Serum chloramphenicol levels and the intramuscular bioavailability of several parenteral formulations of chloramphenicol in ruminants

Abstract

Summary Serum chloramphenicol concentrations were determined by microbiological and chemical assay methods in cows, ewes, and goats treated parenterally with seven different veterinary parenteral chloramphenicol products, including the water soluble sodium succinate ester of chloramphenicol and solutions of 20%, 25% and 50% of chloramphenicol base in various organic solvents. Serum drug concentrations were analyzed for the effect of product formulation differences, dosage, whether the drug was administered i.m. at a single body site or to two sites, and the method of assay, on the absorption from the injection site, peak drug levels, and the persistence in serum of effective concentrations of the drug i.e. 5 to 10 ug / ml. Although differences were observed among the 6 products containing chloramphenicol base in respect to absorption rate and peak serum drug levels, and although these differences significantly influenced the persistence of microbiologically-active serum drug concentrations at the level of ≥ 10 μg / ml, they did not at the level of ≥ 5 μg / ml. In the animal species examined, injections given at 2 sites appeared to influence the duration of predetermined serum drug levels more than the differences among the products in respect of the absorption and elimination rates from serum, the peak serum concentrations, and the dose. The shapes of the concentration-to-time curves in cows and ewes injected with the same dose of a given product were essentially the same, but they were different in goats. Serum chloramphenicol concentrations measured chemically after treatment with chloramphenicol base were 20% to 46% higher than those measured microbiologically. For 60 minutes after the sodium succinate ester had been administered i.v. and i.m. to ewes, the chemically determined chloramphenicol levels were more than twice as high as the respective concentrations determined by microbiological assay, but thereafter, the magnitude of those differences was not greater than observed after treatment with chloramphenicol base. Intramuscular bioavailability of the products containing chloramphenicol base injected at 2 sites was rather poor (51% to 80.5%ofthe dose) and even lower values were calculated after injection at a single site. Results are briefly discussed of the effect of dosage form on the persistence of microbiologically effective serum drug levels. A dose of at least 50 mg / kg to be administered i.m. at two sites are essential prerequisits for chloramphenicol therapy in ruminants.

SÜT ÖRNEKLERİNDE KLORAMFENİKOL KALıNTıLARı

“…N itekim besin değeri olan hayvanlarda sağıtım amacıyla ilaç uygulaması yapıldığı sürece tüketilebilen dokulardaki kloramfenikcl derişimi 2.67-7.03 ppm arasına yükselirken ilaç uygulaması durdurulduktan 72 saat sonra da böyle dokularda 0.162-1.43 ppm derişimlerinde kloramfenikol kalmtısma rastlanabilmektedir (7). Sağınal hayvanlam sistemik olarak uygulanan kloramfenikol kan derişimIerinin~~50'sinden daha yüksek oranlarda (2-6 ppm) süte geçebjl-diği gibi, akut mastitis olgularında parenteral veya meme içi yollardan ilaç uygulandığında süte geçen klöranıfenikol kirliliği katlamalı olarak artabilmek tedii- (20,21,29). Aynı şekilde yumurta tavuklarına yem veya su içerisinde sağıtım dozlarında verilen kloramfenikolün 4.günden itibaren 8000 ppm'e ulaşan boyutlarda yumurtaya geçerek, ancak i5.…”

“…Bu kapsamda olmak üzere, A.B.D. 'inde kloramfenikolün besin değeri olan hayvanlarda kullanımı tümüyle yasaklanırken (1,4), Avrupa Ekonomik Topluluğu başta olmak üzere, diğer çok sayıdaki gelişmiş ülke ve Dünya Sağlık Örgütünce aynı antibiyotiğin yanlızca yetkili veteriner hekimlerce uygulanmasını sağla-yan ve hayvansal besinlerdeki artıkları için sıfır tolerans limitini öngö-ren yasal kısıtlamalar getirilmiştir (8,12,19,21,22,23,32).…”

Pharmacological aspects of chloramphenicol administration by the intramammary route to lactating dairy cows

“…Although CM residues were not detected by microbiological assay, at the injection site 7 days after treatment, the drug was detected by chemical assay in several edible tissues 3 days post treatment (7,9). Several reasons were proposed for the slow, erratic, and incomplete absorption of CM from the i.m.…”

“…> 5 pg/ ml, are barely achieved with doses as high as 50 mg/ kg (2,3,9,10,11,14,15,17). Intramuscular injection of such products at two sites in the upper third of the neck seemed to increase peak serum CM concentrations slightly (9), but during the first 3 days after treatment CM concentrations at the injection site were rather high, regardless of whether the drug had been injected into a single site or two sites (8,9). Extensive damage of muscle tissue at the injection site, lasting at least 7 days, was commonly observed (5,8,9).…”

“…bioavailability of injectable veterinary products containing chloramphenicol base (CM) in adult ruminants is rather poor; serum drug levels of potential therapeutic value, i.e. > 5 pg/ ml, are barely achieved with doses as high as 50 mg/ kg (2,3,9,10,11,14,15,17). Intramuscular injection of such products at two sites in the upper third of the neck seemed to increase peak serum CM concentrations slightly (9), but during the first 3 days after treatment CM concentrations at the injection site were rather high, regardless of whether the drug had been injected into a single site or two sites (8,9).…”