Rhodococcus equi Infection


Background

Rhodococcus equi primarily causes zoonotic infections in grazing animals, mainly horses and foals. [12Although R equi rarely infects immunocompetent humans, it is emerging as an important pathogen in immunocompromised persons.

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 was previously called Corynebacterium equi and is currently grouped with the aerobic actinomycetes. Of the 40 genera in the actinomycetes group, the Rhodococcus genus is placed among the nocardioform bacteria, along with the genera Mycobacterium, Nocardia, Gordonia, Tsukamurella, and Corynebacterium.

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

Pathophysiology

Necrotizing pneumonia is the most common manifestation of R equi infection . Extrapulmonary R equi infections have included wound infection, subcutaneous abscess, brain abscess, thyroid abscess, retroperitoneal abscess, peritonitismeningitispericarditisosteomyelitisendophthalmitislymphadenitislymphangitisseptic arthritis, periprosthetic joint infection, osteitis, bloody diarrhea, and fever of unknown origin, among others. Bacteremia and dissemination of infection follow from the primary infection site, which is usually 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 R equi mesenteric lymphadenitis in a woman undergoing laparotomy for cholelithiasis. [3Hence, 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. [4Nearly 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 in Thailand, about 75% of human isolates expressed VapB, and 25% were avirulent. Most of these patients were infected with HIV. [5]

The expression of VapB is known to vary by geographic 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.

Epidemiology

Frequency

United States

R equi infections have been reported in at least 28 states.

International

R equi infections have been reported on 5 continents. Thus far, a few hundred cases of R equi infections in immunocompromised persons have been reported in the literature. 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

  • 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 R equi infection. [3Relapses are also common after discontinuation of antibiotics. An important site of extrapulmonary relapse is the central nervous system.

R equi infections carry an overall mortality rate of about 25%. In 2 different reports, by Cornish et al [6(1999) and by Harvey and Sunstrum [7(1991), the mortality rate was 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.

Since the advent of highly active antiretroviral therapy (HAART) therapy, mortality rates in HIV-infected patients have decreased. Torres-Tortosa et al conducted a multicenter observation of 67 HIV-infected patients in Spain. [8The mortality rate related to R equi was 34.3%. In a univariate analysis in the same study, factors associated with worse prognosis included multilobar involvement, absence of HAART, and inappropriate antibiotic therapy. In multivariate analysis, absence of HAART was the only factor independently associated with R equi–related mortality. In another literature review by Gundelly et al, the mortality rate among patients with HIV infection on HAART was only about 8%. [51While the mortality rate 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. The high mortality rates associated with R equi infections are due to several factors.

R equi may be misidentified as diphtheroids, Mycobacterium species, or Nocardia species among both immunocompetent and immunocompromised populations.

Patients with R equi infection may receive inappropriate initial antibiotic therapy because of misdiagnosis. R equi pneumonia does not respond to standard empirical treatment with beta-lactams (other than imipenem and meropenem) and tetracyclines. On the other hand, some cases of R equi pneumonia may be susceptible to macrolides and the newer quinolones.

Simultaneous opportunistic infections are common, especially in patients infected with HIV. In this subgroup of patients, the mortality rate directly attributed to R equi infection alone may be less. Capdevila et al (1997) reported on a series of patients infected with HIV who had R equi pneumonia; in this group of patients, the mortality rate directly attributed to R equi infection was only 15.4%. [9In another review of R equi infections in patients infected with HIV, 4 of 12 patients died of R equi infection, while 3 deaths were due to opportunistic infections.

Race

R equi infections have no reported racial predilection.

Sex

In all R equi infections, the male-to-female ratio is about 3:1. The reason for this is not clear; however, among immunocompromised patients, the predilection in males may be explained by the higher prevalence of HIV infection among males.

Age

R equi infections have been described in all age groups, from infants to elderly persons. Separate reviews have found a mean age of infection of 34-38 years.

Infection in children

R equi infections in children differ from those in adults. Immunocompromising conditions, including hematopoietic malignancies, immunosuppression associated with chemotherapy, and HIV infection, account for only about one third of reported R equi infections in children. Pediatric R equi infections account for approximately one third of all cases among immunocompetent individuals, perhaps because of the increased prevalence of trauma among children, predisposing them to localized R equi wound infections .R equi infections in immunocompetent children carry an extremely favorable prognosis.

Prognosis

In general, the prognosis of R equi infection 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 R equi infections and among immunocompetent children.

CLINICAL PRESENTATION


History

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

Pulmonary R equi infections include the following:

  • Fever and cough (>80% of patients with pulmonary R equi 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 presentations of R equi infection include lymphadenopathy, eye drainage and pain, joint pain, altered level of consciousness, bloody diarrhea, and fever of unknown origin. Anemia caused by colonic polyps infected with R equi has also been reported. [10]

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). R equi 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 inhalational, but infections via the oral route (due to ingestion of soil or food) or via direct inoculation due to trauma have also been 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 and include the following:

  • Fever

  • Tachypnea, crackles, and other common physical findings of pneumonia

  • Lymphadenopathy

  • Septic arthritis

  • Corneal laceration, hyperemia, decreased visual acuity, evidence of anterior chamber involvement (eg, 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. [9In 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. [11]

  • Lymphoma, leukemia, and other malignancies: This includes immunosuppression associated with chemotherapy, such as neutropenia. Neutropenic fever due to R equi bacteremia has been described.

  • Transplantation, including solid organ (kidney, liver, heart) and bone marrow. Renal transplantation is the most frequently associated solid organ transplant. Most cases involved immunosuppressed patients who were receiving a combination of steroids and two of the following: azathioprine, mycophenolate, or a calcineurin inhibitor. [12]

  • Chronic renal insufficiency and patients with end-stage renal disease on peritoneal dialysis

  • Alcoholism

  • Diabetes mellitus

  • Patients receiving immunosuppressive therapy, including corticosteroids

R equi infections can also occur in immunocompetent persons. Infections in these patients include pneumonia, endophthalmitis, septic arthritis, traumatic meningitis, brain abscess, fever of unknown origin, lymphangitis, and lymphadenitis. [13A history of trauma should be obtained because about 50% of R equi infections described in immunocompetent patients are due to trauma. A recent case report of granulomatous mastitis due to R equi has been reported in an immunocompetent person

DDx

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Diagnostic Considerations

The differential diagnoses for R equi infections include infections with Mycobacterium tuberculosis, other nontuberculous mycobacteria, Nocardia species, 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 misdiagnosis of Nocardia infection.

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

R equi cavitary pneumonia in a patient infected with HIV or in a patient with neutropenia may 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.

Differential Diagnoses

TREATMENT & MANAGEMENT

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 an R equi pulmonary nodule has been reported in a patient who underwent transplantation.

Surgical Care

Surgical therapy has a definite role in certain R equi infections. Local surgical resection or debridement is recommended in cases of R equi endophthalmitis, osteomyelitis, subcutaneous abscess, paravertebral abscess, and pericardial effusion.

In R equi pneumonia , surgical treatment has no obvious benefit. Some authors recommend surgical treatment such as lobectomy or partial lung resection when the infection has evolved into a large abscess or when the infection is overwhelming. Consideration of surgical resection also seems prudent when an infection fails to respond to antibiotics alone.

Torres-Tortosa (2003) reported that 16.4% of their series of HIV-infected patients required surgical intervention. [8]

In a review by Capdevila et al (1997), 11 of 78 patients infected with HIV who had R equi pneumonia underwent surgery. [9Four 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 and Sunstrum included patients with and without immunocompromised conditions. [7The 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 R equi 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. In another study involving renal transplants, approximately half of the reported cases required surgical intervention. [12]

Two immunocompetent patients with R equi pneumonia underwent 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

Consultation with an infectious disease specialist 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.

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.

Long-Term Monitoring

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.

Further Inpatient Care

Patients with R equi infection should be monitored for clinical improvement following treatment. 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.

MEDICATION


Medication Summary

In vitro susceptibilities

R equi is usually susceptible to the following medications:

  • Erythromycin

  • Azithromycin

  • Clarithromycin

  • Ciprofloxacin

  • Vancomycin

  • Aminoglycosides

  • Rifampin

  • Imipenem

  • Meropenem

  • Linezolid

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. Clarithromycin has been shown to be at least as effective as erythromycin. However, azithromycin seems less active.

Medical treatment

A study based on animals experiments 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. Munoz et al (2008) reported successful linezolid monotherapy for pulmonary R equi infection in a heart transplant recipient. [15However, the initial therapy in this patient consisted of a combination of parenteral antibiotics.

Many authors recommend the 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. Recommendations for combination therapy in HIV-infected patients include imipenem-vancomycin, imipenem-teicoplanin, and combinations based on macrolides and rifampin. [8]

A few cases of brain abscesses and nosocomial meningitis have been reported in immunocompetent patients. In a case report by Scotton et al, a patient with nosocomial meningitis was initially treated with vancomycin and rifampin. [16However, 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 R equi infections. In a case report published by Gabriels et al in 2006, initial monotherapy with levofloxacin was unsuccessful. [17This 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 retrospectively compared combination therapy with azithromycin-rifampin, clarithromycin-rifampin, and erythromycin-rifampin in foals with R equi pneumonia. [18The combination of clarithromycin-rifampin was superior to the other 2 groups of therapy.

In general, pulmonary infections should be treated for a minimum of 2 months. Treatment should initially consist of parenteral antibiotics followed by oral combination therapy. One author has recommended initial therapy with a vancomycin-based regimen followed by oral combination therapy with rifampin plus erythromycin or rifampin plus minocycline. The average duration of antibiotic therapy in a review of R equi infections in renal transplant recipients was 6.5 months. [12]

In immunocompetent patients, a shorter duration of therapy may be considered because R equi infection has been treated successfully with shorter courses. Selective local R equi 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 R equi endophthalmitis, in combination with systemic antibiotics and surgical therapy.

Antibiotics

Class Summary

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

Vancomycin (Vancocin)

Potent antibiotic directed against gram-positive organisms. Useful in the treatment of septicemia and skin-structure infections. Indicated for patients who cannot receive, or whose conditions have failed to respond to, penicillins and cephalosporins or who have infections with resistant staphylococci. To avoid toxicity, current recommendation is to assay vancomycin trough levels after third dose drawn 0.5 h prior to next dosing. Use CrCl to adjust dose in patients diagnosed with renal impairment.

Rifampin (Rimactane, Rifadin)

Inhibits DNA-dependent bacterial, but not mammalian, RNA polymerase.

Erythromycin (EES, E-Mycin, Eryc)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Ciprofloxacin (Cipro)

Fluoroquinolone with activity against streptococci, MRSA, Staphylococcus epidermidis, and most gram-negative organisms, including Pseudomonas, but no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth.

Gentamicin (Garamycin)

Aminoglycoside antibiotic for gram-negative coverage. Follow each regimen by at least a trough level drawn on the third or fourth dose (0.5 h before dosing). May draw a peak level 0.5 h after 30-min infusion.

Imipenem and cilastatin (Primaxin)

For treatment of multiple-organism infections in which other agents do not have wide-spectrum coverage or are contraindicated owing to potential for toxicity.

Meropenem (Merrem IV)

For treatment of multiple-organism infections in which other agents do not have wide-spectrum coverage or are contraindicated owing to potential for toxicity. Has slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared to imipenem.