Consider this tool to reduce antibiotic-associated adverse events in patients with sepsis

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doi:doi: 10.12788/jfp.0538

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Consider this tool to reduce antibiotic-associated adverse events in patients with sepsis

J Fam Pract. 2023 January;72(1):E13-E15 | doi: 10.12788/jfp.0538

By

Timothy Mott, MD, FAAFP

Zachary Orme, DO

Predictive biomarker procalcitonin can aid clinical decision-making on continued antibiotic treatment in this patient population.

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PRACTICE CHANGER

For patients hospitalized with sepsis, consider procalcitonin (PCT)-guided early discontinuation of antibiotic therapy for fewer infection-associated adverse events (AEs).

STRENGTH OF RECOMMENDATION

B: Based on a single randomized clinical trial.¹

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. doi: 10.1164/rccm.202004-1201OC

References

1. 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. doi: 10.1164/rccm.202004-1201OC

2. European Centre for Disease Prevention and Control. US CDC report on antibiotic resistance threats in the United States, 2013. ECDC comment. September 18, 2013. Accessed December 29, 2022. www.ecdc.europa.eu/en/news-events/us-cdc-report-antibiotic-resistance-threats-united-states-2013

3. Peters L, Olson L, Khu DTK, et al. Multiple antibiotic resistance as a risk factor for mortality and prolonged hospital stay: a cohort study among neonatal intensive care patients with hospital-acquired infections caused by gram-negative bacteria in Vietnam. PloS One. 2019;14:e0215666. doi: 10.1371/journal.pone.0215666

4. Cosgrove SE. The relationship between antimicrobial resistance and patient outcomes: mortality, length of hospital stay, and health care costs. Clin Infect Dis. 2006;42(suppl 2):S82-S89. doi: 10.1086/499406

5. Schuetz P, Beishuizen A, Broyles M, et al. Procalcitonin (PCT)-guided antibiotic stewardship: an international experts consensus on optimized clinical use. Clin Chem Lab Med. 2019;57:1308-1318. doi: 10.1515/cclm-2018-1181

6. Schuetz P, Christ-Crain M, Thomann R, et al; ProHOSP Study Group. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA. 2009;302:1059-1066. doi: 10.1001/jama.2009.1297

7. Bouadma L, Luyt CE, Tubach F, et al; 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. doi: 10.1016/S0140-6736(09)61879-1

8. Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet. 2004;363:600-607. doi: 10.1016/S0140-6736(04)15591-8

9. Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med. 2006;174:84-93. doi: 10.1164/rccm.200512-1922OC

10. 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 randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16:819-827. doi: 10.1016/S1473-3099(16)00053-0

11. Nobre V, Harbarth S, Graf JD, et al. Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med. 2008;177:498-505. doi: 10.1164/rccm.200708-1238OC

12. Schuetz P, Wirz Y, Sager R, et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis. Lancet Infect Dis. 2018;18:95-107. doi: 10.1016/S1473-3099(17)30592-3

13. Schuetz P, Chiappa V, Briel M, et al. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med. 2011;171:1322-1331. doi: 10.1001/archin ternmed.2011.318

14. 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. doi: 10.1186/s13054-018-2125-7

15. Elnajdy D, El-Dahiyat F. Antibiotics duration guided by biomarkers in hospitalized adult patients; a systematic review and meta-analysis. Infect Dis (Lond). 2022;54:387-402. doi: 10.1080/23744235.2022.2037701

16. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021;49:e1063-e1143. doi: 10.1097/CCM.0000000000005337

17. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43:304-377. doi: 10.1007/s00134-017-4683-6

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.^5-11Indeed, 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.

This trial demonstrated the benefit of PCT-guided antimicrobial therapy in reducing infection-associated AEs, length of antibiotic treatment, and 28-day mortality for patients with sepsis.

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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