Stability study of daptomycin: identification of degradation products

Abstract

Daptomycin is an antimicrobial agent recently included in the market and used in many parts of the world. It has great importance for the clinical practice nowadays, mainly because it presents selective action against Gram-positive bacteria, including methicillin and vancomycin resistant strains. Although daptomycin have presented success in treating Gram-positive bacterial infections, some reports of daptomycin resistance have emerged in recent years. For this reason, this work aimed performing antibiotic sensitivity testing by broth microdilution method to evaluate the sensitivity of selected Gram-positive bacteria, such as Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Streptococcus pneumoniae and vancomycin-resistant enterococci, against daptomycin. In view of the increasing emergence of multi-resistant bacteria, the need for more effective therapeutic alternatives is in evidence. For this reason, another aim of this work was to perform preliminary tests to check the synergy among daptomycin and other new antimicrobial agents (LP9666, NCL 195 and NCL 219), which are studied by the research group where this work was performed at University of South Australia (UniSA), against selected strains of MRSA. For this, the MIC of single daptomycin was compared with the MIC obtained after the combination with other drugs, using the broth microdilution method. In addition, forced degradation studies are essential because they provide important information about the chemical behavior of the molecule, which can aid in the development of new formulations and the selection of the best packaging material. In this way, the third aim of this work was to perform a forced degradation study of daptomycin reference standard and analyze the degraded samples by HPLC. Daptomycin showed to be very active against MRSA, S. pneumoniae and VRE, although resistance was found for S. aureus (methicillin-sensitive). Although further research is necessary to support the obtained data, this result can be an alert to the medical society regarding the emergence of S. aureus resistance to this important antimicrobial agent. Regarding the preliminary synergy test, it was concluded that the combinations between daptomycin plus LP9666 and daptomycin plus NCL 195 are promising and also deserve further research. Finally, in relation to the stress degradation study, daptomycin showed to be highly sensitive to alkaline, acidic and oxidative conditions, and these factors should be considered when developing a new pharmaceutical dosage form and for choosing the best packaging material. (AU)