AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Rhodococcus equi primarily causes zoonotic infections that affect grazing animals, mainly horses and foals. Although R equi is an unusual cause of infection in immunocompetent humans, it nevertheless is emerging as an important pathogen in those who are immunocompromised.

R equi is a facultative, intracellular, nonmotile, non–spore-forming, gram-positive coccobacillus (an organism that has the ability to exist as a coccus or bacillus or intermediate form). Called Rhodococcus because of its ability to form a red (salmon-colored) pigment, R equi can be weakly acid-fast and bears a similarity to diphtheroids. R equi previously was called Corynebacterium equi and is currently grouped with the aerobic actinomycetes. Of the 40 genera in the actinomycetes group, Rhodococcus is placed among the nocardioform bacteria, along with Mycobacterium, Nocardia, Gordonia, Tsukamurella, and Corynebacterium.

R equi was first isolated in 1923 from foals as Corynebacterium equi. Infection in a human being was first reported in 1967 in a 29-year-old man with plasma cell hepatitis receiving immunosuppressant medications. Since then, it has become an important opportunistic pathogen in immunocompromised patients, especially those with acquired immunodeficiency syndrome (AIDS). Infection with R equi is associated with significant mortality. The organism can be difficult to eradicate, making treatment challenging at times. Increased awareness of the infection may help with early diagnosis and timely treatment. Treatment may require combination antibiotic therapy of prolonged duration, sometimes in combination with surgical therapy.

Pathophysiology

Necrotizing pneumonia is the most common form of infection caused by R equi. Extrapulmonary infections described in human beings include wound infection, subcutaneous abscess, brain abscess, thyroid abscess, retroperitoneal abscess, peritonitis, meningitis, pericarditis, osteomyelitis, endophthalmitis, lymphadenitis, lymphangitis, septic arthritis, osteitis, bloody diarrhea, and fever of unknown origin, among others. Bacteremia and dissemination of infection follow from the primary site of infection, which usually is the lung.

The primary source of infection may also be from the alimentary tract. This hypothesis arises from a few observations. First, in patients infected with human immunodeficiency virus (HIV), R equi has been isolated from the stool, with or without evidence of pneumonia. Second, R equi frequently colonizes the gastrointestinal tract in grazing animals. In addition, Verville and colleagues (1994) described an incidental finding of mesenteric lymphadenitis caused by R equi in a woman undergoing laparotomy for cholelithiasis. Hence, the possibility of asymptomatic carriage in the gastrointestinal tract in human beings, similar to grazing animals, has been proposed. Third, a case of cervical lymphadenitis has been attributed to a history of sucking raw carrots.

In experimental and natural animal infections, R equi acts as an intracellular bacterium, which survives within macrophages and eventually destroys them. Experimental data suggest that R equi is capable of inhibiting oxidative bactericidal functions of polymorphonuclear cells. Electron microscopy of R equi in equine macrophages demonstrates that the organisms appear to avoid being killed by interfering with phagosome-lysosome fusion.

Pathogenesis: Most of the information about the pathogenesis of R equi infections is derived from animal isolates. However, the infection in humans seems to differ from that in foals. Makrai et al demonstrated that a 15- to 17-kd virulence-associated protein antigen (VapA), which is highly virulent, may mediate about 88% of the isolates from foals. Nearly all isolates from pigs are of 20-kd virulence-associated protein antigen (VapB) origin, which is of intermediate virulence. In human beings, only about 20-25% of isolates have been reported to express VapA. However, in a study performed by Takai et al, about 75% of human isolates expressed VapB, and 25% were avirulent. Most of these patients from Thailand were infected with HIV.

The expression of VapB is known to vary with the geographical location. These differences between human and animal R equi infections are important since most of the investigation has involved VapA isolates. Hence, the conclusion drawn from animal models may not be entirely applicable to the pathogenesis of R equi infections in humans.

Frequency

United States

R equi infections are reported in at least 28 states.

International

Infections caused by R equi have been reported on 5 continents of the world. Thus far, a few hundred cases of R equi infections are reported in the literature in immunocompromised. At least 19 cases of R equi infection have been described in immunocompetent patients.

Mortality/Morbidity

• Morbidity is related to complications and chronicity of the infection. Numerous complications are related to R equi infections. R equi pneumonia may be complicated by the following:
• • Abscess
  • Empyema
  • Pleural effusion
  • Hemoptysis
  • Direct chest wall involvement
  • Pneumothorax
• Pericardial tamponade may result from purulent pericarditis. Bacteremia leading to overwhelming sepsis has been reported, more often in immunocompromised patients. In a review by Verville et al (1994), about 47% of patients infected with HIV and 17% of patients with non–HIV-associated immunocompromised conditions had chronic infection. Relapses also are common after discontinuation of antibiotics. An important site of extrapulmonary relapse is the central nervous system.
• The overall mortality rate with R equi infections is about 25%. In 2 different reports, by Cornish et al (1999) and by Harvey and Sunstrum (1991), the mortality rate is 50-55% in patients infected with HIV and 20-25% in patients with non–HIV-associated immunocompromised conditions. In contrast, the mortality rate is only about 11% in immunocompetent patients. While this figure is lower in immunocompetent patients, it is still significant. Lower mortality rates in this subgroup of patients may be due to the fact that localized infections represent about 50% of the cases reported.
• Several reasons exist for the high mortality rates in R equi infections.
• • R equi may be misidentified as diphtheroids, Mycobacterium species, or nocardia. This may happen in immunocompetent as well as in those who are immunocompromised.
  • Patients may receive inappropriate initial antibiotic therapy because of misdiagnosis. R equi infection does not respond to standard empirical treatment of pneumonia with beta-lactams (other than imipenem and meropenem) and tetracyclines. Macrolides and the newer quinolones, on the other hand, may treat R equi pneumonia.
  • Simultaneous opportunistic infections are frequently recognized, especially in patients infected with HIV. In this subgroup of patients, the mortality rate directly attributed to R equi infection alone may be less. In a series of patients infected with HIV who had R equi pneumonia described by Capdevila et al (1997), the mortality rate directly attributed to R equi infection was only 15.4%. In another review of R equi infections in patients infected with HIV, 4 of 12 patients died owing to R equi infection, while 3 deaths were due to opportunistic infections.

Race

No racial differences in incidence have been described.

Sex

Both in individuals who are immunocompromised and in those who are immunocompetent, the male-to-female ratio is about 3:1. The reason for this is not clear; however, in patients who are immunocompromised, it may be explained by the higher prevalence of HIV infection among males.

Age

R equi infections in human beings are described in all age groups, from infants to elderly people. The mean age of infection varies in different reviews from 34-38 years.

Infection in children

R equi infection among children differs from that observed in adults. Immunocompromised conditions account for only about one third of the cases reported. Immunocompromised conditions in children with R equi infections include hematopoietic malignancies, immunosuppression associated with chemotherapy, and HIV infection. Infection in children accounted for approximately one third of cases among immunocompetent individuals, which may be due to increased occurrence of trauma in children, predisposing them to localized wound infections with R equi. Prognosis in immunocompetent children is extremely favorable.

CLINICAL

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History

Onset is generally insidious, and presenting symptoms vary according to the site of infection. Symptoms in immunocompetent patients do not differ from those in immunocompromised patients. In infections secondary to trauma, such as endophthalmitis, septic arthritis, and traumatic meningitis, symptoms may present within 24 hours of the trauma.

• Pulmonary infections
• • Fever and cough (>80% of patients with pulmonary infections)
  • Malaise
  • Chest pain
  • Dyspnea
  • Hemoptysis
  • Weight loss
  • Possible chronic or relapsing course
  • Possible community-acquired pneumonia that fails to respond to empirical treatment
• Other infections: Other presentations of R equi infection include lymphadenopathy, eye drainage and pain, joint pain, altered level of consciousness, bloody diarrhea, or fever of unknown origin. Anemia caused by colonic polyps infected with R equi has also been reported.
• R equi infections can also be acquired nosocomially. Poststernotomy infection after coronary artery bypass grafting has been reported twice, and postneurosurgical brain abscess has been reported once (although not officially). Infection after placement of a ventriculoperitoneal (VP) shunt has also been reported twice.
• Epidemiological history is important. Exposure to soil contaminated with manure is the most likely route of both animal and human infection. Exposure is usually by inhalation, but infections by oral route (due to ingestion of soil or food) or by direct inoculation due to trauma also are well described. A history of animal exposure may be absent.
• • R equi has been found in bovine, porcine, and equine fecal flora and grows best at summer temperatures. Isolation of the organism from the air on horse farms rises with ambient temperature and is highest on dry windy days.
  • In addition, a history concerning any preexisting immunocompromising conditions should be obtained. These include malignancy, recent chemotherapy, solid organ or bone marrow transplantation, diabetes mellitus, alcoholism, and immunosuppressive medications. History pertaining to sexual practices and injection drug use is also important.

Physical

Physical findings depend on the site of infection.

• Fever
• Tachypnea, crackles, and other common physical findings of pneumonia
• Lymphadenopathy
• Septic arthritis
• Corneal laceration, hyperemia, decreased visual acuity, evidence of anterior chamber involvement (such as hypopyon)
• Findings of meningitis
• Soft tissue masses, induration, fluctuance in localized infections consistent with abscesses, examination of postoperative sites

Causes

• About 80-90% of patients with R equi infection are immunocompromised. About 50-60% of the patients have HIV infection, 15-20% have hematopoietic and other malignancies, and 10% are transplant recipients. Infections have been reported in the following immunocompromised conditions:
• • AIDS: In a study by Capdevila et al (1997) of 78 patients infected with HIV who developed R equi pneumonia, 71 patients met criteria for AIDS and at least 60 of 78 patients had CD4⁺ counts of less than 200 cells/µL. In another study, by Donisi et al (1996) involving R equi pneumonia in patients infected with HIV, the mean CD4⁺ count was 47.7 cells/µL.
  • Lymphoma, leukemia, and other malignancies: This includes immunosuppression associated with chemotherapy, such as neutropenia. Neutropenic fever due to bacteremia caused by R equi has been described.
  • Transplantation, including solid organ (kidney, liver, heart), and bone marrow
  • Chronic renal insufficiency and patients with end-stage renal disease on peritoneal dialysis
  • Alcoholism
  • Diabetes mellitus
  • Patients receiving immunosuppressive therapy, including corticosteroids
• Remember that R equi infections can also occur in immunocompetent. Infections in these patients include pneumonia, endophthalmitis, septic arthritis, traumatic meningitis, brain abscess, fever of unknown origin, lymphangitis, and lymphadenitis. A history of trauma should be obtained because about 50% of the infections described in immunocompetent patients are due to trauma.

DIFFERENTIALS

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Other Problems to be Considered

The differential diagnoses for R equi infections include Mycobacterium tuberculosis, other nontuberculous mycobacteria, nocardia, fungi, and diphtheroids.

Because of the variable acid-fast nature of R equi infection and its similarity to pulmonary tuberculosis, patients initially being treated for tuberculosis have been reported.

These coccobacilli may be arranged at right angles to each other, leading to confusion with diphtheroids. In patients with cavitary pneumonia, the sputum finding of diphtheroids and other normal commensals should raise suspicion of R equi as the etiologic agent.

The acid-fast nature and the production of aerial hyphae in certain media may lead to a diagnosis of nocardia infection.

R equi can initially cause an interstitial pneumonia. In patients infected with HIV who have pneumonia, therefore, an initial diagnosis of Pneumocystis jiroveci pneumonia has been made.

Cavitary pneumonia due to R equi in a patient infected with HIV or in a patient with neutropenia can be mistaken for fungal pneumonia.

Other noninfectious conditions that may initially be included in the differential diagnoses include lung nodules caused by metastasis and Wegener granulomatosis.

WORKUP

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Lab Studies

• Complete blood count: This is important for evaluation of leukocytosis, anemia, and neutropenia.
• Chemistry panel
• HIV screening tests: All patients with R equi infection should be screened for HIV because more than half of reported cases involve patients infected with HIV.
• Blood cultures (including lysis centrifugation blood cultures for fungi and mycobacteria): The distinctive salmon-colored colonies may not appear for 4-7 days. Any growth of diphtheroids should be viewed with suspicion. Consider blood cultures also in localized infections. In patients infected with HIV, the rate of positive blood culture results is 83-100%. In immunocompetent patients, blood cultures yield positive results in about 30% of patients.
• Sputum Gram stain and culture: In patients infected with HIV who have pulmonary involvement, the rate of positive sputum culture results may be 60-100%. A positive sputum culture result may be found in only about 35% of immunocompetent patients.
• Stool culture: Obtain a stool culture in a patient infected with HIV who has diarrhea.
• Depending on the site of infection, obtain specimens for culture from other infected sources, such as abscess, eye drainage, and cerebrospinal fluid.

Imaging Studies

• Chest radiograph: Consider a chest radiograph even in patients with extrapulmonary infections.
• • Multiple nodular infiltrates (See Images 1-2) are the usual findings. In patients infected with HIV, a preference for the upper lobes seems to exist. Upper lobes were involved in 55% and lower lobes in 35%. In immunocompetent patients, no definite predilection exists for any particular lobe.
  • If untreated, nodular infiltrates are followed by cavitation. Approximately 54-77% of all patients with R equi infection demonstrate cavitation. Cavitation is more frequently observed in patients infected with HIV (about 67-77%).
  • Other findings on the chest radiograph include interstitial pneumonia, abscesses, and pleural effusion. Cavities observed with R equi infection are thick-walled and may demonstrate air-fluid levels, indicating progression to abscess formation.
• CT scan of the thorax is more sensitive and may show more nodules and cavitation than are observed on a plain radiograph (see Image 3).
• Plain radiographs in osteomyelitis may demonstrate an osteolytic lesion. CT scan and MRI study may demonstrate a mass with a necrotic center. Appropriate imaging is also necessary in cases of meningitis, brain abscess, and abdominal infections.

Other Tests

• Microbiological characteristics
• • R equi is cultured easily in ordinary nonselective media. Large, smooth, irregular, mucoid colonies appear within 48 hours. The salmon-colored pigment rarely appears before 4 days.
  • R equi is a facultative, intracellular, nonmotile, non–spore-forming organism. Gram stain shows pleomorphic gram-positive coccobacilli. The bacteria may be coccoid in solid media, but, in liquid media, they form long rods. The organism may also be inconsistently acid-fast with Ziehl-Nelson staining, depending on the culture media. It may be distinguished from mycobacterial genera with the 14-day arylsulfatase test.
  • R equi is nonfermenting (distinguishing it from pathogenic corynebacteria), gelatinase negative, catalase positive, usually urease positive, and oxidase negative.

Procedures

• Bronchoscopy with washings and bronchoalveolar lavage (BAL) are other diagnostic procedures that may be helpful in obtaining diagnosis. Reviews of R equi infection have reported that specimens obtained with bronchial washings or BAL showed positive results in 46%-66% of patients infected with HIV.
• Other diagnostic procedures that may be necessary in R equi pneumonia include aspiration of pleural fluid, transthoracic needle biopsy, and open lung biopsy.
• Likewise, depending on the site of infection, other procedures may provide the diagnosis. These may include lumbar puncture, biopsy, aspiration of abscess, joint aspiration, bone marrow biopsy, and vitrectomy for endophthalmitis.

Histologic Findings

The ability of R equi to persist in and destroy macrophages is the basis of its pathogenesis. The typical pattern is a necrotizing granulomatous reaction dominated by macrophages filled with granular cytoplasm that shows positive results on periodic acid-Schiff stain and contains large numbers of coccobacilli.

Malacoplakia is an unusual inflammatory disorder with accumulation of characteristic histiocytes with calcified lamellar cytoplasmic bodies (Michaelis-Gutman bodies). Malacoplakia was initially described in lower urinary tract infections, and Escherichia coli is the organism most often implicated. Pulmonary infections with R equi in immunocompromised hosts may have this typical histopathological finding. If malacoplakia is found in pulmonary infections, strongly suspect infection with R equi. Although malacoplakia in immunocompromised patients is mostly found in pulmonary infections, it also has been demonstrated in subcutaneous infections and abscesses.

TREATMENT

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Medical Care

The mainstay of medical care is treatment of the underlying infection with antibiotics and surgical therapy, as described below. Other aspects of medical care include the following:

• Providing good supportive care, including adequate oxygenation with ventilatory support, if necessary
• Maximizing nutritional status
• Diagnosing and treating underlying immunosuppression
• Spontaneous resolution of a pulmonary nodule caused by R equi has been reported in a patient who underwent transplantation.

Surgical Care

• Surgical therapy has a definite role in certain infections. Local surgical resection or debridement is recommended in cases of endophthalmitis, osteomyelitis, subcutaneous abscess, paravertebral abscess, and pericardial effusion.
• In pneumonia caused by R equi, surgical treatment has no obvious benefit. Some authors recommend surgical treatment such as lobectomy or partial lung resection when infection has evolved into a large abscess or when infection is overwhelming. Consideration of surgical resection also seems prudent when an infection fails to respond to antibiotics alone.
• • In one review by Capdevila et al (1997), 11 of 78 patients infected with HIV who had R equi pneumonia underwent surgery. Four of the 11 patients died, 3 cases resolved, the course was unknown in 3 patients, and, in 1 patient, the infection was chronic.
  • A 1991 review by Harvey et al included patients with and without immunocompromised conditions. The overall rate of survival was 75% when surgical resection was combined with antibiotic therapy. Among patients receiving antibiotics alone, the survival rate was 61.1%. Two of 4 patients infected with HIV who received surgical treatment in addition to antibiotics died, while the remaining 2 improved. Also notable is that this study included a few patients with localized extrapulmonary infections.
  • In a review of the infection in patients who underwent transplantation, 3 patients with pneumonia were treated with surgical resection. One of them was cured despite receiving no antibiotics. Of the remaining 2 patients who received additional antibiotic treatment, 1 died (death was due to other causes) and the other had a relapse.
  • Two immunocompetent patients with R equi pneumoniaunderwent surgical resection even before a definitive diagnosis was made. One of them died, while the other was cured.
  • In R equi pneumonia, other surgical therapy, such as drainage of empyema, may be used.

Consultations

Infectious disease consultation is helpful, not only in providing recommendations regarding the diagnosis and management of suspected R equi infection, but also with regards to the management of any underlying immunocompromised condition (eg, HIV/AIDS).

Diet

No dietary modifications modify the disease course.

Activity

No activity modifications are required.

MEDICATION

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In vitro susceptibilities

R equi usually is susceptible to the following:

• Erythromycin
• Ciprofloxacin
• Vancomycin
• Aminoglycosides
• Rifampin
• Imipenem
• Meropenem

R equi is usually resistant to penicillin G, ampicillin, carbenicillin, and cefazolin. Sensitivities to clindamycin, ceftriaxone, trimethoprim, sulfamethoxazole, tetracycline, and chloramphenicol vary. Although the organism sometimes shows sensitivity to beta-lactams in vitro, several reports have described acquired resistance to them during treatment.

Medical treatment

A study based on experiments on animals demonstrated that the effective single agents against R equi include vancomycin, imipenem, and rifampin. In the same study, combinations of antibiotics were not more effective than vancomycin alone. However, combinations of antibiotics may limit the emergence of in vivo antibiotic-resistant mutants.

Many authors recommend use of combination antibiotics. Some also recommend using at least one antibiotic with intracellular penetration (eg, erythromycin, rifampin). In vitro synergy studies demonstrated 4 combinations of antibiotics to be effective against R equi infection (ie, rifampin-erythromycin, rifampin-minocycline, erythromycin-minocycline, imipenem-amikacin). In the same study, the combination of macrolides and aminoglycosides was found to be antagonistic. However, it has been used with success clinically.

A few cases of brain abscesses and nosocomial meningitis have been reported in immunocompetent patients. In one case report by Scotton et al, a patient with nosocomial meningitis was initially treated with vancomycin and rifampin. However, because of continued fever, monotherapy with levofloxacin was instituted with success. Clinical success with vancomycin monotherapy followed by oral sulfamethoxazole-trimethoprim has been documented in an immunocompetent patient with brain abscess, in addition to neurosurgical treatment.

However, monotherapy should generally not be used to treat systemic infections. In a case report published by Gabriels et al in 2006, initial monotherapy with levofloxacin was unsuccessful. This was followed by recurrent infections and death in an immunocompetent patient. The organism was initially sensitive to levofloxacin but later acquired resistance to the antibiotic.

Giguere et al performed a retrospective comparison of combination therapy with azithromycin-rifampin, clarithromycin-rifampin, and erythromycin-rifampin in foals with pneumonia. The combination of clarithromycin-rifampin was superior to the other 2 groups of therapy.

In general, treat pulmonary infections for a minimum of 2 months. Treatment should initially consist of parenteral antibiotics followed by oral combination therapy. One author recommends initial therapy with a vancomycin-based regimen followed by oral combination therapy with rifampin plus erythromycin or rifampin plus minocycline.

In immunocompetent patients, a shorter duration of therapy may be considered because infection has been treated successfully with shorter courses. Selective local infections without evidence of systemic involvement can be treated with shorter courses of antibiotics, with or without local surgical resection. Topical antibiotics have also been used in endophthalmitis, in combination with systemic antibiotics and surgical therapy.

Drug Category: Antibiotics

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.

FOLLOW-UP

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Further Inpatient Care

• Monitor for clinical improvement. Repeat imaging may be necessary. Any pleural effusion that develops may require drainage.
• Provide follow-up care for adverse effects of antibiotics and drug interactions, especially in patients infected with HIV who are on antiretroviral medications.
• Provide good supportive care.
• Consider outpatient management once improvement with antibiotics is observed.

Further Outpatient Care

• Ensure compliance with antibiotics.
• Monitor for resolution. Antibiotics can be discontinued after complete resolution is achieved.
• Watch for relapse, especially in patients infected with HIV.

In/Out Patient Meds

• Outpatient continuation of antibiotics

Deterrence/Prevention

• Patients, especially those who are immunocompromised, should exercise caution in contact with farm animals. This especially is true on dry windy days.
• Implement good hygienic measures when eating fresh farm vegetables.

Prognosis

• In general, prognosis depends on the underlying immunosuppressive conditions and other concurrent infections. Early diagnosis and treatment may prevent chronicity and relapses.
• Prognosis is favorable in most local infections and among children who are immunocompetent.

MISCELLANEOUS

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Medical/Legal Pitfalls

• A high index of suspicion is indeed necessary for early diagnosis. Medical pitfalls are mainly due to delayed diagnosis. This may occur because of the low level of awareness of the infection. Specimens may be wrongfully discarded as contaminant diphtheroids. With greater awareness and improvement in laboratory techniques, R equi infections will be recognized earlier.

MULTIMEDIA

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Media file 1:  Chest radiograph of a patient with Rhodococcus equi infection (see Images 2 and 3) showing multiple nodular infiltrates.
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Media type:  X-RAY

Media file 2:  Chest radiograph of a patient with Rhodococcus equi infection (see Images 1 and 3) demonstrating cavitation of pulmonary nodules.
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Media type:  X-RAY

Media file 3:  Chest CT scan of a patient with Rhodococcus equi infection (see Images 1 and 2) demonstrating nodular infiltrates.
	View Full Size Image
Media type:  CT

REFERENCES

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• Legras A, Lemmens B, Dequin PF, et al. Tamponade due to Rhodococcus equi in acquired immunodeficiency syndrome. Chest. Oct 1994;106(4):1278-9. [Medline].
• Linares MJ, Lopez-Encuentra A, Perea S. Chronic pneumonia caused by Rhodococcus equi in a patient without impaired immunity. Eur Respir J. Jan 1997;10(1):248-50. [Medline].
• Makrai L, Takai S, Tamura M, et al. Characterization of virulence plasmid types in Rhodococcus equi isolates from foals, pigs, humans and soil in Hungary. Vet Microbiol. Sep 24 2002;88(4):377-84. [Medline].
• Moyer DV, Bayer AS. Progressive pulmonary infiltrates and positive blood cultures for weakly acid-fast, gram-positive rods in a 76-year-old woman. Chest. Jul 1993;104(1):259-61. [Medline].
• Munoz P, Burillo A, Palomo J, et al. Rhodococcus equi infection in transplant recipients: case report and review of the literature. Transplantation. Feb 15 1998;65(3):449-53. [Medline].
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Article Last Updated: Jan 9, 2007