Altered pharmacokinetics of linezolid in patients with severe burn injuries

Abstract number: P1249

Vinsonneau C., Lovering A.M., Stephanazi J., Hovsepian L., Carsin H., Birraux G., Bret P., Le Floch R.

Background: Significant physiological changes occur in patients with major thermal burn injuries and result in alterations to the pharmacokinetics (PK) of many agents. These changes usually result in increased drug clearance and therefore it is necessary to increase the dosage of many antiobiotics. Today there is no data available describing the pharmacokinetics of linezolid (LZD) in burn patients and thereby whether doses need to be adjusted in these patients.

Methods: LZD PK were studied in 8 patients with severe burn injuries compared to 8 healthy volunteers matched for gender and weight. Mean (SD) demographic factors for the patients and volunteers were, age 37.0 (11.1) y vs. 37.6 (9.0) y; weight 64.0 (10.7) kg vs. 68.5 (9.4) kg and burnt area 41.0 (20.7) % vs. 0 (0) %. 600 mg LZD was administered as a 1 h infusion and both blood and urine samples were taken up to 72 h post dose and assayed by a validated HPLC method. PK parameters were determined by non-compartmental analysis.

Results: The mean (SD) PK parameters determined for LZD in the patients and healthy volunteers were: AUC0–¥ 42.5 (24.0) mg.h/L vs. 98.1 (29.2) mg.h/L, half life 2.1(1.0)h vs. 4.8(2.0)h and Vss 50.8 (16.8) L vs. 39.6 (5.7) L, respectively. The differences for AUC and T1/2 were statistically significant (P = 0.016; Wilcoxon signed rank sum test), but not the difference for Vss (P = 0.383). Mean concentrations of LZD dropped below the susceptibility breakpoint (EUCAST 4 mg/L) for staphylococci after 4 h in the patients and 10 h in the volunteers.

Conclusion: The PK of LZD were significantly altered in patients with major burn injuries as compared to healthy volunteers. The drug exposure, as assessed by AUC, was reduced by approximately 50% in burn patients suggesting that a different dosage schema might be required. Today it is not clear how this possible difference should be addressed, but for a drug that has time-dependent efficacy, it may be more appropriate to increase the frequency of administration rather than the dose administered.