Abstract
BackgroundGamithromycin is a macrolide approved for the treatment of bovine and swine respiratory diseases. Our study aims to establish the clinical breakpoint and optimum dose regimen for gamithromycin against Haemophilus parasuis in piglets.ResultsGamithromycin was well absorbed and fully bioavailable (87.2–101%) after intramuscular and subcutaneous administrations. The MICs of gamithromycin for 192 clinical H. parasuis isolates ranged from 0.008 to 128 mg/L and the epidemiological cutoff (ECOFF) was calculated as 1.0 mg/L. A large potentiation effect of serum on in vitro susceptibility of gamithromycin was observed for H. parasuis, with broth/serum ratios of 8.93 for MICs and 4.46 for MBCs, respectively. The postantibiotic effects were 1.5 h (1 × MIC) and 2.4 h (4 × MIC), and the postantibiotic sub-MIC effects ranged from 2.7 to 4.3 h. Gamithromycin had rapid and concentration-dependent killing against H. parasuis, and the AUC24h/MIC ratio correlated well with ex vivo efficacy (R2 = 0.97). The AUC24h/MIC targets in serum associated with bacteriostatic, bactericidal and eradication activities were 15.8, 30.3 and 41.2, respectively. The PK/PD-based population dose prediction indicated a probability of target attainment (PTA) for the current marketed dose (6 mg/kg) of 88.9% against H. parasuis. The calculated gamithromycin dose for a PTA ≥ 90% was 6.55 mg/kg. Based on Monte Carlo simulations, the PK/PD cutoff (COPD) was determined to be 0.25 mg/L.ConclusionThe determined cutoffs and PK/PD-based dose prediction will be of great importance in gamithromycin resistance surveillance and serve as an important step in the establishment of optimum dose regimen and clinical breakpoints.
Highlights
Gamithromycin is a macrolide approved for the treatment of bovine and swine respiratory diseases
In naturally occurring bovine respiratory diseases associated with Mannheimia haemolytica and Pasteurella multocida, the area under the concentration-time curve to minimal inhibitory concentration ratio (AUC/MIC) was the pharmacokinetic/pharmacodynamic (PK/PD) index that best predicted the efficacy of gamithromycin [9]
Piglets received the drug IM and SC resulted in AUC0-∞ of 6.63 and 5.72 mg·h/ L that were comparable to the IV AUC0-∞ at the same dose
Summary
Gamithromycin is a macrolide approved for the treatment of bovine and swine respiratory diseases. Our study aims to establish the clinical breakpoint and optimum dose regimen for gamithromycin against Haemophilus parasuis in piglets. Haemophilus parasuis is the etiological agent of Glässer’s disease that causes inflammatory infections such as fibrinous polyserositis, meningitis, arthritis and bronchopneumonia in weaned piglets [1]. There are currently 15 serotypes of H. parasuis and serotypes 1, 5 and 10 are the most virulent causing rapid death of infected piglets [4, 5]. Gamithromycin is a macrolide of the azalide subclass that approved for the treatment of bovine and swine respiratory diseases [7, 8]. PK/PD data for gamithromycin against swine respiratory pathogens including H. parasuis have not been pursued. As the crucial interpretative criteria to categorize the results of antimicrobial susceptibility testing (AST), the clinical breakpoints (CBPs) of gamithromycin for the relevant bacterial target pathogens still remain unclear
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