Increased Incidence of Antimicrobial-Resistant Nontyphoidal Salmonella Infections, United States, 2004–2016

Felicita Medalla; Weidong Gu; Cindy R. Friedman; Michael Judd; Jason Folster; Patricia M. Griffin; Robert M. Hoekstra


Emerging Infectious Diseases. 2021;27(6):1662-1672. 

In This Article


Our analysis indicates that the incidence of resistant Salmonella infections was higher in 2015–2016 than in earlier periods during 2004–2014. The annual incidence of culture-confirmed infections with clinically important resistance increased by 0.68/100,000 persons, a 40% increase in the annual number of infections, during 2015–2016 compared with 2004–2008. Serotypes I 4,[5],12:i:- and Enteritidis were responsible for two thirds of this increase. Ciprofloxacin-nonsusceptible infections accounted for more than half of the increase. Extrapolating to total infections in the US population using a multiplier to account for unreported infections resulted in an estimated ≈63,000 more infections with clinically important resistance per year during 2015–2016 compared with 2004–2008 (from ≈159,000 to ≈222,000 infections).

The increased incidence of ciprofloxacin-nonsusceptible Salmonella infections during 2015–2016 compared with incidence for both 2004–2008 and 2010–2014 is a concerning trend. Serotype Enteritidis contributed the most to this increase. Although the incidence of infections with Enteritidis, the most common serotype, has not changed significantly in >10 years, the percentage of ciprofloxacin-nonsusceptible infections has increased almost steadily.[11,16] Chicken and eggs have been the main domestic sources of Enteritidis infections.[29,30] About 20% of Enteritidis infections are linked to international travel, which is an important source of ciprofloxacin-nonsusceptible Enteritidis infections.[8,31,32]

The incidence of infections with clinically important resistance and ciprofloxacin-nonsusceptibility caused by serotypes categorized as other was higher during 2015–2016 than during 2004–2008. Some of these serotypes are emerging or have concerning levels of resistance, including Dublin, Infantis, Kentucky, Hadar, and Agona.[16,24,33] Some have been associated with resistance, invasive illness, or both.[11,19,23,33]

The decrease in resistant Typhimurium infections might be related to the simultaneous increase in I 4,[5],12:i- infections, which some call monophasic Typhimurium.[16,18,34] In the 1990s, MDR Typhimurium infections increased markedly in Europe and then in the United States.[35,36] Most isolates from these infections that underwent phage typing were definitive type 104.[14,21,35,36] Isolations of this strain have decreased globally; the reasons are not known[36]

Changes in resistance incidence by resistance category and serotype varied by geographic region, with significant increases in most regions for serotypes I 4,[5],12:i:- and Enteritidis. An increase in the incidence of I 4,[5],12:i:- infections with multidrug and ampicillin-only resistance occurred in all 4 regions, with highest increase in the West and Midwest. Pork products have been associated with I 4,[5],12:i:- infections with resistance to ampicillin, sulfonamide, streptomycin, and tetracycline in the West.[34,37] The regional pattern of pork consumption has reflected the regional pattern of pork production, which is highest in the Midwest; 8 of the 10 states with the highest production of swine are in the Midwest.[38,39] A study showed that MDR I 4,[5],12:i:- strains from swine in the Midwest during 2014–2016 were typically resistant to ampicillin, sulfonamide, streptomycin, and tetracycline and probably part of a European clade that has spread in the United States and elsewhere; these strains harbored plasmid-mediated resistance genes, which can be transmitted horizontally to other bacteria.[34] This trend could partly explain the widespread increase in the incidence of MDR I 4,[5],12:i:- infections. International travel could have contributed to an increase in the incidence of ciprofloxacin-nonsusceptible Enteritidis infections, which increased in 3 regions and was highest in the Northeast. International travel has increased since 2014, and residents of northeastern states accounted for more than one third of US travelers during 2015–2016.[40] In the United Kingdom, an increase in these infections has been linked to international travel and imported foods.[41] In the United States, ciprofloxacin-nonsusceptible strains of Enteritidis and other serotypes have been isolated from imported seafood.[42] Plasmid-mediated quinolone-resistance genes have been detected among ciprofloxacin-nonsusceptible isolates in the United States; these genes might contribute to spread of fluoroquinolone nonsusceptibility.[43]

Our use of a Bayesian hierarchical model improved the estimates, as shown by the smoothing of resistance incidence and temporal change lines, by addressing issues related to missing and sparse state-year data.[20,26] Our method of calculating the average difference in incidence between groups of years is more refined than approaches using a negative binomial model because it does not assume homogeneous resistance incidence rates across multiple years.[11,44] It is therefore less likely to underestimate the variability of estimated changes. However, this analysis is subject to the same limitations described in previous reports, including unmeasured sources of bias and uncertainty derived by combining data from separate unlinked surveillance systems.[20,26] Our estimates of significant changes were limited to comparisons with the reference periods used to assess changes in resistance percentages in NARMS annual reports.[16] Our choice to compare a recent 2-year period with earlier 5-year periods balanced the need to assess the most current situation with the need for sufficient data to assess significant changes. Because of the low percentage of isolates showing resistance to trimethoprim/sulfamethoxazole (<3%) or decreased susceptibility to azithromycin (<1%), an important agent used to treat serious infections, we did not provide estimates for these agents.[2,16,18,20] We included infections resistant to ceftriaxone and nonsusceptible to ciprofloxacin in the ceftriaxone/ampicillin-resistance category; they represented only 0.3% of Salmonella isolates submitted to NARMS. The fact that some ciprofloxacin nonsusceptible infections were not included in the ciprofloxacin nonsusceptible category further supports our finding that ciprofloxacin-nonsusceptible infections increased during the study period. Increasing use of culture-independent diagnostic tests by clinical laboratories can change the submission of isolates to public health laboratories and reporting of infections;[11] these changes warrant adjustments in future analyses.[20]

We multiplied estimates of culture-confirmed infections by 29 to account for undiagnosed infections. However, resistant infections are associated with more severe illness, so they might be more likely to be detected.[3–6] Thus, the appropriate multiplier (the ratio of total infections to culture-confirmed infections) for resistant infections might be <29. To calculate undiagnosed Salmonella infections, multipliers of 12 for persons <5 years of age and 23 for persons ≥ 65 years of age have been reported.[45] Although children <5 years of age have the highest incidence of Salmonella infections, older adults might disproportionately account for resistant infections because they are more likely to have serious illness and be hospitalized;[4,5,44–47] therefore, a multiplier of 23 might be an appropriate choice. However, we chose 29 because it was used in a previous estimate of the total number of Salmonella infections in the population[1] and because persons 5–64 years of age account for most culture-confirmed infections reported to CDC and most isolates with clinically important resistance submitted to NARMS.[4,18,44,45] We did not attach uncertainties to the extrapolated total number of resistant infections and changes in that number because uncertainties of the multiplier are not known. Although resistance incidence can vary by demographic subgroup, geographic region, time, and other factors, we did not include additional uncertainties from the extrapolation to the US population using the average 2015–2016 population estimates for the 50 states.[19,21,22,46,47]

Estimates of changes in resistance incidence can help identify trends of greatest concern to set priorities for prevention. Analyses that include the varying distributions of infections by demographic subgroups, season, and recent travel could inform serotype-specific, regional, and source-targeted prevention strategies.[5,11,21,22,31,44–48] The increasing use of whole-genome sequencing by public health laboratories to characterize Salmonella strains will enhance surveillance of antimicrobial-resistant Salmonella from human and nonhuman sources.[49] Antimicrobial agents contribute to resistance wherever they are used, including in food animals and humans.[50] A One Health approach can help in detecting and controlling antimicrobial resistance, which is a complex and multifaceted problem that affects humans, animals, and the environment.[50]