Robert D. Kirkcaldy

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

Summary 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 Preventions 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 (cefRS) 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 cefRS. We found that two of the 118 cefRS isolates lacked a mosaic penA allele, and rechecking showed that these two were susceptible to cefixime. Of the 116 remaining cefRS isolates, 114 (98%) fell into two distinct lineages that have independently acquired mosaic penA allele XXXIV. A major lineage of cefRS 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 aymptomatic infections. Funding American Sexually Transmitted Disease Association, Wellcome Trust, National Institute of General Medical Sciences, and National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Neisseria gonorrhoeae With High-Level Resistance to Azithromycin: Case Report of the First Isolate Identified in the United States

We report on the first Neisseria gonorrhoeae isolate in the United States identified with high-level resistance to azithromycin. This report discusses the epidemiologic case investigation, the molecular studies of resistance-associated mutations and N. gonorrhoeae multiantigen sequence typing, and challenges posed by emerging gonococcal antimicrobial resistance.

Trichomonas vaginalis Antimicrobial Drug Resistance in 6 US Cities, STD Surveillance Network, 2009–2010

Such isolates should undergo drug susceptibility testing periodically to detect emerging resistance.

Extragenital Gonorrhea and Chlamydia Testing and Infection Among Men Who Have Sex With Men—STD Surveillance Network, United States, 2010–2012

BACKGROUND Gonorrhea (GC) and chlamydia (CT) are the most commonly reported notifiable diseases in the United States. The Centers for Disease Control and Prevention recommends that men who have sex with men (MSM) be screened for urogenital GC/CT, rectal GC/CT, and pharyngeal GC. We describe extragenital GC/CT testing and infections among MSM attending sexually transmitted disease (STD) clinics. METHODS The STD Surveillance Network collects patient data from 42 STD clinics. We assessed the proportion of MSM attending these clinics during July 2011-June 2012 who were tested and positive for extragenital GC/CT at their most recent visit or in the preceding 12 months and the number of extragenital infections that would have remained undetected with urethral screening alone. RESULTS Of 21 994 MSM, 83.9% were tested for urogenital GC, 65.9% for pharyngeal GC, 50.4% for rectal GC, 81.4% for urogenital CT, 31.7% for pharyngeal CT, and 45.9% for rectal CT. Of MSM tested, 11.1% tested positive for urogenital GC, 7.9% for pharyngeal GC, 10.2% for rectal GC, 8.4% for urogenital CT, 2.9% for pharyngeal CT, and 14.1% for rectal CT. More than 70% of extragenital GC infections and 85% of extragenital CT infections were associated with negative urethral tests at the same visit and would not have been detected with urethral screening alone. CONCLUSIONS Extragenital GC/CT was common among MSM attending STD clinics, but many MSM were not tested. Most extragenital infections would not have been identified, and likely would have remained untreated, with urethral screening alone. Efforts are needed to facilitate implementation of extragenital GC/CT screening recommendations for MSM.

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.

Neisseria gonorrhoeae Antimicrobial Susceptibility Surveillance - The Gonococcal Isolate Surveillance Project, 27 Sites, United States, 2014.

PROBLEM/CONDITION Gonorrhea is the second most commonly reported notifiable disease in the United States; 350,062 gonorrhea cases were reported in 2014. Sexually transmitted infections caused by Neisseria gonorrhoeae are a cause of pelvic inflammatory disease in women, which can lead to serious reproductive complications including tubal infertility, ectopic pregnancy, and chronic pelvic pain. Prevention of sequelae and of transmission to sexual partners relies largely on prompt detection and effective antimicrobial treatment. However, treatment has been compromised by the absence of routine antimicrobial susceptibility testing in clinical care and evolution of antimicrobial resistance to the antibiotics used to treat gonorrhea. PERIOD COVERED 2014. DESCRIPTION OF THE SYSTEM The Gonococcal Isolate Surveillance Project (GISP) was established in 1986 as a sentinel surveillance system to monitor trends in antimicrobial susceptibilities of N. gonorrhoeae strains in the United States. Each month, N. gonorrhoeae isolates are collected from up to the first 25 men with gonococcal urethritis attending each of the participating sexually transmitted disease (STD) clinics at 27 sites. The number of participating sites has varied over time (21-30 per year). Selected demographic and clinical data are abstracted from medical records. Isolates are tested for antimicrobial susceptibility using agar dilution at one of five regional laboratories. RESULTS A total of 5,093 isolates were collected in 2014. Of these, 25.3% were resistant to tetracycline, 19.2% to ciprofloxacin, and 16.2% to penicillin (plasmid-based, chromosomal, or both). Reduced azithromycin susceptibility (Azi-RS) (defined as minimum inhibitory concentration [MIC] ≥2.0 µg/mL) increased from 0.6% in 2013 to 2.5% in 2014. The increase occurred in all geographic regions, but was greatest in the Midwest, and among all categories of sex of sex partners (men who have sex with men [MSM], men who have sex with men and women [MSMW], and men who have sex with women [MSW]). No Azi-RS isolates exhibited reduced cefixime or ceftriaxone susceptibility (Cfx-RS and Cro-RS, respectively). The prevalence of Cfx-RS (MIC ≥0.25 µg/mL) increased from 0.1% in 2006 to 1.4% in both 2010 and 2011, decreased to 0.4% in 2013, and increased to 0.8% in 2014. Cro-RS (MIC ≥0.125 µg/mL) increased following a similar pattern but at lesser percentages (increased from 0.1% in 2008 to 0.4% in 2011 and decreased to 0.1% in 2013 and 2014). The percentage of isolates resistant to tetracycline, ciprofloxacin, penicillin, or all three antimicrobials, was greater in isolates from MSM than from MSW. INTERPRETATION This is the first report to present comprehensive surveillance data from GISP and summarize gonococcal susceptibility over time, as well as underscore the history and public health implications of emerging cephalosporin resistance. Antimicrobial susceptibility patterns vary by geographic region within the United States and by sex of sex partner. Because dual therapy with ceftriaxone plus azithromycin is the only recommended gonorrhea treatment, increases in azithromycin and cephalosporin MICs are cause for concern that resistance to these antimicrobial agents might be emerging. It is unclear whether increases in the percentage of isolates with Azi-RS mark the beginning of a trend. The percentage of isolates with elevated cefixime MICs increased during 2009-2010, then decreased during 2012-2013 after treatment recommendations were changed in 2010 to recommend dual therapy (with a cephalosporin and a second antibiotic) and a higher dosage of ceftriaxone. Subsequently, the treatment recommendations were changed again in 2012 to no longer recommend cefixime as part of first-line therapy (leaving ceftriaxone-based dual therapy as the only recommended therapy). Despite the MIC decrease (i.e., trend of improved cefixime susceptibility) during 2012-2013, the increase in the number of strains with Cfx-RS in 2014 underscores the potential threat of cephalosporin-resistant N. gonorrhoeae. PUBLIC HEALTH ACTION The National Strategy for Combating Antibiotic-Resistant Bacteria identifies prevention, rapid detection, and control of outbreaks of ceftriaxone-resistant N. gonorrhoeae infection as a priority for U.S. PUBLIC HEALTH ACTION Antimicrobial susceptibility surveillance is conducted to guide development of treatment recommendations for effective therapy and prevention of complications from and transmission of gonorrhea. Federal agencies can use GISP data to develop national treatment recommendations and set research and prevention priorities. Local and state health departments can use GISP data to determine allocation of STD prevention services and resources, guide prevention planning, and communicate best treatment practices to health care providers. Continued surveillance, appropriate treatment, development of new antibiotics, and prevention of transmission remain the best strategies to reduce gonorrhea incidence and morbidity.

The Efficacy and Safety of Gentamicin Plus Azithromycin and Gemifloxacin Plus Azithromycin as Treatment of Uncomplicated Gonorrhea

BACKGROUND Ceftriaxone is the foundation of currently recommended gonorrhea treatment. There is an urgent need for backup treatment options for patients with cephalosporin allergy or infections due to suspected cephalosporin-resistant Neisseria gonorrhoeae. We evaluated the efficacy and tolerability of 2 combinations of existing noncephalosporin antimicrobials for treatment of patients with urogenital gonorrhea. METHODS We conducted a randomized, multisite, open-label, noncomparative trial in 5 outpatient sexually transmitted disease clinic sites in Alabama, California, Maryland, and Pennsylvania. Patients aged 15-60 years diagnosed with uncomplicated urogenital gonorrhea were randomly assigned to either gentamicin 240 mg intramuscularly plus azithromycin 2 g orally, or gemifloxacin 320 mg orally plus azithromycin 2 g orally. The primary outcome was microbiological cure of urogenital infections (negative follow-up culture) at 10-17 days after treatment among 401 participants in the per protocol population. RESULTS Microbiological cure was achieved by 100% (lower 1-sided exact 95% confidence interval [CI] bound, 98.5%) of 202 evaluable participants receiving gentamicin/azithromycin, and 99.5% (lower 1-sided exact 95% CI bound, 97.6%) of 199 evaluable participants receiving gemifloxacin/azithromycin. Gentamicin/azithromycin cured 10 of 10 pharyngeal infections and 1 of 1 rectal infection; gemifloxacin/azithromycin cured 15 of 15 pharyngeal and 5 of 5 rectal infections. Gastrointestinal adverse events were common in both arms. CONCLUSIONS Gentamicin/azithromycin and gemifloxacin/azithromycin were highly effective for treatment of urogenital gonorrhea. Gastrointestinal adverse events may limit routine use. These non-cephalosporin-based regimens may be useful alternative options for patients who cannot be treated with cephalosporin antimicrobials. Additional treatment options for gonorrhea are needed. Clinical Trials Registration. NCT00926796.

Gonococcal Resistance: Are Cephalosporins Next?

The development of resistance to multiple antibiotics has limited treatment options for gonorrhea in many countries. Currently, the Centers for Disease Control and Prevention only recommend cephalosporin antibiotics for treatment of uncomplicated gonorrhea. Although the cephalosporins remain effective, the demonstrated ability of Neisseria gonorrhoeae to develop resistance has raised concerns about the possibility of multidrug-resistant N. gonorrhoeae strains, which include cephalosporin resistance. This article provides a review of global trends in cephalosporin susceptibility among gonococcal isolates, recent findings that deepen our understanding of genetic mechanisms of resistance, and the public health and clinical implications of the potential emergence of cephalosporin-resistant gonorrhea.

Trends in antimicrobial resistance in Neisseria gonorrhoeae in the USA: the Gonococcal Isolate Surveillance Project (GISP), January 2006-June 2012.

Background Neisseria gonorrhoeae has progressively developed resistance to sulfonamides, penicillin, tetracycline and fluoroquinolones, and gonococcal susceptibility to cephalosporins has been declining worldwide. Methods We described trends in gonococcal antimicrobial susceptibility in the USA from January 2006 through June 2012. Susceptibility data for cefixime, ceftriaxone, azithromycin, penicillin, tetracycline and ciprofloxacin were obtained from the Gonococcal Isolate Surveillance Project (GISP), a sentinel surveillance system that monitors antimicrobial susceptibility in urethral gonococcal isolates collected from symptomatic men at 25–30 sexually transmitted disease clinics throughout the USA. Results The percentage of isolates with elevated cefixime minimum inhibitory concentrations (MICs) (≥0.25 µg/mL) increased from 0.1% in 2006 to 1.4% in 2010–2011 and was 1.1% in the first 6 months of 2012. The percentage with elevated ceftriaxone MICs (≥0.125 µg/mL) increased from 0.1% in 2006 to 0.3%–0.4% during 2009 through the first 6 months of 2012. There were no temporal trends in the prevalence of elevated azithromycin MICs (≥2 µg/mL) (0.2%–0.5%). The prevalence of resistance remained high for penicillin (11.2%–13.2%), tetracycline (16.7%–22.8%) and ciprofloxacin (9.6%–14.8%). Conclusions The proportion of gonococcal isolates with elevated cephalosporin MICs increased from 2006 to 2010, but plateaued during 2011 and the first 6 months of 2012. Resistance to previously recommended antimicrobials has persisted. As the number of antimicrobials available for gonorrhoea treatment dwindles, surveillance systems such as GISP will be critical to detect emerging resistance trends and guide treatment decisions.

Factors Related to Increasing Prevalence of Resistance to Ciprofloxacin and Other Antimicrobial Drugs in Neisseria gonorrhoeae, United States

What would you do if you had a sexually transmitted disease that was untreatable with antibiotics? That is the situation we may be heading toward. In the United States, gonorrhea is the second most common reportable infection. Over the years, the organism that causes it, N. gonorrhoeae, has acquired resistance to several classes of antibiotics including, most recently, the fluoroquinolones. In fact, widespread resistance led CDC to stop recommending fluoroquinolones for gonorrhea treatment in 2007. Today, cephalosporin-based combination therapy is the last remaining option currently recommended for gonorrhea treatment. Understanding of the causes of drug resistance is needed so that control measures can be improved and the effectiveness of the few remaining drugs can be maintained. This article investigates possible causes for the emergence of fluoroquinolone-resistant N. gonorrhoeae that occurred several years ago. Fluoroquinolone-resistant strains spread in the United States in the late 1990s and spread more rapidly among men who have sex with men (MSM) than among heterosexual men. One possible explanation for the rise in drug resistance, especially among heterosexuals, is acquisition of resistant gonorrhea through travel. Certain drug-resistant strains of N. gonorrhoeae, particularly the multidrug resistant strains (also resistant to penicillin and tetracycline) circulating among MSM, seemed to be able to reach high prevalence levels through domestic transmission, rather than through frequent importation. After resistance emerged in a geographic area, resistant strains appeared among MSM and heterosexuals within several months. When resistance is detected in either MSM or heterosexuals, prevention efforts should be directed toward both populations.