Response of a clinical Escherichia coli strain to repeated cefquinome exposure in a piglet tissue-cage model

Abstract

Background: In order to provide some basis for effective dosage regimens that optimize efficacy with respect to bacteriological and clinical cures, the in vivo activity of cefquinome against a clinical Escherichia coli (E.coli) strain (the minimum inhibitory concentration value for this strain equals to the MIC 90 value of 0.25 μg/ml for 210 E.coli strains isolated from pigs) was investigated by using a piglet tissue-cage infection model. The aim was to elucidate the pharmacokinetic/pharmacodynamics (PK/PD) index associated with cefquinome efficacy, and then to identify the magnitude of the PK/PD parameter required for different degree of efficacy in clinical treatment. Results: Tissue-cage infection model was established in piglets, and then the animals received intramuscular injection of cefquinome twice a day for 3 days to create a range of different drug exposures. The tissue-cage fluid was collected at 1, 3, 6, 9 and 12 h after every drug administration for drug concentration determination and bacteria counting. Different cefquinome regimens produced different percentages of time during that drug concentrations exceeded the MIC (%T > MIC), ranging from 0 % to 100 %. Cefquinome administration at 0.2, 0.4, 0.6, 0.8, 1, 2 and 4 mg/kg reduced the bacterial count (log 10 CFU/mL) in tissue-cage fluid by -1.00 ± 0.32, -1.83 ± 0.08, -2.33 ± 0.04, -2.96 ± 0.16, -2.99 ± 0.16, -2.93 ± 0.11, -3.43 ± 0.18, respectively. The correlation coefficient of the PK/PD index with antibacterial effect of the drug was 0.90 for %T > MIC, 0.62 for AUC 0-12 /MIC, and 0.61 for C max /MIC, suggesting the most important PK/PD parameter was %T > MIC. A inhibitory form of sigmoid maximum effect (E max) model was used to estimate %T > MIC, and the respective values required for continuous 1/6-log drop, 1/3-log drop and 1/2-log drop of the clinical E.coli count during each 12 h treatment period were 3.97 %, 17.08 % and 52.68 %. Conclusions: The data derived from this study showed that cefquinome exhibited time-dependent killing profile. And from the results of the present study, it can be assumed that when %T > MIC reached 52.68 %, cefquinome could be expected to be effective against a clinical E.coli strain for which the MIC value is below 0.128 μg/ml (3-log drop of bacteria count can be achieved after six successive administrations for 3 days).