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Efficacy of linezolid against Panton–Valentine leukocidin (PVL)-positive meticillin-resistant Staphylococcus aureus (MRSA) in a mouse model of haematogenous pulmonary infection

https://doi.org/10.1016/j.ijantimicag.2009.06.024Get rights and content

Abstract

Many strains of community-acquired meticillin-resistant Staphylococcus aureus (MRSA) have a pore-forming leukotoxin, known as Panton–Valentine leukocidin (PVL), which can cause severe necrotising pneumonia. Linezolid (LZD) is a new antibacterial agent with potent antibacterial activity against MRSA. In this study, a mouse model of haematogenous pulmonary infection was used to compare the efficacies of LZD and vancomycin (VAN) against pulmonary infection caused by PVL-positive S. aureus. Following antibiotic administration for 3 days, the number of viable bacteria (mean ± standard error of the mean) in the control, VAN and LZD groups was 6.77 ± 0.14, 5.29 ± 0.27 and 4.25 ± 0.33 log colony-forming units/lung, respectively. LZD significantly decreased the number of viable bacteria in the lungs compared with the control and VAN groups (P < 0.05). The survival rate at Day 7 post-inoculation was higher in the LZD group (100%) than in the VAN group (50%) or the control group (0%). Histopathological examination and cytokine analysis also showed the beneficial efficacy of LZD compared with VAN. In conclusion, LZD significantly reduced bacterial numbers and inflammation in a mouse model of PVL-positive S. aureus haematogenous infection and improved the survival rate of infected mice compared with VAN. LZD is clinically effective against PVL-positive S. aureus.

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.

Section snippets

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

References (14)

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