Combating Carbapenem-Resistant Enterobacteriaceae Laurence Wright, Pharm.D. ASP Learning Series September 6, 2018 Objectives Review mechanisms for resistance in gram-negative organisms Describe the Ambler classification of β-lactamases Evaluate novel agents for the treatment of carbapenem-resistant Enterobacteriaceae (CRE) Assess the cost impact of various agents Background CRE infection is Bacteremia with CRE reported in reported in roughly CRE is associated every state 18% of LTAC with an increase in patients mortality CRE: carbapenem-resistant Enterobacteriaceae LTAC: long-term acute care Munoz-Price, LS et al. The Lancet. 2013; 13: 785-796. Mechanisms of Resistance Mukerji S, et al. Essays Biochem. 2017 Mar 3;61(1):23-35. Ambler Classification Class Description Narrow-spectrum β-lactamases (early TEM, SHV) A Extended-spectrum β-lactamases (later TEM, SHV; CTX-M) Serine cabapenemases (KPC, SME) B Metallo-β-lactamases (NDM, IMP, VIM) C Cephalosporinases (AmpC enzymes) D Oxacillinases (OXA) Bush, K. J Infect Chemother 2013;19:549–559. β-Lactamase Inhibitors Enzyme Tazobactam Avibactam Vaborbactam Narrow-spectrum Yes Yes Yes β-lactamases ESBLs Yes Yes Yes Serine cabapenemases No Yes Yes Metallo-β-lactamases No No No Cephalosporinases Variable Yes Yes Oxacillinases No Variable No ESBL: extended-spectrum β-lactamase Wong D, et al. Drugs. 2017 Apr;77(6):615-628. Ceftolozane-Tazobactam Ceftolozane is structurally similar to ceftazidime Improved steric hindrance to prevent hydrolysis mediated through AmpC β-lactamases Less impacted by porin loss Tazobactam provides activity against class A (excluding carbapenemases) and class C β-lactamases Skalweit MJ, et al. Drug Design, Development and Therapy. 2015; 9:2919-2925. Ceftolozane-Tazobactam Anaerobes Gram-Positive • Fusobacterium spp. • Some Streptococcus species • Prevotella spp. Gram-Negative Resistance • Broad coverage, including • Serine carbapenemases P. aeruginosa • Class B and D β-lactamases • AmpC hyperproduction Goodlet KJ, et al. Ther Clin Risk Manag. 2016; 12:1811-26. Ceftolozane-Tazobactam FDA Approved Use Dosing • Complicated IAIs • 1.5g IV Q8H for (with CrCl > 50 mL/min metronidazole) • 3g IV Q8H for • Complicated UTIs pneumonias (including (study ongoing) pyelonephritis) • Renally adjusted IAI: intra-abdominal infection UTI: urinary tract infection Zerbaxa® (ceftolozane/tazobactam) [prescribing information]. 2016. Ceftazidime-Avibactam v Avibactam is first non-β-lactam, β-lactamase inhibitor v Activity against class A, C and certain class D β-lactamases v Slowly reversible MIC: mean inhibitory concentration Karlowsky JA et al. Antimicrob Agents Chemother. 2016;60(5):2849–57. Ceftazidime-Avibactam Anaerobes Gram-Positive • MIC90 for Bacteroides fragilis reduced • Same spectrum as ceftazidime from >128 to 16 monotherapy (negligible) • No benefit for other Bacteroides spp., Fusobacterium spp. or other anaerobes Gram-Negative Resistance • Broad coverage, including P. aeruginosa • Diminished outer membrane permeability • Expanded coverage against CRE • Over-expression of efflux pumps • Hyper-production of AmpC CRE: carbapenem-resistant Enterobacteriaceae MIC: mean inhibitory concentration Wong D, et al. Drugs. 2017 Apr;77(6):615-628. Ceftazidime-Avibactam FDA Approved Use Dosing • Complicated IAIs • 2.5g IV Q8H infused (with metronidazole) over 2 hours for CrCl • Complicated UTIs > 50 mL/min (including • Renally adjusted pyelonephritis) • HAP/VAP HAP/VAP: hospital-acQuired, ventilator-associated pneumonia IAI: intra-abdominal infection Avycaz® (ceftazidime/avibactam) [prescribing information]. 2017. Meropenem-Vaborbactam Vaborbactam is a cyclic boronic β-lactamase inhibitor Activity against Class A and C β-lactamases In vitro data from 315 isolates showed vaborbactam restored meropenem activity by 90% Castanheira M et al. Antimicrob Agents Chemother. 2017;61:e00567-17. MIC: mean inhibitory concentration Hackel, MA, et al. Antimicrob Agents Chemother. 2017;62:pii: e01904-17. Meropenem-Vaborbactam Anaerobes Gram-Positive • Excellent coverage (except C. difficile) • Same spectrum as meropenem alone • Same as meropenem alone • No MRSA coverage and some E. faecalis coverage Gram-Negative Resistance • Expanded coverage against CRE • Porin alterations • Anti-pseudomonal activity similar to • Over-expression of efflux pumps meropenem alone • Class B and D β-lactamases CRE: carbapenem-resistant Enterobacteriaceae MRSA: methicillin-resistant S. aureus Wong D, et al. Drugs. 2017 Apr;77(6):615-628. Meropenem-Vaborbactam FDA Approved Use Dosing • Complicated UTIs • 4g (2g meropenem (including + 2g vaborbactam) pyelonephritis) IV Q8H over 3 hours for CrCl > 50 mL/min • Renally adjusted Vabomere® (meropenem/vaborbactam) [prescribing information]. 2017. Cost Implications Product Cost Per Vial (AWP) Cost Per Day Ceftolozane-Tazobactam 1.5g Vial $126.53 $379.59 Ceftazidime-Avibactam 2.5g Vial $393.22 $1,179.66 Meropenem-Vaborbactam 2g Vial $198.00 $1,188.00 AWP: average wholesale price UNC Formulary All 3 Agents Require EITHER ID Consult Team ASP Approval Approval ASP: antimicrobial stewardship program Combating Carbapenem-Resistant Enterobacteriaceae Laurence Wright, Pharm.D. ASP Learning Series September 6, 2018 References Avycaz® (ceftazidime/avibactam) [prescribing information]. Irvine, CA: Allergan USA, Inc; 2017. Bush K, Jacoby GA. Updated functional classification of β-lactamases. Antimicrob Agents Chemother. 2010;54:969-976. doi:10.1128/AAC.01009-09 Bush K. The ABCDs of beta-lactamase nomenclature. J Infect Chemother 2013;19:549–559. Castanheira M, Huband MD, Mendes RE, Flamm RK. Meropenem-vaborbactam tested against contemporary Gram-negative isolates collected worldwide during 2014, including carbapenem-resistant, KPC-producing, multi-drug-resistant, and extensively drug-resistant Enterobacteriaceae. Antimicrob Agents Chemother. 2017;61:e00567-17.doi:10.1128/AAC.00567-17 Goodlet KJ, Nicolau DP, and Nailor MD, Ceftolozane/tazobactam and ceftazidime/avibactam for the treatment of complicated intra-abdominal infections. Ther Clin Risk Manag. 2016; 12:1811-26. Hackel MA, Lomovskaya O, Dudley MN, Karlowsky JA, Sahm DF. In vitro activity of meropenem-vaborbactam against clinical isolates of KPC-positive Enterobacteriaceae. Antimicrob Agents Chemother. 2017;62:pii: e01904-17. doi:10.1128/AAC.01904-17 Healthcare-Associated Infections. Centers for Disease Control and Prevention website https://www.cdc.gov/hai/organisms/cre/trackingcre.html. Updated December 2017. Accessed August 24, 2018. Karlowsky JA, Biedenbach DJ, Kazmierczak KM, et al. Activity of ceftazidime-avibactam against extended-spectrum- and AmpC B-lactamase- producing Enterobacteriaceae collected in the INFORM global surveillance study from 2012 to 2014. Antimicrob Agents Chemother. 2016;60(5):2849–57. Kaye KS, Vazquez J, Mathers A, et al. Meropenem-vaborbactam (Vabomere) vs. best available therapy for CRE infections: TANGO II randomized, controlled phase 3 study results. Poster presented at: ID Week 2017; October 7, 2017; San Diego, CA. References Kaye KS, Bhowmick T, Metallidis S, et al. Effect of Meropenem-Vaborbactam vs Piperacillin-Tazobactam on Clinical Cure or Improvement and Microbial Eradication in Complicated Urinary Tract Infection: The TANGO I Randomized Clinical Trial. JAMA 2018; 319:788. Munoz-Price, LS, Poirel L, Bonomo RA, Schwaber MJ et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. The Lancet. 2013; 13: 785-796. Skalweit MJ. Profile of ceftolozane/tazobactam and its potential in the treatment of complicated intra-abdominal infections. Drug Design, Development and Therapy. 2015; 9:2919-2925. Torres A, Zhong N, Pachl J, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis. 2017;18(3):285–95. Vabomere® (meropenem/vaborbactam) [prescribing information]. Parsippany, NJ: The Medicines Company; 2017. Wong D & van Duin D. Novel Beta-Lactamase Inhibitors: Unlocking Their Potential in Therapy. Drugs. 2017 Apr;77(6):615-628. Zerbaxa® (ceftolozane/tazobactam) [prescribing information]. Whitehouse Station, NJ: Merck & Co; October 2016..