Plasma and Intrapulmonary Pharmacokinetics, and Dosage Regimen Optimization of Linezolid for Treatment of Gram-Positive Cocci Infections in Patients with Pulmonary Infection After Cerebral Hemorrhage

Figures & data

Table 1 The Baseline Characteristics of the Study Subjects

Patient No.	Sex	Age (Years)	WBC (×109/L)	NEU (%)	CrCl (mL/min)	Albumin (g/L)	APACHE II Score	PSI Risk Class	Pathogen
1	Male	67	13.39	87.5	81.72	27.8	18	IV	MRSA
2	Female	83	13.89	82.5	60.53	26.9	16	IV	/
3	Female	70	15.65	88.1	95.67	31.6	24	III	MDR-SP
4	Female	87	16.12	89.2	49.87	29.4	26	IV	/
5	Male	63	15.34	93.5	84.29	39.3	17	III	MRSA
6	Male	53	14.06	85.1	74.42	26.0	21	III	MRSA
7	Male	48	21.22	92.7	159.60	37.5	18	III	MRSA
8	Female	73	12.52	90.5	99.59	53.0	22	III	MDR-SP
9	Male	73	18.80	90	159.21	27.7	21	IV	/
10	Female	68	11.02	81	78.27	33.5	19	III	MRSA

Notes: “/”Indicates that the pathogen is not clear. In order to control the infection as soon as possible, linezolid was given empirically.

Abbreviations: WBC, white blood cell count; NEU, percentage of neutrophils; CrCl, creatinine clearance rate. PSI, Pneumonia Severity Index; MRSA, methicillin-resistant Staphylococcus aureus; MDR-SP, multi-drug resistant Streptococcus pneumoniae.

Table 2 The Pharmacokinetic Parameters of Linezolid in Plasma

Patient No.	T1/2 (h)	Tmax (h)	Cmax (μg/mL)	AUC0-12h (h·μg/mL)	CL (L/h)	Vd (L)
1	5.68	1.00	13.29	61.29	8.41	68.84
2	6.47	1.00	9.86	46.91	10.13	94.63
3	4.62	1.00	11.51	47.78	11.46	76.37
4	12.27	1.00	13.14	83.91	4.46	79.00
5	8.39	1.00	12.71	82.18	5.82	70.36
6	7.29	1.00	15.41	74.73	6.73	70.79
7	6.23	1.00	13.40	68.90	7.52	67.62
8	5.53	1.00	14.05	75.74	7.26	57.96
9	12.47	1.00	12.32	86.54	5.05	90.90
10	6.29	1.00	13.22	76.25	6.94	62.98
Mean±SD	7.52±2.75	1.00±0.00	12.89±1.48	70.42±14.19	7.38±2.17	73.94±11.60

Abbreviations: T_1/2, terminal elimination half-life; Cmax, maximal plasma concentration; Tmax, time to Cmax; AUC_0−12h, area under the concentration versus time curve from 0 to 12 h; CL, total body clearance; Vd, volume of distribution.

Figure 1 Plasma concentration–time curves of linezolid in patients (n=10).

Table 3 The Pharmacokinetic Parameters of Linezolid in the Sputum

Patient No.	T1/2 (h)	Tmax (h)	Cmax (μg/mL)	AUC0-12h (h·μg/mL)	CL (L/h)	Vd (L)
1	9.53	2.00	14.65	85.23	5.34	73.40
2	7.35	2.00	19.06	103.97	4.83	51.26
3	7.67	2.00	20.44	108.70	4.46	49.31
4	6.71	1.00	14.26	88.32	5.65	54.73
5	10.29	2.00	19.11	86.72	4.60	68.23
6	12.7	2.00	15.38	81.66	4.70	86.05
7	12.98	2.00	17.62	104.33	3.39	63.48
8	8.47	2.00	12.18	89.13	5.20	63.54
9	11.63	2.00	17.98	96.22	4.04	67.78
10	10.89	2.00	14.10	85.18	4.84	76.04
Mean±SD	9.82±2.24	1.90±0.32	16.48±2.72	92.95±9.61	4.71±0.65	65.38±11.53

Abbreviations: T_1/2, terminal elimination half-life; Cmax, maximal plasma concentration; T_max, time to C_max; AUC_0−12h, area under the concentration versus time curve from 0 to 12 h; CL, total body clearance; Vd, volume of distribution.

Figure 2 Sputum concentration–time curves of linezolid in patients (n=10).

Table 4 The PTAs of Linezolid in Plasma and Sputum Samples for Different Minimum Inhibitory Concentrations

Dosage Regimens	MIC Values (mg/L)
	0.25	0.5	1	2	4	8	16
Plasma
1200 mg/q12h	100.00	100.00	100.00	99.68	22.43	0.00	0.00
900 mg/q12h	100.00	100.00	100.00	90.37	1.45	0.00	0.00
600 mg/q12h	100.00	100.00	99.65	22.97	0.00	0.00	0.00
300 mg/q12h	100.00	99.66	22.70	0.00	0.00	0.00	0.00
Sputum
1200 mg/q12h	100.00	100.00	100.00	100.00	91.80	0.00	0.00
900 mg/q12h	100.00	100.00	100.00	100.00	7.96	0.00	0.00
600 mg/q12h	100.00	100.00	100.00	91.92	0.00	0.00	0.00
300 mg/q12h	100.00	100.00	92.13	0.00	0.00	0.00	0.00

Note: Green shading indicates a value greater than 90%.

Abbreviations: PTA, probability of target attainment; MIC, minimum inhibitory concentration.

Table 5 Minimum Inhibitory Concentration Values and Distribution Frequency of Linezolid Against Gram Positive Cocci (Data Obtained from the European Committee on Antimicrobial Susceptibility Testing, EUCAST)

MIC (μg/mL)	MRSA		Enterococcus faecalis		Enterococcus faecium		Streptococcus pneumoniae
	Nos	%	Nos	%	Nos	%	Nos	%
0.06	0	0.00	0	0.00	0	0.00	10	0.02
0.125	0	0.00	15	0.05	9	0.06	35	0.06
0.25	0	0.00	36	0.11	27	0.19	593	0.98
0.5	0	0.00	606	1.93	403	2.80	4665	7.75
1	36	1.45	13,977	44.49	4630	32.14	39,282	65.24
2	1304	52.50	16,245	51.71	8936	62.04	15,577	25.87
4	1142	45.97	490	1.56	377	2.62	18	0.03
8	1	0.04	8	0.03	9	0.06	0	0.00
16	1	0.04	7	0.02	1	0.01	0	0.00
32	0	0.00	5	0.02	0	0.00	0	0.00
64	0	0.00	0	0.00	0	0.00	0	0.00
Total	2484	100	31,415	99.92	14,404	99.92	60,207	99.96

Abbreviations: MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus.

Table 6 The CFR Values for Different Dosing Regimens Against MRSA, Enterococcus faecium, Enterococcus faecalis, and Streptococcus pneumoniae in Plasma and Sputum

Dosage Regimens	CFR Values Against Different Bacteria
	MRSA	Enterococcus faecalis	Enterococcus faecium	Streptococcus pneumoniae
Plasma
1200 mg/q12h	64.09	98.48	97.62	99.85
900 mg/q12h	49.56	93.34	91.29	97.43
600 mg/q12h	13.50	58.31	49.33	79.77
300 mg/q12h	0.33	12.18	10.33	23.59
Sputum
1200 mg/q12h	96.15	99.73	99.63	99.95
900 mg/q12h	57.60	98.42	97.44	99.93
600 mg/q12h	49.70	94.12	92.22	97.83
300 mg/q12h	1.34	43.08	32.66	68.92

Note: Green shading indicates a value greater than 90%.

Abbreviations: CFR, cumulative fraction of the response; MRSA, methicillin-resistant Staphylococcus aureus.