Emergence of a dalbavancin induced glycopeptide/lipoglycopeptide non-susceptible Staphylococcus aureus during treatment of a cardiac device-related endocarditis

Abstract

In the present study, we demonstrated the emergence of dalbavancin non-susceptible and teicoplanin-resistant Staphylococcus aureus small colony variants which were selected in vivo through long-term treatment with dalbavancin. A 36-year-old man presented with a cardiac device-related S. aureus endocarditis and received long-term therapy with dalbavancin. Consecutively, two glycopeptide/lipoglycopeptide susceptible and two non-susceptible S. aureus isolates were obtained from blood cultures and the explanted pacemaker wire. The isolates were characterized by: standard typing methods, antimicrobial susceptibility testing, auxotrophic profiling, proliferation assays, scanning and transmission electron microscopy, as well as whole genome sequencing. The isolated SCVs demonstrated a vancomycin-susceptible but dalbavancin non-susceptible and teicoplanin-resistant phenotype whereof the respective MICs of the last isolate were 16- and 84-fold higher than the susceptible strains. All four strains were indistinguishable or at least closely related by standard typing methods (spa, MLST, and PFGE), and whole genome sequencing revealed only eight sequence variants. A consecutive increase in cell wall thickness (up to 2.1-fold), an impaired cell separation with incomplete or multiple cross walls and significantly reduced growth rates were observed in the present study. Therefore, the mutations in pbp2 and the DHH domain of GdpP were identified as the most probable candidates due to their implication in the biosynthesis and metabolism of the staphylococcal cell wall. For the first time, we demonstrated in vivo induced dalbavancin non-susceptible/teicoplanin resistant, but vancomycin and daptomycin susceptible S. aureus SCVs without lipopeptide or glycopeptide pretreatment, thus, indicating the emergence of a novel lipoglycopeptide resistance mechanism.

Advantages of Outpatient Treatment with Long‐Acting Lipoglycopeptides for Serious Gram‐Positive Infections: A Review

“…This issue was simulated and confirmed in vitro, although the development of resistance was not clinically important in an experiment involving nasal colonizers in patients treated with oritavancin for unrelated infections 63,64 . On the other hand, at least two cases of significant treatment‐emergent resistance have been reported in the literature for dalbavancin 65,66 …”

Successful treatment of methicillin-sensitive Staphylococcus aureus tricuspid-valve endocarditis with dalbavancin as an outpatient in a person who injects drugs: A case report

“…In both cases, an increase in vancomycin minimum-inhibitory concentrations were already observed before starting dalbavancin. In a third case without glycopeptide pretreatment, a patient with a cardiac-device related endocarditis, insufficient source control, and long-term dalbavancin therapy over thirty weeks developed dalbavancin nonsusceptibility (Kussmann et al, 2018).…”

In vivo emergence of resistance to cefiderocol in an XDR Pseudomonas aeruginosa and an MDR Citrobacter koseri after prolonged therapy: a case report.

“…Treatment emerging resistance is not limited to Gram-negative non-fermenters, but also concerns many enterobacteriaceae like K. pneumoniae (13). It also affects Gram-positive bacteria (14). All class of antibiotics are concerned including the newest antibiotics (ceftazidime-avibactam, ceftolozanetazobactam, ceftaroline, dalbavancin, etc.)…”