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1325. Things that go Bump in the Night: Combating Klebsiella pneumoniae co-producing New Delhi metallo-beta-lactamase (NDM) and Mobile Colistin Resistance (MCR)

BACKGROUND: The scourge of MBLs among Gram negatives, such New Delhi Metallo-beta-lactamase-producing Klebsiella pneumoniae, has resulted in an overwhelming need for new treatmens. Worryingly, additional acquisition of plasmid-mediated polymyxin resistance through the mcr gene can produce strains re...

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Autores principales: Smith, Nicholas M, Chen, Liang, Boissonneault, Katie Rose, Lodise, Thomas, Holden, Patricia N, Bulitta, Juergen B, Bonomo, Robert A, Kreiswirth, Barry N, Tsuji, Brian T
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7777449/
http://dx.doi.org/10.1093/ofid/ofaa439.1507
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author Smith, Nicholas M
Chen, Liang
Boissonneault, Katie Rose
Lodise, Thomas
Holden, Patricia N
Bulitta, Juergen B
Bonomo, Robert A
Kreiswirth, Barry N
Tsuji, Brian T
author_facet Smith, Nicholas M
Chen, Liang
Boissonneault, Katie Rose
Lodise, Thomas
Holden, Patricia N
Bulitta, Juergen B
Bonomo, Robert A
Kreiswirth, Barry N
Tsuji, Brian T
author_sort Smith, Nicholas M
collection PubMed
description BACKGROUND: The scourge of MBLs among Gram negatives, such New Delhi Metallo-beta-lactamase-producing Klebsiella pneumoniae, has resulted in an overwhelming need for new treatmens. Worryingly, additional acquisition of plasmid-mediated polymyxin resistance through the mcr gene can produce strains resistant to all last line agents. The novel combination of aztreonam (ATM, which is not an MBL substrate) with avibactam (AVI, to inhibit extended spectrum beta-lactamases that inactivate ATM) has been proposed to restore ATM activity. METHODS: K. pneumoniae SZ04 harboring bla(NDM-5), bla(CTX-M-55), and mcr-1 (MIC(ATM) = 128 mg/L, MIC(Polymyxin B) = 4 mg/L, MIC(Amikacin) = 1 mg/L, MIC(ceftazidime/avibactam) > 16/4 mg/L) was studied at two initial inoculum (10(6) and 10(8) cfu/mL) over 24h in static time kills (SCTK). Concentration arrays of 2-, 3-, and 4-drug combinations of low- and package insert-dose polymyxin B (PMB) ± low- and package insert-dose amikacin (AMI) ± package insert dosing of ATM/AVI were simulated in > 200 individual arms of SCTK. Data were summarized using the Log Ratio Area (LRA) which is calculated by integrating the area under the bacterial killing curve, normalizing to the growth control, then log-transforming. A Hill-type function was fit to the data in order to determine the maximum effect (E(max)) and drug concentration for 50% effect (EC(50)). RESULTS: When simulating the maximum free concentration of amikacin 15 mg/kg (52 mg/L) in combination with package insert concentrations of ATM/AVI, there was a marked reduction of 3.22 in the LRA compared to the growth control for the 10(8) cfu/mL starting inocula. Combining ATM with low amikacin (0.813 mg/L) and polymyxin B (0.125 mg/L) resulted in a reduction in LRA of 4.32 at 10(6) cfu/mL. Model fitting results showed a statistically significant difference in EC(50) to amikacin between low and high inocula at 1.24 and 18.1 mg/L, respectively. Combination of AMI with low-concentration PMB (0.125 mg/L) resulted in an increase in the E(max) of amikacin to -5.68. CONCLUSION: The use of ATM/AVI combinations is a promising option against MBL and MCR co-producing K. pneumoniae. Low-dose strategies of polymyxin or amikacin dosing in combination with ATM/AVI is merits further testing for future translation to the clinical setting to improve efficacy and optimize treatment. DISCLOSURES: Thomas Lodise, PharmD, PhD, Paratek Pharmaceuticals, Inc. (Consultant) Robert A. Bonomo, MD, Entasis, Merck, Venatorx (Research Grant or Support)
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spelling pubmed-77774492021-01-07 1325. Things that go Bump in the Night: Combating Klebsiella pneumoniae co-producing New Delhi metallo-beta-lactamase (NDM) and Mobile Colistin Resistance (MCR) Smith, Nicholas M Chen, Liang Boissonneault, Katie Rose Lodise, Thomas Holden, Patricia N Bulitta, Juergen B Bonomo, Robert A Kreiswirth, Barry N Tsuji, Brian T Open Forum Infect Dis Poster Abstracts BACKGROUND: The scourge of MBLs among Gram negatives, such New Delhi Metallo-beta-lactamase-producing Klebsiella pneumoniae, has resulted in an overwhelming need for new treatmens. Worryingly, additional acquisition of plasmid-mediated polymyxin resistance through the mcr gene can produce strains resistant to all last line agents. The novel combination of aztreonam (ATM, which is not an MBL substrate) with avibactam (AVI, to inhibit extended spectrum beta-lactamases that inactivate ATM) has been proposed to restore ATM activity. METHODS: K. pneumoniae SZ04 harboring bla(NDM-5), bla(CTX-M-55), and mcr-1 (MIC(ATM) = 128 mg/L, MIC(Polymyxin B) = 4 mg/L, MIC(Amikacin) = 1 mg/L, MIC(ceftazidime/avibactam) > 16/4 mg/L) was studied at two initial inoculum (10(6) and 10(8) cfu/mL) over 24h in static time kills (SCTK). Concentration arrays of 2-, 3-, and 4-drug combinations of low- and package insert-dose polymyxin B (PMB) ± low- and package insert-dose amikacin (AMI) ± package insert dosing of ATM/AVI were simulated in > 200 individual arms of SCTK. Data were summarized using the Log Ratio Area (LRA) which is calculated by integrating the area under the bacterial killing curve, normalizing to the growth control, then log-transforming. A Hill-type function was fit to the data in order to determine the maximum effect (E(max)) and drug concentration for 50% effect (EC(50)). RESULTS: When simulating the maximum free concentration of amikacin 15 mg/kg (52 mg/L) in combination with package insert concentrations of ATM/AVI, there was a marked reduction of 3.22 in the LRA compared to the growth control for the 10(8) cfu/mL starting inocula. Combining ATM with low amikacin (0.813 mg/L) and polymyxin B (0.125 mg/L) resulted in a reduction in LRA of 4.32 at 10(6) cfu/mL. Model fitting results showed a statistically significant difference in EC(50) to amikacin between low and high inocula at 1.24 and 18.1 mg/L, respectively. Combination of AMI with low-concentration PMB (0.125 mg/L) resulted in an increase in the E(max) of amikacin to -5.68. CONCLUSION: The use of ATM/AVI combinations is a promising option against MBL and MCR co-producing K. pneumoniae. Low-dose strategies of polymyxin or amikacin dosing in combination with ATM/AVI is merits further testing for future translation to the clinical setting to improve efficacy and optimize treatment. DISCLOSURES: Thomas Lodise, PharmD, PhD, Paratek Pharmaceuticals, Inc. (Consultant) Robert A. Bonomo, MD, Entasis, Merck, Venatorx (Research Grant or Support) Oxford University Press 2020-12-31 /pmc/articles/PMC7777449/ http://dx.doi.org/10.1093/ofid/ofaa439.1507 Text en © The Author 2020. 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 Poster Abstracts
Smith, Nicholas M
Chen, Liang
Boissonneault, Katie Rose
Lodise, Thomas
Holden, Patricia N
Bulitta, Juergen B
Bonomo, Robert A
Kreiswirth, Barry N
Tsuji, Brian T
1325. Things that go Bump in the Night: Combating Klebsiella pneumoniae co-producing New Delhi metallo-beta-lactamase (NDM) and Mobile Colistin Resistance (MCR)
title 1325. Things that go Bump in the Night: Combating Klebsiella pneumoniae co-producing New Delhi metallo-beta-lactamase (NDM) and Mobile Colistin Resistance (MCR)
title_full 1325. Things that go Bump in the Night: Combating Klebsiella pneumoniae co-producing New Delhi metallo-beta-lactamase (NDM) and Mobile Colistin Resistance (MCR)
title_fullStr 1325. Things that go Bump in the Night: Combating Klebsiella pneumoniae co-producing New Delhi metallo-beta-lactamase (NDM) and Mobile Colistin Resistance (MCR)
title_full_unstemmed 1325. Things that go Bump in the Night: Combating Klebsiella pneumoniae co-producing New Delhi metallo-beta-lactamase (NDM) and Mobile Colistin Resistance (MCR)
title_short 1325. Things that go Bump in the Night: Combating Klebsiella pneumoniae co-producing New Delhi metallo-beta-lactamase (NDM) and Mobile Colistin Resistance (MCR)
title_sort 1325. things that go bump in the night: combating klebsiella pneumoniae co-producing new delhi metallo-beta-lactamase (ndm) and mobile colistin resistance (mcr)
topic Poster Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7777449/
http://dx.doi.org/10.1093/ofid/ofaa439.1507
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