Dalbavancin exposure in vitro selects for dalbavancin-non-susceptible and vancomycin-intermediate strains of methicillin-resistant Staphylococcus aureus.
Cross-resistance
Daptomycin
Lipoglycopeptide
MRSA
PK/PD
Seesaw effect
VISA
walK
walR
β-lactam
Journal
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
ISSN: 1469-0691
Titre abrégé: Clin Microbiol Infect
Pays: England
ID NLM: 9516420
Informations de publication
Date de publication:
Jun 2021
Jun 2021
Historique:
received:
08
05
2020
revised:
13
08
2020
accepted:
21
08
2020
pubmed:
1
9
2020
medline:
26
8
2021
entrez:
1
9
2020
Statut:
ppublish
Résumé
Dalbavancin is a lipoglycopeptide active against methicillin-resistant Staphylococcus aureus (MRSA). Its long half-life (8.5-16 days) allows for once-weekly or single-dose treatments but could prolong the mutant selection window, promoting resistance and cross-resistance to related antimicrobials such as vancomycin. The objective of this study was to evaluate the capacity of post-distributional pharmacokinetic exposures of dalbavancin to select for resistance and cross-resistance in MRSA. We simulated average, post-distributional exposures of single-dose (1500 mg) dalbavancin (fCmax 9.9 μg/mL, β-elimination t Dalbavancin was bactericidal against most strains for days 1-4 before regrowth of less susceptible subpopulations occurred. Isolates with eight-fold increases in dalbavancin MIC were detected as early as day 4 but increased 64-128-fold in all models by day 28. Vancomycin and daptomycin MICs increased 4-16-fold, exceeding the susceptibly breakpoints for both antibiotics; β-lactam MICs generally decreased by two-to eight-fold, suggesting a dalbavancin-β-lactam seesaw effect, but increased by eight-fold or more in certain isolates. Resistant isolates carried mutations in a variety of genes, most commonly walKR, apt, stp1, and atl. In our in vitro system, post-distributional dalbavancin exposures selected for stable mutants with reduced susceptibility to dalbavancin, vancomycin, and daptomycin, and generally increased susceptibility to β-lactams in all strains of MRSA tested. The clinical significance of these findings remains unclear, but created an opportunity to genotype a unique collection of dalbavancin-resistant strains for the first time. Mutations involved genes previously associated with vancomycin intermediate susceptibility and daptomycin non-susceptibility, most commonly walKR-associated genes.
Identifiants
pubmed: 32866650
pii: S1198-743X(20)30508-5
doi: 10.1016/j.cmi.2020.08.025
pmc: PMC7914275
mid: NIHMS1634068
pii:
doi:
Substances chimiques
Anti-Bacterial Agents
0
Teicoplanin
61036-62-2
Vancomycin
6Q205EH1VU
dalbavancin
808UI9MS5K
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
910.e1-910.e8Subventions
Organisme : NIAID NIH HHS
ID : R01 AI136979
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI132994
Pays : United States
Informations de copyright
Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
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