A group of researchers estimates that infections from antibiotic-resistant strains of non-typhoidal Salmonella have increased 40 percent, based on statistics from 2004-2008 compared with numbers from 2015-2016.

“Clinically important resistance” to ampicillin or ceftriaxone or nonsusceptibility to ciprofloxacin were found while examining an estimated 220,000 infections in 2015-2016 compared with an estimated 159,000 infections in 2004-2008, according to the researchers’ report published in the journal Emerging Infectious Diseases.

“Salmonella is a major cause of foodborne illness in the United States, and antimicrobial-resistant strains pose a serious threat to public health,” the team of scientists wrote.

“Extrapolating to the United States population and accounting for unreported infections, we estimated a 40 percent increase in the annual incidence of infections with clinically important resistance — resistance to ampicillin or ceftriaxone or nonsusceptibility to ciprofloxacin,” according to the journal report.

The researchers were led by Felicita Medalla, an epidemiologist with the National Center for Emerging and Zoonotic Infectious Diseases in the Division of Foodborne, Waterborne, and Environmental Diseases at the U.S. Centers for Disease Control and Prevention. Her research interests include antimicrobial resistance in Salmonella and other foodborne and enteric pathogens.  

From 2004 to 2016, public health laboratories of state and participating local health departments in the 48 contiguous states reported 539,862 culture-confirmed Salmonella infections to Laboratory-based Enteric Disease Surveillance (LEDS). Among the isolates from these Salmonella infections, 89 percent were serotyped. The most common were Enteritidis at 20 percent, Typhimurium at 16 percent, Newport at 11 percent, I 4,[5],12:i:- at 4 percent, and Heidelberg at 4 percent. 

Public health laboratories in the 48 states submitted 28,265 isolates to the National Antimicrobial Resistance Monitoring System (NARMS). Of these isolates, 98 percent were serotyped; the most common were Salmonella Enteritidis at 19 percent, Typhimurium at 16 percent, Newport at 11 percent, I 4,[5],12:i:- at 4 percent, and Heidelberg at 4 percent.

“Changes in the incidence of resistance varied by serotype. Serotypes I 4,[5],12:i:- and Enteritidis were responsible for two-thirds of the increased incidence of clinically important resistance during 2015-2016. Ciprofloxacin-nonsusceptible infections accounted for more than half of the increase. These estimates can help in setting targets and priorities for prevention,” according to the research report.

The increased incidence of ciprofloxacin-nonsusceptible Salmonella infections during 2015 to 2016 compared with incidence for both 2004 to 2008 and 2010 to 2014 is a concerning trend, the researchers said. Serotype Enteritidis contributed the most to this increase. 

Although the incidence of infections with Enteritidis, the most common serotype, has not changed significantly in more than10 years, the percentage of ciprofloxacin-nonsusceptible infections has increased almost steadily. Chicken and eggs have been the main domestic sources of Enteritidis infections. about 20 percent of Enteritidis infections are linked to international travel.

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. Some have been associated with resistance, invasive illness, or both.

Regional considerations

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 regions, with highest increases 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. The regional pattern of pork consumption has reflected the regional pattern of pork production, which is highest in the Midwest. Eight of the 10 states with the highest production of swine are in the Midwest. 

A study showed that multi-drug resistant 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 elsewher. These strains harbored plasmid-mediated resistance genes, which can be transmitted horizontally to other bacteria. 

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 three U.S. 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 U.S. travelers during 2015-2016. In the United Kingdom, an increase in these infections has been linked to international travel and imported foods, according to the report. In the United States, ciprofloxacin-nonsusceptible strains of Salmonella Enteritidis and other serotypes have been isolated from imported seafood.

“Our estimates of significant changes were limited to comparisons with the reference periods used to assess changes in resistance percentages in NARMS annual reports,” the scientists wrote. 

“Our choice to compare a recent two-year period with earlier five-year periods balanced the need to assess the most current situation with the need for sufficient data to assess significant changes.” 

The researchers said the fact that some ciprofloxacin nonsusceptible infections were not included in the ciprofloxacin nonsusceptible category further supports the finding that ciprofloxacin-nonsusceptible infections increased during the study period. They say the increasing use of culture-independent diagnostic tests by clinical laboratories can change the submission of isolates to public health laboratories and reporting of infections. These changes warrant adjustments in future analyses.

Methodology

The researchers 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. Thus, according to the report, the appropriate multiplier — the ratio of total infections to culture-confirmed infections — for resistant infections might be less than 29. To calculate undiagnosed Salmonella infections, multipliers of 12 for persons younger than 5 years of age and 23 for persons 65 years and older have been reported. 

Although children younger than 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, researchers said. 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 and because persons 5 to 64 years of age account for most culture-confirmed infections reported to CDC and most isolates with clinically important resistance submitted to NARMS,” the research report says. 

“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.”

The research team pursued the project partly because 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, they say. 

In the future, 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, according to the scientists. Antimicrobial agents contribute to resistance wherver they are used, including in food animals and humans. 

“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,” the researchers concluded

In addition to the CDC’s Medalla, researchers included Weidong Gu, Cindy R. Friedman, Michael Judd, Jason Folster, Patricia M. Griffin, and Robert M. Hoekstra.