Pharmacodynamics of early, high-dose linezolid against vancomycin-resistant enterococci with elevated MICs and pre-existing genetic mutations
| Autor: | Patricia N. Holden, Brian T. Tsuji, Alan Forrest, Jürgen B. Bulitta, Tanya Brown, Pamela A. Kelchlin, Charles A. Peloquin, Debra Hanna, Laura A. Skerlos |
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| Rok vydání: | 2012 |
| Předmět: |
Microbiology (medical)
Time Factors Population Colony Count Microbial Microbial Sensitivity Tests Pharmacology Enterococcus faecalis chemistry.chemical_compound Pharmacokinetics Vancomycin Acetamides medicine Humans Pharmacology (medical) education Oxazolidinones education.field_of_study Microbial Viability biology Linezolid Vancomycin Resistance Vancomycin-Resistant Enterococci Models Theoretical biochemical phenomena metabolism and nutrition bacterial infections and mycoses biology.organism_classification Anti-Bacterial Agents NONMEM Infectious Diseases chemistry Pharmacodynamics Mutation medicine.drug |
| Zdroj: | Journal of Antimicrobial Chemotherapy. 67:2182-2190 |
| ISSN: | 1460-2091 0305-7453 |
| DOI: | 10.1093/jac/dks201 |
| Popis: | Objectives Vancomycin-resistant enterococci (VRE) have emerged as an important nosocomial pathogen in medical centres worldwide. This study evaluated the impact of front-loading of linezolid on bacterial killing and suppression of resistance against VRE strains with defined genetic mutations. Methods Time-killing experiments over 48 h assessed the concentration effect relationship of linezolid against eight strains of vancomycin-resistant Enterococcus faecalis. A hollow fibre infection model (HFIM) simulated traditional and front-loaded human therapeutic linezolid regimens against VRE strains at 10(6) cfu/mL over 240 h. Translational modelling was performed using S-ADAPT and NONMEM. Results Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity with >2 log(10) cfu/mL killing for all strains with an MIC of 4 and minimal activity against VRE with MICs of 16 and 64 mg/L. Against one strain with no resistant alleles (MIC 4 mg/L), 600 mg of linezolid every 12 h achieved maximal reductions of 0.96 log(10) cfu/mL over 240 h in the HFIM, whereas front-loaded 1200 mg of linezolid every 12 h ×10 doses or 2400 mg of linezolid every 12 h ×10 doses followed by 600 mg of linezolid every 12 h provided significantly improved killing with maximal reductions of 3.02 and 3.46 log(10) cfu/mL. Front-loaded regimens suppressed amplification of resistant subpopulations against VRE strains with no resistant alleles (MIC 4 mg/L) and postponed regrowth of resistant subpopulations against a VRE with 3.2 resistant alleles (MIC 4 mg/L). Modelling yielded excellent population fits (r = 0.934) and identified the number of sensitive alleles as a critical covariate. Conclusions Early, high-dose regimens of linezolid provided promising killing against selected susceptible strains and may be clinically beneficial if early bactericidal activity is necessary. |
| Databáze: | OpenAIRE |
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