Comparison of clinical failure between procalcitonin algorithm-compliant versus procalcitonin algorithm-non-compliant antibiotic prescribing in patients with respiratory tract infections Paola Acevedo, PharmD PGY-1 Pharmacy Practice Resident Atlantic Health System NJSHP Resident Research Forum June 9, 2016

Gonzales R, et al. Clin Infect Dis 2001;33(6): Background  Respiratory tract infections (RTIs) are one of the most common bacterial diagnoses  Current diagnostic methods lack the ability to accurately differentiate between infectious and non-infectious and between viral and bacterial RTIs  Antibiotic overuse contributes to Bacterial resistance Medical costs Drug-related adverse events 2

Schuetz P, et al. CHEST 2012;141(4): Background  Procalcitonin (PCT) is a biomarker released in response to bacterial toxins and bacteria-specific proinflammatory mediators  Studies have shown a strong correlation between elevated PCT levels and presence of systemic bacterial infections  PCT levels are currently being used to Distinguish between bacterial and non-bacterial etiologies for respiratory symptoms As a tool to reduce antibiotic exposure

Schuetz P, et al. JAMA 2013;309(7): Outcomes Associated with PCT Algorithms Meta analysis of 14 studies evaluating different RTIs Results 4211 total patients evaluated PCT Group (n = 2085) Standard of Care (n = 2126) Adjusted Odds Ratio Mortality, no (%)118 (5.7)134 (6.3)0.94 (0.71 – 1.23) Treatment failure, no (%) 398 (19.1)466 (21.9)0.82 (0.71 – 0.97) Total antibiotic exposure, d, median (IQR) 4 (0 – 8)8 (5 – 12) (-3.78 – 3.17) Conclusion PCT-guided antibiotic prescribing led to shorter duration of antibiotics and was not associated with increased mortality or treatment failure 4

5 Procalcitonin Use at Overlook Medical Center (OMC)  May 2013 PCT testing readily available for ordering  September 2013 Standardized PCT algorithm established and published on the hospital intranet

PCT VALUE < 0.1 ng/mL or drop by > 90% from initial value 0.1 – 0.25 ng/mL or drop by > 80% from initial value 0.26 – 0.5 ng/mL > 0.5 ng/mL Strongly Encourage Antibiotic Discontinuation Encourage Antibiotic Discontinuation Discourage Antibiotic Discontinuation Strongly Discourage Antibiotic Discontinuation If antibiotic therapy is initiated:  Check PCT on days 2-3, 4-5, 6-8, and every 2 days after day 8 for guidance of antibiotic therapy  Persistently elevated PCT: suspect complicated course (resistant organism, multisystem organ failure, abscess)  Falsely elevated PCT: eg, severe SIRS and non- septic shock, ARDS, trauma, postoperative, tumor (eg, medullary thyroid cancer, small-cell lung cancer), fungal infection, malaria, renal failure, pancreatitis Consider continuing antibiotics if patients are clinically unstable 6 Procalcitonin Algorithm

7 Study Overview  Rationale Assessing compliance to the PCT algorithm and its effects on clinical failure is key to determine its utility at our institution  Objectives To compare clinical failure rates in patients with a negative PCT level whose antibiotic prescribing was compliant versus non-compliant with the PCT algorithm for RTIs To describe patient related differences between algorithm compliant and noncompliant groups o Compliant: Antibiotics discontinued within 48 hours of negative PCT result

8 Study Design  Single-center, retrospective chart review  Institutional Review Board approval obtained  September 2015 to December 2015  Overlook Medical Center 504 bed community teaching medical center

9 Methods  Patient selection A report of all patients with a PCT level ≤ 0.25 ng/mL was generated through the laboratory database Patients were screened using the established inclusion and exclusion criteria

Inclusion Criteria Exclusion Criteria 10  Patients requiring antibiotics for non- RTIs  Neutropenia (ANC < 500 cells/mcL)  Intensive care unit admission at any point  Initial PCT ≤ 0.25 ng/mL with follow-up PCT > 0.25 ng/mL within 48 hours  Outpatients  RTI not suspected  Patients ≥ 18 years of age  Negative procalcitonin level (≤ 0.25 ng/mL) Methods

11 Primary Endpoint  Clinical failure defined as ≥ 1 of the following  Initiation or re-initiation of antibiotics within 7 days of negative PCT or discontinuation of therapy  Hospital readmission for RTI within 30 days of discharge  Inpatient mortality

12 Secondary Endpoints  Duration of inpatient antibiotic therapy  Occurrence of Clostridium difficile infection within 30 days of negative PCT or initiation of antibiotics, whichever occurred first  Hospital length of stay

13 Statistical Analyses  Categorical data Fisher’s exact test  Continuous data Two sample independent t-test  Ordinal data Mann-Whitney U-test (non parametric data)

191 Patients identified with negative PCT values Included n = 70 PCT Algorithm Compliant n = 42 PCT Algorithm Non-Compliant n = 28 Excluded (n = 121) Required antibiotics for non RTI (42) ICU admission at any point (35) RTI not suspected (24) Outpatient (16) Initial PCT neg. with f/u pos. within 48 hours (2) Neutropenia (2) 14 Enrollment

15 Patient Characteristic Compliant (n = 42) Non-compliant (n = 28) p-value Age, y median (IQR) 69.5 (53.25 – 86.5) 80 (70 – 86.5) Female sex27 (64.3)17 (60.7)0.804 Fever > ◦ F2 (4.8)2 (7.1)1 WBC ≥12,000 or ≤4,000, cells/mcL7 (16.7)13 (46.4)0.014 Initial negative procalcitonin value, ng/mL < – – (69) 11 (26.2) 2 (4.8) 11 (39.3) 9 (32.1) 8 (28.6) Initial PCT positive4 (9.5)6 (21.4)0.332 Infectious disease consultation9 (21.4)9 (32.1)0.405 Pulmonary consultation26 (61.9)16 (57.1)0.804 Comorbidities COPD* Asthma Heart failure Interstitial lung disease Lung cancer 12 (28.6) 5 (11.9) 12 (28.6) 1 (2.4) 4 (9.5) 12 (42.9) 4 (14.3) 6 (21.4) 1 (3.6) Data presented as n (%) unless otherwise specified *COPD = Chronic obstructive pulmonary disease Baseline Characteristics

Patient Characteristic Compliant (n = 42) Non-compliant (n = 28) p-value Respiratory Diagnosis* Aspiration pneumonia Bronchitis Community acquired pneumonia COPD exacerbation Hospital acquired pneumonia Sinusitis 4 (9.5) 3 (7.1) 27 (64.3) 6 (14.3) 2 (4.8) 0 1 (3.6) 20 (71.4) 2 (7.1) 4 (14.3) 1 (3.6) Sputum culture within 72 hrs Positive result 7 (16.7) 1 (14.3) 7 (25) 3 (42.9) Blood culture within 72 hrs Positive result 30 (71.4) 0 25 (89.3) 1 (4) Respiratory pathogen PCR panel within 72 hrs Positive result 25 (59.5) 6 (24) 17 (60.7) 3 (17.6) Legionella or Streptococcus pneumoniae urine antigen within 72 hrs Positive result 13 (31) 0 15 (53.6) Positive chest radiologic findings**17 (43.6)21 (77.8)0.009 Data presented as n (%) unless otherwise specified *Patients may have had more than one respiratory diagnosis **Defined as infiltrate, opacity, consolidation, or cannot exclude possibility of infection on chest CT or x-ray 16 Baseline Characteristics

Endpoint Compliant (n = 42) Non-compliant (n = 28) p-value Clinical failure*6 (14.3)4 (14.3) 1 Initiation or re-initiation of antibiotics within 7 days of negative PCT or discontinuation of therapy 1 (16.7)0 1 Hospital readmission for a RTI within 30 days of discharge 5 (83.3)4 (100) 1 Inpatient mortality 00 1 Data presented as n (%) unless otherwise specified * Patients may have experienced more than one reason for clinical failure 17 Results: Primary Endpoint

Endpoint Compliant (n = 42) Non-compliant (n = 28) p-value Duration of inpatient antibiotic therapy, days2 (0 – 3)5 (3 – 7)<0.001 C. difficile infection, n (%)1 (2.4)01 Hospital length of stay, days4 (3 – 8)6.5 (4 – 10)0.06 Data presented as median (interquartile range) unless otherwise specified 18 Results: Secondary Endpoints

What is the clinical failure rate for patients whose antibiotic prescribing was compliant with the PCT algorithm? A. 60% B. 21.8% C. 14.3% D. 10.1% 19 Assessment Question

Albrich WC, et al. Arch Intern Med 2012;172(9): Discussion  Overall algorithm compliance at OMC was 60% Higher than previous OMC compliance and previously described compliance rate in the US  Longer hospital length of stay in non-compliant group Higher incidence of pulmonary comorbidities o Compliant:18/42 (42.9%) o Non-compliant: 16/28 (57.1%)  Higher incidence of positive chest radiologic findings and leukocytosis in the non-compliant group  Similar rate of clinical failure in compliant group with shorter length of stay and antibiotic duration

21 Limitations  Retrospective chart review  Small sample size  Long-term follow-up Re-admissions to other hospitals/facilities or outpatient physician offices unknown  Atypical organisms may not cause an elevation in PCT levels  Lack of repeat PCT levels in the non-compliant group

22 Conclusion  Shorter duration of antibiotic use with no associated increase in clinical failure in patients whose prescribing was compliant to the PCT algorithm  Future Directions Share results with prescribers as well as the pharmacy and therapeutics committee Re-educate prescribers on the PCT algorithm Continue assessing clinical failure and PCT algorithm compliance

23 Acknowledgements  Esther King, PharmD  Patrick Curtin, PharmD, BCPS  Dimple Patel, PharmD, BCPS-AQ ID  Timothy Lise, PharmD, BCPS  Stephanie Chiu, MPH

Comparison of clinical failure between procalcitonin algorithm-compliant versus procalcitonin algorithm-non-compliant antibiotic prescribing in patients with respiratory tract infections Paola Acevedo, PharmD PGY-1 Pharmacy Practice Resident Atlantic Health System NJSHP Resident Research Forum June 9, Thank you!