Upprepad administrering av trimetoprim/sulfadiazin till neonatala föl : plasmaproteinbindning och effekt på serumbilirubinkoncentrationen

Sammanfattning: Today most dosages used in horse medicine are based on studies in adult horses. Since there are differences between adult and neonatal horses with respect to different pharmacological parameters this can cause problems when administring drugs to neonatal foals. Neonatal sepsis is a common cause of morbidity and mortality in foals and aggressive antibiotic treatment is needed immediately when sepsis is suspected. In Sweden the combination of trimethoprim/sulphadiazine and bensylpenicillin is often used as the initial treatment. When administering drugs, interactions can occur between the drugs and endogenous substances. An example of such an interaction is called "displacement" and refers in this case to the competition for binding places on plasma proteins between drugs and highly protein-bound enogenous substances. Drugs that themselves are highly protein-bound are at a greater risk for displacement. Bilirubin is an example of an endogenous substance that to a great extent (>99 %) is bound to albumin. When displacement occur more free unconjugated bilirubin becomes available systemically and to a greater extent can pass the blood-brain barrier and cause cellular damage, so called kernicterus. Kernicterus has mostly been reported in neonatal children and is rarely seen in animals. Kernicterus in foals in association with trimethoprim/sulfadiazine treatment has not been reported but it is theoretically possible that also foals could be affected. The aims of the study were to evaluate the dosage used today and its safety with respect to displacement of bilirubin. Seven healthy foals were treated with trimethoprim/sulfadiazine, 15 mg/kg q 12 h for three days. Blood samples were taken daily at the same time points during four days and the concentrations of total protein, albumin and bilrubin (total, conjugated, unconjugated and free unconjugated) were analysed in plasma. Blood samples were taken at the same time points in a matched control group with seven healthy foals. No differences in levels between the different parameters were seen betweeen the foals treated with trimetoprim/sulfadiazin and the controls. The concentration of free unconjugated bilirubin was analysed with equilibrium dialysis and no differences were seen between the foals treated with trimetoprim/sulfadiazin and the control group. The protein binding was 23 % for trimethoprim and 14 % for sulfadiazine, which is a bit lower than the protein binding measured in adult horses at 35 % and 20% respectively. The results in this study, and the clinical experience without reported cases of kernicterus associated with treatment of trimethoprim/sulfadiazin, implies that the dosage used today does not seem to enhance the risk of kernicterus in neonatal foals. One should, however, consider that this study was performed on clinically healthy foals. Since it is known that many diseases affect the turnover of different endogenous and exogenous substances, further studies are warranted in which focus should be put on septicaemic foals, younger neonatal and prenatal foals.