Johns Hopkins Antibiotic (ABX) Guide

Nocardia

MICROBIOLOGY

  • Gram-positive branching, beaded, filamentous rod.
    • Weakly acid fast.
    • Grows on special media (Thayer-Martin) in 3-5d.
  • 12 species: N. asteroides 90% (lung +/- CNS disease), N. brasiliensis = mycetoma (tropics), N. farcinica (bad prognosis).
    • More recently detected species include N. nova, N. cyriacigeorica, N. transvalensis, N. otitidcaviatum and N. farcinica.
    • Most common in US: N. nova, N. brazilensis, N. farcinica and N. cyriaciigeorgia.

CLINICAL[Top]

  • Presentation: typically chronic and indolent, mostly occurring in patients with defective cell-mediated immunity (CMI).
    • Suspect in patients with CMI defect (steroids, chronic granulomatous disease [CGD], organ transplant) + indolent lung +/- CNS disease; relatively rare in AIDS.
    • No person-person transmission.
  • Looks like Actinomycetes spp., but acid fast, aerobic and seen mostly in compromised hosts.
    • Smears and culture positive in only 1/3rd of cases; send multiple specimens and warn lab of suspected diagnosis.
  • Dx: Gram stain + AFB stain + sputum cx; rarely seen as colonizer (i.e., take [+] sputum culture seriously).
    • Filamentous branching, beaded, Gram positive rod.
  • As CNS infection seein 40%; if pulmonaryt disease diagnosed, obtain brain MRI.
  • In vitro sensitivity testing: (See Conville et al.[1] and Uhde et al.[2]) showing vastly different results.

SITES OF INFECTION[Top]

  • Lung: indolent pneumonia, abscess, fibronodular infiltrates
  • Brain: abscess or granulomata
  • Disseminated: 20-30% of cases in immunosuppressed hosts including bones, heart, renal, joints, retina, skin, CNS, peritonitis, endocarditis
  • Primary cutaneous: sporotrichoid (non-tropics) or mycetoma (madura foot, tropics)
  • Ocular: keratitis, endophthalmitis

TREATMENT[Top]

Nocardia antimicrobial susceptibilities

  • CDC reported sensitivity data for 765 clinical isolates of Nocardia collected from 1995-2004 with the following results for % resistant[2]: note susceptibilities greatly vary between Nocardia species.
  • In vitro sensitivity tests needed to guide what is usually months of treatment.
    • There are limited data on clinical outcomes based on these results.
    • In vitro sensitivity testing: (See Conville et al.[1] and Uhde et al.[2]) showing vastly different results.

General comments regarding therapy

  • Principles: treat based on host, site of disease, ability to reduce immunodeficiency, and in vitro activity.
    • Traditional recommendations include sulfa-based abx as usually preferred if active.
    • Preferred drugs for resistant strains: linezolid, amikacin and/or impenem/cilastatin.
    • Must treat for 6-12mos.
  • Routes of therapy:

Sulfonamide-based therapies

  • Pulmonary: TMP/SMX 10mg/kg/d (TMP) in 2-4 doses IV x 3-6wks, then PO (2DS twice daily) x >5mos.
  • CNS (AIDS, severe or disseminated disease): TMP/SMX 15mg/kg/d (TMP) IV x 3-6wks, then PO (3 DS twice daily) x 6-12 mos.
  • Severe disease, compromised host, multiple sites: TMP/SMX IV (above doses) + amikacin 7.5mg/kg q 12h (adjust per levels) or oral sulfas 6-12gm/d.
  • Sporotrichoid (cutaneous): TMP/SMX 1 DS twice daily x 4-6mos.
  • Duration:
    • Immunocompetent: 6mos
    • Immunosuppressed: 12mos
    • Immunosuppressed & continued immunosuppression: low dose abx indefinitely, e.g., TMP/SMX DS PO daily.

Sulfa alternatives

Miscellaneous

  • Decrease/reduce immunosuppression, if possible
  • Surgical debridement or drainage, consider for extra-pulmonary lesions.
  • In vitro sensitivity tests important.
  • Sulfa intolerance (esp AIDS): consider desensitization.
  • Sulfa therapy: some get sulfa levels, 2hrs post oral dose. Expect peak of 100-150mg/L.
  • Chronic granulomatous disease pts: should get gamma interferon + sulfa prophylaxis.

Selected Drug Comments

Drug

Recommendation

Amikacin

This is most active and the favored drug for serious nocardiosis. Usually combined with imipenem, less often with ceftriaxone, cefotaxime or TMP/SMX. Major concern is nephrotoxicity (get creatinine every day or every other day) and check vestibular damage (check Romberg q2-5d).

Cefotaxime

or ceftriaxone: Good for N. asteroides, but not for N. farcinica. Published experience is quite good. Often combined with amikacin.

Imipenem/cilastatin

Good in vitro activity against most strains of the N. asteroides complex. Not very active vs most N. brasiliensis. Experience to date clinically is good especially with thoracic nocardiosis. Usually more active than meropenem.

Minocycline

Good drug for nocardiosis, but experience with use as first line agent in patients who have serious disease is limited. May cause dizziness, especially with high doses.

Sulfadiazine

This is a favored sulfa that should work well. Given PO only. Watch for hypersensitivity reaction, and crystalluria when given high doses.

Trimethoprim/sulfamethoxazole

TMP/SMX: sulfonamides are the standard for nocardiosis and TMP/SMX is a familiar and well accepted method to deliver sulfa both PO and IV. The contribution of trimethoprim is not well established. Nearly all strains of Nocardia are susceptible and the clinical track record has been consistently good. Must treat lung, and often with high doses.

Linezolid

Active in vitro, favorable but limited clinical experience. Concerns are cost and long term toxicity.

FOLLOW UP[Top]

  • Cure rates:
    • Soft tissue: 100%,
    • Pulmonary: 90%
    • Dsseminated: 60%
    • CNS: 50%
  • Monitor for relapse x 1yr post-treatment.

OTHER INFORMATION[Top]

  • 60% pts are compromised: chronic steroids is the major risk.
    • Also diabetes, steroids, organ tx, cancer chemotherapy, AIDS.
    • TMP-SMX or dapsone prophylaxis prevents
  • Treatment is normally long (6-12mo) and hard (high dose sulfa, imipenem/amikacin etc); less serious disease can use oral sulfa or minocycline from the start..
  • From reference Sorrell TC, Mandell GL, et al (2012).[3]
    • Classification: aerobic Actinomycetes.
    • Species: 12; most important clinically are N. asteroides complex (includes N. farcinica & N. nova) accounting for 90% of extracutaneous disease; N. brasiliensis - mycetoma.
    • Epidemiology: soil, worldwide. Most common - mycetoma in tropics. Most common outside tropics - pulmonary +/- disseminated, esp. CNS in host with decreased CMI.
    • Clinical:
    1. Mycetoma: tropics, local inoculation, N. brasiliensis, progressive destructive lesions, distal external sinuses. Also caused by Streptomyces & Actinomadura.
    2. Sporotrichoid: lymphocutaneous, local inoculation. N. asteroides.
    3. Pulmonary: inhaled, N. asteroides, indolent, X-ray - infiltrate nodule, cavity, multiple nodules.
    4. Disseminated: pulmonary disease usually at first, N. asteroides 90%, CNS 40% - abscess or granuloma; other sites - eye, renal, joints, bone, heart.

Basis for recommendation[Top]

  1. Sorrell, TC, Mitchell, DH, Iredell, JR. Nocardia species. In: Principles and Practice of Infectious Diseases, 6th ed, Mandell, GL, Bennett, JE, Dolin, R (Eds), Elsevier, Philadelphia 2012. p. 2916.

    Comment: Emphasizes that "{N. asteroides complex" has 3 species: N. asteroides, N. farcinica & N. nova. Importance is that N. farcinica is resistant to tobramycin and third generation cephalosporins; in some studies it is the predominant species in the complex. For treatment: Sulfonamides preferred, TMP-SMX is most common form used (but need for TMP is ?), relevance of in vitro tests is questioned, minocycline data look good, the best in vitro synergy data for parenteral agents is amikacin + imipenem.

References[Top]

  1. Conville PS et al: Multisite reproducibility of the broth microdilution method for susceptibility testing of Nocardia species. J Clin Microbiol 50:1270, 2012  [PMID:22219309]
  2. Uhde KB et al: Antimicrobial-resistant nocardia isolates, United States, 1995-2004. Clin Infect Dis 51:1445, 2010  [PMID:21058914]

    Comment: CDC report of 765 isolates showed most active drugs: linezolid (o resistant) and amikacin (5% resistant), TMP/SMX, minocycline, ceftriaxone, cefotaxine, clarithormycin: all 50-80% resistant.
    Rating: Important

  3. Unkle DW et al: An HIV-infected patient with Nocardia asteroides bilateral pneumonia. AIDS Read 18:566, 2008  [PMID:19062401]

    Comment: AIDS patient with nocardiosis. Responded rapidly to sulfa-trimethoprim and ceftriaxone.

  4. Queipo-Zaragozá JA et al: Nocardial infection in immunosuppressed kidney transplant recipients. Scand J Urol Nephrol 38:168, 2004  [PMID:15204409]

    Comment: Among 1239 kidney transplants there were 5 with nocardiosis. Nocardia brasiliensis accounted for 2 and N. asteroides accounted for 3. Mortality was 2/5.

  5. Peleg AY et al: Risk factors, clinical characteristics, and outcome of Nocardia infection in organ transplant recipients: a matched case-control study. Clin Infect Dis 44:1307, 2007  [PMID:17443467]

    Comment: Case control study of Nocardia infections in organ transplant recipients. The total was 35/5126 (0.6%), most frequently in lung transplants (3.5%) and heart recipients (2.5%). Risks were high dose steroids (RR=27) followed by disseminated disease (n=7). Of 35 cases, 24 (69%) were receiving TMP-SMX to prevent PCP. The cure rate was 89%.
    Rating: Important

  6. Clark NM, Reid GE, AST Infectious Diseases Community of Practice: Nocardia infections in solid organ transplantation. Am J Transplant 13 Suppl 4:83, 2013  [PMID:23465002]

    Comment: Frequency in solid organ transplants is 0.7-3.5%; chronic steroid treatment in 60% of all patients.
    Rating: Important

  7. Smego RA, Moeller MB, Gallis HA: Trimethoprim-sulfamethoxazole therapy for Nocardia infections. Arch Intern Med 143:711, 1983  [PMID:6340623]

    Comment: Cure rates are: Skin/soft tissue - nearly 100%, pulmonary - 90%, disseminated disease 63%, brain abscess - 50%.
    Rating: Important

  8. Pintado V et al: Nocardial infection in patients infected with the human immunodeficiency virus. Clin Microbiol Infect 9:716, 2003  [PMID:12925115]

    Comment: Eight cases encountered in 20 years (0.4% AIDS cases). Response was noted in 6/8 responded to sulfa therapy. Average CD4 was 35/mm(3).

  9. Husain S et al: Nocardia infection in lung transplant recipients. J Heart Lung Transplant 21:354, 2002  [PMID:11897524]

    Comment: Experience at Pittsburg. Frequency of nocardiosis in 0.7-3% in organ transplants. They had 10/473 lung transplants (21%); 6 had received PCP prophylaxis with TMP-SMX. Mortality was 4/10 (40%) including 3/3 with N. farcinica.

  10. Gombert ME, Aulicino TM; Synergism between imipenem and amikacin in combination with other antibiotics against Nocardia asteroides; Antimicro Ag Chemother 1983;24:810.

    Comment: TMP-SMX + amikacin are synergistic in vitro; TMP-SMX + imipenem are additive

  11. Hardak E et al: Clinical spectrum and outcome of Nocardia infection: experience of 15-year period from a single tertiary medical center. Am J Med Sci 343:286, 2012  [PMID:21825961]

    Comment: Review of 53 cases in 15 years at 1,000 bed university hospital in Israel.
    Rating: Important

  12. Jorna T, Taylor J: Disseminated Nocardia infection in a renal transplant patient: the pitfalls of diagnosis and management. BMJ Case Rep 2013:, 2013  [PMID:23505268]

    Comment: Challenges in the complex case differential (TB, MOTT, Rhodococcus) dual infections (here it was CMV), drug interactions with treatment.
    Rating: Important

  13. Tobin EH, Jih WW: Sporotrichoid lymphocutaneous infections: etiology, diagnosis and therapy. Am Fam Physician 63:326, 2001  [PMID:11201697]

    Comment: Major causes are Sporothrix, Nocardia brasiliensis, Mycobacterium marinum or Leishmania brasiliensis. All are managed differently. Infection begins at distal extremity followed by nodular lymphadenitis. Systemic sx are usually absent. Need histology and microbiology. Most are treated for 2-3mos after resolution.

  14. Schlaberg R, Huard RC, Della-Latta P: Nocardia cyriacigeorgica, an emerging pathogen in the United States. J Clin Microbiol 46:265, 2008  [PMID:18003809]

    Comment: N. cyriacigeorgica reported 7 cases of pulmonary infection -- 26% of nocardia isolates. Preferred antibiotics are amikacin and imipenem (>meropenem).
    Rating: Important

  15. Dorman SE et al: Nocardia infection in chronic granulomatous disease. Clin Infect Dis 35:390, 2002  [PMID:12145721]

    Comment: NIH review of 28 infections in 23 pts with CGD - all pulmonary. Disseminated infections in 25%, 33% had concomitant fungal infection. Most responded to sulfonamides. These pts should have interferon gamma and sulfa prophylaxis.

  16. Arduino RC, Johnson PC, Miranda AG: Nocardiosis in renal transplant recipients undergoing immunosuppression with cyclosporine. Clin Infect Dis 16:505, 1993  [PMID:8513056]

    Comment: Report of 9 cases in 1255 transplant recipients given cyclosporine - 8 pulmonary, 2 skin & 1 CNS. Four were treated with amox - clavulanate (Augmentin) and responded.
    Rating: Important

  17. Wortman PD: Treatment of a Nocardia brasiliensis mycetoma with sulfamethoxazole and trimethoprim, amikacin, and amoxicillin and clavulanate. Arch Dermatol 129:564, 1993  [PMID:8481016]

    Comment: Report reviews multiple favorable regimens for mycetoma including TMP-SMX and amoxicillin clavulanate.

  18. Beaman BL, Beaman L: Nocardia species: host-parasite relationships. Clin Microbiol Rev 7:213, 1994  [PMID:8055469]

    Comment: Review of >1000 reported cases. Over 60% had immunocompromised including - diabetes, pul. alveolar proteinosis, steroids, AIDS, organ tx, lymphoma. Pul - indolent pneumonia abscess, fibronodular, diffuse infiltrates. A separate analysis of 71 reported cases in AIDS pts showed lung involvement in 52%, brain 12% & a heterogeneous distribution in other organs.
    Rating: Important

  19. Poonyagariyagorn HK et al: Challenges in the diagnosis and management of Nocardia infections in lung transplant recipients. Transpl Infect Dis 10:403, 2008  [PMID:18823356]

    Comment: Review of 11 cases of nocardiosis. Mean onset was 14 months post transplant. 6 of the 11 were receiving TMP-SMX prophylaxis. Definitive dx required median -- 9 days.
    Rating: Important

  20. Matulionyte R et al: Secular trends of nocardia infection over 15 years in a tertiary care hospital. J Clin Pathol 57:807, 2004  [PMID:15280400]

    Comment: Review of 20 cases in Geneva Hosp - Median time from symptoms to diagnosis was 30 days. Of the 20, 16 involved lung, then CNS (2) and skin (2). All strains were sens. to imipenem and amikacin. TMP-SMX was used in 14 and 5 had ADR's requiring D/C of drug. Cure was achieved in 15, 3 died and 2 had relapse.

  21. van Burik JA et al: Nocardiosis after bone marrow transplantation: a retrospective study. Clin Infect Dis 24:1154, 1997  [PMID:9195074]

    Comment: Review of 27 cases. Median time post transplant - 210 days, all involved allogeneic transplants. 10 were receiving TMP-SMX prophylaxis for PCP 2d/wk. Rx was usually TMP-SMX, often with amikacin or other agent. Cure rate was 84%.

  22. Martínez Tomás R et al: Pulmonary nocardiosis: risk factors and outcomes. Respirology 12:394, 2007  [PMID:17539844]

    Comment: Review of 31 cases in Spain shows greatest risk is steroid treatment (65%); other risks -- organ transplant 27%, COPD 23% and HIV (19%).
    Rating: Important

  23. Smego RA, Gallis HA: The clinical spectrum of Nocardia brasiliensis infection in the United States. Rev Infect Dis 6:164, 1984 Mar-Apr  [PMID:6374833]

    Comment: Review of 7 cases at Duke and 55 reported from U.S. Of the 62, 46 had infections of skin and soft tissue - cellulitis, pustules, ulcers, abscesses, lymphocutaneous syndrome and mycetoma. There were 8 disseminated infections, 6 had lung lesions, only 28% were immunocompromised and all with skin involvement recovered.

  24. Muñoz J et al: Clinical and microbiological features of nocardiosis 1997-2003. J Med Microbiol 56:545, 2007  [PMID:17374898]

    Comment: Review of species distribution of 27 cases of nocardiosis showed N. farcinica (n=9), N. abscessus (n=6), and N. cyriacigeorgica (n=6). All were sensitive to TMP-SMX.
    Rating: Important

  25. Rivero A et al: Successful long-term treatment with linezolid for disseminated infection with multiresistant Nocardia farcinica. Infection 36:389, 2008  [PMID:18629435]

    Comment: Successful case treatment of disseminated multi-resistant N. farcinica using linezolid.
    Rating: Important

  26. Gomez-Flores A et al: In vitro and in vivo activities of antimicrobials against Nocardia brasiliensis. Antimicrob Agents Chemother 48:832, 2004  [PMID:14982772]

    Comment: Tests of N. brasiliensis which is the major cause of mycetoma in Mexico. Active vs >66% were linezolid, gentamicin, amikacin, tobramycin, minocycline, amox-clavulanate, pip-tazo, imipenem and spiramycin. In experimental model the most active was linezolid, then amox-clavulanate + amikacin.
    Rating: Important

  27. Rao SK et al: Nocardia Asteroides keratitis: report of seven patients and literature review. Indian J Ophthalmol 48:217, 2000  [PMID:11217254]

    Comment: The seven cases resulted from infection post corneal trauma or surgery. Mean duration prior to presentation was 33 days (7-75), 5 patients had received topical steroids and 6 had deep corneal infection.

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