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Fungal Meningitis Outbreak in 2012 Marion Kainer MD MPH FRACP - TN Department of Health Sandy Bledsoe - Assistant Vice Chancellor, Risk & Insurance Management, Vanderbilt University Julia Morris - Deputy General Counsel, Vanderbilt University January 24, 2013 AHLA Issues Affecting Academic Medical Centers and Other Teaching Institutions The First Fungal Meningitis Outbreak Case • Late summer/early fall: middle aged man presented with meningitis – History of epidural steroid injections – No immunosuppression – Otherwise healthy • Initially improved with standard therapy Vanderbilt University Vanderbilt University Medical Center Fungal Meningitis Outbreak • Condition deteriorated – antifungal therapy begun • CSF grew Aspergillus fumigatus • Tennessee DOH notified • Death on day 22 of hospitalization Vanderbilt University Vanderbilt University Medical Center Timeline of Major Events Date Major Events Day 1: Tuesday, Sept 18 • Dr. Marion Kainer receives an email from Dr. April 1 case of Pettit, Infectious Diseases Physician, Vanderbilt Aspergillus University Medical Center, about patient with meningitis meningitis caused by a fungus, Aspergillus fumigatus, who had a recent epidural injection at a pain clinic. • Dr. Kainer and Dr. Pettit discuss the case. • Dr. Kainer speaks with Ms. Candace Smith, infection preventionist (IP) at St Thomas Hospital (STH), which is organizationally affiliated with the St Thomas Outpatient Neurosurgical Center (STONC) where the patient received the injection. Vanderbilt University Case Count as Known at That Time Vanderbilt University Medical Center Date Major Events Case Count as Known at That Time Day 3: • IP from STH contacts Dr. Kainer and confirms that Thursday, index case had an epidural steroid injection (ESI) Sept 20 at STONC. Facility Manager of STONC is on vacation, so IP at STH continues to help in investigation. • Dr. Kainer contacts Dr. Perz at the Division of Healthcare Quality Promotion (DHQP), Centers for Disease Control and Prevention (CDC). • STH reports two additional patients with meningitis with high levels of white blood cells but no known cause. Both had undergone ESIs at STONC. Vanderbilt University 1 case of Aspergillus meningitis 2 cases of meningitis, unknown cause, both seeming to be improving No national reports of Aspergillus meningitis Vanderbilt University Medical Center Date Major Events Case Count as Known at That Time Day 4: Friday, Sept 21 • Visit to STONC by TDH staff for careful review of all procedures and the physical environment: no evidence observed of environmental conditions that would have led to fungal contamination of procedures. • TDH contacts CDC and describes findings of site visit. TDH asks CDC to help with laboratory testing of patients with meningitis. • Another patient with meningitis and stroke with a history of ESI at STONC is identified, while VUMC also reports yet another patient. • TDH sent out Health Alert using our TN Health Alert Network (THAN). 1 case of Aspergillus meningitis Vanderbilt University 2 cases of meningitis, unknown cause, both seeming to be improving 1 case of stroke and meningitis, unknown cause 1 case of stroke; no spinal tap done Vanderbilt University Medical Center Date Major Events Case Count as Known at That Time Day 6: Sunday, Sept 23 • IP at STH contacts Dr. Kainer about one new patient and one patient readmitted with meningitis; both had ESI at SONC Day 7: Monday, Sept 24 • Facility manager from STONC has returned from vacation and provides additional information on the facility practices. TDH staff arrange to begin collecting data on patients. • Dr. Kainer contacts State epidemiologist at Massachusetts Department of Health. 1 case Aspergillus meningitis 4 cases of meningitis unknown cause 1 case of stroke, but no spinal tap done Vanderbilt University Vanderbilt University Medical Center Date Major Events Case Count as Known at That Time Day 8: Tuesday, Sept 25 • 2 new cases of meningitis reported to TDH. Both had ESI using MPA from NECC at STONC. • Conference call with TDH, CDC, Massachusetts Department of Health and Board of Registration in Pharmacy (MABRP) and NECC. NECC stated no adverse events reported, no new suppliers of ingredients or changes in procedures. • STONC starts contacting potentially exposed patients. • A new patient who had an ESI at STONC was admitted to STH. 1 case Aspergillus meningitis Vanderbilt University 6 cases of meningitis unknown cause 1 case of stroke, but no spinal tap done 1 case other neurologic problems/abnor mal spinal tap (unknown cause) Vanderbilt University Medical Center Date Day 9: Wed, Sept 26 Day 10: Thurs, Sept 27 Major Events Case Count as Known at That Time Timeline of Major Events • NECC issues voluntary recall for 3 lots of (cont’d) preservative free MPA and provides distribution list of consignees to MABORP and FDA. • TDH and CDC draft an Epi-X Alert. • TDH staff complete first round of epidemiologic studies; preliminary findings supports that MPA is likely source. • TDH asks STONC to contact all patients who had procedures since July 30. • Analysis of the NECC distribution list shows two other clinics in TN received MPA. • North Carolina (NC) reports a patient with meningitis exposed to MPA from NECC. Vanderbilt University Vanderbilt University Medical Center Date Major Events Day 11: Fri, Sept 28 • Still not absolutely clear that MPA from NECC is only possible source of contamination. • CDC notifies all State Health Departments of situation and urges them to contact clinics who do ESIs. • CDC issues another national Epi-X alert indicating that this now is a multi-state outbreak and requesting reports of meningitis. Day 13: Sunday, Sept 30 • TDH and STONC staff continue to abstract data on patients who had procedures since July 1 Day 14: Monday, Oct 1 • TDH holds its first press conference and initiates a daily scheduled press briefing. Vanderbilt University Case Count as Known at That Time 11 cases, 2 deaths Vanderbilt University Medical Center Date Major Events Day 15: Wed Oct 3 18 cases, • CDC issues interim guidance on diagnostics and 2 deaths clinical management using input from an expert fungal clinical panel convened by CDC. • For the first time since the initial report, a tissue biopsy from a case patient shows a fungus. However, the fungus looks different than Aspergillus. More tests must be done to identify it. • TDH analysis of STONC patients suggests that one particular lot of the 3 NECC MPA lots present at STONC is the most likely to make patients sick: Lot 06292012. Vanderbilt University Case Count as Known at That Time Vanderbilt University Medical Center Date Major Events Day 16: Thurs, Oct 4 • A final identification of fungus causing illness still 25 cases, 3 deaths not made, but specimen from another patient who died shows fungus that is not Aspergillus. • FDA announces fungus was seen on microscopic examination of an unopened vial of MPA from Lot 08102012. • This now is very strong evidence that MPA is the cause of the outbreak. • TDH alerts TN healthcare facilities using THAN to cease use of all medications and products from NECC. Vanderbilt University Case Count as Known at That Time Vanderbilt University Medical Center Date Major Events Case Count as Known at That Time Day 17: Friday, Oct 5 TDH opens state health operations center to assist in case tracking, active surveillance, mobilizes regional health operations centers and uses public health nurses to contact hard to reach patients. 29 cases, 3 deaths Day 18: Sat, Oct 6 NECC announces voluntary recall of all NECC products. FDA issues Medwatch alert asking providers to stop using any NECC products. 29 cases, 3 deaths Day 24: Fri, Oct 12 MMWR (CDC publication) is published on clinical presentation of cases. 50 cases, 6 deaths Vanderbilt University Vanderbilt University Medical Center Date Major Events Case Count as Known at That Time Day 26: Sunday, Oct 14 FDA call with States and CDC on concerns about sterility of any product from NECC. 53 cases, 6 deaths Day 27: Monday, Oct 15 • FDA issues Medwatch alert. • TDH works with the Tennessee Hospital Association (THA) to identify and notify patients who received NECC products. 53 cases, 6 deaths Day 29: Wed, Oct 17 TDH identifies that patients who received older vials are much more likely to get sick. 61 cases, 8 deaths Vanderbilt University Vanderbilt University Medical Center Date Major Events Case Count as Known at That Time Day 30: Thurs, Oct 18 • TDH works with CDC experts to develop mathematical model used for decision analysis by CDC about what to do for high risk patients. • For the first time, CDC and FDA confirm presence of Exserohilum rostratum in unopened vials from Lot 0810210@51 63 cases, 8 deaths Day 35: Tuesday, Oct 23 MA Board of Registration in Pharmacy issues report initial preliminary findings. 70 cases, 9 deaths Day 38: Friday, Oct 26 FDA releases copy of FDA form 483. All 50 vials of MPA tested showed contamination (likely fungal). 74 cases, 10 deaths Vanderbilt University Vanderbilt University Medical Center Date Major Events Case Count as Known at That Time Day 48: Tuesday, Nov 6 The New England Journal of Medicine publishes an article written by TDH and CDC investigators on this outbreak. 78 cases, 13 deaths Day 51: Friday, Nov 9 TDH invited to provide testimony to the Senate HELP 81 cases, 13 deaths committee. Vanderbilt University Vanderbilt University Medical Center Lessons Learned Lessons Learned • Compounding and/or repackaging of medications must be performed safely. • Recent investments in public health infrastructure through cooperative agreements from the CDC have supported building public health capacity at the TDH. Vanderbilt University Vanderbilt University Medical Center Lessons Learned (cont’d) • Relationships with Federal partners were critical in the response to this outbreak. – CDC provided invaluable assistance throughout the outbreak including weeknights and weekends – FDA provided valuable information on local inspection findings, as well as laboratory testing of products Vanderbilt University Vanderbilt University Medical Center Lessons Learned (cont’d) • Relationships and Infrastructure Vanderbilt University Vanderbilt University Medical Center Conclusion This has been a devastating outbreak for patients, their families and friends, healthcare providers and clinics. In Tennessee we still have many patients hospitalized and suffering from complications and others who are exposed and frightened that they may become infected. Vanderbilt University Vanderbilt University Medical Center Conclusion Sustained commitment to funding for emergency preparedness and reduction of healthcare associated infections through cooperative agreements from the CDC has supported our productive relationships with our partners and healthcare providers across the state. Vanderbilt University Vanderbilt University Medical Center Conclusion These pre-existing relationships allowed us to respond quickly because we trusted each other. We all need to work together to do our best to prevent such a tragedy from occurring again and to ensure that we have the public health capacity to detect and rapidly respond to any future outbreaks. Vanderbilt University Vanderbilt University Medical Center Legal and Risk Management Considerations • Searching for product in our facility and affiliates – NECC – Ameridose • Potential medical malpractice claims • Case Study Publication – Communication with family – Manuscript review Vanderbilt University Vanderbilt University Medical Center Legal and Risk Management Considerations • Patient notification – Obligations vs. proactive management • Compounding issues – Initial – Ongoing • Insurance coverage limits – how much is appropriate? Vanderbilt University Vanderbilt University Medical Center Additional Legal Issues • HIPAA issues – Public Health Exception – Review prior to NEJM case study publication • Privacy Issues • Balancing Possible liability vs publication/1st Amendment considerations – Press inquiries – local and national Vanderbilt University Vanderbilt University Medical Center Additional Legal Issues (cont’d) • Relationships with Third Parties – – – – Pharmacies Partnerships Holding out to public Branding, reputational risk Vanderbilt University Vanderbilt University Medical Center Vanderbilt University Vanderbilt University Medical Center Additional Legal Issues (cont’d) • Regulatory Issues with Compounding Pharmacies, in-house compounding • Duty of Due Diligence for Purchasing from Compounding Pharmacies – a new standard? Vanderbilt University Vanderbilt University Medical Center Vanderbilt University Vanderbilt University Medical Center Additional Legal Issues (cont’d) • FDA Oversight / State Law Vanderbilt University Vanderbilt University Medical Center Vanderbilt University Selected Pharmacy Sterile Compounding Misadventures Year State Description 1990 Nebraska 4 patients died of a bacterial infection from non-sterile cardioplegia solution compounded in a hospital 1990 Pennsylvania 2 patients lost their vision after becoming infected by Pseuomonas aeruginosa found in indomethacin eye drops compounded in a drug store even though commercial non-steroidal drops were available at the time 1998 California 11 children became septic – 10 tested positive for Enterobacter cloacae blood-stream infections associated with contaminated prefilled saline syringes 2001 California 11 patients contracted Serratia marcescens infections following the injection of betamethasone compounded at a community pharmacy 2001 Missouri 4 children contracted Enterobacter cloacae infections from IV ranitidine compounded in a hospital pharmacy 2002 North Carolina South Carolina 5 patients developed Exophiala infections from contaminated injectable methylPREDNISolone prepared by a compounding pharmacy; one patient died 2002 Michigan Pharmacy preparing injectable methylPREDNISolone and baclofen recalled the products because of contamination with Penicillium mold, Methylobacterium, and/or Mycobacterium chelonae 2003 Missouri Bacteria contamination with Burkholderia cepacia found in at least 2 batches of a compounded inhalant solution used by 19,000 patients with chronic lung diseases 2004 Texas, New York, Michigan, Missouri 36 patients developed Pseudomonas bloodstream infections after receiving heparin/saline flushes from multiple lots of preloaded syringes 2005 New Jersey, California Up to 25 patients contracted Serratia marcescens infections due to contaminated magnesium sulfate minibags prepared by a compounding pharmacy 2005 Minnesota 2 patients were blinded after receiving a compounded trypan blue ophthalmic injection contaminated with Pseudomonas aeruginosa and Burkholderia cepacia Vanderbilt University Vanderbilt University Medical Center Selected Pharmacy Sterile Compounding Misadventures Year State Description 2005 California Sterile talc vials with unwashed stoppers were not sterility tested before distribution from a compounding pharmacy 2005 Maryland 10 patients died after exposure to cardioplegia solution from 2 lots contaminated with gram-negative rods 2006 Nevada 1 baby died from a 1,000-fold zinc overdose (mcg and mg zinc sulfate confused) compounded in a hospital pharmacy 2006 Ohio 1 child died after a compounding error led to administration of chemotherapy in 23.4% sodium chloride injection instead of 0.9% sodium chloride 2007 Washington, Oregon 2, possibly 3, patients died after receiving an IV colchicine product compounded at a concentration higher than standard (4 mg/ml. vs. 0.5 mg/ml) in a compounding pharmacy 2009 Florida 21 horses died after receiving a compounded vitamin supplement containing vitamin B, potassium, magnesium, and selenium (product not approved in the US) 2010 Illinois 1 child died after receiving more than 60 times the amount of sodium chloride prescribed due to a compounding error in a hospital pharmacy 2011 California, Florida, Tennessee 16 patients being treated for wet macular degeneration developed severe eye infections due to contamination of AVASTIN (bevacizumab) during compounding; one patient lost vision, another patient developed a brain infection 2011 Alabama 9 patients among 19 died when parenteral nutrition solutions were contaminated with Serratia marcescens during compounding using non-sterile components to prepare amino acids in a compounding pharmacy 2012 California 9 patients developed fungal endophthalmitis after use of the compounded product Brilliant Blue-G (BBG) or receiving injections of triamcinolone-containing products dispensed from the same compounding pharmacy 2012 Nationwide More than 200 patients contracted fungal meningitis after receiving methlyPREDNISolone acetate injection prepared by a compounding pharmacy that was contaminated with Exserohilum (a brown-black mold) and Aspergillus species Vanderbilt University Vanderbilt University Medical Center Additional Legal Issues (cont’d) • Informed Consent – Duty to inform patients drugs obtained from compounding pharmacy? • Plethora of Plaintiff Attorney Advertisements / Websites Vanderbilt University Vanderbilt University Medical Center Vanderbilt University Vanderbilt University Medical Center