Antibiotic stewardship has become a big talking point for healthcare facilities in the struggle against drug-resistant bacteria. Stewardship strategies designed to reduce inappropriate antibiotic prescription have been shown to cut costs by up to $400,000 a year by decreasing rates of infection and antibiotic resistance. This is often accomplished by changing the behaviour of healthcare practitioners with education, audits, policies or automatic stop orders. However, for patients in the ICU, these measures are not always sufficient for physicians to be confident in their antibiotic treatment plans.

The PCT potential

Withholding antibiotics or stopping them prematurely for a patient with a serious bacterial infection could have adverse consequences, or, at the very least, contribute to a longer hospital stay and higher costs, so it’s critical for physicians to be sure of a patient’s condition with regard to severity and cause. Gauging the severity of an infection is already routinely done using biomarkers such as white blood cell count or C-reactive protein. However, these markers often show up regardless of the source of an infection and, until recently, there was no accepted standard test for diagnosing bacterial sepsis.

That seems to be changing with procalcitonin (PCT), a biomarker for sepsis, which was originally introduced to the clinical world through the B-R-A-H-M-S PCT assay. A biomarker specialist, B-R-A-H-M-S focuses on investigating, developing and manufacturing new procedures to improve diagnosis and treatment of life-threatening conditions. The B-R-A-H-M-S. PCT sensitive Kryptor assay is designed for use with Kryptor, a fully automated immune-analysis instrument, also from B-R-A-H-M-S. B-R-A-H-M-S PCT assays are distributed by parent entity Thermo Fisher Scientific and its various license partner IVD companies.

PCT is a naturally occurring protein that increases above its normal, undetectable levels when the body experiences an inflammatory response, such as sepsis, as well as multiorgan dysfunction. PCT levels directly correlate to bacterial load and the severity of an infection, which makes it an ideal biomarker for sepsis. Another useful characteristic is that in the presence of viral or local infections, PCT levels do not rise dramatically above their normal level of 0.05ng/ml or less, while levels above 0.5ng/ml are indicative of systemic bacterial infection and levels of greater than 2ng/ml are almost always due to bacterial sepsis unless other causes are known.

Dr Michael Meisner, head of ICU at Städtische Klinikum Dresden, was the first to remark on the potential of PCT testing for sepsis diagnosis in a 1996 study, and has been a firm proponent ever since. Städtische Klinikum – the teaching hospital for the Dresden University of Technology – has been using PCT testing for more than 12 years; over the past four years, the hospital has officially made the test part of its antibiotic-stewardship strategy.

"It’s absolutely significant because it’s the only way for us to guide antibiotic treatment and duration of antibiotic treatment in an individual and rational way," Meisner says.

"Until now, we had little information about the activity of the immune system in our clinical routine except for conventional data like temperature, leukocytes or cytokine measurements. It’s the only marker that allows you to reduce the duration of antibiotics individually for the patient’s situation, and this leads to an average of no longer than five days’ treatment."

Improved antibiotic stewardship

PCT testing has been available in the market for over 20 years. Since then, more than 20 randomised, controlled studies have proven its efficacy as an aid to antibiotic stewardship. As the first automated PCT assay on the market, the B-R-A-H-M-S PCT sensitive Kryptor assay was the basis for all clinical algorithms, guidelines and cut-offs applied to PCT.

A multicentre, randomised, controlled, interventional trial on serial PCT measurement, begun in 2009, published its results in The Lancet in February 2016: the ‘Stop antibiotics on guidance of procalcitonin’ (SAPS) study. Covering 15 Dutch hospitals, it assessed the safety and efficacy of using daily PCT measurements to guide antibiotic treatment.

Researchers found that PCT-guided patients had an average treatment duration of five days, compared with seven in the standard-of-care control group. It also resulted in a "significant decrease in mortality": in the one-year follow-up period, patients in the PCT-guided group had a mortality rate of 36% while the control group had a rate of 43% – a 7% lower mortality rate in the PCT group. Meisner supports the SAPS study’s findings.

"I would have been astonished if there had been another result; it is absolutely consistent with our clinical results and what has been shown in other hospitals and studies," he says.

The thorough approach

Measuring PCT can tell physicians whether a patient is septic and how severely, removing the need to continue unnecessary antibiotic treatment in a "better safe than sorry" approach. The test takes roughly 20 minutes to complete, meaning it can be done every day to shed light on a patient’s status as treatment progresses. Meisner’s team has incorporated this into its clinical routine for septic patients to facilitate the early diagnosis of sepsis and encourage effective antibiotic stewardship.

"We always reanalyse the situation each day. We have introduced a basic rule that antibiotics should not be used for more than seven days; if they’re used longer, there has to be a discussion within the team and specialty members, like microbiology, surgery and so on," he explains, also emphasising the user-friendliness of using the protein as a biomarker: "PCT is a very robust protein, so in the pre-clinical setting you do not have to take many precautions. You do not have to cool down the plasma, and you can take plasma or serum."

The algorithms used by Meisner’s team, reached through use of the B-R-A-H-M-S PCT sensitive assay, were also published in The Lancet. A decline of more than 80% from peak PCT levels, or a drop to lower than 0.5ng/ml in ICU patients, is taken as a suggestion to stop antibiotic treatment. This is combined with standard clinical assessment of whether the focus of the infection has been eliminated and systemic inflammation has lessened below harmful levels. The goal is to always take an individual approach to each patient’s treatment.

Highest-quality results

Upfront costs are a significant factor when deciding whether to implement a test as part of the clinical routine. A study published in the Journal of Medical Economics in July 2015, however, investigating the cost-effectiveness of the test – when used to guide the continuation of antibiotic treatment – estimated that using the PCT assay could lower a facility’s overall treatment costs per patient by 9%. The savings came from shorter hospital stays, fewer days of antibiotic treatments and a reduction in the number of blood cultures performed on each patient.

Using the assay to monitor falling PCT levels means that reliability at lower ranges of measurement is critical. Stopping antibiotics before an infection has been dealt with could result in resurgence, while continuing treatment after the infection has subsided uses up resources and extends a patient’s stay, as well as contributing to antibiotic resistance.

Poor copies mean poor results

As the test has gained ground as a diagnostic tool, unlicensed copies of the original assay have begun to hit the market. While the B-R-A-H-M-S PCT assays can be relied upon at the lower threshold of measurement – 0.25ng/ml (for the diagnosis of lower respiratory tract infections in emergency patients) and 0.5ng/ml (for the diagnosis of sepsis in critically ill patients) – the same is not always true for unofficial copies.

Additionally, since routine algorithms and cut-offs for PCT were determined through use of the B-R-A-H-M-S PCT sensitive assay, there is no guarantee that a copy will be precise enough to be used with the same cut-offs. Ensuring concordance at the clinical cut-offs is necessary. There may also be quality deviation between lots and insufficient correlation of measured PCT levels to bacterial infection. Meisner recommends the B-R-A-H-M-S PCT sensitive Kryptor assay for the most reliable results.

"A new test coming out first has to be checked how it behaves in the lower measurement range," Meisner confirms. "I also see a big deviation in the upper ranges, if the assays are not evaluated well. So you must be careful if you take offers that are not approved by the official institutions."

PCT has been incorporated into several sets of clinical guidelines, including the 2016 revisions to the Surviving Sepsis campaign’s ‘International Guidelines for Management of Severe Sepsis and Septic Shock’, which suggest that "measurement of PCT levels can be used to support shortening the duration of antimicrobial therapy in sepsis patients". It also says that PCT levels "can be used to support the discontinuation of empiric antibiotics in patients who initially appeared to have sepsis, but subsequently have limited clinical evidence of infection".

It also appeared in guidelines published by the German Sepsis Society in 2010, which state that "to shorten the duration of antimicrobial therapy, serial PCT measurements may be considered," giving the method a grade C recommendation.

Safe, effective and cost-efficient, PCT represents an important piece of the antibiotic resistance puzzle. Combined with the existing standard of clinical assessment, it gives physicians the ability to use antibiotic prescriptions appropriately without fear for the condition of a critical patient.

To maintain that standard of care, value and efficiency, clinical institutions must be aware of the quality of the test they are using: for the best performance, only the original will do.