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. 2024 Apr 20;20(1):147.
doi: 10.1186/s12917-024-03988-y.

Pharmacokinetic/pharmacodynamic evaluation of gamithromycin against rabbit pasteurellosis

Xin-Yi Wei  1   2 , Jing Zhang  1   2   3 , Yin Zhang  1   2 , Wen-Zhen Fu  1   2 , Long-Gen Zhong  1   2 , Yi-Duo Pan  1   2 , Jian Sun  1   2 , Xiao-Ping Liao  1   2 , Ya-Hong Liu  1   2 , Yu-Feng Zhou  4   5
Affiliations

Pharmacokinetic/pharmacodynamic evaluation of gamithromycin against rabbit pasteurellosis

Xin-Yi Wei et al. BMC Vet Res. .

Abstract

Background: Gamithromycin is an effective therapy for bovine and swine respiratory diseases but not utilized for rabbits. Given its potent activity against respiratory pathogens, we sought to determine the pharmacokinetic profiles, antimicrobial activity and target pharmacokinetic/pharmacodynamic (PK/PD) exposures associated with therapeutic effect of gamithromycin against Pasteurella multocida in rabbits.

Results: Gamithromycin showed favorable PK properties in rabbits, including high subcutaneous bioavailability (86.7 ± 10.7%) and low plasma protein binding (18.5-31.9%). PK analysis identified a mean plasma peak concentration (Cmax) of 1.64 ± 0.86 mg/L and terminal half-life (T1/2) of 31.5 ± 5.74 h after subcutaneous injection. For P. multocida, short post-antibiotic effects (PAE) (1.1-5.3 h) and post-antibiotic sub-inhibitory concentration effects (PA-SME) (6.6-9.1 h) were observed after exposure to gamithromycin at 1 to 4× minimal inhibitory concentration (MIC). Gamithromycin demonstrated concentration-dependent bactericidal activity and the PK/PD index area under the concentration-time curve over 24 h (AUC24h)/MIC correlated well with efficacy (R2 > 0.99). The plasma AUC24h/MIC ratios of gamithromycin associated with the bacteriostatic, bactericidal and bacterial eradication against P. multocida were 15.4, 24.9 and 27.8 h in rabbits, respectively.

Conclusions: Subcutaneous administration of 6 mg/kg gamithromycin reached therapeutic concentrations in rabbit plasma against P. multocida. The PK/PD ratios determined herein in combination with ex vivo activity and favorable rabbit PK indicate that gamithromycin may be used for the treatment of rabbit pasteurellosis.

Keywords: P. Multocida; Gamithromycin; PK/PD; Rabbit.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
In vitro time-killing curves of gamithromycin against P. multocida CVCC 434 in CAMH broth. The limit of detection (LOD) was 40 cfu/mL
Fig. 2
Fig. 2
In vitro PAE and PA-SME values for gamithromycin against P. multocidaCVCC 434. (A) Standard curve constructed by regression of the viable bacterial counts and absorbance (OD600nm) of P. multocida CVCC 434. The solid points represent the observed data and the line represents the best fitting curves as follows: y = 1.0633 ln(x) + 10.929 (R2 = 0.9453). (B-C) The PAEs (B) were measured after initial exposure to gamithromycin at 1× and 4× MIC against P. multocida CVCC 434; The PA-SME (C) was determined after an initial exposure to gamithromycin at 4×MIC. The horizontal bars represent the time required for viable counts of bacteria to increase by 1.0 log10 cfu/mL in the drug removal (PAE) and sub-MIC phase (PA-SME)
Fig. 3
Fig. 3
The plasma time-concentration profiles of gamithromycin in New Zealand rabbits received a single dose intravenous (IV) or subcutaneous (SC) administration at 6 mg/kg (n = 9 per time point). Upper right panel shows details from 0 to 4 h
Fig. 4
Fig. 4
Ex vivo activity of gamithromycin for P. multocida CVCC 434 in plasma samples from the rabbits receiving subcutaneous administration of gamithromycin at 6.0 mg/kg. Numerical values on the right brackets represent the mean free drug concentrations of gamithromycin in rabbit plasma collected at different time points
Fig. 5
Fig. 5
PK/PD relationship of gamithromycin against P. multocida. Correlation plot of ex vivo antimicrobial activity and AUC24h/MIC ratio of gamithromycin based on the sigmoid Emax equation. The line represents the fitting curve of the predicted values, and the points represent observed values of plasma samples collected at time points from 0 to 96 h
See this image and copyright information in PMC

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