Other β-lactamase Inhibitor (BLI) Combinations: Focus on VNRX-5133, WCK 5222 and ETX2514SUL David P. Nicolau, PharmD, FCCP, FIDSA Director, Center for Anti-Infective Research and Development Hartford Hospital Hartford, CT
Disclosures I am a consultant, speakers bureau member or have received research funding from: Achaogen, Bayer, Cepheid, Merck, Melinta, Pfizer, Shionogi, VenatoRx, Wockhardt Advisory Member: Clinical Laboratory Standards Institute (CLSI)
VNRX-5133 is a new-generation boronic acid β-lactamase inhibitor with a broad-spectrum encompassing both serine- and metallo- β- lactamases: Ambler Class A [ESBL and KPC] Class B [NDM and VIM] Class C [AmpC] Class D [OXA] VNRX-5133 The combination of VNRX-5133 with cefepime (FEP), a broad spectrum cephalosporin, has the potential to be a potent and attractive treatment option for infections caused by multi-drug resistant gram-negative bacteria, inclusive of carbapenem-resistant Enterobacteriaceae (CRE) and Pseudomonas aeruginosa VNRX-5133
MICs and β-lactamase Expression of the Isolates Utilized in Murine Efficacy Studies MIC (mg/l) Isolate ID Bacterial Species FEP+VNRX-5133 β-lactamases Encoded FEP 4 mg/l EC 481 Escherichia coli >512 0.125 CTX-M-15 ECL 96 Enterobacter cloacae >512 8 TEM-OSBL, CTX-M-15, ACT-7 ECL 123 Enterobacter cloacae >512 0.5 TEM-OSBL, CTX-M-15, ACT-New Variant, OXA-48 ECL 124 Enterobacter cloacae >512 8 TEM-OSBL, CTX-M-15, ACT-7 KP 329B Klebsiella pneumoniae 512 0.25 SHV-11, OXA-9, SHV-5, KPC-2, TEM-1 KP 510 Klebsiella pneumoniae 256 0.063 CTX-M-11, SHV-11, DHA-1, TEM-1A KP 569 Klebsiella pneumoniae >512 4 OXA-48 & CTX-M-15 KP 575 Klebsiella pneumoniae >512 2 KPC KP 579 Klebsiella pneumoniae >512 16 SHV-11, TEM-1, CTX-M-15, OXA-48 KP 580 Klebsiella pneumoniae >512 8 SHV-OSBL, TEM-OSBL, CTX-M-15, OXA-48 KP 583 Klebsiella pneumoniae >512 4 SHV-32, TEM-1, CTX-M-15, OXA-48 KP 585 Klebsiella pneumoniae 512 8 KPC KP 679 Klebsiella pneumoniae >512 4 OXA-232, OXA-9, TEM-1A, CTX-M-15, OXA-1 KP 686 Klebsiella pneumoniae >512 1 KPC-3, OXA-9, TEM-1A, SHV-11 KP 731 Klebsiella pneumoniae >512 1 SHV-11, TEM-1, KPC-3 KP 732 Klebsiella pneumoniae >512 1 SHV-OSBL, TEM-OSBL, KPC-2 KP 734 Klebsiella pneumoniae >512 2 KPC-3 KP 735 Klebsiella pneumoniae >512 2 KPC-2 KP 736 Klebsiella pneumoniae >512 1 SHV-11, CTX-M-55, OXA-48 KP 737 Klebsiella pneumoniae >512 2 SHV-OSBL, CTX-M-15, OXA-48 KP 738 Klebsiella pneumoniae >512 4 KPC-3 KP 739 Klebsiella pneumoniae >512 8 SHV-11, TEM-1, CTX-M-15, OXA-48 KP 740 Klebsiella pneumoniae >512 8 SHV-OSBL, TEM-OSBL, CTX-M-15, OXA-48 KP 742 Klebsiella pneumoniae >512 8 SHV-11, TEM-1, CTX-M-15, OXA-48 KP 743 Klebsiella pneumoniae >512 8 SHV-11, TEM-1, CTX-M-15, OXA-48 KP 744 Klebsiella pneumoniae >512 4 SHV-32, TEM-1, CTX-M-15, OXA-48 PSA 1593 Pseudomonas aeruginosa >512 4 KPC-2 PSA 1672 Pseudomonas aeruginosa >512 2 AmpC overexpression PSA 1679 Pseudomonas aeruginosa 256 16 AmpC overexpression PSA 1681 Pseudomonas aeruginosa >512 8 AmpC overexpression Abdelraouf K, Almarzoky Abuhussain S, Nicolau DP. IDWeek2018, Abstract No. 1405, San Francisco, California 2018
Comparative Efficacy of Cefepime / VNRX-5133 Humanized Exposures (2/0.5g q8 2h inf) v. Cefepime Alone against Enterobacteriaceae & P. aeruginosa Expressing Various β-lactamases Abdelraouf K, Almarzoky Abuhussain S, Nicolau DP. IDWeek2018, Abstract No. 1405, San Francisco, California 2018
Cefepime Zidebactam (WCK 5222) Zidebactam (WCK5107) new Bicyclo-acyl Hydrazide (BCH) Pharmacophore FEP: Cefepime; ZID: Zidebactam; WCK 5222 is a combination of Cefepime (FEP) and Zidebactam (ZID) 2g + 1g IV q8h 1hr inf ZID is a non-β-lactam, dual acting βlactam Enhancer antibiotic FEP + ZID (WCK5222) have demonstrated synergy through complimentary target (PBPs) attainment Selective PBP activity of ZID (PBP2) and FEP (PBP3) across Gram-negatives FEP + ZID combination has proven efficacy against MDR pathogens (VIM, NDM, OXA) Enterobacteriaceae, P. aeruginosa and A. baumannii Livermore et al. JAC 2017 Moya et al. AAC 2017; Sader et al. JAC 2017 Sader et al. AAC 2017; Moya et al. IDWeek, New Orleans 2017
Neutropenic Murine Lung Model Cyclophosphamide 250 mg/kg (Day -4) Uranyl Nitrate 5 mg/kg (Day -3) Cyclophosphamide 100 mg/kg (Day -1) Cefepime %ft>mic MIC (µg/ml) Human Murine 4 100.00 % 100.00 % 8 92.92% 92.50% 16 66.25% 66.25% 32 41.25% 41.25% 64 18.33% 19.58% Intranasal Inoculation (Day 0) WCK5222 human simulated regimen* Bacterial burden determination Zidebactam %ft>mic MIC (µg/ml) Human Murine 24 hours 4 92.50% 92.50% 8 67.50% 70.00% 16 42.08% 41.25% 32 19.17% 20.42% 64 0.00% 3.75% *WCK5222 human simulated regimen results in murine plasma concentrations that correlate with human exposures (in terms of %ft>mic) following 1-hour IV infusions of: cefepime 2 g q8h and zidebactam 1 g q8h Avery LM, Abdelraouf K, Nicolau DP. 2018. Antimicrob Agents Chemother 62:e00948-18. doi:10.1128/aac.00948-18.
In Vitro Potency of Cefepime Zidebactam (WCK 5222) against A. baumannii A. baumannii β-lactamases Encoded Broth Microdilution MIC (µg/ml) Meropenem Zidebactam Cefepime WCK 5222 163 TEM-1D, ADC-25, OXA-66 2 >512 32 16 182 PER-7, OXA-23, OXA-203 >8 >512 256 16 194 ADC-25, OXA-23, OXA-82 >8 >512 512 16 189 OXA-24, OXA-65, TEM-1B >8 >512 128 32 179 ADC-25, OXA-23, OXA-223 >8 >512 256 32 JJ 5-13 ADC-33, OXA-23, OXA-82 >64 >512 256 32 JJ 12-1 ADC-81-like, OXA-23, OXA-69 >64 >512 256 32 JJ 3-20 ADC-81-like, OXA-24, OXA-65, TEM-1 >64 >512 512 32 160 OXA-24, OXA-65, TEM-1B >8 >512 >512 32 JJ 13-11 ADC-96-like, CARB-16, OXA-10, OXA-23-like, OXA-58, OXA-68, OXA-72 64 >512 >512 32 171 ADC-25, OXA-23, OXA-66 >8 >512 256 64 JJ 4-25 ADC-30, OXA-66, OXA-72 >64 >512 256 64 JJ 1-1 ADC-81-like, OXA-24, OXA-65, TEM-1 >64 >512 >512 64 Avery LM, Abdelraouf K, Nicolau DP. 2018. Antimicrob Agents Chemother 62:e00948-18. doi:10.1128/aac.00948-18.
Remarkable Potency Observed Among All 13 A. baumannii Isolates Bacterial growth was observed in the lungs of animals treated with saline, cefepime, and zidebactam alone WCK5222 (cefepimezidebactam) achieved >2 log 10 kill across all isolates, including isolates with MIC = 64 mg/l As zidebactam does NOT inhibit OXA enzymes that degrade cefepime, these data support the β-lactam enhancer action of zidebactam Avery LM, Abdelraouf K, Nicolau DP. 2018. Antimicrob Agents Chemother 62:e00948-18. doi:10.1128/aac.00948-18.
ETX2514SUL is a Novel Bactericidal β-lactam/β-lactamase Inhibitor Combination Under Development for Intravenous Treatment of Acinetobacter infections Sulbactam Activity as a β-lactamase inhibitor Also a β-lactam with intrinsic activity against A. baumannii Extensively use to treat A. baumannii β-lactamase-mediated resistance now common with MIC 90 >32 mg/l ETX2514 Novel β-lactamase inhibitor Potent broad-spectrum inhibitor of Class D β- lactamases Also potent broadspectrum inhibitor of Class A and C β- lactamases
In vitro activity against Acinetobacter baumannii Activity unchanged in carbapenem-resistant, colistin-resistant and multidrug resistant strains Cumulative % MIC Distribution for globally diverse A. baumannii 0 MIC of sulbactam in the presence of ETX2514 (mg/l) (1) 2011 N = 195 2012 N = 209 2013 N = 207 2014 N =1,131 2015 (2) N = 202 2016 N = 843 2017 N = 825 All N = 3611 0.06 0.12 0.25 0.5 1 2 4 8 16 32 >64 1 3.1 13.8 41.5 65.6 89.7 96.9 97.9 99.5 100 100 0 0.5 2.9 20.1 46.9 79 98.6 100 100 100 100 0 0 4.3 15.9 43.4 73.8 96.5 97.5 99 99 100 1 1.6 7.8 27.9 63.7 88.9 99.6 99.6 99.7 100 100 0 1.0 7.4 43.1 78.7 97.0 99.5 99.5 100 100 100 0.6 5.2 22.8 52.8 80.1 94.8 98.8 99.3 99.5 99.9 100 0.2 0.7 3.8 31.6 63.4 86.8 96.7 97.7 97.9 98.9 99.8 0.7 2.2 10.9 36.7 69.1 90.8 98.6 99.1 99.3 99.7 100.0 1 Combined with 4 mg/l of ETX2514. 2 2015 study performed at JMI; other years performed at IHMA.
ETX2514SUL PK/PD Key PK drivers identified by PK/PD evaluations in vitro and in vivo Exposure targets for sulbactam and for ETX2514 established Sulbactam: 50% Time>MIC ETX2514: AUC 0-24h /MIC = 10 Dosing regimen for Phase 2/3 Sulbactam 1 g plus ETX2514 1 g 3-hour infusion Dosed every 6 hours Probability of target attainment for MIC 4 mg/l is 99% Relationship between ETX02514 AUC 0-24h/τ in the in vitro chemostat model 1 1 A. baumannii ARC5081 (OXA-23; OXA-94): MIC (sulbactam) = 16 mg/l, MIC (sulbactam/etx2514) = 2.9 mg/l.
ETX2514SUL Generally Safe & Well Tolerated in 3 Phase 1 and a Phase 2 Clinical study 139 healthy subjects and 79 patients have received 1 dose of ETX2514 No dose-related systemic adverse events Up to 8 g single dose or 2 g q6h Sulbactam 1 g plus ETX2514 1 g with imipenem/cilastatin 0.5 g Generally well tolerated ETX2514 demonstrated well behaved PK Dose proportional exposure up to 8 g No drug-drug interaction (2-way) with sulbactam and/or imipenem/cilastatin Good pulmonary exposure in healthy subjects PK in patients with renal impairment pending 100.0 ETX2514 Concentration (μg/ml) Mean ETX2514 Concentration in Plasma and Epithelial Lining Fluid (ELF) (n=30) 1 10.0 1.0 0.1 0 1 2 3 4 5 6 Time (hours) Infusion period Plasma ELF ETX2514 ELF AUC 0-6h 40.1 µg h/ml 1 Phase 1 study in 30 healthy subjects receiving sulbactam 1 g and ETX2514 1g infused over 3 hrs q6h
NEW BL BLI Combinations Enhance potency against Carbapenemase- Producing Enterics & PSA Cefepime - VNRX-5113 [KPC, OXA, MBL] Cefepime - Zidebactam [KPC, OXA, MBL] Acinetobacter baumannii Cefepime Zidebactam» Complimentary target (PBP) attainment β-lactam Enhancer Sulbactam - ETX2514 (ETX2514SUL)» Focus activity for Acinetobacter baumannii