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Objectives: We investigated the effect of continuous renal replacement therapy (CRRT) on the pharmacokinetics of trimethoprim and sulfametrole.Patients and Methods: We enrolled critically ill adults undergoing CRRT and critically ill adults with normal or slightly impaired renal function (plasma creatinine concentration <1.5 mg/dL, control group). All patients received trimethoprim/sulfametrole at standard doses. Pharmacokinetics were determined after the first dose and at steady-state. In addition, a population pharmacokinetic model using plasma data was built. We also assessed the renal clearance (CLR) and the extracorporeal clearance in patients undergoing CRRT.Results: Twelve patients were enrolled in the CRRT group and 12 patients in the control group. There was no statistically significant difference in trimethoprim pharmacokinetics between the two groups. In patients on CRRT, total plasma clearance (CLtot) and V of sulfametrole were significantly higher than in the control group. However, sulfametrole exposure was not significantly altered during CRRT. The population pharmacokinetic analysis indicated that neither CRRT intensity nor residual diuresis were significant covariates on trimethoprim or sulfametrole CL. Median CL by continuous venovenous haemofiltration accounted for about one-third of CLtot of trimethoprim and for about one-half of CLtot of sulfametrole. In patients on CRRT, CLR of trimethoprim and sulfametrole were <5% of CLtot.Conclusions: During CRRT, standard doses of trimethoprim/sulfametrole appear to be adequate. [ABSTRACT FROM AUTHOR]

Extracorporeal blood purification techniques such as hemofiltration or albumin dialysis can exert a significant, but not easily predictable influence on plasma pharmacokinetics of antimicrobial agents. The effect of albumin dialysis on the pharmacokinetics of liposomal amphotericin B (AMB) and other lipid-formulated drugs has not been investigated so far. Therefore, plasma concentrations of liberated and liposomal AMB were measured in a patient, who obtained liposomal AMB for suspected invasive mycosis and required albumin dialysis because of cholestatic liver failure caused by graft versus host disease after bone marrow transplantation. Liberated and liposomal AMB were separated by solid phase extraction and measured by high performance liquid chromatography. No excessive AMB elimination took place during albumin dialysis. Plasma levels of liposomal AMB exceeded those of liberated AMB. Pharmacokinetic data were comparable to those obtained previously in patients on hemofiltration and in critically ill patients without extracorporeal blood purification. [ABSTRACT FROM AUTHOR]

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Introduction Clinical studies on the elimination of amphotericin B (AMB) lipid formulations in liver failure have been lacking so far. Therefore, the pharmacokinetics of AMB colloidal dispersion (ABCD) was assessed in critically ill patients with cholestatic liver failure. Patients and methods Time-concentration profiles were determined in critically ill patients with cholestatic liver failure and in critically ill patients with normal hepatic function requiring ABCD for invasive fungal infections. Lipid-associated and liberated AMB were separated by solid phase extraction and quantified by high performance liquid chromatography. Results Three patients with impaired and two patients with normal hepatic function (one patient on day 1, one patient on day 5 of therapy) were enrolled so far. After a single dose of ABCD, the AMB half life was similar in patients with impaired and normal liver function. The AMB clearance was slower in liver failure (0.15 vs. 0.54 L/h/kg for total AMB, 0.22 vs. 0.55 L/h/kg for the liberated AMB fraction and 0.52 vs. 35.6 L/kg for lipid-associated AMB) and the apparent volume of distribution was smaller (2.2 vs. 10.9 L/kg for total AMB, 3.1 vs. 11.2 L/kg for liberated and 8.2 vs. 154.5 L/h/kg for lipid-associated AMB). Conclusion The elimination of ABCD appears to be delayed in cholestatic liver failure. More pharmacokinetic data are required to establish reliable dose recommendations for ABCD in patients with liver failure. [ABSTRACT FROM AUTHOR]

Fungal cholangitis is a potentially life-threatening condition. As amphotericin B (AmB) has a broad antimycotic spectrum, in this study its biliary penetration and activity was determined in two patients treated with liposomal AmB (L-AmB) and in one patient receiving AmB colloidal dispersion (ABCD). Biliary and plasma AmB levels were quantified by high-performance liquid chromatography after purification by solid-phase extraction. For assessment of biliary AmB activity, isolates of Candida albicans , Candida tropicalis , Candida glabrata and Candida krusei were incubated in porcine bile at AmB concentrations of 0.025–5.00 mg/L. In addition, patient bile samples retrieved for AmB quantification were inoculated with the same Candida strains. Biliary AmB concentrations were lower and displayed a slower rise and decline than plasma levels. The highest penetration ratio, as expressed by the ratio between the area under the AmB concentration–time curve in bile and plasma (liberated AmB) over the sampling period (AUC 0– n bile /AUC 0– n LI plasma ), was 0.28. Proliferation of C. albicans and C. tropicalis in bile was similar to that in culture medium, whereas growth of C. glabrata was diminished and proliferation of C. krusei was absent in bile. In comparison with culture medium, AmB activity decreased in spiked porcine bile. In all but one patient bile sample, fungal growth was delayed or lacking even when AmB was not detectable. However, no fungicidal effect was observed in patient bile at AmB concentrations up to 1.28 mg/L. Thus, a reliable response of fungal cholangitis to treatment with L-AmB or ABCD cannot be anticipated. [ABSTRACT FROM AUTHOR]