Trends in Neisseria gonorrhoeae Susceptibility to Cephalosporins in the United States, 2006-2014

Gonorrhea is a common sexually transmitted disease that, if untreated, can cause reproductive health complications. Treatments for gonorrhea have been repeatedly jeopardized by antimicrobial resistance. To ensure effective treatment, the US Centers for Disease Control and Prevention (CDC) periodically updates guidelines based on resistance trends. Following declining cephalosporin susceptibility in several countries, the CDC updated its treatment recommendation in 2010 from single-dose cephalosporin (injectable ceftriaxone or oral cefixime) to intensified combination therapy with either ceftriaxone (at a higher dose than previously recommended) or cefixime plus a second antimicrobial.¹

The CDC updated the guidelines again in 2012 to recommend ceftriaxone-based combination therapy as the single recommended therapy.¹ We describe recent gonococcal cephalosporin susceptibility trends, emphasizing changes following publication of these guidelines.

We analyzed 2006-2014 data from the CDC’s Gonococcal Isolate Surveillance Project (GISP), a sentinel system that monitors antimicrobial susceptibility in urethral isolates from consecutive men with gonorrhea treated at US public clinics for sexually transmitted disease.² Jurisdictions competitively apply to participate. GISP is not designed to be nationally representative, but rather to detect emerging changes in susceptibility. Susceptibility is determined by agar dilution. Isolates with ceftriaxone minimum inhibitory concentrations of 0.125 µg/mL or greater or cefixime minimum inhibitory concentrations of 0.25 µg/mL or greater were categorized as exhibiting reduced susceptibility.

Trends were examined overall (and tested for significance [2-sided P < .05] by the Cochran-Armitage trend test) and stratified by region and sex of the sex partner. Analyses were conducted using SAS version 9.3 (SAS Institute Inc). GISP was determined by the Office of the Associate Director for Science, National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention, CDC to be a surveillance activity rather than human subject research. Isolates are collected during clinical care and separate consent is not required. Gonorrhea is notifiable; health departments have the authority to collect and transmit case data to the CDC.

During 2006-2014, 51 144 isolates were collected in 34 cities. Most isolates were collected in the West (36.6%) or South (32.2%); gay, bisexual, or other men who have sex with men contributed 28.1% of isolates. The percentage of participants treated with 250 mg of ceftriaxone intramuscularly increased from 8.7% (95% CI, 8.0%-9.5%) in 2006 to 96.6% (95% CI, 96.1%-97.1%) in 2014 (P < .001). The percentage of isolates with reduced cefixime susceptibility increased from 0.1% (95% CI, <0.1%-0.2%) in 2006 to 1.4% (95% CI, 1.1%-1.7%) in 2011, and then declined to 0.4% (95% CI, 0.3%-0.6%) in 2013 (P < .001) (Figure).

In 2014, the percentage of isolates was 0.8% (95% CI, 0.5%-1.0%). Among isolates from men who have sex with men, the percentage with reduced susceptibility peaked at 4.0% (95% CI, 3.1%-5.0%) and was 1.3% (95% CI, 0.8%-1.9%) in 2014 (Table). Among men who reported having sex exclusively with women, the percentage remained low. In regard to ceftriaxone, the annual overall percentage of isolates with reduced susceptibility fluctuated between 0.1% (95% CI, <0.1%-0.1%) and 0.4% (95% CI, 0.2%-0.6%) (Figure).

The prevalence of reduced cefixime susceptibility declined nearly 70% between 2011 and 2013, suggesting a halting of drift toward resistance. Although this improvement in susceptibility appears temporally correlated with treatment guideline changes, we cannot establish a causal relationship. Observed susceptibility trends mirror those in other countries, only some of which changed treatment guidance to ceftriaxone-based dual therapy.^3,4 Other factors, such as mutation fitness costs or faltering transmission of a clone, might have contributed to improved susceptibility. The 2014 data, however, suggest that improvements in susceptibility may be short-lived.

Although sampling is systematic, participants and participating sites are not selected at random. Thus, prevalence data from participating sites are not expected to be nationally representative. However, data from the GISP have been found to reflect trends in other US settings and populations.⁵ Not all jurisdictions participated continuously during 2006-2014. GISP data cannot distinguish incident infections from repeated sampling of the same infection (although this is expected to be rare).

The increased prevalence of reduced cefixime susceptibility in 2014 highlights the need to maintain surveillance, search for new therapeutics, and ensure that gonorrhea is treated according to the CDC’s guidelines.

Corresponding Author: Robert D. Kirkcaldy, MD, MPH, Division of STD Prevention, US Centers for Disease Control and Prevention (CDC), 1600 Clifton Rd, Atlanta, GA 30329 (rkirkcaldy@cdc.gov).

Author Contributions: Dr Kirkcaldy had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kirkcaldy, Hook, del Rio, Zenilman.

Acquisition, analysis, or interpretation of data: Kirkcaldy, Soge, del Rio, Kubin, Zenilman, Papp.

Drafting of the manuscript: Kirkcaldy.

Critical revision of the manuscript for important intellectual content: Hook, Soge, del Rio, Kubin, Zenilman, Papp.

Statistical analysis: Kirkcaldy.

Obtained funding: Soge, del Rio.

Administrative, technical, or material support: Kirkcaldy, Hook, Soge, Kubin, Zenilman, Papp.

Study supervision: Kirkcaldy, Zenilman.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Hook reported receiving grants from Becton Dickinson, Hologic, Roche Molecular, and Cempra; serving as a consultant for Rib-X (Melinta) and Cempra; receiving honoraria from Becton Dickinson, Roche Molecular, and Cepheid; and receiving royalties from McGraw-Hill. No other disclosures were reported.

Funding/Support: The Gonococcal Isolate Surveillance Project is funded by the CDC, an agency of the US Department of Health and Human Services.

Role of the Funder/Sponsor: Staff from the CDC had a role in the design and conduct of the study; collection, management, analysis, and interpretation of data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC.