Pharmacokinetics of Intravenous Linezolid in Moderately to Morbidly Obese Adults

Bhalodi, Amira A.; Papasavas, Pavlos; Tishler, Darren; Nicolau, David P.; Kuti, Joseph L.

doi:10.1128/aac.01453-12

Cited by 58 publications

(45 citation statements)

References 23 publications

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“…While the predicted probability for platelet toxicity did not differ noticeably for therapy durations of 14 or 28 days, this prediction may be affected by a time-dependent autoinhibition of linezolid clearance (not included in the current model). The latter model feature was previously reported based on data from healthy volunteers (18,42). Overall, therapy duration was a more important predictor of toxicity than was linezolid dose.…”

Section: Discussionmentioning

confidence: 75%

Clinical Population Pharmacokinetics and Toxicodynamics of Linezolid

Boak

Rayner

Grayson

et al. 2014

Antimicrob Agents Chemother

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h Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/ liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10-to 28-day therapy for platelet nadirs of <100 ؋10 9 / liter. The risk for toxicity did not differ noticeably between 14 and 28 days of therapy and was significantly higher for patients with lower baseline platelet counts. Due to the increased risk of toxicity after longer durations of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose individualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h.

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Section: Discussionmentioning

confidence: 75%

Clinical Population Pharmacokinetics and Toxicodynamics of Linezolid

Boak

Rayner

Grayson

et al. 2014

Antimicrob Agents Chemother

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“…In contrast to the presence of ARDS and lactate, the cofactors weight, creatinine clearance, and impairment of liver function were described previously (15,(18)(19)(20)(21)(22)(23)(24)(25) (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

“…The threshold for antimicrobial efficacy was defined as an AUC 12 of Ͼ100 mg · h/liter. This is based on the results of a large compassionate-use study showing that a higher rate of clinical success is reached when the ratio of the AUC 24 to the MIC of the causative strain is Ͼ80 to 120 (6). Therefore, we considered an AUC 24 /MIC ratio of Ͼ100 to be a relevant pharmacokinetic/pharmacodynamic parameter in accordance with data reported in the literature (8,15).…”

Section: Methodsmentioning

confidence: 99%

“…Several predictors, such as glomerular filtration rate (14,(18)(19)(20)(21)(22), body weight (18,(21)(22)(23)(24)(25), parameters of liver function (15,18,20), renal replacement therapy (15), and comedication such as rifampin (a potent P-glycoprotein inducer) (7), have already been described. However, the effects of other possible covariates, such as the presence of acute respiratory distress syndrome (ARDS), peritonitis, and single nucleotide polymorphisms of the P glycoprotein, remain unclear.…”

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confidence: 99%

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Predictors of Inadequate Linezolid Concentrations after Standard Dosing in Critically Ill Patients

Taubert

Zöller

Maier

et al. 2016

Antimicrob Agents Chemother

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Adequate linezolid blood concentrations have been shown to be associated with an improved clinical outcome. Our goal was to assess new predictors of inadequate linezolid concentrations often observed in critically ill patients. Fifty-two critically ill patients with severe infections receiving standard dosing of linezolid participated in this prospective observational study. Serum samples (median, 32 per patient) were taken on four consecutive days, and total linezolid concentrations were quantified. Covariates influencing linezolid pharmacokinetics were identified by multivariate analysis and a population pharmacokinetic model. Target attainment (area under the concentration-time curve over 12 h [AUC 12 ]/MIC ratio of >50; MIC ‫؍‬ 2 mg/liter) was calculated for both the study patients and a simulated independent patient group (n ‫؍‬ 67,000). Target attainment was observed for only 36% of the population on both days 1 and 4. Independent covariates related to significant decreases of linezolid concentrations included higher weight, creatinine clearance rates, and fibrinogen and antithrombin concentrations, lower concentrations of lactate, and the presence of acute respiratory distress syndrome (ARDS). Linezolid clearance was increased in ARDS patients (by 82%) and in patients with elevated fibrinogen or decreased lactate concentrations. In simulated patients, most covariates, including fibrinogen and lactate concentrations and weight, showed quantitatively minor effects on target attainment (difference of <9% between the first and fourth quartiles of the respective parameters). In contrast, the presence of ARDS had the strongest influence, with only <6% of simulated patients reaching this target. In conclusion, the presence of ARDS was identified as a new and strong predictor of insufficient linezolid concentrations, which might cause treatment failure. Insufficient concentrations might also be a major problem in patients with combined alterations of other covariate parameters. (This study has been registered at ClinicalTrials.gov under registration number NCT01793012.)

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“…Obesity. Data exist that support no need for increased dosing in patients weighing up to 150 kg [68]. However, in obese patients, observed serum levels have been lower than in the nonobese population, with one case report of a patient with a body mass index (BMI) of 37 describing clinical failure because of reduced serum concentration trough levels below the MIC 90 (MIC for 90% of the isolates) [69].…”

Section: Linezolidmentioning

confidence: 99%