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Procalcitonin Measurement for Effective Antibiotic Stewardship

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Offering many advantages over current diagnostic tests for bacterial infection, measurement of circulatory procalcitonin (PCT) represents a method of realizing effective antibiotic stewardship in the battle against antimicrobial resistance (AMR).

Providing quick and easy measurement of serum and plasma PCT levels, and having recently been granted FDA clearance, a powerful diagnostic assay from Fujirebio represents a significant new tool affording faster implementation of appropriate antibiotic treatment.

AMR poses a potentially catastrophic threat

Since the discovery of penicillin in 1928, antibiotics have helped to save millions of lives worldwide. However, overuse of these medications has contributed to the rapid emergence of antimicrobial resistance, the process by which a micro-organism such as a bacterium, virus, fungus or parasite develops the ability to survive exposure to a drug that would normally kill it or stop its growth.

In combination with a significant lack of new antimicrobial drug discovery and development, AMR now poses a potentially serious threat. In the US alone, at least two million people become infected with antibiotic-resistant bacteria annually, with approximately 23,000 of these individuals dying as a result. In addition to the human cost, such infections represent a substantial economic burden since they often result in simultaneous use of multiple antibiotics, extended duration of therapy and long periods of hospitalization.

Antibiotic stewardship, the process of prescribing fewer antibiotics and doing so only when and for as long as necessary, is essential to limit the development of AMR and preserve antibiotic effectiveness. Diagnostic tests to aid decision-making on antibiotic therapy have a growing role. PCT, a biomarker of bacterial infection, is a key analyte of diagnostic testing which promises more effective antibiotic usage.

Antibiotic misuse drives AMR

Antibiotic overuse and inappropriate prescription are major contributing factors to the rising incidence of antibiotic-resistant bacteria. For example, research findings published within The Lancet by Goossens et al. demonstrated a clear correlation between antibiotic consumption and rates of antibiotic resistance across Europe, while many studies have shown that prescribed antibiotics are often unnecessary, inappropriate or sub-optimal.

When exposed to antibiotics, bacteria develop resistance due to genetic mutations as well as from the subsequent transfer of resistance genes between organisms. The frequency with which this resistance occurs is increased through using the wrong choice of therapeutic agent, inappropriate duration of antibiotic therapy or dosing with sub-inhibitory antibiotic concentrations that can instead support genetic alteration. By better understanding the nature of an infection and the causative organism, relevant treatment can be provided and antibiotic misuse reduced.

Current methods to identify systemic bacterial infection

Without a gold standard test for systemic bacterial infection, patient evaluation typically includes a white blood cell count, the growth of blood and sputum cultures and the measurement of c-reactive protein (CRP) and lactate levels. Unfortunately, these analyses are time-consuming, have low specificity to bacterial infections, and can result in mistakenly prescribed antibiotics for viral conditions. Although these tests provide useful insight, a more specific method is required.

The measurement of serum PCT levels allows physicians to determine the presence of systemic bacterial infection shortly after presentation and indicates whether an antibiotic treatment will be appropriate. Additionally, by monitoring PCT levels once treatment has begun, the effectiveness of the antibiotic can be evaluated, and an informed decision made on when treatment should end.

Clinical utility of procalcitonin

Procalcitonin is the precursor to the hormone calcitonin, which has been widely studied due to the pivotal role which it plays in calcium homeostasis. Yet PCT has itself been the subject of numerous research projects more recently, following recognition of its clinical utility as a biomarker for sepsis.

Encoded by the CALC-1 gene, PCT is a 116 amino acid protein that is produced in thyroid C cells. Its expression is induced by elevated calcium levels, as well as by stimuli which include the glucocorticoids, calcitonin gene-related peptide (CGRP), glucagon, gastrin or β-adrenergic stimulation. These exert tight control over PCT production, and in healthy individuals circulatory PCT levels are very low (0.05 ng/mL) since the protein is converted to calcitonin prior to release.

During bacterial infection, PCT can be synthesized by virtually all tissues and organs. Lipopolysaccharide (LPS) or other microbial toxins induce its inflammatory release, resulting in elevated levels within circulation. Measurement of these levels has wide-ranging utility, not least in the treatment of sepsis. Defined as life-threatening organ dysfunction caused by a dysregulated systemic host response to infection, sepsis is a leading cause of hospital deaths. The incidence of sepsis is rising steadily, driven in part by antibiotic resistance.

Graph depicting how the concentration of procalcitonin (µg/L) increases with increasing disease severity.
PCT increase reflects the continuous development from a healthy condition to the most severe states of disease (severe sepsis and septic shock).

The advantages of PCT

In addition to a high degree of specificity for bacterial infections, PCT affords superior kinetics in relation to biomarkers such as CRP and lactate. Typically rising within 3-4 hours of an infectious challenge, peaking within 6-24 hours, and correlating with the severity of the infection, circulatory levels of PCT remain elevated until appropriate therapy is provided, declining only as the infection resolves.

Also rising in response to bacterial infection, serum levels of CRP take considerably longer to peak (2-3 days) than those of PCT. This reduces the utility of CRP as a biomarker of bacterial infection, especially in situations where a more rapid diagnosis is necessary. Furthermore, circulatory levels of CRP can become elevated due to chronic inflammatory conditions, reducing its specificity.

Kinetics of PCT upon infection, compared to TNF-α, IL-6 and CRP.Kinetics of Procalcitonin (PCT) compared to other inflammatory markers upon infection.

Lactate is not specific to bacterial infections but is instead associated with poor tissue perfusion. Serum lactate levels elevate in the later stages of sepsis, when it may be too late to provide effective treatment.

Lumipulse® G B.R.A.H.M.S PCT assay

Designed as an easy to use in vitro diagnostic kit, the Lumipulse® G B.R.A.H.M.S PCT assay utilizes proven chemiluminescent enzyme immunoassay technology to provide quantitative determination of PCT in human serum and plasma samples. Requiring only 60µL sample and with results available in just 35 minutes, the two-step sandwich assay format features excellent precision with a CV of ≤4.7%. The superior capacity of the Lumipulse® G B.R.A.H.M.S PCT assay (120 tests per hour), alongside a measurement range of 0.02 – 100 ng/mL, ensures rapid acquisition of results for multiple patients.

Designed for use on the Lumipulse® G 1200, the Lumipulse® G B.R.A.H.M.S PCT assay aids in:
  • Antibiotic decision making for patients with suspected or confirmed sepsis
  • Risk assessment of critically ill patients for progression to sepsis or septic shock
  • Monitoring over time for evaluation of the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock
  • Antibiotic decision making for patients with suspected or confirmed lower respiratory tract infections (LRTI)
“Serial measurement of procalcitonin levels is a significant innovation for antibiotic stewardship, which may lead to reduced hospitalization stays without adversely affecting patient outcomes”, says Matthew Bell, Vice President Sales and Marketing at Fujirebio, US.

By promoting responsible antimicrobial therapy through more judicious antibiotic use, the Lumipulse® G B.R.A.H.M.S PCT assay enhances clinical decision making, providing more appropriate antibiotic administration and helping to prevent AMR.

For more information about Fujirebio Diagnostics, please call +1 610-240-3800 or visit www.fujirebio-us.com