In Vivo Activity of Cefquinome against Escherichia coli in the Thighs of Neutropenic Mice

Abstract

Cefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity against enteric Gram-negative bacilli such as Escherichia coli. We utilized a neutropenic mouse model of colibacillosis to examine the pharmacodynamic (PD) characteristics of cefquinome, as measured by organism number in homogenized thigh cultures after 24 h of therapy. Serum drug levels following 4-fold-escalating single doses of cefquinome were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic (PK) properties of cefquinome were linear over a dose range of 10 to 640 mg/kg of body weight. Serum half-lives ranged from 0.29 to 0.32 h. Dose fractionation studies over a 24-h dose range of 2.5 to 320 mg/kg were conducted every 3, 6, 12, or 24 h. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. The free percentage of the dosing interval that the serum levels exceed the MIC (fT >MIC ) was the PK-PD index that best correlated with efficacy (R 2 ‫؍‬ 73% for E. coli, compared with 13% for the maximum concentration of the free drug in serum [fC max ]/MIC and 45% for the free-drug area under the concentration-time curve from 0 to 24 h [fAUC 0-24 ]/ MIC). Subsequently, we employed a similar dosing strategy by using 4-fold-increasing total cefquinome doses administered every 4 h to treat animals infected with four additional E. coli isolates. A sigmoid maximum-effect (E max ) model was used to estimate the magnitudes of the %fT >MIC associated with net bacterial stasis, a 1-log 10 CFU reduction from baseline, and a 2-log 10 CFU reduction from baseline; the corresponding values were 28.01% ؎ 2.27%, 37.23% ؎ 4.05%, and 51.69% ؎ 9.72%. The potent bactericidal activity makes cefquinome an attractive option for the treatment of infections caused by E. coli.

In vivo activity of cefquinome against Riemerella anatipestifer using the pericarditis model in the duck

“…Similar to what was found in other β ‐lactams (Vogelman et al ., ; Leggett et al ., ), results from the present studies of multiple dosage regimens indicate that the % f T > MIC the PK/PD parameter best correlated ( R 2 = 86.3%) with the in qvivo antibacterial effects of cefquinome. In the current investigation, the % f T > MIC required to produce a static effect against R. anatipestifer was (22.5 ± 1.3) % of the dosing interval, which was similar to the activity of cefquinome against E. coli (25.86–31.57%) (Shan et al ., ). The cephalosporin %T > MIC target to produce a net bacteriostatic effect has been reported most commonly in the range of 30–40% as long as free drug levels are considered.…”

“…This has been reported in various species following intramuscular (i.m.) administration, such as in camels (Al Taher, ), rabbits (Hwang et al ., ), sheep (Uney et al ., ), cows (Zonca et al ., ), chickens (Xie et al ., ), mice (Shan et al ., ; Wang et al ., ), and pigs (Zhang et al ., ). But the half‐lives at β ‐phase of i.m.…”

Pharmacokinetics of cefquinome after single and repeated subcutaneous administrations in sheep

“…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.…”

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 ).…”