Short communicationEfficacy of linezolid against Panton–Valentine leukocidin (PVL)-positive meticillin-resistant Staphylococcus aureus (MRSA) in a mouse model of haematogenous pulmonary infection
Introduction
Community-acquired meticillin-resistant Staphylococcus aureus (MRSA) infection has been increasing worldwide [1]. Many strains of community-acquired MRSA have a phage harbouring the Panton–Valentine leukocidin (PVL) genes [2], [3], [4]. PVL is a pore-forming leukotoxin [5], [6], and PVL-positive S. aureus can cause primary skin and soft-tissue infections [7] as well as severe necrotising pneumonia in young immunocompetent patients [6], [7]. The mortality rate is 75% [4] and autopsy reveals extensive necrotic and haemorrhagic lesions of the trachea, bronchi, alveolar septa and parenchyma. Thus, new treatment strategies are needed for PVL-positive S. aureus infection.
Linezolid (LZD) has potent antibacterial activity against Gram-positive cocci, vancomycin (VAN)-resistant enterococci and MRSA. LZD has been reported to be more effective than VAN in achieving microbiological eradication for the treatment of MRSA infections [8].
Previously, we established a mouse model of pulmonary infection with S. aureus by intravenous (i.v.) injection of bacteria enmeshed in agar beads [9], [10], [11]. The aim of this study was to compare the activity and efficacy of LZD and VAN against PVL-positive S. aureus haematogenous pulmonary infection in a model mouse.
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Bacterial strains and culture conditions
PVL-positive S. aureus was kindly provided by Prof. T. Yamamoto (Niigata University, Niigata, Japan). The strain was classified as staphylococcal cassette chromosome mec (SCCmec) type IV [6]. The bacteria were stored at −80 °C in a Microbank® (Pro-Lab Diagnostics, Ontario, Canada) until use. Bacteria were grown at 37 °C on Mueller–Hinton II agar (Becton Dickinson and Company, Sparks, MD) or in brain–heart infusion (BHI) broth (BBL Microbiology System, Cockeysville, MD).
Antibiotics
LZD (Pfizer Japan Inc.,
Minimum inhibitory concentration of each antibiotic for Panton–Valentine leukocidin-positive Staphylococcus aureus
The MICs of LZD and VAN for PVL-positive S. aureus were 2 μg/mL and 1 μg/mL, respectively.
Bacteriological effects of antibacterial agents
When antibiotics were administered for 1 day, the number of bacteria in the lungs in the control, VAN and LZD groups was 6.69 ± 0.16, 6.52 ± 0.21 and 6.30 ± 0.22 log CFU/mL, respectively (no statistically significant differences) (Fig. 1a).
When antibiotics were administered for 3 days, the number of bacteria in the lungs in the control group was 6.77 ± 0.14 log CFU/mL. In contrast, the numbers in the VAN and LZD groups
Discussion
The present study is the first report to demonstrate establishment of a mouse model of PVL-positive S. aureus haematogenous pulmonary infection. Moreover, this model was used to compare the efficacy of LZD and VAN. LZD showed beneficial efficacy on bacteriological and histopathological examinations, cytokine levels and survival rates.
We previously reported the effect of LZD against a mouse model of haematogenous pulmonary infection with MRSA NUMR101, which was isolated from clinical samples at
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Antimicrobial and immunomodulatory effects of tedizolid against methicillin-resistant Staphylococcus aureus in a murine model of hematogenous pulmonary infection
2016, International Journal of Medical MicrobiologyCitation Excerpt :In this study, we used a murine model of hematogenous pulmonary infection to assess the effect of the antimicrobial agents on MRSA. Our previous study demonstrated the superiority of LZD over VAN against MRSA (NUMR101), vancomycin-insensitive S. aureus (VISA) or PVL-positive CA-MRSA (Yanagihara et al., 2002; Yanagihara et al., 2009). In this study, amongst all the antimicrobial agents, LZD and TZD significantly improved the survival rate, bacterial count in the lungs and the blood, and histopathological results, compared to the control.
Linezolid Effects on Bacterial Toxin Production and Host Immune Response: Review of the Evidence
2012, Current Therapeutic Research - Clinical and ExperimentalCitation Excerpt :Bacterial numbers detected in lung homogenates were significantly reduced compared with vancomycin in the MRSA-infected mice. In a separate study, Yanagihara et al35 compared the effects of linezolid and vancomycin (100 mg/kg/d IP twice daily for each) on a PVL-positive MRSA strain in the same mouse pulmonary infection model. Again, compared with vancomycin, linezolid significantly reduced the number of viable bacteria and the amount of histopathologic inflammatory damage.
Linezolid vs glycopeptide antibiotics for the treatment of suspected methicillin-resistant Staphylococcus aureus nosocomial pneumonia: A meta-analysis of randomized controlled trials
2011, ChestCitation Excerpt :In addition, subgroup comparisons of MRSA vs non-MRSA-related outcomes were not performed in the studies in this meta-analysis; thus, it would be difficult to argue for publication bias against null findings in this subgroup. Importantly, this meta-analysis does not investigate the efficacy of linezolid as a treatment of community-acquired MRSA; in vitro data, animal studies, and case reports suggest that linezolid may be of benefit for these toxin-producing strains.32–34,42,43 In conclusion, this meta-analysis does not show superiority of linezolid as compared with glycopeptide antibiotics for the treatment of nosocomial pneumonia.
In vitro and in vivo model systems to study microbial biofilm formation
2010, Journal of Microbiological MethodsCitation Excerpt :These agar beads were subsequently transported into the pulmonary circulation to become entrapped in the pulmonary microvasculature. This system has been used to evaluate the efficacy of antibiotics (including linezolid, quinolones and novel carbapenems) (Kihara et al., 2008; Yanagihara et al., 2006, 2008, 2009). A second type of model is a murine model of chronic P. aeruginosa respiratory tract infection, developed to mimick infections observed in diffuse panbronchiolitis (Yanagihara et al., 1997).
Panton-Valentine leukocidin-producing Staphylococcus aureus necrotising pneumonia: Measuring toxin levels in microbiological samples to attest of linezolid clinical efficacy
2010, International Journal of Antimicrobial Agents