Clinical pharmacology of mecillinam in calves

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Abstract
The minimal inhibitory concentrations (MIC) of mecillinam, a novel .beta.-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 .mu.g/ml and 12.5 .mu.g/ml, and the MIC90 values were 1.56 .mu.g/ml and 3.12 .mu.g/ml. The activity of mecillinam against salmonella, Escherichia coli and Pasteurella multocida was similar to or slightly greater than the activities of the first-generation cephalosporins, gentamicin and sulfa/TMP. Mecillinam concentrations .ltoreq. 3.12 .mu.g/ml inhibited the growth of the majority of isolates which were resistant (MIC90 > 100 .mu.g/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 (t1/2.alpha.) was 11.7 min. the elimination half-life (t1/2.beta.) 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 l/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 abtained 30 min after treatment and the i.m. t1/2 was 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. t1/2 of 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), t1/2, and 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, and P. multocida isolates in tissues.

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