ArticleAntimicrobial agents and chemotherapy2012
Front-loaded linezolid regimens result in increased killing and suppression of the accessory gene regulator system of Staphylococcus aureus.
Article in Antimicrobial agents and chemotherapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 31 citations in OpenAlex.
- Optimal dosing and duration of linezolid for the treatment of multidrug-resistant and rifampicin-resistant tuberculosis: an individual patient data meta-analysis.The European respiratory journal · 2025Pooled it
- Integration of individual preclinical and clinical anti-infective PKPD data to predict clinical study outcomes.Clinical and translational science · 2024Trial
- Intracellular survival ofVirulence · 2025Review
- Phenotypic and genotypic changes of Staphylococcus aureus in the presence of the inappropriate concentration of chlorhexidine gluconate.BMC microbiology · 2022Article
- The Inhibition Effect of Linezolid With Reyanning Mixture on MRSA and its Biofilm is More Significant than That of Linezolid Alone.Frontiers in pharmacology · 2021Article
- Generating Robust and Informative NonclinicalAntimicrobial agents and chemotherapy · 2019Review
- Four Decades of β-Lactam Antibiotic Pharmacokinetics in Cystic Fibrosis.Clinical pharmacokinetics · 2019Review
- Review
- The role of infection models and PK/PD modelling for optimising care of critically ill patients with severe infections.Intensive care medicine · 2017Review
- Impact of Staphylococcus aureus accessory gene regulator (agr) system on linezolid efficacy by profiling pharmacodynamics and RNAIII expression.The Journal of antibiotics · 2017Article
- Sequential Evolution of Vancomycin-Intermediate Resistance Alters Virulence in Staphylococcus aureus: Pharmacokinetic/Pharmacodynamic Targets for Vancomycin Exposure.Antimicrobial agents and chemotherapy · 2015Article
- An FDA-Drug Library Screen for Compounds with Bioactivities against Meticillin-Resistant Staphylococcus aureus (MRSA).Antibiotics (Basel, Switzerland) · 2015Article
- Colistin and doripenem combinations against Pseudomonas aeruginosa: profiling the time course of synergistic killing and prevention of resistance.The Journal of antimicrobial chemotherapy · 2015Article
- Two mechanisms of killing of Pseudomonas aeruginosa by tobramycin assessed at multiple inocula via mechanism-based modeling.Antimicrobial agents and chemotherapy · 2015Article
- New dosing strategies for an old antibiotic: pharmacodynamics of front-loaded regimens of colistin at simulated pharmacokinetics in patients with kidney or liver disease.Antimicrobial agents and chemotherapy · 2014Article
- Clinical population pharmacokinetics and toxicodynamics of linezolid.Antimicrobial agents and chemotherapy · 2014Article
- Decreased vancomycin susceptibility in Staphylococcus aureus caused by IS256 tempering of WalKR expression.Antimicrobial agents and chemotherapy · 2013Article
- Quantifying subpopulation synergy for antibiotic combinations via mechanism-based modeling and a sequential dosing design.Antimicrobial agents and chemotherapy · 2013Article
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Front loading is a strategy used to optimize the pharmacodynamic profile of an antibiotic through the administration of high doses early in therapy for a short duration. Our aims were to evaluate the impact of front loading of linezolid regimens on bacterial killing and suppression of resistance and on RNAIII, the effector molecule of the accessory gene regulator system (encoded by agr) in methicillin-resistant Staphylococcus aureus (MRSA). Time-killing experiments over 48 h were utilized for linezolid against four strains of MRSA: USA100, USA300, USA400, and ATCC 29213. A hollow-fiber infection model simulated traditional and front-loaded human therapeutic regimens of linezolid versus USA300 at 10(6) CFU/ml over 240 h. Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity, with reductions of >1 log(10) CFU/ml for all strains. Front-loaded regimens that were administered over 5 days, 1,200 mg every 12 h (q12h) (total, 10 doses) and 2,400 mg q12h (total, 10 doses) followed by 300 mg q12h thereafter, resulted in sustained bactericidal activity, with reductions of the area under the CFU curve of -6.15 and -6.03, respectively, reaching undetectable limits at the 10-day study endpoint. All regimens displayed a reduction in RNAIII relative expression at 24 h and 240 h compared with that of the growth control. Monte Carlo simulations predicted a <1.27× increase in the fractional decreases in platelets for all front-loaded regimens versus the 600 mg q12h regimen, except for the highest-dose front-loaded regimen. Front-loading strategies for linezolid are promising and may be of utility in severe MRSA infections, where early aggressive therapy is necessary.
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