Hospital outcomes of community-acquired COVID-19 versus influenza: Insights from the Swiss hospital-based surveillance of influenza and COVID-19.

BackgroundSince the onset of the COVID-19 pandemic, the disease has frequently been compared with seasonal influenza, but this comparison is based on little empirical data.AimThis study compares in-hospital outcomes for patients with community-acquired COVID-19 and patients with community-acquired influenza in Switzerland.MethodsThis retrospective multi-centre cohort study includes patients > 18 years admitted for COVID-19 or influenza A/B infection determined by RT-PCR. Primary and secondary outcomes were in-hospital mortality and intensive care unit (ICU) admission for patients with COVID-19 or influenza. We used Cox regression (cause-specific and Fine-Gray subdistribution hazard models) to account for time-dependency and competing events with inverse probability weighting to adjust for confounders.ResultsIn 2020, 2,843 patients with COVID-19 from 14 centres were included. Between 2018 and 2020, 1,381 patients with influenza from seven centres were included; 1,722 (61%) of the patients with COVID-19 and 666 (48%) of the patients with influenza were male (p < 0.001). The patients with COVID-19 were younger (median 67 years; interquartile range (IQR): 54-78) than the patients with influenza (median 74 years; IQR: 61-84) (p < 0.001). A larger percentage of patients with COVID-19 (12.8%) than patients with influenza (4.4%) died in hospital (p < 0.001). The final adjusted subdistribution hazard ratio for mortality was 3.01 (95% CI: 2.22-4.09; p < 0.001) for COVID-19 compared with influenza and 2.44 (95% CI: 2.00-3.00, p < 0.001) for ICU admission.ConclusionCommunity-acquired COVID-19 was associated with worse outcomes compared with community-acquired influenza, as the hazards of ICU admission and in-hospital death were about two-fold to three-fold higher.

Evolution of COVID-19 mortality over time: results from the Swiss hospital surveillance system (CH-SUR).

BACKGROUND: When the periods of time during and after the first wave of the ongoing SARS-CoV-2/COVID-19 pandemic in Europe are compared, the associated COVID-19 mortality seems to have decreased substantially. Various factors could explain this trend, including changes in demographic characteristics of infected persons and the improvement of case management. To date, no study has been performed to investigate the evolution of COVID-19 in-hospital mortality in Switzerland, while also accounting for risk factors. METHODS: We investigated the trends in COVID-19-related mortality (in-hospital and in-intermediate/intensive-care) over time in Switzerland, from February 2020 to June 2021, comparing in particular the first and the second wave. We used data from the COVID-19 Hospital-based Surveillance (CH-SUR) database. We performed survival analyses adjusting for well-known risk factors of COVID-19 mortality (age, sex and comorbidities) and accounting for competing risk. RESULTS: Our analysis included 16,984 patients recorded in CH-SUR, with 2201 reported deaths due to COVID-19 (13.0%). We found that overall in-hospital mortality was lower during the second wave of COVID-19 than in the first wave (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.63- 0.78; p <0.001), a decrease apparently not explained by changes in demographic characteristics of patients. In contrast, mortality in intermediate and intensive care significantly increased in the second wave compared with the first wave (HR 1.25, 95% CI 1.05-1.49; p = 0.029), with significant changes in the course of hospitalisation between the first and the second wave. CONCLUSION: We found that, in Switzerland, COVID-19 mortality decreased among hospitalised persons, whereas it increased among patients admitted to intermediate or intensive care, when comparing the second wave to the first wave. We put our findings in perspective with changes over time in case management, treatment strategy, hospital burden and non-pharmaceutical interventions. Further analyses of the potential effect of virus variants and of vaccination on mortality would be crucial to have a complete overview of COVID-19 mortality trends throughout the different phases of the pandemic.

Cohort profile: SARS-CoV-2/COVID-19 hospitalised patients in Switzerland.

BACKGROUND: SARS-CoV-2/COVID-19, which emerged in China in late 2019, rapidly spread across the world with several million victims in 213 countries. Switzerland was severely hit by the virus, with 43,000 confirmed cases as of 1 September 2020. AIM: In cooperation with the Federal Office of Public Health, we set up a surveillance database in February 2020 to monitor hospitalised patients with COVID-19, in addition to their mandatory reporting system. METHODS: Patients hospitalised for more than 24 hours with a positive polymerase chain-reaction test, from 20 Swiss hospitals, are included. Data were collected in a customised case report form based on World Health Organisation recommendations and adapted to local needs. Nosocomial infections were defined as infections for which the onset of symptoms was more than 5 days after the patient’s admission date. RESULTS: As of 1 September 2020, 3645 patients were included. Most patients were male (2168, 59.5%), and aged between 50 and 89 years (2778, 76.2%), with a median age of 68 (interquartile range 54–79). Community infections dominated with 3249 (89.0%) reports. Comorbidities were frequently reported, with hypertension (1481, 61.7%), cardiovascular diseases (948, 39.5%) and diabetes (660, 27.5%) being the most frequent in adults; respiratory diseases and asthma (4, 21.1%), haematological and oncological diseases (3, 15.8%) were the most frequent in children. Complications occurred in 2679 (73.4%) episodes, mostly respiratory diseases (2470, 93.2% in adults; 16, 55.2% in children), and renal (681, 25.7%) and cardiac (631, 23.8%) complications for adults. The second and third most frequent complications in children affected the digestive system and the liver (7, 24.1%). A targeted treatment was given in 1299 (35.6%) episodes, mostly with hydroxychloroquine (989, 76.1%). Intensive care units stays were reported in 578 (15.8%) episodes. A total of 527 (14.5%) deaths were registered, all among adults. CONCLUSION: The surveillance system has been successfully initiated and provides a robust set of data for Switzerland by including about 80% (compared with official statistics) of SARS-CoV-2/COVID-19 hospitalised patients, with similar age and comorbidity distributions. It adds detailed information on the epidemiology, risk factors and clinical course of these cases and, therefore, is a valuable addition to the existing mandatory reporting.

Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy.

Intravenous colistimethate sodium (CMS) is used to treat infections with multiresistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear. In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemodialysis [CVVHD]; median blood flow, 100 ml/min). Intensive sampling was performed on treatment days 1, 3, and 5 after an intravenous CMS loading dose of 9 million international units (MU) (6 MU if body weight was <60 kg) with a consecutive 3-MU (respectively, 2 MU) maintenance dose at 8 h. CMS and colistin concentrations were determined by liquid chromatography with mass spectroscopy. A model-based population pharmacokinetic analysis incorporating CRRT settings was applied to the observations. Sequential model building indicated a monocompartmental distribution for both CMS and colistin, with interindividual variability in both volume and clearance. Hematocrit was shown to affect the efficacy of drug transfer across the filter. CRRT clearance accounted for, on average, 41% of total CMS and 28% of total colistin clearance, confirming enhanced elimination of colistin compared to normal renal function. Target colistin steady-state trough concentrations of at least 2.5 mg/liter were achieved in all patients receiving 3 MU at 8 h. In conclusion, a loading dose of 9 MU followed after 8 h by a maintenance dose of 3 MU every 8 h independent of body weight is expected to achieve therapeutic colistin concentrations in patients undergoing CVVHD using low blood flows. Colistin therapeutic drug monitoring might help to further ensure optimal dosing in individual patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02081560.).

Cerebral venous thrombosis requiring invasive treatment for elevated intracranial pressure in women with combined hormonal contraceptive intake: risk factors, anatomical distribution, and clinical presentation.

OBJECTIVE Women taking combined hormonal contraceptives (CHCs) are generally considered to be at low risk for cerebral venous thrombosis (CVT). When it does occur, however, intensive care and neurosurgical management may, in rare cases, be needed for the control of elevated intracranial pressure (ICP). The use of nonsurgical strategies such as barbiturate coma and induced hypothermia has never been reported in this context. The objective of this study is to determine predictive factors for invasive or surgical ICP treatment and the potential complications of nonsurgical strategies in this population. METHODS The authors conducted a 2-center, retrospective chart review of 168 cases of CVT in women between 2000 and 2012. Eligible patients were classified as having had a mild or a severe clinical course, the latter category including all patients who underwent invasive or surgical ICP treatment and all who had an unfavorable outcome (modified Rankin Scale score ≥ 3 or Glasgow Outcome Scale score ≤ 3). The Mann-Whitney U-test was used for continuous parameters and Fisher's exact test for categorical parameters, and odds ratios were calculated with statistical significance set at p ≤ 0.05. RESULTS Of the 168 patients, 57 (age range 16-49 years) were determined to be eligible for the study. Six patients (10.5%) required invasive or surgical ICP treatment. Three patients (5.3%) developed refractory ICP > 30 mm Hg despite early surgical decompression; 2 of them (3.5%) were treated with barbiturate coma and induced hypothermia, with documented infectious, thromboembolic, and hemorrhagic complications. Coma on admission, thrombosis of the deep venous system with consecutive hydrocephalus, intraventricular hemorrhage, and hemorrhagic venous infarction were associated with a higher frequency of surgical intervention. Coma, quadriparesis on admission, and hydrocephalus were more commonly seen among women with unfavorable outcomes. Thrombosis of the transverse sinus was less common in patients with an unfavorable outcome, with similar distribution in patients needing invasive or surgical ICP treatment. CONCLUSIONS The need for invasive or surgical ICP treatment in women taking CHCs who have CVT is partly predictable on the basis of the clinical and radiological findings on admission. The use of nonsurgical treatments for refractory ICP, such as barbiturate coma and induced hypothermia, is associated with systemic infectious and hematological complications and may worsen morbidity in this patient population. The significance of these factors should be studied in larger multicenter cohorts.

Delayed Sputum Culture Conversion in Tuberculosis-Human Immunodeficiency Virus-Coinfected Patients With Low Isoniazid and Rifampicin Concentrations.

Background: The relationship between concentrations of antituberculosis drugs, sputum culture conversion, and treatment outcome remains unclear. We sought to determine the association between antituberculosis drug concentrations and sputum conversion among patients coinfected with tuberculosis and human immunodeficiency virus (HIV) and receiving first-line antituberculosis drugs. Methods: We enrolled HIV-infected Ugandans with pulmonary tuberculosis. Estimation of first-line antituberculosis drug concentrations was performed 1, 2, and 4 hours after drug intake at 2, 8, and 24 weeks of tuberculosis treatment. Serial sputum cultures were performed at each visit. Time-to-event analysis was used to determine factors associated with sputum culture conversion. Results: We enrolled 268 HIV-infected patients. Patients with low isoniazid and rifampicin concentrations were less likely to have sputum culture conversion before the end of tuberculosis treatment (hazard ratio, 0.54; 95% confidence interval, .37-.77; P = .001) or by the end of follow-up (0.61; .44-.85; P = .003). Patients in the highest quartile for area under the rifampicin and isoniazid concentration-time curves for were twice as likely to experience sputum conversion than those in the lowest quartile. Rifampicin and isoniazid concentrations below the thresholds and weight <55 kg were both risk factors for unfavorable tuberculosis treatment outcomes. Only 4.4% of the participants had treatment failure. Conclusion: Although low antituberculosis drug concentrations did not translate to a high proportion of patients with treatment failure, the association between low concentrations of rifampicin and isoniazid and delayed culture conversion may have implications for tuberculosis transmission. Clinical Trials Registration: NCT01782950.

Cohort profile of a study on outcomes related to tuberculosis and antiretroviral drug concentrations in Uganda: design, methods and patient characteristics of the SOUTH study.

PURPOSE: Tuberculosis (TB) is a leading cause of death among people living with HIV in sub-Saharan Africa. Several factors influence the efficacy of TB treatment by leading to suboptimal drug concentrations and subsequently affecting treatment outcome. The aim of this cohort is to determine the association between anti-TB drug concentrations and TB treatment outcomes. PARTICIPANTS: Patients diagnosed with new pulmonary TB at the integrated TB-HIV outpatient clinic in Kampala, Uganda, were enrolled into the study and started on first-line anti-TB treatment. FINDINGS TO DATE: Between April 2013 and April 2015, the cohort enrolled 268 patients coinfected with TB/HIV ; 57.8% are male with a median age of 34 years (IQR 29-40). The median time between the diagnosis of HIV and the diagnosis of TB is 2 months (IQR 0-22.5). The majority of the patients are antiretroviral therapy naive (75.4%). Our population is severely immunosuppressed with a median CD4 cell count at enrolment of 163 cells/µL (IQR 46-298). Ninety-nine per cent of the patients had a diagnosis of pulmonary TB confirmed by sputum microscopy, Xpert/RIF or culture and 203 (75.7%) have completed TB treatment with 5099 aliquots of blood collected for pharmacokinetic analysis. FUTURE PLANS: This cohort provides a large database of well-characterised patients coinfected with TB/HIV which will facilitate the description of the association between serum drug concentrations and TB treatment outcomes as well as provide a research platform for future substudies including evaluation of virological outcomes. TRIAL REGISTRATION NUMBER: NCT01782950; Pre-results.

Dexmedetomidine-Associated Hyperthermia: A Series of 9 Cases and a Review of the Literature.

Dexmedetomidine, an α2-adrenergic agonist, can be used to perform mild to moderate sedation in critically ill patients. In this case series, 9 cardiovascular intensive care unit patients with hyperthermia during dexmedetomidine administration, suggestive of drug fever, are presented. Hyperthermia (>38.5°C) occurred 6 (4-10) hours (median [interquartile range]) after dexmedetomidine initiation at a dose of 1.0 (0.8-1.3) µg/kg/h and was resolved 3 (1-8) hours after discontinuation of dexmedetomidine. All patients were screened for infectious and noninfectious causes of hyperthermia, and the findings were analyzed by 2 adverse drug reaction (ADR) assessment methods-the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) Causality Assessment and the Naranjo ADR scale. This resulted in a "probable" ADR in all 9 patients (WHO) and a "probable" and "possible" ADR in 1 and 8 patients (Naranjo), respectively. This case series supports published case reports, suggesting that dexmedetomidine administration may be associated with the occurrence of clinically relevant hyperthermia. The underlying mechanisms and risk factors are uncertain and require further research.

Population pharmacokinetics of daptomycin in adult patients undergoing continuous renal replacement therapy.

AIM: The objective of this population pharmacokinetic (PK) analysis was to provide guidance for the dosing interval of daptomycin in patients undergoing continuous renal replacement therapy (CRRT). METHODS: A previously published population PK model for daptomycin was updated with data from patients undergoing continuous veno-venous haemodialysis (CVVHD; n = 9) and continuous veno-venous haemodiafiltration (CVVHDF; n = 8). Model-based simulations were performed to compare the 24 h AUC, Cmax and Cmin of daptomycin following various dosing regimens (4, 6, 8, 10, and 12 mg kg-1 every [Q] 24 h and Q48 h), with the safety and efficacy exposure references for Staphylococcus aureus bacteraemia/right-sided infective endocarditis. RESULTS: The previously developed daptomycin structural population PK model could reasonably describe data from the patients on CRRT. The clearance in patients undergoing CVVHDF and CVVHD was estimated at 0.53 and 0.94 l h-1 , respectively, as compared with 0.75 l h-1 in patients with creatinine clearance (CrCl) ≥ 30 ml min-1 . Daptomycin Q24 h dosing in patients undergoing CRRT resulted in optimal exposure for efficacy, with AUC comparable to that in patients with CrCl ≥ 30 ml min-1 . In contrast, Q48 h dosing was associated with considerably lower AUC24-48h in all patients for doses up to 12 mg kg-1 and is therefore inappropriate. CONCLUSIONS: Q24 h dosing of daptomycin up to 12 mg kg-1 provides comparable drug exposure in patients on CVVHD and in those with CrCl ≥ 30 ml min-1 . Daily daptomycin use up to 8 mg kg-1 doses are appropriate for patients on CVVHDF, but higher doses may increase the risk of toxicity.

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

PURPOSE: Some 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. METHODS: We 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. RESULTS: Among 3444 administered courses of clarithromycin, erythromycin, azithromycin, ciprofloxacin, levofloxacin, or moxifloxacin, there were 1332 (38.7 %) with concomitant use of additional QT-prolonging drugs. Among those, we identified seven cases of drug-related QT prolongation, but 49.1 % had no ECG monitoring. Of all MQAB users, 547 (15.9 %) had hypokalemia. Forty-four MQAB users had contraindicated co-administrations of simvastatin, atorvastatin, or tizanidine and three of those related adverse drug reactions. CONCLUSION: In 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.

Cure of tuberculosis despite serum concentrations of antituberculosis drugs below published reference ranges.

PRINCIPLES: Therapeutic target serum concentrations of first-line antituberculosis drugs have not been well defined in clinical studies in tuberculosis (TB) patients. METHODS: We retrospectively investigated the estimated maximum serum concentrations (eC max) of antituberculosis drugs and clinical outcome of TB patients with therapeutic drug monitoring performed between 2010-2012 at our institution, and follow-up until March 2014. The eC max was defined as the highest serum concentration during a sampling period (2, 4 and 6 hours after drug ingestion). We compared the results with published eC max values, and categorised them as either "within reference range", "low eC max", or "very low eC max".Low/very low eC max-levels were defined as follows: isoniazid 2-3/<2 mg/l, rifampicin 4-8/<4 mg/l, rifabutin 0.2-0.3/<0.2 mg/l, ethambutol 1-2/<0.1 mg/l and pyrazinamide <20 mg/l. RESULTS: Concentrations of antituberculosis drugs in 175 serum samples of 17 patients with TB were analysed. In 12 (71%) patients, multiple therapeutic drug monitoring samples were collected over time, in 5 (29%) patients only one sample was available for therapeutic drug monitoring. Overall, 94% of all patients had at least one low antituberculosis drug concentration. Overall, 64% of all eC max levels were classified as "low" or "very low". The eC max was below the relevant reference range in 80% of isoniazid, 95% of rifampicin, 30% of pyrazinamide, and 30% of ethambutol measurements. All but one patient were cured of tuberculosis. CONCLUSIONS: Although many antituberculosis drug serum concentrations were below the widely used reference ranges, 16 of 17 patients were cured of tuberculosis. These results challenge the use of the published reference ranges for therapeutic drug monitoring.

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.

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 resort's 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.

Low isoniazid and rifampicin concentrations in TB/HIV co-infected patients in Uganda.

INTRODUCTION: There is limited data available on exposure to anti-tuberculosis (TB) drugs in this region. Peloquin has described reference ranges [1] however some studies have demonstrated that patients actually achieve concentrations below these ranges [2]. There is limited data about exposure to anti-TB drugs in the HIV/TB co-infected population in Sub-Saharan Africa. Our objective is to describe the concentration of anti-TB drug levels in a well characterized prospective cohort of adult patients starting treatment for pulmonary TB. METHODS: This study is an ongoing study carried out in the TB/HIV integrated clinic at the Infectious Diseases Institute in Kampala, Uganda. Sputum culture and microscopy was done for all patients. We performed pharmacokinetic blood sampling of anti-TB drugs for 1 hour, 2 hours and 4 hours post dose at 2 weeks, 8 weeks and 24 weeks after initiation of anti-TB treatment using ultraviolet high-performance liquid chromatography (UV-HPLC). We described the maximum concentration (Cmax) of isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) and compare them with the values observed by Peloquin et al. referenced in other studies. RESULTS: We started 113 HIV infected adults on a fixed dose combination of HREZ. The median age of our population was 33 years, of which 52% were male with a median BMI of 19 kg/m(2) and a median CD4 cell count of 142 cells/µL. In 90% of the participants, the diagnosis of TB was based on microscopy and or cultures. The boxplot graph shows the median Cmax and IQR of H and R. CONCLUSION: We observed lower concentrations of isoniazid and rifampicin in our study population of HIV/TB co-infected patients. The implications of these findings are not yet clear. We therefore need to correlate our findings with the response to TB treatment.

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 (R(2) = 0.91, p < 0.001, and R(2) = 0.94, p < 0.001) and between albumin plasma concentration and free daptomycin (R(2) = 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.

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.

Predictors of appropriate ICD therapy in patients with arrhythmogenic right ventricular cardiomyopathy: long term experience of a tertiary care center.

INTRODUCTION: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetically transmitted disease prone to ventricular arrhythmias. We therefore investigated the clinical, echocardiographical and electrophysiological predictors of appropriate implantable cardioverter defibrillator (ICD) therapy in patients with ARVC. METHODS: A retrospective analysis was performed in 26 patients (median age of 40 years at diagnosis, 21 males and 5 females) with ARVC who underwent ICD implantation. RESULTS: Over a median (range) follow-up period of 10 (2.7, 37) years, appropriate ICD therapy for ventricular arrhythmias was documented in 12 (46%) out of 26 patients. In all patients with appropriate ICD therapy the ICD was originally inserted for secondary prevention. Median time from ICD implantation to ICD therapy was 9 months (range 3.6, 54 months). History of heart failure was a significant predictor of appropriate ICD therapy (p = 0.033). Left ventricular disease involvement (p = 0.059) and age at implantation (p = 0.063) were borderline significant predictors. Patients with syncope at time of diagnosis were significantly less likely to receive ICD therapy (p = 0.02). Invasive electrophysiological testing was not significantly associated with appropriate ICD therapy. CONCLUSION: In our cohort of patients with ARVC, history of heart failure was a significant predictor of appropriate ICD therapy, whereas left ventricular involvement and age at time of ICD implantation were of borderline significance. These predictors should be tested in larger prospective cohorts to optimize ICD therapy in this rare cardiomyopathy.

Drug-related problems and factors influencing acceptance of clinical pharmacologists` alerts in a large cohort of neurology inpatients.

QUESTIONS UNDER STUDY/PRINCIPLES: Data regarding the prevalence and types of drug-related problems (DRPs) among neurology inpatients is sparse. The objective of this study was to characterise the types of DRPs seen among neurology inpatients and furthermore to study factors affecting the acceptance of clinical pharmacologists' and pharmacists' recommendations for improving drug safety. METHODS: 1,263 consecutive inpatient cases in a Swiss university hospital neurology unit were assessed for the presence of DRPs over 12 months. Treating neurologists' acceptance of the resulting recommendations was also recorded. Primary outcome measures were types of DRP, recommendations made by clinical pharmacologists and number of recommendations accepted. Factors potentially associated with acceptance were studied using univariate and multivariate generalised estimating equation modelling. RESULTS: Twenty-nine percent of cases demonstrated one or more DRPs. DRPs were the cause of admission in 10 cases (0.8%). In total 494 DRPs were identified and 467 recommendations given, of which 62% were accepted. Factors associated with an increased likelihood of acceptance were prescriptions involving regularly administered drugs (odds ratio [OR] 2.57 95% confidence interval [CI] 1.73-3.80), adverse drug events (OR 2.5; 95% CI 1.29-5.06), known drug side-effect (OR 1.85; 95% CI 1.06-3.22), high-risk drug-drug interactions (OR 3.22; 95% CI 1.07-9.69) and interventions involving changing a drug (OR 2.71; 95% CI 1.17-6.25). CONCLUSION: Clinical pharmacologists and pharmacists can play an important role in identifying DRPs among neurology inpatients. Their recommendations for optimising medication-safety are most likely to be accepted for regular prescriptions, prescriptions associated with an adverse drug event and high-risk drug combinations.

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.