Clinical pharmacology of mecillinam in calves

Soback, S., Bor, A., Paz, R. & Ziv, G. Clinical pharmacology of mecillinam in calves. J. vet. Pharmacol. Therap. 9, 385–393. The minimal inhibitory concentrations (MIC) of mecillinam, a novel β‐amidinopenicillanic acid derivative with unusual activity against Gram‐negative bacteria, were compared with the MIC of cephazolin, cephalothin, amoxycillin, oxytetracycline, chloramphenicol, dihydrostreptomycin, neomycin, kanamycin, gentamicin and sulfadoxin/trimethoprim (TMP) against pathogenic Gram‐negative bacteria recovered from neonatal calves. The MIC values of mecillinam ranged between 0.05 μg/ml and 12.5 μg/ml, and the MIC90values were 1.56 μg/ml and 3.12 μg/ml. The activity of mecillinam against salmonella,Escherichia coliandPasteurella multocidawas similar to or slightly greater than the activities of the first‐generation cephalosporins, gentamicin and sulfa/TMP. Mecillinam concentrations ≤ 3.12 μg/ml inhibited the growth of the majority of isolates which were resistant (MIC90 > 100 μg/ml) to the other antibiotics studied. The minimum bactericidal concentration (MBC) values of mecillinam were two‐ to three‐fold higher than the MIC values. The two‐compartment open model was appropriate for the analysis of serum mecillinam concentrations measured after intravenous administration. The distribution half‐life (t½α) was 11.7 min, the elimination half‐life (t½β) was 53.3 min, and the apparent volume of distribution (Vd(area)) and the distribution volume at steady state (Vd(ss)) were 0.568 and 0.896 1/kg, respectively. The drug was quickly absorbed after intramuscular (i.m.) injection; peak serum drug concentrations were directly related to the dose administered. They were obtained 30 min after treatment and the i.m.t½was approximately 65 min. An aqueous solution of probenecid administered i.m. at 40 mg/kg together with mecillinam resulted in peak serum drug concentrations which were nearly twice the peak observed after the i.m. administration of mecillinam alone and during the first 2 h after treatment the i.m.t½of mecillinam was 110 min. Mecillinam was approximately 25% bound to serum proteins. The duration of free drug concentrations in the tissues after i.m. administration were estimated from the serum drug level data,Vd(ss),t½and the MIC. Computations showed that mecillinam should be administered at 16 mg/kg every 5 h, and with the co‐administration of probenecid the dosage interval can be extended to 6.5 h, in order to maintain effective drug concentrations potentially sufficient to inhibit 90% of the salmonella,E. coli, andP. multocidaisolates in tissues.