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Use of in vitro critical inhibitory concentration, a novel approach to predict in vivo synergistic bactericidal effect of combined amikacin and piperacillin against pseudomonas aeruginosa in a systemic rat infection model
journal contribution
posted on 2006-04-01, 00:00 authored by E Chan, S Zhou, S Sahasranaman, Wei DuanWei DuanPURPOSE: This study was undertaken to explore the use of in vitro critical inhibitory concentration (CIC) as a surrogate marker relating the pharmacokinetic (PK) parameters to in vivo bactericidal synergistic effect [pharmacodynamic (PD)] of amikacin + piperacillin combination against Pseudomonas aeruginosa in a systemic rat infection model. METHODS: The in vitro antibacterial activities of amikacin and piperacillin, alone and in combinations at various ratios of the concentrations, were tested against a standard [5 x 10(5) colony-forming units (CFU)/ml] and a large (1.5 x 10(8) CFU/ml) inoculum of P. aeruginosa ATCC 9027 using a modified survival-time method. The CIC of each individual antibiotic for the different combinations was determined using a cup-plate method. In vivo studies were performed on Sprague-Dawley rats using a systemic model of infection with P. aeruginosa ATCC 9027. PK profiles and in vivo killing effects of the combination at different dosing ratios were studied. RESULTS: An inoculum effect was observed with the antibiotics studied. Synergy was seen against both the inocula at the following concentration ratios: 70% C(ami) + 30% C(pip) and 75% C(ami) + 25% C(pip), where C(ami) and C(pip) are the concentrations of amikacin and piperacillin to produce a 1000-fold decrease in bacterial population over 5 h, respectively. The CIC values determined corroborated with the order of in vitro bacterial killing observed for the antibiotic combinations. The dosing ratio of 12.6 mg/kg amikacin + 36 mg/kg piperacillin (a 70:30 ratio of the individual doses) exhibited the greatest killing in vivo when compared to the other ratios. The PK-PD relationships were described by simple, linear regression equations using the area under the in vivo killing curve as a PD marker and the AUCIC(ami)/CIC(ami) + AUCIC(pip)/CIC(pip), AUC(ami)/CIC(ami) + AUC(pip)/CIC(pip), C(max,ami)/CIC(ami) + C(max,pip)/CIC(pip), and AUCIC(ami)/MIC(ami) + AUCIC(pip)/MIC(pip) as PK markers for the amikacin + piperacillin combination. CONCLUSION: The combination of amikacin and piperacillin exhibited synergistic killing effect on P. aeruginosa that could be modeled using CIC as a surrogate marker relating the PK parameters to in vivo bactericidal effect.
History
Journal
Pharmaceutical researchVolume
23Issue
4Pagination
729 - 741Publisher
Springer New York LLCLocation
New York, N.Y.Publisher DOI
ISSN
0724-8741eISSN
1573-904XLanguage
engPublication classification
C1.1 Refereed article in a scholarly journalCopyright notice
2006, Springer Science + Business Media, Inc.Usage metrics
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amikacin-piperacillin combinationconcentration ratioin vitro critical inhibitory concentrationin vivo bactericidal synergismpharmacokinetic-pharmacodynamic relationshipPseudomonas aeruginosa infectionScience & TechnologyPhysical SciencesLife Sciences & BiomedicineChemistry, MultidisciplinaryPharmacology & PharmacyChemistryBETA-LACTAM ANTIBIOTICSSTAPHYLOCOCCUS-AUREUSANTIBACTERIAL AGENTSINOCULUM SIZEPHARMACODYNAMICSPNEUMONIAIMIPENEMEFFICACYSEPSISSTRAIN
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