Nontyphoidal Salmonella infections are a major cause of human illness in the United States, resulting in ~1.35 million illnesses annually, with ~25% attributed to poultry sources (1,2). Twenty serotypes cause most human infections. Salmonella enterica serotype Infantis (S. Infantis) has re-emerged as a leading serotype with the emergence of a multidrug-resistant strain (3–5). Although most Salmonella infections result in self-limited gastrointestinal illness, antimicrobial agents, particularly fluoroquinolones (e.g., ciprofloxacin) and third-generation cephalosporins (e.g., ceftriaxone), are recommended for patients with severe infections (e.g., bloodstream infections) (6,7). Azithromycin is a treatment option, particularly when resistance to fluoroquinolones and third-generation cephalosporins is a concern (7,8).

The multidrug-resistant S. Infantis strain, now designated as “REPJFX01,” was first identified in the United States from a retail chicken sample collected in 2014; it had a rare extended-spectrum β-lactamase gene, bla_CTX-M-65, conferring resistance to ceftriaxone and other β-lactams (9–11). Subsequent investigations found that the earliest U.S. infections with this S. Infantis strain occurred in 2012 in travelers returning from Peru (12). REPJFX01 typically contains a megaplasmid of emerging Salmonella Infantis (pESI) harboring multiple resistance genes and a chromosomal gyrA87 mutation conferring decreased susceptibility to ciprofloxacin (11,13–17). Additional human infections have since been detected, including outbreaks linked to consumption of chicken (5,11,18). S. Infantis is now among the most common serotypes from U.S. poultry sources (5,15–17).

We describe the epidemiology and antimicrobial resistance of human S. Infantis infections in the United States, including the emergence of REPJFX01, using data from five surveillance and monitoring systems at the Centers for Disease Control and Prevention (CDC). Since 2020, CDC has used whole genome sequencing (WGS) to monitor reoccurring, emerging, or persisting (REP) strains of enteric bacteria, including REPFJX01 (10,11). These systems, varying in scope and methods and including surveillance for overall and outbreak-related Salmonella infections, provide data for an overview of S. Infantis and REPJFX01 infections at the national level and more in-depth analyses of infections in 10 active surveillance sites.

S. Infantis has re-emerged as a major serotype causing Salmonella infections in the United States. In FoodNet, S. Infantis has been among the 10 most commonly reported serotypes since 2013 and increases in incidence have been described in previous annual reports (3,4). We estimate that the average annual incidence of S. Infantis infections was almost twice as high during 2013–2022 as it was during 2003–2012.

An increase in S. Infantis infections during the more recent 10-year period was likely driven by an increase in REPJFX01 S. Infantis, which accounted for nearly one-third of overall S. Infantis infections during 2018–2022. The acquisition of pESI could have allowed S. Infantis to proliferate in U.S. poultry production settings and drive an increase in human infections (5), similar to the spread of S. Infantis in the European poultry production system (13,14,31). The emergence of REPJFX01, typically containing pESI carrying multiple resistance genes and gyrA87 mutation conferring decreased susceptibility to ciprofloxacin, is concerning. Nearly all REPJFX01 isolates had predicted decreased susceptibility to ciprofloxacin, and more than half had predicted resistance to ceftriaxone, limiting first-line treatment options and increasing the likelihood of treatment failures for severe salmonellosis (6–8,22,25). Blood cultures and antimicrobial susceptibility testing (AST) are recommended to tailor the choice of antimicrobial treatment. Because of the low rates of predicted resistance to azithromycin among REPJFX01 and S. Infantis overall, this drug remains a viable treatment option (7–8). However, clinical breakpoints using traditional AST methods to determine resistance to azithromycin among nontyphoidal Salmonella serotypes have not been established by the Clinical and Laboratory Standards Institute (8,25,32,33). Our findings underscore the need for further research on clinical outcomes and other data to support establishing clinical breakpoints for azithromycin and continued monitoring of resistance genes and mechanisms conferring resistance to antimicrobial agents recommended for invasive Salmonella infections (8,32,33).

Comparing S. Infantis with other Salmonella infections, we found differences in demographic and other patient characteristics. These associations appeared to be stronger when we compared the subset of S. Infantis infections caused by REPJFX01 with other Salmonella infections—reflected in higher proportions that were female, ≥45 years (particularly ≥65), had isolates from urine, and reported diabetes, while fever and diarrheal illness were less represented among REPJFX01 infections. These findings suggest that increased urinary isolates among S. Infantis and REPJFX01 infections could represent increased urinary tract infections (UTIs), versus asymptomatic bacteriuria or specimen contamination from feces (34–37), compared with other Salmonella infections. Previous studies support these findings that infections with Salmonella isolated from urine were predominantly among older adults, female patients, and those with underlying conditions (e.g., diabetes) (34–37). There is a growing body of literature on foodborne transmission of pathogens causing UTIs, including a study of Salmonella UTIs using foodborne outbreak data; a small survey of patients from the study documented that consumption of contaminated food occurred before the illnesses (34). In addition to S. Infantis, other serotypes have been isolated more often from urine than serotypes belonging to commonly reported Salmonella groups, suggesting that these serotypes could have a predilection for invading the urinary tract (35, 36). A better understanding of the uropathogenicity of S. Infantis can help clarify mechanisms of Salmonella UTIs (36).

S. Infantis infections were more likely than other Salmonella infections among persons from racial and ethnic minority groups, particularly NH Asian/PI. REPJFX01 infections were more likely than other Salmonella infections in the Northeast. However, S. Infantis infections among NH Asian/PI persons were less likely to be due to REPJFX01. The reasons for these associations are unknown, but may reflect differences in exposures (e.g., meat and other food consumption, food preparation, animal contact) and warrant further investigation of potential interactions between race-ethnicity and region.

There were notable findings from the unadjusted analyses of hospitalization among patients with S. Infantis and REPJFX01, although they were not significant in the multivariable analyses and need to be interpreted with caution. Patients with S. Infantis infections had a lower proportion hospitalized than that for other Salmonella infections. This could be related to S. Infantis being less likely to be isolated from blood and more likely from urine than other Salmonella infections, which include infections caused by Typhimurium and Enteritidis; strains of these two most common serotypes have been associated with multidrug resistance or invasive illness (8,38,39). Patients with REPJFX01 infections had a higher proportion hospitalized than those with non-REPJFX01 infections, suggesting that REPJFX01 can cause more severe illness than non-REPJFX01. This association could be related to the presence of virulence genes associated with pESI. Genomic analyses have shown diversity in S. Infantis subpopulations, and further research is needed to identify Salmonella genes associated with severe illness (40–43). In the multivariable analyses with hospitalization as the dependent variable, adjusted for the serotype (S. Infantis vs. other Salmonella) or strain category (REPJFX01 vs other Salmonella and vs. non-REPJFX01), the strongest predictors were blood isolation (indicating bloodstream infection or severe illness) and older age (≥65 years). Associations between these clinical predictors and hospitalization have been described in previous studies on salmonellosis (8,32,39,44). Hospitalization was not predictable from the serotype or strain category, after adjusting for other factors, including specimen source and patient’s age.

In addition to travel to South America (Ecuador and Peru), which was associated with early U.S. cases (12), travel to the Dominican Republic was reported among patients with REPJFX01 infections. This highlights the need for continued monitoring of international travel destinations that could be associated with increased risk of REPJFX01 infections.

Poultry-associated outbreaks, first reported to NORS in 2012, accounted for most S. Infantis outbreaks linked to a single food or animal category during 2012–2021 (5,11,26,45). S. Infantis was one of three serotypes classified as high burden and increased trajectory from a 2012–2021 study of Salmonella outbreaks associated with consumption of chicken and other meat (46). These findings underscore that strategies for preventing or reducing Salmonella contamination of chicken and other poultry, such as poultry vaccines and other on-farm prevention measures, could help prevent S. Infantis infections, including those caused by REPJFX01 (5,11,26,46–51). Live poultry-associated outbreaks highlight the need for strategies involving partners in human, animal, and environmental health (51,52).

Our analysis had limitations. LEDS and NORS are passive surveillance systems in 50 states and underreporting likely occurs and varies by state and year (21,45). In FoodNet, which conducts active surveillance in 10 sites, the regional differences may not be generalized to the U.S. population but were important considerations in adjusting for potential confounding in the multivariable analyses. We used S. Infantis incidence data from LEDS and FoodNet but did not make formal comparisons between changes in incidence observed in the two systems. Despite differences in population coverage and type of surveillance, incidence rates from LEDS and FoodNet appeared to align, which supports our findings of increased incidence of S. Infantis infections during the more recent period. Associations of S. Infantis and REPJFX01 infections with reported diabetes are notable but should be interpreted with caution because of high percentages of missing data. The proportions of missingness from the comparisons, S. Infantis and REPJFX01 vs. other Salmonella infections, were similar. However, there is potential for bias, particularly if the data were not missing completely at random. Collection of data on diabetes and other comorbidities in FoodNet started in 2018, and thus, we only included such data in the univariable analyses. Despite the limitations, we highlighted the findings on reported history of diabetes from the univariable analyses, which are interesting and consistent with previous studies (34–37). Further investigation to evaluate the pattern of missingness and explore methods, such as multiple imputations or sensitivity analyses, might be appropriate to better understand these associations. Inferences can be affected by the choice of time periods and estimates of significant changes between periods can reflect year-to-year variation within periods rather than sustained trends (22,53). Confidence intervals from the negative binomial models to assess changes in incidence are likely too narrow because of unaccounted sources of uncertainty (e.g., dependence between cases in large multi-year or multi-state outbreaks). That said, our findings of increased incidence of S. Infantis infections were observed in both LEDS and FoodNet and were consistent with other observations (3,4,54). Therefore, although our comparisons were subject to greater uncertainties, these findings have important public health implications. Although our methods and research questions differed from those used by Powell and Williams, which assessed coincident trends from two separate data streams, we found a similar increase in S. Infantis incidence in FoodNet sites (54). In PulseNet, completeness of WGS submissions can vary by state, sequencing was limited before 2015, and use of WGS to identify potential outbreaks started in 2019; similarly, there was variability in completeness of state reporting of PulseNet identifiers in NORS. Therefore, earlier clusters of REPJFX01 may have been difficult to detect. We did not use co-localization, contig analysis, or other supporting methods to assess the linkage of resistance genes to pESI-like plasmids, which was inferred solely on the presence of the IncFIB(pN55391) replicon. Although this approach served as a useful proxy, particularly for screening of pESI-like plasmids among S. Infantis isolates designated as REPJFX01 using the PulseNet definition (i.e., related by cgMLST within a range of 0–82 alleles), we recognize the potential for multiple plasmids to be present in a single isolate and for resistance genes to be chromosomally integrated. Given the size of this plasmid and that routine PulseNet sequencing was performed using short read data, association of specific resistance genes can be challenging, particularly at scale. In NARMS, WGS was limited in earlier years and the 1 in 20 submission scheme yielded a much smaller number of isolates (23,24). Not all S. Infantis outbreaks were captured in NORS, including two live poultry-associated outbreaks that occurred before reporting of animal contact outbreaks began in 2009 (26,51).

The proliferation of S. Infantis in U.S. poultry is likely related to the presence of pESI, conferring selective advantage—including enhanced antimicrobial resistance, resistance to disinfectants, stress tolerance, and virulence; pESI has also shown ability to conjugate into other serotypes (5,13–16,31,40–43,47). Therefore, prevention efforts in poultry production could be critical to limit not only proliferation of S. Infantis and REPJFX01 strains but also the spread of pESI to other serotypes, reports of which are concerning (16,31,47–50). Further research to characterize virulence genes in REPJFX01 isolates from human infections and chicken products, and to assess disinfectant resistance in S. Infantis strains from poultry production environments, could offer important insights into the pathogenic potential of REPJFX01 and the persistence of S. Infantis in food production settings (40–43, 47,48). Because plasmids carrying multidrug resistance may be maintained by selection pressure from use of agents for which there is resistance, judicious antimicrobial use in humans and food animal production is crucial to prevent the emergence and spread of multidrug-resistant Salmonella strains (55). As fluoroquinolone use in U.S. poultry has been prohibited since 2005, other potential drivers of REPJFX01 need to be explored, including use of antimicrobials from other drug classes, particularly those linked to high rates of resistance among REPJFX01 (e.g., aminoglycosides, sulfonamides, tetracyclines), and resistance to commonly used disinfectants in poultry production (47,48,56). Additionally, studies have shown that once resistance-conferring mutations, such as those in gyrA, are established, they can persist in bacterial populations even in the absence of selective pressure due to minimal associated fitness cost. This may help explain the continued presence of fluoroquinolone resistance in Salmonella despite the discontinued use of this drug in poultry (57). International collaboration and a One Health approach can advance the identification and implementation of strategies for addressing this food safety concern in the poultry industry (13,47–50).