Pharmacokinetic/pharmacodynamic relationships and development of resistance of enrofloxacin and cefquinome in combination therapy against Klebsiella pneumoniae in chicks

The antibiotic resistance of Klebsiella pneumoniae poses significant challenges in veterinary clinical settings and threatens poultry production. Veterinarians often employ combination therapy to address this issue. However, the resulting effects are complex and not well understood. This study aims to describe the therapeutic effects of different dosing regimens of enrofloxacin (ENR) and cefquinome (CEQ) in a pharmacokinetic/pharmacodynamic (PK/PD) model using chicks. This experiment utilized a chick pneumonia model, and the dosing regimen of the combination drug was divided into three single-dose groups and three split-dose groups for three consecutive days; The PK/PD fitting analysis was conducted using the Inhibitory Sigmoid Emax model; The alterations in bacterial load of drug-resistant K. pneumoniae CLS2 (Clinical strain) were assessed through viable bacterial counts and minimum inhibitory concentration (MIC); Additionally, the resistance mutations and efflux pump activity of the resistant strains were evaluated. The MICs of ENR and CEQ for CLS2 were 2 µg/mL and 0.125 µg/mL, respectively. The PD results demonstrated that the efficacy of the split-dose group, which received 20 mg/kg of ENR in combination with 20 mg/kg of CEQ (ΔE = 5.66 Log10 CFU/mL), significantly surpassed that of the single-dose group (ΔE = 2.80 Log10 CFU/mL). The combination therapy group, where CEQ was administered at split doses of 4 and 20 mg/kg demonstrated bactericidal activity (ΔE ≥ 3.05 Log10 CFU/mL) and exhibited a substantial clearance effect against K. pneumoniae, respectively. The PK/PD parameters indicated that the parameter value required to achieve a 3 Log10 CFU/mL reduction for %T > MIC(combined) (R2 > 0.900) was calculated at 37.062. ENR administered via intramuscular injection at 10 mg/kg and CEQ at 2.6 mg/kg both twice daily for three consecutive days was effective for addressing pulmonary infections in chicks induced by K. pneumoniae and may also help postpone the development of antibiotic resistance. Furthermore, a thoughtfully formulated combination therapy approach could potentially mitigate the rise of resistant strains.