Impact of Procalcitonin Guidance on Management of Adults Hospitalized with Pneumonia and COPD Exacerbations Derek N. Bremmer, PharmD, BCPS March 10, 2018 Inaugural Three Rivers Antimicrobial Stewardship Symposium

Author Disclosures Authors of this presentation have no disclosures to report concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation.

Objective 1) Discuss the implementation of procalcitonin and the associated outcomes among hospitalized patients with pneumonia and COPD exacerbations.

Background Recent studies have found respiratory viruses to be as common as bacterial pathogens in cases of community-acquired pneumonia (CAP). Traditional culture-based methods, including sputum cultures and blood cultures, provide an etiologic agent in few patients. Therefore, there has been an increased emphasis on the role of biomarkers and molecular methods to help determine a causative pathogen in pneumonia. Procalcitonin (PCT) is a biomarker which has demonstrated the ability to differentiate bacterial versus viral etiologies in lower respiratory tract infections, including pneumonia. Musher DM et al. J Infect. 2013;67:11-8. Jain S et al. N Engl J Med. 2015;373:415-27. Musher DM et al. N Engl J Med. 2014;371:1619-28. Ewig S et al. Chest. 2002;121:1486-92. Haubitz S et al. Expert Rev Respir Med. 2013;7:145-57. Christ-Crain M et al. Eur Respir J. 2007;30:556-73.

Procalcitonin Muller B et al. J Clin Endocrinol Metab. 2001; 86(1):396-404. Christ-Crain M et al. Eur Respir J. 2007; 30(3):556-73. Linscheid P et al. Endocrinology. 2005; 146(6):2699-708. Haeruptle J et al. Eur J Clin Microbiol Infect Dis. 2009; 28(1):55-60. Meisner M. Clin Chem Lab Med. 2000; 38(10):989-95.

ProHosp Study Large multicenter trial > 1300 pts Procalcitonin arm reduced antibiotic exposures: ↓ by 32.4% in CAP; 50.4% in exacerbated COPD No difference in composite outcome including: death, ICU admission, disease-specific complications, or recurrent infection requiring antibiotic treatment within 30 days. Reduction in antibiotics was associated with an approximate 30% decrease in reported side effects. Schuetz P et al. JAMA. 2009;302:1059-66.

Meta-analysis of Procalcitonin Guidance on Management of Acute Respiratory Infections Meta-analysis including 14 prospective randomized trials with 4221 patients Reduced antibiotic exposure: 8d vs. 4d No increase in mortality or treatment failure Schuetz P et al. Clin Infect Dis. 2012;55:651-62.

Procalcitonin Use in Pneumonia and COPD Procalcitonin (PCT) has been studied extensively in randomized controlled trials (RCTs). These prospective RCTs utilize PCT to facilitate the decision of: Determine which patients with pneumonia and COPD exacerbations require antibiotic therapy. Determine when antibiotics may be discontinued safely. In these studies, use of PCT levels results in lower rates of antibiotic exposure without an increase in mortality or treatment failure. Limited data on applicability of PCT use in hospitalized patients outside of controlled study conditions. Christ-Crain M et al. Lancet. 2004;363:600-7. Christ-Crain M et al. Am J Respir Crit Care Med. 2006;174:84-93. Schuetz P et al. JAMA. 2009;302:1059-66. Schuetz P et al. Clin Infect Dis. 2012;55:651-62. Schuetz P et al. JAMA. 2013;309:717-8. Schuetz P et al. Eur J Clin Microbiol Infect Dis. 2010;29:269-77. Albrich et al. Arch Intern Med. 2012;172:715-722.

Implementation of Procalcitonin Availability of procalcitonin Turnaround time Development of a clinical decision making algorithm Key stakeholders Results are back within a couple of hours

Procalcitonin Algorithm Walsh TL et al. Am J Med. 2018; 131(2):201.e1-8. Bremmer DN et al. J Gen Intern Med. 2018; Epub ahead of print.

Procalcitonin Education Education regarding algorithm included: Lectures to house staff and faculty Disseminated algorithm via electronic mail Added algorithm to yearly antimicrobial guide Laminated copies posted in nursing units and residency departments Bi-folded pocket cards distributed to internal medicine practitioners Walsh TL et al. Am J Med. 2018; 131(2):201.e1-8. Bremmer DN et al. J Gen Intern Med. 2018; Epub ahead of print.

Non-infectious Factors That May Elevate Procalcitonin End stage renal disease Surgery or trauma Rhabdomyolysis Cardiogenic shock with vasopressor support Meisner M. Ann Lab Med. 2014; 34:263-73.

Allegheny General Hospital and Western Pennsylvania Hospital Experiences With Procalcitonin

Design Design: Retrospective pre/post intervention cohort study Setting: 2 academic medical centers in Pittsburgh PA Allegheny General Hospital and Western Pennsylvania Hospital Inclusion criteria: Pre-intervention: All patients with a primary diagnosis of pneumonia and COPD using ICD-9 criteria Post-intervention: All patients with a primary diagnosis of pneumonia and COPD using ICD-9 and ICD-10 criteria who had a PCT obtained within 24 hours of admission Study Periods: Pre-intervention: 3/1/14 – 10/31/14 Post-intervention: 3/1/15 – 10/31/15 Walsh TL et al. Am J Med. 2018; 131(2):201.e1-8. Bremmer DN et al. J Gen Intern Med. 2018; Epub ahead of print.

Exclusion Criteria Age < 18 years PCT not obtained within 24 hours of admission (post- intervention) Transfer from outside hospital or left against medical advice Admission to Intensive Care Unit (ICU) within initial 24 hours of admission Concomitant non-pulmonary bacterial infection Immunocompromised status Unable to determine duration of antibiotics prescribed upon discharge Complicated pneumonia, defined as: Staphylococcus aureus or GNR bacteremia Cavitary lung lesion Lung abscess Mechanical ventilation Empyema Walsh TL et al. Am J Med. 2018; 131(2):201.e1-8. Bremmer DN et al. J Gen Intern Med. 2018; Epub ahead of print.

Endpoints Primary: Secondary: Duration of antibiotic therapy Duration of IV antibiotic therapy Hospital length of stay (LOS) All cause 30 day re-admission to hospital Respiratory related re-admission within 30 days Walsh TL et al. Am J Med. 2018; 131(2):201.e1-8. Bremmer DN et al. J Gen Intern Med. 2018; Epub ahead of print.

Pneumonia Cohort Walsh TL et al. Am J Med. 2018; 131(2):201.e1-8.

Background Demographics: Pneumonia Cohort Characteristic Pre-Intervention (n = 152) Post-Intervention (n = 232) P value Age, years (SD) 65.0 (16.8) 64.0 (18.0) 0.60 Female sex, n (%) 76 (50.0) 124 (53.5) 0.53 Race, n (%)   0.88 Caucasian 112 (73.7) 174 (75.0) African American 35 (23.0) 49 (21.1) Other 5 (3.3) 9 (3.9) Chronic lung disease, n(%) 96 (41.4) 0.12 Use of home oxygen, n (%) 31 (20.4) 33 (14.2) CAP, n (%) 107 (70.4) 136 (58.6) 0.02 Walsh TL et al. Am J Med. 2018; 131(2):201.e1-8.

Primary Outcome: Pneumonia Cohort Variable Pre-Intervention (n = 152) Post-Intervention (n = 232) P value Total antibiotic duration, days (SD) 9.9 (3.3) 6.0 (3.8) <0.01 Intravenous antibiotic duration, days (SD) 5.0 (3.1) 3.3 (2.4) Hospital length of stay, days 4.9 3.5 0.01 All-cause 30-day readmission, n (%) 22 (14.5) 35 (15.1) 0.99 Pneumonia related 30-day readmission, n (%) 11 (7.2) 10 (4.3) 0.26 Walsh TL et al. Am J Med. 2018; 131(2):201.e1-8.

Pneumonia Cohort Summary Implementation of procalcitonin guidance at our institutions was associated with: Reduced duration of antibiotics Reduced hospital length of stay No difference in hospital re-admissions Walsh TL et al. Am J Med. 2018; 131(2):201.e1-8.

COPD Cohort Bremmer DN et al. J Gen Intern Med. 2018; Epub ahead of print.

COPD Additional Background GOLD guidelines recommend antibiotics should be given to patients with acute exacerbations who have three cardinal symptoms: Increase in dyspnea, sputum volume, and sputum purulence Have 2 of the cardinal symptoms, if increased purulence of sputum is one of the two symptoms Or require mechanical ventilation Statement from American College of Physicians and the Centers for Disease Control and Prevention: “Determining whether a patient has a viral or non-viral cause can be difficult. The presence of purulent sputum or a change in its color does not signify bacterial infection; purulence is due to the presence of inflammatory cells or sloughed mucosal epithelial cells.” Up to 46% of COPD exacerbation patients are infected with viruses Vogelmeier CF et al. Am J Respir Crit Care Med. 2017: 195(5):557-82. Harris AM et al. Ann Intern Med. 2016: 164(6):425-34. Lieberman D et al. Chest. 2002; 122(4):1264-70.

Procalcitonin in COPD Meta-analysis Meta-analysis including 8 randomized trials with 1062 patients with COPD exacerbations Reduced antibiotic exposure by 3.83 days No differences in clinical outcomes including: Rate of treatment failure Hospital LOS Exacerbation recurrence Mortality Mathioudakis AG et al. Eur Respir Rev. 2017; 26(143):pii: 160073.

Background Demographics: COPD Cohort Characteristic Pre-Intervention (n = 166) Post-Intervention (n = 139) P value Age, years (SD) 66 (12.6) 66 (13.3) 0.82 Female sex, n (%) 92 (55.4%) 94 (67.6%) 0.03 Race, n (%) 0.46 Caucasian 103 (62.1%) 89 (64.0%) African American 55 (33.1%) 47 (33.8%) Other 8 (4.8%) 3 (2.2%) Use of home oxygen, n (%) 57 (34.3%) 54 (38.9%) 0.42 Bremmer DN et al. J Gen Intern Med. 2018; Epub ahead of print.

Outcomes: COPD Cohort Variable Pre-Intervention (n = 166) Post-Intervention (n = 139) P value Total antibiotic duration, days (SD) 5.3 (3.2) 3.0 (2.9) 0.01 Intravenous antibiotic duration, days (SD) 2.5 (2.4) 1.9 (1.8) 0.02 Hospital length of stay, days 4.1 (3.9) 2.9 (2.0) All-cause 30-day readmission, n (%) 24 (14.5%) 23 (16.6%) 0.25 Respiratory related 30-day readmission, n (%) 18 (10.8%) 13 (9.4%) 0.18 16 (11.5%) patients had an elevated procalcitonin (> 0.25 µg/mL) Bremmer DN et al. J Gen Intern Med. 2018; Epub ahead of print.

COPD Cohort Summary Implementation of procalcitonin guidance at our institutions was associated with: Reduced duration of antibiotics Reduced hospital length of stay No difference in hospital re-admissions

Limitations and Strengths Retrospective Severe COPD and pneumonia patients may not have had a procalcitonin Post-discharge data analysis was limited to re-admissions to AGH and WPH Outpatient compliance Education for procalcitonin included duration education Strengths: Real world experience of procalcitonin guidance Defined population based on exclusion criteria ICD 9 – may have led to underestimation of number of pneumonia patients Given in post-intervention cohort if did not have a procalcitonin was excluded – if providers would not have changed therapy regardless of procalcitonin value Visits to other inpatient facilities, urgent care centers, and physicians’ outpatient offices may have been missed, leading to an inability to determine rates of treatment failure or the need to extend or re-introduce antibiotic therapy Shorter durations of therapy in patients with low PCT levels compared to those with elevated PCT levels in the post-intervention cohort suggests that while education may have augmented the shorter mean total duration, PCT guidance remained the driving factor Walsh TL et al. Am J Med. 2018; 131(2):201.e1-8. Bremmer DN et al. J Gen Intern Med. 2018; Epub ahead of print.

Assessment Question Which of the following is not true regarding the impact of procalcitonin guidance for pneumonia and COPD exacerbations? Procalcitonin guidance has been associated with a decreased total duration of antibiotics. Procalcitonin guidance has been associated with an increased rate of hospital re-admissions when utilized for patients with pneumonia or COPD exacerbations. Procalcitonin concentrations are elevated in the setting of renal dysfunction.

Assessment Question Which of the following is not true regarding the impact of procalcitonin guidance for pneumonia and COPD exacerbations? Procalcitonin guidance has been associated with a decreased total duration of antibiotics. Procalcitonin guidance has been associated with an increased rate of hospital re-admissions when utilized for patients with pneumonia or COPD exacerbations. Procalcitonin concentrations are elevated in the setting of renal dysfunction.

Thanks to my co-investigators Thomas Walsh, MD Rasha Abdulmassih, MD Briana DiSilvio, MD Jina Makadia, MD Crystal Hammer, MD Rikinder Sandhu, MD Moeezullah Beg, MD Mouhib Naddour, MD Swati Vishwanathan, MD Noreen Chan-Tompkins, PharmD Daniel Speredelozzi, MD Tamara Trienski, PharmD Matthew Moffa, DO Courtney Watson, MPH Kurt Hu, MD Jim Kuzyck, MT

Impact of Procalcitonin Guidance on Management of Adults Hospitalized with Pneumonia and COPD Exacerbations Derek N. Bremmer, PharmD, BCPS March 10, 2018 Inaugural Three Rivers Antimicrobial Stewardship Symposium