Abstract
Vancomycin is the treatment of choice for infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Clinically, combinations of vancomycin (VAN) and beta-lactams have been shown to improve patient outcomes compared to VAN alone for the treatment of MRSA bloodstream infections. However, VAN is known to cause nephrotoxicity, which could be ameliorated using biocompatible lipid drug delivery systems or liposomes. Previous attempts have been made for encapsulation of VAN in liposomes; however, drug loading has been poor, mainly because of the high aqueous solubility of VAN. In this study, we report a robust method to achieve high loading of VAN and cefazolin (CFZ) in unilamellar liposomes. Liposomes of sizes between 170–198 nm were prepared by modified reverse phase evaporation method and achieved high loading of 40% and 26% (weight/weight) for VAN and CFZ, respectively. Liposomal VAN reduced minimum inhibitory concentration (MIC) values 2-fold in comparison to commercial VAN. The combination of liposomal VAN (LVAN) and liposomal CFZ (LCFZ) demonstrated a 7.9-fold reduction compared to LVAN alone. Rhodamine dye-loaded liposomes demonstrated superior cellular uptake in macrophage-like RAW 264.7 cells. Fluorescent images of LVAN-encapsulating near-infrared (NIR) dye, S0456 (LVAN-S0456) clearly indicated that LVAN-S0456 had reduced renal excretion with very low fluorescent intensity in the kidneys. It is anticipated that the long circulation and reduced kidney clearance of LVAN-S0456 compared to VAN-S0456 injected in mice can lead to enhanced efficacy against MRSA infections with reduced nephrotoxicity. Overall, our developed formulations of VAN when administered alone or in combination with CFZ, provide a rational approach for combating MRSA infections.
Highlights
Methicillin-resistant Staphylococcus aureus (MRSA) is a world-wide major bacterial pathogen responsible for a wide variety of infections ranging from skin and soft tissue to bone and Materials 2018, 11, 1245; doi:10.3390/ma11071245 www.mdpi.com/journal/materialsMaterials 2018, 11, 1245 joint, bloodstream infections, pneumoniae, meningitis, and infective endocarditis
It is anticipated that the long circulation and reduced kidney clearance of liposomal VAN (LVAN)-S0456 compared to VAN-S0456 injected in mice can lead to enhanced efficacy against MRSA infections with reduced nephrotoxicity
Antibiotics like quinopristin/dalfopristin, telithromycin, linezolid, and daptomycin are licensed for clinical use in treating infections, including those caused by MRSA [1]
Summary
Methicillin-resistant Staphylococcus aureus (MRSA) is a world-wide major bacterial pathogen responsible for a wide variety of infections ranging from skin and soft tissue to bone and Materials 2018, 11, 1245; doi:10.3390/ma11071245 www.mdpi.com/journal/materials. The total daily dose of CFZ required to prevent the emergence of VAN resistance in MRSA was 24-fold lower typically used to treat infection [4]. The use of VAN in combination with CFZ should enhance activity against MRSA, but may prevent the emergence of VAN resistance. We believe that VAN liposomes will lower the overall dose exposure of VAN and decrease the associated nephrotoxicity, making it suitable for application in the treatment of MRSA-infected patients. Combination with liposomal CFZ has the potential for lowering the VAN MIC and thereby improving the activity of VAN in the treatment of MRSA infection. This study explains the formulation of VAN and CFZ liposomes by reverse phase evaporation method and testing for antimicrobial activity against MRSA strains. These formulations can translate into successful animal and patient efficacy with an improvement in patient safety
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