Rhodococcus Infections

1. Rhodococcus Infections Morning Report June 29, 2007 Micah Mooberry, MD

2. Background Rhodococcus equi was first recognized as a zoonotic pathogen Original isolation as Corynebacterium equi in 1923 from foals with granulomatous pneumonia (Magnusson) Also commonly isolated in submaxillary adenitis in swine First documented human infection in 1923 – 29 yo male with plasma cell hepatitis on immunosuppresants Only 12 more human cases recorded over the next 15 years

3. Microbiology Originally named Corynebacterium equi based on morphology 1980 – reclassified in genus Rhodococcus after cell wall composition & biochemical reactions found to be more closely related to Nocardia & Mycobacteria Part of the phylogenetic group of nocardioform actinomycetes Soil & water organism found commonly in areas with domesticated animals (horses, pigs, cows)

4. Microbiology Facultative, intracellular, nonmotile, non-fermenting, non-spore forming, pleomorphic gram positive coccobacilli Easily cultured in nonselective media Forms large, smooth, irregular, highly mucoid colonies by 48 hours Pleomorphic: typically appears coccoid but in liquid media forms long rods or short filaments (+/- rudimentary branching) Characteristic rod to coccus growth cycle variation

5. Microbiology Named for its production of red pigment (actually salmon pink) after four days Inconsistently acid fast Presence of tuberculostearic acid and cell wall mycolic acids At least 27 different polysaccharide capsular serotypes (no relationship to virulence) Distinguishing factors: Non-fermenting: unlike Corynebacterium Urease positive: unlike Corynebacterium Lacks aerial hyphae: unlike Nocardia, Streptomyces + rudimentary branching: unlike Mycobacerteriaceae

6. Microbiology

7. Microbiology

8. Histopathology Pathogenesis results from ability to persist in and destroy macrophages Interferes with phagosome-lysosome fusion Typical appearance in infected tissue is a granulomatous reaction dominated by macrophages with granular cytoplasm that is PAS postive Associated with neutrophilic infiltrate and abundant bacteria during active infection

9. Histopathology As infection progresses, often becomes an unusual chronic granulomatous inflammation called malacoplakia Foamy histiocytes/macrophages containing lamellated iron and calcium inclusions (Michaelis-Gutmann bodies) M-G bodies: basophilic staining cytoplasmic bodies containing a central crystalline core surrounded by less dense peripheral zone Results from incomplete intracellular digestion of engulfed bacteria

10. Michaelis-Gutmann bodies

11. Michaelis-Gutmann bodies

12. Histopathology Malacoplakia most commonly is seen in genitourinary tract, often with E. Coli infections When seen within the lung is highly suggestive of Rhodococcus infection

13. Epidemiology Primarily causes disease in immunocrompromised human hosts Of all documented infections: 80-90% immunocompromised Of these, 50-60% HIV, 15-20% hematopoietic or other malignancies, 10% transplant recipients Reported in at least 28 states, and 5 different continents Several hundred cases total reported At least 19 cases reported in immunocompetent hosts

14. Epidemiology Mean age of infection: 34-38 years Reported cases in children as young as 9 months Prognosis in immunocompetent children is extremely favorable Male to female ratio 3:1 (likely a result of the higher prevalence of HIV in males) Inoculation via GI tract, or most commonly via inhalation R equi found in bovine, porcine, and equine fecal flora & grows best at summer temperatures. Isolation from the air rises with ambient temperature and is highest on dry, windy days

15. Clinical Features Necrotizing pneumonia is most common presentation Onset is insidious with high fever and cough (>80% of patients), chills, weight loss, dyspnea, and often hemoptysis Hemoptysis is often severe, requiring transfusions Symptoms identical in immunocompentent hosts

16. Radiographic Findings Multiple nodular infiltrates is most common Preference for upper lobes in HIV ( 55% vs. 35% in lower lobes) Left untreated, nodular infiltrates progress to cavitation with hilar LAD (54-77% of all R equi infections) Mimics Ghon complex of primary M tuberculosis Cavities are thick walled and may demonstrate air-fluid levels Of note, initial CXR can show interstitial pneumonitis mimicking Pneumocystis

17. Radiographic Findings

18. Radiographic Findings

19. Extrapulmonary infection In declining frequency: Bacteremia – very common CNS (abscess, meningitis) – very common Subcutaneous & other soft tissue abscesses Wound infections Septic arthritis Endopthalmitis Indwelling devices Other sites (pharynx, middle ear, lymph nodes, bone, GI tract) Rarely produces a pathologic appearance that resembles Whipple’s disease (Tropheryma whipplei & R equis are both actinomycetes)

20. Extrapulmonary Infection May accompany pneumonia or be the sole presentation More commonly presents weeks to years after discontinuation of antimicrobial therapy for pulmonary disease Recurrence of pulmonary disease may not be associated with late recurrence at another site Extrapulmonary complications have not been reported in normal hosts

21. Morbidity & Mortality Pneumonia may be complicated by abscess, empyema, pleural effusion, and less commonly chest wall invasion and pneumothorax Reported cases of pericardial tamponade from purulent pericarditis Overall mortality = 25% 50-55% in HIV 20-25% in non-HIV immunocompromised 11% in immunocompetent patients

22. Morbidity & Mortality Proposed reasons for high mortality rates: May be misidentified as diptheroids, Mycobacterium species or nocardia Inappropriate empiric antibiotics given (R equi infection does not respond to several empiric treatments for CAP including beta lactams) Underlying immune dysfunction may not be identified and treated in addition to treatment of the pneumonia

23. Treatment Most human isolates are resistant to penicillins, beta lactams and cephalosporins Most isolates susceptible to macrolides, vancomycin, rifampin, FQs, aminoglycosides and imipenem/meropenem Clindamycin, chloramphenicol, tetracycline and TMP/SMX have activity in up to 2/3 of isolates Recommend treatment with antibiotic that can penetrate macrophages

24. Treatment Immunocompetent: single agent may be sufficient Immuncompromised: two or more agents needed Monotherapy not recommended for systemic infection Treatment is generally mimimum of 2 months (initially parenteral) Typical regimen: Macrolide or FQ or Rifampin (all penetrate macrophages) + Vanc + Imipenem or aminoglycoside

25. Treatment When underlying host immune deficit cannot be overcome, pulmonary infection is usually chronic & progressive with periods of remission Hosts with normal immune function generally are cured All patients with HIV should be placed on HAART Prior to HAART, infection led to chronic progression and/or death in > 80% of cases Rifampin contraindicated if on HAART

26. Treatment & Prophylaxis In some cases, surgical resection of infected tissue or draining or abscesses/effusions may be indicated Especially when lung infection has evolved into inflammatory psuedotumor or large abscess Long term & possible indefinite secondary prophylaxis for patients persistently immunosuppressed TMP-SMX or Azithromycin

27. References Uptodate.com; Clinical features; diagnosis; therapy; and prevention of Rhodococcus equi infections. Leonard Slater, MD Uptodate.com; Microbiology; pathogenesis; and epidemiology of rhodococcus equi infections. Leonard Slater, MD. eMedicine.com; Rhodococcus equi. Indira Kedlaya, et al.