Pharmacodynamic modeling of aminoglycosides against Pseudomonas aeruginosa and Acinetobacter baumannii: identifying dosing regimens to suppress resistance development.

Antimicrobial Agents and Chemotherapy
Vincent H TamMichael Nikolaou

Abstract

To facilitate optimal dosing regimen design, we previously developed a mathematical model using time-kill study data to predict the responses of Pseudomonas aeruginosa to various pharmacokinetic profiles of meropenem and levofloxacin. In this study, we extended the model to predict the activities of gentamicin and amikacin exposures against P. aeruginosa and Acinetobacter baumannii, respectively. The input data were from a time-kill study with 10(7) CFU/ml of bacteria at baseline. P. aeruginosa ATCC 27853 was exposed to gentamicin (0 to 16x MIC; MIC = 2 mg/liter), and A. baumannii ATCC BAA 747 was exposed to amikacin (0 to 32x MIC; MIC = 4 mg/liter) for 24 h. Using the estimates of the best-fit model parameters, bacterial responses to various fluctuating aminoglycoside exposures (half-life, 2.5 h) over 72 h were predicted via computer simulation. The computer simulations were subsequently validated using an in vitro hollow-fiber infection model with similar aminoglycoside exposures. A significant initial reduction in the bacterial burden was predicted for all gentamicin exposures examined. However, regrowth over time due to resistance emergence was predicted for regimens with a maximum concentration of the drug (C(max))/MIC (do...Continue Reading

References

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Jul 28, 2006·Antimicrobial Agents and Chemotherapy·Vincent H TamElizabeth A Coyle
Feb 16, 2007·Diagnostic Microbiology and Infectious Disease·Andrea L H KwaVincent H Tam
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Apr 14, 2007·Annals of Biomedical Engineering·Michael NikolaouVincent H Tam
Oct 5, 2007·The Journal of Antimicrobial Chemotherapy·Vincent H TamMichael Nikolaou

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Citations

Mar 12, 2011·The Journal of Antimicrobial Chemotherapy·Pratik BhagundeVincent H Tam
Jan 11, 2012·The Journal of Antimicrobial Chemotherapy·Beining GuoVincent H Tam
Apr 7, 2011·Current Opinion in Infectious Diseases·Lulla OpatowskiLaura Temime
Jan 22, 2011·PLoS Computational Biology·Vincent H Tam, Michael Nikolaou
Nov 17, 2011·Drugs·Spyridon PagkalisMatthew E Falagas
Aug 5, 2010·Wiener klinische Wochenschrift·Sebastian MausBertram Hartmann
May 7, 2009·Expert Opinion on Drug Metabolism & Toxicology·David CzockFrieder Keller
Dec 15, 2015·Expert Opinion on Drug Metabolism & Toxicology·Sherwin K B SyHartmut Derendorf
Jun 23, 2016·The Journal of Antimicrobial Chemotherapy·Wanchana UngphakornElisabet I Nielsen
Apr 29, 2014·The Lancet Infectious Diseases·Jason A RobertsUNKNOWN International Society of Anti-Infective Pharmacology and the Pharmacokinetics and Pharmacodynamics Study Group of the Europe
Jan 24, 2018·Antimicrobial Agents and Chemotherapy·Ali A AlhadabRichard C Brundage
Sep 25, 2018·Journal of Clinical Pharmacology·Jennifer Le, John S Bradley
Mar 24, 2018·Drugs·A J HeffernanJ A Roberts
Feb 6, 2017·The Journal of Antimicrobial Chemotherapy·Vincent H TamRafael Cantón

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