Interim Treatment Guidance for Central Nervous System (CNS) and/or Parameningeal Infections Associated with Injection of Potentially Contaminated Steroid Products

October 16, 2012 11:15 AM EDT

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 Aspergillus species. 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 on treatment options for fungal CNS and/or parameningeal infections in patients associated with this cluster.

This is interim guidance for treatment of adult patients with CNS and/or parameningeal infections associated with injections of potentially contaminated steroid products from the New England Compounding Center.  Interim guidance may change as new information becomes available.

• Consult an infectious disease physician to assist with diagnosis, management, and follow–up, which may be complex and prolonged.
• Initiate empiric antifungal therapy after collecting cerebrospinal fluid for culture using the following regimen in addition to routine empiric treatment protocols to cover for potential bacterial pathogens until the etiology of the patient’s CNS and/or parameningeal infection has been identified:
• Voriconazole, preferably at a dose of 6 mg/kg every 12 hours¹
  • Voriconazole should be continued at a dose of 6 mg/kg every 12 hours, whenever possible, for the duration of treatment. This dose is recommended because ensuring adequate penetration of voriconazole into the CNS is critical.
  • Regular monitoring of serum voriconazole concentrations (e.g., at a weekly interval) is recommended, aiming for trough levels of 2-5 mcg/ml.
  • Patients with more severe disease should be started on voriconazole IV.
  • Patients with mild disease may be started on oral voriconazole at the provider’s discretion. The above target serum levels of voriconazole are readily achievable using the oral form but may require a slightly higher dose and make take longer to achieve if unforeseen problems with gastro-intestinal intolerance or poor absorption are encountered.
  • If provider wants to transition patients initially started on IV voriconazole therapy to oral therapy, this should be done only after a patient is clinically stable or improving, as long as no contraindications to oral therapy exist.
  • Providers and patients should be aware of and monitor for potential adverse effects of voriconazole, including (but not limited to) hepatic toxicity and neurotoxicity.
  • Providers should carefully consider and manage the potential for voriconazole drug interactions in all patients.
• Providers should consider giving liposomal amphotericin B in addition to voriconazole to patients who present with severe disease, and patients started initially on voriconazole monotherapy who do not improve or who experience clinical deterioration.
  • When used, liposomal amphotericin B should preferably be given at a dose of 7.5 mg/kg IV daily (higher than standard dose). The liposomal preparation of amphotericin B [AmBisome] is preferred over other lipid formulations because of better CNS penetration. If nephrotoxicity is a potential concern, particularly in older patients, the dose may be decreased to 5 mg/kg IV daily. Administration of 1L normal saline prior to infusion may be considered to minimize risk of nephrotoxicity. Providers and patients should be aware of and monitor for potential adverse effects of amphotericin B.
  • Avoid routine use of intrathecal amphotericin B, either the deoxycholate or the lipid formulations, due to limited data on its use and associated toxicities.
  • There is currently no clear evidence for the use of adjuvant steroid therapy.

• Adequate duration of antifungal treatment is unknown, but patients likely will require prolonged therapy tailored by the clinical response to treatment. Individual management decisions, including choice of long-term antifungal regimen, should be made in consultation with infectious diseases physicians experienced in the treatment of fungal infections. Although the 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 will likely 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.
• Consideration should be given to obtaining spine imaging studies in patients in whom vertebral osteomyelitis/discitis or epidural abscess are concerns. These complications will prolong the duration of therapy.
• At this time, CDC does not recommend empiric antifungal therapy for symptomatic patients who have normal cerebrospinal fluid laboratory examination. These patients should be closely monitored and re-evaluated for progression of symptoms. Should the patient have progression of symptoms, a lumbar puncture should be repeated immediately, using a different site than was used for the epidural injection when possible.

For additional information on antifungal drugs

• Voriconazole package insert: http://labeling.pfizer.com/ShowLabeling.aspx?id=618
• Liposomal amphotericin B package insert: http://www.astellas.us/docs/ambisome.pdf
• Amphotericin B lipid complex package insert: http://www.sigmatau.com/products/AbelcetPI_May2010.pdf
• Other sources for drug information: http://local-dailymed-3.nlm.nih.gov/dailymed/about.cfm, http://www.nlm.nih.gov/medlineplus/druginformation.html
• FDA information on Voriconazole IV availability: http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm323947.htm

¹Dose adjustments may be needed for certain patients, including (but not necessarily limited to): children, for patients < 40 kg, and patients with hepatic impairment. Oral voriconazole should be taken at least one hour before or after a meal. Consult an infectious diseases specialist and refer to the manufacturer’s instructions.