Consensus Statements of the American College of Veterinary Internal Medicine (ACVIM) provide the veterinary community with up-to-date information on the pathophysiology, diagnosis, and treatment of clinically important animal diseases. The ACVIM Board of Regents oversees selection of relevant topics, identification of panel members with the expertise to draft the statements, and other aspects of assuring the integrity of the process. The statements are derived from evidence-based medicine whenever possible and the panel offers interpretive comments when such evidence is inadequate or contradictory. A draft is prepared by the panel, followed by solicitation of input by the ACVIM membership which may be incorporated into the statement. It is then submitted to the Journal of Veterinary Internal Medicine, where it is edited prior to publication. The authors are solely responsible for the content of the statements.
Diagnosis, Treatment, Control, and Prevention of Infections Caused by Rhodococcus equi in Foals
Version of Record online: 1 NOV 2011
Copyright © 2011 by the American College of Veterinary Internal Medicine
Journal of Veterinary Internal Medicine
Volume 25, Issue 6, pages 1209–1220, November-December 2011
How to Cite
Giguère, S., Cohen, N.D., Keith Chaffin, M., Slovis, N.M., Hondalus, M.K., Hines, S.A. and Prescott, J.F. (2011), Diagnosis, Treatment, Control, and Prevention of Infections Caused by Rhodococcus equi in Foals. Journal of Veterinary Internal Medicine, 25: 1209–1220. doi: 10.1111/j.1939-1676.2011.00835.x
- Issue online: 16 NOV 2011
- Version of Record online: 1 NOV 2011
- Manuscript Accepted: 4 OCT 2011
- Manuscript Received: 22 SEP 2011
- Manuscript Revised: 22 SEP 2011
- Bacterial species;
- Infectious diseases;
- Parenchymal disease;
- Respiratory tract
Rhodococcus equi, a Gram-positive facultative intracellular pathogen, is one of the most common causes of pneumonia in foals. Although R. equi can be cultured from the environment of virtually all horse farms, the clinical disease in foals is endemic at some farms, sporadic at others, and unrecognized at many. On farms where the disease is endemic, costs associated with morbidity and mortality attributable to R. equi may be very high. The purpose of this consensus statement is to provide recommendations regarding the diagnosis, treatment, control, and prevention of infections caused by R. equi in foals.
minimum inhibitory concentration
polymerase chain reaction
pulmonary epithelial lining fluid
Pneumonia is a major cause of disease and death in foals. Rhodococcus equi, a Gram-positive facultative intracellular pathogen, is one of the most common causes of pneumonia in foals. Although R. equi can be cultured from the environment of virtually all horse farms, the clinical disease in foals is endemic at some farms, sporadic at others, and unrecognized at many. On farms where the disease is endemic, costs associated with morbidity and mortality may be very high. The purpose of this consensus statement is to provide recommendations regarding the diagnosis, treatment, control, and prevention of infections caused by R. equi in foals. The level of evidence for a given recommendation was subjectively characterized as strong, moderate, or weak. Strong evidence indicates that a given recommendation is supported by controlled prospective studies, or extensive experimental and observational studies yielding consistent, coherent results. Moderate evidence indicates that a recommendation is based on clinicopathologic data and retrospective case series, or that controlled prospective studies have given conflicting results. Weak evidence indicates that the recommendation is based on uncontrolled studies. Background information about the clinical manifestations, pathogenesis, virulence, and immunity to R. equi is provided in a companion review article.
The definitive diagnosis of bronchopneumonia caused by R. equi should be based on bacteriologic culture or amplification of the vapA gene (hereafter vapA) using polymerase chain reaction (PCR) from a tracheobronchial aspirate (TBA) obtained from a foal with one or more of the following: (1) clinical signs of lower respiratory tract disease; (2) cytological evidence of septic airway inflammation; or (3) radiographic or ultrasonographic evidence of bronchopneumonia. Amplification of vapA using PCR may be done in conjunction with, but should not replace, bacterial culture, because it does not permit identification of other bacterial pathogens and in vitro antimicrobial susceptibility testing of R. equi isolates. The level of evidence for this recommendation is strong.
The definitive diagnosis of extrapulmonary infections (eg, abdominal abscess, osteomyelitis) caused by R. equi must rely on bacteriologic culture or PCR amplification of vapA from samples from the site of infection. The diagnosis of extrapulmonary disorders from sites at which R. equi cannot be detected (eg, uveitis or polysynovitis) should be based on isolation of R. equi from a TBA or other primary sites of infection. The diagnosis of enterocolitis caused by R. equi is problematic because isolation of R. equi from feces cannot be taken as evidence of enterocolitis caused by R. equi. The level of evidence for these recommendations is strong.
Differentiating between lower respiratory tract infections caused by R. equi and those caused by other pathogens is problematic, especially at farms without previous history of R. equi infections. Diagnostic tests, including white blood cell concentration (WBC), measurement of fibrinogen concentrations, ultrasonography, and radiography, may help raise the degree of suspicion that pneumonia in a given foal may be caused by R. equi rather than by another microorganism. In 1 study, WBC >20,000 cells/μL, fibrinogen concentration >700 mg/dL, and evidence of pulmonary abscessation were more likely to be found in foals with pneumonia caused by R. equi than in foals with pneumonia caused by other bacteria. However, there is a considerable overlap in distributions, which precludes the use of fibrinogen concentrations and WBC for diagnosis or prognosis for an individual foal.[1, 2]
Thoracic radiography and ultrasonography are useful in evaluating the severity of pneumonia and response to treatment. Ultrasonographic or radiographic detection of lung abscesses raises the degree of suspicion that pneumonia in a given foal is caused by R. equi. However, detection of pulmonary abscesses, although commonly used as a screening test (see below), is not a definitive diagnostic test.
Independent studies evaluating the performance of serological tests available for diagnosis of infection caused by R. equi at endemic farms have demonstrated these tests either have low sensitivity, low specificity, or both.[3-6] Improving either sensitivity or specificity of ELISA assays by changing the cut-off value of the tests could only be done to the detriment of the other. The presence of antibodies indicates exposure, subclinical infection, or maternal transfer of antibodies, but it does not necessarily indicate infection leading to clinical disease. The current state of knowledge precludes serology to be used as a diagnostic test for R. equi pneumonia.
Bacteriologic culture or PCR amplification of vapA from a tracheobronchial aspirate (TBA) is therefore the only acceptable ways of establishing a diagnosis of R. equi pneumonia. In 1 study, only 7 (64%) of the 11 foals with positive R. equi culture at necropsy, and 57 (64%) of the 89 foals with radiographic evidence of lung abscessation, yielded R. equi from culture of a TBA. However, in 2 other studies, all 17 foals in which R. equi was isolated from lung parenchyma at necropsy yielded the organism from culture of TBAs obtained antemortem, suggesting that culture of a TBA is a valid method for diagnosing R. equi pneumonia.[2, 8] Larger case series are required to more accurately estimate the sensitivity of TBA culture for diagnosis of R. equi pneumonia in foals. Specificity of the test must also be considered. Multiple other pathogens are often isolated concurrently with R. equi. Foals without clinical disease may have R. equi in their trachea as a result of subclinical disease or from inhaling R. equi in contaminated environments. At a farm with endemic R. equi pneumonia, 77 of 216 (35%) foals sampled had positive TBA cultures, but remained free of clinical signs of respiratory disease throughout the season. For this reason, culture or PCR amplification of R. equi from a TBA should be interpreted in the context of cytological and clinical findings. Detection of R. equi from a foal without clinical signs of respiratory disease, cytological evidence of septic airway inflammation, or ultrasonographic or radiographic evidence of pulmonary lesions is probably an incidental finding. Amplification of vapA using PCR has been shown to be more sensitive than bacterial culture in most, but not all studies.[10-12] However, increased sensitivity may also result in a higher incidence of false-positive results because of the detection of very small numbers of R. equi present as environmental contaminants. Moreover, culture offers the advantage of detecting other bacterial pathogens present, and permits in vitro susceptibility testing of recovered pathogens. As a result, PCR amplification of vapA may be done in conjunction with, but should not replace, bacterial culture. The use of PCR assays based on genes other than vapA is not recommended, as these assays would also detect environmental isolates lacking the virulence plasmid which are not known to cause disease in foals.
Isolation of R. equi from nasal or fecal swabs cannot be taken as evidence of disease because of infection with R. equi. Rhodococcus equi can be cultured from the feces of healthy horses even if they live at farms without history of R. equi pneumonia.[13-15] Quantitative culture of the feces of foals at weekly intervals has been advocated to aid in early diagnosis of R. equi infections, because the fecal concentration of R. equi increased at the same time as clinical signs of respiratory disease appeared in a few foals. However, a single fecal sample from a foal has no diagnostic value because of individual and farm-to-farm variation in the number of R. equi in feces.[13-15] Furthermore, a negative fecal culture may not be helpful in excluding R. equi infection, because only 5 (17%) of 30 foals with confirmed R. equi pneumonia had positive fecal cultures. Similarly, bacterial culture and PCR amplification of nasal swabs are insensitive for diagnosis of R. equi pneumonia.[10, 11, 16]
The combination of a macrolide (erythromycin, azithromycin, or clarithromycin) with rifampin is the recommended treatment for infection caused by R. equi, based on in vitro activity data, pharmacokinetic studies, and retrospective studies. The level of evidence for this recommendation is moderate, with no randomized controlled studies available to substantiate it.
Although evidence exists that foals infected with macrolide- and rifampin-resistant isolates of R. equi might have a worse prognosis than foals infected with susceptible isolates, there is currently inadequate evidence to recommend a specific drug for the treatment of foals infected with resistant isolates.
A wide variety of antimicrobial agents are active against R. equi in vitro. However, many of these drugs are reported to be ineffective in vivo, probably because of poor cellular uptake and resulting low intracellular concentrations. For example, in a retrospective study, all 17 foals with R. equi pneumonia treated with the combination of penicillin and gentamicin died despite the fact that all isolates were sensitive to gentamicin. The combination of rifampin and erythromycin became the treatment of choice in the 1980s and has apparently reduced foal mortality relative to historical data.[7, 18] However, there are no controlled studies directly comparing the efficacy of erythromycin and rifampin to that of other antimicrobial agents. In recent years, clarithromycin or azithromycin, both newer-generation macrolides, often replace erythromycin in the combination with rifampin. Macrolides and rifampin are highly active against R. equi in vitro, but only exert bacteriostatic activity. As a result, macrolides exert time-dependent activity against R. equi in vitro. The minimum concentration at which 90% of R. equi isolates are inhibited (MIC90) is 0.12, 0.25, and 1.0 μg/mL, for clarithromycin, erythromycin, and azithromycin, respectively. The combination of a macrolide and rifampin is synergistic both in vitro and in vivo, and the use of the 2 classes of drugs in combination reduces the likelihood of R. equi resistance to either drug.[20, 22]
The recommended dosage for rifampin is 5 mg/kg q12 h, orally. The recommended dosages for macrolides are listed in Table 1. Several formulations of erythromycin are commercially available. Although each formulation shows slight differences in bioavailability and elimination, they all result in therapeutic concentrations at recommended dosages. However, the bioavailability of erythromycin in foals is lower when foals are not fasted (mean ± SD: 26 ± 15% when fasted and 8 ± 7% when fed). Advantages of azithromycin and clarithromycin over erythromycin in foals include considerably enhanced oral bioavailabilities especially in the absence of fasting, prolonged half-lives, and much higher concentrations in pulmonary epithelial lining fluid (PELF) and bronchoalveolar cells (Table 1).[25-28] These properties of the newer-generation macrolides contribute to their lower dosages and longer dosing intervals.
|Recommended oral dosage (mg/kg)||25q 6–8 h||7.5 q12 h||10 q24–48a|
|MIC90 of R. equi isolates (μg/mL)b||0.25||0.12||1.00|
|Oral bioavailability (%)||25 ± 15c–8 ± 7d||57 ± 12d||54 ± 23d|
|Single oral dose (10 mg/kg; fasted)|
|Cmax plasma (μg/mL)||0.80 ± 0.74||0.94 ± 0.31||0.83 ± 0.19|
|Cmax PELF (μg/mL)||ND||48.96 ± 13.26||10.00 ± 7.46|
|Cmax BAL cells (μg/mL)||1.02 ± 1.11||74.20 ± 45.80||49.92 ± 26.94|
|t1/2 plasma (h)||2.2 ± 2.6||4.0 ± 2.1||25.7 ± 15.4|
|t1/2 PELF (h)||ND||8.6 ± 4.2||34.8 ± 30.9|
|t1/2 BAL cells (h)||ND||10.7 ± 7.1||54.4 ± 17.5|
|Steady state at recommended dosages (fed)|
|Cmax plasma (μg/mL)||0.38 ± 0.32||0.88 ± 0.19||0.63 ± 0.10|
|Cmax PELF (μg/mL)||NA||76.23 ± 59.43||11.51 ± 12.67|
|Cmax BAL cells (μg/mL)||NA||269.00 ± 232.24||89.68 ± 44.25|
In general, plasma concentrations of macrolides in humans and cattle are considerably lower than the MIC of the pathogens against which these drugs have been proven to be effective. Thus, plasma concentrations of macrolides are considered poor predictors of in vivo efficacy against respiratory pathogens, whereas drug concentrations at the site of infection provide more clinically relevant information. Measurement of drug concentration in PELF and cells collected by bronchoalveolar lavage is a widely used method to estimate antimicrobial concentrations at the site of infection for antimicrobials intended to treat lower respiratory tract infections in humans.[29, 30] Concentrations of clarithromycin in PELF and bronchoalveolar cells of foals are considerably higher than concentrations reported after administration of azithromycin or erythromycin to foals (Table 1).[26-28] However, clarithromycin concentrations at these sites decrease rapidly, whereas the release of azithromycin from cells is much slower, resulting in sustained concentrations of azithromycin in tissues for days after discontinuation of treatment. There are no data from randomized prospective studies comparing the relative efficacy of erythromycin, clarithromycin, and azithromycin in pneumonic foals. In a retrospective study, the combination clarithromycin-rifampin was significantly more effective than erythromycin-rifampin or azithromycin-rifampin, especially in foals with severe radiographic lesions. However, these results must be interpreted with caution, because foals were not randomly distributed to treatment groups and because of biases from retrospective data. Nevertheless, these data are the best available evidence to guide macrolide selection in foals with R. equi pneumonia. Recent studies demonstrate that concurrent treatment with rifampin considerably decreases plasma, PELF, and bronchoalveolar cell concentrations of clarithromycin and potentially other macrolides.[31, 32] However, there are no studies in foals comparing the clinical efficacy of the combination of a macrolide with rifampin to a macrolide alone. Until it is documented that a macrolide alone is as effective as the combination with rifampin, the combination of a macrolide (erythromycin, azithromycin, or clarithromycin) with rifampin remains the recommended treatment.
Resolution of clinical signs, normalization of plasma fibrinogen concentrations, and radiographic or ultrasonographic resolution of lung lesions are commonly used to guide the duration of treatment that generally ranges between 3 and 12 weeks, depending on the severity of the initial lesions and response to treatment. Foals treated based on subclinical lesions identified during ultrasonographic screening typically do not require as long a treatment period as foals in respiratory distress with severe pulmonary lesions. As addressed below, many foals with subclinical ultrasonographic lesions clear the infection without treatment. Currently, there are no validated criteria to differentiate foals with subclinical ultrasonographic lesions that will clear the infection from those that will progress to clinical disease.
Although well tolerated by most foals, the combination of erythromycin, clarithromycin, or azithromycin with rifampin commonly causes diarrhea. Often, the diarrhea is self-limiting and does not necessitate cessation of treatment; however, affected foals should be monitored carefully, because some may develop severe diarrhea, leading to dehydration and electrolyte loss that necessitate intensive fluid therapy and cessation of oral macrolides. The incidence of diarrhea in foals treated with erythromycin-rifampin has ranged between 17 and 36%.[19, 34] During periods of very hot or humid weather, an idiosyncratic reaction characterized by severe hyperthermia and tachypnea has been described in foals treated with erythromycin. Anecdotal reports suggest that these reactions may also occasionally occur with newer macrolides. Severe enterocolitis has also been reported in mares whose foals are treated with erythromycin, presumably by disrupting the mare's normal colonic microflora after ingestion of small amounts of active drug during coprophagia or by contamination of feeders or water buckets with drug present on the foal's muzzle. This complication seems to be rare. Enterocolitis in mares has been reproduced experimentally by administration of subtherapeutic doses of erythromycin. In some cases, the severe enterocolitis in the mares of treated foals is associated with Clostridium difficile.
Availability of a long-acting macrolide antimicrobial agent providing sustained therapeutic concentrations at the site of infection would result in less frequent administration, which in turn might improve compliance. Tulathromycin, a semisynthetic macrolide approved for use in swine and cattle, has been shown to concentrate in the bronchoalveolar cells of foals after intramuscular administration. Tulathromycin was recently compared with azithromycin-rifampin for the treatment of foals with subclinical pneumonia, as identified using ultrasonographic screening on a farm with a high cumulative incidence of R. equi infections. Although differences in survival were not statistically significant, pulmonary abscesses, 1 week after initiation of treatment with tulathromycin, were significantly larger, and duration of treatment was significantly longer, indicating that tulathromycin is not as effective as standard treatment with azithromycin–rifampin. These results might be explained by the fact that tulathromycin is poorly active against R. equi in vitro with a MIC90 > 64 μg/mL. This concentration is more than 100-fold higher than achievable tulathromycin concentrations in bronchoalveolar cells after intramuscular administration at the recommended dose of 2.5 mg/kg. Tilmicosin, another long-acting macrolide approved for use in swine and cattle, is also poorly active against R. equi (MIC90 of 32 μg/mL), and administration to foals sometimes results in swelling at the site of injection. As a result, tulathromycin and tilmicosin are not recommended for use in foals with pneumonia caused by R. equi. In contrast, gamithromycin, a long-acting macrolide approved for the treatment and prevention of respiratory disease in nonlactating cattle, is active against R. equi in vitro (MIC90 = 1.0 μg/mL). Intramuscular administration of gamithromycin at a dosage of 6 mg/kg maintains bronchoalveolar cell concentrations above the MIC90 for R. equi for approximately 7 days. However, treatment with gamithromycin is not recommended until the clinical efficacy and the safety of the drug have been established.
Treatment of foals infected with macrolide- and rifampin-resistant isolates or treatment of foals with adverse reactions to the combination macrolide–rifampin
Although the vast majority of R. equi isolates from foals are highly susceptible to macrolides and rifampin, strains resistant to either drug class have been encountered. Rifampin should not be used alone, because this increases the chance of resistance developing,[20, 41] as a result of mutations in the RNA polymerase β subunit encoded by the rpoB gene.[42, 43] Progressive development of resistance to both erythromycin and rifampin during treatment is extremely rare, but has been reported. In a recent study, the overall prevalence of resistant isolates in Texas and Florida over a 10-year-period was 4%.In the same study, the odds of death were 7 times higher in foals infected with resistant isolates. In addition, the study demonstrated that isolates of R. equi susceptible to macrolides were sometimes misclassified as resistant; therefore, it is reasonable to request retesting/validation of resistance by the testing laboratory. The molecular mechanisms of macrolide resistance of R. equi isolates have not been determined, but R. equi isolates resistant to erythromycin, clarithromycin, or azithromycin are almost invariably resistant to the other 2 macrolides.
Treatment of foals developing severe diarrhea during macrolide treatment, or treatment of foals infected with resistant isolates, is problematic because of the limited range of effective alternatives. Macrolide- and rifampin-resistant isolates of R. equi are susceptible in vitro to fluoroquinolones, aminoglycosides, oxazolidinones, and glycopeptide antimicrobials.[17, 39] In 1 study, 18 of 24 isolates were also susceptible to chloramphenicol, tetracycline, and trimethoprim-sulfamethoxazole. Currently, there are no data to indicate the preferred antimicrobial agent(s) for the treatment of foals infected with isolates resistant to macrolides and rifampin.
Although objective data regarding efficacy are lacking, several other classes of antimicrobial agents have been used to treat R. equi in foals. Oral doxycycline in combination with rifampin has been used with anecdotal success to treat foals with pneumonia caused by R. equi. The recommended dosage for doxycycline in foals is 10 mg/kg q12 h orally. This dosage results in serum, pulmonary epithelial lining fluid, and bronchoalveolar cell concentrations above the MIC90 of R. equi isolates (1.0 μg/mL) for the entire dosing interval. Chloramphenicol can be administered orally and achieves high concentrations within phagocytic cells in other species. The recommended dosage regimen is 50 mg/kg q6 h orally. However, the fact that only 70% of R. equi isolates are susceptible to this drug and the potential human health risk make this drug a less attractive alternative. High doses of a trimethoprim-sulfonamide combination (30 mg/kg of combination q8 or 12 h, orally) have been used alone or in combination with rifampin in foals with mild or early R. equi pneumonia, or for continued treatment in foals responding well to other antimicrobials. Currently, there are insufficient data to recommend the use of these antimicrobial agents for treating infections caused by R. equi.
Nursing care, provision of adequate nutrition and hydration, and maintaining the foal in a cool and well-ventilated environment are important. Humidified oxygen delivered by pharyngeal insufflation in moderately hypoxemic foals, or by percutaneous transtracheal oxygenation in severely hypoxemic patients, is indicated. Judicious use of nonsteroidal anti-inflammatory drugs might reduce fever and improve attitude and appetite in febrile, lethargic, anorectic foals. Nebulization with saline, antimicrobial agents, or bronchodilators has been advocated but there are no data to either support or refute these therapeutic practices. Immune-mediated extrapulmonary disorders such as polysynovitis generally resolve with successful treatment of the accompanying pneumonia. Exercise should be limited but not eliminated in foals with polysynovitis. In addition to appropriate systemic antimicrobial treatment, foals with R. equi septic arthritis or osteomyelitis often require aggressive local treatment such as joint lavage, surgical debridement, and IV or intraosseous regional limb perfusion with antimicrobial agents. The prognosis for foals with abdominal abscesses is poor, although rare cases will respond to long-term antimicrobial treatment.[47, 48] Surgical removal or marsupialization has been attempted in some foals, but abdominal adhesions usually result in inability to resect the abscess.
Before the introduction of the combination of erythromycin and rifampin as the treatment of choice in the early 1980s, the prognosis of R. equi infected foals was poor with survival rates as low as 20%. Using erythromycin and rifampin, Hillidge reported a successful outcome (as assessed by survival) in 50 (88%) of 57 foals with confirmed R. equi pneumonia. Studies from referral centers, where severely affected cases are probably more prevalent, have revealed survival proportions ranging between 59 and 72%.[19, 50, 51] In contrast, the survival rate at farms using a screening program to identify and treat foals with subclinical lesions has resulted in survival proportions of nearly 100%.[52, 53] It is likely, however, that many of these foals would have recovered without treatment.
The impact of R. equi infections on future athletic performance has been examined. No significant differences in total earnings, average earning index, and age at the 1st race were observed when comparing 30 horses that previously had R. equi pneumonia with either their dams’ other progeny or the North American averages. More recently, 54% of 83 foals (N = 45) that survived R. equi pneumonia had at least 1 racing start when compared with 65% of their birth cohort, suggesting that horses contracting R. equi pneumonia as foals may be somewhat less likely to race as adults. However, consistent with a previous report, the racing performance of those foals that raced was not different from that of the US racing population. In summary, prognosis for performance after successful treatment of uncomplicated R. equi pneumonia should be regarded as excellent.
Control and Prevention
Methods for control and prevention include using screening tests for early detection of R. equi pneumonia, environmental management, chemoprophylaxis, and prevention using either passive or active immunization.
Implementing some form of screening for early identification is recommended for controlling R. equi pneumonia at farms with recurrent history of foals affected by this disease. The level of evidence for this recommendation is relatively weak, with no controlled studies available to substantiate it.
Pneumonia caused by R. equi is an insidious disease in which clinical signs may not be apparent until pathologic changes are well progressed.[55, 56] Consequently, the rationale for screening is the supposition that detecting foals in the early stages of disease will improve therapeutic outcomes, because evidence exists that advanced progression of disease is associated with poorer prognosis. Controlled studies documenting reduction in mortality attributable to R. equi pneumonia after screening, are lacking. In the authors’ experience, the apparent incidence (morbidity) will generally be increased by screening testing whenever positive screening test results are considered presumptively diagnostic. The reason that positive screening results are often interpreted as presumptively diagnostic is because the predictive value of positive results of screening tests at endemic farms is considered to be high. Moreover, substantiating the cause of pneumonia by isolating virulent R. equi from fluid obtained by tracheobronchial aspiration is eschewed by many practicing veterinarians at breeding farms because of risks of the procedure posed to foals, costs for the procedure, the aforementioned presumed high positive predictive value of test results, and because false-negative test results may be more likely in early stages of disease. Subclinical disease has been described after both experimental and natural infection.[9, 57] In general, the cumulative incidence of clinical signs of pneumonia attributed to R. equi at affected farms in the United States has been approximately 10–20% from birth to weaning (although many farms may experience greater cumulative incidences).[58, 59] In contrast, the cumulative incidence at R. equi-endemic farms of foals with sonographic evidence of pulmonary abscessation or consolidation is generally between 30 and 60%, in the authors’ anecdotal experience. The finding that cumulative incidences of clinical disease tend to be lower than those described anecdotally for sonographically detectable lesions indicates that many pre/subclinically affected foals may resolve without intervention. Because it remains unknown what proportion or which specific foals might recover spontaneously from subclinical disease, and because R. equi infections can cause severe disease, many breeding farms elect to treat all foals with positive results of screening tests. Uncontrolled studies suggest that screening may reduce the mortality attributable to R. equi pneumonia.[53, 60] Thus, in the absence of a vaccine or other effective methods for preventing this devastating disease, screening is recommended to control R. equi at endemic farms. Implementing screening testing at farms that are only sporadically affected by R. equi pneumonia may not be warranted.
A variety of screening techniques performed serially have been described, including visual inspection of foals, monitoring rectal temperatures, clinical signs of pneumonia or extrapulmonary disorders, hematologic parameters, serology, and thoracic imaging using either radiography or ultrasonography, with the empiric recommendation that screening begin around 3 weeks of age. To the authors’ knowledge, systematic comparisons among these tests have not been performed. Thus, a specific recommendation for any particular screening test cannot be made, and it is likely that the optimal approach for screening may vary among farms on the basis of cumulative incidence of disease, resources available for control and prevention, and preferences of the attending veterinarian(s) and farm management.
Some tests appear to be ineffective for screening. Current knowledge indicates that serum concentrations of either antibodies against R. equi, serum amyloid A, or plasma fibrinogen do not appear to be useful screening tests[4, 6, 62]; further evaluation of serum amyloid A with newer methods of detection and more frequent sampling may be warranted.
White blood cell concentrations performed at monthly intervals appeared to have clinically acceptable sensitivity and specificity for early detection of R. equi pneumonia at 1 farm (viz, sensitivity of approximately 79% and specificity of 91% at a cut-off value of 15,000 cells/μL). The principal limitations of using WBC for screening are the time and effort required to collect blood samples from foals, the lag from time of submission, and the potential for false-positive results attributable to other infectious or inflammatory conditions that may be common among foals or stress-associated leukocytosis.
To the authors’ knowledge, use of ultrasonography for screening to detect R. equi pneumonia has not been systematically evaluated. As a result of the various advantages and limitations associated with this approach to screening, it has both proponents and opponents. Advantages of thoracic ultrasonography include (1) the procedure can be performed relatively quickly for an individual foal; (2) competence with the procedure can be rapidly developed; (3) results are immediately available; (4) the procedure may be more sensitive than radiography for detecting lesions in their early stages of development or in certain regions where soft tissue structures are superimposed over regions of the lung; (5) results are specific for the presence of pulmonary pathology (as contrasted with, for example, results of WBC); and (6) evidence from uncontrolled studies that mortality attributable to R. equi was eradicated using ultrasonographic screening. Disadvantages of ultrasonographic screening include the costs to the farm for repetitive sonographic examinations, the increased labor needed to handle foals repetitively, and an increased number of foals treated for presumptive R. equi pneumonia as a result of the aforementioned apparent increase in cumulative incidence. A consequence of any screening program that results in a greater numbers of foals being treated for presumptive R. equi pneumonia is that it will lead to higher costs to the farm/foal-owners, increased risk of adverse events associated with treatment, and further development of resistance to macrolides. Despite the limitations of screening methods, it is the authors’ belief that, in the absence of a highly effective method for prevention such as a vaccine, diligent application of screening tests in foals for earlier detection of disease is an important tool for controlling R. equi pneumonia at farms where it is endemic.
It remains unclear whether treatment of all subclinically affected foals is appropriate. A recent controlled clinical trial at an endemic farm demonstrated that many foals with subclinical pulmonary lesions recover without treatment, and that treatment of foals having subclinical pulmonary lesions with azithromycin-rifampin did not accelerate recovery compared with a placebo. These results indicate that mass antimicrobial treatment of all foals with small subclinical pulmonary abscesses was unnecessary at that farm. The extent to which these results may be extrapolated to other farms remains unknown because the proportion of foals that recover without treatment may vary by farm, geographic region, and age at which foals lesions are detected. Additional studies are needed to determine the risks and benefits of treating subclinically affected foals.
Although R. equi pneumonia has been positively associated with the density of mares and foals at farms and airborne concentrations of virulent R. equi, and negatively associated with foaling at pasture, there is inadequate evidence to recommend environmental interventions to control or prevent R. equi pneumonia.
Some farms do not have affected foals, some farms have foals affected sporadically, and some farms experience the disease on a recurrent basis, suggesting that environmental conditions influence the occurrence of this disease. The odds of developing R. equi pneumonia appear to be related to the density of mares and foals per acre at horse breeding farms.[58, 59, 64, 65]A reduction in the number of mares at a farm reportedly reduced the cumulative incidence of R. equi relative to preceding years, and the authors are aware of similar anecdotes from farms. However, such data must be interpreted with caution in light of the considerable year-to-year variation in incidence that can occur within farms. The impact of reducing density of mares and foals for decreasing the incidence of R. equi pneumonia will remain unresolved until observational or experimental studies can be conducted to address this question. It seems reasonable that reducing density be considered as an approach for decreasing the incidence of R. equi pneumonia.
Rhodococcus equi is a soil saprophyte that is also found commonly in herbivore feces. Geochemical properties of soil have been associated with odds of disease caused by Mycobacterium avium ssp. paratuberculosis, another facultative intracellular pathogen phylogenetically related to R. equi. In Texas, however, soil geochemistry did not appear to be associated with occurrence of R. equi pneumonia at farms; similar studies from other geographic regions have not been reported, to the authors’ knowledge, although the odds of recovering virulent R. equi from soil samples tended to be greater from soils with pH < 6 than from samples that had pH ≥ 6, in Australia. Neither the presence nor the concentration of virulent R. equi in soil is positively associated with either increased odds or increased cumulative incidence of R. equi pneumonia at breeding farms in North America or Australia.[65, 69, 70] Removing feces from paddocks or avoiding spreading manure on pastures (whether manure was composted or not) did not decrease the odds of farms being affected by R. equi pneumonia; however, these management practices are probably important for controlling parasitic and other infectious diseases.
Airborne concentrations of R. equi were correlated with disease incidence at Thoroughbred breeding farms in Australia. Factors associated with increased air concentration of R. equi at these farms included site (holding pens/lanes relative to paddocks), warmer ambient temperature, less soil moisture, reduced grass height, and later date during the foaling season. In Kentucky, concentrations of airborne R. equi were lower between midnight and 6 am than later times, and the presence of horses at the sampling site appeared to increase the airborne concentrations of virulent R. equi; these findings suggest that airborne concentrations may be increased by greater activity and density of horses at sites where foals are housed. Irrigation of holding pens at a farm with foals affected by R. equi was demonstrated to reduce the frequency of recovery of virulent R. equi in air samples from these pens. These results should be interpreted with caution, however, because samples were collected in sequential years (rather than with contemporaneous controls); moreover, there was no significant reduction in cumulative incidence of R. equi pneumonia at the farm. It remains to be determined whether the positive association between airborne concentrations of virulent R. equi with cumulative incidence of R. equi pneumonia is a cause or effect. Thus, it is uncertain whether methods for reducing airborne concentrations would be effective for controlling or preventing R. equi pneumonia.
Evidence exists that foaling at pasture may reduce the occurrence of R. equi pneumonia. In a survey, foaling at pasture was significantly associated with decreased odds of R. equi pneumonia; however, this observation could have been confounded by other management practices or other unaccounted factors. The airborne concentrations of virulent R. equi in barns were significantly lower than in paddock samples from 3 farms in Ireland. Being born and maintained in pasture significantly reduced the cumulative incidence of R. equi pneumonia at a breeding farm in Brazil, but these findings must be interpreted with considerable caution pending replication because they were based on historical controls. Moreover, there may be practical and veterinary medical considerations that prevent this strategy from being adapted by some farms, even if it were effective.
A practical management question often posed to the authors is whether foals with R. equi pneumonia should be isolated from other foals. Relative to adult horses, foals typically shed higher concentrations of virulent R. equi in their feces, and 2 pneumonic foals shed higher concentrations of R. equi in their feces than did unaffected foals from the same environment. Thus, foals represent a source of environmental contamination, and pneumonic foals appear to pose a greater risk. Although it might seem prudent to restrict diseased foals from being housed in paddocks that will be used to hold other mares and foals, there is no evidence to indicate that shedding by affected foals into the environment causes pneumonia in other foals. Air samples from the breathing zone of pneumonic foals had higher concentrations of virulent R. equi than environmental air samples collected from lanes and pens at farms at their farms. However, concentrations of virulent R. equi from air samples collected from the breathing zones were not significantly different between pneumonic foals and healthy controls, indicating that affected foals do not represent a greater risk than other foals for aerosol transmission. There is no compelling evidence that R. equi infection is contagious among foals, and exposure to virulent R. equi appears to be widespread in the environment of foals.[65, 69, 70] Thus, currently there is no evidence to indicate that affected foals should be isolated from other foals.
In summary, no environmental management practice has sufficient evidence on which to base recommendations for controlling and preventing R. equi pneumonia. Further evaluation of certain practices, such as foaling at pasture and reducing either airborne concentrations of virulent R. equi or density of mares and foals, is merited.
Chemoprophylaxis to prevent R. equi pneumonia with macrolides or other classes of antimicrobial drugs is not recommended because of conflicting evidence of efficacy and concerns for promoting resistance of R. equi and other bacteria to these drugs. The level of evidence for this recommendation is moderate.
Because an effective vaccine is lacking, use of antimicrobial agents to prevent R. equi pneumonia has been examined. Two studies from different laboratories using different study designs have evaluated the use of azithromycin for chemoprophylaxis. In a randomized, controlled trial conducted in the United States among 338 foals at 10 farms, the cumulative incidence of R. equi pneumonia was reduced from 21% among untreated foals to 5% among foals that received azithromycin (10 mg/kg; PO; q48 h for the first 14 days of life beginning on the first day of life). In contrast, in a study conducted among 70 foals at a large breeding farm in Germany, the incidence of abscessing pneumonia was not significantly different between foals that received azithromycin (10 mg/kg; PO; q24 h for the first 28 days of life) for prevention of abscessing pneumonia (cumulative incidence = 60%) and foals that did not receive azithromycin for chemoprophylaxis (cumulative incidence = 69%); however, the age at onset of abscessing pneumonia was delayed in treated foals. Neither study was fully masked, nor were placebos used. The reason for the discrepancy between studies remains unknown, but it does not appear to relate to either the dosage or duration of azithromycin treatment. Other possible explanations include differences between studies in case definitions, the extent of selection bias, methods of randomization, incidence of disease, risk factors for disease, and possibly drug formulation. Nevertheless, use of azithromycin is not considered an acceptable approach for chemoprophylaxis because widespread use of this drug would create greater pressure for emergence of macrolide resistance among bacteria. Evidence exists that prognosis is worse for foals with R. equi pneumonia from which macrolide-resistant isolates have been recovered.
Gallium maltolate is a metal-based compound with antimicrobial properties that has been demonstrated to reduce replication of R. equi in pure culture, and within macrophages to reduce tissue concentrations of R. equi in mice after experimental infection, and to be bioavailable and safe in foals. Chemoprophylaxis with gallium maltolate (30 mg/kg; PO; q24 h for the first 14 days of life) failed to reduce the incidence of R. equi pneumonia in a placebo-controlled trial of 438 foals at 12 farms in the United States.
Administration of commercially available and licensed plasma containing antibody against R. equi is recommended as an aid for preventing pneumonia caused by R. equi at endemic farms. The level of evidence for this recommendation is moderate. However, the ideal age and minimal effective dose of hyperimmune plasma (HIP) require further research. Transfusion of HIP is not completely effective and therefore does not eliminate the need for screening or careful monitoring of foals at risk.
Intravenous administration of HIP obtained from horses vaccinated against R. equi using various antigens has generally proved effective in significantly reducing the severity of R. equi pneumonia in foals after experimental challenge.[57, 83, 84] However, studies evaluating the efficacy of various HIP preparations under field conditions have given equivocal results. Although the data are conflicting and not all trials have shown a statistically significant reduction in the cumulative incidence of R. equi pneumonia, 5 of 7 studies have demonstrated reduction of relative risk, suggesting some benefit of HIP transfusion (Table 2). The studies summarized in Table 2 used different immunization protocols to hyperimmunize the donors. As a result, it is not possible to make recommendations regarding the most appropriate immunization protocols for plasma donors. Intravenous administration of purified immunoglobulins obtained from horses immunized with recombinant VapA and VapC to foals reduced the severity of pneumonia after high-dose experimental challenge with R. equi to a degree similar to that provided by commercially available HIP. This demonstrates that immunoglobulins, predominantly against VapA and VapC, are responsible for the protection conferred by HIP. Therefore, administration of plasma obtained from horses that are not hyperimmunized against R. equi is not recommended. As endemicity of R. equi at farms does not appear to be explained by farm-specific isolates, and because foals may be infected with multiples strains, there is no need to administer plasma that is produced from immunizing horses with isolates of R. equi obtained from a given farm; transfusion of plasma from horses that have been immunized against any virulent (ie VapA-positive) strain of R. equi should suffice. Use of HIP licensed as an aid in the control of R. equi pneumonia is recommended (rather than plasma simply obtained from horses hyperimmunized against R. equi), because licensure ensures standard of potency, purity, and safety. Currently, there is insufficient information to recommend one brand of licensed antibody product over another.
|Incidencea with Plasma (Proportion)||Incidencea without Plasma (Proportion)||Relative Risk Reductionb (%)||P < .05||Number of Administrations (Age at Administration [days])||Reference|
|3% (3/101)||43% (6/14)||93||Yes||1 (1–60)|||
|5.7% (14/246)||53.4% (7/13)||89||Yes||1 (1–40)|||
|6.3% (1/16)||27.7% (23/83)||77||No||1 (10–39)|||
|19.1% (13/68)||30.0% (24/80)||37||No||2 (1–10 and 30–50)|||
|29.0 (103/355)||45.3% (58/128)||36||Yes||2c (1–3 and 14–30)|||
|6.8% (2/29)||4.6% (5/107)||−48||No||Not provided|||
|29.4% (10/34)||21.1% (12/57)||−39||No||1 (≤2)|||
The optimal amount of plasma to be transfused and the optimal age at which transfusion should occur remain to be determined. Administration of HIP 9 days after aerosol infection of foals with R. equi did not confer protection, suggesting that administration of HIP before infection is important. As a result of evidence that many foals become infected early in life, it is commonly recommended that foals receive transfusion of at least 1 L of HIP no later than the 2nd day of life. Because early administration may result in the decline of passively transferred antibody to a nonprotective level at a time when foals are still susceptible to R. equi and when environmental challenge is high, it is a common practice to administer a 2nd dose of HIP at 2–4 weeks of age.
Transfusion of HIP is not completely effective and therefore does not eliminate the need for screening or careful monitoring of foals at risk. In addition to being incompletely effective, transfusion of HIP carries some risk to foals, both in terms of trauma that may occur during handling and adverse reactions to transfusions. The process is also time- and labor-intensive, and expensive. The cost-effectiveness of transfusion depends on the value of the foals and the prevalence of disease at a given farm.
There is inadequate evidence to recommend active immunization of mares or foals to control or prevent R. equi pneumonia.
The evidence from mouse models, immune adult horses, and the study of other similar intracellular pathogens strongly suggests that an active immunization strategy to prevent R. equi disease will need to induce antigen-specific Type 1 cell-mediated responses. Antibody responses alone are unlikely to be protective. At a minimum, protective responses produced by an efficacious vaccine are likely to include CD4+ Th1 lymphocytes that secrete interferon-gamma in response to R. equi antigens and (possibly) CD8+ T lymphocytes that recognize and kill R. equi infected cells (see companion article in the same issue). There also may be other as yet undefined requirements. As foals are exposed and possibly infected in the first days or weeks of life, an effective immunization strategy will likely need to be initiated shortly after birth.
The relative immunologic hyporesponsiveness that characterizes early life probably represents the primary obstacle to an active immunization strategy. However, there is evidence that vaccination is an achievable goal. For example, immunologic studies have demonstrated adult-like IFN-gamma responses of foals to R. equi. Likewise, even at endemic farms where all foals are presumably exposed to high doses of virulent R. equi, a majority of foals effectively resist disease and go on to develop protective immune responses that prevent rhodococcal pneumonia throughout adult life. A novel strategy will probably be required to induce or at least prime these responses in the first weeks of a foal's life. In a promising study, intragastric inoculation of neonatal foals with virulent R. equi protected foals from a subsequent respiratory challenge that produced severe disease in controls. Inoculation of virulent bacteria is not an acceptable real-world strategy. However, it unequivocally demonstrates that young foals can mount protective immune responses. An effective vaccine to prevent rhodococcal pneumonia in foals is unlikely to come easily. A long-term view encompassing basic science research and empirical vaccine trials will be required.
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