Interpretation
Linezolid is the first of the oxazolidinone antibiotics to gain worldwide acceptance for treating severe infections caused by methicillin- or vancomycin- resistant gram positive bacteria, as well as drug resistant tuberculosis. Minimum inhibitory concentrations (MIC90) are reported to be ≤ 2 mg/L for S. aureus, E. faecalis, E. faecium, S. pneumoniae, and coagulase-negative streptococcus isolates. MIC90 for M. tuberculosis is reported as 0.5 mg/L.
Treatment efficacy has been linked two pharmacokinetic parameters – the ratio of the daily area under the plasma concentration curve to the minimum inhibitory concentration (AUC24/MIC), and the proportion of time that the plasma concentration is above the minimum inhibitory concentration (%T>MIC) for the organism. Because AUC and trough concentrations are highly correlated, measurements of trough linezolid concentrations (Cmin) have been used to ensure effective therapy by targeting Cmin above the known MIC or MIC90 (typically 2 mg/L), or by targeting a trough concentration which predicts AUC to be over 80-120 times MIC.
Adverse effects associated with linezolid treatment limit its use, and include peripheral neuropathy, liver dysfunction, and suppression of bone marrow, leading to anaemia,
thrombocytopenia, and pancytopenia. The occurrence of these effects correlates with both dose and duration of treatment. Studies suggest adverse events can be minimised by dose management to keep linezolid trough concentrations below 7 mg/L (for treatment duration ≤14 days), or below 2 mg/L for the longer treatment durations associated with tuberculosis.
Significant variability in pharmacokinetics has been observed in certain patient groups (impaired creatinine clearance, critically ill patients, neonates, patients on haemodialysis, and patients taking P-glycoprotein inducers, such as levothyroxine). Only 50% of hospital patients given the standard dose of 600 mg twice daily achieved concentrations within a target therapeutic range of 2 – 7 mg/L, highlighting the importance of TDM for Linezolid.
Linezolid drug concentrations should not be the only means of therapeutic drug management. The assay should be used in conjunction with information available from clinical evaluations and other diagnostic procedures. Clinicians should carefully monitor patients during therapy and dosage adjustments.
Reference Intervals
In general, the target trough linezolid concentration is 2-7 mg/L (based on a presumed pathogen MIC of 2 mg/L). Seek expert advice on appropriate targets for organisms with different MICs, or for alternative targets such as AUC or time above MIC.
Test Method
The ARK Linezolid Assay is a homogeneous immunoassay based on competition between drug in the specimen and linezolid labelled with recombinant enzyme glucose-6-phosphate dehydrogenase (rG6PDH) for binding to the antibody reagent. As the latter binds antibody, enzyme activity decreases. In the presence of drug from the specimen, enzyme activity increases and is directly related to the drug concentration. Active enzyme converts the coenzyme nicotinamide adenine dinucleotide (NAD) to NADH that is measured spectrophotometrically as a rate of change in absorbance. Endogenous serum G6PDH does not interfere with the results because the coenzyme NAD functions only with the bacterial enzyme used in the assay.
