Antibacterial activity of mupirocin (pseudomonic acid), a new antibiotic for topical use

Abstract

Mupirocin (pseudomonic acid A), an antibiotic produced by Pseudomonasfluorescens, showed a high level of activity against staphylococci and streptococci and against certain gram-negative bacteria, including Haemophilus influenzae and Neisseria gonorrhoeae, but was much less active against most gram-negative bacilli and anaerobes. Nearly all clinical isolates of Staphylococcus aureus and Staphylococcus epidermidis, including multiply resistant strains, were susceptible (mupirocin MIC, o0.5 ,ug/ml). There was no cross-resistance between mupirocin and clinically available antibiotics, and the selection of resistant variants in vitro occurred at a low frequency. Mupirocin was highly bound (95% bound) to the protein of human serum, and activity was reduced 10-to 20-fold in the presence of human serum. The activity of mupirocin was not greatly influenced by inoculum size but was significantly enhanced in acid medium. In tests of bactericidal activity, MBCs were 8-to 32-fold higher than MICs and the antibiotic demonstrated a slow bactericidal action in time-kill tests, resulting in 90 to 99% killing after 24 h at 37°C.The isolation and characterization of a group of antibacterial substances produced by Pseudomonas fluorescens was reported by Fuller et al. (7), and the name pseudomonic acid was ascribed to the major metabolite, which accounted for most of the antibacterial activity observed. Subsequent investigations revealed, in addition, the presence of three chemically related compounds as minor metabolites; for convenience, the substances were termed pseudomonic acids A (the major metabolite), B, C, and D (3-5, 11) ( Fig. 1). More recently, the term mupirocin has been adopted as the approved name for pseudomonic acid A.Pharmacokinetic studies in animals and in human volunteer subjects showed that mupirocin was well absorbed after oral and parenteral administration but serum antibiotic concentrations were short-lived as a result of extensive degradation to the antibacterially inactive metabolite, monic acid A (1; Beecham research laboratories, unpublished data), which is formed by hydrolysis of the ester linkage between the nucleus and the side chain of mupirocin (Fig. 1). Accordingly, the studies reported here were designed to investigate the antibacterial properties of mupirocin as an antibiotic for topical usage.MATERIALS AND METHODS Antibiotics. Mupirocin was used as the sodium salt in these studies. Standard antibiotics were obtained from the following manufacturers: benzylpenicillin, cloxacillin, and methicillin, Beecham Pharmaceuticals; erythromycin, Eli Lilly & Co.; fusidic acid, Leo Laboratories Ltd.; gentamicin, Nicholas Laboratories Ltd.; neomycin, the Upjohn Co.Bacteria. Most of the cultures tested were clinical strains of bacteria isolated from infections of the skin and other sources.MICs. Serial dilutions of mupirocin were added to 18-ml volumes of molten Mueller-Hinton agar (Difco Laboratories) in petri dishes. The medium was supplemented with horse blood for tests with streptococci (5% [vol/vol] for ...

Enhanced Activity of Rifalazil in Combination with Levofloxacin, Linezolid, or Mupirocin against Staphylococcus aureus In Vitro

“…Interestingly, using this less conventional definition, and with our high initial cell density protocol, we found apparent synergy between rifalazil and mupirocin against log phase S. aureus when mupirocin was used at either 1.5 or 5ϫthe MIC (again, these curves were combined for simplicity because of substantially equivalent results). It has been shown previously that the frequency of spontaneous mupirocin-resistant S. aureus mutants in vitro was less than or equal to 1.0ϫ10 Ϫ9 [9]. We found that the combination of rifalazil and mupirocin suppressed the proliferation of Rif R mutants by approximately 6-Log 10 at 24 hours.…”

“…The spontaneous resistance frequency to linezolid is low in S. aureus (Ͻ8ϫ10 Ϫ11 ), and resistance is slow to develop [7]. Mupirocin, a drug used topically to treat S. aureus and Streptococcus pyogenes skin infections [8,9] and S. aureus nasal colonization [10], was found recently to show synergistic activity with amoxicillin-clavulanate against MSSA and MRSA in an in vitro time kill model [11]. We therefore wished to investigate its potential to interact favorably with rifalazil.…”

Development and validation of a liquid chromatographic method for in vitro mupirocin quantification in both skin layers and percutaneous penetration studies

“…Mupirocin has excellent activity against staphylococci (including methicillin-resistant strains), streptococci, and gram-negative organisms such as Haemophilus influenzae , Neisseria gonorrhoeae, and Moraxella catarrhalis [2].…”

A continuous assay for monitoring the synthetic and proofreading activities of multiple aminoacyl-tRNA synthetases for high-throughput drug discovery

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