Linezolid (ZYVOX®, Pfizer, Inc.) [(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]-acetamide] is an oxazolidinone derivative with a predominantly bacteriostatic effect against severe infections caused by methicillin- or vancomycin-resistant Gram-positive bacteria.1
ZYVOX is indicated in adults and children for the treatment of the following infections caused by susceptible Gram-positive bacteria: Nosocomial pneumonia; Community-acquired pneumonia; Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis; Uncomplicated skin and skin structure infections; Vancomycin resistant Enterococcus faecium infections.
A steady state, trough (pre-dose) sample is generally accepted as most consistent for therapeutic drug monitoring of linezolid
Samples are centrifuged and serum aliquoted for analysis. Store samples at 2-8 C
Clarified specimens may be stored up to one week at 2 to 8°C. If testing will be delayed more than one week, specimens should be stored frozen (<20°C) for up to four weeks prior to being tested.
Interference studies were conducted using CLSI EP7-A2 as a guideline. Clinically high concentrations of potentially interfering substances in serum with known levels of linezolid (2.0 μg/mL and 10.0 μg/mL) were evaluated. Each sample was assayed using the ARK Linezolid Assay, along with a serum control of linezolid. Measurement of linezolid resulted in ≤10% error in the presence of interfering substances at the levels tested.
Chilled (2 - 8 degrees Celsius)
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.
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.
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.
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