telavancin and Endocarditis--Bacterial

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

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

We compared the efficacy of telavancin (TLV) and daptomycin (DAP) in an experimental rabbit endocarditis model caused by two clinically derived daptomycin-resistant (DAP

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Daptomycin; Endocarditis, Bacterial; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Rabbits

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

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

Daptomycin-nonsusceptible (DNS) Staphylococcus aureus strains have been reported over the last several years. Telavancin is a lipoglycopeptide with a dual mechanism of action, as it inhibits peptidoglycan polymerization/cross-linking and disrupts the membrane potential. Three clinical DNS S. aureus strains, CB1814, R6212, and SA-684, were evaluated in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model with simulated endocardial vegetations (starting inoculum, 10(8.5) CFU/g) for 120 h. Simulated regimens included telavancin at 10 mg/kg every 24 h (q24h; peak, 87.5 mg/liter; t(1/2), 7.5 h), daptomycin at 6 mg/kg q24h (peak, 95.7 mg/liter; t(1/2), 8 h), and vancomycin at 1 g q12h (peak, 30 mg/liter; t(1/2), 6 h). Differences in CFU/g between regimens at 24 through 120 h were evaluated by analysis of variance with a Tukey's post hoc test. Bactericidal activity was defined as a ≥3-log(10) CFU/g decrease in colony count from the initial inoculum. MIC values were 1, 0.25, and 0.5 mg/liter (telavancin), 4, 2, and 2 mg/liter (daptomycin), and 2, 2, and 2 mg/liter (vancomycin) for CB1814, R6212, and SA-684, respectively. Telavancin displayed bactericidal activities against R6212 (32 to 120 h; -4.31 log(10) CFU/g), SA-684 (56 to 120 h; -3.06 log(10) CFU/g), and CB1814 (48 to 120 h; -4.9 log(10) CFU/g). Daptomycin displayed initial bactericidal activity followed by regrowth with all three strains. Vancomycin did not exhibit sustained bactericidal activity against any strain. At 120 h, telavancin was significantly better at reducing colony counts than vancomycin against all three tested strains and better than daptomycin against CB1814 (P < 0.05). Telavancin displayed bactericidal activity in vitro against DNS S. aureus isolates.

Topics: Aminoglycosides; Anti-Bacterial Agents; Colony Count, Microbial; Daptomycin; Drug Resistance, Bacterial; Endocarditis, Bacterial; Humans; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Models, Biological; Staphylococcus aureus; 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

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

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

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