Methods: We tested isolates for responses to CZA alone (1 and 4x MIC; avibactam fixed at 4 µg/mL), and in combination with colistin (COL; 2 µg/mL), fosfomycin (FOS; 100 µg/mL + 25 µg/mL G6P), gentamicin (GEN; 2 µg/mL), MER (8 µg/mL), and tigecycline (TGC; 2 µg/mL) by time-kill using a starting inoculum of 1x108 cFu/mL. Log-kills were calculated as log cFu/mL decrease from time 0; 24h was the primary endpoint.
Results: 30 KPC-Kp isolates were studied (22 KPC-2 and 8 KPC-3); all isolates were CZA-susceptible (MIC range: 0.125 – 4 µg/mL). 53% harbored ompK36 mutations (8 each with IS5 and 134-135 DG insertions). Mean log-kills by CZA at 1x and 4x MIC were 2.00 and 2.35, respectively; CZA was bactericidal (≥3-log kill) at 24h against 33% and 50%, respectively. CZA mean log-kills at 4x MIC were greater for KPC-3 (3.81) than KPC-2 (1.82) isolates (P=0.03), but did not vary by porin genotype (P=0.44). GEN was the most active single agent and was bactericidal against 57%; the mean log-kill was 3.06. In combination with CZA, rates of synergy (>2-log kill in combo) with COL, FOS, GEN, MER, and TGC were 83%, 60%, 40%, 87%, and 7%, respectively. The corresponding rates of bactericidal activity were 87%, 77%, 80%, 100%, and 30%, respectively. Antagonism (>1-log kill by most active single agent) was identified in 7%, 23%, 20%, 0%, and 27% with CZA + COL, FOS, GEN, MER, and TGC, respectively. Mean log-kills by CZA + MER were greater among isolates with wild-type (6.58) versus mutant (5.48) ompK36 (P=0.0006), and isolates harboring KPC-3 (7.02) versus KPC-2 (5.63; P=0.0004). CZA + COL responses were attenuated among isolates with COL MICs ≥2 (log-kills 2.88 vs 7.94; P=0.0009), but not affected by ompK36 genotype (P=0.53). Among isolates with COL MICs <2; log-kills were greater for CZA + COL (7.94) than CZA + MER (6.44; P<0.0001).
Conclusion: A 2-drug combination of CZA + MEM results in high rates of synergy and bactericidal activity against genetically-diverse KPC-Kp. Mean log-kills were less among isolates with mutations in ompK36. CZA + COL was highly active against isolates ompK36 mutations, but contingent on COL susceptibility.
K. Morder, None
C. J. Clancy, None
M. H. Nguyen, Merck: Grant Investigator , Research grant . Astellas: Grant Investigator , Research grant .
R. K. Shields, Allergan: Grant Investigator , Research grant . Pfizer: Consultant and Scientific Advisor , Speaker honorarium . Shionogi: Scientific Advisor , Consulting fee . Roche: Grant Investigator , Research grant . Venatorx: Grant Investigator , Research grant . Medicines Company: Grant Investigator and Scientific Advisor , Consulting fee and Research grant . Accelerate Diagnostics: Scientific Advisor , Consulting fee .