Compounding Pharmacies

Meningitis outbreak shines light on compounding pharmacies

BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e7432 (Published 5 November 2012)
Cite this as: BMJ 2012;345:e7432

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British Medical Journal

Re: Meningitis outbreak shines light on compounding pharmacies

Response to Shaughnessy (1) (BMJ Article)

In his November 2012 BMJ article (1) regarding iatrogenic infections caused by compounding pharmacies, Allen Shaughnessy reports “In the past year …… two deaths in Alabama are alleged to have occurred due to contaminated intravenous nutritional supplements provided by a compounding pharmacy.”

In fact, nine deaths occurred among 19 patients who developed Serratia marcescens bacteremia in six Alabama hospitals that were infusing contaminated total parenteral nutrition [TPN] solutions produced by a compounding pharmacy. (2-6)

Initially, during March 2011, five Serratia bloodstream infections were identified among patients receiving TPN at one Alabama hospital. Receipt of TPN from a single compounding pharmacy was identified as a common source. An investigation was conducted by the Food and Drug Administration [FDA], the Centers for Disease Control and Prevention [CDC], and the Alabama state department of health. A total of 19 case-patients (age range 38 to 94 years) from six hospitals were identified from 1/24/2011 to 3/14/2011. There were nine fatalities. The attack rate among adult TPN recipients for development of Serratia bacteremia was 35%.

Investigation of the pharmacy’s process for producing TPN solutions resulted in identification of multiple breaches involving compounding and sterilizing amino acids for TPN formulations: prolonged periods between compounding and sterilization (amino acids were mixed in water as early as 1-2 days prior to filtration); failure to pre-filter particulate matter out of solution; excessive particulate matter in the pre-filtered solution caused a reduction in flow across the 0.2 micron filter membrane, necessitating replacement of the filter anywhere from 1-5 times during the sterilization process; and, inadequate sampling for sterility testing.

Serratia marcescens was cultured from patients’ TPN bags, the amino acid mixing container, the amino acid stirrer, an open bag of L-valine amino acid powder, and a water faucet used by the pharmacy for the compounding process. Serratia marcescens isolates cultured from compounded preparations and environmental samples were indistinguishable from 14 case-patient blood isolates by pulsed-field gel electrophoresis. The investigation concluded that the pharmacy’s failure to follow recommended practices for high-risk compounding of an amino acid component of TPN resulted in the outbreak of Serratia bacteremia with a 47% fatality rate [see Table].

In April 2011, the Institute for Safe Medication Practices [ISMP] wrote the following regarding Alabama’s iatrogenic Serratia bacteremia outbreak:
“Any type of sterile compounding activities must be undertaken with great care and in compliance with the United States Pharmacopeia [USP] Chapter <797>. It is tragic events like this that compelled USP to first establish <797> …… Chapter <797> describes a network of systems and processes to prevent patient harm and fatality from microbial contamination and excessive bacterial endotoxins in compounded sterile preparations …… As we move forward and learn from this most recent (Alabama) outbreak, we are calling upon all state boards of pharmacy to expect compounding pharmacies to comply with all aspects of <797>, and to survey these pharmacies regularly to enforce compliance.” (7) In October 2011, Gupta and colleagues at the CDC underscored that in order to avoid similar outbreaks, pharmacies must understand and adhere to current guidelines for compounding sterile preparations. (4)

Despite an unprecedented decade-long [2001-2011] cascade of iatrogenic bacterial and fungal infection outbreaks (8-9) that generated numerous pleas for compounding-sterility-compliance, year 2012 would nevertheless proceed to be plagued by yet additional contamination outbreaks caused by compounding pharmacies: the 9-state 43-case outbreak of post-procedural fungal endophthalmitis (10) , and the ongoing 19-state outbreak of fungal infections [meningitis, stroke, paraspinal/spinal, peripheral joint] that has sickened 620 patients and caused 39 deaths as of 17 December 2012. (11-12)

Abe M. Macher M.D.
Volunteer Educator for the American Jail Association
Retired 30-year Veteran of the U.S. Public Health Service
Rockville, Maryland, USA
abemacher@hotmail.com

References

[1] Shaughnessy AF. Meningitis outbreak shines light on compounding pharmacies. BMJ 2012;345:e7432.

[2] Weber T. Update on DHQP’s response support to recent outbreak investigations. Health Care Infection Control Practices Advisory Committee Meeting. 14-15 June 2012, Atlanta. Division of Healthcare Quality Promotion (DHQP), National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention. Pages 27-28.

[3] Gupta N, Hocevar S, O’Connell H, Stevens K, Massingale S, McIntyre M, et al. Serratia marcescens bloodstream infections in patients receiving total parenteral nutrition --- Alabama, 2011. 61st Annual Epidemic Intelligence Service (EIS) Conference. Atlanta, 16-20 April 2012. Abstract, April 19, Page 117.

[4] Gupta N, Hosevar SN, O’Connell H, Stevens KM, McIntyre MG, Kuhar DT, et al. Investigation of an outbreak of Serratia marcescens bloodstream infections in patients receiving total parenteral nutrition --- Alabama, 2011. Annual Meeting of the Infectious Disease Society of America. Boston, 20-23 October 2011. Poster Presentation 617, 21 October 2011.

[5] McIntyre M. CDC and ADPH continue investigation of outbreak linked to TPN. Alabama Department of Public Health News Release, 30 March 2011. Available at www.adph.org. Accessed 17 December 2012.

[6] Food and Drug Administration (FDA). Warning Letter [No. 2012-NOL-15] to Advanced Specialty Pharmacy dba Meds IV. Inspections, Compliance, Enforcement, and Criminal Investigations (FDA). 16 March 2012. Available at www.fda.gov. Accessed 17 December 2012.

[7] Institute for Safe Medication Practices (ISMP). TPN-related deaths call for FDA guidance and pharmacy board oversight of USP <797>. ISMP Medication Safety Alert ! (Acute Care Edition). 7 April 2011. Available at www.ismp.org. Accessed 17 December 2012.

[8] Institute for Safe Medication Practices (ISMP). Sterile compounding tragedy is a symptom of a broken system on many levels. ISMP Medication Safety Alert ! (Acute Care Edition). 2012;17(21):1-4.

[9] Macher AM. Iatrogenic fungal meningitis outbreak of 2002. Annals of Internal Medicine. Letter-to-the-Editor. In press. [Published Online, 20 November 2012 and 5 December 2012, as Comment on “Iatrogenic fungal meningitis: Tragedy repeated”, Perfect JR, Annals of Internal Medicine, 2012;157(11):825-826 --- Epub ahead of print 18 October 2012].

[10] Centers for Disease Control and Prevention (CDC). Notes from the field: Multistate outbreak of postprocedural fungal endophthalmitis associated with a single compounding pharmacy --- United States, March-April 2012. MMWR Morb Mortal Wkly Rep 61(17):310-311.

[11] Centers for Disease Control and Prevention (CDC). Multistate outbreak of fungal infection associated with injection of methylprednisolone acetate solution from a single compounding pharmacy --- United States, 2012. MMWR Morb Mortal Wkly Rep 2012 Oct 19;61:839-842.

[12] Centers for Disease Control and Prevention (CDC). Multistate fungal meningitis outbreak --- Current case count. 17 December 2012. Available at www.cdc.gov/hai/outbreaks/meningitis-map.html. Accessed 17 December 2012.

Table:

Serratia Bacteremia and Fatalities among 19 Patients at 6 Alabama Hospitals: Contaminated Compounded TPN --- January-March 2011 (Reference 5)

• Baptist Princeton
o 7 cases
o 4 deaths

• Baptist Shelby
o 5 cases
o 2 deaths

• Medical West
o 3 cases
o 1 death

• Select Specialty Hospital of Birmingham
o 2 cases
o 1 death

• Baptist Medical Center Prattville
o 1 case
o 1 death

• Cooper Green Mercy
o 1 case
o no deaths

Competing interests: None declared

Abe M. Macher, Retired Clinical Pathologist, 30-year veteran of the U.S. Public Health Service

Volunteer Educator for the American Jail Association, 10301 Grosvenor Place, Rockville MD 20852 USA

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Compounding Pharmacies is a scientific procedure as old as history of mankind. Poison may be added in compounding as it may in manufacturing. England, USA or India may not be the exceptions: it is possible everywhere in the world where people live and need medicine for relief and cure from disease.

The findings of Allen F Shaughnessy brought to light the fact that film recording and countercheck mechanisms since not applied to poison in dispensed medicine may not detect it till injury or death suffered by the patient. Author is right that there must be some mechanism to test and film the material, methods, dispensing and results since it relates to precious human life. Random sampling, likewise, for film recorded drug safety analysis or tests sounds good to check for poisonous ingredients. And provision of appropriate compensation to those injured or diseased by erroneously compounded or manufactured medicine or medical device must be there and applied bya non-medical and unrelated and removed judicial apparatus.

Competing interests: None declared

Mohammed Naim, Professor, Pathology

JNMC AMU Aligarh India, JNMC AMU Aligarh 202002 India

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While the world debates the pros and cons of compounding pharmacies, there is another form of compounding which takes place commonly at least in India.

Many doctors (some of them quacks) run their own pharmacy where mixtures for common conditions like fever, cough etc. are made and sold to patients. Often such mixtures are a combination of some antibiotic with analgesic and corticosteroid.

The perils are obvious!

Competing interests: None declared

Sandeep Saluja, PHYSICIAN

Saran Ashram, DAYALBAGH

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