1385. Efficacy of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE): Solutions for Metallo-β-lactamase producing-Enterobacteriaceae (MBL)
Session: Poster Abstract Session: PK/PD Studies
Friday, October 5, 2018
Room: S Poster Hall
Background: Novel antibiotics will not be available to combat the threat of MBLs until 2021. One strategy to overcome MBLs is to combine CAZ-AVI + ATM. ATM is not hydrolysed by MBLs and AVI offers protection for ATM and CAZ vs. ESBLs and AmpCs. The combination also offers a theoretical advantage to inactivating multiple PBPs by using dual β-lactam therapy. Our objective was to define optimal dosing profiles for clinical use of ATM to add to CAZ-AVI in the Hollow Fiber Infection Model (HFIM).

Methods: E. coli ARLG-1013 (blaNDM-1, blaCTX-M, blaCMY, blaTEM) and K. pneumoniae ARLG-1002 (blaNDM-1, blaCTXM-15, blaDHA, blaSHV, blaTEM) were studied at a 7.5 log10 CFU/ml in the HFIM. Human dosing regimens of CAZ-AVI 2g/0.5g q8h (2h infusion) and ATM 2g q8h (2h inf.) were simulated in alone and in combination. Continuous infusion (CI) regimens of CAZ-AVI 6g/1.5g per day CI + ATM 6g/day CI and q8h regimens were given simultaneously and sequentially (ATM given 2h after CAZ-AVI). Resistant subpopulations were profiled on single (ATM), double (CAZ/AVI) and triple (ATM/CAZ/AVI) drug plates containing 2/2/4, 8/8/4, or 32/32/4 mg/L over 7 days.

Results: Against E. coli ARLG-1013, ATM alone mirrored growth control (+3.14 at 168h) (All units Log10 CFU/ml change vs. baseline). CAZ-AVI alone showed some intrinsic activity (+1.19 at 168h). CAZ-AVI 2g/0.5g q8h (2h inf.) + ATM 2g q8h (2h inf.) given sequentially resulted regrowth and stasis (+0.34 at 168h) vs. the simultaneous combination resulted initial bactericidal activity (-3.53 killing within 28h) which regrew at (-0.90 at 168h). All CI regimens were effective. CAZ-AVI 6g/1.5g per day CI + ATM 6g/day CI resulted in dramatic killing (up to -5.78 killing within 50h) which was sustained (up to -3.90 killing at 168h). Comparing the infusion time of CAZ/AVI + ATM on bacterial killing: CI + CI > 2h + 2h > 30 min + 30 min. CI + CI resulted in complete suppression of resistance over 7 days. Against K. pneumoniae ARLG-1002, CAZ/AVI (CI) + ATM (CI) resulted in early synergy (>5.0 log killing within 24h) and suppression of resistance for more than 168h.

Conclusion: The combination of CAZ-AVI + ATM was highly synergistic and suppressed resistance against MBL Enterobacteriaceae in HFIM. ATM efficacy in combination was driven by %T>MIC. A phase I study will assess safety to provide patients a critically important solution against “untreatable” Gram negatives.

Thomas P. Lodise, PharmD, PhD1, Nicholas M. Smith, Pharm.D.2, Patricia Holden, B.S.2, J Nicholas O'Donnell, PharmD, MSc3, Tyler Bedard, Pharm.D.2, Robert A. Bonomo, MD4 and Brian T. Tsuji, PharmD2, (1)Albany College of Pharmacy, Albany, NY, (2)University at Buffalo, SUNY, Buffalo, NY, (3)Albany Medical Center, Albany, NY, (4)Medicine, Case Western Reserve University, Cleveland, OH

Disclosures:

T. P. Lodise, paratek: Consultant and Scientific Advisor , Consulting fee .

N. M. Smith, None

P. Holden, None

J. N. O'Donnell, None

T. Bedard, None

R. A. Bonomo, None

B. T. Tsuji, Nabriva: Consultant , Consulting fee . Achaogen: Grant Investigator , Educational grant . ARLG, DCRI: Grant Investigator , Grant recipient . NIH/NIAID: Grant Investigator , Grant recipient .

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