title: In vivo efficacy of the novel aminoglycoside ACHN-490 in murine infection models.
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.
authors.affiliation: Achaogen, Inc., 7000 Shoreline Court, Suite 371, South San Francisco, California 94080, USA.
authors.forename: Noe
authors.initials: N
authors.lastname: Reyes
authors.forename: James B
authors.initials: JB
authors.lastname: Aggen
authors.forename: Corwin F
authors.initials: CF
authors.lastname: Kostrub
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D004926:Escherichia coli / Q000187:drug effects / Q000472:pathogenicity; D007710:Klebsiella Infections / Q000188:drug therapy; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000472:pathogenicity; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000472:pathogenicity; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D013848:Thigh / Q000473:pathology
chemical_list: D000617:Aminoglycosides