Shawn D. Anderson

Ceftobiprole: An Extended-Spectrum Anti–Methicillin-Resistant Staphylococcus aureus Cephalosporin

Objective: To summarize and evaluate the literature concerning ceftobiprole. Data Sources: Literature identification was conducted through MEDLINE (1966–February 2008) and International Pharmaceutical Abstracts (1970–February 2008) using the terms ceftobiprole, medocaril, BAL 5788, RO-5788, BAL 9141, RO 63-9141, pynolidinone cephalosporin. MRSA, complicated skin and skin-structure infections (cSSSIs), community-acquired pneumonia, and nosocomial pneumonia. Additional publications were identified through a review of articles and abstracts from infectious disease meetings. Study Selection and Data Extraction: All articles in English were evaluated and all pertinent information was included. Data Synthesis: Ceftobiprole medocaril is an extended-spectrum cephalosporin with activity against methicillin-reslstant Staphylococcus spp., vancomycin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis, Enterobacteriaceae, and Pseudomonas aeruginosa. Inactivity includes extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae and Enterococcus faecium. Preliminary data suggest that ceftobiprole may be effective with a 1-hour infusion of 500 mg every 12 hours for gram-positive infections and 500 mg every 8 hours with a 2-hour infusion for polymicrobial infections. Two clinical trials support these dosing regimens for cSSSIs. Ceftobiprole was noninferior to vancomycin in suspected gram-positive cSSSIs, with cure rates of 93.3% and 93.5%, respectively. Furthermore, ceftobiprole was noninferior to vancomycin and ceftazidime in polymicrobial cSSSIs (cure rates 90.5% vs 90.2%, respectively). Although the total number of adverse effects was similar to those of the comparator, more patients in the ceftobiprole group experienced nausea, vomiting, and dysgeusia. Conclusions: The activity of ceftobiprole and limited clinical data suggest that it may be useful as empiric monotherapy for cSSSI and in combination with other antimicrobials in lower respiratory tract infections for which Phase 3 clinical trials are currently exploring. Although not shown in vitro, ceftobiprole may induce resistance due to its broad spectrum of activity. Approval is expected for the treatment of cSSSI.

Efficacy and Safety of Ticagrelor: A Reversible P2Y12 Receptor Antagonist

Objective: To summarize the pharmacokinetic and pharmacodynamic properties of ticagrelor, a selective P2Y12 receptor antagonist, and evaluate its role in the treatment of patients with acute coronary syndromes (ACS). Data Sources: A literature search was conducted in MEDLINE (1966–November 2009), International Pharmaceutical Abstracts (1970–November 2009), and EMBASE (1990–November 2009) using the MeSH terms and key words AZD6140, ticagrelor, P2Y12 receptor antagonist, cardiovascular disease, ACS, atherothrombosis, and platelets. Study Selection And Data Extraction: Selected studies evaluated the pharmacology, pharmacokinetics, pharmacodynamics, safety, and efficacy of ticagrelor for the treatment of ACS. Data Synthesis: Ticagrelor selectively and reversibly blocks the P2Y12 receptor, inhibiting platelet aggregation and preventing amplification of platelet activation. Optimal dosing strategy as determined by ticagrelors pharmacokinetic and pharmacodynamic profile is a loading dose of 180 mg followed by 90 mg by mouth twice daily. At these doses, greater platelet inhibition is observed with ticagrelor as compared to clopidogrel 75 mg once daily in both clopidogrel-experienced and -naïve patients. Studies in patients experiencing ACS concluded that ticagrelor reduced the rate of cardiovascular death, nonfatal myocardial infarction, stent thrombosis, and overall mortality compared to clopidogrel without increasing major bleeding when administered with standard therapy for ACS. There was no significant difference in the risk of stroke with ticagrelor compared to clopidogrel; however, intracranial bleeding was more common with ticagrelor. Ticagrelor is well tolerated; however, minor bleeding, dyspnea, hypotension, nausea, and ventricular pauses were reported more frequently than with clopidogrel. Reversible inhibition with ticagrelor may allow for more rapid surgical intervention after discontinuation, suggesting greater flexibility in treatment of ACS. Conclusions: Ticagrelors improved pharmacokinetic and pharmacodynamic profile builds upon the limitations of currently available P2Y12 receptor antagonists. Ticagrelor represents a promising approach for the prevention of cardiovascular events in patients with ACS.

Lack of Correlation Between Thiazide-Induced Hyperglycemia and Hypokalemia: Subgroup Analysis of Results from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study

Study Objective. To determine whether changes in serum glucose, serum potassium, and plasma insulin levels are correlated in a cohort of hypertensive patients.

Endothelin receptor antagonists as antihypertensives: the next frontier

The endothelin system is a pivotal player along the continuum of cardiovascular disease. There is convincing evidence that the system not only exerts a potent pressor effect but also promotes end-organ damage independent from blood pressure changes. The role of endothelin receptor antagonists (ERAs) in the treatment of hypertension is rapidly evolving. Recent studies demonstrate a formidable antihypertensive effect. Utility of ERAs is likely to be greatest in patients with resistant hypertension. Beyond blood pressure lowering, ERAs exert several properties that may confer additional protection, including effects on endothelial function, atherosclerosis, arterial stiffening, renal function and proteinuria. The full potential of this class will only be realized when the results of ongoing and future studies in hypertension, heart failure and other forms of cardiovascular disease are completed.

Discordant Effects of β‐Blockade on Central Aortic Systolic and Brachial Systolic Blood Pressure: Considerations Beyond the Cuff

The role of β‐blockers in uncomplicated hypertension has been challenged recently. Compared with other antihypertensives, β‐blockers are less effective for preventing cardiovascular events in patients with uncomplicated hypertension. Moreover, a recent meta‐analysis of placebo‐controlled clinical trials concluded that atenolol is not more efficacious than placebo for preventing cardiovascular events in patients with hypertension. Although these agents lower blood pressure measured conventionally over the brachial artery with a blood pressure cuff, they do not exert a commensurate effect on blood pressure in the central aorta. Central aortic blood pressure and aortic augmentation index are strong predictors of left ventricular hypertrophy, an independent risk factor for cardiovascular events. Emerging data are illuminating the antihypertensive paradox whereby antihypertensive agents may elicit discordant effects on central and peripheral blood pressure and hemodynamics. Vasodilatory antihypertensives, such as renin‐angiotensin‐aldosterone system inhibitors and calcium channel blockers, elicit reductions in central aortic blood pressure equal to or greater than that in the brachial artery. Conversely, β‐blockers lower central aortic blood pressure to a lesser degree even when blood pressure measured by sphygmomanometry is reduced substantially. Given the strong relationship between central aortic blood pressure and target organ damage, the effectiveness of β‐blockers may be overestimated in practice on the basis of conventional blood pressure measurements alone. Differences in central and peripheral blood pressure may account for the lack of cardiovascular protection afforded by β‐blockers in clinical trials and could account for a portion of the apparent “benefit beyond blood pressure” reduction with other classes of antihypertensive agents. Future studies should aim to better clarify the role of central aortic blood pressure in the treatment of hypertension. In the meantime, the effects of antihypertensive drugs on blood pressure “beyond the brachial blood pressure cuff” should be considered when prescribing antihypertensive agents for a patient.

Letter by Reeder and Anderson Regarding Article, “Heart Failure is a Risk Factor for Orthopedic Fracture: A Population-Based Analysis of 16 294 Patients”

Results from the trial by van Diepen and colleagues1 found a statistically significant association between the diagnosis of heart failure (HF) and risk of orthopedic fracture in a large cohort of elderly patients with known cardiovascular disease. Although a pathophysiological link between HF and osteoporosis remains to be determined, the authors offer a potential cause beyond that of shared risk factors. The backbone of the proposed mechanism in HF is elevated aldosterone levels, which have been associated with increased urinary calcium and magnesium excretion, hyperparathyroidism, and diminished bone mineral density. One relationship that also deserves recognition is the association between HF, hyponatremia, …

Coenzyme Q10 and Creatine in Heart Failure: Micronutrients, Macrobenefit?

Heart failure (HF) therapy over the last 3 decades has primarily focused on neurohormonal, hemodynamic, and electrophysiologic dimensions to reduce morbidity and mortality. Considerably less emphasis has been placed on energy substrate and micronutrient deficiencies in patients with HF. Micronutrient deficiencies have been identified in the failing human heart and have been associated with defective energy metabolism in cardiac myocytes.1 Plasma and myocardial levels of various micronutrients are known to be reduced in HF patients as compared to control populations. However, considerable debate continues as to whether low levels of micronutrients, such as coenzyme Q10 or creatine, are markers of or causes for systolic heart failure.2 Coenzyme Q10 (also known as ubiquinone) and creatine are both endogenously produced and acquired in a diet higher in red meat, poultry, and fish. Coenzyme Q10 is an important mediator of mitochondrial adenosine triphosphate production, is an antioxidant, and is thought to stabilize cell membranes. Creatine is an important mediator of energy metabolism in all muscle types. Dietary supplementation with either agent increases tissue concentrations and improves delivery to the myocardium. A host of small observational studies have shown benefit for coenzyme Q10 in regard to surrogate end points like ejection fraction, cardiac index, quality of life, and exercise capacity. However large, well-designed trials of coenzyme Q10 and creatine supplementation in HF are lacking, and hard end points (such as mortality and HF hospitalizations) have not been studied. The largest trial of coenzyme Q10 supplementation in HF patients to date was observational in nature.3 A recent meta-analysis of coenzyme Q10 supplementation in HF was undertaken in 2006.4 Eleven trials were included, all of which were double-blind, prospective, and placebo-controlled. The outcome measures studied in these trials included ejection fraction, cardiac output, cardiac index, stroke volume, and stroke index. Ten trials assessed ejection fraction, which improved by 3.7% (95% confidence interval [CI] 1.6–5.8). Two trials found a significant improvement in cardiac output (0.28 L/min [95% CI 0.03–0.53]) and stroke index (5.7 mL/m2 [95% CI 1.02–10.3]). Cardiac

Letter Regarding Article by Leeper et al, “Statin Use in Patients With Extremely Low Low-Density Lipoprotein Levels Is Associated With Improved Survival”

To the Editor: In the August 7, 2007, issue of Circulation , Leeper and colleagues1 report that statin therapy is associated with 35% improved survival in patients with low-density lipoprotein (LDL) values <60 mg/dL. The authors suggest that benefits are derived from the pleiotropic effects of statins, such as a reduction in inflammation, restoration of endothelial function, and …