Table 2.

Plasma and epithelial lining fluid concentrations of β-lactam/β-lactamase inhibitor combination products in healthy subjects

Antibacterial agent	Dosage regimen	Subjects [n]	Sampling time [h]a	Ratio of ELF to plasma based on AUC	Plasma concentration [µg/mL]b	ELF concentration [µg/mL]b	References
Piperacillin/tazobactam	Piperacillin 4 g IV q6h × 3 doses	5	0.5	0.26c	263 ± 45	58.8 ± 12.5	[19]
		5	1		152 ± 24	31.0 ± 10.9
		5	2		69.5 ± 19.8	19.7 ± 9.5
		5	4		14.8 ± 6.0	6.4 ± 4.5
		5	6		3.4 ± 1.1	3.0 ± 1.0
	Tazobactam 0.5 g IV q6h × 3 doses	5	0.5	0.54c	29.9 ± 6.1	15.3 ± 7.8
		5	1		19.0 ± 2.6	7.2 ± 2.8
		5	2		9.6 ± 2.4	5.2 ± 3.2
		5	4		1.9 ± 2.4	1.8 ± 1.2
		5	6		0.7 ± 0.2	1.0 ± 1.0
Ceftolozane/tazobactam	Ceftolozane 1 g IV q8h × 3 doses	5	1	0.48d	58.5 ± 7.8	21.8 ± 6.4
		5	2		34.0 ± 3.8	14.9 ± 3.0
		5	4		14.3 ± 2.4	9.3 ± 6.0
		5	6		5.5 ± 1.6	4.9 ± 2.4
		5	8		3.9 ± 1.4	4.2 ± 2.5
	Tazobactam 0.5 g IV q8h × 3 doses	5	1	0.44d	15.2 ± 1.9	4.5 ± 1.1
		5	2		3.9 ± 0.7	1.7 ± 0.6
		5	4		0.7 ± 0.1	0.5 ± 0.2
		5	6		0.2 ± 0e	0.2 ± 0.1f
		5	8		BQLg	0.3 ± 0.1e
Ceftazidime/avibactam	Ceftazidime 2000 mg IV q8h × 9 doses	22	2	0.31d	NR	NR	[24]
			4
			6
			8
	Ceftazidime 3000 mg IV q8h × 9 doses	21	2	0.32d	NR	NR
			4
			6
			8
	Avibactam 500 mg IV q8h × 9 doses	22	2	0.35d	NR	NR
			4
			6
			8
	Avibactam 1000 mg IV q8h × 9 doses	21	2	0.32d	NR	NR
			4
			6
			8
Cefepime/zidebactam	Cefepime 2 g IV q8h × 7 doses	6	0.5	0.39d	84.06 ± 17.94	26.31 ± 9.89	[30]
		5	1.25		107.0 ± 11.03	35.24 ± 3.89
		6	3		45.97 ± 6.16	19.77 ± 3.71
		6	6		14.43 ± 4.76	7.62 ± 4.56
		6	8		8.50 ± 4.34	4.62 ± 1.63
		6	10		3.73 ± 2.24	2.18 ± 0.84
	Zidebactam 1 g IV q8h × 7 doses	6	0.5	0.38d	36.03 ± 6.94	11.41 ± 4.46
		5	1.25		45.80 ± 3.29	14.61 ± 1.87
		6	3		19.65 ± 3.22	7.59 ± 1.77
		6	6		5.89 ± 1.89	2.77 ± 1.54
		6	8		3.30 ± 1.65	2.80 ± 3.27
		6	10		1.55 ± 0.90	0.74 ± 0.33
Cefepime/enmetazobactam	Cefepime 2 g IV over 2 h q8h × 9 doses	19	2	0.61h	NR	NR	[35]
			4
			6
			8
	Enmetazobactam 1 g IV over 2 h q8h × 9 doses	19	2	0.53h	NR	NR
			4
			6
			8
Meropenem/vaborbactam	Meropenem 2 g IV q8h × 3 doses	5	1.5	0.63d/0.65i	41.2 ± 5.02	21.4 ± 3.96	[39]
		5	3.25		47.7 ± 7.28	28.3 ± 6.69
		5	4		23.8 ± 4.30	16.1 ± 4.77
		5	6		7.24 ± 2.79	7.51 ± 5.29
		5	8		1.36 ± 0.51	2.51 ± 1.13
	Vaborbactam 2 g IV q8h × 3 doses	5	1.5	0.53d/0.79j	42.1 ± 5.00	18.6 ± 3.76
		5	3.25		51.1 ± 6.78	26.1 ± 7.12
		5	4		28.2 ± 5.32	15.7 ± 3.36
		5	6		10.8 ± 2.82	8.04 ± 5.81
		5	8		2.74 ± 1.12	2.61 ± 1.35
Imipenem/relebactam	Imipenem 500 mg IV q6h × 5 doses	4	0.5	0.44k/0.55l	NR	32.09 (21.26, 48.44)m	[40]
		4	1.0			20.27 (13.43, 30.59)m
		4	1.5			16.47 (10.92, 24.87)m
		4	3.0			5.99 (3.97, 9.04)m
	Relebactam 250 mg IV q6h × 5 doses	4	0.5	0.43k/0.54l	NR	14.93 (9.89, 22.53)m
		4	1.0			10.93 (7.24, 16.50)m
		4	1.5			9.49 (6.29, 14.32)m
		4	3.0			4.27 (2.83, 6.45)m
Sulbactam/durlobactam	Sulbactam 1 g IV q6h × 3 doses	6	1	0.50c/0.81n	17.28 ± 2.97	9.22 ± 2.25	[46]
		6	2.5		21.42 ± 3.31	10.25 ± 2.29
		6	3.25		12.03 ± 2.66	5.67 ± 1.74
		6	4		8.58 ± 1.90	4.64 ± 1.56
		6	6		2.24 ± 1.01	1.27 ± 0.49
	Durlobactam 1 g IV q6h × 3 doses	6	1	0.37c/0.41o	24.33 ± 3.35	9.14 ± 1.51
		6	2.5		31.23 ± 3.80	10.47 ± 1.70
		6	3.25		20.78 ± 4.54	7.14 ± 1.66
		6	4		15.10 ± 2.68	6.03 ± 1.88
		6	6		5.33 ± 1.80	2.15 ± 0.78

ELF epithelial lining fluid, AUC area under the concentration-time curve, IV intravenously, BQL below quantitative limit of detection, NR not reported, SD standard deviation, qxh every x hours

^aSampling time after the last dose

^bTotal plasma and ELF concentrations reported as mean ± SD

^cBased on the ratio of AUC₆ in ELF to AUC₆ in total plasma

^dBased on the ratio of AUC₈ in ELF to AUC₈ in total plasma

^eTwo of five subjects had concentrations equal to or above the quantitative limit of detection of 0.1 µg/mL

^fFive of five subjects had concentrations BQL of 0.1 µg/mL

^gThree of five subjects had concentrations equal to or above the quantitative limit of detection of 1.0 ng/mL

^hBased on the ratio of AUC₂₄ in ELF to AUC₂₄ in total plasma (calculated from Bayesian posterior estimates)

ⁱBased on the ratio of AUC₈ in ELF to AUC₈ in unbound plasma, assuming 2% protein binding in plasma

^jBased on the ratio of AUC₈ in ELF to AUC₈ in unbound plasma, assuming 33% protein binding in plasma

^kBased on the ratio of AUC_∞ in ELF to AUC_∞ in total plasma

^lBased on the ratio of AUC_∞ in ELF to AUC_∞ in unbound plasma, assuming 20% protein binding in plasma

^mGeometric mean (95% confidence interval) reported in units of µM

ⁿBased on the ratio of AUC₆ in ELF to AUC₆ in unbound plasma, assuming 38% protein binding in plasma

^oBased on the ratio of AUC₆ in ELF to AUC₆ in unbound plasma, assuming 10% protein binding in plasma