E-mail: cdcinfo@cdc.gov Web: www.cdc.govThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. CS227550-A

National Center for Emerging and Zoonotic Infectious DiseasesDivision of Healthcare Quality Promotion

SummaryFigure 7. Summary of the TPN compounding process highlighting areas of contamination with Serratia

marcescens — Pharmacy A, Alabama

Epidemiologic Investigation

� 19 case-patients were identified among patients receiving TPN from Pharmacy A in 2011; 17 of these cases occurred from March 5th – 12th.

� Cases were identified from all six hospitals receiving TPN from Pharmacy A. � S. marcescens BSIs occurred in only adult recipients of TPN.

Pharmacy A Investigation � Pharmacy A recently began compounding and sterilizing amino acids for use in adult TPN preparations. � Multiple breaches were discovered in this process: prolonged periods between compounding and

sterilization, failure to pre-filter particulate matter out of solution, replacement of the filter during sterilization, and inadequate sampling for sterility testing.

Laboratory Investigation � S. marcescens was identified from several compounded preparations and environmental samples

obtained from Pharmacy A, including equipment used to compound amino acids. � All isolates were genetically related to clinical isolates obtained from 14 case-patients by PFGE.

Background � Serratia marcescens is a gram-negative bacteria that is ubiquitous in the environment and is a

known cause of health care-associated infections. � Multiple outbreaks of S. marcescens bloodstream infections (BSIs) have resulted from contamination

of pharmacy-compounded preparations. � Total parenteral nutrition (TPN), which requires compounding under highly sterile conditions, is a

nutrient-rich preparation which can act as favorable growth media for microorganisms. � In March 2011, an unusual cluster of S. marcescens BSIs was reported among TPN recipients in one

hospital; an investigation was initiated by the Alabama Department of Public Health.

Figure 1. Timeline of the outbreak of Serratia marcescens bloodstream infections in Alabama — March 2011

MethodsCase Definition:

� S. marcescens BSI occurring in patients receiving TPN from Pharmacy A between January 1, 2011 and March 15, 2011.

Case Finding: � Healthcare facilities receiving TPN from Pharmacy A were contacted and interviewed. � Hospital pharmacy and microbiology records were reviewed to identify cases.

Case Review: � Clinical and microbiology records of cases were reviewed to assess risk factors and describe clinical

outcomes.

Pharmacy A Investigation: � On-site assessment of the pharmacy. � Detailed interviews with pharmacy staff. � Direct observation of TPN compounding.

Laboratory Methods: � Bacterial cultures: TPN preparations, TPN ingredients, environmental samples from Pharmacy A. � S. marcescens isolates obtained from clinical cultures, environmental cultures, and TPN preparations

were tested for genetic relatedness using pulsed-field gel electrophoresis (PFGE).

Investigation Objectives � To determine the extent of the outbreak of S. marcescens BSIs � To review the role of pharmacy-compounded TPN in the outbreak � To review TPN compounding practices at Pharmacy A and identify potential sources of

contamination

Limitations � Pharmacy A was not in operation at the time of investigation; information obtained through interviews

and an on-site assessment may not accurately reflect prior practice. � It is difficult to assess the degree of contribution of S. marcescens infection to the morbidity and mortality

of patients with multiple underlying illnesses.

ResultsEPIDEMIOLOGIC INVESTIGATION

Figure 2. TPN Customers of Pharmacy A — 2011

Table 1. Characteristics of patients with S. marcescens BSIs among TPN recipients of Pharmacy A — January 1, 2011 to March 15, 2011

Number of cases 19Number of healthcare facilities 6Age in years

Median 56(Range) (38-94)

SexFemale 11Male 8

Higher level of care* 11Deaths 9

*Higher level of care required as a result of Serratia infection

Figure 3. Epidemic curve of Serratia macescens bloodstream infections among patients in hospitals receiving total parenteral nutrition (TPN) from Pharmacy A,

by TPN status — April 2010 to March 2011

Table 2. Attack Rates Among Patient Receiving TPN from Pharmacy A — March 1 − March 15, 2011

Number of S. marcescens BSIs

Number of Patients Receiving TPN Attack Rate

Neonates 0 7 0%*Adults 17 41 41%Overall 17 48 35%

Only adult patients became infected with S. marcescens; this finding helped inform the on-site investigation of Pharmacy A.

Investigation of an Outbreak of Serratia marcescens Bloodstream Infections in Patients Receiving Total Parenteral Nutrition — Alabama, 2011Neil Gupta, MD1,2, Susan N. Hocevar, MD1,2, Heather O’Connell, PhD2, Kelly M. Stevens, MS3, Mary G. McIntyre, MD, MPH3, David T. Kuhar, MD2, Judith Noble-Wang, PhD2, Alexander J. Kallen, MD, MPH2

1Epidemic Intelligence Service, Atlanta, Georgia, 2Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, 3Alabama Department of Public Health, Montgomery, Alabama

March 2011

March 5th–12th

Five patients in one Alabama hospital develop

S. marcescens bloodstream infections

March 14th –15th

Infection preventionist recognizes cluster; total parenteral nutrition (TPN) from a single compounding pharmacy (Pharmacy A) identified as a common exposure.

Pharmacy A notified about cases. Compounding held and TPN bags tested. Customers (healthcare facilities) notified.

March 18th–21st

Contact made with additional facilities receiving TPN from

Pharmacy A. At least 11 additionalS. marcescens

BSIs identified

March 16th–17th

Local/ state public health authorities and CDC notified.

Public health investigation begins

March 22nd

CDC team arrives in the field to assist Alabama Dept. of Public Health with

investigation.

Conclusions and Recommendations � High-risk compounding of an amino acid component of TPN was initiated due to a national shortage. � Failure to follow several recommended practices resulted in an outbreak of S. marcescens BSIs with a 47%

fatality rate among case-patients. � Clinician awareness made an important contribution to outbreak detection and response. � Tap water was the likely source of introduction of S. marcescens and deviation from United States

Pharmacopeia 797 standards during amino acid filtration likely led to subsequent contamination of TPN at Pharmacy A.

� In order to prevent similar outbreaks from occurring in the future, pharmacies must understand and conform to current standards for compounding sterile preparations, particularly in the face of drug shortages.

PHARMACY A INVESTIGATIONPharmacy A Description:

� Established in 2005; registered with the AL Board of Pharmacy & DEA � Compounding of multiple preparations, including TPN, cardioplegia,

electrolytes, and antimicrobials � Most TPN ingredients were provided in sterile, manufacturer-provided

containers. However, few ingredients were sterilized on-site at the facility. One of these ingredients was a 15% amino acid solution

Amino acids:

� October 2010 — national shortage in amino acid supply used in adult TPN preparations

� Pharmacy A responded by compounding and sterilizing amino acids on-site at the facility using a 0.2µm filter

Figure 4. Process for compounding the 15% amino acid solution — Pharmacy A, Alabama

Nonsterile, bulk amino acid powders (left) were compounded in sterile water in a 100L-mixing container (right). Batches of 80–100 liters were made at one time. Following compounding, amino acids were sterilized via filtration.

Figure 5. Process for sterilizing the 15% amino acid solution by filtration — Pharmacy A, Alabama

The 100 L-mixing container was brought in to the clean room for sterilization. A peristaltic pump was used to move the solution through the 0.2µm capsule filter. The solution was filtered in to 2 or 3L sterile bags until the entire 80–100L batch of amino acids was filter-sterilized.

Observations during amino acid filtration

� On occasion, amino acids were mixed in water >6 hours prior to sterilization, sometimes as early as 1–2 days prior to filtration.

� Excessive particulate matter was noted in the pre-filtered solution. This caused a reduction in flow across the filter membrane, necessitating replacement of the filter anywhere from 1-5 times during the sterilization process.

� Two syringes containing 10–12 mL each of the sterilized solution were set aside for sterility testing.

� Following filtration, the 100 L-mixing container was cleaned with tap water and detergent and allowed to air dry. Per report, the container was rinsed with sterile water prior to re-use.

Sterility testing:

� The majority of cases received one of two amino acid lots in the days prior to their S. marcescens infections.

� Both lots were positive for endotoxin; one significantly above the established limit (0.2 EU/mg).

� Both lots underwent sterility testing and were reported as ‘sterile.’ However, less than 25 mL of each 80–100L lot were tested.

� Amino acids were already used in TPN preparations prior to the laboratory reports of endotoxin and sterility testing results.

LABORATORY INVESTIGATIONTable 3. Microbiological results of environmental samples and compounded

preparations from Pharmacy A

Specimen description Culture resultTPN bags (non-case patients; 3 tested) S. marcescens not foundTPN bags (case-patients; 4 tested) S. marcescens (3 of 4)TPN test bags (2 tested) S. marcescens (2 of 2)Amino acid lot (Pharmacy A) S. marcescensAmino acid mixing container S. marcescensAmino acid stirrer S. marcescensL-Valine powdered solid* S. marcescensTap water faucet (anteroom) S. marcescensMixed water from tap (anteroom) S. marcescens not foundHandsoap, detergent (anteroom) S. marcescens not foundDistilled water, sterile water S. marcescens not foundPhone, clock radio (clean room) S. marcescens not found

*S. marcescens was not found in any of the other 17 amino acid powders tested

Figure 6. Pulsed-Field Gel Electrophoresis (PFGE) results of S. marcescens isolates

obtained during the outbreak investigation

Hospital Q (Prattville)

Hospital S (Alabaster)

Hospital W (Bessemer)

Hospital G (Birmingham)

Hospital L(Birmingham)

Hospital P (Birmingham)

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6

8

10

12

14

16

18

20

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TPN

No TPN

100 L Mixing Container

PeristalticPump

0.2µm Capsule Filter

2–3 Liter Sterile Bag

100

8060

100

96.6

100

61.3

60.2

52.8

44.9

Patient G01

TPN bag 1TPN bag 2

Amino acid solution

Patient W01Patient W03Patient P04Non-TPN related Serratia

Patient P06Patient P03Patient P05Patient P02Patient P07Patient S03Patient S01Patient S02Patient S05Patient S04

TPN from patient S04TPN from patient S02 TPN from patient P06TPN from patient S04

Amino acid stirrerAmino acid mixing containerAnteroom tap faucetL-valine

Unrelated Serratia #1Unrelated Serratia #2Unrelated Serratia #3Unrelated Serratia #4

Contact InformationNeil Gupta, MD Epidemic Intelligence Service Officer

LCDR, U.S. Public Health Service Prevention and Response Branch

Division of Healthcare Quality Promotion Centers for Disease Control and Prevention

1600 Clifton Road NE, MS A-35 Phone: (404) 639-4000

Fax: (404) 639-2647 Email: Ngupta1@cdc.gov