Abstract: During veno-venous extracorporeal membrane oxygenation (vv ECMO) therapy, antimicrobial
drugs are frequently used, and appropriate dosing is challenging due to there being limited data
to support the dosage. Linezolid is effective against multidrug-resistant Gram-positive pathogens
frequently isolated in ECMO patients. In total, 53 steady-state linezolid levels were obtained following
600 mg intravenous (IV) injections every 8 h, and these were used to develop a population
pharmacokinetic (PopPK) model in patients with COVID-19-associated acute respiratory distress
syndrome (CARDS) on vv ECMO. The data were analyzed using a nonlinear mixed-effects modelling
approach. Monte Carlo simulation generated 5000 patients’ individual PK parameters and
corresponding concentration–time profiles using the PopPK model, following the administration
of 600 mg/8 h (a higher-than-standard dosing) and 600 mg/12 h (standard). The probabilities of
pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) and the cumulative fraction of
responses (CFR) for three pathogens were calculated and compared between the two dosing scenarios.
Linezolid 600 mg/8 h was predicted to achieve greater than or equal to 85%Tf>MIC in at least 90% of
the patients with CARDS on vv ECMO compared to only approximately two thirds of the patients
after dosing every 12 h at a minimal inhibitory concentration (MIC) of 2 mg/L. In addition, for the
same MIC, fAUC24/MIC ≥ 80 was achieved in almost three times the number of patients following
an 8-h versus a 12-h interval. PopPK simulation predicted that a significantly higher proportion of
the patients with CARDS on vv ECMO would achieve the PK/PD targets following the 8-h dosing
interval compared to standard linezolid dosing. Nevertheless, the safety concern, in particular, for
thrombocytopenia, with higher-than-standard linezolid dosage is reasonable, and consequently,
monitoring is essential.
