Pharmacokinetic/Pharmacodynamic Profiles of Tiamulin in an Experimental Intratracheal Infection Model of Mycoplasma gallisepticum

Abstract

Mycoplasma gallisepticum is the most important pathogen in poultry among four pathogenic Mycoplasma species. Tiamulin is a pleuromutilin antibiotic that shows a great activity against M. gallisepticum and has been approved for use in veterinary medicine particularly for poultry. However, the pharmacokinetic/pharmacodynamics (PK/PD) profiles of tiamulin against M. gallisepticum are not well understood. Therefore, in the current studies, we investigated the in vivo PK/PD profiles of tiamulin using a well-established experimental intratracheal infection model of M. gallisepticum. The efficacy of tiamulin against M. gallisepticum was studied in 8-day-old chickens after intramuscular (i.m.) administration at 10 doses between 0–80 mg/kg. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to evaluate the PK parameters of tiamulin following i.m. administration at doses of 5, 40, and 80 mg/kg in Mycoplasma gallisepticum-infected neutropenic chickens. Real-time PCR (RT-PCR) was used for quantitative detection of M. gallisepticum. The MIC of tiamulin against M. gallisepticum strain S6 was 0.03 μg/mL. The PK/PD index, AUC24h/MIC, correlated well with the in vivo antibacterial efficacy. The in vivo data suggest that animal dosage regimens should supply AUC24h/MIC of tiamulin of 382.68 h for 2 log10 ccu equivalents M. gallisepticum reduction. To attain that goal, the administered dose is expected to be 45 mg/kg b.w. for treatment of M. gallisepticum infection with an MIC90 of 0.03 μg/mL.

Pharmacokinetics and relative bioavailability of tiamulin in broiler chicken as influenced by different routes of administration

“…When tiamulin was administered orally through crop, the effective plasma concentration (>0.03 µg/ml) was maintained up to 12 hr (Table , Figure ), which was more than the MIC reported against M. gallisepticum (Xia et al, ). A second peak was observed at around 5–6 hr, which could be attributed to enterohepatic recycling of tiamulin during biliary excretion (Xia et al, ). The mean C max, 0.73 µg/ml was attained at around 1.5 hr (Table ) which was lower than that recorded after intramuscular administration at the same dose as reported by Xia et al ().…”

“…A second peak was observed at around 5–6 hr, which could be attributed to enterohepatic recycling of tiamulin during biliary excretion (Xia et al, ). The mean C max, 0.73 µg/ml was attained at around 1.5 hr (Table ) which was lower than that recorded after intramuscular administration at the same dose as reported by Xia et al (). This suggests that the oral absorption of drug is possibly hindered by intestinal factors.…”

“…Tiamulin is a concentration‐ and time‐dependent bacteriostatic drug (Burch, ), and hence the surrogate parameters AUC/MIC, C max /MIC, and T > MIC were calculated for assessing the clinical efficacy of tiamulin using the reported MIC ‐ 0.03µg/ml for M. gallisepticum (Xia et al, ). AUC 0‐24hr /MIC ratio of “in‐water” and “in‐feed” groups were 141 and 111, respectively, which could totally eradicate the organisms in plasma.…”

“…The causative organism, M. gallisepticum, is highly sensitive to quinolones, tetracyclines, macrolides, and tiamulin (Arzey & Arzey, 1992;Yang et al 2016;Yang, Sun, Zhao, Wang, & Wang, 2015). Tiamulin, a pleuromutilin derivative, is an ideal anti-mycoplasmal drug, due to its distinct advantages such as relatively high cure rate, very low "minimum inhibitory concentration" (MIC), least resistance development, and shorter withdrawal period (Islam, Klein, & Burch, 2009;Xia et al, 2016), and its use is approved in India.…”

“…The disposition kinetics of tiamulin in chicken has been demonstrated after administration through oral (directly into crop) (Laber & Schutze, 1977) and intramuscular route (Xia et al, 2016). However, in flock conditions, drugs are commonly administered by mixing with drinking water or feed.…”