7537
Clindamycin is an antibiotic recommended in veterinary medicine for treatment of \nstaphylococcal and anaerobic infections in small animals.\nThe aims of this study were to validate a chromatographic method for clindamycin quantification in canine and feline plasma. Characterize the pharmacokinetics...
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| Formato: | Tesis doctoral acceptedVersion |
| Lenguaje: | Español |
| Publicado: |
Universidad de Buenos Aires. Facultad de Ciencias Veterinarias
2023
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=avaposgra&cl=CL1&d=HWA_7537 https://repositoriouba.sisbi.uba.ar/gsdl/collect/avaposgra/index/assoc/HWA_7537.dir/7537.PDF |
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| Sumario: | Clindamycin is an antibiotic recommended in veterinary medicine for treatment of \nstaphylococcal and anaerobic infections in small animals.\nThe aims of this study were to validate a chromatographic method for clindamycin quantification in canine and feline plasma. Characterize the pharmacokinetics \nbehaviour of clindamycin administered intravenously and orally to domestic dogs and cats. Compare the pharmacokinetics of clindamycin between canines and felines. To \nestablish and compare the influence of food on the pharmacokinetic profile of \nclindamycin administered orally in dogs and cats. Define its pharmacodynamics profile \non bacterial strains isolated from infection sites in cats and dogs by MIC determination.\nEstablish pharmacodynamics interactions that occur when combining clindamycin with \nother antimicrobials frequently used in small animals. Based on this suggest or not the use of antibiotic associations of clindamycin in domestic canines and felines. Calculate the pharmacokinetic/pharmacodynamics parameters (PK/PD) that predicts the \ntherapeutic efficacy of this antibiotic for the studied situations, administration route, fasted and fed state, animal species. And propose rational dosage regimens for \nclindamycin administered intravenously and orally, both fasting and with food, to \ncanines and felines.\nThe pharmacokinetic study was carried out by a cross over design (2x2x2). Clindamycin was administered intravenously in both species at a dose of 10 mg/kg, orally in dogs at a dose of 8.3 ± 1.1 mg/kg and orally in cats at 15 mg/kg. When administered the antibiotic with food, the animals received their ration and immediately afterwards the drug was administered orally with some water to ensure swallowing.\nQuantification of the antibiotic in plasma was performed using the HPLC method with UV detection. The antibiotic susceptibility profile of the microorganisms that cause \ninfection in small animals was established by the broth macrodilution method and MIC determination. The interaction study between clindamycin and other antimicrobials frequently used in small animal medicine, gentamicin, ampicillin, enrofloxacin and \ndoxycycline, was carried out using the in vitro Checkerboard method. The PK/PD analysis for this drug was performed by calculating the efficacy predictors t>MIC and AUC0-24/MIC.\nAfter intravenous administration, clindamycin was widely distributed in canines as well as felines with a Vc of 0.96 l/kg and 0.94 l/kg, respectively. Elimination process was \nslower in canines with a Cl of 0.28 l/h/kg and elimination half-life of 3,36 h, while in \nfelines these parameters were 0.45 l/h/kg and 2.56 h respectively (p<0.05).\nAfter oral administration in fasted state, clindamycin was rapidly absorbed in both \nspecies, with a Tmax in dogs of 1.12 h and in cats of 0.57 h, being significantly earlier in this last one (p<0,05). Oral bioavailability was good, 61.9% for dogs and 94.8% for cats.\nThe presence of food in the gastrointestinal tract did not significantly modify the oral \nbioavailability of the antibiotic, being in dogs 50.4% and in cats 90.3%. Absorption rate\nin both species showed significant changes (p<0.05), being improved in dogs with a Tmax of 0.75 h and delayed in cats, with a Tmax of 0.96 h.\nMIC50 of the pathogen Staphylococcus pseudintermedius isolated in dogs and cats was 0.12 µg/ml, while the MIC90 was higher than 4 µg/ml, concentration from which these bacteria are classified as resistant to clindamycin. The percentage of resistance for these microorganisms was 38%.\nClindamycin interaction analysed by the Checkerboard method, with doxycycline, ampicillin, enrofloxacin and gentamicin on S. pseudintermedius was indifference for all combinations, except for doxycycline, where synergism was detected in one of the antibiotic intersections.\nThe efficacy predictor PK/PD t>MIC50 after the intravenous administration of \nclindamycin to canines and cats was 15 h and 13 h, respectively, with an optimal \ndosage interval of 24 h. After oral administration of the antibiotic to dogs, in fasted and fed state, the t>MIC50 was 9 h for both conditions, and therefore the appropriate dosage interval would be 12 h. In cats, this predictor took higher values, showing in fasted animals 12 h while in fed animals 13 h, resulting in a dosage interval of 24 h.\nThe second predictor of efficacy calculated was AUC0-24/MIC50, for intravenous route in \ndogs, fasting and oral with food the results were 329, 159 and 134, respectively, while in cats they were 210, 257 and 286.\nAfter intravenous administration of clindamycin to dogs and cats, it distributed rapidly, \nwidely and similar in both species. On the other hand, the elimination process occurred faster in cats than in dogs. Oral absorption of clindamycin in fasted state was rapid, showing good bioavailability in both species, but higher in cats than in dogs. The presence of food did not significantly modify the oral bioavailability of the antimicrobial in any of the species in study. A different behaviour was found in the speed of absorption of the antibiotic given with food, while in dogs, the antimicrobial orally\nadministered was absorbed faster, in cats it was absorbed slower. The sensitivity of the studied staphylococci strains was moderate, showing a considerable percentage of \nmicroorganisms resistant to this antibiotic. When combining clindamycin in vitro with other antimicrobials frequently used in small animals, the result obtained was \nindifferent for all combinations except for doxycycline, with which synergism was detected. The efficacy predictor t>MIC was prolonged in both species, allowing in \nfelines a dosage interval of 24 hours at the doses used, while in canines the interval for the oral route should be reduced to 12 hours. As there are no reference values in human or veterinary medicine for the efficacy predictor ABC0-24/CIM, we stablished \nvalues for both species with the doses used in this study. |
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