Exposure to benzylpenicillin after different dosage regimens in growing pigs

Björn Bengtsson,Märit Pringle,Per Wallgren,Marie Sjölund,Carl Ekstrand,Ulf Bondesson

doi:10.1186/s13028-020-00552-0

Abstract

BackgroundPenicillin is important for treatment of pigs, but data on its absorption and disposition in pigs are sparse. This is reflected by the variation in recommended dosages in the literature. Inadequate dosage may lead to treatment failure and selection of resistant bacteria. To optimize treatment regimens, plasma exposure to benzylpenicillin for two sustained release formulations of procaine benzylpenicillin for intramuscular administration was studied in growing pigs by means of tandem mass spectrometry (UPLC–MS/MS). One formulation was an aqueous suspension, Ethacilin® vet (ETH), and the other an oily suspension, Ultrapen vet (UPA). Benzylpenicillin exposure after intravenous administration of potassium benzylpenicillin was also explored. Exposure profiles were first studied after single administrations of the approved dosages in healthy pigs and then after repeated administration of different dosages in pigs inoculated intranasally with an Actinobacillus pleuropneumoniae serotype 2 strain.ResultsAfter intravenous administration of benzylpenicillin (n = 6), maximum plasma concentration (Cmax), 1860–9318 µg/L, was observed after 15 min. At four h, plasma concentrations decreased to 15–76 µg/L. After intramuscular administration of ETH (n = 6) Cmax, 1000–4270 µg/L, was observed within one h (tmax) in 5 pigs but at four h in one pig. Cmax for UPA (n = 6), 910–3220 µg/L, was observed within one h in three pigs, but at four or 24 h in three pigs. For both ETH and UPA, the terminal phase was characterized by slow decline compared with intravenous administration. Repeated administration of different dosages of ETH and UPA in pigs inoculated with A. pleuropneumoniae (n = 54) showed that the approved dose for UPA (30 mg/kg, qd) but not for ETH (20 mg/kg, qd) gave adequate plasma exposure for bacteria with a penicillin MIC of 500 µg/L. However, more frequent dosing of ETH (bid) or increased dosage gave an adequate exposure.ConclusionsThe approved dosage of ETH provided insufficient plasma exposure for adequate therapy of infections caused by A. pleuropneumoniae or other bacteria with a penicillin MIC of 500 µg/L. More frequent ETH dosing (bid) or an increased dosage would improve exposure. The approved dosage of UPA however provided adequate exposure.

Highlights

Penicillin is important for treatment of pigs, but data on its absorption and disposition in pigs are sparse
Single dose exposure to benzylpenicillin after IV and IM dosing to healthy pigs (Part I) After IV administration of Bensylpenicillin Meda (BPM) 10 or 20 mg/kg, plasma concentrations decreased from 1860–9318 μg/L at 0.25 h to 15–76 μg/L at 4 h (2–3 orders of magnitude)
Benzylpenicillin plasma concentration was lower than the limit of quantification (10 μg/L) twelve h after administration in four pigs and after 24 h in the remaining two pigs

Summary

Introduction

Penicillin is important for treatment of pigs, but data on its absorption and disposition in pigs are sparse This is reflected by the variation in recommended dosages in the literature. Benzylpenicillin dominates antibiotic use for pigs in Sweden, data on basic pharmacokinetic and pharmacodynamic properties (PK/PD) of penicillin in pigs are sparse and emanate from studies performed in healthy animals [11,12,13]. This is reflected by the variation in recommended dosages in the literature [11,12,13]. Oil-based formulations of procaine benzylpenicillin are considered to prolong absorption time even further [14]

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