Treating methicillin-resistant Staphylococcus aureus (MRSA) bone infection with focused ultrasound combined thermally sensitive liposomes

Abstract

Objective

Chronic bone infection caused by Staphylococcus aureus biofilms in children and adults is characterized by reduced antibiotic sensitivity. In this study, we assessed ‘heat-targeted, on-demand’ antibiotic delivery for S. aureus killing by combining ciprofloxacin (CIP)-laden low-temperature sensitive liposomes (LTSLs) with local high-intensity focused ultrasound (HIFU) induced bone heating in a rat model of bone infection.

Methods

CIP-LTSLs were prepared using the thin-film hydration and extrusion method. Bone infection was established by surgically implanting an orthopedic K-wire colonized with methicillin-resistant S. aureus (MRSA) strain into rat’s femurs. For bone heating, ultrasound-guided HIFU exposures were performed to achieve a local temperature of 40–42 °C (∼15 min) concurrently with intravenous injection of CIP-LTSLs or CIP. CIP biodistribution was determined spectrophotometrically and therapeutic efficacy was determined by bacteriological, histological and scanning electron microscopy (SEM) analyses.

Results

CIP-LTSLs in the range of 183.5 nm ± 1.91 showed an encapsulation efficiency of >70% at 37 °C and a complete release at ∼42 °C. The metal implantation method yielded medullary osteomyelitis characterized by suppurative changes (bacterial and pus pockets) by day 10 in bones and adjoining muscle tissues. HIFU heating significantly improved CIP delivery from LTSLs in bones, resulting in a significant reduction in MRSA load compared to HIFU and CIP alone groups. These were also verified by histology and SEM, wherein a distinct reduction in S. aureus population in the infected metal wires and tissues from the combinatorial therapy was noted.

Conclusion

HIFU improved CIP delivery to bones, achieving clearance of hard-to-treat MRSA biofilms.

Keywords:

• MRSA
• HIFU
• LTSL
• biofilm
• antibiotic

Acknowledgements

The authors thank the Oklahoma Center for Advancement of Science & Technology (OCAST), the Focused Ultrasound Foundation and the Kerr Endowment at Oklahoma State University for supporting this research.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

We thank the Oklahoma Center for the Advancement of Science and Technology (OCAST), the Focused Ultrasound Foundation, and the Kerr Chair at Oklahoma State University for supporting the research work.