By Samuel Nadler, MD, PhD

Critical Care, Pulmonary Medicine, The Polyclinic Madison Center, Seattle; Clinical Instructor, University of Washington, Seattle

SYNOPSIS: By shortening the duration of antibiotic therapy, a procalcitonin-guided protocol decreased the rate of infection-associated adverse effects, decreased costs, and reduced mortality in patient with sepsis.

SOURCE: Kyriazopoulou E, Liaskou-Antoniou L, Adamis G, et al. Procalcitonin to reduce long-term infection-associated adverse events in sepsis. A randomized trial. Am J Respir Crit Care Med 2021;203:202-210.

Achieving the optimal duration for antimicrobial therapy in sepsis remains a challenge. Published guidelines make recommendations, but the prescribed duration of antibiotics commonly exceeds these recommendations. Having a biomarker-driven protocol to limit antibiotic exposure could decrease antibiotic exposure and improve outcomes.

The PROGRESS trial (Procalcitonin-Guided Antimicrobial Therapy to Reduce Long-Term Sequelae of Infections) is a multicenter, pragmatic, randomized controlled trial using procalcitonin-driven protocols to discontinue antibiotics in patients admitted with sepsis. Patients meeting Sepsis-3 definitions were randomized to standard of care (SOC) or procalcitonin (PCT)-driven protocols in which antibiotics were discontinued if PCT levels were reduced by at least 80% from admission or the absolute level was below 0.5 mcg/L at least five days after starting treatment. Patients were excluded from this study if they had indications for prolonged antibiotic therapy, viral or parasitic infections, tuberculosis, cystic fibrosis, human immunodeficiency virus (HIV), or were pregnant or lactating. Exceptions were allowed for unstable patients with fever and/or shock. The primary outcome was the rate of infection-associated adverse events (IAAEs) within 180 days, including new cases of Clostridioides difficile, new multidrug-resistant organisms (MDRO), or death associated with these infections. Secondary outcomes included length of antibiotic therapy, 28-day and 180-day mortality, and cost of hospitalization.

Overall, 266 patients were enrolled, mostly with community-acquired pneumonia (CAP) (43.8%) or healthcare-associated pneumonia (HCAP) (16.8%); other infections included pyelonephritis (37.1%) and bloodstream infections (1.2%). Most commonly, a pathogen was not identified (84%), and empiric antibiotics were prescribed. Using the PCT-driven protocol, the duration of antibiotic therapy was reduced from a median of 10 days to five days (P < 0.001). The rate of IAAEs was decreased from 15.3% to 7.2% (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.19-0.99; P = 0.045). Hospital mortality improved from 25.2% in the SOC group to 13.6% in the PCT group (OR, 0.47; 95% CI, 0.25-0.89; P = 0.03). The cost of hospitalization decreased from 1,183.49 to 956.99 (P = 0.05). In a multivariate analysis of patients who developed IAAEs, PCT guidance was protective (hazard ratio [HR], 0.38; 95% CI, 0.17-0.95; P = 0.01) while dementia, bacteremia, and intake of a carbapenem increased the risk of IAAEs (HR, 4.3, 2.93, 2.91, respectively).

Commentary

The PROGRESS study adds to a growing body of literature that PCT-driven protocols can reduce antibiotic duration and reduce complications from antibiotic use without adversely influencing mortality. A previous meta-analysis by Wirz et al of studies that included PCT-driven protocols in sepsis confirmed decreased antimicrobial exposure and suggested improved mortality.1 However, in many of these studies, the discontinuation of antibiotics was a recommendation, and adherence was highly variable. For example, in the largest of these studies from the Netherlands that included 1,546 patients, there was only 44% adherence.2 The reason for nonadherence to the recommendation in this study was most commonly “other reasons or not specified” (61.1%) or “physician considers risk of discontinuation of antibiotics too high” (12.7%), rather than more objective findings, such as “patient still has fever” (5.7%) or “patient is not stable” (6.1%). The positive effects of protocolized discontinuation of antibiotics often was attenuated by physician discomfort rather than objective data. In the PROGRESS study, there was high adherence to protocol. Thus, the effect of a PCT-driven protocol might be to enable physicians to use objective data to drive discontinuation of antibiotics.

The decrease in antibiotic exposures by PCT-driven protocols changes the duration of treatment to be more guideline-concordant. In the PROGRESS trial, most patients were admitted with CAP/HCAP, and antibiotic duration decreased from 10 to five days. Current American Thoracic Society/Infectious Diseases Society of America guidelines for the treatment of CAP recommend an antibiotic duration of five to seven days.3 Thus, the effect of the protocol was to drive toward more guideline-concordant care. This could have been accomplished without PCT measurement, and simple adherence with published standards. Again, the effect of a PCT-driven protocol may be to improve the comfort of physicians discontinuing antibiotics to conform with established guidelines.

In summary, the PROGRESS study demonstrates that a PCT-driven protocol can reduce the duration of antibiotics, decrease adverse effects caused by antibiotics, and improve outcomes for patients with sepsis. 

REFERENCES

  1. Wirz Y, Meier MA, Bouadma L, et al. Effect of procalcitonin-guided antibiotic treatment on clinical outcomes in intensive care unit patients with infection and sepsis patients: A patient-level meta-analysis of randomized trials. Crit Care 2018;22:191.
  2. de Jong E, van Oers JA, Beishuizen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: A randomized, controlled, open-label trial. Lancet Infect Dis 2016;16:819-827.
  3. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired pneumonia: An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med 2019;200:e45-e67.