Demonstration of pharmacometric applications to anti-infective chemotherapy.

Abstract

We developed a population pharmacokinetic model for efavirenz in pediatric HIV patients to guide dosing and decrease incidence of subtherapeutic levels. Data comprised of 3172 plasma concentrations collected over 4 years from 96 HIV-1 infected children who participated in the Pediatric AIDS Clinical Trials Group 382 (PACTG382) study. A one compartment model adequately described the data and the allometric size model accounted for the effect of body size on oral clearance and apparent volume of distribution. A sigmoid Emax maturation model demonstrated an increase in oral clearance by age to reach 90% of its mature level by the age of 9 months. The bioavailability of oral liquid formulations relative to the capsule formulation was also found to increase by age to reach 90% of its mature value of 0.79 by the age of 8 years. CYP2B6-G516T polymorphism was associated with a 51% decrease in oral clearance while MDR1-C3435T polymorphism has shown no effect. The final model showed good predictability performance and its application to improve dosing in pediatrics warrants further investigation.

Appropriate initial treatment choices for methicillin resistant Staphylococcus aureus (MRSA) infections are very critical especially in the intensive care units (ICU) settings. We compared the ability of ceftobiprole, dalbavancin, daptomycin, tigecycline, linezolid and vancomycin to achieve their requisite PK/PD targets against MRSA isolates collected from ICU settings. Ceftobiprole and dalbavancin were found to have the highest probability of achieving favorable outcome against MRSA infections in the ICU. The susceptibility results suggested a further reduction of the vancomycin breakpoint to 1 μg/ml.

We also employed a recently developed quantitative methodology to characterize the killing effect of vancomycin and rifampin combination against MRSA biofilm. The results suggest antagonism between vancomycin and rifampin against MRSA biofilm. The quantitative approach used provides a scientific rationale for further in vivo investigations which should allow a better understanding of the therapeutic potential of this combination in biofilm-associated MRSA infections. Finally, we compared the activities of moxifloxacin and vancomycin against MRSA and MRSE biofilms. Moxifloxacin exhibited a superior anti-biofilm activity suggesting potential benefit in treatment of MRSA and MRSE biofilm associated infections.