Antimicrobial stewardship in managing septic patients November 11, 2017 Samuel L. Aitken, PharmD, BCPS (AQ-ID) Clinical Pharmacy Specialist, Infectious Diseases slaitken@mdanderson.org
Conflict of interest statement I have no conflicts of interest relevant to the content of this presentation Advisory boards within the last 12 months The Medicines Company Zavante Therapeutics Achaogen Melinta Current / pending research support Merck The Medicines Company
Objectives 1. Identify when and why to de-escalate antibiotics in critically ill patients 2. Discuss methods for incorporating antimicrobial stewardship in the ICU
The guideline-driven approach to antimicrobials Selection recommend empiric broad-spectrum therapy with one or more antimicrobials (strong, moderate) recommend against combination therapy for the routine treatment of neutropenic sepsis/bacteremia (strong, moderate) De-escalation recommend that empiric antimicrobial therapy be narrowed once pathogen identification and sensitivities are established and/or adequate clinical improvement is noted (BPS) recommend de-escalation within the first few days in response to clinical improvement this applies to both targeted and empiric combination therapy (BPS) recommend daily assessment for de-escalation (BPS) Rhodes S, et al. Crit Care Med 2017;45(3):486-552
De-escalation does not have a consistent definition Commonly used synonyms for de-escalation: Narrowing Streamlining Reducing How I prefer to think of de-escalation: Targeting specific organisms Stopping unnecessary drug therapy One component of antimicrobial stewardship programs
Rationale for broad-spectrum antimicrobial use
Early initiation of appropriate antibiotics determines mortality in septic patients Treatment directed at the likely pathogen and resistance pattern is essential Kumar A, et al. Chest 2006;34(6):1589-96
Percent of confirmed infections MD Anderson Four primary pathogens account for half of microbiologically-confirmed sepsis 25 21.4 20 15 14.7 10 7.7 7.3 5 0 E. coli S. aureus K. pneumoniae P. aeruginosa Primary pathogen identified in 71% of all cases of sepsis Kumar A, et al. Chest 2009;136(5):1237-48
Just how common is antibiotic resistance in the ICU? Antibiotic resistance is not as common as we think at a national level Resistant organisms still must be considered in empiric therapy Sader HS, et al. Diagnostic Microbiol Infect Dis 2014;78:443-8
Like politics, all resistance is local Site-specific antibiograms are frequently different than national averages Local epidemiology is key to rational antimicrobial selection Aitken SL. Unpublished data
Why is antibiotic de-escalation and discontinuation important?
Definitive combination therapy with aminogylcosides for bacteremia likely does more harm than good Nephrotoxicity 64% lower in monotherapy group (number needed to harm: 15) Similar results seen in pediatric patients Paul M,, et al. BMJ 2004;328(7441):668 Tamma PD, et al. JAMA Pediatr 2013;167(10):903-10
Combination therapy is no better as definitive therapy even for P. aeruginosa infections Other studies show no benefit of definitive combination therapy in P. aeruginosa ventilator-associated pneumonia Role of combination empiric therapy is still being debated Paul M, et al. Clin Infect Dis 2013;57(2):217-20 Garnacho-Montero J, et al. Crit Care Med 2007;35(8):1888-95
Vancomycin and piperacillin-tazobactam are synergistically nephrotoxic Onset of nephrotoxicity is sooner than with vancomycin and other β-lactams Limited data in critically ill patients, but overall findings are similar Critically ill pediatric patients also see increased nephrotoxicity Luther M, et al. Crit Care Med 2017;ePub ahead of print (Oct. 28) Holsen MR, et al. Pediatr Crit Care Med 2017;ePub ahead of print (Sep. 12)
Percentage of patients MD Anderson C. difficile risk increases with cumulative antibiotic use 40 35 30 25 20 15 10 5 0 < 4 4-7 8-18 > 18 Duration of antibiotic therapy CDI Cases Non-CDI Controls Cumulative number of antibiotics used also increases CDI risk Stevens V, et al. Clin Infect Dis 2011;53(1):42
Percent with antibiotic exposure MD Anderson Prolonged carbapenem use leads to colonization with carbapenem-resistant Gram negatives 70 60 50 40 30 20 10 0 0 days 1-3 days 4-21 days Duration of prior imipenem exposure Colonized Non-colonized Majority of resistance occurred through non-transmissible mechanisms Armand-Lefèvre, et al. Antimicrob Agents Chemother 2013;57(3):1488-95
Infection with resistant organisms is a predictable consequence of prolonged antibiotic use Percent with prior receipt of antibiotics MDR P. aeruginosa No MDR P. aeruginosa p-value Carbapenem, > 3 days 27 13 0.002 Fluoroquinolone, > 4 days 27 13 0.001 Aminoglycoside, >5 days 32 16 <0.001 Cefepime, > 9 days 16 5 0.001 Pip-tazo, > 12 days 34 17 <0.001 MDR multidrug resistant If antibiotics aren t needed, stop them as soon as possible Just in case can have serious consequences down the road Lodise TP, et al. Antimicrob Agents Chemother 2007;51(2):417-22 Lodise TP, et al. Infect Control Hosp Epidemiol 2007;28(8):959-65
But is antibiotic de-escalation actually safe in the ICU? All studies performed to this point have major bias The data on downstream development of resistance are terrible Tabah A, et al. Clin Infect Dis 2016;62(8):1009-17
How can stewardship be successfully implemented in the ICU?
The key to stewardship is a team-based approach Critical care Infection control Infectious diseases The patient! Informatics Antimicrobial stewardship Clinical microbiology
The MD Anderson approach to stewardship - ABX Aitken SL, ICAAC 2015 Tverdek FP, et al. J Antimicrob Stewardship 2017; in press Targeted antibiotics Daptomycin Linezolid Meropenem Tigecycline Vancomycin Ceftazidime-avibactam Ceftolozane-tazobactam Targeted services Leukemia Stem cell transplantation Lymphoma / myeloma All ID consultant services
A completely passive email reduces antibiotic use No active enforcement or verification of responses Semi-regular compliance summaries provided at the departmental level Aitken SL, ICAAC 2015 Tverdek FP, et al. J Antimicrob Stewardship 2017; in press
Time for a time-out? Anyone on the team can do a checklist assessment Can easily be customized to meet your needs Aitken SL, ECCMID 2016
Percent of eligible patients MD Anderson Antibiotic checklists are safe and effective 30 25 20 15 10 5 0 p = 0.50 p = 0.62 p = 0.57 p = 0.62 1.4 3.2 Admit to ICU within 7 days 15.7 12.7 New documented infection Checklist 15.9 12.9 Recurrent fever Historic controls 18.6 19.1 Restart of antibiotic Antibiotic discontinuation rate at day 3 increased from 56% to 73% with checklist Required active maintenance and nudging to force use Aitken SL, ECCMID 2016
Conclusions Broad-spectrum antibiotics frequently are not needed Prolonged use of any antibiotic can have serious downstream consequences De-escalation may help prevent some of these bad outcomes Stewardship needs to be individualized to the patient and the hospital
Acknowledgements The MDACC Antimicrobial Stewardship Team Micah Bhatti Farnaz Foolad Pat McDaneld Frank Tverdek Victor Mulanovich
Antimicrobial stewardship in managing septic patients November 11, 2017 Samuel L. Aitken, PharmD, BCPS (AQ-ID) Clinical Pharmacy Specialist, Infectious Diseases slaitken@mdanderson.org