L. FULTZ, S. GIGUÈRE*, L. J. BERGHAUS, G. S. GROVER† and D. A. MERRITT†
Department of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, USA † Metabolism and Safety, Zoetis, Kalamazoo, Michigan, USA.
Summary
Reasons for performing study:
Administration of ceftiofur sodium via nebulisation has been recommended for the treatment of bronchopneumonia in horses, despite the lack of pharmacokinetic and safety data.
Objectives:
To compare concentrations of desfuroylceftiofur acetamide (DCA) in plasma and pulmonary epithelial lining fluid (PELF) of foals after nebulisation or i.m. administration of ceftiofur sodium and to determine if nebulisation of ceftiofur sodium induces airway inflammation.
Study design:
Randomised experimental study.
Methods:
Six weanling foals received ceftiofur sodium (2.2 mg/kg bwt daily for 5 doses) by the i.m. route and 6 foals received the same dose by nebulisation. Concentrations of DCA in plasma and PELF were measured after Doses 1 and 5, and differential cell counts were performed on bronchoalveolar lavage samples obtained after Dose 5.
Results:
Foals receiving ceftiofur sodium via nebulisation had significantly lower peak concentrations (0.15 ± 0.12 vs. 6.15 ± 0.75 mg/l) and area under the curve (1.26 ± 0.96 vs. 37.63 ± 4.01 mg•h/l) in plasma compared with those receiving the drug by the i.m. route. In contrast, foals receiving ceftiofur sodium via nebulisation had significantly higher peak concentrations (4.52 ± 2.91 vs. 0.73 ± 0.73 mg/l) and area under the curve (24.14 ± 14.09 vs. 5.91 ± 3.28 mg•h/l) in PELF compared with those receiving the drug by the i.m. route. Cell concentration and differential cell count in bronchoalveolar lavage fluid of foals nebulised with ceftiofur sodium were not significantly different from those of foals nebulised with saline.
Conclusions:
Administration of ceftiofur sodium via nebulisation is well tolerated and DCA concentrations in PELF remain above the minimum inhibitory concentration of the drug required to inhibit the growth of 90% of Streptococcus zooepidemicus for approximately 24 h after administration. Nebulised ceftiofur sodium warrants further investigation for the treatment of bacterial infections of the lower respiratory tract in horses.
Introduction
Pneumonia is the leading cause of morbidity and mortality in foals in the USA [1]. The mortality rate has been estimated to be about 6% across the USA [1]. It is likely, however, that the true incidence of infection is much higher and that many cases of infection go unrecognised. Indeed, careful weekly physical examination of more than 200 Thoroughbred foals on 10 farms demonstrated an average morbidity from bacterial infection of the distal respiratory tract of 82% [2]. Streptococcus equi ssp. zooepidemicus (S. zooepidemicus) is by far the most common bacterial pathogen isolated from pneumonia in older foals [3]. A variety of other bacterial pathogens such as Rhodococcus equi, Klebsiella spp., Escherichia coli, Pasteurella spp., Bordetella bronchiseptica and Actinobacillus spp. may be isolated as primary pathogens, or may occur in association with S. zooepidemicus [3].
Ceftiofur sodium is a third-generation cephalosporin approved for the treatment of lower respiratory tract infections caused by susceptible strains of S. zooepidemicus in horses. Once administered parenterally, ceftiofur is rapidly metabolised into desfuroylceftiofur [4]. The in vitro activity of desfuroylceftiofur against common Gram-negative pathogens and streptococci is almost identical to that of ceftiofur [5]. With the exception of R. equi, ceftiofur exerts good in vitro activity against all the pathogens associated with pneumonia in foals [6]. The outcome of respiratory tract infection is more closely associated with antimicrobial drug concentrations within the airways than with concentrations in serum [7]. Measurement of drug concentration in pulmonary epithelial lining fluid (PELF) is a widely used method to estimate antimicrobial concentrations at the site of infection for antimicrobials intended to treat lower respiratory tract infections caused by extracellular pathogens [8]. Nebulisation of antimicrobial agents has been proposed as a method to increase drug concentrations in the lungs while minimising systemic concentrations and potential toxicity. In calves inoculated intrabronchially with Mannheimia haemolytica, nebulised ceftiofur sodium was more effective at preventing mortality than i.m. administration of the same drug [9].
As a basis for this study, we hypothesised that nebulised ceftiofur sodium would achieve higher concentrations of desfuroylceftiofur acetamide (DCA) in PELF than i.m. administration. The objectives of this study were to determine and compare concentrations of DCA in plasma and PELF of foals after nebulisation or i.m. administration of ceftiofur sodium and to determine if nebulisation of ceftiofur sodium induces airway inflammation in weanling foals.
