Linezolid Dampens Neutrophil-Mediated Inflammation in Methicillin-Resistant Staphylococcus aureus-Induced Pneumonia and Protects the Lung of Associated Damages

Jacqueline, Cédric; Broquet, Alexis; Roquilly, Antoine; Davieau, Marion; Caillon, Jocelyne; Altare, Frédéric; Potel, G.; Asehnoune, Karim

doi:10.1093/infdis/jiu145

Cited by 30 publications

(30 citation statements)

References 45 publications

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“…Taken together, these results confirm that, compared with the control, CSE-USA300 is hypervirulent in mice, regardless of their genetic background, as exhibited by increased pulmonary CFUs at 24 hours PI. In response to USA300 infection, respiratory epithelial cells and AMs secrete cytokines and chemokines to induce inflammation (TNF-a, IL-1b) and recruit neutrophils (KC, MIP2) between 2 and 8 hours PI (36,37). Once recruited, neutrophils are the main source of proinflammatory cytokines and, thus, the sustained presence of activated neutrophils plays a central role in the development of acute lung injury (38).…”

Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Extract–Exposed Methicillin-Resistant Staphylococcus aureus Regulates Leukocyte Function for Pulmonary Persistence

Caskey

Singh²,

Paudel³

et al. 2016

Am J Respir Cell Mol Biol

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Cigarette smoke (CS) predisposes exposed individuals to respiratory infections not only by suppressing immune response but also by enhancing the virulence of pathogenic bacteria. As per our observations, in methicillin-resistant Staphylococcus aureus strain USA300, CS extract (CSE) potentiates biofilm formation via the down-regulation of quorum-sensing regulon accessory gene regulator. Because accessory gene regulator is a global regulator of the staphylococcal virulome, in the present study we sought to identify the effects of CS exposure on staphylococcal gene expression using RNAseq. Comparative analysis of RNAseq profiles revealed the upregulation of important virulence genes encoding surface adhesins (fibronectin-and fibrinogen-binding proteins A and B and clumping factor B) and proteins involved in immune evasion, such as staphylocoagulase, staphylococcal protein A, and nuclease. In concurrence with the RNAseq data, we observed: (1) significant up-regulation of the ability of CSE-exposed USA300 to evade phagocytosis by macrophages and neutrophils, a known function of staphylococcal protein A; and (2) twofold higher (P , 0.001) number of CSE-exposed USA300 escaping neutrophil extracellular trap-mediated killing by neutrophils as a result of CS-mediated induction of nuclease. Importantly, in three different mouse strains, C57BL6/J, Balb/C, and A/J, we observed significantly higher pulmonary bacterial burden in animals infected with CSEexposed USA300 as compared with medium-exposed control USA300. Taken together, these observations indicate that bioactive chemicals in CS induce hypervirulence by augmenting the ability of USA300 to evade bactericidal functions of leukocytes, such as phagocytosis and neutrophil extracellular trap-mediated killing.

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Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Extract–Exposed Methicillin-Resistant Staphylococcus aureus Regulates Leukocyte Function for Pulmonary Persistence

Caskey

Singh²,

Paudel³

et al. 2016

Am J Respir Cell Mol Biol

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“…Additionally, only linezolid significantly decreased neutrophil infiltration in infected lung tissues, as documented by Ly6G-immunostaining. Consistently, it was concluded that, despite linezolid and vancomycin showed similar antibacterial activity in MRSAinfected lung, linezolid could be superior to vancomycin in MRSA pneumonia by modulating the inflammatory reaction and by protecting the lung from MRSA-associated damages [66].…”

Section: Linezolid Vs Vancomycin In the Treatment Of Mrsa-related Pnementioning

confidence: 86%

“…However, other authors have recently postulated that lung protection of linezolid from pathogen-associated damages in pneumonia could be related to the prevention of an excessive inflammatory response [66]. In a mouse model of MRSA-induced pneumonia treated with linezolid or with vancomycin, no difference was found between linezolid-treated and vancomycintreated animals in terms of decrease of bacterial burden in lung after 48 h of treatment.…”

Section: Linezolid Vs Vancomycin In the Treatment Of Mrsa-related Pnementioning

confidence: 92%

Clinical pharmacological approach for balancing the use of daptomycin and linezolid in comparison with that of vancomycin in the treatment of MRSA-related infections

Pea

Petrosillo

Garau

2015

Expert Review of Anti-infective Therapy

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Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most challenging bacterial pathogens responsible for severe infections among hospitalized patients. In recent years there is increasing evidence that the clinical efficacy of vancomycin is progressively decreasing. Although daptomycin and linezolid are valuable alternatives to vancomycin for the treatment of MRSA-related bloodstream infections and pneumonia, respectively, a great deal of debate exists about their role in daily clinical practice due to cost-effectiveness issues. In this article we put into perspective the importance of pharmacokinetic/pharmacodynamic (PK/PD) considerations based on recent experimental and clinical data to argue whether they could be helpful in identifying clinical conditions in which these agents could be advantageous as compared to vancomycin.

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“…Given that HA-MRSA is substantially less virulent, it is difficult to establish a severe pneumonia model by transtracheal infection using HA-MRSA. A few studies have attempted to use a murine transtracheal pneumonia model of HA-MRSA (27)(28)(29) by inoculating a high load of MRSA (up to 10 7 to 10 9 CFU/mouse) via tracheal injection. At least 2 ϫ 10 9 CFU/mouse was necessary to induce lethal MRSA pneumonia, even in a neutropenic mouse model treated with cyclophosphamide (29).…”

Section: Discussionmentioning

confidence: 99%

“…Differential cell counts were performed by counting 100 cells. To validate the effect of antibiotics on inflammatory cytokines in this MRSA pneumonia model, we examined the concentration of two previously validated mouse cytokines (27,28,44), macrophage inflammatory protein-2 (MIP-2) and interleukin-6 (IL-6) using enzyme-linked immunosorbent assay (ELISA) kits (R&D Systems, Minneapolis, MN) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Efficacy of Azithromycin in a Mouse Pneumonia Model against Hospital-Acquired Methicillin-Resistant Staphylococcus aureus

Yamashita

Nagaoka

Kimura

et al. 2019

Antimicrob Agents Chemother

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The use of macrolides against pneumonia has been reported to improve survival; however, little is known about their efficacy against methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. In this study, we investigated the effect of azithromycin (AZM) and compared it with that of vancomycin (VCM) and daptomycin (DAP) in a murine model of MRSA pneumonia. Mice were infected with MRSA by intratracheal injection and then treated with AZM, VCM, or DAP. The therapeutic effect of AZM, in combination or not with the other drugs, was compared in vivo, whereas the effect of AZM on MRSA growth and toxin mRNA expression was evaluated in vitro. In vivo, the AZM-treated group showed significantly longer survival and fewer bacteria in the lungs 24 h after infection than the untreated group, as well as the other anti-MRSA drug groups. No significant decrease in cytokine levels (interleukin-6 [IL-6] and macrophage inflammatory protein-2 [MIP-2]) in bronchoalveolar lavage fluid or toxin expression levels (α-hemolysin [Hla] and staphylococcal protein A [Spa]) was observed following AZM treatment. In vitro, AZM suppressed the growth of MRSA in late log phase but not in stationary phase. No suppressive effect against toxin production was observed following AZM treatment in vitro. In conclusion, contrary to the situation in vitro, AZM was effective against MRSA growth in vivo in our pneumonia model, substantially improving survival. The suppressive effect on MRSA growth at the initial stage of pneumonia could underlie the potential mechanism of AZM action against MRSA pneumonia.

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Linezolid Dampens Neutrophil-Mediated Inflammation in Methicillin-Resistant Staphylococcus aureus-Induced Pneumonia and Protects the Lung of Associated Damages

Abstract: Our results indicate that linezolid could be superior to vancomycin for the management of MRSA pneumonia by attenuating an excessive inflammatory reaction and protecting the lung from pathogen-associated damages.

Cited by 30 publications

References 45 publications

Cigarette Smoke Extract–Exposed Methicillin-Resistant Staphylococcus aureus Regulates Leukocyte Function for Pulmonary Persistence

Cigarette Smoke Extract–Exposed Methicillin-Resistant Staphylococcus aureus Regulates Leukocyte Function for Pulmonary Persistence

Clinical pharmacological approach for balancing the use of daptomycin and linezolid in comparison with that of vancomycin in the treatment of MRSA-related infections

Efficacy of Azithromycin in a Mouse Pneumonia Model against Hospital-Acquired Methicillin-Resistant Staphylococcus aureus

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