FDA, CDC Investigate Fungal Meningitis Outbreak
The FDA, CDC, and the Massachusetts Department of Public Health continue to investigate an outbreak of fungal meningitis among patients who received contaminated steroid injections. As of November 7, 2012, a total of 414 cases of fungal meningitis, stroke due to presumed fungal meningitis, or other CNS-related infection have been diagnosed, and 31 people have died.
The outbreak has been linked to three lots of methylprednisolone acetate, an injectable steroid used to treat pain and swelling associated with arthritis and other joint disorders, manufactured by the New England Compounding Center (NECC). In addition, a patient who received an epidural injection of triamcinolone acetonide produced by NECC may now have meningitis, according to the FDA. Triamcinolone acetonide is an injectable steroid used to treat arthritis. The FDA has not yet confirmed that the infections were caused by an NECC product.
The FDA advises health care providers not to use any products made at NECC. “At this point in the FDA’s investigation, the sterility of any injectable drugs, including ophthalmic drugs that are injectable or used in conjunction with eye surgery, and cardioplegic solutions produced by NECC are of significant concern,” Stephen King, public affairs specialist at the FDA, told Neurology Reviews.
Although patients who received injections of NECC’s methylprednisolone acetate are still at risk, the outbreak has been contained and the product recalls have foreclosed the possibility of further infections, said Avindra Nath, MD, Chief, Section of Infections of the Nervous System and Clinical Director of NINDS in Bethesda, Maryland, in an interview with Neurology Reviews.
Precedents for the Current Outbreak
The current outbreak of fungal meningitis is similar to a smaller outbreak that occurred in 2002. That year, five patients were diagnosed with fungal meningitis after receiving paraspinal injections of a steroid contaminated with Wangiella Exophiala dermatitidis. As in the current outbreak, the drug had been prepared by a compounding pharmacy. Contaminated epidural injections were also linked with one case of Aspergillus meningitis in Minnesota and six cases in Sri Lanka in 2007.
How to Reduce the Risk of Contamination
Contamination can occur at the site of drug administration, as well as at the manufacturing site. Emergency conditions and contaminated needles or syringes could potentially cause infection. “You can minimize the possibility [of contamination] by putting good practices, rules, and regulations in place, but you may not be able to entirely eliminate it,” said Dr. Nath.
Fungal Meningitis Differs From Bacterial and Viral Meningitis
Unlike viral meningitis and bacterial meningitis, which usually produce acute and dramatic symptoms, fungal meningitis is often insidious. Patients may present with headache, but frequently do not have the other classic symptoms of meningitis such as photophobia, neck stiffness, or fever, said Michael Wilson, MD, Instructor in Neurology and Internal Medicine at Boston University School of Medicine. “Also, until late in the disease, they may not have a focal neurologic deficit, like arm weakness or gait difficulty, that would clearly alert a doctor to the fact that there’s an actual CNS process going on,” Dr. Wilson told Neurology Reviews.
After injection with a contaminated drug, the fungus tends to collect in the base of the brain or at the bottom of the spinal cord, and symptoms often involve the cranial nerves or lower extremities, said Dr. Nath. Patients can develop dysphagia, dysphonia, facial weakness, and impaired hearing. Aspergillus tends to occlude blood vessels and may cause stroke-like symptoms, he added.
If an immunocompetent person who has gotten a steroid injection for back pain presents with more pain, “the initial thought is not to do a lumbar puncture to look for a fungal infection,” noted Dr. Wilson. “If the pain syndrome is somehow different from the one he or she had before,” or if the patient has a new neurologic deficit or signs of meningismus, “that’s always a tip-off,” he added.
Treating Patients With Fungal Meningitis
Voriconazole became the drug of choice during the 2002 outbreak, and the CDC is now recommending a dose of 6 mg/kg every 12 hours for patients with fungal meningitis, with a goal serum trough level of 2–5 µg/mL. The agency recommends that treatment continue for at least three months.
The drug “has good penetration into the CNS” and efficiently cleared infections in some patients in 2002, said John R. Perfect, MD, Chief of the Division of Infectious Diseases at Duke University Medical Center in Durham, North Carolina. Dr. Perfect recognized and treated patients with fungal meningitis during the 2002 outbreak. Voriconazole causes hallucinations and other visual side effects in more than 50% of patients, however. Other side effects could include delirium and photopsia, and neurologists could be confused about whether the symptoms result from the infection or from the drug, Dr. Perfect told Neurology Reviews. “The incidence is high enough that it should clearly be considered a complication during treatment and adjusted for accordingly,” he added.
For patients with severe meningitis, or patients who have not improved on voriconazole, the CDC recommends supplementing voriconazole with 5 mg/kg to 6 mg/kg of liposomal IV amphotericin B daily.
Neurologists’ Role in Responding to the Outbreak
Observers are asking whether gaps in regulation enabled the outbreak to occur. Until regulatory questions have been answered, “there may be an extra onus on hospitals and other facilities that use compounded medications to do site-based testing to ensure that they are sterile,” said Dr. Wilson. In the context of the current outbreak, neurologists should keep an open mind when they are working up and treating patients. “If they don’t respond in the way you would expect, continue broadening your differential diagnosis and be aggressive about the diagnostic work-up,” said Dr. Wilson.
“The thing to emphasize to neurologists is that if they find an unusual organism in the CSF causing meningitis, especially if they see fungal meningitis in an immune-competent individual, the possibility of iatrogenic contamination should be considered very high,” said Dr. Nath. Neurologists should report such cases to authorities so that they can be investigated and prevented, he added. “The sooner we catch it, the easier it is to find the other patients and treat them.”
Timeline of the Meningitis Outbreak
The current outbreak began on September 18, 2012, when a clinician in Tennessee alerted that state’s department of health that a patient who had received an epidural steroid injection had developed Aspergillus fumigatus meningitis. An ensuing investigation identified eight more patients in Tennessee and North Carolina with clinically diagnosed meningitis.
The initial investigation into the outbreak, conducted by the CDC and the North Carolina Department of Health and Human Services, linked the meningitis to three lots of preservative-free methylprednisolone acetate (80 mg/mL) produced and distributed by NECC in Framingham, Massachusetts. The CDC and state health departments estimate that 14,000 patients may have received injections from the three implicated lots. Nearly 97% have been contacted for follow-up.
NECC agreed to cooperate with the ongoing investigation of its product and voluntarily recalled the three lots on September 26, 2012. The company ceased its manufacturing operations on October 3 after expanding the recall to include all lots of the drug and all lots of sterile products intended for intrathecal injection. NECC recalled all of its remaining products on October 6.
The company surrendered its license to the Massachusetts Department of Public Health. At the request of the department, two of the company’s pharmacists, Barry Cadden and Glenn Chinn, agreed to stop practicing clinical pharmacy, pending the completion of the investigation. Mr. Cadden is a principal owner and operational manager of NECC.
On October 18, the FDA and the CDC confirmed the presence of Exserohilum rostratum in unopened vials of preservative-free methylprednisolone acetate from two of the three implicated lots made by NECC. The agencies also linked steroid injections from these lots to the multistate outbreak of fungal meningitis. Testing on the third implicated lot of methylprednisolone acetate and other NECC injectable medications is ongoing. Congress subpoenaed Mr. Cadden on November 6 to answer questions about the outbreak.
A Second Company Under Investigation
In addition to NECC, Mr. Cadden is a principal owner of Ameridose, another drug manufacturer. On October 12, the FDA and the Massachusetts Board of Pharmacy launched a joint inspection of Ameridose’s Westborough, Massachusetts, facility to determine whether certain aspects of compounding practices and facility conditions observed at NECC were also in place at the Ameridose site. The FDA will evaluate whether Ameridose’s procedures and facilities can produce and distribute sterile drug products safely. To date, no contamination has been found in products made by Ameridose.
Ameridose ceased all manufacturing and compounding operations on October 10, 2012. Ameridose and its partnering distributor, Alanaus Pharmaceuticals (of which Mr. Cadden is a principal owner), agreed to stop distributing all products manufactured and compounded by Ameridose or any of the companies under shared ownership until October 22. Mr. Cadden also resigned from his managerial positions at the three companies.
Investigation Finds Violations at NECC
In violation of its state pharmacy license, NECC manufactured and distributed sterile products in bulk, according to the preliminary results of an investigation conducted by the FDA and the Massachusetts Department of Public Health. The company did not have the patient-specific prescriptions required by state law.
In addition, NECC distributed two of the recalled lots of methylprednisolone acetate without waiting to receive the results of sterility testing. Company records also showed a systemic failure to sterilize products for the required amount of time, according to the investigation.
Conditions at the facility, including powder hoods that were not thoroughly cleaned, dirt-trapping mats in poor condition, and a leaking boiler next to the clean room, “created an environment susceptible to contaminant growth,” according to the Massachusetts Department of Public Health.
Centers for Disease Control and Prevention (CDC). Multistate outbreak of fungal infection associated with injection of methylprednisolone acetate solution from a single compounding pharmacy—United States, 2012. MMWR Morb Mortal Wkly Rep. 2012;61:839-842.
Kauffman CA, Pappas PG, Patterson TF. Fungal infections associated with contaminated methylprednisolone injections—preliminary report. N Engl J Med. 2012 Oct 19 [Epub ahead of print].
Pettit AC, Kropski JA, Castilho JL, et al. The index case for the fungal meningitis outbreak in the United States. N Engl J Med. 2012 Oct 19 [Epub ahead of print].