Straight from the Horse’s Lung: Rhodococcus Equi

Originally described as a pathogen in 1923, Corynebacterium equi was isolated from the lungs of ten foals (aka a young horse) who had pneumonia (1). Its name was later changed to rhodococcus (aka red coccus), and can be mistaken for mycobacterium spp due to its sometimes acid-fast appearance (2). It is known to infect horses, cattle, swine, and sheep causing lymphadenitis, mediastinitis, and pyometra, and it is related to Nocardia, Corynebacterium, Mycobacterium, and Gordonia spp. Infection of humans is likely mediated via inhalation, given its propensity to cause pneumonia in immunocompromised hosts exposed to livestock or farming environments (3). Its pathological hallmark include malakoplakia, which is a dense infiltration of foamy histiocytes with intracellular coccobacilli and scattered concentric basophilic inclusions. It has been described as a facultative, intracellular pathogen infecting macrophages and surviving inside lysosomes as well as human alveolar epithelial cells. Here, I’ll review the presentation of rhodococcus equi in humans, which is primarily a severe pulmonary infection in an AIDS patient.

The course of pneumonia is usually insidious, with fever, fatigue, cough, and dyspnea being the predominant symptoms. Sputum production is variable, with chest X-ray demonstrating unilobar infiltrates which progress over 2-3 weeks into cavitary lesions. An observational, multicenter cohort of 67 HIV-positive patients (4) found the most common symptoms were fever (91%), cough (88.1%), expectoration (85%), and chest pain (45%). 

Imaging revealed cavitations in 45 patients and multilobar involvement in 13 patients. Pulmonary involvement was seen in 95.5% of patients, with 59.8% having bacteremia. Moreover, univariate analysis found that absence of ART (RR 53.4, 95% CI 1.7-1,669) and multilobar pneumonia (RR 3.1, 95% CI 1.2 to 7.9) was strongly associated with increased mortality. Similarly, a retrospective study of 12 HIV-positive patients found the most common symptoms were  cough and fever (5). 42% of cases presented with cavitary lesions on CXR, followed by consolidation in 33%. Notably, none of the patients had any exposure to foals or horses. A sample of 12-HIV positive patients demonstrates that most presentations are usually pulmonary (6):

A series of 12 cases found that immunocompetent patients can also present with community acquired pneumonia, however wound infections are also seen (7). In their literature review, pneumonia accounted for 76% of cases with 82% of patients having the lung as the only site of infection. Moreover, 86% of patients had some degree of immunocompromise with half being due to HIV. 

There were no fatalities in the immunocompetent case series:

As it is the usual for AIDS-related diseases, Rhodococcus can be one amongst the many concurrent conditions. An analysis of 24-HIV infected patients, many had a concomitant opportunistic infection, including CMV chorioretinitis, candida esophagitis, cryptococcus meningitis, disseminated MAC, and PJP pneumonia (8). 14 out of 24 patients had some sort of exposure, including 7 who were in contact with horses and 4 who were sharing a room with a patient with R. equi pneumonia. Fever, cough, chest pain, hemoptysis, and dyspnea were the most common symptoms, with imaging revealing interstitial pneumonia, consolidation in 9 patients, and cavitary lesions in 18. Relapse was common, with 14 suffering relapses. 

A review of 11 patients found that 8 had advanced AIDS, with 5 having simultaneous opportunistic infections at the time of R. equi infection (9). The presentation for HIV- and non-HIV infected patients were very similar, however mortality was significantly higher in HIV-infected patients:

Other associated immunosuppressive states included solid organ transplantation, bone marrow transplantation, insulin-dependent diabetes, and Hodgkin’s disease. In a series of 12 patients, 8 had fever and cough, 7 had cavitary lesions and 6 had multiple nodules in imaging (10). Pathology revealed a necrotizing cavitary lung or soft tissue mass composed of dense histiocytic infiltrate with eosinophilic granular cytoplasm. A case-control study of 18 hematopoietic stem cell transplant patients found that the predominant types of infections involving Rhodococcus were pneumonia in 61% and bacteremia in 56% (11). In those who had pneumonia, 73% had infiltrative disease, 73% had nodular disease, and 18% had cavitary disease. These 18 patients were matched with 36 controls and univariate analysis demonstrated that the type of immunosuppression did not influence the risk of rhodococcus:

Interestingly, type 2 diabetes mellitus and a recent opportunistic infection were risk factors for infection. Moreover, cases of rhodococcus have been identified in patients with solid organ transplants, with a review highlighting 29 such cases, predominantly presenting as pneumonia (12). Not surprisingly, this cohort had varying degrees of findings on their chest x-ray, including abscess, nodules, infiltrates, and cavities. A handful of these cases were complicated by infections at other sites, including paravertebral soft tissue mass, brain cystic lesions, and osteomyelitis of the femur. Similarly, a series of 29 patients revealed the following breakdown of risk factors and clinical complications (13):

Antibiotic Therapy

I’d like to call this the “evidence free” zone of the topic. Given the rarity of this disease, there is no robust data to recommend one type of therapy over another. Several reviews on the pathophysiology recommend drugs such as macrolides, rifampicins, and quinolones to be used, as they tend to be cell-penetrating drugs that can more appropriately target this intracellular infection (14):

Drugs such as beta-lactams, aminoglycosides, or glycopeptides tend to not penetrate macrophages and should be used in combination with something like macrolides. Another review highlights that nearly 90% of isolates tend to be susceptible to macrolides, carbapenems, rifampin, and ciprofloxacin with prolonged therapy with at least 2 antibiotics being the norm, ranging from 6 to 9 months (15). This recommendation comes from case series and in vitro susceptibility. Indeed, antibiogram from several case series confirms the above findings, with aminoglycosides and vancomycin also having good profiles (4, 5, 7, 9):

Older cohorts suggest that the combination of aminopenicillins and beta-lactamase inhibitors may be susceptible. For instance, one cohort of 107 strains found no resistance to amox-clav, amp-sulbactam, or imipenem with high degrees of resistance to aminopenicillins and clindamycin (16)::

An in vitro study found that the combination of penicillin and erythromycin were more likely to be synergistic, followed by rifampicin and erythromycin (17):

The most active antibiotics in a 100 strain cohort found that penicillin G, doxycycline, erythromycin, and aminoglycosides were the most active (18):

Overall, empiric therapy with vancomycin and a carbapenem OR with a macrolide is reasonable with tailoring to dual therapy that includes rifampin or macrolide or quinolones. Basically, anything that allows the targeting of intracellular organisms. Duration of therapy is difficult to ascertain. One report of 7 patients highlights 2 recurrences, one of which occurred within 5 months of treatment (19), suggesting that therapy may require long durations and follow up focus of infection with imaging. Indeed, up to date suggests a minimum of 2 months of therapy.

References:

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2. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. Philadelphia, PA :Elsevier/Saunders, 2015.
3. Yamshchikov AV, Schuetz A, Lyon GM. Rhodococcus equi infection. Lancet Infect Dis. 2010 May;10(5):350-9. doi: 10.1016/S1473-3099(10)70068-2. PMID: 20417417.
4. Torres-Tortosa M, Arrizabalaga J, Villanueva JL, Gálvez J, Leyes M, Valencia ME, Flores J, Peña JM, Pérez-Cecilia E, Quereda C; Grupo Andaluz para el estudio de las Enfermedades Infecciosas; Grupo de estudio de SIDA of the Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Prognosis and clinical evaluation of infection caused by Rhodococcus equi in HIV-infected patients: a multicenter study of 67 cases. Chest. 2003 Jun;123(6):1970-6. doi: 10.1378/chest.123.6.1970. PMID: 12796176.
5. Donisi A, Suardi MG, Casari S, Longo M, Cadeo GP, Carosi G. Rhodococcus equi infection in HIV-infected patients. AIDS. 1996 Apr;10(4):359-62. doi: 10.1097/00002030-199604000-00002. PMID: 8728038.
6. Emmons W, Reichwein B, Winslow DL. Rhodococcus equi infection in the patient with AIDS: literature review and report of an unusual case. Rev Infect Dis. 1991 Jan-Feb;13(1):91-6. doi: 10.1093/clinids/13.1.91. PMID: 2017640.
7. Verville TD, Huycke MM, Greenfield RA, Fine DP, Kuhls TL, Slater LN. Rhodococcus equi infections of humans. 12 cases and a review of the literature. Medicine (Baltimore). 1994 May;73(3):119-32. doi: 10.1097/00005792-199405000-00001. PMID: 8190035.
8. Arlotti M, Zoboli G, Moscatelli GL, Magnani G, Maserati R, Borghi V, Andreoni M, Libanore M, Bonazzi L, Piscina A, Ciammarughi R. Rhodococcus equi infection in HIV-positive subjects: a retrospective analysis of 24 cases. Scand J Infect Dis. 1996;28(5):463-7. doi: 10.3109/00365549609037941. PMID: 8953675.
9. Harvey RL, Sunstrum JC. Rhodococcus equi infection in patients with and without human immunodeficiency virus infection. Rev Infect Dis. 1991 Jan-Feb;13(1):139-45. doi: 10.1093/clinids/13.1.139. PMID: 2017613.
10. Scott MA, Graham BS, Verrall R, Dixon R, Schaffner W, Tham KT. Rhodococcus equi–an increasingly recognized opportunistic pathogen. Report of 12 cases and review of 65 cases in the literature. Am J Clin Pathol. 1995 May;103(5):649-55. doi: 10.1093/ajcp/103.5.649. PMID: 7741114.
11. Vergidis P, Ariza-Heredia EJ, Nellore A, Kotton CN, Kaul DR, Morris MI, Kelesidis T, Shah H, Park SY, Nguyen MH, Razonable RR. Rhodococcus Infection in Solid Organ and Hematopoietic Stem Cell Transplant Recipients1. Emerg Infect Dis. 2017 Mar;23(3):510-512. doi: 10.3201/eid2303.160633. PMID: 28221102; PMCID: PMC5382763.
12. Arya B, Hussian S, Hariharan S. Rhodococcus equi pneumonia in a renal transplant patient: a case report and review of literature. Clin Transplant. 2004 Dec;18(6):748-52. doi: 10.1111/j.1399-0012.2004.00276.x. PMID: 15516256.
13. Lasky JA, Pulkingham N, Powers MA, Durack DT. Rhodococcus equi causing human pulmonary infection: review of 29 cases. South Med J. 1991 Oct;84(10):1217-20. doi: 10.1097/00007611-199110000-00014. PMID: 1925723.
14. Cisek AA, Rzewuska M, Witkowski L, Binek M. Antimicrobial resistance in Rhodococcus equi. Acta Biochim Pol. 2014;61(4):633-8. Epub 2014 Nov 4. PMID: 25371917.
15. Lin WV, Kruse RL, Yang K, Musher DM. Diagnosis and management of pulmonary infection due to Rhodococcus equi. Clin Microbiol Infect. 2019 Mar;25(3):310-315. doi: 10.1016/j.cmi.2018.04.033. Epub 2018 May 16. PMID: 29777923.
16. McNeil MM, Brown JM. Distribution and antimicrobial susceptibility of Rhodococcus equi from clinical specimens. Eur J Epidemiol. 1992 May;8(3):437-43. doi: 10.1007/BF00158580. PMID: 1397208.
17. Prescott JF, Nicholson VM. The effects of combinations of selected antibiotics on the growth of Corynebacterium equi. J Vet Pharmacol Ther. 1984 Mar;7(1):61-4. doi: 10.1111/j.1365-2885.1984.tb00880.x. PMID: 6561258.
18. Woolcock JB, Mutimer MD. Corynebacterium equi: in vitro susceptibility to twenty-six antimicrobial agents. Antimicrob Agents Chemother. 1980 Dec;18(6):976-7. doi: 10.1128/AAC.18.6.976. PMID: 7235683; PMCID: PMC353000.
19. Po-Ren Hsueh, Chien-Ching Hung, Lee-Jeng Teng, Ming-Chih Yu, Yu-Chi Chen, Hua-Kung Wang, Kwen-Tay Luh, Report of Invasive Rhodococcus equi Infections in Taiwan, with an Emphasis on the Emergence of Multidrug-Resistant Strains, Clinical Infectious Diseases, Volume 27, Issue 2, August 1998, Pages 370–375, https://doi.org/10.1086/514667