Evaluation of susceptibility patterns of Pseudomonas aeruginosa in respiratory vs. non-respiratory infections and implications for empiric treatment Stephanie Weisberg, PharmD PGY-1 Pharmacy Resident St. Joseph’s/Candler Health System Co-Investigators: Natalie Labrador, PharmD Candidate 2017; Geneen Gibson, PharmD, MS, BCPS (AQ-ID)

Disclosure Statement Disclosure statement: these individuals have the following to disclose concerning possible personal or financial relationships with commercial entities (or their competitors) that may be referenced in this presentation Stephanie Weisberg, PharmD: nothing to disclose Natalie Labrador, PharmD Candidate: nothing to disclose Geneen Gibson, PharmD, MS, BCPS (AQ-ID) : nothing to disclose

Background Pseudomonas aeruginosa Non-lactose fermenting Gram negative bacillus Potential for multi-drug resistance Suspected pathogen in many healthcare-associated infections Pier (2015) Mandell

ATS and IDSA (2005) Am J Respir Crit Care Med Background Combination Therapy Concept initially came from empiric treatment of pneumonia in patients at high risk for multidrug-resistant organisms (MDROs) At St. Joseph’s/Candler Health System Extrapolated and applied to other infections Sometimes used for definitive treatment, after susceptibilities are known Including combination of inhaled and systemic antibiotics ATS and IDSA (2005) Am J Respir Crit Care Med

Background Current IDSA Guideline Recommendations: Specific criteria to evaluate pneumonia patients and make decision for mono- vs. combination empiric therapy Goal of combination therapy is to empirically treat 95% of patients with agent active against pathogen No recommendations for combination therapy outside of pneumonia and septic shock Kalil (2016) Clin Infect Dis Rhodes (2016) Intensive Care Med Stevens (2014) Clin Infect Dis Hooton (2010) Clin Infect Dis

Background Current IDSA Guideline Recommendations: Do not use combination therapy for definitive treatment unless patient remains in septic shock or at high risk of death Use of inhaled antibiotics in combination with systemic antibiotics only recommended for pneumonia caused by Gram-negative bacillus susceptible to only aminoglycosides or polymixins Kalil (2016) Clin Infect Dis Rhodes (2016) Intensive Care Med

Study Objectives Primary Objective Secondary Objectives Susceptibility patterns of P. aeruginosa from respiratory sources compared to non-respiratory sources Secondary Objectives Impact of prescribed empiric treatment on Total antibiotic days of therapy Use of combination definitive treatment Use of inhaled antibiotics Adverse drug events Total antibiotic cost

Study Center St. Joseph’s/Candler Health System Community health system with 714 inpatient beds divided between two anchor hospitals

Methods Study design Population Retrospective, observational investigation Population Adult inpatients treated at St. Joseph’s/Candler Health System from August 1, 2015 to July 31, 2016 that were initiated on empiric antibiotics for the treatment of P. aeruginosa from respiratory, blood, wound, urinary or other source

Methods Inclusion Criteria: Exclusion Criteria: Adults  18 years of age Treated inpatient at St. Joseph’s/Candler from August 1, 2015 to July 31, 2016 Positive culture for P. aeruginosa from respiratory, blood, wound, urinary, or other source Treated with empiric antibiotics for at least 24 hours Exclusion Criteria: Positive culture for another gram-negative organism during admission that resulted prior to or at the same time as P. aeruginosa Urine culture growing < 100,000 CFU Included at prior visit Lack of susceptibility data

Methods Primary Outcomes Percentage of isolates susceptible to at least one agent in the first-prescribed empiric regimen Percentage of isolates susceptible to first-prescribed empiric anti-pseudomonal β-lactam Percentage of isolates susceptible to individual non-β-lactam agent in first-prescribed empiric regimen

Methods Secondary Outcomes Total antibiotic days of therapy (Gram-negative active agents only) Combination therapy for definitive treatment Use of inhaled antibiotics Adverse drug events Assay documented C. difficile infection after receiving empiric therapy Total antibiotic cost (Gram-negative active agents only)

Methods Treatment Groups Categorized based on source of infection Respiratory Non-Respiratory Wound, urine, blood, other Primary and secondary outcomes were compared between groups

Methods Data analysis Chi-square or Fisher’s exact tests were used for categorical variables Student’s t-test was used for continuous variables p<0.05 was considered statistically significant

Patient Selection 526 patients screened 391 patients met inclusion criteria *Exclusions: 177 second Gram negative organism 70 urine culture < 100,000 CFU 10 included previously 18 missing susceptibility data 275 patients were excluded* 526 patients screened - 135 patients (35 not PSAR, 43 not inpatient, 57 no empiric tx) 391 patients met initial inclusion - 275 patients (177 growing another gram neg, 70 urine < 100,000, 10 previous included, 18 missing susceptibility data) 116 patients analyzed (42 resp, 74 non-resp) 42 patients in respiratory group 74 patients in non-respiratory group

Demographics Respiratory n = 42 Non-Respiratory n = 74 p-value 0.0004 Age (years ± SD) 66.0 ± 14.4 67.5 ± 14.6 0.5941 Gender, n(%) Male 21 (50.0) 48 (64.9) 0.1177 Female 26 (35.1) SBP (mm Hg ± SD) 125 ± 20 133 ± 26 0.0874 DBP (mm Hg ± SD) 72 ± 16 73 ± 14 0.7263 # of SIRS Criteria (AVG ± SD) 1.57 ± 1.11 1.16 ± 1.07 0.0528 # of MDRO Risk Factors (AVG ± SD) 1.76 ± 1.49 0.93 ± 0.94 0.0004   IV ABX w/in 90 days, n(%) 19 (45.2) 46 (62.2) 0.0775 ICU Admission, n(%) 8 (10.8) < 0.0001 Mechanical Ventilation, n(%) 20 (47.6) 3 (4.1) High Invasive Device Score*, n(%) 16 (38.1) 12 (16.2) 0.0083 Combination Empiric Therapy, n(%) 15 (20.3) 0.0382 *Presence of both a Foley catheter and a central line

Primary Outcomes p = 0.041 p = 0.0186 p = 0.6974

Secondary Outcomes Respiratory n = 42 Non-Respiratory n = 74 p-value Total Antibiotic Days (Days ± SD) 14.95 ± 12.85 9.27 ± 7.16 0.0027 Combination Definitive Treatment, n(%)   Including inhaled antibiotics 21 (50.0) 9 (12.2) < 0.0001 Systemic antibiotics only 10 (23.8) 0.1064 Inhaled antibiotics, n(%) 14 (33.3) - Adverse Drug Events, n(%) 2 (4.76) 6 (8.11) 0.4957 Diarrhea 1 4 Other 2 Hospital-acquired C. difficile, n(%) 0 (0) 1 (1.35) 0.4515 Cost ($ ± SD) 11003 ± 10542 1982 ± 2008 3308 ± 6628 0.1122

Combination Empiric Therapy

Discussion The percentage of isolates susceptible to the initial empiric regimen was significantly higher in the non- respiratory group The susceptibility rates were higher for initial β-lactam than for initial non-β-lactam in both groups This statistically significant difference held up for patients with non-respiratory infections initiated on a combination empiric regimen Patients with respiratory P. aeruginosa were more likely to be treated with definitive combination therapy, most of which included inhaled antibiotics

Limitations The small, retrospective cohort nature limits the external validity of the results Due to exclusion criteria, many of the sickest patients were excluded from this study The inclusion of nebulized antibiotics introduces some bias as these are not utilized for non-respiratory sources of infection

Conclusions Patients presenting with non-respiratory sources of infection likely do not need to be started on combination empiric treatment against P. aeruginosa Antibiotic regimens should be deescalated appropriately once susceptibilities return

Acknowledgements Geneen Gibson, PharmD, MS, BCPS (AQ-ID) Bruce Jones, PharmD, BCPS Rachel Musgrove, PharmD Natalie Labrador, PharmD Candidate

Objective and Self-Assessment Presentation Objective: Identify specific patient populations or disease states that require combination therapy for empiric treatment of P. aeruginosa. Self-Assessment: Which patient or disease state factors would prompt the use of combination empiric treatment of P. aeruginosa? Respiratory source of infection AND Septic shock OR History or high risk of MDROs

References Pier, G. B., & Ramphal, R. (2015). Pseudomonas aeruginosa. In Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. Philadelphia, PA: Elsevier. American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA). Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare- associated Pneumonia. Am J Respir Crit Care Med. 2005;171:388-416. Kalil, A. C., Metersky, M. L., Klompas, M., Muscedere, J., Sweeney, D. A., Palmer, L. B., . . . Brozek, J. L. (2016, July 14). Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. Clinical Infectious Diseases, 63(5). doi:10.1093/cid/ciw353 Rhodes, A., Evans, L., Dellinger, R. P., Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2016. Intensive Care Med Intensive Care Medicine. Bliziotis, I. A., Petrosillo, N., Michalopoulos, A., Samonis, G., & Falagas, M. E. (2011, October 26). Impact of Definitive Therapy with Beta-Lactam Monotherapy or Combination with an Aminoglycoside or a Quinolone for Pseudomonas aeruginosa Bacteremia. PLoS ONE, 6(10). doi:10.1371/journal.pone.0026470

References Aloush, V., Navon-Venezia, S., Seigman-Igra, Y., Cabili, S., & Carmeli, Y. (2005, October 23). Multidrug-Resistant Pseudomonas aeruginosa: Risk Factors and Clinical Impact. Antimicrobial Agents and Chemotherapy, 50(1), 43-48. doi:10.1128/aac.50.1.43-48.2006 Stevens, D. L., Bisno, A. L., Chambers, H. F., Dellinger, E. P., Goldstein, E. J., Gorbach, S. L., . . . Wade, J. C. (2014, June 18). Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America. Clinical Infectious Diseases, 59(2). doi:10.1093/cid/ciu296 Hooton, T. M., Bradley, S. F., Cardenas, D. D., Colgan, R., Geerlings, S. E., Rice, J. C., . . . Nicolle, L. E. (2010, March 01). Diagnosis, Prevention, and Treatment of Catheter-Associated Urinary Tract Infection in Adults: 2009 International Clinical Practice Guidelines from the Infectious Diseases Society of America. Clinical Infectious Diseases, 50(5), 625-663. doi:10.1086/650482 Dellinger, R. P., Levy, M. M., Rhodes, A., Annane, D., Gerlach, H., Opal, S. M., . . . Moreno, R. (2013, January 30). Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012. Intensive Care Med Intensive Care Medicine, 39(2), 165-228. doi:10.1007/s00134-012-2769-8

Evaluation of susceptibility patterns of Pseudomonas aeruginosa in respiratory vs. non-respiratory infections and implications for empiric treatment Stephanie Weisberg, PharmD PGY-1 Pharmacy Resident St. Joseph’s/Candler Health System Co-Investigators: Natalie Labrador, PharmD Candidate 2017; Geneen Gibson, PharmD, MS, BCPS (AQ-ID)