Efficacy of the new lantibiotic NAI-107 in experimental infections induced by multidrug-resistant Gram-positive pathogens - PubMed (original) (raw)

Efficacy of the new lantibiotic NAI-107 in experimental infections induced by multidrug-resistant Gram-positive pathogens

Daniela Jabés et al. Antimicrob Agents Chemother. 2011 Apr.

Abstract

NAI-107 is a novel lantibiotic active against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide-intermediate S. aureus (GISA), and vancomycin-resistant enterococci (VRE). The aim of this study was to evaluate the in vivo efficacy of NAI-107 in animal models of severe infection. In acute lethal infections induced with a penicillin-intermediate Streptococcus pneumoniae strain in immunocompetent mice, or with MRSA, GISA, and VRE strains in neutropenic mice, the 50% effective dose (ED(50)) values of NAI-107 were comparable or lower than those of reference compounds, irrespective of the strain and immune status (0.51 to 14.2 mg/kg of body weight for intravenous [i.v.] NAI-107, 5.1 to 22.4 for oral linezolid, and 22.4 for subcutaneous [s.c.] vancomycin). In the granuloma pouch model induced in rats with a MRSA strain, intravenous NAI-107 showed a dose-proportional bactericidal activity that, at a single 40-mg/kg dose, compared with 2 20-mg/kg doses at a 12-h or 24-h interval, caused a 3-log(10)-CFU/ml reduction of viable MRSA in exudates that persisted for more than 72 h. Rat endocarditis was induced with a MRSA strain and treated for five consecutive days. In a first experiment, using 5, 10, or 20 mg/kg/day, and in a second experiment, when 10 mg/kg at 12-h intervals was compared to 20 mg/kg/day, intravenous NAI-107 was effective in reducing the bacterial load in heart vegetations in a dose-proportional manner. Trough plasma levels, as determined on days 2 and 5, were several times higher than the NAI-107 minimal bactericidal concentration (MBC). NAI-107 binding to rat and human serum ranges between 93% and 98.6%. The rapid bactericidal activity of NAI-107 observed in vitro was thus confirmed by the efficacy in several models of experimental infection induced by Gram-positive pathogens, supporting further investigation of the compound.

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Figures

FIG. 1.

FIG. 1.

In vivo bactericidal activity of NAI-107 in the rat granuloma pouch model induced by S. aureus 1400. (A) Effects of single 10-mg/kg (circles), 20-mg/kg (triangles), and 40-mg/kg (diamonds) i.v. doses on bacterial counts (log10 CFU/ml) in pouch exudates over time. (B) Effects of 2 20-mg/kg doses i.v. every 24 h (q24) (filled triangles) and 2 20-mg/kg doses i.v. q12 (empty triangle) in comparison with two 100-mg/kg doses i.m. q12 (circles) of vancomycin on bacterial counts (log10 CFU/ml) in pouch exudates over time. Untreated controls are represented by filled squares. The error bars indicate standard deviation.

FIG. 2.

FIG. 2.

Efficacies of NAI-107 and vancomycin in reducing the bacterial load in heart vegetations in a model of rat endocarditis caused by S. aureus 1524. “Start” and “end” indicate bacterial loads at the start (17 h after infection) and end (5 days) of therapy, respectively. Each symbol represents the viable bacterial counts determined in each animal, while the horizontal lines represent the average value for each group. (A) NAI-107 at 5, 10, and 20 mg/kg i.v. q12 compared to 100 mg/kg i.m. q12 of vancomycin. Three animals treated with 5 mg/kg i.v. and two treated with 20 mg/kg i.v. of NAI-107 and two animals treated with 100 mg/kg i.m. of vancomycin were excluded from the statistical analysis due to incorrect placement of the catheter. *, P < 0.05 compared to start of therapy; **, _P_ < 0.001 compared to start of therapy and NAI-107 at 5 mg/kg and _P_ < 0.01 compared to vancomycin; ***, _P_ < 0.001 compared to start of therapy, NAI-107 at 5 mg/kg, and vancomycin. (B) NAI-107 at 10 mg/kg q12 versus 20 mg/kg i.v. q24 compared to 100 mg/kg i.m. q12 of vancomycin. One animal treated with 10 mg/kg i.v. of NAI-107 was excluded from the statistical evaluation due to incorrect placement of the catether. *, _P_ < 0.01 and _P_ > 0.001 compared to control groups and vancomycin, respectively; **, P < 0.001 compared to start and end of therapy.

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