Pharmacokinetics and pharmacodynamics of aminoglycosides

• The pharmacokinetics of amikacin in humans and the pharmacodynamic effects, i.e. initial killing and postantibiotic effect (P AE), of the aminoglycosides were studied in this thesis. For1y-five elderly patients with serious infections were treated in a prospective, comparative and randomized pharmacokinetic study with amikacin given once or twice daily. The administration of a single dose of 15 mg!kg of amikacin yielded a higher peak concentration (55 mg/1) in comparison to the peak concentration (33 mg!l) when the same total dose was given twice daily. The area under the curve (AUC) was the same regardless of the mode of administration. The kinetics of amikacin, 11 mg/kg and 15 mg/kg were studied during a 24 h interval. Using a hiexponential equation the average serum half-lives were quite long, 4.4 - 5.2 h. In practice, a uni-exponential equation is often used, and this may lead to incorrect conclusions about the elimination rate of amikacin. When given to our elderly patients the peak concentration of 11 mg/kg of arnikacin ( 42 mg!l) seems to be sufficiently high in relation to the MICs of important isolated pathogens, i.e. ,2>10 x MIC. Thus this dose may be sufficient for elderly patients when given once daily. The in vitro postantibiotic effects (P AE) of amikacin, gentamicin, netilmicin and tobramycin onGram-negative bacteria and on staphylococci were studied by a bioluminescent assay of bacterial ATP. This method simplified the P AE studies and made such studies possible at high aminoglycoside concentrations. The length of the P AE was concentration-dependent for all the aminoglycosides studied. The mean P AE values of the Gram-negative strains and of the Staphylococcus aureus strains ranged between 3 to 7 h at the aminoglycoside concentrations normally reached in serum during standard dosing. The P AE of arnikacin alone, and in combination with ceftazidime, ceftriaxone or piperacillin, on Gram-negative bacteria and on enterococci was also studied. The combination of 13-lactam antibiotics with amikacin induced longer P AEs than the sum of P AEs of the individual drugs. This synergistic P AE was seen especially when the 13-lactam antibiotics were combined with amikacin concentrations close to MIC. Amikacin alone induced no P AEon the Enterococcus .faecalis strains. APAE of 1.6 h at the most resulted from exposure to piperacillin. In combination, amikacin and piperacillin increased the P AE to 5.5 h. In conclusion, with regard to the pharmacokinetics and the pharmacodynamics there is strong support for the once daily dosing regimens of aminoglycosides. The results of this study could also haveimpact on dosing regimens of antimicrobial combinations and might lead to administration of lower doses of potentially toxic drugs without loss of efficacy.

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MEDICINE

MEDICIN

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