telavancin and Gram-Positive-Bacterial-Infections

Glycopeptides have an established role in the management of infective endocarditis, and feature in current treatment guidelines. Newer lipoglycopeptide agents (dalbavancin, telavancin and oritavancin), which are analogues of glycopeptides with structural modifications giving rise to added novel mechanisms of antimicrobial activity, are approved for the treatment of Gram-positive skin and skin structure infections, and also for nosocomial pneumonia (only telavancin has approval for the latter indication). Recent evidence has also emerged to support their use in the treatment of bone and joint infections. This article reviews the current literature on dalbavancin and telavancin in the treatment of infective endocarditis, a condition for which the role of these agents is yet to be established.

Topics: Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Endocarditis, Bacterial; Female; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Male; Microbial Sensitivity Tests; Middle Aged

Telavancin is a novel lipoglycopeptide derivative of vancomycin that has activity against Gram-positive aerobic and anerobic bacteria, for the treatment of serious infections, including complicated skin and skin structure infections (cSSSI) and pneumonia.. This article was compiled through searches on telavancin up to December 2015 in the PubMed and the clinicaltrials.gov databases; the FDA and European Medicine Agency (EMA) websites. In our review, particular attention was paid to those articles that reviewed the pharmacokinetic characteristics of the drug and animal models of infection. We also searched for evidence of the efficacy of telavancin as demonstrated in clinical trials, safety and tolerability data and have compiled a summary of clinical trials on telavancin in pneumonia.. Telavancin is approved in Europe and the USA for the treatment of nosocomial pneumonia caused by methicillin resistant Staphylococcus aureus when other alternatives are not suitable.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Cross Infection; Disease Models, Animal; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Pneumonia, Staphylococcal

Telavancin was the first marketed lipoglycopeptide. Although licensed in Europe in 2011 for the treatment of nosocomial pneumonia caused by meticillin-resistant Staphylococcus aureus (MRSA), it did not become clinically available until March 2014. Given the limited clinical experience with telavancin in Europe, this review provides an overview of its antimicrobial and clinical activity as well as its position among today's antimicrobials, with particular focus on the implications of its licensing requirements. Telavancin has potent in vitro activity against isolates of Gram-positive pathogens, including MRSA and glycopeptide-intermediate S. aureus strains. In addition, at clinically attainable doses telavancin inhibits Gram-positive isolates of antibiotic-resistant strains from biofilm models. The in vitro potency of telavancin has been corroborated in the clinical setting. Comparative clinical studies of telavancin demonstrate non-inferiority compared with vancomycin in the treatment of hospital-acquired Gram-positive pneumonia, with high cure rates for telavancin-treated patients with monomicrobial S. aureus infection, including isolates with reduced vancomycin susceptibility. These studies also demonstrate an overall similar safety profile for telavancin and vancomycin, although importantly, patients with moderate-to-severe renal impairment at baseline are at greater risk for mortality with telavancin and this feature must be taken into account when selecting patients for its usage. In Europe, telavancin is a useful alternative for patients with difficult-to-treat, hospital-acquired MRSA pneumonia when there are very few alternatives. For example, it should be considered in such patients when vancomycin and linezolid are not suitable and where renal function permits.

Topics: Aminoglycosides; Anti-Bacterial Agents; Cross Infection; Drug-Related Side Effects and Adverse Reactions; Europe; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides

Gram-positive cocci are the most frequent aetiology of community and nosocomially bacterial acquired infections. The prevalence of multidrug-resistant gram-positive bacteria is increasing and is associated with high morbidity and mortality. New antibiotics will be available in the European market during the next months. This revision is focused on lipoglycopeptides, new cephalosporins active against methicillin-resistant Staphylococcus aureus (MRSA) and the new oxazolidinone, tedizolid. The purpose of this review is to describe their in vitro activity, pharmacokinetic and pharmacodynamic characteristics, and experience from clinical trials.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Cephalosporins; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Oxazoles

Telavancin (TD-6424) was discovered in 2000 and became the first marketed semisynthetic lipoglycopeptide in 2009. This parenteral antibacterial agent has a dual mechanism of action and potent in vitro activity against gram-positive pathogens, including methicillin-resistant Staphylococcus aureus and isolates with reduced vancomycin susceptibility. Pharmacokinetic and pharmacodynamic analyses support the concentration-dependent activity and once-daily dosing regimen of telavancin. A changing regulatory approval process, manufacturing obstacles, and the termination of a commercialization partnership have challenged the development and marketing of telavancin. The commercial operations for telavancin have been restored, a new manufacturer has been secured, and reliable product supplies are available for clinical use. In addition, telavancin continues to be supported by ongoing clinical research with the recent launch of the Telavancin Observational Use Registry (TOUR; NCT02288234) in the United States and an international phase 3, randomized trial comparing telavancin with standard therapy for the treatment of patients with complicated S. aureus bacteremia, including endocarditis (NCT02208063).

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Disease Models, Animal; Drug Approval; Drug Discovery; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; United States; United States Food and Drug Administration

Skin and soft-tissue infections (SSTIs) are an important cause of morbidity and mortality among hospitalized patients and a major therapeutic challenge for clinicians. Although uncomplicated SSTIs are managed successfully on an outpatient basis, more serious infections extending to the subcutaneous tissue, fascia, or muscle require complex management. Early diagnosis, selection of appropriate antimicrobials, and timely surgical intervention are key to successful treatment. Surgical-site infections, an important category of SSTI, occur in approximately half a million patients in North America annually. SSTIs are also a potential source for life-threatening bacteremia and metastatic abscesses. Gram-positive organisms, such as Staphylococcus aureus and Streptococcus pyogenes, are the dominant organisms isolated early in the infectious process, whereas gram-negative organisms are found in chronic wounds. Methicillin-resistant S. aureus (MRSA) is a potential bloodstream invader that requires aggressive antimicrobial treatment and surgery. Recent concerns regarding vancomycin activity include heteroresistance in MRSA and increase in the minimum inhibitory concentrations (>1 or 2 µg/mL); however, alternative agents, such as telavancin, daptomycin, linezolid, ceftaroline, dalbavancin, oritavancin, and tedizolid, are now available for the treatment of severe MRSA infections. Here, we present a review of the epidemiology, etiology, and available treatment options for the management of SSTIs.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clinical Trials as Topic; Daptomycin; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; North America; Oxazolidinones; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections

Oritavancin, telavancin, and dalbavancin are recently marketed lipoglycopeptides that exhibit remarkable differences to conventional molecules. While dalbavancin inhibits the late stages of peptidoglycan synthesis by mainly impairing transglycosylase activity, oritavancin and telavancin anchor in the bacterial membrane by the lipophilic side chain linked to their disaccharidic moiety, disrupting membrane integrity and causing bacteriolysis. Oritavancin keeps activity against vancomycin-resistant enterocococci, being a stronger inhibitor of transpeptidase than of transglycosylase activity. These molecules have potent activity against Gram-positive organisms, most notably staphylococci (including methicillin-resistant Staphylococcus aureus and to some extent vancomycin-intermediate S. aureus), streptococci (including multidrug-resistant pneumococci), and Clostridia. All agents are indicated for the treatment of acute bacterial skin and skin structure infections, and telavancin, for hospital-acquired and ventilator-associated bacterial pneumonia. While telavancin is administered daily at 10 mg/kg, the remarkably long half-lives of oritavancin and dalbavancin allow for infrequent dosing (single dose of 1200 mg for oritavancin and 1000 mg at day 1 followed by 500 mg at day 8 for dalbavancin), which could be exploited in the future for outpatient therapy. Among possible safety issues evidenced during clinical development were an increased risk of developing osteomyelitis with oritavancin; taste disturbance, nephrotoxicity, and risk of corrected QT interval prolongation (especially in the presence of at-risk co-medications) with telavancin; and elevation of hepatic enzymes with dalbavancin. Interference with coagulation tests has been reported with oritavancin and telavancin. These drugs proved non-inferior to conventional treatments in clinical trials but their advantages may be better evidenced upon future evaluation in more severe infections.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Teicoplanin

The purpose of this comparative review is to provide clinical information on the semisynthetic lipoglycopeptides (telavancin, oritavancin, and dalbavancin) for the management of gram-positive infections.. A PubMed search was conducted using the following terms: telavancin, dalbavancin, and oritavancin. Clinical trials evaluating pharmacokinetic properties, pharmacodynamic properties, clinical efficacy, and safety profiles were included in the review.. The lipoglycopeptides are approximately 4- to 8-fold more potent than vancomycin against gram-positive organisms, including activity against vancomycin-intermediate or vancomycin-resistant strains of Staphylococcus and Enterococcus species. In addition, oritavancin maintains activity against Enterococcus species harboring vanA operon. Clinical trial data revealed equal efficacy to vancomycin in the management of acute bacterial skin and skin structure infections and, in the case of telavancin, hospital-acquired pneumonia. A benefit of oritavancin and dalbavancin is that a full course of therapy consists of a single- or 2-dose regimen, respectively. These agents are well tolerated with similar adverse event rates to vancomycin. Telavancin requires a thorough assessment before initiation of therapy to minimize the risk of acute kidney injury and teratogenicity.. The lipoglycopeptides enhance the antibiotic gram-positive armamentarium at a time when methicillin-resistant Staphylococcus aureus prevalence and overall resistance is at an all-time high. These agents serve to fill different clinical roles in the management of gram-positive infections. On the basis of the available data, telavancin should be considered a plausible agent for the management of gram-positive organisms when patients do not respond or develop adverse effects to vancomycin. Dalbavancin and oritavancin are new therapeutic options, and their potency and pharmacokinetic properties may provide benefit over existing therapies. Clinical trial data indicate that patients with signs or symptoms of skin and skin structure infections may be successfully treated using 1 or 2 doses of these agents. Eliminating the need for inpatient admission, central catheter placement, and/or daily outpatient parenteral antibiotic therapy is a major advance in treatment of skin and skin structure infections. This strategy may reduce costs associated with resource utilization and iatrogenic morbidity, resulting in overall improvements in care.

Topics: Aminoglycosides; Anti-Bacterial Agents; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Lipopeptides; Methicillin-Resistant Staphylococcus aureus; Teicoplanin; Vancomycin; Vancomycin-Resistant Enterococci

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 AUC0-24h/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.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Resistance, Bacterial; Drug Resistance, Multiple; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Lipoglycopeptides; Mice

Bacterial infections, particularly those due to gram-positive bacteria, continue to predominate in patients with cancer. Coagulase-negative and coagulase-positive staphylococci and enterococci remain as common pathogenic microorganisms. Clostridium difficile has emerged as a significant pathogen. Major clinical syndromes include vascular catheter-related infection, febrile neutropenia, diarrhea and colitis. Rising antimicrobial resistance among gram-positive bacteria is of serious concern. The clinical utility of penicillin against streptococci and vancomycin against coagulase-negative and coagulase-positive staphylococci and enterococci may be rapidly diminishing. Liberal empiric use of vancomycin during neutropenic fever needs careful reconsideration. Newer promising anti-gram-positive bacterial drugs with activity against methicillin-resistant staphylococci include daptomycin, linezolid, tigecycline and telavancin. However, toxicity concerns, limited data in immunocompromised populations and high cost prevent the widespread use of these drugs among patients with cancer.

Topics: Acetamides; Aminoglycosides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Linezolid; Lipoglycopeptides; Minocycline; Neoplasms; Oxazolidinones; Tigecycline

The epidemiology and antibiotic resistance of Staphylococcus aureus have evolved, underscoring the need for novel antibiotics, particularly against methicillin-resistant S. aureus (MRSA). Telavancin is a bactericidal lipoglycopeptide with potent activity against Gram-positive pathogens.. To systematically review and synthesize the available evidence from randomized controlled trials (RCTs) evaluating telavancin in the treatment of patients with infections due to Gram-positive organisms with the methodology of meta-analysis.. Six RCTs comparing telavancin with vancomycin were included; 4 (2229 patients) referred to complicated skin and soft tissue infections (cSSTIs) and 2 (1503 patients) to hospital-acquired pneumonia (HAP). Regarding cSSTIs, telavancin and vancomycin showed comparable efficacy in clinically evaluable patients (odds ratio [OR] =1.10 [95% confidence intervals: 0.82-1.48]). Among patients with MRSA infection, telavancin showed higher eradication rates (OR=1.71 [1.08-2.70]) and a trend towards better clinical response (OR=1.55 [0.93-2.58]). Regarding HAP, telavancin was non-inferior to vancomycin in terms of clinical response in two Phase III RCTs; mortality rates for the pooled trials were comparable with telavancin (20%) and vancomycin (18.6%). Pooled data from cSSTIs and HAP studies on telavancin 10 mg/kg indicated higher rates of serum creatinine increases (OR=2.22 [1.38-3.57]), serious adverse events (OR=1.53 [1.05-2.24]), and adverse event-related withdrawals (OR=1.49 [1.14-1.95]) among telavancin recipients.. Telavancin might be an alternative to vancomycin in cases of difficult-to-treat MRSA infections. The potent antistaphylococcal activity of telavancin should be weighted against the potential for nephrotoxicity.

Topics: Aminoglycosides; Anti-Bacterial Agents; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Randomized Controlled Trials as Topic

Hospital-acquired pneumonia is a common infection, associated with substantial mortality. Despite the increasing prevalence of nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA), approved treatment options for this pathogen are limited.. This article reviews the pharmacokinetics, dosing, preclinical studies and clinical efficacy, and safety of telavancin, with a particular focus on results from trials in nosocomial pneumonia. PubMed and Congress websites were searched for relevant articles published between 2003 and 2010.. Telavancin is a lipoglycopeptide antibiotic with rapid, bactericidal activity against MRSA, and may provide another option for the treatment of nosocomial pneumonia, owing to Gram-positive pathogens.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Cross Infection; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Staphylococcal; Skin Diseases, Bacterial

Resistance to antibiotics among gram-positive bacteria, especially enterococci and staphylococci, has led to the need to develop new antibiotics. Vancomycin, a glycopeptide antibiotic, has been used for over 3 decades to treat serious methicillin-resistant Staphylococcus aureus infections. The increased frequency of multidrug-resistant bacteria, especially vancomycin-resistant strains, has focused interest on three new lipoglycopeptides for the treatment of infections caused by gram-positive bacteria: oritavancin, dalbavancin, and telavancin. Although oritavancin and dalbavancin are still in development, telavancin received approval from the United States Food and Drug Administration in September 2009 for treatment of complicated skin and skin structure infections. Structurally different from vancomycin and teicoplanin, all three lipoglycopeptides have greater potency and less potential for development of resistant organisms. Of particular importance is the activity of oritavancin, dalbavancin, and telavancin against vancomycin-resistant organisms. In addition, the pharmacokinetic properties of these new antimicrobials substantially differ from those of vancomycin. Both oritavancin and dalbavancin have long terminal half-lives, which may allow for infrequent dosing. In addition, oritavancin is primarily cleared through hepatic pathways, which makes it potentially useful in patients with renal compromise. In animal models, these new lipoglycopeptides were effective in treating serious gram-positive infections, including complicated skin and skin structure infections, endocarditis, bacteremia, and pneumonia; in clinical studies, however, efficacy was shown only in complicated skin and skin structure infections for all three agents. According to preliminary data, the adverse-effect profile of these lipoglycopeptides is generally similar to that of drugs currently used to treat severe gram-positive infections. However, further evaluation and monitoring is necessary as more patients are exposed to these agents. As antimicrobial resistance continues to increase worldwide, the lipoglycopeptides may provide clinicians with a useful antimicrobial in the continued fight against multidrug-resistant gram-positive bacteria.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Drug Resistance, Multiple; Drug Synergism; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Half-Life; Humans; Lipoglycopeptides; Teicoplanin; Vancomycin Resistance

Dalbavancin, oritavancin and telavancin are semisynthetic lipoglycopeptides that demonstrate promise for the treatment of patients with infections caused by multi-drug-resistant Gram-positive pathogens. Each of these agents contains a heptapeptide core, common to all glycopeptides, which enables them to inhibit transglycosylation and transpeptidation (cell wall synthesis). Modifications to the heptapeptide core result in different in vitro activities for the three semisynthetic lipoglycopeptides. All three lipoglycopeptides contain lipophilic side chains, which prolong their half-life, help to anchor the agents to the cell membrane and increase their activity against Gram-positive cocci. In addition to inhibiting cell wall synthesis, telavancin and oritavancin are also able to disrupt bacterial membrane integrity and increase membrane permeability; oritavancin also inhibits RNA synthesis. Enterococci exhibiting the VanA phenotype (resistance to both vancomycin and teicoplanin) are resistant to both dalbavancin and telavancin, while oritavancin retains activity. Dalbavancin, oritavancin and telavancin exhibit activity against VanB vancomycin-resistant enterococci. All three lipoglycopeptides demonstrate potent in vitro activity against Staphylococcus aureus and Staphylococcus epidermidis regardless of their susceptibility to meticillin, as well as Streptococcus spp. Both dalbavancin and telavancin are active against vancomycin-intermediate S. aureus (VISA), but display poor activity versus vancomycin-resistant S. aureus (VRSA). Oritavancin is active against both VISA and VRSA. Telavancin displays greater activity against Clostridium spp. than dalbavancin, oritavancin or vancomycin. The half-life of dalbavancin ranges from 147 to 258 hours, which allows for once-weekly dosing, the half-life of oritavancin of 393 hours may allow for one dose per treatment course, while telavancin requires daily administration. Dalbavancin and telavancin exhibit concentration-dependent activity and AUC/MIC (area under the concentration-time curve to minimum inhibitory concentration ratio) is the pharmacodynamic parameter that best describes their activities. Oritavancin's activity is also considered concentration-dependent in vitro, while in vivo its activity has been described by both concentration and time-dependent models; however, AUC/MIC is the pharmacodynamic parameter that best describes its activity. Clinical trials involving patients with complicated skin and skin st

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Drug Interactions; Drug Resistance, Multiple, Bacterial; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Molecular Structure; Teicoplanin; Treatment Outcome

Telavancin, a lipoglycopeptide antibiotic, is a semisynthetic derivative of vancomycin. It was approved by the US Food and Drug Administration (FDA) in 2009 for the treatment of complicated skin and skin structure infections (cSSSIs) caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus.. This article summarizes the pharmacology, in vitro and in vivo activity, pharmacokinetic properties, and clinical efficacy and tolerability of telavancin.. Relevant information was identified through a search of MEDLINE (1966-August 2010), Iowa Drug Information Service (1966-August 2010), International Pharmaceutical Abstracts (1970-August 2010), and Google Scholar using the terms telavancin, lipoglycopeptide, and TD-6424. Abstracts and posters from scientific meetings, as well as documents submitted by the manufacturer of telavancin to the FDA as part of the approval process, were consulted. In vivo and in vitro experimental and clinical studies and review articles that provided information on the activity, mechanism of action, pharmacologic and pharmacokinetic properties, clinical efficacy, and tolerability of telavancin were reviewed.. In vitro, telavancin has potent activity against S aureus, including methicillin-resistant strains; Streptococcus pneumoniae; and vancomycin-susceptible enterococci with MICs generally <1 μg/mL. Telavancin appears to have a dual mechanism of action, inhibiting cell wall formation and disrupting the cell membrane. In Phase III studies (ATLAS 1 and ATLAS 2), telavancin was found to be noninferior to vancomycin, with clinical cure rates of 88.3% and 87.1%, respectively, in clinically evaluable patients in the treatment of cSSSIs (difference, 1.2%; 95% CI, -2.1 to 4.6; P = NS). The effectiveness of telavancin in the treatment of hospital-acquired pneumonia was assessed in 2 Phase III studies (ATTAIN 1 and ATTAIN 2). Preliminary findings were that the effectiveness of telavancin was not significantly different from that of vancomycin, with cure rates of 82.7% and 80.9% in the clinically evaluable population, respectively (difference, 1.8%; 95% CI, -4.1 to 7.7; P = NS). The most commonly (>10%) reported adverse events included taste disturbances, nausea, headache, vomiting, foamy urine, constipation, and insomnia.. In clinical trials, the effectiveness of telavancin was not significantly different from that of vancomycin in the treatment of cSSSIs, and telavancin was generally well tolerated.

Topics: Adult; Aminoglycosides; Anti-Bacterial Agents; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Molecular Structure; Skin Diseases, Infectious

To review the pharmacology, antimicrobial activity, pharmacokinetics, clinical applications, and safety of telavancin, a new lipoglycopeptide antibiotic.. Literature was obtained from MEDLINE (1966-April 2009) and International Pharmaceutical Abstracts (1971-April 2009) using the search terms telavancin and TD-6424, and also from Theravance, Inc., and Astellas Pharma US, Inc.. Available English-language articles were reviewed, as well as information obtained from Theravance, Inc., and Astellas Pharma US, Inc.. Telavancin has rapid bactericidal activity against gram-positive aerobic and anaerobic bacteria through multiple mechanisms of action. In vitro and Phase 2 in vivo data support the efficacy of telavancin against antibiotic-resistant gram-positive organisms. On March 4, 2008, the Food and Drug Administration (FDA) accepted as complete for review Theravance's response to the October 19, 2007, New Drug Application approvable letter for telavancin to be used as treatment for complicated skin and skin structure infections (cSSSIs) caused by gram-positive bacteria. QTc interval prolongation has been reported, although the clinical impact of this has not been determined. Drug interactions have not been identified as of yet.. Telavancin is currently under review by the FDA for the treatment of cSSSIs caused by gram-positive bacteria. The completion of Phase 3 trials will determine whether telavancin will have a role in the treatment of other infections caused by resistant gram-positive bacteria.

Topics: Aminoglycosides; Anti-Infective Agents; Clinical Trials as Topic; Drug Interactions; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Models, Molecular; Skin Diseases, Bacterial; Soft Tissue Infections

Telavancin is a lipoglycopeptide derivative of vancomycin. Similar to vancomycin, it demonstrates activity in vitro against a variety of Gram-positive pathogens, including but not limited to methicillin-resistant Staphylococccus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP). Modifications to vancomycin's structure expanded telavancin's spectrum of activity in vitro to include organisms such as glycopeptide-intermediate S. aureus (GISA), vancomycin-resistant S. aureus (VRSA) and vancomycin-resistant enterococci (VRE). However, the clinical implications of this are currently unknown. Similar to other glycopeptides, televancin binds to the D-alanyl-D-alanine (D-Ala-D-Ala) terminus in Gram-positive organisms, resulting in inhibition of bacterial cell wall synthesis. In addition, telavancin causes depolarization of the bacterial cell membrane and increased membrane permeability. The resulting activity in vitro is rapidly bactericidal and concentration dependent, with the ratio of area under the time concentration curve to minimum inhibitory concentration (AUC/MIC) as the best predictor of activity in animal models to date. In humans, telavancin exhibits a pharmacokinetic profile that permits once-daily intravenous administration. Doses of 7.5 and 10 mg/kg/day have been studied in clinical trials. The need for dosage adjustments based on age, gender and obesity appear unnecessary. In addition, moderate hepatic impairment does not appreciably alter the pharmacokinetics of the drug. Because telavancin is extensively cleared by the kidneys, dosage adjustments will be required in patients with moderate to severe renal impairment. Published phase II and III clinical trials have shown telavancin to be comparable to standard therapy for the treatment of complicated skin and soft tissue infections. Clinical trials in the treatment of S. aureus bacteremia and hospital-acquired pneumonia are under way. Adverse effects overall appear to be mild and reversible, with taste disturbance, foamy urine, headache, procedural site pain, nausea and vomiting being the most commonly reported. However, renal toxicity was reported more frequently with telavancin than with vancomycin in two phase III clinical trials (3% versus 1%). Prolongation of the corrected QT (QTc) interval has been more common with telavancin than comparator agents, but no clinically significant electrocardiogram (ECG) changes or cardiac abnormalities have been observed to date. Although h

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Clinical Trials as Topic; Disease Models, Animal; Drug Resistance, Bacterial; Economics, Pharmaceutical; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides

Several new antimicrobials demonstrate in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and other Gram-positive bacteria. Data from large surveys indicate that linezolid, daptomycin, and tigecycline are almost universally active against MRSA. Linezolid and tigecycline inhibit both Enterococcus faecium and Enterococcus faecalis at low concentrations; daptomycin is somewhat more potent against the latter. The investigational agents dalbavancin and telavancin are more potent than vancomycin against vancomycin-susceptible organisms. Dalbavancin inhibits vanB type VRE at low concentrations, but is not active against vanA type VRE. Telavancin is less active against VRE than against vancomycin-susceptible enterococci, but minimum inhibitory concentrations are lower than those of vancomycin against VRE. With continued careful use of available antimicrobials, the vast majority of these organisms should remain susceptible to 1 or more of the agents discussed for the foreseeable future.

Topics: Aminoglycosides; Anti-Bacterial Agents; Cephalosporins; Drug Resistance, Multiple, Bacterial; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Teicoplanin; Vancomycin

An overview of the mechanism of action, dosing, clinical indications, and toxicities of the glycopeptide vancomycin is provided. The emerging gram-positive bacterial resistance to antimicrobials and its mechanisms are reviewed. Strategies to control this emergence of resistance are expected to be proposed. Newer antimicrobial agents that have activity against vancomycin-resistant organisms are now available and play a critical role in the treatment of life-threatening infections.

Topics: Aminoglycosides; Anti-Bacterial Agents; Daptomycin; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Peptides, Cyclic; Teicoplanin; Vancomycin; Virginiamycin

The increase in infections caused by resistant Gram-positive organisms has led to an urgent need for new antibiotics. Telavancin is a rapidly bactericidal lipoglycopeptide with multiple mechanisms of action, including concentration-dependent inhibition of bacterial cell wall synthesis and disruption of the functional integrity of the cell membrane. Telavancin is active against a wide variety of Gram-positive organisms including Staphylococcus aureus with resistance to methicillin, reduced susceptibility to vancomycin, and full resistance to vancomycin. Telavacin is approximately 90% protein bound; it has a serum half-life of around 8 h and a prolonged postantibiotic effect, allowing once daily administration. Telavancin is eliminated principally through the urine, requiring dose adjustment in patients with renal impairment. The efficacy and safety of telavancin was demonstrated in a large program of patients with complicated skin and skin structure infections. Development of resistance has not been detected in clinical strains. Adverse events include taste disturbance, nausea and vomiting; a small proportion of patients experienced reversible increase in serum creatinine. Two large Phase III studies in patients with healthcare associated pneumonia were recently completed. Telavancin has the potential to become an important therapeutic option to treat serious infections produced by resistant Gram-positive cocci, particularly those caused by methicillin-resistant S. aureus.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Drug Resistance, Bacterial; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides

Two glycopeptide analogues of vancomycin and teicoplanin have been developed with improved pharmacokinetic/pharmacodynamic parameters. Dalbavancin was derived from teicoplanin, and telavancin is a derivative of vancomycin. The half-life of dalbavancin in humans is 147-258 h (6-11 days) allowing for weekly administration. Dalbavancin possesses more potent in vitro activity than vancomycin or teicoplanin. Dalbavancin has been investigated in uncomplicated and complicated skin and skin structure infections (SSSIs) in clinical trials and has demonstrated equivalent or superior (versus vancomycin only) efficacy versus comparators. Telavancin exhibits a dual mechanism of action, low potential for resistance development and is active against resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Clinical trials involving SSSIs have demonstrated equivalent or superior (versus vancomycin for MRSA) efficacy compared with a standard therapy. Both telavancin and dalbavancin show promise as alternative treatments for patients with serious infections caused by resistant Gram-positive pathogens.

Topics: Aminoglycosides; Animals; Clinical Trials as Topic; Drug Resistance, Multiple, Bacterial; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Liposomes; Teicoplanin

Telavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin. It has broad-spectrum activity against gram-positive bacteria, including strains with reduced susceptibility to vancomycin. Telavancin's multifunctional mechanism of action, including inhibition of peptidoglycan synthesis and disruption of membrane potential, account for this enhanced activity as well as rapid bactericidal properties. In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae, as well as methicillin-resistant, glycopeptide-intermediate, and vancomycin-resistant Staphylococcus aureus. The agent also displays activity against many gram-positive anaerobic organisms. Predictable linear pharmacokinetics have been demonstrated over a wide range of doses, with the most common adverse effects being taste disturbance and nausea. Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins, and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication. Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens, including drug-resistant pathogens. Further clinical experience will clarify its role in therapy.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Interactions; Drug Resistance, Bacterial; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests

Telavancin, a once-daily dosing lipoglycopeptide derived from vancomycin, has a broad-spectrum microbiologic activity against gram-positive bacteria, including vancomycin-resistant staphylococci. Telavancin displays a dual mode of action and a rapid bactericidal killing. The in vitro activity of telavancin is superior to vancomycin and comparable with, or greater than, linezolid, daptomycin and other novel lipoglycopeptides. Telavancin is effective against gram-positive pathogens in animal models of soft tissue infections and deep-seated infections including endocarditis, pneumonia and bacteremia. Clinical experience with telavancin in Phase II and III studies for complicated skin and skin structure infections have demonstrated similar efficacy and tolerability compared with standard anti-staphylococcal beta-lactams and vancomycin. Telavancin is in Phase III studies for nosocomial pneumonia. Telavancin seems to be promising as a novel agent for empiric therapy or as an alternative agent in serious infections caused by clinically important resistant gram-positive pathogens such as methicillin-resistant Staphylococcus aureus, vancomycin intermediate-susceptible S. aureus, vancomycin-resistant S. aureus and vancomycin-resistant enterococci.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Drug Resistance, Bacterial; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides

The pharmacology, activity, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, dosage, and place in therapy of telavancin are reviewed.. Telavancin is a lipoglycopeptide antimicrobial agent under development for use in the treatment of multidrug-resistant gram-positive infections. Telavancin, like vancomycin, inhibits cell-wall biosynthesis by binding to late-stage cell-wall precursors. However, unlike vancomycin, telavancin also depolarizes the bacterial cell membrane and disrupts its functional integrity. Telavancin has concentration-dependent bactericidal activity and is active against gram-positive aerobic and anaerobic organisms. It is highly protein bound (93%) and has a volume of distribution of 115 mL/kg and a half-life of approximately eight hours. Telavancin is eliminated renally, and a dosage reduction is required in renally impaired patients. Animal models suggest that telavancin may be effective in the treatment of soft-tissue infections, bacteremia, endocarditis, meningitis, and pneumonia caused by gram-positive pathogens. Telavancin was not inferior to standard treatment for complicated skin and soft-tissue infections in two Phase II clinical trials and two Phase III clinical trials. A new drug application has been submitted for this indication, and Phase III trials to evaluate use in hospital-acquired-pneumonia, including infections caused by methicillin-resistant Staphylococcus aureus (MRSA), are planned. Adverse effects include metallic taste, nausea, vomiting, headache, foamy urine, Q-Tc-interval prolongation, hypokalemia, and serum creatinine increases. In trials evaluating telavancin for skin and soft-tissue infections, the dosage was 10 mg/kg i.v. once daily.. Telavancin is a promising new agent for gram-positive infections and may offer an alternative to vancomycin for MRSA-associated infections.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Resistance, Multiple, Bacterial; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Vancomycin

Theravance is developing telavancin, an injectable peptidoglycan inhibitor antibiotic for potential use in the treatment of Gram-positive bacterial infection. Phase III trials in complicated skin and skin structure infections commenced in September 2004.

Topics: Aminoglycosides; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Contraindications; Drug Evaluation, Preclinical; Gram-Positive Bacterial Infections; Lipoglycopeptides; Structure-Activity Relationship

Vancomycin and teicoplanin are the two glycopeptides currently used in the clinics for the treatment of multiresistant infections by Gram-positive organisms. The development of resistance in enterococci and staphylococci has stimulated the search for new derivatives with improved activity, particularly against strains resistant to conventional derivatives. Three of these, obtained by hemi-synthesis starting from natural compounds, are now in clinical development (oritavancin and telavancin, as derivatives of vancomycin; and dalbavancin, as a derivative of teicoplanin). The presence of a lipophilic tail on these molecules results in them having a prolonged half-life. It also modifies their mode of action, conferring to them a concentration-dependent bactericidal activity. Their spectrum of activity includes methicillin-susceptible or methicillin-resistant staphylococci, penicillin-resistant pneumococci and enterococci (including vancomycin-resistant strains for oritavancin and telavancin). Ongoing clinical studies are evaluating the efficacy and safety of these molecules for the treatment of complicated skin and soft tissue infections and bactereamia, in a once-daily (oritavancin, telavancin) or once-weekly (dalbavancin) scheme of administration. Despite these remarkable properties, the use of these potent molecules should be restricted to severe infections by multiresistant organisms to limit the risk of selection of resistance.

Topics: Aminoglycosides; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Randomized Controlled Trials as Topic; Structure-Activity Relationship; Teicoplanin; Vancomycin

Gram-positive bacterial infections are an important cause of morbidity and death among cancer patients, despite current therapy. In this case-control study, we evaluated the clinical outcomes and safety of telavancin in cancer patients with uncomplicated Gram-positive bloodstream infections (BSIs). Between March 2011 and May 2013, we enrolled cancer patients with uncomplicated Gram-positive BSIs to receive intravenous telavancin therapy for at least 14 days for Staphylococcus aureus and 7 days for other Gram-positive cocci. Patients with baseline creatinine clearance (CLCR) values of >50 ml/min received 10 mg/kg/day of telavancin, and those with CLCR values between 30 and 49 ml/min received 7.5 mg/kg/day. Patients were compared with a retrospective cohort of 39 historical patients with Gram-positive BSIs, matched for underlying malignancy, infecting organism, and neutropenia status, who had been treated with vancomycin. A total of 78 patients were analyzed, with 39 in each group. The most common pathogen causing BSIs was S. aureus (51%), followed by alpha-hemolytic streptococci (23%), Enterococcus spp. (15%), coagulase-negative staphylococci (8%), and beta-hemolytic streptococci (3%). Sixty-two percent of patients had hematological malignancies, and 38% had solid tumors; 51% of the patients were neutropenic. The overall response rate determined by clinical outcome and microbiological eradication at 72 h following the initiation of therapy, in the absence of relapse, deep-seated infections, and/or infection-related death, was better with telavancin than with vancomycin (86% versus 61%; P = 0.013). Rates of drug-related adverse events were similar in the two groups (telavancin, 31%; vancomycin, 23%; P = 0.79), with similar rates of renal adverse events. Telavancin may provide a useful alternative to standard vancomycin therapy for Gram-positive BSIs in cancer patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01321879.).

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Female; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Hematologic Neoplasms; Humans; Lipoglycopeptides; Male; Microbial Sensitivity Tests; Middle Aged; Neutropenia; Pilot Projects; Recurrence; Treatment Outcome; Vancomycin

When hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP) is caused by gram-positive and gram-negative pathogens or both (mixed infections), the adequacy of gram-negative coverage (GNC) can confound the assessment of a gram-positive agent under study. This analysis examines the influence of gram-negative infections and the adequacy of GNC on clinical efficacy and all-cause mortality in the telavancin HABP/VABP phase 3 ATTAIN trials (Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia).. This post hoc analysis evaluated 3 patient groups from ATTAIN: (1) gram-positive-only infections, (2) gram-positive-only and mixed infections-adequate GNC, and (3) gram-negative-only infections and mixed infections with inadequate GNC. For each, clinical efficacy at test of cure and all-cause mortality at day 28 were compared for telavancin and vancomycin.. In the ATTAIN safety population there were 16 more deaths in the telavancin arms than in the vancomycin arms. Of these, 13 were in patients with gram-negative-only infections (n = 9) or with mixed infections and inadequate GNC (n = 4) and all had estimated baseline creatinine clearances of <30ml/min. Based on this analysis, clinical response and all-cause mortality could be confounded because there were more patients with gram-negative pathogens at baseline and more patients received inadequate treatment of these gram-negative infections in the telavancin groups.

Topics: Adult; Aminoglycosides; Anti-Bacterial Agents; Coinfection; Cross Infection; Double-Blind Method; Female; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Hospital Mortality; Humans; Lipoglycopeptides; Male; Middle Aged; Pneumonia, Ventilator-Associated; Time Factors; Treatment Outcome; Vancomycin; Young Adult

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.

Topics: Adult; Aminoglycosides; Anti-Bacterial Agents; Community-Acquired Infections; Drug Resistance, Bacterial; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Skin; Skin Diseases, Bacterial; Staphylococcal Skin Infections; Staphylococcus aureus; Vancomycin

Telavancin is an investigational, rapidly bactericidal lipoglycopeptide with a multifunctional mechanism of action.. We conducted 2 parallel, randomized, double-blind, active-control, phase 3 studies with a prespecified pooled analysis design. Patients aged > or = 18 years who had complicated skin and skin-structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin (10 mg/kg intravenously every 24 h) or vancomycin (1 g intravenously every 12 h).. A total of 1867 patients were randomized and received > or = 1 dose of study medication. In the clinically evaluable population, at 7-14 days after receipt of the last antibiotic dose, success was achieved in 88% and 87% of patients who received telavancin and vancomycin, respectively (95% confidence interval for the difference, -2.1 to 4.6). Methicillin-resistant Staphylococcus aureus was isolated at baseline from samples from 579 clinically evaluable patients. Among these patients with methicillin-resistant S. aureus infection, cure rates were 91% among patients who received telavancin and 86% among patients who received vancomycin (95% confidence interval for the difference, -1.1 to 9.3). Microbiologic eradication among patients infected with methicillin-resistant S. aureus was 90% in the telavancin treatment group and 85% in the vancomycin treatment group (95% confidence interval for the difference, -0.9 to 9.8). Therapy was discontinued because of adverse events in 8% and 6% of patients who received telavancin and vancomycin, respectively. Except for mild taste disturbance, nausea, vomiting, and serum creatinine concentration elevation in the telavancin treatment group and pruritus in the vancomycin treatment group, adverse events were similar between groups with regard to type and severity.. Telavancin given once daily is at least as effective as vancomycin for the treatment of patients with complicated skin and skin-structure infections, including those infected with methicillin-resistant S. aureus.

Topics: Adult; Aminoglycosides; Double-Blind Method; Female; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Male; Middle Aged; Skin Diseases, Infectious; Treatment Outcome; Vancomycin

Telavancin is a bactericidal lipoglycopeptide with a multifunctional mechanism of action. We conducted a randomized, double blind, active-control phase II trial. Patients > or = 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.

Topics: Adult; Aminoglycosides; Anti-Bacterial Agents; Double-Blind Method; Female; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Male; Penicillins; Skin Diseases, Bacterial; Treatment Outcome; Vancomycin

Telavancin, a novel lipoglycopeptide, exerts concentration-dependent, rapid bactericidal activity on account of its multiple mechanisms of action. Telavancin is highly active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate, and vancomycin-resistant strains.. We conducted a randomized, double-blind, controlled, phase-2 clinical trial. Patients > or = 18 years of age with a diagnosis of complicated skin and soft-tissue infection caused by suspected or confirmed gram-positive organisms were randomized to receive either intravenously administered telavancin once daily or standard therapy (antistaphylococcal penicillin 4 times daily or vancomycin twice daily).. For the study, 167 patients were randomized and received at least 1 dose of study medication. Success rates were similar in all analysis populations at the test-of-cure evaluation. Of patients with S. aureus infection at baseline (n = 102), 80% of the telavancin group were cured and 77% of the standard therapy group were cured. For patients with MRSA infection at baseline (n = 48), cure rates were 82% for the telavancin group and 69% for the standard therapy group. Microbiologic eradication in patients with MRSA infection was 84% for the telavancin group versus 74% for the standard therapy group. MIC90 values were lower for telavancin in all tested strains of S. aureus (< or = 0.25 ug/mL) compared with the MIC90 values for vancomycin and oxacillin. Similar proportions of patients discontinued therapy for adverse events in both treatment groups (approximately 5%). Fewer serious adverse events were reported in the telavancin group (4 events) than were for the standard therapy group (9).. Clinical and microbiological results of this study support the further development of telavancin, especially for treatment of infection due to MRSA.

Topics: Adult; Aminoglycosides; Anti-Bacterial Agents; Double-Blind Method; Female; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Male; Middle Aged; Penicillins; Skin Diseases, Bacterial; Soft Tissue Infections; Vancomycin

Multicenter surveillance of antimicrobial susceptibility was performed for 235 vancomycin-resistant Enterococcus faecium (VREfm) isolates from 18 Taiwanese hospitals. The minimum inhibitory concentrations (MICs) of eravacycline, omadacycline, lipoglycopeptides, and other comparator antibiotics were determined using the broth microdilution method. Nearly all isolates of VREfm were not susceptible to teicoplanin, dalbavancin, and telavancin, with susceptibility rates of 0.5%, 1.7% and 0.5%, respectively. Tigecycline and eravacycline were active against 93.2% and 89.7% of the VREfm isolates, respectively. Moreover, the susceptibility rates of quinupristin/dalfopristin, tedizolid, and linezolid were 59.1%, 84.2%, and 77.4%, respectively. Additionally, 94% of the VREfm isolates were classified as susceptible to daptomycin, and the MICs of omadacycline required to inhibit VREfm growth by 50% and 90% were 0.12 and 0.5 mg/L, respectively. Susceptibility rates of VREfm isolates to synthetic tetracyclines and daptomycin were slightly lower and to oxazolidinone-class antibiotics were much lower in Taiwan than those in other parts of the world. Continuous monitoring of VREfm resistance to novel antibiotics, including synthetic tetracyclines, oxazolidinone-class antibiotics, and daptomycin, is needed in Taiwan.

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Daptomycin; Drug Resistance, Bacterial; Enterococcus faecium; Epidemiological Monitoring; Gram-Positive Bacterial Infections; Humans; Linezolid; Lipoglycopeptides; Microbial Sensitivity Tests; Oxazolidinones; Taiwan; Tetracyclines; Tetrazoles; Tigecycline; Vancomycin; Vancomycin-Resistant Enterococci; Virginiamycin

The propensity of oritavancin to select for stably elevated oritavancin minimum inhibitory concentrations (MICs) was studied by serial passaging of strains in broth containing oritavancin for 20days. Seven clinical strains of Enterococcus faecalis and E. faecium were studied; they included vancomycin-susceptible and both VanA and VanB vancomycin-resistant isolates. Stepwise oritavancin selection yielded stably elevated oritavancin MICs in six of the seven strains, with MIC increases ranging from 4-32-fold. By comparison, stepwise selection with comparator agents dalbavancin (4- to >128-fold MIC increases), telavancin (4-8-fold MIC increases) and daptomycin (4-32-fold MIC increases) also yielded selectants with elevated MICs of the respective agents. Oritavancin selectants retained parental MICs of vancomycin, daptomycin, linezolid and rifampicin. Some, but not all of the oritavancin selectants also showed MIC increases to the lipoglycopeptides telavancin, dalbavancin and teicoplanin, suggesting that within the lipoglycopeptide class, different mechanisms of action may be elucidated.

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacterial Proteins; Carbon-Oxygen Ligases; Daptomycin; Drug Resistance, Multiple, Bacterial; Enterococcus faecalis; Enterococcus faecium; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Teicoplanin; Vancomycin; Vancomycin Resistance

Infective endocarditis (IE) one-year mortality rates approach 40%. Here, we report two native valve Enterococcus faecalis IE cases in patients successfully treated with telavancin. An 88-year-old with mitral valve endocarditis and a penicillin allergy, initially treated with intravenous vancomycin, was switched to telavancin. A 69-year-old, who previously received amoxicillin and intravenous vancomycin for presumed enterococcal bacteraemia, was diagnosed with dual valve endocarditis for which he received telavancin. Both received six weeks of telavancin. Neither had telavancin-related adverse events, evidence of infection at six months, nor required telavancin dosing adjustments. Documented use of novel treatments for serious enterococcal infections is needed.

Topics: Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Endocarditis; Enterococcus faecalis; Female; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Male; Salvage Therapy; Treatment Outcome

To reassess the activity of telavancin when tested against Gram-positive clinical pathogens recovered from hospitalized patients in European and adjacent regions using a revised broth microdilution method.. 11 601 consecutive, non-duplicate isolates originating from 36 institutions among 18 countries recovered between 2011 and 2013 were tested for susceptibility using a revised broth microdilution method for telavancin. Interpretive telavancin breakpoints appropriate for the method were those recently approved by the FDA and EUCAST, as available.. Telavancin (MIC50/90, 0.03/0.06 mg/l; 100.0% susceptible) was equally potent against methicillin-susceptible ((MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus. All Enterococcus faecalis was susceptible to telavancin (MIC50/90, 0.12/0.12 mg/l) and inhibited at the susceptibility breakpoint (i.e. ≤ 0.25 mg/l), except for VanA-phenotype vancomycin-resistant isolates (telavancin MIC, >1 mg/l). Telavancin ( ≤ 0.015/0.03 mg/l) was active against vancomycin-susceptible Enterococcus faecium, while higher MIC values were obtained for VanA strains. Telavancin (both MIC50 and MIC90, ≤ 0.015 mg/l) was potent against Streptococcus pneumoniae, beta-haemolytic streptococci (MIC50/90, ≤ 0.015/0.06 mg/l) and viridans group streptococci (MIC50/90, ≤ 0.015/0.03 mg/l).. Telavancin exhibited potent activity against this contemporary (2011-2013) collection of organisms, inhibiting indicated pathogens at or below the FDA/EUCAST-approved breakpoints for susceptibility. VanA-phenotype enterococci were less susceptible to telavancin, a feature observed using the previous testing method. These results redefine telavancin's activity against isolates from Europe.

Topics: Aminoglycosides; Anti-Bacterial Agents; Europe; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Hospitals; Humans; Israel; Lipoglycopeptides; Microbial Sensitivity Tests; Russia

Telavancin had MIC50 and MIC90 values of 0.03 and 0.06 μg/ml (100.0% susceptible), respectively, against methicillin-resistant and -susceptible Staphylococcus aureus. Telavancin was active against vancomycin-susceptible Enterococcus faecalis (MIC50/90, 0.12/0.12 μg/ml; 100% susceptible) and Enterococcus faecium (MIC50/90, 0.03/0.06 μg/ml), while higher MIC values were obtained against vancomycin-resistant E. faecium (MIC50/90, 1/2 μg/ml) and E. faecalis (MIC50/90, >2/>2 μg/ml). Streptococci showed telavancin modal MIC results of ≤ 0.015 μg/ml, except against Streptococcus agalactiae (i.e., 0.03 μg/ml). This study reestablishes the telavancin spectrum of activity against isolates recovered from the United States (2011-2012) using the revised broth microdilution method.

Topics: Aminoglycosides; Anti-Bacterial Agents; Cross Infection; Drug Resistance, Bacterial; Enterococcus faecalis; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; United States

A revised broth microdilution susceptibility testing method for telavancin was approved by the Food and Drug Administration (FDA). Telavancin activity was assessed against Gram-positive pathogens collected worldwide (2013) using the revised method. A total of 12,346 isolates from 90 sites were included as part of the Telavancin International Surveillance Program for the Americas, Europe, and Asia-Pacific. Telavancin had MIC50 and MIC90 values of 0.03 and 0.06 μg/mL, respectively, against staphylococci, regardless of methicillin susceptibility, and inhibited all Staphylococcus aureus at ≤0.12 μg/mL (revised FDA breakpoint). Telavancin was 8-fold more active than daptomycin (MIC50/90, 0.25/0.5 μg/mL) and 16- to 32-fold more active than vancomycin (MIC50/90, 1/1 μg/mL) and linezolid (MIC50/90, 1/1 μg/mL) against methicillin-resistant S. aureus. All 692 vancomycin-susceptible Enterococcus faecalis were inhibited by telavancin (MIC50/90, 0.12/0.12 μg/mL) at ≤0.25 μg/mL (FDA breakpoint), except for 1 strain (MIC, 0.5 μg/mL). All Enterococcus faecium and E. faecalis with telavancin MIC values of ≥0.5 and ≥1 μg/mL, respectively, had a VanA phenotype. A comparison data analysis based on the MIC90 demonstrated that telavancin was at least 8-fold more potent than comparators against vancomycin-susceptible enterococci. Streptococci showed telavancin MIC50 values of ≤0.015 μg/mL, except for Streptococcus agalactiae (MIC50, 0.03 μg/mL). These in vitro results obtained by the recently approved susceptibility testing method establish a new benchmark of telavancin activity worldwide.

Topics: Americas; Aminoglycosides; Anti-Bacterial Agents; Asia; Europe; Global Health; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Lipoglycopeptides; Microbial Sensitivity Tests; United States

Telavancin is a semisynthetic lipoglycopeptide derivative of vancomycin. Telavancin has a dual mechanism of antibacterial action, disrupting peptidoglycan synthesis and cell membrane function. In 2014, the Clinical and Laboratory Standards Institute (CLSI) revised the antimicrobial susceptibility testing method for telavancin, resulting in minimum inhibitory concentration (MIC) determinations that are more accurate and reproducible and demonstrate greater in vitro potency than shown with the previous testing method. The CLSI testing method changes coincided with revised telavancin MIC interpretive break point criteria for susceptibility approved by the US Food and Drug Administration for Staphylococcus aureus (≤0.12 µg/mL), Streptococcus pyogenes (≤0.12 µg/mL), Streptococcus agalactiae (≤0.12 µg/mL), Streptococcus anginosus group (≤0.06 µg/mL), and Enterococcus faecalis (vancomycin susceptible, ≤0.25 µg/mL). Telavancin is equally potent against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). It demonstrates activity against isolates of heterogeneous vancomycin-intermediate S. aureus and vancomycin-intermediate S. aureus but is poorly active against vancomycin-resistant S. aureus. It also demonstrates potent activity against Staphylococcus epidermidis and Streptococcus spp. (MIC90 ≤0.03 µg/mL). Thus far, it has not been possible to select for high-level telavancin resistance in the laboratory using serially passaged clinical isolates of MRSA and MSSA.

Topics: Aminoglycosides; Anti-Bacterial Agents; Drug Resistance, Bacterial; Enterococcus; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus; Streptococcus

Telavancin is a dual action, bactericidal lipoglycopeptide. Its in vitro activity was compared with vancomycin and linezolid against 392 Gram-positive isolates from cancer patients. MIC90 values (μg ml(-1)) for telavancin, vancomycin and linezolid were determined for methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), methicillin-susceptible (MS), methicillin-resistant (MR), coagulase-negative staphylococci (CoNS), viridans group streptococci (VGS), Streptococcus pneumoniae, Bacillus species, Corynebacterium species and Micrococcus species. Telavancin had potent activity against β-hemolytic streptococci and Staphylococcus lugdunensis. Whereas 100% of MRSA and 98% of MSSA had vancomycin MICs ⩾ 1.0 μg ml(-1) (minimum inhibitory concentrations (MICs) at which poor clinical responses have been reported), the highest telavancin MIC was 0.38 μg ml(-1). For CoNS, 95% of MS and 100% of MR isolates had vancomycin MICs ⩾ 1.0 μg ml(-1), whereas the highest telavancin MIC was 0.38 μg ml(-1). Furthermore, 48% of VGS had vancomycin MICs ⩾ 1.0 μg ml(-1), whereas the highest telavancin MIC was 0.064 μg ml(-1). A similar pattern was noticed for S. lugdunensis, Bacillus species, Corynebacterium species and β-hemolytic streptococci. These data suggest that telavancin and linezolid have potent activity against most Gram-positive organisms that cause infections in cancer patients. Consequently, they may be considered as alternatives to vancomycin, especially in institutions wherein a substantial proportion of infections are caused by organisms with vancomycin MICs ⩾ 1.0 μg ml(-1).

Topics: Acetamides; Aminoglycosides; Anti-Bacterial Agents; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Linezolid; Lipoglycopeptides; Microbial Sensitivity Tests; Neoplasms; Oxazolidinones; Vancomycin

This study updates the activity of telavancin against Gram-positive pathogens collected from USA hospitals (2007-2009). Telavancin (MIC(50/90), 0.12/0.25 μg/mL) was active against coagulase-negative staphylococci and methicillin-resistant Staphylococcus aureus (100% susceptible), for which only daptomycin (MIC(50/90), 0.25/0.5 μg/mL; 99% susceptible) and quinupristin/dalfopristin (MIC(50/90), ≤ 0.25-0.5/0.5 μg/mL; 99% susceptible) exhibited similar activity. Telavancin (MIC(50/90), 0.25/0.5 μg/mL) inhibited 96.5% of Enterococcus faecalis at the Food and Drug Administration breakpoint (MIC, ≤ 1 μg/mL), where ampicillin (99.9% susceptible), daptomycin (99.9% susceptible), and linezolid (100% susceptible) also demonstrated high-level coverage. Telavancin inhibited, respectively, 100.0% and 91.7% of VanB-phenotype E. faecalis and E. faecium at ≤ 1 μg/mL, whereas it was less active against VanA strains. Telavancin was uniformly active against Streptococcus pneumoniae and resistant subsets, and demonstrated good potency (MIC(90), 0.06-0.12 μg/mL) against other streptococci, regardless of resistance to other drugs. This assessment reveals potent activity of telavancin against Gram-positive isolates collected from USA hospitals with no evidence of emergence of resistance.

Topics: Aminoglycosides; Anti-Bacterial Agents; Cross Infection; Daptomycin; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Hospitals; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; United States; Virginiamycin

The antibacterial effects of telavancin, vancomycin, and teicoplanin against six Staphylococcus aureus strains (1 methicillin-susceptible S. aureus [MSSA] strain, 4 methicillin-resistant S. aureus [MRSA] strains, and 1 vancomycin-intermediate S. aureus [VISA] strain) and three Enterococcus sp. strains (1 Enterococcus faecalis strain, 1 Enterococcus faecium strain, and 1 vancomycin-resistant E. faecium [VREF] strain) were compared using an in vitro pharmacokinetic model of infection. Analyzing the data from all five vancomycin-susceptible S. aureus (VSSA) strains or all 4 MRSA strains showed that telavancin was superior in its antibacterial effect as measured by the area under the bacterial kill curve at 24 h (AUBKC(24)) and 48 h (AUBKC(48)) in comparison to vancomycin or teicoplanin (P < 0.05). Telavancin was also superior to vancomycin and teicoplanin in terms of its greater early killing effect (P < 0.05). Against the three Enterococcus spp. tested, telavancin was superior to vancomycin in terms of its AUBKC(24), AUBKC(48), and greater early bactericidal effect (P < 0.05). Dose-ranging studies were performed to provide free-drug area under the concentration-time curve over 24 h in the steady state divided by the MIC (fAUC/MIC) exposures from 0 to 1,617 (7 to 14 exposures per strain) for 5 VSSA, 4 VISA, and the 3 Enterococcus strains. The fAUC/MIC values for a 24-h bacteriostatic effect and a 1-log-unit drop in the viable count were 43.1 ± 38.4 and 50.0 ± 39.0 for VSSA, 3.2 ± 1.3 and 4.3 ± 1.3 for VISA, and 15.1 ± 8.8 and 40.1 ± 29.4 for the Enterococcus spp., respectively. The reason for the paradoxically low fAUC/MIC values for VISA strains is unknown. There was emergence of resistance to telavancin in the dose-ranging studies, as indicated by subpopulations able to grow on plates containing 2× MIC telavancin concentrations compared to the preexposure population analysis profiles. Changes in population analysis profiles were less likely with enterococci than with S. aureus, and the greatest risk of changed profiles occurred for both species at fAUC/MIC ratios of 1 to 10. Maintaining a fAUC/MIC ratio of >50 reduced the risk of subpopulations able to grow on antibiotic-containing media emerging. These data help explain the clinical effectiveness of telavancin against MRSA and indicate that telavancin may have clinically useful activity against Enterococcus spp., and perhaps also VISA, at human doses of 10 mg/kg of body weight/day. In addition, they suppo

Topics: Aminoglycosides; Anti-Bacterial Agents; Culture Media; Enterococcus; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Models, Biological; Staphylococcus aureus; Teicoplanin; Vancomycin

Topics: Aminoglycosides; Anti-Bacterial Agents; Cross Infection; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Pneumonia, Bacterial; Treatment Outcome; Vancomycin

Topics: Aminoglycosides; Anti-Bacterial Agents; Drug Interactions; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Skin Diseases, Bacterial; Treatment Outcome

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 microg/mL; 100.0% susceptible), CoNS (MIC(50/90), 0.12/0.25 microg/mL), vancomycin-susceptible Enterococcus faecalis (MIC(50/90), 0.25/0.5 microg/mL; 100.0% susceptible), Enterococcus faecium (MIC(50/90), 0.06/0.12 microg/mL), Streptococcus pneumoniae (MIC(50/90), < or =0.015/0.03 microg/mL), viridans group Streptococcus spp. (MIC(50/90), 0.03/0.06 microg/mL; 100.0% susceptible), and beta-hemolytic Streptococcus spp. (MIC(50/90), 0.03/0.12 microg/mL; 99.8% susceptible). Telavancin had potent activity against vancomycin-nonsusceptible, teicoplanin-susceptible (VanB) E. faecalis (MIC(50/90), 0.25/0.5 microg/mL) and E. faecium (MIC(50/90), 0.06/0.25 microg/mL). These in vitro results show continued activity for telavancin, which represents an important alternative available for treating cSSSI.

Topics: Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Female; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Male; Microbial Sensitivity Tests; Middle Aged

The antimicrobial activity of telavancin against 2279 clinical Gram-positive cocci obtained from patients with nosocomial pneumonia [NP; including those with ventilator-acquired pneumonia (VAP)] located in numerous medical centres worldwide was evaluated.. A contemporary collection of 2279 non-duplicate consecutive Gram-positive clinical isolates were submitted from 87 hospitals located in North America (913 isolates), Latin America (222 isolates), Europe (690 isolates), and the Asia-Pacific region (454 isolates) as part of the international telavancin surveillance programme for 2007-08. Isolates were tested for susceptibility by the reference broth microdilution method (with 2%-5% lysed horse blood added for testing of streptococci). Interpretive criteria were those from CLSI (M100-S20, 2010) except for telavancin, for which the susceptible breakpoints approved by the US FDA were applied.. Telavancin was highly active against Staphylococcus aureus (MIC(90), 0.25 mg/L; 100% susceptible), coagulase-negative staphylococci (MIC(90), 0.25 mg/L), Streptococcus pneumoniae (MIC(90), 0.03 mg/L), viridans group streptococci (MIC(90), 0.06 mg/L; 100% susceptible), β-haemolytic streptococci (MIC(90), 0.06 mg/L; 100% susceptible) and vancomycin-susceptible enterococci (MIC(90), 0.5 mg/L; 100% susceptible). Telavancin inhibited all staphylococci at ≤ 0.5 mg/L. Among enterococci non-susceptible to vancomycin (all Enterococcus faecium), telavancin was active against isolates exhibiting a VanB phenotype (MIC, 0.06-0.12 mg/L), but less potent against VanA strains (MIC, ≥ 2 mg/L).. Telavancin demonstrated equal or greater potency than the comparators (vancomycin, teicoplanin, daptomycin, linezolid and quinupristin/dalfopristin) against Gram-positive pathogens implicated in NP. Telavancin showed elevated MIC values only against enterococcus isolates showing a VanA phenotype. The continued appearance of multidrug-resistant pathogens among Gram-positive isolates, mainly S. aureus, necessitates the introduction of new agents and longitudinal surveillance to monitor for the potential emergence of resistance.

Topics: Aminoglycosides; Anti-Bacterial Agents; Asia; Cross Infection; Culture Media; Europe; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Latin America; Lipoglycopeptides; Microbial Sensitivity Tests; North America; Pacific Islands; Pneumonia, Bacterial; Respiratory System; United States

Telavancin is approved in the United States and Canada for the treatment of complicated skin and skin structure infections (cSSSI) in adults caused by susceptible Gram-positive organisms. The antimicrobial activity of telavancin and comparators was evaluated against 5,027 (2007-2008) Gram-positive bacteria responsible for SSSI in medical centers in Asia-Pacific, European, Latin American, and North American regions. Telavancin was active against Staphylococcus aureus (MIC₅₀(/)₉₀, 0.12/0.25 mg/l; 100.0% susceptible) and coagulase-negative staphylococci (MIC₅₀(/)₉₀, 0.12/0.25 mg/l). telavancin inhibited all Enterococcus faecalis, including four strains displaying a VanB phenotype, at ≤ 1 mg/L (MIC₅₀(/)₉₀, 0.25/0.5 mg/l), except for two isolates with a VanA phenotype (MIC, >2 mg/l). Vancomycin-susceptible and VanB vancomycin-resistant E. faecium were inhibited by telavancin at ≤ 0.25 mg/L, while this drug exhibited elevated MIC values (≥ 0.5 mg/l) against E. faecium of VanA phenotype (MIC₅₀(/)₉₀, 2/>2 mg/l). Telavancin was potent against β-haemolytic streptococci (MIC₅₀(/)₉₀, 0.03/0.12 mg/l; 100.0% susceptible) and viridans group streptococci (MIC₅₀(/)₉₀, 0.03/0.06 mg/l; 100.0% susceptible). These in vitro data document the activity of telavancin against contemporary Gram-positive isolates and support its clinical use for the treatment of cSSSI caused by the indicated pathogens.

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacterial Toxins; Drug Resistance, Bacterial; Enterococcus; Exotoxins; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Leukocidins; Lipoglycopeptides; Microbial Sensitivity Tests; Population Surveillance; Skin; Skin Diseases, Bacterial; Staphylococcal Skin Infections; Staphylococcus; Staphylococcus aureus; Streptococcus; Vancomycin

Telavancin is an investigational, rapidly bactericidal lipoglycopeptide antibiotic that is being developed to treat serious infections caused by gram-positive bacteria. A baseline prospective surveillance study was conducted to assess telavancin activity, in comparison with other agents, against contemporary clinical isolates collected from 2004 to 2005 from across the United States. Nearly 4,000 isolates were collected, including staphylococci, enterococci, and streptococci (pneumococci, beta-hemolytic, and viridans). Telavancin had potent activity against Staphylococcus aureus and coagulase-negative staphylococci (MIC range, 0.03 to 1.0 microg/ml), independent of resistance to methicillin or to multiple agents. Telavancin activity was particularly potent against all streptococcal groups (MIC(90)s, 0.03 to 0.12 microg/ml). Telavancin had excellent activity against vancomycin-susceptible enterococci (MIC(90), 1 microg/ml) and was active against VanB strains of vancomycin-resistant enterococci (MIC(90), 2 microg/ml) but less active against VanA strains (MIC(90), 8 to 16 microg/ml). Telavancin also demonstrated activity against vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus strains (MICs, 0.5 microg/ml to 1.0 microg/ml and 1.0 microg/ml to 4.0 microg/ml, respectively). These data may support the efficacy of telavancin for treatment of serious infections with a wide range of gram-positive organisms.

Topics: Aminoglycosides; Anti-Bacterial Agents; Drug Resistance, Bacterial; Enterococcus; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Prospective Studies; Staphylococcus aureus; Streptococcus; Streptococcus pneumoniae; United States

The in vitro activity of telavancin was tested against 743 predominantly antimicrobial-resistant, gram-positive isolates. Telavancin was highly active against methicillin-resistant staphylococci (MIC(90), 0.5 to 1 microg/ml), streptococci (all MICs, < or =0.12 microg/ml), and VanB-type enterococci (all MICs, < or =2 microg/ml). Time-kill studies demonstrated the potent bactericidal activity of telavancin.

Topics: Aminoglycosides; Anti-Bacterial Agents; Drug Resistance, Bacterial; Enterococcus; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; In Vitro Techniques; Lipoglycopeptides; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcus; Streptococcus

Telavancin is a novel semi-synthetic lipoglycopeptide currently in late-stage clinical development for the treatment of serious infections due to Gram-positive bacteria. The objective of this study was to provide a baseline prospective assessment of its in vitro activity against a large and diverse collection of Gram-positive clinical isolates from Europe and Israel.. Gram-positive clinical isolates, collected between October 2004 and December 2005 from 36 hospital laboratories in 15 countries, were tested by broth microdilution using CLSI methodology.. In total, 3206 isolates were collected. Telavancin had potent activity against Staphylococcus aureus and coagulase-negative staphylococci (MIC range < or =0.015 to 2 mg/L), independent of resistance to methicillin or to multiple drugs. Telavancin had particularly strong activity against streptococcal isolates (MIC range < or =0.001 to 0.5 mg/L), including penicillin-resistant and multiple drug-resistant Streptococcus pneumoniae and erythromycin non-susceptible beta-haemolytic and viridans group streptococci. Telavancin also had excellent activity against vancomycin-susceptible enterococci (MIC(90) 0.5 mg/L), and although its MICs were elevated against VanA strains (Enterococcus faecalis MIC(90) 8 mg/L and Enterococcus faecium MIC(90) 4 mg/L), its MIC(90) was substantially lower than observed with available glycopeptides.. Telavancin has potent in vitro activity against contemporary Gram-positive clinical isolates from diverse geographic areas in Europe and Israel.

Topics: Adult; Aminoglycosides; Anti-Bacterial Agents; Child; Child, Preschool; Europe; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Israel; Lipoglycopeptides; Microbial Sensitivity Tests

The in vitro activity of telavancin was tested against 620 gram-positive isolates. For staphylococci, MICs at which 50 and 90% of isolates were inhibited (MIC(50) and MIC(90)) were both 0.25 microg/ml, irrespective of methicillin resistance. MIC(50) and MIC(90) were 0.25 and 0.5 microg/ml for vancomycin-susceptible enterococci and 1 and 2 microg/ml for vancomycin-resistant enterococci, respectively. Streptococcus pneumoniae, group A and B beta-hemolytic streptococci, and viridans streptococci were inhibited by < or =0.12 microg/ml.

Topics: Aminoglycosides; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Europe; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcus aureus; Streptococcus agalactiae; Streptococcus pyogenes; Vancomycin Resistance; Viridans Streptococci

We compared the in vitro activity of telavancin with that of vancomycin, teicoplanin, linezolid, quinupristin/dalfopristin, moxifloxacin and ampicillin, penicillin or oxacillin as appropriate, by the NCCLS/EUCAST and BSAC methods.. The organisms (n = 401) included in the study were patient isolates from St Thomas' Hospital and were selected to include representatives of the clinically important Gram-positive aerobic species. Susceptibility testing was performed by agar dilution methods on Mueller-Hinton agar according to the NCCLS/EUCAST guidelines, in comparison with Iso-Sensitest agar according to the BSAC guidelines.. Telavancin was active against all the Gram-positive species tested and nearly 90% of isolates included in the study had telavancin MICs 64 mg/L had telavancin MIC ranges of 0.5-8 and 2-16 mg/L, respectively. There was no evidence of cross-resistance with other comparator drugs. The results for telavancin for the two susceptibility testing methods were mostly either the same or within one doubling dilution.. The susceptibility breakpoints for telavancin have yet to be established, but it would appear that telavancin has superior potency to the other tested glycopeptides, and on a weight-for-weight basis displays activity that is comparable to, or better than, that of the other agents tested.

Topics: Aminoglycosides; Anti-Bacterial Agents; Anti-Infective Agents; Culture Media; Dose-Response Relationship, Drug; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests

Telavancin is a new semisynthetic glycopeptide anti-infective with multiple mechanisms of action, including inhibition of bacterial membrane phospholipid synthesis and inhibition of bacterial cell wall synthesis. We determined the in vitro activities of telavancin, vancomycin, daptomycin, linezolid, quinupristin-dalfopristin, imipenem, piperacillin-tazobactam, and ampicillin against 268 clinical isolates of anaerobic gram-positive organisms and 31 Corynebacterium strains using agar dilution methods according to National Committee for Clinical Laboratory Standards procedures. Plates with daptomycin were supplemented with Ca(2+) to 50 mg/liter. The MICs at which 90% of isolates tested were inhibited (MIC(90)s) for telavancin and vancomycin were as follows: Actinomyces spp. (n = 45), 0.25 and 1 microg/ml, respectively; Clostridium difficile (n = 14), 0.25 and 1 microg/ml, respectively; Clostridium ramosum (n = 16), 1 and 4 microg/ml, respectively; Clostridium innocuum (n = 15), 4 and 16 microg/ml, respectively; Clostridium clostridioforme (n = 15), 8 and 1 microg/ml, respectively; Eubacterium group (n = 33), 0.25 and 2 microg/ml, respectively; Lactobacillus spp. (n = 26), 0.5 and 4 microg/ml, respectively; Propionibacterium spp. (n = 34), 0.125 and 0.5 microg/ml, respectively; Peptostreptococcus spp. (n = 52), 0.125 and 0.5 microg/ml, respectively; and Corynebacterium spp. (n = 31), 0.03 and 0.5 microg/ml, respectively. The activity of TD-6424 was similar to that of quinupristin-dalfopristin for most strains except C. clostridioforme and Lactobacillus casei, where quinupristin-dalfopristin was three- to fivefold more active. Daptomycin had decreased activity (MIC > 4 microg/ml) against 14 strains of Actinomyces spp. and all C. ramosum, Eubacterium lentum, and Lactobacillus plantarum strains. Linezolid showed decreased activity (MIC > 4 microg/ml) against C. ramosum, two strains of C. difficile, and 15 strains of Lactobacillus spp. Imipenem and piperacillin-tazobactam were active against >98% of strains. The MICs of ampicillin for eight Clostridium spp. and three strains of L. casei were >1 microg/ml. The MIC(90) of TD-6424 for all strains tested was

Topics: Adult; Aminoglycosides; Anti-Bacterial Agents; Bacteria, Aerobic; Bacteria, Anaerobic; Corynebacterium; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests

Telavancin (TD-6424) is a novel lipoglycopeptide that produces rapid and concentration-dependent killing of clinically relevant gram-positive organisms in vitro. The present studies evaluated the in vivo pharmacodynamics of telavancin in the mouse neutropenic thigh (MNT) and mouse subcutaneous infection (MSI) animal models. Pharmacokinetic-pharmacodynamic studies in the MNT model demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio was the best predictor of efficacy. Telavancin produced dose-dependent reduction of thigh titers of several organisms, including methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), penicillin-susceptible and -resistant strains of Streptococcus pneumoniae, and vancomycin-resistant Enterococcus faecalis. The 50% effective dose (ED50) estimates for telavancin ranged from 0.5 to 6.6 mg/kg of body weight (administered intravenously), and titers were reduced by up to 3 log10 CFU/g from pretreatment values. Against MRSA ATCC 33591, telavancin was 4- and 30-fold more potent (on an ED50 basis) than vancomycin and linezolid, respectively. Against MSSA ATCC 13709, telavancin was 16- and 40-fold more potent than vancomycin and nafcillin, respectively. Telavancin, vancomycin, and linezolid were all efficacious and more potent against MRSA ATCC 33591 in the MSI model compared to the MNT model. This deviation in potency was, however, disproportionately greater for vancomycin and linezolid than for telavancin, suggesting that activity of telavancin is less affected by the immune status. The findings of these studies collectively suggest that once-daily dosing of telavancin may provide an effective approach for the treatment of clinically relevant infections with gram-positive organisms.

Topics: Acetamides; Aminoglycosides; Animals; Anti-Bacterial Agents; Area Under Curve; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Endpoint Determination; Female; Gram-Positive Bacterial Infections; Linezolid; Lipoglycopeptides; Methicillin Resistance; Mice; Muscle, Skeletal; Nafcillin; Neutropenia; Oxazolidinones; Protein Binding; Staphylococcal Infections; Subcutaneous Tissue; Vancomycin