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Quadruple-Checkerboard: A Modification of the Three-Dimensional Checkerboard for Studying Drug Combinations

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'Old' antibiotics for emerging multidrug-resistant bacteria.

Phillip J Bergen¹, Cornelia B Landersdorfer, Hee Ji Lee

¹Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Melbourne, Australia.

Current Opinion in Infectious Diseases

|October 9, 2012

Summary

The redevelopment of older antibiotics like colistin, fusidic acid, and fosfomycin is crucial for combating multidrug-resistant bacteria. Modern methods optimize their use, improving patient outcomes and preserving antibiotic effectiveness.

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Area of Science:

Microbiology
Pharmacology
Infectious Diseases

Background:

Rising bacterial resistance and a shortage of new antibiotics necessitate the re-evaluation of older antimicrobial agents.
Previously used antibiotics require redevelopment to meet contemporary standards and optimize therapeutic efficacy.

Purpose of the Study:

To review the successful redevelopment of colistin as an exemplar for optimizing 'old' antibiotics.
To discuss the application of modern drug development techniques to colistin, fusidic acid, and fosfomycin.

Main Methods:

Utilizing state-of-the-art analytical, microbiological, and pharmacokinetic/pharmacodynamic (PK/PD) methods.
Developing scientifically based dosing algorithms for specific patient populations, including those with renal impairment.

Main Results:

Redevelopment of colistin enhanced understanding of its chemistry, PK/PD, and clinical application.
A dosing algorithm for colistin in critically ill patients was established.
Nephrotoxicity of colistin necessitates further investigation into rational combination therapies.

Conclusions:

Modern analytical and PK/PD methods can facilitate the optimized clinical use of older antibiotics.
Similar approaches are being applied to fosfomycin and fusidic acid to improve their therapeutic utility.
Rational redevelopment strategies are essential for preserving the effectiveness of these vital antimicrobial agents.