Virulence-Suppressing Effects of Linezolid on Methicillin-Resistant Staphylococcus aureus: Possible Contribution to Early Defervescence

ABSTRACTIn the present study, immunomodulatory effects of linezolid (LZD) on methicillin-resistanceStaphylococcus aureus(MRSA) infections were evaluated. We have retrospectively reviewed treatment effects of LZD on 52 patients with severe MRSA infections. Sixty-four percent of the febrile patients demonstrated significant defervescence within 3 days, despite the presence of positive culture results. We speculated that this finding might be due to early anti-inflammatory effects of LZD, and to investigate this further we initiatedin vivoexperiments using mice MRSA pneumonia models. Mice were treated with either LZD or vancomycin (VCM) immediately after intranasal administration of MRSA. Bacterial numbers and levels of inflammatory cytokines in the lungs were determined. Although the bacterial burden in the lungs was not apparently different between the two groups, LZD but not VCM treatment significantly reduced induction of inflammatory cytokines in the lungs (P< 0.05). To evaluate whether this anti-inflammatory response was due to suppression of virulence factor expression, filter-sterilized supernatants of MRSA incubated in broth overnight with sub-MICs of LZD were subcutaneously administered to mice. To clarify whether LZD possesses direct host-modulating activity, cytokine responses to the supernatants were examined in mice pretreated with LZD. Interestingly, MRSA solutions prepared in the presence of sub-MICs of LZD revealed significant suppression of interleukin 6 (IL-6) in a dose-dependent manner (P< 0.05), but pretreatment of mice with LZD revealed no changes in cytokines. These findings suggest that sub-MICs of LZD might suppress virulence factors of MRSA, which may be associated with a reduction in endogenous pyrogens. These data may explain at least in part early defervescence observed in LZD-treated individuals.

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AUC/MIC Pharmacodynamic Target Is Not a Good Predictor of Vancomycin Efficacy in Methicillin-Resistant Staphylococcus aureus Experimental Endocarditis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02486-16 ◽

2017 ◽

Vol 61 (6) ◽

Cited By ~ 5

Author(s):

Ximena Castañeda ◽

Cristina García-de-la-Mària ◽

Oriol Gasch ◽

Juan M. Pericas ◽

Yolanda Armero ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Good Predictor ◽

Methicillin Resistant Staphylococcus Aureus ◽

Area Under The Curve ◽

Methicillin Resistant ◽

Bacterial Counts ◽

Content Type ◽

Treatment Groups ◽

Mrsa Strains

ABSTRACT The aim of this in vivo study was to compare the efficacy of vancomycin at standard doses (VAN-SD) to that of VAN at adjusted doses (VAN-AD) in achieving a VAN area under the curve/MIC ratio (AUC/MIC) of ≥400 against three methicillin-resistant Staphylococcus aureus (MRSA) strains with different microdilution VAN MICs in an experimental endocarditis model. The valve vegetation bacterial counts after 48 h of VAN therapy were compared, and no differences were observed between the two treatment groups for any of the three strains tested. Overall, for VAN-SD and VAN-AD, the rates of sterile vegetations were 15/45 (33.3%) and 21/49 (42.8%) (P = 0.343), while the medians (interquartile ranges [IQRs]) for log10 CFU/g of vegetation were 2 (0 to 6.9) and 2 (0 to 4.5) (P = 0.384), respectively. In conclusion, this VAN AUC/MIC pharmacodynamic target was not a good predictor of vancomycin efficacy in MRSA experimental endocarditis.

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Anti-inflammatory Potential of Silk Sericin

Natural Product Communications ◽

10.1177/1934578x1300800424 ◽

2013 ◽

Vol 8 (4) ◽

pp. 1934578X1300800 ◽

Cited By ~ 4

Author(s):

Pornanong Aramwit ◽

Pasarapa Towiwat ◽

Teerapol Srichana

Keyword(s):

Negative Control ◽

Dependent Manner ◽

Silk Sericin ◽

Plantar Surface ◽

Cox 2 ◽

Anti Inflammatory ◽

The Right ◽

Dose Dependent ◽

Control Water

Silk sericin was found to suppress the production of pro-inflammatory cytokines, which are related to the inflammatory reaction. The objectives of this study were to investigate the anti-inflammatory effect of sericin in vivo using the carrageenan-induced rat edema model and changes in the histology of tissues. The effects of sericin on the expression of COX-2 and iNOS were also evaluated. Sericin solutions at 0.004-0.080 mg/mL were applied topically to the top of the hind paw and carrageenan (1.0 mg) was injected subcutaneously to the plantar surface of the right hind paw. Our results indicated that sericin significantly reduced the inflammation in rats’ paw compared with the negative control (water and acetone) and its effect at 0.080 mg/mL was only slightly lower than that of 1.0% w/v indomethacin. Similar numbers of polymorphonuclear and macrophage cells were found in rats’ tissue treated with indomethacin and sericin solution, while the numbers were significantly higher in their absence. The gene expression results by RT-PCR showed that the COX-2 and iNOS genes were down-regulated in samples treated with sericin in a dose dependent manner. These data indicated that the anti-inflammatory properties of sericin may be partly attributable to the suppression of the COX-2 enzyme and nitric oxide production.

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Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper

Antioxidants ◽

10.3390/antiox9111113 ◽

2020 ◽

Vol 9 (11) ◽

pp. 1113

Author(s):

Pamela Maher

Keyword(s):

Transition Metals ◽

Neurodegenerative Diseases ◽

Dependent Manner ◽

Copper Binding ◽

Drug Candidates ◽

Beneficial Effects ◽

Anti Inflammatory ◽

Dose Dependent

Alterations occur in the homeostasis of the transition metals iron (Fe2+) and copper (Cu2+) during aging and these are further amplified in neurodegenerative diseases, including Alzheimer’s disease (AD). These observations suggest that the most effective drug candidates for AD might be those that can reduce these alterations. The flavonoid fisetin has both neuroprotective and anti-inflammatory activity both in vitro and in vivo and can bind both iron and copper suggesting that its chelating activity might play a role in its beneficial effects. To test this idea, the effects of iron and copper on both the neuroprotective and anti-inflammatory activities of fisetin were examined. It is shown that while fisetin can reduce the potentiation of cell death by iron and copper in response to treatments that lower glutathione levels, it is much less effective when the metals are combined with other inducers of oxidative stress. In addition, iron but not copper reduces the anti-inflammatory effects of fisetin in a dose-dependent manner. These effects correlate with the ability of iron but not copper to block the induction of the antioxidant transcription factor, Nrf2, by fisetin. In contrast, although the flavanone sterubin also binds iron, the metal has no effect on sterubin’s ability to induce Nrf2 or protect cells from toxic or pro-inflammatory insults. Together, these results suggest that while iron and copper binding could contribute to the beneficial effects of neuroprotective compounds in the context of neurodegenerative diseases, the consequences of this binding need to be fully examined for each compound.

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ComparativeIn VivoEfficacies of Epithelial Lining Fluid Exposures of Tedizolid, Linezolid, and Vancomycin for Methicillin-Resistant Staphylococcus aureus in a Mouse Pneumonia Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.06427-11 ◽

2012 ◽

Vol 56 (5) ◽

pp. 2342-2346 ◽

Cited By ~ 37

Author(s):

Pamela R. Tessier ◽

Rebecca A. Keel ◽

Mao Hagihara ◽

Jared L. Crandon ◽

David P. Nicolau

Keyword(s):

Staphylococcus Aureus ◽

Methicillin Resistant Staphylococcus Aureus ◽

Bacterial Density ◽

Epithelial Lining ◽

Control Groups ◽

Epithelial Lining Fluid ◽

Methicillin Resistant ◽

Content Type ◽

Treatment Groups

ABSTRACTThe antibacterial efficacies of tedizolid phosphate (TZD), linezolid, and vancomycin regimens simulating human exposures at the infection site against methicillin-resistantStaphylococcus aureus(MRSA) were compared in anin vivomouse pneumonia model. Immunocompetent BALB/c mice were orally inoculated with one of three strains of MRSA and subsequently administered 20 mg/kg TZD every 24 hours (q24h), 120 mg/kg linezolid q12h, or 25 mg/kg vancomycin q12h over 24 h. These regimens produced epithelial lining fluid exposures comparable to human exposures observed following intravenous regimens of 200 mg TZD q24h, 600 mg linezolid q12h, and 1 g vancomycin q12h. The differences in CFU after 24 h of treatment were compared between control and treatment groups. Vehicle-dosed control groups increased in bacterial density an average of 1.1 logs. All treatments reduced the bacterial density at 24 h with an average of 1.2, 1.6, and 0.1 logs for TZD, linezolid, and vancomycin, respectively. The efficacy of TZD versus linezolid regimens against the three MRSA isolates was not statistically different (P> 0.05), although both treatments were significantly different from controls. In contrast, the vancomycin regimen was significantly different from TZD against one MRSA isolate and from linezolid against all isolates. The vancomycin regimen was less protective than either the TZD or linezolid regimens, with overall survival of 61.1% versus 94.7% or 89.5%, respectively. At human simulated exposures to epithelial lining fluid, vancomycin resulted in minimal reductions in bacterial counts and higher mortality compared to those of either TZD or linezolid. TZD and linezolid showed similar efficacies in this MRSA pneumonia model.

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Piperine Plays an Anti-Inflammatory Role inStaphylococcus aureusEndometritis by Inhibiting Activation of NF-κB and MAPK Pathways in Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/8597208 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Wen-jun Zhai ◽

Zhen-biao Zhang ◽

Nian-nian Xu ◽

Ying-fang Guo ◽

Changwei Qiu ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Inflammatory Response ◽

Mouse Model ◽

Biological Activities ◽

Dependent Manner ◽

Pathogenic Microorganisms ◽

Histopathological Changes ◽

Natural Medicine ◽

Anti Inflammatory ◽

Dose Dependent

Endometritis is commonly caused by pathogenic microorganisms, includingStaphylococcus aureus(S. aureus). Piperine, which is a natural medicine, has shown a variety of biological activities. To explore the effect and mechanism of piperine onS. aureusendometritis, a mouse model ofS. aureusendometritis was successfully established in the present study. Histopathological changes were observed with H&E staining, cytokines were analyzed by ELISA, mRNA was analyzed by qPCR, and proteins were detected by western blot. The results showed that piperine could significantly alleviate inflammatory injury inS. aureusendometritis. The qPCR and ELISA results showed that piperine effectively reduced theS. aureus-induced overexpression of TNF-α, IL-1β, and IL-6 but increased the expression of IL-10. TheS. aureus-induced inflammation was related to TLR-2 and TLR-4 because the results showed that their expression was increased inS. aureusinfection but then decreased with piperine treatment. To further confirm that piperine caused an anti-inflammatory response by targeting NF-κB and MAPKs, the expression of I-κB, p65, p38, ERK, and JNK was measured. The phosphorylation of I-κB, p65, p38, ERK, and JNK was inhibited by piperine in a dose-dependent manner. All of the results indicated that piperine may be a potential anti-inflammatory drug both in endometritis and in otherS. aureus-induced diseases.

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Physiologically relevant aspirin concentrations trigger immunostimulatory cytokine production by human leukocytes

PLoS ONE ◽

10.1371/journal.pone.0254606 ◽

2021 ◽

Vol 16 (8) ◽

pp. e0254606

Author(s):

Regine Brox ◽

Holger Hackstein

Keyword(s):

Acetylsalicylic Acid ◽

Inflammatory Cytokines ◽

Whole Blood ◽

Plasma Concentrations ◽

Immunomodulatory Activity ◽

Prostaglandin E ◽

Dependent Manner ◽

Cox 2 ◽

Anti Inflammatory

Acetylsalicylic acid is a globally used non-steroidal anti-inflammatory drug (NSAID) with diverse pharmacological properties, although its mechanism of immune regulation during inflammation (especially at in vivo relevant doses) remains largely speculative. Given the increase in clinical perspective of Acetylsalicylic acid in various diseases and cancer prevention, this study aimed to investigate the immunomodulatory role of physiological Acetylsalicylic acid concentrations (0.005, 0.02 and 0.2 mg/ml) in a human whole blood of infection-induced inflammation. We describe a simple, highly reliable whole blood assay using an array of toll-like receptor (TLR) ligands 1–9 in order to systematically explore the immunomodulatory activity of Acetylsalicylic acid plasma concentrations in physiologically relevant conditions. Release of inflammatory cytokines and production of prostaglandin E2 (PGE2) were determined directly in plasma supernatant. Experiments demonstrate for the first time that plasma concentrations of Acetylsalicylic acid significantly increased TLR ligand-triggered IL-1β, IL-10, and IL-6 production in a dose-dependent manner. In contrast, indomethacin did not exhibit this capacity, whereas cyclooxygenase (COX)-2 selective NSAID, celecoxib, induced a similar pattern like Acetylsalicylic acid, suggesting a possible relevance of COX-2. Accordingly, we found that exogenous addition of COX downstream product, PGE2, attenuates the TLR ligand-mediated cytokine secretion by augmenting production of anti-inflammatory cytokines and inhibiting release of pro-inflammatory cytokines. Low PGE2 levels were at least involved in the enhanced IL-1β production by Acetylsalicylic acid.

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The N-Terminal Domain of Thrombomodulin Sequesters HMGB1: A Novel Anti-Inflammatory Mechanism.

Blood ◽

10.1182/blood.v104.11.3435.3435 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3435-3435

Author(s):

Kazuhiro Abeyama ◽

Yasushi Yoshimoto ◽

Ikuro Maruyama

Keyword(s):

Protein C ◽

Statistical Significance ◽

Dependent Manner ◽

Protective Effects ◽

Binding Studies ◽

Terminal Domain ◽

Anti Inflammatory ◽

Dose Dependent

Abstract Thrombomodulin (TM) is an endothelial anticoagulant cofactor that promotes thrombin-mediated formation of activated protein C (APC), the latter an enzyme with potent anti-coagulant and anti-inflammatory properties. We have found that the N-terminal, lectin-like domain (D1) of thrombomodulin has unique anti-inflammatory properties. Thrombomodulin, via D1, binds high mobility group-B1 DNA binding protein (HMGB1), a factor closely associated with necrotic cell damage following its release from the nucleus, thereby preventing leukocyte activation in vitro, and ultraviolet radiation-induced cutaneous inflammation and lipopolysaccharide-induced lethality in vivo. Our data also demonstrate anti-inflammatory properties of a peptide spanning the D1 domain of TM and suggest its therapeutic potential. These findings highlight a novel mechanism through which an endothelial cofactor, TM, suppresses inflammation; i.e., sequestration of mediators thereby preventing their interaction with cell surface receptors on effector cells in the vasculature. Results: TM binds HMGB1 and prevents expression of pro-inflammatory activity. Our co-culture studies of leukocytes and HUVEC, and results in the cutaneous irritation model suggested that early release of a mediator, such as HMGB1, might contribute importantly to cellular activation in inflammation at later time points. In this context, TM might have the ability to decrease HMGB1-mediated inflammatory events. Binding studies using surface plasmon resonance (SPR), performed to directly assess the interaction of TM and immobilized HMGB1, demonstrated dose-dependent binding in the nanomolar range (Kd ~232 nM). Furthermore, addition of rhs-TM decreased, in a dose-dependent manner, the binding of HMGB1 to RAGE through the its N-terminal domain, but not anti-coagulant domain. TM and the N-terminal-derived TM peptide have anti-inflammatory effects in settings where HMGB1 is a likely key mediator. In HMGB1-mediated skin inflammation model, systemic administration of rhs-TM, its lectin-like domain and sRAGE resulted in a significant blunting of the inflammatory response. In contrast, the effect of anti-coagulant domain, although showing a trend toward decreased ear swelling, did not achieve statistical significance (anticoagulant domain has anti-inflammatory effects in vivo that probably reflect its ability to support thrombin-mediated activation of protein C; the latter does not occur in vitro after inactivation of the protein C zymogen by heat treatment). In view of recent data suggesting a link between HMGB1 released from injured tissue and endotoxin-induced lethality in mice, we also tested whether rhs-TM and its lectin-like domain might also have protective effects in this model. We employed a dose of intraperitoneal (IP) LPS (10 mg/kg) resulting in 100% lethality by 96 hrs. Systemic (IP) treatment of animals with anti-HMGB1 IgY had a protective effect with respect to lethality at 4 days, whereas the same regimen of nonimmune IgY was without effect. Similarly, IP administration of rhs-TM and its N-teminal lectin domain, but not anti-coagulant domain had complete protective effects compared with anti-HMGB1 IgY. Conclusion: Our findings have elucidated an unexpected anti-inflammatory property of TM residing in the D1 domain, namely binding of HMGB1.

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Telavancin Is Active against Experimental Aortic Valve Endocarditis Caused by Daptomycin- and Methicillin-Resistant Staphylococcus aureus Strains

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01877-16 ◽

2016 ◽

Vol 61 (2) ◽

Cited By ~ 5

Author(s):

Wessam Abdelhady ◽

Arnold S. Bayer ◽

Rachelle Gonzales ◽

Liang Li ◽

Yan Q. Xiong

Keyword(s):

Staphylococcus Aureus ◽

Aortic Valve ◽

Untreated Control ◽

Methicillin Resistant Staphylococcus Aureus ◽

Infection Model ◽

Methicillin Resistant ◽

Content Type ◽

Mrsa Strains ◽

Culture Negative

ABSTRACT We compared the efficacy of telavancin (TLV) and daptomycin (DAP) in an experimental rabbit endocarditis model caused by two clinically derived daptomycin-resistant (DAPr) methicillin-resistant Staphylococcus aureus (MRSA) strains. TLV treatment significantly reduced MRSA densities in all target tissues and increased the percentage of these organs rendered culture negative compared to those with the untreated control or DAP-treated animals. These results demonstrate that TLV has potent in vivo efficacy against DAPr MRSA isolates in this invasive endovascular infection model.

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Virulent Bacteriophages Can Target O104:H4 Enteroaggregative Escherichia coli in the Mouse Intestine

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00602-12 ◽

2012 ◽

Vol 56 (12) ◽

pp. 6235-6242 ◽

Cited By ~ 59

Author(s):

Damien Maura ◽

Matthieu Galtier ◽

Chantal Le Bouguénec ◽

Laurent Debarbieux

Keyword(s):

Escherichia Coli ◽

Dependent Manner ◽

Content Type ◽

Intestinal Pathogens ◽

Colonization Model ◽

Mouse Intestine ◽

Further Development ◽

Dose Dependent

ABSTRACTIn vivobacteriophage targeting of enteroaggregativeEscherichia coli(EAEC) was assessed using a mouse intestinal model of colonization with the O104:H4 55989Str strain and a cocktail of three virulent bacteriophages. The colonization model was shown to mimic asymptomatic intestinal carriage found in humans. The addition of the cocktail to drinking water for 24 h strongly decreased ileal and weakly decreased fecal 55989Str concentrations in a dose-dependent manner. These decreases in ileal and fecal bacterial concentrations were only transient, since 55989Str concentrations returned to their original levels 3 days later. These transient decreases were independent of the mouse microbiota, as similar results were obtained with axenic mice. We studied the infectivity of each bacteriophage in the ileal and fecal environments and found that 55989Str bacteria in the mouse ileum were permissive to all three bacteriophages, whereas those in the feces were permissive to only one bacteriophage. Our results provide the first demonstration that bacterial permissivity to infection with virulent bacteriophages is not uniform throughout the gut; this highlights the need for a detailed characterization of the interactions between bacteria and bacteriophagesin vivofor the further development of phage therapy targeting intestinal pathogens found in the gut of asymptomatic human carriers.

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Therapeutic efficacy of BO-3482, a novel dithiocarbamate carbapenem, in mice infected with methicillin-resistant Staphylococcus aureus.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.10.2278 ◽

1997 ◽

Vol 41 (10) ◽

pp. 2278-2281 ◽

Cited By ~ 25

Author(s):

R Nagano ◽

K Shibata ◽

T Naito ◽

A Fuse ◽

K Asano ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Therapeutic Efficacy ◽

Methicillin Resistant Staphylococcus Aureus ◽

Infection Model ◽

Dependent Manner ◽

Methicillin Resistant ◽

Mrsa Strains ◽

Systemic Infections

The in vivo activity of BO-3482, which has a dithiocarbamate chain at the C-2 position of 1beta-methyl-carbapenem, was compared with those of vancomycin and imipenem in murine models of septicemia and thigh infection with methicillin-resistant Staphylococcus aureus (MRSA). Because BO-3482 was more susceptible than imipenem to renal dehydropeptidase I in a kinetic study of hydrolysis by this renal enzyme, the therapeutic efficacy of BO-3482 was determined during coadministration with cilastatin. In the septicemia models, which involved two homogeneous MRSA strains and one heterogeneous MRSA strain, the 50% effective doses were, respectively, 4.80, 6.06, and 0.46 mg/kg of body weight for BO-3482; 5.56, 2.15, and 1.79 mg/kg for vancomycin; and >200, >200, and 15.9 mg/kg for imipenem. BO-3482 was also as effective as vancomycin in an MRSA septicemia model with mice with cyclophosphamide-induced immunosuppression. In the thigh infection model with a homogeneous MRSA strain, the bacterial counts in tissues treated with BO-3482-cilastatin were significantly reduced in a dose-dependent manner compared with the counts in those treated with vancomycin and imipenem-cilastatin (P < 0.001). These results indicate that BO-3482-cilastatin is as effective as vancomycin in murine systemic infections and is more bactericidal than vancomycin in local-tissue infections. The potent in vivo activity of BO-3482-cilastatin against such MRSA infections can be ascribed to the good in vitro anti-MRSA activity and improved pharmacokinetics in mice when BO-3482 is combined with cilastatin and to the bactericidal nature of the carbapenem.

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