Pharmacodynamic Evaluation and PK/PD-Based Dose Prediction of Tulathromycin: A Potential New Indication for Streptococcus suis Infection

Abstract

Tulathromycin is the first member of the triamilide antimicrobial drugs that has been registered in more than 30 countries. The goal of this study is to provide a potential new indication of tulathromycin for Streptococcus suis infections. We investigated the pharmacokinetic and ex vivo pharmacodynamics of tulathromycin against experimental S. suis infection in piglets. Tulathromycin demonstrated a relatively long elimination half-life (74.1 h) and a mean residence time of 97.6 h after a single intramuscular administration. The minimal inhibitory concentration (MIC) and bactericidal concentration in serum were markedly lower than those in broth culture, with Mueller–Hinton broth/serum ratios of 40.3 and 11.4, respectively. The post-antibiotic effects were at 1.27 h (1× MIC) and 2.03 h (4× MIC) and the post-antibiotic sub-MIC effect values ranged from 2.47 to 3.10 h. The ratio of the area under the concentration–time curve divided by the MIC (AUC/MIC) correlated well with the ex vivo antimicrobial effectiveness of tulathromycin (R2 = 0.9711). The calculated AUC12h/MIC ratios in serum required to produce the net bacterial stasis, 1-log10 and 2-log10 killing activities were 9.62, 18.9, and 32.7, respectively. Based on the results of Monte Carlo simulation, a dosage regimen of 3.56 mg/kg tulathromycin was estimated to be effective, achieving for a bacteriostatic activity against S. suis infection over 5 days period. Tulathromycin may become a potential option for the treatment of S. suis infections.

Epidemiological and PK/PD cutoff values determination and PK/PD-based dose assessment of gamithromycin against Haemophilus parasuis in piglets

“…This difference in susceptibility agreed with the previous findings, in which a similar 4 to 16-fold reduction in tildipirosin MIC was observed for A. pleuropneumoniae by addition of 50% serum to broth medium [14]. More recently, our study regarding tulathromycin demonstrated that incorporation of increasing proportion of serum to broth from 25 to 75% progressively reduced the MIC against S. suis [13].…”

“…The AUC 24h /MIC targets for gamithromycin against H. parasuis associated with bactericidal and eradication effects were 30.3 h and 41.2 h, respectively. This microbiological response in ex vivo PK/PD model was similar to or in excess of previously approved veterinary macrolides such as tulathromycin and tildipirosin [13,23].…”

“…This resulted in the underestimate of gamithromycin clinical efficacy by measuring MICs in broth medium. In fact, the serum effects on antimicrobial activity of macrolides have been reported for most fastidious respiratory pathogens [11,13]. In our study, the MICs of gamithromycin against H. parasuis in porcine serum were significantly lower than that in HTM.…”

“…The 19 H. parasuis isolates were selected to cover five different provinces of China and the whole range of gamithromycin MICs. The MBC was determined using the The scaling factor that bridged the MICs between HTM and serum has been taken into account when calculating the PTA spot-plate technique to achieve a 3.0 log 10 decrease in the inoculum counts [11,13]. The epidemiological cutoff [ECOFF; synonym of wildtype cutoff (CO WT )] was the MIC that best describes the end of the wild-type distribution [33].…”

“…The PAE and PA-SME were defined as follows: PAE or PA-SME = T or T PA -C, where T or T PA is the time required for bacteria to increase by 1.0 log 10 cfu/mL in drug removal and sub-MIC treated phases, respectively. C is the corresponding time for untreated control [13].…”