Lysostaphin Cream Eradicates Staphylococcus aureus Nasal Colonization in a Cotton Rat Model

Abstract

The anterior nares are a primary ecologic niche for Staphylococcus aureus, and nasal colonization by this opportunistic pathogen increases the risk of development of S. aureus infection. Clearance of S. aureus nasal colonization greatly reduces this risk. Mupirocin ointment is the current standard of care for clearance of S. aureus nasal colonization, but resistance to this antibiotic is emerging. Lysostaphin is a glycylglycine endopeptidase which specifically cleaves the cross-linking pentaglycine bridges in the cell walls of staphylococci. Lysostaphin is extremely staphylocidal (MIC at which 90% of isolates are inhibited, 0.001 to 0.064 g/ml) and rapidly lyses both actively growing and quiescent S. aureus. This study demonstrates that a single application of 0.5% lysostaphin (actual dose, ϳ150 g of lysostaphin), formulated in a petrolatum-based cream, dramatically reduces S. aureus nasal colonization in 100% of animals tested and eradicates S. aureus nasal colonization in 93% of animals in a cotton rat model. A single dose of lysostaphin cream is more effective than a single dose of mupirocin ointment in eradicating S. aureus nasal colonization in this animal model. The lantibiotic peptide nisin, which has potent in vitro antistaphylococcal activity, was ineffective in reducing staphylococcal nasal carriage in this model. Nasal colonization was not reduced after three treatments with 5% nisin (ϳ1,500 g/dose) in any of the treated animals. Lysostaphin formulated in cream may prove to be a superior alternative to mupirocin ointment for clearance of S. aureus nasal colonization. Staphylococcus aureus infection remains one of the most common nosocomial and community-acquired infections (1).With the continuing emergence of methicillin-resistant S. aureus (MRSA) (22) and strains of S. aureus that are intermediately resistant to glycopeptides (45) and the isolation of the first clinical strain of S. aureus that is fully vancomycin resistant (5), S. aureus is becoming an even more difficult health problem to address, particularly in settings such as hospitals and nursing homes.The anterior nares of humans are a principal ecologic niche for both methicillin-sensitive S. aureus (MSSA) and MRSA (17,26,28,51). Indeed, nasal carriage of S. aureus has been repeatedly shown to have a significant epidemiological link with subsequent development of staphylococcal disease, particularly for those requiring major surgery, implanted devices, hemodialysis, or treatment in intensive care units (6,7,18,33,37,49,53). In healthy humans there appear to be three patterns of S. aureus nasal carriage: noncarriers, intermittent carriers, and chronic carriers. One study (26) estimates the distribution of these carriers to be 20, 60, and 20%, respectively. This suggests that a significant portion of the population is at risk for development of staphylococcal disease linked to nasal carriage of S. aureus. People at greatest risk include those with diminished immunity and those with other chronic diseases (26).Studies suggest that clearance of ...

Catalase (KatA) and Alkyl Hydroperoxide Reductase (AhpC) Have Compensatory Roles in Peroxide Stress Resistance and Are Required for Survival, Persistence, and Nasal Colonization inStaphylococcus aureus

“…Nasal colonization by S. aureus strains was determined using a cotton rat model as described previously (29). Comparison of strains was evaluated on the recovery of bacteria using Student's t test.…”

“…There is a significant link between S. aureus nasal colonization and development of S. aureus infections (29). The cotton rat (Sigmodon hispidus) has been used to study human respiratory pathogens, due to its susceptibility to human diseases and similarity in disease progression and its epithelial tissue, which is comparable to that of humans (29). Nasal colonization by ahpC and katA mutants and the wild type was tested as described previously (10).…”

Extension of nasal anti-Staphylococcus aureus efficacy of lysostaphin by its incorporation into a chitosan-o/w cream

“…Beeswax was obtained from Shanghai Herb&Bee products Co., Ltd (Shanghai, China). Lysostaphin (139 U/mg) was produced by Shanghai High-Tech United Biological R&D Co., Ltd (Shanghai, China); 5 mg/g lysostaphin formulated in a petrolatum-based cream (LPC) was prepared by the method based on Kokai-Kun et al (2003).…”

“…However, Amidi et al (2010) reviewed that the short residence time of the current formulations in the nasal cavity due to mucociliary clearance posed a severe limitation for the drug delivery in the nasal cavity. Kokai-Kun et al (2003) and Walsh et al (2004) prepared a semi-solid cream and found that the cream greatly enhanced the efficacy of lysostaphin against S.aureus nasal colonization in cotton rats. Walsh et al (2004) also prepared a chitosan formulation and found that the formulation could significantly prolong the residence time of lysostaphin in the nose.…”

Surmounting antimicrobial resistance in the Millennium Superbug: Staphylococcus aureus

“…Lysostaphin has a maximum bactericidal concentration of 0.16-2.5µg/ml against MRSA [151]. Lysostaphin-based products have been developed for clinical trials in the USA by Biosynexus Inc. [152]. Clinical antibiotic-resistant S. aureus exhibited sensitivity to recombinant lysostaphin, highlighting the pre-clinical efficacy of the enzyme as an antibiotic [153].…”