Effect of milking frequency and dosing interval on the pharmacokinetics of cephapirin after intramammary infusion in lactating dairy cows

Abstract

The objective was to determine the effect of milking frequency and dosing interval on pharmacokinetics of cephapirin after intramammary infusion. Six healthy Holstein cows were administered cephapirin (200 mg) into 1 rear mammary gland after each of 2 milkings. Cows were milked twice daily (2x) and dosed at a 12-h interval or 3 times daily (3x) and dosed at an 8- or 16-h interval. A duplicated Latin square design allowed each cow to receive all 3 frequency-dose treatments, with intervening washout periods. Concentrations of cephapirin (CEPH) and desacetylcephapirin (DAC) in milk from the treated glands were determined at each milking after infusion using liquid chromatography-mass spectrometry. Data were fitted using 1- and 2-compartment pharmacokinetic models, as well as a noncompartmental model. Cephapirin was rapidly metabolized to DAC in the mammary gland, with DAC being the predominant agent in milk until 48 h after infusion. Pharmacokinetics of CEPH and DAC were similar for all treatment groups, with a 1-compartment model providing a better fit than a 2-compartment model in most instances. Milking frequency did not affect the length of time that milk CEPH concentration exceeded MIC(50) or MIC(90) values (the minimum inhibitory antimicrobial concentration needed to inhibit 50 or 90% of microbial activity, respectively) for common mastitis pathogens, except that cows milked 3x and dosed at a 16-h interval maintained inhibitory concentrations approximately 8 h longer than those dosed at an 8-h interval. Time for milk CEPH concentration to reach the FDA tolerance did not differ among treatment groups [mean +/- SD; 68 +/- 20, 66 +/- 22, and 57 +/- 18 h after last treatment for cows treated at 12, 16, and 8 h, respectively]. Mean residence time for CEPH in the mammary gland was linearly and negatively associated with the volume of milk produced. Calculated CEPH concentration in composite milk from all 4 mammary glands was below the FDA tolerance in all cows by 96 h after the last infusion, which is the labeled withholding time for the preparation used. Our findings suggest that this CEPH preparation, which is labeled for 2 doses 12 h apart, could be administered at a 16-h interval in herds milking 3x, with no significant effect on inhibitory concentrations in milk or withdrawal time; extended withdrawal times would be prudent for cows with very low milk production. Further investigation is needed to determine if milking frequency affects CEPH pharmacokinetics in cows with clinical mastitis.

Pharmacokinetics in foremilk and antimicrobial activity of cephapirin following intramammary administration in healthy andStaphylococcus aureus-infected cows

“…hand-collected milk before the application of the milking device) and this could have influenced the results. In the present study, cephapirin concentrations in milk samples were markedly higher than those reported by Stockler et al (2009aStockler et al ( , 2009b. In foremilk antimicrobial concentrations could be twice as high as in other milk fractions.…”

Elimination of erythromycin in milk after intramammary administration in cows with specific mastitis: relation to dose, milking frequency and udder health

“…A similar observation was recorded by Nouws and Ziv (1979) who found that following single intramammary administration of 1,200 mg of erythromycin in lactating cows, drug was well distributed in the various body tissues such as liver, kidney and muscles. Further, the passage rates to systemic circulation seem to vary with the antibiotic, e.g., oxacillin: 64% to 82% (Bansal et al 2003) and cephapirin: 30% to 40% (Stockler et al 2009). Knappstein et al (2006) expressed this drug disposition pattern in terms of the milk to serum concentration ratios; great differences were shown to occur between antibiotics and in relation to the udder health.…”

“…The rate of elimination of drug from udder is important; in many cases, residues were detected in milk after the recommended longest withdrawal times (Romnee 1995). Many factors, e.g., physicochemical properties of drug, volume of drug infused, udder health status, and milking frequency can alter the rate and extent of drug elimination in milk following intramammary administration (Gehring and Smith 2006;Knappstein et al 2006;Stockler et al 2009). The withdrawal time decreased with the increasing milking frequency, e.g., cefquinome and procaine penicillin, or did not show any change, e.g., cloxacillin (Knappstein et al 2006).…”

Pharmacokinetics and pharmacodynamics of a novel amoxicillin/sulbactam/prednisolone intramammary infusion in lactating cows after repeated administrations

“…According to Whitten et al and Stockler et al, milk composition and milk drug concentrations differed between fore-milk, pooled milk and milk strippings (Stockler et al 2009;Whitten et al 2012). In this study, fore-milk was collected from a single intramammary quarter to study the PK-PD of CAIMM in lactating cows.…”

“…In this study, fore-milk was collected from a single intramammary quarter to study the PK-PD of CAIMM in lactating cows. However, pooled milking samples are inappropriate for estimation of milk drug concentrations needed for evaluation of efficacy (Stockler et al 2009). Pharmaceutical products which are administered to food producing animals have the potential of leading to the introduction of drug residues into the human food chain.…”