Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of Dalbavancin Alone and in Combination with Ceftaroline against Methicillin-Resistant Strains (MRSA) of Staphylococcus aureus

Abstract

BackgroundGlycopeptide antibiotics, principally, vancomycin, have been the first armamentarium against MRSA. However, Staphylococcus aureus strains have now developed reduced susceptibility to common glycopeptides. (DAL) is a novel, 2 ndgeneration lipoglycopeptide antibiotic with reported activity against Gram-positive bacterial pathogens, including MRSA. The long lipophilic lateral chain in DAL’s structure extends its half-life and promotes its anchoring to the cell membrane (vancomycin lacks this side chain). While a considerable amount of data is available on susceptibility testing for this agent, information regarding the potential for synergy with β-lactams with newer lipoglycopeptides, including dalbavancin, is lacking. Our objective was to evaluate the impact of DAL or vancomycin (VAN) in combination with ceftaroline (CPT) against MRSA.MethodsMRSA 494 was studied in six different regimens independently. All the experiments were performed in one-compartment PK/PD models in duplicate during 7 days. DAL 1,500 mg day one fCmax = 30.1 µg/mL, VAN 2 g q12hr fCmax = 36 µg/mL, CPT 600 mg every 12 hours fCmax = 17.04 µg/mL, DAL 1,500 mg day 1 plus CPT 600 mg q12hr, VAN 2 g q12hr plus Ceftaroline 600 mg q12hr and Growth Control. Antibiotic carry over was accounted for by washing and centrifugation of the samples. Model samples were plated and counted using an automated colony counter and differences in log 10CFU/mL between regimens was evaluated.ResultsCombination of DAL + CPT offered a significant reduction in log10CFU/mL amounts (more than 5 log10 CFU/mL and up to detection limits) in 24 hours compared with CPT alone. CPT alone demonstrated bactericidal activity with a reduction >3 log10CFU/mL by 32 hours although regrowth without resistance was observed after 72 hours. Mean CFU/mL for DAL models reached detection limits in 72 hours and no regrowth was detected after this time.ConclusionCombination of DAL+ ceftaroline offers encouraging results for MRSA strain 494. This combination therapy can potentially lead to optimizing patient outcomes and preserving dalbavancin therapy for serious MRSA infections through utilization of ideal combinations and dose exposures.Disclosures M. J. Rybak, Allergen: Scientific Advisor, Consulting fee.