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On July 5, 2002, a woman aged 77 years with chronic low back pain was admitted to hospital A in North Carolina with a 4-day history of progressive diffuse headache, fever, chills, and malaise with subsequent development of vertigo, nausea, and vomiting. She was febrile (38.0 °C) and had slight nuchal rigidity. Analysis of the cerebrospinal fluid (CSF) was consistent with meningitis. The patient showed no improvement while taking antibacterial drugs, and a follow-up CSF analysis on July 18 revealed yeast-like elements on microscopic examination. The woman was treated with amphotericin B and transferred to hospital B in North Carolina. On July 24, a fungus cultured from the CSF was identified as Exophiala (Wangiella) dermatitidis. Amphotericin B was discontinued, and voriconazole and flucytosine were started. The patient's condition continued to deteriorate, and she died 51 days after hospitalization. She had been treated at pain management clinic A in North Carolina and had received lumbar epidural injections with methylprednisolone acetate 100 and 35 days before hospital admission. The injectable methylprednisolone had been prepared by compounding pharmacy A in South Carolina.
On August 14, 2002, a woman aged 61 years who was being treated for chronic low back pain at pain management clinic A was admitted to hospital A after CSF obtained during a myelogram was consistent with meningitis. The patient had a 3- to 5-day history of mild headache, subjective fever, chills, sweats, and mild neck stiffness. She had received lumbar epidural injections at pain management clinic A 84 and 34 days before hospital admission. The injections contained methylprednisolone acetate prepared by compounding pharmacy A. A CSF culture grew yeast, later identified as E. dermatitidis, 27 days after collection. The patient was begun on intravenous voriconazole and later switched to oral voriconazole; as of December 5 (70 d into therapy), her condition had improved.
Clinicians from hospital A notified the NCDPH of the 2 cases of E. dermatitidis meningitis; 3 additional cases have been identified. Case 3 occurred in a woman aged 71 years who had E. dermatitidis meningitis. She was admitted to hospital B in North Carolina on July 8 and had received epidural methylprednisolone acetate injections at pain management clinic B 82, 55, and 35 days before hospitalization. Case 4 occurred in a woman aged 65 years who had E. dermatitidis meningitis. She was admitted to hospital C in North Carolina on October 8 and had received epidural methylprednisolone acetate injections at pain management clinic A 116 days before hospitalization. Case 5 occurred in a woman aged 52 years who had E. dermatitidis sacroiliitis. She was admitted to hospital D in North Carolina on November 4 and had received intraarticular methylprednisolone acetate injections at pain management clinic B 103 and 152 days before hospitalization.
Compounding pharmacy A was the source of the methylprednisolone acetate administered to all 5 patients with exophiala infections. The pharmacy had been supplying the compounded product to hospitals and pain management clinics in 5 states after a proprietary form of methylprednisolone acetate injectable suspension (Depo Medrol, Pharmacia Corp., Peapack, NJ) became difficult to obtain from the manufacturer. An investigation of compounding pharmacy A by the South Carolina Board of Pharmacy (SCBP) found improper performance of an autoclave with no written procedures for autoclave operation, no testing for sterility or appropriate checking of quality indicators, and inadequate clean-room practices. Microbiologic culture at the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) of unopened vials from 3 separate lots of injectable methylprednisolone obtained from compounding pharmacy A yielded E. dermatitidis. On September 27, the SCBP ordered the pharmacy to halt further sale of compounded drug products. Injectable drugs had been distributed to physicians, hospitals, clinics, and consumers in 11 states (Connecticut, Illinois, Indiana, Kentucky, Louisiana, Massachusetts, Mississippi, New Hampshire, North Carolina, South Carolina, Virginia). FDA inspection of the compounding facility revealed that the firm failed to have adequate controls to ensure necessary sterility, including the absence of appropriate testing for potency and sterility before distribution. On November 15, based on the lack of assurance that the pharmacy's products were sterile, the FDA announced a nationwide alert about all injectable drug products prepared by the pharmacy.
E. dermatitidis is a neurotropic, dark pigment-forming fungus found in soil and is an uncommon cause of human illness. Limited data are available on treatment; however, in vitro data suggest that amphotericin B, itraconazole, terbinafine, and voriconazole might be effective. Isolates from 4 of the infected persons reported were tested in vitro and were susceptible to voriconazole, itraconazole, and amphotericin B. Voriconazole was chosen for treating the 5 persons reported because of in vitro susceptibility results and availability of an oral form of the drug.
Clinicians or laboratorians diagnosing any cases of E. dermatitidis should determine if the patient had received injections of methylprednisolone in the past year. Although the implicated product has been recalled, clinicians should be aware that cases might still occur because of the possible long incubation period of the fungal infection.
Some health-system pharmacists might not realize that they are purchasing injectables prepared through compounding. Purchasers of pharmaceuticals should determine if supplies are provided from a compounding pharmacy that is licensed in their state and that follows appropriate measures to ensure that injectable products are free of contamination. In most states, compounding pharmacies are not required to report adverse events associated with their products to state or federal agencies. Such reporting to the FDA is required for pharmaceutical manufacturing companies. (MMWR 2002;51:1109-12)
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