Does linezolid modulate lung innate immunity in a murine model of methicillin-resistant Staphylococcus aureus pneumonia?*

Akinnusi, Morohunfolu E.; Hattemer, Angela; Gao, Wei; El-Solh, Ali

doi:10.1097/ccm.0b013e31821bd79e

Cited by 19 publications

(16 citation statements)

References 41 publications

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“…This is the first study to show that LZD did not have an effect on genome-wide host lung innate immunity at the mRNA level. This novel finding is consistent with the previous findings reported by Akinnusi et al (2011), who showed that LZD exhibits a minimal modulatory effect on protein levels of IL-6 and MCP-5 in a murine model of MRSA-pneumonia [12]. However, Garcia-Roca et al (2006) demonstrated that LZD significantly suppressed the synthesis of the cytokines (IL6, TNFα, IL-1ra and IL-1β) in human peripheral blood mononuclear cells [26].…”

Section: Discussionsupporting

confidence: 93%

“…In addition, exotoxin release leads to a corresponding increase in induction of tumor necrosis factor, which can be also suppressed with LZD [9-11]. Using a murine model of pneumonia, Akinnusi et al (2011) reported that LZD and VAN have comparable effects in modulating the expression of metalloproteinases (MMPs) in bronchoalveolar lavage fluid (BALF) and in regulating neutrophil activation [12]. They concluded that LZD exhibits a minimal modulatory effect on innate immunity in the animal model of MRSA pneumonia.…”

Section: Introductionmentioning

confidence: 99%

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Linezolid Exerts Greater Bacterial Clearance but No Modification of Host Lung Gene Expression Profiling: A Mouse MRSA Pneumonia Model

et al. 2013

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BackgroundLinezolid (LZD) is beneficial to patients with MRSA pneumonia, but whether and how LZD influences global host lung immune responses at the mRNA level during MRSA-mediated pneumonia is still unknown.MethodsA lethal mouse model of MRSA pneumonia mediated by USA300 was employed to study the influence of LZD on survival, while the sublethal mouse model was used to examine the effect of LZD on bacterial clearance and lung gene expression during MRSA pneumonia. LZD (100mg/kg/day, IP) was given to C57Bl6 mice for three days. On Day 1 and Day 3 post infection, bronchoalveolar lavage fluid (BALF) protein concentration and levels of cytokines including IL6, TNFα, IL1β, Interferon-γ and IL17 were measured. In the sublethal model, left lungs were used to determine bacterial clearance and right lungs for whole-genome transcriptional profiling of lung immune responses.ResultsLZD therapy significantly improved survival and bacterial clearance. It also significantly decreased BALF protein concentration and levels of cytokines including IL6, IL1β, Interferon-γ and IL17. No significant gene expression changes in the mouse lungs were associated with LZD therapy.ConclusionLZD is beneficial to MRSA pneumonia, but it does not modulate host lung immune responses at the transcriptional level.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Linezolid Exerts Greater Bacterial Clearance but No Modification of Host Lung Gene Expression Profiling: A Mouse MRSA Pneumonia Model

et al. 2013

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“…LZD (0.4 mg/mouse; 12 mg/kg of body weight) or vancomycin (VCM) (Shionogi & Co., Ltd., Osaka, Japan) (1 mg/mouse; 40 mg/kg) was subcutaneously (s.c.) admin-istered to mice immediately after intranasal administration of MRSA suspension (30 l/mouse; approximately 10 6 to 10 7 CFU/mouse). The administration doses of LZD and VCM were determined by reference to the previous reports (1,2,12,13,30,31). In some experiments, lower doses of LZD than described in the previous reports were selected to evaluate antiinflammatory effects not related to the bacterial killing effects.…”

Section: Datamentioning

confidence: 99%

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

Yoshizawa

Tateda

Saga

et al. 2012

Antimicrob Agents Chemother

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bIn the present study, immunomodulatory effects of linezolid (LZD) on methicillin-resistance Staphylococcus 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 initiated in vivo experiments 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. L inezoid (LZD) (Zyvox; Pfizer, Japan) is the first available agent in a new class of antimocrobials called oxazolidinones and was approved in Japan in 2006 for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections, such as sepsis, skin and soft tissue infections, surgical site infections, and pneumonia. It has a unique mechanism of action, which is inhibition of bacterial protein synthesis at the initiation step of protein biosynthesis (24), resulting in good efficacy in treating Gram-positive bacterial infections.Recently, several classes of antimicrobial agents, such as macrolides and quinolones, are reported to possess certain immunomodulatory effects (6,7,11,16,22,29). In particular, protein synthesis-suppressing antibiotics, such as clindamycin and macrolides, can induce a general inhibition of virulence factor expression, such as alpha-toxin (14,17,21,23,32). Although several investigators have reported immunomodulatory activity of LZD (4,5,8,9), the precise mechanism and its contribution to the clinical course are poorly understood.After approval of LZD for MRSA infections, administration of LZD has been used generally to treat patients with severe MRSA infections. ...

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“…While some murine studies have supported this hypothesis, others do not (1,2,14). The lack of considerable benefit with linezolid over vancomycin in mouse models of S. aureus infection has raised uncertainties about the potential benefits of linezolid in humans (6).…”

mentioning

confidence: 99%

Linezolid Is Superior to Vancomycin in Experimental Pneumonia Caused by Superantigen-Producing Staphylococcus aureus in HLA Class II Transgenic Mice

Karau

Tilahun

Schmidt³

et al. 2012

Antimicrob Agents Chemother

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Superantigens (SAg), the potent activators of the immune system, are important determinants of Staphylococcus aureus virulence and pathogenicity. Superior response to SAg in human leukocyte antigen (HLA)-DR3 transgenic mice rendered them more susceptible than C57BL/6 mice to pneumonia caused by SAg-producing strains of S. aureus. Linezolid, a bacterial protein synthesis inhibitor, was superior to vancomycin in inhibiting SAg production by S. aureus in vitro and conferred greater protection from pneumonia caused by SAg-producing staphylococci.T he pathogenicity and virulence of Staphylococcus aureus are determined by several exotoxins, and the superantigens (SAg) are one such family of exotoxins. SAg are the most powerful biological activators of T lymphocytes and other cells of the immune system (9). Through this property, SAg divert the immune response against the bacterium, thereby helping in bacterial immune evasion (5, 15). At the same time, massive immune activation caused by SAg is by itself pathogenic. A higher prevalence of many exotoxins, including the SAg, in community-associated methicillin-resistant S. aureus (CA-MRSA) strains may facilitate infection of healthy individuals (4,8,(10)(11)(12)19).Considering these factors, antibacterials such as linezolid that inhibit staphylococcal exotoxin (including the SAg) synthesis may be advantageous over bactericidal agents in treating infections caused by toxigenic S. aureus. While some murine studies have supported this hypothesis, others do not (1, 2, 14). The lack of considerable benefit with linezolid over vancomycin in mouse models of S. aureus infection has raised uncertainties about the potential benefits of linezolid in humans (6). Considering the enormous differences in the sensitivities of humans and conventional laboratory mice to SAg (conventional mice are believed to be 10 11 times more resistant to SAg than humans [10]), we hypothesized that the benefits of linezolid or similar antibacterial agents do not become apparent in conventional mice. On the other hand, these agents might in fact be useful in humans. Since transgenic mice expressing HLA class II molecules respond robustly to SAg similarly to humans (barring certain species-level differences such as absence of emetic response in mice), they are more susceptible to S. aureus and Streptococcus pyogenes (which also produces SAg) infections than conventional mice (13,16,17). Therefore, we evaluated the activities of linezolid and vancomycin, particularly their abilities to inhibit SAg production, and compared their effectiveness in pneumonia induced by toxigenic S. aureus strains, using human leukocyte antigen (HLA) class II transgenic mice.In support of the divergent response between conventional and HLA class II transgenic mice to SAg, splenocytes from HLA-DR3 transgenic mice responded more robustly to a purified staphylococcal SAg, staphylococcal enterotoxin B (SEB), than splenocytes from B6 mice (Fig. 1A). In addition, culture supernatants from a clinical S. aureus isolate capable of produ...

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Does linezolid modulate lung innate immunity in a murine model of methicillin-resistant Staphylococcus aureus pneumonia?*

Abstract: Linezolid did not display an advantage over vancomycin in modulating pulmonary innate immune response in a murine model of methicillin-resistant S. aureus pneumonia.

Cited by 19 publications

References 41 publications

Linezolid Exerts Greater Bacterial Clearance but No Modification of Host Lung Gene Expression Profiling: A Mouse MRSA Pneumonia Model

Linezolid Exerts Greater Bacterial Clearance but No Modification of Host Lung Gene Expression Profiling: A Mouse MRSA Pneumonia Model

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

Linezolid Is Superior to Vancomycin in Experimental Pneumonia Caused by Superantigen-Producing Staphylococcus aureus in HLA Class II Transgenic Mice

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