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Published Date: 2002-12-12 23:50:00
Subject: PRO> Fungal meningitis, contaminated drug - USA (03)
Archive Number: 20021212.6046

FUNGAL MENINGITIS, CONTAMINATED DRUG - USA (03)
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International Society for Infectious Diseases
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Date: 12 Dec 2002
From: ProMED-mail <promed@promedmail.org>
Source: MMWR 13 Dec 2002 51(49);1109-1112 [edited]
<http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5149a1.htm>

_Exophiala_ Infection from Contaminated Injectable Steroids Prepared
by a Compounding Pharmacy - United States, July - November 2002
----------------------------------------
In the USA, pharmacists compound medications to meet unique patient
drug requirements or to prepare drug products that are not available
commercially (1). In September 2002, the North Carolina Division of
Public Health (NCDPH) was notified of 2 cases of meningitis caused by
a rare fungus in patients who had received epidural injections at
outpatient pain management clinics. This report describes 5 cases of
fungal infection associated with contaminated drugs prepared at a
compounding pharmacy. Clinicians should consider improperly
compounded medications as a possible source of infection in patients
after epidural or intra-articular injections.
Case Reports
Case 1. On 5 Jul 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 (100.4 F [38.0 C]) and had slight nuchal rigidity. Analysis
of cerebrospinal fluid (CSF) was consistent with meningitis: 979
white blood cells (WBC)/mm3 (normal: <10 WBC/mm3) with 63 percent
neutrophils, protein of 134 mg/dL (normal: 15-45 mg/dL), and glucose
of 38 mg/dL (normal: 40-80 mg/dL).
The patient showed no improvement on antibacterial drugs, and a
follow-up CSF analysis on 18 Jul 18 2002 revealed yeast-like elements
on microscopic examination. The patient was treated with amphotericin
B and transferred to hospital B in North Carolina. On 24 Jul 2002, a
fungus cultured from 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.
The patient 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.
Case 2. On 14 Aug 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 (820 WBC/mm3 with 52 percent neutrophils, protein of 108
mg/dL, and glucose of 57 mg/dL). The patient had a 3-5 day history of
mild headache, subjective fever, chills, sweats, and mild neck
stiffness. The patient 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. CSF 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 5 Dec (70 days into therapy), her condition had improved.
Additional cases: Clinicians from hospital A notified 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 8 Jul
2002 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 8 Oct
2002 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 4
Nov 2002 and had received intra-articular methylprednisolone acetate
injections at pain management clinic B 103 and 152 days before
hospitalization.
Investigation of Compounding Pharmacy A
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 MedrolÆ,
Pharmacia Corp., Peapack, New Jersey) 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 as outlined in the American
Society of Health-System Pharmacists (ASHP) guidance for
pharmacy-prepared sterile products (2).
Microbiologic culture at 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 27 Sep 2002, 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, and 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 15 Nov 2002, based on
the lack of assurance that the pharmacy's products were sterile, FDA
announced a nationwide alert about all injectable drug products
prepared by the pharmacy.
All sites that received injectable methylprednisolone prepared by
compounding pharmacy A have been contacted and have returned all
unused products for testing. Treating clinicians were informed of the
investigation of the adulterated product. In 2 states, patients who
might have received the product were sent letters directing them to
seek medical attention if they developed symptoms, and laboratories
were instructed to notify state officials if they isolated _E.
dermatitidis_ from clinical specimens.
[MMWR] Editorial Note:
As of 5 Dec 2002, 5 cases of _Exophiala_ infection associated with
injectable medication from compounding pharmacy A had occurred. Cases
occurred up to 152 days following an injection.
Pharmacy compounding is the process of combining drug ingredients to
prepare medications that are not commercially available or to alter
commercially available medications to meet specific patient needs
such as dye-free or liquid formulations (3). The practice of
compounding has been reported to be increasing, with an estimated 43
000 compounded medications prepared daily in the United States (4,5).
Pharmacists traditionally have prepared medications to fulfill
individual prescription requests or manipulated reasonable quantities
of human drugs on receipt of a valid prescription for an individually
identified patient from a licensed practitioner. Some compounding is
legal under state laws, and, when appropriate, FDA can exercise its
enforcement discretion regarding new drugs and certain other
requirements of the federal Food, Drug, and Cosmetic Act (6).
On-site investigation of compounding pharmacy A by state and federal
regulators identified several instances of nonadherence to sterile
technique. Microbiologic cultures at CDC and FDA of
methylprednisolone from unopened vials prepared by compounding
pharmacy A yielded isolates of _E. dermatitidis_. This fungus caused
the death from meningitis in one patient, sacroiliitis in another,
and meningitis in 3 other patients who had received either epidural
or intra-articular injections of methylprednisolone compounded at
pharmacy A. Other recent clusters of infections associated with
products prepared by compounding pharmacies include _Serratia_
meningitis from epidural injections of betamethasone in California
(Contra Costa Health Services, unpublished data, 2002) and
_Chryseomonas_ meningitis from epidural injections of
methylprednisolone in Michigan (CDC, unpublished data, 2002). These
meningitis clusters all occurred among patients who received epidural
injections for chronic pain management.
_E. dermatitidis_ is a neurotropic, dark pigment-forming fungus found
in soil and is an uncommon cause of human illness (7). Limited data
are available on treatment; however, in vitro data suggest that
amphotericin B, itraconazole, terbinafine, and voriconazole might be
effective (8). Isolates from 4 of the 5 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 Exophiala should
determine whether the patient had received injections of
methylprednisolone in the last 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. Patients with possible injection-associated Exophiala
infections should be reported to their state health department and to
CDC, telephone 800-893-0485; such information should be exchanged
rapidly with other state and local health departments. Clinicians
should consider the possibility of contaminated medication as a
source of infection in patients after epidural or intra-articular
injections. Compounding pharmacies should ensure that pharmacy staff
are trained appropriately and that proper sterile technique is
followed in accordance with existing standards from ASHP (2) and the
United States Pharmacopeia (<http://www.usp.org>). FDA has outlined
specific activities that help distinguish the role of compounding
pharmacies from that of pharmaceutical manufacturing (4).
Some health-system pharmacists might not realize that they are
purchasing injectables prepared through compounding (1). Purchasers
of pharmaceuticals should determine whether 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 FDA is required for
pharmaceutical manufacturing companies. Health-care professionals and
compounding pharmacies are urged to report contaminated compounded
drug products or adverse events associated with compounded drug
products to their state boards of pharmacy and health departments. To
help prevent further cases, practitioners also are encouraged to
submit such reports to FDA's MedWatch program by telephone at
1-800-332-1088 or at
<http://www.fda.gov/medwatch/report.htm>.
References
1.Young D. Outsourced compounding can be problematic: community
pharmacies linked to contaminated injectables. Available at
<http://www.ashp.org/public/pubs/ajhp/current/12a-news_oursourced.pdf>.
2.American Society of Health-System Pharmacists. ASHP guidelines on
quality assurance for pharmacy-prepared sterile products. Am J Health
Sys Pharm
2000; 57:1150-69.
3.International Academy of Compounding Pharmacists. About
compounding. Available at:
<http://www.iacprx.org/about_compounding/index.html>.
4.Smith LK. Regulatory and operational issues of founding a
compounding pharmacy. International Journal of Pharmaceutical
Compounding 2002;6:434-7.
5.Professional Compounding Centers of America. History of
compounding. Available at
<http://www.pccarx.com/about_comp.asp>.
6.U.S. Food and Drug Administration. Compliance policy guidance for
Food and Drug Administration staff and industry. Section 460-200,
pharmacy compounding. Available at
<http://www.fda.gov/ora/compliance_ref/cpg/cpgdrg/cpg460-200.html>.
7.Matsumoto T, Matsuda T, McGinnis MR, Ajello L. Clinical and
mycological spectra of Wangiella dermatitidis infections. Mycoses
1993;36:145-55.
8.Meletiadis J, Meis JF, de Hoog GS, Verweij PE. In vitro
susceptibilities of 11 clinical isolates of Exophiala species to six
antifungal drugs. Mycoses 2000;43:309-12.
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