BACKGROUND\nOBJECTIVES\nPATIENTS AND METHODS\nRESULTS\nCONCLUSIONS\nLinezolid in combination with rifampicin has been used in treatment of infective endocarditis especially for patients infected... Show moreBACKGROUND\nOBJECTIVES\nPATIENTS AND METHODS\nRESULTS\nCONCLUSIONS\nLinezolid in combination with rifampicin has been used in treatment of infective endocarditis especially for patients infected with staphylococci.\nBecause rifampicin has been reported to reduce the plasma concentration of linezolid, the present study aimed to characterize the population pharmacokinetics of linezolid for the purpose of quantifying an effect of rifampicin cotreatment. In addition, the possibility of compensation by dosage adjustments was evaluated.\nPharmacokinetic measurements were performed in 62 patients treated with linezolid for left-sided infective endocarditis in the Partial Oral Endocarditis Treatment (POET) trial. Fifteen patients were cotreated with rifampicin. A total of 437 linezolid plasma concentrations were obtained. The pharmacokinetic data were adequately described by a one-compartment model with first-order absorption and first-order elimination.\nWe demonstrated a substantial increase of linezolid clearance by 150% (95% CI: 78%-251%), when combined with rifampicin. The final model was evaluated by goodness-of-fit plots showing an acceptable fit, and a visual predictive check validated the model. Model-based dosing simulations showed that rifampicin cotreatment decreased the PTA of linezolid from 94.3% to 34.9% and from 52.7% to 3.5% for MICs of 2 mg/L and 4 mg/L, respectively.\nA substantial interaction between linezolid and rifampicin was detected in patients with infective endocarditis, and the interaction was stronger than previously reported. Model-based simulations showed that increasing the linezolid dose might compensate without increasing the risk of adverse effects to the same degree. Show less
Bock, M.; Theut, A.M.; Hasselt, J.G.C. van; Wang, H.; Fuursted, K.; Høiby, N.; ... ; Moser, C. 2023
BACKGROUND\nMETHODS\nRESULTS\nCONCLUSION\nIn the POET (Partial Oral Endocarditis Treatment) trial, oral step-down therapy was noninferior to full-length intravenous antibiotic administration. The... Show moreBACKGROUND\nMETHODS\nRESULTS\nCONCLUSION\nIn the POET (Partial Oral Endocarditis Treatment) trial, oral step-down therapy was noninferior to full-length intravenous antibiotic administration. The aim of the present study was to perform pharmacokinetic/pharmacodynamic analyses for oral treatments of infective endocarditis to assess the probabilities of target attainment (PTAs).\nPlasma concentrations of oral antibiotics were measured at day 1 and 5. Minimal inhibitory concentrations (MICs) were determined for the bacteria causing infective endocarditis (streptococci, staphylococci, or enterococci). Pharmacokinetic/pharmacodynamic targets were predefined according to literature using time above MIC or the ratio of area under the curve to MIC. Population pharmacokinetic modeling and pharmacokinetic/pharmacodynamic analyses were done for amoxicillin, dicloxacillin, linezolid, moxifloxacin, and rifampicin, and PTAs were calculated.\nA total of 236 patients participated in this POET substudy. For amoxicillin and linezolid, the PTAs were 88%-100%. For moxifloxacin and rifampicin, the PTAs were 71%-100%. Using a clinical breakpoint for staphylococci, the PTAs for dicloxacillin were 9%-17%.Seventy-four patients at day 1 and 65 patients at day 5 had available pharmacokinetic and MIC data for two oral antibiotics. Of those, 13 patients at day 1 and 14 patients at day 5 did only reach the target for one antibiotic. One patient did not reach target for any of the two antibiotics.\nFor the individual orally administered antibiotic, the majority of patients reached the target level. Patients with sub-target levels were compensated by the administration of two different antibiotics. The findings support the efficacy of oral step-down antibiotic treatment in patients with infective endocarditis. Show less
