2565. In vitro synergistic bacterial killing of imipenem and ceftaroline against Mycobacterium abscessus; a static concentration time-kill analysis

BACKGROUND: Mycobacterium abscessus (Mab) represents a significant clinical challenge, with a rising incidence in recent times. The current therapeutic approach, which involves prolonged IV administration of amikacin, is associated with notable toxicities. Consequently, there is a pressing need to explore safe alternatives in antibiotic therapy. This study aimed to evaluate the in-vitro synergistic effect of a double β-lactam (DBL) combination which is safe for all ages. METHODS: We conducted static concentration time-kill (SCTK) studies utilizing Mab strain ATCC19977 over 10 days in duplicate. SCTK evaluated the impact of imipenem (IPM) and ceftaroline (CFT) in both monotherapy and combination therapy on bacterial killing (inoculum: 6 log(10) CFU/mL). To counteract the recognized extent of thermal degradation of β-lactams, predetermined quantities of IPM and CFT were added every 24 hours. Synergistic killing was estimated in the S-ADAPT software. In addition, the post-antibiotic effect (PAE) was measured following a 2-hour exposure to β-lactams. The β-lactams were removed by exchange with drug-free broth after centrifugation. RESULTS: DBL of IPM+CFT exhibited synergistic bactericidal activity, surpassing that of monotherapy with rapid regrowth observed in 1-3 days. Monotherapy demonstrated up to ∼1.5 log(10) killing followed by near-complete regrowth over a period of 10 days. DBL demonstrated significant synergistic killing, resulting in rapid and the most extensive reduction (∼3.5 Log(10) CFU/mL) and suppression of regrowth over 10 days. The addition of a β-lactamase inhibitor reduced the CFT concentration required for bacterial killing, resulting in synergistic bacterial killing at an achievable concentrations in-vivo mouse studies and clinical trials in the future. Furthermore, PAE were 4 minutes for IPM and 2 hours for CFT. Strikingly, the DBL at a concentration of 1xMIC demonstrated noteworthy bacteriostatic activity, with the suppression of bacterial growth lasting up to 14 h. [Figure: see text] CONCLUSION: DBL therapy yielded the most rapid and extensive killing of Mab with limited regrowth. The β-lactamase inhibitor was efficacious in inhibiting a broad-spectrum β-lactamase (bla(Mab)). The prolonged PAE observed in the DBL of IPM plus CFT may prove beneficial for intermittent dosing regimen. DISCLOSURES: Robert A. bonomo, MD, Entasis, Merck, VenatoRx, Wockhardt: Grant/Research Support