Clinical pharmacology of mecillinam in calves

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 microgram/ml and 12.5 micrograms/ml, and the MIC90 values were 1.56 micrograms/ml and 3.12 micrograms/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 less than or equal to 3.12 micrograms/ml inhibited the growth of the majority of isolates which were resistant (MIC90 greater than 100 micrograms/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 obtained 30 min after treatment and the i.m. t1/2 was approximately 65 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical pharmacokinetics of five oral cephalosporins in calves

The minimal inhibitory concentrations (MIC) of cephalexin, cephradine, cefaclor, cefatrizine and cefadroxil for Salmonella species, Escherichia coli and Pasteurella multocida isolated previously from young calves were determined. The MIC90 values for cephalexin, cephradine and cefadroxil ranged between 3.12 micrograms ml-1 and 12.5 micrograms ml-1, whereas those of cefatrizine and cefaclor were 3.12 micrograms ml-1 and 0.78 microgram ml-1, respectively. Each drug was administered intravenously and orally to groups of pre-ruminating calves and orally to early ruminating calves. Although the pharmacokinetic characteristics of the drugs after intravenous injection were similar to other beta-lactam antibiotics, significant differences between the cephalosporins examined were found in respect of certain kinetic parameters. The drugs showed rapid absorption into the systemic circulation after oral administration to pre-ruminating calves but the elimination half-life values (t1/2 beta) varied between three hours (cefaclor and cefadroxil) and nine hours (cefatrizine). The bioavailability of the drugs was about 35 per cent of the administered dose. Co-administration of probenecid with each antibiotic caused a twofold or greater increase in peak serum drug concentrations (Cmax) but the effect on t1/2 beta was variable. Cephalexin, cephradine and cefaclor given to the ruminating calves resulted in very low serum or plasma concentrations and their use should be restricted to younger calves. Cefadroxil was found to give the highest serum concentrations in this age group but had significantly lower bioavailability when compared with the unweaned calves. Provisional oral dosage regimens were computed for each cephalosporin on the basis of the MIC data and the kinetic parameters derived from intravenous and oral drug administration.     

Pharmacokinetics of single doses of cefoxitin given by the intravenous and intramuscular routes to unweaned calves

Cefoxitin pharmacokinetics and bioavailability were studied in unweaned calves. The antibiotic was administered to nine calves intravenously (i.v.), to seven calves intramuscularly (i.m.) at 20 mg/kg and to eight calves i.m. at 20 mg/kg together with probenecid at 40 mg/kg. Serum concentration versus time data were analysed using statistical moment theory (SMT). The i.v. data were also fitted by a linear, open two-compartment model. The elimination half-life (t1/2) was 66.9 +/- 6.9 min (mean +/- SD) after i.v. and 81.0 +/- 10.9 min after i.m. administration. The t1/2 increased to 125.5 +/- 15.6 min by the co-administration of probenecid. The total body clearance (ClT) was 4.88 +/- 1.71 ml/min/kg and the volume of distribution (Vss) 0.3187 +/- 0.0950 l/kg. The mean residence time (MRT) was 68.2 +/- 12.3 min after i.v. and 118.6 +/- 16.8 min after i.m. injection and increased to 211.5 +/- 16.8 min by the co-administration of probenecid. The mean absorption time (MAT) was 50.6 min and the estimated bioavailability (F) of cefoxitin after i.m. administration was 73.8%. The cefoxitin protein binding ranged from 55.0 to 42.0% at concentrations from 2 to 50 micrograms/ml. The MIC90 values for cefoxitin were 6.25 micrograms/ml for E. coli and Salmonella group B isolates, 3.13 micrograms/ml for Salmonella group C and D and Pasteurella multocida. There were no statistically significant differences between the pharmacokinetic parameters calculated by SMT or compartmental analysis. SMT provided an additional independent parameter, the MRT, for characterization of drug disposition kinetics.     

Clinical pharmacology of apramycin in calves

The minimal inhibitory concentrations (MIC) of apramycin, a unique aminocyclitol antibiotic, were compared with the MIC of dihydrostreptomycin and neomycin for 323 Salmonella, 178 Escherichia coli and twenty-six Pasteurella multocida isolates recovered from newborn calves. Apramycin exhibited better in vitro anti-bacterial activity than dihydrostreptomycin and neomycin; isolates of Salmonella group B and E. coli resistant to the latter were sensitive to apramycin. The two-compartment open model was appropriate for the analysis of serum apramycin concentrations measured after intravenous (i.v.) administration. The distribution half-life (t 1/2 alpha) of the drug was 28 min, the elimination half-life (t 1/2 beta) was 4.4 h, and the apparent volume of distribution (V1) and the distribution volume at steady state (Vdss) were 0.34 and 0.71 l/kg, respectively. The drug was quickly and completely absorbed after intramuscular (i.m.) injection; peak serum drug concentrations were directly related to the dose administered, they were obtained 1-2 h after treatment and the i.m. t 1/2 beta was 5 h. There was no evidence of drug accumulation in the serum after three daily i.m. injections at 20 mg/kg. More than 95% of the i.v. and i.m. doses were recovered in the urine within 96 h post-treatment but the cumulative percentage of drug recovery in the urine after oral treatment was 11%. The durations of free drug concentrations in the tissues after i.v. and i.m. injection were estimated from the serum drug level data, percent of serum protein binding, Vdss, t 1/2 beta, and the MIC. Computations showed that apramycin should be administered i.m. at 20 mg/kg every 24 h in order to maintain in tissues potentially effective drug concentrations sufficient to inhibit 50% of the Salmonella, E. coli, and P. multocida isolates, and at 12-h intervals to inhibit 90% of the isolates.     

Probenecid effect on cefuroxime pharmacokinetics in calves

Cefuroxime pharmacokinetics were studied in unweaned calves. The antibiotic was administered at 10 mg/kg to six calves i.v., to 12 calves i.m. and to ten of the previous 12 calves i.m. at 10 mg/kg together with probenecid at 40 mg/kg. Intramuscular doses of cefuroxime alone at 20 mg/kg were given to seven calves; to five of these calves cefuroxime was also given together with probenecid at 40 mg/kg and at 80 mg/kg. The serum concentration-time data were analyzed using statistical moment theory (SMT). The elimination half-life (t1/2) was 69.2 min (harmonic mean) after i.v. and 64.8 min and 64.9 min following i.m. administration of the lower and higher dose, respectively. Co-administration of probenecid did not affect the t1/2. The mean residence time (MRT) was 80.9 +/- 23.5 min (mean +/- SD) after i.v. and 117.8 +/- 9.3 min and 117.7 +/- 5.4 min after i.m. administration of cefuroxime at 10 and 20 mg/kg, respectively. The MRTi.m. following administration of cefuroxime at 10 mg/kg together with probenecid at 40 mg/kg was 140.0 +/- 8.8 min. The MRTi.m. values were 132.8 +/- 2.3 min and 150.8 +/- 5.1 min after cefuroxime was given at 20 mg/kg together with probenecid at 40 mg/kg or 80 mg/kg, respectively. The total body clearance (ClT) was 3.56 +/- 1.11 ml/min/kg and the volume of distribution at steady state (Vd(ss] 0.270 +/- 0.051 l/kg. The MIC90 values of cefuroxime were 16 micrograms/ml for E. coli and Salmonella isolates, 0.5 microgram/ml for Pasteurella multocida and 2.0 micrograms/ml for P. haemolytica.     

Clinical pharmacology of cefixime in unweaned calves

Cefixime is a unique third-generation oral cephalosporin. Its in vitro activity and pharmacokinetic properties have been studied to assess its potential for use in the therapy of newborn calf infections due to gram-negative bacteria. The minimum inhibitory concentrations of cefixime for 90% (MIC₅₀) of field isolates of Escherichia coli. Salmonella and Pasteurella were 0.10–0.40 μg/mL. The serum disposition kinetics of cefixime following intravenous and oral administration was evaluated. The elimination half-life of cefixime after intravenous and oral administration was 3.5–4.0 h, the steady-state volume of distribution was 0.34 L/kg and approximately 90% of the drug was bound to serum proteins. Oral absorption was comparatively slow and bioavailability values for single 5 mg/kg doses were 20.2% after the administration of 200 mg of cefixime in capsules, 28.3% after dosing an aqueous solution of cefixime and 35.7% after fasted calves received the solution of cefixime. Mean serum drug concentrations 12 h after the cefixime solution was administered orally (5 mg/kg) were 1.05 μg/mL for the milk-fed calves and 1.76 μg/mL for the fasted calves. Computations showed that mean free drug concentrations equal to the MIC₅₀ of the drug for gram-negative pathogens associated with newborn calf infections can be maintained in tissues by multiple treatments at 5 mg/kg every 12 h or 10 mg/kg every 24 h.     

Minimum inhibitory concentrations of tulathromycin against respiratory bacterial pathogens isolated from clinical cases in European cattle and swine and variability arising from changes in in vitro methodology

The in vitro activity of tulathromycin was evaluated against common bovine and porcine respiratory pathogens collected from outbreaks of clinical disease across eight European countries from 1998 to 2001. Minimum inhibitory concentrations (MICs) for one isolate of each bacterial species from each outbreak were determined using a broth microdilution technique. The lowest concentrations inhibiting the growth of 90% of isolates (MIC90) for tulathromycin were 2 microg/ml for Mannheimia (Pasteurella) haemolytica, 1 microg/ml for Pasteurella multocida (bovine), and 2 microg/ml for Pasteurella multocida (porcine) and ranged from 0.5 to 4 microg/ml for Histophilus somni (Haemophilus somnus) and from 4 to 16 microg/ml for Actinobacillus pleuropneumoniae. Isolates were retested in the presence of serum. The activity of tulathromycin against fastidious organisms was affected by culture conditions, and MICs were reduced in the presence of serum.     

Apramycin: minimal inhibitory concentrations for avian Escherichia coli and serum levels after intramuscular injection in turkeys

The minimal inhibitory concentrations (MIC) of apramycin, a unique aminocyclitol antibiotic, for 100 Escherichia coli isolates recovered from clinical cases of avian colibacillosis were determined using the agar dilution method. All isolates were inhibited at apramycin concentration of 8.0 micrograms/ml; 90 and 50% of the isolates were inhibited at 6.6 and 3.4 micrograms/ml, respectively. A commercial injectable product containing 200 mg apramycin/ml was administered intramuscularly (i.m.) to groups of 6- and 12-week-old turkeys at 10, 15 and 20 mg/kg. Apramycin was quickly absorbed from the i.m. injection site. Mean peak serum drug concentrations were reached 1 h after treatment and were 19.5, 27.5 and 36.0 micrograms/ml, respectively. The serum elimination half-life (t 1/2) of the drug ranged between 1.75 h for the 10 mg/kg dose and 2.5 h for the 20 mg/kg dose. Very low concentrations of the drug were found 24 h after treatment. Duration of serum apramycin concentrations in relation to the MIC, dose, and age of birds was determined.     

Pharmacokinetics of single doses of cefoperazone given by the intravenous and intramuscular routes to unweaned calves

Cefoperazone pharmacokinetics were studied in unweaned calves. The antibiotic was administered to 10 calves intravenously, to eight calves intramuscularly at 20 mg kg-1 and to 10 calves intramuscularly at 20 mg kg-1 together with probenecid at 40 mg kg-1. Serum concentration versus time data were analysed by non-compartmental methods based on the statistical moment theory. The intravenous data were also fitted by a linear, open two-compartment model. The terminal halflife of cefoperazone was 127.9 +/- 28.2 min (mean +/- SD) after intravenous and 136.9 +/- 19.6 min after intramuscular administration. The t1/2 was increased to 257.3 +/- 127.3 min by the co-administration of probenecid. The total body clearance was 8.16 +/- 1.60 ml min-1 kg-1 and the volume of distribution at steady state was 0.713 +/- 0.167 litre kg-1. The mean residence time values were 87.2 +/- 10.6 min after intravenous and 140.3 +/- 20.6 min after intramuscular injection and were increased to 264.5 +/- 99.8 min by the co-administration of probenecid. The estimated mean absorption time was 53.1 min and the estimated bioavailability after intramuscular administration was 76.3 per cent. The minimal inhibitory concentration (MIC90) values of cefoperazone ranged from 0.5 to 2 micrograms ml-1 for Escherichia coli, salmonella groups C, D and E and Pasteurella multocida isolates. Salmonella group B strains appeared to be highly resistant to cefoperazone with MIC90 greater than 32 micrograms ml-1. There were no significant differences between the pharmacokinetic variables calculated by statistical moment theory or compartmental analysis indicating central compartment output of cefoperazone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical pharmacokinetics of flumequine in calves

The minimal inhibitory concentration (MIC) of flumequine for 249 Salmonella, 126 Escherichia coli, and 22 Pasteurella multocida isolates recovered from clinical cases of neonatal calf diarrhoea, pneumonia and sudden death was less than or equal to 0.78 microgram/ml. The pharmacokinetics of flumequine in calves was investigated after intravenous (i.v.), intramuscular (i.m.) and oral administration. The two-compartment open model was used for the analysis of serum drug concentrations measured after rapid i.v. ('bolus') injection. The distribution half-life (t1/2 alpha) was 13 min, elimination half-life (t1/2 beta) was 2.25 h, the apparent area volume of distribution (Vd(area)), and the volume of distribution at steady state (Vd(ss)) were 1.48 and 1.43 l/kg, respectively. Flumequine was quickly and completely absorbed into the systemic circulation after i.m. administration of a soluble drug formulation; a mean peak serum drug concentration (Cmax) of 6.2 micrograms/ml was attained 30 min after treatment at 10 mg/kg and was similar to the concentration measured 30 min after an equal dose of the drug was injected i.v. On the other hand, the i.m. bioavailability of two injectable oily suspensions of the drug was 44%; both formulations failed to produce serum drug concentrations of potential clinical significance after administration at 20 mg/kg. The drug was rapidly absorbed after oral administration; the oral bioavailability ranged between 55.7% for the 5 mg/kg dose and 92.5% for the 20 mg/kg dose. Concomitant i.m. or oral administration of probenecid at 40 mg/kg did not change the Cmax of the flumequine but slightly decreased its elimination rate. Flumequine was 74.5% bound in serum. Kinetic data generated from single dose i.v., i.m. and oral drug administration were used to calculate practical dosage recommendations. Calculations showed that the soluble drug formulation should be administered i.m. at 25 mg/kg every 12 h, or alternatively at 50 mg/kg every 24 h. The drug should be administered orally at 30 and 60 mg/kg every 12 and 24 h, respectively. Very large, and in our opinion impractical, doses of flumequine formulated as oily suspension are required to produce serum drug concentrations of potential clinical value.     

Selection of an aminoglycoside antibiotic for administration to horses

The serum concentrations of the aminoglycosides neomycin, kanamycin and streptomycin were determined after intravenous (iv) and intramuscular (im) administration. These values were then related to the minimum inhibitory concentrations (MIC) of a number of equine pathogenic bacteria to determine the duration of therapeutic serum concentrations of the aminoglycosides in the horse. Pharmacokinetic analysis of the data using neomycin as the example revealed a mean (+/- sd) peak serum concentration of 23.2 +/- 10.2 micrograms/ml present at 30 mins, and at 8 h the serum concentration was 2.8 +/- 0.8 micrograms/ml. From the pharmacological analysis of concentration-time data it was shown that neomycin was very rapidly absorbed from the im injection site, with an absorption half-time of 0.16 +/- 0.05 and was well absorbed (systemic availability was 73.7 +/- 26.9 per cent). A peak tissue level, which represented 40 per cent of the amount of drug in the body, was obtained at 32 mins after injection of the drug. At 8 h, the fractions of the dose in the central and peripheral compartments of the model were 1.5 per cent and 2.5 per cent respectively, and 96 per cent was the cumulative amount eliminated up to that time. Based on the MIC values of the majority of isolates of Corynebacterium equi, and only a few isolates of Klebsiella pneumoniae, Escherichia coli, Salmonella typhimurium and Streptococcus equi, one would expect a serum concentration of more than 2 micrograms neomycin/ml up to 8 h following im dosage (10 mg/kg) to be therapeutically effective.     

In vitro susceptibility of avian Escherichia coli and Pasteurella multocida to danofloxacin and five other antimicrobials.

The in vitro susceptibility of Escherichia coli and Pasteurella multocida isolated from poultry was determined to danofloxacin, a novel fluoroquinolone, and five other commonly used antimicrobials. A total of 1737 E. coli field isolates and 107 P. multocida isolates were tested by veterinary diagnostic laboratories in Europe, Japan, South Africa, and North America during the period 1989-91. The antimicrobial susceptibility of these isolates was determined using the Sensititre broth microdilution technique. The minimum inhibitory concentrations (MIC) of danofloxacin, furaltadone, lincomycin, oxytetracycline, spectinomycin, and trimethoprim:sulfamethoxazole that prevented growth of 90% of the bacteria were 0.25 > 64, > 64, > 64, > 128, and > 16 micrograms/ml, respectively, against E. coli isolates and 0.25, 64, 64, 16, 128, and 8 micrograms/ml, respectively, against P. multocida isolates. Danofloxacin demonstrated considerable in vitro potency against these important poultry pathogens, many of which showed extensive resistance to the other antimicrobials tested.     

Amoxycillin and clavulanic acid combination in the treatment of experimentally induced bacterial cystitis in cats

Clavulanic acid (CA) competitively inhibits beta-lactamase hydrolysis of penicillins in vitro. Treatment with amoxycillin combined with clavulanic acid (A-CA) was compared with placebo in a blind study in cats with experimental cystitis caused by Escherichia coli demonstrating in vitro resistance to amoxycillin. Bacterial cystitis was induced in 20 cats by bladder infusion of 5 ml of 0.05 per cent alcoholic salicylic acid followed after 24 hours by a brain-heart infusion broth of E coli (10(8) colony forming units ml-1) previously found to be resistant to amoxycillin in vitro (minimum inhibitory concentration over 512 micrograms ml-1). Four days after infection, cats were randomly divided into two groups of 10 and treated with amoxycillin combined with clavulanic acid or placebo for 10 days. When compared to the placebo-treated group, the A-CA treated group showed: reduced quantitative bacterial counts in urine on days 7 (P less than 0.001) and 14 (P less than 0.02); reduced culture positive urine on days 7 (P less than 0.001) and 14 (P less than 0.001); and less severe inflammation on histological examination of the bladder and urethra (P less than 0.01). It was concluded that A-CA was effective in reducing the bacterial count and reducing the histopathological changes in the bladder and urethra in an experimental model of acute bacterial cystitis in cats infected with an E coli demonstrating in vitro resistance to amoxycillin.     

The importance of pets as reservoirs of resistant Enterococcus strains,with special reference to vancomycin

The purpose of the present study was to determine the prevalence of antibiotic resistance, with special attention to vancomycin, in 104 strains of Enterococcus, which is the sentinel bacterium isolated from dog and cat faeces samples. The phenotypic characterization of the isolates classified them as E. faecium (58%), E. avium (41%) and E. faecalis (1%). Sensitivity testing used the diffusion method according to the recommendations of CASFM (Comite de l'Antibiogramme de la Société Fran?aise de Microbiogie), to oxacillin, amoxycillin, amoxycilin + clavulanic acid, ampicillin, piperacillin, cefoperazone, imipenem, enrofloxacin, ciprofloxacin, ofloxacin, nalidixic acid, tetracycline, lincomycin, erythromicin and vancomycin. Minimum inhibitory concentration (MIC) determination by E test revealed a MIC to vancomycin of between 0.5 microg/ml and 3 microg/ml. All the strains were resistant to nalidixic acid, erythromycin, cefoperazone and oxacillin. We detected resistance to amoxycillin + clavulanic acid in 1.9% of isolates, to amoxycillin in 4.8%, to piperacillin in 13.5%, and to ampicillin in 21.2% of strains. A high prevalence of antibiotic resistance to lincomycin, tetracycline, enrofloxacin, ciprofloxacin and ofloxacin was found in 98.1%, 95.2%, 76.9%, 73.1% and 64.4% of strains, respectively. Resistance to vancomycin was not found, which indicates that there is no transmission risk of vancomycin-resistant enterococcal strains to man or transfer of their resistance genes to other bacteria belonging to the endogenous flora of humans.     

Cefadroxil in the horse: pharmacokinetics and in vitro antibacterial activity

Sodium cefadroxil was administered as a single intravenous dose (25 mg/kg) to six healthy adult mares. Plasma samples were collected over a 24-h period and cefadroxil concentrations were measured by microbiological assay. The pharmacokinetic behavior of the drug was appropriately described in terms of a one-compartment open model. Values for the major pharmacokinetic terms were: extrapolated initial plasma concentration = 59.2 +/- 15.0 micrograms/ml; half-life = 46 +/- 20 min; apparent volume of distribution = 462 +/- 191 ml/kg; and body clearance = 7.0 +/- 0.6 ml/min.kg. In a subsequent study, a suspension of cefadroxil monohydrate was administered intragastrically (25 mg/kg) to the same six horses. Plasma concentrations of the drug peaked at 1-2 h but, in general, absorption was both poor and inconsistent. The data were unsuitable for determination of cefadroxil bioavailability from this oral dosage form. Ninety-nine isolates of eleven bacterial species obtained from clinically ill horses were tested for susceptibility to cefadroxil. All strains of Streptococcus equi, Streptococcus zooepidemicus, coagulase-positive staphylococci, Corynebacterium pseudotuberculosis and five out of six strains of Actinobacillus suis were highly susceptible to the drug (MIC less than 4 micrograms/ml). Escherichia coli, Klebsiella pneumoniae and Salmonella sp. showed intermediate susceptibility (MIC 4-16 micrograms/ml), while all isolates of Corynebacterium (Rhodococcus) equi, Enterobacter cloacae and Pseudomonas aeruginosa proved to be highly resistant to cefadroxil (MIC greater than 128 micrograms/ml).     

In vitro activity of flumequine in comparison with several other antimicrobial agents against five pathogens isolated in calves in The Netherlands

The in vitro activity of flumequine in comparison with several other drugs was tested against 17 P. multocida, 16 P. haemolytica, 21 S. dublin, 21 S. typhimurium and 21 E. coli strains, isolated in (veal) calves in the Netherlands. The MIC50 of flumequine for the respective pasteurellas was 0.25 and 1 microgram/ml, for the salmonellas and E. coli 0.5 micrograms/ml. In comparison with flumequine, enrofloxacin and ciprofloxacin showed higher in vitro activity, with MIC50 less than or equal to 0.008 micrograms/ml for ciprofloxacin. Decreased susceptibility of the pasteurellas was found for kanamycin, neomycin, streptomycin, gentamicin, oxytetracycline and doxycycline. The MIC50 of minocycline for P. multocida was 0.5 micrograms/ml and there was no cross resistance with the other tetracyclines. P. multocida was very susceptible to ampicillin (MIC50 less than or equal to 0.03 micrograms/ml), P. haemolytica, however, was 100% resistant to this drug. Both pasteurellas were susceptible to cephalothin and approximately 50% of the strains of both bacteria were resistant to chloramphenicol. The MIC50 of either spiramycin or tylosin was greater than or equal to their respective breakpoint-MIC values. Both pasteurellas were susceptible to the combination of trimethoprim and sulphamethoxazole. However, for P. multocida, the addition of sulphamethoxazole to trimethoprim had no synergistic effect on its MIC. In comparison with trimethorpim, aditoprim was less potent. Therefore only P. multocida was susceptible to aditoprim.     

Elevation and prolongation of serum ampicillin and amoxycillin concentrations in calves by the concomitant administration of probenecid

The effects of probenecid on serum ampicillin and amoxycillin concentrations were investigated in 1–5 week old calves after oral and parenteral drug administration. Ampicillin trihydrate was administered orally at 250mg/calf, after an overnight fast, alone and with 1.5g probenecid. Peak serum ampicillin concentrations were elevated from 0.60 to 1.22 μg/ml by the co-administration of probenecid. In calves given 0.5 g amoxycillin trihydrate with the milk replacer, peak serum drug concentration increased from 1.74 to 3.16 μg/ml when 1.5 g probenecid was given too. Maximal effect of probenecid administered orally was with the 1.5 g/calf dose with considerably lesser increase in peak serum amoxycillin being observed with doses of 0.5 g, 1 g and 2 g/calf. After parenteral injection of probenecid solution at 1 g and 2 g/calf serum ampicillin concentrations peaked at more than twice the concentrations measured after equal doses of the two antibiotics were injected alone. The co-administration of 2 g probenecid and 1 g sodium ampicillin or 0.5 g sodium amoxycillin parenterally resulted in peak antibiotic concentrations considered to be effective against some of the more resistant pathogenic Gram-negative bacteria associated with diseases in calves and serum antibiotic concentrations 5 μg/ml were maintained during 5–6 h as opposed to 2–3 h after the antibiotics were injected alone. Oral administration of 1.5 g probenecid at three consecutive milk feeding times did not alter serum urea or serum creatinine concentrations.     

Pharmacokinetics of single-dose administration of moxalactam in unweaned calves

Twenty-nine healthy 17- to 29-day-old unweaned Israeli-Friesian male calves were each given a single IV or IM injection of 10 or 20 mg of moxalactam disodium/kg of body weight. Serum concentrations were measured serially during a 12-hour period. Serum concentration vs time profiles were analyzed by use of linear least-squares regression analysis and the statistical moment theory. The elimination half-lives after IV administration were 143.7 +/- 30.2 minutes and 155.5 +/- 10.5 minutes (harmonic mean +/- SD) at dosages of 10 and 20 mg of moxalactam/kg of body weight, respectively. Corresponding mean residence time values were 153.1 +/- 26.8 minutes and 169.9 +/- 19.3 minutes (arithmetic mean +/- SD). Mean residence time values after IM administration were 200.4 +/- 17.5 minutes and 198.4 +/- 19.9 minutes at dosages of 10 and 20 mg/kg, respectively. The volumes of distribution at steady state were 0.285 +/- 0.073 L/kg and 0.313 +/- 0.020 L/kg and total body clearance values were 1.96 +/- 0.69 ml/min/kg and 1.86 +/- 0.18 ml/min/kg after administration of dosages of 10 and 20 mg/kg, respectively. Moxalactam was rapidly absorbed from the IM injection site and peak serum concentrations occurred at 1 hour. The estimated bioavailability ranged from 69.8 to 79.1%. The amount of serum protein binding was 53.4, 55.0, and 61.5% when a concentration of moxalactam was at 50, 10, and 2 micrograms/ml, respectively. The minimal inhibitory concentrations of moxalactam ranged from 0.01 to 0.2 micrograms/ml against Salmonella and Escherichia coli strains and from 0.005 to 6.25 micrograms/ml against Pasteurella multocida strains.     

Salmonellosis in veal calves. Some therapeutic aspects

The present investigation was undertaken to improve regimens dosage of amoxycillin, chloramphenicol or trimethoprim-sulphadiazine in Salmonella dublin infected veal calves. The pharmacokinetics of these drugs were studied after i.v., oral, and i.m. administration (bioavailability, local irritation at the injection site, volume of distribution, and elimination half life). The most important conclusion was that amoxycillin, chloramphenicol, and trimethoprim were suitable for oral administration to veal calves, although the bioavailability of chloramphenicol and trimethoprim was significantly less when concurrently administered with a milk replacer. In vitro, the antibacterial activities of these drugs were compared. Addition of trimethoprim to sulphadiazine lowered its MIC for S. dublin, but sulphadiazine reduced the killing rate compared to that of trimethoprim alone. In the efficacy studies the activities of several serum enzymes and the plasma concentrations of Fe, Zn, and Cu were measured, but it appeared, that these biochemical parameters were no better than the clinical parameters body temperature and body weight. Using optimal dosage regimens based on MIC values and blood levels, treatment with either of the three drugs was of equal efficacy.     

Comparative clinical pharmacology of amikacin and kanamycin in dairy calves.

The in vitro susceptibility of Escherichia coli, Salmonella sp, Pasteurella multocida, and Pseudomonas aeruginosa strains isolated from young calves and their environment to kanamycin and its semisynthetic derivative--amikacin, was compared by the tube dilution method. The minimal inhibitory concentration of amikacin was two- to fourfold lower than the minimal inhibitory concentration of kanamycin for the Salmonella group B, Ps aeruginosa and P multocida strains examined, whereas the E coli and Salmonella group D strains were eqaully susceptible to the 2 antibiotics. The concentrations of amikacin and kanamycin in the serum of calves after single intramuscular injections at 10, 25, and 50 mg/kg were determined, and differences between the 2 antibiotics were not observed. Intramuscular dosage schedules were calculated, based on the sensitivity of the different bacterial strains and the duration of effective serum drug concentrations.