BETHESDA, MD 27 October 2011—An improper filtration process let Serratia marcescens in tap water pass into two batches of pharmacy-prepared amino acid solution and then into hospital patients, a joint federal–state investigation has determined.
The amino acid solution, said Neil Gupta, an epidemic intelligence service officer with the Centers for Disease Control and Prevention (CDC), had been prepared from scratch by a compounding pharmacy that he identified only as "Pharmacy A."
He said this pharmacy "sterilized" 80- to 100-L batches of 15% amino acid solution because of a national shortage of the manufacturer-provided product. The pharmacy then incorporated its amino acid solution into adult parenteral nutrient solutions for distribution in Alabama.
In all, according to the state department of public health, the 2011 outbreak of S. marcescens bacteremia involved 19 patients at six hospitals in central Alabama: Cooper Green Mercy Hospital, Medical West, Prattville Baptist Hospital, Princeton Baptist Medical Center, Select Specialty Hospital—Birmingham, and Shelby Baptist Medical Center.
Nine of the patients died, the department said.
From tap water to bloodstream. Gupta credited an infection preventionist at one of the hospitals for recognizing five inpatients with S. marcescens bacteremia as a "cluster" that had been exposed to parenteral nutrient solutions prepared by the same pharmacy.
He said the hospital immediately notified the compounding pharmacy, which immediately contacted health care facilities that had received its parenteral nutrient solutions. The pharmacy, he said, also ceased preparing parenteral nutrient solutions.
Gupta said investigators found related S. marcescens isolates in blood samples from all of the patients who were tested and in samples from the tap water faucet that was sometimes the source of water for cleaning the 100-L container in which the nonsterile amino acid powders were mixed with sterile water.
Related isolates were also found in the 100-L mixing container itself and in samples from a batch of purportedly sterile 15% amino acid solution and three of four bags of parenteral nutrient solution that had been prepared for patients who had the bacteremia.
Deviations from standards. Gupta, speaking during a September 20 webinar presented by CDC and the United States Pharmacopeia, described four ways in which the pharmacy’s process of sterilization by filtration deviated from United States Pharmacopeia (USP) chapter 797, "Pharmaceutical Compounding—Sterile Preparations."
No prefilter. Because the pharmacy had ceased making the amino acid solution before the CDC team arrived, Gupta said, the investigators learned about the pharmacy’s procedures from interviews with personnel and observation of a pharmacist preparing a mock parenteral nutrient solution.
The personnel reported that "occasionally there was excessive particulate matter" in the 100-L container after mixing the amino acid powders with sterile water, he said.
Despite that observation, Gupta said, personnel did not place a prefilter upstream to the 0.2-µm capsule filter when attempting to sterilize the amino acid solution.
USP chapter 797 states that, when using filtration to sterilize a solution "known to contain excessive particulate matter" and that has a high potential for microbial contamination, place a "prefilter of larger-porosity membrane" upstream to the sterilizing filter. The purpose is to maximize the efficiency of the sterilizing filter.
Replacement of filter during sterilization process. Gupta said pharmacy personnel reported replacing the 0.2-µm capsule filter one to five times during the filtration of a single batch of amino acid solution. They did this, he said, because the particulate matter in the liquid slowed flow across the filter membrane.
USP chapter 797 states that the filter’s dimensions and the liquid must "permit the sterilization process to be completed rapidly, without the replacement of the filter during the process."
Delay in sterilization. Pharmacy personnel told Gupta that they occasionally mixed the amino acid powders and sterile water more than six hours—maybe as much as two days—before attempting sterilization.
USP chapter 797 states that a water-containing preparation that was nonsterile during the compounding procedure must undergo sterilization within six hours after completion of the compounding procedure. The purpose is to minimize the generation of endotoxins.
Inadequate sample sizes for sterility tests. Gupta said pharmacy personnel removed two samples, 10–12 mL apiece, from each 80–100-L batch of amino acid solution after the filtration process.
That total sample size, he said, "was grossly inadequate to detect the growth of infectious microorganisms."
According to USP chapter 797, the pharmacy-prepared 15% amino acid solution had to meet the sterility test described in chapter 71 because of the number of single-dose containers made at one time. The latter chapter specifies 2% of a batch or 10 containers, "whichever is less," as the minimum number of items to be tested.
Ramifications. Gupta’s description of the S. marcescens bacteremia outbreak matches the information in Alabama Department of Public Health press releases that identified Meds IV, in Birmingham, as the producer of the contaminated parenteral nutrient solutions.
The public health department said Meds IV recalled all its i.v. preparations on March 24, nine days after Gupta said the pharmacy first received word that its products might have contained a contaminant.
That initial communication came from Shelby Baptist Medical Center, part of Baptist Health System, hospital officials told the Shelby County Reporter.
The health system’s chief medical officer said the hospital’s infection control manager had noticed that five patients had been diagnosed with S. marcescens bacteremia in a four-day period. Further work, with the help of other staff members, quickly pointed to the parenteral nutrient solutions as a likely source of the outbreak.
Shelby Baptist, the hospital’s president told the newspaper, had been doing business with Meds IV "for more than 10 years" without any quality-related issues.
Baptist Health, through its communications office, had no comment for this AJHP news story.
Six of the nine people who died in the outbreak were patients at hospitals in the health system, the state public health department has reported.
According to James S. Ward, the attorney for the Alabama State Board of Pharmacy, Meds IV had a permit to operate as a "parenteral pharmacy" and was regularly inspected. Also, the pharmacy’s pharmacists met the state’s requirements to work as parenteral pharmacists.
Ward said parenteral pharmacies must comply with USP chapter 797.
Parenteral pharmacists, according to an online FAQ from the state board of pharmacy, "shall have attended a one-time, five-hour approved parenteral certification course, including didactic and hands-on experience, requiring a written exam as part of the training."
Meds IV, Ward said, closed in March and turned in its permit.
