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217. Combination Salvage Therapy with Cefazolin Plus Ertapenem for Refractory Methicillin-Susceptible Staphylococcus aureus Bacteremia

BACKGROUND: Suboptimal therapy against methicillin-sensitive Staphylococcus aureus (MSSA) may have catastrophic consequences in severe infections such as endocarditis or epidural abscess. High MSSA inocula have been associated with clinical failure in patients receiving cefazolin (CZ), particularly...

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Autores principales: Rose Ulloa, Erlinda, Singh, Kavindra V, Geriak, Matthew, Haddad, Fadi, Murray, Barbara E, Nizet, Victor, Sakoulas, George
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810444/
http://dx.doi.org/10.1093/ofid/ofz360.292
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author Rose Ulloa, Erlinda
Singh, Kavindra V
Geriak, Matthew
Haddad, Fadi
Murray, Barbara E
Nizet, Victor
Sakoulas, George
author_facet Rose Ulloa, Erlinda
Singh, Kavindra V
Geriak, Matthew
Haddad, Fadi
Murray, Barbara E
Nizet, Victor
Sakoulas, George
author_sort Rose Ulloa, Erlinda
collection PubMed
description BACKGROUND: Suboptimal therapy against methicillin-sensitive Staphylococcus aureus (MSSA) may have catastrophic consequences in severe infections such as endocarditis or epidural abscess. High MSSA inocula have been associated with clinical failure in patients receiving cefazolin (CZ), particularly when used at low doses, associated with a CZ inoculum effect. We previously described that adding ertapenem (ETP) to CZ led to synergism against MSSA and sensitized the pathogen to host innate immune factors. Here we expand our experience with CZ plus ETP as salvage therapy for 11 cases of refractory MSSA bacteremia (lacking source control problems) and explore CZ+ETP combination in vitro and in vivo. METHODS: Six available MSSA strains from patients treated with CZ+ETP for refractory bacteremia were tested in Mueller–Hinton Broth or RPMI media at standard (10(5) CFU/mL) or high (10(7) CFU/mL) inocula by MIC, checkerboard, and time-kill assays using ETP, CZ or nafcillin (NAF) alone vs. ETP+NAF or ETP+CZ. Disk diffusion synergy assays between CZ and ETP were also performed. CZ, ETP and CZ+ETP were tested in a rat endocarditis model using well described MSSA, TX0117 and TX0117c. RESULTS: 11 consecutive patients with MSSA bacteremia (6 confirmed endocarditis) refractory to standard CZ or NAF rapidly cleared with CZ+ETP. 9 patients had daily positive blood cultures, and 8 cleared in ≤24 hr, including those with ≥2 cm vegetations. All 11 survived hospitalization. In MHB, 3/6 MSSA exhibited a CZ inoculum effect (CZ MIC >3 log(2) in 10(7) vs. 10(5) CFU/mL), but only 1 showed a significant CZ inoculum effect in RPMI. CZ+ETP was significantly more efficacious than CZ in a rat model of MSSA endocarditis utilizing a strain displaying a CZ inoculum effect, despite only modest benefit observed in vitro for 6 MSSA isolates. CONCLUSION: CZ+ETP combination therapy yielded profound clinical success in severe MSSA infections with high bacterial densities, as demonstrated by rapid bacteremia clearance. Enhanced efficacy was also observed in a rat endocarditis model. The anti-staphylococcal activity of CZ+ETP in vivo exceeded that observed in vitro, consistent with our prior observations of host innate immune cooperativity with the regimen. CZ+ETP warrants further study for the treatment of refractory MSSA bacteremia and endocarditis. DISCLOSURES: All authors: No reported disclosures.
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spelling pubmed-68104442019-10-28 217. Combination Salvage Therapy with Cefazolin Plus Ertapenem for Refractory Methicillin-Susceptible Staphylococcus aureus Bacteremia Rose Ulloa, Erlinda Singh, Kavindra V Geriak, Matthew Haddad, Fadi Murray, Barbara E Nizet, Victor Sakoulas, George Open Forum Infect Dis Abstracts BACKGROUND: Suboptimal therapy against methicillin-sensitive Staphylococcus aureus (MSSA) may have catastrophic consequences in severe infections such as endocarditis or epidural abscess. High MSSA inocula have been associated with clinical failure in patients receiving cefazolin (CZ), particularly when used at low doses, associated with a CZ inoculum effect. We previously described that adding ertapenem (ETP) to CZ led to synergism against MSSA and sensitized the pathogen to host innate immune factors. Here we expand our experience with CZ plus ETP as salvage therapy for 11 cases of refractory MSSA bacteremia (lacking source control problems) and explore CZ+ETP combination in vitro and in vivo. METHODS: Six available MSSA strains from patients treated with CZ+ETP for refractory bacteremia were tested in Mueller–Hinton Broth or RPMI media at standard (10(5) CFU/mL) or high (10(7) CFU/mL) inocula by MIC, checkerboard, and time-kill assays using ETP, CZ or nafcillin (NAF) alone vs. ETP+NAF or ETP+CZ. Disk diffusion synergy assays between CZ and ETP were also performed. CZ, ETP and CZ+ETP were tested in a rat endocarditis model using well described MSSA, TX0117 and TX0117c. RESULTS: 11 consecutive patients with MSSA bacteremia (6 confirmed endocarditis) refractory to standard CZ or NAF rapidly cleared with CZ+ETP. 9 patients had daily positive blood cultures, and 8 cleared in ≤24 hr, including those with ≥2 cm vegetations. All 11 survived hospitalization. In MHB, 3/6 MSSA exhibited a CZ inoculum effect (CZ MIC >3 log(2) in 10(7) vs. 10(5) CFU/mL), but only 1 showed a significant CZ inoculum effect in RPMI. CZ+ETP was significantly more efficacious than CZ in a rat model of MSSA endocarditis utilizing a strain displaying a CZ inoculum effect, despite only modest benefit observed in vitro for 6 MSSA isolates. CONCLUSION: CZ+ETP combination therapy yielded profound clinical success in severe MSSA infections with high bacterial densities, as demonstrated by rapid bacteremia clearance. Enhanced efficacy was also observed in a rat endocarditis model. The anti-staphylococcal activity of CZ+ETP in vivo exceeded that observed in vitro, consistent with our prior observations of host innate immune cooperativity with the regimen. CZ+ETP warrants further study for the treatment of refractory MSSA bacteremia and endocarditis. DISCLOSURES: All authors: No reported disclosures. Oxford University Press 2019-10-23 /pmc/articles/PMC6810444/ http://dx.doi.org/10.1093/ofid/ofz360.292 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Abstracts
Rose Ulloa, Erlinda
Singh, Kavindra V
Geriak, Matthew
Haddad, Fadi
Murray, Barbara E
Nizet, Victor
Sakoulas, George
217. Combination Salvage Therapy with Cefazolin Plus Ertapenem for Refractory Methicillin-Susceptible Staphylococcus aureus Bacteremia
title 217. Combination Salvage Therapy with Cefazolin Plus Ertapenem for Refractory Methicillin-Susceptible Staphylococcus aureus Bacteremia
title_full 217. Combination Salvage Therapy with Cefazolin Plus Ertapenem for Refractory Methicillin-Susceptible Staphylococcus aureus Bacteremia
title_fullStr 217. Combination Salvage Therapy with Cefazolin Plus Ertapenem for Refractory Methicillin-Susceptible Staphylococcus aureus Bacteremia
title_full_unstemmed 217. Combination Salvage Therapy with Cefazolin Plus Ertapenem for Refractory Methicillin-Susceptible Staphylococcus aureus Bacteremia
title_short 217. Combination Salvage Therapy with Cefazolin Plus Ertapenem for Refractory Methicillin-Susceptible Staphylococcus aureus Bacteremia
title_sort 217. combination salvage therapy with cefazolin plus ertapenem for refractory methicillin-susceptible staphylococcus aureus bacteremia
topic Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810444/
http://dx.doi.org/10.1093/ofid/ofz360.292
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