Chemical formula: C₃₀H₄₇NO₄S Molecular mass: 517.763 g/mol PubChem compound: 6918462
Retapamulin is a semi-synthetic derivative of the compound pleuromutilin, which is isolated through fermentation from Clitopilus passeckerianus (formerly Pleurotus passeckerianus).
Retapamulin selectively inhibits bacterial protein synthesis by interacting at a unique site on the 50S subunit of the bacterial ribosome that is distinct from the binding sites of other non-pleuromutilin antibacterial agents that interact with the ribosome.
Data indicate that the binding site involves ribosomal protein L3 and is in the region of the ribosomal P site and peptidyl transferase centre. By virtue of binding to this site, pleuromutilins inhibit peptidyl transfer, partially block P-site interactions, and prevent normal formation of active 50S ribosomal subunits. Therefore the pleuromutilins appear to inhibit bacterial protein synthesis by multiple mechanisms.
Retapamulin is predominantly bacteriostatic against S. aureus and S. pyogenes.
Due to its distinct mode of action, target specific cross-resistance with other classes of antibacterial agents is rare.
In vitro, three mechanisms have been identified which reduce susceptibility to retapamulin. One involves mutations in ribosomal protein L3, the second is a non-specific efflux mechanism (ABC transporter vgaAv). This non-target specific efflux mechanism has also been demonstrated to reduce the in vitro activity of streptogramin A.
Susceptibility to pleuromutilins can also be affected by the Cfr rRNA methyltransferase, which confers cross-resistance to phenicols, lincosamides and streptogramin A in staphylococci.
Retapamulin MICs of 2-64 µg/ml have been reported for clinical isolates of S. aureus possessing either the efflux or cfr resistance mechanisms described above. For S. aureus isolates with laboratorygenerated mutations in ribosomal protein L3, retapamulin MICs were 0.25-4 µg/ml. While the S. aureus epidemiological cut off value for retapamulin is 0.5 µg/ml, the clinical significance of isolates with elevated retapamulin MICs is unknown due to the potential for high local concentrations (20,000 µg/ml) of retapamulin on the skin.
No development of resistance was observed during treatment with retapamulin in the clinical study programme and all clinical isolates were inhibited by retapamulin concentrations of <2 µg/ml.
The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infection is questionable.
Commonly susceptible species:
Staphylococcus aureus*$
Streptococcus pyogenes*
Streptococcus agalactiae
Inherently resistant organisms
Enterobacteriaceae
Pseudomonas aeruginosa
Enterococcus faecalis
$ In vitro, retapamulin was equally active against methicillin-susceptible and methicillin-resistant strains of S. aureus. Retapamulin should not be used to treat infections known or thought likely to be due to MRSA.
* Activity has been satisfactorily demonstrated in clinical studies
In a study conducted in healthy adult subjects, 10 mg/g retapamulin ointment was applied daily to intact and to abraded skin under occlusion for up to 7 days. Systemic exposure following topical application of retapamulin through intact skin was very low. The geometric mean Cmax value in plasma after application to 200 cm² of abraded skin was 9.75 ng/ml on day 1 and 8.79 ng/ml on day 7, and the maximum individual systemic exposure (Cmax) recorded was 22.1 ng/ml.
Single plasma samples were obtained from 516 adult and paediatric patients who received topical treatment with retapamulin 10 mg/g ointment twice daily for 5 days for the treatment of secondarily infected traumatic lesions. Sampling occurred pre-dose for adult subjects on days 3 or 4, and between 0-12 hours after the last application for paediatric subjects on days 3 or 4. The majority of samples (89%) were below the lower limit of quantitation (0.5 ng/ml). Of the samples that had measurable concentrations 90% had retapamulin concentrations less than 2.5 ng/ml. The maximum measured plasma concentration of retapamulin was 10.7 ng/ml in adults and 18.5 ng/ml in paediatric patients (aged 2-17 years).
Single plasma samples were obtained approximately 4-8 hours after the first application on days 3 or 4 from patients aged from 2 months to 2 years with impetigo or with secondarily infected traumatic lesions or dermatoses (note that retapamulin is not indicated for use in secondarily infected dermatoses). Retapamulin concentrations were measurable in 46% (36/79) of samples (range 0.52 to 177.3 ng/ml) but the majority of these samples (27/36; 75%) contained <5.0 ng/ml.
Among the children aged from 9 months to 2 years plasma concentrations of retapamulin were measurable in 32% (16/50) of samples. A single retapamulin concentration (95.1 ng/ml) exceeded the highest concentration observed in patients aged 2-17 years (18.5 ng/ml). This plasma concentration was observed in a child with a secondary infected dermatosis, for which retapamulin is not indicated for use.
Retapamulin is not recommended for use in children aged less than 9 months. In children aged from 2 months to 9 months plasma concentrations of retapamulin were measurable in 69% (20/29) of samples. Four plasma retapamulin concentrations (26.9, 80.3, 174.3, and 177.3 ng/ml) exceeded the highest concentration observed in patients aged 2-17 years (18.5 ng/ml).
Due to the very low systemic exposures, tissue distribution of retapamulin has not been investigated in humans.
In vitro, retapamulin was shown to be a P-glycoprotein (Pgp) substrate and inhibitor.
However, the maximum individual systemic exposure in humans following topical application of 10 mg/g ointment on 200 cm² of abraded skin (Cmax=22 ng/ml; AUC=238 ng.h/ml) was 660-fold lower than the retapamulin IC50 for Pgp inhibition.
Retapamulin is approximately 94% bound to human plasma proteins.
The in vitro oxidative metabolism of retapamulin in human liver microsomes was primarily mediated by CYP3A4 with minor contributions from CYP2C8 and CYP2D6.
Retapamulin elimination in humans has not been investigated.
No pharmacokinetic data are available in patients with renal or hepatic impairment. However, due to the low systemic plasma levels that have been observed, no safety problems are foreseen.
In 14-day (50, 150 or 450 mg/kg) oral toxicity studies in rats there was evidence of adaptive hepatic and thyroid changes. Neither of these findings is of clinical relevance.
In monkeys dosed orally (50, 150 or 450 mg/kg) for 14 days there was dose-related emesis.
Carcinogenesis, mutagenesis, reproductive toxicity Long-term studies in animals to evaluate carcinogenic potential have not been conducted with retapamulin.
There was no evidence of genotoxicity when evaluated in vitro for gene mutation and/or chromosomal effects in the mouse lymphoma cell assay, in cultured human peripheral blood lymphocytes, or when evaluated in vivo for chromosomal effects in a rat micronucleus test.
There was no evidence of impaired fertility in male or female rats at oral doses of 50, 150, or 450 mg/kg/day, resulting in exposure margins of up to 5-times the highest human estimated exposure (topical application to 200 cm² abraded skin: AUC 238 ng.h/ml).
In an embryotoxicity study in rats, developmental toxicity (decreased fetal body weight and delayed skeletal ossification) and maternal toxicity were observed at oral doses of ≥150 mg/kg/day (corresponding to ≥3 times the human estimated exposure (see above). There were no treatmentrelated malformations in rats.
Retapamulin was given as a continuous intravenous infusion to pregnant rabbits from day 7 to day 19 of gestation. Maternal toxicity was demonstrated at dosages of ≥7.2 mg/kg/day corresponding to ≥8 times the estimated human exposure (see above). There was no treatment-related effect on embryofetal development.
No studies to evaluate effects of retapamulin on pre-/postnatal development were performed. However, there were no systemic effects on juvenile rats with topical application of retapamulin ointment.
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