Dual β-Lactam Combinations Highly Active against <named-content content-type="genus-species">Mycobacterium abscessus</named-content> Complex <italic toggle="yes">In Vitro</italic>

ABSTRACT As a consequence of a growing population of immunocompromised individuals, including transplant recipients and cystic fibrosis patients, there has been a dramatic increase in chronic infections caused by Mycobacterium abscessus complex (MABC) strains that are usually recalcitrant to effecti...

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Autores principales:	R. Pandey, L. Chen, C. Manca, S. Jenkins, L. Glaser, C. Vinnard, G. Stone, J. Lee, B. Mathema, E. L. Nuermberger, R. A. Bonomo, B. N. Kreiswirth
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	beta-lactamases beta-lactams multidrug resistance Mycobacterium abscessus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6b136e4b4afc4e06a253b65312e2594f
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spelling	oai:doaj.org-article:6b136e4b4afc4e06a253b65312e2594f2021-11-15T15:55:14ZDual β-Lactam Combinations Highly Active against <named-content content-type="genus-species">Mycobacterium abscessus</named-content> Complex <italic toggle="yes">In Vitro</italic>10.1128/mBio.02895-182150-7511https://doaj.org/article/6b136e4b4afc4e06a253b65312e2594f2019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02895-18https://doaj.org/toc/2150-7511ABSTRACT As a consequence of a growing population of immunocompromised individuals, including transplant recipients and cystic fibrosis patients, there has been a dramatic increase in chronic infections caused by Mycobacterium abscessus complex (MABC) strains that are usually recalcitrant to effective antibiotic therapy. The recent rise of macrolide resistance in MABC has further complicated this clinical dilemma, dramatizing the need for novel agents. The repurposing of current antibiotics is one rapid path from discovery to patient care. In this study, we have discovered that dual β-lactams, and specifically the combination of ceftazidime with either ceftaroline or imipenem, are synergistic and have clinically relevant activities, with MIC50s of 0.25 (ceftaroline with 100 µg/ml ceftazidime) and 0.5 µg/ml (imipenem with 100 µg/ml ceftazidime) against clinical MABC isolates. Similar synergy was observed in time-kill studies against the M. abscessus ATCC 19977 strain using clinically achievable concentrations of either imipenem (4 µg/ml) or ceftaroline (2 µg/ml), as the addition of ceftazidime at concentrations of ≥50 µg/ml showed a persistent bactericidal effect over 5 days. Treatment of THP-1 human macrophages infected with three different M. abscessus clinical isolates supported the in vitro findings, as the combination of 100 µg/ml ceftazidime and 0.125 µg/ml ceftaroline or 100 µg/ml ceftazidime and 0.25 µg/ml imipenem dramatically reduced the CFU counts to near baseline levels of infection. This study’s finding that there is synergy between certain β-lactam combinations against M. abscessus infection provides optimism toward identifying an optimum dual β-lactam treatment regimen. IMPORTANCE The emergence of chronic MABC infections among immunocompromised populations and their inherent and acquired resistance to effective antibiotic therapy have created clinical challenges in advancing patients for transplant surgery and treating those with disease. There is an urgent need for new treatment regimens, and the repurposing of existing antibiotics provides a rapid strategy to advance a laboratory finding to patient care. Our recent discoveries that dual β-lactams, specifically the combination of ceftazidime with ceftaroline or ceftazidime with imipenem, have significant in vitro MIC values and kill curve activities and are effective against infected THP-1 human macrophages provide optimism for a dual β-lactam treatment strategy against MABC infections. The unexpected synergistic activities reported in this study create a new path of discovery to repurpose the large family of β-lactam drugs.R. PandeyL. ChenC. MancaS. JenkinsL. GlaserC. VinnardG. StoneJ. LeeB. MathemaE. L. NuermbergerR. A. BonomoB. N. KreiswirthAmerican Society for Microbiologyarticlebeta-lactamasesbeta-lactamsmultidrug resistanceMycobacterium abscessusMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	beta-lactamases beta-lactams multidrug resistance Mycobacterium abscessus Microbiology QR1-502
spellingShingle	beta-lactamases beta-lactams multidrug resistance Mycobacterium abscessus Microbiology QR1-502 R. Pandey L. Chen C. Manca S. Jenkins L. Glaser C. Vinnard G. Stone J. Lee B. Mathema E. L. Nuermberger R. A. Bonomo B. N. Kreiswirth Dual β-Lactam Combinations Highly Active against <named-content content-type="genus-species">Mycobacterium abscessus</named-content> Complex <italic toggle="yes">In Vitro</italic>
description	ABSTRACT As a consequence of a growing population of immunocompromised individuals, including transplant recipients and cystic fibrosis patients, there has been a dramatic increase in chronic infections caused by Mycobacterium abscessus complex (MABC) strains that are usually recalcitrant to effective antibiotic therapy. The recent rise of macrolide resistance in MABC has further complicated this clinical dilemma, dramatizing the need for novel agents. The repurposing of current antibiotics is one rapid path from discovery to patient care. In this study, we have discovered that dual β-lactams, and specifically the combination of ceftazidime with either ceftaroline or imipenem, are synergistic and have clinically relevant activities, with MIC50s of 0.25 (ceftaroline with 100 µg/ml ceftazidime) and 0.5 µg/ml (imipenem with 100 µg/ml ceftazidime) against clinical MABC isolates. Similar synergy was observed in time-kill studies against the M. abscessus ATCC 19977 strain using clinically achievable concentrations of either imipenem (4 µg/ml) or ceftaroline (2 µg/ml), as the addition of ceftazidime at concentrations of ≥50 µg/ml showed a persistent bactericidal effect over 5 days. Treatment of THP-1 human macrophages infected with three different M. abscessus clinical isolates supported the in vitro findings, as the combination of 100 µg/ml ceftazidime and 0.125 µg/ml ceftaroline or 100 µg/ml ceftazidime and 0.25 µg/ml imipenem dramatically reduced the CFU counts to near baseline levels of infection. This study’s finding that there is synergy between certain β-lactam combinations against M. abscessus infection provides optimism toward identifying an optimum dual β-lactam treatment regimen. IMPORTANCE The emergence of chronic MABC infections among immunocompromised populations and their inherent and acquired resistance to effective antibiotic therapy have created clinical challenges in advancing patients for transplant surgery and treating those with disease. There is an urgent need for new treatment regimens, and the repurposing of existing antibiotics provides a rapid strategy to advance a laboratory finding to patient care. Our recent discoveries that dual β-lactams, specifically the combination of ceftazidime with ceftaroline or ceftazidime with imipenem, have significant in vitro MIC values and kill curve activities and are effective against infected THP-1 human macrophages provide optimism for a dual β-lactam treatment strategy against MABC infections. The unexpected synergistic activities reported in this study create a new path of discovery to repurpose the large family of β-lactam drugs.
format	article
author	R. Pandey L. Chen C. Manca S. Jenkins L. Glaser C. Vinnard G. Stone J. Lee B. Mathema E. L. Nuermberger R. A. Bonomo B. N. Kreiswirth
author_facet	R. Pandey L. Chen C. Manca S. Jenkins L. Glaser C. Vinnard G. Stone J. Lee B. Mathema E. L. Nuermberger R. A. Bonomo B. N. Kreiswirth
author_sort	R. Pandey
title	Dual β-Lactam Combinations Highly Active against <named-content content-type="genus-species">Mycobacterium abscessus</named-content> Complex <italic toggle="yes">In Vitro</italic>
title_short	Dual β-Lactam Combinations Highly Active against <named-content content-type="genus-species">Mycobacterium abscessus</named-content> Complex <italic toggle="yes">In Vitro</italic>
title_full	Dual β-Lactam Combinations Highly Active against <named-content content-type="genus-species">Mycobacterium abscessus</named-content> Complex <italic toggle="yes">In Vitro</italic>
title_fullStr	Dual β-Lactam Combinations Highly Active against <named-content content-type="genus-species">Mycobacterium abscessus</named-content> Complex <italic toggle="yes">In Vitro</italic>
title_full_unstemmed	Dual β-Lactam Combinations Highly Active against <named-content content-type="genus-species">Mycobacterium abscessus</named-content> Complex <italic toggle="yes">In Vitro</italic>
title_sort	dual β-lactam combinations highly active against <named-content content-type="genus-species">mycobacterium abscessus</named-content> complex <italic toggle="yes">in vitro</italic>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/6b136e4b4afc4e06a253b65312e2594f
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Dual β-Lactam Combinations Highly Active against <named-content content-type="genus-species">Mycobacterium abscessus</named-content> Complex <italic toggle="yes">In Vitro</italic>

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