Randomized Controlled Trial of the Safety and Efficacy of Daptomycin versus Standard-of-Care Therapy for Management of Patients with Osteomyelitis Associated with Prosthetic Devices Undergoing Two-Stage Revision Arthroplasty

The prevalence of Staphylococcus aureus causing prosthetic joint infection (PJI) supports investigation of higher doses of daptomycin in the management of PJI. This was a prospective, randomized controlled trial studying safety and efficacy of daptomycin (6 and 8 mg/kg of body weight) compared with standard-of-care therapy for PJI. This open-label study randomized 75 patients undergoing 2-stage revision arthroplasty to daptomycin at 6 or 8 mg/kg or a comparator (vancomycin, teicoplanin, or semisynthetic penicillin). After prosthesis removal, patients received 6 weeks of antibiotic treatment and a 2- to 6-week antibiotic-free period before implantation of a new prosthesis. Test of cure (TOC) was within 1 to 2 weeks after reimplantation. The primary objective was evaluation of creatine phosphokinase (CPK) levels. Secondary objectives were clinical efficacy and microbiological assessments. Of 73 CPK safety population patients, CPK elevation of >500 U/liter occurred in 4 of 25 (16.0%) (daptomycin, 6 mg/kg) and 5 of 23 (21.7%) (daptomycin, 8 mg/kg) daptomycin-treated patients and 2 of 25 (8.0%) comparator patients. Adverse-event rates were similar among daptomycin and comparator groups. Among modified intent-to-treat patients at TOC, clinical success rates were 14 of 24 (58.3%) for 6 mg/kg daptomycin, 14 of 23 (60.9%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for the comparator. Overall microbiological success at TOC was 12 of 24 (50.0%) for 6 mg/kg daptomycin, 12 of 23 (52.2%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for comparator patients. In conclusion, daptomycin at 6 and 8 mg/kg given for up to 6 weeks was safe and appeared to be effective in managing staphylococcal PJI using a 2-stage revision arthroplasty technique in a total of 49 patients.     

Ezetimibe: a novel option for lowering cholesterol

Elevated low-density lipoprotein (LDL)-cholesterol is associated with a significantly increased risk of coronary heart disease but lowering LDL-cholesterol to levels established in current National Cholesterol Education Program (NCEP) guidelines provides significant risk reduction. Nevertheless, many patients receiving lipid-lowering therapy, particularly those at highest coronary heart disease risk, do not reach LDL-cholesterol goals with their current medications. Ezetimibe (Zetia^®, Merck Schering-Plough) is the first of a new class of lipid-lowering drugs known as cholesterol absorption inhibitors. Ezetimibe has a favorable pharmacokinetic profile, which allows it to be administered once daily and to be given in conjunction with statins. In a series of randomized, controlled, multicenter studies, ezetimibe produced significant improvements in levels of LDL-cholesterol and other lipid parameters when used as monotherapy, with a safety profile comparable with that of placebo. Furthermore, coadministration of ezetimibe with a statin (simvastatin, atorvastatin, lovastatin, or pravastatin) was more effective than statin monotherapy in lowering LDL-cholesterol and improving other lipid parameters. Moreover, coadministration of ezetimibe with a statin allowed a greater percentage of patients to achieve treatment goals established in NCEP guidelines. The safety and side-effect profile of ezetimibe plus statin coadministration therapy was generally comparable with that of statin monotherapy. These studies establish ezetimibe as an effective lipid-lowering agent, which will likely be useful in the management of a broad range of patients with hypercholesterolemia. Ezetimibe can be used in conjunction with a statin at the beginning of therapy, or it can be added if patients do not achieve their LDL-cholesterol goal with statins alone.     

Considerations for safe use of statins: liver enzyme abnormalities and muscle toxicitiy

Statins play an important role in the care of patients with cardiovascular disease and have a good safety record in clinical practice. The risk of hepatic injury caused by statins is estimated to be about 1 percent, similar to that of patients taking a placebo. Patients with transaminase levels no more than three times the upper limit of normal can continue taking statins; often the elevations will resolve spontaneously. Coexisting elevations of transaminase levels from nonalcoholic fatty liver disease and stable hepatitis B and C viral infections are not contra- indications to statin use. Although myalgias are common with statin use, myositis and rhabdomyolysis are rare. When prescribed at one-half the recommended maximal dosage or less, statins are associated with an incidence of myopathy similar to that of placebo; therefore, rou- tine monitoring of creatine kinase levels in asymptomatic patients is not recommended. Myopathic symptoms usually resolve approximately two months after discontinuing the statin, and the same statin can be restarted at a lower dosage, or patients can try a different statin. Clinically important drugs that interact with statins and increase the risk of adverse effects include fibrates, diltiazem, verapamil, and amiodarone.     

Safety and clinical outcomes among older adults receiving daptomycin therapy: Insights from a patient registry

Background: Serious gram-positive bacterial infections are an important cause of morbidity and mortality among older adults and can present significant challenges to clinicians. Data evaluating the safety and effectiveness of newer agents in this population are limited.Objective: Daptomycin is a lipopeptide with activity against resistant gram-positive organisms. To better understand the overall safety and effectiveness of daptomycin in older adults (≥66 years of age), the authors reviewed the data that were collected as part of an ongoing registry maintained by Cubist Pharmaceuticals, Inc. (Lexington, Massachusetts), the manufacturer of daptomycin.Methods: The Cubicin Outcomes Registry and Experience (CORE) is a multicenter, retrospective registry designed to collect postmarketing clinical data on patients who received daptomycin. The CORE data collected from 58 institutions across the United States between January 1, 2005, and December 31, 2007, were analyzed to better understand the overall safety profile of daptomycin and the clinical outcomes of older adults who were treated with this agent. Patients were considered to be nonevaluable if the medical record did not contain sufficient information to determine response at the end of therapy. Nonevaluable patients were excluded from the clinical outcome analysis but included in the safety analysis.Results: The registry contained 1073 patients aged ≥66 years who received daptomycin; 23.8% (255/1073) were ≥81 years of age. Overall, 18.1% (194/1073) of patients experienced 324 adverse events, and 6.2% (67/1073) of patients experienced 97 adverse events that were considered possibly related to treatment with daptomycin. The most frequently reported adverse events that were considered possibly treatment related included creatine phosphokinase (CPK) elevations, gastrointestinal disorders, and skin rashes. Among the 67 patients who experienced ≥1 adverse event that was possibly related to daptomycin, 30 discontinued therapy due to the adverse event (13 due to CPK elevation). Overall, 78.7% (844/1073) of patients were considered evaluable for clinical outcomes. The clinical success rate for all evaluable patients was 90.2% (761/844). The success rate for evaluable patients ≥81 years of age (88.6% [171/193]) was comparable to that of the overall population.Conclusion: Experience with daptomycin in this group of older adults suggests good tolerability and clinical outcomes that are consistent with the results of other studies published to date.     

Ezetimibe: a novel option for lowering cholesterol

Elevated low-density lipoprotein (LDL)-cholesterol is associated with a significantly increased risk of coronary heart disease but lowering LDL-cholesterol to levels established in current National Cholesterol Education Program (NCEP) guidelines provides significant risk reduction. Nevertheless, many patients receiving lipid-lowering therapy, particularly those at highest coronary heart disease risk, do not reach LDL-cholesterol goals with their current medications. Ezetimibe (Zetia, Merck Schering-Plough) is the first of a new class of lipid-lowering drugs known as cholesterol absorption inhibitors. Ezetimibe has a favorable pharmacokinetic profile, which allows it to be administered once daily and to be given in conjunction with statins. In a series of randomized, controlled, multicenter studies, ezetimibe produced significant improvements in levels of LDL-cholesterol and other lipid parameters when used as monotherapy, with a safety profile comparable with that of placebo. Furthermore, coadministration of ezetimibe with a statin (simvastatin, atorvastatin, lovastatin, or pravastatin) was more effective than statin monotherapy in lowering LDL-cholesterol and improving other lipid parameters. Moreover, coadministration of ezetimibe with a statin allowed a greater percentage of patients to achieve treatment goals established in NCEP guidelines. The safety and side-effect profile of ezetimibe plus statin coadministration therapy was generally comparable with that of statin monotherapy. These studies establish ezetimibe as an effective lipid-lowering agent, which will likely be useful in the management of a broad range of patients with hypercholesterolemia. Ezetimibe can be used in conjunction with a statin at the beginning of therapy, or it can be added if patients do not achieve their LDL-cholesterol goal with statins alone.     

Daptomycin Pharmacokinetics and Pharmacodynamics in a Pooled Sample of Patients Receiving Thrice-Weekly Hemodialysis

While the pharmacokinetic (PK) properties of daptomycin in hemodialysis (HD) patients have been evaluated previously by three groups, resultant dosing recommendations have varied. To address this clinical conundrum, this study combined concentration-time data from these PK evaluations and derived uniform dosing recommendations among patients on HD receiving daptomycin. A two-compartment model with separate HD and non-HD clearance terms was fit to the PK data from these studies by using BigNPAG. Embedded with PK parameters from the population PK analysis, 5,000-subject Monte Carlo simulations (MCS) were performed to identify HD dosing schemes that provided efficacy (cumulative and daily area under the concentration-time curve [AUC] values) and toxicity (trough concentrations of ≥24.3 mg/liter) profiles comparable to those from simulations employing the daptomycin PK model derived from the Staphylococcus aureus bacteremia–infective endocarditis (SAB-IE) study. Separate HD dosing schemes were sought for the two weekly interdialytic periods (48 and 72 h). For the 48-h interdialytic period, intra- and post-HD dosing provided the most isometric cumulative and daily AUCs. For the 72-h interdialytic period, all HD dosing schemes provided noncumulative AUC values from 48 to 72 h (AUC_48–72) that were <50% of the SAB-IE AUC_48–72 values. Increasing the parent dose by 50% intra- or post-HD provided comparable AUC_48–72 values, while maintaining acceptable trough concentration (C_min) values. When efficacy and toxicity profiles were evaluated for each individual study, higher probabilities for C_min reaching ≥24.3 mg/liter were observed in one of the three studies. Given the high probability of C_min being ≥24.3 mg/liter in one of the three studies, more intensive creatine phosphokinase (CPK) monitoring may be warranted in HD patients receiving daptomycin.     

Early Initiation of Evolocumab Treatment in Chinese Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention

PurposeEvolocumab has been shown to improve cardiovascular outcomes in patients with stable atherosclerotic disease. Whether this benefit persists in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) remains undetermined. This study aimed to evaluate the efficacy and safety of the early initiation of evolocumab in Chinese patients with ACS undergoing PCI.MethodsThis retrospective cohort study involved 1564 consecutive patients who had been hospitalized with ACS and underwent PCI, and who had elevated LDL-C levels (≥1.8 mmol/L after receiving high-intensity statin therapy for ≥4 weeks; ≥2.3 mmol/L after receiving low- or moderate-intensity statin; or ≥3.2 mmol/L without statin therapy). Patients who received evolocumab (initiated in-hospital and after 18 months) were included in the evolocumab group (n = 414), and all other patients were included in the control group (n = 1150). The primary outcome at 18 months was a composite of ischemic stroke, cardiovascular death, myocardial infarction, hospitalization for unstable angina, or coronary revascularization. The evolocumab treatment effect on the primary outcome was assessed in all prespecified subgroups.FindingsAt 18 months, evolocumab combined with statins reduced LDL-C levels from baseline levels by 42.48% compared with statins alone. After multivariable adjustment, evolocumab combined with statins significantly reduced the primary outcome (8.2% vs 12.4%; adjusted hazard ratio, 0.65; 95% CI, 0.45–0.95; P = 0.025). In addition, evolocumab consistently reduced the primary outcome across the major subgroups. For the safety outcomes, no significant differences between the groups were observed in any adverse events.ImplicationsAmong Chinese patients who underwent PCI for ACS, the early initiation of evolocumab combined with statin treatment effectively reduced LDL-C levels and lowered the incidence of recurrent ischemic cardiovascular events, with satisfactory tolerability and safety. Chinese Clinical Trial Registry identifier: ChiCTR2100049364.     

The reality of treating dyslipidaemia in patients with coronary heart disease: a primary care survey

Management of hyperlipidaemia in patients with ischaemic heart disease is suboptimal despite the proven benefit of statin therapy. Significant improvement in management has been shown in the EUROASPIRE II study. It is unclear, however, whether such changes have also occurred in primary care. We aimed to evaluate the use of statin therapy by performing a cross-sectional survey of 300 patients with CHD aged >30 years from three general practices. A total of 249 (83%) of the 300 patients had their cholesterol measured and 141 (47%) were on statin therapy; 129 (43% of total) achieved a target cholesterol of <5 mmol/l, of whom 85 (64%) were on statin therapy. Of the remaining 120 patients whose cholesterol exceeded 5 mmol/l, 56 (47%) were on statin therapy Thus 60% (85/141) of those on statin therapy achieved adequate control compared with 40% (44/108) without statins (p<0.008). Those patients with CHD diagnosed on objective evidence were more likely to receive statin therapy (55.5%). Many patients with CHD are still not receiving appropriate secondary prevention. Those on statin therapy are more likely to achieve target levels <5 mmol/l. The average doses of statins vary and are lower than the evidence-based doses used in previous large-scale studies, which may help explain the persistence of failed treatment.     

Efficacy and Safety of Fenofibrate-Statin Combination Therapy in Patients With Inadequately Controlled Triglyceride Levels Despite Previous Statin Monotherapy: A Multicenter,Randomized, Double-blind,Phase IV Study

PurposeResidual cardiovascular risk reduction by fenofibrate in patients with high serum triglyceride (TG) levels despite previous statin monotherapy is not well characterized. The purpose of this study was to evaluate the efficacy and safety of a combination of choline fenofibrate and statin in patients with inadequately controlled TG levels despite previous statin monotherapy.MethodsThis prospective, multicenter, randomized, double-blind study was conducted in Korea. A total of 133 patients with controlled LDL-C but elevated TG levels, already receiving statin monotherapy, were enrolled in the study, which was conducted from July 2018 to December 2019. Patients were randomly assigned to receive combination therapy with choline fenofibrate and statin or statin monotherapy in a 1:1 ratio. After 8 weeks of treatment, the lipid profiles and safety parameters of the patients in the 2 groups were compared.FindingsThe study included 127 patients (64 in the combination group and 63 in the control group) older than 19 years. After 8 weeks of therapy, mean serum TG levels significantly decreased from 269.8 to 145.5 mg/dL (P < 0.0001) in the combination therapy group, whereas no significant changes occurred in the statin monotherapy group (from 271.1 to 280.5 mg/dL). Contrarily, the mean serum HDLC levels significantly increased from 45.0 to 50.4 mg/dL (P = 0.0004) in the combination therapy group, whereas there were no significant changes in the monotherapy group (from 44.3 to 44.7 mg/dL). There were no additional serious adverse events in the combination therapy group compared with the statin monotherapy group.ImplicationsThe combination therapy using choline fenofibrate and statin was found to be effective in serum TG control and likely tolerable in patients with high TG levels despite statin monotherapy. A larger study, conducted for a longer duration, is needed to evaluate the effectiveness of this combination in reducing cardiovascular risk. ClinicalTrials.gov identifier: NCT03874260.     

Statin intake is associated with decreased insulin sensitivity during cardiac surgery

OBJECTIVE Surgical trauma impairs intraoperative insulin sensitivity and is associated with postoperative adverse events. Recently, preprocedural statin therapy is recommended for patients with coronary artery disease. However, statin therapy is reported to increase insulin resistance and the risk of new-onset diabetes. Thus, we investigated the association between preoperative statin therapy and intraoperative insulin sensitivity in nondiabetic, dyslipidemic patients undergoing coronary artery bypass grafting. RESEARCH DESIGN AND METHODS In this prospective, nonrandomized trial, patients taking lipophilic statins were assigned to the statin group and hypercholesterolemic patients not receiving any statins were allocated to the control group. Insulin sensitivity was assessed by the hyperinsulinemic-normoglycemic clamp technique during surgery. The mean, SD of blood glucose, and the coefficient of variation (CV) after surgery were calculated for each patient. The association between statin use and intraoperative insulin sensitivity was tested by multiple regression analysis. RESULTS We studied 120 patients. In both groups, insulin sensitivity gradually decreased during surgery with values being on average ～20% lower in the statin than in the control group. In the statin group, the mean blood glucose in the intensive care unit was higher than in the control group (153 ± 20 vs. 140 ± 20 mg/dL; P < 0.001). The oscillation of blood glucose was larger in the statin group (SD, P < 0.001; CV, P = 0.001). Multiple regression analysis showed that statin use was independently associated with intraoperative insulin sensitivity (β = -0.16; P = 0.03). CONCLUSIONS Preoperative use of lipophilic statins is associated with increased insulin resistance during cardiac surgery in nondiabetic, dyslipidemic patients.     

Evaluation of Daptomycin Exposure and Efficacy and Safety Endpoints To Support Risk-versus-Benefit Considerations

The choice of an antimicrobial agent must balance optimization of efficacy endpoints with the minimization of safety events. The risk versus benefit of daptomycin for patients with Staphylococcus aureus bacteremia with or without infective endocarditis receiving daptomycin at 6, 8, and 10 mg/kg of body weight/day was assessed. The relationships between the area under the concentration-time curve over 24 h (AUC)/MIC ratio and both clinical response and time to decreased susceptibility were evaluated using data from patients with such infections who received daptomycin at 6 mg/kg/day. Using these relationships, plus the previously identified relationship between the minimum concentration and an elevation in the creatine phosphokinase (CPK) concentration (CPK elevation) (S. M. Bhavnani, C. M. Rubino, P. G. Ambrose, and G. L. Drusano, Clin Infect Dis 50:1568–1574, 2010) and Monte Carlo simulation, the probability of each outcome by MIC for daptomycin at 6, 8, and 10 mg/kg/day was calculated. The function for exposure-response relationships for clinical response (P = 0.06) and time to decreased susceptibility (P = 0.01) resembled U and inverted U shapes, respectively. Multivariable analyses demonstrated AUC/MIC ratio, creatinine clearance, albumin concentration, and disease category to be predictors of clinical response. The results of simulations failed to demonstrate large improvements in the probabilities of clinical success among cohorts of simulated patients defined by the above-described predictive factors or the probability of decreased susceptibility at 30 days when the daptomycin dose was increased from 6 to 10 mg/kg/day. The probability of CPK elevation increased from 0.073 to 0.156 over this dose range. These data can be used to inform risk-versus-benefit decisions for daptomycin dose selection in patients with S. aureus bacteremia with or without infective endocarditis. The risk of CPK elevation, which is reversible, should be weighed in the context of the mortality and severe morbidity associated with these types of serious staphylococcal infections.     

Optimizing LDL-C lowering with statins

Clinical studies have demonstrated the efficacy of statins in reducing low-density lipoprotein cholesterol (LDL-C) and lowering coronary heart disease risk. However, many patients receiving statin therapy in clinical practice are not achieving their LDL-C goals. Generally, statins are initiated at starting doses, and doses should be titrated as needed until the goal of therapy is achieved or a second lipid-lowering drug is required; titration is required in the majority of patients who receive less efficacious agents. Most patients receiving statin therapy in clinical practice are maintained on their starting dose, and this frequently results in inadequate control of elevated cholesterol levels. A number of factors may limit dose titration in clinical practice, including the cost of therapy, safety of prescribing statins at high doses and the additional office visits required for evaluations and monitoring. There may be several solutions to this problem. The choice of statin appears to be one of the important factors influencing the success of therapy. Selecting a statin that provides greater LDL-C lowering enables more patients to achieve LDL-C goals, and the majority of patients can be effectively treated with starting doses of the more efficacious statins. Another factor influencing the success of therapy is the willingness to add other drugs to a statin to enhance LDL-C lowering. Choices here include niacin, a bile acid sequestrant, and ezetimibe, a new cholesterol absorption inhibitor. Of these approaches, use of a more efficacious statin is preferred to combination therapy because of cost, safety, effectiveness, and simplicity issues.     

Safety and efficacy of combined gemfibrozil-lovastatin therapy for primary dyslipoproteinemias

In 25 patients with primary dyslipoproteinemias and severe premature atherosclerosis, during an average combined Lopid-Mevacor treatment span of 12.5 months per patient, our specific aim was to assess safety and efficacy of open-label therapy with diet, gemfibrozil (Lopid), and lovastatin (Mevacor). Because targeted lipid values were not reached on diet alone (low-density lipoprotein cholesterol [LDLC] less than 120 mg/dl, high-density lipoprotein cholesterol [HDLC] greater than 35 mg/dl or total cholesterol [TC]/HDLC less than 4.5), the patients received Lopid, 1.2 gm/day as their initial lipid-lowering drug. Because targeted lipid levels were not reached with Lopid treatment alone after 3 or more months, Mevacor was added, with 17 subjects receiving 20 mg/day, five receiving 40 mg, two receiving 60 mg, and one receiving 80 mg. Outpatient visits were repeated during combined therapy every 6 to 8 weeks, with an average of 6.4 visits per subject, 162 measurements of fasting lipids and liver function tests, and 127 measurements of creatine phosphokinase (CPK). By selection, all patients had normal liver function (gamma-glutamyltransferase, serum glutamic-oxaloacetic transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT) levels) and normal CPK levels at baseline. No gamma-glutamyltransferase levels were high during combined therapy. Of the 162 liver function test measurements, five (3.1%) SGOT levels and three (1.9%) SGPT levels were high. Of 127 CPK measurements, three (2.4%) were high; one subject had a high CPK measurement, and one subject had two high measurements for CPK. No symptomatic myositis or myalgias developed in the subjects; none had palpable skeletal muscle tenderness.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of statin therapy on infection-related mortality in patients with atherosclerotic diseases

OBJECTIVE: Statins have pleiotropic effects that are independent of their lipid-lowering ability. We have previously shown that prior statin therapy is associated with a decreased risk of severe sepsis in patients admitted with acute bacterial infection. The aim of this study was to determine whether statin therapy is associated with a decreased risk of infection-related mortality. DESIGN: A prospective, observational, population-based study. SETTING: Tertiary university medical center. PATIENTS: Using a computerized database, 11,490 patients with atherosclerotic diseases were identified and followed for up to 3 yrs. Two groups of patients were compared: those receiving statins in the final month before follow-up termination and those who were not. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was infection-related mortality. Of the 11,362 patients included in the final analysis, 5,698 (50.1%) belonged to the statin group. Median follow-up was 19.8 months (interquartile range, 14.3-33.3). The risk of infection-related mortality was significantly lower in the statin compared with the no-statin group (0.9% vs. 4.1%), reflecting a relative risk of 0.22 (95% confidence interval, 0.17-0.28). Stepwise Cox proportional hazard survival analysis including a propensity score for receiving statins revealed that the protective effect of statins adjusted for all known potential confounders remained highly significant (hazard ratio, 0.37; 95% confidence interval, 0.27-0.52). CONCLUSIONS: Therapy with statins may be associated with a reduced risk of infection-related mortality. This protective effect is independent of all known comorbidities and dissipates when the medication is discontinued. If this finding is supported by prospective controlled trials, statins may play an important role in the primary prevention of infection-related mortality.     

Multicenter Evaluation of the Clinical Outcomes of Daptomycin with and without Concomitant β-Lactams in Patients with Staphylococcus aureus Bacteremia and Mild to Moderate Renal Impairment

Patients with underlying renal disease may be vulnerable to vancomycin-mediated nephrotoxicity and Staphylococcus aureus bacteremia treatment failure. In light of recent data demonstrating the successful use of β-lactam plus daptomycin in very difficult cases of S. aureus bacteremia, we examined safety and clinical outcomes for patients who received daptomycin with or without concomitant β-lactams. We identified 106 patients who received daptomycin for S. aureus bacteremia, had mild or moderate renal insufficiency according to FDA criteria, and enrolled in the Cubicin Outcomes Registry and Experience (CORE), a multicenter registry, from 2005 to 2009. Daptomycin treatment success was 81%. Overall treatment efficacy was slightly enhanced with the addition of a β-lactam (87% versus 78%; P = 0.336), but this trend was most pronounced for bacteremia associated with endocarditis or bone/joint infection or bacteremia from an unknown source (90% versus 57%; P = 0.061). Factors associated with reduced daptomycin efficacy (by logistic regression) were an unknown source of bacteremia (odds ratio [OR] = 7.59; 95% confidence interval [CI] = 1.55 to 37.2), moderate renal impairment (OR = 9.11; 95% CI = 1.46 to 56.8), and prior vancomycin failure (OR = 11.2; 95% CI = 1.95 to 64.5). Two patients experienced an increase in creatine phosphokinase (CPK) that resolved after stopping daptomycin. No patients developed worsening renal insufficiency related to daptomycin. In conclusion, daptomycin appeared to be effective and well tolerated in patients with S. aureus bacteremia and mild to moderate renal insufficiency. Daptomycin treatment efficacy might be enhanced with β-lactam combination therapy in primary endovascular and bone/joint infections. Additional studies will be necessary to confirm these findings.     

Evaluation of daptomycin pharmacodynamics and resistance at various dosage regimens against Staphylococcus aureus isolates with reduced susceptibilities to daptomycin in an in vitro pharmacodynamic model with simulated endocardial vegetations

The need to investigate novel dosing regimens and combinations is essential in combating poor treatment outcomes for Staphylococcus aureus bacteremia and endocarditis. We evaluated the impact of simulated standard- and high-dose daptomycin in combination with gentamicin or rifampin against daptomycin-susceptible and nonsusceptible matched strains of S. aureus. These strains were collected from the daptomycin bacteremia and endocarditis clinical trial and consisted of three susceptible strains (MIC, 0.25 mg/liter) and four nonsusceptible isolates (MICs, 2 to 4 mg/liter). Daptomycin regimens of 6 and 10 mg/kg of body weight daily alone and in combination with gentamicin at 5 mg/kg daily or rifampin at 300 mg every 8 h were evaluated using an in vitro model with simulated endocardial vegetations over 96 h. Rapid bactericidal activity, identified by time to 99.9% kill, was displayed in all regimens with the daptomycin-susceptible strains. Concentration-dependent activity was noted by more-rapid killing with the 10-mg/kg/day dose. The addition of gentamicin improved activity in the majority of susceptible isolates. Daptomycin 6-mg/kg/day monotherapy displayed bactericidal activity for only one of the nonsusceptible isolates and for only two isolates with increased doses of 10 mg/kg/day. Combination regimens demonstrated improvement with some but not all nonsusceptible isolates. Three isolates developed a reduction in daptomycin susceptibility with 6-mg/kg/day monotherapy, but this was suppressed with both combination therapy and high-dose daptomycin. These results suggest that high-dose daptomycin therapy and combination therapy may be reasonable treatment options for susceptible isolates; however, more investigations are needed to confirm the variability of these regimens with nonsusceptible isolates.     

The effect of pre‐hospital statins therapy on incidence of in‐hospital death and total MACCE in patients with PCI

Objective: To investigate the influence of preoperative statin therapy on rate of major adverse cardiac and cerebrovascular events (MACCE) during hospital stay after successful percutaneous coronary intervention (PCI). Methods: Review of patients who underwent PCI between June 2003 and September 2005 (n = 3893) at Beijing Anzhen Hospital of Capital University of Medical Science. (Group I, on statins, n = 3361; group II, not on statins, n = 532). To investigate if preoperative statin therapy was independently associated with the reduction in the risk of adverse postoperative outcomes after PCI. Prognostic factors were assessed using Cox multivariate regression analysis to determine if preoperative statin therapy was independently associated with a reduction in the risk of adverse postoperative outcomes. Results: Our study demonstrated that preoperative statin therapy was not associated with a reduction in risk of mortality and overall MACCE during the hospital stay (0·3% vs. 0·4%; 1·4% vs. 1·2%P > 0·05, respectively).Compared with patients not receiving statins therapy, the hazard ratio for mortality in hospital was 0·738 (95% CI, 0·499–1·211, P = 0·229). Conclusions: Preoperative statin therapy did not reduce the risk of mortality and the rates of MACCE during the hospital stay after successful PCI. Cox multivariate regression analysis showed that independent prognostic parameters for mortality were Age, LVEF<50%, Triple vessel CAD, and DM (diabetes mellitus).     

Evaluation of Ceftaroline,Vancomycin, Daptomycin,or Ceftaroline plus Daptomycin against Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus in an In Vitro Pharmacokinetic/Pharmacodynamic Model of Simulated Endocardial Vegetations

Infective endocarditis (IE) caused by methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin and daptomycin has few adequate therapeutic options. Ceftaroline (CPT) is bactericidal against daptomycin (DAP)-nonsusceptible (DNS) and vancomycin-intermediate MRSA, but supporting data are limited for IE. This study evaluated the activities of ceftaroline, vancomycin, daptomycin, and the combination of ceftaroline plus daptomycin against DNS MRSA in a pharmacokinetic/pharmacodynamic (PK/PD) model of simulated endocardial vegetations (SEVs). Simulations of ceftaroline-fosamil (600 mg) every 8 h (q8h) (maximum concentration of drug in serum [C_max], 21.3 mg/liter; half-life [t_1/2], 2.66 h), daptomycin (10 mg/kg of body weight/day) (C_max, 129.7 mg/liter; t_1/2, 8 h), vancomycin (1 g) q8h (minimum concentration of drug in serum [C_min], 20 mg/liter; t_1/2, 5 h), and ceftaroline plus daptomycin were evaluated against 3 clinical DNS, vancomycin-intermediate MRSA in a two-compartment, in vitro, PK/PD SEV model over 96 h with a starting inoculum of ∼8 log₁₀ CFU/g. Bactericidal activity was defined as a ≥3-log₁₀ CFU/g reduction from the starting inoculum. Therapeutic enhancement of combinations was defined as ≥2-log₁₀ CFU/g reduction over the most active agent alone. MIC values for daptomycin, vancomycin, and ceftaroline were 4 mg/liter, 4 to 8 mg/liter, and 0.5 to 1 mg/liter, respectively, for all strains. At simulated exposures, vancomycin was bacteriostatic, but daptomycin and ceftaroline were bactericidal. By 96 h, ceftaroline monotherapy offered significantly improved killing compared to other agents against one strain. The combination of DAP plus CPT demonstrated therapeutic enhancement, resulting in significantly improved killing versus either agent alone against 2/3 (67%) strains. CPT demonstrated bactericidal activity against DNS, vancomycin-intermediate MRSA at high bacterial densities. Ceftaroline plus daptomycin may offer more rapid and sustained activity against some MRSA in the setting of high-inoculum infections like IE and should also be considered.     

Effects of Apnea,Obesity, and Statin Therapy on Proprotein Convertase Subtilisin/Kexin 9 Levels in Patients with Obstructive Sleep Apnea

ObjectivesObstructive sleep apnea (OSA) is a common condition closely related to obesity, insulin resistance, dyslipidemia, and cardiovascular disease. The aim of this study was to explore the possible relationship between OSA and proprotein convertase subtilisin/kexin type 9 (PCSK9).MethodsFull-night polysomnography was performed on 150 participants who were divided into three groups: controls, OSA patients on statin therapy, and OSA patients not on statin therapy. Biochemical markers, plasma low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclasses, and PCSK9 were determined.ResultsPCSK9 was highest in OSA patients on statins compared to the control group and to OSA patients not on statins (p = 0.036 and p = 0.039, respectively), after adjustment for body mass index (BMI). LDL diameter was greater in OSA patients not on statins compared to OSA patients on statins (p = 0.032). PCSK9 was highest in the group of patients with all three risk factors (diagnosed OSA, statins, BMI ≥25 kg/m²) compared to groups with no, one, and two risk factors (p = 0.031, p = 0.001, and p = 0.029, respectively). Presence of OSA, statin therapy, and BMI ≥25 kg/m² when combined were independently associated with higher levels of PCSK9 when adjusted for antihypertensive therapy, small dense LDL, and HDL 3c subclass (odds ratio = 2.849; interquartile range [1.026–7.912], p = 0.044).ConclusionStatin therapy was closely related to PCSK9. OSA along with obesity and statin use induces elevation of PCSK9.     

Lipid-lowering: can ezetimibe help close the treatment gap?

Most patients who should be on lipid-lowering therapy are not receiving it, and most patients who are receiving it are not reaching their appropriate low-density lipoprotein (LDL) goals. This is in part because physicians and patients fear side effects of statins and other lipid-lowering agents. Ezetimibe (Zetia), a new lipid-lowering drug, may help physicians close this "treatment gap" in more patients, especially in combination with a statin.