Description
Mupirocin (pseudomonic acid A) is an antibiotic produced by Pseudomonas
fluorescens. It is useful in the treatment of dermal infections, especially those
involving S. aureus and S. epidermidis.
Originator
Beecham (United Kingdom)
Definition
ChEBI: An alpha,beta-unsaturated ester resulting from the formal condensation of the alcoholic hydroxy group of 9-hydroxynonanoic acid with the carboxy group of (2E)-4-[(2S)-tetrahydro-2
-pyran-2-yl]-3-methylbut-2-enoic acid in which the tetrahydropyranyl ring is substituted at positions 3 and 4 by hydroxy groups and at position 5 by a {(2S,3S)-3-[(2S,3S)-3-hydro
ybutan-2-yl]oxiran-2-yl}methyl group. Originally isolated from the Gram-negative bacterium Pseudomonas fluorescens, it is used as a topical antibiotic for the treatment of Gram-positive bacterial infections.
Indications
Mupirocin (Bactroban, Centany) is a topical antibiotic produced by fermented
Pseudomonas fluorescens. It has a narrow spectrum of activity, mostly against
gram-positive aerobic bacteria (including Staphylococcus and methicillin-resistant
Staphylococcus) and many strains of Streptococcus. It is also active against some
gram-negative aerobic bacteria but is inactive against anaerobes, Chlamydia, and
fungi. It has proved equal in efficacy in the treatment of impetigo when compared
with oral erythromycin, with fewer adverse side effects.
Mupirocin does not interfere with wound healing. It is active only on topical
administration and is converted to an inert molecule on systemic administration.
Prolonged use of mupirocin increases the risk of evolution of resistant organisms.
Themechanism of action has not yet been fully classified, but it does differ from other
available antiinfective agents, and there is little chance of cross-resistance developing.
Also, unlike many other topical antibiotics, it rarely causes allergic sensitization.
Manufacturing Process
Production and recovery of Antibacterially active pseudomonic acid and
Pseudomonic acid A
Pseudomonas fluorescens, strain NCIB 10586 was grown in submerged culture
at 30°C in a medium containing 1% corn steep liquor and 0.5% glucose in a
basic salts solution. The maximum yield of the antibiotic occurred after 24
hours and all of the detectable activity was in the culture fluid. After the
addition of barium chloride (0.5%) the cells and precipitated non-active
contaminant material were removed by centrifugation. The activity was
progressively concentrated by partitioning into isobutylmethyl ketone (IBMK)
(0.2 vol) at pH 4.5 water (0.8 vol) at pH 8.5, and then IBMK (0.25 vol) at pH
4.5 followed by evaporation to a small volume under reduced pressure. After
a further partition into water at pH 8.5 and then adjustment to pH 7-8 the
aqueous solution was freeze dried to give the sodium salt which could be
stored at 0°C for several months, without loss of activity. The antibiotic
extract was stable within the range pH 4-9 at 37°C for 24 hours. Outside
these limits rapid loss of activity occurred. The sodium salt showed a broad antibacterial spectrum against Gram positive and Gram negative bacteria,
showed low toxicity and was bacteriostatic against S. aureus (N.C.T.C. 6571)
and E. coli (M.R.E. 600).
Further purification of the crude acid was effected by chromatography on
Amberlite XAD-2 polystyrene resin with a linear gradient produced by adding
0.1 N methanolic ammonia, to 0.01 N aqueous ammonia. A series of low
molecular weight acids was eluted first, followed by a fraction (30-60%
elution) that possessed the major part of the antibacterial (biological) activity
Purification of Pseudomonic acid and Pseudomonic Acid A
The produced biologically active material upon methylation with diazomethane
in ether showed two spots by thin layer chromatography corresponding to
methyl pseudomonate as the major component and a minor amount of
component methyl pseudomonate-A (ratio ca 9:1 by wt.).
Methyl pseudomonate was separated from methyl pseudomonate-A by
preparative layer silica gel (GF245) chromatography on development with
chloroform/isopropanol (9:1). 50% of methyl pseudomonate was recovered
from the impure residue by crystallization from benzene/petroleum ether to
give colorless needles of m.p. 76.5-78°C.
Acetylation of the methyl ester with pyridine/acetic anhydride affords a
triacetate. Reduction of the methyl ester with LiAlH4 in THF afforded 1,9-
dihydroxynonanoate, m.p. 46°C.
Brand name
Bactroban (GlaxoSmithKline); Centany (Johnson & Johnson).
Therapeutic Function
Antibiotic
Antimicrobial activity
It is active against staphylococci and streptococci, but also Neisseria and Haemophilus spp. Enterococcus faecalis tends to be sensitive whereas E. faecium is usually resistant. Activity against Staph. aureus is affected by inoculum such that a 10-fold increase in the inoculum causes doubling of the minimum inhibitory concentration (MIC) in vitro. Activity also decreases as pH increases above the normal skin pH of 5.5.
Acquired resistance
Before the introduction of mupirocin, resistance in Staph. aureus was uncommon, with a natural mutation frequency of 1 in 109. However, shortly after the agent was introduced, mupirocin-resistant strains began to emerge. They are of two types: low level (MIC 8–256 mg/mL) and high level (MIC >256 mg/mL).
High-level resistance, in contrast, is linked to the acquisition of a transmissible resistance gene MupA that may co-transfer with other antimicrobial resistance genes. Strains that express MupA are not clinically susceptible to mupirocin.
Several studies suggest that widespread use of prophylactic mupirocin may result in increased levels of resistance. In Canada increasing use of mupirocin across the country led to high-level mupirocin resistance, rising from 1.6% to 7% over a 9-year period.
General Description
Mupirocin (pseudomonic acid A, Bactroban) is the majorcomponent of a family of structurally related antibiotics,pseudomonic acids A to D, produced by the submergedfermentation of Pseudomonas fluorescens. Although theantimicrobial properties of P. fluorescens were recordedas early as 1887, it was not until 1971 that Fuller et al.identified the metabolites responsible for this activity. Thestructure of the major and most potent metabolite,pseudomonic acid A (which represents 90%–95% of the activefraction from P. fluorescens), was later confirmed bychemical synthesis to be the 9-hydroxynonanoic acidester of monic acid.
The use of mupirocin is confined to external applications.280 Systemic administration of the antibiotic resultsin rapid hydrolysis by esterases to monic acid, which is inactivein vivo because of its inability to penetrate bacteria.Mupirocin has been used for the topical treatment ofimpetigo, eczema, and folliculitis secondarily infected bysusceptible bacteria, especially staphylococci and -hemolyticstreptococci. The spectrum of antibacterial activityof mupirocin is confined to Gram-positive and Gramnegativecocci, including staphylococci, streptococci,Neisseria spp., and M. catarrhalis. The activity of the antibioticagainst most Gram-negative and Gram-positivebacilli is generally poor, with the exception of H. influenzae.It is not effective against enterococci or anaerobicbacteria.
Mupirocin interferes with RNA synthesis and protein synthesisin susceptible bacteria. It specifically and reversiblybinds with bacterial isoleucyl tRNA synthase to preventthe incorporation of isoleucine into bacterial proteins.282High-level, plasmid-mediated mupirocin resistance in S. aureushas been attributed to the elaboration of a modifiedisoleucyl tRNA that does not bind mupirocin.283 Inherent resistancein bacilli is likely because of poor cellular penetrationof the antibiotic.
Pharmaceutical Applications
Mupirocin is an antimicrobial substance originally derived from Pseudomonas fluorescens. It is a mixture of pseudomonic acids with more than 90% of the commercial product being pseudomonic acid A.
It has activity predominantly against Gram-positive bacteria and its main use is as a topical agent for the eradication of carriage of methicillin-resistant Staphylococcus aureus (MRSA). It is also used as a topical treatment for superficial skin infections caused by Grampositive organisms such as impetigo.
Pharmacokinetics
Following parenteral administration, mupirocin is rapidly destroyed by non-specific esterases (possibly in renal or liver tissues since it is reasonably stable in blood) to inactive monic acid and its conjugates. It is strongly protein bound. About 0.25% is absorbed from intact skin. The skin ointment, but not the cream, contains polyethylene glycol, which may be absorbed significantly when applied to open wounds or damaged skin, including burns.
Clinical Use
Mupirocin is mainly used as a nasal cream as part of the regimen to decolonize patients who have been found to carry methicillin-resistant Staph. aureus. It can also be applied to tracheostomy, gastrostomy and other sites that are frequently colonized with MRSA.
The use of mupirocin as a means of controlling outbreaks of infection due to MRSA appears to be of only marginal benefit in an endemic situation.
A Cochrane Review of nine randomized controlled trials of use of mupirocin to prevent subsequent Staph. aureus infections in nasal carriers of the organism found a statistically significant reduction in such infections at any site. A small study of local therapy to reduce the risk of peritonitis in patients on continuous ambulatory peritoneal dialysis (CAPD) found that mupirocin applied three times weekly to the dialysis catheter exit site resulted in a 92% reduction in the rate of peritonitis
Veterinary Drugs and Treatments
Mupirocin is approved for treating topical infections in dogs caused by susceptible strains of Staphylococcal aureus or Staphylococcal
intermedius. It may also be of use in other species and conditions (e.g., feline acne, equine pyoderma, superficial pyoderma, interdigital
abscesses, pressure point pyodermas, etc). It also shows activity against other gram-positive pathogens: Corynebacterium sp, Clostridium
sp and Actinomyces spp.
Mupirocin is not related structurally to other commercially available antibiotics and acts by inhibiting bacterial protein synthesis
by binding to bacterial isoleucyl transfer-RNA sythetase. Its principle activity is against Gram-positive cocci (Staphylococcal spp. and
Streptococcal spp.), including beta-lactamase producing and methicillin-resistant strains. While bacterial resistance is rare, resistant
strains of Staphylococcal aureus have been identified and resistance transference is thought to be plasmid-mediated. Cross-resistance with
other antimicrobials has not been identified. Mupirocin also has activity against some Gram-negative bacteria, but is not used clinically
for infections caused by those bacteria.
Mupirocin is not significantly absorbed through the skin into the systemic circulation, but does penetrate well into granulomatous
deep pyoderma lesions and is not suitable for application to burns.
References
1) Sutherland et al. (1985), Antibacterial activity of mupirocin (pseudomonic acid), a new antibiotic for topical use; Antimicrob. Agents Chemother., 27 495
2) Rudresh et al. (2015), Prevalence of Mupirocin Resistance Among Staphylococci, its Clinical Significance and Relationship to Clinical Use; J. Lab. Physicians, 7 103
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