Emerging Extended-Spectrum Cephalosporin Resistance in Neisseria gonorrhoeae

Abstract

Over the last several decades, Neisseria gonorrhoeae has sequentially developed resistance to the agents recommended by the CDC and the Public Health Service for the treatment of gonorrhea. During the 1970s and through the 1990s, penicillin, tetracyclines, and the fluoroquinolones were recommended and subsequently removed as the therapy of choice for gonorrhea, leaving intramuscular ceftriaxone and the oral cephalosporin cefixime as the sole agents recommended for treatment of gonorrhea in 2010. In the late 1990s, treatment failures following oral cefixime therapy were recognized in Japan and the Far East, and subsequently, cefixime treatment failures were reported from the United Kingdom, Europe, and the United States. Gonococcal isolates from these cases showed diminished susceptibility to both cefixime and ceftriaxone, and molecular studies have shown that N. gonorrhoeae isolates with elevated cephalosporin MICs have genetic alterations primarily in the chromosomal penA gene, which encodes penicillin-binding protein 2. The altered proteins bind cephalosporins less efficiently, and isolates phenotypically demonstrate diminished cephalosporin susceptibility and elevated cefixime and ceftriaxone MICs. The penA alleles in these strains have a “mosaic” composition, as they contain nucleic acid sequences that were acquired from commensal Neisseria species. The strains also have genetic alterations in several other chromosomal loci that contribute to incremental cephalosporin resistance. With the utility of extended-spectrum cephalosporins for gonorrhea treatment being threatened, older agents (e.g., gentamicin and ertapenem) and newly developed antimicrobials (e.g., solithromycin) are now being evaluated as possible treatment options. The CDC has issued guidelines for the public health response to the emergence of cephalosporin-resistant N. gonorrhoeae. This plan includes improvements in gonococcal surveillance, identification by clinicians of “probable” and “suspected” treatment failures, the re-establishment of culture-based testing, and the timely performance of antimicrobial susceptibility testing on isolates obtained from treatment failures. Potential problems central to implementation of the response plan are also addressed.