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Integrated pharmacokinetic–pharmacodynamic modeling to evaluate empiric carbapenem therapy in bloodstream infections
OBJECTIVES: Treatment for nosocomial bloodstream infections (BSI) caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) is challenging. Rising antimicrobial resistance, especially in extended spectrum beta-lactamase production, inadvertently increases empiric carbapenem consumption. Three...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
SAGE Publications
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166767/ https://www.ncbi.nlm.nih.gov/pubmed/30310294 http://dx.doi.org/10.2147/IDR.S168191 |
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author | Lim, Tze-Peng Wang, Reyna Poh, Gang Quan Koh, Tse-Hsien Tan, Thean-Yen Lee, Winnie Teo, Jocelyn Qi-Min Cai, Yiying Tan, Thuan-Tong Ee, Pui Lai Rachel Kwa, Andrea L |
author_facet | Lim, Tze-Peng Wang, Reyna Poh, Gang Quan Koh, Tse-Hsien Tan, Thean-Yen Lee, Winnie Teo, Jocelyn Qi-Min Cai, Yiying Tan, Thuan-Tong Ee, Pui Lai Rachel Kwa, Andrea L |
author_sort | Lim, Tze-Peng |
collection | PubMed |
description | OBJECTIVES: Treatment for nosocomial bloodstream infections (BSI) caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) is challenging. Rising antimicrobial resistance, especially in extended spectrum beta-lactamase production, inadvertently increases empiric carbapenem consumption. Three antipseudomonal carbapenems (imipenem, meropenem [MER], and doripenem [DOR]) are available commercially against MDR GNB in Singapore. The study aims to determine the most optimal empiric carbapenem dosing regimens (CDR) and evaluate their cost-effectiveness for GNB-BSI in the face of increasing MDR GNB. METHODS: Carbapenem minimum inhibitory concentrations (MICs) were generated for non-repeat GNB-BSI obtained in 2013–2014 from two hospitals. Monte Carlo simulations were used to assess the cumulative fraction of response (CFR) of various CDRs using the percentage of time above MIC for 40% (%T > MIC of 40%) as the pharmacokinetic (PK)–pharmacodynamic (PD) parameter for efficacy. Carbapenem costs were based on patient antibiotic costs. Antibiotic cost-effectiveness was calculated as total daily drug cost/CFR. RESULTS: A total of 1,140 bloodstream isolates were collected. They comprised 116 Acinetobacter baumannii, 237 Pseudomonas aeruginosa, and 787 Enterobacteriaceae. All CDRs achieved ~40, ~80, and ≥90% CFRs against A. baumannii, P. aeruginosa, and Enterobacteriaceae, respectively. Against P. aeruginosa, MER 2 g every 8 h infused over 3 h and DOR 1 g every 8 h infused over 4 h achieved CFRs 84 and 81%, respectively. Against Enterobacteriaceae, the cost of MER 2 g every 8 h infused over 3 h was the lowest among the three carbapenems at $0.40/percentage of CFR. CONCLUSION: This study demonstrates the utility of PK–PD modeling to formulate the optimal selection of a cost-effective empiric CDR in antibiotics guidelines and formulary inclusion. The findings support the selection of high MER doses of prolonged infusions as empiric coverage for GNB-BSI in our institutions. |
format | Online Article Text |
id | pubmed-6166767 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | SAGE Publications |
record_format | MEDLINE/PubMed |
spelling | pubmed-61667672018-10-11 Integrated pharmacokinetic–pharmacodynamic modeling to evaluate empiric carbapenem therapy in bloodstream infections Lim, Tze-Peng Wang, Reyna Poh, Gang Quan Koh, Tse-Hsien Tan, Thean-Yen Lee, Winnie Teo, Jocelyn Qi-Min Cai, Yiying Tan, Thuan-Tong Ee, Pui Lai Rachel Kwa, Andrea L Infect Drug Resist Original Research OBJECTIVES: Treatment for nosocomial bloodstream infections (BSI) caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) is challenging. Rising antimicrobial resistance, especially in extended spectrum beta-lactamase production, inadvertently increases empiric carbapenem consumption. Three antipseudomonal carbapenems (imipenem, meropenem [MER], and doripenem [DOR]) are available commercially against MDR GNB in Singapore. The study aims to determine the most optimal empiric carbapenem dosing regimens (CDR) and evaluate their cost-effectiveness for GNB-BSI in the face of increasing MDR GNB. METHODS: Carbapenem minimum inhibitory concentrations (MICs) were generated for non-repeat GNB-BSI obtained in 2013–2014 from two hospitals. Monte Carlo simulations were used to assess the cumulative fraction of response (CFR) of various CDRs using the percentage of time above MIC for 40% (%T > MIC of 40%) as the pharmacokinetic (PK)–pharmacodynamic (PD) parameter for efficacy. Carbapenem costs were based on patient antibiotic costs. Antibiotic cost-effectiveness was calculated as total daily drug cost/CFR. RESULTS: A total of 1,140 bloodstream isolates were collected. They comprised 116 Acinetobacter baumannii, 237 Pseudomonas aeruginosa, and 787 Enterobacteriaceae. All CDRs achieved ~40, ~80, and ≥90% CFRs against A. baumannii, P. aeruginosa, and Enterobacteriaceae, respectively. Against P. aeruginosa, MER 2 g every 8 h infused over 3 h and DOR 1 g every 8 h infused over 4 h achieved CFRs 84 and 81%, respectively. Against Enterobacteriaceae, the cost of MER 2 g every 8 h infused over 3 h was the lowest among the three carbapenems at $0.40/percentage of CFR. CONCLUSION: This study demonstrates the utility of PK–PD modeling to formulate the optimal selection of a cost-effective empiric CDR in antibiotics guidelines and formulary inclusion. The findings support the selection of high MER doses of prolonged infusions as empiric coverage for GNB-BSI in our institutions. SAGE Publications 2018-09-27 /pmc/articles/PMC6166767/ /pubmed/30310294 http://dx.doi.org/10.2147/IDR.S168191 Text en © 2018 Lim et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Original Research Lim, Tze-Peng Wang, Reyna Poh, Gang Quan Koh, Tse-Hsien Tan, Thean-Yen Lee, Winnie Teo, Jocelyn Qi-Min Cai, Yiying Tan, Thuan-Tong Ee, Pui Lai Rachel Kwa, Andrea L Integrated pharmacokinetic–pharmacodynamic modeling to evaluate empiric carbapenem therapy in bloodstream infections |
title | Integrated pharmacokinetic–pharmacodynamic modeling to evaluate empiric carbapenem therapy in bloodstream infections |
title_full | Integrated pharmacokinetic–pharmacodynamic modeling to evaluate empiric carbapenem therapy in bloodstream infections |
title_fullStr | Integrated pharmacokinetic–pharmacodynamic modeling to evaluate empiric carbapenem therapy in bloodstream infections |
title_full_unstemmed | Integrated pharmacokinetic–pharmacodynamic modeling to evaluate empiric carbapenem therapy in bloodstream infections |
title_short | Integrated pharmacokinetic–pharmacodynamic modeling to evaluate empiric carbapenem therapy in bloodstream infections |
title_sort | integrated pharmacokinetic–pharmacodynamic modeling to evaluate empiric carbapenem therapy in bloodstream infections |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166767/ https://www.ncbi.nlm.nih.gov/pubmed/30310294 http://dx.doi.org/10.2147/IDR.S168191 |
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