Abstract
To evaluate the relationship between pharmacokinetic/pharmacodynamic (PK/PD) parameters and changes in susceptibility and resistance frequency of Actinobacillus pleuropneumoniae CVCC 259, a piglet tissue cage (TC) infection model was established. After A. pleuropneumoniae populations maintained at 108 CFU/mL in TCs, piglets were treated with various doses of danofloxacin once daily for 5 consecutive days by intramuscular injection. Both the concentrations of danofloxacin and the population of vial cells were determined. Changes in susceptibility and resistance frequency were monitored. Polymerase chain reaction (PCR) amplification of quinolone resistance-determining regions (QRDRs) and DNA sequencing were performed to identify point mutations in gyrA, gyrB, parC, and parE genes. Furthermore, the susceptibility of mutants to danofloxacin and enrofloxacin was determined in the presence or absence of reserpine to assess whether the mutants were caused by efflux pumps. The MICs and resistant frequency of A. pleuropneumoniae both increased when danofloxacin concentrations fluctuated between MIC99 (0.05 μg/mL) and MPC (mutant prevention concentration, 0.4 μg/mL). As for PK/PD parameters, the resistant mutants were selected and enriched when AUC24h/MIC99 ranged from 34.68 to 148.65 h or AUC24h/MPC ranged from 4.33 to 18.58 h. Substitutions of Ser-83→Tyr or Ser-83→Phe in gyrA and Lys-53→Glu in parC were observed. The susceptibility of mutants obtained via danofloxacin treatment at 1.25 and 2.5 mg/kg were less affected by reserpine. These results demonstrate that maintaining the value of AUC24h/MPC above 18.58 h may produce a desirable antibacterial effect and protect against A. pleuropneumoniae resistance to danofloxacin.
Highlights
Actinobacillus pleuropneumoniae is the causative agent of porcine pleuropneumonia, a severe respiratory disease that is a global problem in pig production
We aimed to demonstrate that this model could elucidate the relationship between emergence of resistant A. pleuropneumoniae and PK/PD parameters associated with danofloxacin
The time-kill curves are depicted in Figure 1 and exhibit the antibacterial effect of danofloxcin against A. pleuropneumoniae CVCC259 in tissue cage fluid (TCF) after different doses were administered
Summary
Actinobacillus pleuropneumoniae is the causative agent of porcine pleuropneumonia, a severe respiratory disease that is a global problem in pig production. The acute form of this disease is highly contagious and often fatal, resulting in considerable economic losses to pig producers (GutiérrezMartín et al, 2006; Matter et al, 2007; Bossé et al, 2015). Antibacterial therapy was a highly effective and common measure in controlling this disease. Resistant mutants increased gradually due to the misuse of antibacterials. According to a recent report, the MIC frequency distribution of danofloxacin against A. pleuropneumoniae gradually increased during 2011–2015 in both the United States and Canada (Sweeney et al, 2017). A rational antibiotic dosing regimen should be optimized, to eradicate bacterial infections and to inhibit the emergence and proliferation of antibiotic-resistant strains (Toutain et al, 2002)
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