Variability of pharmacokinetic parameters in patients receiving different dosages of daptomycin: is therapeutic drug monitoring necessary?

Pharmacokinetic studies of daptomycin in septic patients indicate that pharmacokinetic parameters may be altered. The purpose of this clinical investigation is to determine the pharmacokinetics of daptomycin in a population of hospitalized patients with clinically significant gram-positive infections and receiving daptomycin. Daptomycin was measured using an isocratic HPLC technique. Thirty-five patients suffering from gram-positive severe infections and receiving daptomycin were included in the study. Patients were divided into two groups, depending on the dose of daptomycin received: group A, including 24 patients receiving 6 mg/kg/day daptomycin and group B, 11 patients receiving 8 mg/kg/day. Patients receiving a daptomycin dosage of 8 mg/kg/day had significantly higher values of mean C max and AUC0-24. Each group was further divided into three subgroups, according to the creatinine clearance (CrCl) values: (1) patients with a CrCl >80 ml/min, (2) patients with CrCl ranging between 80 and 40 ml/min, and (3) patients with CrCl <40 ml/min. Compared to patients with normal renal function, those with CrCl <40 ml/min had higher mean values of minimum concentration (C min) (p < 0.001), AUC0-24 (p = 0.03), and prolonged plasma half-time (p < 0.001). These differences were present both in patients receiving 6 and those with 8 mg/kg/day. However, in each of the three subgroups with different degrees of renal function a marked variability of pharmacokinetics parameters was observed. The factors associated with increased mortality were an infection acquired in the ICU, hypoalbuminemia, and AUC/MIC <666. The marked variability that characterizes daptomycin pharmacokinetics in these patients suggest the monitoring of the main pharmacokinetic parameters in this clinical setting.

Peripheral extracorporeal membrane oxygenation system as salvage treatment of patients with refractory cardiogenic shock: preliminary outcome evaluation.

The novel Permanent Life Support (PLS; Maquet, Jostra Medizintechnik AG, Hirrlingen, Germany) as peripheral veno-arterial extracorporeal membrane oxygenation (ECMO) support system has been investigated as treatment for patients with refractory cardiogenic shock (CS). Between January 2007 and July 2011, 73 consecutive adult patients were supported on peripheral PLS ECMO system at our institution (55 men; age 60.3 ± 11.6 years, range: 23-84 years). Indications for support were failure to wean from cardiopulmonary bypass in the setting of postcardiotomy (n = 50) and primary donor graft failure (n = 8), post-acute myocardial infarction CS (n = 12), and CS on chronic heart failure (n = 3). Mean support time was 10.9 ± 7.6 days (range: 2-34 days). Overall, 26 (35.6%) patients died on ECMO. Among survivors on ECMO, 44 (60.2%) patients were successfully weaned from support, and three (4.1%) were switched to a mid-long-term ventricular assist device. Thirty-three (45.2%) were successfully discharged. The following variables were significantly different if survivors and nonsurvivors on ECMO were compared: age (P = 0.04), female gender (P < 0.01), cardiopulmonary resuscitation before ECMO (P < 0.01), lactate level before ECMO (P = 0.01), number of platelets, fresh frozen plasma units, and packed red blood cells (PRBCs) transfused during ECMO support (P = 0.03, P = 0.02, and P < 0.01), blood lactate level (P = 0.01), and creatine kinase isoenzyme MB (CK-MB) relative index 72 h after ECMO initiation (P < 0.001), and multiple organ failure on ECMO (P < 0.01). Stepwise logistic regression identified blood lactate level and CK-MB relative index at 72 h after ECMO initiation, and number of PRBCs transfused on ECMO as significant predictors of mortality on ECMO (P = 0.011, odds ratio [OR] = 2.48; 95% confidence interval [CI] = 1.11-3.12; P = 0.012, OR = 2.81, 95% CI = 1.026-2.531; and P = 0.012, OR = 1.94, 95% CI = 1.02-5.21; respectively). Patients with an initial poor hemodynamic status could benefit by rapid peripheral installation of PLS ECMO. The blood lactate level, CK-MB relative index, and PRBCs transfused should be strictly monitored during ECMO support.

Levosimendan versus intra-aortic balloon pump in high-risk cardiac surgery patients.

OBJECTIVE: Patients with severe left ventricular dysfunction receive inotropic and mechanical circulatory support with an intra-aortic balloon pump (IABP) during the perioperative phase of cardiac surgery. The authors performed the first comparison of levosimendan versus an IABP in patients with poor left ventricular function undergoing cardiac surgery. DESIGN: A case-matched study. SETTING: A teaching hospital. PARTICIPANTS: Twenty-two heart failure patients scheduled to undergo elective coronary artery bypass graft surgery with or without concomitant mitral surgery. INTERVENTIONS: Eleven patients received levosimendan at a dose of 0.1 µg/kg/min for 24 hours without an initial bolus. The control group, also 11 patients, received a preoperative IABP. The intensive care unit stay was the major endpoint of this study. Biochemical, hemodynamic, and echocardiographic data were collected together with the time on mechanical ventilation and 30-day mortality. MEASUREMENTS AND MAIN RESULTS: The length of intensive care unit stay was reduced in patients receiving levosimendan (median, 2.5; range, 1-3 days) compared with those receiving an IABP (median, 5; range, 3-6 days; p = 0.01). No deaths occurred in the levosimendan group; 1 patient died in the intra-aortic balloon pump group. CONCLUSIONS: Patients receiving levosimendan had a shorter duration of intensive care stay than peers who received a preoperative IABP. The findings of this pilot study should be investigated further in a large randomized controlled study.

Daptomycin serum levels in critical patients undergoing continuous renal replacement.

BACKGROUND: Daptomycin pharmacokinetics has not been extensively studied in patients undergoing continuous renal replacement therapy (CRRT). METHODS: The aim of the study was to collect pharmacokinetics and clinical data of patients undergoing CRRT and receiving daptomycin therapy. Daptomycin was measured using an isocratic high-performance liquid chromatography technique. RESULTS: Three patients with bloodstream infection underwent CVVHD and three CVVHDF. CVVHDF patients had significantly lower mean AUC(0-24) and C(max) values. A significant decrease in plasma levels was observed in a CVVHDF patient using 'high cut-off' hemofilters. CONCLUSION: Increasing doses of daptomycin should be considered in critical patients, especially those undergoing CVVHDF.

Weaning from venovenous extracorporeal membrane oxygenation without anticoagulation: is it possible?

A 19-year-old man affected with severe acute respiratory distress syndrome that was unresponsive to medical treatment was successfully weaned without anticoagulation therapy from venovenous extracorporeal membrane oxygenation (ECMO) because of life-threatening bleeding. The patient received venovenous ECMO with double peripheral cannulation. Heparin infusion was discontinued on day 10 for severe bleeding from thoracic and mediastinal drainages until the ECMO was removed. The weaning was performed while keeping the blood flow unchanged, only gas flows were gradually decreased. The patient was discontinued from ECMO and extubated after pulmonary function improved. Based on this single experience, management and weaning without any anticoagulant agent might be possible.

Levitronix CentriMag third-generation magnetically levitated continuous flow pump as bridge to solution.

The Levitronix CentriMag (Levitronix LLC, Waltham, MA) ventricular assist device (VAD) is a magnetically levitated rotary pump designed for temporary extracorporeal support. Between February 2004 and May 2010, 42 consecutive adult patients were supported with Levitronix at our institution (32 men; age 62.3 ± 10.5 years, range: 31-76 years). Indications for support were (group A, n = 37) failure to wean from the cardiopulmonary bypass in the setting of postcardiotomy (n = 23), primary donor graft failure (n = 4), or right ventricular failure after axial left VAD (LVAD) placement (n = 10) and (group B, n = 5) refractory heart failure after acute myocardial infarction. The mean support time was 11.2 ± 6.8 days (range: 3-43 days) in group A and 8.6 ± 4.3 days (range: 5-11 days) in group B. In the postcardiotomy cohort (group A), 11 (47.8%) patients were weaned from support as all were supported graft failure patients. Eight patients of axial LVAD cohort were weaned from right VAD (RVAD). One patient was bridged to heart transplantation (Htx). Thirteen (35.1%) patients died on support in group A. In group B, one patient was bridged to Htx and four died on support. In overall population, bleeding requiring reoperation occurred in 15 (35.7%) cases and cerebral major events in four (9.5%). There were no device failures. Of the 23 (54.7%) patients who recovered and were discharged home, 20 (47.6%) are presently alive, and additionally, two patients of both groups who were bridged to Htx (overall n = 22, 52.3%). The Levitronix proved to be useful in patients previously considered nonsuitable for transplantation or long-term assist device. The device was technically easy to manage, and the results were encouraging.