The Potential Use of Ceftazidime-Avibactam Against Carbapenem Resistant Klebsiella pneumoniae Clinical Isolates Harboring Different Carbapenemase Types in a Thai University Hospital

Figures & data

Table 1 In vitro Susceptibility and Percentage of Susceptibility Among Ceftazidime-Avibactam (CZA) and Comparator Agents Against Carbapenem-Resistant Klebsiella pneumoniae (CRKP) Clinical Isolates

Agents	MIC Range (µg/mL)	MIC50 (µg/mL)	MIC90 (µg/mL)	Percentage of Susceptible Strains
Ceftazidime-avibactam	0.125->256	2	>256	47.7%
Ceftazidime	8- >32	>32	>32	0%
Cefepime	4 - >32	>32	>32	0%
Ertapenem	2 - > 4	>4	>4	0%
Imipenem	≤0.5 - >8	>8	>8	18.3%
Meropenem	≤0.5 - >8	>8	>8	12.2%
Piperacillin-tazobactam	64 - >64	>64	>64	0%
Amikacin	≤8–32	≤8	≤8	97.9%
Gentamicin	≤2 ->8	≤2	4	91.8%
Ciprofloxacin	0.12 - >2	>2	>2	4%
Levofloxacin	1 - >8	>8	>8	0%
Tigecycline	≤0.25 – 4	0.5	1	79.6%*
Trimethoprim-sulfamethoxazole	≤1 - >4	>4	>4	10.2%
Colistin	≤1 - >4	≤1	>4	67.3%

Notes: *Interpreted according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST).²³

Abbreviations: MIC, minimum inhibitory concentration; MIC₅₀, minimum inhibitory concentration required to inhibit the growth of 50% of organisms; MIC₉₀, minimum inhibitory concentration required to inhibit the growth of 90% of organisms.

Table 2 CZA Minimum Inhibitory Concentration Values, Zone Inhibition of CZA and Interpretive Categories by CLSI and EUCAST Against Various Carbapenemase Types of CRKP Clinical Isolates (n=49)

No	Types of Carbapenemase	MIC Values (µg/mL) of CZA	Zone Inhibition (mm.) of CZA	Interpretive Categories
				CLSI	EUCAST
1	OXA-48	0.125	28	S	S
2	OXA-48	0.19	31	S	S
3	OXA-48	0.25	29	S	S
4	OXA-48	0.38	26	S	S
5	OXA-48	0.38	26	S	S
6	OXA-48	0.5	27	S	S
7	OXA-48	0.75	26	S	S
8	OXA-48	0.75	30	S	S
9	OXA-48	0.75	30	S	S
10	OXA-48	0.75	27	S	S
11	OXA-48	1	32	S	S
12	OXA-48	1	31	S	S
13	OXA-48	1	30	S	S
14	OXA-48	1	25	S	S
15	OXA-48	1	24	S	S
16	OXA-48	1	25	S	S
17	OXA-48	1	25	S	S
18	OXA-48	1.5	24	S	S
19	OXA-48	1.5	26	S	S
20	OXA-48	>256	16	R	S
21	OXA-48	>256	16	R	S
22	NDM	>256	16	R	S
23	OXA-48 + NDM	2	14	R	S
24	OXA-48 + NDM	2	15	R	S
25	OXA-48 + NDM	>256	15	R	S
26	OXA-48 + NDM	>256	14	R	S
27	OXA-48 + NDM	>256	15	R	S
28	OXA-48 + NDM	>256	13	R	S
29	OXA-48 + NDM	>256	14	R	S
30	OXA-48 + NDM	>256	14	R	S
31	OXA-48 + NDM	>256	15	R	S
32	OXA-48 + NDM	>256	14	R	S
33	OXA-48 + NDM	>256	15	R	S
34	OXA-48 + NDM	>256	15	R	S
35	OXA-48 + NDM	>256	14	R	S
36	OXA-48 + NDM	>256	16	R	S
37	OXA-48 + NDM	>256	14	R	S
38	OXA-48 + NDM	>256	15	R	S
39	OXA-48 + NDM	>256	13	R	S
40	OXA-48 + NDM	>256	14	R	S
41	OXA-48 + NDM	>256	15	R	S
42	OXA-48 + NDM	>256	12	R	R
43	OXA-48 + NDM	>256	6	R	R
44	OXA-48	n/a	26	S	S
45	OXA-48	n/a	26	S	S
46	OXA-48	n/a	27	S	S
47	OXA-48	n/a	26	S	S
48	OXA-48	n/a	26	S	S
49	NA	2	24	S	S

Abbreviations: CLSI, the Clinical and Laboratory Standards Institute; CZA, ceftazidime-avibactam; EUCAST, the European Committee on Antimicrobial Susceptibility Testing; MIC, minimum inhibitory concentration; NA, nonapplicable for cabapenemase typing; n/a, non-applicable for MIC testing; NDM, New Delhi metallo-beta-lactamase; OXA-48, oxacillinase-48; S, susceptible; R, resistance.

Table 3 PTA for Different CZA Regimens Among Critically Ill Patients According to Kidney Function (Creatinine Clearance) at Steady State with Ceftazidime Targets of %fTime>MIC ≥ 50 and 100% with Avibactam Targets of 100%fT ≥ 0.5 µg/mL

PK/PD Targets	Dosage regimens of CZA			PTA (%)
					CZA MIC (µg/mL) Against CRKP Isolates								AVI
	Loading Dose	Maintenance Dose	Infusion Time	0.125	0.25	0.5	1	2	4	8	16	32	fT ≥ 0.5 100%
fTime>MIC ≥50%	2.5 g	2.5 g q8h	0.5h	100	100	100	100	100	99	97	89	64	88
		2.5 g q8h	1h	100	100	100	100	100	99	98	91	63	89
		2.5 g q8h	2h	100	100	100	100	100	100	99	93	66	91
		2.5 g q8h	3h	100	100	100	100	100	100	99	94	68	94
fTime>MIC 100%	2.5 g	2.5 g q8h	0.5h	100	99	99	98	95	90	81	63	35	88
		2.5 g q8h	1h	100	99	99	98	95	91	82	64	36	89
		2.5 g q8h	2h	100	100	99	99	97	93	85	68	39	91
		2.5 g q8h	3h	100	100	100	99	98	95	87	71	43	94

Notes: Color codes: green boxes indicate strongly recommended dose based on ≥90% PTA.

Abbreviations: PTA, probability of target attainment; AVI, avibactam; g, gram; h, hour; MIC, minimum inhibitory concentration; CAZ, ceftazidime; CZA, ceftazidime/avibactam; CRKP, carbapenem-resistant Klebsiella pneumoniae; PTA, probability of target attainment; %fTime>MIC, percentage of free drug time exceeding the MIC.

Table 4 CFR (%) of CZA Regimens with Various Dosing Regimens According to Carbapenemase Types and Disk Diffusion Interpretation

PK/PD Targets	CZA Regimens			CFR (%)
	Loading Dose	Maintenance Dose	Infusion Time	Carbapenemase Types			Disk Diffusion Interpreted by
				All Types	OXA-48	NDM	CLSI	EUCAST
fTime>MIC ≥50%	2.5 g	2.5 g q8h	0.5h	50	90	9	100	52
		2.5 g q8h	1h	50	90	9	100	52
		2.5 g q8h	2h	50	90	9	100	52
		2.5 g q8h	3h	50	90	9	100	52
fTime>MIC 100%	2.5 g	2.5 g q8h	0.5h	49	89	9	98	51
		2.5 g q8h	1h	49	89	9	98	51
		2.5 g q8h	2h	49	90	9	99	52
		2.5 g q8h	3h	50	90	9	99	52

Notes: Color codes: green boxes Strongly recommended dose based on ≥90% CFR.

Abbreviations: CFR, cumulative fraction of response; CLSI, the Clinical and Laboratory Standards Institute; CZA, ceftazidime-avibactam; EUCAST, the European Committee on Antimicrobial Susceptibility Testing; g, gram; h, hour; NDM, New Delhi metallo-beta-lactamase; OXA-48, oxacillinase-48; %fTime>MIC, percentage of free drug time exceeding the MIC.

The European Committee on Antimicrobial Susceptibility Testing. European Committee on Antimicrobial Susceptibility Testing Breakpoint tables for interpretation of MICs and zone diameters Version 11; Published 2021. Available from: http://www.eucast.org/clinical_breakpoints/. Accessed 318, 2021.

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