How to calculate clearance of highly protein-bound drugs during continuous venovenous hemofiltration demonstrated with flucloxacillin.
BACKGROUND
Flucloxacillin is an important antimicrobial drug in the treatment of infections with Staphylococcus aureus and therefore is often used in staphylococcal infections. Furthermore, flucloxacillin has a high protein binding rate as for example ceftriaxone or teicoplanin--drugs which have formerly been characterized as not being dialyzable.


METHODS
The pharmacokinetic parameters of 4.0 g flucloxacillin every 8 h were examined in 10 intensive care patients during continuous venovenous hemofiltration (CVVH) using a polyamide capillary hemofilter. In addition, the difficulty of calculating the hemofiltration clearance of a highly protein-bound drug is described.


RESULTS
Flucloxacillin serum levels were significantly lowered (56.9 +/- 24.0%) even though only 15% of the drug was detected in the ultrafiltrate. Elimination half-life, total body clearance and sieving coefficient were 4.9 +/- 0.7 h, 117.2 +/- 79.1 ml/min and 0.21 +/- 0.09, respectively. These discrepancies can be explained by the high protein binding of flucloxacillin, the adsorbing property of polyamide and the equation in order to calculate hemofiltration clearance. The unbound fraction of a 4.0 g flucloxacillin dosage facilitates time above the minimum inhibitory concentration (T > MIC) of 60% only for strains up to a minimum inhibitory concentration (MIC) of 0.5 mg/l.


CONCLUSIONS
Based on the data of this study, we conclude that intensive care patients with staphylococcal infections on CVVH should be treated with 4.0 g flucloxacillin every 8 h which was safe and well tolerated. Moreover, further studies with highly protein-bound drugs are recommended to check the classical 'hemodialysis' equation as the standard equation in calculating the CVVH clearance of highly protein-bound drugs.
Meyer
Brigitte
B
Department of Internal Medicine I, Division of Infectious Diseases, University of Vienna, Vienna, Austria.
Ahmed el Gendy
Salwa
S
Delle Karth
Georg
G
Locker
Gottfried J
GJ
Heinz
Gottfried
G
Jaeger
Walter
W
Thalhammer
Florian
F
D000368:Aged; D019540:Area Under Curve; D003422:Critical Care; D005260:Female; D005436:Floxacillin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006207:Half-Life; D006440:Hemofiltration; D006801:Humans; D008297:Male; D008875:Middle Aged; D010406:Penicillins / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011485:Protein Binding; D015610:Serum Bactericidal Test; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000378:metabolism
D010406:Penicillins; D005436:Floxacillin