Interim Treatment Guidance for Central Nervous System and Parameningeal Infections Associated with Injection of Contaminated Steroid Products
March 4, 2013 4:00 PM EDT
What's New in Treatment Guidance?
The current guidance provides new information on non first-line medications, surgical management of parameningeal disease, duration of anti-fungal treatment, and monitoring after cessation of anti-fungal treatment.
This is interim guidance for treatment of adult patients with central nervous system (CNS) infections (including meningitis, stroke, and arachnoiditis1) and/or parameningeal infections (epidural or paraspinal abscess, discitis or osteomyelitis, and sacroiliac infection) associated with injections of contaminated steroid products from the New England Compounding Center. Parameningeal infections include any infections at or near the site of injection into the spinal or paraspinal area, including the sacroiliac joint. Interim guidance may change as new information becomes available.
These recommendations are based upon 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, the pharmacokinetics of antifungal agents, and the clinical course, including complications (e.g., arachnoiditis, mycotic aneurysms, development of new CNS or epidural abscesses or masses, and stroke) that have been found during the course of treatment among some patients with fungal infections associated with this outbreak. CDC continues to consult with national experts and clinicians managing these patients 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. Optimal therapy for these infections has not been established and may be complex and prolonged. Expert consultation is particularly important because overall clinical experience is so limited. CDC has established a clinical consultant network for physicians which can be reached by calling CDC info: 1-800-CDC-INFO.
Considerations for Antifungal Therapy in Patients with CNS and/or Parameningeal Infection
The diagnosis of CNS and/or parameningeal infections should be suspected in patients who received injections with one of the three implicated lots of methylprednisolone and who has either increased pain at the injection site, MRI evidence of inflammation or unexplained pleocytosis in the CSF.
Antifungal therapy should be initiated after collecting appropriate specimens (CSF, abscess fluid, tissue) for culture and PCR, 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. Specific tests to identify fungus are often negative in patients with fungal infection. Confirmation of fungus by culture, PCR, or pathology has been found in approximately 30% of cases to date.
- Providers should give voriconazole, preferably at an initial dose of 6 milligrams per kilogram (mg/kg) every 12 hours2. This dose is recommended in order to ensure rapid and adequate penetration of voriconazole into the CNS, as well as allowing for blood levels to come up quickly.
- 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. There is however substantial overlap between levels in patients for both toxic and nontoxic side effects, so clinicians should monitor patients and not just blood levels.
- 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 given on an empty stomach, 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 gastrointestinal intolerance or poor absorption are encountered.
- Providers should carefully consider and manage potential voriconazole drug interactions in all patients. Potential adverse effects of voriconazole include (but are not limited to) hepatic toxicity and neurotoxicity. Liver function tests should be closely monitored. Minor elevations of transaminases and alkaline phosphatase are common, but severe hepatotoxicity can also occur. Visual hallucinations are not rare and often respond to dose reduction and reassurance. Discontinuance of voriconazole should not be automatic. Although some side effects of voriconazole are dose-related, others appear to not be related to high voriconazole serum concentrations. Frequently, patients who have levels within the therapeutic range complain of a "foggy" feeling, being unable to make decisions, and forgetfulness. Nausea, anorexia, and fatigue are commonly experienced. Chapped lips are very common, some patients have noticed alopecia. Sun sensitivity while on voriconazole can be severe and patients who have received many months of voriconazole may be at increased risk of skin cancer. Another rare complication of long term voriconazole is periostitis, which can present as bone pain and elevated alkaline phosphatase.
- Providers should strongly consider giving liposomal amphotericin B in addition to voriconazole to patients who present with severe disease and patients who do not improve or who experience clinical deterioration or who manifest new sites of disease activity while on voriconazole monotherapy. 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.
- The routine use of intrathecal amphotericin B formulations is not recommended, due to limited data on their use and associated toxicities.
Considerations Regarding Other Antifungal Medications
It is important to continue to use voriconazole or amphotericin B as primary treatment. Side effects, such as hallucinations with voriconazole and minor elevations in creatinine with amphotericin are to be expected in some patients and may not necessitate discontinuation of those drugs. If such mild to moderate side effects can be managed by adjusting doses, continuation of first-line agents is preferred. Some patients may be unable to tolerate voriconazole (due to hepatotoxicity or other severe side effects) or amphotericin B (due to severe nephrotoxicity or other serious adverse reactions). For these patients and those with other contraindications to voriconazole and amphotericin B, some infectious diseases clinicians have used other anti-fungal agents such as posaconazole or itraconazole. These medications have variable pharmacokinetics within the CNS and their effectiveness for treatment of infections associated with this outbreak is not established. However, use of these drugs deserves consideration when first line therapies can not be safely administered to the patient. Decisions to change anti-fungal therapy should be made in consultation with an infectious disease physician experienced in the treatment of fungal infections.
Considerations for Surgical Management of Parameningeal Disease
Individual patient management decisions, including surgical debridement and drainage of abscess fluid, should be made in consultation with surgical teams and infectious diseases physicians. Some clinical teams have performed surgical drainage rapidly after diagnosis as an adjunct to antifungal therapy on patients with localized abscesses and phlegmons at the injection site. Whether this clinical approach is superior to antifungal therapy alone is currently unknown.
Considerations Regarding Duration of Antifungal Treatment for CNS Infections With and Without Parameningeal Disease
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. The appropriate duration of therapy will likely vary substantially depending upon individual patient circumstances as well as severity of CNS disease. In general, patients with meningitis alone will likely need a minimum of 3 months of antifungal treatment. Patients with more severe CNS disease including complications such as arachnoiditis or stroke, those with persistent CSF abnormalities, or those who have underlying immunosuppression will likely need to continue antifungal treatment for 6 months to 1 year. Follow-up monitoring after completion of therapy is important to detect potential relapse of infection (see section Considerations for Monitoring Clinical Status After Cessation of Anti-fungal Treatment).
Considerations Regarding Duration of Antifungal Treatment for Parameningeal Infections not Associated with CNS Disease
Adequate duration of antifungal treatment is unknown, and patients likely will require prolonged therapy tailored by the clinical response to treatment. Appropriate management of these infections will likely vary substantially depending upon individual patient circumstances, a minimum of 3-6 months of antifungal treatment should be considered in patients with parameningeal infection. Treatment will likely need to continue for at least 6 months or longer in patients with more severe disease (e.g., discitis or osteomyelitis), underlying immunosuppression, and other complications that may not be amenable to surgical treatment. Follow-up monitoring after completion of therapy is important to detect potential relapse of infection (see section Considerations for Monitoring Clinical Status After Cessation of Anti-fungal Treatment).
Considerations for Monitoring Clinical Status After Cessation of Antifungal Treatment
Because adequate duration of treatment and the potential for relapse are unknown, close monitoring of patients in whom antifungal therapy has been discontinued is essential. Patients with recurrent symptoms or worsening pain should be evaluated promptly. There should be a low threshold for performing lumbar puncture or imaging to diagnose relapsed infection. Radiologic abnormalities may persist for several months after clinical symptoms have resolved.
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 red blood cells (RBC) 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.