Dalbavancin exposure in vitro selects for dalbavancin-non-susceptible and vancomycin-intermediate strains of methicillin-resistant Staphylococcus aureus

• Published in: Clinical microbiology and infection Vol. 27; no. 6; pp. 910.e1 - 910.e8
• Main Authors: Werth, Brian J., Ashford, Nathaniel K., Penewit, Kelsi, Waalkes, Adam, Holmes, Elizabeth A., Ross, Dylan H., Shen, Tianwei, Hines, Kelly M., Salipante, Stephen J., Xu, Libin
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2021
• Subjects: Cross-resistance; Daptomycin; Lipoglycopeptide; MRSA; PK/PD; Seesaw effect; VISA; walK; walR; β-lactam; Lipoglycopeptide; PK/PD; Cross-resistance; Daptomycin; MRSA; walR; VISA; Seesaw effect; β-lactam; walK
• ISSN: 1198-743X; 1469-0691
• DOI: 10.1016/j.cmi.2020.08.025

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 t1/2 204 h) in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model for 28 days (672 h) against five MRSA strains and one methicillin-susceptible strain (MSSA). Samples were collected at least daily, and surviving colonies were enumerated and screened for resistance on drug-free and dalbavancin-supplemented medium respectively. Isolates from resistance screening plates were subjected to whole-genome sequencing (WGS) and susceptibly testing against dalbavancin, vancomycin, daptomycin, and six β-lactams with varying penicillin-binding protein (PBP) affinities. 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.