Selective treatment strategies can combat antimicrobial resistance while protecting foals from R. equi

Rhodococcus equi is a hardy bacterium that lives in the soil and horse feces. It replicates in horse manure, so on densely stocked farms such as breeding operations, the environment can become heavily contaminated. When the bacterium becomes aerosolized—primarily due to environmental factors such as wind, dry conditions, and soil disturbances—foals can inhale it, potentially becoming infected.

Two forms of the bacterium exist: an avirulent form that is essentially benign for foals and another that is a virulent form. The virulent, disease-causing form has a specific genetic element called a plasmid with a gene that codes for a protein called the virulence-associated protein or VapA.

“The VapA protein enables R. equi to replicate inside immune cells in the lungs of foals, alveolar macrophages, leading to abscesses forming in the lung. This disease process is similar to what happens in tuberculosis, where the bacterium known as Mycobacterium tuberculosis is able to replicate in alveolar macrophages of humans to cause pneumonia,” explains Noah Cohen, VMD, MPH, PhD, Dipl. ACVIM, of Texas A&M University’s College of Veterinary Medicine & Biomedical Sciences, in College Station. Cohen is professor of equine internal medicine, Glenn Blodgett Chair in Equine Studies, and associate department head for research and graduate studies in the college’s Department of Large Animal Clinical Sciences.

Foals living on endemic farms are exposed to virulent R. equi from birth and can become infected at a very young age. But most foals don’t exhibit clinical signs of pneumonia until they are 1 to 3 months old or older. Signs in foals resemble what we would see in a child: fever, lethargy, and coughing.

Experts say R. equi pneumonia poses significant challenges for the equine
industry due to a number of different factors, including:

1. The high costs of prevention/treatment;
2. The economic losses associated with foal mortality in severe cases; and
3. The reduced athletic potential of recovered foals as adults.

Further, antimicrobial resistance to medications often used to treat this condition adds to the complexity of managing R. equi.

In this article we’ll review some important facts about diagnosing and treating R. equi pneumonia, address issues related to antimicrobial resistance, and describe the work underway to create a not-so-secret weapon to fight this historically indomitable bacterium: a vaccine.

Fact No. 1: R. equi infection often leads to a self-resolving subclinical (without obvious clinical signs) pneumonia that typically does not need to be treated.

Veterinarians first started using thoracic ultrasonography in 2001 to screen foals for the presence of abscesses within the lungs suggestive of R. equi pneumonia.

“Studies conducted in 2005 and 2008 indicate that thoracic ultrasound screening and treatment of subclinical cases decreased the incidence of pneumonia and decreased the number of hospitalized foals,” says Angela Bordin, MS, PhD, assistant professor in the Department of Large Animal Clinical Sciences at Texas A&M.

This led to the widespread adoption of a screen-and-treat approach, where veterinarians began treating foals with evidence of pulmonary abscesses, even if the foals showed no clinical signs of pneumonia. 

In additional studies researchers discovered the following:

Fact No 2: Thoracic ultrasound exams at farms with endemic R. equi show that often more than 50% of foals are subclinically infected.

Fact No. 3: An estimated 70-85% of subclinically infected foals heal over time without treatment.

“This information led to the realization that not all foals with lung abscesses attributed to R. equi need to be treated,” explains Cohen.

But it was too late.

The Screen-and-Treat Fallout

“Thoracic ultrasound allows us to identify foals that have a lesion/abscess in their lungs before they have clinical disease,” says Bordin. “These lesions can progress to a severe pneumonia. Given there is no vaccine available, and the variability associated with Re-HIP administration (that of R.-equi-specific hyperimmune plasma), it is understandable that thoracic ultrasound seemed an attractive way to detect and treat foals with subclinical pneumonia.”

Avoiding R. equi infection is important because of the economic and welfare implications for farms and their horses.

“But the screen-and-treat strategy came with a price,” she continues. “Antimicrobial resistance in clinical isolates of R. equi from foals was rare before 2001, but it increased significantly after thoracic ultrasound screening. To exemplify, one study documented a higher prevalence of multidrug-resistant R. equi from 2007 to 2017 compared to 1999 to 2006 (Huber, 2018). In another study multidrug-resistant R. equi were isolated from soil samples of 76 out of 100 horse-breeding farms (Huber, 2019).”

Cohen concurs, adding, “As a result of the widespread, unnecessary use of antibiotics in foals without clinical signs of pneumonia, strains of R. equi resistant to the class of antibiotics most effective for treatment of rhodococcal pneumonia in foals began to emerge.”

A Closer Look at Antimicrobial Resistance to R. equi

“Antimicrobial resistance in R. equi is primarily driven by the acquisition of plasmids, which carry resistance genes for multiple antibiotics, including macrolides, aminoglycosides, and tetracyclines,” says Laura Huber, DVM, MSc, PhD, Dipl. ACVPM, assistant professor at the College of Veterinary Medicine, Auburn University, in Alabama. “These plasmids enable horizontal gene transfer between bacteria, allowing R. equi to rapidly acquire and spread resistance within microbial communities.”

Huber explains that the accumulation of antimicrobial residues from past antibiotic use can persist in the environment for many years, creating ongoing selective pressure that helps sustain antimicrobial resistance even after antibiotic use ends. In other words, the lingering antibiotics allow bacteria possessing resistant genes to survive and reproduce while killing off susceptible bacteria, leading to a population dominated by resistant strains over time.

“Our team is investigating the potential impact of antibiotic treatments in foals on the contamination of horse farm soil with antimicrobial residues,” says Huber. “We’re specifically studying how long these residues persist in the soil and how they contribute to the maintenance and spread of antimicrobial resistance, focusing on the long-term environmental effects of antibiotic use in animal care.”

And antimicrobial resistance can spread between different bacteria and species, creating a significant risk to other animals and humans.

“Rhodococcus equi is an ideal model for the One Health concept, as it links human, animal, and environmental health,” explains Huber. “The bacterium can be transmitted from the soil to both animals and humans, illustrating the interconnectedness of environmental, animal, and human health in the spread of infectious diseases and antimicrobial resistance.”

Treat for R. equi When Needed

Despite the bleak picture as far as R. equi antimicrobial resistance, Cohen stresses the importance of recognizing sick foals.

Fact No. 4: Foals diagnosed with R. equi pneumonia should be treated.

“The challenging part for veterinarians is that we do not yet know which foals will self-cure and which will require treatment,” says Cohen.

He and other experts say vets can make an R. equi pneumonia diagnosis based on:

• Farm history of R. equi pneumonia;
• Foals 1 to 6 six months old on the farm;
• The presence of appropriate clinical signs;
• Thoracic ultrasound or X rays showing lung abscesses or consolidation (areas filled with a substance besides air);
• Blood work showing a high white cell count and elevated concentration of inflammation-associated proteins such as fibrinogen or serum amyloid A; and
• Culture and microscopic examination (cytology) of a sterilely collected aspirate from the upper respiratory tract (trachea/bronchioles) to isolate and visualize bacteria and, ideally, identification of the VapA gene by polymerase chain reaction test (PCR).

Fact No. 5: Vets should not rely solely on thoracic ultrasonography to decide which foals to treat.

Further, veterinarians should not rely solely on blood work, such as a complete blood cell count, to diagnose R. equi; it’s better to also have cytologic or PCR evidence.

Fact No. 6: Foals infected with resistant strains of R. equi have a significantly lower survival rate compared to those infected with antimicrobial-susceptible strains.

When treating foals, experts have long recommended using a combination of rifampin and the macrolides azithromycin, clarithromycin, or tulathromycin. When resistance to rifampin exists, veterinarians can use the tetracycline antibiotic doxycycline as a substitute. But are these substitutions as effective as the rifampin/azithromycin combination once was?

“There needs to be more research on that,” Bordin says.

Preventive Strategies: The Elusive Vaccine and Re-HIP Therapy

Fact No. 7: Preventing disease is preferrable to overtreating. The goal of a prevention program is to reduce clinical pneumonia cases, thereby decreasing antimicrobial use and the subsequent development of antimicrobial resistance.

Vaccination

For many infectious diseases, vaccination has proven to be an effective preventive measure, decreasing the incidence and severity of diseases. But R. equi has proven a difficult pathogen for vaccine creation.

Various factors contribute to the challenge of developing a vaccine for R. equi. For example, this is an intracellular pathogen, and we lack a clear understanding of the immunity that protects against it.

“Foals are exposed to R. equi from birth and are most susceptible to infection when they are very young,” Cohen explains. “Their immune systems are naive and immature such that many foals can’t mount effective immune responses. But we know that giving foals the virulent organism in large numbers by stomach tube provides protection against infection, so we know that they can mount protective immune responses within the first few weeks of life.”

In his most recent attempt at creating a vaccine, Cohen, together with his research team, created a messenger RNA (mRNA) vaccine that encodes the VapA protein. After delivery—injection, in this case—the vaccine produces VapA in small amounts, which stimulates the foal’s immune system to mount immune responses to virulent R. equi strains. These immune responses are innate, meaning a general defense that happens immediately, and adaptive, which is a more specific response that occurs later.

“The vaccine did not work very well when delivered via nebulization directly to the lungs,” he notes. “When we gave it intramuscularly, that seemed to stimulate immune responses.”

Cohen says additional studies are needed to further determine if this mRNA vaccine is indeed worth pursuing in foals, or if efforts should return to producing an mRNA (or other) vaccine administered to pregnant mares instead.

“Vaccinating the mares may result in the production of antibodies against VapA that can be transferred to their foals through the colostrum and milk to protect the foal during the highly vulnerable period in the first weeks of life,” says Cohen. 

R. equi-Specific Hyperimmune Plasma (Re-HIP)

Most farms with endemic R. equi rely on Re-HIP for preventing infection in young foals. These plasma products are produced from mares vaccinated against R. equi using a product designed for adult horses. Foals receive Re-HIP intravenously shortly after birth, but the mechanism of action is unclear.

Although the approach was once considered controversial as far as its efficacy, Cohen says, “The bulk of the evidence indicates protective effects of transfusing hyperimmune plasma to foals, but the protective effects are not complete and vary among plasma products, farms, and individual foals. While we need better evidence in the form of well-controlled trials to get clearer evidence, current knowledge indicates that Re-HIP is the best prevention that we have available at this time.”

Fact No. 8: Experts recommend administering 2 liters of Re-HIP that has high activity against VapA to foals within the first day of life.

This conclusion is based largely on studies conducted by Cohen’s team, including a pinnacle study by Susanne Khan in 2019 published in Equine Veterinary Education.

“I think at most endemic farms, it makes sense both medically and financially to transfuse with anti-rhodococcal plasma because there is no effective alternative for controlling R. equi pneumonia,” says Cohen.

However, he notes that the advantages of Re-HIP are not as apparent on nonendemic horse farms.

“The decision as to whether to use Re-HIP needs to be made by the farm veterinarian, farm manager, and owners of the foals to assess both the risk of the disease and their levels of risk aversion,” Cohen says. “At nonendemic farms it is less clear whether costs and risks of Re-HIP outweigh the potential benefits of preventing something that may not be present.”

Future Directions in R. equi Research

Veterinarians gained valuable insights into R. equi through routine treatment following thoracic ultrasound screening in the early 2000s (based on the work of Steeve Giguère, DVM, PhD, Dipl. ACVIM, and others). However, our sources say much more research is necessary to get ahead of this economically draining disease. Specifically, vets need effective and efficient preventive strategies, ideally in the form of a vaccine, to prevent neonatal morbidity and mortality. 

“Because of limited availability of research funding, it will take years for researchers to test their ideas surrounding mare and foal vaccines,” says Cohen. “But we are nothing if not persistent and will continue to work hard to try to investigate an approach to protect foals.”

On the antibiotic-resistance front, Huber adds, “Responsible antibiotic use can slow the spread of antimicrobial resistance.”

She says veterinarians should use ultrasound to detect R. equi early and institute more targeted management, rather than relying on the screen-and-treat program. This approach would help reduce unnecessary antibiotic use. “Developing clear guidelines that combine ultrasound findings with clinical signs is crucial to avoid overuse of antimicrobials and ensuring that antibiotics are only administered when truly necessary,” says Huber. “While these approaches can help manage antimicrobial resistance, fully reversing the damage will require broader strategies, including improved (antimicrobial) stewardship and environmental control.”