|Pharmacotherapeutic group: Antibiotics and chemotherapeutics for dermatological use, Antibiotics for topical use. ATC code: D06AX13|
Mode of actionRetapamulin 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.
Mechanism of resistance 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 laboratory-generated 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.
Antibacterial spectrumThe 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.
$ In vitro, retapamulin was equally active against methicillin-susceptible and methicillin-resistant strains of S. aureus. However, see section 4.4 and below regarding clinical efficacy against MRSA. 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
|Commonly susceptible species|
|Staphylococcus aureus* $|
|Inherently resistant organisms|
Information from clinical trialsVery few MRSA were isolated in studies in impetigo and all were clinical successes (100%: 8/8). In studies in impetigo and in two studies of secondarily infected open wounds (SIOW), clinical success rates were high for retapamulin in patients with mupirocin-resistant S. aureus (100%: 11/11) or fusidic acid-resistant S. aureus (96.7%: 29/30). However, in the two studies that enrolled patients with SIOW the efficacy of retapamulin in infections due to MRSA was inadequate (75.7%). No differences were observed in the in vitro activity of retapamulin versus S. aureus whether the isolates were susceptible or resistant to methicillin.The explanation for lower clinical efficacy against MRSA in SIOW is unclear and it may have been influenced by the presence of a particular MRSA clone. In the case of treatment failure associated with S. aureus, the presence of strains possessing additional virulence factors (such as Panton-Valentine Leukocidin) should be considered. Clinical Success Rates at Follow up for SIOW patients with S. aureus
CI: confidence interval. Exact CI is calculated using the F-distribution method.$: the response rate for MRSA due to PVL+ MRSA was 8/13 (62%)A multicentre, randomised, double-blind, study compared the efficacy of retapamulin ointment to placebo ointment for the treatment of SIOW. The study failed to meet the primary end point which was the clinical success rate at follow-up (day 12 14) for subjects in the Intent to Treat Clinical population (see Table below).
||Success Rate (%)
||95% Exact CI
||Success Rate (%)
|S. aureus (all)
| MRSA $||28/37
Clinical Response at Follow-up (day 12-14), by Analysis population
CI: confidence interval. Confidence interval was not adjusted for multiplicity.
ITTC- Intent to Treat Clinical Primary Efficacy Population; PPC Per Protocol Clinical Primary Efficacy population; ITTB- Intent to Treat Bacteriological evaluable, Primary Efficacy Population; PPB Per Protocol Bacteriologically evaluable, Primary Efficacy Population.
However, when adjusted for baseline wound characteristics including pathogen, wound size and severity, the clinical success rate of retapamulin was superior to placebo for the primary efficacy endpoint (p=0.0336). Lesions of subjects treated with retapamulin healed more quickly by the End of therapy visit (day 7-9), with a reduction in size of the lesions by 77.3% compared to 43.5% for placebo treated subjects. However by the Follow-up visit this difference was less pronounced, (88.6% vs, 81% for retapamulin and placebo treated subjects respectively).In the Intent to Treat Bacteriological evaluable population, the clinical success rate of retapamulin (76.4%: 139/182) was statistically superior to that of placebo (64.3%; 54/84). This difference was primarily due to the higher success rate observed in retapamulin-treated subjects with infections caused by S. aureus in comparison to placebo treated subjects (see Table below). However, retapamulin showed no advantage over placebo in subjects with SIOW due to S. pyogenes.Clinical Success rates at Follow-up for Intent to Treat Bacteriological Evaluable SIOW subjects with S. aureus and S. pyogenes
||Difference in success rates (%)
||95% CI (%)
CI: confidence interval. Exact CI is calculated using the F-distribution method
||Success rate (%)
||95% Exact CI
||Success rate (%)
|S. aureus (all)
|S. pyogenes ||29/36