Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 15/2003

01-12-2003 | Original Research Article

Clinical Pharmacodynamics of Linezolid in Seriously Ill Patients Treated in a Compassionate Use Programme

Authors: Dr Craig R. Rayner, Alan Forrest, Alison K. Meagher, Mary C. Birmingham, Jerome J. Schentag

Published in: Clinical Pharmacokinetics | Issue 15/2003

Login to get access

Abstract

Objective: To characterise the pharmacokinetic-pharmacodynamic relationships for linezolid efficacy.
Design and study population: Retrospective nonblinded analysis of severely debilitated adult patients with numerous comorbid conditions and complicated infections enrolled under the manufacturers’s compassionate use programme.
Methods: Patients received intravenous or oral linezolid 600mg every 12 hours. Plasma concentrations were obtained and a multicompartmental pharmacokinetic model was fitted. Numerical integration of the fitted functions provided the area under the concentration-time curve over 24 hours (AUC), the ratio of AUC to minimum inhibitory concentration (AUC/MIC) and the percentage of time that plasma concentrations exceeded the MIC (%T>MIC).
Main outcome measures: Modelled pharmacodynamic outcomes of efficacy included probabilities of eradication and clinical cure (multifactorial logistic regression, nonparametric tree-based modelling, nonlinear regression) and time to bacterial eradication (Kaplan-Meier and Cox proportional hazards regression). Factors considered included AUC/MIC, %T>MIC, site of infection, bacterial species and MIC, and other medical conditions.
Results: There were 288 cases evaluable by at least one of the efficacy outcomes. Both %T>MIC and AUC/MIC were highly correlated (Spearman r2 = 0.868). In our analyses, within specific infection sites, the probability of eradication and clinical cure appeared to be related to AUC/MIC (eradication: bacteraemia, skin and skin structure infection [SSSI], lower respiratory tract infection [LRTI], bone infection; clinical cure: bacteraemia, LRTI) and %T>MIC (eradication: bacteraemia, SSSI, LRTI; clinical cure: bacteraemia, LRTI). Time to bacterial eradication for bacteraemias appeared to be related to the AUC, %T>MIC and AUC/ MIC. For most sites, AUC/MIC and %T>MIC models performed similarly. Conclusions: Higher success rates for linezolid may occur at AUC/MIC values of 80–120 for bacteraemia, LRTI and SSSI. Chance of success in bacteraemia, LRTI and SSSI also appear to be higher when concentrations remain above the MIC for the entire dosing interval.
Footnotes
1
Use of tradenames is for product identification only and does not imply endorsement.
 
Literature
1.
Ashtekar DR, Costa-Periera R, Shrinivasan T, et al. Oxazolidinones, a new class of synthetic antituberculosis agent: in vitro and in vivo activities of dup-721 against Mycobacterium tuberculosis. Diagn Microbiol Infect Dis 1991 Nov–Dec; 14(6): 465–71PubMedCrossRef
2.
Dresser LD, Rybak MJ. The pharmacologic and bacteriologic properties of oxazolidinones, a new class of synthetic antimicrobials. Pharmacotherapy 1998 May–Jun; 18(3): 456–62PubMed
3.
Jernigan DB, Cetron MS, Breiman RF. Defining the public health impact of drug-resistant Streptococcus pneumoniae: report of a working group. MMWR Morb Mortal Wkly Rep 1996; 45(RR-1): 1–20
4.
Jones RN, Johnson DM, Erwin ME. In vitro antimicrobial activities and spectra of u-100592 and u-100766, two novel fluorinated oxazolidinones. Antimicrob Agents Chemother 1996; 40(3): 720–6PubMed
5.
Wooton M, Howe RA, Walsh TR. In-vitro activity of a range of old and new antimicrobials to hetero-vancomycin-intermediate staphylococcus aureus [abstract 2313]. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20; Toronto
6.
Welshman IR, Sisson TA, Jungbluth GL, et al. Linezolid absolute bioavailability and the effect of food on oral bioavailability. Biopharm Drug Dispos 2001; 22(3): 91–7PubMedCrossRef
7.
Stalker D, Wajsczuk CP, Batts DH. Linezolid safety, tolerance, and pharmacokinetics after intravenous dosing twice daily for 7.5 days [abstract A-116]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto
8.
Stalker D, Wajsczuk CP, Batts DH. Linezolid safety, tolerance, and pharmacokinetics following oral dosing twice daily for 14.5 days [abstract A-115]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto
9.
Slatter JG, Stalker DJ, Feenstra KL, et al. Pharmacokinetics, metabolism, and excretion of linezolid following an oral dose of [(14)C] linezolid to healthy human subjects. Drug Metab Dispos 2001; 29(8): 1136–45PubMed
10.
Meagher AK, Forrest A, Rayner CR, et al. Population pharmacokinetics of linezolid in patients treated in a compassionate-use program. Antimicrob Agents Chemother 2003; 47(2): 548–53PubMedCrossRef
11.
Zyvox® (linezolid) [package insert]. Kalamazoo, Michigan: Pharmacia, 2002
12.
Bostic GD, Perri MB, Thal LA, et al. Comparative in vitro and bactericidal activity of oxazolidinone antibiotics against multidrug-resistant enterococci. Diagn Microbiol Infect Dis 1998; 30(2): 109–12PubMedCrossRef
13.
Gunderson BW, Ibrahim KH, Peloquin CA, et al. Comparison of linezolid activities under aerobic and anaerobic conditions against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Antimicrob Agents Chemother 2003; 47(1): 398–9PubMedCrossRef
14.
Forrest A, Nix DE, Ballow CH, et al. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 1993; 37(5): 1073–81PubMedCrossRef
15.
Thomas JK, Forrest A, Bhavnani SM, et al. Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy. Antimicrob Agents Chemother 1998; 42(3): 521–7PubMed
16.
Andes D, van Ogtrop ML, Peng J, et al. In vivo pharmacodynamics of a new oxazolidinone (linezolid). Antimicrob Agents Chemother 2002; 46(11): 3484–9PubMedCrossRef
17.
Jacqueline C, Batard E, Perez L, et al. In vivo efficacy of continuous infusion versus intermittent dosing of linezolid compared to vancomycin in a methicillin-resistant Staphylococcus aureus rabbit endocarditis model. Antimicrob Agents Chemother 2002; 46(12): 3706–11PubMedCrossRef
18.
Hyatt JM, Ballow CH, Forrest A. Safety and efficacy of linezolid (pnu-100766) in eradication of nasal Staphylococcus aureus [abstract A-4]. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998; San Diego (CA)
19.
Birmingham MC, Rayner CR, Meagher AK, et al. Linezolid for the treatment of multidrug-resistant, gram-positive infections: experience from a compassionate-use program. Clin Infect Dis 2003; 36(2): 159–68PubMedCrossRef
20.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16(1): 31–41PubMedCrossRef
21.
McCabe WR, Jackson GG. Gram-negative bacteremia. Arch Intern Med 1962; 110: 847–55CrossRef
22.
Steimer JL, Mallet A, Golmard JL, et al. Alternative approaches to estimation of population pharmacokinetic parameters: comparison with the nonlinear mixed-effect model. Drug Metab Rev 1984; 15(1–2): 265–92PubMedCrossRef
23.
Ds’Argenio DZ, Schumitzky A. A program package for simulation and parameter estimation in pharmacokinetic systems. Comput Programs Biomed 1979; 9(2): 115–34CrossRef
24.
Ds’Argenio DZ, Schumitzky A. Adapt II users’s guide: pharmacokinetic-pharmacodynamic systems analysis software. Los Angeles (CA): Biomedical Simulations Resource, 1997
25.
Wilkinson L. Systat: the system for statistics. Chicago (IL): SPSS Inc, 1998
26.
Akaike H. A Bayesian extension of the minimum AIC procedure of autoregressive model fitting. Biometrika 1979; 66: 237–42CrossRef
27.
Cammarata S, Hafkin B, Todd WM. Efficacy of linezolid in community acquired S. pneumoniae pneumonia [abstract]. Am J Respir Crit Care Med 1999, 159 (S)
28.
Rubinstein E, Cammarata S, Oliphant T, et al. Linezolid (pnu-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis 2001; 32(3): 402–12PubMedCrossRef
29.
Cammarata S, Hafkin B, Demke DM. Efficacy of linezolid in skin and soft tissue infections [abstract]. Clin Microbiol Infect 1999, 5 (S)
30.
Stevens DL, Herr D, Lampiris H, et al. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2002; 34(11): 1481–90PubMedCrossRef
31.
Stevens DL, Smith LG, Bruss JB, et al. Randomized comparison of linezolid (pnu-100766) versus oxacillin-dicloxacillin for treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2000; 44(12): 3408–13PubMedCrossRef
32.
33.
Rayner CR, Forrest A, Meagher A, et al. Population (pop) pharmacodynamics (pd) of linezolid (1) in seriously-ill adult patients (pts) from a compassionate-use protocol [abstract 1390]. 40th Interscience Congress on Antimicrobial Agents and Chemotherapy; Toronto; 2000
Metadata
Title
Clinical Pharmacodynamics of Linezolid in Seriously Ill Patients Treated in a Compassionate Use Programme
Authors
Dr Craig R. Rayner
Alan Forrest
Alison K. Meagher
Mary C. Birmingham
Jerome J. Schentag
Publication date
01-12-2003
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 15/2003
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.2165/00003088-200342150-00007

Other articles of this Issue 15/2003

Clinical Pharmacokinetics 15/2003 Go to the issue

Original Research Article

Nonparametric Expectation Maximisation (NPEM) Population Pharmacokinetic Analysis of Caffeine Disposition from Sparse Data in Adult Caucasians

Review Article

Role of Orphan Nuclear Receptors in the Regulation of Drug-Metabolising Enzymes

Acknowledgments

Acknowledgement

Leading Article

Bone-Specific Drug Delivery Systems

Review Article

Clinical Pharmacokinetics of Galantamine

Review Article

Stereoselectivity in the Pharmacodynamics and Pharmacokinetics of the Chiral Antimalarial Drugs