The clinical implications of observational studies regarding procalcitonin (PCT) are often limited. Factors such as variations in disease definitions and patient groups, the use of semi-quantitative PCT assays, and methodological issues like observer bias, selection bias, and sample availability, along with co-infection and colonization, can affect study outcomes. To address these limitations, numerous randomized controlled trials have explored using PCT to inform decisions regarding the initiation and duration of antibiotic therapy—an approach known as antibiotic stewardship. The effectiveness of PCT in these studies was gauged by clinical outcomes, based on the assumption that patient recovery without antibiotics indicates the absence of a bacterial illness requiring such treatment. Notably, all intervention studies employed fully automated, highly sensitive PCT assays. These assays provide results within one hour in an emergency department, enabling real-time, informed decision-making. Several PCT testing options are now available, including KRYPTOR, VIDAS system (Biomerieux), Liaison BRAHMS PCT (DiaSorin) and the Elecsys BRAHMS PCT (Roche Diagnostics).
Published research on antibiotic stewardship frequently employs similar clinical algorithms that provide recommendations for or against antibiotic treatment based on PCT cut-off ranges. For patients at moderate risk with respiratory tract infections in the emergency department (Figure 2), algorithms advise initiating or discontinuing antibiotic therapy based on four distinct cut-off ranges. Initial antibiotics were often withheld from patients with a low risk of systemic infection, such as those with acute bronchitis or exacerbations of chronic obstructive pulmonary disease (ECOPD). Clinical re-evaluation and repeated PCT measurements were recommended within 6 to 24 hours if the patient’s condition did not improve spontaneously. If PCT values increased and antibiotic therapy was started, repeated PCT measurements were advised every one to two days, depending on the severity of the disease. Antibiotics were discontinued when PCT levels fell within the same cut-off ranges or showed a marked decrease of 80% to 90% from high initial levels (e.g., >5 μg/l). To ensure patient safety, specific criteria were established to overrule the algorithm in cases of life-threatening disease or the immediate need for ICU admission. For high-risk patients in the ICU (Figure 3), algorithms focused on discontinuing antibiotic therapy when the patient showed clinical recovery and PCT levels decreased to ‘normal’ levels or by at least 80% to 90%.
Impact on Respiratory Infections
The initial intervention study, which evaluated PCT as a guide for antibiotic decisions, involved patients with various types and severities of respiratory infections. While clinical outcomes were similar in both groups, the PCT-guided group exhibited significantly lower rates of antibiotic prescriptions (44% versus 83%), particularly among patients with ECOPD and acute bronchitis. Subsequent trials examined the effect of PCT guidance on antibiotic discontinuation in community-acquired pneumonia (CAP) and ECOPD. PCT guidance reduced the duration of antibiotic therapy by 65% in CAP patients and the prescription of antibiotics from 72% to 40% in ECOPD patients. A later multicenter trial corroborated these findings, demonstrating a 32% reduction in antibiotic use for CAP, a 50% reduction for ECOPD, and a 65% reduction for acute bronchitis. Antibiotic exposure in ECOPD and acute bronchitis was primarily reduced by avoiding treatment initiation, whereas for CAP, the reduction was mainly due to shorter therapy durations. Importantly, the overall rate of adverse events was similar in both study arms, indicating a risk difference of no more than 0.4% for PCT-guided patients. Patients with bacteremia CAP had markedly increased PCT concentrations, which resulted in longer treatment durations compared to culture-negative CAP patients with a lower infection-related risk. Similar results in patients with respiratory infections were reported in trials from Denmark and China, and more recently from an observational quality control survey conducted in Switzerland.
The Role of PCT in Primary Care
The overuse of antibiotics is arguably most prevalent in primary care, where as many as 75% of patients with upper and lower respiratory infections receive antibiotics, despite the predominantly viral origin of these conditions. Two multicenter primary care trials, designed for non-inferiority in clinical outcomes, investigated the safety and feasibility of PCT-guided algorithms in patients with upper and lower respiratory infections, mainly relying on an initial PCT measurement. Both trials showed substantial reductions in antibiotic exposure (by 75% and 42%) and similar clinical outcomes, particularly a comparable time to recovery.
Applications in the ICU Setting
In higher-risk patients within the ICU setting, various trials have assessed the use of PCT, primarily for guiding the discontinuation of antibiotics. The initial proof-of-concept study revealed a four-day reduction in antibiotic therapy duration for patients with severe sepsis, although this was only evident in the per-protocol analysis. A subsequent large multicenter trial in France validated this concept in over 600 patients. PCT-guided patients showed similar 30-day mortality rates and relapse rates, but significantly more antibiotic-free days alive (14.3 versus 11.6). Another multinational ICU study focused on ventilator-associated pneumonia and found that PCT guidance resulted in a higher number of antibiotic-free days alive (13 versus 9.5 days). Two German studies evaluated the effect of PCT guidance in surgical ICU patients with suspected bacterial infections post-operatively. PCT guidance significantly reduced antibiotic therapy and maintained similar medical outcomes. Additionally, the length of intensive care treatment in the PCT-guided group was significantly shorter than in the control group (15.5 versus 17.7 days), aligning with the findings of the initial ICU study. The use of PCT for discontinuing antibiotics in ICU patients remains limited by a relatively small number of patients included in past trials, and further large-scale validation is needed. Ongoing trials focusing on this patient population should offer additional insights into the benefits and potential risks of PCT use in ICU patients.
Conclusion
Procalcitonin (PCT) serves as a valuable biomarker, acting as A Condition To Guide Present And Future Decision-making in antibiotic stewardship. Its integration into clinical algorithms has shown promise in reducing unnecessary antibiotic use, shortening treatment durations, and improving patient outcomes across various healthcare settings. As research continues to evolve, PCT’s role in optimizing antibiotic therapy and combating antimicrobial resistance is poised to expand, ensuring more effective and judicious use of these critical medications.
