Novel modeling framework to guide design of optimal dosing strategies for β-lactamase inhibitors.

Antimicrobial Agents and Chemotherapy
Pratik BhagundeVincent H Tam

Abstract

The scarcity of new antibiotics against drug-resistant bacteria has led to the development of inhibitors targeting specific resistance mechanisms, which aim to restore the effectiveness of existing agents. However, there are few guidelines for the optimal dosing of inhibitors. Extending the utility of mathematical modeling, which has been used as a decision support tool for antibiotic dosing regimen design, we developed a novel mathematical modeling framework to guide optimal dosing strategies for a beta-lactamase inhibitor. To illustrate our approach, MK-7655 was used in combination with imipenem against a clinical isolate of Klebsiella pneumoniae known to produce KPC-2. A theoretical concept capturing fluctuating susceptibility over time was used to define a novel pharmacodynamic index (time above instantaneous MIC [T>MIC(i)]). The MK-7655 concentration-dependent MIC reduction was characterized by using a modified sigmoid maximum effect (E(max))-type model. Various dosing regimens of MK-7655 were simulated to achieve escalating T>MIC(i) values in the presence of a clinical dose of imipenem (500 mg every 6 h). The effectiveness of these dosing exposures was subsequently validated by using a hollow-fiber infection model (HFIM)....Continue Reading

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Mar 12, 2011·The Journal of Antimicrobial Chemotherapy·Pratik BhagundeVincent H Tam

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Citations

Aug 27, 2014·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Francisco PimentaManuel Simões
Nov 13, 2013·Expert Opinion on Investigational Drugs·Ze-Qi XuJohn Flavin
Jul 4, 2012·Current Opinion in Pharmacology·Karen Bush
Aug 21, 2015·Pharmacotherapy·Evan J ZasowskiMichael J Rybak
Aug 1, 2015·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Dakshina ChilukuriJoseph G Toerner
Apr 5, 2016·Expert Review of Anti-infective Therapy·Bradley J Gardiner, Yoav Golan
Feb 11, 2018·Pharmacotherapy·Sarah Christina Jane Jorgensen, Michael Joseph Rybak
Apr 4, 2018·Antimicrobial Agents and Chemotherapy·Krisztina M Papp-WallaceRobert A Bonomo
Jan 1, 2014·Antimicrobial Agents and Chemotherapy·Sarah M DrawzRobert A Bonomo
Oct 5, 2013·Clinical Microbiology Reviews·Michael J Pucci, Karen Bush
Jan 11, 2019·Expert Opinion on Drug Metabolism & Toxicology·Ilias KaraiskosHelen Giamarellou
Dec 12, 2018·Antimicrobial Agents and Chemotherapy·Henrietta AbodakpiVincent H Tam
Jun 21, 2019·The Journal of Antimicrobial Chemotherapy·Alan R NoelAlasdair P MacGowan
Jul 26, 2019·Expert Review of Anti-infective Therapy·Marguerite L Monogue, David P Nicolau
Aug 22, 2020·Expert Opinion on Pharmacotherapy·S G KuiperC van Nieuwkoop
Jan 13, 2017·The Journal of Antimicrobial Chemotherapy·Sherwin K B SyHartmut Derendorf
Feb 6, 2017·Journal of Pharmacokinetics and Pharmacodynamics·Karen Bush, Malcolm G P Page
Nov 13, 2020·Clinical Microbiology Reviews·Dafna YahavLeonard Leibovici

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