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.
Table 1. Recommended dosages, minimum inhibitory concentrations, as well as plasma and pulmonary concentrations (mean ± SD) of macrolides commonly used for the treatment of Rhodococcus equi infections in foals.
|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.