1385. Efficacy of Ceftazidime–Avibactam in Combination with Aztreonam (COMBINE): Solutions for Metallo-β-Lactamase Producing-Enterobacteriaceae (MBL). (26th November 2018)

• Record Type: Journal Article
• Authors: Lodise, Thomas P; Smith, Nicholas M; Holden, Patricia; O'Donnell, J Nicholas; Bedard, Tyler; Bonomo, Robert A; Tsuji, Brian T
• Is Part Of: Open forum infectious diseases. Volume 5(2018)Supplement 1
• Page Start: S425
• Page End: S425
• Publication Date: 2018-11-26
• Subjects: Communicable diseases -- Periodicals; Medical microbiology -- Periodicals; Infection -- Periodicals; 616.9
• DOI: 10.1093/ofid/ofy210.1216
• Languages: English
• ISSNs: 2328-8957

Abstract

Abstract: 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 ( bla NDM-1, bla CTX-M, bla CMY, bla TEM ) and K. pneumoniae ARLG-1002 ( bla NDM-1, bla CTXM-15, bla DHA, bla SHV, bla TEM ) were studied at a 7.5 log10 CFU/mL in the HFIM. Human dosing regimens of CAZ-AVI 2 g/0.5 g q8h (2 hours infusion) and ATM 2 g q8h (2 hours infusion) were simulated in alone and in combination. Continuous infusion (CI) regimens of CAZ-AVI 6 g/1.5 g per day CI + ATM 6 g/day CI and q8h regimens were given simultaneously and sequentially (ATM given 2 hours 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 168 hours) (All units Log10 CFU/mL change vs. baseline). CAZ-AVI alone showed some intrinsic activity (+1.19 at 168 hours). CAZ-AVI 2g/0.5g q8h (2 hours infusion) + ATM 2g q8h (2 hours infusion) given sequentially resulted regrowth and stasis (+0.34 at 168 hours) vs. the simultaneous combination resulted initial bactericidal activity (-3.53 killing within 28 hours) which regrew at (−0.90 at 168 hours). All CI regimens were effective. CAZ-AVI 6g/1.5g per day CI + ATM 6 g/day CI resulted in dramatic killing (up to -5.78 killing within 50 hours) which was sustained (up to -3.90 killing at 168 hours). Comparing the infusion time of CAZ/AVI + ATM on bacterial killing: CI + CI > 2 hours + 2 hours > 30 minutes + 30 minutes. 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 24 hours) and suppression of resistance for more than 168 hours. 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. Disclosures: T. P. Lodise, paratek: Consultant and Scientific Advisor, Consulting fee. B. T. Tsuji, Nabriva: Consultant, Consulting fee. Achaogen: Grant Investigator, Educational grant. ARLG, DCRI: Grant Investigator, Grant recipient. NIH/NIAID: Grant Investigator, Grant recipient.