Dalbavancin Alone and in Combination with Ceftaroline against Four Different Phenotypes of Staphylococcus aureus in a Simulated Pharmacodynamic/Pharmacokinetic Model

Abstract

Glycopeptides such as vancomycin have been used as the first-line therapy against MRSA infections for over half a century. Reduced susceptibility and emergence of resistance to first-generation glycopeptides has led to development of second-generation lipoglycopeptide derivatives such as dalbavancin which hold broader ranges of activity and enhanced pharmacokinetic properties. We evaluated the MIC values for a total of 100 isolates, including 25 methicillin-resistant Staphylococcus aureus (MRSA), 25 heterogeneus vancomycin-intermediate S. aureus, 25 daptomycin nonsusceptible (DNS), and 25 vancomycin-intermediate S. aureus strains against dalbavancin, ceftaroline, and vancomycin alone and in combination. Dalbavancin was highly active against hVISA, DNS, and MRSA strains, achieving 96 to 100% susceptibility and 72% susceptibility against VISA strains. The combination of dalbavancin plus ceftaroline reduced dalbavancin MICs 62.5-fold and demonstrated enhanced killing against all four phenotypes in pharmacokinetic/pharmacodynamic models. Four strains of the aforementioned phenotypes were randomly chosen for pharmacodynamic/pharmacokinetic simulation models. Of interest, while both dalbavancin and vancomycin in combination with ceftaroline demonstrated significant improvement in glycopeptide fAUC/MIC values against these four phenotypes, the dalbavancin-ceftaroline combinations exhibited a 44- to 11,270-fold higher fAUC/MIC value in comparison to vancomycin-ceftaroline combinations. In addition, the time to detection limit was reduced for this combination (24 to 32 h) versus the vancomycin-ceftaroline combination (24 to 72h). To our knowledge, this is the first comprehensive study of dalbavancin and vancomycin combinations with ceftaroline. These data provide a novel approach for combating recalcitrant MRSA infections.

Bacteriophage Therapeutics: A Primer for Clinicians on Phage‐Antibiotic Combinations

“…The inverse was also shown, in which antibiotics induced a phenotypic change in bacteria that caused increased predation by phages . Interestingly, a similar hypothesis, known as the seesaw effect, was also shown between β‐lactams and glycopeptides/lipopeptides with S. aureus …”

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

“…We have generated new insights into the mechanisms of dalbavancin resistance, cross-resistance, and the seesaw effect; however, the demonstrated efficacy of dalbavancin in our models should be interpreted cautiously. Another in vitro study with a similar design demonstrated sustained bactericidal activity of dalbavancin against MRSA strains for !7 days, but that study appears to have used concentrations far exceeding reasonable free-drug exposures expected in a patient, and their model was continued for only 7 days [42]. Resistance to dalbavancin in our models only emerged from days 11e18.…”

Dalbavancin, Vancomycin and Daptomycin Alone and in Combination with Cefazolin against Resistant Phenotypes of Staphylococcus aureus in a Pharmacokinetic/Pharmacodynamic Model

“…(EasySpiral Pro, Intersciences, Worborn, MA, USA). In an effort to eliminate the DAL carryover in the DAL-containing samples (DAL alone and DAL + CFZ), the centrifugation method was utilized twice as reported previously [ 32 ]. Briefly, the samples were centrifuged, following the centrifugation 0.9 mL of the supernatant was removed, and 0.9 ml of normal saline was added in its place.…”

“…The DAP PK evaluations were confirmed by a validated high-performance liquid chromatography assay that conformed to the guidelines set forth by the College of American Pathologists [ 38 ]. The VAN samples were analyzed using our HPLC methods, as previously described [ 32 ]. The HPLC assays demonstrated a coefficient of variation less than 10% for all standards, performed in duplicate.…”