The objective of this study was to quantify the impact of continuous venovenous haemodiafiltration (CVVHDF) on amino-glycoside pharmacokinetics and to suggest dosing strategies to improve therapeutic outcomes for these drugs in critically ill patients treated with CVVHDF. There has been limited published data on aminoglycoside pharmacokinetics during CRRT. This data deficit had led to subtherapeutic dosing, identified by a retrospective evaluation of amikacin and gentamicin serum concentrations, in patients treated with CVVHDF, undertaken as part of this research.
A prospective pharmacokinetic evaluation of amino-glycoside pharmacokinetics during CVVHDF was undertaken. Pharmacokinetic profiles of once-daily doses of intravenous amikacin and gentamicin were obtained from blood and dialysate/ultrafiltrate samples for 12 critically ill patients treated with CVVHDF using varying flow rates (1 l/hour dialysate plus 2 l/hour filtration fluid or 2 l/hour dialysate plus 2 l/hour filtration fluid, extracorporeal blood flow 200 ml/min). Drug concentrations were measured using an immunoassay.
The mean clearance of gentamicin due to CVVHDF was 2.3 ± 0.3 l/hour (82.1 ± 11.3% of total body clearance (TBC)). The sieving coefficient (SC) was 0.85 ± 0.05. The CVVHDF clearance of amikacin was 2.8 ± 0.5 l/hour (93.0 ± 7.8% TBC). The SC for amikacin was 0.88 ± 0.06. The difference in gentamicin clearance versus amikacin clearance reflects differences in CVVHDF conditions. The mean effluent flow rate among the patient sample treated with gentamicin was 2.7 l/hour compared with 3.5 l/hour for amikacin. There was a strong correlation between creatinine clearance by the filter and measured drug clearance (P < 0.001). Individual patient estimates of aminoglycoside pharmacokinetic parameters (k, Vd) obtained during CVVHDF were used to allow appropriate dosage adjustment. Individualized pharmacokinetic–pharmacodynamic goals (e.g. Cpmax/MIC ratio) were used as indicators of adequate aminoglycoside dosing. The mean gentamicin and amikacin half-lives (approximately 8 hours) during CVVHDF therapy were far shorter than those previously reported in the literature for less efficient forms of renal replacement therapy. Failure to adjust for increased aminoglycoside clearance capacity due to CVVHDF carries a risk of subtherapeutic dosing and therapy failure.
Dosing strategies on the basis of pharmacokinetic analysis of serum drug concentrations, effluent fluid drug concentrations and CVVHDF conditions improved therapeutic outcomes for aminoglycoside drug therapy.