Pharmacokinetics of linezolid in septic patients with and without extended dialysis

Swoboda, Stefanie; Ober, Michael; Lichtenstern, Christoph; Saleh, Soundos; Schwenger, Vedat; Sonntag, Hans‐Günther; Haefeli, Walter E.; Hempel, Georg; Hoppe-Tichy, Torsten; Weigand, Markus

doi:10.1007/s00228-009-0766-9

Cited by 70 publications

(67 citation statements)

References 32 publications

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“…Therefore, there was a high variability of linezolid AUC 0-24h and C min values, with C min values differing more than 100-fold between the different patients and more than 30-fold within single patients. These data are in line with other studies observing very low, usually insufficient AUC 0-24h or C min linezolid values [6][7][8] and also in line with papers showing C min values differing more than 50-fold between different patients [8,9].…”

supporting

confidence: 93%

Continuous administration of linezolid in pneumonia: what is the level of proof?

Mimoz¹,

Montravers²,

Paiva³

2014

Intensive Care Med

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Linezolid, the first available oxazolidinone derivative, has been shown to be an interesting alternative to glycopeptides against resistant gram-positive strains [1]. It distributes well into the lung, with mean percentage penetration in epithelial lining fluid of approximately 100 %, indicating that serum concentrations adequately predict antibiotic concentrations at the target site for extracellular respiratory tract pathogens [1]. Linezolid is a time-dependent antimicrobial agent with a reduced postantibiotic effect. The best pharmacokinetic/pharmacodynamic (PK/PD) parameters to define its activity are time with serum concentrations higher than the minimum inhibitory concentration (T [ MIC) and area under the serum concentration-time curve/minimum inhibitory concentration (AUC/MIC) ratio [1]. Linezolid is mainly a bacteriostatic antimicrobial agent with T [ MIC of at least 40 % being predictive of its efficacy. This objective can be easily achieved for pathogens with MICs of 2-4 mg/l by administration of standard dosing (600 mg intravenously twice a day) in healthy volunteers, suggesting that continuous infusion, the best antimicrobial administration modality for most time-dependent antibiotics as it prolongs effective serum concentrations, may not be essential [1].During the initial phase of septic shock, however, alterations in pharmacokinetic parameters, mostly due to an increase in the volume of drug distribution and/or drug clearance, are frequently observed [2]. These modifications vary from one patient to another and in a single patient from one day to another [2]. They may lead to suboptimal serum and tissue concentrations when drugs are given at the dosage studied in healthy volunteers or in less seriously ill patients. Moreover, critically ill septic patients should be considered as immunosuppressed, and antimicrobials with bactericidal activity may be more effective than those exhibiting only bacteriostatic activity [3]. In an in vivo model of endocarditis, linezolid demonstrated bactericidal activity when T [ MIC was maintained for [75 % of the dosing interval [4]. On the basis of these considerations, achieving T [ MIC close to 100 % is probably the key to obtaining the highest success rate with linezolid in ICU patients.Recently, Zoller et al. [5] showed that there was a high variability of linezolid serum concentrations after standard dosing in 30 critically ill infected patients with a median body mass index of 26 kg/m 2 (range 16-35 kg/ m 2 ), mostly with lung infections. Optimal pharmacodynamic exposure over 24 h, with AUC 0-24h values between 200 and 400 mg h/l and with C min values between 2 and 10 mg/l, could be observed for only 30 and 43 % of the patients, respectively. Regarding these AUC 0-24h and C min values, 63 and 50 % of the patients, respectively, had linezolid concentrations below the lower limit of the corresponding target concentration range and only 7 % Intensive Care Med (2015) 41:157-159

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supporting

confidence: 93%

Continuous administration of linezolid in pneumonia: what is the level of proof?

Mimoz¹,

Montravers²,

Paiva³

2014

Intensive Care Med

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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: 72%

“…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). A concentration of 2 mg/liter, which inhibits Ͼ90% of relevant causative strains (31,32), was used as the MIC.…”

Section: Methodsmentioning

confidence: 99%

“…is recommended for all adult patients by the product information and has been included in treatment guidelines. However, recent studies have observed a high variability of linezolid blood concentrations, with partly insufficient concentrations in critically ill patients treated by this standard scheme (13)(14)(15)(16)(17). We recently observed that 19 of 30 critically ill patients had insufficient concentrations and that 2 of them reached potentially toxic serum concentrations (13).…”

mentioning

confidence: 97%

“…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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Antimicrobial dosing in prolonged intermittent renal replacement therapy: a systematic review

Rawlins

Misko

Roberts

2021

Pharmacy Practice and Res

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Aim: The research aim was to conduct a systematic review of the literature regarding the pharmacokinetics (PK) and dosing of antimicrobials in prolonged intermittent renal replacement therapy (PIRRT), a hybrid form of dialysis becoming increasingly utilised in critical care. Methods: A literature review was performed using PubMed from database inception to October 2020 according to the PRISMA guidelines. All papers published in English language were included in the review. Two researchers independently conducted literature searches, screened abstracts and full text and came to agreement as to which articles were suitable for inclusion before compiling the relevant data into a spreadsheet. The types of papers retrieved varied between case reports, single and multiple dose pharmacokinetic studies and Monte Carlo simulations. Results: A total of 149 articles were found in the initial literature review and via other sources. Of these papers, 50 articles were deemed eligible for inclusion. These studies included one to 34 patients. PIRRT settings varied between institutions, including filter surface area, duration of PIRRT and type of dialyser used. With the exception of vancomycin and meropenem, few antimicrobials had sufficient data available from which reasonable empiric dosing regimens can be recommended. Conclusion:There is limited data to guide dosing of antimicrobials during PIRRT. More studies are required to understand how dosing can be optimised in this population of critically ill patients.

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Pharmacokinetics of linezolid in septic patients with and without extended dialysis

Cited by 70 publications

References 32 publications

Continuous administration of linezolid in pneumonia: what is the level of proof?

Continuous administration of linezolid in pneumonia: what is the level of proof?

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

Antimicrobial dosing in prolonged intermittent renal replacement therapy: a systematic review

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