1 figure omitted
In the United States, 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 two cases of meningitis caused by a
rare fungus in patients who had received epidural injections at outpatient
pain management clinics. This report describes five cases of fungal infection
associated with contaminated drugs prepared at a compounding pharmacy. Clinicians
should consider the possibility of improperly compounded medications as a
source of infection in patients after epidural or intra-articular injections.
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 (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% 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 July
18 revealed yeast-like elements on microscopic examination. The patient was
treated with amphotericin B and transferred to hospital B in North Carolina.
On July 24, 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.
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 (820
WBC/mm3 with 52% 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 December
5 (70 days into therapy), her condition had improved.
Additional cases. Clinicians from hospital A notified NCDPH of the two
cases of E. dermatitidis meningitis; three 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 intra-articular 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 five patients with Exophiala infections.
The pharmacy had been supplying the compounded product to hospitals and pain
management clinics in five states after a proprietary form of methylprednisolone
acetate injectable suspension (Depo Medrol®, 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 three separate lots of injectable methylprednisolone
obtained from compounding pharmacy A yielded E. dermatitidis. On September 27, 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 November 15, 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 two 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.
J Engemann, MD, K Kaye, MD, G Cox, MD, J Perfect, MD, W Schell, MS,
SA McGarry, MD, Duke Univ, Durham; K Patterson, MD, S Edupuganti, MD, Univ
of North Carolina, Chapel Hill; P Cook, MD, East Carolina Univ, Greenville;
WA Rutala, PhD, DJ Weber, MD, KK Hoffmann, MS, Statewide Program in Infection
Control and Epidemiology and Univ of North Carolina, Chapel Hill; J Engel,
MD, North Carolina State Dept of Health and Human Svcs, Raleigh, North Carolina.
S Young, E Durant, K McKinnon, N Cobb, South Carolina Board of Pharmacy, Columbia;
L Bell, MD, J Gibson, MD, South Carolina Dept of Health and Environmental
Control. D Jernigan, MD, M Arduino, PhD, S Fridkin, MD, L Archibald, MD, L
Sehulster, PhD, Div of Healthcare Quality Promotion; J Morgan, MD, R Hajjeh,
MD, M Brandt, PhD, D Warnoch, PhD, Div of Bacterial and Mycotic Diseases,
National Center for Infectious Diseases; WA Duffus, MD, EIS Officer, CDC.
As of December 5, five 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 three 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 four of the five infected persons reported were tested in vitro and were
susceptible to voriconazole, itraconazole, and amphotericin B. Voriconazole
was chosen for treating the five 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 if 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 ASHP2 and the United
States Pharmacopeia (http://www.usp.org). FDA has outlined
specific activities that help distinguish the role of compounding pharmacies
from pharmaceutical manufacturing.4
Some health-system pharmacists might not realize that they are purchasing
injectables prepared through compounding.1 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 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: 8 available
Exophiala. JAMA. 2003;289(3):291-293. doi:10.1001/jama.289.3.291