telavancin and Staphylococcal-Infections

The objective of this study was to systematically review and evaluate the efficacy and safety of telavancin and vancomycin in the treatment of infections due to methicillin-resistant Staphylococcus aureus (MRSA).. We performed a systematic literature search using Pubmed, Embase, VIP Chinese Science and Technique Journals Database, and Wanfang Database resulting in the inclusion of seven publications in this study. Outcomes were calculated using pooled relative risk (RR) and 95% confidence interval (CI). Publication bias was also assessed.. Seven studies comparing telavancin with vancomycin in the treatment of MRSA-caused infections were included in the analysis. There was a higher treatment success rate (reported as clinical evaluation, 1,420 patients, RR = 1.05, 95% CI = 1.01 - 1.10) in telavancin compared to vancomycin. However, there was also a significant difference in serious adverse events reported (3,622 patients, RR = 1.28, 95% CI = 1.11 - 1.50) when comparing telavancin with vancomycin. The results also showed increased creatinine level (3,185 patients, RR = 2.13, 95% CI = 1.72 - 2.64) in telavancin treatment.. Telavancin is a reliable alternative to vancomycin in the treatment of MRSA-confirmed infections despite the incidence of serious adverse events. The potential for telavancin-induced serious adverse events and nephrotoxicity should be taken into consideration before treatment.
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Topics: Aminoglycosides; Anti-Bacterial Agents; Humans; Kidney Diseases; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Treatment Outcome; Vancomycin

Telavancin (TLV) is a lipoglycopeptide derivative of vancomycin (VAN), which has activity against Gram-positive aerobic bacteria, and is especially effective against methicillin-resistant Staphylococcus aureus (MRSA) and Gram-positive bacteria resistant to VAN. Comparative clinical studies of TLV have demonstrated noninferiority compared with VAN in the treatment of hospital-acquired Gram-positive pneumonia, with high cure rates for TLV-treated patients with monomicrobial S. aureus infection, including isolates with reduced VAN susceptibility. The results based on the patients' clinical response were supported by supplemental post-hoc analyses of 28-day mortality. In Europe and the USA, TLV is approved as a useful alternative for patients with difficult-to-treat, hospital-acquired MRSA pneumonia when there are very few alternatives. The present article reviews TLV's pharmacological characteristics and clinical efficacy resulting from clinical trials giving a detailed picture of its properties and position in the management of hospital-acquired pneumonia.

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

Staphylococcus aureus bacteremia (SAB) is one of the most common serious bacterial infections and the most frequent invasive infection due to methicillin-resistant S. aureus (MRSA). Treatment is challenging, particularly for MRSA, because of limited treatment options. Telavancin is a bactericidal lipoglycopeptide antibiotic that is active against a range of clinically relevant gram-positive pathogens including MRSA. In experimental animal models of sepsis telavancin was shown to be more effective than vancomycin. In clinically evaluable patients enrolled in a pilot study of uncomplicated SAB, cure rates were 88% for telavancin and 89% for standard therapy. Among patients with infection due to only gram-positive pathogens enrolled in the 2 phase 3 studies of telavancin for treatment of hospital-acquired pneumonia, cure rates for those with bacteremic S. aureus pneumonia were 41% (9/22, telavancin) and 40% (10/25, vancomycin) with identical mortality rates. These data support further evaluation of telavancin in larger, prospective studies of SAB.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Bacteremia; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease Models, Animal; Humans; Lipoglycopeptides; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome

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

Hospital-acquired pneumonia (HAP) due to gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major cause of morbid conditions and death. Telavancin is a lipoglycopeptide antibiotic with potent in vitro activity against a range of gram-positive pathogens, including MRSA, methicillin-susceptible S. aureus, and Streptococcus species. In 2 phase 3 clinical trials, telavancin was noninferior to vancomycin in patients with HAP due to gram-positive pathogens. Clinically evaluable patients with S. aureus as the sole pathogen or S. aureus with a vancomycin minimum inhibitory concentration >1 µg/mL, however, had higher cure rates with telavancin than with vancomycin. In patients with bacteremic HAP, telavancin resulted in clearance of blood cultures. It was associated with increased serum creatinine levels and higher mortality rates in patients with moderate to severe renal impairment at baseline; however, on subsequent analysis, the outcomes seemed to have been at least partially affected by the adequacy of empiric gram-negative antimicrobial therapy. Thus, clinicians need to consider the risk-benefit balance when choosing telavancin in patients with severe renal impairment at baseline. Overall, these data support the use of telavancin in the treatment of HAP due to S. aureus, including MRSA and strains with elevated vancomycin minimum inhibitory concentrations, but clinicians should always weigh the risks and benefits of various treatment options.

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Clinical Trials, Phase III as Topic; Cross Infection; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Pneumonia, Ventilator-Associated; Staphylococcal Infections

Telavancin (Vibativ(®)), a lipoglycopeptide antibacterial agent, exhibits potent in vitro activity against Gram-positive bacteria associated with nosocomial pneumonia infections, including meticillin/oxacillin-resistant Staphylococcus aureus (MRSA) isolates and S. aureus isolates with reduced susceptibility to vancomycin. In two multinational trials in adult patients with nosocomial pneumonia caused by Gram-positive bacteria, including infections caused by MRSA isolates, a 1-h intravenous infusion of telavancin 10 mg/kg once daily was noninferior to intravenous vancomycin 1 g every 12 h in terms of clinical cure rates in the all-treated (AT) and clinically evaluable (CE) populations at the follow-up/test-of-cure (FU/TOC) visit. At this visit, clinical cure rates in the AT populations of both groups were approximately 60 %, with rates increasing to ≥80 % in the CE population. Pooled analyses of these trials also generally showed no significant between-group differences in clinical cure rates at the FU/TOC visit in the AT, CE and microbiologically evaluable (ME) populations. In the ME population, clinical cure rates were generally similar in the telavancin and vancomycin groups, irrespective of whether infections were mono- or polymicrobial, or caused by MRSA or methicillin/oxacillin-susceptible S. aureus isolates. Telavancin was generally well tolerated in patients with nosocomial pneumonia participating in clinical trials, with a tolerability profile that was generally similar to that of vancomycin. Telavancin offers an alternative treatment option in patients with nosocomial pneumonia caused by Gram-positive S. aureus, including those caused by MRSA and S. aureus isolates with reduced susceptibility to vancomycin.

Topics: Aminoglycosides; Anti-Bacterial Agents; Clinical Trials as Topic; Cross Infection; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Pneumonia; Staphylococcal Infections

Treatment options for hospital-acquired pneumonia caused by Gram-positive organisms are far from ideal. The increase in vancomycin MICs among methicillin-resistant Staphylococcus aureus (MRSA) isolates, and the slow bactericidal action and poor lung penetration of vancomycin have driven the search for an alternative agent. Telavancin, a once-daily lipoglycopeptide, displays strong bactericidal activity against S. aureus. Two large Phase III randomized trials have recently compared intravenous telavancin (10 mg/kg every 24 h) with vancomycin (1 g intravenously every 12 h) for 7-21 days for the treatment of hospital-acquired pneumonia caused by Gram positives. No significant differences were observed in the cure rates in the all-treated (n = 1503), the clinically evaluable (n = 654) and the microbiologically evaluable (n =480) populations. Telavancin performed better than vancomycin in patients with monomicrobial S. aureus pneumonia (84.2 vs 74.3%; 95% CI: 0.7-19.1), with MRSA (81.8 vs 74.1%; 95% CI: -3.5 to 19.3), and with strains having vancomycin MICs ≥1 µg/ml (87.1 vs 74.3; 95% CI: 0.5-23). The rate of adverse events, including serious adverse events, was similar in both groups, with a slightly higher rate of serum creatinine increase in the telavancin-treated group. Based on these results, telavancin (already approved for this indication by the EMA) could certainly be added to the current treatment options, particularly in patients with MRSA pneumonia.

Topics: Aminoglycosides; Anti-Bacterial Agents; Creatinine; Cross Infection; Drug Administration Schedule; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Pneumonia, Bacterial; Randomized Controlled Trials as Topic; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Vancomycin

There is a choice of anti-MRSA antibiotic available with proven efficacy in the treatment of complicated skin and skin structure infection (cSSSI). Additional anti-MRSA antibiotics are in development, which have the potential to influence how such infections are managed. The emergence of resistance to current anti-MRSA agents, toxicity, and general lack of oral agents with proven efficacy for deep seated infection justify the development of new agents. However, there is a relative dearth of information specific to patients with orthopaedic-related infection. Combination therapy is often used in these patients, although there is a paucity of controlled trial data to support particular antibiotic combinations. As the choice of anti-MRSA agents increases, so does the need to identify which are best for the large variety of infections included in the group of cSSSIs. This is particular true for infections occurring in orthopaedic patients where poorly vascularised tissue, trauma or implanted prosthetic material, pose specific challenges.

Topics: Aminoglycosides; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Glycopeptides; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Skin Diseases, Bacterial; Soft Tissue Infections; Staphylococcal Infections; Teicoplanin

Current antibiotics available for the treatment of healthcare-associated pneumonia (HCAP) may result in clinical failure due to resistance development, side effect intolerance, or poor pharmacokinetic-pharmacodynamic profiles. New agents active against common HCAP pathogens are needed. The mechanism of action, spectrum of activity, pharmacokinetics, adverse effects, and clinical efficacy of seven new agents in clinical development or recently approved with either methicillin-resistant Staphylococcus aureus (MRSA) or pseudomonal activity are reviewed. They include doripenem, a new antipseudomonal carbapenem; ceftobiprole and ceftaroline, two anti-MRSA cephalosporins; iclaprim, a selective dihydrofolate reductase antagonist; and three glycopeptides, dalbavancin, telavancin, and oritavancin.

Topics: Aminoglycosides; Anti-Bacterial Agents; Carbapenems; Ceftaroline; Cephalosporins; Cross Infection; Doripenem; Glycopeptides; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Pseudomonas Infections; Pyrimidines; Staphylococcal Infections; Teicoplanin

Serious infections caused by Gram-positive bacteria, particularly multi-drug resistant, are an important cause of morbidity and mortality in patients admitted to intensive care units. Thus, new antibiotics covering these pathogens are urgently needed.. To review characteristics of telavancin, a novel antibiotic intended to use for treating infections caused by difficult Gram-positive bacteria, such as Staphylococcus aureus, resistant to meticillin or vancomycin, multi-drug-resistant Streptococcus pneumoniae or glycopeptide-resistant enterococci.. The studies on microbiological activity, clinical efficacy and safety of telavancin were reviewed.. Telavancin is a lipoglycopeptide administered intravenously once-daily and excreted with urine. It proved to be microbiologically active against numerous Gram-positive pathogens including drug-resistant staphylococci, enterococci and pneumococci. Large randomized Phase II and III clinical trials on efficacy and safety of telavancin in treating complicated skin and skin structure infections reported telavancin to be non-inferior to standard treatment (mostly vancomycin). Preliminary data on telavancin in hospital-acquired pneumonia, including ventilator-associated pneumonia, documented that telavancin was efficacious for this indication. Overall incidence of adverse events was similar for telavancin and the comparator arms. Mild and transient disgeusia, nausea and vomiting resulted to be more frequent in telavancin group. Increase in creatinine values was also observed in telavancin arm.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Cross Infection; Drug Resistance, Multiple, Bacterial; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections

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

In bacterial and fungal infections, optimal outcomes are obtained through the timely provision of adequate antimicrobial coverage in an initial anti-infective treatment regimen. However, selecting appropriate antimicrobial regimens to treat infections in the intensive care unit is challenging because of the expansion of antibiotic resistance. Multidrug anti-infective regimens are typically needed to adequately cover common important pathogens in ICUs. Here, we describe novel antibacterial agents in the late stages of clinical development that show potential for treating methicillin-resistant Staphylococcus aureus (MRSA) infections. These include the fifth-generation cephalosporins, ceftaroline and ceftobiprole; the glycopeptides, dalbavancin, oritavancin, and telavancin; and iclaprim.

Topics: Aminoglycosides; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Glycopeptides; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Pyrimidines; Staphylococcal Infections; Teicoplanin

Infection by Staphylococcus aureus in critically ill patients is usually associated with antimicrobial resistance and high mortality. A more effective antibiotic treatment is needed to replace older drugs that have limited efficacy. Novel substances active on methicillin-resistant Staphylococcus aureus, which are already available on the market or are still in development, are discussed in this review, with emphasis on nosocomial infections.. A number of new antibiotics are on the market (linezolid, quinupristin-dalfopristin, daptomycin) and there is good evidence regarding their efficacy, especially in methicillin-resistant Staphylococcus aureus infections. Linezolid is, to date, the best alternative in treating nosocomial pneumonia by methicillin-resistant Staphylococcus aureus. It is cost-effective; resistance levels are still very low but there are some concerns regarding its adverse events. Quinupristin-dalfopristin shows good activity in vitro but its efficacy in patients with pneumonia by methicillin-resistant Staphylococcus aureus is modest. Daptomycin is not recommended for pulmonary infections because of its reduced penetration in the lung tissue. Under current phase III trials in patients with nosocomial infections are tigecycline, ceftobiprole, and three new glycopeptides, all with particular activity against methicillin-resistant Staphylococcus aureus.. For the moment, there are limited and rather expensive therapeutic options for the infections by Staphylococcus aureus in the critically ill. No dramatic superiority of the new drugs in comparison to the standard therapies was observed in most of the clinical trials. Better results on the efficacy of the drugs under investigation are expected.

Topics: Acetamides; Aminoglycosides; Anti-Bacterial Agents; Cephalosporins; Clinical Trials as Topic; Critical Illness; Daptomycin; Drug Resistance, Multiple, Bacterial; Glycopeptides; Humans; Linezolid; Lipoglycopeptides; Methicillin Resistance; Minocycline; Oxazolidinones; Staphylococcal Infections; Teicoplanin; Tigecycline; Virginiamycin

Staphylococcus aureus bacteremia is a common infection associated with significant morbidity and mortality. Telavancin is a bactericidal lipoglycopeptide active against Gram-positive pathogens, including methicillin-resistant S. aureus (MRSA). We conducted a randomized, double-blind, Phase 2 trial in patients with uncomplicated S. aureus bacteremia.. Patients were randomized to either telavancin or standard therapy (vancomycin or anti-staphylococcal penicillin) for 14 days. Continuation criteria were set to avoid complicated S. aureus bacteremia. The primary end point was clinical cure at 84 days.. In total, 60 patients were randomized and 58 received ≥1 study medication dose (all-treated), 31 patients fulfilled inclusion/exclusion and continuation criteria (all-treated target [ATT]) (telavancin 15, standard therapy 16), and 17 patients were clinically evaluable (CE) (telavancin 8, standard therapy 9). Mean age (ATT) was 60 years. Intravenous catheters were the most common source of S. aureus bacteremia and ~50% of patients had MRSA. A similar proportion of CE patients were cured in the telavancin (88%) and standard therapy (89%) groups. All patients with MRSA bacteremia were cured and one patient with MSSA bacteremia failed study treatment in each group. Although adverse events (AEs) were more common in the telavancin ATT group (90% vs. 72%), AEs leading to drug discontinuation were similar (7%) in both treatment arms. Potentially clinically significant increases in serum creatinine (≥1.5 mg/dl and at least 50% greater than baseline) were more common in the telavancin group (20% vs. 7%).. This study suggests that telavancin may have utility for treatment of uncomplicated S. aureus bacteremia; additional studies are warranted. (Telavancin for Treatment of Uncomplicated Staphylococcus Aureus Bacteremia (ASSURE); NCT00062647).

Topics: Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Catheter-Related Infections; Double-Blind Method; Female; Humans; Lipoglycopeptides; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Penicillins; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Vancomycin

Telavancin biological activity, determined by serum titers against a reference strain of Staphylococcus aureus, was maintained in the serum of subjects with severe renal impairment or end-stage renal disease suggesting that there is no apparent effect of renal function on in vitro activity of telavancin.

Topics: Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Female; Humans; Kidney Failure, Chronic; Lipoglycopeptides; Male; Microbial Sensitivity Tests; Middle Aged; Reference Values; Renal Insufficiency; Staphylococcal Infections; Staphylococcus aureus

We compared telavancin with vancomycin for the treatment of complicated skin and skin-structure infections (cSSSI) caused by Gram-positive bacteria.. This was a retrospective analysis of clinical and microbiologic efficacy assessed at test-of-cure (7 to 14 days after completing therapy) in 194 patients from 2 randomized, double-blind clinical trials comparing telavancin (10 mg/kg intravenous [IV] every 24 hours; n = 101) with vancomycin (1 g IV every 12 hours; n = 93) for the treatment of cSSSI.. Baseline characteristics were similar for both treatment groups. Clinical cure and microbiologic eradication rates demonstrated consistent trends favoring telavancin over vancomycin; however, the differences were not statistically significant. The incidence of adverse events was mostly similar between groups.. The efficacy of telavancin was at least equivalent to that of vancomycin for the treatment of cSSSI. These data suggest that telavancin may be a useful alternative for treatment of cSSSI caused by S. aureus, particularly MRSA.

Topics: Aged; Aminoglycosides; Anti-Bacterial Agents; Double-Blind Method; Female; Humans; Lipoglycopeptides; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Retrospective Studies; Skin Diseases, Infectious; Staphylococcal Infections; Surgical Wound Infection; Vancomycin

The in vitro antimicrobial activities of telavancin and comparator antimicrobials were evaluated against recent Staphylococcus aureus (S. aureus) clinical isolates collected in the United States of America (USA).. A total of 15882 S. aureus isolates were collected (2014-2016) as part of the SENTRY Antimicrobial Surveillance Program from sites located in all US Census Bureau divisions. Broth microdilution MIC values were measured using current reference methods. Data were stratified by year and census division, and resistance rates were analysed for significant trends. Previously published data on methicillin-resistant S. aureus (MRSA) and multidrug-resistant (MDR) MRSA isolates (collected 2011-2013) were merged with the current isolate set to examine longer term resistance trends.. The sustained potent activity of telavancin against US S. aureus isolates (100% susceptible) and the high rates of MRSA and MDR MRSA in the USA support the continued use of telavancin to treat indicated serious infections caused by S. aureus.

Topics: Aminoglycosides; Anti-Bacterial Agents; Drug Resistance, Bacterial; Epidemiological Monitoring; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; United States

Historically, vancomycin has been considered a primary therapeutic option for treating infections with Staphylococcus aureus, but isolates with reduced vancomycin susceptibility (SA-RVS) (MIC ≥ 4 μg/mL) have emerged. Telavancin, a semisynthetic lipoglycopeptide, is an alternative treatment option for S. aureus, but data examining telavancin activity against SA-RVS are limited. In the present study, we characterize 300 isolates of S. aureus isolates (50 vancomycin-susceptible (VSSA) isolates and 250 SA-RVS isolates) from a large tertiary care, academic medical center, 51.8% of which were methicillin resistant (MRSA). Sixteen (6.4%) SA-RVS isolates were non-susceptible to telavancin, whereas all VSSA isolates were susceptible. Additionally, 3.6% of SA-RVS isolates were non-susceptible to daptomycin, with three (1.2%) isolates testing non-susceptible to both telavancin and daptomycin. When tested against other classes of antimicrobials, there were no statistical differences in susceptibility of VSSA and SA-RVS isolates, except for the fluoroquinolones (ciprofloxacin and moxifloxacin). Molecular characterization of the isolates showed that SCCmec types II and IV together represented over half of the SA-RVS isolates; 12.0% of the VSSA isolates were SCCmec type II. Using RepPCR, we detected 16 distinct strain types in this isolate collection, and tst-1 (gene encoding the Staphylococcus toxic shock syndrome super-antigen) carriage was low (5.4%). Overall, we show that in addition to reduced vancomycin susceptibility, a small, but clinically significant, proportion of SA-RVS isolates also demonstrate reduced susceptibility to both telavancin and daptomycin.

Topics: Academic Medical Centers; Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Bacterial Proteins; Daptomycin; Drug Tolerance; Female; Humans; Lipoglycopeptides; Male; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Staphylococcal Infections; Staphylococcus aureus; Tertiary Care Centers; Vancomycin; Young Adult

Susceptibility testing is usually performed under standardized conditions for comparison of the activity of antimicrobial agents and the susceptibility of strains, but this does not reflect potential pathophysiological alterations at the infection site. While some impact factors have been studied already, there is a lack of knowledge about how different factors interact pharmacodynamically. We investigated the impact of albumin, pH and temperature in various combinations on the antimicrobial activity of glycopeptides.. Determination of minimal inhibitory concentrations (MICs) and time-kill curves were performed for telavancin, vancomycin and teicoplanin using 20 clinical isolates of Staphylococcus aureus and ATCC29213. The impact of the addition of 12% albumin, pH reduction to pH6, and temperature ranging from 32°C to 42°C was studied and compared to the standard setting in the reference medium Mueller Hinton broth (MHB).. At pH7 and 37°C the addition of albumin increased median MICs four-fold, eight-fold and two-fold for telavancin, teicoplanin and vancomycin, respectively. While changing temperature or pH alone had a moderate impact, the combination of albumin addition, pH decrease and temperature increase led to the maximum reduction of activity of 16-fold for teicoplanin compared to the standard setting. Temperature increase to 42°C increased the effect of albumin for teicoplanin and telavancin, resulting in ratios of 15.9 and 8. In contrast, reducing pH with concomitant albumin addition reduced the effect of albumin addition alone for telavancin, resulting in a ratio of 2 instead of 4.. Combining different impact factors showed a highly heterogeneous impact on the activity of glycopeptides. It might be misleading to take only protein binding into consideration in pharmacokinetic/pharmacodynamic (PK/PD) models.

Topics: Albumins; Aminoglycosides; Anti-Infective Agents; Glycopeptides; Humans; Hydrogen-Ion Concentration; Lipoglycopeptides; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Teicoplanin; Temperature; Vancomycin

Telavancin was evaluated against S. aureus isolates with reduced susceptibility to other antimicrobial agents using two broth microdilution methods and Etest® strips. The three methods provided comparable results. Differences in telavancin susceptibility versus non-susceptibility were noted mainly in the VISA-daptomycin non-susceptible group of isolates. In this group the percent susceptibility was 38% for the Etest® method and 50% and 54% for the 2 broth microdilution methods. All differences in susceptibility were within one 2-fold dilution.

Topics: Aminoglycosides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Reproducibility of Results; Staphylococcal Infections; Staphylococcus aureus

Telavancin is a lipoglycopeptide semi-synthetic derivative of vancomycin used for select infections caused by Gram-positive bacteria including

Topics: Acute Kidney Injury; Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Humans; Lipoglycopeptides; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Nephritis, Interstitial; Staphylococcal Infections

This is a retrospective analysis of patients with osteomyelitis who received telavancin at some time during their treatment course. The primary outcome was the percent of patients cured or improved at the end of telavancin therapy (EOTT). The secondary outcome was the percent of patients cured or improved three months after discontinuation of telavancin therapy. There were 32 cases of osteomyelitis with methicillin-resistant Staphylococcus aureus identified in 17 (56.7%), methicillin-sensitive Staphylococcus aureus 2(6.6%), coagulase negative staphylococci 6 (20.0%) and other pathogens, 5 (16.7%). At EOTT, 87.5% of patients had their osteomyelitis cured and 94.6% had the infection cured at three months after telavancin was completed. The most common adverse events associated with telavancin were gastrointestinal in nature (nausea (25.8%), vomiting (9.7%) and diarrhea (3.2%)) followed by metallic taste (6.5%). A favorable outcome was achieved for many patients receiving the antimicrobial regimen that included telavancin for the treatment of osteomyelitis.

Topics: Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Bacteria; Female; Follow-Up Studies; Humans; Lipoglycopeptides; Male; Middle Aged; Osteomyelitis; Retrospective Studies; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; United States

Patients with end-stage renal disease (ESRD) requiring intermittent haemodialysis (IHD) are at high risk of MRSA bacteraemia (MRSA-B) and often fail first-line therapy. The safety, effectiveness and optimal dosing of telavancin for MRSA-B in this patient population are unclear.. We aimed to describe clinical outcomes of telavancin in the treatment of refractory MRSA-B in patients with ESRD requiring IHD.. This was a retrospective study of hospitalized patients at two tertiary care academic medical centres with recurrent or persistent (≥3 days) MRSA-B treated with telavancin monotherapy. Outcomes included duration of MRSA-B (pre-telavancin versus post-telavancin) and microbiological failure (duration of MRSA-B ≥3 days after initiation of telavancin).. Telavancin dosed 10 mg/kg three times weekly post-IHD or 10 mg/kg every 48 h resulted in microbiological cure in 7/8 (87.5%) refractory MRSA-B cases. Telavancin monotherapy was associated with a significant reduction in median duration of bacteraemia [16 days pre-telavancin (IQR 8-19 days) versus 1 day post-telavancin (IQR 0-2 days); P = 0.018]. Telavancin was well tolerated by all patients and no adverse events were reported.. Telavancin was very safe and highly effective in the treatment of refractory MRSA-B in a cohort of patients with ESRD requiring IHD. These data support the utility of telavancin in the armamentarium against refractory MRSA-B, particularly in the high-risk IHD-dependent population.

Topics: Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Female; Hospitalization; Humans; Kidney Failure, Chronic; Lipoglycopeptides; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Renal Dialysis; Retrospective Studies; Staphylococcal Infections; Tertiary Care Centers; Treatment Outcome

The most common pathogen in pediatric cystic fibrosis (CF) patients is Staphylococcus aureus, and drug-resistant species are associated with negative outcomes. Methicillin-resistant Staphylococcus aureus (MRSA) is notoriously hard to treat because many antibiotics are not FDA approved for children and drug allergies or intolerances can prohibit the use of others. Telavancin is currently indicated for hospital-acquired pneumonia and ventilator-associated pneumonia caused by MRSA, but it has not been studied in patients with CF or in pediatrics. As a semi-synthetic derivative of vancomycin, it is unknown if cross-reactivity with telavancin occurs in patients with vancomycin hypersensitivity or intolerance. In this case series, we describe three adolescent patients with CF and previous intolerance to vancomycin who received telavancin for bronchopulmonary exacerbations.

Topics: Adolescent; Aminoglycosides; Anti-Bacterial Agents; Child; Cross Infection; Cystic Fibrosis; Drug Hypersensitivity; Female; Humans; Lipoglycopeptides; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Treatment Outcome; Vancomycin

This retrospective, case series describes our experience with the use of telavancin in patients with methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis and prosthetic joint infection. The primary objectives were clinical outcomes and adverse events (AEs), and a secondary outcome described microbiological susceptibility. Fourteen patients were enrolled. Median duration of therapy was 58 days, and four patients had concurrent bacteremia. End-of-treatment outcomes were available in 78% of patients, with a clinical success rate of 91%. Thirty-day and 12-month outcomes were also obtained. Seven patients experienced AEs. Infusion-related reactions were most common, and three AEs required discontinuation of therapy. All MRSA isolates had a telavancin MIC ≤0.06μg/ml, which is susceptible. This study indicates that telavancin may have a role in treatment of MRSA osteomyelitis and prosthetic joint infection. Our study describes clinical success and adverse events for long duration of therapy, up to 8 weeks.

Topics: Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Body Mass Index; Female; Follow-Up Studies; Humans; Joint Diseases; Lipoglycopeptides; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Osteomyelitis; Retrospective Studies; Staphylococcal Infections

Topics: Aminoglycosides; Anti-Bacterial Agents; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Neoplasms; Staphylococcal Infections; Time Factors; Vancomycin

MRSA strains of clonal complexes (CCs) 5, 8, 30 and 45 are leading causes of complicated endovascular infections associated with suboptimal clinical outcomes. Telavancin is a novel anti-MRSA agent that both inhibits bacterial cell wall synthesis and disrupts membranes by depolarization.. In this study, we compared the in vitro susceptibility and in vivo efficacy of telavancin versus daptomycin in an experimental rabbit infective endocarditis (IE) model caused by four MRSA strains representing each of the above CC types.. All study strains were susceptible to telavancin (MICs of ≤0.12 mg/L) and daptomycin (MICs of ≤0.5 mg/L). In vitro time-kill analyses revealed that supra-MIC levels of telavancin were effective at preventing regrowth at 24 h of incubation. In the IE animal model for all CC types, treatment with telavancin produced significantly greater reductions in MRSA counts as compared with daptomycin-treated animals in all target tissues. Moreover, telavancin-treated animals had a significantly higher percentage of sterile tissue cultures versus daptomycin-treated animals (e.g. 78%-100% versus 0% sterile vegetations and 100% versus 0%-11% sterile kidneys and spleen, in the telavancin- and daptomycin-treated animals, respectively).. These results suggest that telavancin exhibits significantly greater efficacies versus daptomycin in treating experimental IE caused by MRSA clinical isolates across four common CC types.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Daptomycin; Disease Models, Animal; Endocarditis, Bacterial; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Rabbits; Staphylococcal Infections; Vancomycin

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

Telavancin had MIC50, MIC90, and MIC100 values of 0.03, 0.06, and 0.12 μg/ml, respectively, against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and non-multidrug-resistant (non-MDR) and MDR subsets. MRSA with elevated MIC values for vancomycin (2 to 4 μg/ml) or daptomycin (1 to 2 μg/ml) had telavancin MIC50 (0.06 μg/ml) values 2-fold higher than those of isolates with lower MIC results (MIC50, 0.03 μg/ml). However, telavancin had MIC90 and MIC100 results of 0.06 and 0.12 μg/ml (100% susceptible), respectively, regardless of the MRSA subset.

Topics: Aminoglycosides; Anti-Bacterial Agents; Daptomycin; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; United States; Vancomycin

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and infective endocarditis (IE) have become increasingly difficult to treat over the past decade, with suboptimal response rates of less than 50%. Although vancomycin and daptomycin are standard therapeutic options, treatment failures with either or both agents are common. Telavancin is a lipoglycopeptide antibiotic with activity against MRSA. In vitro, telavancin displays bactericidal activity and has lower minimum inhibitory concentrations to MRSA than vancomycin.. We present a retrospective, case-series report of 14 patients treated with telavancin for refractory MRSA bacteremia with and without IE at our institution from 9 September 2010 to 2 April 2012.. Of the 14 patients who received telavancin for refractory MRSA bacteremia and IE, eight survived their inpatient admission and were able to be followed for 30 days. The overall survival rate was 57% (n = 8). Of the eight surviving patients, five were diagnosed with MRSA IE and the remaining three were diagnosed with complicated MRSA bacteremia. All six patients who did not survive the inpatient admission were diagnosed with left-sided IE involving the mitral valves.. This retrospective case series provides clinical evidence for the use of telavancin as a treatment option for refractory MRSA bacteremia and IE. With limited effective agents in the treatment of MRSA-complicated bacteremia and IE, telavancin represents a potential treatment option. Further randomized, controlled trials are necessary to define the optimal role of telavancin in the treatment of MRSA bacteremia and IE.

Topics: Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Endocarditis, Bacterial; Female; Humans; Lipoglycopeptides; Male; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Retrospective Studies; Salvage Therapy; Staphylococcal Infections; Survival Rate; Time Factors; Young Adult

Tissue- and device-associated biofilm infections are important medical problems. These infections are difficult to treat due to a high-level of tolerance to antibiotics. Telavancin has been studied in several in vitro biofilm models and has demonstrated efficacy against staphylococcal and enterococcal-associated biofilm infections, including those formed by methicillin-resistant Staphylococcus aureus. Telavancin was effective against the difficult-to-treat vancomycin- and glycopeptide-intermediate strains of S. aureus in these models. Furthermore, the efficacy of telavancin has been evaluated in several biofilm-related in vivo models, including osteomyelitis, endocarditis and device-associated infections in rabbits. Overall, telavancin exhibited similar or greater efficacy than vancomycin and other comparators in these animal models and maintained activity against vancomycin-intermediate and daptomycin nonsusceptible strains of S. aureus.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Biofilms; Disease Models, Animal; Endocarditis, Bacterial; Enterococcus; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Osteomyelitis; Staphylococcal Infections; Staphylococcus aureus

Topics: Aminoglycosides; Anti-Bacterial Agents; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections

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

Staphylococcus aureus possesses exceptional virulence and a remarkable ability to adapt in the face of antibiotic therapy. We examined the in vitro evolution of S. aureus in response to escalating vancomycin exposure by evaluating bacterial killing and the progression of resistance. A hollow-fiber infection model was utilized to simulate human doses of vancomycin increasing from 0.5 to 4 g every 12 h (q12h) versus a high inoculum (10(8) CFU/ml) of methicillin-resistant S. aureus (MRSA) USA300 and USA400. Host-pathogen interactions using Galleria mellonella and accessory gene regulator (agr) expression were studied in serially obtained isolates. In both USA300 and USA400 MRSA isolates, vancomycin exposure up to 2 g q12h resulted in persistence and regrowth, whereas 4 g administered q12h achieved sustained killing against both strains. As vancomycin exposure increased from 0.5 to 2 g q12h, the bacterial population shifted toward vancomycin-intermediate resistance, and collateral increases in the MICs of daptomycin and televancin were observed over 10 days. Guideline-recommended exposure of a ratio of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC (fAUC/MIC ratio) of 200 displayed a 0.344-log bacterial reduction in area, whereas fAUC/MICs of 371 and 554 were needed to achieve 1.00- and 2.00-log reductions in area, respectively. The stepwise increase in resistance paralleled a decrease in G. mellonella mortality (P = 0.021) and a gradual decline of RNAIII expression over 10 days. Currently recommended doses of vancomycin resulted in amplification of resistance and collateral damage to other antibiotics. Decreases in agr expression and virulence during therapy may be an adaptive mechanism of S. aureus persistence.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Daptomycin; Host-Pathogen Interactions; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Moths; RNA, Bacterial; Staphylococcal Infections; Vancomycin; Vancomycin Resistance

The alarming growth of antibiotic resistant superbugs such as vancomycin-resistant Enterococci and Staphylococci has become a major global health hazard. To address this issue, we report the development of lipophilic cationic vancomycin analogues possessing excellent antibacterial activity against several drug-resistant strains. Compared to vancomycin, efficacy greater than 1000-fold was demonstrated against vancomycin-resistant Enterococci (VRE). Significantly, unlike vancomycin, these compounds were shown to be bactericidal at low concentrations and did not induce bacterial resistance. An optimized compound in the series, compared to vancomycin, showed higher activity in methicillin-resistant Staphylococcus aureus (MRSA) infected mouse model and exhibited superior antibacterial activity in whole blood with no observed toxicity. The remarkable activity of these compounds is attributed to the incorporation of a new membrane disruption mechanism into vancomycin and opens up a great opportunity for the development of novel antibiotics.

Topics: Animals; Bacteremia; Cell Membrane Permeability; Drug Resistance, Bacterial; Enterococcus; Female; HeLa Cells; Hemolysis; Humans; Mice; Microbial Sensitivity Tests; Neutropenia; Quaternary Ammonium Compounds; Staphylococcal Infections; Staphylococcus; Structure-Activity Relationship; Triazoles; Vancomycin

Beta-lactams enhance the killing activity of vancomycin. Due to structural and mechanistic similarities between vancomycin and telavancin, we investigated the activity of telavancin combined with nafcillin and imipenem compared to the known synergistic combination of telavancin and gentamicin. Thirty strains of Staphylococcus aureus, 10 methicillin-susceptible S. aureus (MSSA), 10 methicillin-resistant S. aureus (MRSA), and 10 heterogeneously vancomycin-intermediate S. aureus (hVISA), were tested for synergy by time-kill methodology. Six strains (2 each of MSSA, MRSA, and hVISA) were further evaluated in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated regimens of 10 mg/kg of body weight of telavancin once daily alone and combined with 2 g nafcillin every 4 h, 500 mg imipenem every 6 h, or 5 mg/kg gentamicin once daily over 72 h. In the synergy test, 67% of strains displayed synergy with the combination of telavancin and gentamicin, 70% with telavancin and nafcillin, and 63% with telavancin and imipenem. In the PK/PD model, the activities of all three combinations against MRSA and hVISA were superior to all individual drugs alone (P ≤ 0.002) and were similar to each other (P ≥ 0.187). The activities of all three combinations against MSSA were generally similar to each other except for one strain where the combination of telavancin and imipenem was superior to all other regimens (P ≤ 0.011). The activity of the combination of telavancin and beta-lactam agents was similar to that of telavancin and gentamicin against S. aureus, including resistant strains. Because beta-lactam combinations are less likely to be nephrotoxic than telavancin plus gentamicin, these beta-lactam combinations may have clinical utility.

Topics: Aminoglycosides; Anti-Bacterial Agents; Drug Synergism; Drug Therapy, Combination; Gentamicins; Humans; Imipenem; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Models, Biological; Nafcillin; Staphylococcal Infections; Staphylococcus aureus; Vancomycin Resistance

The activity of telavancin was compared with vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) in planktonic culture and biofilms grown using a range of in vitro models. Antibiotic efficacy was determined using 24 clinical isolates, including healthcare-associated (HA)-MRSA, community-associated (CA)-MRSA and isolates with reduced (intermediate) susceptibility to vancomycin (VISA). Activity against biofilms was compared using three models: 96-peg plates, 96-well flat-bottom plates and a flow-cell system. Cell death was evaluated using a metabolic dye and Live/Dead staining. The planktonic minimum inhibitory concentration (MIC) range for telavancin was lower than that for vancomycin (0.06-0.25 mg/l and 0.5-8 mg/l, respectively). Vancomycin (100 × MIC) killed, on average, 59% of cells in HA-MRSA biofilms grown on 96-peg plates, 44% of cells in CA-MRSA biofilms and 26% of cells in VISA biofilms. Telavancin (100 × MIC) killed, on average, 63%, 49% and 41% of cells, respectively. The antibiotics showed similar efficacy against MRSA biofilms but telavancin was more effective against those formed by VISA isolates. In the flow-cell system, antibiotic cell killing was enhanced with both antibiotics, killing up to 80% of biofilm-associated cells. The variance in cell killing displayed when biofilms were grown using different systems highlights the importance of selecting an appropriate model for antimicrobial efficacy tests. The flow-cell system more closely reflects conditions encountered during infection and is possibly more clinically relevant than a 96-well plate system. Despite differences between the models evaluated, telavancin typically demonstrated improved efficacy over vancomycin, indicating the potential value of the agent in the treatment of biofilm-mediated infections caused by S. aureus, especially multidrug-resistant isolates.

Topics: Aminoglycosides; Anti-Bacterial Agents; Biofilms; Drug Resistance, Multiple, Bacterial; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Microbial Viability; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

Vancomycin-intermediate Staphylococcus aureus (VISA) infections are an emerging problem and antibiotic options are limited. We report the first case, to our knowledge, of heteroresistant VISA mediastinitis and bacteremia in a patient with a ventricular assist device who underwent orthotopic heart transplantation with clinical cure.

Topics: Adult; Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Debridement; Defibrillators, Implantable; Female; Heart Transplantation; Heart-Assist Devices; Humans; Lipoglycopeptides; Mediastinitis; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Vancomycin; Vancomycin Resistance

To describe the tolerance to long-term telavancin therapy among inpatients as it relates to nephrotoxicity.. Retrospective cohort study of adult patients who received telavancin at the Barnes-Jewish Hospital from 1 September 2009 to 1 December 2010. Patients who received less than three doses of telavancin, were on haemodialysis prior to telavancin administration or died within 48 h of initial telavancin administration were excluded.. Twenty-one patients received telavancin and met the inclusion criteria. Seven of 21 patients (33%) developed acute renal insufficiency during therapy. Patients who developed acute renal insufficiency had a mean glomerular filtration rate reduction of 56 mL/min/1.73 m(2). In the univariate analysis, high body mass index (P=0.025), use of intravenous contrast dye (P=0.017) and prior serum vancomycin trough levels >20 mg/L (P=0.017) were associated with developing acute renal insufficiency. Two patients required haemodialysis; two had persistent renal insufficiency.. Supratherapeutic vancomycin trough levels, high body mass index and receipt of intravenous contrast dye prior to telavancin therapy were associated with acute renal insufficiency.

Topics: Acute Kidney Injury; Adult; Aged; Aminoglycosides; Anti-Infective Agents; Cohort Studies; Female; Humans; Lipoglycopeptides; Male; Middle Aged; Retrospective Studies; Risk Factors; Staphylococcal Infections; Survival Analysis

Topics: Aminoglycosides; Anti-Bacterial Agents; Arthritis, Infectious; Humans; Lipoglycopeptides; Male; Methicillin Resistance; Middle Aged; Prosthesis-Related Infections; Staphylococcal Infections; Staphylococcus epidermidis; Treatment Outcome

To report a case of multidrug-resistant osteomyelitis successfully treated with telavancin, rifampin, and meropenem.. An 18-year-old male with spina bifida was treated primarily in the outpatient setting over the course of 133 days with multiple antimicrobials for a recurrent right calcaneal wound and osteomyelitis infection. Initial cultures were positive for methicillin-resistant Staphylococcus aureus and coagulase-negative Staphylococcus, which were treated with intravenous vancomycin 1 g every 12 hours, increased after 13 days to 1.5 g every 12 hours with addition of rifampin 300 mg twice daily, both of which were discontinued on day 22 due to leukopenia (white blood cell count 3.0 × 10(3)/μL) and neutropenia (absolute neutrophil count 0.2 × 10(3)/μL). Daptomycin 8 mg/kg/day was then initiated with rifampin 300 mg twice daily; treatment was discontinued after 49 days due to an elevated creatine kinase level of 1831 U/L (baseline 86). Intravenous meropenem 1 g every 8 hours was again initiated on day 83 following additional identification of quinolone-resistant Pseudomonas aeruginosa from the soft tissue of the right foot. Intravenous vancomycin 1 g every 12 hours was also restarted at this time for persistent coagulase-negative Staphylococcus and oral rifampin 300 mg twice daily was again added. Adverse events again required the discontinuation of vancomycin on day 91. The eventual drug therapy regimen consisted of telavancin 750 mg/day for 42 days, meropenem for 50 days, and oral rifampin for 50 days. At the end of treatment, the patient's right heel wound had almost completely closed. He was without recurrence or treatment-related adverse events at follow-up 1 year later.. Antimicrobial selection for osteomyelitis infections presents a challenge to the clinician due to patient intolerance, increasing antimicrobial resistance, and variable antimicrobial penetration at the site of infection. To our knowledge, this is the first case report of the successful use of a regimen including telavancin for the treatment of a recurrent, coagulase-negative Staphylococcus osteomyelitis infection.. In this complex case involving a polymicrobial infection of the right calcaneal bone and surrounding soft tissue, eventual drug therapy including telavancin, meropenem, and rifampin resulted in a successful clinical response.

Topics: Adolescent; Aminoglycosides; Anti-Bacterial Agents; Coinfection; Drug Therapy, Combination; Humans; Lipoglycopeptides; Male; Meropenem; Osteomyelitis; Rifampin; Staphylococcal Infections; Thienamycins; Treatment Outcome

Treatment failure of methicillin-resistant Staphylococcus aureus (MRSA) remains an important concern. In order to investigate new MRSA treatment modalities, we used standard time-kill assays to determine the in vitro killing rate of 22 strains of MRSA by vancomycin, telavancin, daptomycin, and ceftaroline. Studies were carried out with 7-10-times the minimum bactericidal concentrations of each antibiotic in broth culture for 24 h, with subculture at 4, 8, and 24 h. We found that killing by ceftaroline closely paralleled that of vancomycin. Telavancin killed bacteria significantly more slowly, whereas daptomycin killed significantly more rapidly.

Topics: Aminoglycosides; Analysis of Variance; Anti-Bacterial Agents; Ceftaroline; Cephalosporins; Colony Count, Microbial; Daptomycin; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcal Infections; Vancomycin

A number of cases of both methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains that have developed daptomycin resistance (DAP-R) have been reported. Telavancin (TLV) is a lipoglycopeptide agent with a dual mechanism of activity (cell wall synthesis inhibition plus depolarization of the bacterial cell membrane). Five recent daptomycin-susceptible (DAP-S)/DAP-R MRSA isogenic strain pairs were evaluated for in vitro TLV susceptibility. All five DAP-R strains (DAP MICs ranging from 2 to 4 μg/ml) were susceptible to TLV (MICs of ≤0.38 μg/ml). In vitro time-kill analyses also revealed that several TLV concentrations (1-, 2-, and 4-fold MICs) caused rapid killing against the DAP-R strains. Moreover, for 3 of 5 DAP-R strains (REF2145, A215, and B(2.0)), supra-MICs of TLV were effective at preventing regrowth at 24 h of incubation. Further, the combination of TLV plus oxacillin (at 0.25× or 0.50× MIC for each agent) increased killing of DAP-R MRSA strains REF2145 and A215 at 24 h (∼2-log and 5-log reductions versus TLV and oxacillin alone, respectively). Finally, using a rabbit model of aortic valve endocarditis caused by DAP-R strain REF2145, TLV therapy produced a mean reduction of >4.5 log(10) CFU/g in vegetations, kidneys, and spleen compared to untreated or DAP-treated rabbits. Moreover, TLV-treated rabbits had a significantly higher percentage of sterile tissue cultures (87% in vegetations and 100% in kidney and spleen) than all other treatment groups (P < 0.0001). Together, these results demonstrate that TLV has potent bactericidal activity in vitro and in vivo against DAP-R MRSA isolates.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Aortic Valve; Daptomycin; Disease Models, Animal; Drug Administration Schedule; Endocarditis, Bacterial; Female; Kidney; Lipoglycopeptides; Methicillin; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Rabbits; Spleen; Staphylococcal Infections; Time Factors

In phase 3 studies of the efficacy of telavancin for the treatment of hospital-acquired pneumonia, 704 Gram-positive and 627 Gram-negative aerobic bacterial pathogens were obtained at baseline from 1503 patients. The majority of Gram-positive isolates (n = 650 [92%]) were Staphylococcus aureus, of which 410 (63%) were methicillin-resistant (MRSA). Of the MRSA isolates, 9.5% were identified as heterogeneous vancomycin-intermediate S. aureus. All Gram-positive isolates were inhibited by ≤1 μg/mL of telavancin.

Topics: Aminoglycosides; Anti-Bacterial Agents; Carrier State; Clinical Trials, Phase III as Topic; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Vancomycin Resistance

Two novel lipoglycopeptides, dalbavancin and telavancin, and relevant comparative agents were tested for in vitro activity against clinical isolates of staphylococci and streptococci collected in the cross-Canada surveillance study, CANWARD, in 2007-2009. The rank order of potency (based on MIC(90) [μg/mL], i.e., the concentration of antimicrobial agent required to inhibit the growth of 90% of isolates tested) of glycopeptides against both Staphylococcus aureus and Staphylococcus epidermidis was dalbavancin (0.06 μg/mL) >telavancin (0.5 μg/mL) > vancomycin (1-2 μg/mL); concurrent susceptibility or resistance to oxacillin in staphylococci did not affect potency of glycopeptides. Dalbavancin and telavancin also demonstrated potent activity against Streptococcus pneumoniae, including penicillin-resistant isolates (MIC(90), ≤ 0.03 μg/mL; ≤ 0.06 μg/mL), and Streptococcus pyogenes (≤ 0.03 μg/mL; 0.06 μg/mL). Based on their robust in vitro activities, dalbavancin and telavancin have the potential to treat Gram-positive infections caused by methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae.

Topics: Aminoglycosides; Anti-Bacterial Agents; Canada; Hospitals; Humans; Lipoglycopeptides; Methicillin Resistance; Microbial Sensitivity Tests; Penicillin Resistance; Staphylococcal Infections; Staphylococcus; Staphylococcus aureus; Staphylococcus epidermidis; Streptococcal Infections; Streptococcus; Streptococcus pneumoniae; Streptococcus pyogenes; Teicoplanin; Vancomycin

Selective pressure from glycopeptide use has led to non-susceptible strains of Staphylococcus aureus, including heterogeneously vancomycin-intermediate S. aureus (hVISA). Treatment of hVISA infections with vancomycin has been associated with treatment failure, therefore new treatments are required. The objective of this study was to evaluate the activity of telavancin, vancomycin and linezolid against hVISA clinical strains. Twenty-five hVISA isolates were evaluated for minimum inhibitory concentrations (MICs) by microdilution and for bactericidal activity by time-kill analysis [starting inoculum ca. 10(6)colony-forming units (CFU)/mL and ca. 10(8)CFU/mL] against telavancin, vancomycin and linezolid. MICs for 50% and 90% of the organisms (MIC(50) and MIC(90) values, respectively) were, respectively, 0.5mg/L and 1mg/L for telavancin and 2mg/L and 2mg/L for both vancomycin and linezolid. In time-kill studies, telavancin was bactericidal against all strains at plasma peak and trough concentrations and at low and high inocula. At low inoculum, the time to bactericidal activity (defined as 99.9% kill from initial inoculum) (T(99.9)) for telavancin was 5.6 ± 3.2 h at peak concentration and 12.3 ± 5.2 h at trough concentration. This was superior to vancomycin (P<0.001), which had a T(99.9) of 18.8 ± 2.1 h at peak concentration and 19.1 ± 2.2 h at trough concentration. At high inoculum, telavancin had a T(99.9) of 16.3 ± 3.2 h at peak concentration and 21.4 ± 2.5 h at trough concentration, whilst vancomycin did not consistently achieve bactericidal activity. Linezolid was not bactericidal against any strain at either concentration or inoculum. In conclusion, the killing activity of telavancin against hVISA was found to be superior to vancomycin and linezolid.

Topics: Acetamides; Aminoglycosides; Anti-Bacterial Agents; Humans; Linezolid; Lipoglycopeptides; Microbial Sensitivity Tests; Microbial Viability; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Time Factors; Vancomycin; Vancomycin Resistance

Topics: Acetamides; Aminoglycosides; Anti-Bacterial Agents; Daptomycin; Echocardiography, Transesophageal; Endocarditis, Bacterial; Humans; Linezolid; Lipoglycopeptides; Magnetic Resonance Imaging; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Mitral Valve; Oxazolidinones; Paraparesis; Staphylococcal Infections; Treatment Failure

Topics: Acetamides; Aminoglycosides; Anti-Bacterial Agents; Daptomycin; Humans; Linezolid; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Minocycline; Osteomyelitis; Oxazolidinones; Staphylococcal Infections; Tigecycline; Vancomycin

Topics: Acute Generalized Exanthematous Pustulosis; Aminoglycosides; Anti-Bacterial Agents; Drug Eruptions; Female; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Middle Aged; Staphylococcal Infections

The activity of telavancin and comparators was assessed against a contemporary (2007 and 2008) global collection of 10,000 isolates of Staphylococcus aureus. Telavancin was very active against methicillin-susceptible and -resistant S. aureus (MSSA and MRSA, respectively; MIC(50/90) for both, 0.12/0.25 microg/ml; 100.0% susceptible). This agent was 2-, 4-, and 8-fold more potent than daptomycin (MIC(90), 0.5 microg/ml), vancomycin or quinupristin-dalfopristin (MIC(90), 1 microg/ml), and linezolid (MIC(90), 2 microg/ml) against MRSA, respectively. These data show a potent activity of telavancin tested against a current global collection of S. aureus.

Topics: Acetamides; Aminoglycosides; Anti-Bacterial Agents; Daptomycin; Drug Resistance, Bacterial; Humans; In Vitro Techniques; Linezolid; Lipoglycopeptides; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Virginiamycin

Telavancin displays potent in vitro and in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA), including strains with reduced susceptibility to vancomycin. We compared the efficacies of telavancin and vancomycin against MRSA strains with vancomycin MICs of ≥1 μg/ml in a neutropenic murine lung infection model. Thirteen clinical MRSA isolates (7 vancomycin-susceptible, 2 vancomycin-heteroresistant [hVISA], and 4 vancomycin-intermediate [VISA] isolates) were tested after 24 h, and 7 isolates (1 hVISA and 4 VISA isolates) were tested after 48 h of exposure. Mice were administered subcutaneous doses of telavancin at 40 mg/kg of body weight every 12 h (q12h) or of vancomycin at 110 mg/kg q12h; doses were designed to simulate the area under the concentration-time curve for the free, unbound fraction of drug (fAUC) observed for humans given telavancin at 10 mg/kg q24h or vancomycin at 1 g q12h. Efficacy was expressed as the 24- or 48-h change in lung bacterial density from pretreatment counts. At dose initiation, the mean bacterial load was 6.16 ± 0.26 log(10) CFU/ml, which increased by averages of 1.26 ± 0.55 and 1.74 ± 0.68 log in untreated mice after 24 and 48 h, respectively. At both time points, similar CFU reductions were noted for telavancin and vancomycin against MRSA, with vancomycin MICs of ≤2 μg/ml. Both drugs were similarly efficacious after 24 and 48 h of treatment against the hVISA strains tested. Against VISA isolates, telavancin reduced bacterial burdens significantly more than vancomycin for 1 of 4 isolates after 24 h and for 3 of 4 isolates after 48 h. These data support the potential utility of telavancin for the treatment of MRSA pneumonia caused by pathogens with reduced susceptibility to vancomycin.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Disease Models, Animal; Female; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Pneumonia; Staphylococcal Infections; Vancomycin

Infections caused by heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) are associated with high rates of vancomycin treatment failure. Telavancin is a bactericidal lipoglycopeptide active in vitro against Gram-positive pathogens including hVISA and vancomycin-intermediate S. aureus (VISA). This study characterizes the microbiological activity of telavancin against vancomycin-susceptible S. aureus (VSSA), hVISA and VISA strains.. Reference strains of VSSA, hVISA and VISA were assessed for potential telavancin heteroresistance by population analysis. In addition, the efficacies of telavancin (40 mg/kg subcutaneously every 12 h for 4 days) and vancomycin (110 mg/kg subcutaneously every 12 h for 8 days) were compared in a neutropenic murine model (immunocompromised female non-Swiss albino mice) of bacteraemia caused by hVISA strain Mu3. Blood and spleen bacterial titres were quantified from cohorts of mice euthanized pre-treatment and at 24 h intervals post-treatment for 8 days.. Telavancin was active against all strains of S. aureus tested, with MIC values < or =0.5 mg/L. Population analyses revealed no evidence of subpopulations with reduced susceptibility to telavancin. In the murine bacteraemia model of hVISA infection, all animals were bacteraemic pre-treatment and mortality was 100% within 16-24 h post-infection in untreated animals. Treatment with telavancin was associated with lower spleen bacterial titres, lower rates of bacteraemia and lower overall mortality than treatment with vancomycin.. These in vitro and pre-clinical in vivo studies demonstrate that telavancin has the potential to be efficacious in infections caused by hVISA.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Bacteremia; Blood; Disease Models, Animal; Female; Lipoglycopeptides; Mice; Microbial Sensitivity Tests; Spleen; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Vancomycin Resistance

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Endocarditis, Bacterial; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Infections; Treatment Outcome

The activity of telavancin was evaluated against Staphylococcus spp. collected from European hospitals as part of an international surveillance study (2007-2008). A total of 7534 staphylococcal clinical isolates [5726 Staphylococcus aureus and 1808 coagulase-negative staphylococci (CoNS)] were included. Isolates were tested for susceptibility according to reference methods and minimum inhibitory concentration (MIC) values were interpreted based on Clinical and Laboratory Standards Institute (CLSI) 2010 and European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2009 criteria. Telavancin breakpoints approved by the US Food and Drug Administration (FDA) were applied. Telavancin activity was evaluated against meticillin-resistant S. aureus (MRSA) displaying several antibiogram resistance patterns, including multidrug-resistant isolates. Telavancin was active against S. aureus [MIC(50/90) values (MICs for 50% and 90% of the isolates, respectively)=0.12/0.25mg/L; 100.0% susceptible] and CoNS (MIC(50/90)=0.12/0.25mg/L), inhibiting all isolates at < or =0.5mg/L. Similar results were observed when S. aureus were stratified by year or country of origin (MIC(50/90)=0.12/0.25mg/L). When MRSA isolates were clustered according to 48 different resistance patterns, telavancin showed consistent MIC(90) values (0.25mg/L) regardless of multidrug resistance. Amongst CoNS, telavancin was slightly more active against Staphylococcus capitis, Staphylococcus epidermidis, Staphylococcus hominis, Staphylococcus lugdunensis and Staphylococcus xylosus (MIC(50)=0.12 mg/L) compared with Staphylococcus haemolyticus, Staphylococcus saprophyticus and Staphylococcus warneri (MIC(50)=0.25mg/L). Overall, telavancin exhibited MIC(90) results two- to eight-fold lower than comparators (daptomycin, quinupristin/dalfopristin, vancomycin and linezolid). Based upon MIC(90) values, telavancin demonstrated potent in vitro activity against a contemporary (2007-2008) collection of Staphylococcus spp. recovered from nearly 30 European medical centres.

Topics: Aminoglycosides; Anti-Bacterial Agents; Coagulase; Drug Resistance, Bacterial; Europe; Hospitalization; Humans; Lipoglycopeptides; Microbial Sensitivity Tests; Population Surveillance; Staphylococcal Infections; Staphylococcus; Staphylococcus aureus

Emerging infections caused by vancomycin-intermediate Staphylococcus aureus (VISA) isolates are more likely to be associated with treatment failures than infections caused by other types of S. aureus. We present a case of pacemaker lead infective endocarditis caused by a non-daptomycin-susceptible strain of VISA. After 8 weeks of parenteral telavancin therapy, the patient achieved microbiological and clinical cure.

Topics: Aminoglycosides; Anti-Bacterial Agents; Endocarditis; Female; Humans; Lipoglycopeptides; Middle Aged; Pacemaker, Artificial; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Vancomycin

Telavancin is an investigational lipoglycopeptide antibiotic that is active against gram-positive pathogens. In an in vivo rabbit model, subtherapeutic (15-mg/kg) and therapeutic (30- or 45-mg/kg) doses of telavancin were demonstrated to be noninferior and superior to vancomycin (20 mg/kg), respectively, for preventing subcutaneous implant colonization and infection by Staphylococcus aureus.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Catheter-Related Infections; Female; Lipoglycopeptides; Rabbits; Staphylococcal Infections; Vancomycin

Staphylococcus aureus is the most common pathogen isolated in osteomyelitis. This study evaluated the efficacies of telavancin (an investigational, rapidly bactericidal lipoglycopeptide with a multifunctional mechanism of action against Gram-positive bacteria), vancomycin and linezolid in a rabbit methicillin-resistant S. aureus (MRSA) osteomyelitis model.. Localized osteomyelitis was induced in New Zealand White rabbits by percutaneous injection of 10(6) cfu of MRSA clinical isolate 168-1 into the intramedullary cavity. Two weeks post-infection, rabbits with radiographically confirmed, localized proximal tibial osteomyelitis were randomized into four groups (n = 15 per group): untreated controls; vancomycin 30 mg/kg subcutaneously every 12 h; linezolid 60 mg/kg orally every 8 h; and telavancin 30 mg/kg subcutaneously every 12 h. After 4 weeks of antibiotic treatment, animals were left untreated for 2 weeks. Rabbits were then euthanized and the tibias harvested. Bone matrix and marrow from each tibia were cultured and bacterial counts determined.. For MRSA isolate 168-1, the MIC was 0.25 mg/L for telavancin, 0.5 mg/L for vancomycin and 0.5 mg/L for linezolid. Tibial cultures were positive for MRSA in 9 of 15 (60%) untreated controls, and 3 of 15 (20%) telavancin-treated, 3 of 15 (20%) vancomycin-treated and 4 of 14 (29%) linezolid-treated rabbits.. Telavancin has comparable efficacy to vancomycin and linezolid in a rabbit model of MRSA osteomyelitis.

Topics: Acetamides; Aminoglycosides; Animals; Anti-Bacterial Agents; Bone Marrow; Colony Count, Microbial; Linezolid; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Osteomyelitis; Oxazolidinones; Rabbits; Random Allocation; Staphylococcal Infections; Treatment Outcome; Vancomycin

The aim of the study was to compare the efficacies of telavancin and vancomycin against glycopeptide-intermediate Staphylococcus aureus (GISA) and heterogeneous vancomycin-intermediate S. aureus (hVISA) in a neutropenic murine bacteraemia model.. Immunocompromised mice (female non-Swiss albino, 18-30 g) were inoculated intraperitoneally with 10(7) cfu/mL of GISA (strain HIP-5836 or Mu50) or hVISA (strain Mu3). Infected mice received a subcutaneous dose of telavancin (40 mg/kg) or vancomycin (110 mg/kg) at 4 and 16 h post-inoculation. Control animals received a subcutaneous dose of vehicle at 4 h post-inoculation only. Blood and spleen bacterial titres were quantified in drug-treated mice at 16, 28 and 52 h post-inoculation.. Telavancin was 8-fold more potent than vancomycin against HIP-5836 (MIC 1 versus 8 mg/L), 16-fold more potent against Mu50 (MIC 0.5 versus 8 mg/L) and 8-fold more potent against Mu3 (MIC 0.25 versus 2 mg/L). Telavancin produced significant (P < 0.05) and sustained reductions in blood and spleen titres from pre-treatment levels in mice infected with HIP-5836, Mu50 or Mu3. Vancomycin lowered blood and spleen HIP-5836 counts transiently, but did not lower blood or spleen Mu50 or Mu3 counts significantly at any timepoint. Reductions in blood and spleen HIP-5836 and Mu3 titres and in spleen Mu50 titres at 52 h post-inoculation were significantly greater with telavancin than vancomycin (P < 0.05).. Telavancin was more efficacious than vancomycin in clearing infections caused by GISA strains HIP-5836 and Mu50 and hVISA strain Mu3 in a neutropenic mouse bacteraemia model. Further evaluation of telavancin for GISA and hVISA bacteraemia is warranted.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Bacteremia; Blood; Colony Count, Microbial; Drug Resistance, Bacterial; Female; Glycopeptides; Lipoglycopeptides; Mice; Spleen; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Vancomycin

Telavancin is the first available lipoglycopeptide antibacterial agent. It is active against Gram-positive bacteria, including meticillin/oxacillin-resistant Staphylococcus aureus (MRSA) strains associated with complicated skin and skin structure infections (cSSSIs). In randomized, double-blind trials, intravenous telavancin 10 mg/kg once daily (administered as a 1-hour infusion) was effective in the treatment of adult patients with cSSSIs, including those with infections caused by MRSA, as shown by clinical cure rates in clinically evaluable, all-treated and microbiologically evaluable populations at the test-of-cure (TOC) visit. Telavancin 10 mg/kg once daily was noninferior to intravenous vancomycin 1 g every 12 hours, with clinical cure rates of 88% versus 87% at the TOC visit in pooled data from the clinically evaluable population (n = 1489) of two phase III trials. Pooled clinical cure rates in telavancin recipients at the TOC visit were also not significantly different from those in vancomycin recipients in the all-treated or microbiologically evaluable populations, including microbiologically evaluable subgroups with baseline infections caused by MRSA, meticillin-susceptible S. aureus or other Gram-positive pathogens. Telavancin was generally well tolerated in patients with cSSSIs, with most adverse events being of mild or moderate severity.

Topics: Adult; Aminoglycosides; Animals; Anti-Bacterial Agents; Cross Infection; Disease Models, Animal; Drug Administration Schedule; Drug Interactions; Drug Resistance, Multiple, Bacterial; Gram-Positive Bacteria; Humans; Lipoglycopeptides; Methicillin; Methicillin Resistance; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxacillin; Skin Diseases, Infectious; Staphylococcal Infections; Treatment Outcome; Vancomycin

Topics: Adult; Aminoglycosides; Anti-Bacterial Agents; Drug Approval; Drug Discovery; Drug Resistance, Bacterial; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Randomized Controlled Trials as Topic; Skin Diseases, Bacterial; Staphylococcal Infections; United States; United States Food and Drug Administration

The efficacy of telavancin, a novel lipoglycopeptide, was evaluated in experimental endocarditis in rabbits using two clinical isolates of glycopeptide-intermediate Staphylococcus aureus: ATCC 700788 and HIP 5836. Infected rabbits were treated for 2 days with telavancin (10 mg/kg of body weight once daily intravenously) or vancomycin (1 g twice daily intravenously), administered with a computer-controlled infusion pump system simulating human serum kinetics. Vegetations were harvested at 16 h postinoculation in the control group and at the end of treatment in the drug-treated group. For ATCC 700788, MICs and minimal bactericidal concentrations (MBCs), respectively, were 1 mg/liter and 4 mg/liter for telavancin and 8 mg/liter and 128 mg/liter for vancomycin. For HIP 5836, MICs and MBCs, respectively, were 4 mg/liter and 8 mg/liter for telavancin and 8 mg/liter and 128 mg/liter for vancomycin. Peak and trough levels were 90 microg/ml and 6 microg/ml, respectively, for telavancin and 46 microg/ml and 6 microg/ml, respectively, for vancomycin. In glycopeptide-intermediate S. aureus ATCC 700788, telavancin sterilized 6 of 16 vegetations (37%), whereas vancomycin sterilized 4 of 20 (20%) (P = 0.29) compared with 0 of 17 in the control group. In HIP 5836 experiments, telavancin and vancomycin sterilized 5 of 16 (31%) and 1 of 15 (7%) vegetations (P = 0.17), respectively, compared with none in the control group. Telavancin reduced vegetation titers by 2.0 and 2.3 logs greater than vancomycin for the ATCC 700788 (4.6 [2.0 to 5.8] versus 6.6 [2.0 to 6.9] log CFU/g vegetation; P = 0.05) and HIP 5836 (4.4 [2.0 to 7.4] versus 6.7 [4.5 to 8.7] log CFU/g vegetation; P = 0.09) strains, respectively; these differences did not reach statistical significance. All isolates from vegetations remained susceptible to telavancin after therapy. The results suggest that telavancin may be an effective treatment for endocarditis caused by glycopeptide-intermediate S. aureus.

Topics: Aminoglycosides; Animals; Anti-Infective Agents; Aortic Valve; Colony Count, Microbial; Endocarditis, Bacterial; Heart Valve Diseases; Humans; Infusion Pumps; Infusions, Intravenous; Lipoglycopeptides; Microbial Sensitivity Tests; Models, Theoretical; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Time Factors; Treatment Outcome; Vancomycin

This study compared the activity of telavancin, a novel multivalent lipoglycopeptide with rapid bactericidal activity, with those of five standard antibiotics for methicillin-resistant Staphylococcus aureus (MRSA) against isolates of community-associated MRSA (CA-MRSA).. Microdilution tests performed according to CLSI guidelines using cation-adjusted Mueller-Hinton broth were used to determine the MIC values of telavancin, quinupristin/dalfopristin, vancomycin, trimethoprim/sulfamethoxazole, linezolid and daptomycin versus 60 CA-MRSA isolates. MBC values of telavancin were determined according to CLSI guidelines and American Society for Microbiology standards. PFGE was performed using the restriction enzyme SmaI. Samples from three predominant pulsed-field types were typed by multilocus sequence typing. Staphylococcal cassette chromosome mec typing was determined by multiplex PCR. The Panton-Valentine leucocidin (PVL) genes (lukS-PV and lukF-PV) were identified by PCR.. The telavancin MIC90 and MBC90 values for this collection of 60 CA-MRSA isolates were 0.5 and 1 mg/L, respectively, with MIC and MBC values both ranging from 0.25 to 1 mg/L. Telavancin was found to be bactericidal in this study, as its MBC was no more than 2-fold higher than its MIC for all CA-MRSA isolates tested except one. (A single isolate yielded an MBC/MIC ratio of 4.) PVL- and non-PVL-producing strains demonstrated similar susceptibility to telavancin and comparator agents.. Based on in vitro activity, telavancin should be an effective agent against CA-MRSA.

Topics: Aminoglycosides; Anti-Bacterial Agents; Bacterial Typing Techniques; Cholesterol Side-Chain Cleavage Enzyme; Cloning, Molecular; Community-Acquired Infections; Humans; Leukocidins; Lipoglycopeptides; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) is characterized by variations (sometimes extreme) by country and geographic region. The conventional association of MRSA with healthcare settings has been upset by the emergence of community-associated MRSA infections in many areas. With this surge in MRSA comes a renewed interest in alternative agents to vancomycin for treatment of MRSA infections, including older drugs, such as clindamycin, doxycycline and trimethoprim- sulfamethoxazole. Newer agents, such as linezolid and daptomycin, are aiming to improve on the poor cure rates found with vancomycin in serious MRSA infections, but definitive studies showing superiority of these drugs are not yet available. Finally, the drug-development pipeline contains a number of agents for the treatment of MRSA infections, including enhanced glycopeptides (dalbavancin, oritavancin and telavancin) and anti-MRSA cephalosporins (ceftobiprole). As MRSA becomes the 'new normal' in many areas, clinicians will have to sort out the proper role of a dozen or more anti-MRSA drugs.

Topics: Acetamides; Aminoglycosides; Anti-Bacterial Agents; Cephalosporins; Clindamycin; Daptomycin; Doxycycline; Folic Acid Antagonists; Global Health; Glycopeptides; Humans; Linezolid; Lipoglycopeptides; Methicillin; Methicillin Resistance; Minocycline; Oxazolidinones; Prevalence; Staphylococcal Infections; Staphylococcus aureus; Sulfamethoxazole; Teicoplanin; Tigecycline; Trimethoprim; Vancomycin

In vitro antimicrobial activity of telavancin, a rapidly bactericidal lipoglycopeptide, was evaluated against 1500 strains of MRSA recently isolated in Japan. Telavancin had potent activity, with MIC values that ranged from 0.12 microg/ml to 0.5 microg/ml and a MIC90 value of 0.5 microg/ml. The MIC90s of vancomycin and linezolid were 1.0microg/ml and 2 microg/ml, respectively. No vancomycin intermediate resistant or vancomycin-resistant MRSAs were detected in this surveillance study.

Topics: Aminoglycosides; Anti-Bacterial Agents; Humans; Japan; Lipoglycopeptides; Methicillin Resistance; Microbial Sensitivity Tests; Models, Molecular; Staphylococcal Infections; Staphylococcus aureus

The penetration of telavancin was 2% into inflamed meninges and ca. 1 per thousand into noninflamed meninges after two intravenous injections (30 mg/kg of body weight). In experimental meningitis, telavancin was significantly superior to vancomycin combined with ceftriaxone against a penicillin-resistant pneumococcal strain. Against a methicillin-sensitive staphylococcal strain, telavancin was slightly but not significantly superior to vancomycin.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Disease Models, Animal; Lipoglycopeptides; Meningitis, Bacterial; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Penicillin Resistance; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Streptococcus pneumoniae

The efficacy of telavancin, a bactericidal lipoglycopeptide, was compared with vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) in an immunocompromised murine model of bacteraemia.. Immunocompromised mice were inoculated intraperitoneally with S. aureus ATCC 33591 and treated with two subcutaneous doses (once every 12 h) of vehicle or test compound. Mouse pharmacokinetic data were generated and used to choose doses of telavancin (40 mg/kg) and vancomycin (110 mg/kg) in order to equate clinical exposures. Reduction in bacterial titre (in blood and spleen) and mortality were the two pharmacodynamic endpoints of the study.. Mortality was 100% in animals treated with vehicle or vancomycin but was significantly lower (7%) in telavancin-treated animals. Telavancin produced significantly greater reductions in blood and spleen bacterial titres compared with vancomycin.. The data described here demonstrate that telavancin's in vivo bactericidal activity is superior to that of vancomycin against a single strain of MRSA and results in successful infection resolution and, consequently, improved survival in the murine bacteraemia model.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Bacteremia; Blood; Disease Models, Animal; Lipoglycopeptides; Methicillin Resistance; Mice; Spleen; Staphylococcal Infections; Staphylococcus aureus; Survival Analysis; Vancomycin

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Cephalosporins; Clinical Trials as Topic; Drug Design; Humans; Incidence; Lipoglycopeptides; Methicillin Resistance; Minocycline; Molecular Structure; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Thiazoles; Tigecycline

The activities of telavancin and vancomycin were compared in vitro and in the rabbit model of aortic valve endocarditis against a methicillin-resistant Staphylococcus aureus strain, COL, and a vancomycin-intermediate S. aureus (VISA) strain, HIP 5836. Telavancin was bactericidal in time-kill studies at a concentration of 5 microg/ml against both COL and HIP5836. Vancomycin was bacteriostatic at 5 microg/ml and bactericidal at 10 microg/ml against COL and was bacteriostatic at 10 microg/ml against VISA strain HIP 5836. Compared to untreated controls, a twice-daily regimen of 30 mg/kg of telavancin reduced mean aortic valve vegetation titers of the COL strain by 4.7 log(10) CFU/g after 4 days of therapy and sterilized 6/11 vegetations compared to 3.4 log(10) CFU/g with 3/10 vegetations sterilized for a regimen of twice-daily vancomycin, 30 mg/kg; these differences were not statistically significant. Telavancin was significantly more effective than vancomycin in the VISA model, producing a 5.5 log(10) CFU/g reduction versus no reduction in CFU with vancomycin. In experiments comparing 2-day regimens of telavancin at 30 mg/kg and 50 mg/kg twice daily, organisms were rapidly eliminated from vegetations, but the effect was not different between the two doses. These results suggest that telavancin may be an effective treatment for endocarditis and other serious staphylococcal infections accompanied by bacteremia, including infections caused by staphylococci not susceptible to vancomycin.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Aortic Valve; Disease Models, Animal; Drug Resistance, Bacterial; Endocarditis, Bacterial; Heart Valve Diseases; Humans; Lipoglycopeptides; Methicillin Resistance; Microbial Sensitivity Tests; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Vancomycin

The efficacy of telavancin, a bactericidal lipoglycopeptide, was compared to that of vancomycin and linezolid against methicillin-resistant Staphylococcus aureus (MRSA) in a murine pneumonia model. Telavancin produced greater reductions in lung bacterial titer and mortality than did vancomycin and linezolid at human doses equivalent to those described by the area under the concentration-time curve. These results suggest the potential utility of telavancin for treatment of MRSA pneumonia.

Topics: Aminoglycosides; Animals; Anti-Infective Agents; Drug Resistance, Bacterial; Female; Glycopeptides; Lipoglycopeptides; Methicillin Resistance; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Neutropenia; Pneumonia, Staphylococcal; Staphylococcal Infections; Staphylococcus aureus

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