Staphylococcus aureus is a Gram-positive organism that is responsible for various infections such as skin abscess, osteomyelitis, and lung infection among patients with cystic fibrosis and chronic obstructive pulmonary disease (COPD).1-3 The treatment of S. aureus infection is complicated when foreign medical devices such as catheters, ventriculoperitoneal shunts, prosthetic joints and heart valves are present. These devices can serve as areas of biofilm formation. Biofilms are complex structures comprised of exopolysaccharide sheath and bacterial clusters.4,5 The biofilm matrix contributes to antimicrobial failure as it serves as a barrier against antibiotic penetration, facilitating bacterial persistence and mutation. Biofilms are not only confined to abiotic devices, but are also associated with biotic surfaces such as epithelial or dental surfaces.3
Levofloxacin, a newer-generation fluoroquinolone, has demonstrated good in vitro staphylococcal activity. However, based on published pharmacokinetic and pharmacodynamic data, high doses are typically recommended for staphylococcal infections.6 Gupta and colleagues recently published results of their experiments improving levofloxacin lung delivery and staphylococcal activity.7 The authors theorized that the antimicrobial activity of levofloxacin can be enhanced by lysozyme (1,4-beta-N-acetylmuramidase) – known to cleave glycosidic bonds in bacterial peptidoglycan wall.8 The investigators further developed an inhaled liposomal drug combination to improve levofloxacin-lysozyme lung delivery.9,10
Preformed biofilms in vitro were subjected to various combinations of levofloxacin and lysozyme. Results showed that even at sub-minimum inhibitory concentration, levofloxacin eradicated more than 85% of preformed biofilm when combined with lysozyme. The authors theorized that this enhanced activity is likely secondary to cell wall degradation of S. aureus by lysozyme. Using pH gradient method, levofloxacin was actively loaded into the liposomes and was then spray-dried with lysozyme solution. Entrapment efficiency of levofloxacin in liposome was greater than 80%. Levofloxacin liposome had a prolonged cumulative release of 85% at the end of 12 hours. This liposomal formation was found to improve drug retention in the lungs compared to levofloxacin solution.
To further investigate the therapeutic effect of the levofloxacin-lysozyme combination, female Wistar rats were inoculated with S. aureus intratracheally. The infected rats were randomized into untreated, levofloxacin solution alone (2 mg/kg), and levofloxacin liposome (2mg/kg) combined with lysozyme (2500 U/kg). Treatments were administered intratracheally once a day for two days. Histologic analysis of untreated rat lungs showed higher mRNA expression of inflammatory markers, cytokine levels and microbial load. Conversely, rats treated with the levofloxacin liposome-lysozyme combination had decreased local and systemic inflammation as well as controlled microbial burden. The combination was found to be safe as shown by the lack of histologic changes in rat organs in acute toxicity studies.
Inhaled levofloxacin liposome-lysozyme combination is a promising formulation to overcome biofilm-related staphylococcal respiratory infection.
Source:
Inhalable Levofloxacin Liposomes Complemented with Lysozyme for Treatment of Pulmonary Infection in Rats: Effective Antimicrobial and Antibiofilm Strategy.
PMID: 29464594
Link: https://www.ncbi.nlm.nih.gov/pubmed/29464594
References:
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