title: Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy.
abstract: The objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (fT>MIC). To closer emulate the conditions of the in vivo model, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake: piuA, piuC, pirR, fecI, and pvdS. Against four P. aeruginosa isolates, SMC-3176 displayed predictable efficacy corresponding to the fT>MIC using the MIC in CDMHB (R(2) = 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for P. aeruginosa isolate JJ 4-36, as the in vivo responses were inconsistent with fT>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which in vivo failures of another siderophore-conjugated β-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in P. aeruginosa due to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial in vivo testing is warranted for compounds using the siderophore approach to thoroughly screen for this in vitro-in vivo disconnect in P. aeruginosa.
authors.affiliation: Infection Innovative Medicines, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA aryunkimpharmd@gmail.com.
authors.forename: Aryun
authors.initials: A
authors.lastname: Kim
authors.affiliation: Infection Innovative Medicines, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Kutschke
authors.affiliation: Infection Innovative Medicines, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Ehmann
authors.affiliation: Infection Innovative Medicines, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Patey
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: Jared L
authors.initials: JL
authors.lastname: Crandon
authors.affiliation: Infection Innovative Medicines, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Elise
authors.initials: E
authors.lastname: Gorseth
authors.affiliation: Infection Innovative Medicines, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Alita A
authors.initials: AA
authors.lastname: Miller
authors.affiliation: Infection Innovative Medicines, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: McLaughlin
authors.affiliation: Infection Innovative Medicines, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Blinn
authors.affiliation: Infection Innovative Medicines, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: April
authors.initials: A
authors.lastname: Chen
authors.affiliation: Infection Innovative Medicines, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Asha S
authors.initials: AS
authors.lastname: Nayar
authors.affiliation: Infection Innovative Medicines, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Dangel
authors.affiliation: Infection Innovative Medicines, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Andy S
authors.initials: AS
authors.lastname: Tsai
authors.affiliation: Infection Innovative Medicines, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rooney
authors.affiliation: Infection Innovative Medicines, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Kerry E
authors.initials: KE
authors.lastname: Murphy-Benenato
authors.affiliation: Infection Innovative Medicines, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Eakin
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001384:Azetidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D005260:Female; D007501:Iron / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000378:metabolism; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000378:metabolism*; D017262:Siderophores / Q000493:pharmacokinetics / Q000494:pharmacology*; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001384:Azetidines; D009842:Oligopeptides; C000610589:SMC-3176; D017262:Siderophores; D013449:Sulfonamides; C042453:pyoverdin; D007501:Iron; D001618:beta-Lactamases