Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium that causes over half the cases of hospital-acquired pneumonia (1-3). It may also be referred to as multidrug-resistant and oxacillin-resistant S. aureus (ORSA). More particularly, MRSA is resistant to a large group of antibiotics called the beta-lactams, which include the penicillins, cephalosporins, and carbapenems. Many strains are also resistant to fluoroquinolones. Vancomycin remains one of only two antimicrobial agents approved by the US Food and Drug Administration (FDA) for treatment of MRSA pneumonia, but its clinical failure rates exceed 30% (4). Explanations for poor therapeutic outcomes include slow, time-dependent bactericidal activity; inadequate dosing; poor penetration into lung tissue and alveolar macrophages (5-11); and reduced susceptibility (4, 12, 13). S. aureus is an intracellular and extracellular pathogen (14, 15) that can survive with phagocytes and evade the immune system (16, 17).
Liposome-encapsulation of antimicrobials potentially offers enhanced pharmacokinetics, pharmacodynamics, and decreased toxicity over standard formulations (18, 19). Accumulating higher antimicrobial concentrations in infected tissues would allow for increased uptake by activated tissue macrophages (20, 21), and presumably improve treatment efficacy. Building on that concept, it has been shown that the attachment of polyethylene glycol (PEG) molecules to the surfaces of liposomes effectively delivers the chemotherapeutic drug, gemcitabine, to pancreatic cancer tumor cells. (Cosco D, et al., Cancer Chemotherapy and Pharmacology, 64:(5)1009-1020 (2009). The encapsulation of antimicrobials with PEGylated liposomes for use in formulations to treat or prevent bacterial infections, however, has never been described. Indeed, potent antibiotics like vancomycin are often relied upon as a last resort for the treatment of bacteria that are resistant to commonly used antibiotics (e.g., MRSA). However, the effectiveness of vancomycin is reduced by the fact that it poorly penetrates lung tissue. Such problems are commonly experienced during the treatment of MRSA infections of the lungs. Therefore, this invention employs surface PEGylated liposome-encapsulation to more effectively deliver the ‘drug-to-bug’ by depositing a higher concentration of vancomycin into lung tissue as compared to standard vancomycin formulation.
USPTO Backgrounds
USPTO Backgrounds