706. Ceftazidime-avibactam (CZA) and meropenem (MER) are Synergistic and Bactericidal against Genetically-diverse KPC-producing Klebsiella pneumoniae (Kp)
Session: Poster Abstract Session: Resistance Mechanisms: Gram-Negative
Thursday, October 4, 2018
Room: S Poster Hall
Background: We previously showed that CZA MICs are higher among KPC-3 Kp and KPC-2 Kp with porin mutations. Clinical resistance has emerged among KPC-3 Kp. Here, we tested various agents in combination with CZA for synergistic and bactericidal activity.

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.

Chelsea Jones, BA1, Ellen Kline, MS1, Kristin Morder, BA2, Cornelius J. Clancy, M.D.3, M. Hong Nguyen, MD4 and Ryan K. Shields, PharmD5, (1)University of Pittsburgh, Pittsburgh, PA, (2)University of Pittsbugh, Pittsburgh, PA, (3)Infectious Diseases, University of Pittsburgh, Pittsburgh, PA, (4)Infectious Disease, University of Pittsburgh, Pittsburgh, PA, (5)University of Pittsburgh, School of Medicine, Pittsburgh, PA


C. Jones, None

E. Kline, None

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 .

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