Antibiofilm and intraosteoblastic activities of rifamycins against Staphylococcus aureus: promising in vitro profile of rifabutin.

Abstract

BACKGROUND:

Targeting biofilm-embedded and intraosteoblastic Staphylococcus aureus, rifampicin gained a pivotal role in bone and joint infection (BJI) treatment. Two other rifamycins, rifabutin and rifapentine, may represent better-tolerated alternatives, but their activity against bacterial reservoirs associated with BJI chronicity has never been evaluated.

OBJECTIVES:

To evaluate the activities of rifampicin, rifabutin and rifapentine in osteoblast infection models.

METHODS:

Using three S. aureus isolates, rifamycins were compared regarding: (i) their intracellular activity in 'acute' (24 h) and 'chronic' (7 days) osteoblast infection models at 0.1× MIC, 1× MIC, 10× MIC and 100× MIC, while impacting infection-induced cytotoxicity (MTT assay), intracellular phenol-soluble modulin (PSM) secretion (RT-PCR), resistance selection and small colony variant (SCV) emergence; and (ii) their minimal biofilm eradication concentration (MBEC) and their MIC to prevent biofilm formation (bMIC).

RESULTS:

At 0.1× MIC, only rifabutin significantly reduced intracellular inoculum and PSM secretion. All rifamycins allowed a 50% reduction of intraosteoblastic inoculum at higher concentrations, with no difference between acute and chronic infection models, while reducing infection-induced cytotoxicity and PSM secretion. Dose-dependent emergence of intracellular SCVs was observed for all molecules. No intracellular emergence of resistance was detected. bMICs were equivalent for all molecules, but MBEC90s of rifapentine and rifabutin were 10- to 100-fold lower than those of rifampicin, respectively.

CONCLUSIONS:

All rifamycins are efficient in reducing the S. aureus intraosteoblastic reservoir while limiting infection-induced cytotoxicity, with a higher activity of rifabutin at low concentrations. All molecules prevent biofilm formation, but only rifapentine and rifabutin consistently reduce formed biofilm-embedded bacteria for all isolates. The activity of rifabutin at lower doses highlights its therapeutic potential.

• Authors: Lélia Abad, Jérôme Josse, Jason Tasse, Sébastien Lustig, Tristan Ferry, Alan Diot, Frédéric Laurent, Florent Valour
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 75 Issue 6 Pg. 1466-1473 (06 01 2020) ISSN: 1460-2091 [Electronic] England
• PMID: 32125419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Anti-Bacterial Agents
• Rifamycins
• Rifabutin

Topics

• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Biofilms
• Humans
• Microbial Sensitivity Tests
• Rifabutin (pharmacology)
• Rifamycins (pharmacology)
• Staphylococcal Infections (drug therapy)
• Staphylococcus aureus