Pharmacokinetics of tildipirosin in porcine plasma, lung tissue, and bronchial fluid and effects of test conditions on in vitro activity against reference strains and field isolates of Actinobacillus pleuropneumoniae

Abstract

Rose, M, Menge, M, Bohland, C, Zschiesche, E, Wilhelm, C, Kilp, S, Metz, W, Allan, M, Röpke, R, Nürnberger, M Pharmacokinetics of tildipirosin in porcine plasma, lung tissue, and bronchial fluid and effects of test conditions on in vitro activity against reference strains and field isolates of Actinobacillus pleuropneumoniae. J. vet. Pharmacol. Therap. 36, 140–153. The pharmacokinetics of tildipirosin (Zuprevo® 40 mg/mL solution for injection for pigs), a novel 16‐membered‐ring macrolide for the treatment for swine respiratory disease (SRD), was investigated in studies collecting blood plasma and postmortem samples of lung tissue and bronchial fluid (BF) from swine. In view of factors influencing the in vitro activity of macrolides, and for the interpretation of tildipirosin pharmacokinetics in relation to minimum inhibitory concentrations (MIC), additional experiments were conducted to study the effects of pH, carbon dioxide‐enriched atmosphere, buffers, and serum on tildipirosin MICs for various reference strains and Actinobacillus (A.) pleuropneumoniae field isolates. After single intramuscular (i.m.) injection at 4 mg/kg body weight, maximum plasma concentration (Cmax) was 0.9 μg/mL observed within 23 min (Tmax). Mean residence time from the time of dosing to the time of last measurable concentration (MRTlast) and terminal half‐life (T1/2) both were about 4 days. A dose–response relationship with no significant sex effect is observed for area under the plasma concentration–time curve from time 0 to the last sampling time with a quantifiable drug concentration (AUClast) over the range of doses up to 6 mg/kg. However, linear dose proportionality could not be proven with statistical methods. The time–concentration profile of tildipirosin in BF and lung far exceeded that in blood plasma. In lung, tildipirosin concentrations reached 3.1 μg/g at 2 h, peaked at 4.3 μg/g at day 1, and slowly declined to 0.8 μg/g at day 17. In BF, tildipirosin levels were 14.3, 7.0, and 6.5 μg/g at days 5, 10, and 14. T1/2 in lung was ∼7 days. Tildipirosin is rapidly and extensively distributed to the respiratory tract followed by slow elimination. Culture media pH and carbon dioxide‐enriched atmosphere (CO2‐EA) had a marked impact on in vitro activity of tildipirosin in reference strains of various rapidly growing aerobic and fastidious bacteria including Histophilus (H.) somni ATCC 700025 and A. pleuropneumoniae ATCC 27090. For A. pleuropneumoniae ATCC 27090 testing conditions without CO2‐EA resulted in reduced acidification of culture media pH and a reduction in the minimum inhibitory concentrations compared to standard in vitro test conditions by 2 log2 dilution steps (4‐fold) from 8 to 2 μg/mL. Supplementary buffering of standard culture media resulted in a reduction in the A. pleuropneumoniae (n = 8) MIC range by 4 log2 dilution steps (16‐fold) from 8–16 to 0.5–1 μg/mL. Incremental supplementation of culture media with 50% serum resulted in noticeable shifts to lower minimum or maximum MICs by at least 2 log2 dilution steps (≥4‐...

A large potentiation effect of serum on the in vitro potency of tulathromycin against Mannheimia haemolytica and Pasteurella multocida

“…More recently, Rose et al . (Rose et al ., ) reported that, for the novel veterinary macrolide tildipirosin, the addition to broth of increasing amounts of serum (from 5 to 50%) progressively reduced the MIC for six bacterial species harvested from pigs. Interestingly, MIC ratios for pure broth:broth supplemented with 50% serum were highest for S. aureus (8‐64:1) and least for M. haemolytica (2‐4:1) and P. multocida (1–2:1).…”

Pharmacokinetics of tildipirosin in beagle dogs

“…Almost without exception, TD, like most macrolides, has been classified as time‐dependent killing drugs and therefore is best described by the PK/PD parameter time above MIC ( T > MIC ) for newer macrolides appears to be the best correlate with therapeutic effect. For example, a previous study reported that MIC 90 of TD for Actinobacillus pleuropneumoniae in pigs was 2,000 ng/ml (Rose et al., ). The concentration of tildipirosin was approximately 100 times higher in porcine lung than plasma during days 1–14 after i.m.…”

“…The concentration of tildipirosin was approximately 100 times higher in porcine lung than plasma during days 1–14 after i.m. administration (Rose et al., ). Although in the current study, the C max of TD (approximately 1,000 ng/ml) in canine plasma after 4 mg/kg i.m.…”

In vivo porcine lipopolysaccharide inflammation models to study immunomodulation of drugs

“…Bacteria, such as Actinobacillus pleuropneumoniae, Pasteurella multocida, Haemophilus parasuis and Mycoplasma hyopneumoniae are major pathogens involved in swine respiratory disease (SRD). Escherichia coli on the other hand, is one of the most important causes of postweaning diarrhea in pigs (Fairbrother et al, 2005;Rose et al, 2013).…”