Therapeutic Drug Monitoring of Linezolid in Drug-Resistant Tuberculosis Patients: Clinical Factors and Hematological Toxicities

Figures & data

Table 1 Demographic and Clinical Characteristics of the Included Patients

Demographics	Total Patients (n=76)
Age (years)	59 (39.5, 69.25)
No. of male (%)	53 (69.73%)
Weight (kg)	57.78±11.64
Body-mass index (kg/m^2)	20.73 (17.96, 23.01)
Drug manufacturer (Pfizer/Hansoh)	34/42
Biochemical indicators
Serum Albumin	36.3 (31.6, 40.1)
Creatinine clearance (Ccr, mL/min)	77.99 (55.5, 113.29)
Blood Urea Nitrogen (BUN)	4.865 (3.69, 6.28)
Alanine aminotransferase (ALT, U/L)	24 (14.75, 24.75)
Aspartate aminotransferase (AST, U/L)	20 (11.75, 34)
Comorbidities
Diabetes mellitus	21 (27.63%)
Hypertension	15 (19.74%)
Chronic liver disease	12 (15.79%)
Lung disease	25 (32.89%)
Drug resistance level
RR-TB/MDR-TB	43 (56.58%)
Pre-XDR-TB	25 (32.89%)
XDR-TB	8 (10.53%)
Linezolid treatment and concentration
Cmax (mg/L)	13.47 (10.41, 15.34)
Time of first TDM (days)	7 (5, 11)

Abbreviations: RR-TB, rifampicin-resistant tuberculosis; MDR-TB, multidrug-resistant tuberculosis; Pre-XDR-TB, Pre-extensively drug-resistant tuberculosis; XDR-TB, extensively drug-resistant tuberculosis.

Figure 1 The patients’ inclusion flow chart. 76 DR-TB patients were included in the analysis of linezolid concentration and hematological toxicity.

Table 2 Univariate Analysis Results

Variable	Plasma Concentration (mg/L)		χ2	P
	<12	>12
Gender
Male	29 (78.38)	24 (61.54)	1.186	0.1778
Female	8 (21.62)	15 (38.46)
Age (year)
≧65	7 (18.92)	16 (41.03)	4.397	0.0360
<65	30 (81.08)	23 (58.97)
Weight (kg)
<60	13 (30.23)	30 (69.77)	9.976	0.0016
≧60	22 (66.67)	11 (33.33)
Ccr (mL/sec)
<80	16 (43.24)	27 (69.23)	5.219	0.0223
≧80	21 (56.76)	12 (30.77)
AST (U/L)
<40	28 (75.68)	31 (83.78)	0.3345	0.5630
≧40	9 (24.32)	6 (16.22)
ALT (U/L)
<50	31 (81.58)	33 (86.84)	0.09896	0.7531
≧50	7 (18.42)	5 (13.16)
ALB (U/L)
<35	11 (29.73)	20 (51.28)	2.814	0.0935
≧35	26 (70.27)	19 (48.72)
Diabetes mellitus
With	9 (24.32)	12 (30.77)	0.1379	0.7103
Without	28 (75.68)	27 (69.23)
Hypertension
With	6 (19.35)	9 (25.71)	0.1031	0.7482
Without	25 (80.65)	26 (74.29)
Chronic liver disease
With	2 (6.90)	10 (21.28)	1.812	0.1782
Without	27 (93.10)	37 (78.72)
Lung disease
With	10 (40.00)	15 (49.02)	0.2463	0.6197
Without	25 (60.00)	26 (50.98)
Manufacturer
Henjie	17 (45.95)	17 (43.59)	0.04262	0.8364
Zyvox	20 (54.05)	22 (56.41)

Abbreviations: Ccr, Creatinine clearance; AST, Aspartate aminotransferase; ALT, Alanine aminotransferase; ALB, Albumin.

Table 3 Multivariate Analysis Results

Variable	Coefficient	S	Wald χ^2	P value	OR (95% CI)
Age	1.219	0.580	4.412	0.036	3.383 (1.085, 10.551)
Weight	1.310	0.517	6.421	0.011	3.705 (1.345, 10.204)
Ccr	0.990	0.481	4.242	0.039	2.692 (1.049, 6.909)

Figure 2 Univariate analysis results of linezolid. The Cmax between different age (A), weight (B), Ccr (Creatinine clearance) (C). *P< 0.05, **P<0.01.

Figure 3 Biochemical indexes of patients before and after linezolid therapy. The change of hemoglobin (A), platelet count (B), white blood cells (C) before and after linezolid treatment. ***P<0.001, ns means no significance.

Figure 4 Distribution of linezolid concentrations in patients with or without hematological toxicity. Linezolid Cmax of linezolid with or without anemia (A), thrombocytopenia (B), leukopenia (C). *P<0.05, ns means no significance.

Figure 5 ROC curve for predicting hematological toxicity of linezolid C_max.