- Open Access
Using procalcitonin to guide antimicrobial duration in sepsis: asking the same questions will not bring different answers
Critical Carevolume 18, Article number: 142 (2014)
Severe sepsis is a major healthcare problem and the early initiation of antimicrobials is one of the few measures associated with improved outcomes. However, antibiotic overuse is an increasing problem in critical care. Of several potential biomarkers for antibiotic stewardship, procalcitonin represents the most widely studied and validated. In this commentary we address the current literature on the use of biomarkers to guide antimicrobial therapy in the critically ill and discuss its limitations and future directions.
In a previous issue of Critical Care, Prkno and colleagues report a meta-analysis of the current literature evaluating the role of procalcitonin (PCT) to guide the duration of antimicrobial therapy in patients with severe sepsis and septic shock admitted to the ICU . In these patients early initiation of antimicrobials is one of the few measures associated with improved outcomes in this high mortality scenario . However, overuse of antimicrobials - related either to missed opportunities to reduce the spectrum of activity or to unnecessarily long treatment regimens - has become an increasing problem in the past decades. Besides being associated with worse outcomes, antimicrobial resistance is becoming even more worrisome.
Clinical judgment remains the most valuable tool when decisions regarding the use of antibiotics are taken, but with important shortcomings. While features of disease severity at presentation may be quite nonspecific, the characteristics of clinical response to therapy are usually inaccurate and occur late in the course of disease. In such a scenario, biomarkers have been proposed as important tools to aid the decision-making process. Of several potential candidates, PCT represents the most widely studied and validated.
What becomes clearer from current studies in sepsis
Several systematic reviews have addressed the issue of PCT-guided therapy. Prkno and colleagues  focused on critically ill patients with severe sepsis or septic shock. By doing so, they cleverly avoided biases related to the heterogeneity of studied patients, specifically the wide variation of severity that may exist between infected individuals (for example, from mild to severe community-acquired pneumonia) . Using these inclusion criteria, seven randomized clinical trials were enrolled, totaling 1,075 patients. As their main conclusions, Prkno and colleagues provide a clear message for ICU physicians: we can safely reduce the duration of antimicrobial therapy in patients with severe sepsis or septic shock using PCT-guided protocols (hazard ratio 1.27, 95% confidence interval 1.01 to 1.53). Nevertheless, the authors acknowledge the many limitations of their study (for example, heterogeneity of PCT protocols) and emphasize that further information on major outcomes, such as length of stay and mortality, is required from future studies.
Limitations of current studies and their clinical implications
Despite their important contribution, most trials evaluating PCT-guided antibiotic therapy present several limitations that preclude their safe extrapolation to the clinical decision-making process . Namely, the high rate of patient exclusion (reaching >80% in the Svoboda and colleagues trial ) and the high rate of algorithm overruling (reaching >50% in the PRORATA trial ) disregard the impact of renal failure as well as renal replacement therapy on PCT levels, and above all the heterogeneity of duration of antibiotic therapy in the controls. Contrary to Prkno and colleagues’ opinion, since 2003 [6, 7] it has been clear that the duration of antibiotic therapy could be safely reduced in critically ill patients to 6 to 8 days. Consequently, this duration of therapy should be used as the best care in clinical trials. Besides, some infections (for example, infectious endocarditis, and nosocomial infections due to Pseudomonas aeruginosa or Acinetobacter baumannii) were not systematically evaluated. Finally, the costs associated with daily measurement of PCT in all ICU patients should not be ignored, since we have cheaper and widely available alternatives with proven safety and efficacy .
Improving the design of future studies and the current clinical use of biomarkers in sepsis
With the previously mentioned shortcomings in mind, it is legitimate to ask how can we properly use biomarkers such as PCT and C-reactive protein (CRP) to guide antimicrobial therapy (initiation and duration) in severe sepsis. First, we believe that future clinical trials should use less strict entry criteria that would better reflect our real-life ICU patients with sepsis. Second, a great deal of effort must be made to conduct multicenter studies involving large numbers of patients, ideally in different regions of the world. Lastly, biomarker-guided strategies must be tested against a comparator that actually reflects the 'best care' (that is, implementation of the best available evidence), and not the highly variable 'standard care'. In our opinion, it means comparing PCT algorithms with control treatment in which the maximum durations of antibiotic therapy is setup in 7 days, or even in 5 days (for example, severe sepsis without shock) [6, 7, 9]. Until these studies are performed and their results become available, clinicians should perhaps use a 'double-trigger' strategy as proposed by Oliveira and colleagues . In all patients, antibiotics were stopped according to the clinical course and either decreases in biomarker levels, according to an algorithm, or the completion of 7 days of treatment, whichever came first. In this single-center study evaluating patients with severe sepsis and septic shock, PCT or CRP were similarly effective to ensure early interruption of antibiotics (day 4/5).
To achieve safe and efficient short-course antimicrobial therapy in severe sepsis we propose an algorithm that may aid clinicians in their decision-making process (Figure 1). Using such a protocol, which remains to be validated in multicenter studies, we would be applying two very sound and validated concepts: patients with a fast response pattern to antibiotic therapy (early and substantial decrease in biomarker levels) have better outcomes [10–12]; and most cases of severe infections may be treated with 7 days of antibiotic therapy [6, 7, 9].
Prkno A, Wacker C, Brunkhorst FM, Schlattman P: Procalcitonin-guided therapy in intensive care unit patients with severe sepsis and septic shock – a systematic review and meta-analysis. Crit Care 2014, 17: R291.
Levy MM, Artigas A, Phillips GS, Rhodes A, Beale R, Osborn T, Vincent JL, Townsend S, Lemeshow S, Dellinger RP: Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: a prospective cohort study. Lancet Infect Dis 2012, 12: 919-924. 10.1016/S1473-3099(12)70239-6
Póvoa P, Salluh JIF: Biomarker-guided antibiotic therapy in adult critically ill patients: a critical review. Ann Intensive Care 2012, 2: 32. 10.1186/2110-5820-2-32
Svoboda P, Kantorová I, Scheer P, Radvanova J, Radvan M: Can procalcitonin help us in timing of re-intervention in septic patients after multiple trauma or major surgery? Hepatogastroenterology 2007, 54: 359-363.
Bouadma L, Luyt CE, Tubach F, Cracco C, Alvarez A, Schwebel C, Schortgen F, Lasocki S, Veber B, Dehoux M, Bernard M, Pasquet B, Régnier B, Brun-Buisson C, Chastre J, Wolff M, PRORATA trial group: Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010, 375: 463-474. 10.1016/S0140-6736(09)61879-1
Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, Wermert D, Clementi E, Gonzalez J, Jusserand D, Asfar P, Perrin D, Fieux F, Aubas S, PneumA Trial Group: Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA 2003, 290: 2588-2598. 10.1001/jama.290.19.2588
Micek ST, Ward S, Fraser VJ, Kollef MH: A randomized controlled trial of an antibiotic discontinuation policy for clinically suspected ventilator-associated pneumonia. Chest 2004, 125: 1791-1799. 10.1378/chest.125.5.1791
Oliveira CF, Botoni FA, Oliveira CR, Silva CB, Pereira HA, Serufo JC, Nobre V: Procalcitonin versus C-reactive protein for guiding antibiotic therapy in sepsis: a randomized trial. Crit Care Med 2013, 41: 2336-2343. 10.1097/CCM.0b013e31828e969f
Corona A, Wilson APR, Grassi M, Singer M: Short-course monotherapy strategy for treating bacteremia in the critically ill. Minerva Anestesiol 2006, 72: 841-857.
Coelho LM, Salluh JI, Soares M, Bozza FA, Verdeal JC, Castro-Faria-Neto HC, Silva JR L e, Bozza PT, Póvoa P: Patterns of C-reactive protein RATIO response in severe community-acquired pneumonia: a cohort study. Crit Care 2012, 16: R53. 10.1186/cc11291
Póvoa P, Souza-Dantas VC, Soares M, Salluh JI: C-reactive protein in critically ill cancer patients with sepsis: influence of neutropenia. Crit Care 2011, 15: R129. 10.1186/cc10242
Charles PE, Tinel C, Barbar S, Aho S, Prin S, Doise JM, Olsson NO, Blettery B, Quenot JP: Procalcitonin kinetics within the first days of sepsis: relationship with the appropriateness of antibiotic therapy and the outcome. Crit Care 2009, 13: R38. 10.1186/cc7751
PP has an unrestricted research grant from ThermoFisher Scientific and Virogates. The other authors state that they have no competing interests.
Authors’ original submitted files for images
Below are the links to the authors’ original submitted files for images.