Nightmare Bacteria. Disclosures. Technician Objectives. Pharmacist Objectives. Carbapenem Resistance in Carbapenem Resistance in 2017

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1 Nightmare Bacteria How to Deal with the Reality of Carbapenem-resistant Organisms Disclosures I have no conflicts of interest relative to the content of this presentation Matthew L. Brown, Pharm.D., BCPS Antimicrobial Stewardship Pharmacist, UAB Hospital Alabama Society of Health system Pharmacy Annual Clinical Meeting, Birmingham, Alabama September 29, 2017 Pharmacist Objectives Technician Objectives Describe mechanisms of carbapenem resistance Design treatment regimens for carbapenemresistant organisms Identify emerging antibiotics with activity against carbapenem resistant organisms Describe the impact of carbapenem resistance on public health Identify antibiotics used to treat carbapenemresistant organisms Recognize antibiotic doses used to treat carbapenem resistant organisms Carbapenem Resistance in 2005 Carbapenem Resistance in 2017 Braykov NB, et al. Infect Control Hosp Epidemiol. 2013;34(3) Centers for Disease Control and Prevention 2017

2 Carbapenem resistant Organisms Carbapenem Resistance Mechanisms Growing threat to public health Enterobacteriaceae Pseudomonas aeruginosa Acinetobacter baumannii Limited therapeutic options High mortality rate Tacconelli E, et al. WHO 2017 Kaye KS, et al. Pharmacotherapy 2015;35(10): Carbapenemase producers KPC OXA NDM IMP VIM Carbapenem resistant Organisms Non carbapenemase producers Contain combinations of: ESBL AmpC Porin mutations Efflux pumps Altered binding sites Clinical and Laboratory Standards Institute 2017 Gniadek TJ, et al. J Clin Microbiol 2016;54: Antibiotic Armamentarium Treatment Considerations Core agents Adjunctive Agents Carbapenem + polymyxin Ceftazidime avibactam Meropenem vaborbactam Aminoglycoside Tigecycline Fosfomycin Rifampin Ertapenem Combination vs. monotherapy Site of infection Dose optimization Duration of therapy Adverse effects Role of novel agents Perez F, et al. Exp Opin Pharmacother 2016;17(6): Thaden JT, et al. Virulence 2017;8(4): The Medicines Company 2017 Combination vs. Monotherapy Combination vs. Monotherapy Mortality 50% 40% 30% 20% 10% 0% p = Combination vs. Monotherapy Carbapenem combo vs. Non carbapenem combo Carbapenem MIC 8 vs. Carbapenem MIC >8 Daikos GL, et al. Antimicrob Agents Chemother 2014;58(4): Combination Therapy Monotherapy Recommended if using traditional agents* Use carbapenem containing combination if carbapenem MIC 8 May be reasonable for urinary tract infections in non critically ill patients *Benefit of combination therapy with novel agents is unclear Perez F, et al. Exp Opin Pharmacother 2016;17(6): King M, et al. Antimicrob Agents Chemother 2017;61(7):e

3 Site of Infection Dose optimization Select Sites Considerations Bloodstream Typically avoid tigecycline Pulmonary Consider adjunctive use of inhaled agents (e.g., colistin, aminoglycosides) Intra abdominal Tigecycline may be a useful adjunct Urinary Aminoglycoside or fosfomycin may be useful Can use colistin, but avoid polymyxin B Avoid tigecycline Central nervous system Consider adjunctive use of intraventricular agents (e.g., colistin, polymyxin B, aminoglycosides) Drug Class Carbapenems Polymyxins Aminoglycosides Tigecycline Dose Optimization Strategies High dose, prolonged infusions Meropenem 2 g every 8 hours, 3 4 hour infusion Loading dose recommended Polymyxin B does not need renal dosage adjustment Once daily dosing Gentamicin or tobramycin 7 10 mg/kg Amikacin mg/kg High dose 200 mg loading dose, then 100 mg every 12 hours Nation RL, et al. Clin Infect Dis 2014;59(1) Pogue JM, et al. Clin Microbiol Infect 2017;23: Duration of Therapy Adverse Effects Optimal duration has not been determined Prolonged therapy should be avoided to minimize further development of resistance Drug Class Carbapenems Select Adverse Effects Seizures (more likely with high doses or dual carbapenem therapy) Utilize evidence based durations according to the site of infection Consider the clinical response of the patient Guidance by an infectious diseases physician is preferred Giamarellou H. Int J Antimicrob Agents 2010;1 25 Zavascki AP, et al. Expert Rev Anti Infect Ther 2013;11(12): Spellberg B. JAMA Intern Med 2016;176(9): Polymyxins Aminoglycosides Tigecycline Nephrotoxicity: colistin (~55%); polymyxin B (~30%) Neurotoxicity Nephrotoxicity (less likely with once daily dosing; shortest possible course) Gastrointestinal effects may be more severe and doselimiting when using high dose therapy Novel Agents Ceftazidime avibactam and meropenem vaborbactam Active against many (but not all) carbapenemases Combine ceftazidime avibactam with aztreonam for metallo β lactamases More effective and less toxic than traditional options Limited clinical experience Resistance already detected Thaden JT, et al. Virulence 2017;8(4): Davido B, et al. Antimicrob Agents Chemother 2017;e Castanheira M, et al. Antimicrob Agents Chemother 2016;60(9): The Medicines Company Day Survival Ceftazidime avibactam vs. Others 100% 80% 60% 40% 20% 0% Carbapenem resistant Klebsiella pneumoniae Bacteremia p = 0.01 Ceftazidimeavibactam p = 0.07 Carbapenem + Colistin p = 0.03 Carbapenem + Aminoglycoside p = Other regimens

4 Other Carbapenem resistant Organisms Emerging Therapies Organism Specific Considerations Pseudomonas aeruginosa Non carbapenem β lactams may have activity Ceftolozane tazobactam has excellent activity Benefit of combination therapy is less clear Acinetobacter baumannii Use ampicillin sulbactam if active ( 6 g sulbactam/day) High dose minocycline (200 mg BID) may be useful Carbapenem containing combination therapy preferred Maraolo AE, et al. Expert Rev Anti Infect Ther 2017 Buehrle DJ, et al. Antimicrob Agents Chemother 2017;61(1):e Fishbain J, et al. Clin Infect Dis 2010;51(1):79 84 Viehman JA, et al. Drugs 2014;74: Lashinsky JN, et al. Infect Dis Ther 2017;6: Imipenem relebactam Plazomicin Eravacycline Aztreonam avibactam Ceftaroline avibactam Alternative agents: Antibiodies, bacteriophages, vaccines, etc. Bush K, et al. J Pharmacokinet Pharmacodyn 2017;44: Czaplewski L, et al. Lancet Infect Dis 2016;16: Summary Carbapenem resistant organisms are an increasing threat to public health The best approach to treatment has not been determined Novel agents seem to offer enhanced efficacy and safety compared with traditional treatment options Braykov NB, Eber MR, Klein EY, et al. Trends in resistance to carbapenems and third generation cephalosporins among clinical isolates of Klebsiella pneumoniae in the United States, Infect Control Hosp Epidemiol. 2013;34(3). Tracking CRE. [Internet]. Atlanta, GA: Centers for Disease Control and Prevention; 2015 Jul 8 [updated 2017 Sept 7; cited 2017 Sept 10]. Available from: Tacconelli E, Magrini N, Carmeli Y, et al. Global priority list of antibiotic resistant bacteria to guide research, discovery, and development of new antibiotics. WHO 2017:1 7. Kaye KS and Pogue JM. Infections caused by resistant Gram negative bacteria: epidemiology and management. Pharmacotherapy 2015;35(10): CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 27th ed. CLSI document M100S. Wayne, PA: Clinical and Laboratory Standards Institute; Gniadek TJ, et al. Carbapenem resistant non glucose fermenting Gram negative bacilli: the missing piece to the puzzle. J Clin Microbiol 2016;54: Morrill HJ, Pogue JM, Kaye KS, LaPlante KL. Treatment options for infections. Open Forum Infect Dis 2015:1 15. Perez F, El Chakhtoura NG, Papp Wallace KM, et al. Treatment options for infections caused by carbapenem resistant Enterobacteriaceae: can we apply precision medicine to antimicrobial chemotherapy? Exp Opin Pharmacother 2016;17(6): Thaden JT, Pogue JM, Kaye KS. Role of newer and re emerging older agents in the treatment of infections caused by carbapenem resistant Enterobacteriaceae. Virulence 2017;8(4): The Medicines Company announces TANGO 2 trial of meropenem vaborbactam (formerly, Carbavance) stopped early for superior benefit risk compared to best alternative therapy for CRE. [Internet]. Parsippany, NJ: The Medicines Company; 2017 Jul 25 [cited 2017 Sept 7]. Available from: company announces tango 2 trial meropenemvaborbactam formerly carbavance. Daikos GL, Tsaousi S, Tzouvelekis LS, et al. Carbapenemase producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother 2014;58(4): Shields RK, Nguyen MH, Chen L, et al. Ceftazidime avibactam is superior to other treatment regimens against carbapenem resistant Klebsiella pneumoniae bacteremia. Antimicrob Agents Chemother 2017;61(8):e King M, Heil E, Kuriakose S, et al. Multicenter study of outcomes with ceftazidime avibactam in patients with carbapenem resistant Enterobacteriaceae infections. Antimicrob Agents Chemother 2017;61(7):e Pogue JM, Ortwine JK, Kaye KS. Clinical considerations for optimal use of the polymyxins: a focus on agent selection and dosing. Clin Microbiol Infect 2017;23: Nation RL, Velkov T, Li J. Colistin and polymyxin B: peas in a pod, or chalk and cheese? Clin Infect Dis 2014;59(1) Giamarellou H. Multidrug resistant Gram negative bacteria: how to treat and for how long. Int J Antimicrob Agents 2010;1 25. Zavascki AP, Bulitta JB, Landersdorfer CB. Combination therapy for carbapenem resistant Gram negative bacteria. Expert Rev Anti Infect Ther 2013;11(12): Spellberg B. The new antibiotic mantra shorter is better. JAMA Intern Med 2016;176(9): Castanheira M, Rhomberg PR, Flamm RK, Jones RN. Effect of the β lactamase inhibitor vaborbactam combined with meropenem against serine carbapenemase producing Enterobacteriaceae. Antimicrob Agents Chemother 2016;60(9): Davido B, Fellous L, Lawrence C, et al. Ceftazidime Avibactam and aztreonam an interesting strategy to overcome β lactam resistance conferred by metallo β lactamases in Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother 2017;e Maraolo AE, Cascella M, Corcione S, et al. Management of multidrug resistant Pseudomonas aeruginosa in the intensive care unit: state of the art. Expert Rev Anti Infect Ther 2017;1 11. Buehrle DJ, Shields RK, Clarke LG, Potoski BA, et al. Carbapenem resistant Pseudomonas aeruginosa bacteremia: risk factors for mortality and microbiologic treatment failure. Antimicrob Agents Chemother 2017;61(1):e Fishbain J, Peleg AY. Treatment of Acinetobacter infections. Clin Infect Dis 2010;51(1): Viehman JA, Nguyen MH, Doi Y. Treatment options for carbapenem resistant and extensively drug resistant Acinetobacter baumannii infections. Drugs 2014;74: Lashinsky JN, Henig O, Pogue JM, Kaye KS. Minocycline for the treatment of multidrug and extensively drug resistant A. baumannii: a review. Infect Dis Ther 2017;6: Bush K, Page MGP. What we may expect from novel antibacterial agents in the pipeline with respect to resistance and pharmacodynamic principles. J Pharmacokinet Pharmacodyn 2017;44: Czaplewski L, Bax R, Clokie M, Dawson M, et al. Alternatives to antibiotics a pipeline portfolio review. Lancet Infect Dis 2016;16:

5 Self assessment Question 1 Carbapenem resistant organisms have not been isolated in Alabama. A. True B. False Self assessment Question 2 When using a carbapenem to treat carbapenemresistant organisms, use: A. Traditional doses B. Low doses, intermittent infusions C. High doses, prolonged infusions D. Never use a carbapenem when it is resistant in vitro Self assessment Question 3 Novel agents, such as ceftazidime avibactam, seem to be more effective and less toxic than traditional agents used to treat carbapenem resistant organisms. A. True B. False Nightmare Bacteria How to Deal with the Reality of Carbapenem-resistant Organisms Matthew L. Brown, Pharm.D., BCPS Antimicrobial Stewardship Pharmacist, UAB Hospital Alabama Society of Health system Pharmacy Annual Clinical Meeting, Birmingham, Alabama September 29, 2017