A review of telavancin in the treatment of complicated skin and skin structure infections (cSSSI)

Telavancin is a novel antibiotic being investigated for the treatment of serious infections caused by Gram-positive bacteria, including complicated skin and skin structure infections (cSSSI) and pneumonia. This once-daily intravenous lipoglycopeptide exerts rapid bactericidal activity via a dual mechanism of action. It is intended for use to combat infections caused by Staphylococcus aureus and other Gram-positive bacteria, including methicillin-resistant and vancomycin-intermediate strains of S. aureus (MRSA and VISA, respectively). Vancomycin is the current gold standard in treating serious infections caused by Gram-positive bacteria, especially MRSA. In recent clinical trials, telavancin has shown excellent efficacy in phase II and III multinational, randomized, double-blinded studies of cSSSI. In the phase II FAST 2 study, which compared telavancin 10 mg/kg intravenously q 24 h vs standard therapy (an antistaphylococcal penicillin at 2 g IV q 6 h or vancomycin 1 gm IV q 12 h), the clinical success rate in the telavancin-treated group was 96% vs 94% in the standard therapy group. In two identical phase III trials comparing telavancin versus vancomycin at the doses of the FAST 2 study for cSSSI, the clinical cure rates were 88.3% and 87.1%, respectively. Two additional phase III clinical trials investigating telavancin for use in hospital-acquired pneumonia, caused by Gram-positive bacteria are currently ongoing. Telavancin is currently under regulatory review in both the United States and Europe for the indication of treatment of cSSSI

Clevidipine for severe hypertension in patients with renal dysfunction: A VELOCITY trial analysis

Introduction. Acute and severe hypertension is common, especially in patients with renal dysfunction (RD). Clevidipine is a rapidly acting (t½∼1 min) intravenous (IV) dihydropyridine calcium-channel blocker metabolized by blood and tissue esterases and may be useful in patients with RD. The purpose of this analysis was to assess the safety and efficacy of clevidipine in patients with RD. Methods. VELOCITY, a multicenter open-label study of severe hypertension, enrolled 126 patients with persistent systolic blood pressure (SBP) >180 mmHg. Investigators pre-specified a SBP initial target range (ITR) for each patient to be achieved within 30 min. Blood pressure monitoring was by cuff. Clevidipine was infused via peripheral IV at 2 mg/h for at least 3 min, then doubled every 3 min as needed to a maximum of 32 mg/h (non-weightbased treat-to-target protocol). Per protocol, clevidipine was continued for at least 18 h (96 h maximum). RD was diagnosed and reported as an end-organ injury by the investigator and was defined as requiring dialysis or an initial creatinine >2.0 mg/dl. Primary endpoints were the percentage of patients within the ITR by 30 min and the percentage below the ITR after 3 min of clevidipine infusion. Results. Of the 24 patients with moderate to severe RD, most (13/24) were dialysis dependent. Forty-six percent were male, with mean age 51 >14 years; 63% were black and 96% had a hypertension history. Median time to achieve the ITR was 8.5 min. Almost 90% of patients reached the ITR in 30 min without evidence of overshoot and were maintained on clevidipine through 18 h. Most patients (88%) transitioned to oral antihypertensive therapy within 6 h of clevidipine termination. Conclusions. This report is the first demonstrating that clevidipine is safe and effective in RD complicated by severe hypertension. Prolonged infusion maintained blood pressure within a target range and allowed successful transition to oral therapy

Efficacy and safety of telithromycin 800 mg once daily for 7 days in community-acquired pneumonia: an open-label, multicenter study

BACKGROUND: Community-acquired pneumonia (CAP) remains a major cause of morbidity and mortality throughout the world. Telithromycin (a new ketolide) has shown good in vitro activity against the key causative pathogens of CAP, including S pneumoniae resistant to penicillin and/or macrolides. METHODS: The efficacy and safety of telithromycin 800 mg orally once daily for 7 days in the treatment of CAP were assessed in an open-label, multicenter study of 442 adults. RESULTS: Of 149 microbiologically evaluable patients, 57 (9 bacteremic) had Streptococcus pneumoniae. Of the 57 S pneumoniae pathogens isolated in these patients, 9 (2 bacteremic) were penicillin- or erythromycin-resistant; all 57 were susceptible to telithromycin and were eradicated. Other pathogens and their eradication rates were: Haemophilus influenzae (96%), Moraxella catarrhalis (100%), Staphylococcus aureus (80%), and Legionella spp. (100%). The overall bacteriologic eradication rate was 91.9%. Of the 357 clinically evaluable patients, clinical cure was achieved in 332 (93%). In the 430 patients evaluable for safety, the most common drug-related adverse events were diarrhea (8.1%) and nausea (5.8%). CONCLUSION: Telithromycin 800 mg once daily for 7 days is an effective and well-tolerated oral monotherapy and offers a new treatment option for CAP patients, including those with resistant S pneumoniae

Telavancin versus Standard Therapy for Treatment of Complicated Skin and Skin Structure Infections Caused by Gram-Positive Bacteria: FAST 2 Study

Telavancin is a bactericidal lipoglycopeptide with a multifunctional mechanism of action. We conducted a randomized, double blind, active-control phase II trial. Patients ≥18 years of age with complicated skin and skin structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin at 10 mg/kg intravenously every 24 h (q24h) or standard therapy (antistaphylococcal penicillin at 2 g q6h or vancomycin at 1 g q12h). A total of 195 patients were randomized and received at least one dose of study medication. Clinical success rates were similar in all analysis populations at test of cure. In microbiologically evaluable patients with Staphylococcus aureus at baseline (n = 91), 96% of the telavancin group and 90% of the standard-therapy group were cured. Among patients with methicillin-resistant S. aureus (MRSA) at baseline (n = 45), clinical cure rates were also 96% for telavancin and 90% for standard therapy. Microbiologic eradication in patients with S. aureus infection was better with telavancin compared to standard therapy (92% versus 78%, P = 0.07) and significantly better in patients with MRSA (92% versus 68%; P = 0.04). Therapy was discontinued for an adverse event (AE) in 6% and 3% of the patients receiving telavancin and standard therapy, respectively. Except for two cases of rash in the telavancin group, these AEs were similar in type and severity in the two groups. The overall incidences and severities of AEs and laboratory abnormalities were similar between the two groups. These data support the ongoing studies assessing the efficacy and safety of telavancin in the treatment of serious gram-positive infections, particularly involving MRSA

Clevidipine in acute heart failure: results of the A study of blood pressure control in acute heart failure - a pilot study (PRONTO)

Background Rapid blood pressure (BP) control improves dyspnea in hypertensive acute heart failure (AHF). Although effective antihypertensives, calcium-channel blockers are poorly studied in AHF. Clevidipine is a rapidly acting, arterial selective intravenous calcium-channel blocker. Our purpose was to determine the efficacy and safety of clevidipine vs standardof- care intravenous antihypertensive therapy (SOC) in hypertensive AHF.Methods This is a randomized, open-label, active control study of clevidipine vs SOC in emergency department patients with AHF having systolic BP >= 160 mm Hg and dyspnea >= 50 on a 100-mm visual analog scale (VAS). Coprimary end points were median time to, and percent attaining, a systolic BP within a prespecified target BP range (TBPR) at 30 minutes. Dyspnea reduction was the main secondary end point.Results Of 104 patients (mean [SD] age 61 [14.9] years, 52% female, 80% African American), 51 received clevidipine and 53 received SOC. Baseline mean (SD) systolic BP and VAS dyspnea were 186.5 (23.4) mm Hg and 64.8 (19.6) mm. More clevidipine patients (71%) reached TBPR than did those receiving SOC (37%; P =.002), and clevidipine was faster to TBPR (P =.0006). At 45 minutes, clevidipine patients had greater mean (SD) VAS dyspnea improvement than did SOC patients (-37 [20.9] vs -28 mm [21.7], P =.02), a difference that remained significant up to 3 hours. Serious adverse events (24% vs 19%) and 30-day mortality (3 vs 2) were similar between clevedipine and SOC, respectively, and there were no deaths during study drug administration.Conclusions In hypertensive AHF, clevidipine safely and rapidly reduces BP and improves dyspnea more effectively than SOC

Comparison of the Efficacy and Safety of Oritavancin Front-Loaded Dosing Regimens to Daily Dosing: an Analysis of the SIMPLIFI Trial ▿

Oritavancin is a novel lipoglycopeptide with demonstrated effectiveness against complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). The pharmacokinetic and pharmacodynamic profile of oritavancin is favorable for single or infrequent dosing. A phase 2, multicenter, randomized, double-blind, parallel, active-comparator study (ClinicalTrials.gov identifier, NCT00514527) of single and infrequent dosing of intravenous (i.v.) oritavancin for the treatment of cSSSI caused by Gram-positive pathogens (wound infections, major abscess, and cellulitis) was undertaken to evaluate the noninferiority of front-loaded dosing regimens compared to a daily-dosing regimen. A total of 302 patients ≥18 years of age were randomized equally to one of three oritavancin treatment groups, receiving either a daily dose (200 mg) administered for 3 to 7 days, a single dose (1,200 mg), or an infrequent dose (800-mg dose, with the option for an additional 400 mg on day 5). The primary efficacy was defined as a clinical response in clinically evaluable (CE) patients assessed at days 21 to 29 (test of cure [TOC]). The cure rates in the CE population were 72.4% (55/76) in the daily-dose group, 81.5% (66/81) in the 1,200-mg-single-dose group, and 77.5% (55/71) in the infrequent-dose group. In patients with MRSA at baseline, the cure rates were 78.3% (18/23), 73.0% (27/37), and 87.0% (20/23) in the daily-, 1,200-mg-single-, and infrequent-dose groups, respectively; however, the study was not powered to assess outcomes in the MRSA subpopulation, and given the heterogeneity of the types of infection and the small sample size, these do not suggest any true differences in efficacy rates for these pathogens. The frequencies of adverse events were similar among treatment groups. The results of this study show that single- and infrequent-dosing schedules of oritavancin were as efficacious as daily administration and had a similar safety profile in treating cSSSI caused by Gram-positive pathogens, including MRSA