Pharmacokinetics of Intravenous and Oral Linezolid in Adults with Cystic Fibrosis

Abstract

Linezolid is a treatment option for methicillin-resistant Staphylococcus aureus (MRSA) infections in cystic fibrosis (CF) patients. Little is known, however, about its pharmacokinetics in this population. Eight adults with CF were randomized to receive intravenous (i.v.) and oral linezolid at 600 mg twice daily for 9 doses in a crossover design with a 9-day washout. Plasma samples were collected after the first and ninth doses of each phase. Population pharmacokinetic analyses were performed by nonlinear mixed-effects modeling using a previously described 2-compartment model with time-dependent clearance inhibition. Monte Carlo simulation was performed to assess the activities of the linezolid dosing regimens against 42 contemporary MRSA isolates recovered from CF patients. The following pharmacokinetic parameter estimates were observed for the population: absorption rate constant, 1.91 h ؊1 ; clearance, 9.54 liters/h; volume of central compartment, 26.8 liters; volume of peripheral compartment, 17.3 liters; and intercompartmental clearance, 104 liters/h. Linezolid demonstrated nonlinear clearance after 9 doses, which was reduced by a mean of 38.9% (range, 28.8 to 59.9%). Mean bioavailability was 85% (range, 47 to 131%). At steady state, 600 mg given twice daily produced 93.0% and 87.2% probabilities of obtaining the target pharmacodynamic exposure against the MRSA isolates for the i.v. and oral formulations, respectively. Thrice-daily dosing increased the probabilities to 97.0% and 95.6%, respectively. Linezolid pharmacokinetics in these adults with CF were well described by a 2-compartment model with time-dependent clearance inhibition. Standard i.v. and oral dosing regimens should be sufficient to reliably attain pharmacodynamic targets against most MRSA isolates; however, more frequent dosing may be required for isolates with MICs of >2 g/ml.

Pharmacokinetics of Intravenous Linezolid in Moderately to Morbidly Obese Adults

“…When one considers that the reported clearance in this model is the maximum initial clearance and then is reduced by the fraction of RCLF, the mean population clearance reported by Plock and colleagues is reduced to 8.48 liters/h over time and that of our obese population is reduced to 6.5 liters/h. Both values are among those reported in other linezolid pharmacokinetic studies (13,19,20,26,27). Thus, it can at least be determined based on these data that the obese bariatric patients in our study do not have higher clearance and reduced AUC exposure compared to other studies.…”

“…As in other studies, linezolid concentrations in this obese population of bariatric patients fit a 2-compartment model with nonlinear clearance (13,14,26,27). Based on the log likelihood and Akaike information criterion, the model originally described by Plock and colleagues (14) resulted in the best fit of the data.…”

Antibiotic Management of Lung Infections in Cystic Fibrosis. I. The Microbiome, Methicillin-Resistant Staphylococcus aureus, Gram-Negative Bacteria, and Multiple Infections

“…A trough concentration of 15 to 20 mg/ml, which is the practice of most CF physicians based on a recent survey (36), should be the considered target. Linezolid dosing may need adjustment in children with CF (37) but not adults (38). Because approximately 80% of patients with CF with chronic MRSA may also be infected with P. aeruginosa, linezolid, rather than vancomycin with its associated renal effects, may be a good option in these patients who require antipseudomonal treatment with other nephrotoxic drugs, such as aminoglycosides.…”

Rapid Emergence of Resistance to Linezolid and Mutator Phenotypes in Staphylococcus aureus Isolates from an Adult Cystic Fibrosis Patient

“…Conditions for the emergence of resistance to LZD in CF patients thus probably involve additional factors, such as pharmacokinetics. Despite similar LZD levels in sputum and serum (17), the bioavailability of LZD was reported to be reduced in CF patients (18), and a twice-daily 600-mg regimen was suggested to be insufficient to reach the target pharmacodynamic exposure for strains presenting with MICs above the 1-to 2-g/ml range (18,19). In this report, the isolates preceeding the emergence of LZD resistance did not show MICs exceeding 2.0 g/ml, but wide interindividual pharmacodynamic variations have been reported (17) and further work in this population is needed to evaluate the benefit in resistance prevention and the potential adverse effects associated with the administration of a third daily dose (20).…”