1580. Colistin Potentiates the In Vitro Activity of Meropenem–Vaborbactam (M/V) Against Some, but not All KPC-producing Klebsiella pneumoniae (KPC-Kp)

BACKGROUND: M/V demonstrates potent in vitro activity against KPC-producing organisms. It is unclear whether the combination interacts synergistically with other active agents. METHODS: We tested isolates for responses to M/V alone (1 and 4x MIC; V fixed at 8 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), and tigecycline (TGC; 2 µg/mL) by time-kill using a starting inoculum of 1 × 10(8) cFu/mL. 24h was the primary endpoint. RESULTS: 16 KPC-Kp isolates were studied (7 KPC-2 and 9 KPC-3); all were M/V-susceptible (MIC range: 0.015 – 4 µg/mL). 44% harbored ompK36 mutations (4 IS5 promoter insertion, 2 134–135 DG duplication, and 1 premature stop codon). Median M/V MICs were higher against isolates with mutant ompK36 (0.25 vs. 0.03; P = 0.002). Mean log-kills by M/V at 1x and 4x were -0.50 and -2.41, respectively; M/V was bactericidal (≥3-log kill) against 6% and 56%, respectively (Figure 1). Mean log-kills at 4× were greater against KPC-2 (-3.79) than KPC-3 (−1.33) isolates (P = 0.09), and among isolates with (−3.31) vs. without (−1.71) ompK36 mutations (P = 0.11). GEN was the most active single agent (bactericidal against 56%, mean log-kill = −3.04). In combo with M/V, rates of synergy (>2-log kill in combo) with COL, FOS, GEN, and TGC were 44%, 19%, 12.5%, and 12.5%, respectively (Figure 2). Corresponding rates of bactericidal activity were 44%, 25%, 69%, and 31%, respectively. Antagonism (> 1-log kill by most active single agent) was identified for each combo against 2 isolates. Mean log-kills by M/V + GEN were greater against isolates with GEN MICs ≤1 (−7.16) vs. ≥2 (−1.66; P = 0.001), reflecting the activity of GEN alone. Mean log-kills by M/V + COL were greater against isolates with IS5 insertions (-6.32) compared with wild type (−2.38) or other mutations (−1.77) in ompK36. Responses to M/V + FOS were not dependent upon FOS MIC, but log-kills were greater against mutant (-2.13) vs. wild-type (0.01) ompK36 (P = 0.03). CONCLUSION: M/V + GEN is rapidly cidal if GEN MICs are ≤1, while M/V + COL resulted in highest rates of synergy against diverse KPC-Kp. Mean log-kills were highest among isolates with IS5 promoter insertions suggesting a potential role for COL combination therapy against KPC-Kp isolates with decreased outer membrane permeability. [Image: see text] [Image: see text] DISCLOSURES: All authors: No reported disclosures.