Strategies and Implementation: Pre-authorization vs. Post-prescription Edina Avdic, Pharm.D., MBA, BCPS, AQ-ID Associate Director, Antimicrobial Stewardship Program Program Director, Infectious Diseases Pharmacy Residency The Johns Hopkins Hospital

Objectives State one advantage and one disadvantage for each pre-authorization and prospective audit and feedback review strategy

The Johns Hopkins Hospital (JHH) Tertiary academic medical center 1,194 beds 205 pediatric beds Adult patient care 6 adult ICUs Oncology center Organ transplant Multiple surgical and medicine services and subspecialties OB/GYN Training Residency and fellowship training in various disciplines

Antimicrobial Stewardship Program at The Johns Hopkins Hospital Adult Program - 2002 0.75 ID physician, 1ID pharmacist 2014-second ID pharmacist 2016-second ID physician Additional support Clinical pharmacy specialists-2002 ID fellows-2002 ID pharmacy resident-2007 Clinical pharmacists-2014 Collaborators Hospital epidemiology & infection control Microbiology laboratory Pharmacy ID division Medicine and surgery departments

Stewardship Strategies Revision and publication of Antibiotic Guidelines Pre-authorization (PPA) Post-prescription review with feedback (PPRF) IV to PO conversion Dose optimization Syndrome interventions Rapid diagnostics interventions Pharmacy-driven interventions Education and research

Formulary Restrictions and Pre-Authorization (PPA) at JHH Pre-authorization-implemented in 1980s by ID division Authorized prescriber pages “antibiotic approval pager” between 8 am-10 pm 7 days per week In 2002 responsibility and oversight was transferred to ASP ID pharmacist and clinical pharmacy specialists answer pager from 8 am-4 pm M-F 3 ID pharmacists answer pager during the day M-F as of 2015 Clinical pharmacy specialists grant approvals for their services Evenings and weekends ID fellows answer pager >30 restricted antimicrobials Selected antimicrobials require approval by ASP team member 24/7 All non-formulary agents require approval

Why Did We Want to Compare Two Core ASP Strategies? Both strategies have been effective in reducing antibiotic use in the healthcare setting Each strategy has its pros and cons No study comparing the two strategies head-to-head Most of our stewardship resources were dedicated to pre-authorization Post-prescription review with feedback was not routinely performed by ASP We were curious to see which strategy was more effective in our hospital -This also leads to unnecessary antibiotic use and ADEs

Study Setting 4 medicine firms (internal medicine services) Assistant Chief of Service (ACS) is attending for the entire year Internal medicine housestaff assigned to the same firm throughout residency Dedicated internal medicine clinical pharmacy specialists Approve restricted antimicrobials & recommend de-escalation ASP: 1 ID pharmacist and 0.75 ID physician Grants approval for ASP restricted antimicrobials, back up for clinical pharmacy specialist Patients General internal medicine problems Always admitted to the same firm Tamma PD, et al. Clin Infect Dis 2017;64(5):537-543

Study Participants Adult inpatients on general wards admitted to 1 of the 4 medicine “firm” services Timing: September 2013 to June 2014 Patients were included if they were receiving antimicrobial therapy Exclusions: Chronic prophylactic antimicrobials Antimicrobials used for non-infectious reasons Patients who were on firm service <24 hours Tamma PD, et al. Clin Infect Dis 2017;64(5):537-543

Antibiotics and Restrictions AmBisome* Ceftriaxone Linezolid* Amikacin* Cephalexin Meropenem* Amoxicillin Ciprofloxacin* Metronidazole Amoxicillin/clavulanate Clarithromycin Micafungin* Amphotericin B decoxicolate Clindamycin Moxifloxacin Ampicillin Colistin* Nitrofurantoin Ampicillin/sulbactam Dapsone Norfloxacin Azithromycin Daptomycin** Oxacillin Aztreonam* Doxycycline Penicillin Cefazolin Dicloxacillin Piperacillin/tazobactam* Cefepime* Ertapenem Rifampin Cefotetan Ethambutol Tigecycline* Cefpodoxime Fluconazole* Trimethoprim/sulfamethoxazole Ceftaroline** Fosfomycin* Tobramycin Ceftazidime* Gentamicin Vancomycin* *Restricted to standard approval; **Restricted to ASP approval 24/7

Study Design Tamma PD, et al. Clin Infect Dis 2017;64(5):537-543 We conducted a qua- si-experimental, crossover trial of PPA and PPRF in 4 medical wards at The Johns Hopkins Hospital (JHH) to compare these 2 antibiotic stewardship strategies in the acute-care setting. Tamma PD, et al. Clin Infect Dis 2017;64(5):537-543

Intervention Pre-authorization arm Post-prescription arm Approvals granted by firm pharmacist/ID fellow Post-prescription arm All restrictions were removed At 48-72 hours ASP team (ID physician and ID pharmacist) visited team in person to provide feedback M-F, including a printed description of the case with recommendations Recommendations were not documented in the chart Clinical specialties refrained from commenting on antimicrobial therapy If results of diagnostic data were not yet available, recommendations were made once this information was known. If the patient was being seen by the infectious diseases consult service at the time of PPRF, the ASP discussed its recommendations with the consult service prior to making recommendations to the firm. Tamma PD, et al. Clin Infect Dis 2017;64(5):537-543

Results: Antibiotic Indications   Most Common Indications on Day 3 PPA N=473 PPRF N=447  P-value Urinary tract infection 24.9% 23.5 0.71 Skin and soft tissue infection 16.7% 13.3% 0.26 Community-acquired pneumonia 11.9% 14.4% 0.41 Osteoarticular infection 10% 9.1% 0.68 Clostridium difficile infection 7.8% 8.5% 0.77 COPD exacerbation 7.4% 7.9% 0.88 Intra-abdominal infection 6.8% 5.9% 0.74 Healthcare-associated pneumonia 6.3% 5.1% 0.60 Aspiration pneumonia 2.6% 4.2% 0.39 As adjudicated by ASP team Top 3 indications were present on day 1 PPA-pre-authorization; PPRW-post-prescription review with feedback Tamma PD, et al. Clin Infect Dis 2017;64(5):537-543

Results: Antibiotic Therapy Day 1 Day 3   PPA N=778 PPRW N=730 P-value Antibiotic regimen inappropriate 33.7% 41.1% <0.01 57.3% 36.4% Antibiotic therapy not indicated 17.7% 22.1% 0.04 35.5% 23.6% No bacterial infection 15.7% 19.3% 0.07 30.7% 16.0% Antibiotic therapy too broad 14.5% 17.9% 0.08 20.9% 12.3% Unnecessarily broad GN coverage 4.2% 6.7% 6.2% 4.1% 0.17 PPA-pre-authorization; PPRW-post-prescription review with feedback Tamma PD, et al. Clin Infect Dis 2017;64(5):537-543

Results: Days of Antibiotic Therapy PPA Median LOT in PPA and PPRF was 7 and 5 days (p<0.01) PPRF PPRF Time series analysis PPA Tamma PD, et al. Clin Infect Dis 2017;64(5):537-543

Results: Clinical Outcomes There were no differences in CDI episodes, duration of hospital stay or in-hospital mortality between the two study arms CDI episodes: 4% in PPA vs. 3% in PPRF (p=0.4) Median duration of hospital stay: 3 days in both groups (p=0.99) In-hospital mortality: 11% in PPA vs. 14% in PPRF (p=0.44) Tamma PD, et al. Clin Infect Dis 2017;64(5):537-543

Audience Question #4 Which of the following statements is FALSE about pre-authorization and prospective audit and feedback? Pre-authorization is a real time resource intensive in comparison to prospective audit and feedback Neither intervention effective in reducing antibiotic use Pre-authorization optimizes empiric antibiotic choices Prospective audit and feedback optimizes de-escalation and duration of therapy

Conclusions Pre-authorization can significantly reduce inappropriate therapy on day 1 Influencing unnecessary antibiotic starts and unnecessary broad spectrum gram-negative coverage Post-prescription review can significantly reduce inappropriate therapy on day 3 Influencing antibiotic discontinuation when no infection has been identified and de-escalating broad spectrum antibiotics Post-prescription can significantly reduce overall antibiotic duration of therapy Combination of both type of interventions would be ideal for antimicrobial stewardship programs

Questions ? Thank you! Email: eavdic1@jhmi.edu

Results: Antibiotic Therapy Day 1 Day 3   PPA N=778 PPRW N=730 P-value Antibiotic regimen inappropriate 33.7% 41.1% <0.01 57.3% 36.4% Antibiotic therapy not indicated 17.7% 22.1% 0.04 35.5% 23.6% No bacterial infection 15.7% 19.3% 0.07 30.7% 16.0% Treatment course completed 1.2% 1.5% 0.65 2.9% 5.8% 0.03 Prophylaxis not indicated 0.9% 0.62 1.9% 1.7% 1.0 Antibiotic therapy too broad 14.5% 17.9% 0.08 20.9% 12.3% Unnecessary redundant-coverage 2.2% 0.57 1.1% 0.28 Unnecessary MRSA coverage 5.0% 4.9% 1.00 6.5% 3.7% 0.06 Unnecessary broad GN coverage 4.2% 6.7% 6.2% 4.1% 0.17 Unnecessary GN coverage 1.8% 0.69 3.8% Unnecessary GP coverage 0.6% 0.4% 0.73 1% 0% n/a Unnecessary anaerobic coverage 0.16 0.59 Antimicrobial therapy too narrow 0.7% 0.43 Equally effective, more cost-effective options existed 0.3% 0.68 0.2% PPA-pre-authorization; PPRW-post-prescription review with feedback; GN-gram negative; GP-gram positive Tamma PD, et al. Clin Infect Dis. 2017;64(5):537-543