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  • Open Access

Efficacy of linezolid (LZD), vancomycin (VAN) and its combinations with rifampin (RIF) in the treatment of experimental meningitis due to methicillin-resistant Staphylococcus aureus

  • 1Email author,
  • 1,
  • 1,
  • 1,
  • 1,
  • 1,
  • 1 and
  • 1
BMC Proceedings20082 (Suppl 1) :P21

https://doi.org/10.1186/1753-6561-2-s1-p21

  • Published:

Keywords

  • Lactate
  • Meningitis
  • Bactericidal Activity
  • Vancomycin
  • Staphylococcus Aureus

Objective

To study the in vitro and in vivo activity of LZD, VAN and its combinations with RIF in a rabbit meningitis model, caused by two strains of S. aureus with different susceptibilities to glycopeptides.

Methods

In vitro

MICs (mg/L): Strain A (LZD = 2, VAN = 1, RIF = 0.018) and B (LZD = 4, VAN = 8, RIF = 512). The bactericidal activity and synergy (time-kill curves) were studied over 24 h. Drugs were tested for a range of concentrations according to their MICs and achievable human serum levels (1/4x-4xMIC) against both strains.

In vivo

New Zealand rabbits (2.5–3 kg) were used, with an inoculum of 8.5–9 Log cfu/mL. PK/PD parameters (blood and CSF) were determined (Cmax [mg/L]; AUC [mg.h/L]; t1/2 [h]; t > MIC [h]; AUC/MIC) after a single dose of each antimicrobial on infected rabbits. In the therapy experiments, animals (n = 6 per schedule) were grouped in untreated (CON), or treated with LZD (20 mg/kg), VAN (25 mg/kg every 4 hours, 4 doses), RIF (15 mg/kg) every 24 hours (1 dose), LZD+RIF or VAN+RIF. CSF variables analyzed at 0, 4, 6 and 24 h of treatment were: bacterial concentration (Log10 cfu/mL), WBC (cells/mL), lactate (mmol/L) and protein concentration (g/L). Statistical Analysis: Wilcoxon and Anova test were used.

Results

In vitro

The following schedules were bactericidal: Strain A: LZD (4xMIC) and the following combinations RIF (2xMIC)+LZD(4xMIC), RIF (1xMIC)+LZD (1/2xMIC), RIF (1/2xMIC)+LZD (1xMIC); and strain B: VAN (4xMIC, 2xMIC) and the combinations of both drugs with RIF.

In vivo

PK/PD Cmax (μg/mL): Blood: LZD 20.84, VAN 59.59, RIF 52.38, CSF: LZD 4.64, VAN 4.12; RIF 1.22. Percentage of penetration: LZD 19%; VAN 15%; RIF 3.8%.

Bacterial concentration (0, 4, 6, 24 h): Strain A: CON (4.94, 4.48, 4.76, 4.65), LZD (4.96, 4.71, 4.81, 4.27), VAN (5.25, 4.62, 4.30, 4.95), RIF (5.32, 5.65, 5.19, 4.80), LDZ+RIF (4.85, 4.90, 4.82, 4.17) and VAN+RIF (5.34, 5.30, 5.36, 4.61); Strain B: CON (5.19, 4.67, 4.81, 4.37), LZD (4.85, 4.37, 4.18, 3.67), VAN (5.00, 5.63, 4.79, 4.79) and LDZ+RIF (5.02, 4.90, 4.53, 4.21). For Strain B, LZD and LZD+RIF significantly reduced bacterial concentration (24 h vs. 0 h, p < 0.05). LZD reduced the CSF lactate and proteins levels (24 h vs. 0 h, p < 0.05).

Conclusion

In this model of experimental meningitis caused by a GISA strain, linezolid and linezolid plus rifampin were effective reducing the CSF bacterial concentration and inflammatory parameters.

Authors’ Affiliations

(1)
IDIBELL, Hospital Universitari de Bellvitge, L' Hospitalet de Llobregat, Barcelona, 08907, Spain

Copyright

© Garrigósc et al; licensee BioMed Central Ltd. 2008

This article is published under license to BioMed Central Ltd.

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