 0.2% to 4.7%, and the proportion with an elevated ceftriaxone MIC increased from 0% to 1.0%. There is concern that this pattern is reminiscent of the pattern that was seen with the emergence of fluoroquinolone-resistant N. gonorrhoeae (QRNG): detection first in Hawaii and then the western United States, before spreading widely in the continental United States. While the first QRNG cases were detected among heterosexuals, QRNG became widespread in the continental United States among men who have sex with men (MSM) with gonorrhea before becoming widespread among heterosexuals. It is likely Ceph-R NG infections will emerge in the United States. A significant challenge to developing an effective response strategy is the lack of a successful model for prevention and control of antimicrobial-resistant N. gonorrhoeae. In previous efforts to address the emergence of penicillinase-producing N. gonorrhoeae (PPNG) and QRNG,CDC and the United States public health community have been unable to prevent or control the introduction and spread of antimicrobial-resistant N. gonorrhoeae, even when more effective alternative antimicrobial options were available and greater resources were available for patient and partner follow-up. Limiting the impact of antimicrobial-resistant N. gonorrhoeae will require a concerted and sustained effort involving multidisciplinary groups. Although new drug classes or synergistic combinations of different antimicrobials may be identified for the treatment of Ceph-R NG and multidrug-resistant N. gonorrhoeae, it is critical to prepare for the emergence of Ceph-R NG in the current reality of limited treatment options and limited public health resources. This public health response plan identifies strategies for enhanced surveillance to detect the emergence of Ceph-R NG in the United States and outlines programmatic steps that can be taken to mitigate the impact until cost-effective treatment alternatives can be identified. The effectiveness of this plan should be closely monitored, and the plan should be periodically reviewed and revised, based on updated surveillance, epidemiological and clinical data.Acknowledgments -- Guide to acronyms -- Background -- Objectives -- Surveillance for cephalosporin-resistant N. gonorrhoeae (Ceph-R NG) -- Working case definitions for Ceph-R NG -- Challenges to surveillance for Ceph-R NG -- Expansion of culture and antimicrobial susceptibility testing (AST) capacity -- Recommended Clinical Management and Public Health Response Following Detection of Suspect or Probable Ceph-R NG -- Guidance on test of cure -- Guidance on partner services and management of partners of suspected or probable Ceph-R NG -- Monitoring the effectiveness of the Ceph-R NG response plan -- Role of enhanced gonorrhea prevention and control activities -- Need for alternative treatment options -- Conclusions -- References -- Appendix I. Contact information and selected web resources -- Appendix II. Sample regulatory language for mandated reporting of AST results -- Appendix III. CLSI cefixime and ceftriaxone agar dilution MIC and disk diffusion zone diameter standards for N. gonorrhoeae -- Appendix IV. Interview record for gonorrhea/chlamydia.August 2012This document was prepared by Sarah Kidd, Robert Kirkcaldy, Tun Ye, John Papp, David Trees, and Steven J. Shapiro, Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention.Mode of access: Internet as an Acrobat .pdf file (457.33 KB, 43 p.).System requirements: Adobe Acrobat Reader.Includes bibliographical references (p. 20-21)