1980. Daptomycin Plus Ceftaroline Against Daptomycin-Resistant Enterococcus faecium in a Rat Model of Experimental Endocarditis
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall
Background: Vancomycin-resistant Enterococcus faecium are difficult nosocomial pathogens to treat. Daptomycin (DAP) is a key front-line bactericidal antibiotic against VRE. Development of DAP resistance during therapy raises concerns about the role of DAP monotherapy in severe enterococcal infections. Limited previous data suggest that ceftaroline (CPT) enhances the in vitro activity of DAP against enterococci. We sought to evaluate the in vivo activity of DAP plus CPT against a DAP-R strain of E. faecium using an experimental infective endocarditis (IE) rat model.

Methods: MICs and time-kill assays were performed using standard methods. IE was produced in carotid artery and jugular vein catheterized rats by intracardiac inoculation of 10X the ID90 of E. faecium HOU497. Therapy (3 days, via infusion pump) was begun 24 h after inoculation. Some animals were sacrificed at the time of therapy initiation to evaluate bacterial loads (T=0). Drug regimens included i) CPT, 30 min, 40 mg/kg q8h, ii) DAP, 45.3 mg/kg by infusion over 7h, q24h (human dose equivalent of 6 mg/kg) and iii) CPT at same doses. Animals (≥ 7 rats/group) were sacrificed 16 h after the last antibiotic dose. Colony forming units (CFU)/gm of vegetations were obtained and compared with T=0 controls.

Results: DAP and CPT MICs for HOU497 were 16 and 256 μg/ml, respectively. In in vitro time-kill assays, DAP was not bactericidal against HOU497 but addition of CPT increased activity of DAP against HOU497 by 1 log10 reduction. Compared with T=0, therapy with DAP alone showed a non-significant reduction in mean CFU/gm of vegetations (P=0.3066). Addition of CPT to DAP significantly decreased bacterial burdens in vegetations compared to DAP alone from 5.4+0.7 to 3.3+1 CFU/gm (P=0.0332).

Conclusion: Our in vitro and in vivo results suggest that the addition of CPT to DAP may increase the in vivo efficacy of DAP against DAP-resistant E. faecium isolates.

Daniel Smith, M.D.1, Kavindra Singh, Ph.D.1, Truc Tran, PharmD1, Cesar Arias, MD, PhD, FIDSA2 and Barbara Murray, M.D.1, (1)Internal Medicine, University of Texas McGovern Medical School at Houston, Houston, TX, (2)Department of Internal Medicine, University of Texas McGovern Medical School at Houston, Houston, TX

Disclosures:

D. Smith, None

K. Singh, Cubist/Merck: Grant Investigator , Research grant

T. Tran, None

C. Arias, Forest: Grant Investigator and Speaker's Bureau , Research support
Theravance: Consultant , Grant Investigator and Speaker's Bureau , Grant recipient and Speaker honorarium
Pfizer: Grant Investigator , Scientific Advisor and Speaker's Bureau , Grant recipient and Speaker honorarium
Cubist: Consultant , Grant Investigator and Scientific Advisor , Consulting fee , Grant recipient and Speaker honorarium
Bayer: Consultant and Scientific Advisor , Consulting fee
Merck: Grant Investigator and Speaker's Bureau , Research grant and Speaker honorarium
Astra-Zeneca: Speaker's Bureau , Speaker honorarium
Novartis: Speaker's Bureau , Speaker honorarium
The Medicines Company: Speaker's Bureau , Speaker honorarium

B. Murray, Forest/Actavis: Grant Investigator , Research grant
Cubist/Merck: Grant Investigator , Research support
Theravance: Grant Investigator , Research grant
AstraZeneca: Scientific Advisor , Consulting fee

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