Rapid resistance development to three antistaphylococcal therapies in antibiotic-tolerant staphylococcus aureus bacteremia

Abstract

Understating how antibiotic tolerance impacts subsequent resistance development in the clinical setting is important to identifying effective therapeutic interventions and prevention measures. This study describes a patient case of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia which rapidly developed resistance to three primary MRSA therapies and identifies genetic and metabolic changes selected in vivo that are associated with rapid resistance evolution. Index blood cultures displayed susceptibility to all (non-beta-lactam) antibiotics with the exception of trimethoprim/ sulfamethoxazole. One month after initial presentation, during the same encounter, blood cultures were again positive for MRSA, now displaying intermediate resistance to vancomycin and ceftaroline and resistance to daptomycin. Two weeks later, blood cultures were positive for a third time, still intermediate resistant to vancomycin and ceftaroline and resistant to daptomycin. Mutations in mprF and vraT were common to all multidrug resistant isolates whereas mutations in tagH, agrB and saeR and secondary mprF mutation emerged sequentially and transiently resulting in distinct in vitro phenotypes. The baseline mutation rate of the patient isolates was unremarkable ruling out the hypermutator phenotype as a contributor to the rapid emergence of resistance. However, the index isolate demonstrated pronounced tolerance to the antibiotic daptomycin, a phenotype that facilitates the subsequent development of resistance during antibiotic exposure. This study exemplifies the capacity of antibiotic-tolerant pathogens to rapidly develop both stable and transient genetic and phenotypic changes, over the course of a single patient encounter.

The Complex Intracellular Lifecycle of Staphylococcus aureus Contributes to Reduced Antibiotic Efficacy and Persistent Bacteremia

“…Natural products also are being explored against SCVs including tomatidine and its derivatives noted to block F0F1ATPase [46]. These molecules also synergize with aminoglycosides and prevent SCV formation [47] Antimicrobial Resistance, Tolerance, and Persistence in S. aureus Contribute to Persistent Bacteremia While major attention is rightfully given toward antimicrobial resistance in S. aureus, the occurrence of antimicrobial tolerance and persistence also represents significant issues for antimicrobial therapy [48][49][50][51]. The observations of antimicrobial tolerance and persistence in S. aureus represent a growing area of interest and investigation [52,53].…”

“…These tolerant populations may enter a dormancy state or reduce cellular processes to survive antimicrobial pressure through reduction in active targets (e.g., reduced cell wall replication) [52]. Antimicrobial tolerance may be acquired through either genetic mutation triggered from environmental conditions (e.g., reduced oxygen or nutrients) or antibiotics [50,52,54]. In contrast to tolerance, persistence is a subset of the bacterial population that can survive high concentrations of antimicrobial exposure.…”

Antimicrobial Activity of Graphene Oxide Contributes to Alteration of Key Stress-Related and Membrane Bound Proteins

“…The depletion in this protein was previously found to thicken the cell wall due to autolysin sequestration. 64 In addition to this TarL protein, which is believed to be involved in synthesis of the ribitol phosphate polymer of cell wall teichoic acid by using the activated precursor, CDP-ribitol, 65 was found to be drastically downregulated upon GO treatment. TarL was downregulated by 2.1-fold, 3.5-fold and 3.6-fold in S. aureus after 4 h, 8 h and 24 h of GO treatment respectively.…”

Growth Arrest of Staphylococcus aureus Induces Daptomycin Tolerance via Cell Wall Remodelling

“…While there is currently no evidence to indicate that bactericidal antibiotics lead to better outcomes for patients than do bacteriostatic drugs ( 59 – 62 ), there is growing evidence that antibiotic tolerance is an underappreciated cause of treatment failure ( 13 , 15 , 63 – 65 ), and tolerance has also been shown to be a stepping stone to resistance ( 16 , 17 ). A recent clinical example of this comes from a patient with relapsing MRSA bacteremia that was initially caused by a daptomycin-tolerant strain but gave rise to isolates that were daptomycin nonsusceptible during subsequent periods of relapse ( 66 ).…”