R. Equi Overtreatment Fuels Multispecies, Multidrug Resistance
Years of extensive treatment for Rhodococcus equi in potentially affected foals has apparently led to a “vicious cycle” of antimicrobial resistance in multiple pathogen (disease-causing organism) species found in horses and their environments, according to one expert.

Aiming for zero mortality, caretakers have often provided blanket antibiotic treatment to all at-risk foals identified through screening programs. But, in doing so, they might have inadvertently contributed to a perplexing and challenging issue of drug resistance in strains of R. equi, Enterococcus, and other pathogenic bacteria, said Nathan Slovis, DVM, Dipl. ACVIM, CHT, director of the McGee Center at Hagyard Equine Medical Institute, in Lexington, Kentucky.

“The widespread use of macrolides and rifampin (a class and type of antibiotic, respectively) in the horse—and really on horse farms—results in the propagation of resistance to macrolides in Rhodococcus equi, but also resistance of other fecal bacteria to many of the antimicrobials,” Slovis said during the 2021 American Association of Equine Practitioners convention, held Dec. 4-8 in Nashville, Tennessee.

R. Equi on Breeding Farms

Rhodococcus equi is a Gram-positive bacterial species that enters the cells and, for unknown reasons, resists being killed there through the normal white blood cell response. It can lead to fever, pneumonia, intestinal issues, and death in foals younger than 6 months, and most affected foals are younger than 3 months.

Mares and foals shed the bacteria in their feces, where the microbes can live in the soil before being ingested by grazing horses. From there, they replicate in the gastrointestinal tracts of foals (not in adults). Some foals become very sick when infected, but others do not, Slovis said. The reasons for that remain unclear—although researchers know the bacterial strain must at least be accompanied by the virulence-associated protein A antigens (VapA)–which has been identified as a key virulence factor of R. equi, meaning its presence is necessary to cause disease. Vaccine development has mostly been unsuccessful, so breeders have asked veterinarians to find other ways to prevent R.-equi-related deaths on their clients’ farms.

“(Breeders) said, ‘We’re losing a million dollars’ worth of foals a year; we can’t afford that,’ or they’ve got that valuable foal that’s once in a lifetime, and they lose it,” Slovis said. “And now they’re like, ‘I don’t care what the cost is … I want zero mortality.’ But what are we going to do for that?”

In the early 2000s veterinarians tried using ultrasonographic screening. At their direction, caretakers started running systematic pulmonary (lung) ultrasound examinations on all young foals on a breeding farm. Any foal found with lesions that might suggest R. equi would receive antibiotic treatment with macrolides and rifampin.

The method worked, said Slovis. R. equi pneumonia was practically eliminated. “We were giving each other high-fives because we’d found the way; we knew how to stop mortality,” he said. “We thought we had this.”

The Rise of Resistomes

Within a few years, however, caretakers started seeing foals getting sick and not responding to treatment. “This was kind of alarming,” he said. “We were wondering, ‘Boy, is this screening causing problems?’ ”

A few years later, study results suggested more than 75% of soil samples from 100 tested breeding farms contained R. equi resistant to macrolides and/or rifampin—with 97.7% of those resistant to both. More studies revealed the resistance wasn’t just limited to the soil: Scientists found it in isolates in flooring and the air, as well. Further research indicated resistance was related to a specific gene in the bacteria—termed a “resistome”—and that the blanket antibiotic treatments were altering the animals’ gut microbiota. Treatment was increasing antimicrobial resistance in not only the target bacteria—R. equi—but also multiple other bacterial species on the farm, such as Enterococcus.

“This is a bug that we’re not even trying to kill, and we’re getting resistance to doxycycline—and we’re not even treating with doxycycline!” Slovis said.

The researchers concluded that overtreatment with macrolides and rifampin as part of the lung-screening program was leading to the spread of resistomes (an inherited set of genes related to resistance) conferring resistance to multiple kinds of antimicrobials in multiple species of pathogenic bacteria, Slovis said.

This unintended effect resulted from a genuine and understandable effort by veterinarians to respond to their clients’ needs and save the lives of more foals, he explained.

“What do the farms want?” Slovis said. “They don’t want to see any deaths. So we’re nervous, and what do we do? We overtreat. We see a small little lesion in that lung, and we treat it. We know that 99% of those subclinical cases of Rhodococcus equi would get better on their own. But we as veterinarians—same as with medical doctors—we’re afraid and don’t want to make any mistakes. We don’t want to have a client come up to us at a party saying, ‘Hey, remember that foal you looked at last week? Well, he’s dead.’ We want to do what’s right.”

“What’s right” has become a greater challenge, balancing the risks to an individual foal with the risks of losing antimicrobials’ power against pathogens across breeding farms, said Slovis.

Fortunately, when antimicrobial treatments stop, antimicrobial resistance starts dropping in the R. equi strains on the farm within a matter of weeks, he said.

“The goal (now) is prevention,” Slovis said. “And antimicrobial stewardship is something we need to be definitely thinking about.”