Abstract and Introduction
In atopic dermatitis (AD), the stratum corneum of patients appears to have alterations that predispose them to colonization and invasion by various bacteria, most notably Staphylococcus aureus (S. aureus). This bacterial co-existence is accepted to be an important factor in AD disease activity. Exactly when to initiate antimicrobial treatment is controversial, but such intervention, when warranted, has repeatedly been demonstrated to improve the course of AD. However, the increase in antibiotic resistance presents a therapeutic challenge in the management of AD patients, which highlights the need for novel mechanism topical antibacterial agents. Retapamulin is a relatively new pleuromutilin antibiotic designed for topical use. In vitro studies have demonstrated its low potential for the development of antibacterial resistance and high degree of potency against Gram-positive bacteria found in skin infections, including many S. aureus strains that are resistant to methicillin, fusidic acid, and mupirocin. Clinical studies exploring the treatment of secondarily infected dermatitis reveal that the efficacy of topical retapamulin is comparable to a 10-day course of oral cephalexin or to topical fusidic acid. Retapamulin appears to be a much needed antimicrobial option for treating the AD population due to their common carriage of bacterial pathogens and frequency of infectious complications.
Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease that affects approximately 20% of children and 1–3% of adults; incidence is on the rise due to modern environmental factors in addition to genetic predisposition.[1–5] AD is a condition that encompasses eczematous changes within the epidermis, consisting of a multifaceted underlying etiology including, but not limited to, epidermal barrier dysfunction, atopic diathesis, and an increased incidence of secondary infections.[3,4,6] Acute lesions are characterized by erythema, oozing, and crusting, whereas chronic lesions can feature papules and lichenification. Affected individuals experience a decreased quality of life that is secondary to intermittent skin eruptions and difficult-to-control pruritus.[7,8]
One of the main factors in the pathogenesis of AD involves a compromised function of the natural skin barrier. AD patients are deficient in ceramides, the sphingolipid constituents of protective and potently antimicrobial lamellar sheets in the stratum corneum.[9,10] A second factor is a reduced amount of antimicrobial peptides in the skin of AD patients.[4,5,10] Keratinocytes produce 2 major classes of innate antimicrobials: B-defensins and cathelicidins; both are essential to defend the skin against bacterial invasion. In AD, the high concentrations of interleukin-10 and T2 helper cytokines cause a down regulation in the production of these antimicrobial peptides. Furthermore, the skin of AD patients has decreased moisture content. Together, these alterations in the microenvironment of the skin predispose AD patients to widespread microbial colonization and infection. For instance, it has been reported that AD patients have a 200- fold increase in S. aureus colonization when compared with individuals with healthy skin.[4,11] On both lesional and nonlesional skin, >90% of AD patients are colonized by S. aureus, whereas the prevalence is only 5–20% in non-AD individuals.[7,8,12] Among AD patients, the mean colonization density of S. aureus is markedly higher within the atopic lesions.[4,8,11] The presence of such a high microbial load is associated with increased disease severity.[1,2,8]
Overview of Standard Treatment
Standard AD care includes topical glucocorticoids as firstline agents, followed by newer options, such as calcineurin inhibitors and anti-IgE antibodies. With regard to secondary infections, antimicrobial therapy can either be administered orally or topically. Topical antimicrobials are preferentially given due to the fact that administration can be directly targeted to the infected area, therefore reducing the potential for systemic side-effects, such as gastrointestinal distress and undesired drug interactions. Until recently, topical antimicrobials have been limited in availability; the main options include fusidic acid (introduced in 1962) and mupirocin (introduced in 1985). Recent reports indicate that multiple bacterial organisms have successfully developed resistance to these 2 drugs.[14,15] This rising prevalence increasingly limits their use to specific conditions, e.g., systemic fusidic acid for severe bone infections and topical mupiricin to eradicate nasal methicillin-resistant Staphylococcus aureus (MRSA). However, due to the aforementioned phenomena of increased susceptibility to colonization with microorganisms, combined with a compromised ability to defend against them, the addition of antimicrobial therapy to the standard care regimen of AD is recommended in certain clinical circumstances, which include:
early signs of secondary bacterial infection;
AD exacerbation that cannot be otherwise explained; and
AD that is poorly controlled by monotherapy with topical anti-inflammatories.
Retapamulin ointment 1% (Altabax®/Altargo®, GlaxoSmithKline) is the first approved pleuromutilin antimicrobial for the treatment of uncomplicated superficial skin infections caused by staphylococcal, streptococcal, and anaerobic Grampositive organisms; it is not substantially effective against Gram-negative organisms.[16,17] Currently, it is approved for use in the EU for patients with impetigo or small infected wounds, and in the US for impetigo. Retapamulin has not received US FDA approval for MRSA skin infections. However, based on in vitro studies and incidental clinical trials data, it holds promise in the treatment of bacterial skin infections owing to its high in vitro potency against many common skin pathogens, low potential for development of bacterial resistance, and targeted application to the sites of involvement without significant systemic exposure.[13,16,18]
Retapamulin is a semisynthetic pleuromutilin derivative isolated from Clitopilus scyphoides (an edible mushroom) and functions by selectively targeting the 50S subunit of bacterial ribosomes to inhibit protein synthesis. It acts at a site distinct from other available drugs; therefore, crossresistance is not yet a concern. The in vitro minimum inhibitory concentration required to suppress the growth of 90% of organisms (MIC90) by retapamulin was 0.12g/ml against S. aureus, including methicillin- and mupirocinresistant, and Staphylococcus Epidermidis isolates. Retapamulin was also shown to be very active against Streptococcus Pyogenes (S. Pyogenes), approximately 1000 times as potent as mupiricin or fusidic acid.
A large study of over 6500 bacterial isolates, including staphylococcus and streptococcus from 13 countries, obtained from both hospital and community settings, further demonstrated the in vitro efficacy of retapamulin against these bacteria. Between 2005–2006, this Global Surveillance Program found retapamulin to also be effective against strains of S. aureus with resistance to methicillin, mupirocin, and fusidic acid.[19–21] Other in vitro studies have reported similar findings. In addition to Gram-positive coverage, retapamulin has shown mixed antimicrobial activity against anaerobes[14,22] and exhibited very minimal efficacy against enterococci and Gram-negative bacteria. Despite this in vitro data, clinical studies thus far have focused on Gram-positive skin infections. A low potential for the development of bacterial resistance has also been reported with retapamulin, and if resistance does develop, it does so very gradually and by mechanisms distinct from those known to occur against other available antimicrobial options.[23,24] The main mechanisms of resistance are twofold and include mutations in the retapamulin ribosomal binding site and a non-target-specific efflux mechanism.[25–27] These results have been reproduced in both single-step and multistep passage studies.[14,23,24]
Efficacy of Retapamulin
The overall findings from multiple trials indicate that retapamulin is a safe therapeutic alternative and it is at least as effective as conventional treatment options.
Skin Therapy Letter. 2010;15(1):1 © 2010
Cite this: Retapamulin: What is the Role of This Topical Antimicrobial in the Treatment of Bacterial Infections in Atopic Dermatitis? - Medscape - Jan 01, 2010.