Evaluation of <i>in-vitro</i> susceptibility of ß-lactam-resistant Gram-negative bacilli to ceftazidime-avibactam and ceftolozane-tazobactam from clinical samples of a general hospital in southern Brazil

Carvalho, Thaisa Noceti; Kobs, Vanessa Cristine; Hille, Daniela; Deglmann, Roseneide Campos; Melo, Luiz Henrique; França, Paulo Henrique Condeixa de

doi:10.1590/0037-8682-0277-2022

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Major Article • Rev. Soc. Bras. Med. Trop. 56 • 2023 • https://doi.org/10.1590/0037-8682-0277-2022 copy

Evaluation of in-vitro susceptibility of ß-lactam-resistant Gram-negative bacilli to ceftazidime-avibactam and ceftolozane-tazobactam from clinical samples of a general hospital in southern Brazil

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Background:

The spread of carbapenemase- and extended-spectrum β-lactamase (ESBL)-producing gram-negative bacilli (GNB) represent a global public health threat that limits therapeutic options for hospitalized patients. This study aimed to evaluate the in-vitro susceptibility of β-lactam-resistant GNB to ceftazidime-avibactam (C/A) and ceftolozane-tazobactam (C/T), and investigate the molecular determinants of resistance.

Methods:

Overall, 101 clinical isolates of Enterobacterales and Pseudomonas aeruginosa collected from a general hospital in Brazil were analyzed. Susceptibility to the antimicrobial agents was evaluated using an automated method, and the minimum inhibitory concentrations (MIC50/90) of C/A and C/T were determined using Etest^®. The β-lactamase-encoding genes were investigated using polymerase chain reaction.

Results:

High susceptibility to C/A and C/T was observed among ESBL-producing Enterobacterales (100% and 97.3% for CLSI and 83.8% for BRCAST, respectively) and carbapenem-resistant P. aeruginosa (92.3% and 87.2%, respectively). Carbapenemase-producing Klebsiella pneumoniae exhibited high resistance to C/T (80%- CLSI or 100%- BRCAST) but high susceptibility to C/A (93.4%). All carbapenem-resistant K. pneumoniae isolates were susceptible to C/A, whereas only one isolate was susceptible to C/T. Both antimicrobials were inactive against metallo-β-lactamase-producing K. pneumoniae isolates. Resistance genes were concomitantly identified in 44 (44.9%) isolates, with bla _CTX-M and bla _SHV being the most common.

Conclusions:

C/A and C/T were active against microorganisms with β-lactam-resistant phenotypes, except when resistance was mediated by metallo-β-lactamases. Most C/A- and C/T-resistant isolates concomitantly carried two or more β-lactamase-encoding genes (62.5% and 77.4%, respectively).

Keywords:
Antimicrobial resistance; Gram-negative bacilli; Ceftazidime-avibactam; Ceftolozane-tazobactam; In vitro activity; Genetic marker

	MIC frequency (%)												MIC interpretation (%)						MIC (mg/L)
Group of microorganisms (N)													CLSI			BRCAST
	<1	1	2	3	4	6	8	12	24	32	48	>256	S	I	R	S	I	R	MIC 50	MIC 90	Range
Pseudomonas aeruginosa - CR (39)	15.4	46.2	56.4	66.7	87.2	92.3	94.9			97.4		100	87.2	7.7	5.1	87.2		12.8	2	6	0.38 - >256
Enterobacterales - ESBL (37)	67.6	83.8	97.3									100	97.3		2.7	83.8		16.2	<1	2	0.125 - >256
Klebsiella pneumoniae - KPC (15)			13.3		20.0		26.7	33.3	53.3	60.0	86.7	100	13.3	6.6	80.0			100	24	>256	2,0 - >256
Klebsiella pneumoniae - MβL (4)												100			100			100	>256	>256	>256 - >256
Klebsiella pneumoniae - CR (3)	33.3								66.7		100		33.3		66.6	33.3		66.6	24	48	0.50 - 48
CESP group - CR (3)							33.3					100			100			100	>256	>256	8 - >256

	MIC frequency (%)										MIC interpretation (%)			MIC (mg/L)
Group of microorganisms (N)											CLSI and BRCAST
	<1	1	2	3	4	6	8	12	24	>256	S	I	R	MIC 50	MIC 90	Range
Pseudomonas aeruginosa - CR (39)	2.6	33.3	43.6	69.2	76.9	89.7	92.3	94.9	97.4	100	92.3		7.7	3	8	0.50 - >256
Enterobacterales - ESBL (37)	89.2	97.3		100							100			<1	1	0.125 - 3
Klebsiella pneumoniae - KPC (15)	26.7	86.7	93.3							100	93.3		6.6	1	2	0.38 - >256
Klebsiella pneumoniae - MβL (4)										100			100	>256	>256	>256 - >256
Klebsiella pneumoniae - CR (3)	33.3		66.7		100						100			2	4	0.75 - 4
CESP group - CR (3)		33.3			66.7			100			66.7		33.3	4	12	1 - 12

Phenotypic resistance	Species (N)	β-Lactamase genes	Isolates (n)	Isolates (%)
ESBL	Escherichia coli (27)	*bla* _CTX-M	26	96.3
		*bla* _SHV	17	63
	Klebsiella pneumoniae (7)	*bla* _CTX-M	7	100
		*bla* _SHV	6	85.7
	Proteus mirabilis (2)	*bla* _CTX-M	2	100
	Klebsiella ozaenae (1)	*bla* _SHV	1	100
		*bla* _CTX-M	1	100
KPC	Klebsiella pneumoniae (15)	*bla* _KPC	15	100
		*bla* _SHV	14	93.3
		*bla* _CTX-M	12	80
		*bla* _NDM-1	1	6.7
		*bla* _VIM	1	6.7
CR	Pseudomonas aeruginosa (36)	*bla* _CTX-M	14	38.9
		*bla* _SHV	5	13.9
		*bla* _KPC	2	5.6
		*bla* _VIM	1	2.8
	Klebsiella pneumoniae (3)	*bla* _CTX-M	3	100
		*bla* _SHV	3	100
	Klebsiella pneumoniae (3)	*bla* _NDM-1	1	33.3
	Enterobacter cloacae (2)	*bla* _CTX-M	1	50
	Serratia marcescens (1)	*bla* _KPC	1	100
MβL	Klebsiella pneumoniae (4)	*bla* _SHV	4	100
		*bla* _NDM-1	3	75

Phenotypic resistance	Species	Isolates (n)	β-Lactamase genes	Phenotype
Phenotypic resistance	Species	Isolates (n)	β-Lactamase genes	C/A	C/T
ESBL	Escherichia coli	15	*bla* _CTX-M *, bla* _SHV	S	S
		10	*bla* _CTX-M	S	S
		1	*bla* _CTX-M , bla _SHV	S	R
		1	*bla* _SHV	S	S
	Klebsiella pneumoniae	5	*bla* _CTX-M	S	S
		1	*bla* _CTX-M , bla _SHV	S	R
		1	*bla* _CTX-M	S	R
	Proteus mirabilis	2	*bla* _CTX-M	S	R
	Klebsiella ozaenae	1	*bla* _CTX-M , bla _SHV	S	R
KPC	Klebsiella pneumoniae	9	*bla* _KPC *, bla* _CTX-M *, bla* _SHV	S	R
		2	*bla* _KPC *, bla* _SHV	S	R
		1	*bla* _KPC *, bla* _CTX-M *, bla* _SHV *, bla* _NDM-1	S	R
		1	*bla* _KPC, *bla* _CTX-M *, bla* _SHV *, bla* _VIM	S	R
		1	*bla* _KPC *, bla* _CTX-M	S	R
		1	*bla* _KPC *, bla* _SHV	R	R
CR	Pseudomonas aeruginosa	7	*bla* _CTX-M	S	S
		2	*bla* _CTX-M , bla _SHV	S	S
		1	*bla* _KPC *, bla* _CTX-M	S	S
		1	*bla* _KPC *, bla* _CTX-M *, bla* _SHV	S	S
		1	*bla* _SHV	S	S
		1	*bla* _VIM	S	S
		1	*bla* _CTX-M	R	S
		1	*bla* _CTX-M	S	R
		1	*bla* _CTX-M , bla _SHV	R	R
	Klebsiella pneumoniae	2	*bla* _CTX-M , bla _SHV	S	R
		1	*bla* _CTX-M , bla _SHV *, bla* _NDM-1	S	S
	Enterobacter cloacae	1	*bla* _CTX-M	R	R
	Serratia marcescens	1	*bla* _KPC	S	R
MβL	Klebsiella pneumoniae	3	*bla* _SHV *, bla* _NDM-1	R	R
		1	*bla* _SHV	R	R

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[1] Corresponding author: Thaisa Noceti Carvalho. e-mail:thaisanoceti@gmail.com