Mupirocin (as Mupirocin Calcium) 20 Mg/ml Topical Cream

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

There are insufficient human data to establish whether there is a drug-associated risk with mupirocin cream in pregnant women. Systemic absorption of mupirocin through intact human skin is minimal following topical administration of mupirocin cream [see Clinical Pharmacology (12.3)]. No developmental toxicity was observed in rats or rabbits treated with mupirocin subcutaneously during organogenesis at doses of 160 or 40 mg per kg per day, respectively (22 and 11 times the human topical dose based on calculations of dose divided by the entire body surface area).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data: Developmental toxicity studies have been performed with mupirocin administered subcutaneously to rats and rabbits at doses up to 160 mg per kg per day during organogenesis. This dose is 22 and 43 times, respectively, the human topical dose (approximately 60 mg mupirocin per day) based on calculations of dose divided by the entire body surface area. Maternal toxicity was observed (body weight loss/decreased body weight gain and reduced feeding) in both species with no evidence of developmental toxicity in rats. In rabbits, excessive maternal toxicity at the high dose precluded the evaluation of fetal outcomes. There was no developmental toxicity in rabbits at 40 mg per kg per day, 11 times the human topical dose based on calculations of dose divided by the entire body surface area.

Mupirocin administered subcutaneously to rats in a prenatal and postnatal development study (dosed during late gestation through lactation) was associated with reduced offspring viability in the early postnatal period at a dose of 106.7 mg per kg, in the presence of injection site irritation and/or subcutaneous hemorrhaging. This dose is 14 times the human topical dose based on calculations of dose divided by the entire body surface area. The no-observed adverse effect level in this study was 44.2 mg per kg per day, which is 6 times the human topical dose.

It is not known whether mupirocin is present in human milk, has effects on the breastfed child, or has effects on milk production. However, breastfeeding is not expected to result in exposure of the child to the drug due to the minimal systemic absorption of mupirocin in humans following topical administration of mupirocin cream [see Clinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for mupirocin cream and any potential adverse effects on the breastfed child from mupirocin cream or from the underlying maternal condition.

Clinical Considerations

To minimize oral exposure of the drug to children, a breast and/or nipple being treated with mupirocin cream should be thoroughly washed prior to breastfeeding.

Systemic absorption of mupirocin through intact human skin is minimal. The systemic absorption of mupirocin was studied following application of mupirocin cream 3 times daily for 5 days to various skin lesions greater than 10 cm in length or 100 cm² in area in 16 adults (aged 29 to 60 years) and 10 children (aged 3 to 12 years). Some systemic absorption was observed as evidenced by the detection of the metabolite, monic acid, in urine. Data from this trial indicated more frequent occurrence of percutaneous absorption in children (90% of subjects) compared with adults (44% of subjects); however, the observed urinary concentrations in children (0.07 to 1.3 mcg per mL [1 pediatric subject had no detectable level]) are within the observed range (0.08 to 10.03 mcg per mL [9 adults had no detectable level]) in the adult population. In general, the degree of percutaneous absorption following multiple dosing appears to be minimal in adults and children.

The effect of the concurrent application of mupirocin cream with other topical products has not been studied [see Dosage and Administration (2)].

Elimination

In a trial conducted in 7 healthy adult male subjects, the elimination half-life after intravenous administration of mupirocin was 20 to 40 minutes for mupirocin and 30 to 80 minutes for monic acid.

Metabolism: Following intravenous or oral administration, mupirocin is rapidly metabolized. The principal metabolite, monic acid, demonstrates no antibacterial activity.

Excretion: Monic acid is predominantly eliminated by renal excretion.

Mechanism of Action

Mupirocin inhibits bacterial protein synthesis by reversibly and specifically binding to bacterial isoleucyl-transfer RNA (tRNA) synthetase.

Mupirocin is bactericidal at concentrations achieved by topical administration. Mupirocin is highly protein bound (greater than 97%) and the effect of wound secretions on the minimum inhibitory concentrations (MICs) of mupirocin has not been determined.

Resistance

When mupirocin resistance occurs, it results from the production of a modified isoleucyl-tRNA synthetase, or the acquisition of, by genetic transfer, a plasmid mediating a new isoleucyl-tRNA synthetase. High-level plasmid-mediated resistance (MIC ≥512 mcg/mL) has been reported in increasing numbers of isolates of S. aureus and with higher frequency in coagulase-negative staphylococci. Mupirocin resistance occurs with greater frequency in methicillin-resistant than methicillin-susceptible staphylococci.

Cross Resistance

Due to its mode of action, mupirocin does not demonstrate cross resistance with other classes of antimicrobial agents.

Antimicrobial Activity

Mupirocin has been shown to be active against susceptible isolates of S. aureus and S. pyogenes, both in vitro and in clinical trials [see Indications and Usage (1)]. The following in vitro data are available, but their clinical significance is unknown. Mupirocin is active against most isolates of Staphylococcus epidermidis.

Susceptibility Test Methods

High-level mupirocin resistance (≥512 mcg/mL) may be determined using standard disk diffusion or broth microdilution tests.^1,2 Because of the occurrence of mupirocin resistance in methicillin-resistant S. aureus (MRSA), it is appropriate to test MRSA populations for mupirocin susceptibility prior to the use of mupirocin using a standardized method.^3,4,5

Results of the following studies performed with mupirocin calcium or mupirocin sodium in vitro and in vivo did not indicate a potential for genotoxicity: rat primary hepatocyte unscheduled DNA synthesis, sediment analysis for DNA strand breaks, Salmonella reversion test (Ames), Escherichia coli mutation assay, metaphase analysis of human lymphocytes, mouse lymphoma assay, and bone marrow micronuclei assay in mice.

In a fertility/reproductive performance study (with dosing through lactation), mupirocin administered subcutaneously to male and female rats at doses up to 100 mg per kg per day which is 14 times the human topical dose (approximately 60 mg mupirocin per day) based on calculations of dose divided by the entire body surface area, did not result in impaired fertility or impaired reproductive performance attributable to mupirocin.