Study rationale: central venous catheters are commonly used in conventional dialysis [16.5% (4768 patients) of the patients undergoing hemodialysis in France in 2010]. Their main complication is Catheter related Blood Stream Infection (CRBSI), which is associated with substantial morbidity and mortality. Staphylococcus sp, particularly Meticillin Resistant Staphylococcus Aureus (MRSA) is frequently associated with CRBSI. Treatment is based on catheter withdrawal and anti-Staphylococci parenteral antibiotic therapy. Vancomycin is the first line treatment but Daptomycin is an alternative treatment when Minimum Inhibitory Concentrations (MIC) of Vancomycin are≥ 2 µg/ml.
However, removal of the catheter is an important issue among patients on hemodialysis, and the prevalence of MRSA and Coagulase Negative Staphylococci (CoNS) with elevated MIC to Vancomycin is increasing. Before setting up a clinical study to assess Daptomycin efficacy and safety in hemodialysis patients with infected catheter, pharmacokinetics parameters need to be collected. This is the aim of this pilot pharmacokinetics study in this specific population. In such context, Daptomycin is an interesting alternative as it is effective in MRSA and CoNS infections, is well tolerated and has shown to penetrate into bio films in vitro (Raad AAC 2007 ; Aslam AJIC 2008, Leite CM 2011) which could be of advantage when treating infected devices. A few studies showed satisfying pharmacokinetics parameters among non-infected patients with conventional hemodialysis where Daptomycin was administered at 6mg/kg/dialysis. Daptomycin has been shown to be a concentration-dependent antibiotic, and the AUC/minimum inhibitory concentration (MIC) ratio is the PK-PD parameter that is most closely linked with antibacterial activity (Bowker 2009; Dandekar 2003; Louie 2001; Safdar 2004). However, there is no single optimal AUC/MIC ratio associated with maximal effect throughout the literature (Bowker 2009; Dandekar 2003; Louie 2001; Safdar 2004). In some patients, Falcone (CID 2013) observed an increased Daptomycin clearance and lower exposition to drug in critically ill patients, correlated with infection severity and MRSA bacteremia. Recent data suggest that 10mg/kg/d among patient without renal impairment is a preferred dosing to avoid resistance and maximize the antibacterial effect: indeed it seems to be the dose associated with the best benefit/risk ratio (Soon IJAA 2013), with good bacteriostatic and bactericidal activity on strains with MIC< 2 µg/mL, and low toxicity risk.
However, data are scarse on Daptomycin at 10mg/kg among patients with gram positive infections on hemodialysis. Since the literature is inconclusive on the definitive AUC/MIC threshold, we need an AUC distribution resulting from dosing schemes under chronic hemodialysis, as it is the PK target the most closely linked to effect. It is therefore important to better characterize Daptomycin PK in infected patients on hemodialysis.
Hence, we evaluate the pharmacokinetics of Daptomycin at 10mg/kg after each of 3 consecutive dialysis sessions among patients with central catheter related blood stream infections on hemodialysis.