Retapamulin

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Abstract
Topical retapamulin (Altabax™, Altargo®) is the first pleuromutilin antibacterial approved for the treatment of uncomplicated superficial skin infections caused by Staphylococcus aureus (excluding meticillin-resistant S. aureus [MRSA]) and Streptococcus pyogenes in patients aged ≥9 months. In the EU, retapamulin is indicated for use in patients with impetigo or with infected small lacerations, abrasions or sutured wounds (without abscesses); in the US, it is indicated for use in patients with impetigo. Retapamulin has a novel site of action on bacterial ribosomes. In clinical trials in patients with impetigo, topical retapamulin 1% ointment twice daily for 5 days (the approved regimen) was superior to placebo; treatment with retapamulin was noninferior to that with topical fusidic acid. In patients with secondarily infected traumatic lesions, treatment with retapamulin was noninferi-or to that with oral cefalexin, although the efficacy of retapamulin was reduced in patients with MRSA infections or superficial abscesses. Retapamulin was well tolerated in both paediatric and adult patients, and the majority of adverse events were of mild to moderate severity. Thus, the introduction of topical retapamulin 1% ointment extends the treatment options available in the management of impetigo and uncomplicated secondarily infected traumatic lesions. Retapamulin is a tricyclic pleuromutilin derivative that inhibits bacterial protein synthesis by selective binding to ribosomes. It is active against S. aureus and S. pyogenes, pathogens commonly associated with superficial skin infections (such as impetigo and secondarily infected traumatic lesions or open wounds). The minimum inhibitory concentrations required to inhibit 90% of isolates in various S. aureus or S. pyogenes isolates ranged from ≤0.03 to 0.25 mg/L, including MRSA, mupirocin-and fusidic acid-resistant S. aureus, and erythro-mycin-resistant S. pyogenes. Retapamulin is mainly bacteriostatic, rather than bactericidal, against S. aureus and S. pyogenes. Mechanisms of retapamulin resistance include step-wise mutations in the ribosomal protein L3 region and the acquisition of the adenosine triphosphate-binding cassette transporter transposon-borne gene (vgaAv variant). In addition, retapamulin has a novel binding site among current antibacterials in clinical use; pathogens resistant to other antibac-terials do not show cross-reactivity to retapamulin in vitro. No development of resistance was reported from clinical trials following 5 days of retapamulin treatment. Systemic exposure after topical administration of retapamulin 1% ointment is low. Peak plasma concentrations in the majority of patients were below the level of quantification in a large clinical trial in which retapamulin was given at the approved dosage. Consequently, the pharmacokinetic properties of the drug have not been extensively investigated. Although retapamulin is primarily metabolized by cytochrome P450 (CYP) 3A4, administration of retapamulin is not expected to affect the metabolism of other CYP substrates. Age or renal or hepatic impairment are not expected to affect systemic exposure to retapamulin. In randomized, double-or observer-blind trials, topical retapamulin 1% ointment for 5 days was significantly more effective than placebo and was noninferior to topical fusidic acid for 7 days in paediatric or adult patients with impetigo. In a comparative trial with retapamulin and fusidic acid, clinical success rates were 99.1% and 94.0% and bacteriological success rates were 99.2% and 93.0% (p ≤0.022; per-protocol populations). The between-group difference was not significant in the clinical intent-to-treat population. Treatment with topical retapamulin for 5 days was noninferior to treatment with oral cefalexin for 10 days in achieving a clinical response in patients with secondarily infected traumatic lesions (89.5% vs 91.9%). The respective bacteriological success rates were 89.2% and 90.2%. However, retapamulin efficacy was reduced in patients with MRSA infection (clinical success rate of 68.6% vs 88.5% in cefalexin recipients) and with superficial abscesses (the between-group difference was −2.2% in patients with open wounds vs −4.2% in patients with superficial abscesses). Topical retapamulin 1% ointment was well tolerated in the 2115 paediatric or adult patients receiving the drug in clinical trials. Most adverse events were mild to moderate in severity and occurred at an incidence of ≤1%. Treatment-related adverse events were reported in 6% of retapamulin recipients, 7% of cefalexin recipients, 3% of placebo recipients and one fusidic acid recipient (0.6%). The most common treatment-related adverse events were application site irritation (1.4%) with retapamulin, diarrhoea (1.7%) with cefalexin and application site pruritus (1.4%) or paraesthesia (1.4%) with placebo ointment. Retapamulin treatment was not associated with any serious adverse events.