The emerging threat of untreatable gonococcal infection.

n engl j med 366;6 nejm.org february 9, 2012 485 Gonorrhea is the second most commonly reported communicable disease in the United States, with an estimated incidence of more than 600,000 cases annually. It disproportionately affects vulnerable populations such as minorities who are marginalized because of race, ethnic group, or sexual orientation. Unfortunately, Neisseria gonorrhoeae has always readily developed resistance to antimicrobial agents: it became resistant to sulfanilamide in the 1940s, penicillins and tetracyclines in the 1980s, and fluoroquinolones by 2007.1 When the prevalence of antimicrobial resistance in the Gonococcal Isolate Surveillance Project (GISP) exceeds 5%, national treatment recommendations are changed to focus on other effective drugs. However, the treatment options recommended by the Centers for Disease Control and Prevention (CDC) are now limited to third-generation cephalosporins.2 But susceptibility to cephalosporins has been decreasing rapidly.3 The proportion of GISP isolates for which the minimum inhibitory concentration (MIC) of cefixime is elevated (≥0.25 μg per milliliter) has increased by a factor of 17 — from 0.1% in 2006 to 1.7% in the first 6 months of 2011. (Although the MIC breakpoints for resistance to cephalosporin have not been defined, the Clinical and Laboratory Standards Institute defines susceptibility to cefixime and ceftriaxone as MICs of 0.25 μg per milliliter or below.) The increases were most pronounced in the western United States (from 0.2% to 3.6%) and among men who have sex with men (from 0.2% to 4.7%) (see graph). Although only one isolate (0.04% of those in the GISP) had a MIC of ceftriaxone of 0.25 μg per milliliter in the first half of 2011, the proportion of GISP isolates with an elevated ceftriaxone MIC (≥0.125 μg per milliliter) has increased by a factor of 10 since 2006 (from 0.05% to 0.50%). Again, increases were greatest in the west (from 0.04% to 1.90%) and among men who have sex with men (from 0.0% to 1.0%). These geographic and demographic patterns are worrisome because they mirror those observed during the emergence of fluoroquinolone-resistant N. gonorrhoeae. Reduced susceptibility to cephalosporins results from the combined effects of several chromosomal gene mutations, including mutations in penA, the gene that encodes penicillin-binding protein 2 (PBP2); penB, which affects drug entry through an outer membrane protein channel (PorB1b), and mtrR, a repressor of the MtrCDE-encoded pump. A novel DNA cassette with multiple penA mutations (mosaic penA) is common in strains with reduced susThe Emerging Threat of Untreatable Gonococcal Infection