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CDC - Outbreak of Fungal Meningitis - Clinician Guidance

Catbird

Catbird

Senior Moderator
What Should Physicians Be Doing?

October 14, 2012 8:00 PM EDT


Find out if you have administered a potentially contaminated medication from New England Compounding Center. The three potentially contaminated lots are:

  • 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

Contact patients who have been exposed. All patients who have received medication from one of these three lots should be immediately contacted directly to determine if they are having any symptoms.

It is important to note that infected patients have presented with mild symptoms, only slightly worse than baseline.


Refer symptomatic patients for a diagnostic procedure. For patients who received epidural injection with medication from the lots listed above and have any 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.

When diagnostic lumbar punctures are performed, they should be done through a site other than the site used for epidural injection when possible. The clinical investigation of patients associated with this cluster is ongoing and this recommendation may change as new information becomes available.

Interim instructions regarding diagnostic testing and treatment options are available at http://www.cdc.gov/HAI/outbreaks/meningitis.html.


Report concerning cases to public health. Physicians should report suspected cases to their state health department.

Clinicians are also requested to 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


Use appropriate treatment for fungal meningitis and fungal joint infections.

Fungal Meningitis

Initiate empiric antifungal therapy after collecting cerebrospinal fluid for culture using the appropriate regimen found in the Interim Treatment Guidance for Central Nervous System (CNS) and/or Parameningeal Infections Associated with Injection of Potentially Contaminated Steroid Products in addition to routine empiric treatment protocols to cover for potential bacterial pathogens until the etiology of the patient?s CNS and/or parameningeal infection has been identified:


Fungal Joint Infections

When empiric antifungal therapy is initiated, use the appropriate regimen found in the Interim Treatment Options for Septic Arthritis Associated With Injection of Potentially Contaminated Steroid Products until the etiology of the patient?s septic arthritis has been identified.
 
Re: CDC - Outbreak of Fungal Meningitis - Clinician Guidance

Frequently Asked Questions for Clinicians: Multistate Fungal Meningitis Outbreak Investigation

October 14, 2012 8:00 PM EDT


About the Outbreak

Background
The Centers for Disease Control and Prevention (CDC) with state and local health departments and the Food and Drug Administration (FDA) are investigating a multistate meningitis outbreak of fungal infections among patients who have received a steroid injection of a potentially contaminated product into the spinal area. This form of meningitis is not contagious. The investigation also includes fungal infections associated with injections in a peripheral joint space, such as a knee, shoulder or ankle.

See Current Situation Update

How many cases have been reported?
Updates about the investigation, including case counts, are available at http://www.cdc.gov/hai/outbreaks/meningitis.html.

What is causing these infections?
The infections are caused by a fungus. At this point, the original source of the outbreak has not been determined; however, all infected patients identified thus far have received preservative-free (PF) methylprednisolone acetate (80mg/ml) from among the three lots voluntarily recalled by the New England Compounding Center in Framingham, Massachusetts, on September 26, 2012. These three lots are:

  • 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

These medications were used for other types of injections, including injections into the joint (e.g., knee). To date, CDC has only identified infections in patients who received epidural steroid injections with these medications. However, patients who received other types of injections with these products may also be at risk.

Which states received the potentially contaminated medication?
Twenty-three states have received medication from the New England Compounding Center.

The names of the facilities that have received medication from one of these lots are available at http://www.cdc.gov/hai/outbreaks/meningitis-facilities-map.html.

Are other medications from the New England Compounding Center located in Framingham, Massachusetts associated with infections?
To date, CDC has not received reports of infections linked to other products from the New England Compounding Center. However, out of an abundance of caution, CDC recommends that patients cease use of any product produced by the New England Compounding Center until further information is available. A list of products produced by the New England Compounding Center can be found through the FDA website at http://www.fda.gov/Drugs/DrugSafety/ucm322734.htmExternal Web Site Icon.

If patients have taken or used medications from New England Compounding Center, and they are worried that they are ill because of use of one of these products, they should seek medical attention. Again, CDC has not received any reports of infection linked to other products from New England Compounding Center


Is there a role for prophylaxis or lumbar puncture in asymptomatic patients?


Prophylaxis
Currently, CDC emphasizes the need for rapid clinical evaluation and diagnosis, if indicated. Prophylaxis is not recommended at this time. For more information, please see Interim Guidance for Management of Asymptomatic Persons Exposed to Potentially Contaminated Steroid Products.

Lumbar Puncture
At this time, CDC does not recommend performing lumbar puncture in exposed patients who are currently asymptomatic. These patients should be closely monitored for development of symptoms, with a low threshold for performing lumbar puncture if the patient should become symptomatic. The clinical investigation of patients associated with this outbreak is ongoing, and this recommendation may change as new information becomes available. For more information, please see Interim Guidance for Management of Asymptomatic Persons Exposed to Potentially Contaminated Steroid Products.


Can patients continuing receiving treatment with epidural steroid injections?


It is not clear if or how additional epidural or intra-articular steroid injections may increase the risk of developing fungal meningitis or septic arthritis in patients who received epidural or intra-articular injections with a New England Compounding Center product and who are currently asymptomatic. Steroids are immunosuppressive and it is therefore possible they could increase risk in patients with sub-clinical infection; however, the duration of infection risk resulting from prior exposure to a contaminated steroid product is finite, albeit unknown. Patients should discuss the need for additional injections with their providers. For more information, please see Interim Guidance for Management of Asymptomatic Persons Exposed to Potentially Contaminated Steroid Products.
 
Re: CDC - Outbreak of Fungal Meningitis - Clinician Guidance

Frequently Asked Questions for Clinicians: Multistate Fungal Meningitis Outbreak Investigation

October 15, 2012 7:00 PM EDT


About the Outbreak

Background
The Centers for Disease Control and Prevention (CDC) with state and local health departments and the Food and Drug Administration (FDA) are investigating a multistate meningitis outbreak of fungal infections among patients who have received a steroid injection of a potentially contaminated product into the spinal area. This form of meningitis is not contagious. The investigation also includes fungal infections associated with injections in a peripheral joint space, such as a knee, shoulder or ankle.

See Current Situation Update

How many cases have been reported?
Updates about the investigation, including case counts, are available at http://www.cdc.gov/hai/outbreaks/meningitis.html.

What is causing these infections?
The infections are caused by a fungus. At this point, the original source of the outbreak has not been determined; however, all infected patients identified thus far have received preservative-free (PF) methylprednisolone acetate (80mg/ml) from among the three lots voluntarily recalled by the New England Compounding Center in Framingham, Massachusetts, on September 26, 2012. These three lots are:

  • 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

These medications were used for other types of injections, including injections into the joint (e.g., knee). To date, CDC has only identified infections in patients who received epidural steroid injections with these medications. However, patients who received other types of injections with these products may also be at risk.

Which states received the potentially contaminated medication?
Twenty-three states have received medication from the New England Compounding Center.

The names of the facilities that have received medication from one of these lots are available at http://www.cdc.gov/hai/outbreaks/meningitis-facilities-map.html.

Are other medications from the New England Compounding Center located in Framingham, Massachusetts associated with infections?
To date, CDC has not received reports of infections linked to other products from the New England Compounding Center. However, out of an abundance of caution, CDC recommends that patients cease use of any product produced by the New England Compounding Center until further information is available. A list of products produced by the New England Compounding Center can be found through the FDA website at http://www.fda.gov/Drugs/DrugSafety/ucm322734.htm

If patients have taken or used medications from New England Compounding Center, and they are worried that they are ill because of use of one of these products, they should seek medical attention. Again, CDC has not received any reports of infection linked to other products from New England Compounding Center.

Are the treatment recommendations for infections that might be associated with other NECC products referenced by the FDA October 15 announcement the same as those for infections associated with methylprednisolone?
This is preliminary information and CDC does not have firm evidence that fungal infections have been caused by exposure to other NECC products. Out of an abundance of caution, FDA has advised clinicians to follow up with patients to whom they have administered an injectable product, including an ophthalmic drug that is injectable or used in conjunction with eye surgery, or a cardioplegic solution purchased from or produced by NECC after May 21, 2012. Therefore, in patients who report signs and symptoms of infection following high-risk exposure to one of these NECC products (e.g., exposure of product to sterile body site), clinicians should perform a thorough diagnostic evaluation to exclude fungal infection. Consultation with an infectious diseases 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 http://www.cdc.gov/hai/outbreaks/clinicians/index.html

It is important to note that investigation of the mentioned patients is ongoing, and guidance may change if additional information becomes available.

Is there a role for prophylaxis or lumbar puncture in asymptomatic patients?


Prophylaxis
Currently, CDC emphasizes the need for rapid clinical evaluation and diagnosis, if indicated. Prophylaxis is not recommended at this time. For more information, please see Interim Guidance for Management of Asymptomatic Persons Exposed to Potentially Contaminated Steroid Products.

Lumbar Puncture
At this time, CDC does not recommend performing lumbar puncture in exposed patients who are currently asymptomatic. These patients should be closely monitored for development of symptoms, with a low threshold for performing lumbar puncture if the patient should become symptomatic. The clinical investigation of patients associated with this outbreak is ongoing, and this recommendation may change as new information becomes available. For more information, please see Interim Guidance for Management of Asymptomatic Persons Exposed to Potentially Contaminated Steroid Products.


Can patients continuing receiving treatment with epidural steroid injections?


It is not clear if or how additional epidural or intra-articular steroid injections may increase the risk of developing fungal meningitis or septic arthritis in patients who received epidural or intra-articular injections with a New England Compounding Center product and who are currently asymptomatic. Steroids are immunosuppressive and it is therefore possible they could increase risk in patients with sub-clinical infection; however, the duration of infection risk resulting from prior exposure to a contaminated steroid product is finite, albeit unknown. Patients should discuss the need for additional injections with their providers. For more information, please see Interim Guidance for Management of Asymptomatic Persons Exposed to Potentially Contaminated Steroid Products.
 
Re: CDC - Outbreak of Fungal Meningitis - Clinician Guidance

Multistate Fungal Meningitis Outbreak Investigation
​

Interim Treatment Guidance for Osteoarticular Infections Associated With Injection of Contaminated Steroid Products​


October 23, 2012 11:00 PM EDT

Rationale:

This is interim guidance for treatment of adult patients with osteoarticular infections associated with intra-articular injections of contaminated steroid products from the New England Compounding Center. Interim guidance may change as new information becomes available.
These recommendations are based upon growing evidence that Exserohilum rostratum (a brown-black mold) is the predominant pathogen in this outbreak, and expert opinion and published literature indicating that voriconazole may be effective in treating infections due to brown-black molds as well as infections due to Aspergillus species. Recommendations are also based on considerations related to the anatomic site of infection and pharmacokinetics of antifungal agents. CDC continues to consult with national experts about treatment options for fungal osteoarticular infections in patients associated with this outbreak.


Infectious Diseases Physician Consultation:

  • Consult an infectious diseases physician to assist with patient diagnosis, management, and follow up, which may be complex and prolonged.


Diagnostic Considerations:

  • Thorough diagnostic evaluation is essential, and should include collection of synovial fluid and/or synovial tissue prior to initiation of treatment. Samples should be sent or fungal culture, molecular testing, and histopathological examination, in addition to the standard tests for bacterial infection and crystal-induced disease.
  • Physicians should use their best judgment in regard to imaging the osteoarticular structure(s) that may be infected. For large joints, such as knees, if there is a consideration of adjacent osteomyelitis, then imaging should be performed. Imaging may be particularly important in the evaluation of joint spaces such as the sacroiliac joint, where osteomyelitis may be more common and from which obtaining a diagnostic specimen of synovial fluid may be more difficult. Similarly, for patients in whom complaints of back pain are worrisome for the development of discitis/vertebral osteomyelitis, imaging should be performed. In some of these cases, repeat imaging may be required as the progression of the infection may be slow and imaging findings suggestive or diagnostic of osteomyelitis may not be evident for two weeks or more following initial presentation.
  • Note that a negative fungal culture or negative fungal polymerase chain reaction (PCR) test from a diagnostic specimen obtained from a joint space or bone does not rule out infection. Active fungal infection may be present even when these tests are negative.


Empiric Antifungal Therapy:

  • Routine empiric antibacterial therapy should be used according to the judgment of the physician while awaiting results of diagnostic studies.
  • In clinically stable patients with peripheral joint infection, it may be reasonable to wait 48-72 hours before initiating empiric antifungal therapy, to allow time for identification of alternative diagnoses (e.g., bacterial arthritis, crystal-induced arthritis, etc.). This decision should be made at the discretion of the provider.


    When empiric antifungal therapy is initiated, the following regimen is suggested until the etiology of the patient?s septic arthritis has been identified:
  • For discitis, vertebral osteomyelitis, and epidural abscess give voriconazole at a dose of 6 milligrams per kilogram (mg/kg) every 12 hours1. For osteoarticular infections that do not involve the spine, give voriconazole, beginning with a loading dose of 6 mg/kg every 12 hours for two doses, followed by 4 mg/kg every 12 hours *1.

  • A blood specimen for serum voriconazole trough level measurement should be collected on the 5th day of voriconazole treatment, and the dose of voriconazole should be adjusted based on this trough level, aiming for a trough level range of 2 to 5 micrograms per milliliter (mcg/ml). Serum voriconazole trough levels greater than 5 mcg/ml should be avoided because of the risk of neurotoxicity and other drug-related adverse events.​
  • Regular monitoring of serum voriconazole trough levels once per week should occur for the initial 4-6 weeks of voriconazole treatment and when dose adjustments are made. Dose adjustments should be made as needed to maintain serum voriconazole trough levels within the range of 2 to 5 mcg/ml.​
  • Patients with more severe osteoarticular infection, clinical instability, discitis, vertebral osteomyelitis, or epidural abscess should be started on voriconazole IV. If the provider wants to transition patients initially treated with IV voriconazole to oral voriconazole, this should be done only after a patient is clinically stable or improving, as long as no contraindications to oral therapy exist.​
  • Patients with mild osteoarticular infection not involving the spine who are able to take oral voriconazole as prescribed and who are able to be monitored closely may be started on oral voriconazole at the provider?s discretion. Patients on oral voriconazole should be treated with a loading dose of 6 mg/kg every 12 hours for two doses, followed by 4 mg/kg every 12 hours, with monitoring of serum voriconazole trough levels as above and dose adjustment as necessary. The target range for serum voriconazole trough levels (2 to 5 mcg/ml) is readily achievable using the oral form of the drug, but may require a slightly higher dose and may take longer to achieve if unforeseen problems with gastrointestinal intolerance or poor absorption are encountered.​
  • Providers and patients should be aware of and monitor for potential adverse effects of voriconazole, including (but not limited to) hepatic toxicity and neurotoxicity. Liver function tests should be closely monitored. The occurrence of hallucinations may be an indication of neurotoxicity and elevated serum voriconazole levels, and should prompt collection of a blood specimen for serum voriconazole trough level measurement and voriconazole dose adjustment.​
  • Providers should carefully consider and manage the potential for voriconazole drug interactions in all patients.
    [*]​
  • A lipid formulation of amphotericin B at a dose of 5 mg/kg IV daily should be considered in addition to voriconazole in patients with severe osteoarticular infection and/or patients with clinical instability. Nephrotoxicity is a common complication of amphotericin B therapy, including therapy with lipid formulations of amphotericin B. Kidney function and electrolytes should be monitored closely in patients receiving any amphotericin B formulation. Administration of 1 liter of normal saline IV prior to amphotericin B infusion may be considered to minimize risk of nephrotoxicity. Providers and patients should also be aware of and monitor for other potential adverse effects of amphotericin B formulations.​
  • Alternate therapies to consider for patients who are unable to tolerate treatment with voriconazole include lipid formulations of amphotericin B, posaconazole, and itraconazole. Therapeutic drug monitoring should be performed for patients treated with posaconazole or itraconazole. Consultation with an infectious diseases physician should be sought regarding dosages and monitoring of these agents. Fluconazole should NOT be used.​


Other Treatment Considerations:

  • Arthroscopy with joint lavage and debridement should be considered in consultation with an orthopedic surgeon, or a neurosurgeon in the case of vertebral osteomyelitis.


Considerations Regarding Duration of Treatment:

  • Adequate duration of antifungal treatment is unknown, and it is likely that patients will require prolonged therapy tailored by the clinical response to treatment. Individual patient management decisions, including choice of long-term antifungal treatment regimens, should be made in consultation with infectious diseases physicians experienced in the treatment of fungal infections. While adequate duration of therapy is unknown and will likely vary substantially depending upon individual patient circumstances, a minimum of 3 months of antifungal treatment should be considered. Treatment may need to continue for longer than 3 months in patients with more severe disease, bone infection, underlying immunosuppression, etc. Clinicians should be vigilant for potential relapse of infection after completion of therapy.


*1Dose adjustments may be needed for certain patients, including (but not necessarily limited to): children (who often need a higher dose) and patients with hepatic impairment (who may need a lower dose). Dosing of voriconazole in obese patients should be discussed with an infectious diseases physician. Oral voriconazole should be taken at least one hour before or after a meal. Consult an infectious diseases physician and refer to the manufacturer?s instructions.

For additional information on antifungal drugs:


 
Re: CDC - Outbreak of Fungal Meningitis - Clinician Guidance

Multistate Fungal Meningitis Outbreak Investigation​

Interim Guidance for Management of Asymptomatic Persons Exposed to Potentially Contaminated Steroid Products​


October 23, 2012 11:00 PM EDT


Management of asymptomatic patients who received epidural or paraspinal injections with contaminated steroid products

  • CDC continues to assess and revise interim guidance to clinicians involved in the management of patients who received injections with contaminated steroid products distributed by the New England Compounding Center (NECC). Since early in the outbreak, CDC has recommended against antifungal prophylactic or presumptive treatment of exposed asymptomatic patients in the absence of diagnostic testing with results indicating meningitis. This recommendation remains unchanged. Nevertheless, CDC recognizes the need to assist clinicians in managing asymptomatic patients who received epidural or paraspinal injections with contaminated steroid products. On October 23, 2012, CDC issued updated interim guidance to clinicians based on new data that has become available during this investigation. More?


Antifungal prophylaxis for patients who received intra-articular injections with potentially contaminated steroid products

  • At this time, CDC does not recommend initiation of antifungal prophylaxis in exposed patients who are asymptomatic or have no change in baseline joint symptoms. These patients should be closely monitored for development of symptoms or for changes in, or worsening of, baseline symptoms, with a low threshold for performing diagnostic evaluation should the patient become symptomatic or experience changes in, or worsening of, baseline symptoms.


Continued treatment with epidural steroid injections
  • It is not clear if or how additional epidural or intra-articular steroid injections may increase the risk of developing fungal meningitis or septic arthritis in patients who received epidural or intra-articular injections with a New England Compounding Center product and who are currently asymptomatic. Steroids are immunosuppressive and it is therefore possible they could increase risk in patients with sub-clinical infection; however, the duration of infection risk resulting from prior exposure to a contaminated steroid product is finite, albeit unknown. Patients should discuss the need for additional injections with their providers.
 
Re: CDC - Outbreak of Fungal Meningitis - Clinician Guidance

Multistate Fungal Meningitis Outbreak Investigation​

Guidance on Management of Asymptomatic Patients Who Received Epidural or Paraspinal Injections with Contaminated Steroid Products *1​


October 23, 2012 11:00 PM EDT

CDC is updating its guidance on management of asymptomatic persons who received epidural or paraspinal injections with contaminated steroid products, *1 based upon additional data that have become available during the course of the investigation of this outbreak. The guidance and estimates are based on data currently available to CDC. Additional data that are gathered from existing and newly reported cases of infection, when combined with previous data, may alter the guidance and estimates. Clinicians and others with patients under their care who use the guidance and estimates should check CDC?s website for the most up-to-date information, since it is subject to change periodically.

Additional data from cohorts of case-patients in this outbreak indicate that patients who received epidural or paraspinal injections with contaminated steroid product within the last 6 weeks (42 days) may be at greatest risk of developing meningitis and therefore additional monitoring should be considered. The information provided in this update provides additional guidance to clinicians to assist them in determining the strategy for monitoring such patients.

CDC?s recommendation on prophylactic use of antifungal agents remains unchanged. At this time CDC does not recommend initiation of antifungal treatment in the absence of diagnostic testing with results indicating meningitis in exposed patients who are asymptomatic. However, these persons should be closely monitored.


Guidance for asymptomatic patients who received their last epidural or paraspinal injection with contaminated steroid product1 within the last 6 weeks (42 days)

  • Option 1. This option is consistent with the existing recommended strategy.
  • Continue to closely monitor for development of symptoms, with a low threshold for performing lumbar puncture should the patient become symptomatic. When diagnostic lumbar punctures are performed, they should be done through a site other than the site used for epidural injection when possible.
  • Option 2. This option, which is estimated to reduce the maximal risk of stroke or death from approximately 0.4% to 0.3% in comparison to option 1, may also be considered.
  • Perform lumbar puncture, through a site other than the site used for epidural injection when possible.​
  • If the cerebrospinal fluid (CSF) examination shows less than or equal to 5 white blood cells (WBC), the patient should continue to be followed very closely for onset of symptoms. If the patient remains asymptomatic, consider repeating weekly lumbar punctures until 6 weeks (42 days) have passed since the last epidural or paraspinal injection with contaminated steroid product,1 at which time the patient can be monitored closely for the development of symptoms, with a low threshold for performing lumbar puncture should the patient become symptomatic.​
  • Patients with greater than 5 WBCs in CSF should be treated for fungal meningitis according to current treatment guidance.​
  • In making a management decision, clinicians should also consider the risk associated with lumbar puncture (e.g., post-lumbar puncture headache, CSF leak, the theoretical risk that fungi could be transferred from the epidural space into the subarachnoid space of a patient who has received epidural or paraspinal injections with contaminated steroid products *1).​


Guidance for asymptomatic patients who received their last epidural or paraspinal injection with contaminated steroid product1 greater than 6 weeks (42 days) ago

Patients who received their last epidural or paraspinal injection with contaminated steroid product1 greater than 6 weeks (42 days) ago should continue to be closely monitored as previously recommended for development of symptoms, with a low threshold for performing lumbar puncture should the patient become symptomatic. When diagnostic lumbar punctures are performed, they should be done through a site other than the site used for epidural injection when possible.
  • At this time CDC does not recommend initiation of antifungal treatment in the absence of diagnostic testing with results indicating meningitis in exposed patients who are asymptomatic. Currently available data do not suggest an added benefit to this approach in comparison to the strategies outlined above, and many patients may experience serious adverse drug events associated with treatment.​

Decisions on management of asymptomatic patients who received epidural or paraspinal injections with contaminated steroid products *1 should be made by the patient and provider after a thorough consideration of the potential risks and benefits for that individual patient.


Background


  • To further inform decisions regarding management of asymptomatic patients who have received epidural or paraspinal injections with contaminated steroid products,1 CDC has developed a decision analysis model to estimate the potential incremental risks and benefits of administering antifungal agents to asymptomatic persons compared with the currently recommended strategy. The decision analysis model uses data collected in the ongoing outbreak investigation, information from the medical literature regarding the toxicity of recommended antifungal medications, and opinion of clinical experts on fungal infection. The results of the decision analysis are preliminary and subject to change as new information becomes available.
  • The analysis suggests that the period of greatest risk for the development of fungal meningitis is during the first 6 weeks (42 days) after receiving an epidural or paraspinal injection with a contaminated steroid product.1 As of October 22, 2012, at least 26 days should have passed since any patient received an injection with medication from these lots given that the medication was recalled on September 26, 2012. The estimated remaining risk of developing meningitis is likely to be no greater than 5% on the 26th day following their last epidural or paraspinal injection, and then decreases to a risk of no greater than 1% by 6 weeks (42 days) following injection. The majority of these patients will have risks of meningitis much lower than the estimated risks quoted above, and their risk will continue to decrease as more time elapses since their last injection.
  • The estimated remaining risk of stroke or death is likely to be no greater than 0.4% on the 26th day following their last epidural or paraspinal injection, and then decreases to a risk of no greater than 0.08% by 6 weeks (42 days) following injection. The majority of these patients will have risks of stroke or death much lower than the estimated risks quoted above, and their risk will continue to decrease as more time elapses since their last injection (see Figure).


chart-2.png

This graph plots the percentage risk of stroke or death for patients by two management options described above. The calculation of percentage risk calculation is based upon a decision model that assumes a high risk exposure based upon lot number, vial age, and cumulative dose received. The majority of exposed patients will have risks lower than those plotted on the graph.

*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
 
Re: CDC - Outbreak of Fungal Meningitis - Clinician Guidance

Multistate Fungal Meningitis Outbreak Investigation​
http://www.cdc.gov/hai/outbreaks/clinicians/faq_meningitis_outbreak.htmlhttp://www.cdc.gov/hai/outbreaks/clinicians/faq_meningitis_outbreak.htmlhttp://www.cdc.gov/hai/outbreaks/clinicians/faq_meningitis_outbreak.html

October 23, 2012 9:00 PM EDT

About the Outbreak

Background
The Centers for Disease Control and Prevention (CDC) with state and local health departments and the Food and Drug Administration (FDA) are investigating a multistate meningitis outbreak of fungal infections among patients who have received a steroid injection of a potentially contaminated product into the spinal area. This form of meningitis is not contagious. The investigation also includes fungal infections associated with injections in a peripheral joint space, such as a knee, shoulder or ankle.

See Current Situation Update


How many cases have been reported?

Updates about the investigation, including case counts, are available at http://www.cdc.gov/hai/outbreaks/meningitis.html.


What is causing these infections?

The infections are caused by a fungus. At this point, the original source of the outbreak has not been determined; however, all infected patients identified thus far have received preservative-free (PF) methylprednisolone acetate (80mg/ml) from among the three lots voluntarily recalled by the New England Compounding Center in Framingham, Massachusetts, on September 26, 2012. These three lots are:

  • 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

These medications were used for other types of injections, including injections into the joint (e.g., knee). To date, CDC has only identified infections in patients who received epidural steroid injections with these medications. However, patients who received other types of injections with these products may also be at risk.


Which states received the potentially contaminated medication?

Twenty-three states have received medication from the New England Compounding Center.

The names of the facilities that have received medication from one of these lots are available at http://www.cdc.gov/hai/outbreaks/meningitis-facilities-map.html.


Are other medications from the New England Compounding Center located in Framingham, Massachusetts associated with infections?

To date, CDC has not received reports of infections linked to other products from the New England Compounding Center. However, out of an abundance of caution, CDC recommends that patients cease use of any product produced by the New England Compounding Center until further information is available. A list of products produced by the New England Compounding Center can be found through the FDA website at http://www.fda.gov/Drugs/DrugSafety/ucm322734.htm

If patients have taken or used medications from New England Compounding Center, and they are worried that they are ill because of use of one of these products, they should seek medical attention. Again, CDC has not received any reports of infection linked to other products from New England Compounding Center.


Are the treatment recommendations for infections that might be associated with other NECC products referenced by the FDA October 15 announcement the same as those for infections associated with methylprednisolone?

This is preliminary information and CDC does not have firm evidence that fungal infections have been caused by exposure to other NECC products. Out of an abundance of caution, FDA has advised clinicians to follow up with patients to whom they have administered an injectable product, including an ophthalmic drug that is injectable or used in conjunction with eye surgery, or a cardioplegic solution purchased from or produced by NECC after May 21, 2012. Therefore, in patients who report signs and symptoms of infection following high-risk exposure to one of these NECC products (e.g., exposure of product to sterile body site), clinicians should perform a thorough diagnostic evaluation to exclude fungal infection. Consultation with an infectious diseases 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 http://www.cdc.gov/hai/outbreaks/clinicians/index.html

It is important to note that investigation of the mentioned patients is ongoing, and guidance may change if additional information becomes available.


Is there a role for presumptive treatment in the management of asymptomatic patients?


Should asymptomatic patients who received epidural or paraspinal injections with contaminated steroid medication be treated for fungal meningitis?

Since early in the outbreak, CDC has recommended against antifungal prophylactic or presumptive treatment of exposed asymptomatic patients in the absence of diagnostic testing with results indicating meningitis. This recommendation remains unchanged. Nevertheless, CDC recognizes the need to assist clinicians in managing asymptomatic patients who received epidural or paraspinal injections with contaminated steroid products. CDC has updated Guidance on Management of Asymptomatic Patients Who Received Epidural or Paraspinal Injections with Contaminated Steroid Products to assist clinicians in the management of asymptomatic exposed patients. To help inform this guidance, CDC developed a decision analysis model to estimate the potential incremental risks and benefits of administering antifungal agents to asymptomatic persons compared with the strategy of providing no antifungal presumptive treatment. CDC?s model suggests that there is no added benefit to providing antifungal therapy to patients who have no signs of meningitis. For patients who received their injection within the last 6 weeks (42 days), CDC has advised that clinicians consider the option of performing a lumbar puncture to look for evidence of meningitis.


For asymptomatic patients who received epidural or paraspinal injections with contaminated steroid medication, what are the risks that they will develop fungal meningitis?


CDC?s analysis suggests that the period of greatest risk for development of fungal meningitis is the first 6 weeks (42 days) after receiving an epidural or paraspinal injection with methylprednisolone acetate from one of the three recalled lots distributed by the New England Compounding Center. As of October 22, 2012, a period of 26 days will have passed since any patient received an injection with medication from these lots (the lots were recalled on September 26, 2012). The estimated remaining risk for developing meningitis is likely to be no greater than 8% on the 26th day after the patient?s last epidural or paraspinal infection, and then decreases to a risk of no greater than 1.2% by 42 days after the last patient?s injection. Based on current information, CDC projects that the majority of these patients will have risks of meningitis that are much lower than the estimates noted here, and their risk will continue to decrease as more time elapses since their last injection.


For asymptomatic patients who received epidural or paraspinal injections with contaminated steroid medication, what are the risks of more severe outcomes, such as stroke or death?

The estimated remaining risk of stroke or death is likely to be no greater than 0.7% on the 26th day following their last epidural or paraspinal injection, and then decreases to a risk of no greater than 0.08% by 42 days after the patient?s last injection. The majority of these patients will have risks of stroke or death that are much lower than the estimates noted here, and their risk will continue to decrease as more time elapses since their last injection.


What are the treatment options for asymptomatic patients who received epidural or paraspinal injections with contaminated steroid medication?


CDC does not recommend preemptive antifungal treatment therapy for people who received a contaminated steroid injection but who do not have any symptoms. However, there is a small chance of fungal meningitis or stroke in these patients. CDC?s analysis indicates that patients who received injections with contaminated steroid products within the last 6 weeks (42 days) may be at greatest risk for fungal meningitis, and therefore additional monitoring should be considered. CDC?s expanded interim guidance provides two management options for patients who received their last injection with contaminated steroid product within the last 42 days and who are asymptomatic:

  • Option 1: Continue monitoring and test only if symptoms appear.
  • Continue to closely monitor for development of symptoms, with a low threshold for performing lumbar puncture should the patient become symptomatic. When diagnostic lumbar punctures are performed, they should be done through a site other than the site used for epidural injection when possible. ? Option 2: Monitor, test, and treat.

  • Option 2 is estimated to reduce the risk for stroke or death from approximately 0.4% to 0.3% in comparison to option 1.

  • Perform lumber puncture, preferably through a site other than the site used for epidural injection when possible.​
  • If the cerebral spinal fluid (CSF) examination shows less than or equal to 5 white blood cells (WBC), the patient should continue to be followed very closely for onset of symptoms. If the patient remains asymptomatic, repeat weekly lumbar puncture until 6 weeks (42 days) have passed since the last epidural or paraspinal injection with contaminated steroid product, at which time the patient can be monitored closely for the development of symptoms, with a low threshold for performing lumbar puncture should the patient become symptomatic.​
  • Patients with greater than 5 WBCs in their CSF should be treated for fungal meningitis according to current CDC treatment guidance.​
  • In making a patient management decision, clinicians should also consider the risk associated with lumbar puncture, including the theoretical risk that fungi could be transferred from the epidural space into the subarachnoid space of a patient who has received epidural or paraspinal injections with contaminated steroid products.
    [*]​
Patient who received their last epidural or paraspinal injection with contaminated steroid product more than 6 weeks (42 days) ago should continue to be closely monitored for development of symptoms, with a low threshold for performing lumbar puncture should the patient become symptomatic.


What are the side effects of being tested on a regular basis for fungal meningitis (lumbar puncture)?

The side effects of lumbar puncture include post-lumbar headache, bleeding, and the theoretical risk that fungi could be transferred from the epidural space into the subarachnoid space of a patient who has received epidural or paraspinal injections with contaminated steroid products. Increasing the number of lumbar punctures will increase the risk of side effects.


What are the side effects of the anti-fungal therapy for fungal meningitis?
Antifungal treatment with voriconazole carries significant risk of hallucinations and other neurologic side effects, and liver damage. CDC recommends careful discussion of risks and benefits between physicians and their patients.


Can patients continue receiving treatment with epidural steroid injections?

It is not clear if or how additional epidural or intra-articular steroid injections may increase the risk of developing fungal meningitis or septic arthritis in patients who received epidural or intra-articular injections with a New England Compounding Center product and who are currently asymptomatic. Steroids are immunosuppressive and it is therefore possible they could increase risk in patients with sub-clinical infection; however, the duration of infection risk resulting from prior exposure to a contaminated steroid product is finite, albeit unknown. Patients should discuss the need for additional injections with their providers. For more information, please see Interim Guidance for Management of Asymptomatic Persons Exposed to Potentially Contaminated Steroid Products.
 
Re: CDC - Outbreak of Fungal Meningitis - Clinician Guidance

Multistate Fungal Meningitis Outbreak Investigation​

Infections under Investigation in Patients Exposed to NECC Products Other than the 3 Contaminated Lots of Methylprednisolone Acetate *1​


October 24, 2012 4:30 PM EDT


Meningitis, Spinal or Paraspinal Infection

A person who developed any of the following after epidural or paraspinal (*2) injection after May 21, 2012 of an NECC product (*1):

  • Meningitis (*3) of unknown etiology.
  • Osteomyelitis, abscess or other infection (e.g., soft tissue infection) of unknown etiology, in the spinal or paraspinal structures at or near the site of injection.

Fungal Infection of Interest

A person who developed fungal infection in a normally sterile site (*4) with laboratory evidence by culture, histopathology, molecular (e.g. NAAT or PCR), or positive galactomannan test following administration of an NECC product into a sterile site after May 21, 2012.

*1.Products from NECC other than the 3 contaminated lots (05212012@68, 06292012@26, 08102012@51) of methylprednisolone acetate.

*2.Paraspinal injections include, but are not limited to, spinal facet joint injection, sacroiliac joint injection,or spinal or paraspinal nerve root/ganglion block.

*3.Clinically diagnosed meningitis with one or more of the following symptoms: headache, fever, stiff neck, or photophobia, in addition to a CSF profile showing pleocytosis (>5 white blood cells, adjusting for presence of red blood cells by subtracting 1 white blood cell for every 500 red blood cells present) regardless of glucose or protein levels.

*4.Normally sterile sites include blood, CSF, pleural fluid, peritoneal fluid, pericardial fluid, surgical aspirate, bone, joint fluid, or internal body site (e.g., eye, lymph node or brain).
 
Re: CDC - Outbreak of Fungal Meningitis - Clinician Guidance

The Clinician FAQ has been updated to include information on the subsequent cases of spinal epidural abscess and arachnoiditis.

Excerpt from:

Multistate Fungal Meningitis Outbreak Investigation​

Frequently Asked Questions for Clinicians: Multistate Outbreak of Fungal Meningitis and Other Infections​


Background
The Centers for Disease Control and Prevention (CDC) with state and local health departments and the Food and Drug Administration (FDA) are investigating a multistate outbreak of fungal meningitis and other infections among patients who received contaminated preservative-free MPA steroid injections from New England Compounding Center (NECC) into the spinal area. This form of meningitis is not contagious. The investigation also includes fungal infections associated with injections in a peripheral joint space, such as a knee, shoulder or ankle.

CDC has recently become aware of reports of spinal epidural abscess and arachnoiditis among a number of patients undergoing treatment for fungal meningitis. Information for clinicians is included below.

snip

Epidural Abscess and Arachnoiditis


There have been media reports of spinal epidural abscesses and arachnoiditis among patients who received treatment for meningitis. What are these conditions and their symptoms?

CDC has received preliminary reports of spinal epidural abscesses and arachnoiditis occurring among a portion of patients undergoing treatment for fungal meningitis due to this outbreak. CDC does not know at this time how many patients developed these disorders or why they occurred. Both conditions are rare but serious disorders in the general population that require prompt medical attention.

  • A spinal epidural abscess is characterized by inflammation and a collection of pus around the spine. Spinal epidural abscesses sometimes result in swelling in the affected area (e.g., near the site where contaminated steroid mediation was injected).
  • Common symptoms can include fever, headache, back pain, and neurological problems (e.g., weakness, unusual changes in sensation)​

  • Arachnoiditis is a disorder caused by the inflammation of the arachnoid, one of the membranes that surrounds and protects the nerves of the spinal cord. The condition can be caused by irritation from chemicals, infection, or direct injury to the spine.
  • Symptoms can include numbness, tingling, and a characteristic stinging and burning pain in the lower back or legs. Some people with arachnoiditis may have debilitating muscle cramps, twitches, or spasms. The condition may also affect the bladder, bowel, and sexual function. In severe cases, arachnoiditis may cause paralysis of the lower limbs.
    [*] For more information about arachnoiditis, see the National Institute of Neurological Disorders and Stroke?s website.​


Should patients presenting with arachnoiditis be treated even if this condition is not specifically mentioned in the CDC case definitions for this outbreak?

Yes. The case definition for this outbreak is a surveillance tool developed to assist with the identification and reporting of cases. The case definition is not intended to guide clinical decision-making and patient management. Patients who present with signs and symptoms of arachnoiditis should be clinically assessed on the basis of clinical judgment and managed accordingly. CDC will continue working with clinicians and public health officials to obtain more information about the occurrence of arachnoiditis in these patients and refine its clinical guidance as needed.
 
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