Efficacy of telavancin against glycopeptide-intermediate Staphylococcus aureus in the neutropenic mouse bacteraemia model.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

In vitro activity of telavancin against resistant gram-positive bacteria.

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

Efficacy of telavancin in a murine model of pneumonia induced by methicillin-susceptible Staphylococcus aureus.

OBJECTIVES: To assess the efficacy of telavancin, a rapidly bactericidal lipoglycopeptide, and three comparator agents in a murine model of pneumonia induced by methicillin-susceptible Staphylococcus aureus (MSSA). METHODS: Female Bagg inbred albino c-strain (BALB/c) mice were rendered neutropenic and infected by intranasal inoculation (50 microL) of 10(7) cfu of S. aureus ATCC 29213. Infected mice were then allocated to one of five treatment arms: subcutaneous (sc) telavancin 40 mg/kg every 12 h, sc nafcillin 40 mg/kg every 4 h, sc vancomycin 110 mg/kg every 12 h, intravenous linezolid 80 mg/kg every 12 h or no drug (control group). Test compounds were studied under low and high pre-treatment titre conditions by initiating drug treatment at 4 and 8 h post-inoculation, respectively. Drug doses were calculated to simulate human exposures (area under the curve or t > MIC) at therapeutic doses. Lungs were harvested and homogenized 24 and 48 h after inoculation to determine the bacterial titre. RESULTS: At 48 h post-inoculation in the low and high pre-treatment titre groups, respectively, telavancin produced greater reductions (from pre-treatment values) in bacterial burden (-4.3 and -3.2 log(10) cfu/g) than nafcillin (-1.3 and -1.8 log(10) cfu/g), vancomycin (-2.9 and -2.2 log(10) cfu/g) and linezolid (-0.4 and +0.3 log(10) cfu/g). CONCLUSIONS: These findings support the potential clinical utility of telavancin in the treatment of MSSA pneumonia.

DNA binding ligands with improved in vitro and in vivo potency against drug-resistant Staphylococcus aureus.

Potent in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA) has been difficult to achieve with previously reported DNA binding antibacterials. Herein, we describe an efficient access to a focused library of new analogues yielding compounds with improved activity in a mouse peritonitis model. The most potent molecules (14 and 19) exhibit efficacy against MRSA at ED50 values of approximately 1 and approximately 5 mg/kg, respectively, and display excellent in vitro activity against vancomycin-resistant S. aureus.

In vitro antimicrobial activity of GSQ1530, a new heteroaromatic polycyclic compound.

GSQ1530 is a compound derived from a newly identified class of antibiotics referred to as heteroaromatic polycyclic (HARP) antibiotics. The aim of this study was to assess the in vitro antimicrobial activity of GSQ1530. By using an NCCLS broth microdilution assay, the activities of GSQ1530 and other antibiotics were coevaluated against 215 clinical isolates. The MICs at which 90% of isolates are inhibited (MIC(90)s) of GSQ1530 for methicillin-susceptible Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) were 2 and 4 micro g/ml, respectively. The MIC(90)s of GSQ1530 for the streptococci tested were 2 micro g/ml or less, regardless of their susceptibilities to other antibiotics. The MIC(90) of GSQ1530 for the enterococci tested (including vancomycin-resistant enterococci) was 4 micro g/ml. No cross-resistance was found between GSQ1530 and other known antibiotics. In a separate assay, GSQ1530 demonstrated excellent activity against vancomycin-intermediate-susceptible staphylococci (MIC(90), 1 micro g/ml). The minimal bactericidal concentration test was conducted with 73 clinical isolates; GSQ1530 was cidal against streptococci and staphylococci but static against enterococci. An in vitro killing kinetic study revealed a time-dependent profile, with at least a 3-log reduction of bacterial growth within 6 h after exposure to four times the MICs of GSQ1530 for both S. aureus and Streptococcus pneumoniae. The checkerboard study showed that GSQ1530 had a synergistic interaction with rifampin against MRSA. The test medium was found to have little effect on in vitro antimicrobial potency. The MICs of GSQ1530 for gram-positive cocci were 4- to 32-fold higher in the presence of serum proteins. GSQ1530 has high levels of plasma protein binding (91 and 89% for rat and human plasma, respectively). These preliminary results demonstrate that GSQ1530, a representative compound of our novel HARP antibiotics, has broad-spectrum activity against gram-positive bacteria. This novel class of antibacterial compounds is profiled in vivo to assess the therapeutic potential in humans. Ongoing in vivo studies will assess whether this class of molecules has promising in vivo efficacy and safety profiles.

In vitro antibacterial activity of the peptide deformylase inhibitor BB-83698.

OBJECTIVES: BB-83698 is a peptide deformylase inhibitor currently in clinical trials in Europe. The purpose of this study was to provide additional susceptibility data from clinical isolates, including drug-resistant strains. METHODS: The in vitro activities of BB-83698 and comparators were determined against 281 streptococci, 154 Staphylococcus aureus, 110 Haemophilus influenzae and 50 Moraxella catarrhalis strains selected for their resistance phenotypes. Broth microdilution MICs and MBCs were determined according to NCCLS guidelines. RESULTS: The MIC90s were 0.25-0.5 mg/L for S. pneumoniae, including penicillin-, erythromycin-, levofloxacin- and multidrug-resistant strains. The MIC90s for Streptococcus pyogenes and Streptococcus agalactiae were 0.12 mg/L and for viridans streptococci, the MIC90 was 0.5 mg/L. Against S. aureus, including oxacillin- and levofloxacin-resistant strains, and vancomycin-intermediate strains, the MIC90 was 8 mg/L. Against beta-lactamase-negative and -positive H. influenzae, the MIC90s were 32 and 64 mg/L, respectively, and against both beta-lactamase-negative and -positive M. catarrhalis the MIC90 was 0.12 mg/L. In MBC studies, the ratio of MBC/MIC was 1:1 or 2:1 against 31% of S. pneumoniae, 33% of S. aureus, 63% of H. influenzae and 9% of M. catarrhalis. CONCLUSIONS: Although BB-83698 has reduced in vitro activity against H. influenzae, it is a potent antimicrobial with excellent activity against streptococci and Moraxella.

DNA binding ligands targeting drug-resistant Gram-positive bacteria. Part 2: C-terminal benzimidazoles and derivatives.

The synthesis and in vitro potency of DNA minor-groove binding antibacterials lacking the C-terminal amide bond are described. The crescent shaped molecules bear the positively charged amino group at an internal pyrrole unit instead of the C-terminus. Three structural parameters were investigated: the N-terminal unit, the internal amino group, and the C-terminal ring system. Several compounds demonstrated good in vitro potency against various Gram-positive bacteria and some molecules were moderately active against Escherichia coli, a representative Gram-negative strain.