ILLUSTRATIVE CASE
A 52-year-old woman presents to the emergency department complaining of dysuria and a fever. Her work-up yields a diagnosis of sepsis secondary to pyelonephritis and bacteremia. She is admitted and started on broad-spectrum antimicrobial therapy. The patient’s symptoms improve significantly over the next 48 hours of treatment. When should antibiotic therapy be discontinued to reduce the patient’s risk for antibiotic-associated AEs and to optimize antimicrobial stewardship?
Antimicrobial resistance is a growing public health risk associated with considerable morbidity and mortality, extended hospitalization, and increased medical expenditures.2-4 Antibiotic stewardship is vital in curbing antimicrobial resistance. The predictive biomarker PCT has emerged as both a diagnostic and prognostic agent for numerous infectious diseases. It has recently received much attention as an adjunct to clinical judgment for discontinuation of antibiotic therapy in hospitalized patients with lower respiratory tract infections and/or sepsis.5-11 Indeed, use of PCT guidance in these patients has resulted in decreased AEs, as well as an enhanced survival benefit.5-15
The utility of PCT-guided early discontinuation of antibiotics had yet to be studied in an expanded population of hospitalized patients with sepsis—especially with regard to AEs associated with multidrug-resistant organisms (MDROs) and Clostridioides difficile (formerly Clostridium difficile). The Surviving Sepsis Campaign’s 2021 international guidelines support the use of PCT in conjunction with clinical evaluation for shortening the duration of antibiotic therapy (“weak recommendation, low quality of evidence”).16 They also suggest daily reassessment for de-escalation of antibiotic use (“weak recommendation, very low quality of evidence”) as a possible way to decrease MDROs and AEs but state that more and better trials are needed.15
STUDY SUMMARY
PCT-guided intervention reduced infection-associated AEs
This pragmatic, real-world, multicenter, randomized clinical trial evaluated the use of PCT-guided early discontinuation of antibiotic therapy in patients with sepsis, in hopes of decreasing infection-associated AEs related to prolonged antibiotic exposure.1 The trial took place in 7 hospitals in Athens, Greece, with 266 patients randomized to the PCT-guided intervention or the standard of care (SOC)—the 2016 international guidelines for the management of sepsis and septic shock from the Surviving Sepsis campaign.17 Study participants had sepsis, as defined by a sequential organ failure assessment (SOFA) score ≥ 2, and infections that included pneumonia, pyelonephritis, or bacteremia.16 Pregnancy, lactation, HIV infection with a low CD4 count, neutropenia, cystic fibrosis, and viral, parasitic, or tuberculosis infections were exclusion criteria. Of note, all patients were managed on general medical wards and not in intensive care units.
Serum PCT samples were collected at baseline and then at Day 5 of therapy. Discontinuation of antibiotic therapy in the PCT trial arm occurred once PCT levels were ≤ 0.5 mcg/L or were reduced by at least 80%. If PCT levels did not meet one of these criteria, the lab test would be repeated daily and antibiotic therapy would continue until the rule was met. Neither patients nor investigators were blinded to the treatment assignments, but investigators in the SOC arm were kept unaware of Day 5 PCT results. In the PCT arm, 71% of participants met Day 5 criteria for stopping antibiotics, and a retrospective analysis indicated that a near-identical 70% in the SOC arm also would have met the same criteria.
The assessment of stool colonization with either C difficile or MDROs was done by stool cultures at baseline and on Days 7, 28, and 180.
The primary outcome of infection-associated AEs, which was evaluated at 180 days, was defined as new cases of C difficile or MDRO infection, or death associated with baseline infection with either C difficile or an MDRO. Of the 133 participants allocated to each trial arm, 8 patients in the intervention group and 2 in the SOC group withdrew consent prior to treatment in the intervention group, with the remaining 125 and 131 participants, respectively, completing the interventions and not lost to follow-up.
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