PubMed · 4822311
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O Garborg. 1974-02-25. [Fucidin].. https://pubmed.ncbi.nlm.nih.gov/4822311/
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OBJECTIVE: Fusidic acid with rifampicin is used for the treatment of severe staphylococcal infection, particularly prosthetic joint infections. Previous studies using twice daily fusidic acid showed rifampicin increases fusidic acid clearance, potentially causing sub-therapeutic concentrations. It is uncertain whether this occurs with three-times daily dosing. This study sought to re-evaluate this potential drug-drug interaction. METHODS: In this prospective, open-label drug-drug interaction population pharmacokinetic (PK) study, participants were randomized to receive fusidic acid or rifampicin for 24 hours, followed by combination therapy for the duration of treatment. Drug concentration assays used liquid-chromatography mass spectroscopy on dried blood spots. Population PK models were built for fusidic acid, rifampicin and 25-desacetyl rifampicin. RESULTS: Ten participants were recruited. Inter-individual variability for both absorption (98.1%) and clearance (77.8%) were high for fusidic acid. A population pharmacokinetic model for fusidic acid revealed that early autoinhibition dominated over later rifampicin-mediated induction, resulting in a net decrease in fusidic acid clearance. The mean fusidic acid area under the curve during each dosing interval (AUCτ) at steady state was 1.76-fold [0.049, 34.918] higher relative to Day 1, despite high uncertainty.Large inter-individual (110%) variability in absorption was observed for rifampicin. There was no apparent effect on rifampicin metabolism by fusidic acid co-administration, however, fusidic acid decreased clearance of 25-desacetyl rifampicin. CONCLUSION: In patients treated with fusidic acid three times daily in combination with rifampicin, autoinhibition potentially counteracted rifampicin induction such that fusidic acid concentrations were not reduced. Rifampicin clearance was not affected by fusidic acid, but 25-desacetyl rifampicin clearance was decreased. There was large inter-individual variability in the observed concentrations and final parameter estimates.
Elongation factor (EF) G promotes tRNA translocation on the ribosome. We present three-dimensional reconstructions, obtained by cryo-electron microscopy, of EF-G-ribosome complexes before and after translocation. In the pretranslocation state, domain 1 of EF-G interacts with the L7/12 stalk on the 50S subunit, while domain 4 contacts the shoulder of the 30S subunit in the region where protein S4 is located. During translocation, EF-G experiences an extensive reorientation, such that, after translocation, domain 4 reaches into the decoding center. The factor assumes different conformations before and after translocation. The structure of the ribosome is changed substantially in the pretranslocation state, in particular at the head-to-body junction in the 30S subunit, suggesting a possible mechanism of translocation.
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