Natascia Corti

Novel anticoagulants in the therapy of peripheral arterial and coronary artery disease.

Anticoagulant and antiplatelet drugs are used and studied in numerous trials for primary and secondary prevention of atherothrombosis since decades. The annual rate for cardiovascular morbidity and mortality is high in patients following an acute coronary syndrome and in patients with peripheral arterial disease (PAD) due to concomitant cardiac and cerebrovascular diseases. Plaque rupture and subsequent thrombosis involves activation of both platelets and coagulation factors. Therefore the combination of aspirin and warfarin to improve prevention of atherothrombosis compared to antiplatelet therapy alone was studied but could not be established due to significantly increased risk of major bleeding compared to a nonsignificant reduction in ischemic events. During the past two decades, clinical trials focused on combined antiplatelet therapies for the prevention of secondary events following acute coronary syndromes and very recently on the new oral anticoagulants in combination with antiplatelet therapy. This review discusses the role of the new oral anticoagulants such as Factor IIa (thrombin) and Factor Xa inhibitors in atherothrombosis, their pharmacological properties and recently published clinical data in secondary prevention of atherothrombotic events and potential implications for patients with PAD.

Liver Transplantation because of Acute Liver Failure due to Heme Arginate Overdose in a Patient with Acute Intermittent Porphyria.

In acute attacks of acute intermittent porphyria, the mainstay of treatment is glucose and heme arginate administration. We present the case of a 58-year-old patient with acute liver failure requiring urgent liver transplantation after erroneous 6-fold overdose of heme arginate during an acute attack. As recommended in the product information, albumin and charcoal were administered and hemodiafiltration was started, which could not prevent acute liver failure, requiring super-urgent liver transplantation after 6 days. The explanted liver showed no preexisting liver cirrhosis, but signs of subacute liver injury and starting regeneration. The patient recovered within a short time. A literature review revealed four poorly documented cases of potential hepatic and/or renal toxicity of hematin or heme arginate. This is the first published case report of acute liver failure requiring super-urgent liver transplantation after accidental heme arginate overdose. The literature and recommendations in case of heme arginate overdose are summarized. Knowledge of a potentially fatal course is important for the management of future cases. If acute liver failure in case of heme arginate overdose is progressive, super-urgent liver transplantation has to be evaluated.

Electronic prescribing increases uptake of clinical pharmacologists' recommendations in the hospital setting

AIMSnTo determine whether electronic prescribing facilitates the uptake of clinical pharmacologists recommendations for improving drug safety in medical inpatients.nnnMETHODSnElectronic case records and prescription charts (either electronic or paper) of 502 patients hospitalized on medical wards in a large Swiss teaching hospital between January 2009 and January 2010 were studied by four junior and four senior clinical pharmacologists. Drug-related problems were identified and interventions proposed. The implementation and time delays of these proposed interventions were compared between the patients for whom paper drug charts were used and the patients for whom electronic drug charts were used.nnnRESULTSnOne hundred and fifty-eight drug-related problems in 109 hospital admissions were identified and 145 recommendations were made, of which 51% were implemented. Admissions with an electronic prescription chart (n= 90) were found to have 2.74 times higher odds for implementation of the change than those with a paper prescription chart (n= 53) (95% confidence interval 1.2, 6.3, P= 0.018, adjusted for any dependency introduced by patient, ward or clinical team; follow-up for two cases missing). The time delay between recommendations being made and their implementation (if any) was minimal (median 1 day) and did not differ between the two groups.nnnCONCLUSIONSnElectronic prescribing in this hospital setting was associated with increased implementation of clinical pharmacologists recommendations for improving drug safety when compared with handwritten prescribing on paper.

Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers

BackgroundBenzimidazoles are often used concomitantly with protease inhibitors in patients with helminthic disease and HIV infection. Low bioavailability and extensive first-pass metabolism make benzimidazoles prone to pharmacokinetic drug interactions. The aim of the present study was to investigate potential drug interactions between the benzimidazoles albendazole and mebendazole and the potent CYP3A4 inhibitor ritonavir.MethodsSixteen healthy volunteers were administered a single oral dose of 1,000xa0mg mebendazole or 400xa0mg albendazole (2u2009×u2009nu2009=u20098). AUC, Cmax, and t1/2 of mebendazole, albendazole, and albendazole sulfoxide were studied in absence and after short-term (2 doses) and long-term (8xa0days) treatment with ritonavir 200xa0mg bid.ResultsPharmacokinetic parameters of albendazole and mebendazole were not changed by short-term administration of ritonavir. However, long-term administration of ritonavir resulted in significant changes in albendazole and mebendazole disposition, with a significant decrease in AUC0-24 (27 and 43% of baseline for albendazole and mebendazole, respectively) and Cmax (26 and 41% of baseline, respectively).ConclusionThe AUC0-24 of benzimidazoles decreased after long-term use of ritonavir, while no changes in pharmacokinetic profiles were observed under short-term administration. These findings might help to optimize benzimidazole efficacy when used in combination with protease inhibitors.

Trimethoprim/Sulfamethoxazole Pharmacokinetics in Two Patients Undergoing Continuous Venovenous Hemodiafiltration

Objective: To determine the extent of elimination of trimethoprim (TMP) and sulfamethoxazole (SMX) via continuous venovenous hemodiafiltration (CVVHDF) in 2 critically ill patients with renal failure. Case Summary: A 62-year-old woman with Pneumocystis jirovecii pneumonia (PCP) was admitted to our intensive care unit for severe acute respiratory distress syndrome. A 77-year-old man was admitted for aortic root replacement and developed septic shock and nosocomial pneumonia due to Stenotrophomonas maltophilia. Both patients developed acute renal failure, necessitating CVVHDF. They were treated with intravenous TMP/SMX adapted to renal function. The first patient received TMP 6.4 mg/kg/day and SMX 32 mg/kg/day, corresponding to 50% of the recommended high-dose TMP/SMX regimen in PCP patients. The second patient received TMP 1.7 mg/kg/day and SMX 8.6 mg/kg/day, corresponding to 50% of the usual dose in bacterial infections. We determined peak and trough serum TMP and SMX concentrations and the extent of TMP/SMX CVVHDF clearance at steady-state while the patients were still anuric and oliguric. Discussion: Data on TMP and SMX pharmacokinetics in CVVHDF are lacking and dosing recommendations are inconclusive. In both patients, CVVHDF clearance of TMP ranged from 21.5 to 28.9 mL/min, corresponding with normal renal clearance (20–80 mL/min). SMX clearance in CVVHDF showed high variability (18.7, 26.7, and 42.6 mL/min) and exceeded renal clearance values in normal renal function (1–5 mL/min). Accordingly, peak TMP serum concentrations were within the recommended range in the patient treated with a reduced TMP/SMX dose for PCP, whereas her SMX peak concentrations were only one third of recommended target concentrations. Conclusions: Our data indicate that both TMP and SMX are removed by CVVHDF to a significant degree, and dose reduction of TMP/SMX in CVVHDF bears the risk of underdosing. Given variability in drug exposure in critically ill patients, therapeutic drug monitoring is advisable in anuric or oliguric patients undergoing continuous renal replacement therapy to ensure optimal TMP/SMX dosing.

High-throughput hydrophilic interaction chromatography coupled to tandem mass spectrometry for the optimized quantification of the anti-Gram-negatives antibiotic colistin A/B and its pro-drug colistimethate

Colistin is a last resorts antibacterial treatment in critically ill patients with multi-drug resistant Gram-negative infections. As appropriate colistin exposure is the key for maximizing efficacy while minimizing toxicity, individualized dosing optimization guided by therapeutic drug monitoring is a top clinical priority. Objective of the present work was to develop a rapid and robust HPLC-MS/MS assay for quantification of colistin plasma concentrations. This novel methodology validated according to international standards simultaneously quantifies the microbiologically active compounds colistin A and B, plus the pro-drug colistin methanesulfonate (colistimethate, CMS). 96-well micro-Elution SPE on Oasis Hydrophilic-Lipophilic-Balanced (HLB) followed by direct analysis by Hydrophilic Interaction Liquid Chromatography (HILIC) with Ethylene Bridged Hybrid--BEH--Amide phase column coupled to tandem mass spectrometry allows a high-throughput with no significant matrix effect. The technique is highly sensitive (limit of quantification 0.014 and 0.006 μg/mL for colistin A and B), precise (intra-/inter-assay CV 0.6-8.4%) and accurate (intra-/inter-assay deviation from nominal concentrations -4.4 to +6.3%) over the clinically relevant analytical range 0.05-20 μg/mL. Colistin A and B in plasma and whole blood samples are reliably quantified over 48 h at room temperature and at +4°C (<6% deviation from nominal values) and after three freeze-thaw cycles. Colistimethate acidic hydrolysis (1M H2SO4) to colistin A and B in plasma was completed in vitro after 15 min of sonication while the pro-drug hydrolyzed spontaneously in plasma ex vivo after 4 h at room temperature: this information is of utmost importance for interpretation of analytical results. Quantification is precise and accurate when using serum, citrated or EDTA plasma as biological matrix, while use of heparin plasma is not appropriate. This new analytical technique providing optimized quantification in real-life conditions of the microbiologically active compounds colistin A and B offers a highly efficient tool for routine therapeutic drug monitoring aimed at individualizing drug dosing against life-threatening infections.

Experience with daptomycin daily dosing in ICU patients undergoing continuous renal replacement therapy

PurposeFor critically ill patients undergoing continuous renal replacement therapy (CRRT), daptomycin dosing recommendations are scarce. We, therefore, retrospectively assessed routinely measured daptomycin plasma concentrations, daptomycin dose administered and microbiological data in 11 critically ill patients with Gram-positive infections that had received daptomycin once daily.MethodsThe retrospective analysis included critically ill patients treated at the intensive care unit (ICU) who had daptomycin plasma concentrations measured.ResultsDaptomycin dose ranged from 3 to 8xa0mg/kg/q24xa0h in patients undergoing CRRT (nxa0=xa07) and 6 to 10xa0mg/kg/q24xa0h in patients without CRRT (nxa0=xa04). Peak and trough concentrations showed a high intra- and inter-patient variability in both groups, independent of the dosage per kg body weight. No drug accumulation was detected in CRRT patients with once-daily daptomycin dosing. Causative pathogens were Enterococcus faecium (nxa0=xa06), coagulase-negative Staphylococcus (nxa0=xa02), Staphylococcus aureus (nxa0=xa02) and unknown in one patient. Microbiological eradication was successful in 8 of 11 patients. Two of three patients with unsuccessful microbiological eradication and fatal outcome had an Enterococcus faecium infection.ConclusionIn critically ill patients undergoing CRRT, daptomycin exposure with once-daily dosing was similar to ICU patients with normal renal function, but lower compared to healthy volunteers. Our data suggest that daptomycin once-daily dosing is appropriate in patients undergoing CRRT.

Pharmacokinetics of Daily Daptomycin in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy

Background: The optimal daptomycin dosing regimen for critically ill patients undergoing continuous renal replacement therapy (CRRT) has still to be established. Methods: Daptomycin pharmacokinetics was determined in 9 patients after administration of 6 mg/kg/day over 5 days. Results: At steady state, which was reached by day 3, the area under the curve over 24 h (AUC24h) was 667.4 ± 356.6 mg·h/l, and the maximum concentration (Cmax) was 66.9 ±25.3 mg/l. Mean CRRT clearance accounted for 48% (range 32-67%) of total clearance (mean 10.2 ml/min, range 6.1-18 ml/min). Significant correlations were observed between Cmax, minimum concentration (Cmin) and AUC24h (R2 = 0.91, p < 0.001, and R2 = 0.94, p < 0.001) and between albumin plasma concentration and free daptomycin (R2 = 0.7, p = 0.009). Conclusion: No significant accumulation occurred with a daily daptomycin dose of 6 mg/kg in patients undergoing CRRT with an effluent flow rate of >30 ml/kg/h. The quantification of trough concentrations (Cmin) appears to be a good surrogate to estimate AUC24h and to monitor daptomycin treatment in patients undergoing CRRT.

Drug safety of macrolide and quinolone antibiotics in a tertiary care hospital: administration of interacting co-medication and QT prolongation

PurposeSome macrolide and quinolone antibiotics (MQABs) are associated with QT prolongation and life-threatening torsade de pointes (TdP) arrhythmia. MQAB may also inhibit cytochrome P450 isoenzymes and thereby cause pharmacokinetic drug interactions (DDIs). There is limited data on the frequency and management of such risks in clinical practice. We aimed to quantify co-administration of MQAB with interacting drugs and associated adverse drug reactions.MethodsWe conducted an observational study within our pharmacoepidemiological database derived from electronic medical records of a tertiary care hospital. Among all users of MQAB associated with TdP, we determined the prevalence of additional QT-prolonging drugs and risk factors and identified contraindicated co-administrations of simvastatin, atorvastatin, or tizanidine. Electrocardiographic (ECG) monitoring and associated adverse events were validated in medical records.ResultsAmong 3444 administered courses of clarithromycin, erythromycin, azithromycin, ciprofloxacin, levofloxacin, or moxifloxacin, there were 1332 (38.7xa0%) with concomitant use of additional QT-prolonging drugs. Among those, we identified seven cases of drug-related QT prolongation, but 49.1xa0% had no ECG monitoring. Of all MQAB users, 547 (15.9xa0%) had hypokalemia. Forty-four MQAB users had contraindicated co-administrations of simvastatin, atorvastatin, or tizanidine and three of those related adverse drug reactions.ConclusionIn the studied real-life setting, we found a considerable number of MQAB users with additional risk factors for TdP but no ECG monitoring. However, adverse drug reactions were rarely found, and costs vs. benefits of ECG monitoring have to be weighted. In contrast, avoidable risk factors and selected contraindicated pharmacokinetic interactions are clear targets for implementation as automated alerts in electronic prescribing systems.

Therapeutic Drug Monitoring of Daptomycin: A Retrospective Monocentric Analysis.

Background: Daptomycin dose is adjusted to body weight and renal function and is usually not guided by therapeutic drug monitoring. Daptomycin plasma concentration measurement was established at our institution in January 2009 and is now increasingly being used. The aim of this study was to describe and characterize variability in daptomycin exposure during routine clinical therapy. Methods: We collected daptomycin plasma concentrations that were measured at our institution during the period January 2009–July 2012. Additional clinical and demographic data and their association with daptomycin exposure were tested by a multilevel linear regression analysis. Results: A total of 332 daptomycin plasma concentrations were determined in 86 patients. Sixty-six percent (n = 218) of all determinations were trough concentrations (Cmin), and 34% (n = 114) were peak concentrations (Cmax). Cmin ranged 2–68 mg/L (median, 16.7 mg/L), and Cmax 20–236 mg/L (median, 66.2 mg/L). A significant positive association of total dose, albumin, creatinine and a significant negative association of dose interval and intermittent hemodialysis with Cmin were found in the regression analysis. Total dose and intensive care unit (ICU) stay were significantly associated with Cmax (P < 0.05). However, only 28% (P < 0.005) of Cmin variability and 8% (P = 0.08) of Cmax variability were explained by the factors included in the analysis. Conclusions: Daptomycin plasma concentrations are often unpredictable as shown by highly variable drug exposure that is only partially explained by dose administered and underlying renal function.