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. 2011 Apr;55(4):1728-33.
doi: 10.1128/AAC.00862-10. Epub 2011 Jan 31.

In vivo efficacy of the novel aminoglycoside ACHN-490 in murine infection models

Noe Reyes  1 , James B Aggen, Corwin F Kostrub
Affiliations

In vivo efficacy of the novel aminoglycoside ACHN-490 in murine infection models

Noe Reyes et al. Antimicrob Agents Chemother. 2011 Apr.

Abstract

Aminoglycosides are broad-spectrum antibiotics with particular clinical utility against life-threatening infections. As resistance to antibiotics, including aminoglycosides, continues to grow, there is a need for new and effective antimicrobial agents. ACHN-490 is a novel aminoglycoside in clinical development with activity against multidrug-resistant Gram-negative and select Gram-positive pathogens. Here we assess the in vivo efficacy of ACHN-490 against a variety of common pathogens in two murine models: the septicemia and neutropenic thigh models. When its activity against a gentamicin-susceptible strain of Escherichia coli was tested in the septicemia model, ACHN-490 improved 7-day survival with a dose-response profile similar to that of gentamicin, with 100% survival seen at doses of 1.6 mg/kg of body weight and above. In animals infected with a gentamicin-susceptible strain of Pseudomonas aeruginosa, treatment with either ACHN-490 or gentamicin led to 100% survival at doses of 16 mg/kg and above in the septicemia model. ACHN-490 was also effective in the neutropenic thigh model, reducing multidrug-resistant Enterobacteriaceae family and methicillin-resistant Staphylococcus aureus strains, as well as broadly susceptible strains, to static levels with dose-dependent activity. Against gentamicin-sensitive Enterobacteriaceae and methicillin-resistant S. aureus, the efficacy of ACHN-490 was comparable to that of gentamicin. However, gentamicin-resistant Enterobacteriaceae strains and those harboring the Klebsiella pneumoniae carbapenemase responded to ACHN-490 but not gentamicin, with static doses ranging from 12 mg/kg to 64 mg/kg for ACHN-490. These results suggest that ACHN-490 has the potential to become a clinically useful agent against drug-resistant pathogens, including Enterobacteriaceae, P. aeruginosa, and methicillin-resistant S. aureus, and support further development of this promising novel aminoglycoside.

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Figures

FIG. 1.
FIG. 1.
Structure of ACHN-490.
FIG. 2.
FIG. 2.
Efficacy of ACHN-490 and comparator aminoglycosides in septicemia model.
FIG. 3.
FIG. 3.
Efficacy of ACHN-490 and comparator antibiotics against Enterobacteriaceae in neutropenic thigh model.
FIG. 4.
FIG. 4.
Efficacy of ACHN-490 and comparator antibiotics against S. aureus in neutropenic thigh model.
See this image and copyright information in PMC

References

    1. Aggen, J. B., et al. 2010. Synthesis and spectrum of the neoglycoside ACHN-490. Antimicrob. Agents Chemother. 54:4636-4642. - PMC - PubMed
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