title: Evaluation of in vitro synergy between vertilmicin and ceftazidime against Pseudomonas aeruginosa using a semi-mechanistic pharmacokinetic/pharmacodynamic model.
abstract: The aim of this study was to develop a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model to evaluate the in vitro synergy between vertilmicin and ceftazidime against Pseudomonas aeruginosa. The in vitro antimicrobial activity of vertilmicin alone was initially assessed by static and dynamic time-kill experiments against three bacterial strains, including MSSA, MRSA and P. aeruginosa. The combined killing effect with ceftazidime was then evaluated in a static time-kill study against P. aeruginosa. Vertilmicin displayed a concentration-dependent killing effect against the three bacterial strains, and its short half-life may possibly have a dramatic impact on antimicrobial activities. A two-compartment pharmacodynamic model consisting of drug-susceptible and -resistant compartments was developed to characterise the relationship between drug exposure and bacterial response for the time-kill curves from both monotherapy and combination therapy. Loewe additivity was incorporated into the pharmacodynamic model to describe the drug-drug interactive effect in the combination therapy. For monotherapy, the estimated EC50 of the dynamic time-kill study against each strain was close to its MIC but was higher than that of the static time-kill study. The EC50 of combination therapy was estimated at 2.67 mg/L compared with 4.54 mg/L in monotherapy, indicating an enhanced bactericidal capacity. The drug-drug interactive effect was not significantly synergistic but highly varied at each specific combination. Potential synergistic combinations could be screened using PK/PD modelling and simulation. These results demonstrated that PK/PD modelling provides an innovative approach to assist dose selection of combination vertilmicin and ceftazidime for future clinical study design.
authors.affiliation: School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Luning
authors.initials: L
authors.lastname: Zhuang
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Sherwin K B
authors.initials: SK
authors.lastname: Sy
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Huiming
authors.initials: H
authors.lastname: Xia
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Rajendra P
authors.initials: RP
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Midas B
authors.initials: MB
authors.lastname: Mulder
authors.affiliation: Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
authors.forename: Changxiao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA. Electronic address: hartmut@ufl.edu.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Derendorf
mesh_terms: D000617:Aminoglycosides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002442:Ceftazidime / Q000493:pharmacokinetics / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; C487733:vertilmicin; D002442:Ceftazidime
keywords: Combination therapy; PK/PD modelling; Time–kill curve; Vertilmicin