title: In vivo pharmacodynamics of new lipopeptide MX-2401.
abstract: MX-2401 is a novel lipopeptide (amphomycin analog) with a broad-spectrum bactericidal activity against Gram-positive organisms. We used murine thigh and lung infection models in neutropenic and normal mice to characterize the in vivo pharmacokinetic/pharmacodynamic (PK/PD) activities of MX-2401. The compound (2.5 to 40 mg/kg of body weight) demonstrated linear PK characterized by an area under the concentration-time curve (AUC) of 228 to 3,265 μg·h/ml and half-lives of 5.7 to 8.8 h. MICs ranged from 0.25 to 2 μg/ml. The in vivo postantibiotic effect was prolonged (8.5 h with Staphylococcus aureus and 10.3 to 12.3 with Streptococcus pneumoniae). MX-2401 exhibited dose-dependent in vivo activity against various strains of S. pneumoniae and S. aureus; penicillin and macrolide resistance in the pneumococci and methicillin resistance in the staphylococci had no impact on the antimicrobial activity of the drug. To determine which PK/PD index correlated best with MX-2401 activity, dose fractionation studies over a 72-hour period were performed. The maximum concentration of drug in serum divided by the MIC (C(max)/MIC) correlated best with the efficacy for both S. aureus and S. pneumoniae. Static doses required free-drug C(max)/MIC values of 0.683 to 1.06. Free-drug 72-h AUC/MIC values for the static dose were in the range of 7.49 to 32.3 and were less than expected. The drug showed modest enhancement in activity in the presence of white blood cells (1.7- to 3.4-fold). The potency of the drug in the lung was only marginally lower than in the thigh (1.3- to 1.9-fold). Based on its PK/PD profile, MX-2401 appears to be a promising new lipopeptide agent for treatment of infections by Gram-positive bacteria, including those induced by antibiotic-resistant pathogens.
authors.affiliation: Division of Infectious Disease, University of Wisconsin School of Medicine and Public Health, MFCB, 5th Floor, 1685 Highland Avenue, Madison, WI 53705-2281, USA. wac@medicine.wisc.edu
authors.forename: W A
authors.initials: WA
authors.lastname: Craig
authors.forename: D R
authors.initials: DR
authors.lastname: Andes
authors.forename: T
authors.initials: T
authors.lastname: Stamstad
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D055666:Lipopeptides / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D011008:Pneumococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D055666:Lipopeptides; C556453:MX-2401