More than 50 sealed vials from the NECC and from samples collected from the recalled lots around the country have tested positive for fungal contaminants, but tests have not yet determined whether or not they are the same as the organisms found in patients.
On Oct. 10, the FDA and the Massachusetts Department of Pharmacy launched a joint inspection of Ameridose, a compounding pharmacy that was founded by the same people who opened the NECC, Dr. Autor said. The agency could not be sure that the same practices that were present at the NECC were also present at Ameridose, which voluntarily ceased operations until at least Oct. 22. Drugs produced by Ameridose and its partnering distributor, Alantos Pharmaceuticals, as well as other pharmacies under joint ownership, have ceased distribution of compounded drugs, but there has been no direct evidence to suggest that compounded products produced by Ameridose have been contaminated and no products have been recalled, said Dr. Madeleine Biondolillo, director of the Massachusetts Department of Public Health and Human Services’ Bureau of Health Care Safety and Quality.
The Massachusetts Department of Public Health on Oct. 10 sent a letter to compounding pharmacies in the state to reinforce the rules they must abide by, and the Board of Pharmacy issued an order for all compounding pharmacies to sign an affidavit "attesting compliance with all pertinent laws and regulations," Dr. Biondolillo said.
The recent FDA investigation is not the first for the NECC, which received a warning letter from the agency in 2006 for acting like a drug manufacturer in distributing and selling large quantities of compounded drugs.
The NECC apparently did not stop distributing its compounded drugs across state lines in large quantities despite the warning letter, previous inspections, and being under a consent agreement with Massachusetts. "The enforcement in this case and other compounding cases is complicated greatly by litigation and a lack of clarity in the law, and while we have done some with clear authority, we cannot do all," said Dr. Autor, noting that no federal or state agency is tracking the volume of medications that are prepared and distributed in compounding pharmacies.
"Once the immediate crisis is contained, we want to work with Congress, compounders, states, and all other stakeholders to try to prevent tragedies like this in the future," Dr. Autor said.
Dr. Biondolillo agreed. "We urge Congress to act quickly to address the need for new laws on the federal level to fill in the regulatory gaps so that there is clear authority over regulating these practices."
The Association of American Physicians and Surgeons, however, cautioned against taking any legislative action too quickly because the nature of the NECC’s business was different from most compounding pharmacies. "The CDC has not released any proof that the small outbreak was caused by anything improper done by a compounding pharmacy," the association said in a statement, noting that "most compounding pharmacies focus on customized preparations with tight quality controls, and they should remain under state, not federal, regulation."
Now that Exserohilum is one of the potential causes of the outbreak, the CDC has broadened the scope of treatment guidance to recommend treating patients with confirmed fungal meningitis with two antifungal drugs, voriconazole and liposomal amphotericin B, which are "very strong and can be very difficult for patients to tolerate over a long period of time," said Dr. Weber, noting that the CDC is working with clinical experts to determine the best dose and the best length of time to treat patients.
The CDC notes that infected patients have presented approximately 1-4 weeks (median of 2 weeks, with the longest being 42 days) following injection with a variety of symptoms, including fever, new or worsening headache, nausea, and new neurologic deficit (consistent with deep brain stroke). The potentially contaminated injections were given starting May 21, 2012.
"We want to emphasize that fungal infections can be slow to develop, and if there are indeed reports of longer periods of time between injection and onset to symptoms ... patients and their doctors will need to be vigilant for at least several months following the injection," said Dr. Weber, who is also chief of the prevention and response branch in the CDC’s Division of Healthcare Quality Promotion.
Nearly all patients have reported headache, whereas about half of patients have had back pain, fever, or nausea, most of which have been mild in nature. CSF obtained from these patients has typically shown elevated white cell count (with a predominance of neutrophils), low glucose, and elevated protein, according to the CDC.