Multistate Outbreak of Fungal Meningitis and Other Infections

Vials and test tubes on top of a periodic table.

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

October 23, 2012 11:00 PM EDT

Rationale

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 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 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 tolerate 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.