Ретапамулин

Описание

Antibacterial retapamulin is a derivative of the natural product pleuromutilin and was developed by Glaxo and approved in the US in 2007 for the treatment of skin infections. It has a unique mechanism of action, inhibiting bacterial protein synthesis by inhibiting the larger subunit of the ribosome, and thus has no cross resistance to other antibacterial agents. Pleuromutilin is a tricyclic diterpenoid that was first isolated in 1951 from the edible mushroom Pleurotus mutilus. The first semisynthetic analogs tiamulin and valnemulin, developed for veterinary use, have been shown to interact uniquely with bacterial ribosomes by high affinity binding to a site on the 50S subunit. Binding to this site interferes with ribosomal peptidyl transferase activity, blocks P-site interactions, and prevents the evolution of active 50S ribosomal subunits. Retapamulin, the first pleuromutilin approved for human use, behaves similarly to selectively inhibit bacterial protein synthesis. This novel mechanism of action has been implicated in the lack of in vitro target-specific cross-resistance with other classes of antibiotics.

Использование

Retapamulin is a topical antibiotic, which binds to both E. coli and S. aureus ribosomes with similar potencies with Kd of 3 nM

Фармацевтические приложения

A semisynthetic pleuromutilin formulated as a 1% ointment for topical use. It is active against staphylococci (MIC 0.12 mg/L), including methicillin-resistant strains, and against streptococci (MIC 0.03–0.25 mg/L), including Str. pyogenes and Str. pneumoniae. Most enterococci and Gramnegative bacilli are resistant. Propionibacteria are susceptible, suggesting that it might be useful in acne. Early indications suggest that resistance does not emerge readily, but experience with veterinary pleuromutilins indicates that chromosomal resistance may develop with extended use.
It is metabolized in the liver and rapidly excreted, precluding use in systemic infection. Systemic exposure is said to be low following topical application and it appears safe, but there are few data on absorption through broken and unbroken skin. Principal side effects noted include local irritation and occasional allergic reactions. Licensed use is presently restricted to the treatment of impetigo and uncomplicated skin infections. Possible value in methicillin-resistant Staph. aureus (MRSA) infection or carriage has not yet been established.

Побочные эффекты

The most frequent adverse event was application site irritation, but other side effects, occurring in o2% of patients, included headache, diarrhea, nausea, and nasopharyngitis. While there are no contraindications, it is recommended that pregnant women only use retapamulin when the potential benefits outweigh the potential risks since animal reproductive studies are not always predictive of human response. Likewise, nursing mothers are cautioned about the unknown possibility of retapamulin excretion in breast milk.