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 ...
Lysostaphin is a 27-kDa endopeptidase that enzymatically disrupts the cell wall of Staphylococcus aureus and is a promising candidate for treating S. aureus blood-borne infections. It would be extremely useful to define conditions that would both increase lysostaphin's in vivo half-life to allow for more effective tissue distribution and reduce its immunogenicity. Conjugation of polyethylene glycol (PEG) to lysostaphin (PEGylation) was investigated as a means to accomplish these goals. Rather than using linear forms of PEG, branched PEGs were chosen as the initial candidates because their large spatial volumes prevent entry of the polymer into the enzyme's active sites, which could potentially reduce enzymatic function. Enzymatic activity for most PEGylated lysostaphins was reduced, but these compounds were still considerably active compared to unconjugated lysostaphin, with conjugates that had lower degrees of PEG modification having greater activity than those with higher degrees. PEGylated lysostaphin injected intravenously had a serum drug half-life of up to 24 h and resulted in much higher plasma drug concentrations than an equal dose of unconjugated lysostaphin, which had a half-life of less than 1 h. Finally, reduced binding affinity was shown for PEGylated lysostaphin in an antilysostaphin capture enzyme-linked immunosorbent assay, with some PEG-lysostaphin conjugates having binding affinities that were reduced more than 10-fold compared to unconjugated lysostaphin. These findings demonstrate that PEGylation of lysostaphin, while diminishing its S. aureus killing activity, results in prolonged serum drug persistence and reduced antibody binding. These features should significantly enhance lysostaphin's therapeutic value as an intravenous "antibiotic" against S. aureus.
Lysostaphin is an endopeptidase that kills Staphylococcus aureus, a predominant organism in catheterrelated infections. Lysostaphin-coated catheters prevented catheter colonization by several strains of S. aureus, and activity was maintained for at least 4 days. Prophylactic use of lysostaphin in catheters may help prevent the occurrence of catheter-related staphylococcal infections.Catheter-related infections continue to be a significant source of morbidity and mortality in patients requiring catheterization (6,10,12,15) and increase medical expenses by prolonging hospitalization (7). Catheter infections are most commonly caused by staphylococci, either coagulase-negative staphylococci (CoNS) or Staphylococcus aureus. Currently, six types of antiseptic catheters have been tested in clinical trials: cefazolin-, teicoplanin-, vancomycin-, silver-, chlorohexidinesilver sulfadiazine-, and minocycline-rifampin-coated catheters (3, 7). However, only the minocycline-rifampin-and chlorohexidine-silver sulfadiazine-coated catheters have been shown to reduce the incidence of catheter-related bloodstream infections, and long-term efficacy has not been shown (3,7,16). Lysostaphin is an endopeptidase that cleaves the cross-linking pentaglycine bridges of the cell wall of staphylococci (2,5,8,11,14,17). Lysostaphin is highly active against S. aureus because of the prevalence of pentaglycine cross-linking in the cell wall of S. aureus and has lesser activity against CoNS (2, 4). This study demonstrated that lysostaphin is readily adsorbed onto catheter surfaces while maintaining its staphylolytic activity and may have the potential to decrease the incidence of S. aureus-and CoNS-related catheter infections.Lysostaphin, obtained from AMBI, Inc., was coated onto two different plastic surfaces, polystyrene and FEP polymer, a Teflon-like material used in Angiocath catheters produced by Becton Dickinson. Twenty-four-well polystyrene plates were coated overnight at 4°C with 300 l of 10, 1, or 0.1 mg of lysostaphin/ml diluted in phosphate-buffered saline (PBS). The lumenal side of the catheters was coated for 1 h at room temperature with 0.1 mg of lysostaphin/ml. The coated surfaces were washed extensively with 50 ml of PBS, and the last aliquot of wash solution was tested to confirm the absence of unbound lysostaphin. The surfaces were challenged with an inoculum of about 10 4 S. aureus capsule type 5 organisms (SA5; clinical isolate) in tryptic soy broth, incubated for 1 to 2 h, and then streaked onto blood agar to enumerate surviving colonies (Table 1). On average, 610 CFU was recovered from the polystyrene control wells, whereas only 3 CFU remained in the lysostaphin-coated wells, a 99.5% reduction in bacterial counts. The lysostaphin-coated catheters were completely cleared of bacteria as compared to control catheters, from which an average of 493 CFU was recovered. The killing was not concentration dependent in the range of 10 to 0.1 mg/ml, as all three concentrations reduced bacterial titers to the same level. These results s...
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