title: Revisiting Beta-lactams - PK/PD improves dosing of old antibiotics.
abstract: Pre-clinical pharmacokinetic-pharmacodynamic assessments indicate Beta-lactam antibiotics have time-dependent killing, variable persistent antibiotic effects and that free drug T>MIC is the dominant pharmacodynamic index. Prolonged or continuous infusion therapy has improved microbiological responses in pathogens with MICs at or 2-4 fold higher than existing EUCAST clinical breakpoints in pre-clinical studies. Human population pharmacokinetic modelling combined with Monte Carlo Simulation indicates improved pharmacodynamic target attainment rates and hence predicts improved clinical responses for those pathogens with raised MICs. However, the majority of human clinical trials comparing prolonged or continuous infusion to intermittent injection have failed to show superior clinical cures and for the most part microbiological successes. The exception being in various subgroup analyses. Future clinical trials need to focus on defining the T>MIC sizes associated with clinical or microbiological cure in man, on those subgroups of patients where continuous, or prolonged infusion, is likely to be of greatest benefit, seek to reduce pharmacokinetic variability by the use of therapeutic drug monitoring and include measurement of the risks of emergence of resistance in target pathogens At present, the clinical evidence base for prolonged or continuous infusion therapy is insufficiently strong to support widespread use.
authors.affiliation: Bristol Centre for Antimicrobial Research & Evaluation, University of Bristol & North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, UK. alasdair.macgowan@nbt.nhs.uk
authors.forename: Alasdair
authors.initials: A
authors.lastname: MacGowan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D024881:Drug Resistance, Bacterial; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008826:Microbial Sensitivity Tests; D047090:beta-Lactams / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams