Emerging Azithromycin Resistance among Nontyphoidal Salmonella Isolates in the United States

Background: Antimicrobial resistance among nontyphoidal Salmonella (NTS) is a serious public health threat. Resistance to azithromycin, a clinically-important antimicrobial, has historically been rare in NTS in the United States but is often plasmid-mediated. We evaluated trends and assessed characteristics of national NTS isolates with azithromycin resistance.

Methods: In 2011–2016, US health departments submitted every 20^th NTS isolate for surveillance and additional outbreak isolates to CDC’s National Antimicrobial Resistance Monitoring System laboratory, where they were tested for antimicrobial susceptibility by broth microdilution to 14 drugs, including azithromycin. Resistance to azithromycin was defined by a minimum inhibitory concentration of ≥32 µg/mL based on the current Clinical and Laboratory Standards Institute’s investigational breakpoint for Salmonella Typhi. A subset of isolates underwent whole genome sequencing; sequences were screened for the presence of resistance determinants. Epidemiological characteristics were reviewed when available.

Results: We identified 29 NTS isolates with azithromycin resistance representing 22 different serotypes from 19 states. The prevalence of azithromycin resistance among surveillance isolates increased from 1.4 per 1000 isolates tested in 2011–2014 to 3.7 per 1000 in 2015–2016 (P = 0.014). In addition to azithromycin resistance, most isolates were multidrug resistant; 16 (55%) were resistant to agents from ≥5 antimicrobial classes. Of 16 sequenced isolates with resistance genes detected, 13 (81%) had mphA and 2 (13%) had mphE. Median patient age was 45 years (interquartile range 21–61.5; n = 29); 13 (46%; n = 28) were male. Of 15 patients with travel histories, 5 (33%) traveled to Asia, 2 (13%) traveled to Latin America, and 1 (7%) traveled to Europe prior to illness onset.

Conclusion: Azithromycin resistance among NTS is increasing in the United States, though it remains rare. The rise is associated with the emergence of plasmid-mediated macrolide resistance genes mphA and mphE, raising concern for spread of resistance among bacteria. Resistance determinants may enter the United States via international travelers, while frequent clinical use of azithromycin may contribute to selective pressure domestically.