A Brief History of Evolving Diagnostics and Therapy for Gonorrhea: Lessons Learned.

Progressively decreasing susceptibility of Neisseria gonorrhoeae to the antibiotics recommended for treatment has raised concerns about the public health threat of antibiotic resistant gonorrhea. This is not a new process, and the organism has reliably developed resistance to all modern antibiotics used for treatment since the dawn of the antibiotic era. The history of changing recommendations for gonorrhea therapy is complex, however, and has been influenced by diagnostic test methods and surveillance. Understanding the impact of these influences may provide insights into current approaches to address this reemerging public health challenge. We reviewed available methods for gonorrhea diagnosis, and public health recommendations for gonorrhea treatment. The literature review was supplemented by qualitative interviews with senior investigators whose research helped shape gonorrhea management strategies over the past 50 years. The process of development of antimicrobial resistance to the antibiotics widely used for treatment seems to be inexorable. Many currently voiced concerns are similar to those raised in the past. The public health threat of increasing antimicrobial resistance by N. gonorrhoeae has been amplified as a result of a smaller pipeline introducing new drugs for gonorrhea treatment. Improved methods for gonorrhea diagnosis have also repeatedly influenced appreciation of the burden of disease caused by N. gonorrhoeae. US Public Health Service leadership has also shaped and improved the management of this important public health problem.

An Illustration of the Potential Health and Economic Benefits of Combating Antibiotic-Resistant Gonorrhea.

Preventing the emergence of ceftriaxone-resistant Neisseria gonorrhoeae can potentially avert hundreds of millions of dollars in direct medical costs of gonorrhea and gonorrhea-attributable HIV infections. In the illustrative scenario we examined, emerging ceftriaxone resistance could lead to 1.2 million additional N. gonorrhoeae infections within 10 years, costing $378.2 million.

Ciprofloxacin resistance and gonorrhea incidence rates in 17 cities, United States, 1991-2006.

Antimicrobial drug resistance can hinder gonorrhea prevention and control efforts. In this study, we analyzed historical ciprofloxacin resistance data and gonorrhea incidence data to examine the possible effect of antimicrobial drug resistance on gonorrhea incidence at the population level. We analyzed data from the Gonococcal Isolate Surveillance Project and city-level gonorrhea incidence rates from surveillance data for 17 cities during 1991-2006. We found a strong positive association between ciprofloxacin resistance and gonorrhea incidence rates at the city level during this period. Their association was consistent with predictions of mathematical models in which resistance to treatment can increase gonorrhea incidence rates through factors such as increased duration of infection. These findings highlight the possibility of future increases in gonorrhea incidence caused by emerging cephalosporin resistance.

Genomic epidemiology of Neisseria gonorrhoeae with reduced susceptibility to cefixime in the USA: a retrospective observational study.

BACKGROUND: The emergence of Neisseria gonorrhoeae with decreased susceptibility to extended spectrum cephalosporins raises the prospect of untreatable gonorrhoea. In the absence of new treatments, efforts to slow the increasing incidence of resistant gonococcus require insight into the factors that contribute to its emergence and spread. We assessed the relatedness between isolates in the USA and reconstructed likely spread of lineages through different sexual networks. METHODS: We sequenced the genomes of 236 isolates of N gonorrhoeae collected by the Centers for Disease Control and Prevention's Gonococcal Isolate Surveillance Project (GISP) from sentinel public sexually transmitted disease clinics in the USA, including 118 (97%) of the isolates from 2009-10 in GISP with reduced susceptibility to cefixime (cef(RS)) and 118 cefixime-susceptible isolates from GISP matched as closely as possible by location, collection date, and sexual orientation. We assessed the association between antimicrobial resistance genotype and phenotype and correlated phylogenetic clustering with location and sexual orientation. FINDINGS: Mosaic penA XXXIV had a high positive predictive value for cef(RS). We found that two of the 118 cef(RS) isolates lacked a mosaic penA allele, and rechecking showed that these two were susceptible to cefixime. Of the 116 remaining cef(RS) isolates, 114 (98%) fell into two distinct lineages that have independently acquired mosaic penA allele XXXIV. A major lineage of cef(RS) strains spread eastward, predominantly through a sexual network of men who have sex with men. Eight of nine inferred transitions between sexual networks were introductions from men who have sex with men into the heterosexual population. INTERPRETATION: Genomic methods might aid efforts to slow the spread of antibiotic-resistant N gonorrhoeae through augmentation of gonococcal outbreak surveillance and identification of populations that could benefit from increased screening for asymptomatic infections.

Neisseria gonorrhoeae antimicrobial resistance among men who have sex with men and men who have sex exclusively with women: the Gonococcal Isolate Surveillance Project, 2005-2010.

BACKGROUND: Gonorrhea treatment has been complicated by antimicrobial resistance in Neisseria gonorrhoeae. Gonococcal fluoroquinolone resistance emerged more rapidly among men who have sex with men (MSM) than men who have sex exclusively with women (MSW). OBJECTIVE: To determine whether N. gonorrhoeae urethral isolates from MSM were more likely than isolates from MSW to exhibit resistance to or elevated minimum inhibitory concentrations (MICs) of antimicrobials used to treat gonorrhea. DESIGN: 6 years of surveillance data from the Gonococcal Isolate Surveillance Project. SETTING: Publicly funded sexually transmitted disease clinics in 30 U.S. cities. PATIENTS: Men with a total of 34 600 episodes of symptomatic urethral gonorrhea. MEASUREMENTS: Percentage of isolates exhibiting resistance or elevated MICs and adjusted odds ratios for resistance or elevated MICs among isolates from MSM compared with isolates from MSW. RESULTS: In all U.S. regions except the West, isolates from MSM were significantly more likely to exhibit elevated MICs of ceftriaxone and azithromycin than isolates from MSW (P < 0.050). Isolates from MSM had a high prevalence of resistance to ciprofloxacin, penicillin, and tetracycline and were significantly more likely to exhibit antimicrobial resistance than isolates from MSW (P < 0.001). LIMITATIONS: Sentinel surveillance may not be representative of all patients with gonorrhea. HIV status, travel history, and antimicrobial use data were missing for some patients. CONCLUSION: Men who have sex with men are vulnerable to the emerging threat of antimicrobial-resistant N. gonorrhoeae. Because antimicrobial susceptibility testing is not routinely done in clinical practice, clinicians should monitor for treatment failures among MSM diagnosed with gonorrhea. Strengthened prevention strategies for MSM and new antimicrobial treatment options are needed.

Emergence of increased azithromycin resistance during unsuccessful treatment of Neisseria gonorrhoeae infection with azithromycin (Portland, OR, 2011).

We describe the emergence of an azithromycin-resistant Neisseria gonorrhoeae variant in a man from Portland, Oregon, during sole treatment with 2 g azithromycin. This report highlights the ease with which gonococcal macrolide resistance can emerge, the threat of multidrug resistant N. gonorrhoeae, and the need for adherence to Centers for Disease Control and Prevention treatment guidelines.