Burkholderia Outbreak Proves Any Drug Product Can Be Risky

When pharmacists think about managing high-risk medications, nonprescription docusate sodium oral liquid doesn't normally make the list, said Jeffrey Wagner, pharmacy director at Texas Children's Hospital (TCH) in Houston.

But one such product, manufactured by PharmaTech LLC and sold under multiple brand names, was linked to an outbreak of Burkholderia cepacia infections affecting 63 hospitalized patients in 10 states last year, including several patients at TCH.

Wagner found it unsettling that a clinically indicated drug that was meant to increase patients' comfort—by relieving constipation—instead caused serious harm. And he said there are probably several other routinely administered products that are presumed to be harmless but could, under similar circumstances, make vulnerable patients ill.

"It just makes you wonder," Wagner said.

TCH identified 24 cases of B. cepacia infection from February through July 2016 in infants and very young children in the hospital's pediatric and cardiovascular intensive care units. Wagner said the patients had cancer or other conditions that made them vulnerable to infection.

All but 3 cases involved B. cepacia isolates that matched the genetic profile of bacteria that were eventually found as a contaminant in a PharmaTech-manufactured docusate sodium product, according to published reports from TCH.

Wagner said the initial investigation of the source of the infections focused on environmental monitoring and the observation of clinical activities, with guidance from the Centers for Disease Control and Prevention (CDC).

"We didn't know what it was. So we were just hunting down the path of what could have exposed these patients to the bacteria," he said.

Because 18 cases manifested as respiratory infections, medication exposure wasn't initially a focus of the probe.

When environmental monitoring failed to detect the bacterium, the infection-control team reached out to the pharmacy department. A clinical pharmacist then ran reports to see which medications the infected patients had in common.

"There were two medications that came up on the list. One was docusate sodium," Wagner said.

Wagner said microbiological testing confirmed the presence of B. cepacia in a stock bottle of PharmaTech's Rugby-branded docusate sodium product, Diocto, and in unit dose syringes that had been repackaged for the hospital by an FDA-registered outsourcing facility.

After an "urgent meeting," he said, TCH halted the use of docusate sodium oral liquid throughout the organization.

As these events unfolded, Wagner learned that the same strain of B. cepacia found at TCH had also caused an outbreak at a children's hospital in another state. Because a national recall had not yet been initiated, Wagner used a children's hospital listserver to inform other institutions about the outbreak and urged them to consider temporarily halting the use of docusate sodium oral liquid.

"Many of them decided to follow our lead," he said.

As the investigation progressed, Wagner said, the pharmacy created a spreadsheet with tracking information on every lot of the suspect docusate sodium, including source bottles and repackaged unit dose products.

He said the hospital was able to leverage its electronic medical records system to quickly identify patients currently taking docusate sodium and discontinue the therapy. A pop-up was created to warn prescribers that the drug was no longer available at TCH and instruct them to choose an alternative therapy.

"I think we learned pretty quickly the value of the electronic medical record," he said.

The outbreak illustrated several places in the supply chain that could have resulted in contamination of the docusate sodium product.

Docusate sodium active pharmaceutical ingredient is produced by Laxachem Organics Pvt. Ltd. of India. FDA on August 11, 2016, banned all U.S. imports of products from Laxachem—not because of product contamination but because the company refused to let FDA inspectors into its facility.

At the other end of the supply chain, the contamination could have occurred at the facility that repackaged bulk docusate sodium liquid for TCH. But that turned out not to be the case.

FDA in October 2016 announced that PharmaTech's water system was the source of the B. cepacia responsible for the outbreak.

According to the agency's inspection report, 3 lots of PharmaTech's Diocto brand of docusate sodium oral liquid tested positive for B. cepacia, as did a water sample collected from the production facility's reverse osmosis water purification system. The report states that water from this system was used to clean manufacturing equipment surfaces and is also a component of Diocto and other liquid drug products made by the company.

FDA's inspectors found several deviations from good manufacturing practices at the Davie, Florida, manufacturing facility. These included the failure to monitor water quality and to establish and follow procedures that are "designed to prevent objectionable microorganisms in drug products not required to be sterile."

Inspectors also found that PharmaTech did not appropriately test each batch of finished drug product for the presence of objectionable organisms. And the report describes instances in which the company failed to investigate customer reports of contaminants or to seek the root cause of PharmaTech's own findings of microbial contamination.

PharmaTech officially recalled its docusate sodium liquid products in July 2016, about a week into FDA's onsite inspection of the facility. In August, the company recalled all of its liquid products.
The recalls were preceded by public health advisories from CDC cautioning against the use of liquid docusate sodium, first in immunocompromised patients and then in all patients.

Wagner said it was interesting to be involved in a process that led to a national drug product recall. He said FDA and CDC were very responsive as the outbreak unfolded at TCH. But he was surprised at the amount of time it took for PharmaTech to launch the recall after the presence of B. cepacia had been confirmed in the hospital's products.

"We had already recalled all of our product at Texas Children's Hospital and basically removed it from formulary," he said. "We reached out to the manufacturer to let them know of our concerns. It was pretty hard to get the company to respond."

Wagner said he didn't fully appreciate, until the outbreak occurred, that a certain "level of tolerance" exists for the presence of microorganisms in nonsterile preparations.

For most patients, he said, that's not a problem—but that's not the case for patients with a compromised immune system, as the outbreak demonstrated.

FDA in March held a webinar for small businesses about the agency's recommendations for the manufacturing of nonsterile products. The presentation emphasized that microbes require water to proliferate and that manufacturers must take steps to limit such proliferation in nonsterile aqueous products.

The webinar named B. cepacia as a microbe of concern and described several recent incidents of product contamination that led to recalls, including the docusate sodium recall.

Wagner said TCH's infectious diseases team suspects that the B. cepacia became established in patients' throats after oral administration and later infected their lungs.

"We don't know, but we believe that's the route," he said.

He said docusate sodium oral liquid was recently added back to TCH's formulary but is ordered much less often than before the outbreak.

[This news story appears in the May 15, 2017, issue of AJHP.]