oritavancin and Gram-Positive-Bacterial-Infections

Treatment of serious gram-positive infections presents multiple challenges. Treatment often results in prolonged hospitalization for administration of intravenous antimicrobials and presents an inefficient use of hospital resources. Prolonged hospitalization is typically also unfavorable to patient preferences and potentially subjects patients to additional health care-associated complications. Current strategies of transition to outpatient settings-outpatient parenteral antimicrobial therapy and use of oral antibiotics-often do not adequately serve vulnerable populations for whom there is often no alternative to inpatient therapy. Specifically, people who use drugs, those who cannot reliably adhere to unsupervised treatment (poor mental or physical health), people with complicating life circumstances (e.g., homelessness, incarceration, rural location), and those with inadequate health insurance remain hospitalized for weeks longer than persons without such conditions. We suspected that long-acting lipoglycopeptides (laLGP), such as dalbavancin and oritavancin, may be useful in patient transitions to outpatient settings. Thus, we conducted a search of the peer-reviewed literature using the PubMed, Google Scholar, and MEDLINE databases. Based on accumulating literature, it appears that laLGPs offer a reliable alternative therapeutic strategy that addresses many of the personal and systemic barriers to the traditional transitioning approaches. Current evidence also suggests that these agents may be cost-effective from patient, payer, and hospital perspectives. Barriers to broader use of laLGPs include, among others, a relative lack of prospective data regarding efficacy in serious infections, a narrow United States Food and Drug Administration-approved indication restricted to only acute bacterial skin and skin structure infections, and lack of reimbursement infrastructure for inpatient settings.

Topics: Anti-Bacterial Agents; Delayed-Action Preparations; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Outpatients; Teicoplanin

There is increasing interest in the use of oritavancin and dalbavancin for complicated Gram-positive infections as an alternative to in-hospital intravenous or outpatient antimicrobial therapy.. To evaluate the efficacy and safety of long-acting lipoglycopeptides (laLGPs) in patients with osteoarticular, cardiovascular, intravascular-catheter-related and other complicated infections.. A systematic literature search was performed using 'dalbavancin' and 'oritavancin' as search terms. For inclusion in this review, studies had to include at least one human subject treated for an indication other than acute bacterial skin and skin structure infections. The primary outcome for this review was clinical success as defined by each individual study, and patients were stratified by type of infection.. In total, 38 studies (18 randomized controlled trials/case series and 20 case reports) met the inclusion criteria. The most common off-label indication for oritavancin and dalbavancin was osteoarticular infection, with a median success rate of 73% [interquartile range (IQR) 58-85%] among the 14 studies with more than one patient. The success rate for endocarditis and cardiac-device-related infections was 68% (IQR 56-86%) among nine studies, and the success rate for catheter-related bloodstream infection was 75% (IQR 59-90%) among seven studies. Among the 16 studies of almost 700 patients receiving laLGPs, there were 98 reports of adverse events, resulting in 13% of treated patients reporting an event.. This review provides evidence that laLGPs are safe and efficacious for osteoarticular, cardiovascular, intravascular-catheter-related and other complicated infections. Further research is needed to confirm these results.

Topics: Anti-Bacterial Agents; Bone Diseases, Infectious; Cardiovascular Infections; Catheter-Related Infections; Female; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Male; Teicoplanin; Treatment Outcome

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

To review the pharmacology, pharmacokinetics, drug interactions, microbiologic profile, dosage and administration, safety, clinical efficacy, and potential place in therapy for the new lipoglycopetide, oritavancin.. MEDLINE and PubMed searches of available literature in English were conducted for oritavancin. Principal supplementary sources include the Food and Drug Administration (FDA) package insert, and FDA/European Medicines Agency guidances on acute bacterial skin and skin structure infections (ABSSSI).. Information from all stages of clinical development was evaluated to provide an overview of oritavancin, from in vitro susceptibility, to early human studies, to the latter stages of clinical trials.. Oritavancin is a lipoglycopeptide antibiotic that has a mechanism of action and broad-spectrum gram-positive coverage similar to other glycopeptides. Compared with other glycopeptides, oritavancin minimum inhibitory concentrations tend to be lower. Oritavancin also has coverage against glycopeptide-resistant gram-positive organisms. Oritavancin does not require dose adjustment for mild-to-moderate hepatic or renal impairment, and its prolonged half-life of 245 hours allows for a one-time administration in the treatment of ABSSSI. In phase 2 and 3 clinical trials, oritavancin was shown to be well-tolerated in addition to being noninferior to vancomycin for the treatment of ABSSSI. The most common side effects experienced were gastrointestinal in nature.. Oritavancin was approved by FDA for the treatment of ABSSSI in August 2014 and is marketed under the trade name Orbactiv. Its reduced dosing and monitoring requirements and efficacy against resistant gram-positive pathogens provide a unique profile that distinguishes it from current options in the treatment of ABSSSI.

Topics: Anti-Bacterial Agents; Drug Interactions; Drug Monitoring; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Skin Diseases, Bacterial

The growing problem of antimicrobial resistance among bacterial pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), has reached a critical state. Tedizolid phosphate, dalbavancin, and oritavancin have recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and represent the next generation of oxazolidinones and lipoglycopeptides. All three agents exhibit in vitro activity and clinical efficacy against MRSA. Tedizolid phosphate and oritavancin demonstrate in vitro activity against VRE. These new Gram-positive agents are reviewed here.

Topics: Anti-Infective Agents; Drug Approval; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Organophosphates; Oxazoles; Teicoplanin; United States; Vancomycin-Resistant Enterococci

Oritavancin, a lipoglycopeptide antibiotic, recently received US FDA approval for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI). Oritavancin, unlike other intravenous antibiotics that are currently available for the treatment of ABSSSI (e.g., vancomycin, daptomycin, telavancin, dalbavancin), offers the option of a single-dose complete regimen. The dosing schedule of oritavancin eliminates the need for an indwelling catheter and introduces the possibility of avoidance of a hospital admission; although, treatment in non-hospital settings has not been adequately evaluated in clinical trials. The availability of oritavancin adds another agent to our antibiotic armamentarium providing dosing flexibility and an alternative treatment option for treatment of ABSSSI caused by susceptible bacteria, including methicillin-resistant Staphylococcus aureus.

Topics: Acute Disease; Anti-Bacterial Agents; Drug Administration Schedule; Drug Approval; Drug Dosage Calculations; Enterococcus faecalis; Enterococcus faecium; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Injections, Intravenous; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Randomized Controlled Trials as Topic; Skin Diseases, Bacterial; Streptococcus

Oritavancin is a lipoglycopeptide antibiotic that has been shown to be effective for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). This antibiotic has multiple mechanisms of action including inhibiting peptidoglycan cell wall synthesis and disrupting bacterial cell membrane, leading to cell death. Oritavancin is highly active against common gram-positive pathogens including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, vancomycin-resistant S. aureus, and vancomycin-resistant enterococci. The drug is administered as a single intravenous dose of 1200 mg over 3 hours in adult patients, and because of its terminal half-life of 393 hours, repeat dosing is not required in the treatment of ABSSIs. There is a very slow elimination from tissue sites, and no dosing adjustments are required for renal or hepatic insufficiency. Two clinical trials have demonstrated noninferiority compared with vancomycin in the treatment of ABSSSIs. Other than liver enzyme elevation and the occurrence of osteomyelitis, oritavancin has been associated with adverse events similar to those of vancomycin in follow-up for up to 60 days. Patients should be monitored for osteomyelitis and alternate therapy given in the case of confirmed or suspected osteomyelitis. Although oritavancin is an attractive antibiotic to consider in the outpatient area, its efficacy and safety in the treatment of other sites of infection are yet to be established.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Enzymes; Glycopeptides; Gram-Positive Bacterial Infections; Half-Life; Humans; Lipoglycopeptides; Liver; Osteomyelitis; Skin Diseases, Bacterial; Soft Tissue Infections

Health care-associated infections, especially those caused by multidrug-resistant gram-positive organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), are a growing public health threat. In 2014, the U.S. Food and Drug Administration approved two new lipoglycopeptides, oritavancin and dalbavancin, for the treatment of acute bacterial skin and skin structure infections. The rationale for the development of these antimicrobials was partly to aid in the battle against vancomycin resistance in both Staphylococcus and Enterococcus. Considered a subclass of the glycopeptide antibiotics, the new lipoglycopeptides have similar mechanisms of action of binding to the carboxyl terminal d-alanyl-d-alanine residue of the growing peptide chains but differ from their parent glycopeptides by the addition of lipophilic tails. This addition allows for these agents to have prolonged half-lives, giving them unique dosing profiles. In addition, by concentrating at the site of action, they have increased potency against MRSA compared with vancomycin, the current mainstay of therapy. In this review, we focus on comparing and contrasting these two new agents with regard to their pharmacology, mechanisms of action, spectrum of activity, safety profiles, dosage and administration, and drug and laboratory interactions, and we review the clinical trials evaluating their use.

Topics: Animals; Anti-Bacterial Agents; Cross Infection; Drug Interactions; Glycopeptides; Gram-Positive Bacterial Infections; Half-Life; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Randomized Controlled Trials as Topic; Skin Diseases, Bacterial; Teicoplanin; United States; Vancomycin Resistance

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

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

Oritavancin is a lipoglycopeptide antibiotic under investigation for the treatment of serious infections caused by Gram-positive bacteria. Oritavancin has demonstrated rapid dose-dependent bactericidal activity towards vancomycin-susceptible and -resistant enterococci, meticillin-susceptible and -resistant Staphylococcus aureus, vancomycin-intermediate S. aureus (VISA), heteroresistant VISA (hVISA), vancomycin-resistant S. aureus (VRSA) and small-colony variants of S. aureus. It is also active against Clostridium difficile. Upon intravenous administration, oritavancin displays a three-compartment pharmacokinetic model, dose proportionality, a distribution volume of ca. 110 L, a terminal elimination half-life in excess of 2 weeks and it is not metabolised. Its pharmacodynamic properties make it an ideal antibiotic for a once-daily or even single-dose regimen. Oritavancin is currently under review by the US Food and Drug Administration. So far, oritavancin has demonstrated efficacy in two pivotal Phase III trials conducted in patients with complicated skin and skin-structure infections in which oritavancin was compared with vancomycin plus cefalexin. In both trials, the primary endpoint (clinical cure in clinically evaluable patients at first follow-up with a 10% non-inferiority margin) was met, with the advantages of shorter duration of therapy and fewer adverse events. Further results indicating its activity against bacteria growing in biofilms as well as stationary-phase bacteria open the way for its use to treat prosthetic device infections, which is to be investigated in upcoming trials.

Topics: Anti-Bacterial Agents; Biofilms; Clinical Trials as Topic; Clostridioides difficile; Enterococcus; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Staphylococcus aureus; United States

Nosocomial and community-acquired infections caused by Gram-positive pathogens continue to be a challenge, mainly due to the increasing rates of resistance among Staphylococcus spp. and Enterococcus spp. Oritavancin, a new parenteral semisynthetic glycopeptide, possessing rapid bactericidal action and an antimicrobial spectrum containing all Gram-positive pathogens (streptococci, staphylococci, enterococci--vancomycin-resistant enterococci included--and Clostridia spp.) irrespective of their resistance status to the precursor molecule of vancomycin, is expected to file a new drug application by the first trimester of 2008. Once-daily dosing, good penetration into macrophages, in vitro activity against bacteria embedded in biofilms and low adverse reaction potential are further considered as oritavancin's advantages over existing drugs. While waiting for the results of supplementary Phase III studies to be announced, preliminary reports suggest the new drug will be a welcome addition to the existing antimicrobial armamentarium against Gram-positive cocci.

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

Oritavancin is a lipoglycopeptide antibiotic with activity against aerobic and anaerobic Gram-positive bacteria. Oritavancin separates itself from other glycopeptides through its potent in vitro activity against resistant isolates of Staphylococcus aureus, Enterococcus spp. and Streptococcus spp. Oritavancin possesses a long half-life that should allow, at maximum, once-daily dosing. Currently, oritavancin has completed two Phase III trials and one Phase II trial for the treatment of complicated skin and skin structure infections, and two Phase II trials for the treatment of Gram-positive bacteremia. In all instances, oritavancin displayed favorable outcomes and was noninferior to comparator agents (vancomycin followed by oral cephalexin) when a comparison was made. Further studies are necessary to fully characterize dose and clinical role.

Topics: Anti-Bacterial Agents; Bacteremia; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Half-Life; Humans; Lipoglycopeptides; Soft Tissue Infections; Treatment Outcome

Oritavancin, a new semisynthetic glycopeptide has a spectrum of activity similar to vancomycin, although it exhibits potent antimicrobial activity against vancomycin-resistant staphylococci and enterococci species. It has a long-terminal half-life of 360 h, is highly protein bound and has been dosed once-daily in clinical trials. Oritavancin has been studied in complicated skin and skin structure infections where it was noninferior to the comparator group of vancomycin/cephalexin. Thus far, oritavancin has a favorable side-effect profile and appears promising in the treatment of multidrug resistant Gram-positive bacteria.

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

The advent of multidrug-resistant gram-positive aerobes such as Staphylococcus aureus, Streptococcus pneumoniae, and the enterococci, which are resistant to beta-lactams, vancomycin, and a host of other commonly used antimicrobials, has complicated our approach to antibiotic therapy. Despite marketing of the first oxazolidinone, linezolid, and the streptogramin combination, quinupristin-dalfopristin, an urgent need exists for more agents to combat these pathogens. Two such agents, the glycopeptide oritavancin (LY333328) and the glycylcycline tigecycline (GAR-936), are in phase III clinical trials. These agents, which require parenteral administration, exhibit substantial in vitro activity against a variety of gram-positive aerobes and anaerobes, including the multidrug-resistant organisms listed previously. Only tigecycline demonstrates useful activity against gram-negative organisms. Combination therapy of these agents with ampicillin or aminoglycosides frequently leads to synergistic in vitro activity against multidrug-resistant staphylococci and streptococci. These agents are also active in a variety of animal models of systemic and localized infections. Few published efficacy and tolerability data are available in humans. If controlled clinical trial data verify these agents' efficacy and tolerability, both drugs should become welcome additions to the available antimicrobials. However, restricting their use to the treatment of infections caused by bacteria resistant to other antimicrobials, especially multidrug-resistant staphylococci and streptococci, may prolong their clinical utility by retarding the development of resistance. Careful surveillance of bacterial sensitivity to these agents should be undertaken to assist clinicians in the decision whether or not to use these agents empirically to treat infections caused by suspected multidrug-resistant gram-positive pathogens.

Topics: Animals; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Drugs, Investigational; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Injections, Intravenous; Lipoglycopeptides; Minocycline; Tigecycline

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

Oritavancin (LY333328) is a semisynthetic glycopeptide antibiotic having excellent bactericidal activity against glycopeptide-susceptible and -resistant Gram-positive bacteria. Oritavancin is the N-alkyl-p-chlorophenylbenzyl derivative of chloroeremomycin (LY264826) and is currently in phase III clinical trials for use in Gram-positive infections. Studies show that oritavancin and related alkyl glycopeptides inhibit bacterial cell wall formation by blocking the transglycosylation step in peptidoglycan biosynthesis in a substrate-dependent manner. As with other glycopeptide antibiotics, including vancomycin, the effects of oritavancin on cell wall synthesis are attributable to interactions with dipeptidyl residues of peptidoglycan precursors. Unlike vancomycin, however, oritavancin is strongly dimerized and can anchor to the cytoplasmic membrane, the latter facilitated by its alkyl side chain. Cooperative interactions derived from dimerization and membrane anchoring in situ can be of sufficient strength to enable binding to either dipeptidyl or didepsipeptidyl peptidoglycan residues of vancomycin-susceptible and -resistant enterococci, respectively. This review describes the antibacterial activity of oritavancin, and examines the evidence supporting the proposed mechanism of action for this agent and related analogs.

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Models, Molecular; Peptidoglycan; Vancomycin; Vancomycin Resistance

To review pharmacology, pharmacokinetic and therapeutic use of glycopeptides in intensive care units.. Extraction from Medline database of French and English articles on glycopeptides and search along with major review articles.. The collected articles were reviewed and selected according to their quality and originality. The more recent data were selected.. Glycopeptides are bactericidal antibiotics which are only active against Gram positive species acting by inhibiting peptidoglycan synthesis. They had been in clinical use for almost 30 years without high-level resistance underlining. For ten years, there have been disturbing reports of first, resistance to vancomycin in enterococcal species and more recently in strains of Staphylococcus aureus by complex and large mechanisms of action. This new resistances may lead to a therapeutic impasse and a fatal issue for infected patients. The only response to this situation is the respect of prescription rules and the careful use of antibiotics.. Considering their spectrum, glycopeptides are an antibiotic family which importance is fundamental to treat infected patients of intensive care units. Staff members of intensive care units are responsible for their good use.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Carbon-Oxygen Ligases; Carboxypeptidases; Critical Care; Depression, Chemical; Drug Design; Drug Interactions; Drug Resistance, Microbial; Drug Utilization; Enzyme Inhibitors; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Infusions, Intravenous; Lipoglycopeptides; Membrane Proteins; Operon; Peptide Synthases; Peptidoglycan; Serine-Type D-Ala-D-Ala Carboxypeptidase; Teicoplanin; Transcription Factors; Vancomycin; Vancomycin Resistance

Infections caused by multiple-resistant Gram-positive organisms continue to occur at an alarming rate worldwide. Two new and unique antimicrobial agents targeted specifically against such organisms, quinupristin/dalfopristin and linezolid, have been approved for use in the USA in the past year and will play an important role in the treatment of life-threatening infections. In addition, several new fluoroquinolones have been approved recently or will be available in the near future to aid in the treatment of infections caused by resistant strains of Streptococcus pneumoniae.

Topics: Acetamides; Anti-Bacterial Agents; Clinical Trials as Topic; Drug Approval; Fluoroquinolones; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Linezolid; Lipoglycopeptides; Oxazolidinones; Virginiamycin

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Double-Blind Method; Female; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Male; Microbial Sensitivity Tests; Middle Aged; Skin Diseases, Bacterial; Treatment Outcome; Young Adult

Oritavancin is a lipoglycopeptide antibiotic with rapid bactericidal activity against gram-positive bacteria. Its concentration-dependent activity and long half-life allow for single-dose treatment.. In a randomized, double-blind trial, adults with acute bacterial skin and skin structure infections (ABSSSIs) received either a single intravenous 1200-mg dose of oritavancin or 7-10 days of twice-daily vancomycin. Three efficacy endpoints were tested for noninferiority: (1) primary composite endpoint at 48-72 hours (cessation of spreading or reduction in lesion size, absence of fever, and no rescue antibiotic); (2) investigator-assessed clinical cure 7-14 days after end of treatment; and (3) ≥20% reduction in lesion area at 48-72 hours.. A total of 503 and 502 patients comprised the modified intent-to-treat population for oritavancin and vancomycin, respectively. All 3 efficacy endpoints met the 10% noninferiority margin: the primary composite endpoint (80.1% vs 82.9%; 95% confidence interval [CI], -7.5 to 2.0), investigator-assessed clinical cure (82.7% vs 80.5%; 95% CI, -2.6 to 7.0), and proportion of patients attaining ≥20% reduction in lesion area (85.9% vs 85.3%; 95% CI, -3.7 to 5.0) for oritavancin vs vancomycin, respectively. Efficacy outcomes by pathogen, including methicillin-resistant Staphylococcus aureus and the frequency of adverse events, were similar between treatment groups.. A single 1200-mg dose of oritavancin was noninferior to 7-10 days of vancomycin in treating ABSSSIs caused by gram-positive pathogens, and was well tolerated. Oritavancin provides a single-dose alternative to multidose therapies for the treatment of ABSSSIs. Clinical Trials Registration. NCT01252732.

Topics: Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Double-Blind Method; Female; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Male; Middle Aged; Skin Diseases, Bacterial; Soft Tissue Infections; Treatment Outcome; Vancomycin; Young Adult

Treatment of complicated infections in persons who inject drugs (PWID) and patients experiencing homelessness poses a unique challenge to clinicians. Long-acting lipoglycopeptide antibiotics, such as oritavancin, may facilitate extended courses of outpatient intravenous therapy while avoiding the need for central lines, improving compliance and thus increasing the chance of clinical cure.. Retrospective chart review of adult PWID who received at least one dose of oritavancin for a gram-positive infection between 1/1/17 and 6/30/19 at a large safety net hospital.. Twenty three PWID received 24 courses of at least one dose of oritavancin for a gram-positive infection; 16 were experiencing homelessness at the time of diagnosis. Methicillin resistant Staphylococcus aureus (MRSA) was the most common infecting pathogen and bone or joint the most frequent infection site. Nineteen encounters resulted in clinical cure, including 5 whose conditions improved despite non-adherence to their prescribed regimen. Three patients experienced a non-favorable outcome. Two patients experienced mild adverse drug reactions that did not interfere with therapy; no patients died while on therapy.. Oritavancin may be a clinically effective treatment option for the management of complicated gram-positive infections in PWID and patients experiencing homelessness. Further studies should be performed to validate these results.

Topics: Adult; Anti-Bacterial Agents; Drug Users; Female; Gram-Positive Bacterial Infections; Humans; Ill-Housed Persons; Lipoglycopeptides; Male; Middle Aged; Retrospective Studies; Substance-Related Disorders; Treatment Outcome; Young Adult

The optimal treatment for serious infections due to Enterococcus spp. is unknown although combination antimicrobial therapy is often recommended for invasive infections to achieve bactericidal activity and improve clinical outcomes. Oritavancin is a novel lipoglycopeptide agent with in vitro activity against enterococci, including vancomycin-resistant VanA-type Enterococcus faecium. Data on its activity in combination with other antibacterials are limited. The objective of this study was to evaluate the activity of oritavancin alone and in combination with ceftriaxone, daptomycin, gentamicin, linezolid and rifampicin against vancomycin-susceptible and -resistant enterococci in in vitro time-kill analyses.. Five enterococcal strains were used for all experiments: three vancomycin-resistant VanA-type E. faecium clinical bloodstream isolates, vancomycin-resistant VanA-type E. faecium ATCC 700221 and vancomycin-susceptible Enterococcus faecalis ATCC 29212. Individual drugs were tested at ¼, ½, 1, 2 and 4× MIC. Oritavancin combination experiments were performed with each agent at ¼× MIC.. Daptomycin was the most active single agent and was bactericidal against all strains at 4× MIC, followed by oritavancin, which was bactericidal against all three clinical VRE strains at ≥2× MIC. In combination experiments at ¼× MIC, oritavancin was synergistic with gentamicin against strains not displaying high-level aminoglycoside resistance. No other synergy against VRE strains was observed in any experiment. Strain- and drug-dependent antagonism was observed for many combinations.. These in vitro data do not support the routine use of combination therapy with oritavancin in the treatment of infections due to VRE.

Topics: Anti-Bacterial Agents; Bacteremia; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Enterococcus; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Vancomycin; Vancomycin-Resistant Enterococci

The optimal therapy for serious enterococcal infections, especially vancomycin-resistant enterococci (VRE), remains unclear, although combination therapy is often recommended. Oritavancin has demonstrated in-vitro activity against VRE, but data evaluating oritavancin in combination with other agents and in in-vivo systems are lacking. The objective of this study was to evaluate the efficacy of oritavancin alone and in combination with ceftriaxone, daptomycin, gentamicin, linezolid and rifampin against vancomycin-susceptible enterococci and VRE in an in-vivo Galleria mellonella survival model.. Five enterococcal strains were used: three clinical isolates (VRE S38141, VRE H19570, VRE W21579), Enterococcus faecium ATCC 700221 and Enterococcus faecalis ATCC 29212. G. mellonella larvae were inoculated with the test strain followed by the test drug at humanized weight-based dose alone or in combination within 1 h of inoculation. After injection, larvae were incubated at 37°C and survival was measured daily for 7 days. Survival was plotted using the Kaplan-Meier method, and differences between groups were determined via the log-rank test. Mean survival times were also determined.. Each single agent improved survival significantly compared with the untreated control strain. Oritavancin was the most efficacious single agent, and led to a significant increase in survival compared with ceftriaxone, gentamicin and daptomycin. Compared with oritavancin alone, none of the oritavancin combinations tested were significantly better, and mean survival times were comparable.. Oritavancin monotherapy had the highest survival rate at 7 days, and none of the combinations tested showed improved survival over oritavancin alone. These data add to the body of literature rebutting the routine use of combination therapy with oritavancin for the treatment of infections due to VRE.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Therapy, Combination; Enterococcus faecalis; Enterococcus faecium; Gram-Positive Bacterial Infections; Lepidoptera; Lipoglycopeptides; Survival Analysis; Treatment Outcome; Vancomycin-Resistant Enterococci

Weekly oritavancin plus ampicillin continuous infusion combination therapy was used to successfully treat a deep spine vancomycin-resistant

Topics: Ampicillin; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Drug Synergism; Enterococcus faecium; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Male; Microbial Sensitivity Tests; Middle Aged; Osteomyelitis; Vancomycin; Vancomycin-Resistant Enterococci

Long-acting lipoglycopeptides (laLGPs) are FDA approved only for acute bacterial skin and skin structure infections (ABSSSIs). However, these antibiotics show promise for off-label use, reductions in hospital length of stay (LOS) and healthcare cost savings.. To assess the effectiveness, safety, impact on LOS and estimated cost savings from laLGP treatment for Gram-positive infections.. Retrospective cohort of adult patients who received at least one dose of laLGPs at the University of Colorado Health system. Descriptive statistics were utilized for analysis.. Of 59 patients screened, 56 were included: mean age 47 years, 59% male and 30% injection drug users/polysubstance abusers (dalbavancin, 71%; oritavancin, 25%; both, 4%). Most common indications for laLGP: ABSSSIs (36%), osteomyelitis (27%) and endocarditis (9%). Most common isolated pathogens: MSSA and MRSA (25% and 19%, respectively), Enterococcus faecalis (11%) and CoNS (11%). Previous antibiotics were administered for a median of 13 days (IQR = 7.0-24.5 days) and laLGPs for a median of one dose (IQR = 1-2 doses). Ten (18%) patients were lost to follow-up. Clinical failure was found in 7/47 (15%) cases with adequate follow-up. Mild adverse effects occurred in six (11%) patients. Projected reduction in hospital LOS and health-system costs were 514 days (9.18 days/person average) and $963456.72 ($17204.58/person average), respectively.. Prospective trials are needed to validate the use of these antibiotics for Gram-positive infections in practice, with the hope that they will reduce hospital LOS and the need for daily antibiotic infusions to provide alternative options for patients not qualifying for outpatient parenteral antimicrobial therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colorado; Female; Gram-Positive Bacterial Infections; Hospitals; Humans; Length of Stay; Lipoglycopeptides; Male; Middle Aged; Off-Label Use; Retrospective Studies; Teicoplanin; Treatment Outcome; Young Adult

Topics: Anti-Bacterial Agents; Daptomycin; Enterococcus faecium; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Vancomycin; Vancomycin Resistance; Vancomycin-Resistant Enterococci

The in vitro activity of oritavancin was assessed against clinically relevant Gram-positive pathogens causing infections in cancer patients in European and US hospitals.. A total of 1357 Gram-positive cocci (GPC) were included. Isolates were predominantly from bloodstream infections (54.6%). The most frequently isolated GPC were Staphylococcus aureus (43.6%), CoNS (14.4%) and Enterococcus spp. (22.0%).. Oritavancin (99.8% susceptible) showed modal MIC, MIC50 and MIC90 results of 0.015, 0.015-0.03 and 0.06 mg/L, respectively, when tested against S. aureus, regardless of methicillin susceptibility or geographical region. CoNS isolates from the USA demonstrated an MIC90 of oritavancin (MIC90, 0.12 mg/L) that was slightly higher than that for isolates from European countries (MIC90 0.06 mg/L). Oritavancin inhibited all Enterococcus faecalis and Enterococcus faecium, including VRE, at ≤ 0.25 mg/L. Oritavancin exhibited MIC50 results of 0.03 and 0.008-0.015 mg/L when tested against isolates of β-haemolytic streptococci and viridans group streptococci, respectively, regardless of geographical region.. Oritavancin had potent activity in vitro against this contemporary collection of European and US GPC isolates from cancer patients.

Topics: Anti-Bacterial Agents; Europe; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Hospitals; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Neoplasms; United States

Topics: Anti-Bacterial Agents; Culture Media; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests

Topics: Anti-Bacterial Agents; Bacteremia; Cross Infection; Europe; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Hospitals; Humans; Lipoglycopeptides; United States

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

Topics: Anti-Bacterial Agents; Cross Infection; Enterococcus; Enterococcus faecalis; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Vancomycin; Vancomycin Resistance

Oritavancin possesses activity against vancomycin-resistant enterococci (VRE) and methicillin-resistantStaphylococcus aureus(MRSA).In vitrodata suggest synergy between beta-lactams (BLs) and vancomycin or daptomycin, agents similar to oritavancin. We evaluated the activities of BLs combined with oritavancin against MRSA and VRE. Oritavancin MICs were determined for 30 strains, 5 each of MRSA, daptomycin-nonsusceptible (DNS) MRSA, vancomycin-intermediate MRSA (VISA), heteroresistant VISA (hVISA), vancomycin-resistantEnterococcus faecalis, and vancomycin-resistantEnterococcus faecium Oritavancin MICs were determined in the presence of subinhibitory concentrations of BLs. Oritavancin combined with ceftaroline, cefazolin, or nafcillin was evaluated for lethal synergy against MRSA, and oritavancin combined with ceftaroline, ampicillin, or ertapenem was evaluated for lethal synergy against VRE in 24-h time-kill assays. Oritavancin at 0.5× the MIC was combined with BLs at 0.5× the MIC or the biological free peak concentration, whichever one was lower. Synergy was defined as a ≥2-log10-CFU/ml difference between the killing achieved with the combination and that achieved with the most active single agent at 24 h. Oritavancin MICs were ≤0.125 μg/ml for all MRSA isolates except three VISA isolates with MICs of 0.25 μg/ml. Oritavancin MICs for VRE ranged from 0.03 to 0.125 μg/ml. Oritavancin in combination with ceftaroline was synergistic against all MRSA phenotypes and statistically superior to all other combinations against DNS MRSA, hVISA, and MRSA isolates (P< 0.02). Oritavancin in combination with cefazolin and oritavancin in combination with nafcillin were also synergistic against all MRSA strains. Synergy between oritavancin and all BLs was revealed against VRE strain 8019, while synergy between oritavancin and ampicillin or ertapenem but not ceftaroline was demonstrated against VRE strain R7164. The data support the potential use of oritavancin in combination with BLs, especially oritavancin in combination with ceftaroline, for the treatment of infections caused by MRSA. The data from the present study are not as strong for oritavancin in combination with BLs for VRE. Further study of both MRSA and VRE in more complex models is warranted.

Topics: Anti-Bacterial Agents; beta-Lactams; Cefazolin; Ceftaroline; Cephalosporins; Daptomycin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Ertapenem; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Nafcillin; Staphylococcal Infections; Vancomycin; Vancomycin-Resistant Enterococci

Oritavancin is a new lipoglycopeptide antibacterial agent with an exceptionally long terminal half-life and a rapid bactericidal effect. Multiple mechanisms of action lead to a broad activity against Gram-positive bacteria, such as staphylococci, streptococci and enterococci, including methicillin-resistant Staphylococcus aureus. Its long terminal half-life allows for single-dose treatment of acute bacterial skin and skin structure infections. Oritavancin was found to be safe and effective in treating acute bacterial skin and skin structure infections in adults and it is currently approved in the USA and in Europe for this indication. Unfortunately, data for other indications are lacking. Here, we review chemistry, microbiology, pharmacology, efficacy and tolerability of oritavancin.

Topics: Adult; Anti-Bacterial Agents; Enterococcus; Europe; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Half-Life; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Skin Infections; Streptococcus

To assess oritavancin activity in vitro against clinically relevant Gram-positive pathogens causing skin and soft-tissue infections (SSTIs) in European and US hospitals.. 13 262 consecutive and unique isolates deemed to be responsible for SSTIs were included. Isolates originated from 36 and 27 institutions in Europe (Israel included) and the USA, respectively, between 2010 and 2013.. Oritavancin (98.8% susceptible) showed modal MIC, MIC50 and MIC90 results of 0.03, 0.03 and 0.06 mg/L, respectively, for Staphylococcus aureus. CoNS from the USA (MIC50, 0.015 mg/L) demonstrated an MIC50 value of oritavancin slightly lower than those from Europe (MIC50, 0.03 mg/L). Overall, vancomycin-resistant (VanA-phenotype) Enterococcus faecalis had oritavancin MICs (MIC50/90, 0.25/0.5 mg/L) that were 16-fold higher than those obtained for vancomycin-susceptible isolates (MIC50/90, 0.015/0.03 mg/L; 99.2%-99.8% susceptible); nevertheless, oritavancin inhibited all VanA E. faecalis at ≤0.5 mg/L. Equivalent oritavancin MICs (MIC50/90, 0.004/0.008 mg/L) were noted for all VanB and vancomycin-susceptible Enterococcus faecium, while higher MICs (MIC50/90, 0.03/0.12 mg/L) were obtained for VanA strains. Oritavancin had low MICs against the overall populations of Streptococcus pyogenes (MIC50/90, 0.03/0.12 mg/L; 98.4%-98.6% susceptible), Streptococcus agalactiae (MIC50/90, 0.03/0.06 mg/L; 97.9%-98.0% susceptible) and the Streptococcus anginosus group (MIC50/90, 0.008/0.015 mg/L; 100.0% susceptible), with slightly higher MICs for Streptococcus dysgalactiae (MIC50/90, 0.06/0.25 mg/L; ≥98.3% susceptible).. Oritavancin had potent activity in vitro against this contemporary collection of European and US isolates causing SSTIs. These results describe oritavancin activity against Gram-positive pathogens collected shortly prior to its regulatory approval in the USA.

Topics: Anti-Bacterial Agents; Cross Infection; Drug Resistance, Bacterial; Europe; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Public Health Surveillance; Skin Diseases, Bacterial; Soft Tissue Infections; United States

To assess the oritavancin spectrum and activity against 2811 rarer species of coagulase-negative staphylococci (CoNS), streptococci and other Gram-positive species.. A total of 2057 CoNS (14 species), 674 streptococci (7 groups) and 80 other Gram-positive species (3 genera) collected over a 5 year period as part of the SENTRY Program (2008-12) were included. Isolates were primarily identified by the participating laboratory and identification was confirmed by the reference monitoring laboratory (JMI Laboratories, North Liberty, IA, USA). Isolates were tested for susceptibility by broth microdilution following the CLSI M07-A9 and M100-S23 documents.. Overall, oritavancin was active against all CoNS (MIC50/MIC90, 0.015/0.06 mg/L), with MIC50 values of ≤0.008-0.03 mg/L. Streptococci exhibited oritavancin MIC50 results of ≤0.008 mg/L, except for the Streptococcus bovis (0.03 mg/L), Streptococcus dysgalactiae (0.06 mg/L) and Streptococcus salivarius/vestibularis (0.06 mg/L) groups. Micrococcus spp., Listeria monocytogenes and Corynebacterium spp. had oritavancin MIC50 results of ≤0.008 mg/L.. This study expands the oritavancin in vitro data against several species of Gram-positive organisms.

Topics: Anti-Bacterial Agents; Cross Infection; Global Health; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Hospitals; Humans; Inhibitory Concentration 50; Lipoglycopeptides; Microbial Sensitivity Tests; Staphylococcus; Streptococcus

Gram-positive pathogens isolated in 15 Canadian hospital laboratories between 2011 and 2013 were tested for susceptibility to oritavancin and comparative antimicrobial agents using the Clinical and Laboratory Standards Institute broth microdilution method. Oritavancin demonstrated in vitro activity equivalent to, or more potent than, vancomycin, daptomycin, linezolid, and tigecycline against the isolates of methicillin-susceptible Staphylococcus aureus (n=1460; oritavancin MIC90, 0.06 μg/mL; 99.7% oritavancin-susceptible), methicillin-resistant S. aureus (n=427; oritavancin MIC90, 0.06 μg/mL; 99.5% oritavancin-susceptible), Streptococcus pyogenes (n=132; oritavancin MIC90, 0.25 μg/mL; 99.2% oritavancin-susceptible), Streptococcus agalactiae (n=156; oritavancin MIC90, 0.12 μg/mL; 100% oritavancin-susceptible), and Enterococcus faecalis (n=304; oritavancin MIC90, 0.06 μg/mL; 98.7% oritavancin-susceptible) tested.

Topics: Anti-Bacterial Agents; Canada; Drug Resistance, Bacterial; Enterococcus faecalis; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Laboratories, Hospital; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Vancomycin

Oritavancin exhibited potent activity against vancomycin-susceptible (MIC(50) and MIC(90), 0.015/0.03 μg/ml) and vanB-carrying E. faecalis isolates (MIC(50) and MIC(90), 0.015 and 0.015 μg/ml). Higher (16- to 32-fold) MIC(50)s and MIC(90)s for vanA-harboring E. faecalis were noted (MIC(50) and MIC(90), 0.25 and 0.5 μg/ml), although oritavancin inhibited all strains at ≤ 0.5 μg/ml. Vancomycin-susceptible and vanB-carrying E. faecium strains (MIC(50) and MIC(90), ≤ 0.008 and ≤ 0.008 μg/ml for both) were very susceptible to oritavancin, as were VanA-producing isolates (MIC(50) and MIC(90), 0.03 and 0.06 μg/ml). Oritavancin exhibited good in vitro potency against this collection of organisms, including vancomycin-resistant enterococci.

Topics: Anti-Bacterial Agents; Bacteremia; Enterococcus faecalis; Enterococcus faecium; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Vancomycin; Vancomycin Resistance

Oritavancin is in the final stages of clinical development for treatment of acute bacterial skin and skin structure infections. This drug has demonstrated potent activity against staphylococci (minimum inhibitory concentration [MIC] for which 90% of isolates are inhibited [MIC(90)], 0.06 μg/mL), enterococci (MIC(90), ≤ 0.008 to 0.5 μg/mL), and streptococci (MIC(90), ≤ 0.008 to 0.12 μg/mL), including enhanced potency against vancomycin-resistant enterococci. During the clinical development of oritavancin, it was demonstrated that this molecule binds to plastic labware surfaces and that this feature was likely responsible for interlaboratory variability observed from in vitro investigations before 2006. Therefore, reference broth microdilution methods and MIC ranges for quality control strains were reestablished using media supplemented with a surfactant (polysorbate-80, 0.002%). These were followed by numerous experiments to reassess the in vitro characteristics of oritavancin; the results originating from those studies are summarized here. The oritavancin activity tested against a resistance surveillance collection of 12,367 Gram-positive clinical pathogens and resistant subsets from the United States (2008-2009) is also presented, with the highest MIC among staphylococci at only 0.25 μg/mL. In vitro results for oritavancin indicate wide potential use against Gram-positive pathogens.

Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Drug Synergism; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Population Surveillance; United States

Oritavancin is a novel glycopeptide antibiotic with concentration-dependent killing of Gram-positive cocci and pharmacokinetics characterized by extensive tissue distribution and a long terminal half-life. Its development was hindered by a 16- to 32-fold underestimation of activity against staphylococci and enterococci because of oritavancin's sticking to vials and tubes. Dose-fractionation studies in animal models suggested the peak concentration was the major index for efficacy. Once-daily intravenous administration of oritavancin was effective in methicillin-resistant Staphylococcus aureus (MRSA) endocarditis, penicillin-susceptible and cephalosporin-resistant pneumococcal meningitis in rabbits, staphylococcal and enterococcal central venous catheter infections in rats, and 24-hour postprophylaxis of inhaled anthrax in mice. Orally administered oritavancin was more effective than vancomycin in Clostridium difficile infection in hamsters. Pharmacodynamics suggested that a single dose of oritavancin at 1200 mg would be efficacious in humans. Simulation of this dose in neutropenic mice was highly effective in methicillin-sensitive S. aureus and MRSA thigh and bacteremia infections and pneumococcal lung infections.

Topics: Animals; Anti-Bacterial Agents; Cricetinae; Disease Models, Animal; Drug Administration Schedule; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Mice; Rabbits; Rats

The treatment of infections caused by vancomycin-resistant enterococci (VRE) has become an important clinical challenge and compromises the care of critically ill patients. A striking increase in the frequency of nosocomial isolation of multidrug-resistant Enterococcus faecium has dramatically reduced the therapeutic alternatives because the majority of E. faecium isolates are resistant to ampicillin and vancomycin. Only 2 agents have US Food and Drug Administration approval for the treatment of VRE (E. faecium) infections, namely, linezolid and quinupristin/dalfopristin (Q/D). However, the use of these compounds in severe VRE infections is hampered by the lack of in vivo bactericidal activity, reports of therapeutic failures with monotherapy, a requirement for central venous access for administration (Q/D), and adverse-effect profile. The lipopeptide antimicrobial daptomycin has in vitro bactericidal activity against VRE; however, clinical use of this compound for VRE has not been well studied, and the reports of resistance emerging during therapy at the approved doses are worrisome. Tigecycline has in vitro bacteriostatic activity against VRE, but its clinical use for serious enterococcal infections is unclear due to low serum levels and static effect. Thus, current reliable therapies for VRE appear to be limited, and clinical data that use the above compounds are certainly scant. Oritavancin is an investigational semisynthetic glycopeptide with potent in vitro activity against VRE (both VanA and VanB phenotypes). Although review of the available preclinical data indicates that this compound used as a single agent is likely to have important limitations for the treatment of a severe VRE infection (ie, endocarditis), combination of oritavancin with other agents such as aminoglycosides may offer promise and deserves further investigation, as does use of oritavancin for less serious infections as monotherapy for vancomycin-susceptible and multidrug-resistant enterococci.

Topics: Animals; Anti-Bacterial Agents; Colony Count, Microbial; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Enterococcus; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Rabbits; Rats; Vancomycin Resistance

Oritavancin is a new antibiotic for the treatment of serious infections with Gram-positive bacteria. It has been shown to be effective against methicillin-susceptible and -resistant Staphylococcus aureus as well as enterococci. With a terminal half-life of 393 hours, oritavancin lends itself to a convenient and potentially cost-effective single-dose regimen. The single-dose regimen is currently being evaluated in pivotal phase 3 studies. This unique property provides an opportunity to assure consistent, effective, and safe treatment for serious infections while reducing the costs of care through the elimination of multiple infusions, reduced medical care staff, shorter hospital stays, and avoidance of hospital-acquired infections. These features seem ideal for the use of oritavancin in the outpatient management of serious infections. The impact that oritavancin will have on outpatient therapy is unclear. Current models will need to change with only a single infusion. Physician monitoring of the infection and underlying diseases may not be as frequent despite the need for close follow-up and frequent evaluations. There will be less need for a team of outpatient infusion specialists. Outpatient therapy will be compensated less without multiple infusions. With the possibility of fewer physician and other medical visits, there will be more responsibility for the patient and family and a reliance on patients to care for themselves. Although oritavancin offers tremendous theoretical advantages in the outpatient treatment of serious infections, care should be taken to assure the quality of care through changes in reimbursement, patient education, and development of systems to monitor care and outcomes.

Topics: Ambulatory Care; Anti-Bacterial Agents; Glycopeptides; Gram-Positive Bacterial Infections; Half-Life; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus

Topics: Anti-Bacterial Agents; Europe; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Teicoplanin; Vancomycin

Oritavancin, a lipoglycopeptide, possesses bactericidal activity against Gram-positive bacteria including vancomycin-resistant Staphylococcus aureus and enterococci. To understand the time dependence of oritavancin activity, we have undertaken time-kill experiments against isolates of S. aureus, Enterococcus faecalis and Enterococcus faecium, including recent antibiotic-resistant strains.. Six strains of S. aureus [methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA)] and five strains of enterococci [vancomycin-susceptible enterococci (VSE) and vancomycin-resistant enterococci (VRE; both VanA and VanB)] were tested in time-kill assays; oritavancin assays included 0.002% polysorbate-80 to ensure quantitative drug recovery. Oritavancin and comparators vancomycin, teicoplanin, linezolid and daptomycin were tested at static concentrations approximating their free peak (fC(max)) and free trough (fC(min)) in plasma when administered at standard doses for complicated skin and skin structure infections.. Oritavancin showed concentration-dependent killing of all strains tested: at its fC(max) predicted from a 200 mg dose in humans, oritavancin exerted bactericidal activity (> or =3 log kill relative to starting inoculum) against MSSA, MRSA and VRSA within 1 h and against VSE between 11 and 24 h. At predicted fC(max) from an 800 mg dose, oritavancin was bactericidal against VISA strains at 24 h and against VRE at 10 h.. Oritavancin displayed concentration-dependent killing of MSSA, MRSA, VRSA, VISA, VSE and VRE. Oritavancin was more rapidly bactericidal against all strains tested than were vancomycin, teicoplanin, linezolid or daptomycin at physiologically relevant concentrations. These data support the conclusion that oritavancin exerts concentration-dependent bactericidal activity on recent, drug-resistant isolates of S. aureus and enterococci.

Topics: Anti-Bacterial Agents; Dose-Response Relationship, Drug; Enterococcus faecalis; Enterococcus faecium; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Microbial Viability; Staphylococcal Infections; Staphylococcus aureus; Time Factors

Infections may complicate cardiovascular surgery or may require surgery as an adjunct to successful treatment. Staphylococci, which are among the major pathogenic bacteria causing such infections, can be resistant to many of the older antibiotics.. The properties of several newer antimicrobial agents, recently approved or still investigational, were reviewed, with an emphasis on in vitro activities against staphylococci.. The 2 approved agents, linezolid and quinupristin-dalfopristin, and several investigational agents being developed demonstrate in vitro antimicrobial activity against staphylococci. Three of these agents, daptomycin, which was approved by the US Food and Drug Administration in September 2003, and oritavancin and dalbavancin, which are in advanced stages of clinical development, are discussed.. Although clinical studies are required, the in vitro anti-staphylococcal activities of several agents suggest that these antimicrobial agents might be useful options for some infections in patients who are intolerant of older antibiotics or who are infected with organisms that are resistant to older agents.

Topics: Acetamides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Linezolid; Lipoglycopeptides; Methicillin Resistance; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Teicoplanin; Virginiamycin

Oritavancin (LY333328) is a novel glycopeptide with activity against Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. We compared the effects of pH and growth phase on the activity of oritavancin and vancomycin against methicillin-resistant S. aureus and vancomycin-susceptible and -resistant E. faecium. Killing curve methods were used to evaluate the effect of growth phase (stationary versus exponential) and pH (6.4, 7.4 and 8.0). An inoculum of 10(6) cfu/mL was used for all experiments. Growth phase of S. aureus and vancomycin-susceptible E. faecium did not influence the rate and killing activity of oritavancin. The rate of killing by oritavancin against the vancomycin-resistant E. faecium strain was significantly faster and the reduction in cfu/mL at 24 h was significantly greater when the organism was in exponential compared with stationary growth phase (P < 0.05). In exponential growth phase, time to 99.9% killing was achieved in 0.6 +/- 0.01 h for the vancomycin-resistant strain, whereas in stationary growth phase, oritavancin did not decrease the inoculum by 99.9% within 24 h. Oritavancin's activity against S. aureus and vancomycin-susceptible E. faecium was not influenced by the pH conditions tested. Oritivancin's killing activity against the vancomycin-resistant E. faecium strain was significantly enhanced when tested at pH 7.4 and 8.0 (P < 0.05). Our study has demonstrated that oritavancin's activity does not seem to be influenced by the growth phase of the organisms or the pH of the environment when tested against sensitive strains of S. aureus and E. faecium. However, oritavancin's activity might be reduced against vancomycin-resistant E. faecium strains in stationary growth phase, as seen in infective endocarditis or when organisms are exposed to an acidic environment.

Topics: Anti-Bacterial Agents; Colony Count, Microbial; Culture Media; Enterococcus faecium; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Hydrogen-Ion Concentration; Lipoglycopeptides; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcus aureus; Time Factors; Vancomycin; Vancomycin Resistance

A rat central venous catheter (CVC) infection model was used to assess the activity of LY333328 against vancomycin-resistant Enterococcus faecium (VRE). Via the CVC, animals were challenged with 10(6) cfu of Enterococcus faecium with the VanA phenotype. Eight rats received a single dose of LY333328 and eight rats received saline. Seventy-five per cent of control animals had peripheral bacteraemia and 87.5% had VRE recovered from explanted CVCs at the time they were killed, as compared with 0 and 12.5%, respectively, of the LY333328-treated animals (P < 0.01). All animals in the control group had evidence of metastatic disease compared with none of the treated group (P < 0.01). LY333328 was effective against the strain of VRE tested in this model.

Topics: Animals; Anti-Bacterial Agents; Catheters, Indwelling; Disease Models, Animal; Enterococcus faecium; Glycopeptides; Gram-Positive Bacterial Infections; Lipoglycopeptides; Male; Prosthesis-Related Infections; Rats; Rats, Sprague-Dawley; Vancomycin Resistance

In vitro resistance of community-acquired and nosocomial strains of Enterococcus faecalis isolated in Badajoz (Spain) were determined by a microdilution method. The isolates were identified with conventional MicroScan Pos Combo 4 I dehydrated panels. No resistance to glycopeptides was found, but LY333328 was 2-4 times more active than vancomycin. In the nosocomial strains, high-level resistance to streptomycin (HLRS) was 54.7%, and high-level resistance to gentamicin (HLRG) was 38.1%. Resistance to ciprofloxacin and trovafloxacin was 45.3 and 38.9%, respectively. In the community-acquired isolates, HLRS, HLRG, resistance to ciprofloxacin and resistance to trovafloxacin were 44.2, 17.3, 15.4 and 13.5%, respectively. Trovafloxacin was 2-4 times more active than ciprofloxacin against both groups of strains. An association between high-level resistance to aminoglycosides and resistance to fluoroquinolones was noted. The resistance to aminoglycosides did not influence the activity of vancomycin and LY333328.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Ciprofloxacin; Community-Acquired Infections; Cross Infection; Drug Resistance, Bacterial; Enterococcus faecalis; Fluoroquinolones; Gentamicins; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Incidence; Lipoglycopeptides; Microbial Sensitivity Tests; Naphthyridines; Spain; Streptomycin; Vancomycin

Topics: Animals; Anti-Bacterial Agents; Glycopeptides; Gram-Positive Bacterial Infections; Gram-Positive Cocci; Humans; Lipoglycopeptides; Microbial Sensitivity Tests

Topics: Adult; Anti-Bacterial Agents; Drug Resistance, Microbial; Enterococcus faecalis; Glycopeptides; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Male; Microbial Sensitivity Tests

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Enterococcus faecalis; Enterococcus faecium; Glycopeptides; Gram-Positive Bacterial Infections; Humans; In Vitro Techniques; Lipoglycopeptides; Microbial Sensitivity Tests; Teicoplanin; Vancomycin

LY333328 is a semisynthetic N-alkyl derivative of LY264826, a naturally occurring structural analog of vancomycin. LY333328 was evaluated for its in vitro inhibitory and bactericidal activities in comparison with those of the two currently available glycopeptides (vancomycin and teicoplanin). Glycopeptide-susceptible test strains included a total of 311 isolates (most of clinical origin) from the genera Staphylococcus, Enterococcus, Streptococcus, Aerococcus, Gemella, Lactococcus, Listeria, Corynebacterium, and Clostridium. Test strains resistant or intermediate to vancomycin and/or teicoplanin included 56 clinical isolates of Enterococcus (of the VanA, VanB, and VanC phenotypes) and 32 clinical isolates of Staphylococcus (S. haemolyticus, S. epidermidis, and S. aureus), 31 strains of gram-positive genera outside the spectrum of activity of vancomycin (Leuconostoc, Pediococcus, Lactobacillus, and Erysipelothrix), and laboratory-derived organisms obtained after exposure of susceptible Staphylococcus isolates to teicoplanin (6 strains) or laboratory-derived organisms with resistance determinants received from VanA enterococci (2 Enterococcus and 25 Listeria transconjugants). LY333328 was highly active against staphylococci, enterococci, and listeriae (whether they were clinical or laboratory-derived strains) resistant to the currently available glycopeptides. In particular, the MICs of LY333328 did not vary substantially between teicoplanin-susceptible and teicoplanin-resistant staphylococci and between vancomycin-susceptible and vancomycin-resistant enterococci. LY333328 demonstrated fairly good inhibitory activity even against most strains of Leuconostoc, Pediococcus, and Erysipelothrix (MIC range, 1 to 8 microg/ml), whereas it proved less active (although much more active than vancomycin or teicoplanin) against Lactobacillus strains. In minimal bactericidal concentration (MBC) and time-kill studies, LY333328 demonstrated excellent bactericidal activity; enterococci, in particular, which were largely tolerant of vancomycin and teicoplanin, were uniformly killed by LY333328, with MBC-to-MIC ratios of 4 to 8 for most vancomycin-susceptible and vancomycin-resistant strains. In attempts to select for resistant clones, no survivors stably growing in the presence of 10 microg of LY333328 per ml were obtained from the Staphylococcus and Enterococcus test strains exposed to the drug.

Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Teicoplanin; Vancomycin