A desire for better antimicrobial stewardship led Los Angeles County + University of Southern California (LAC+USC) Medical Center to implement testing for procalcitonin (PCT), a protein released in response to bacterial infections, to guide the treatment of sepsis and respiratory infections.

This PCT testing strategy has become common in Europe. However, it hasn’t been as widely embraced in the United States. A growing number of PCT tests have made it more accessible and affordable for U.S. labs, but debate continues about the value of the test in improving clinical care.

“There are definitely some pros and cons to use of procalcitonin and the jury is still out on whether it has helped curb use of antibiotics at our institution,” said Allison Chambliss, PhD, director of clinical chemistry and point-of-care testing at LAC+USC. “But I believe that the positive impact has been that it has allowed providers to give second thought about antibiotic use.”

Discordant Data

If LAC+USC has yet to see clear-cut benefits from implementing PCT testing, it is not alone. While some studies have found PCT results helpful in moderating antibiotic therapy, others have drawn less definitive conclusions. On the plus side, a PCT level below 0.25 μg/L may suggest that a patient with a respiratory infection doesn’t need antibiotics. Monitoring PCT levels over time also may help clinicians determine when it is safe to stop antibiotics. A recent meta-analysis of PCT testing in respiratory infections found it associated with lower 30-day mortality, an average 2.4-day reduction in antibiotic exposure, and a 25% reduction in antibiotic associated adverse events (JAMA 2018;319:925-6).

“There used to be a lot of discussion about safety because, when you don’t use antibiotics or you shorten antibiotic duration, physicians are worried about the outcome of their patients,” said review co-author Philipp Schuetz, MD, MPH, chief physician of endocrinology, diabetes, clinical nutrition, and internal medicine at Universität Basel and the Kantonsspital Aarau in Switzerland. “But this analysis shows that this is a very safe way to use antibiotics with improvement of clinical outcome.”

A multicenter prospective U.S.-based study by Schuetz and colleagues of 858 patients with sepsis found that an 80% decrease in PCT levels between baseline and day 4 of treatment predicted patient survival (Crit Care Med 2017;45:781–9). A review Schuetz coauthored also found a 1.49-day reduction in the duration of antibiotics (Crit Care Med 2018;46:691–8). PCT testing for sepsis helps individualize therapy, he said, but cautioned that it is not 100% accurate and should be used in conjunction with other tools.

“If you have a sick patient, a sepsis patient in the emergency department, you should start your whole sepsis bundle and then use procalcitonin more as a monitoring marker for the patient,” Schuetz said.

Not all studies have found a clinical benefit. A meta-analysis of PCT testing found an average 1.28 day reduction in antibiotic therapy in patients with sepsis but no reduction in mortality, mechanical ventilation, clinical severity, or reinfection (Cochrane Database Syst Rev 2017; doi: 0.1002/14651858.CD010959.pub2).

Benefits Tied to Usage

Suboptimal use of PCT tests in the real world may also limit its benefits. A recent retrospective cohort study that included 20,750 U.S. sepsis patients found that about 1 in 5 had a PCT measurement (Clin Infect Dis 2017;64:1509-15). Of those, only 1 in 3 had the serial measurements of PCT recommended by the Infectious Diseases Society of America as part of antibiotic stewardship programs. This analysis didn’t find a reduction in antibiotic use, the incidence of Clostridium difficile infections, or in hospital mortality.

The study’s senior author, Allan Walkey, MD, MSc, an associate professor of medicine at Boston University School of Medicine, cautioned that the data were from 2012 when hospitals may not have been using some of the rapid tests now available. If physicians have to wait a day or two for a result it may “eliminate the potential benefit.” A recent survey he led of Massachusetts’ hospitals found few currently offer rapid tests (Ann Am Thorac Soc 2017;14:1489–91).

Walkey suggested that better implementation of PCT testing may help. For example, he suggested having algorithms for PCT use and setting up a system in which a first PCT test order automatically triggers a follow-up test. “If you are deciding to use it in your hospitals, there are ways to implement it that mirror what was done in the trials,” he said.

Cost: A Stumbling Block?

The relatively high cost of PCT testing also has held back some labs from offering it. “There’s no denying that procalcitonin is an expensive test, especially when there was only one Food and Drug Administration [FDA]-approved assay,” said Joshua Hayden, PhD, assistant director of the central laboratory at Weill Cornell Medicine in New York City. But the availability of more FDA-approved tests has helped.

Siloed budgets also make PCT testing a difficult investment for laboratories, Schuetz said. He explained that labs incur the tests’ cost while pharmacies may reap any savings from decreased antibiotic use, so if institutions aren’t looking globally at costs and benefits PCT testing can be hard to justify. Hayden agreed. But a recent cost-effectiveness analysis found that PCT testing beginning on day 1 of intensive care unit admission for sepsis reduced hospital stays by 1.2 days and saved patients an average of $2,757 on total hospital costs, though lab costs were $81 higher (Chest 2017;151:23-33).

“Procalcitonin is a great example of why we need to change the paradigm of lab testing and lab reimbursement,” Hayden said. “We need to start thinking, we do lab testing so that we enjoy the benefits of higher quality, higher value care.”

The availability of tests with more rapid turnaround times has also helped. Initially, Hayden’s lab was running PCT tests in batches 3 times a day with an average turnaround time of 6 hours. Recently, the lab implemented a new system with a more rapid turnaround. “Now, you can get your result back in time to decide what to do with the next dose of antibiotics,” Hayden said.

A Team Approach

“Labs want to make sure that if they’re going to invest in procalcitonin testing, they have a comprehensive team that is going to make sure that it is ordered appropriately,” Hayden said.

Both LAC+USC and Weill Cornell Medicine provide clinicians with detailed interpretation algorithms and reference intervals and have educated appropriate departments. Pharmacists also discuss PCT testing during daily rounds.

Now that we’ve had the test for over a year, we see much more appropriate ordering patterns,” said Chambliss. She noted that some hospitals limit PCT test orders to certain departments or clinicians to ensure proper use.

Consulting with the departments that would use the test is a good place to start, Hayden suggested. Chambliss said she and her colleagues aim for a 2-hour turnaround for PCT tests ordered stat. But at some institutions longer turnarounds such as 4 to 6 hours may be sufficient. “If a lab is worried about providing a rapid turnaround, ask your clinical colleagues. It may not be needed as quickly as one might think,” she said.

There also are some unanswered questions about the use of PCT. More study of its use in infections other than sepsis and respiratory infections is needed, Schuetz said. In addition, some controversy remains about appropriate PCT test cutoffs. LAC+USC and Weill Cornell Medicine use cutoffs that are common in the field based on the studies to date. But many of those studies used older versions of the test and there isn’t much comparative data available about newer tests.

“There are a lot more assays out there than there used to be, and we don’t have good data as far as how harmonized these assays are,” Chambliss said. For now, she and her colleagues are collecting data and collaborating with laboratorians at other institutions to optimize and assess the use of PCT.

Bridget M. Kuehn is a science writer in Brookfield, Illinois.+Email: bridgetmkuehn@gmail.com.