Left ventricular assist device-related infections: does the time of onset matter?

A frequent complication of left ventricular assist devices (LVAD) is the LVAD-associated infections (LVADIs). Contamination may occur during initial surgery/admission or at a later time. We studied the clinical manifestations and outcomes of LVADIs depending on the time of the onset. Patients implanted with LVADs at our institution between August 2009 and December 2014 were included. Patients were stratified into 2 groups based on whether the infection occurred early (< 180 days) or late (≥ 180 days) after LVAD implantation. Out of 37 overall LVADI episodes, 16 (43%) and 21 (57%) occurred early or late after device implantation, respectively. Median time to first LVADI was 88 ± 35 vs. 456 ± 187 days between groups. While superficial driveline-related infection was the most common LVADI type for both groups (56 vs. 71%, p = 0.489), driveline drainage was more prevalent in the late group (24 vs. 69%; p = 0.009). Early LVADIs involved more gram-positive flora, mostly Staphylococcus aureus (69 vs. 33%, p = 0.049), whereas late LVADIs involved more gram-negative pathogens, mostly Pseudomonas aueroginosa (25 vs. 57%; p = 0.045). High rates of treatment failure were consistent between groups (88 vs. 71%, p = 0.384). Compared with superficial LVADI, deeper infections were associated with an increase in mortality (13 vs 46%, p = 0.046). We concluded that early onset with likely in-hospital contamination involved more gram-positive flora, whereas late infection involved more gram-negative flora. Regardless of timing, success of antibacterial treatment was dismal, and infection depth correlated with poorer outcomes.

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.

Can Pharmacokinetic and Pharmacodynamic Principles Be Applied to the Treatment of Multidrug-Resistant Acinetobacter?

OBJECTIVE: To discuss treatment options that can be used for treatment of Acinetobac/erinfections. DATA SOURCES: A MEDLINE search (1966-November 2010) was conducted to identify English-language literature on pharmacotherapy of Acinetobacter and the bibliographies of pertinent articles. Programs and abstracts from infectious diseases meetings were also searched. Search terms included Acinetobacter, multidrug resistance, pharmacokinetics, pharmacodynamics, Monte Carlo simulation, nosocomial pneumonia, carbapenems, polymyxins, sulbactam, aminoglycosides, tetracyclines, tigecycline, rifampin, and fluoroquinolones. DATA SELECTION AND DATA EXTRACTION: All articles were critically evaluated and all pertinent information was included in this review. DATA SYNTHESIS: Multidrug resistant (MDR) Acinetobacter, defined as resistance to 3 or more antimicrobial classes, has increased over the past decade. The incidence of carbapenem-resistant Acinetobacter is also increasing, leading to an increased use of dose optimization techniques and/or alternative antimicrobials, which is driven by local susceptibility patterns. However, Acinetobacter infections that are resistant to all commercially available antibiotics have been reported. General principles are available to guide dose optimization of aminoglycosides, ß-lactams, fluoroquinolones, and tigecycline for infections due to gram-negative pathogens. Unfortunately, data specific to patients with Acinetobacter infections are limited. Recent pharmacokinetic-pharmacodynamic information has shed light on colistin dosing. The dilemma with colistin is its concentration-dependent killing, which makes once-daily dosing seem like an attractive option, but its short postantibiotic effect limits a clinician's ability to extend the dosing interval. Localized delivery of antimicrobials is also an attractive option due to the ability to increase drug concentration at the infection site while minimizing systemic adverse events, but more data are needed regarding this approach. CONCLUSIONS: Increased reliance on dosage optimization, combination therapy, and localized delivery of antimicrobials are methods to pursue positive clinical outcomes in MDR Acinetobacter infections since novel antimicrobials will not be available for several years. Well-designed clinical trials with MDR Acinetobacter are needed to define the best treatment options for these patients.

Empiric therapy for gram-negative pathogens in nosocomial and health care-associated pneumonia: starting with the end in mind.

Nosocomial pneumonia is a major cause of morbidity and mortality for hospitalized patients. Antimicrobial resistance is increasing, creating a strain between ensuring the provision of adequate empiric therapy and slowing the development of antimicrobial resistance. Excessive antimicrobial therapy places patients are at greater risk of drug interactions, adverse events, and superinfections. Ways to maximize adequate empiric therapy include (1) categorizing each patient's risk of being infected with a multidrug-resistant pathogen and knowledge of local susceptibility patterns, (2) de-escalating antimicrobial therapy to decrease the rates of superinfections such as Clostridium difficile, and (3) limiting the duration of therapy to decrease the likelihood of adverse events, drug interactions, and antimicrobial resistance. Pharmacodynamically enhanced dosing regimens also have the potential to improve clinical outcomes and slow the development of antimicrobial resistance. Drugs whose killing is optimized by the percentage time above the minimum inhibitory concentration (MIC), such as beta-lactams, can be given by continuous or extended infusion to provide superior pharmacodynamic (PD) target attainment rates compared with traditional regimens. Drugs whose killing is optimized with a high-peak plasma concentration to MIC ratio (eg, aminoglycosides) should be administered once daily to maximize the likelihood of achieve optimal target attainment rates. Drugs whose killing is optimized by the ratio of the area under the curve (AUC) to MIC ratio (eg, fluoroquinolones) depend on the total daily dose as opposed to the dosing schedule or infusion time. Determining the optimal drug dosing schedules for obese patients remains critical because these patients have may have significantly increased volumes of distribution and clearance rates compared to normal weight patients. Optimizing the use of current antimicrobials is paramount to ensure quality treatment options are available, given the lack of gram-negative antimicrobials in the pipeline.

Musculoskeletal toxicities in patients receiving concomitant statin and daptomycin therapy.

PURPOSE: This article evaluates the musculoskeletal safety of concomitant therapy with daptomycin and Hydroxymethylglutaryl-coenzyme A (HMG CoA) reductase inhibitors (statins). SUMMARY: Often indicated for severe gram-positive infections, daptomycin is commonly administered with statins but there is limited guidance on the appropriate management of concomitant therapy with daptomycin and statins. A narrative review was conducted to review contemporary clinical evidence of the safety of concomitant therapy with daptomycin and statins. A total of 5 studies were identified comparing daptomycin monotherapy versus daptomycin and statin concomitant therapy for the primary outcome of creatine phosphokinase (CPK) elevations in a variety of patient populations with systemic, skin/soft tissue, and bone/joint infections. Of these studies, 4 also compared myalgia or myopathy as a secondary outcome. Case studies, the case-control study and 1 prospective registry comparing statin alone versus daptomycin and statin concomitant therapy were excluded. These studies showed that concomitant therapy with daptomycin and statin was not significantly associated with CPK elevation or higher event rate of myalgia or myopathy, compared to daptomycin monotherapy. CONCLUSION: Published cohort studies do not demonstrate a statistically significant difference in the rate of CPK elevations or musculoskeletal toxicities between patients receiving daptomycin monotherapy and daptomycin plus a statin. Patients receiving statins who start daptomycin therapy should continue statin but with weekly monitoring of CPK levels. Continuation of statins is especially important in high-risk patients receiving statins for secondary prevention for atherosclerotic cardiovascular diseases. If myalgia develops, it is reasonable to evaluate the degree of CPK elevation and reassess the need for statin use during daptomycin treatment.

Key articles and guidelines in the management of acute coronary syndromes and in percutaneous coronary intervention: 2007 update.

Clinical evidence in the management of acute coronary syndromes (ACS) and in percutaneous coronary intervention (PCI) continues to evolve at a rapid pace. For clinicians to provide optimal care for these patients, it is important to keep up with new information as it becomes available. With the existence of numerous pharmacologic agents, abundance of major clinical trials, and several nationally recognized clinical guidelines, compiling the needed reference material to make evidence-based decisions on the care of patients with ACS or those undergoing PCI can be difficult for clinicians. Therefore, we provide an update to the first compiled bibliography of key articles and guidelines relative to patients with ACS published in Pharmacotherapy in 2004. A number of guidelines and practice-changing literature have been published since the initial 2004 document. We hope that this compilation will serve as a resource for pharmacists, physicians, nurses, residents, and students responsible for the care of patients with coronary heart disease.

Chronologic Changes and Correlates of Loop Diuretic Dose in Patients with Left Ventricular Assist Device.

No study has systematically evaluated the prevalence and dosages of diuretic use for patients after left ventricular assist device (LVAD) implantation. The primary objective was to characterize chronologic change in prevalence and doses of loop diuretics after LVAD placement. The secondary objective was to identify correlates of actual doses of loop diuretics. We retrospectively reviewed medical records of adult patients with LVAD implantation at the University of Kentucky. Prevalence of diuretic use and furosemide equivalent dose were assessed before LVAD implantation and at seven time points thereafter: 1 week, 1 month, 3 months, 6 months, 1 year, 18 months, and 2 years. Correlation analyses and linear mixed modeling were used to identify correlates of diuretic dose before and after LVAD implantation. Eighty-two consecutive eligible patients were reviewed. The prevalence of loop diuretic use was 95% at baseline but significantly lower than that at all subsequent time points (p < 0.048 for all). Nevertheless, more than half of patients on whom we had such follow-up data were on loop diuretics 2 years after LVAD implantation. Average furosemide equivalent dose was significantly lower at every time point after implantation compared with baseline (p < 0.006 for all). Blood urine nitrogen (BUN) was the most robust predictor of dose after LVAD implant. The prevalence and average furosemide equivalent dose were significantly reduced after LVAD implantation, but the use of loop diuretic remained more than 50% for up to 2 years. Consistent association with BUN may indirectly indicate overuse of diuretics post-LVAD implant.

Amiodarone use in patients with documented allergy to iodine-containing compounds.

The popularity of amiodarone has grown due to its effectiveness in converting arrhythmia and its formulation availability. Formulations of the drug also contain iodine; the iodine content is 75 mg in a 200-mg tablet of amiodarone and 18.7 mg/ml in the intravenous solution. Approximately 10% of the iodine content of oral amiodarone is released into the circulatory system and may increase the risks of hypersensitivity reactions in iodine-sensitive patients. Documented allergies to contrast media or shellfish should not imply that a patient is allergic to iodine. Reactions to contrast media are likely due to the high osmolar or ionic content of the dye. The primary allergen in shellfish that stimulates allergic reactions is tropomyosin. Although amiodarone can cause thyroid disorders due to the high iodine load delivered to the body with each dose, no known association exists between amiodarone and reactions to contrast media or shellfish. Three patients whose medical charts listed an allergy to iodine were administered amiodarone for chemical cardioversion of arrhythmia to normal sinus rhythm. No anaphylactic or anaphylactoid reactions were observed in any of the patients during oral or intravenous amiodarone administration. In patients with true iodine hypersensitivity, however, the potential for such reactions exists.

Dose Related Patterns of Ventricular Arrhythmia due to Carvedilol Withdrawal in Patients with Systolic Heart Failure.

OBJECTIVES: This study evaluates the impact of carvedilol dose changes on the ventricular arrhythmia event rates for patients > 18 years of age with systolic heart failure and examines dose dependent effects of carvedilol withdrawal in dose reduction and discontinuation subgroups. METHODS: This retrospective cohort study included patients with systolic heart failure (EF < 40%) receiving carvedilol. The primary outcome was incidence of ventricular arrhythmia. Ventricular arrhythmia event rates were compared among carvedilol dose continuation, reduction and discontinuation groups. To assess dose dependent effects of beta-blocker withdrawal, dose reduction and discontinuation groups were divided into subgroups. RESULTS: Dose discontinuation (n=64) or reduction group (n=83) had significantly higher ventricular arrhythmia rates compared with dose continuation group (n=262) (65.6 vs. 33.7 vs. 15.3%, p < 0.001 for both comparisons). Dose discontinuation group also had a significantly higher ventricular arrhythmia event rate compared with dose reduction group (p<0.001). There were no significant differences in ventricular arrhythmia event rates among dose discontinuation or reduction subgroups. CONCLUSION: Continuation of carvedilol therapy was associated with a substantially lower ventricular arrhythmia event rate compared with reduction or discontinuation of carvedilol therapy. Dose dependent effects of beta-blocker withdrawal in subgroup analyses were not found.

The role of the clinical pharmacist in the care of patients with cardiovascular disease.

Team-based cardiovascular care, including the use of clinical pharmacists, can efficiently deliver high-quality care. This Joint Council Perspectives paper from the Cardiovascular Team and Prevention Councils of the American College of Cardiology provides background information on the clinical pharmacist's role, training, certification, and potential utilization in a variety of practice models. Selected systematic reviews and meta-analyses, highlighting the benefit of clinical pharmacy services, are summarized. Clinical pharmacists have a substantial effect in a wide variety of roles in inpatient and ambulatory settings, largely through optimization of drug use, avoidance of adverse drug events, and transitional care activities focusing on medication reconciliation and patient education. Expansion of clinical pharmacy services is often impeded by policy, legislation, and compensation barriers. Multidisciplinary organizations, including the American College of Cardiology, should support efforts to overcome these barriers, allowing pharmacists to deliver high-quality patient care to the full extent of their education and training.

Key articles and guidelines relative to treatment of patients with acute coronary syndromes.

Patients with cardiovascular disease who have acute coronary syndromes (ACS) are at risk of significant morbidity and mortality. Also, treatment of these patients in the early-phase setting has a significant financial impact on the health care system. With the existence of numerous pharmacologic agents, abundance of major clinical trials, and several nationally recognized clinical guidelines, compiling the needed reference material to make evidence-based decisions on the care of patients with ACS can be difficult for clinicians. To assist clinicians in this endeavor, we complied pertinent articles and guidelines that have shaped the current treatment of patients with ACS. Owing to the rapidly evolving body of evidence in the management of ACS, this compilation will require periodic updating.

Empiric weight-based vancomycin in intensive care unit patients with methicillin-resistant Staphylococcus aureus bacteremia.

BACKGROUND: Previous studies were conducted in all hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia to determine safety and effectiveness of guideline-recommended, weight-based dosing of vancomycin. In these studies, it was observed that severely ill patients (Pitt bacteremia score ≥4 or intensive care unit [ICU] patients) were at an increased risk of mortality and/or nephrotoxicity. Therefore, a subanalysis of the effect of guideline-recommended vancomycin dosing on in-hospital mortality and nephrotoxicity in ICU patients with MRSA bacteremia was conducted. METHODS: This multicenter, retrospective, cohort study was conducted in a subset of ICU patients from a previous MRSA bacteremia study. Patients were ≥18 years old and received ≥48 hours of empiric vancomycin from July 1, 2002, to June 30, 2008. The incidence of nephrotoxicity and in-hospital mortality was compared in patients who received guideline-recommended dosing (at least 15 mg/kg per dose) to patients who received non-guideline-recommended dosing of vancomycin. Multivariable generalized linear mixed-effects models were constructed to determine independent risk factors for in-hospital mortality and nephrotoxicity. RESULTS: Guideline-recommended dosing was received by 34% of patients (n = 137). Nephrotoxicity occurred in 35% of patients receiving guideline-recommended dosing and 39% receiving non-guideline-recommended dosing (P = 0.67). In-hospital mortality rate was 24% among patients who received guideline-recommended dosing compared with 31% for non-guideline-recommended dosing (P = 0.40). Guideline-recommended dosing was not associated with nephrotoxicity (odds ratio: 1.10; 95% confidence interval: 0.43-2.79) or in-hospital mortality (odds ratio: 0.54; 95% confidence interval: 0.22-1.36) in the multivariable analysis. CONCLUSIONS: Guideline-recommended dosing of vancomycin in ICU patients with MRSA bacteremia is not significantly associated with nephrotoxicity or in-hospital mortality. However, the 7% absolute difference for in-hospital mortality suggests that larger studies are needed.

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.

Perioperative management of antiplatelet agents.

Perioperative management of antiplatelet agents is a common challenge with the increased number of patients requiring long-term therapy following coronary stenting. Debate currently exists regarding if and when to discontinue antiplatelet therapy prior to elective surgery. The delicate balance between decreasing the risk of bleeding intraoperatively and minimizing the risk of stent thrombosis in patients who are already at a high thrombotic risk is a major concern. This article summarizes the information available for perioperative management of common antiplatelet agents, as well as antiplatelet agents in development.

Ranolazine for the treatment of refractory angina in a veterans population.

BACKGROUND: Pivotal ranolazine trials did not require optimization of conventional medical therapy including coronary revascularization and antianginal drug therapy prior to ranolazine use. This case series describes the use of ranolazine for the treatment of chronic stable angina refractory to maximal medical treatment in a veterans population. RESULTS: A total of 18 patients with a median age of 66 years were identified. All patients had prior percutaneous coronary intervention and/or coronary artery bypass graft surgery; 83% had three-vessel coronary artery disease, with left main disease present in 39% of patients. Prior to initiating ranolazine, antianginal use consisted of beta blockers (94%), long-acting nitrates (83%) and calcium channel blockers (61%). Median blood pressure (116.2/61.8 mmHg) and pulse (65 beats per min) were controlled. Median preranolazine angina episodes and sublingual nitroglycerin (SLNTG) doses per week were 14 and 10, respectively, with a Canadian Cardiovascular Society (CCS) angina grade of III-IV in 67% of patients. After initiation of ranolazine, median angina episodes per week and SLNTG doses used per week decreased to 0.7 and 0, respectively, with CCS grade of III-IV declining to 17%. Of the 18 subjects enrolled, 44% had complete resolution of angina episodes. CONCLUSION: The addition of ranolazine to maximally tolerated conventional antianginal drug therapy post coronary revascularization was associated with decreases in angina episodes and SLNTG utilization and improvement in CCS angina grades. Ranolazine may provide an effective treatment option for revascularized patients with refractory angina.

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.

Evaluation of bleeding complications associated with glycoprotein IIb/IIIa inhibitors.

BACKGROUND: Platelet glycoprotein IIb/IIIa inhibitors are used with aspirin and heparin to decrease rates of death, myocardial infarction, and urgent revascularization in patients with acute coronary syndromes. OBJECTIVE: To determine whether bleeding event rates differed among 3 glycoprotein IIb/IIIa inhibitors prescribed in a high-risk, elderly veteran population and identify risk factors for bleeding. METHODS: A retrospective chart analysis of patients who received abciximab, eptifibatide, or tirofiban was conducted. chi(2) Analysis evaluated the incidence of bleeding complications, and stepwise regression analysis was utilized to identify bleeding risk factors. Parameters evaluated as possible risk factors for bleeding included age, renal function, weight, heparin and glycoprotein IIb/IIIa inhibitor dosing and infusion duration, concomitant antiplatelet and/or anticoagulant medications or disease states, and baseline hemoglobin, hematocrit, or platelet counts. RESULTS: Of 348 patients whose charts were reviewed, 79 patients were included. There were 37.9% who received abciximab (n = 30), 30.3% who received eptifibatide (n = 24), and 31.6% who received tirofiban (n = 25). Twenty-one bleeding events not related to coronary artery bypass grafting occurred: only 1 major bleed (tirofiban) and 20 minor bleeds. Bleeding rates were not significantly different between groups: abciximab 30% (n = 9), eptifibatide 21% (n = 5), and tirofiban 28% (n = 7). Significant risk factors for bleeding included patient weight, infusion duration, and baseline platelet count (p = 0.024). Patients who bled received significantly more transfusions of packed red blood cells and platelets than patients with no bleeding (p = 0.047). CONCLUSIONS: Although bleeding complications did not differ significantly between the 3 drugs, several risk factors for bleeding events were identified. A considerable rate of bleeding events occurred in this high-risk patient population.