Pharmacokinetic and pharmacodynamic properties of gamithromycin in turkey poults with respect to Ornithobacterium rhinotracheale

Abstract

The macrolide gamithromycin (GAM) has the ability to accumulate in tissues of the respiratory tract. Consequently, GAM might be a suitable antibiotic to treat bacterial respiratory infections in poultry, such as Ornithobacterium rhinotracheale. As O. rhinotracheale infections are common in turkey flocks, the aim of this study was to determine the pharmacokinetic (PK) parameters of GAM in plasma, lung tissue, and pulmonary epithelial lining fluid (PELF) of turkeys and to correlate them with pharmacodynamic (PD) characteristics (PK/PD). The animal experiment was performed with 64 turkeys, which received either a subcutaneous (SC, n=32) or an oral (PO, n=32) bolus of 6 mg GAM/kg body weight (BW). GAM concentrations in plasma, lung tissue, and PELF were measured at different time points post administration (p.a.), and PK characteristics were determined using non-compartmental modeling. The maximum plasma concentration after PO administration was ten-fold lower than after SC injection (0.087 and 0.89 μg/mL, respectively), whereas there was no difference in lung concentrations between both routes of administration. However, lung concentrations at day 1 p.a. were significantly higher than plasma levels for both routes of administration (2.22 and 3.66 μg/g for PO and SC, respectively). Consequently, lung/plasma ratios were high, up to 50 and 80 after PO and SC administration, respectively. GAM could not be detected in PELF, although this might be attributed to the collection method of PELF in birds. The GAM minimum inhibitory concentration (MIC) was determined for 38 O. rhinotracheale strains; MIC50 and MIC90 were 2 and >32 μg/mL, respectively. PK/PD correlation for lung tissue demonstrated that the time above the MIC90 of the susceptible population (2 μg/mL) was 1 day after PO bolus and 3.5 days after SC administration. The area under the curve (AUClast)/MIC ratios for lung tissue after SC and PO administration were 233 and 90, respectively. To conclude, GAM is highly distributed to lung tissue in turkey poults, suggesting that it has the potential to be used to treat respiratory infections such as O. rhinotracheale.

Efficacy of gamithromycin againstOrnithobacterium rhinotrachealein turkey poults pre-infected with avian metapneumovirus

“…An earlier study demonstrated different plasma PK properties of GAM between these routes of administration in turkeys, mainly with respect to the bioavailability. There is a lower absorption of the antimicrobial after PO administration compared to SC, with a relative bioavailability of GAM after PO administration of only 25% (Watteyn et al, 2015). In the current study, a slightly improved clinical recovery was observed after SC administration of GAM, compared to the PO administration.…”

“…In the current study, a slightly improved clinical recovery was observed after SC administration of GAM, compared to the PO administration. This can be explained by the PK parameters in lung tissue, since a difference in mean maximum concentration obtained after single SC and PO administration of the same dose was seen in lung tissue, that is, 3.66 and 2.22 µg/g after SC and PO administration, respectively (Watteyn et al, 2015). Moreover, the mean elimination half-life of GAM in lung tissue was 92.6 and 59.9 h after SC and PO administration, respectively, which implies a longer availability of the drug in lung tissue after SC dosing.…”

“…The minimum inhibitory concentration (MIC) of GAM against this strain is 0.5 µg/ml (Watteyn et al, 2015). LMG 9086 T was serotyped as type A in an agar gel precipitation test, kindly performed by Professor Hafez (Institute of Poultry Diseases, Free University of Berlin, Germany; Hafez & Sting, 1999).…”

“…Hence, antimicrobial drug therapy is most frequently applied, but the sensitivity of O. rhinotracheale to antibiotics is strain dependent and geography related. For example, most turkey isolates from Germany and the Netherlands are resistant to enrofloxacin, while 98% of isolates from France and 71% of isolates from Belgium are susceptible (Devriese et al, 1995;Dudouyt et al, 1995;Devriese et al, 2001;Hafez & Vandamme, 2011;Schwarz et al, 2012;Watteyn et al, 2015). The efficacy of antimicrobial therapy via the drinking water has already been tested for different antimicrobial drugs using an O. rhinotracheale infection model in turkeys.…”

“…At present, it is only registered for use in cattle to treat bovine respiratory disease. GAM is a long-acting antibiotic with accumulation in lung tissue as supported by its extended elimination half-life and large volume of distribution in several animal species, including turkeys (Huang, 2010;Giguère et al, 2011;Watteyn et al, 2013;Wyns et al, 2014;Watteyn et al, 2015).…”