Empiric guideline-recommended weight-based vancomycin dosing and nephrotoxicity rates in patients with methicillin-resistant Staphylococcus aureus bacteremia: a retrospective cohort study.

BACKGROUND: Previous studies have established a correlation between vancomycin troughs and nephrotoxicity. However, data are currently lacking regarding the effect of guideline-recommended weight-based dosing on nephrotoxicity in methicillin-resistant Staphylococcus aureus bacteremia (MRSAB). METHODS: Adults who were at least 18 years of age with methicillin-resistant Staphylococcus aureus bacteremia and received of empiric vancomycin therapy for at least 48 hours (01/07/2002 and 30/06/2008) were included in this multicenter, retrospective cohort study. The association between guideline-recommended, weight-based vancomycin dosing (at least 15 mg/kg/dose) and nephrotoxicity (increase in serum creatinine (SCr) by more than 0.5 mg/dl or at least a 50% increase from baseline on at least two consecutive laboratory tests) was evaluated. Potential independent associations were evaluated using a multivariable general linear mixed-effect model. RESULTS: Overall, 23% of patients developed nephrotoxicity. Thirty-four percent of the 337 patients who met study criteria received weight-based dosing. The cohort was composed of 69% males with a median age of 55 years. The most common sources of MRSAB included skin/soft tissue (32%), catheter-related bloodstream bacteremia (20%), pulmonary (18%). Eighty-six percent of patients received twice daily dosing. Similar rates of nephrotoxicity were observed regardless of the receipt of guideline-recommended dosing (22% vs. 24%, OR 0.91 [95% CI 0.53-1.56]). This finding was confirmed in the multivariable analysis (OR 1.52 [95% CI 0.75-3.08]). Independent predictors of nephrotoxicity were (OR, 95% CI) vancomycin duration of greater than 15 days (3.36, 1.79-6.34), weight over 100 kg (2.74, 1.27-5.91), Pitt bacteremia score of 4 or greater (2.73, 1.29-5.79), vancomycin trough higher than 20 mcg/ml (2.36, 1.07-5.20), and age over 52 years (2.10, 1.08-4.08). CONCLUSIONS: Over one out of five patients in this study developed nephrotoxicity while receiving vancomycin for MRSAB. The receipt of guideline-recommended, weight-based vancomycin was not an independent risk factor for the development of nephrotoxicity.

Empiric guideline-recommended weight-based vancomycin dosing and mortality in methicillin-resistant Staphylococcus aureus bacteremia: a retrospective cohort study.

BACKGROUND: No studies have evaluated the effect of guideline-recommended weight-based dosing on in-hospital mortality of patients with methicillin-resistant Staphylococcus aureus bacteremia. METHODS: This was a multicenter, retrospective, cohort study of patients with methicillin-resistant Staphylococcus aureus bacteremia receiving at least 48 hours of empiric vancomycin therapy between 01/07/2002 and 30/06/2008. We compared in-hospital mortality for patients treated empirically with weight-based, guideline-recommended vancomycin doses (at least 15 mg/kg/dose) to those treated with less than 15 mg/kg/dose. We used a general linear mixed multivariable model analysis with variables identified a priori through a conceptual framework based on the literature. RESULTS: A total of 337 patients who were admitted to the three hospitals were included in the cohort. One-third of patients received vancomycin empirically at the guideline-recommended dose. Guideline-recommended dosing was not associated with in-hospital mortality in the univariable (16% vs. 13%, OR 1.26 [95%CI 0.67-2.39]) or multivariable (OR 0.71, 95%CI 0.33-1.55) analysis. Independent predictors of in-hospital mortality were ICU admission, Pitt bacteremia score of 4 or greater, age 53 years or greater, and nephrotoxicity. CONCLUSIONS: Empiric use of weight-based, guideline-recommended empiric vancomycin dosing was not associated with reduced mortality in this multicenter study.

Treatment of Alzheimer disease.

Alzheimer disease is the most common form of dementia, affecting nearly one-half [corrected] of Americans older than 85 years. It is characterized by progressive memory loss and cognitive decline. Amyloid plaque accumulation, neurofibrillary tau tangles, and depletion of acetylcholine are among the pathologic manifestations of Alzheimer disease. Although there are no proven modalities for preventing Alzheimer disease, hypertension treatment, omega-3 fatty acid supplementation, physical activity, and cognitive engagement demonstrate modest potential. Acetylcholinesterase inhibitors are first-line medications for the treatment of Alzheimer disease, and are associated with mild improvements in cognitive function, behavior, and activities of daily living; however, the clinical relevance of these effects is unclear. The most common adverse effects of acetylcholinesterase inhibitors are nausea, vomiting, diarrhea, dizziness, confusion, and cardiac arrhythmias. Short-term use of the N-methyl-D-aspartate receptor antagonist memantine can modestly improve measures of cognition, behavior, and activities of daily living in patients with moderate to severe Alzheimer disease. Memantine can also be used in combination with acetylcholinesterase inhibitors. Memantine is generally well tolerated, but whether its benefits produce clinically meaningful improvement is controversial. Although N-methyl-D-aspartate receptor antagonists and acetylcholinesterase inhibitors can slow the progression of Alzheimer disease, no pharmacologic agents can reverse the progression. Atypical antipsychotics can improve some behavioral symptoms, but have been associated with increased mortality rates in older patients with dementia. There is conflicting evidence about the benefit of selegiline, testosterone, and ginkgo for the treatment of Alzheimer disease. There is no evidence supporting the beneficial effects of vitamin E, estrogen, or nonsteroidal anti-inflammatory drug therapy.

Vancomycin-associated nephrotoxicity: grave concern or death by character assassination?

Vancomycin-associated nephrotoxicity was reported in 0% to 5% of patients in the 1980s. This has been confirmed by numerous clinical trials comparing novel anti-methicillin-resistant Staphylococcus aureus agents with vancomycin at the Food and Drug Administration-approved dosage of 1 g every 12 hours. Treatment failures of vancomycin in patients with methicillin-resistant S. aureus infections have been reported despite in vitro susceptibility. These failures have led to the use of vancomycin doses higher than those approved by the Food and Drug Administration. Higher doses are being administered to achieve goal vancomycin trough concentrations of 10 to 20 microg/mL recommended by several clinical practice guidelines endorsed by the Infectious Diseases Society of America. Recent studies suggest that increased rates of nephrotoxicity are associated with aggressive vancomycin dosing. These increased rates are confounded by concomitant nephrotoxins, renal insufficiency, or changing hemodynamics. These studies also have demonstrated that vancomycin's nephrotoxicity risk is minimal in patients without risk factors for nephrotoxicity. Clinicians unwilling to dose vancomycin in accordance with clinical practice guidelines should use an alternative agent because inadequate dosing increases the likelihood of selecting heteroresistant methicillin-resistant S. aureus isolates.

Advances in oral anticoagulants: focus on dabigatran etexilate.

Vitamin K antagonists, predominantly warfarin, have been the cornerstone of anticoagulation therapy for many decades. However, warfarin use is associated with limitations such as a slow onset of action, a narrow therapeutic index, numerous drug interactions, and frequent monitoring is required of prothrombin time and the international normalized ratio. These shortcomings prompted the development of new oral anticoagulants. Dabigatran etexilate is a novel, oral, reversible, direct thrombin inhibitor that acts on the terminal steps of the coagulation cascade overcoming many of warfarin's limitations. Currently, dabigatran etexilate is approved in multiple regions including Europe and Canada, for the primary prevention of venous thromboembolism in adults who have undergone total hip replacement or total knee replacement surgery. A Phase III trial demonstrated noninferiority of dabigatran etexlitate compared with warfarin for the prevention of stroke in patients with atrial fibrillation, and one Phase III trial showed superiority. There are several ongoing trials investigating the acute treatment of venous thromboembolism.

Effect of oral corticosteroids on chronic warfarin therapy.

BACKGROUND: A potential drug interaction exists between oral corticosteroids and warfarin, but there is limited documentation. OBJECTIVE: To evaluate the potential drug interaction between oral corticosteroids and long-term warfarin therapy. METHODS: A retrospective review was conducted of 387 medical records for active patients within an anticoagulation clinic. Inclusion criteria were stable anticoagulation therapy, short-term oral corticosteroid therapy, international normalized ratio (INR) recorded within 30 days prior to corticosteroid initiation (pre-INR), and INR recorded during corticosteroid therapy or within 14 days of discontinuation (post-INR). Patients were excluded if they had been started on any antibiotic or other drug with a probable interaction with warfarin at the same time as corticosteroid initiation. Thirty-two patient encounters met the predetermined inclusion and exclusion criteria. The primary outcome assessed was the difference between pre- and post-INR values. Secondary endpoints included bleeding events, emergency department (ED) visits, hospitalizations, and warfarin dose modifications. RESULTS: The mean difference between pre- and post-INR values was 1.24 (95% CI 0.86 to 1.62). Ninety-seven percent of the 32 patient encounters resulted in a change in their post-INR value, and 62.5% of patients had supratherapeutic INR values at the post-corticosteroid assessment. The majority of patients assessed had an elevation of their INR following concomitant use of warfarin and corticosteroids. The INR change was observed at a mean +/- SD of 6.7 +/- 3.3 days following the first dose of corticosteroid. Overall, 16 patients (50%) required a modification of their anticoagulation therapy during or following corticosteroid therapy. Only one adverse event of minor epistaxis was reported, and no ED visits or hospitalizations occurred as a consequence of the drug combination. CONCLUSIONS: Use of oral corticosteroids in patients on long-term warfarin therapy may result in a clinically significant interaction, which requires close INR monitoring and possible warfarin dose reduction.