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Published Date: 2012-10-05 22:29:22
Subject: PRO/EDR> Aspergillus meningitis - USA (03): contaminated drug
Archive Number: 20121005.1326188

ASPERGILLUS MENINGITIS - USA (03): CONTAMINATED DRUG
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[1]
Date: Fri 5 Oct 2012
Source: NBC News, Associated Press (AP) report [edited]
http://vitals.nbcnews.com/_news/2012/10/05/14241074-hundreds-may-be-at-risk-in-meningitis-outbreak?lite

The potential scope of the meningitis outbreak that has killed at least 5 people widened dramatically Thu 4 Oct 2012, as health officials warned that hundreds, perhaps thousands, of patients who got steroid back injections in 23 states could be at risk. Clinics and medical centers rushed to contact patients who may have received the apparently fungus-contaminated shots and the FDA urged doctors not to use any products at all from the Massachusetts pharmacy that supplied the suspect steroid solution. It is not clear how many patients received tainted injections, or even whether everyone who got one will get sick.

So far, 35 people in 6 states -- Tennessee (25), Virginia (4), Maryland (2), Florida (2), North Carolina (1) and Indiana (1) -- have contracted fungal meningitis, and 5 of them have died, according to the CDC. All had received steroid shots for back pain, a highly common treatment.

In an alarming indication the outbreak could get a lot bigger, Massachusetts health officials said the pharmacy involved, the New England Compounding Center [NECC] of Framingham, MA, has recalled 3 lots consisting of a total of 17 676 single-dose vials of the steroid, preservative-free methylprednisolone acetate. An unknown number of those vials reached 75 clinics and other facilities in 23 states between July 2012 and September 2012, federal health officials said. Several hundred of the vials, maybe more, have been returned unused, a Massachusetts official said.

But many other vials were used. At a clinic in Evansville, Indiana, more than 500 patients got injections from the suspect lots, officials said. At 2 clinics in Tennessee, more than 900 patients, perhaps many more, did.

The investigation began about 2 weeks ago after a case was diagnosed in Tennessee. The time from infection to onset of symptoms is anywhere from a few days to a month, so the number of people stricken could rise.

Investigators this week found contamination in a sealed vial of the steroid at the New England company, according to FDA officials. Tests are under way to determine if it is the same fungus blamed in the outbreak. The company has shut down operations and said it is working with regulators to identify the source of the infection.

"Out of an abundance of caution, we advise all health care practitioners not to use any product" from the company, said Ilisa Bernstein, director of compliance for the FDA's Center for Drug Evaluation and Research.

The type of fungal meningitis involved is not contagious like the more common forms. It is caused by a fungus often found in leaf mold and is treated with high-dose antifungal medications, usually given intravenously in a hospital. The common mold _Aspergillus_ was cultured from 5 patients, the CDC said Thursday [4 Oct 2012].

The New England company is what is known as a compounding pharmacy. These pharmacies custom-mix solutions, creams, and other medications in doses or in forms that generally aren't commercially available. Other compounding pharmacies have been blamed in recent years for serious and sometimes deadly outbreaks caused by contaminated medicines. Compounding pharmacies are not regulated as closely as drug manufacturers, and their products are not subject to FDA approval.

A national shortage of many drugs has forced doctors to seek custom-made alternatives from compounding pharmacies. The New England company at the center of the outbreak makes dozens of other medical products, state officials said. But neither the company nor health officials would identify them.

The company said in a statement Thursday [4 Oct 2012] that despite the FDA warning, "there is no indication of any potential issues with other products." It called the deaths and illnesses tragic and added: "The thoughts and prayers of everyone employed by NECC are with those who have been affected."

A 2011 state inspection of the Framingham facility gave the business a clean bill of health.

[Byline: Mike Stobbe]

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[This posting reports that "smoking" drug, that is, isolation of the same organism from the alleged vehicle, has occurred. - Mod.LL]

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[2]
Date: Thu 4 Oct 2012
Source: CDC, Healthcare-associated Infections (HAIs) [edited]
http://www.cdc.gov/HAI/outbreaks/meningitis.html

CDC is coordinating a multistate investigation of meningitis 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.

Case Count: 35; states: 6; deaths: 5

Instructions for Clinical Teams Regarding Diagnostic Testing - Outbreak of Unknown Meningitis as of 3 Oct 2012
(http://www.cdc.gov/hai/pdfs/outbreaks/Outbreak-diagnostic-protocol-cleared.pdf)
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The etiology of this cluster of meningitis has not yet been determined. Potential infectious causes may include fungal pathogens as well as less commonly identified bacteria. The following algorithm has been developed to help guide clinicians in their diagnostic work-up of a patient with meningitis of unknown etiology who meets the outbreak definition (1). These instructions are meant to supplement routine laboratory and microbiologic test deemed necessary by the clinical team and should not replace existing diagnostic protocol.

CSF: When possible, collect large volume of CSF (10-20 mL) for testing. Please save a minimum of 10 mL of CSF to send to state health departments and CDC for further testing (2). This should be an unspun sample or a fresh unadulterated sample. In addition to routine gram stain and bacterial cultures (including aerobic and anaerobic), fungal and AFB smears and cultures should be obtained. All cultures should be held for at least 2-3 weeks prior to discarding

Specifically for the work-up of possible fungal pathogens:
- If patients have intraventricular shunts/drains, obtain large volume of CSF to culture for fungi from this source.
- Send CSF sample for _Aspergillus_ galactomannan assay if available (3).
- Serum: send specimen for _Aspergillus_ galactomannan assay.
- Other tests: in addition to routine blood cultures, consider obtaining fungal and AFB blood cultures. Other potentially infected fluid collections should be sampled (such as aspiration of epidural abscess) and sent for microbiologic testing as described above for CSF specimens (including fungal smear).
- Tissue specimens (including post mortem specimens): any relevant tissue specimens sent for histopathology should be stained and reviewed for infectious agents, including fungi (silver stain). Please save specimens to send to state health departments and CDC for further evaluation (2). Please send available autopsy specimens to CDC for further evaluation. See attached guidance for specimen collection and processing (2).

Interim Treatment Options - Outbreak of Unknown Meningitis as of 3 Oct 2012
(http://www.cdc.gov/hai/pdfs/outbreaks/Treatment-Options-10-3-2012-cleared.pdf)
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At present, the etiologic agent of this cluster of meningitis has not been clearly identified. However, a mold species has been isolated from CNS specimens from at least 2 patients linked to the outbreak, 1 of whom also had _Propionibacterium acnes_ of unclear clinical significance isolated from a postmortem CNS specimen. 2 additional patients have preliminary histopathologic evidence of fungal infection.

When treating patients with meningitis who meet the outbreak case definition (1), clinicians should continue to follow routine treatment protocols for meningitis of unclear etiology, including covering for potential bacterial causes of meningitis. In addition, until the etiology is better defined, clinicians are encouraged to add empiric antifungal therapy to the treatment regimen because of the severe adverse outcomes of untreated fungal meningitis. CDC has consulted with national experts on the following guidance; these treatment options for fungal meningitis in patients associated with this cluster are interim, and may change as new information becomes available.

Initiate empiric antifungal therapy using the following regimen:
- At a minimum, all patients should receive voriconazole (if no contraindications), preferably at a dose of 6 mg/kg every 12 hours (IV initially) and to continue on this high dose for the duration of treatment, if possible. Periodic monitoring of serum concentration is advisable.
- Consider combination therapy with liposomal amphotericin B (preferred over other lipid formulations), preferably at a higher dose of 7.5 mg/kg IV daily. If nephrotoxicity is a potential concern, particularly in older patients, the dose may be decreased to 5 mg/kg IV daily. Administration of 1 L normal saline prior to infusion may be considered to minimize risk of nephrotoxicity.
- Avoid use of intrathecal amphotericin B, either the deoxycholate or the lipid formulations, due to limited data on its use and associated toxicities.

There is currently no clear evidence for the use of adjuvant steroid therapy. If used, careful monitoring of clinical status is warranted.

Adequate duration of treatment is unknown but likely will require prolonged antifungal therapy (e.g., months) tailored by the clinical response to infection. Individual management decisions, including choice of long-term antifungal regimen, should be made in consultation with infectious disease physicians experienced in the treatment of fungal meningitis. Clinicians should be vigilant for potential relapse of infection.

References
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1. A person with meningitis of sub-acute onset (1-4 weeks) following epidural injection after 1 Jul 2012. Meningitis is defined as having 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).
2. Please contact the State Health Department and State Public Health Laboratory to coordinate shipment of specimens to CDC for further testing. Please refer to the attached documents for handling of specimens and shipment instructions.
3. The _Aspergillus_ galactomannan assay (Platelia; BioRad) has been FDA approved only for serum. However there are some published case series reporting its utility in identifying cases of _Aspergillus_ meningitis, where the test has been done on CSF samples on a research basis.

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[The CDC report is conservatively not calling _Aspergillus_ as the growing cluster etiology. If the "smoking" drug is indeed true, this is a very incriminating event. ProMED-mail awaits more information regarding the scope of the outbreak and what the species of the mold is. - Mod.LL]

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