Comparative Surveillance Study of Telavancin Activity against Recently Collected Gram-Positive Clinical Isolates from across the United States

The reference broth microdilution (BMD) antimicrobial susceptibility testing method for telavancin was revised to include dimethyl sulfoxide (DMSO) as a solvent and diluent for frozen-form panel preparation, following the CLSI recommendations for water-insoluble agents. Polysorbate 80 (P-80) was also added to the test medium to minimize proven drug losses associated with binding to plastic surfaces. Four hundred sixty-two Gram-positive isolates, including a challenge set of organisms with reduced susceptibilities to comparator agents, were selected and tested using the revised method for telavancin, and the MIC results were compared with those tested by the previously established method and several Sensititre dry-form BMD panel formulations. The revised method provided MIC results 2-to 8-fold lower than the previous method when tested against staphylococci and enterococci, resulting in MIC 50 values of 0.03 to 0.06 g/ml for staphylococci and 0.03 and 0.12 g/ml for Enterococcus faecium and Enterococcus faecalis, respectively. Less-significant MIC decreases (1 to 2 log 2 dilution steps) were observed when testing streptococci in broth supplemented with blood, which showed similar MIC 50 values for both methods. However, Streptococcus pneumoniae had MIC 50 results of 0.008 and 0.03 g/ml when tested by the revised and previous methods, respectively. Highest essential agreement rates (>94.0%) were noted for one candidate dry-form panel formulation compared to the revised test. The revised BMD method provides lower MIC results for telavancin, especially when tested against staphylococci and enterococci. This is secondary to the use of DMSO for panel production and the presence of P-80, which ensure the proper telavancin testing concentration and result in a more accurate MIC determination. Moreover, earlier studies where the previous method was applied underestimated the in vitro drug potency.T elavancin is a lipoglycopeptide antibiotic with potent in vitro bactericidal activity when tested against Gram-positive bacteria, including methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-intermediate S. aureus (VISA), heterogeneous VISA (hVISA), and multidrug-resistant (MDR) streptococci and enterococci (1, 2). Telavancin is approved in the United States and Canada for the treatment of patients with complicated skin and skin structure infections due to susceptible Gram-positive pathogens and in the United States and Europe for the treatment of hospital-acquired bacterial pneumonia, including ventilator-associated bacterial pneumonia (HABP/VABP) due to susceptible isolates of S. aureus (MRSA strains only in Europe), when alternative medicines are unsuitable (3).During the development of dalbavancin, also a lipoglycopeptide, the use of polysorbate 80 (P-80) (0.002%, final testing concentration) was shown to be essential for accurate MIC susceptibility testing determinations (4). Subsequent investigations for oritavancin (another lipoglycopeptide) demonstrated that the addi...

Section: Resultscontrasting

confidence: 41%

Revised Reference Broth Microdilution Method for Testing Telavancin: Effect on MIC Results and Correlation with Other Testing Methodologies

Farrell

Mendes

Rhomberg

et al. 2014

“…In contrast, telavancin, an investigational lipoglycopeptide with a dual mechanism of action, is potent, with MICs of Յ1 g/ml against all MRSA phenotypes (including hVISA and VISA) with the exception of some VRSA strains (12,13,19,23). Telavancin was recently approved in the United States and Canada for treatment of complicated skin and skin structure infections due to Gram-positive pathogens (26)(27)(28), including MRSA, and is under investigation as a oncedaily treatment for hospital-acquired pneumonia caused by Gram-positive bacteria (25).…”

mentioning

confidence: 99%

Antistaphylococcal Activities of Telavancin Tested Alone and in Combination by Time-Kill Assay

Lin

Pankuch

Ednie

et al. 2010

Synergy time-kill studies against 40 methicillin-resistant Staphylococcus aureus (MRSA) strains of differing resistance phenotypes were conducted. Subinhibitory concentrations of telavancin were combined with sub-MIC concentrations of other antimicrobial agents that might be used in combination with telavancin to provide Gram-negative coverage. The highest incidence of synergy was found after 24 h with gentamicin (90% of strains), followed by ceftriaxone (88%), rifampin and meropenem (each 65%), cefepime (45%), and ciprofloxacin (38%) for combinations tested at or below the intermediate breakpoint for each agent.

“…Telavancin exhibits more potent in vitro and in vivo activity than vancomycin against methicillin-susceptible S. aureus (MSSA), MRSA, VISA, and VRSA (10,14,23,26,30).…”

mentioning

confidence: 99%

Further Insights into the Mode of Action of the Lipoglycopeptide Telavancin through Global Gene Expression Studies

Song

Lunde

Benton

et al. 2012

Self Cite

bTelavancin is a novel semisynthetic lipoglycopeptide derivative of vancomycin with a decylaminoethyl side chain that is active against Gram-positive bacteria, including Staphylococcus aureus strains resistant to methicillin or vancomycin. A dual mechanism of action has been proposed for telavancin involving inhibition of peptidoglycan biosynthesis and membrane depolarization. Here we report the results of genome-wide transcriptional profiling of the response of S. aureus to telavancin using microarrays. Short (15-min) challenge of S. aureus with telavancin revealed strong expression of the cell wall stress stimulon, a characteristic response to inhibition of cell wall biosynthesis. In the transcriptome obtained after 60-min telavancin challenge, in addition to induction of the cell wall stress stimulon, there was induction of various genes, including lrgA and lrgB, lysine biosynthesis operon (dap) genes, vraD and vraE, and hlgC, that have been reported to be induced by known membrane-depolarizing and active agents, including carbonyl cyanide m-chlorophenylhydrazone, daptomycin, bacitracin, and other antimicrobial peptides These genes were either not induced or only weakly induced by the parent molecule vancomycin. We suggest that expression of these genes is a response of the cell to mitigate and detoxify such molecules and is diagnostic of a membrane-depolarizing or membrane-active molecule. The results indicate that telavancin causes early and significant induction of the cell wall stress stimulon due to strong inhibition of peptidoglycan biosynthesis, with evidence in support of membrane depolarization and membrane activity that is expressed after a longer duration of drug treatment.