Elimination of daptomycin in a patient with acute renal failure undergoing extended daily dialysis

Sir,Daptomycin is a new intravenous cyclic lipopeptide antibiotic, representing a new class of antibiotics with a spectrum of activity similar to vancomycin. It is licensed in the USA and Europe for the treatment of complicated skin and soft tissue infections caused by Gram-positive organisms including both susceptible and resistant strains of Staphylococcus aureus at a dose of 4 mg/kg once daily.1 Additionally it has been licensed in both the USA and Europe for the treatment of various infections due to susceptible organisms, including serious and life-threatening Gram-positive infections, vancomycin-resistant enterococcal infections and right-sided endocarditis with associated bacteraemia at 6 mg/kg once daily.1 The pharmacokinetic and pharmacodynamic properties of daptomycin allow for once-daily dosing. Daptomycin (1620.67 Da) has 92% plasma protein binding in vitro. In healthy adult humans, daptomycin has a volume of distribution of 0.1 L/kg and a plasma elimination half-life of ∼9 h, and is primarily excreted unchanged by the kidneys. Patients with a creatinine clearance <30 mL/min exhibit mean AUC values twice those of patients with normal renal function; patients on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD) had mean AUC values three times those with normal renal function. Daptomycin is removed by haemodialysis; ∼15% of an administered dose is eliminated in a 4 h haemodialysis session and ∼11% after 48 h of CAPD.2 Therefore, in patients with reduced renal function, including those receiving haemodialysis and peritoneal dialysis, the recommended dose interval is 48 h.2 In intensive care patients suffering from sepsis and multiple organ failure, extended daily dialysis (EDD) represents an important extracorporeal renal replacement therapy that is increasingly used in intensive care units (ICUs) throughout Europe, the United States and Brazil.3 EDD removes drugs such as levofloxacin, meropenem and also vancomycin more efficiently compared with standard intermittent haemodialysis (IHD) three times a week or continuous renal replacement therapy.4,5 As there are no data on daptomycin, we determined single dose daptomycin pharmacokinetics in a patient with aortic valve infective endocarditis associated with septic shock and acute renal failure undergoing EDD. A 67-year-old Caucasian male (110 kg total body weight, serum albumin 21 g/L) was admitted to the ICU with a rapidly processing aortic valve acute infective endocarditis with negative blood cultures. Over the next hours after admission, the patient developed septic shock and acute renal failure. Antibiotic therapy with daptomycin (dose 6 mg/kg body weight, over a period of 30 min), ciprofloxacin and tazobactam was initiated against possible infection with vancomycin-resistant enterococci and multiresistant S. aureus. On day 1, daptomycin plasma levels were measured before the start of the daptomycin infusion, at the end of the 30 min infusion, as well as 30, 60, 90,180, 360, 480 and 840 min after the end of the infusion. The next of kin consented to these additional blood draws. Furthermore, a sample of the total collected dialysate was obtained to calculate the absolute amount of daptomycin in the dialysate. EDD over a period of 12 h was performed using the GENIUS® batch dialysis system (Fresenius Medical Care, Germany) with a polysulphone high-flux dialyser (F60S, surface area 1.3 m2; Fresenius Medical Care), a dialysate flow of 100 mL/min and a blood flow of 200 mL/min. Daptomycin concentrations were determined by HPLC using the method of Dvorchik et al.6 with slight modifications. The calibration curve was linear over a concentration range of 0.5–200 mg/L. The coefficients of accuracy and precision were below 5%. The calculated single dose pharmacokinetic parameters after the initial dose of daptomycin and the comparison with data on IHD given in the literature are presented in Table 1. The total amount of daptomycin in the total collected dialysate was 346 mg. Pharmacokinetic parameters calculated from the presented case in comparison with the pharmacokinetic parameters for chronic haemodialysis patients Pharmacokinetic parameters calculated from the presented case in comparison with the pharmacokinetic parameters for chronic haemodialysis patients To our knowledge, this is the first report on the pharmacokinetics of daptomycin in a patient undergoing EDD. Although Dvorchik et al.2 reported that only 15% of an administered dose of daptomycin is eliminated during a 4 h haemodialysis session, data from an in vitro model of continuous haemofiltration and haemodialysis by Chruchwell et al.7 suggested that these forms of renal replacement therapy can remove a substantial amount of the drug. The clearance varied with the filter type, dialysate flow and ultrafiltration rate used,7 important information that is not reported in the study by Dvorchik et al.2 Our data suggest that EDD—by definition an intermittent mode of renal replacement therapy—eliminates daptomycin effectively and to a larger extent than regular IHD. Thus, dosing daptomycin every 48 h, as recommended for a regular haemodialysis, would result in a significant under dosing, which could be associated with a substantial risk, especially in septic patients in the ICU. However, one has to consider that daptomycin is known to exhibit a post-antibiotic effect that might, to some degree, compensate for the increased elimination of the drug.8 This report has several limitations, e.g. the fact that the distribution volume of any drug is altered in septic shock and the fact that the low albumin concentration facilitated removal of the protein-bound daptomycin. Thus, prospective studies have to elaborate dosing recommendations for daptomycin in patients with renal failure in the ICU treated with novel modes of renal replacement therapy. C. J. is acting as an independent consultant/speaker for pharmaceutical companies. T. W. has received funds for speaking at symposia organized on behalf of Novartis. J. T. K. has received funds for speaking at symposia organized on behalf of Fresenius Medical Care and has also received funds for research from Fresenius Medical Care. Other authors: none to declare.