Source: U.S. Food and Drug Administration (FDA) (Accessed: 5/8/2013)

Source: U.S. Food and Drug Administration (FDA) (Accessed: 4/29/2013)

Source: U.S. Food and Drug Administration (FDA) (Accessed: 4/23/2013)

Source: U.S. Food and Drug Administration (FDA) (Accessed: 4/16/2013)

Source: U.S. Food and Drug Administration (FDA) (Accessed: 3/18/2013)

Source: U.S. Food and Drug Administration (FDA) (Accessed: 3/18/2013)

Summary

• CDC and state partners have analyzed new preliminary data based on recent Magnetic Resonance Imaging (MRI) studies among patients who had spinal or paraspinal injection with contaminated MPA from NECC. These findings demonstrate that among patients with no previous evidence of infection, and with new or worsening symptoms at or near the site of their injection, more than 50% had findings suggestive of a localized spinal or paraspinal infection, including epidural abscess, phlegmon, arachnoiditis, discitis, or vertebral osteomyelitis.
• This new information suggests that some patients who received spinal or paraspinal injections with implicated MPA from NECC may currently have an unrecognized, localized spinal or paraspinal infection.
• CDC is therefore re-emphasizing the guidance from the November 20 HAN advisory that recommended clinicians remain vigilant for evidence of fungal infection in these patients and use an assertive approach for clinical management and follow-up of these patients. CDC continues to recommend MRI with contrast of the symptomatic area(s) in patients with new or worsening symptoms at or near their injection site following spinal or paraspinal injection of implicated MPA.
• In addition, CDC is recommending that clinicians should consider obtaining an MRI with contrast of the injection site in patients with persistent but baseline symptoms because the presentation of these spinal or paraspinal infections can be subtle and difficult to distinguish from a patient’s baseline chronic pain.

• In Michigan, Tennessee, and North Carolina, MRI testing was recently done on 128 patients who had no previous evidence of infection and had new or worsening symptoms at or near the site of their spinal or paraspinal injection. Of these, 67 (52%) had findings suggestive of localized infection, including epidural abscess, phlegmon, arachnoiditis, discitis, or vertebral osteomyelitis.
• Furthermore, of 109 different patients reporting persistent but baseline symptoms at or near the site of their spinal or paraspinal injection, 15 (14%) also had abnormal MRI findings suggestive of infection. These preliminary data are from a single hospital and may not be generalizable to all exposed patients. An additional 27 (25%) of these patients had non-specific enhancement of soft tissue or other paraspinal structures; the clinical significance of such findings is unclear and may represent either early infection or non-infectious process.

• Patients:
  • Patients who have received an epidural injection from one of the three implicated lots of MPA1 and who have continued, worsening, or new symptoms at or near the site of their spinal injection should seek evaluation by their medical provider for the possibility of a localized infection such as an epidural abscess. This includes patients who initially received epidural steroid injections for pain and continue to have persistent baseline pain.

• Clinicians:
  • As a part of continued monitoring of patients who received an injection with implicated MPA, clinicians should consider re-evaluating patients for signs and symptoms suggestive of infection, including continued, worsening, or new symptoms at or near the site of their injection.
  • When deciding whether to obtain an MRI, clinicians should take into account the preliminary data presented above and obtain a careful history of the patient’s past and current symptoms.
  • In general, clinicians should obtain an MRI with contrast of the symptomatic area(s) in patients who received a spinal or paraspinal injection with implicated MPA and have new or worsening symptoms at or near the site of their injection.
  • Clinicians should consider obtaining an MRI with contrast of the symptomatic area(s) in patients with persistent but baseline symptoms following spinal or paraspinal injection of the implicated MPA because the presentation of these spinal or paraspinal infections can be subtle and difficult to distinguish from a patient's baseline chronic pain.
  • Clinicians should also consider reviewing MRI results with a neuroradiologist because of potential difficulties in interpreting imaging results for these patients.

Summary: As part of the ongoing investigation of the multistate outbreak of fungal meningitis and other infections, the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) continue to test medical products from the New England Compounding Center (NECC) in Framingham, Mass. CDC and FDA are reporting today additional microbial contamination identified in NECC products, which updates the November 1, 2012 Health Alert Network advisory. This update includes the following key points:

• CDC and FDA have identified additional microbial contaminationin unopened vials of betamethasone, cardioplegia, and triamcinolone solutions distributed and recalled from NECC.
• These include bacteria known as Bacillus, and fungal species including Aspergillus tubingensis, Aspergillus fumigatus, Cladosporiumspecies, and Penicillium species.
• Although rare, some of the identified Bacillus species can be human pathogens. Some of the fungal organisms identified, particularly Aspergillus fumigatus, are known to cause disease in humans. It is not known how product contamination with these organisms could affect patients clinically.
• To date, although CDC has received reports of illness in patients who have received the medications listed in the table below, including some patients who had evidence of meningeal inflammation, CDC and public health officials have no reports of laboratory-confirmed bacterial or fungal meningitis, spinal, or paraspinal infections caused by these products.
• The available epidemiological and laboratory data do not, at this time, support evidence of an outbreak of infections linked to usage of non-methylprednisolone NECC products.
• CDC's recommendations to healthcare providers for diagnosing and treating symptomatic patients who have received NECC products have not changed as a result of these findings.
• CDC continues to recommend that clinicians remain alert for the possibility that infections may have resulted from injection of NECC products, and that routine laboratory and microbiologic tests, including bacterial and fungal cultures, should be obtained as deemed necessary by treating clinicians.
• Clinicians should continue to report infections potentially related to NECC products to FDA's MedWatch and to state health departments.

Background

On September 26, 2012, NECC voluntarily recalled three lots of preservative-free methylprednisolone acetate (PF) 80mg/ml¹ associated with the multistate outbreak of fungal meningitis and other infections. As previously confirmed by CDC and FDA, the fungus Exserohilum rostratum was identified from two different lots of NECC-supplied, preservative-free methylprednisolone acetate (Lot #06292012@26 and Lot #08102012@51); testing on the third implicated lot of preservative-free methylprednisolone acetate (Lot #05212012@68) has yet to identify fungal growth. Two types of fungus not known to be human pathogens were also identified from product from the two tested lots, namely Rhodotorula laryngis and Rhizopus stolonifer. Among these fungal organisms, only Exserohilum rostratum has been associated with human infections in this outbreak.

On October 6, NECC expanded its recall to include all products in circulationthat were distributed from its facility in Framingham, Mass. As part of the ongoing investigation, FDA and CDC have been testing various NECC products for evidence of contamination. Laboratory testing at CDC and FDA has found bacterial and/or fungal contamination in unopened vials of betamethasone, cardioplegia, and triamcinolone solutions distributed and recalled from NECC, as shown in the table below.

*Identification of other bacteria for this product is pending.

Recommendations to Healthcare Providers

FDA released a MedWatch Safety Alert on October 15 stating that the sterility of any injectable drugs, including ophthalmic drugs that are injectable or used in conjunction with eye surgery, and cardioplegic solutions produced by NECC is of significant concern. The safety alert further advised healthcare providers to follow-up with patients who were administered any of these products purchased from or distributed by NECC on or after May 21, 2012. A sample notification letter to assist with this process is available.

CDC’s recommendations to healthcare providers for diagnosing and treating symptomatic patients who have received NECC products have not changed as a result of the laboratory findings reported here. CDC continues to recommend that clinicians remain vigilant for the possibility that infections may have resulted from injection of NECC products, and that routine laboratory and microbiologic tests, including bacterial and fungal cultures, should be obtained as deemed necessary by treating clinicians.

There has been no prior systematic surveillance for adverse events following epidural steroid injections; however, infection is a known, although likely rare, risk that has been documented in the medical literature. To date, although CDC is aware of reports of illness in patients who have received these medications, including some patients who had evidence of meningeal inflammation, CDC and other public health officials have no reports of laboratory-confirmed bacterial or fungal meningitis, or spinal or paraspinal infections caused by these products. The available epidemiological and laboratory data do not, at this time, support evidence of an outbreak of infections linked to usage of non-methylprednisolone NECC products.

However, because it is possible that some of the organisms listed in the table above can cause human disease, clinicians should continue to include bacterial and/or fungal infection in the differential diagnosis when evaluating symptomatic patients who were exposed to these medications, including consideration of empiric antifungal therapy.

Consultation with an infectious disease specialist is strongly encouraged to help make treatment decisions in these cases. If the evaluation of these patients is suggestive of fungal infection, please consult existing CDC treatment guidance associated with this outbreak.

Physicians should continue to report infections potentially related to NECC products to FDA's MedWatch and to state health departments.
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[1] NECC 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

• Update: Multistate Outbreak of Fungal Meningitis and Other Infections Associated with Contaminated Steroid Medication
• CDC clinical conference call (COCA Call) next Tuesday, November 27^th at 2—3pm ET

Update: Multistate Outbreak of Fungal Meningitis and Other Infections Associated with Contaminated Steroid Medication

Summary: The Centers for Disease Control and Prevention (CDC) continues to work closely with state public health departments on a multistate investigation of fungal meningitis and other infections among patients who received a methylprednisolone acetate (MPA) injection prepared by the New England Compounding Center (NECC) in Framingham, Mass. This HAN notice provides updated information on the following:

• Epidural abscess and other clinical syndromes being diagnosed in exposed patients
• Diagnostic and treatment recommendations for clinicians 

Background: As of November 19, 2012, a total of 490 cases, which includes 34 deaths, have been reported in 19 states (see CDC’s website for up-to-date information about case count and distribution by state). Exserohilum rostratum continues to be the predominant fungus identified in patients and confirmed by the CDC laboratory.

Clinical Syndromes Reported to CDC

Currently, more than 7 weeks after the three implicated lots of MPA1 were recalled, CDC continues to receive reports of fungal infection in exposed patients. Previously, the majority of new cases reported to CDC were patients with fungal meningitis following injection.

Although cases of fungal meningitis continue to be reported, CDC has recently observed an increase in the number of patients presenting with evidence of epidural abscess, phlegmon, discitis, vertebral osteomyelitis, or arachnoiditis at or near the site of injection. These complications have occurred in patients with and without evidence of fungal meningitis.

Of the 91 cases reported to CDC since November 4, 2012, a total of 26 (29%) were classified as meningitis, 61 (67%) had spinal or paraspinal epidural abscess or osteomyelitis, 2 (2%) had peripheral joint infection, and 2 (2%) had more than one condition (Figure 1).

Figure 1

Note: Data presented in Figure 1 are preliminary and subject to change. Additional patients may ultimately meet multiple case definitions (e.g., meningitis and osteomyelitis/abscess) as more time elapses and additional information is provided to CDC. Reporting dates to CDC may lag behind onset dates.

Diagnostic and Treatment Guidance

As a reminder, CDC’s current diagnostic and treatment guidance addresses management of patients with epidural abscess or other complications at or near the injection site. These localized infections may occur in isolation or in patients previously diagnosed with fungal meningitis. Although patients with these localized infections frequently have new or worsening back pain, symptoms may be mild or clinically difficult to distinguish from the patient’s baseline chronic pain. Based on current information, CDC recommends the following diagnostic protocol:

• In patients with new or worsening symptoms at or near the injection site, physicians should obtain an MRI with contrast of the symptomatic area(s), if not contraindicated. This recommendation also applies to patients being treated for meningitis. In some cases, radiologic evidence of abscess or phlegmon has become apparent on repeat MRI studies performed subsequent to an initially normal imaging procedure. Clinicians should therefore have a low threshold for repeat MRI studies in patients who continue to have symptoms localizing to the site of injection, even after a normal study. However, the optimal duration between MRI studies is unknown.
• CDC has received reports of patients being treated for fungal meningitis who had no previous evidence of localized infection at the site of injection, but who were subsequently found to have evidence of localized infection (e.g., epidural abscess, phlegmon, discitis, vertebral osteomyelitis, or arachnoiditis) on imaging studies. Therefore, in patients being treated for meningitis, even in the absence of new or worsening symptoms at or near the injection site, clinicians should strongly consider obtaining an MRI of the injection site approximately 2-3 weeks after diagnosis of meningitis. Early identification of new disease may facilitate additional specific interventions (e.g., drainage) and provide information for measuring effectiveness of therapy thereafter.
• For patients demonstrated to have epidural abscess, phlegmon, discitis, vertebral osteomyelitis, or arachnoiditis, early consultation with a neurosurgeon to discusswhether surgical management, including debridement, is warranted in addition to antifungal therapy (for information about antifungal therapy, see Interim Treatment Guidance for Central Nervous System and Parameningeal Infections Associated with Injection of Contaminated Steroid Products http://www.cdc.gov/hai/outbreaks/clinicians/guidance_cns.html).

CDC continues to gather data from existing and newly reported cases of infection and will use this information to inform updates to existing guidance. Healthcare professionals with patients under their care should check CDC’s website for the most up-to-date clinical guidance because information is subject to change.

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NECC 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

CDC clinical conference call (COCA Call) next Tuesday, November 27^th at 2—3pm ET

Date: Tuesday, November 27th, 2012 – Save the Date

Time: 2:00 – 3:00 pm (Eastern Time)

Speakers: Melissa K. Schaefer, MD (CDC); Benjamin Park, MD (CDC) and John Jernigan, MD (CDC)

Call-in number and additional details forthcoming

Indications of two unusual clinical complications – epidural abscess and arachnoiditis – among a portion of patients undergoing treatment for meningitis associated with injections of a contaminated steroid medication, preservative-free methylprednisolone acetate

During the course of this investigation, CDC has worked closely with a group of fungal infectious disease experts who provided their individual input to help CDC develop interim guidance and other information about clinical aspects of the outbreak, including patient management and treatment. The guidance documents have been updated regularly as CDC and its partners have learned more about the outbreak; the latest versions are available on CDC’s outbreak-related Clinician Guidance webpage at http://www.cdc.gov/hai/outbreaks/clinicians/index.html. CDC has also advised that healthcare providers involved in the treatment of these patients consult with an infectious disease medical specialist because of the diagnostic and clinical challenges presented by these fungal infections.

CDC has recently become aware of reports of epidural abscess and arachnoiditis among a number of patients undergoing treatment for fungal meningitis associated with injections of contaminated steroid. Spinal epidural abscesses are characterized by inflammation and a collection of pus around the spine, sometimes resulting in swelling of the infected areas (though several recently reported patients with this condition had no detectable swelling). Arachnoiditis is caused by inflammation of the arachnoid, one of the membranes that surround and protect the nerves of the spinal cord. Both conditions are normally rare but serious disorders that require prompt medical attention. Most of these early reports have been for patients in Michigan and Tennessee, but other states have reported patients with these conditions as well. CDC is working with clinicians and public health officials to obtain more information and refine its clinical guidance as needed.

For additional information about the outbreak of fungal meningitis and other infections, see CDC’s website at http://www.cdc.gov/hai/outbreaks/meningitis.html.