FDA Statement on Fungal Meningitis Outbreak

[10-5-2012] FDA is working closely with the CDC and state partners to investigate an outbreak of meningitis among patients who had received an epidural steroid injection.  Investigation into the exact source of the outbreak is still ongoing, but the outbreak is associated with a potentially contaminated medication. 

That product is preservative-free methylprednisolone acetate (80mg/ml), an injectable steroid produced and distributed by New England Compounding Center (NECC) in Framingham, Massachusetts.  CDC’s interim data show that all infected patients received injection with this product.  As of Oct 3, 2012, NECC has voluntarily shut down.

FDA has observed fungal contamination by direct microscopic examination of foreign matter taken from a sealed vial of methylprednisolone acetate collected from NECC.  FDA is in the process of conducting additional microbial testing to confirm the exact species of the fungus.  As part of the ongoing investigation, FDA will continue to work closely with CDC and state authorities to determine whether this sample taken from the product matches the organism found in patients. We are working diligently to expedite that process.

Out of an abundance of caution, FDA is taking the additional step of recommending that health care professionals and consumers not use any product that was produced by NECC at this time. In addition, FDA requests that health care professionals retain and secure all remaining products purchased from NECC until FDA provides further instructions regarding the disposition of these products.  

Users should also notify FDA of any complaints or problems associated with these products.  These reports may be made to MedWatch, the FDA’s voluntary reporting program, by phone at 1-800-FDA-1088 or on line atwww.fda.gov/medwatch/report.htm.

Questions and Answers on Fungal Meningitis Outbreak

Q1. What is FDA’s role in the investigation?

A1. FDA was been working closely with CDC, several state health departments, and the Massachusetts Board of Pharmacy to investigate the scope and cause of the outbreak of fungal meningitis. FDA inspectors in the New England District Office, in cooperation with the Massachusetts Board of Registration in Pharmacy have been conducting an inspection of the New England Compounding Center.  FDA has observed fungal contamination in a sealed vial of methylprednisolone acetate collected from NECC, and is in the process of conducting additional testing to confirm the species of the fungus.

Q2. Is New England Compounding Center still producing sterile injectable products?

A2. No. The firm voluntarily ceased all operations and surrendered its license to the Massachusetts Board of Registration in Pharmacy on October 3, 2012.

Q3.  What should health care providers do to protect their patients from the threat of potential contamination?

A3. Although the investigation into the source of the outbreak is still ongoing, if you have purchased a product from NECC, we are advising you not to use it at this time.  This includes all products compounded and distributed at NECC; not just the ones that have been recalled.   Please see the CDC website for additional information.

Q4. Are there other FDA approved epidural steroid injections that can be used?

A4. There are FDA approved versions of methylprednisolone acetate injection on the market, available with or without preservatives. The FDA-approved products are not approved for epidural administration.

Q5. Does FDA anticipate a shortage of epidural steroid injection drug supply ?

A5. No. FDA’s drug shortage office has confirmed that NECC’s voluntary shutdown will not affect the nationwide supply of methylprednisolone acetate.

Multistate Meningitis Outbreak Investigation

Summary:

CDC is coordinating a multistate investigation ofmeningitis among patients who received epidural steroid injections (medication injected into the spine). Several of these patients have had strokes related to the meningitis. In several patients, the meningitis was found to be caused by a fungus that is common in the environment but rarely causes meningitis. This form of meningitis is not contagious. The source of the fungus has not yet been identified, and the cause of infections in the other patients is still being assessed.

Patient Information:

Is the source of the outbreak known?
CDC is investigating medications and products that are associated with this outbreak of meningitis. At this point, there is not enough evidence to determine the original source of the outbreak, however there is a link to an injectable steroid medication.  The lots of medication that were given to patients have been recalled by the manufacturer.

What are the states that received the implicated product?
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, Virginia, Texas, and West Virginia

What is meningitis?
Meningitis refers to inflammation of the protective membranes covering the brain and spinal cord known as the meninges. The inflammation is usually caused by an infection frequently with a bacteria or virus, but meningitis can also be caused by less common pathogens such as fungi. The severity of illness and the treatment for meningitis differ depending on the cause. Thus, it is important to know the specific cause of meningitis.

What is fungal meningitis?
Fungal meningitis occurs when the protective membranes that cover the brain and spinal cord are infected with a fungus.  Fungal meningitis can develop after a fungus spreads through the bloodstream from somewhere else in the body, as a result of the fungus being introduced directly into the central nervous system, or by direct extension from an infected body site next to the central nervous system.  

Is fungal meningitis common after epidural injections?
Epidural injections are generally very safe procedures, and complications are rare.  Fungal meningitis is an extremely rare cause of meningitis overall, including after epidural injections. The type of epidural medication given to patients affected by this outbreak is not the same type of medication as that given to women during childbirth.

What are the symptoms of fungal meningitis?
Symptoms of fungal meningitis are similar to symptoms of other forms of meningitis, however they often appear more gradually and can be very mild at first.  In addition to typical meningitis symptoms, like headache, fever, nausea, and stiffness of the neck, people with fungal meningitis may also experience confusion, dizziness, and discomfort from bright lights. Patients might just have one or two of these symptoms.

This is an official

CDC HEALTH ADVISORY

Distributed via the CDC Health Alert Network
October 4, 2012, 17:05 ET (5:05 PM ET)
CDCHAN-00327

Meningitis and Stroke Associated with Potentially Contaminated Product

Summary

The Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) are coordinating a multi-state investigation of fungal meningitis among patients who received an epidural steroid injection. Several of these patients also suffered strokes that are believed to have resulted from their infection.  As of October 4, 2012, five deaths have been reported. Fungal meningitis is not transmitted from person to person.  These cases are associated with a potentially contaminated medication.  Investigation into the exact source is ongoing; however, interim data show that all infected patients received injection with preservative-free methylprednisolone acetate (80mg/ml) prepared by New England Compounding Center, located in Framingham, MA.

Background

On September 21, 2012, CDC was notified by the Tennessee Department of Health of a patient with the onset of meningitis approximately 19 days following epidural steroid injection at a Tennessee ambulatory surgery center (ASC). Initial cultures of cerebrospinal fluid (CSF) and blood were negative; subsequently, Aspergillus fumigatus was isolated from CSF by fungal culture. On September 28, investigators identified a case outside of Tennessee, possibly indicating contamination of a widely distributed medication. As of October 4, a total of 35 cases* in the following six states have been identified with a clinical picture consistent with fungal infection: Florida (2 cases), Indiana (1 case), Tennessee (25 cases, including 3 deaths), Maryland (2 cases,including 1 death), North Carolina (1 case), and Virginia (4 cases, including 1 death). Fungus has been identified in specimens obtained from five patients, one of whom also had Propionobacterium acnes, of unclear clinical significance, isolated from a post-mortem central nervous system specimen.

Infected patients have presented approximately 1 to 4 weeks following their injection with a variety of symptoms, including fever, new or worsening headache, nausea, and new neurological deficit (consistent with deep brain stroke). Some of these patients’ symptoms were very 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.

Recommendations

On September 25, 2012, the New England Compounding Center located in Framingham, MA voluntarily recalled the following lots of methylprednisolone acetate (PF) 80mg/ml:

• Methylprednisolone Acetate (PF) 80 mg/ml Injection, Lot #05212012@68, BUD 11/17/2012
• Methylprednisolone Acetate (PF) 80 mg/ml Injection, Lot #06292012@26, BUD 12/26/2012
• Methylprednisolone Acetate (PF) 80 mg/ml Injection, Lot #08102012@51, BUD 2/6/2013

On October 3, 2012, the compounding center ceased all production and initiated recall of all methylprednisolone acetate and other drug products prepared for intrathecal administration.

Physicians should contact patients who have had an injection (e.g., spinal, joint) using any of the three lots of methylprednisolone acetate listed above to determine if they are having any symptoms.  Although all cases detected to date occurred after injections with products from these three lots, out of an abundance of caution, CDC and FDA recommend that healthcare professionals cease use of any product produced by the New England Compounding Center until further information is available.

For patients who received epidural injection and have symptoms of meningitis or basilar stroke, a diagnostic lumbar puncture (LP) should be performed, if not contraindicated. Because presenting symptoms of some patients with meningitis have been mild and not classic for meningitis (e.g., new or worsening headache without fever or neck stiffness), physicians should have a low threshold for LP. While CDC is aware of infections occurring only in patients who have received epidural steroid injections, patients who received other types of injection with methylprednisolone acetate from those three lots should also be contacted to assess for signs of infection (e.g., swelling, increasing pain, redness, warmth at the injection site) and should be encouraged to seek evaluation (e.g., arthrocentesis) if such symptoms exist.

For guidance on diagnostic testing that should be performed on patient specimens, physicians can go tohttp://www.cdc.gov/hai/outbreaks/meningitis.html. State health departments should be informed of patients undergoing evaluation. Clinicians should report any suspected adverse events following use of these products to FDA's MedWatch program at 1-800-332-1088 or www.fda.gov/medwatch.

*Case Definition
1: A person with meningitis1 of sub-acute onset (1-4 weeks) following epidural injection after July 1, 2012. 
2: A person, who has not received a lumbar puncture, with basilar stroke 1-4 weeks following epidural injection after July 1, 20122.
3. A person with evidence of spinal osteomyelitis or epidural abscess at the site of an epidural injection diagnosed 1-4 weeks after epidural injection after July 1, 2012.
¹clinically diagnosed meningitis meaning 1 or more of the following symptoms: headache, fever, stiff neck, or photophobia and a CSF profile consistent with meningitis (elevated protein/low glucose/pleocytosis)
²These people, if possible, should have an LP.

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