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.
T. P. Lodise,
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 .