. Author manuscript; available in PMC: 2019 May 10.

Published in final edited form as: J Med Chem. 2018 Apr 20;61(9):4067–4086. doi: 10.1021/acs.jmedchem.8b00091

Table 4.

In Vivo Efficacy of Cefepime-2, Meropenem-3, and Comparators in the Peritonitis Model

strains	β-lactamases	infecting load CFU/mouse	treatment protocol^a	antibiotics	MIC (μg/mL)^b	PD⁵⁰ (mg/kg)	PD⁹⁰ (mg/kg)
A. baumannii NCTC 13301	OXA-23, OXA-51	3.5 × 10⁵	+1 h PI, 2 doses	cefepime	>256	>100	>100
		3.5 × 10⁵	+1 h PI, 2 doses	cefepime-2^c	16	100 + 23.23	100 + 52.30
		3.5 × 10⁶	+1 h PI, 2 doses	meropenem^d	32	>100	>100
				meropenem-3	1	25 + 16.30	25 + 23.71
				tigecycline	1	>6.25	>6.25
			3 doses	colistin	1	16.57	NA
A. baumannii NCTC 13303	OXA-26, OXA-51- like	2.5 × 10⁶	+1 h PI, 2 doses	cefepime	64	>200	>200
			+1 h PI, 2 doses	cefepime-2	16	50 + <23.23	50 + 23.23
			+2 h PI, 2 doses	meropenem	256	>100	>100
				meropenem-3	16	50 + 24.01	50 + 49.38
				tigecycline	1	>6.25	>6.25
			3 doses	colistin	0.5	11.72	18.72
A. baumannii SL46	OXA-23, OXA-51	3 × 10⁶	+1 h PI, 2 doses	cefepime	>512	>200	>200
			+1 h PI, 2 doses	cefepime-2	32	50 + 23.23	100 + 52.30
			+2 h PI, 2 doses	meropenem	64	>100	>100
			+2 h PI, 2 doses	meropenem-3	8	50 + 24.91	50 + 66.17

Abbreviations: PI, postinfection; 2 doses, the drugs were administered twice, 3 h apart; 3 doses, the drugs were administered thrice, 3 h apart.

For MIC determinations, 3 was used at a fixed 8 μg/mL concentration. Cefepime-2 MICs were determined at 1:1 ratio.

Compound 2 as a monotherapy at 200 mg/kg did not result in protection of infected animals.

Meropenem was administered in combination with cilastatin (1:1) due to meropenem’s instability to murine renal DHP-1.⁵⁰