Efficacy of linezolid alone and in combination with rifampin in staphylococcal experimental foreign-body infection
Abstract number: 1733_1272
Murillo O., Euba G., Domenech A., Garcia A., Tubau F., Cabellos C., Gudiol F., Ariza J.
Objectives: To test the efficacy of linezolid alone (L) or combined with rifampin (R) against methicillin-susceptible Staphylococcus aureus (Sa) in comparison with cloxacillin (O) + R and R alone in vitro and in vivo in a rat tissue cage model of foreign-body infection.
Methods:In vitro studies: MICs (mg/L) of Sa (ATCC 29213) were L 4, O 0.5 and R 0.015. MBCs and 24 h kill-curves were performed in both the log-phase (EXP) and stationary phase (STP). Drugs were tested for a range of concentrations according to their MICs and achievable levels in human serum. Animal studies: Two Teflon tissue cages with 2 PMMA cover-slips each were subcutaneously implanted in rats. Three weeks after surgery, tissue-cage fluid (TCF) was inoculated with Sa and three weeks later, therapy was started and administered for 7 or 10 days. Therapeutic groups were (mg·kg/h): L (35/12), R (25/12), O (200/12) + R, L+R and controls (C). All groups were compared at days 7 and 10 (except for the O+R group, which was only evaluated at day 7) after the initiation of therapy. Quantitative cultures of TCF before and at the end of therapy were performed and differences between bacterial counts used as criteria of efficacy. Screening of R- or L-resistant strains was performed with culture of samples in agar plates containing R or L at 4 mg/mL.
Results: MBCs (mg/L) in the EXP and in the STP of Sa were respectively: 1, >256 (O); 64, >256 (L) and >8, >8 (R). Time-kill studies in the STP showed indifference and no bactericidal activity for any combination of L+R and O+R. Bacterial killing in TCF (means of decrease in log cfu/mL) at day 7 was (n): L 0.63 (26), R 1.2 (26), L+R 1.01 (28), O+R 1.29 (20) and C 0.33 (20). All groups showed better result than C (p < 0.05, ANOVA) and O+R and R were also better than L (p < 0.05). After 10 days of therapy the killing in TCF was L 1.22 (15), L+R 1.44 (16), R 0.1 (13) and C 0.4 (18); L and L+R were better than R and C (p < 0.05). Neither R- nor L-resistant strains were detected in TCF for combined therapies, whereas R-resistant Sa using R alone was observed in 90% and 100% of cases at days 7 and 10, respectively.
Conclusions: Combinations L+R and O+R were likely efficacious and as active as R alone, but both prevented the emergence of R-resistant Sa. L+R increased the efficacy with time in contrast with the decreased activity of R alone due to the growth of resistant strains. L alone was less effective although development of L-resistant Sa was not observed.
|Session name:||European Society of Clinical Microbiology and Infectious Diseases|
|Location:||ICC, Munich, Germany|
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