Dalbavancin, a long-acting lipoglycopeptide for the treatment of multidrug-resistant Gram-positive bacteria

Dalbavancin is a new lipoglycopeptide antibiotic in late-stage clinical development as a once-weekly treatment for serious infections including skin and skin structure infections. Its in vitro potency is greater than that of vancomycin, with a MIC(90) of 0.06 mg/l for Staphylococcus aureus and coagulase-negative staphylococci (irrespective of oxacillin susceptibility), 0.06-0.12 mg/l for vancomycin-susceptible Enterococcus spp. and 0.003 mg/l or less for Streptococcus pneumoniae or beta-hemolytic streptococci. Dalbavancin has dual routes of elimination. The results of Phase II/III studies show clinical efficiency in complicated skin and skin structure infection. During clinical trials, dalbavancin was as effective as linezolid or vancomycin in the treatment of patients with complicated skin and skin structure infection, including those with methicillin-resistant S. aureus. An additional Phase II study demonstrated efficacy in catheter-related bacteremia. Other preliminary in vitro and in vivo data have identified putative interest of dalbavancin in endocarditis, osteitis, diabetic foot, respiratory tract or joint infection.     

Dalbavancin: a new option for the treatment of gram-positive infections

OBJECTIVE: To review the pharmacology, microbiology, chemistry, in vitro susceptibility, pharmacokinetics, clinical efficacy, safety, tolerability, dosage, and administration of dalbavancin, a new semisynthetic lipoglycopeptide. DATA SOURCES: A MEDLINE search, restricted to the English language, was conducted from 1966 through January 2006. Supplementary sources included program abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy, American Society of Microbiology, and the Infectious Diseases Society of America from 2000 to 2005 and information available from the manufacturer's Web site. STUDY SELECTION AND DATA EXTRACTION: In vitro and preclinical studies, as well as Phase I, II, and III clinical trials, were evaluated to summarize the microbiology, pharmacology, clinical efficacy, and safety of dalbavancin. All published trials and abstracts citing dalbavancin were selected. DATA SYNTHESIS: Dalbavancin, a novel lipoglycopeptide, has a mechanism of action similar to that of other glycopeptides. It has in vitro activity against a variety of gram-positive organisms, but no activity against gram-negative or vancomycin-resistant enterococci that possess VanA gene. Due to its prolonged half-life (6-10 days), dalbavancin can be administered intravenously once weekly. In Phase II and III clinical trials, dalbavancin was effective and well tolerated for the treatment of skin and soft-tissue infections, catheter-related bloodstream infections, and skin and skin-structure infections. To date, adverse events are mild and limited; the most common include pyrexia, headache, nausea, oral candidiasis, diarrhea, and constipation. CONCLUSIONS: Dalbavancin appears to be a promising antimicrobial agent for the treatment of gram-positive infections. A new drug application was filed with the Food and Drug Administration (FDA) in December 2004. The FDA issued an approvable letter in 2005 for dalbavancin. If approved, dalbavancin is expected to be launched in the first quarter of 2006.     

Dalbavancin: a novel antimicrobial

The increasing incidence of serious infections because of Gram-positive pathogens and the rising cost in parenteral administration of antimicrobials has inspired the development of a novel antibiotic. Dalbavancin is the first once a week antibiotic with activity against a broad range of Gram-positive pathogens. A large multicentre, pivotal, Phase III clinical trial, which included 854 patients with complicated skin and skin structure infections, compared 1-2 doses of dalbavancin vs. linezolid. The results demonstrated non-inferiority and a comparable safety profile. With its unique pharmacokinetic profile, ease of use and excellent safety profile, dalbavancin should provide a valuable addition to the armamentarium used to treat infections because of Gram-positive cocci.     

Dalbavancin activity against selected populations of antimicrobial-resistant Gram-positive pathogens

Dalbavancin, a dimethylaminepropyl amide derivative of the lipoglycopeptide A40926, was tested against 375 antimicrobial-resistant Gram-positive pathogens collected worldwide during 2001-2003. The isolates were tested by reference and Clinical Laboratory Standards Institute broth microdilution susceptibility methods, and dalbavancin was compared with over 20 other antimicrobials. Vancomycin resistance determinants among enterococci were identified using PCR primer sets for vanA and vanB. Dalbavancin was generally more potent than vancomycin or teicoplanin. Dalbavancin was highly active against penicillin- and ceftriaxone-resistant Streptococcus pneumoniae strains (MIC(90), < or = 0.016 microg/mL). Dalbavancin was also very active against teicoplanin-nonsusceptible coagulase-negative staphylococci (CoNS; MIC range, 0.03-0.25 microg/mL), but dalbavancin MIC results were slightly elevated compared with wild type strains. Dalbavancin inhibited vanB enterococci (MIC range, 0.03-0.12 microg/mL) and was active against other resistant, non-vanA enterococcal species. However, vanA enterococcal strains were not as susceptible to dalbavancin (MIC50, 16 microg/mL). In summary, dalbavancin was very active against a wide spectrum of resistant Gram-positive isolates and demonstrated greater potency than vancomycin or teicoplanin.     

Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections

Infections caused by drug-resistant pathogens are on the rise. Daptomycin, a cyclic lipopeptide with activity against most Gram-positive pathogens, including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus, is a newly US-FDA approved antimicrobial for complicated skin and skin structure infections (cSSSI). Daptomycin has a unique mechanism of action that results in destruction of the membrane potential. The rapid bactericidal activity of daptomycin makes it an attractive antibiotic for serious Gram-positive infections.     

Daptomycin: a rapidly bactericidal lipopeptide for the treatment of Gram-positive infections

Antimicrobial resistance among Gram-positive organisms continues to increase and has reached epidemic proportions in a number of countries and within medical centers worldwide. Daptomycin is a new lipopeptide antibiotic with rapid bactericidal activity against Staphylococcus aureus. It is also active against coagulase-negative staphylococci, enterococci and streptococci. It exerts its effect through cell membrane disruption that results in dissipation of the membrane potential. Daptomycin exhibits a prolonged postantibiotic effect and is well tolerated. In Phase III clinical trials, daptomycin was found to be similar in efficacy to standard therapy in complicated skin and skin structure infections. More recently, it was approved for the treatment of S. aureus bacteremia and right-sided endocarditis. Daptomycin is not indicated for pulmonary infections. Preliminary data suggest that daptomycin may be effective in urinary tract, bone and joint infections. However, randomized clinical trials are needed to confirm these findings. Daptomycin is an effective antimicrobial agent for the treatment of various serious Gram-positive infections, especially those caused by methicillin-resistant S. aureus.     

Linezolid in the treatment of Gram-positive prosthetic joint infections

OBJECTIVES: To investigate the clinical efficacy and safety of linezolid in the treatment of Gram-positive prosthetic hip and knee infections. MATERIALS AND METHODS: A retrospective evaluation of patients hospitalized in the Department of Infectious Diseases of San Martino Hospital in Genoa with the diagnosis of Gram-positive prosthetic joint infection and treated with intravenous and/or oral linezolid. Primary end points were the patient clinical outcome at the end of treatment and at long-term follow-up (up to 12 months after the end of treatment). RESULTS: Between May 1999 and September 2003, 20 patients with prosthetic joint infection were treated with linezolid. Pathogens isolated were: methicillin-resistant Staphylococcus aureus (MRSA), 14 strains; methicillin-resistant coagulase-negative staphylococci, five strains; and Enterococcus spp., one strain. The overall duration of treatment was 7.2 +/- 2 weeks (range 6-10 weeks). Patients were given intravenous therapy for 3-7 days as inpatients, then were changed as outpatients to oral therapy under weekly laboratory testing. At long-term follow-up (1 year), we observed four cases of failure due to relapsing infections. The other 16 patients treated with linezolid did not need further surgical substitution of prosthesis or surgical joint revision. Linezolid was well tolerated, and no drug-related events leading to discontinuation of treatment were recorded. CONCLUSIONS: Our data indicate that linezolid may be an effective alternative therapy for orthopaedic infections caused by Gram-positive resistant pathogens and that a prospective and comparative evaluation of linezolid in this setting is necessary.     

Linezolid compared with teicoplanin for the treatment of suspected or proven Gram-positive infections

The efficacy, safety and tolerability of linezolid was compared with teicoplanin in a randomized, controlled, open-label, multicentre study of 430 patients with suspected or proven Gram-positive infection. Patients received intravenous (iv) +/- oral linezolid 600 mg every 12 h (n = 215) or iv or intramuscular teicoplanin (n = 215) for up to 28 days. Clinical outcomes in the intent-to-treat (ITT) and clinically-evaluable populations and microbiological success rates in microbiologically evaluable patients were assessed at follow-up (test of cure). Investigator assessed clinical cure rates at end of treatment (EOT) in ITT patients treated with linezolid (95.5%) were superior to those of teicoplanin (87.6%) for all infections combined, indicating a 7.9% statistically significant treatment advantage for linezolid (P = 0.005, 95% CI: 2.5, 13.2). Clinical cure rates by baseline diagnosis were consistently higher at EOT for the linezolid versus teicoplanin groups with skin and soft tissue infection (96.6% versus 92.8%), pneumonia (96.2% versus 92.9%) and bacteraemia (88.5% versus 56.7%). The 31.8% treatment advantage in bacteraemic patients (but not for those seen in the other infection categories) for linezolid-treated patients was statistically significant (P = 0.009, 95% CI: 10.2, 53.4). Bacterial eradication rates for linezolid exceeded those of teicoplanin for all infection sites combined but this did not reach statistical significance (81.9% versus 69.8%, respectively; P = 0.056). Adverse event rates were similar between the treatment groups, were mild to moderate in severity, and resolved quickly following treatment. The linezolid group experienced a higher incidence of drug related adverse events (30% versus 17%; P = 0.002), and notably of gastrointestinal effects (13.0% versus 1.9%, P = 0.001). However, antibiotic discontinuation rates as a result of drug related adverse events were similar (4.7% in the linezolid group versus 3.7%). Linezolid was clinically superior to teicoplanin in the treatment of Gram-positive infections.     

Worldwide summary of telavancin spectrum and potency against Gram-positive pathogens: 2007 to 2008 surveillance results

Telavancin was approved in the United States and Canada for the treatment of adult patients with complicated skin and skin-structure infections (cSSSI) caused by susceptible Gram-positive isolates. In this study, telavancin and comparator antimicrobial activities were determined against a total of 24?017 clinical isolates, including Staphylococcus aureus, coagulase-negative Staphylococcus spp. (CoNS), Enterococcus spp., and various Streptococcus spp. Overall, telavancin was highly active across all geographic regions for S. aureus (MIC_50/90, 0.12/0.25 μg/mL; 100.0% susceptible), CoNS (MIC_50/90, 0.12/0.25 μg/mL), vancomycin-susceptible Enterococcus faecalis (MIC_50/90, 0.25/0.5 μg/mL; 100.0% susceptible), Enterococcus faecium (MIC_50/90, 0.06/0.12 μg/mL), Streptococcus pneumoniae (MIC_50/90, ≤0.015/0.03 μg/mL), viridans group Streptococcus spp. (MIC_50/90, 0.03/0.06 μg/mL; 100.0% susceptible), and β-hemolytic Streptococcus spp. (MIC_50/90, 0.03/0.12 μg/mL; 99.8% susceptible). Telavancin had potent activity against vancomycin-nonsusceptible, teicoplanin-susceptible (VanB) E. faecalis (MIC_50/90, 0.25/0.5 μg/mL) and E. faecium (MIC_50/90, 0.06/0.25 μg/mL). These in vitro results show continued activity for telavancin, which represents an important alternative available for treating cSSSI.     

In vitro activity of telavancin against Gram-positive isolates from complicated skin and skin structure infections: results from 2 phase 3 (ATLAS) clinical studies

During phase 3 clinical studies of telavancin for treatment of complicated skin and skin structure infections, a total of 1530 aerobic Gram-positive isolates were identified at baseline. The majority of these strains were Staphylococcus aureus (n = 1214; 62% methicillin-resistant). All isolates were inhibited by ≤1 μg/mL of telavancin.     

Gram-positive infections: pharmacy issues and strategy for quinupristin/dalfopristin

The development of the first streptogramin antibiotic, quinupristin/dalfopristin represents an attempt to bring new antimicrobial strategies on line to combat the menacing problem of Gram-positive-resistant bacteria. With introduction to the medical center formulary, the pharmacy will need to be aware of several practical issues surrounding the use of quinupristin/dalfopristin. Cost and unit size will be important issues. Initially, this drug will only be available in 500-mg vials which may not always accommodate the suggested dose of 7.5 mg/kg of actual body weight. In addition, the drug can only be reconstituted with D5W or sterile water, and it can not be mixed with normal saline, heparin, or other drugs. Institutions adding this drug to their formularies must address the expected logistical concerns with their medical, nursing, and pharmacy staffs prior to patient usage.     

Efficacy of telavancin,a lipoglycopeptide antibiotic,in experimental models of Gram-positive infection

Telavancin is a parenteral lipoglycopeptide antibiotic with a dual mechanism of action contributing to bactericidal activity against multidrug-resistant Gram-positive pathogens. It has been approved for the treatment of complicated skin and skin structure infections due to susceptible Gram-positive bacteria and hospital-acquired/ventilator-associated bacterial pneumonia due to Staphylococcus aureus when other alternatives are unsuitable. Telavancin has been demonstrated to be efficacious in multiple animal models of soft tissue, cardiac, systemic, lung, bone, brain and device-associated infections involving clinically relevant Gram-positive pathogens, including methicillin-resistant S. aureus, glycopeptide-intermediate S. aureus, heterogeneous vancomycin-intermediate S. aureus and daptomycin non-susceptible methicillin-resistant S. aureus. The AUC_0–24h/MIC ratio is the primary pharmacodynamically-linked pharmacokinetic parameter. The preclinical data for telavancin supports further investigative clinical evaluation of its efficacy in additional serious infections caused by susceptible Gram-positive pathogens.     

New therapeutic agents for resistant Gram-positive infections

Gram-positive bacteria are an increasingly common cause of community acquired and nosocomial infections, and their resistance to antibiotics is increasing. The recent reports from several continents of methicillin-resistant Staphylococcus aureus with reduced glycopeptide-susceptibility is of grave concern. New agents are required to meet these threats and several classes of compounds are under development. This review focuses on agents that have been recently licensed or are presently in clinical development for the treatment of serious multidrug-resistant staphylococcal, enterococcal and pneumococcal infections, including methicillin-resistant S. aureus and vancomycin-resistant enterococci.     

New therapeutic agents for resistant Gram-positive infections

Gram-positive bacteria are an increasingly common cause of community acquired and nosocomial infections, and their resistance to antibiotics is increasing. The recent reports from several continents of methicillin-resistant Staphylococcus aureus with reduced glycopeptide-susceptibility is of grave concern. New agents are required to meet these threats and several classes of compounds are under development. This review focuses on agents that have been recently licensed or are presently in clinical development for the treatment of serious multidrug-resistant staphylococcal, enterococcal and pneumococcal infections, including methicillin-resistant S. aureus and vancomycin-resistant enterococci.     

Population pharmacokinetics of telavancin in healthy subjects and patients with infections

A population pharmacokinetic model of telavancin, a lipoglycopeptide antibiotic, was developed and used to identify sources of interindividual variability. Data were obtained from healthy subjects (seven phase 1 studies), patients with complicated skin and skin structure infections (cSSSI; two phase 2 and two phase 3 studies), and patients with hospital-acquired pneumonia (HAP; two phase 3 studies). A two-compartment open model with zero-order input best fit the telavancin data from healthy individuals and patients with cSSSI or HAP. Telavancin clearance was highly correlated with renal function and, to a lesser extent, with body weight. Other covariates were related to at least one parameter in cSSSI (gender, bacterial eradication, and surgery) or HAP (age of ≥ 75 years) but did not markedly affect exposure. These analyses support current dosing recommendations for telavancin based on patient weight and renal function.     

Comparative study on safety of linezolid and vancomycin in the treatment of infants and neonates for Gram-positive bacterial infections

Background

Vancomycin has been the common antimicrobial treatment for Gram-positive infection even in neonates and infants, while it is difficult to adjust blood concentration. Linezolid is also effective for Gram-positive infection, and is not necessary to monitor drug blood concentration. Primary objective of this study was to compare the safety of linezolid and vancomycin in infants and neonates for resistant Gram-positive infections.