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Therapy of Rhodococcus Equi Infections in Foals

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Therapy of Rhodococcus Equi Infections in Foals IN-DEPTH: RHODOCOCCUS EQUI Therapy of Rhodococcus equi Infections in Foals Steeve Gigue`re, DVM, PhD, Diplomate ACVIM The combination of a macrolide (erythromycin, azithromycin, or clarithromycin) with rifampin re- mains the mainstay of therapy. Although the vast majority of Rhodococcus equi isolates are still susceptible to these antimicrobials, the frequency of macrolide-rifampin–resistant isolates seems to be increasing. Author’s address: College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602; e-mail: [email protected]. © 2010 AAEP. 1. Introduction lates are inhibited (MIC90) is 0.12, 0.25, and A wide variety of antimicrobial agents are active 1.0 ␮g/ml for clarithromycin, erythromycin, and 5 against Rhodococcus equi in vitro. However, be- azithromycin, respectively. The combination of a cause R. equi is a facultative intracellular pathogen macrolide and rifampin is synergistic both in vitro surviving and replicating in macrophages, many of and in vivo, and the use of the two classes of drugs in these drugs are ineffective in vivo. For example, in combination reduces the likelihood of R. equi resis- one study, all 17 foals with R. equi pneumonia tance to either drug.4,6 Rifampin and macrolides treated with the combination of penicillin and gen- are lipid soluble, allowing them to penetrate cell tamicin died despite the fact that all isolates were membranes and caseous material. sensitive to gentamicin.1 The combination of ri- The recommended doses are listed in Table fampin and erythromycin became the treatment of 1. Several formulations of erythromycin are com- choice in the 1980s and has dramatically reduced mercially available. Although they all show slight foal mortality at least compared with historical data differences in bioavailability and elimination, they since its introduction.1,2 In recent years, clarithro- all result in therapeutic concentrations at recom- mycin or azithromycin, both newer-generation mac- mended doses. Advantages of azithromycin and rolides, often replaces erythromycin in combination clarithromycin over erythromycin in foals include 3 with rifampin. enhanced oral bioavailability, prolonged half-lives, and much higher concentrations in bronchoalveolar 2. Macrolides and Rifampin cells and pulmonary epithelial lining fluid (Table 7–10 Macrolides and rifampin are highly active against 1). These properties of the newer-generation R. equi in vitro but only exert bacteriostatic activi- macrolides contribute to their lower doses and longer ty.4 As a result, macrolides exert time-dependent dosing intervals. Concentrations of clarithromycin activity against R. equi in vitro. Of the three mac- in pulmonary epithelial lining fluid and broncho- rolides listed above, clarithromycin is the most alveolar cells of foals at steady state are consider- active against R. equi in vitro. The minimum in- ably higher than concentrations reported after daily hibitory concentration at which 90% of R. equi iso- administration of azithromycin to foals.8,9 However, NOTES AAEP PROCEEDINGS ր Vol. 56 ր 2010 125 IN-DEPTH: RHODOCOCCUS EQUI Table 1. Recommended Dosages, MICs, and Relative Serum and Pulmonary Concentrations of Macrolides Commonly Used for Treatment of R. equi Infections in Foals Erythromycin Clarithromycin Azithromycin Recommended oral dosage (mg/kg) 25, q 6–8 h 7.5, q 12 h 10 q, 24–48* ␮ † MIC90 of R. equi isolates ( g/ml) 0.25 0.12 1.00 Oral bioavailability (%) 8‡–26§ 57‡ 56‡ Plasma concentrations ϩϩϩ PELF and BAL cell concentrations Ϯ ϩϩϩ ϩϩ Plasma half-life ϩϩϩϩ PELF and BAL cell half-life ϩ ϩ ϩϩϩ *Administration q 24 h for 5 days and q 48 h thereafter. † MIC90, minimum inhibitory concentration that inhibits growth of at least 90% of isolates. ‡Mean oral bioavailability after fasting. §Mean bioavailability with ad libitum access to milk, water, and hay. PELF, pulmonary epithelial lining fluid; BAL, bronchoalveolar lavage. clarithromycin concentrations at these sites de- ranged between 17% and 36%.3,12 During surges of crease rapidly, whereas the release of azithromycin very hot weather, an idiosyncratic reaction charac- from cells is much slower, resulting in sustained con- terized by severe hyperthermia and tachypnea has centrations of azithromycin in tissues for days after been described in foals treated with erythromycin.12 discontinuation of therapy.7–10 In a retrospective Anecdotal reports suggest that these reactions may study, the combination clarithromycin-rifampin occasionally occur with newer macrolides as well. was significantly more effective than erythromycin- Administration of antipyretic drugs and placing the rifampin or azithromycin-rifampin, especially in foals foal in a cool environment will treat this problem. with severe radiographic lesions.3 Severe enterocolitis has also been reported in mares Tulathromycin, a semi-synthetic macrolide re- whose foals are being treated with erythromycin, cently approved for use in swine and cattle, was presumably because of disruption of the mare’s nor- recently compared with azithromycin-rifampin for mal colonic microflora after ingestion of small the treatment of foals with subclinical pneumonia as amounts of active drug during coprophagia or from identified by ultrasonographic screening on a farm contamination of feeders or water buckets with drug with a high incidence of R. equi infections. Pulmo- present on the foal’s muzzle.13 nary lesions 1 wk after initiation of treatment with tulathromycin were significant larger and duration 3. Bacterial Resistance to Commonly Used of therapy was significantly longer, indicating that Antimicrobial Agents tulathromycin is not as effective as standard ther- Although the vast majority of R. equi isolates from apy with azithromycin-rifampin.11 Tulathromycin foals are highly susceptible to macrolides and ri- is currently not recommended for use in foals, at fampin, resistant strains to either drug class have least until the drug is proven effective in foals with been encountered. The percentage of R. equi iso- clinical pneumonia caused by R. equi. Tilmicosin, lates resistant to either macrolides or rifampin has another macrolide approved for use in swine and ranged between 0% and 4% depending on the cattle, is not active against R. equi, and administra- study.5,14 Rifampin should not be used in mono- tion to foals sometimes result in swelling at the site therapy because this increases the chance of resis- of injection.9 tance developing.4,15 Rifampin resistance is Resolution of clinical signs, normalization of conferred by mutations in the RNA polymerase ␤ plasma fibrinogen concentrations, and radiographic subunit encoded by the rpoB gene.16,17 Progressive or ultrasonographic resolution of lung lesions are development of resistance to both erythromycin and commonly used to guide the duration of therapy, rifampin during treatment is extremely rare, but it which generally ranges between 2 and 12 wk, de- has been reported.18 In a recent study, the overall pending on the severity of the initial lesions and prevalence of resistant isolates in Texas and Florida response to therapy. over a 10-yr period was 4%.19 In the same study, Although well tolerated by most foals, macrolides the survival proportion of foals infected with resis- commonly cause diarrhea. Most of the time, the tant R. equi isolates was significantly lower than diarrhea is self-limiting and does not necessitate that of foals receiving the same treatment from cessation of therapy. Affected foals should be mon- which susceptible isolates were cultured. The odds itored carefully because some may develop severe of non-survival were seven times higher in foals diarrhea, leading to dehydration and electrolyte loss infected with resistant isolates.19 In addition, the that necessitate intensive fluid therapy and cessa- study showed that isolates of R. equi susceptible tion of oral macrolides. The incidence of diarrhea to macrolides are sometimes misclassified as resis- in foals treated with erythromycin-rifampin has tant; therefore, it is reasonable to request re-testing/ 126 2010 ր Vol. 56 ր AAEP PROCEEDINGS IN-DEPTH: RHODOCOCCUS EQUI validation of resistance by the testing laboratory. hypoxemic animals, is indicated.22 Judicious use of The molecular mechanisms of macrolide resistance non-steroidal anti-inflammatory drugs is of value in in R. equi isolates have not been determined, but reducing fever and improving attitude and appetite R. equi isolates resistant to one of the three macro- in febrile, depressed, anorectic foals. Nebulization lides listed above are typically resistant to the other may be helpful in selected cases with tenacious se- two as well. cretions and non-productive cough. However, most cases of R. equi pneumonia do not benefit from neb- 4. Alternative Antimicrobial Agents ulization, and the procedure is stressful to some Therapy of foals developing severe diarrhea during foals. Similarly, bronchodilators are rarely helpful macrolide therapy or therapy of foals infected with clinically in foals with pneumonia caused by R. equi. resistant isolates is problematic because of the lim- In addition to appropriate systemic antimicrobial ited range of alternative effective drugs. Oral therapy, foals with R. equi septic arthritis or osteo- doxycycline in combination with rifampin has been myelitis often require aggressive local therapy such used successfully for the treatment of foals with as joint lavage, surgical debridement, and IV or pneumonia caused by R. equi. Recommended dos- intraosseous regional limb perfusion with antimi- age
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