Use of an In Vitro Pharmacodynamic Model to Derive a Linezolid Regimen that Optimizes Bacterial Kill and Prevents Emergence of Resistance in Bacillus anthracis

Ordway Research Institute, Albany, NY; US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD; Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany

^* To whom correspondence should be addressed. Email: alouie{at}ordwayresearch.org.

	Abstract

Background: Simulating the average non-protein bound (free) human serum concentration-time profiles for linezolid in an in vitro pharmacodynamic model, we characterized the pharmacodynamic parameter(s) of linezolid predictive of kill and for prevention of resistance in Bacillus anthracis (BA).

Methods and Results: In 10-day dose-ranging studies, the average exposure for 700 mg of linezolid given once-daily (QD) resulted in >3 log(CFU/ml) declines in BA without resistance selection. Linezolid at 600 mg QD amplified for resistance. With twice daily (Q12 hr) dosing, linezolid at 500 mg Q12 hr was required for resistance prevention. In dose-fractionation studies, killing of BA was predicted by AUC/MIC. However, resistance prevention was linked to Cmax/MIC. Monte Carlo simulations predicted that linezolid at 1,100 mg QD would produce in 96.7% of human subjects a free 24h-AUC that would match or exceed the average 24h-AUC of 78.5 mg.h/L generated by linezolid 700 mg QD, while reproducing the shape of the concentration-time profile for this pharmacodynamically-optimized regimen. However, linezolid at 700 mg Q12 hr (cumulative daily dosage of 1,400 mg) would produce an exposure that would equal or exceed the average free 24-hr AUC of 90 mg.h/L generated by linezolid 500 mg Q12 hr in 93.8% of human subjects.

Conclusion: In our in vitro studies, the QD administered, pharmacodynamically-optimized regimen for linezolid killed drug-susceptible BA and prevented resistance emergence at lower dosages than Q12 hr regimens. The lower dosage for the pharmacodynamically-optimized regimen may decrease drug toxicity. Also, the QD administration schedule may improve patient compliance.