Fungal Meningitis Outbreak Exposes Lack of Regulatory Oversight

The compounding pharmacy at the heart of the ongoing federal and Massachusetts state investigation into contaminated lots of methylprednisolone acetate has been accused of illegally selling the medication in large batches across state lines, a development that prompted officials during an Oct. 11 telebriefing on the meningitis outbreak to call for improved oversight of such pharmacies at the federal level.

The actions of the New England Compounding Center (NECC) in Framingham, Mass., the pharmacy that has been the focus of the investigation into contaminated preparations of the steroid, would constitute it to be a drug manufacturer under Massachusetts law, which allows compounding only on the receipt of a patient-specific prescription. The NECC had sold the contaminated lots to clinics in 23 states before the Food and Drug Administration worked with the pharmacy to recall the steroid on Sept. 26, and then on Oct. 6 voluntarily recalled all of the compounded products in circulation that had been made at its Framingham, Mass., facility. The company voluntarily shut down its operations Oct. 3.

Photo courtesy CDC

Fungal meningitis cases and deaths in people who received epidural injections of the contaminated methylprednisolone acetate continue to rise, but investigators at the FDA and the Centers for Disease Control and Prevention have begun to determine which fungal species are present in patients and in contaminated vials of the steroid. Many tests are still unfinished.

Cultures of cerebrospinal fluid and histopathologic analysis of specimens have so far indicated fungal infection with Aspergillus species in 1 patient and Exserohilum species in 10 patients. The FDA has found fungal contamination by direct microscopic examination of foreign matter taken from sealed vials of the steroid collected from the NECC and from clinics that received the recalled lots.

"We know that fungus such as Exserohilum can be difficult to detect in samples from patients. Patients and their physicians should not assume fungal testing that is negative means there is no infection," Dr. J. Todd Weber, the CDC’s incident manager of the multistate meningitis outbreak, said during the telebriefing. In these cases, patients should still be treated for fungal meningitis. He noted that Exserohilum previously has not been observed to cause fungal meningitis, which historically is itself "very rare."

Dr. Weber reported that of the nearly 14,000 people who received an epidural or intra-articular injection with the steroid from recalled lots, more than 12,000 have now been contacted and those with symptoms of meningitis or possible joint infection have been referred to their physicians.

As of Oct. 11, the outbreak has caused 169 cases of meningitis and 14 deaths in 11 states: Florida (7 cases, including 2 deaths), Indiana (21 cases, including 1 death), Tennessee (49 cases, including 6 deaths), Maryland (13 cases, including 1 death), Michigan, (38 cases, including 3 deaths), North Carolina (2 cases), Virginia (30 cases, including 1 death), Ohio (3 cases), New Jersey (2 cases), Minnesota (3 cases), and Idaho (1 case). The meningitis cases have all been linked to epidural injections with methylprednisolone acetate compounded by the NECC. Production lots of the steroid at doses of 40 mg/mL and 80 mg/mL have been recalled, as well as all other products currently in circulation that were compounded at and distributed from the facility in Framingham.

The CDC is currently investigating one case of an ankle joint infection associated with an injection of the steroid in Michigan, but the laboratory results have not been completed to confirm whether or not it was caused by fungal infection, according to Dr. Weber. "We expect that through additional patient notification efforts, we may see additional patients come forward with infections of the joints. These patients may present with symptoms, including fever [and] increased pain, redness, warmth, or swelling in the joint where they received the injection or at the injection site."

In addition to identifying and assisting patients who may have been potentially exposed to the contaminated drug, the Massachusetts Department of Pharmacy and the FDA are reviewing the processes and procedures of the NECC. The FDA is also looking into the source of the ingredients used to make the compounded methylprednisolone acetate, said Deborah M. Autor, J.D., deputy commissioner for global regulatory operations and policy at the FDA.

FDA investigations during Oct. 2-10 ruled out Busse Hospital Disposables Inc. in New York as a possible source of at least one case at a Tennessee pain clinic as well as epidural trays from a New Orleans pain clinic that had been central to the outbreak, Dr. Autor said.

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.

The 23 states that received the implicated lots of medication are California, Connecticut, Florida, Georgia, Idaho, Illinois, Indiana, Maryland, Michigan, Minnesota, North Carolina, New Hampshire, New Jersey, Nevada, New York, Ohio, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Virginia, and West Virginia.

All reports of complaints or problems associated with these products should be made at the MedWatch website, the FDA’s voluntary reporting program, or by calling 800-FDA-1088.

The compounding pharmacy at the heart of the ongoing federal and Massachusetts state investigation into contaminated lots of methylprednisolone acetate has been accused of illegally selling the medication in large batches across state lines, a development that prompted officials during an Oct. 11 telebriefing on the meningitis outbreak to call for improved oversight of such pharmacies at the federal level.

The actions of the New England Compounding Center (NECC) in Framingham, Mass., the pharmacy that has been the focus of the investigation into contaminated preparations of the steroid, would constitute it to be a drug manufacturer under Massachusetts law, which allows compounding only on the receipt of a patient-specific prescription. The NECC had sold the contaminated lots to clinics in 23 states before the Food and Drug Administration worked with the pharmacy to recall the steroid on Sept. 26, and then on Oct. 6 voluntarily recalled all of the compounded products in circulation that had been made at its Framingham, Mass., facility. The company voluntarily shut down its operations Oct. 3.

Photo courtesy CDC

Fungal meningitis cases and deaths in people who received epidural injections of the contaminated methylprednisolone acetate continue to rise, but investigators at the FDA and the Centers for Disease Control and Prevention have begun to determine which fungal species are present in patients and in contaminated vials of the steroid. Many tests are still unfinished.

Cultures of cerebrospinal fluid and histopathologic analysis of specimens have so far indicated fungal infection with Aspergillus species in 1 patient and Exserohilum species in 10 patients. The FDA has found fungal contamination by direct microscopic examination of foreign matter taken from sealed vials of the steroid collected from the NECC and from clinics that received the recalled lots.

"We know that fungus such as Exserohilum can be difficult to detect in samples from patients. Patients and their physicians should not assume fungal testing that is negative means there is no infection," Dr. J. Todd Weber, the CDC’s incident manager of the multistate meningitis outbreak, said during the telebriefing. In these cases, patients should still be treated for fungal meningitis. He noted that Exserohilum previously has not been observed to cause fungal meningitis, which historically is itself "very rare."

Dr. Weber reported that of the nearly 14,000 people who received an epidural or intra-articular injection with the steroid from recalled lots, more than 12,000 have now been contacted and those with symptoms of meningitis or possible joint infection have been referred to their physicians.

As of Oct. 11, the outbreak has caused 169 cases of meningitis and 14 deaths in 11 states: Florida (7 cases, including 2 deaths), Indiana (21 cases, including 1 death), Tennessee (49 cases, including 6 deaths), Maryland (13 cases, including 1 death), Michigan, (38 cases, including 3 deaths), North Carolina (2 cases), Virginia (30 cases, including 1 death), Ohio (3 cases), New Jersey (2 cases), Minnesota (3 cases), and Idaho (1 case). The meningitis cases have all been linked to epidural injections with methylprednisolone acetate compounded by the NECC. Production lots of the steroid at doses of 40 mg/mL and 80 mg/mL have been recalled, as well as all other products currently in circulation that were compounded at and distributed from the facility in Framingham.

The CDC is currently investigating one case of an ankle joint infection associated with an injection of the steroid in Michigan, but the laboratory results have not been completed to confirm whether or not it was caused by fungal infection, according to Dr. Weber. "We expect that through additional patient notification efforts, we may see additional patients come forward with infections of the joints. These patients may present with symptoms, including fever [and] increased pain, redness, warmth, or swelling in the joint where they received the injection or at the injection site."

In addition to identifying and assisting patients who may have been potentially exposed to the contaminated drug, the Massachusetts Department of Pharmacy and the FDA are reviewing the processes and procedures of the NECC. The FDA is also looking into the source of the ingredients used to make the compounded methylprednisolone acetate, said Deborah M. Autor, J.D., deputy commissioner for global regulatory operations and policy at the FDA.

FDA investigations during Oct. 2-10 ruled out Busse Hospital Disposables Inc. in New York as a possible source of at least one case at a Tennessee pain clinic as well as epidural trays from a New Orleans pain clinic that had been central to the outbreak, Dr. Autor said.

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.

The 23 states that received the implicated lots of medication are California, Connecticut, Florida, Georgia, Idaho, Illinois, Indiana, Maryland, Michigan, Minnesota, North Carolina, New Hampshire, New Jersey, Nevada, New York, Ohio, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Virginia, and West Virginia.

All reports of complaints or problems associated with these products should be made at the MedWatch website, the FDA’s voluntary reporting program, or by calling 800-FDA-1088.

The compounding pharmacy at the heart of the ongoing federal and Massachusetts state investigation into contaminated lots of methylprednisolone acetate has been accused of illegally selling the medication in large batches across state lines, a development that prompted officials during an Oct. 11 telebriefing on the meningitis outbreak to call for improved oversight of such pharmacies at the federal level.

The actions of the New England Compounding Center (NECC) in Framingham, Mass., the pharmacy that has been the focus of the investigation into contaminated preparations of the steroid, would constitute it to be a drug manufacturer under Massachusetts law, which allows compounding only on the receipt of a patient-specific prescription. The NECC had sold the contaminated lots to clinics in 23 states before the Food and Drug Administration worked with the pharmacy to recall the steroid on Sept. 26, and then on Oct. 6 voluntarily recalled all of the compounded products in circulation that had been made at its Framingham, Mass., facility. The company voluntarily shut down its operations Oct. 3.

Photo courtesy CDC

Fungal meningitis cases and deaths in people who received epidural injections of the contaminated methylprednisolone acetate continue to rise, but investigators at the FDA and the Centers for Disease Control and Prevention have begun to determine which fungal species are present in patients and in contaminated vials of the steroid. Many tests are still unfinished.

Cultures of cerebrospinal fluid and histopathologic analysis of specimens have so far indicated fungal infection with Aspergillus species in 1 patient and Exserohilum species in 10 patients. The FDA has found fungal contamination by direct microscopic examination of foreign matter taken from sealed vials of the steroid collected from the NECC and from clinics that received the recalled lots.

"We know that fungus such as Exserohilum can be difficult to detect in samples from patients. Patients and their physicians should not assume fungal testing that is negative means there is no infection," Dr. J. Todd Weber, the CDC’s incident manager of the multistate meningitis outbreak, said during the telebriefing. In these cases, patients should still be treated for fungal meningitis. He noted that Exserohilum previously has not been observed to cause fungal meningitis, which historically is itself "very rare."

Dr. Weber reported that of the nearly 14,000 people who received an epidural or intra-articular injection with the steroid from recalled lots, more than 12,000 have now been contacted and those with symptoms of meningitis or possible joint infection have been referred to their physicians.

As of Oct. 11, the outbreak has caused 169 cases of meningitis and 14 deaths in 11 states: Florida (7 cases, including 2 deaths), Indiana (21 cases, including 1 death), Tennessee (49 cases, including 6 deaths), Maryland (13 cases, including 1 death), Michigan, (38 cases, including 3 deaths), North Carolina (2 cases), Virginia (30 cases, including 1 death), Ohio (3 cases), New Jersey (2 cases), Minnesota (3 cases), and Idaho (1 case). The meningitis cases have all been linked to epidural injections with methylprednisolone acetate compounded by the NECC. Production lots of the steroid at doses of 40 mg/mL and 80 mg/mL have been recalled, as well as all other products currently in circulation that were compounded at and distributed from the facility in Framingham.

The CDC is currently investigating one case of an ankle joint infection associated with an injection of the steroid in Michigan, but the laboratory results have not been completed to confirm whether or not it was caused by fungal infection, according to Dr. Weber. "We expect that through additional patient notification efforts, we may see additional patients come forward with infections of the joints. These patients may present with symptoms, including fever [and] increased pain, redness, warmth, or swelling in the joint where they received the injection or at the injection site."

In addition to identifying and assisting patients who may have been potentially exposed to the contaminated drug, the Massachusetts Department of Pharmacy and the FDA are reviewing the processes and procedures of the NECC. The FDA is also looking into the source of the ingredients used to make the compounded methylprednisolone acetate, said Deborah M. Autor, J.D., deputy commissioner for global regulatory operations and policy at the FDA.

FDA investigations during Oct. 2-10 ruled out Busse Hospital Disposables Inc. in New York as a possible source of at least one case at a Tennessee pain clinic as well as epidural trays from a New Orleans pain clinic that had been central to the outbreak, Dr. Autor said.

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.

The 23 states that received the implicated lots of medication are California, Connecticut, Florida, Georgia, Idaho, Illinois, Indiana, Maryland, Michigan, Minnesota, North Carolina, New Hampshire, New Jersey, Nevada, New York, Ohio, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Virginia, and West Virginia.

All reports of complaints or problems associated with these products should be made at the MedWatch website, the FDA’s voluntary reporting program, or by calling 800-FDA-1088.