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

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

October 23, 2012 9:00 PM EDT

Rationale:

This is interim guidance for treatment of adult patients with CNS infections (including meningitis1) and/or parameningeal infections associated with 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 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 about treatment options for fungal CNS and parameningeal 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:

  • Note that a negative fungal culture or negative fungal polymerase chain reaction (PCR) test from a diagnostic specimen obtained from a CNS or parameningeal site does not rule out infection. Active fungal infection may be present even when these tests are negative.
  • Because some patients who have fungal meningitis may also have or may develop epidural abscess, discitis, or vertebral osteomyelitis, usually heralded by persistent back pain, consideration should be given to obtaining spine imaging of the area that is painful. These types of complications will likely prolong therapy and may also require surgical intervention.

Empiric Antifungal Therapy:

  • Initiate empiric antifungal therapy(after collecting cerebrospinal fluid for culture) using the following regimen, in addition to routine empiric treatment protocols for other pathogens, until the etiology of the patient's CNS and/or parameningeal infection has been identified.
    • Providers should give voriconazole, preferably at a dose of 6 milligrams per kilogram (mg/kg) every 12 hours2. This dose is recommended because ensuring adequate penetration of voriconazole into the CNS is critical.
      • 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.
      • In most cases it is suggested that patients should be started on intravenous (IV) voriconazole. 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.
      • Although it is recommended that most patients with CNS or parameningeal infections be started on IV voriconazole, patients with mild disease 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 dose of 6 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.
    • Providers should consider giving liposomal amphotericin B in addition to voriconazoleto patients who present with severe disease, and patients started initially on voriconazole monotherapy who do not improve or who experience clinical deterioration. Liposomal amphotericin B may also be considered as an alternative to voriconazole in patients who are unable to tolerate voriconazole.
      • When used, liposomal amphotericin B should be given at a dose of 5 to 6 mg/kg IV daily. The liposomal preparation of amphotericin B [AmBisome®] is preferred over other lipid formulations because of better CNS penetration. 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.
      • Higher doses of liposomal amphotericin B (7.5 mg/kg IV daily) may be considered for patients who are not improving, recognizing the potential for increased nephrotoxicity on this higher dose.
      • Avoid the routine use of intrathecal amphotericin B formulations, due to limited data on their use and associated toxicities.

Considerations Regarding Duration of Antifungal Treatment:

  • Adequate duration of antifungal treatment is unknown, and patients likely 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 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.

Empiric Antifungal Therapy for Symptomatic Patients with 5 or Fewer CSF White Blood Cells (WBC):

  • At this time, CDC does not recommend empiric antifungal therapy for symptomatic patients who have 5 or fewer WBC in the CSF at the time of diagnostic lumbar puncture. These patients should be closely monitored and re-evaluated for persistent symptoms. Should the patient have persistence of symptoms, a lumbar puncture should be repeated, using a different site than was used for the epidural injection when possible (recommended for any lumbar puncture when evaluating patients associated with this outbreak).

1 Symptoms consistent with meningitis in addition to CSF WBC greater than 5 in a non-traumatic lumbar puncture. If a traumatic lumbar puncture is suspected, a corrected CSF WBC count can be calculated by subtracting one WBC for every 500 RBCs present in the CSF.

2 Dose 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 specialist and refer to the manufacturer's instructions.

Source: http://www.cdc.gov/HAI/outbreaks/clinicians/guidance_cns.html

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