Ashley Hall Snyder1, Brian J Werth2, Katie E Barber1, George Sakoulas3, Michael J Rybak4. 1. Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48201, USA. 2. Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48201, USA Department of Pharmacy, University of Washington, Seattle, WA 98195, USA. 3. Department of Pediatrics, University of San Diego School of Medicine, San Diego, CA 92123, USA Infectious Diseases, Sharp Memorial Hospital, San Diego, CA 92123, USA. 4. Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Detroit, MI 48201, USA School of Medicine, Wayne State University, Detroit, MI 48201, USA m.rybak@wayne.edu.
Abstract
OBJECTIVES: Daptomycin has demonstrated synergy with β-lactams against Enterococcus faecium and this combination has been used successfully to treat infections refractory to daptomycin. We investigated daptomycin alone and combined with ceftriaxone against vancomycin-resistant enterococci (VRE) in an in vitro pharmacokinetic/pharmacodynamic simulated endocardial vegetation (SEV) model. METHODS: Daptomycin (6 and 12 mg/kg/day) with and without 2 g of ceftriaxone every 24 h were evaluated against two clinical E. faecium strains (8019 and 5938) and one Enterococcus faecalis (6981) in a 96 h in vitro pharmacokinetic/pharmacodynamic SEV model. FITC-labelled poly-l-lysine was used to assess β-lactam-induced changes in cell surface charge. RESULTS: For 8019 and 6981, daptomycin 6 mg/kg with ceftriaxone and daptomycin 12 mg/kg alone and in combination with ceftriaxone displayed significantly more activity than daptomycin 6 mg/kg alone from 48 to 96 h (P ≤ 0.005). The addition of ceftriaxone significantly enhanced activity of daptomycin 6 mg/kg against both strains at 96 h (8019, reductions -0.55 versus 3.64 log10 cfu/g; 6981, reductions 1.11 versus 5.67 log10 cfu/g; P < 0.001) and improved daptomycin 12 mg/kg against 8019 at 96 h. Daptomycin 12 mg/kg plus ceftriaxone displayed no appreciable activity against 5938 (daptomycin MIC 32 mg/L). Daptomycin non-susceptibility developed in 8019 and 6981 versus daptomycin 6 mg/kg by 96 h. Ampicillin or ceftriaxone exposure reduced daptomycin surface charge in 8019, resulting in significantly increased FITC-poly-l-lysine binding. CONCLUSIONS: The combination of daptomycin and ceftriaxone may be promising for eradicating high-inoculum, deep-seated enterococcal infections. Further research is warranted to examine the enhancement of daptomycin and innate immunity killing of VRE by ceftriaxone and other β-lactams.
OBJECTIVES:Daptomycin has demonstrated synergy with β-lactams against Enterococcus faecium and this combination has been used successfully to treat infections refractory to daptomycin. We investigated daptomycin alone and combined with ceftriaxone against vancomycin-resistant enterococci (VRE) in an in vitro pharmacokinetic/pharmacodynamic simulated endocardial vegetation (SEV) model. METHODS:Daptomycin (6 and 12 mg/kg/day) with and without 2 g of ceftriaxone every 24 h were evaluated against two clinical E. faecium strains (8019 and 5938) and one Enterococcus faecalis (6981) in a 96 h in vitro pharmacokinetic/pharmacodynamic SEV model. FITC-labelled poly-l-lysine was used to assess β-lactam-induced changes in cell surface charge. RESULTS: For 8019 and 6981, daptomycin 6 mg/kg with ceftriaxone and daptomycin 12 mg/kg alone and in combination with ceftriaxone displayed significantly more activity than daptomycin 6 mg/kg alone from 48 to 96 h (P ≤ 0.005). The addition of ceftriaxone significantly enhanced activity of daptomycin 6 mg/kg against both strains at 96 h (8019, reductions -0.55 versus 3.64 log10 cfu/g; 6981, reductions 1.11 versus 5.67 log10 cfu/g; P < 0.001) and improved daptomycin 12 mg/kg against 8019 at 96 h. Daptomycin 12 mg/kg plus ceftriaxone displayed no appreciable activity against 5938 (daptomycin MIC 32 mg/L). Daptomycin non-susceptibility developed in 8019 and 6981 versus daptomycin 6 mg/kg by 96 h. Ampicillin or ceftriaxone exposure reduced daptomycin surface charge in 8019, resulting in significantly increased FITC-poly-l-lysine binding. CONCLUSIONS: The combination of daptomycin and ceftriaxone may be promising for eradicating high-inoculum, deep-seated enterococcal infections. Further research is warranted to examine the enhancement of daptomycin and innate immunity killing of VRE by ceftriaxone and other β-lactams.
Authors: Ashley D Hall Snyder; Brian J Werth; Poochit Nonejuie; John P McRoberts; Joe Pogliano; George Sakoulas; Juwon Yim; Nivedita Singh; Michael J Rybak Journal: Antimicrob Agents Chemother Date: 2016-09-23 Impact factor: 5.191
Authors: Razieh Kebriaei; Seth A Rice; Kyle C Stamper; Ravin Seepersaud; Cristina Garcia-de-la-Maria; Nagendra N Mishra; Jose M Miro; Cesar A Arias; Truc T Tran; Paul M Sullam; Arnold S Bayer; Michael J Rybak Journal: Antimicrob Agents Chemother Date: 2019-05-24 Impact factor: 5.191
Authors: Jordan R Smith; Katie E Barber; Animesh Raut; Mostafa Aboutaleb; George Sakoulas; Michael J Rybak Journal: J Antimicrob Chemother Date: 2015-02-01 Impact factor: 5.790
Authors: Razieh Kebriaei; Seth A Rice; Kavindra V Singh; Kyle C Stamper; An Q Dinh; Rafael Rios; Lorena Diaz; Barbara E Murray; Jose M Munita; Truc T Tran; Cesar A Arias; Michael J Rybak Journal: Antimicrob Agents Chemother Date: 2018-07-27 Impact factor: 5.191