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Interim Treatment Guidance for Osteoarticular Infections Associated With Injection of Contaminated Steroid Products

On Behalf of | Nov 7, 2012 | Fungal Meningitis

October 23, 2012 11:00 PM EDT


This is interim guidance  for treatment of adult patients with osteoarticular infections associated with  intra-articular injections of contaminated steroid products from the New  England Compounding Center.  Interim guidance may change as new  information becomes available.

  These recommendations are  based upon growing evidence that Exserohilum rostratum (a brown-black  mold) is the predominant pathogen in this outbreak, and expert opinion and  published literature indicating that voriconazole may be effective in treating  infections due to brown-black molds as well as infections due to Aspergillusspecies. Recommendations are also based on considerations related to the  anatomic site of infection and pharmacokinetics of antifungal agents. CDC  continues to consult with national experts about treatment options for fungal osteoarticular  infections in patients associated with this outbreak.

Infectious  Diseases Physician Consultation:

  • Consult  an infectious diseases physician to assist with patient diagnosis, management,  and follow up, which may be complex and prolonged.
  • Diagnostic Considerations:

    • Thorough  diagnostic evaluation is essential, and should include collection of synovial  fluid and/or synovial tissue prior to initiation of treatment. Samples should  be sent or  fungal culture, molecular testing, and histopathological examination, in addition  to the standard tests for bacterial infection and crystal-induced disease.
    • Physicians  should use their best judgment in regard to imaging the osteoarticular  structure(s) that may be infected. For large joints, such as knees, if there is  a consideration of adjacent osteomyelitis, then imaging should be performed. Imaging  may be particularly important in the evaluation of joint spaces such as the  sacroiliac joint, where osteomyelitis may be more common and from which  obtaining a diagnostic specimen of synovial fluid may be more difficult. Similarly, for patients in whom complaints of  back pain are worrisome for the development of discitis/vertebral  osteomyelitis, imaging should be performed. In some of these cases, repeat  imaging may be required as the progression of the infection may be slow and imaging  findings suggestive or diagnostic of osteomyelitis may not be evident for two  weeks or more following initial presentation.
    • Note that a negative fungal culture or  negative fungal polymerase chain reaction (PCR) test from a diagnostic specimen  obtained from a joint space or bone does not rule out infection.  Active  fungal infection may be present even when these tests are negative.

    Empiric Antifungal Therapy:

    • Routine  empiric antibacterial therapy should be used according to the judgment of the  physician while awaiting results of diagnostic studies.
    • In  clinically stable patients with peripheral joint infection, it may be  reasonable to wait 48-72 hours before initiating empiric antifungal therapy, to  allow time for identification of alternative diagnoses (e.g., bacterial  arthritis, crystal-induced arthritis, etc.). This decision should be made at  the discretion of the provider.
    • When  empiric antifungal therapy is initiated, the following regimen is  suggested until the etiology of the patient’s septic arthritis has been  identified:
      • For  discitis, vertebral osteomyelitis, and epidural abscess give voriconazole at  a dose of 6 milligrams per kilogram (mg/kg) every 12 hours1. For osteoarticular infections that do not involve the  spine, give voriconazole, beginning  with a loading dose of 6 mg/kg every 12 hours for two doses, followed by 4  mg/kg every 12 hours1.
        • A  blood specimen for serum voriconazole trough level measurement should be  collected on the 5th day of voriconazole treatment, and the dose of  voriconazole should be adjusted based on this trough level, aiming for a trough  level range of 2 to 5 micrograms per milliliter (mcg/ml). Serum voriconazole  trough levels greater than 5 mcg/ml should be avoided because of the risk of  neurotoxicity and other drug-related adverse events.
        • Regular  monitoring of serum voriconazole trough levels once per week should occur for  the initial 4-6 weeks of voriconazole treatment and when dose adjustments are  made. Dose adjustments should be made as needed to maintain serum voriconazole  trough levels within the range of 2 to 5 mcg/ml.
        • Patients  with more severe osteoarticular infection, clinical instability, discitis,  vertebral osteomyelitis, or epidural abscess should be started on voriconazole  IV. If the provider wants to transition patients initially treated with IV  voriconazole to oral voriconazole, this should be done only after a patient is  clinically stable or improving, as long as no contraindications to oral therapy  exist.
        • Patients  with mild osteoarticular infection not involving the spine who are able to take  oral voriconazole as prescribed and who are able to be monitored closely may be  started on oral voriconazole at the provider’s discretion. Patients on oral  voriconazole should be treated with a loading dose of 6 mg/kg every 12 hours  for two doses, followed by 4 mg/kg every 12 hours, with monitoring of serum  voriconazole trough levels as above and dose adjustment as necessary. The  target range for serum voriconazole trough levels (2 to 5 mcg/ml) is readily  achievable using the oral form of the drug, but may require a slightly higher  dose and may take longer to achieve if unforeseen problems with  gastrointestinal intolerance or poor absorption are encountered.
        • Providers  and patients should be aware of and monitor for potential adverse effects of voriconazole,  including (but not limited to) hepatic toxicity and neurotoxicity. Liver  function tests should be closely monitored. The occurrence of hallucinations may  be an indication of neurotoxicity and elevated serum voriconazole levels, and  should prompt collection of a blood specimen for serum voriconazole trough  level measurement and voriconazole dose adjustment.
        • Providers  should carefully consider and manage the potential for voriconazole drug  interactions in all patients.
      • A lipid formulation of amphotericin B at a dose of 5 mg/kg IV daily should be considered in addition to voriconazole in patients with severe osteoarticular infection and/or patients with clinical instability. Nephrotoxicity is a common complication of amphotericin B therapy, including therapy with lipid formulations of amphotericin B. Kidney function and electrolytes should be monitored closely in patients receiving any amphotericin B formulation.  Administration of 1 liter of normal saline IV prior to amphotericin B infusion may be considered to minimize risk of nephrotoxicity. Providers and patients should also be aware of and monitor for other potential adverse effects of amphotericin B formulations.
      • Alternate therapies to consider for patients who are unable to lerate treatment with voriconazole include lipid formulations of amphotericin B, posaconazole, and itraconazole. Therapeutic drug monitoring should be performed for patients treated with posaconazole or itraconazole. Consultation with an infectious diseases physician should be sought regarding dosages and monitoring of these agents. Fluconazole should NOT be used.

    Other Treatment Considerations:

    • Arthroscopy  with joint lavage and debridement should be considered in consultation with an  orthopedic surgeon, or a neurosurgeon in the case of vertebral osteomyelitis.

    Considerations Regarding Duration of  Treatment:

    • Adequate  duration of antifungal treatment is unknown, and it is likely that patients  will require prolonged therapy tailored by the clinical response to treatment.  Individual patient management decisions, including choice of long-term  antifungal treatment regimens, should be made in consultation with infectious diseases  physicians experienced in the treatment of fungal infections. While adequate  duration of therapy is unknown and will likely vary substantially depending  upon individual patient circumstances, a minimum of 3 months of antifungal  treatment should be considered. Treatment may need to continue for longer than  3 months in patients with more severe disease, bone infection, underlying  immunosuppression, etc. Clinicians should be vigilant for potential relapse of  infection after completion of therapy.

    1Dose adjustments may be needed for certain patients,  including (but not necessarily limited to): children (who often need a higher  dose) and patients with hepatic impairment (who may need a lower dose). Dosing  of voriconazole in obese patients should be discussed with an infectious  diseases physician. Oral voriconazole should be taken at least one hour before  or after a meal. Consult an infectious diseases physician and refer to the  manufacturer’s instructions.


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