Previous fungal meningitis outbreak a decade ago resulted in no oversight changes

November 5, 2012

First, David Brannon couldn’t believe it. Then he couldn’t stand hearing about it.

Hundreds of people were ill with fungal meningitis they had contracted after getting pain-killing injections made by a compounding pharmacy in Massachusetts. Dozens were dead, and the numbers were still rising.

“It’s quite painful to follow, actually,” said the 60-year-old North Carolina lawyer, recalling a similar outbreak that killed his mother, Mary Virginia Scyster, in 2002. “It took my mother 66 days to die.”

Scyster was a victim in an outbreak eerily similar to the one now unfolding. In both, a steroid called methylprednisolone acetate became contaminated with black fungus during production by compounding pharmacies making large quantities of the drug.

In 2002, at least seven people got sick and two died after being injected with a drug made by a South Carolina pharmacy. In the current outbreak, 419 people have become ill and 30 have died.

Despite the much higher numbers, nothing much has changed. Mass production of high-risk medicines by local drug stores continues — not only in South Carolina but in most other states as well.

“There appear to be no lessons learned from our outbreak in terms of oversight and regulation of these pharmacies,” said Jeffrey Engel, a 58-year-old physician who as North Carolina’s state epidemiologist investigated the 2002 incident. All the cases occurred in North Carolina.

His view is shared by the infectious diseases expert who diagnosed Scyster’s rare infection.

“It’s déjà vu for sure,” said Srilatha Edupuganti, 44, who was at the University of North Carolina in Chapel Hill and is now at Emory University in Atlanta. “It’s painful that it’s happening again.”

In the earlier incident, health authorities recalled the drug made by Urgent Care Pharmacy of Spartanburg, S.C. South Carolina’s Board of Pharmacy found the pharmacy unsanitary and its sterilization practices inadequate. It suspended the pharmacist’s license for four years and fined him $10,000. Ultimately, the drug store closed and lawsuits were filed.

In the current outbreak, officials recalled tainted lots produced by New England Compounding Center of Framingham, Mass.

“I’m struck that this happened again,” said Engel, who now heads the Council of State and Territorial Epidemiologists in Atlanta. “There should be a cease and desist until safety can be guaranteed. Where is the next one happening?”

Traditional compounding involves a pharmacist making a drug only after getting a prescription with an individual patient’s name on it. Urgent Care Pharmacy and New England Compounding Center were involved in a different type of compounding, which involved the small-batch mass production of drugs — including the riskiest ones, “sterile injectables — by gowned technicians working in clean rooms with special ventilation.

This type of drug-making in pharmacies continues because 42 states permit some form of what’s known as “compounding for office use.” That allows pharmacists to prepare many doses of a drug without patient-specific prescriptions and to provide them to doctors’ offices and clinics based on those places’ regular need.

Compounding pharmacies are regulated by state boards of pharmacy and aren’t held to the same workplace standards and sterility requirements of pharmaceutical plants. Instead, most follow less strict standards — USP 797 — set by an organization called the United States Pharmacopeia. While the Food and Drug Administration can shut down any drug-making activity, in practice it gets involved with compounding pharmacies only if there are complaints of contamination or mislabeling — or after a disaster is underway.

The past outbreak

Mary Virginia Scyster and her husband, David, retired to Pinehurst, N.C., not only for the great golf courses but also because of the town’s reputation for excellent medical care.

In the spring of 2002, Scyster, who was 77, twisted her back while playing golf. The pain persisted and she went to a doctor, who injected the area with an anti-inflammatory steroid. When the drug’s effect wore off, she returned and got a second injection.

“Within two weeks, she was in bed with a headache that wouldn’t quit,” recalled her son, David Brannon. “She resisted going to the hospital, and finally my father just put her in the car and took her. She never came home again.”

Unbeknownst to her, between the first and second shots, the pain clinic at Moore Regional Hospital in Pinehurst had turned to a new source for methylprednisolone when its usual supplier, the drug company Pharmacia, temporarily stopped making it. Between May 6 and June 5, the pain clinic bought 557 vials of methylprednisolone from Urgent Care Pharmacy.

About 140 miles to the east, in Jacksonville, Johnston Pain Clinic also turned to Urgent Care, buying 525 vials of methylprednisolone over five months.

“I couldn’t get what I wanted from anybody else,” recalled anesthesiologist Scott Johnston, now 53. It was there that Vivian Conrad, a 71-year-old retired dispatcher for the sheriff’s department with arthritis, got an injection in her back on June 3.

For both women, weeks or months passed before their infections were fully diagnosed.

When Scyster didn’t improve after two weeks of therapy for bacterial meningitis, a second spinal tap was done. It showed microscopic fungus. She was immediately transferred to Duke University Medical Center, where a world authority on fungal meningitis worked. There, Exophiala dermatitidis, a species that sometimes darkens the tile of bathrooms, was identified.

“By the time she got to the hospital she was never out of pain,” recalled Brannon, her son. “She had a lot of visual hallucinations. It was very frightening for her. Sometimes she would realize what was going on and sometimes she wasn’t with us.”

She died on Aug. 25, 2002.

It gets worse

In the meantime, Vivian Conrad, who lived with her husband in the Atlantic Coast community of Emerald Isle, N.C., was baffling physicians.

“One particular weekend, I remember she was having bad headaches and had had them all week long,” recalled Conrad’s daughter, Chiquita Prestwood, a 63-year-old bookkeeper in Lenoir, N.C. “I asked where they were and she told me toward her neck. I said, ‘Mom, that sounds like meningitis. Why don’t you call your doctor?’ ”

When the weekend was over she did and was admitted to a hospital in Morehead City on July 8.

Her symptoms, however, resembled those of a stroke, and after eight days she was discharged home. Two weeks later, she was readmitted. She got no better. On Aug. 20, she was transferred to a hospital in Greenville, N.C. Fungal meningitis was diagnosed after that.

“They said her spinal fluid, which should be clear, was almost pure pus,” her daughter said.

What happened next is unclear. Either with a tip from a Greenville physician or by the observation of an infectious diseases physician at Duke, the cases of Scyster, now dead, and Conrad, still alive, were put together. Engel, the state epidemiologist, was notified and started to investigate.

On Sept. 27, the South Carolina Board of Pharmacy ordered Urgent Care to close. The pharmacy recalled the methylprednisolone, but it refused to recall other products, which had been shipped to 11 states. On Nov. 15, the FDA issued a nationwide alert against using them.

In early December, the Centers for Disease Control and Prevention described in its newsletter, Morbidity and Mortality Weekly Report, four cases of meningitis and one case of joint infection in North Carolina caused by Exophiala fungus.

Meanwhile, Vivian Conrad spiralled downward.

“It was like her brain was pickled with this infection,” Prestwood said. “She tried to say something, and the words came out jumbled. She knew it was not coming out as she intended. It was very frustrating for her.”

Confined to her bed with only enough balance to get to a bedside commode, she died on Nov. 10, 2003 — 17 months after the injection that infected her.

Legality of compounding

The legal wrangling that followed the 2002 outbreak made clear that making compounded drugs by the hundreds of doses — as Urgent Care did with methylprednisolone — was okay in South Carolina, even though a simple reading of the law might lead one to think otherwise.

South Carolina law allows compounding “in anticipation of prescription drug orders based on routine, regularly observed prescribing patterns.” The key idea is that compounders must have a “historical basis” for what they make. They can’t just produce thousands of doses of something and hope someone buys it the way drug companies do.

“Compounding . . . in anticipation of receiving prescriptions without a historical basis . . .is considered manufacturing,” the state law said.

Citing that language, the insurance company that sold a policy to R. Ken Mason Jr., Urgent Care’s supervising pharmacist, argued it shouldn’t have to cover his damages because he was acting as a drug manufacturer, not a compounder. But a federal district court didn’t agree with that argument and neither did the U.S. Court of Appeals for the 4th Circuit.

In the appeals court opinion, J. Harvie Wilkinson III wrote that patient-specific prescriptions weren’t necessary “when a pharmacy produces drugs on the basis of historical data, for physicians’ office administration,” and that historical data don’t have to “be derived from the practitioner who ultimately receives the batch in question.”

In other words, if a compounding pharmacy has an idea of how much demand it expects for a drug, it can make that much in advance without a prescription.

Defined that way, “compounding for office use” could allow pharmacies to produce thousand-dose batches of drugs week after week — just like pharmaceutical factories but without the standards required of them.

Defenders of the practice say this expansive view of compounding is necessary. Compounding is an essential part of American medicine and compounding pharmacies need to have their products on hand when doctors order them, they say.

“It is almost impractical to have it any other way,” said Jeffrey Gibbs, a Washington lawyer who was associate chief counsel for enforcement at the FDA from 1980 to 1984.

Others feel differently.

“I just don’t have any confidence in the compounding pharmacies,” said Burt Place, 59, an anesthesiologist at the Pinehurst pain clinic both now and during the 2002 outbreak. “I think anybody would be insane to use them.”

The aftermath

Few people in South Carolina are willing to talk about pharmaceutical compounding or the 2002 outbreak that’s a miniature version of the current one.

One who is willing is Davis C. Hook Jr., a 71-year-old pharmacist who served a six-year term on the Board of Pharmacy, leaving in 2009. He said that “15 to 20” pharmacies compound for office use in South Carolina today. Hawthorne Pharmacy in Columbia, where he works part time, is one. It supplies compounded sterile injectables to about 15 pain clinics, orthopedists and ophthalmologists.

“I just hate it, because it just gives a black eye to compounding,” he said of the current outbreak.

The FDA ultimately identified Exophiala fungus in three lots of methylprednisolone made by Urgent Care Pharmacy. How it got there is unknown.

Urgent Care’s supervising pharmacist, R. Ken Mason Jr., was fined $10,000 and put on probation by the Board of Pharmacy for four years. He now works at a drug store in Boiling Springs, S.C., and wouldn’t talk to a reporter. He does not do compounding. The owner of the long-shuttered pharmacy, W. Ray Burns, has an inactive pharmacy license and didn’t answer phone messages.

Mason’s insurance policy reportedly had a $1 million cap. Vivian Conrad’s survivors got about $900,000 in damages, according to her daughter. From that, lawyer’s fees and payments to Medicare were deducted. Conrad’s husband also paid for two months of voriconazole, the antifungal medicine, at $10,000 a month before Pfizer, the drug’s makers, agreed to give it to her for free.

Prestwood recalled that at the settlement conference “my request was an apology from them because I would never see my mother smile again. I was told that the man realized what his actions had done. But there was never an apology.”

Alice Crites contributed to this report.

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