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

Abstract

BackgroundIn 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 MIC90 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.ResultsTissue-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 (log10 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 AUC0–12/MIC, and 0.61 for Cmax/MIC, suggesting the most important PK/PD parameter was %T > MIC. A inhibitory form of sigmoid maximum effect (Emax) 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 %.ConclusionsThe 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).

Pharmacokinetics of cefquinome after single and repeated subcutaneous administrations in sheep

“…The in vitro efficacy of CFQ for these pathogens has been reported by various workers (Batzias, 2009;Chin, Gu, Fang, & Neu, 1992;Ehinger, Schmidt, & Kietzmann, 2006;FDA, 2006;Limbert et al, 1991;Luhofer et al, 2004;Meyns, Croubels, Verheyen, Sustronck, & Maes, 2006;Murphy, Erwin, & Jones, 1994;Thomas et al, 2006). (Gu et al, 2015;Guo et al, 2015;Qiu et al, 2016;Shan, Liang, Wang, Li, & Zeng, 2014;Wang et al, 2014). In this study, % (Roberts et al, 2010;Smiet, Haritova, Heil, Fink-Gremmels, & Wijnberg, 2012;Zhang et al, 2014) have been recommended in critically ill patients and patients with compromised immune responses.…”

“…In this study, the hypothetical MIC values (0.125‐2 μg/ml), which based on MIC 90 values of 0.016‐1 μg/ml reported for susceptible pathogens above and the susceptibility breakpoint of 2 μg/ml recommended by the AVID (Working Group for Veterinary Medicines and Diagnosis of Infections) in Germany (AVID, ), were used to calculate %T > MIC. Studies recommend T > MIC values of 40%–70% for CFQ (Gu et al., ; Guo et al., ; Qiu et al., ; Shan, Liang, Wang, Li, & Zeng, ; Wang et al., ). In this study, % T > MIC values for two administration routes were calculated using V darea determined following IV administration of CFQ.…”

“…Due to its broad antibacterial spectrum and excellent efficacy, CFQ has the potential to become a valuable antibiotic in the treatment of infectious diseases in sheep. The successful therapeutic use of CFQ, time‐dependent antibiotic, requires knowledge of its pharmacokinetics and pharmacodynamics (PK/PD) (Ahmad et al., ; Gu et al., ; Guo et al., ; Thomas, Thomas, & Wilhelm, ; Wang, Shan, Ding, Liang, & Zeng, ; Zhang et al., ). For this purpose, the useful pharmacokinetic/pharmacodynamic (PK/PD) parameter, which calculated using the apparent volume of distribution and elimination half‐life and the minimum inhibitory concentration (MIC), is the percentage of time interval (%T > MIC) that plasma concentration remains above MIC (Turnidge, ).…”

Plasma and synovial fluid pharmacokinetics of cefquinome following the administration of multiple doses in horses

“…In this study, T > MIC was calculated using the hypothetical MIC values (0.125–2 μg/mL) that were established based on MIC 90 values of 0.016–2 μg/mL reported for susceptible horse pathogens (Thomas et al ., ) and the susceptibility breakpoint of 2 μg/mL. In vitro and in vivo animal data support T > MIC values of 40–70% between CFQ doses (Shan et al ., ; Wang et al ., ; Gu et al ., ; Guo et al ., ; Qiu et al ., ). This pharmacodynamic target was provided by the administration of 1, 2, 4, and 6 mg/kg doses of CFQ at 12‐h intervals, with MIC values of ≤0.25, ≤0.5, ≤1, and ≤1, respectively, for bacteria (Table ).…”

“…Cefquinome has low activity against methicillin-resistant S. aureus and very limited activity against gram-negative anaerobes, Pseudomonas aeruginosa and Rhodococcus equi in vitro (Limbert et al, 1991;Bottner et al, 1995;Thomas et al, 2006). The antibacterial activity of CFQ generally displays time-dependent characteristics (Thomas et al, 2006;Wang et al, 2014;Zhang et al, 2014a;Ahmad et al, 2015;Gu et al, 2015;Guo et al, 2015). It has been reported that the pharmacokinetics/pharmacodynamics (PK/ PD) index that correlates with the therapeutic efficacy of the beta-lactam antibiotic is the amount of time (%T > MIC) that the drug levels remain above the minimum inhibitory concentration (MIC) (Craig, 1998;Turnidge, 1998;McKellar et al, 2004).…”