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 for doxycycline in foals is 10 mg/kg, PO, q 12 h.20 crobial agents. The prognosis of foals with abdom- This dosage results in serum, pulmonary epithelial inal abscesses is poor, although rare cases will lining fluid, and bronchoalveolar cell concentrations respond to long-term antimicrobial therapy.23,24 ␮ above the MIC90 of R. equi isolates (1.0 g/ml) for Surgical removal or marsupialization has been at- the entire dosing interval. Doxycyline is bacterio- tempted in some foals, but abdominal adhesions static against R. equi, but the drug is highly syner- usually result in the inability to resect the lesion gistic with rifampin and with macrolides in vitro. and in chronic intermittent episodes of colic. Therefore, doxycycline could also be combined with a macrolide for the treatment of rifampin-resistant 6. Prognosis isolates. Chloramphenicol can be administered Before the introduction of the combination of eryth- orally and achieves high concentrations within romycin and rifampin as the treatment of choice in phagocytic cells in other species. The recom- the early 1980s, the prognosis of R. equi–infected mended dosage regimen is 50 mg/kg, PO,q6h. foals was poor, with reported survival rates as low as However, the fact that only 70% of R. equi isolates 20%.25 Using erythromycin and rifampin, Hillidge2 are susceptible to this drug and the potential human reported a successful outcome (as assessed by sur- health risk make this drug a less attractive alterna- vival) in 50 (88%) of 57 foals with confirmed R. equi tive. High doses of a trimethoprim-sulfonamide pneumonia. Studies in referral centers, more likely (TMS) combination (30 mg/kg of combination, PO, q to see the most severely affected cases, have shown 8 or 12 h) have been used alone or in combination survival rates ranging between 59% and 72%.3,26,27 with rifampin in foals with mild or early R. equi pneumonia or for continued therapy in foals re- References 1 sponding well to other antimicrobials. However, 1. Sweeney CR, Sweeney RW, Divers TJ. Rhodococcus equi TMS is not subjectively as effective as the combina- pneumonia in 48 foals: response to antimicrobial therapy. tion macrolide-rifampin. Vet Microbiol 1987;14:329–336. In an experimental model of R. equi infection in 2. Hillidge CJ. Use of erythromycin-rifampin combination in treatment of Rhodococcus equi pneumonia. Vet Microbiol immunosuppressed mice, the most effective drugs 1987;14:337–342. in monotherapy were found to be, in order of ef- 3. Gigue`re S, Jacks S, Roberts GD, et al. Retrospective com- fectiveness, vancomycin, imipenem, and rifampin.21 parison of azithromycin, clarithromycin, and erythromycin Amikacin, erythromycin, ciprofloxacin, or minocy- for the treatment of foals with Rhodococcus equi pneumonia. cline in monotherapy did not lead to a significant J Vet Intern Med 2004;18:568–573. 4. Nordmann P, Ronco E. In-vitro antimicrobial susceptibility decrease in bacterial counts. The most active drugs of Rhodococcus equi. J Antimicrob Chemother 1992;29:383– in combination were those including vancomycin or 393. rifampin, but these combinations were not signifi- 5. Jacks S, Gigue`re S, Nguyen A. In vitro susceptibilities of cantly different from vancomycin monotherapy.21 Rhodococcus equi and other common equine pathogens to azithromycin, clarithromycin and 20 other antimicrobials. Vancomycin and imipenem in foals should only be Antimicrob Agents Chemother 2003;47:1742–1745. used for the treatment of life-threatening R. equi 6. Prescott JF, Nicholson VM. The effects of combinations of infections caused by isolates confirmed to be resis- selected antibiotics on the growth of Corynebacterium equi. tant to all other possible alternatives. J Vet Pharmacol Ther 1984;7:61–64. 7. Davis JL, Gardner SY, Jones SL, et al. Pharmacokinetics of 5. Ancillary Therapies azithromycin in foals after i.v. and oral dose and disposition into phagocytes. J Vet Pharmacol Ther 2002;25:99–104. Nursing care, provision of adequate nutrition and 8. Jacks S, Gigue`re S, Gronwall PR, et al. Pharmacokinetics of hydration, and maintaining the foal in a cool and azithromycin and concentration in body fluids and broncho- well-ventilated environment are important. Oxy- alveolar cells in foals. Am J Vet Res 2001;62:1870–1875. 9. Womble A, Gigue`re S, Murthy YV, et al. Pulmonary dispo- gen therapy using humidified oxygen by pharyngeal sition of tilmicosin in foals and in vitro activity against insufflation in moderately hypoxemic foals, or by Rhodococcus equi and other common equine bacterial patho- percutaneous transtracheal oxygenation in severely gens. J Vet Pharmacol Ther 2006;29:561–568.

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10. Suarez-Mier G, Gigue`re S, Lee EA. Pulmonary disposition fampin in a foal during treatment for Rhodococcus equi pneu- of erythromycin, azithromycin, and clarithromycin in foals, monia. Equine Vet J 1994;26:246–248. J Vet Pharmacol Ther 2007;30:109–115. 19. Gigue`re S, Lee E, Williams E, et al. Prevalence of Rhodo- 11. Venner M, Kerth R, Klug E. Evaluation of tulathromycin in coccus equi isolates resistant to macrolides or rifampin and the treatment of pulmonary abscesses in foals. Vet J 2007; outcome of infected foals. J Am Vet Med Assoc 2010;237:74– 174:418–421. 81. 12. Stratton-Phelps M, Wilson WD, Gardner IA. Risk of ad- 20. Womble A, Gigue`re S, Lee EA. Pharmacokinetics of oral verse effects in pneumonic foals treated with erythromycin doxycycline and concentrations in body fluids and broncho- versus other antibiotics: 143 cases (1986–1996). JAmVet alveolar cells of foals. J Vet Pharmacol Ther 2007;30:187– Med Assoc 2000;217:68–73. 193. 13. Baverud V, Franklin A, Gunnarsson A, et al. Clostridium 21. Nordmann P, Kerestedjian JJ, Ronco E. Therapy of Rho- difficile associated with acute colitis in mares when their dococcus equi disseminated infections in nude mice. Anti- foals are treated with erythromycin and rifampicin for microb Agents Chemother 1992;36:1244–1248. Rhodococcus equi pneumonia. Equine Vet J 1998;30:482– 22. Hoffman AM, Viel L. A percutaneous transtracheal cathe- 488. ter system for improved oxygenation in foals with respiratory 14. McNeil MM, Brown JM. Distribution and antimicrobial distress. Equine Vet J 1992;24:239–241. susceptibility of Rhodococcus equi from clinical specimens. 23. Reuss SM, Chaffin MK, Cohen ND. Extrapulmonary disor- Eur J Epidemiol 1992;8:437–443. ders associated with Rhodococcus equi infection in foals: a 15. Takai S, Takeda K, Nakano Y et al. Emergence of rifampin- retrospective study of 150 cases (1987–2007). J Am Vet Med resistant Rhodococcus equi in an infected foal. J Clin Mi- Assoc 2009;235:855–863. crobiol 1997;35:1904–1908. 24. Valdes A, Johnson JR. Septic pleuritis and abdominal ab- 16. Fines M, Pronost S, Maillard K, et al. Characterization of scess formation caused by Rhodococcus equi in a foal. JAm mutations in the rpoB gene associated with rifampin resis- Vet Med Assoc 2005;227:960–963. tance in Rhodococcus equi isolated from foals. J Clin Micro- 25. Elissalde GS, Renshaw HW, Walberg JA. Corynebacterium biol 2001;39:2784–2787. equi: an interhost review with emphasis on the foal. Comp 17. Asoh N, Watanabe H, Fines-Guyon M, et al. Emergence of Immunol Microbiol Infect Dis 1980;3:433–445. rifampin-resistant Rhodococcus equi with several types of 26. Ainsworth DM, Eicker SW, Yeagar AE, et al. Associations mutations in the rpoB gene among AIDS patients in northern between physical examination, laboratory, and radiographic Thailand. J Clin Microbiol 2003;41:2337–2340. findings and outcome and subsequent racing performance 18. Kenney DG, Robbins SC, Prescott JF, et al. Development of of foals with Rhodococcus equi infection: 115 cases (1984– reactive arthritis and resistance to erythromycin and ri- 1992). J Am Vet Med Assoc 1998;213:510–515.

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