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PATHOGENS

• Member of anaerobic actinomycetes group, aerobic and grow slowly on media. Appears as branching, beaded filamentous Gram-positive bacteria.
• Weakly acid fast due to the presence of intermediate mycolic acids in their cell wall, distinguishes from Actinomyces. May produce sulfur granules, especially in mycetomas.
• Ubiquitous in environment. Most infections acquired by inhalation or direct inoculation.
• Most common species causing human disease: N. asteroides complex (80% non-cutaneous infections, most CNS), N. brasiliensis (more common in tropics), N. farcinca (more virulent, and antibiotic-resistant), N. nova, N. otitidiscaviarum, N. transvalensis.

CLINICAL

• Uncommon pathogen mainly affecting immunocompromised with T-cell dysfunction. Suspect in immunocompromised, especially if evaluating pulmonary/CNS/cutaneous disease.
• Subacute presentation common. Most cases occur with CD4 <200. History of corticosteroid use may be additional risk factor.
• Uncommon in HIV (2%). Cases have occurred despite TMP-SMX prophylaxis (for PCP).
• Pulmonary: most common presentation (40%), may mimic TB. Presents with nodules, infiltrates (diffuse or reticulonodular), cavities or lung abscess. Granulomata may be seen on biopsy. Pulmonary infiltrates (as opposed to nodules) more common in setting of HIV.
• Cutaneous: nodules, ulcers or lymphocutaneous (sporotrichoid) presentations. Sinus tracts or soft tissue swelling should heighten suspicion. Mycetoma seen in tropics, esp. S. and Central America, mostly N. brasiliensis.
• CNS: brain abscess or mass lesions with granulomas. CNS lesions common, up to 44% in disseminated infection. Spinal cord lesions or meningitis rare.
• Other: dissemination, keratitis, sinusitis, endophthalmitis, bone and joint infection, renal, cardiac, peritonitis.

DIAGNOSIS

• Dx: generally made from smear or Cx of respiratory secretions, skin Bx or aspirate of deep tissue. Bacteremia uncommon. May not grow in Cx, so Dx may require stains of secretions or tissue.
• Gram stain most sensitive method (51-64%) to visualize Nocardia in clinical specimens. Modified acid fast stain used only to confirm acid fastness of organisms detected by Gram stain. Cx yields range 70-95% based on reported literature.
• Dx often difficult, may miss on routine specimens. Warn micro lab, especially for respiratory specimens, as selective Thayer-Martin media may increase yield. Multiple specimens also improve yield.
• Obtain brain MRI in pts with pulmonary or disseminated disease even without localizing signs or Sx. Firm Dx generally obviates need for brain Bx.

TREATMENT

• Optimal regimen unclear. Sulfa drugs usually considered first line, high rates of intolerance with HIV. Consider desensitization.
• Antimicrobial susceptibility testing may guide choices, but not always available or well-standardized.
• Preferred: TMP-SMX  (15mg/kg/d + 75mg/kg/d) IV or PO in 4 divided doses. May consider decreasing TMP/SMX dose (to TMP component 10mg/kg/d) after clinical improvement.
• Monitoring: if on PO regimen, obtain 2-hr post -peak sulfonamide level (goal 100-150 mg/L) to guide dosing.
• Alternative: imipenem/cilastatin 500 mg IV q6h + amikacin 7.5mg/kg q12h x 2-4 wks or clinical improvement followed by oral regimen.
• Alternative: 3rd generation cephalosporins, eg ceftriaxone 2g IV q12-24h IV, offer good CNS penetration; often used in combination with amikacin 7.5mg/kg q12h x 2-4 wks or clinical improvement followed by PO regimen.
• Some consider early use of imipenem or ceftriaxone +/- amikacin in severely ill based on clinical and animal data suggesting they are the most active against Nocardia.
• Surgery or aspiration may be considered for large brain abscesses or extraneural abscesses not responding to medical therapy.
• Rx duration: in immune competent, generally 6 mos, with 12 mos for CNS disease. Switch to oral regimen with clinical improvement. Longer parenteral therapy may be needed for slow responses.
• Use indefinite low dose oral suppression in pts with advanced HIV or significant immunosuppression to prevent relapse. Note: TMP-SMX DS bid likely sufficient, but SS qd or DS 3x/wk insufficient.

• Older sulfonamides have good clinical efficacy, but maintain hydration to avoid oliguria, crystalluria.
• Sulfadiazine 6-12 g/d 4-6 divided doses, to obtain 2hr post serum level 100-150mg/L.
• Sulfisoxazole 6-12 g/d 4-6 divided doses, to obtain 2hr post serum level 100-150mg/L.
• Minocycline 100-200 mg PO bid (resistance described with N. brasiliensis).
• Amoxicillin + clavulanate 500 mg PO tid.
• Linezolid 600 mg PO bid. Appears to have outstanding activity in vitro Nocardia spp., but little clinical data to judge use.

• N. farcinica ~10% strains resistant to imipenem, high rates of resistance to amoxicillin/clavulanate, minocycline.
• N. nova sensitive to ampicillin but not amoxicillin/clavulanate.
• N. otitidiscaviarum often resistant to sulfonamides.
• N. pseudobrasiliensis (subset of N. brasiliensis) usually resistant to minocycline.
• N. transvalensis generally not sensitive to amikacin, ~10% strains resistant to imipenem.

• TMP-SMX  (5 mg/kg TMP component) divided in 2-4 doses/d PO
• Minocycline 100mg PO bid
• Duration of treatment usually 1-3 mos. Prolonged therapy usually required for mycetoma cure.

Drug Comments

FOLLOW UP

• Expect to see clinical improvement within 7-10 d. Switch to PO a judgment call, but use of parenteral ABx for 3-6 wk common before switch.
• Consider drug resistance as most likely cause of lack of response +/- need for drainage or lack of drug penetration.
• Cure rates: 100% soft tissue, 90% pulmonary, 63% disseminated, <50% CNS. Not clear that HIV-related immune suppression makes difference compared to historical series.
• Monitor for relapse for 1 yr post-therapy.

OTHER INFORMATION

• Consider Nocardia in TB suspects not responding to antituberculous therapy.
• Do not dismiss isolate as contaminant or colonizer, though cases described rarely.
• Sulfonamide-based therapy preferred often because of primarily non-HIV case series suggesting reduced mortality.
• Nocardia culture and sensitivity testing best performed in reference labs: contact local/state health department or CDC special pathogens branch (404) 639-3158 or R Wallace lab (903) 877-7680.

Basis for Recommendations

• Lederman ER, Crum NF; A case series and focused review of nocardiosis: clinical and microbiologic aspects.; Medicine (Baltimore); 2004; Vol. 83; pp. 300-13;
  ISSN: 0025-7974;
  PUBMED: 15342974
  Rating: Basis for recommendation
  Comments:Sulfonamide-containing regimens remain standard of care, especially for Nocardia pulmonary infections.
  
  
• Author opinion ;
  Rating: Basis for recommendation
  Comments: Author opinion
  
  

REFERENCES

REFERENCED WITHIN THIS GUIDE

• Rhodococcus equi
• Toxoplasmosis