Table 1.

MICs (mg/L) of ceftazidime-avibactam (CZA), meropenem and meropenem in combination with CZA determined on E. cloacae KPC-3 (RD26), and a subset of CZA resistant mutants obtained after exposure to cytotoxic agents (Dacarbazine (Dc10), azacitidine (Az0.5), cyclophosphamide (Cyclo2.5), mitoxantrone (Mtx5), daunorubicin (Dn50) used at the concentrations of 10, 0.5, 2.5, 5 and 50 mg/L respectively), and on E. coli TOP10 electroporated with pBR322 plasmid harboring the same bla_KPC genes. MICs of antibiotics and mutations in bla_KPC observed in E. cloacae KPC-3 (RD26) of CZA-resistant mutants and transformants_a, selected after exposure to cytotoxic agents.

Cytotoxic agent	Isolates	MIC (mg/L)			Identified mutation in blaKPC	Reference
		Ceftazidime-Avibactam	Meropenem	Meropenem + Ceftazidime-Avibactam
—	RD26 (KPC-3)	4	16	0.023
	Top10-pBR322-RD26	1	1.5	0.016
Dc10	RD26-1	16	0.094	0.047	R164P	Winkler et al.
	—	—	—	—
Dc10	RD26-2	32	0.094	0.032	R164P	Winkler et al.
	Top10-pBR322-RD26-2	24	0.032	0.012
Az0.5	RD26-3	16	0.125	0.047	D179H	This study
	Top10-pBR322-RD26-3	24	0.032	0.016
Dc10	RD26-4	32	0.125	0.064	D179Y	Livermore et al.
		—	—	—
Dc10	RD26-5	12	0.38	0.023	T243M	Haidar et al.
	Top10-pBR322-RD26-5	12	0.064	0.016
Mito5	RD26-6	32	2	0.032	G175-S-A-I-P-G-D176	This study
	Top10-pBR322-RD26-6	24	0.023	0.016
Cyclo2.5	RD26-7	48	0.094	0.047	D176-∆A177-∆R178-∆D179-T180	This study
	Top10-pBR322-RD26-7	24	0.064	0.016
Dc10	RD26-8	32	1	0.032	K273-D-D-K-Y274	KPC-29
	Top10-pBR322-RD26-8	24	0.125	0.023
Dn50	RD26-9	32	0.125	0.047	C238-∆G239-∆V240-Y241	This study
	Top10-pBR322-RD26-9	64	0.023	0.023

^aTransformants were obtained by cloning bla_KPC (wild-type and mutated) in pBR322 plasmids and electroporated in E. coli Top10.