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 Guide Editors
 Editor In Chief
    Joel E. Gallant, MD, MPH

Pharmacology Editor
    Paul Pham, PharmD, BCPS

Zambia Guideline Team
   Peter Mwaba MMed PhD FRCP
   Alywn Mwinga MMed
   Isaac Zulu MMed MPH
   Velepie Mtonga MMed
   Albert Mwango MBChB
   Jabbin Mulwanda MMed FCS
 

 

 

Diagnosis>Opportunistic Infections>
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Nocardiosis

Michael Melia, M.D. and Paul G. Auwaerter, M.D.
09-29-2009

Zambia Specific Information

  • Little epidemiologic data from Africa: in 1 older autopsy study from Ivory Coast, 4% of HIV+ pts dying on a general medical ward had pulmonary nocardiosis (ratio of pulmonary nocardiosis to TB of 1:9); in 2nd study from Ethiopia, 3% of HIV+ TB suspects actually had nocardiosis.
  • In Zambia pulmonary nocardiosis difficult to distinguish clinically from TB.
  • Dx could be made from Gram, modified Ziehl-Neelsen, or acid fast stain, but no Cx methods available.
  • Treatment with cotrimoxazole (TMP/SMX) as below.

REFERENCES

Zambia Information Author: David Riedel, M.D.

PATHOGENS

  • Member of aerobic actinomycetes group. Grows slowly on media. Appear as branching, beaded filamentous Gram-positive rods.
  • Variably acid fast due to presence of intermediate mycolic acids in cell wall, distinguishes from Actinomyces. May produce sulfur granules, especially in mycetomas.
  • Ubiquitous in environment. Most infections acquired by inhalation or direct inoculation.
  • Many (possibly all) isolates previously identified as "N. asteroides" now known to have been mis-identified based on current lab standards; type strain of N. asteroides does not appear to have been recovered from recent clinical isolates.
  • Human pathogens include N. abscessus (former N. asteroides Type I drug susceptibility pattern), N. brevicatena/paucivorans complex (Type II), N. nova complex (III), N. transvalensis (IV), N. farcinica (V; more virulent), and N. cyriacigeorgica (VI), as well as N. brasiliensis (more common in tropics and actinomycetoma) and N. pseudobrasiliensis.
  • Each species/complex generally has stereotyped anti-microbial susceptibility patterns.

CLINICAL

  • Uncommon pathogen mainly affecting immunocompromised persons with T-cell dysfunction. Suspect in immunocompromised, especially if evaluating fevers with or without pulmonary, CNS, or cutaneous disease. Extracutaneous disease rare in the immunocompetent.
  • Subacute presentation common. Most cases occur with CD4 <200. History of corticosteroid use (especially recent, high-dose) and recent CMV disease may be additional risk factors.
  • Uncommon in HIV (less than 2% in several case series; up to 5% in autopsy studies). Cases have occurred despite TMP-SMX prophylaxis (for PCP).
  • Pulmonary: primary site of infection in >2/3 of cases, may mimic TB. Sx non-specific. Protean radiographic manifestations: can present with nodules, infiltrates (diffuse or reticulonodular), cavities, or lung abscess. Pulmonary infiltrates (as opposed to nodules) more common in setting of HIV. Granulomata only occasionally seen on Bx.
  • Cutaneous: cellulitis, ulcers, 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, occasionally with granulomas. CNS lesions common, up to 44% in disseminated infection; can be asymptomatic Spinal cord lesions or meningitis rare.
  • Other sites: disseminated infection, keratitis, sinusitis, endophthalmitis, bone and joint infection, renal, cardiac, peritonitis, bacteremia.
  • Half of cases present with disseminated disease. 20% present with extrapulmonary disease only.

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. Specimens should ideally be held for 2-3 weeks before discarding.
  • If present, granules should be washed, crushed, and examined for organisms.
  • 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

Pulmonary, Disseminated, CNS Infection

  • Sulfonamides usually considered part of optimal therapy based on historical case series of successful treatment.  Given high rates of intolerance with HIV, consider desensitization in pts with sulfa allergy.
  • Little data correlating antimicrobial susceptibility testing with clinical outcomes, but appropriate to use susceptibility testing to guide therapy.
  • Preferred (severe disease): TMP-SMX (10 mg/kg/d TMP...75 mg/kg/d SMX) IV in 3-4 divided doses PLUS amikacin 7.5 mg/kg IV q12h PLUS imipenem/cilastin 500 mg IV q6h OR ceftriaxone 2 grams IV q12-24h. Streamline regimen after 3-6 weeks or with clinical improvement.
  • Preferred (mild-moderate disease): TMP-SMX  (15 mg/kg/d TMP + 75 mg/kg/d SMX) IV or PO in 4 divided doses. May consider decreasing TMP/SMX dose (to TMP component 10 mg/kg/d) after clinical improvement.
  • Alternative: imipenem/cilastatin 500 mg IV q6h + amikacin 7.5 mg/kg q12h x 2-4 wks or clinical improvement followed by oral regimen.
  • Alternative: 3rd generation cephalosporins, eg ceftriaxone 2 g IV q12-24h IV, offer good CNS penetration; often used in combination with amikacin 7.5 mg/kg q12h x 2-4 wks or clinical improvement followed by PO regimen.
  • Monitoring: if on PO sulfonamide-based regimen, obtain 2-hr post-peak sulfonamide level (goal 100-150 mg/L) to guide dosing.
  • Surgery or aspiration may be considered for large brain abscesses or extraneural abscesses not responding to medical therapy, although many such abscesses respond to medical therapy alone.
  • Rx duration: in immune competent, generally 6 mos; 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 twice-daily likely sufficient, but SS once daily or DS 3x/wk insufficient.
Oral Alternatives

  • Caveat: While sulfonamides and linezolid are nearly always active in vitro, antimicrobial susceptibility testing should guide selection of all other oral agents given variable susceptibilities between species.
  • Older sulfonamides have good clinical efficacy, but maintain hydration to avoid oliguria, crystalluria.
  • Sulfadiazine 6-12 g/d in 4-6 divided doses, to obtain 2hr post serum level 100-150mg/L.
  • Sulfisoxazole 6-12 g/d in 4-6 divided doses, to obtain 2hr post serum level 100-150mg/L.
  • Minocycline 100-200 mg PO twice daily.
  • Amoxicillin + clavulanate 500 mg PO 3 times-daily.
  • Linezolid 600 mg PO twice-daily. Appears to have outstanding activity in vitro against Nocardia spp., but little clinical data to judge use. Those that have been published support its effectiveness, however.
  • Moxifloxacin 400 mg PO once-daily. Some case reports arguing for, others against. Likely the most effective fluoroquinolone.
  • Clarithromycin 500 mg PO twice-daily successful in one case report.
Species Specific Treatment

  • N. abscessus: often resistant to imipenem.
  • N. nova: sensitive to ampicillin but not amoxicillin/clavulanate. Very low MICs to imipenem and amikacin. Typically clarithromycin susceptible.
  • N. transvalensis: generally not sensitive to amikacin, ~10% strains resistant to imipenem. Often susceptible to ciprofloxacin.
  • N. farcinica: ~10-20% strains resistant to imipenem, high rates of resistance to amoxicillin, cephalosporins. Fluoroquinolones, particularly moxifloxacin, may be active.
  • N. cyriacigeorgica: almost always resistant to FQs and clarithromycin; often resistant to ampicillin and amoxicillin-clavulanate.
  • N. brasiliensis: often resistant to ciprofloxacin and clarithromycin but susceptible to minocycline and amoxicillin-clavulanate.
  • N. pseudobrasiliensis: usually resistant to minocycline and amoxicillin-clavulanate but susceptible to ciprofloxacin and clarithromycin.
  • N. otitidiscaviarum: often resistant to sulfonamides.
Local, Lymphocutaneous Disease

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

Drug Comments

DrugRecommendations/Comments
Trimethoprim + Sulfamethoxazole Remains standard therapy, mainly because of perceived superiority in reducing mortality. Early in vitro studies also suggest synergy with both amikacin and imipenem. Often difficult to employ in sulfonamide-sensitive pts.
Amikacin Displays excellent in vitro synergism with most drugs against most species with the exception of N. transvalensis. More active than TMP-SMX in one murine model.
Imipenem/Cilastatin Often employed if severe or unresponsive infection exists. Usually combined with amikacin, both for possible synergy and because no species are resistant to both amikacin and imipenem. More active than TMP-SMX in a murine model.
Ceftriaxone Cephalosporin alternative to imipenem that offers good activity against most Nocardia  isolates. Often combined with amikacin for severe disease. both for possible synergy and because no spp. resistant to both amikacin and ceftriaxone.
Linezolid  Excellent in vitro activity, but clinical experience limited to case report descriptions of successful treatment; associated with clinical improvement or cure in 11/11 published cases.
Amoxicillin + Clavulanate  Possible oral alternative in persons intolerant of sulfonamides; agent of choice for N. brasiliensis infection in persons with adverse sulfonamide reaction. Note N. nova generally susceptible to amoxicillin and ampicillin but resistant to amoxicillin-clavulanate based on clavulanate-inducible beta-lactamase.
Minocycline Most well-studied of the tetracyclines for Nocardia, offering non-sulfonamide oral alternative. Sometimes used in combination with amoxicillin/clavulanate or sulfonamide. Now rarely used once susceptibility results available.
Sulfadiazine Member of older sulfonamide class that is acceptable for therapy, although pts may develop renal dysfunction if fluid intake insufficient.
 Moxifloxacin Possible oral alternative in persons intolerant of sulfonamides, but clinical experience also limited to case reports. Use susceptibility testing as a guide.
 Clarithromycin Possible oral alternative in persons intolerant of sulfonamides, but clinical experience also limited to case reports. Use susceptibility testing as a guide.

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, as high as 80% for disseminated disease, 13-60% for CNS disease (despite adequate therapy). 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: No guidelines exist for treatment of Nocardia.

REFERENCES

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