Brian J. Barnes

Nationwide Antibiogram Analysis Using NCCLS M39-A Guidelines

ABSTRACT Lack of standardization in antibiogram (ABGM) preparation (the overall profile of antimicrobial susceptibility results of a microbial species to a battery of antimicrobial agents) has not been addressed until recently. The objective of this study was to analyze current antibiograms using the recently published NCCLS M39-A guidelines for preparation of antibiograms to identify areas for improvement in the reporting of antibiogram susceptibility data. Antibiograms from across the United States were obtained by various methods, including direct mailings, Internet searches, and professional contacts. Each ABGM collected was analyzed using prospectively defined elements from the M39-A guidelines. Additionally, seven quality indicators were also evaluated to look for the reporting of any atypical or inappropriate susceptibility data. The 209 antibiograms collected from 149 institutions showed at least 85% compliance to 5 of the 10 M39-A elements analyzed. Clinically relevant elements not met included annual analysis, duplicate isolate notation, and the exclusion of organisms with fewer than 10 isolates. As for the quality indicators evaluated, unexpected results included the 7% of antibiograms that reported <100% vancomycin susceptibility for Staphylococcus aureus, 24% that had inconsistent beta-lactam susceptibility for Staphylococcus aureus, 20% that reported <100% imipenem susceptibility for Escherichia coli, and 37% that reported >0% ampicillin susceptibility for Klebsiella pneumoniae. These findings suggest that antibiograms should be reviewed thoroughly by infectious disease specialists (physicians and pharmacists), clinical microbiologists, and infection control personnel for identification of abnormal findings prior to distribution.

Drug-induced arrhythmias.

The objective of this review is to characterize the mechanisms, risk factors, and offending pharmacotherapeutic agents that may cause drug-induced arrhythmias in critically ill patients. PubMed, other databases, and citation review were used to identify relevant published literature. The authors independently selected studies based on relevance to the topic. Numerous drugs have the potential to cause drug-induced arrhythmias. Drugs commonly administered to critically ill patients are capable of precipitating arrhythmias and include antiarrhythmics, antianginals, antiemetics, gastrointestinal stimulants, antibacterials, narcotics, antipsychotics, inotropes, digoxin, anesthetic agents, bronchodilators, and drugs that cause electrolyte imbalances and bradyarrhythmias. Drug-induced arrhythmias are insidious but prevalent. Critically ill patients frequently experience drug-induced arrhythmias; however, enhanced appreciation for this adverse event has the potential to improve prevention, treatment, patient safety, and outcomes in this patient population.

Eplerenone: A Selective Aldosterone Receptor Antagonist for Patients with Heart Failure

OBJECTIVE: To evaluate the pharmacology, pharmacokinetics, safety, and clinical use of eplerenone in heart failure (HF). DATA SOURCES: English-language MEDLINE searches were performed from 1966 to May 2004. Key words included eplerenone, aldosterone receptor antagonist, heart failure, myocardial infarction, left-ventricular dysfunction, and cost-effectiveness. Additional references were identified from bibliographies of selected articles. STUDY SELECTION AND DATA EXTRACTION: Human trials evaluating the efficacy, safety, and cost-effectiveness of aldosterone receptor antagonists in HF were evaluated. DATA SYNTHESIS: Eplerenone is the first selective aldosterone receptor antagonist. The drug is indicated to improve the survival of stable patients with left-ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of HF following acute myocardial infarction. Efficacy and safety in this population have been demonstrated in a large, randomized clinical trial. Eplerenone is associated with severe and sometimes life-threatening hyperkalemia. Patients with reduced renal function and diabetes, as well as those on other drugs that increase potassium levels, are at highest risk. Eplerenone is metabolized by the cytochrome P450 system and may interact with drugs that interfere with this system. A major advantage of eplerenone over the nonselective aldosterone receptor antagonist spironolactone is lack of binding to progesterone and androgen receptors, which is associated with drug-induced gynecomastia, breast pain, and impotence. CONCLUSIONS: The addition of eplerenone to traditional HF therapy has been shown to reduce morbidity and mortality in patients who develop left-ventricular dysfunction after acute myocardial infarction. Eplerenones selectivity reduces sex hormone—related adverse effects. Despite these benefits, the overall cost-effectiveness has yet to be determined.

Potential Use of Statins to Prevent Atrial Fibrillation After Coronary Artery Bypass Surgery

Objective: To review the published literature evaluating the effectiveness of statin therapy for preventing postoperative atrial fibrillation (POAF) after coronary artery bypass graft (CABG) surgery, Data Sources: A MEDLINE search was performed (1950–October 2007) using the search terms statins, HMG-CoA reductase inhibitors, coronary artery bypass graft, cardiac surgery, and atrial fibrillation, Study Selection and Data Extraction: All articles published in English describing or evaluating the use of statins in humans to prevent atrial fibrillation (AF) were included. Additional pertinent articles were identified from reference lists. Data Synthesis: POAF is a common complication following CABG surgery that is associated with significant morbidity. Current preventive strategies include the use of β-blockers and antiarrhythmic drugs such as amiodarono and Sotalol. Accumulating evidence suggests that statins may also reduce the risk of POAF. Numerous studies in nonsurgical cardiovascular patients have found reduced rates of AF with statins. In patients who have undergone CABG, several observational studies have also documented benefit. One randomized controlled trial reported a significant reduction in the risk of POAF and reduced length of hospital stay in patients given preoperative atorvastatin beginning 7 days before surgery. Ongoing research suggests that statins may reduce the risk of AF through pleiotropic effects independent of cholesterol lowering such as reductions in inflammation, oxidative damage, neurohormonal activation, and thrombosis. Conclusions: While the current evidence evaluating the use of statins to prevent POAF is encouraging, definitive conclusions cannot be drawn. However, because statins are widely used in cardiac patients for other indications and are not associated with the risks inherent to antiarrhythmic drugs, their value as an adjunct to current preventive strategies (or POAF deserves further study. Additional research is needed to examine the effectiveness of statins in risk-stratified patients undergoing CABG surgery and the impact on patient outcomes and attributed costs.

Impact of Bisphosphonates on the Risk of Atrial Fibrillation

Osteoporosis is a major public health problem resulting in significant morbidity, mortality, and utilization of healthcare resources. Bisphosphonates are the most widely prescribed drugs for increasing bone mass and preventing osteoporosis-related fractures. Although these drugs have proven efficacy and are generally considered safe, a clinical trial of once-yearly zoledronic acid reported an unexpected increase in the risk of cardiac arrhythmias, primarily due to serious atrial fibrillation (AF). Subsequently, a post hoc analysis of another clinical trial reported a nonsignificant trend toward an increased risk of serious AF. Based on these concerns, the US FDA issued a cautionary advisory and is conducting an ongoing safety review.A major limitation of the clinical trials was the fact that none were designed or powered to evaluate arrhythmia endpoints. In search of more definitive answers, several observational studies using both population-based cohort and case-control designs have attempted to verify this association. However, only two studies, one cohort and one case-control study, have found a positive association, while six additional studies have reported negative findings. While most of the observational studies attempted to control for confounders, the chosen variables have varied considerably, and other key potential confounders such as smoking were not controlled for in any of the studies.Because the occurrence of AF events in the studies was relatively low, four meta-analyses have been conducted to increase sample size by using pooled data from multiple studies. Again, results have been inconsistent, with two of the analyses reporting a significant increase in serious AF and two finding no association.Additionally, no direct evidence has identified any underlying mechanism to explain an increased arrhythmia risk with bisphosphonate therapy. However, several possible mechanisms have been proposed, including an activated inflammatory state, altered electrolytes impacting cardiac conduction, and long-term atrial structural changes.Due to the widespread use of bisphosphonates in a population for whom the baseline risk of AF also increases with advancing age, further prospective assessment of this possible association is clearly warranted. If an association does exist between bisphosphonates and an increased risk for AF, several additional questions will need to be answered including impact of baseline risk, the time course for increased risk, relationship to drug dose, and whether or not this represents a drug-class adverse effect. Until definitive evidence is available, clinicians will continue to have to make clinical judgments based on the available and often inconsistent evidence to date. To provide further perspective on this possible association, we performed a systematic search of the PubMed database from 1966 to 30 June 2010, drug regulatory websites, and drug manufacturer websites. In this review we summarize the findings from clinical trials, observational studies, and meta-analyses evaluating the risk of AF following bisphosphonate exposure, and discuss possible mechanisms that could explain an increased risk.

Enterobacter cloacae Ventriculitis Successfully Treated with Cefepime and Gentamicin: Case Report and Review of the Literature

A 55‐year‐old woman was found unresponsive and subsequently was diagnosed with a subarachnoid hemorrhage secondary to a right posterior communicating artery aneurysm. The development of hydrocephalus and decreased mental status necessitated placement of an intraventricular catheter; 18 days later she was diagnosed with Enterobacter cloacae ventriculitis. After treatment was begun with intravenous cefepime 2 g every 8 hours and intraventricular gentamicin 5 mg every 24 hours, the catheter was replaced. Cerebrospinal fluid (CSF) and plasma cefepime concentrations and a CSF trough gentamicin concentration were obtained. Intraventricular gentamicin was administered for 6 days and cefepime for 21 days; both clinical and microbiologic resolution of the ventriculitis occurred. The literature reports limited clinical experience with cefepime for the treatment of central nervous system infections in humans. This case report provides clinical evidence to support administration of intravenous cefepime in critically ill adult patients with Enterobacter ventriculitis. Because CSF is easily obtained from patients with intraventricular catheters, strong consideration should be given to monitoring CSF cefepime concentrations in concert with the minimum inhibitory concentration of the offending pathogen to help assure the efficacy of this approach to therapy.

Impact of a community-based diabetes self-management program on key metabolic parameters

Objective: Characterize the impact of a pharmacist-led diabetes self-management program on three key metabolic parameters: glycosylated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), and mean arterial blood pressure (MAP) among employee health program participants. Methods: A self-insured company in the Kansas City metropolitan area began offering a pharmacist-led diabetes self-management program to eligible company employees and their dependents in 2008. A retrospective pre-post analysis was conducted to determine if the program affected key metabolic parameters in participants by determining mean change after one year of participation. Results: Among 183 program participants, 65 participants met inclusion criteria. All three key metabolic parameters were significantly reduced from baseline to one year of program participation: HbA1c decreased from 8.1 % to 7.3% (p=0.007); LDL-C decreased from 108.3 mg/dL to 96.4 mg/dL (p=0.009); and MAP decreased from 96.1 to 92.3 mm Hg (p=0.005). Conclusions: The pharmacist-led diabetes self-management program demonstrated significant reductions in HbA1c, LDL-C, and MAP from baseline to one year of program participation. Improvements were statistically significant and clinically relevant for each parameter. Previous studies indicate these reductions may cause reduced overall healthcare costs.

Statin intolerance and vitamin D supplementation: Sunny, but a few clouds remain...

Dear Editor, We read with interest the article by Khayznikov et al., regarding the resolution of statin intolerance with vitamin D repletion.[1] We too have tried this strategy among a similarly statin intolerant population (median – three previous statins) and believe vitamin D supplementation plays a role in treating certain individuals. Our results demonstrated that vitamin D repletion to >30 ng/ml, allowed 53% (18/34) of the intolerant patients to utilize some form of alternative or daily statin dosing or a higher dose among those receiving a statin but experiencing tolerable symptoms, for at least four months (mean follow up 8.5 + 4.4 months). Our findings are encouraging but well below the 88-95% statin tolerability rates reported in the present study. Directly comparing study populations and results is not feasible; however, one potential explanation for response differences may be the vitamin D level achieved. For instance, the vitamin D levels among those tolerating the statin rechallenge in our group was 44 ng/ml compared to 53-55 ng/ml in the current report, suggesting that perhaps our vitamin D repletion was incomplete, despite each group falling within the range suggested by the Endocrine Society.[2] Another factor that we believe played a prominent role in the resolution of myalgic symptoms in the current study was the predominant utilization of rosuvastatin. The authors recognize that rosuvastatin is less frequently associated with myotoxicity; however, this should not be minimized. In fact, the same research center performed a similar study, and determined that the vast majority of previously statin intolerant subjects reported no adverse effects when rechallenged with rosuvastatin 5-10 mg daily.[3] Lastly, we agree with the authors that an optimal study evaluating statin intolerance would be blinded and placebo-controlled, given the subjective nature of most myotoxicity. In fact, this design was recently utilized to assess various lipid-altering agents, including the investigational proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, among subjects unable to tolerate two or more different statins because of unexplained muscle-related symptoms.[4] After successful completion of a four-week single-blind placebo run-in period, subjects were randomized in a double-blind manner to a PCSK9 injection Q two weeks + oral placebo daily, ezetimibe 10 mg daily + placebo injection Q two weeks, or atorvastatin 20 mg daily + placebo injection Q two weeks, for 24 weeks. Such a study design provided novel, insightful, and revealing findings with regard to statin intolerance. For example, the trial demonstrated that 6.9% of subjects were excluded from randomization due to muscle-related adverse events during the placebo run-in period. Further, 75% of the previously intolerant patients tolerated the atorvastatin 20 mg daily for the duration of the 24-week study period. Such results strongly highlight the subjectivity of statin intolerance and the major influence of a placebo effect in many patients. Statin intolerance, especially among patients with previous sensitivity to multiple agents, is a complex and poorly understood issue that remains a clinical challenge. In the present study, vitamin D repletion likely improved muscle function and resolved symptoms in some patients. However, the vitamin D supplementation may have also provided a placebo effect, while the utilization of rosuvastatin further enhanced response. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

An update on the diagnosis, complications, and treatment of heparin-induced thrombocytopenia

This continuing feature will update readers on recent developments in cardiovascular pharmacotherapy. Cardiovascular disease remains the number one killer in the US, and more clinical outcome trials have been conducted in cardiology than in any other field of medicine. Given this rapidly expanding knowledge base, pharmacists can have a significant impact on prevention and treatment — if they keep current with developments in drug therapy.

MP54-13 MALNUTRITION STATUS AND AN INTERVENTION FOR MALNUTRITION IN PATIENTS UNDERGOING RADICAL CYSTECTOMY

INTRODUCTION AND OBJECTIVES: Underdiagnosing malnutrition in high-risk surgical patients is problematic. Rapid skeletal muscle wasting is a serious and common complication following radical cystectomy (RC) to treat muscle-invasive bladder cancer. Specialized immunonutrition (SIM) intake before and after RC may help counteract muscle wasting in the post-operative period. METHODS: Men with muscle-invasive cancer scheduled for radical cystectomy were randomly assigned to oral SIM providing supplemental L-arginine, fish oil, vitamin A, and nucleotides (n 1⁄4 14) or a calorieand nitrogen-matched oral nutrition supplement [ONS (n 1⁄4 15)] for 5 days before and 5 days after RC. Malnutrition was assessed by a trained research team using the Patient-Generated Subjective Global Assessment (PG-SGA) tool. Dual Energy X-Ray Absorptiometry scans were obtained at baseline, 14 days, and 30 days after surgery to calculate relative skeletal muscle index (RSMI). Discrepancies between the malnutrition diagnoses using the PG-SGA tool and the UHC Billing database on the same patients were compared. RESULTS: Using the PG-SGA tool, 21% of patients were identified as well nourished, 66% were moderately malnourished, and 14% were severely malnourished prior to RC. Billed and coded data showed 86% of patients were well nourished, 7% were moderately malnourished, and 7% were severely malnourished prior to RC. Relative Skeletal Muscle Index (RSMI) was better preserved in the SIM group at 14 days (7% vs. 17% in the ONS group). CONCLUSIONS: The large discrepancy between patients identified as malnourished using the PG-SGA as compared to the billing data suggests a problem of underdiagnosing malnutrition in this population. Improving nutrition status through specialized immunonutrition could be a low risk, high-impact means of counteracting muscle wasting after RC for bladder cancer.