Linezolid and rifampin: Drug interaction contrary to expectations?

Egle, Hannes; Trittler, Rainer; Kümmerer, Klaus; Lemmen, Sebastian

doi:10.1016/j.clpt.2005.01.020

Cited by 74 publications

(44 citation statements)

References 3 publications

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“…Rifampicin, a well-known inducer of P-glycoprotein and cytochrome P450 enzymes, decreases linezolid serum levels in critically ill patients [25]. Another study confirmed this finding in healthy volunteers [26,27]. GEBHART et al [25] suggest the interaction to be mediated by Pglycoprotein, since an in vitro study has shown that linezolid is not metabolised by cytochrome P450 enzymes [28].…”

Section: Discussionsupporting

confidence: 68%

Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients

et al. 2013

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The use of linezolid for the treatment of multidrug-resistant tuberculosis is limited by doseand time-dependent toxicity. Recently, we reported a case of pharmacokinetic drug-drug interaction between linezolid and clarithromycin that resulted in increased linezolid exposure. The aim of this prospective pharmacokinetic study is to quantify the effect of clarithromycin on the exposure of linezolid.Subjects were included in an open-label, single-centre, single-arm, fixed-order pharmacokinetic interaction study. All subjects received 300 mg linezolid twice daily during the entire study, consecutively co-administered with 250 mg and 500 mg clarithromycin once daily. Steady-state serum curves of linezolid and clarithromycin were analysed using validated methods, and differences between pharmacokinetic parameters were calculated.Linezolid exposure increased by a median (interquartile range) of 44% (23-102%, p50.043) after coadministration of 500 mg clarithromycin (n55) compared to baseline, whereas 250 mg clarithromycin had no statistically significant effect. Co-administration was well tolerated by most patients; none experienced severe adverse effects. One patient reported common toxicity criteria grade 2 gastrointestinal adverse events.In this study, we showed that clarithromycin significantly increased linezolid serum exposure after combining clarithromycin with linezolid in multidrug-resistant tuberculosis patients. The drug-drug interaction is possibly P-glycoprotein-mediated. Due to large interpatient variability, therapeutic drug monitoring is advisable to determine individual effect size. @ERSpublications Clarithromycin significantly increased linezolid serum exposure in multidrug-resistant tuberculosis patients

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Section: Discussionsupporting

confidence: 68%

Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients

et al. 2013

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“…Considering the metabolism of linezolid as a pathway of nonenzymatic oxidation as previously suggested (47), the more rapid elimination may be caused by increased oxidative stress in the septic patients compared to non-critically ill patients (32). In a recent short notice, Egle et al reported decreased linezolid plasma concentrations due to an interaction with rifampin (13).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Unbound Linezolid in Plasma and Tissue Interstitium of Critically Ill Patients after Multiple Dosing Using Microdialysis

Buerger

Plock

Dehghanyar

et al. 2006

Antimicrob Agents Chemother

112

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The antimicrobial agent linezolid is approved for the treatment of severe infections caused by, e.g., methicillin-resistant Staphylococcus strains. In order to evaluate the penetration of linezolid into the interstitial space fluid (ISF) of subcutaneous adipose tissue and skeletal muscle of the target population, a microdialysis study was performed with 12 patients with sepsis or septic shock after multiple intravenous infusions. Unbound linezolid concentrations were determined for plasma and microdialysates by use of a validated high-performance liquid chromatography method. Individual compartmental pharmacokinetic (PK) analysis was performed using WinNonlin. In vivo microdialysis was found to be feasible for the determination of unbound linezolid concentrations at steady state in the ISF of critically ill patients. On average, linezolid showed good distribution into ISF but with high interindividual variability. A two-compartment model was fitted to unbound concentrations in plasma with a geometric mean distribution volume of 62.9 liters and a mean clearance of 9.18 liters/h at steady state. However, disposition characteristics changed intraindividually within the time course. In addition, an integrated model for simultaneous prediction of concentrations in all matrices was developed and revealed similar results. Based on the model-predicted unbound concentrations in ISF, a scheme of more-frequent daily dosing of linezolid for some critically ill patients might be taken into consideration to avoid subinhibitory unbound concentrations in the infected tissue. The developed integrated model will be a valuable basis for further PK data analysis to explore refined dosing guidelines that achieve effective antimicrobial therapy in all patients by use of the population PK approach.

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“…The combination of linezolid and rifampicin is an attractive oral alternative in foreign-body infections; however, two studies performed in healthy volunteers have analysed this interaction and both articles showed a reduction of ca. 30% in the AUC of linezolid [76,77]. In addition, two cases of orthopaedic implant infections treated with this combination had a low linezolid serum concentration that was associated with clinical failure [78].…”

Section: Critically Ill Patientsmentioning

confidence: 99%

Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?

Edwards

Andini

Esposito

et al. 2014

Journal of Global Antimicrobial Resistance

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Linezolid and rifampin: Drug interaction contrary to expectations?

Cited by 74 publications

References 3 publications

Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients

Clarithromycin increases linezolid exposure in multidrug-resistant tuberculosis patients

Pharmacokinetics of Unbound Linezolid in Plasma and Tissue Interstitium of Critically Ill Patients after Multiple Dosing Using Microdialysis

Treatment options for methicillin-resistant Staphylococcus aureus (MRSA) infection: Where are we now?

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