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New England Compounding Center (NECC): Tracking the Sources of Fungal Infections

Reporter: Alan F. Kaul, R.Ph., Pharm.D,, M.S., M.B.A, FCCP

The cause of the outbreak or fungal infections caused by contaminated steroids prepared by NECC has now been confirmed and treatment guidelines for those patients affected are in place.  Unfortunately, the toll in human lives and suffering cannot be rectified.  Clearly, compounding pharmacies are licensed by each state to produce products to meet individual patient needs. They are not legally licensed to manufacture drugs for mass distribution as is a pharmaceutical manufacturer that is licensed and inspected by the FDA.

The question of how to preclude further human disasters such as this is not yet resolved.  Painting all compounding pharmacies as unreliable as some have suggested does an enormous discredit to those pharmacists operating safe and reliable facilities where sterility testing meets or exceeds recommended standards. Political grandstanding also does a disservice towards working towards a viable answer. Should the Pharmacy Compounding Accreditation Board (PCAB), an organization that inspects and certifies that its members meet or exceed USP Chapter 797 standards be given deemed status like The Joint Commission or other similar accrediting organizations to accredit compounding pharmacies? Should state Boards Of Registrations in Pharmacy of Public Health Departments be funded for additional staff to monitor and inspect sterile compounding pharmacies? If so, will the additional expense be paid by the state, the compounding pharmacies, or the patients requiring the specially prepared drugs? Ultimately, the taxpayers will be required to pay for the requisite safeguards.  While the answer is still unresolved, careful though should be given to all possible options including a combination of them in moving forward.  The status quo is not an acceptable solution to meet the needs of providing safe and effective drugs to the public.

Investigations have now confirmed that NECC is the pharmacy linked to the deadly outbreak of fungal infections caused by Exserohilum rostratum, Aspergillus fumigatus, and Cladosporium species. An estimated 14,000 patients in 23 states received steroidal injections between May 21 to September 26, 2012 from lots of drugs prepared by NECC on May 21, June 29, and August 10, 2012. These three suspected lots of drugs prepared from steroids contained 17,676 doses were shipped to 75 locations. Three hundred forty-four infections including meningitis and those of the joints and 25 deaths have been attributed to the contaminated drugs.  As of October 22, 2012, there were 54 patients with CDC confirmed fungal meningitis. Of those, 52 were due to Exserohilum rostratum and one each due to Aspergillus fumigatus, and Cladosporium species.

Several hospitals including Saint Joseph Mercy Ann Arbor Hospital (Ypsilanti, MI), a Baltimore-area emergency room, Saint Thomas Hospital (Nashville, TN) independently noted patients presenting with symptoms including headaches, sensation to light, and neck stiffness, vertigo, double-vision, and loss of muscle co-ordination. In some patients, spinal taps were suggestive of meningitis and treatment was begun. However, infectious disease specialists were unable to identify the pathogen causing the infections. In late summer, across the United States, the same pattern appeared; patients with life-threating infections and an unknown cause. In North Carolina, a 77 year-old generally healthy female patient received the third of thee epidural injections for back pain. In September, she began experiencing terrible headaches. After multiple trips for medical care and being misdiagnosed with migraines and undergoing a brain scan, a family member insisted that she be hospitalized until they could diagnose her illness. A spinal tap was performed and spinal fluid was cultured. Meningitis of an unknown cause was diagnosed.

In Tennessee a man in his 50’s who initially responded to treatment for meningitis and went home returned to Vanderbilt University Medical when his infection reappeared. The patient presented visibly ill and had unintelligible speech. Dr. April Petit an infectious disease specialist ordered the laboratory to test for unusual microbes and also fungi.  The later generally is found in immunocompromised patients. The laboratory reported that the cerebrospinal fluid culture grew Aspergillus.  After again reviewing the patient’s medical history, Dr. Petit noted that the patient had received an epidural steroid injection at the Saint Thomas Outpatient Neurosurgery Center several weeks prior to the onset of his symptoms.  She contacted the Tennessee Department of Health on September 18.

The TN Department of Health contacted Saint Thomas infection prevention staff and learned that another patient who had received an epidural steroid injection at the same facility followed a similar clinical path. Saint Thomas closed its Outpatient Neurosurgery Department on September 20 and TN notified the CDC.  State health officials in TN conducted an inspection of the Saint Thomas Outpatient neurosurgery Department to try to determine the etiology of the infection. Some considerations included improper infection control procedures, contaminated equipment, and contaminated drug.

Within a few days, several more cases of rare fungal meningitis was identified that developed between July 30 and September 18 and the TN Department of Health notified the MA Department of Public Health. The patients shared four commonalties, one being that they ad received an injection of methylprednisolone acetate manufactured by NECC.  On September 25, MA state regulators requested NECC provide a list of all medical centers that had received shipments of the suspect steroid.  They learned that the three suspect lots of drugs totaling 17,676 doses had been shipped to 75 centers.

As the CDC conducted its investigation of sites that had received the drug, they learned that other cases outside of TN had occurred including North Carolina and Michigan.  The CDC issued a health advisory.  Because of the rarity of fungal meningitis, few researchers and clinicians were accustomed to dealing with it. CDC convened an expert advisory panel to develop recommended treatment guidelines.  In addition to the initial discovery of Aspergillus fumigatus, thesubsequent cases were discovered to be caused principally by the black mold, Exserohilum rostratum.  Experts concurred that while cases caused by the former fungus were rare, cases caused by the later were even rarer and treatment options were not well identified. Many effected patients were elderly and had other co-morbidities further complicating distinguishing symptoms and making the choice of pharmacotherapy with drugs often associated with serious side effects even more difficult.

Multidisciplinary teams quickly developed expertise at Saint Joseph Mercy Ann Arbor where 66 patients were being treated.  The team included the Chief Medical Officer, pharmacists, emergency room physicians, infectious disease specialists convened for daily discussions and updates.  Drug regimens for each patient were finely tuned and a special clinic was opened to assist patients in managing their disease.

As the saga continued, more patients in multiple states were identified and treated. Unfortunately, the epidemic had already taken its grim toll.

http://www.cdc.gov/hai/outbreaks/currentsituation/

http://www.fda.gov/Drugs/DrugSafety/FungalMeningitis/default.htm

The United States Food and Drug Administration (FDA) continues to reiterate that there should be follow-up with patients who meet the following three conditions:

  1. The medication used was an injectable product purchased from or produced by NECC, including an ophthalmic drug that is an injectable used in conjunction the eye surgery, or a cardioplegic solution,
  2. The medication was shipped by NECC on or after May 21, 2012, and
  3. The medication was administered on or after May 21, 2012.

On October 22, 2012, the FDA made available a list of customers (no product information available) of NECC from May 21, 2012 sorted by state which can be found at:

http://www.fda.gov/downloads/Drugs/DrugSafety/FungalMeningitis/UCM325467.pdf

On October 23, 2012, the Centers for Disease Control and Prevention (CDC) issued a an Official Health Advisory Issuance of Guidance on Management of Asymptomatic Patients Who Received Epidural or Paraspinal Injections with Contaminated Steroid Products. CDC continues to recommend against treating using antifungal prophylaxis for treating exposed asymptomatic patients without a diagnostic testing indication meningitis. They indicate that the greatest risk of developing an infection is within the first six weeks 942 days) after injection. As an increased benefit from prophylaxis has not been demonstrated from currently available data, additional monitoring of these patients should be considered.

http://emergency.cdc.gov/HAN/han00330.asp

http://bostonglobe.com/lifestyle/health-wellness/2012/10/27/doctors-piece-together-rare-cases-fungal-meningitis-uncover-outbreak/55SIHvy58Pf8lCB0yFvpHJ/story.html

Outbreak baffled doctors until they saw common cause

By  Carolyn Y. Johnson   |   G L O B E S T AF F        O C T O B E R  2 8 ,  2 0 1 2

JEFF KOWALSKY FOR THE BOSTON GLOBE

Rhonda Hall, who had a steroid injection, talked with Anurag Malani, infectious disease specialist at a

Michigan hospital.

It was Labor Day weekend when the first patients began to trickle into an Ypsilanti, Mich., hospital complaining of headaches, sensitivity to light, and neck stiffness. Laboratory tests of the patients’ spinal fluid strongly suggested meningitis and physicians started treatment.

But in a cluster of offices on the third floor, four of Saint Joseph Mercy Ann Arbor Hospital’s infectious disease specialists wrestled with a puzzle: Why couldn’t the laboratory identify the microbe causing the infection?

 Later that week and some 500 miles away, a 51­ year­ old woman developed a powerful headache radiating into her face and headed to a Baltimore ­area emergency room. She was discharged after a normal brain scan, but returned the next day with distressing symptoms: double vision, nausea, vertigo, and a loss of muscle coordination. As her condition worsened, a spinal tap provided no clues to the underlying cause.

And then in mid­ September, Dr. Robert Latham at Saint Thomas Hospital in Nashville, Tenn., found himself perplexed by the case of a woman who returned to the hospital after a treatment for meningitis stopped working. Lab tests showed signs of a raging infection, but similarly, he could not identify the culprit.

At hospitals scattered across the country, it was the horror story of the waning days of summer. Teams of physicians faced the same medical mystery — patients with life­ threatening infections with an unknown cause. There were subtle hints that they were dealing with a highly unusual illness, and astute clinicians and state and federal health officials worked to connect the dots. Ultimately, they would discover that these seemingly isolated cases were the leading edge of an outbreak of a fungal meningitis so rare that many doctors will never see a case in their lifetimes.

 The cases would quickly be linked to three batches of an injected steroid produced by a Framingham compounding pharmacy, but by that time 14,000 people in 23 states had received the injections for back and joint pain. More than 300 have fallen ill, and 25 have died.

Still immersed in treating the illness, most doctors have not had time to reflect on it. But Latham compared the initial confusion, frustration, and growing alarm to the early 1980s, before HIV had been identified as the cause of AIDS. The impact of a tainted drug could never be compared to that global epidemic, but at Saint Thomas, where 38 patients have now been treated, the medical team had the same feeling of being overwhelmed by an unknown that was bigger than anyone imagined.

 “When the HIV patients first started presenting, we were all scratching our heads, saying, ‘What in the devil is this?’ ” Latham said. “Those of us here at Saint Thomas are having an experience similar to San Francisco General in the early 1980s, when young men were walking in” with pneumonia and cancer.

This time, the patients walking in were mostly middle­age and elderly, with signs of meningitis.

The struggle for answers

Elwina Shaw of Denton, N.C., received the third of a set of epidural injections for back pain at the end of August. A vibrant 77­year­old, Shaw was generally healthy, said her daughter, Dawn Frank, aside from a little bit of knee pain and the back trouble. She wanted back surgery, but she had been steered instead toward the shots to see whether they would help.

Shaw was working in her garden one day in September when she got a terrible headache, Frank recalled. Shaw went to the doctor, and at first was told she was having migraines. But they didn’t go away. She went to the hospital for a brain scan, but it still wasn’t clear what was wrong. She was sent home, Frank said, and was told it might be a virus.

Finally, on September 25, Frank brought her mother back to the hospital, determined that doctors would not send her away until they could figure out what was wrong. Near midnight, she remembers, they did a lumbar puncture, drawing out a sample of spinal fluid.

Frank prayed it would not be bad. Shaw’s 80 ­year ­old husband, Rex, needed her. A talented seamstress, eloquent writer, and a woman of great faith, she filled their home and lives with grace and love. She never drew attention to herself, and had always embraced being a homemaker and mother.

 The test results were clear: meningitis of unknown cause. Unbeknownst to her physicians and her family, Elwina Shaw had joined the constellation of cases that were challenging doctors and wrenching families in other states.

In Michigan, patients who responded initially to treatment for meningitis returned to the hospital, worse. In Maryland, the 51­year­old woman’s spinal fluid was tested for bacterial infection and viruses ranging from West Nile to herpes as medical teams tried to treat her, according to a report published in the  Annals of Internal Medicine . Within a week and a half of being admitted to the hospital, she was brain dead. In Tennessee, doctors were struggling to figure out how to help the woman who had seemed to recover, then relapsed.

Dr. Varsha Moudgal, an infectious disease specialist at Saint Joseph Mercy Ann Arbor in Michigan, said physicians there had been mulling over several unusual aspects of their handful of cases. Some patients seemed almost too well, Moudgal said, explaining that meningitis patients with the kind of sky­high counts of immune cells and extremely low glucose levels doctors measured would typically have more symptoms, such as altered mental abilities.

“They came in and didn’t appear to be as ill as their cerebrospinal fluid picture suggested,” Moudgal said. “They were talking to us. They were sitting up.”

Others had severe symptoms but their lab tests suggested their infections were not that bad.

The doctors turned to specialists in microbiology and pathology, asking them to rack their brains for better diagnostic methods. Physicians scoured the medical literature to see whether past cases could teach them how to treat their growing cluster of patients. Dr. Anurag Malani said he heard rumbles of a case at another hospital that echoed theirs.

“We knew something was wrong, but it was hard to put a finger on it,” Malani said. “In hindsight, I think a lot of other places were feeling the same frustration.”

Meanwhile, in Tennessee, Dr. April Pettit, an infectious disease specialist at Vanderbilt University Medical Center, had been struggling with the same disturbing pattern: A man in his 50s with what appeared to be meningitis. He initially responded to treatment, went home, and then returned, the infection careening out of control.

 When he came back, she reported in the  New England Journal of Medicine this month, he was visibly ill and his speech unintelligible. Searching for answers, she told the laboratory to test for unusual microbes, such as fungi, even though such infections are quite rare, usually occurring in people with suppressed immune systems.

“On morning rounds, Dr. Pettit gets a call from the microbiology laboratory,” said Dr. William Schaffner, an infectious disease specialist at Vanderbilt who is familiar with the case. “She steps out to get the call, and she receives the information the cerebrospinal fluid has grown a fungus: aspergillus. She is dumbfounded.”

A common denominator

Pettit reviewed her patient’s history, to see whether there was anything unusual, anything that could explain why an otherwise healthy, middle­aged man with no immune system problems could have gotten such a rare type of meningitis. Several weeks earlier, she learned, he had received an epidural steroid injection at Saint Thomas Outpatient Neurosurgery Center. It was the only thing that stood out. She contacted the Tennessee Department of Health.

Dr. Marion Kainer of the health department immediately got in touch with the infection prevention staff at Saint Thomas. She told them of the man in his 50s, whose disease had followed much the same trajectory as their patient — and who had also received an injection. Latham knew his patient had also gotten an epidural injection at the hospital’s neurosurgery clinic, but previously he had no reason to connect it to her symptoms.

“The fact we had two people with strange presentations, related to the epidural injection, I hope would have been a bellwether for us,” Latham said. But that day, they got an even clearer message that something larger was going on: Another person had been admitted with similar symptoms. That person had also had an injection at the same place.

Saint Thomas closed its Outpatient Neurosurgery Center on Thursday, Sept. 20, and Tennessee notified the Centers for Disease Control and Prevention in Atlanta. Latham accompanied state health officials on an inspection of the facility to see whether there were any clues as to where the infection had come from: Did the clinic have the proper infection ­control policies and procedures? Was there a chance equipment had been contaminated? Could it have been a contaminated drug?

 By that Sunday, other probable cases had been identified in Tennessee, and the next day the Tennessee Department of Health contacted their counterparts in Massachusetts. Late in the evening, the Tennessee officials told the Bay State regulators of six rare fungal meningitis cases that had developed between July 30 and Sept. 18 in their state. The patients had at least four things in common: one being that they had received an injection of methylprednisolone acetate made by New England Compounding Center.

A day later, state regulators asked the owners of the Framingham compounding pharmacy to compile a list of all the medical centers that had been shipped medication from three batches of the steroid that federal officials had flagged as suspicious. The lots, prepared on May 21, June 29, and Aug. 10, the officials learned, had been shipped to 75 locations — and they contained 17,676 doses.

The next day, Sept. 26, the company voluntarily recalled the products, but there was still no firm connection between the drugs and the outbreak.

Then, physicians at the High Point Regional Health System in North Carolina, where Elwina Shaw was being treated, received a call from the CDC. The High Point Surgery Center was among the places that received doses of the drug. The agency official asked whether there were any patients with symptoms similar to the Tennessee cases, according to hospital spokeswoman Tracie Blackmon. High Point did have such a patient, the hospital confirmed.

The CDC later said in a health advisory that it was that first case outside of Tennessee that was “possibly indicating contamination of a widely distributed medication.” Frank said her family was told her mother’s case helped point the finger at the contaminated drug. “The steroid was the common denominator,” Frank said.

The doctors in Michigan began to hear news reports of what was going on in Tennessee. They began to realize the common thread was the epidural injections their patients had received at a nearby clinic.

Treating an outbreak

Pinpointing the source of the infection was only the first step. Public health officials now realized that many more people were likely to be hospitalized in the coming weeks, but they had little idea how to treat them. Fungal meningitis occurs infrequently, and the circle of researchers who study such infections is small.

 The CDC convened a panel of experts to develop advice for physicians on what symptoms to watch for, how to best treat it, and when to start antifungal medications. Complicating matters was the fact that while the initial case in Tennessee involved a fungus called Aspergillus fumigatus, the subsequent cases were mainly caused by a black mold called Exserohilum rostratum.

Cases of meningitis caused by aspergillus were rare, say specialists in fungal diseases, but cases caused by black mold were even more so, making the outbreak almost entirely untrodden medical ground. The large number of elderly victims was another challenge, because many had chronic conditions that could make it difficult to distinguish symptoms or that make them unable to tolerate the harsh drugs.

Expertise rapidly developed at the centers that were hardest hit. At Saint Joseph Mercy Ann Arbor, where 66 patients had been treated as of Friday, there was a daily 9 a.m. “huddle” of health care providers, followed by a call that drew together people from across the hospital, from the chief medical officer to pharmacists to emergency room doctors to the infectious disease specialists.

Drug regimens were fine­tuned to diminish side effects, and a special clinic was set up to help patients manage the disease.

Patients will have to take the antifungal drugs for a minimum of three months — and possibly as long as a year.

More staff were brought in to help manage the flood of people who came to be tested for meningitis. On their busiest day, 66 spinal taps were drawn; during the last month, a couple hundred have been performed, Malani said.

Three patients have died, but two fell ill before the meningitis cases were connected to a fungus.

By the time Rhonda Hall showed up at the hospital a week and a half ago, systems and procedures were in place and the pace had slowed. The 49­year­old bus driver from Brighton, Mich., was in an accident a year ago that still causes her pain. She had recently had surgery on her left ankle and got a steroid injection in her hip.

Soon after, Hall found herself clutching the side of her mattress just to get out of bed, and she realized that it wasn’t just an after­effect of the surgery. Something was wrong with her hip.

After hearing about the contaminated injections on the news, she called and learned she had gotten one of the bad shots. She was diagnosed with a bone infection.

“I was very scared in the beginning,” Hall said last week, just before going into surgery to flush out the infected joint. “Now it’s to the point . . . I want it over with so I can start healing and feeling better.”

The lessons learned by physicians came too late for Elwina Shaw. During her time in the North Carolina hospital, Shaw had two strokes, her daughter said, but she was able to write her name in cursive and walk afterward. Her family was hopeful.

But her condition worsened, and she died Friday, Oct. 19. On that day, the CDC reported that 271 people were infected, 21 deceased.

Carolyn Y. Johnson can be reached at  cjohnson@globe.com. Follow her on Twitter

@carolynyjohnson.

© 2012 THE NEW YORK TIMES COMPANY

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