Nearly 14,000 Patients Exposed to Recalled Lots of Contaminated Methylprednisolone Acetate

In an update from the Centers for Disease Control and Prevention (CDC) on Oct. 11, 2012, J. Todd Weber, MD, incident manager of the multistate meningitis outbreak and chief of the Prevention and Response Branch of the Division of Healthcare Quality Promotion at the CDC, announced that almost 14,000 patients may have been exposed to the three indicated lots of preservative-free methylprednisolone acetate produced by the New England Compounding Center (NECC).
 
"The 14,000 patients received the medication as a steroid injection either into the spinal area or into a joint space such as a knee, shoulder or ankle," said Weber. "Through the tremendous efforts of our state and local public health departments and utilizing CDC's Emergency Operations Center to staff a call center to contact patients, we are happy to say that together, we have successfully contacted over 12,000 or 90 percent of these nearly 14,000 patients. CDC and public health officials are referring any patients who have symptoms to possible meningitis or possible joint infection to their physician who can evaluate them further.  However, we know we are not out of the woods yet." 

In these notifications, Weber said public health authorities are making sure patients understand that should they develop symptoms of meningitis or joint infections in the coming weeks, they need to seek medical care immediately.  "Among people with meningitis for whom we have  clinical information available, the onset of symptoms is typically between one and four weeks following injection," Weber said.  "However, we want to emphasize that we know fungal infections can be slow to develop, and that there are indeed reports of longer periods of time between the injection and the onset of symptoms so patients and their doctors will need to be vigilant for at least several months following the injection.  Patients with meningitis have presented with a variety of symptoms including fever, new or worsening headache, nausea or a new neurological deficit consistent with a deep brain stroke. Almost all patients have reported headaches and half have reported fever, back pain or nausea. Some of these patients' symptoms were mild. Given the severity of the fungal meningitis, time is of the essence.  We know we can save lives by identifying patients early and getting them on appropriate anti-fungal therapy. "

As of Oct. 11, 2012, there are 169 meningitis cases that have resulted in 14 deaths across 11 states, according to Weber. 

"Additionally, we have one joint infection case that has just been reported to us," he said. "This person received an injection from one of the three recalled lots.  Laboratory results are not complete at the time so we cannot be sure if this is a fungal infection."  A breakdown of the number of cases per state is available on CDC's website. 

Weber also discussed the fungi that has been identified to date in this outbreak.  "As we reported a week ago, the first patient with fungal meningitis from Tennessee had an infection from a fungus known as Aspergillus, since that time the laboratory confirmed cases of fungal meningitis have all had infections caused by a different fungus known as Exserohilum," Weber said. "To date CDC laboratories have confirmed the presence of fungus Exserohilum in 10 people with meningitis, and the fungus Aspergillus in only one person with meningitis. That was our first patient. We are aware of three additional Exserohilum cases confirmed by other laboratories." 

Weber added, "We know that fungus such as Exserohilum can be difficult to detect from samples from patients. Patients and their clinicians should not assume fungal testing that is negative, means there is no infection. In other words, patients who received an injection with one of the three recalled lots of steroids may be diagnosed with meningitis, but their fungal testing may be negative. In these cases, patients should still be treated for fungal meningitis. Similarly, curing these infections requires prolonged treatment and patients should adhere to the treatment recommendations of their physician. The CDC's laboratory continues to get specimens for testing daily.  Although we are not prepared to say that Exserohilum is the sole cause of these injections we are certainly seeing a predominance of that fungus among the patients with meningitis. Let me emphasize that historically, fungal meningitis is very rare and Exserohilum has not been seen previously as a cause of fungal meningitis. This is new territory for public health and the clinical community."

Weber also addressed what this laboratory testing means for patients: "Knowing the type of fungus causing these infections will directly impact the treatment regimen we are recommending for patients.  CDC has convened a panel of the nation's leading clinical fungal experts who are working with us to ensure that our diagnostic and treatment guidance is appropriate for identifying and treating these patients should they become ill. We initially started with a treatment recommendation that was narrow in scope. Once we had laboratory confirmation of Exserohilum infections we broadened the scope of the treatment guidance to ensure that we were giving the patients an appropriate regimen to fight these fungal infections.  At the present time we are recommending that patients with confirmed fungal meningitis receive two anti-fungal drugs, -- voriconazole and lipsomal amphotericin B. These drugs are very strong and can be very difficult for patients to tolerate over a long period of time. We are working with our clinical experts to determine the best dose and the best length of time to treat patients. As additional information comes in from CDC's laboratory, and from FDA's testing of the vials of medications that were in the facility, it is possible that our clinical recommendation will change. We are working quickly to gather as much information as possible to ensure that doctors and nurses who are treating any patients with fungal meningitis have the necessary information they need to appropriately care for these patients." 

In his comments Weber also acknowledged the work occurring across the country by state and local health departments during this investigation. "Last week we mentioned the rapid work by the Tennessee Department of Health in piecing together the information from the initial cases and helping CDC and FDA crack open this investigation," said Weber.  "Today, we talked about the work by the Michigan Department of Community Health in identifying the first case of fungal joint infection. I also would like to acknowledge the Virginia Department of Health was the first to identify that the patients presenting fungal meningitis was in the rare form cause by Exserohilum. Their laboratory was the first to make this connection and put CDC further ahead in the clinical investigation.  Over the weekend, public health officials worked tirelessly to track down 14,000 patients in 23 states that had been exposed to the implicated medication.  Additionally, CDC has stood up our Emergency Operations Center to better respond to this outbreak and is working 24/7 to ensure that patients are notified, clinicians have the necessary information to treat these patients, clinical specimens are tested and fungal isolates are promptly identified. These examples demonstrate the public health efforts to save lives and protect people." Weber continued, "This outbreak highlights the need to ensure that all products, processes and procedures used in healthcare are safe. CDC is committed to working with our federal partners at FDA to ensure that long-term strategies are put into place to prevent contaminated medication from entering our healthcare system. We want patients who access healthcare to be confident they are not going to get a potentially devastating illness as a result of their care. This is a necessary safety net that all Americans deserve."
 
Deborah M. Autor, JD, deputy commissioner for global regulatory operations and policy at the Food and Drug Administration (FDA), provided an overview of where the agency stands in its investigation:  "First, FDA is working closely with the CDC and state partners, to investigate this meningitis outbreak.  It has occurred among patients who have received an epidural steroid injection. The investigation into the exact source of the outbreak is still ongoing, but a contaminated product is suspected to be the cause of the outbreak. The suspected injectable steroid was compounded and distributed by New England Compounding Center NECC. The process of producing sterile drugs is highly complex and must be done with great skill and care. Compounding pharmacies have a responsibility to have processes in place to ensure that they are producing quality drug products that are safe.  Failure to do so puts patients at risk." 

Autor also provided a timeline of the FDA's investigation: "On Sept. 26, 2012, the Massachusetts Board of Pharmacy initiated an inspection at NECC. On Oct. 1, 2012, FDA and the Massachusetts Board of Pharmacy together inspected NECC. On Oct. 3, 2012, New England Compounding Center discontinued all operations and voluntarily surrendered its pharmacy registration to the Massachusetts Board of Registration in Pharmacy. No products have been produced or distributed by the facility since Oct. 3, and none of the injectable steroid at issue has been produced since Sept. 26. On Oct. 6, 2012, the NECC, following an earlier recommendation by FDA that none of the firm's compounded products be used, announced a voluntary recall of all products currently in circulation that were compounded at and distributed from this facility. FDA and the Massachusetts State Board of Pharmacy are continuing with our joint inspection of NECC. As one part our inspection, FDA's investigators are taking samples of materials from the NECC facility and testing those samples in an FDA laboratory.  We are also reviewing the processes, procedures, and documentation at the facility. We are conducting a thorough investigation. FDA has also collected product samples from clinical facilities around the country that reported ill cases and/or had remaining quantities of methylprednisolone acetate supplied by NECC. FDA investigators also initiated an inspection on Oct.2, of Busse Hospital Inc., of New York, the firm that provided custom epidural trays to the Tennessee pain clinic, which had an event. The epidural trays were used in conjunction with spinal injections administered at the Tennessee pain clinic and initially considered one of the suspect items associated with the outbreak; they have since been ruled out. The inspection spanned Oct. 2-10 included inspection of Busse's sterilization firm in Long Island, N.Y. The firms have demonstrated good manufacturing practices. Concurrently, FDA inspectors in New Orleans collected epidural trays from the New Orleans pain clinic central to the outbreak. The epidural trays common to a number of the pain clinics have been analyzed by FDA's Winchester Engineering and Analytical Center lab for fungus. The trays have been negative for fungus implicated in the outbreak."
 
Autor continued, "FDA has confirmed fungal contaminant in multiple sealed vials of methylprednisolone acetate injection both at the pharmacy sites from samples collected around the country. FDA in partnership with CDC, is in the process of identifying the exact species of the fungus whether is similar to organism found in the patients. At this time, FDA labs have a number of ongoing analyses of samples taken from NECC and from around the country. These tests are in process, and we will share further information as soon as it is available. Yesterday, also working closely with Massachusetts Board of Pharmacy, FDA launched a joint inspection at Ameridose, as part of our efforts to protect the public health. Because there appears to be a business relationship between Ameridose and NECC, and as a precautionary measure, FDA intends to determine whether certain aspects of compounding practices and facility conditions observed at NECC may also be present at the Ameridose facility. As part of this inspection, FDA will review whether Ameridose has procedures and facilities necessary to assess the firm's ability to safely produce and provide sterile drug products.  At the same time that we initiated the inspection with the Massachusetts Board of Pharmacy, the State was able to have Ameridose voluntarily cease operations until Oct. 22."
 
"Although NECC has recalled all products, we want to be sure that no product compounded by NECC remains on the shelves and we are urging clinics, doctors' offices, and hospitals to check their drug supplies and purchasing records to determine if they have purchased products from NECC," Autor emphasized. "They should immediately remove and isolate those products from their supply. NECC will be providing further instructions regarding the disposition of the products at a future date. We will continue working with CDC, state health authorities and boards of pharmacy and patient care clinics to notify the public if we determine any other NECC products pose any risks. Again, we give our heartfelt sympathy to all patients and family members who are affected by this situation.  We hope that all who touch pharmacy compounding pharmacists as pharmacies, doctors, regulators, law-makers, and others can come together, work together, to try to prevent such tragedies in the future."
 
Also see: New England Compounding Center Establishes Recall Operations Center

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