PCT leads the way in antimicrobial stewardship

Anne Paxton

August 2019—Antibiotic treatment of sepsis patients often has to rely on clinical observation and educated guesswork as clinicians wait for a culture to determine whether the infection is bacterial, viral, or possibly fungal. But with the FDA’s recent approval of automated platforms for procalcitonin assays and mounting evidence of PCT’s value as a biomarker, hospital laboratories are turning to PCT to diagnose sepsis and guide antimicrobial stewardship.

[showad block=5]Europe has been 10 or 20 years ahead of the U.S. in adopting PCT to help with antibiotic stewardship, says John Boreyko, PharmD, a clinical infectious disease pharmacist and co-director of the antimicrobial stewardship program at Duke Regional ­Hospital, Durham, NC. He watched PCT’s widening use in Europe to guide antimicrobial therapy in recent years, and in 2014 he wanted his hospital to be an early U.S. adopter of PCT for the same purpose.

It didn’t happen overnight. “It took me almost two years to get through the process of filing a business plan and showing that we have enough patients who will benefit from the test.” But since early 2016, Duke Regional has been using PCT, and he sees other hospitals making the same move. PCT is still not mainstream but the ball is rolling, Dr. Boreyko says. He estimates that close to 50 percent of hospitals are now using this biomarker in addressing sepsis.

The other two hospitals in the Duke University Health System plan to implement PCT by the end of this year, he says.

“I think PCT testing is growing rapidly because we have so much data out there to support that PCT decreases the antimicrobial burden, yet it doesn’t cause any adverse reactions as far as injury or mortality.”

One new study points also to cost savings. Published April 23 in PLOS ONE, the study used a health economic decision model to compare the costs and effects of PCT-guided care for hospitalized patients with suspected sepsis or lower respiratory tract infection. It found that such care is associated with a reduction in antibiotic days, shorter length of stay on the regular ward and intensive care unit, shorter duration of mechanical ventilation, and fewer patients at risk for antibiotic-resistant or C. difficile infection. Total costs of sepsis care for the PCT group compared with standard care were 26 percent lower—$11,311 per patient. For patients with LRT infections, costs were lower by 17.7 percent (Mewes JC, et al. 2019;​14[4]:e0214222).

In contrast with the initial PCT studies, which were done in Europe, “I would say probably 75 percent of all PCT studies in the last five years have been either multinational or conducted in the U.S.”—a necessary stage for the biomarker to win acceptance here, Dr. Boreyko says. “We need to start doing more studies in the U.S. to see if the European findings are generalizable.”

Duke Regional’s laboratory uses PCT for sepsis patients, first to establish a baseline and, second, as a way to de-escalate antibiotics in culture-negative patients. “If a patient has a high PCT and high risk of sepsis from a bacterial source at baseline, when we get a second PCT level, based on the half-life, it should be 50 percent below baseline. If it’s close to that, we know the antibiotic we’re using is correct and we don’t have to look for another source of infection. In the third and final test, if it’s 80 percent below the baseline, then we know we can start de-escalating or stopping antibiotics and that’s a culture-negative patient.” If the PCT is negative, “That’s just another piece of evidence that the patient is having viral respiratory symptoms and not bacterial.”

Caveats apply to this algorithm, of course. For example, “There are patients who have sepsis in addition to lung cancer and if their renal dysfunction is from the sepsis, then they will have a markedly elevated PCT. If you are a dialysis patient or have chronic kidney disease stage three or four, we’d expect your PCT to be elevated even though you won’t be infected. The algorithm does not take this into account. We just have to train physicians that you can get a PCT if you want, but you need to take the value with a grain of salt.”

In fact, training of clinicians is crucial and has to be ongoing, he emphasizes. “There’s always going to be overuse or misuse of procalcitonin and you just have to continually educate,” he says. “When we did our education, we let clinicians know what the limitations were and that PCT should be drawn only in certain populations. For the most part they do pretty well, but they may need reminding that sometimes they shouldn’t have ordered PCT because we can’t assess it.”

As clinicians gain more experience, Dr. Boreyko believes they will come to trust the test as fully as he does. “You’re only going to trust the test by seeing scores of patients and understanding that there were no adverse reactions based on using the test to make clinical decisions. But you need to see for yourself.”

His hospital tracks antibiotic consumption to make sure it is at the same level or declining. However, “It’s too early to say,” he says, whether antibiotic use is dropping in the ICU at his hospital. “It’s sort of hard to prove you can reduce length of stay, use less antibiotics, or extubate the patient earlier” by introducing a test like PCT, “because most patients have some other comorbidity that’s causing them to be in the ICU.” And a significant number of patients are lost to follow-up.

Within a couple of years, he expects that “at least for lower respiratory tract infections, we will have at least 500 patients we can use to compare two cohorts that are following a PCT guideline.” An early “snapshot” study of admissions to the ER for LRT infection at his hospital already suggests the effect of PCT might be dramatic. Before adoption of PCT, 550 LRT infection patients had a 30-day same-cause rate of readmission to the ER of 5.4 percent. He compared those patients with the LRT infection patients admitted in the first year of the hospital’s use of PCT for LRT infection.

“After PCT was implemented, the same 30-day rate of re-presentation to the emergency room or same-cause readmission dropped to 0.4 percent—approximately a 92 percent decrease” in that measure alone. He doesn’t predict that a repeat study will have such striking results. In reality, “It’s probably closer to a 50 to 70 percent reduction, but that’s still a significant difference.”

Dr. Boreyko hopes that, by 2020, PCT use will be even more mainstream and available not only in hospitals but also in large clinics and physician offices, where potentially unnecessary antibiotics might first be prescribed for a patient.

But he is not of the view that PCT is playing an increasingly central role in ameliorating sepsis. “Not at all,” he says. “All we’re doing is hopefully identifying if the patient is septic and decreasing antibiotic use in a culture-negative patient. The main benefit of PCT is conservation of antibiotic use, which we hope is going to reduce resistant organisms that could potentially cause you to have repeat sepsis down the road.”

The UC Davis Health laboratory implemented PCT in December 2014, after years of waiting for it to become available on an automated platform, says Nam Tran, PhD, associate professor of clinical chemistry, special chemistry, toxicology, and point-of-care testing at UC Davis Health, which has the largest level one trauma center north of San Francisco. UC Davis previously offered only same-day results because of the available platform but immediately “jumped to the Roche instrument once it became FDA approved to enable stat testing,” he says.

UC Davis was such an early adopter of the use of PCT for sepsis recognition and antibiotic de-escalation that most of the algorithms for the application at the time were theoretical rather than tested. “They were performed in nicely controlled studies, but pragmatic studies were quite limited,” Dr. Tran says.

In the U.S., sepsis is present in more than half of hospital deaths, Dr. Tran says, though sepsis may not be the primary diagnosis. “Sepsis can be caught up front in the ER, but there is still a good number of cases where sepsis was not present at admission and diagnosed later.” At UC Davis, there is a sizable high-risk patient population, including cancer, transplant, and burn patients. “Our burn patients are unique in that regard, since your skin is your primary barrier against the world—without it, your infection risk increases dramatically.”

Burn patients have a higher proportion of fungal infections than the average, which is roughly 10 percent of sepsis cases; however, some studies suggest even higher numbers approaching 25 percent, Dr. Tran notes. Although PCT is not a test for fungi, “If the PCT is low or negative and you still suspect some foreign infection and one possibility is fungi, the negative PCT could lead doctors to realize maybe they should do a fungal culture, for example.” But making such decisions still depends on the skill and experience of the doctors, he adds.

It’s not too early to draw conclusions about the impact of PCT on his laboratory and clinical care at Davis, Dr. Tran says. “We’ve been using PCT for a while. We are seeing trends in decreased antibiotic use, and we are also seeing folks moderate their use of certain molecular tests based on PCT results.”

“We are slowly optimizing algorithms and workflows as physicians get used to a structured PCT testing process,” he continues. “One of the most important things in PCT or any test like this is not just how good a biomarker it is, but how well you educate the staff and implement it. If you have only half your hospital using the guidelines for the test, you are at best 50 percent successful and more likely just a complete failure.”

Dr. Tran recommends engaging the education mission on multiple fronts. “The key is to identify champions in key services like the ED and the ICUs. We did the usual emails, flyers, and blogs, including a Web blog that is publicly available. We even had information posted on Facebook to aid in disseminating best lab test practices. Then we showed up at hospital committee meetings and had our champions continually push these ideas within their respective services. After implementation, we come back and check to see how we are doing, see our weak points, then re-engage, addressing those weak points to perpetually keep the message going.”

The next phase will be a move to full electronic decision support with PCT along with a prediction tool inside the electronic health record to push it even further, he says. “We are going from word-of-mouth education to paper-based algorithmic approaches to, now, electronic implementation with sophisticated prediction tools and beyond. That has been our effort for the last couple of years for many diagnostics, not just PCT.”

Intrapatient variability can bring problems when it comes to interpreting PCT results, he says. “The good news is with the algorithms to de-escalate, we are looking at a percent change relative to the initial value for each patient. So the variability is more or less controlled for by testing serially in a patient.” With that said, “We all know patients are all different.” For example, studies have shown that burn patients’ baseline PCT is higher than that of a normal person; the value would be considered abnormal in a non-burn patient, he points out.

For what PCT is used for today, the variability is acceptable, in his view. “As it gets better, we will find out we are missing some part of the big picture, just as with cardiac troponin. As that test became more sensitive, we realized there is a lot of variability; the biomarker is leaking into our bloodstream under different health conditions. Does that mean anything? We don’t fully know—it has brought up new questions today. That is the process of science.”