Pharmacokinetic studies of linezolid and teicoplanin in the critically ill

Whitehouse, Tony; Cepeda, Jorge; Shulman, Rob; Aarons, Leon; Nalda-Molina, Ricardo; Tobin, C. M.; MacGowan, Alasdair; Shaw, Steve; Kibbler, C; Singer, Mervyn; Wilson, A.P.R.

doi:10.1093/jac/dki014

Cited by 73 publications

(62 citation statements)

References 32 publications

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“…The increase in the volume of distribution in critically ill patients might be caused by fluid retention due to an insufficiency of elimination pathways and/or high fluid input resulting in significant "third spacing." In accordance with the results obtained by Meagher et al, we did not observe any significant increase in minimum and maximum concentrations over time in critically ill patients (32), while Whitehouse et al (53) described a distinctive linezolid accumulation in this patient population. Compared to healthy volunteers, our study patients had a significantly decreased drug exposition expressed as AUC ss after multiple dosing (P ϭ 0.017) (data not shown) due to substantially increased clearance values.…”

Section: Discussionsupporting

confidence: 93%

“…After the unbound concentrations in plasma alone were analyzed, an integrated pharmacokinetic model based on plasma and ISF concentrations was developed. The use of a two-compartment model for the description of unbound linezolid pharmacokinetics in plasma is in concordance with the results of other investigations (32,53). While never before reported for linezolid, comodeling of unbound plasma and ISF concentrations with an individual compartmental PK analysis approach (12,20,38) or by using population pharmacokinetic analysis techniques (6,50,51) for other drugs has previously been described, but application is still rare.…”

Section: Discussionsupporting

confidence: 85%

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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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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 85%

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 high variability in the values of the linezolid serum and CSF concentrations/pharmacokinetic parameters (mainly AUC and CL values) noted in this study is consistent with that reported in previous studies with critically ill patients (19,22,27) and healthy volunteers (18) and may be partly explained by interindividual variability in age and sex (11), body weight (27), and renal clearance (4). More specifically, significant correlations were found between maximum serum linezolid concentrations/CSF linezolid concentrations and body weight and, consequently, creatinine clearance in our study patients.…”

Section: Discussionsupporting

confidence: 91%

“…administration of linezolid to healthy volunteers and patients with infections, i.e., 45.5 to 57.0 liters and 7.4 to 9.2 liters/h, respectively (2,18,23). Also, in a previous study with critically ill patients in an ICU (27), a comparable mean volume of distribution was found, i.e., 0.63 liter/kg, whereas the value in our study was 0.77 liter/kg. In contrast, the mean t 1/2 serum (6.5 h), steady-state C max (18.6 g/ml), and AUC serum (128.7 g · h/ml) were found to be higher in our critically ill neurosurgical patients than in healthy volunteers and patients with ventilator-associated pneumonia, i.e., 4.4 to 4.8 h, 15.1 to 17.7 g/ml, and 77.3 to 93.4 g · h/ml, respectively, with a SAPS II score of 40 Ϯ 13.…”

Section: Discussionsupporting

confidence: 50%

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Serum and Cerebrospinal Fluid Concentrations of Linezolid in Neurosurgical Patients

Myrianthefs

Markantonis

Vlachos

et al. 2006

Antimicrob Agents Chemother

103

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Linezolid is a new antimicrobial agent effective against drug-resistant gram-positive pathogens commonly responsible for central nervous system (CNS) infections in neurosurgical patients hospitalized in intensive care units. In order to study the penetration of this antimicrobial into the cerebrospinal fluid (CSF) of such patients, the disposition of linezolid in serum and CSF was studied in 14 neurosurgical patients given linezolid at 600 mg twice daily (1-h intravenous infusion) for the treatment of CNS infections caused by gram-positive pathogens or for prophylactic chemotherapy. Serum and CSF linezolid steady-state concentrations were analyzed by high-pressure liquid chromatography, and the concentration-time profiles obtained were analyzed to estimate pharmacokinetic parameters. The mean ؎ standard deviation (SD) linezolid maximum and minimum measured concentrations were 18.6 ؎ 9.6 g/ml and 5.6 ؎ 5.0 g/ml, respectively, in serum and 10.8 ؎ 5.7 g/ml and 6.1 ؎ 4.2 g/ml, respectively, in CSF. The mean ؎ SD areas under the concentration-time curves (AUCs) were 128.7 ؎ 83.9 g · h/ml for serum and 101.6 ؎ 59.6 g · h/ml for CSF, with a mean penetration ratio for the AUC for CSF to the AUC for serum of 0.66. The mean elimination half-life of linezolid in CSF was longer than that in serum (19.1 ؎ 19.0 h and 6.5 ؎ 3.6 h, respectively). The serum and CSF linezolid concentrations exceeded the pharmacodynamic breakpoint of 4 g/ml for susceptible target pathogens for the entire dosing interval in the majority of patients. These findings suggest that linezolid may achieve adequate concentrations in the CSF of patients requiring antibiotics for the management or prophylaxis of CNS infections caused by gram-positive pathogens.Linezolid is the first member of a new synthetic class of antimicrobials, the oxazolidinones, to be used in clinical practice. It acts by selectively inhibiting the initiation of bacterial protein synthesis with a unique mechanism that precludes cross-resistance to currently available agents (10). In vitro and in vivo studies have demonstrated that linezolid has significant bacteriostatic activity against multiresistant gram-positive pathogens, such as coagulase-negative Staphylococcus species, Staphylococcus aureus, vancomycin-resistant enterococci, and Streptococcus pneumoniae, with MIC 90 s generally ranging from 0.5 to 4 g/ml (5, 26).Gram-positive cocci, mainly staphylococci, are the most frequent pathogens involved in central nervous system (CNS) postneurosurgical infections (26). Severe CNS infections caused by gram-positive pathogens may also be related to head trauma with skull fracture in neurosurgical patients, especially in the presence of an external drainage or ventriculoperitoneal shunt. Thus, these patients require antibiotics either for the management of infections or for prophylaxis against such infections. The frequency of CNS infections subsequent to neurosurgical procedures is estimated to be ϳ4% (25). As the epidemiology of CNS infection in neurosurgical patients evolves and the pr...

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Glycopeptides

Gyssens

2013

Fundamentals of Antimicrobial Pharmacokinetics and Pharmacodynamics

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Glycopeptides are a class of antibiotic drugs that is composed of glycosylated cyclic or polycyclic nonribosomal peptides. Older molecules used in clinical practice are vancomycin and teicoplanin. Oritavancin, dalbavancin, and telavancin belong to the subclass of lipoglycopeptides. Glycopeptides inhibit bacterial cell wall peptoglycan synthesis of aerobic and anaerobic Gram-positive bacteria. Glyco (lipo)peptides are not absorbed orally and have to be administered intravenously. In this chapter, the pharmacokinetics (Pk) and the pharmacodynamics (Pd) of the glycopeptides are studied. Pk in serum as well as protein binding and elimination are reviewed. Pharmacodynamic data include MICs of Gram-positive bacteria, PK/Pd effects in in vitro systems, animal models and human studies. Adverse effects of glycopeptides on the host are concentration related nephro-and ototoxicity. In the past, because of fear of toxicity, the older glycopeptides have been underdosed in many settings. The implementation of Pk/Pd knowledge into clinical practice by e.g. administering higher doses of vancomycin and teicoplanin and using continuous infusion of vancomycin is urgently needed. This chapter contains clinical vignettes showing the benefi t of Therapeutic Drug Monitoring of glycopeptides.

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Pharmacokinetic studies of linezolid and teicoplanin in the critically ill

Cited by 73 publications

References 32 publications

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

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

Serum and Cerebrospinal Fluid Concentrations of Linezolid in Neurosurgical Patients

Glycopeptides

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