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NEJM: Relapse of Fungal Meningitis Associated with Contaminated Methylprednisolone

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  • NEJM: Relapse of Fungal Meningitis Associated with Contaminated Methylprednisolone


    "Relapse of Fungal Meningitis Associated with Contaminated Methylprednisolone

    May 29, 2013DOI: 10.1056/NEJMc1306560

    To the Editor:

    Since September 2012, the Centers for Disease Control and Prevention (CDC) and state and local health departments have been investigating an outbreak of fungal infections...As of May 6, 2013, a total of 741 cases have been reported in 20 states, with 55 deaths. The primary pathogen isolated from patient specimens has been Exserohilum rostratum, which has also been recovered from sealed vials of methylprednisolone acetate. Before this outbreak, human infections with E. rostratum were rarely reported.2,3

    Little is known about the management of E. rostratum infections, especially when the disease involves the central nervous system. The current guidance4 suggests 3 to 6 months of antifungal therapy for parameningeal infections, with longer therapy in patients with severe disease (e.g., diskitis or osteomyelitis). For patients with meningitis, a minimum of 3 months of treatment is recommended, with up to 1 year of treatment recommended for patients with severe central nervous system involvement (e.g., stroke or arachnoiditis).

    An 80-year-old man with no history of an immunosuppressive condition received a lumbar epidural glucocorticoid injection with lot #06292012@26 of methylprednisolone acetate on September 12, 2012. He was taking medications for benign prostatic hypertrophy and elevated blood pressure but was not taking immunosuppressive medication (e.g., prednisone). He presented on October 4 with headache and neck pain. Lumbar puncture showed a white-cell count in the cerebrospinal fluid (CSF) of 119 cells per milliliter, and polymerase-chain-reaction (PCR) assay at the CDC was negative for fungi. After 1 day of treatment with liposomal amphotericin B, therapy was switched to voriconazole, with trough levels ranging from 3.0 to 10.7 μg per milliliter (reference range, 1.0 to 5.5). On January 11, 2013, examination of the CSF showed 5 white cells per milliliter. Voriconazole was discontinued on February 19, after 41/2 months of therapy. On March 11, 2013, the patient presented to the emergency department with headache and neck pain; CSF analysis showed 2075 white cells per milliliter; PCR assay of the specimen at the CDC was positive for E. rostratum. No localized disease was visualized on magnetic resonance imaging of the lumbar spine. The patient was admitted with relapsed fungal meningitis. Voriconazole was restarted, and the patient was discharged home 4 days later. At a home visit conducted by the health department 2 weeks later, the patient reported only fatigue.

    This case shows the possibility for relapsed infection among patients after more than 4 months of antifungal therapy, resolution of symptoms, and normalization of the CSF white-cell count. Although the CDC is aware of patients who have not had a relapse of disease after 3 or 4 months of antifungal treatment, the risk of relapse should be considered when deciding whether to discontinue antifungal therapy... After the discontinuation of antifungal therapy, clinicians should remain vigilant for recrudescence of infection...

    Because exserohilum meningitis is a new clinical entity, it is not known whether the current treatment guidance is sufficient. Some patients with central nervous system infection may require prolonged antifungal therapy owing to the chronic nature of fungal diseases and the difficulty in maintaining adequate drug concentrations in the CSF. The frequency of relapse after cessation of antifungal therapy in other fungal infections of the central nervous system, such as coccidioidal meningitis, has led to recommendations of lifetime antifungal treatment.5 At this time, the CDC has not revised its treatment guidance as a result of this single report, but the CDC continues to actively review clinical data and reports.

    Rachel M. Smith, M.D., M.P.H.
    Centers for Disease Control and Prevention, Atlanta, GA

    Margaret Tipple, M.D.
    Virginia Department of Health, Richmond, VA

    Muddasar N. Chaudry, M.D.
    LewisGale Medical Center, Salem, VA

    Melissa K. Schaefer, M.D.
    Benjamin J. Park, M.D.
    Centers for Disease Control and Prevention, Atlanta, GA

    The views expressed in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

    Disclosure forms provided by the authors are available with the full text of this letter at

    This letter was published on May 29, 2013, at
    5 References


    Smith RM, Schaefer MK, Kainer MA, et al. Fungal infections associated with contaminated methylprednisolone injections ? preliminary report. N Engl J Med 2012. DOI: 10.1056/NEJMoa1213978.


    Adler A, Yaniv I, Samra Z, et al. Exserohilum: an emerging human pathogen. Eur J Clin Microbiol Infect Dis 2006;25:247-253[Erratum, Eur J Clin Microbiol Infect Dis 2006;25:254-6.]
    CrossRef | Web of Science | Medline


    Derber C, Elam K, Bearman G. Invasive sinonasal disease due to dematiaceous fungi in immunocompromised individuals: case report and review of the literature. Int J Infect Dis 2010;14:Suppl 3:e329-e332
    CrossRef | Web of Science | Medline


    Interim treatment guidance for central nervous system and parameningeal infections associated with injection of contaminated steroid products. Atlanta: Centers for Disease Control and Prevention, 2013 (


    Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis 2005;41:1217-1223
    CrossRef | Web of Science | Medline

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