In September, an outbreak of fungal meningitis due to contaminated steroid injections prepared by the New England Compounding Center (NECC) began in Tennessee. When this issue of Pharmacy Today went to press, 268 cases of this rare and potentially fatal—albeit noncontagious—disease had been reported in 16 states; 21 patients had reportedly died. This contamination has been described as “unprecedented” in a New England Journal of Medicine review.
Figure 1. Cases of meningitis reported in the U.S. as of October 19, 2012.
Source: CDC. Multistate Meningitis Outbreak Case Count.
The illnesses have been linked to three lots of methylprednisolone acetate compounded in Massachusetts by NECC. The lots were initially recalled on September 26; on October 6, that recall was expanded to include all products made at NECC. According to CDC, 76 health care facilities in 23 states received products from the three initially recalled lots.
CDC has estimated that some 14,000 patients have received medication from the recalled lots, according to J. Todd Weber, MD, Incident Manager of the Multistate Meningitis Outbreak and Chief of the Prevention and Response Branch in the CDC Division of Healthcare Quality Promotion. Nearly 97% have been contacted, CDC and FDA estimate.
“We know we are not out of the woods yet,” Weber continued, noting that fungal infections can be slow to develop, and in some cases could take several months, although 1 week to 4 weeks is more common. He urged health professionals to continue reaching out to patients who may have received a contaminated product, noting that “we can save lives by identifying patients early.”
FDA has created a patient notification letter, available on the agency’s website, to aid health professionals in contacting patients who may have been administered any injectable product, including ophthalmic drugs, or cardioplegic solution purchased from or produced by NECC after May 21, 2012. In addition to the 268 cases of meningitis linked to spinal injections, 3 peripheral joint infections have been reported. No deaths have been associated with the peripheral joint infections, however.
On October 18, FDA and CDC announced that the agencies had confirmed the presence of the fungus Exserohilum rostratum in one of the three methylprednisolone lots from NECC. E. rostratum is commonly found on plant debris, in soil, and in water, and human infections associated with the fungus are uncommon, according to the New England Journal of Medicine review article. Testing on the other lots was still under way when Today went to print.
Figure 2. Exserohilum rostratum
Source: CDC. Other pathogenic fungi.
An Aspergillus fungus was initially thought to be the culprit, Weber said during an October 11 news conference, as it was found in the first patient diagnosed with fungal meningitis linked to the NECC products. All other cases confirmed by the CDC laboratories, however, were caused by Exserohilum fungus. Weber noted that fungal meningitis is a rare condition and has never been linked to Exserohilum before, describing it as “new territory” for CDC.
According to CDC’s official recommendation for clinicians, “presenting symptoms of some patients with meningitis have been mild and not classic for meningitis (e.g., new or worsening headache without fever or neck stiffness).” As a result the agency has urged physicians to use a “low threshold” for performing diagnostic lumbar puncture. Signs and symptoms of meningitis include headache, fever, stiff neck, photophobia, weakness or numbness in any part of the body, or slurred speech, accompanied by a positive cerebrospinal fluid test.
CDC has recommended an empiric antifungal regimen with of voriconazole 6 mg/kg every 12 hours. Patients with more severe disease should be started on voriconazole I.V., while those with a more mild disease can be started on an oral regimen. The agency recommended regular monitoring of serum voriconazole concentration, with target trough levels of 2–5 µg/mL.
CDC also recommended that providers consider adding I.V. liposomal amphotericin B 7.5 mg/kg daily to the treatment regimen for patients who present with severe disease and patients who do not respond to voriconazole monotherapy. The duration of therapy is unknown at this point, but will likely require months and should be tailored to clinical response to treatment. More extensive information is available on the CDC website (http://apha.us/T3ll4h).
CDC does not recommend antifungal prophylaxis or lumbar puncture in asymptomatic patients, nor does it recommend empiric antifungal therapy in symptomatic patients with normal cerebrospinal fluid profiles. The agency also noted that intrathecal amphotericin B should be avoided due to limited data on its toxicity.
In a statement, APhA expressed its support for “compounding that is done according to defined standards and within the triad relationship of the physician, pharmacist and patient working together to individualize care for maximum patient benefit.”
The Association added, “Importantly, compounding is performed in response to a prescription from a licensed prescriber for an individual patient and allows pharmacists to use their extensive medication knowledge and expertise to produce individualized medication formulations that meet patient’s needs and improve health outcomes.” APhA also noted that compounding is regulated by state boards of pharmacy, FDA is responsible for the ingredients used, and the compounding pharmacists are “expected to follow appropriate procedures for the types of products that are compounded.”
APhA also emphasized its dedication to working with FDA, CDC, the Pharmacy Compounding Accreditation Board, the United States Pharmacopeia, state boards of pharmacy, and other industry stakeholders to ensure the enforcement of good compounding practices and standards.
In an October 11 news conference, Deborah Autor, JD, FDA Deputy Commissioner for Global Regulatory Operations and Policy, said, “We want to work with Congress, compounders, states, and all other stakeholders … to prevent tragedies like this in the future.” She added that “compounding pharmacies have a responsibility to have processes in place to ensure that their products are safe.” The agency’s drug shortage office has also confirmed that the NECC recall will not affect the nation’s supply of methylprednisolone acetate.
Madeleine Biondolillo, MD, Director of the Massachusetts Department of Public Health Bureau of Health Care Safety and Quality, alleged in the news conference that NECC “appears” to have violated state regulations requiring that compounds be linked to patient-specific prescriptions only. The Massachusetts Board of Pharmacy has issued an alert to all pharmacies in the state reinforcing the rules and requirements of compounding, she added. “We urge Congress to act quickly,” Biondolillo said, calling for “clear authority” on compounding rules.