Pharmacology: Pharmacodynamics: Mechanism of Action: Mupirocin is a novel antibiotic produced through fermentation by Pseudomonas fluorescens. Mupirocin inhibits isoleucyl transfer-RNA synthetase, thereby arresting bacterial protein synthesis. Due to this particular mode of action and its unique chemical structure, mupirocin does not show any cross-resistance with other clinically available antibiotics.
Mupirocin has bacteriostatic properties at minimum inhibitory concentrations and bactericidal properties at the higher concentrations reached when applied locally.
Pharmacodynamic Effects: Activity: Mupirocin is a topical antibacterial agent showing in vivo activity against Staphylococcus aureus (including methicillin-resistant strains), S. epidermidis and beta-haemolytic Streptococcus species.
The in vitro spectrum of activity includes the following bacteria: Commonly Susceptible Species: Staphylococcus aureus1,2; Staphylococcus epidermidis1,2; Coagulase-negative staphylococci1,2; Streptococcus species1; Haemophilus influenzae; Neisseria gonorrhoeae; Neisseria meningitidis; Moraxella catarrhalis; Pasteurella multocida.
1Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.
2Including beta-lactamase producing strains and methicillin-resistant strains.
Resistant Species: Corynebacterium species; Enterobacteriaceae; Gram negative non-fermenting rods; Micrococcus species; Anaerobes.
Mupirocin susceptibility (MIC) breakpoints for Staphylococcus spp.: Susceptible: less than or equal to 1 microgram/ml; Intermediate: 2 to 256 micrograms/ml; Resistant: greater than 256 micrograms/ml.
Resistance mechanisms: Low-level resistance in staphylococci (MICs 8 to 256 micrograms/ml) has been shown to be due to changes in the native isoleucyl tRNA synthetase enzyme. High-level resistance in staphylococci (MICs greater than or equal to 512 micrograms/ml) has been shown to be due to a distinct, plasmid encoded isoleucyl tRNA synthetase enzyme. Intrinsic resistance in Gram-negative organisms such as the Enterobacteriaceae could be due to poor penetration into the bacterial cell.
Pharmacokinetics: Absorption: Cream: Systemic absorption of mupirocin through intact human skin is low although it may occur through broken/diseased skin. However, clinical trials have shown that when given systemically, it is metabolised to the microbiologically inactive metabolite monic acid and rapidly excreted.
Ointment: Mupirocin penetrates intact human skin but the rate of systemic absorption appears to be low.
Elimination: Cream: Mupirocin is rapidly eliminated from the body by metabolism to its inactive metabolite monic acid which is rapidly excreted by the kidney.
Excretion: Ointment: Systemically absorbed mupirocin is rapidly metabolised to the inactive metabolite monic acid and quickly excreted by the kidneys.
Special Patient Populations: Ointment: Elderly patients: No restrictions unless there is evidence of moderate or severe renal impairment (see Precautions).
Toxicology: Pre-Clinical Information: Carcinogenesis/Mutagenesis: Carcinogenesis: Carcinogenicity studies with mupirocin have not been conducted.
Genotoxicity: Mupirocin was not mutagenic in Salmonella typhimurium or Escherichia coli (Ames assay). In a Yahagi assay, small increases in Salmonella typhimurium TA98 were observed at highly cytotoxic concentrations. In an in vitro mammalian gene mutation assay (MLA), no increase in mutation frequency was observed in the absence of metabolic activation. In the presence of metabolic activation, small increases in mutation frequency were observed at highly cytotoxic concentrations. However, no effects were observed in, yeast cell assays for gene conversion/mutation, an in vitro human lymphocyte assay or in an in vitro unscheduled DNA synthesis (UDS) assay.
Furthermore, an in vivo mouse micronucleus assay (chromosome damage) and a rat Comet assay (DNA strand breakage) were negative, indicating the small increases observed at highly cytotoxic concentrations in vitro do not translate to the in vivo situation.
Reproductive Toxicology: Fertility: Mupirocin administered subcutaneously to male rats 10 weeks prior to mating and to female rats 15 days prior to mating until 20 days post coitum at doses up to 100 mg/kg/day had no effect on fertility.
Pregnancy: In embryo-foetal development studies in rats there was no evidence of developmental toxicity at subcutaneous doses up to 375 mg/kg/day.
In an embryo-foetal development study in rabbits at subcutaneous doses up to 160 mg/kg/day, maternal toxicity (impaired weight gain and severe injection site irritation) at the high dose resulted in abortion or poor litter performance. However, there was no evidence of developmental toxicity in foetuses of rabbits maintaining pregnancy to term.