Diagnosis, treatment, control, and prevention of infections caused by Rhodococcus equi 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 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.     

Pulmonary disposition of erythromycin, azithromycin, and clarithromycin in foals

The objectives of the present study were to determine and compare the pulmonary disposition of azithromycin, clarithromycin, and erythromycin in foals. A single dose (10 mg/kg) of azithromycin, clarithromycin, or erythromycin was administered intragastrically to six healthy 1- to 3-month-old foals using an orthogonal design. Activity of the drugs was measured in serum, pulmonary epithelial lining fluid (PELF), and bronchoalveolar lavage (BAL) cells by use of a microbiologic assay. Peak drug activity in PELF was significantly higher in foals treated with clarithromycin (48.96+/-13.26 microg/mL) than in foals treated with azithromycin (10.00+/-7.46 microg/mL). Quantifiable erythromycin activity in PELF was only found in two of six foals. Peak drug activity in BAL cells was not significantly different between azithromycin (49.92+/-26.94 microg/mL) and clarithromycin (74.20+/-45.80 microg/mL) but activity for both drugs was significantly higher than that of erythromycin (1.02+/-1.11 microg/mL). Terminal half-life of azithromycin in serum (25.7+/-15.4 h), PELF (34.8+/-30.9 h), and BAL cells (54.4+/-17.5 h) was significantly longer than that of both clarithromycin and erythromycin. Peak azithromycin and clarithromycin activity was significantly higher in BAL cells, followed by PELF, and serum. In contrast, peak erythromycin activity in BAL cells was not significantly different from that of serum.     

Diagnostic contribution of thoracic ultrasonography in 17 foals with Rhodococcus equi pneumonia

The aim of this retrospective study was to determine the clinical usefulness of thoracic ultrasonography compared to thoracic radiography in evaluation of Rhodococcus equi pneumonia. Criteria for patient inclusion in this study were: (1) isolation of R. equi from transtracheal aspirate, (2) radiographic evaluation of the pulmonary parenchyma, and (3) sonographic evaluation of the pulmonary parenchyma. Seventeen foals met this criteria and their medical records were reviewed. Pyogranulomatous pneumonia was identified radiographically in 13 foals. Severe consolidative pneumonia with no detectable abscessation was identified radiographically in three others. Both consolidation and abscessation were identified radiographically in one. In this foal only consolidation was ultrasonographically identified. Ultrasonographically, pulmonary abscessation was identified in 12 foals and pulmonary consolidation with no detectable abscessation was identified in three others. Sonographic examination allowed detection of only pleural irregularities in one foal, which was subsequently found to have pyogranulomatous pneumonia radiographically. Results indicate that ultrasonography may be an accurate alternative imaging modality for detection of pulmonary pathology attributed to R. equi pneumonia in foals when thoracic radiography is not available.     

Association of pneumonia in foals caused by Rhodococcus equi with farm soil geochemistry

OBJECTIVE: To quantify and compare geochemical factors in surface soils from horse-breeding farms with horses with pneumonia caused by Rhodococcus equi (affected farms) and horse-breeding farms with no history of pneumonia caused by R equi (unaffected farms). SAMPLE POPULATION: Soil from 24 R equi-affected farms and 21 unaffected farms. PROCEDURE: Equine veterinary practitioners throughout Texas submitted surface soil samples from areas most frequented by foals, on R equi-affected and unaffected horse-breeding farms in their practice. Soil samples were assayed for the following factors: pH, salinity, nitrate, phosphorus, potassium, calcium, magnesium, sodium, sulfur, zinc, iron, manganese, and copper. Median values for all factors were recorded, and differences between affected and unaffected farms were compared. RESULTS: Significant differences in soil factors were not detected between affected and unaffected farms; hence, there was no association between those factors and R equi disease status of the farms. CONCLUSIONS AND CLINICAL RELEVANCE: The surface soil factors monitored in this study were not significant risk factors for pneumonia caused by R equi. As such, it is not possible to determine whether foals on a given farm are at increased risk of developing disease caused by R equi on the basis of these factors. Data do not support altering surface soil for factors examined, such as alkalinization by applying lime, as viable control strategies for R equi.     

Farm characteristics and management practices associated with development of Rhodococcus equi pneumonia in foals

OBJECTIVE: To identify farm characteristics and management practices associated with development of Rhodococcus equi pneumonia in foals. DESIGN: Prospective case-control study. ANIMALS: 5230 foals on 138 breeding farms with 9136 horses. PROCEDURE: During 2003, participating veterinarians provided data from 1 or 2 farms with > or =1 foal with R equi pneumonia and unaffected farms. Data from affected and unaffected farms were compared by use of logistic regression analysis. RESULTS: A number of variables relating to farm size and desirable management practices were significantly associated with increased odds of farms being affected with R equi pneumonia. By use of multivariate logistic regression, affected farms were determined significantly more likely to have raised Thoroughbreds, housed > or =15 foals, used concrete floors in foaling stalls, and tested foals for passive transfer of immunity than unaffected farms. These results remained significant even after accounting for exposure of foals to other breeding farms during the first month of life. Conclusions and Clinical Relevance-Breeding farms with large acreage and a large number of mares and foals have greater odds of being affected by R equi pneumonia. Clinical relevance of associations with Thoroughbred breed and concrete flooring in foaling stalls remains uncertain. Desirable management factors commonly used on farms were not effective for controlling or preventing development of R equi pneumonia. This finding indicates a need to focus on host factors that influence disease development.     

Evaluation of nasotracheal aspiration as a diagnostic tool for Rhodococcus equi pneumonia in foals

The reliability of preparing bacteriological cultures from nasotracheal aspirates of foals routinely in order to diagnose R. equi pneumonia in foals was studied by isolating Rhodococcus equi from specimens obtained from 96 foals by nasotracheal aspiration with a silicon catheter. Results were compared with specimens obtained from 21 foals by transtracheal aspiration (percutaneous tracheal puncture). These 117 foals showed clinical signs of respiratory tract infection at sampling. R. equi was isolated from 14 of 21 (66.7%) specimens by transtracheal aspiration and from 59 of 96 (61.4%) specimens by nasotracheal aspiration, 649 of 655 isolates (99.1%) from the 73 positive specimens were virulent R. equi, and the culture-positive foals were diagnosed as having R. equi pneumonia. To assess the contamination of aspirates by organisms from the nasopharynx, the results of R. equi isolation from nasal swabs obtained from 56 of the 96 foals were compared to those obtained by nasotracheal aspiration from the same foals. R. equi was isolated from 2 of the 56 nasal swabs: one from a tracheal aspirate was positive, and the other was not. These results suggest that the nasotracheal aspiration technique, which is noninvasive and not associated with complications, could be used as an alternative to the transtracheal aspiration method, especially for the diagnosis of R. equi pneumonia in foals.     

Rhodococcus equi: clinical manifestations, virulence, and immunity

Pneumonia is a major cause of disease and death in foals. Rhodococcus equi, a gram-positive facultative intracellular pathogen, is a common cause of pneumonia in foals. This article reviews the clinical manifestations of infection caused by R. equi in foals and summarizes current knowledge regarding mechanisms of virulence of, and immunity to, R. equi. A complementary consensus statement providing recommendations for the diagnosis, treatment, control, and prevention of infections caused by R. equi in foals can be found in the same issue of the Journal.     

Association of disease with isolation and virulence of Rhodococcus equi from farm soil and foals with pneumonia

OBJECTIVE: To determine whether isolation and virulence of Rhodococcus equi from soil and infected foals are associated with clinical disease. DESIGN: Cross-sectional and case-control study. SAMPLE POPULATION: R equi isolates from 50 foals with pneumonia and soil samples from 33 farms with and 33 farms without a history of R equi infection (affected and control, respectively). PROCEDURE: R equi was selectively isolated from soil samples. Soil and clinical isolates were evaluated for virulence-associated protein antigen plasmids (VapA-P) and resistance to the beta-lactam antibiotics penicillin G and cephalothin. Microbiologic cultures and VapA-P assays were performed at 2 independent laboratories. RESULTS: VapA-P was detected in 49 of 50 (98%) clinical isolates; there was complete agreement between laboratories. Rhodococcus equi was isolated from soil on 28 of 33 (84.8%) affected farms and 24 of 33 (72.7%) control farms, but there was poor agreement between laboratories. Virulence-associated protein antigen plasmids were detected on 14 of 66 (21.2%) farms by either laboratory, but results agreed for only 1 of the 14 VapA-P-positive farms. We did not detect significant associations between disease status and isolation of R equi from soil, detection of VapA-P in soil isolates, or resistance of soil isolates to beta-lactam antibiotics. No association between beta-lactam antibiotic resistance and presence of VapA-P was detected. CONCLUSIONS AND CLINICAL RELEVANCE: On the basis of soil microbiologic culture and VapA-P assay results, it is not possible to determine whether foals on a given farm are at increased risk of developing disease caused by R equi.     

Association of soil concentrations of Rhodococcus equi and incidence of pneumonia attributable to Rhodococcus equi in foals on farms in central Kentucky

OBJECTIVE: To determine whether soil concentrations of total or virulent Rhodococcus equi differed among breeding farms with and without foals with pneumonia caused by R equi. SAMPLE POPULATION: 37 farms in central Kentucky. Procedures-During January, March, and July 2006, the total concentration of R equi and concentration of virulent R equi were determined by use of quantitative bacteriologic culture and a colony immunoblot technique, respectively, in soil specimens obtained from farms. Differences in concentrations and proportion of virulent isolates within and among time points were compared among farms. RESULTS: Soil concentrations of total or virulent R equi did not vary among farms at any time point. Virulent R equi were identified in soil samples from all farms. Greater density of mares and foals was significantly associated with farms having foals with pneumonia attributable to R equi. Among farms with affected foals, there was a significant association of increased incidence of pneumonia attributable to R equi with an increase in the proportion of virulent bacteria between samples collected in March and July. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that virulent R equi were commonly recovered from soil of horse breeding farms in central Kentucky, regardless of the status of foals with pneumonia attributable to R equi on each farm. The incidence of foals with pneumonia attributable to R equi can be expected to be higher at farms with a greater density of mares and foals.     

Evaluation of equine immunoglobulin specific for Rhodococcus equi virulence-associated proteins A and C for use in protecting foals against Rhodococcus equi-induced pneumonia

OBJECTIVE: To determine whether purified equine immunoglobulin specific for Rhodococcus equi virulence-associated proteins A and C (VapA and VapC) can confer passive protection against R. equi-induced pneumonia in foals. ANIMALS: Twenty-eight 3-week-old mixed-breed pony foals. PROCEDURE: 7 foals received IV injections of equine hyperimmune plasma (HIP) against whole-cell R. equi, and 7 received purified equine immunoglobulin specific for VapA and VapC 1 day prior to intrabronchial infection with R. equi strain 103+. Eleven foals were not treated prior to infection, and 3 control foals were neither treated nor infected. Heart rate, respiratory rate, and rectal temperature were recorded twice daily, and serum fibrinogen concentration and WBC count were determined every other day following infection. Foals were euthanatized 14 days following infection, and lung lesions and concentration of R. equi in lungs were assessed. RESULTS: The onset of clinical signs of pneumonia was significantly delayed in the HIP- and immunoglobulin-treated groups, compared with the untreated infected group. Moreover, pulmonary lesions were less severe in the treated groups, and significantly fewer R. equi organisms were cultured from the lungs of treated foals. CONCLUSIONS AND CLINICAL RELEVANCE: Degree of protection against R. equi-induced pneumonia provided by purified immunoglobulin specific for VapA and VapC was similar to that provided by commercially available HIP. Results not only suggest that immunoglobulin is the primary component of HIP that confers protection against R. equi-induced pneumonia in foals but also indicate that antibodies against R. equi VapA and VapC are protective.     

Evaluation of equine breeding farm characteristics as risk factors for development of Rhodococcus equi pneumonia in foals

OBJECTIVE: To identify farm characteristics as risk factors for the development of Rhodococcus equi pneumonia in foals. DESIGN: Prospective matched case-control study. ANIMALS: 2,764 foals on 64 equine breeding farms with 9,991 horses. PROCEDURE: During 1997, participating veterinarians completed paired data collection forms, 1 for a farm with > or = 1 foal with R equi pneumonia and 1 for an unaffected control farm. Matched data were compared by use of conditional logistic regression analysis. RESULTS: Farm characteristics found in bivariate analyses to be associated with increased risk for pneumonia caused by R equi in foals included > 200 farm acres, > or = 60 acres used in the husbandry of horses, > 160 horses, > or = 10 mares housed permanently on the farm (resident mares), > 17 foals, > 0.25 foals/acre, and the presence of transient mares (mares brought temporarily to the farm for breeding or foaling) and their foals. Affected farms were significantly more likely to be > 200 acres in size and have > or = 10 resident dam-foal pairs, whereas control farms were significantly more likely to have > or = 75% of their dam-foal pairs housed permanently on the farm. CONCLUSIONS AND CLINICAL RELEVANCE: Breeding farms with large acreage, a large number of mares and foals, high foal density, and a population of transient mares and foals are at high risk for foals developing pneumonia caused by R equi.     

Chemoprophylactic effects of azithromycin against Rhodococcus equi-induced pneumonia among foals at equine breeding farms with endemic infections

OBJECTIVE: To determine the effect of azithromycin chemoprophylaxis on the cumulative incidence of pneumonia caused by Rhodococcus equi, age at onset of pneumonia, and minimum inhibitory concentration (MIC) of azithromycin for R equi isolates cultured from fecal and clinical samples. DESIGN: Controlled, randomized clinical trial. ANIMALS: 338 foals born and raised at 10 equine breeding farms; each farm had a history of endemic R equi infections. PROCEDURES: Group 1 foals were control foals, and group 2 foals were treated with azithromycin (10 mg/kg [4.5 mg/lb], PO, q 48 h) during the first 2 weeks after birth. Foals were monitored for development of pneumonia attributable to R equi infection and for adverse effects of azithromycin. Isolates of R equi were tested for susceptibility to azithromycin. RESULTS: The proportion of R equi-affected foals was significantly higher for control foals (20.8%) than for azithromycin-treated foals (5.3%). Adverse effects of azithromycin treatment were not detected, and there were no significant differences between groups for the MICs of azithromycin for R equi isolates cultured from fecal or clinical samples. CONCLUSIONS AND CLINICAL RELEVANCE: Azithromycin chemoprophylaxis effectively reduced the cumulative incidence of pneumonia attributable to R equi among foals at breeding farms with endemic R equi infections. There was no evidence of resistance to azithromycin. Nonetheless, caution must be used because it is possible that resistance could develop with widespread use of azithromycin as a preventative treatment. Further investigation is needed before azithromycin chemoprophylaxis can be recommended for control of R equi infections.     

Rhodococcus equi pneumonia in the foal--part 2: diagnostics, treatment and disease management

Various challenges face clinicians and farm managers in diagnosing, treating and preventing Rhodococcus equi pneumonia. The use of ultrasound imaging has aided in the early diagnosis of the disease, reducing treatment duration and improving therapeutic outcomes. Antimicrobial resistance in R. equi is an emerging issue that necessitates prudent antimicrobial therapy of diseased foals. Alternative methods of disease transmission, such as contagious foal-to-foal aerosol transmission, may need to be addressed to complement dust reduction environmental strategies and to minimise the overall risk of exposure of foals to highly concentrated inhaled doses of the organism. Effective management of foals and land aimed at reducing aerosol exposure to virulent R. equi is likely to yield significant reductions in the prevalence and severity of R. equi pneumonia.     

Dynamics of equi-factor antibodies in sera of foals kept on farms with differing histories of Rhodococcus equi pneumonia

The occurrence of equi-factor antibodies in sera of mares and their foals was studied on two horse breeding farms, one of which (Farm A) had a positive and the other (farm B) a negative history of R. equi infection of foals. The equi-factor neutralization (EFN) and the reverse Elek-Ouchterlony (REO) precipitation were used as assays. On Farm A, 25 mares positive in both tests (EFN+ REO+) and 25 mares negative in both tests (EFN- REO-) was chosen. On Farm B, a group of 25 EFN- REO+ mares and a group of 25 EFN- REO- mares were studied. The first serum samplings in mares were 1 week ante partum and the subsequent samplings in both mares and foals were in the first week after birth and at the end of every month of the foals' age up to 6 months, with further samplings at 8 and 12 months. A higher number of seropositive foals was found on Farm A, but the difference between Farms A and B was not significant. The smallest number, with the lowest titres, was among the foals of EFN- REO+ dams. The number of foals positive in the REO test was higher than in the EFN test. The onset of EFN positivity was found in foals on both farms in the first month of their age, always culminating in the third and fourth months in titres varying between 1:64 and 1:2048, after which time it fell until it disappeared altogether or reached values of 1:4. The results showed the widespread nature of subclinical infection with R. equi on horse farms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rhodococcus equi foal pneumonia: Update on epidemiology,immunity, treatment and prevention

Pneumonia in foals caused by the bacterium Rhodococcus equi has a worldwide distribution and is a common cause of disease and death for foals. The purpose of this narrative review was to summarise recent developments pertaining to the epidemiology, immune responses, treatment, and prevention of rhodococcal pneumonia of foals. Screening tests have been used to implement earlier detection and treatment of foals with presumed subclinical R. equi pneumonia to reduce mortality and severity of disease. Unfortunately, this practice has been linked to the emergence of antimicrobial-resistant R. equi in North America. Correlates of protective immunity for R. equi infections of foals remain elusive, but recent evidence indicates that innate immune responses are important both for mediating killing and orchestrating adaptive immune responses. A macrolide antimicrobial in combination with rifampin remains the recommended treatment for foals with R. equi pneumonia. Great need exists to identify which antimicrobial combination is most effective for treating foals with R. equi pneumonia and to limit emergence of antimicrobial-resistant strains. In the absence of an effective vaccine against R. equi, passive immunisation remains the only commercially available method for effectively reducing the incidence of R. equi pneumonia. Because passive immunisation is expensive, labour-intensive and carries risks for foals, great need exists to develop alternative approaches for passive and active immunisation.     

Hematologic and immunophenotypic factors associated with development of Rhodococcus equi pneumonia of foals at equine breeding farms with endemic infection

Rhodococcus equi causes severe pyogranulomatous pneumonia in foals and in immunocompromised people. In mice, both CD4+ and CD8+ T lymphocytes contribute to host defense against R. equi, but CD4+ T lymphocytes are required for pulmonary clearance of the bacteria. In this prospective study of 208 foals at two equine breeding farms with endemic R. equi infections, we collected peripheral blood samples at 2 and 4 weeks of age and at the time of diagnosis of R. equi pneumonia. Samples were analyzed for concentrations of total and differential leukocytes, EqCD4+ and EqCD8+ T lymphocytes, and B lymphocytes. Thirty (14.4%) foals developed R. equi pneumonia. At the 2nd week of life, affected foals had significantly lower concentrations of white blood cells (WBC) and segmented neutrophils, significantly lower proportions of EqCD4+ T lymphocytes, and significantly higher proportions of EqCD8+ T lymphocytes. The EqCD4:EqCD8 ratio was significantly lower for affected foals. At the 4th week of life, affected foals had significantly lower concentrations of segmented neutrophils and EqCD4+ T lymphocytes than did unaffected foals. The ratio of EqCD4:EqCD8 was significantly lower for affected foals. Two- and 4-week-old foals with ratios of EqCD4:EqCD8<3 were significantly more likely to develop R. equi pneumonia. There was a significant farm effect which diluted our statistical power to detect differences; however; after adjusting for the farm effect, 2-week-old foals with ratios of EqCD4:EqCD8<3 remained significantly more likely to develop R. equi pneumonia. There were no significant differences in immunophenotypic variables between affected foals (at the time of diagnosis) and age-matched control foals. These data suggest that there are hematologic and immunophenotypic differences between affected and unaffected foals during the first 2-4 weeks of life, prior to onset of clinical signs of R. equi pneumonia. These differences may represent important immunologic mechanisms associated with increased susceptibility of individual foals to infection with R. equi. Because there was considerable overlap between values for affected and unaffected foals, we cannot yet recommend immunophenotyping of foals at endemically-infected farms as a clinically useful screening tool to identify foals at increased risk of developing R. equi pneumonia.     

Efficacy of Mass Antimicrobial Treatment of Foals with Subclinical Pulmonary Abscesses Associated with Rhodococcus equi

Background

Mass antimicrobial treatment of foals with small subclinical ultrasonographic pulmonary lesions is empirical practice on many farms with endemic disease caused by Rhodococcus equi.

Hypothesis

Mass antimicrobial treatment of foals with subclinical ultrasonographic pulmonary lesions is unnecessary.

Animals

One hundred and eight foals on a farm endemic for infections caused by R. equi.

Methods

Controlled, randomized, and double‐blinded prospective study. Foals with ultrasonographic evidence of pulmonary abscesses 5.0–10 cm in diameter (n = 108) were randomly allocated in 5 treatment groups: (1) tulathromycin IM; (2) doxycycline monotherapy PO; (3) doxycycline with rifampin PO; (4) azithromycin with rifampin PO, and (5) saline IM as a placebo. Physical examination and thoracic ultrasonography were performed by individuals unaware of treatment group assignment. Foals with evidence of disease progression were removed from the study and treated with azithromycin‐rifampin.

Results

Overall, 22/25 (88%) foals in the placebo group recovered without the need for treatment. The proportion of foals that had evidence of disease progression did not differ significantly between the treatment groups (P > .05). Although the median duration of treatment was significantly (P < .05) shorter in foals treated with azithromycin‐rifampin (46 days) compared with foals treated with the placebo (73 days), the time frame of ultrasonographic lesion resolution did not differ significantly between the treatment groups.

Conclusions and Clinical Importance

The majority of foals with subclinical pulmonary abscesses <10 cm in diameter recover without antimicrobial treatment and treatment of affected foals does not provide a clear benefit over administration of a placebo.