Retapamulin: What is the Role of this Topical Antimicrobial in the Treatment of Bacterial Infections in Atopic Dermatitis?

M. N. Moody, MD, MPH¹; L. K. Morrison, MD²; S. K. Tyring, MD, PhD, MBA^2,3

¹The University of Texas Medical School at Houston, Houston, TX, USA

²Center for Clinical Studies, Houston, TX, USA

³Department of Dermatology, University of Texas Health Sciences Center, Houston, TX, USA

ABSTRACT

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.

Key Words:
antibacterial, atopic dermatitis, retapamulin, skin infections

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: Β-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.⁵ 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.¹³ 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).¹⁴ 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:⁴

a) early signs of secondary bacterial infection;

b) AD exacerbation that cannot be otherwise explained; and

c) AD that is poorly controlled by monotherapy with topical anti-inflammatories.

Topical Retapamulin

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.¹⁴ 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.¹⁵

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.¹⁸ In addition to Gram-positive coverage,²¹ 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.

Impetigo

One of the initial retapamulin trials consisted of 7 days of treatment with topical retapamulin 1% vs. placebo for impetigo in 210 patients. Clinical success rates were significantly higher for the retapamulin-treated group as compared with placebo (85.6% vs. 52.1%). Microbiological success rates were even higher for retapamulin vs. placebo (91.2% vs. 50.9%).²⁸

A multicenter trial of noninferiority comparison of retapamulin ointment 1% twice daily for 5 days with sodium fusidate ointment 2% 3 times daily for 7 days was completed. Over 500 adults and children ≥9 months of age with impetigo were treated in this randomized, observer-blinded phase 3 study. The group treated with retapamulin exhibited a 99% clinical success rate vs. 94% in the sodium fusidate treated arm. Cases of MRSA isolated at baseline were treated in the retapamulin group (n=8) and in the sodium fusidate group (n=2); both agents were 100% effective in treating these cases of MRSA impetigo.¹³

Secondarily Infected Traumatic Lesions

For the treatment of secondarily infected traumatic lesions, over 1900 patients participated in 2 identical, randomized, double-blind, controlled, multicenter trials of retapamulin 1% ointment twice daily for 5 days vs. oral cephalexin 500mg twice daily for 10 days.²⁹ Retapamulin was approximately 90% effective in successfully treating these skin infections compared with 92% for cephalexin. Compliance rates were significantly higher in the retapamulin group. Another randomized, double-blind, double-dummy noninferiority trial with 547 adults and children ≥9 months of age with secondarily infected dermatitis (SID) was performed with retapamulin.¹⁶ Patients with SID were randomized to treatment with retapamulin ointment 1% twice daily for 5 days or oral cephalexin 500mg twice daily for 10 days. Clinical success rates were 86% and 90%, respectively.

Potential Side-Effects of Retapamulin

The most common adverse event with the use of retapamulin ointment was localized application site irritation (e.g., pruritis), which was reported by less than 2% of all patients. Additionally, there exist 2 newly published case reports detailing allergic contact dermatitis as a result of retapamulin usage.^30,31 These patients ranged in age from 6 to 79 years and were all diagnostically worked up via patch testing, which identified retapamulin as the cause and excluded other ingredients in the formulation. While this has been reported as an extremely rare occurrence, no detailed studies have yet been conducted to estimate its true incidence. Nonetheless, a limited duration regimen of topical retapamulin can still ease AD progression and increase compliance vs. other longer term topical treatments or oral regimens. Improved treatment compliance may also contribute to decreased resistance.

The Use of Antibiotics in AD Treatment

Conflicting data exists with regard to the role of antibiotic therapy in the treatment of AD. One controlled study showed that systemic cloxacillin or erythromycin cleared S. aureus with at least 6 months of sustained clinical improvement.³² However, a second study among patients with no overt signs of infection indicated that there was no improvement after flucloxacillin treatment.³³ Numerous open and doubleblinded placebo-controlled experiments have since evaluated the combination of corticosteroids with topical antimicrobials in AD treatment. The majority of findings from these studies have shown significant benefit (1 of these studies specified benefit only in the case of severe disease), which included decreased colonization density and at least partial improvement of skin lesions. However, 1 study showed only marginal improvement and 2 showed no benefit.^7,8,10,34-37

Bacterial Decolonization

A meta-analysis by Birnie et al. investigated whether or not interventions to decrease S. aureus colonization in AD patients should be prescribed.¹ They looked at 21 studies and analyzed different eradication mechanisms, and concluded that treatment simply to decrease the colony load of S. aureus in AD patients without an overt infection was not recommended. However, the study team stated that this conclusion is limited by multiple factors, such as poor study design, improper reporting of results, and failure to include outcome findings related to quality of life and longterm improvement. The investigators do recommend further research in this area.

Conclusion

Finite topical antimicrobial therapy (for approximately 2 weeks) can be an important addition to the standard treatment of AD in many instances, especially when there are overt signs of a secondary infection or if manifestations cannot be well controlled with anti-inflammatories alone. Data is conflicting as to exactly when antimicrobials should be introduced for the treatment of AD, but following their use, overall improvement in disease course has been shown in multiple studies. Considering that resistance to current topical antimicrobials is increasing, leading to further challenges in treating skin infections, the need for new treatment options is very real. The advent of retapamulin offers a safe, effective, and distinct alternative to its predecessors, and can serve as an adjunctive therapeutic option in specified AD patients. While no clinical trials with retapamulin have been performed specifically for AD, its safety and efficacy are proven in uncomplicated superficial skin infections involving the same bacterial isolates, notably S. aureus, MRSA, and S. pyogenes.

References

1. Birnie AJ, Bath-Hextall FJ, Ravenscroft JC, et al. Interventions to reduce Staphylococcus aureus in the management of atopic eczema. Cochrane Database Syst Rev (3):CD003871 (2008).
2. Gilani SJ, Gonzalez M, Hussain I, et al. Staphylococcus aureus re-colonization in atopic dermatitis: beyond the skin. Clin Exp Dermatol 30(1):10-3 (2005 Jan).
3. Katoh N. Future perspectives in the treatment of atopic dermatitis. J Dermatol 36(7):367-76 (2009 Jul).
4. Lin YT, Wang CT, Chiang BL. Role of bacterial pathogens in atopic dermatitis. Clin Rev Allergy Immunol 33(3):167-77 (2007 Dec).
5. Novak N. New insights into the mechanism and management of allergic diseases: atopic dermatitis. Allergy 64(2):265-75 (2009 Feb).
6. Komine M. Analysis of the mechanism for the development of allergic skin inflammation and the application for its treatment: keratinocytes in atopic dermatitis – their pathogenic involvement. J Pharmacol Sci 110(3):260-4 (2009 Jul).
7. Breuer K, HÄussler S, Kapp A, et al. Staphylococcus aureus: colonizing features and influence of an antibacterial treatment in adults with atopic dermatitis. Br J Dermatol 147(1):55-61 (2002 Jul).
8. Gong JQ, Lin L, Lin T, et al. Skin colonization by Staphylococcus aureus in patients with eczema and atopic dermatitis and relevant combined topical therapy: a double-blind multicentre randomized controlled trial. Br J Dermatol 155(4):680-7 (2006 Oct).
9. Arikawa J, Ishibashi M, Kawashima M, et al. Decreased levels of sphingosine, a natural antimicrobial agent, may be associated with vulnerability of the stratum corneum from patients with atopic dermatitis to colonization by Staphylococcus aureus. J Invest Dermatol 119(2):433-9 (2002 Aug).
10. Biedermann T. Dissecting the role of infections in atopic dermatitis. Acta Derm Venereol 86(2):99-109 (2006).
11. Kedzierska A, Kapinska-Mrowiecka M, Czubak-Macugowska M, et al. Susceptibility testing and resistance phenotype detection in Staphylococcus aureus strains isolated from patients with atopic dermatitis, with apparent and recurrent skin colonization. Br J Dermatol 159(6):1290-9 (2008 Dec).
12. Hauser C, Wuethrich B, Matter L, et al. Staphylococcus aureus skin colonization in atopic dermatitis patients. Dermatologica 170(1):35-9 (1985).
13. Oranje AP, Chosidow O, Sacchidanand S, et al. Topical retapamulin ointment, 1%, versus sodium fusidate ointment, 2%, for impetigo: a randomized, observer-blinded, noninferiority study. Dermatology 215(4):331-40 (2007).
14. Yang LP, Keam SJ. Retapamulin: a review of its use in the management of impetigo and other uncomplicated superficial skin infections. Drugs 68(6):855-73 (2008).
15. Rittenhouse S, Biswas S, Broskey J, et al. Selection of retapamulin, a novel pleuromutilin for topical use. Antimicrob Agents Chemother 50(11):3882-5 (2006 Nov).
16. Parish LC, Jorizzo JL, Breton JJ, et al. Topical retapamulin ointment (1%, wt/wt) twice daily for 5 days versus oral cephalexin twice daily for 10 days in the treatment of secondarily infected dermatitis: results of a randomized controlled trial. J Am Acad Dermatol 55(6):1003-13 (2006 Dec).
17. Yang LP, Keam SJ. Spotlight on retapamulin in impetigo and other uncomplicated superficial skin infections. Am J Clin Dermatol 9(6):411-3 (2008).
18. Woodford N, Afzal-Shah M, Warner M, et al. In vitro activity of retapamulin against Staphylococcus aureus isolates resistant to fusidic acid and mupirocin. J Antimicrob Chemother 62(4):766-8 (2008 Oct).
19. Scangarella-Oman NE, Shawar RM, Bouchillon S, et al. Microbiological profile of a new topical antibacterial: retapamulin ointment 1%. Expert Rev Anti Infect Ther 7(3):269-79 (2009 Apr).
20. Jones RN, Fritsche TR, Sader HS, et al. Activity of retapamulin (SB-275833), a novel pleuromutilin, against selected resistant gram-positive cocci. Antimicrob Agents Chemother 50(7):2583-6 (2006 Jul).
21. Pankuch GA, Lin G, Hoellman DB, et al. Activity of retapamulin against Streptococcus pyogenes and Staphylococcus aureus evaluated by agar dilution, microdilution, E-test, and disk diffusion methodologies. Antimicrob Agents Chemother 50(5):1727-30 (2006 May).
22. Odou MF, Muller C, Calvet L, et al. In vitro activity against anaerobes of retapamulin, a new topical antibiotic for treatment of skin infections. J Antimicrob Chemother 59(4):646-51 (2007 Apr).
23. Kosowska-Shick K, Clark C, Credito K, et al. Single- and multistep resistance selection studies on the activity of retapamulin compared to other agents against Staphylococcus aureus and Streptococcus pyogenes. Antimicrob Agents Chemother 50(2):765-9 (2006 Feb).
24. Gentry DR, Rittenhouse SF, McCloskey L, et al. Stepwise exposure of Staphylococcus aureus to pleuromutilins is associated with stepwise acquisition of mutations in rplC and minimally affects susceptibility to retapamulin. Antimicrob Agents Chemother 51(6):2048-52 (2007 Jun).
25. Davidovich C, Bashan A, Auerbach-Nevo T, et al. Induced-fit tightens pleuromutilins binding to ribosomes and remote interactions enable their selectivity. Proc Natl Acad Sci U S A 104(11):4291-6 (2007 Mar 13).
26. Champney WS, Rodgers WK. Retapamulin inhibition of translation and 50S ribosomal subunit formation in Staphylococcus aureus cells. Antimicrob Agents Chemother 51(9):3385-7 (2007 Sep).
27. Yan K, Madden L, Choudhry AE, et al. Biochemical characterization of the interactions of the novel pleuromutilin derivative retapamulin with bacterial ribosomes. Antimicrob Agents Chemother 50(11):3875-81 (2006 Nov).
28. Koning S, van der Wouden JC, Chosidow O, et al. Efficacy and safety of retapamulin ointment as treatment of impetigo: randomized double-blind multicentre placebo-controlled trial. Br J Dermatol 158(5):1077-82 (2008 May).
29. Free A, Roth E, Dalessandro M, et al. Retapamulin ointment twice daily for 5 days vs oral cephalexin twice daily for 10 days for empiric treatment of secondarily infected traumatic lesions of the skin. Skinmed 5(5):224-32 (2006 Sep-Oct).
30. Schalock PC. Allergic contact dermatitis to retapamulin ointment. Contact Dermatitis 61(2):126 (2009 Aug).
31. Warshaw EM, Toby Mathias CG, Baker DR. Allergic contact dermatitis from retapamulin ointment. Dermatitis 20(4):220-1 (2009 Aug).
32. Dhar S, Kanwar AJ, Kaur S, et al. Role of bacterial flora in the pathogenesis & management of atopic dermatitis. Indian J Med Res 95:234-8 (1992 Sep).
33. Ewing CI, Ashcroft C, Gibbs AC, et al. Flucloxacillin in the treatment of atopic dermatitis. Br J Dermatol 138(6):1022-9 (1998 Jun).
34. Hjorth N, Schmidt H, Thomsen K. Fusidic acid plus betamethasone in infected or potentially infected eczema. Pharmatherapeutica 4(2):126-31 (1985).
35. Huang JT, Abrams M, Tlougan B, et al. Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics 123(5):e808-14 (2009 May).
36. Leyden JJ, Kligman AM. The case for steroid–antibiotic combinations. Br J Dermatol 96(2):179-87 (1977 Feb).
37. Wachs GN, Maibach HI. Co-operative double-blind trial of an antibiotic/corticoid combination in impetiginized atopic dermatitis. Br J Dermatol 95(3):323-8 (1976 Sep).