Clinical Pharmacokinetics of Linezolid, a Novel Oxazolidinone Antibacterial

Abstract

Linezolid is the first antibacterial to be approved from the oxazolidinone class. The drug has substantial antimicrobial activity against Gram-positive organisms such as streptococci, staphylococci and enterococci, including species resistant to conventional antibacterial treatment. Linezolid is fully bioavailable following oral administration when compared with intravenous administration. Maximum plasma linezolid concentrations are usually achieved between 1 and 2 hours after oral administration. Food slightly decreases the rate, but not the extent, of absorption. The distribution of linezolid is approximately equivalent to total body water, and there is low protein binding (31%) to serum albumin. The elimination half-life of linezolid is 5-7 hours, and twice-daily administration of 400-600 mg provides steady-state concentrations in the therapeutic range. Linezolid is mainly cleared by non-renal clearance to two metabolites and renal clearance of the parent compound. Approximately 50% of an administered dose appears in the urine as the two major metabolites, and approximately 35% appears as parent drug. A small degree of nonlinearity has been observed, with a 30% decrease in clearance after a 5-fold increase in dose. The nonlinearity is not relevant over the therapeutic dosage range. Plasma linezolid concentrations in elderly patients, patients with mild to moderate hepatic impairment or mild to severe renal impairment are similar to those achieved in young or healthy volunteers. Higher concentrations are observed in women as compared with men, but the difference is not sufficient to warrant an adjustment in dosage. In patients with severe renal impairment requiring haemodialysis, the exposure to the two primary metabolites was 7 to 8-fold higher than in patients with normal renal function. Therefore, linezolid should be used with caution in patients with severe renal insufficiency. A higher clearance of linezolid was found in children as compared with adults, and therefore higher daily dosages per kg bodyweight are required in children. There is no pharmacokinetic interaction when linezolid is coadministered with aztreonam, gentamicin or warfarin. Linezolid is a mild, reversible, inhibitor of monoamine oxidases A and B. Coadministration of linezolid with the adrenergic agents pseudoephedrine and phenylpropanolamine resulted in increases in blood pressure relative to these agents alone or to placebo. The degree of the change in blood pressure was within that associated with normal daily activities. No interaction was observed when linezolid was coadministered with the serotonergic agent dextromethorphan.

Pharmacokinetics of linezolid in septic patients with and without extended dialysis

“…Due to these factors, plasma and tissue concentrations of antibiotics are often suboptimal when drugs are administered at dosages suggested for healthy volunteers [23]. In our patient cohort, large interindividual variations in plasma concentrations and low C min values were associated with an increase in the Cl and volume of distribution relative to those found in healthy volunteers [24]. The increased CI may be a result of renal replacement therapy, and the increased volume of distribution may be due to septic conditions, such as edema.…”

“…Pharmacokinetic / pharmacodynamic indices Table 5 shows time above MIC (T > MIC), AUC 24 , and the ratio AUC 24 to MIC (AUC 24 /MIC) of both groups (patients with or without ED) and for patients with or without previous liver transplantation/resection. The calculation was made with a MIC based on the susceptibility breakpoint for linezolid being 4 mg/L [20].…”

Pharmacokinetic/pharmacodynamic (PK/PD) considerations in the management of Gram-positive bacteraemia

“…This is the first member of a new class of antibacterial agents, the oxazolidinones, which act by inhibiting the formation of bacterial protein synthesis initiation complex, possibly by distorting the binding site for initiator tRNA [36]. It is a valid therapeutic alternative to glycopeptides against multiresistant Gram-positive strains such as staphylococci, streptococci and enterococci, which are particularly frequent in the ICU [37].…”

Linezolid use in Medicin Therapy against Multiresistant Bacteria-A Review

“…It is metabolized in the liver, however, it does not present interactions with cytochrome P450, reaching high concentrations in the lungs, bones, muscles, cerebrospinal fluid and skin. The adverse effects are headache, diarrhea, insomnia, constipation and vertigo, as well as haematological effects such as thrombocytopenia, especially in prolonged treatments, being reversible with the suspension of the drug [7][8][9][41][42][43] Low levels of resistance were observed and may be associated with mutations in ribosomal RNA, however, it is suggested to perform susceptibility tests to this antimicrobial before the start of antibiotic therapy [7,9,44,45].…”