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  IN THIS Article
 ::  Abstract
 :: Introduction
 :: Pharmacology
 :: Mechanism of Action
 :: Pharmacokinetics
 :: Dose
 ::  Antimicrobial Sp...
 :: Drug Interactions
 :: Indications
 :: Formulation
 ::  Adverse Drug Rea...
 :: Studies
 :: Conclusions
 ::  References
 ::  Article Tables

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  Table of Contents     
DRUG REVIEW
Year : 2013  |  Volume : 59  |  Issue : 2  |  Page : 127-130

Retapamulin: A newer topical antibiotic


1 Department of Pediatrics, Maulana Azad Medical College and Associated Lok Nayak Hospital, New Delhi, India
2 Department of Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi, India

Date of Submission10-Mar-2013
Date of Decision08-Apr-2013
Date of Acceptance15-Apr-2013
Date of Web Publication21-Jun-2013

Correspondence Address:
A Parakh
Department of Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi
India
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DOI: 10.4103/0022-3859.113842

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 :: Abstract 

Impetigo is a common childhood skin infection. There are reports of increasing drug resistance to the currently used topical antibiotics including fusidic acid and mupirocin. Retapamulin is a newer topical agent of pleuromutilin class approved by the Food and Drug Administration for treatment of impetigo in children and has been recently made available in the Indian market. It has been demonstrated to have low potential for the development of antibacterial resistance and a high degree of potency against poly drug resistant Gram-positive bacteria found in skin infections including Staphylococcus aureus strains. The drug is safe owing to low systemic absorption and has only minimal side-effect of local irritation at the site of application.


Keywords: Impetigo, retapamulin, topical antibiotics


How to cite this article:
Dhingra D, Parakh A, Ramachandran S. Retapamulin: A newer topical antibiotic. J Postgrad Med 2013;59:127-30

How to cite this URL:
Dhingra D, Parakh A, Ramachandran S. Retapamulin: A newer topical antibiotic. J Postgrad Med [serial online] 2013 [cited 2014 Jul 31];59:127-30. Available from: http://www.jpgmonline.com/text.asp?2013/59/2/127/113842



 :: Introduction Top


Uncomplicated skin infections are one of the most common reasons for doctor visits particularly in children. [1] Impetigo is the most common and highly contagious superficial skin infection caused by gram-positive organisms viz Staphylococcus aureus and Streptococcus pyogenes. [2] Topical antibiotics such as fusidic acid and mupirocin have remained the mainstay of treatment. Commonly used topical antibiotics are summarized in [Table 1]. However, multidrug resistance amongst S. aureus is now a widespread problem.
Table 1: Comparison of various topical antibiotics used in skin infections

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Retapamulin, a new antibacterial approved by Food and Drug administration (FDA) in 2007 for topical treatment of impetigo in children above 9 months has been recently made available in Indian market. This article briefly highlights the clinical pharmacology, indications, and therapeutic efficacy of this drug in Indian perspective.


 :: Pharmacology Top


Retapamulin is a derivative of pleuromutilin, derived from Pleurotus mutilins, now called clitopilus scyphoides, an edible mushroom. [3]


 :: Mechanism of Action Top


The pleuromutilin class has a unique mode of action, which involves inhibition of protein synthesis by primarily inhibiting ribosomal activity at three sites: By selectively binding to a site on the 50S subunit of the bacterial ribosome, binding to protein L3 at site P of the ribosome and inhibiting ribosomal peptidyl transferase activity. This is a novel site of binding, which differs from other ribosome binding non pleuromutilin antibiotics, which minimizes development of resistance against retapamulin. [4]


 :: Pharmacokinetics Top


The drug is 94% protein bound and is primarily metabolized in the liver by mono-oxygenation and N demethylation. It has a low bioavailability and hence systemic side effects are low after local application.


 :: Dose Top


A thin layer of retapamulin is to be applied for topical treatment of impetigo (up to 100 cm 2 in total area in adults or 2% total body surface area in children 9 months and above). [5] Before application affected skin may be washed and pat dried with a towel. Gently and thoroughly the ointment may be massaged over the affected area avoiding contact with eyes or mouth. The area may be covered with a thin sterile bandage. [6]


 :: Antimicrobial Spectrum Top


Retapamulin is effective against gram-positive organisms and only some gram-negative organisms. It is active against S. aureus, S. pyogenes, Streptococcus agalactia, β hemolytic streptococci, streptococcus viridians, and coagulase negative staphylococci. [2] Retapamulin has shown significant in vitro activity against anaerobes. In a study evaluating 232 anaerobic isolates, at a level of <2 mg/L retapamulin was found to be inhibiting 90% strains. Based on inhibitory concentrations, retapamulin was found to be more effective than clindamycin, metronidazole and ceftriaxone against bacteroides fragilis, clostridium perfringes, propionibacterium acnes. [7]


 :: Drug Interactions Top


Drug interactions are few owing to low systemic absorption. The drug is primarily metabolized by Cytochrome P450 (CYP) 3A4, but its administration is not seen with alteration of metabolism of other substrates of CYP3A4. The drug does not require alterations in dosages in patients with renal or hepatic impairment. [5]


 :: Indications Top


The US FDA approved retapamulin 1% for use in adults and children >9 months and older for the topical treatment of impetigo (up to 100 cm 2 area in adults and 2% total body surface area in pediatric patients). However, in the European Union retapamulin 1% is approved for use in patients with impetigo or those with infected lacerations, abrasions, sutured wounds without abscesses. [8] However, retapamulin is not indicated for impetigo secondary to methicillin resistant Staphylococcus aureus (MRSA). [5]


 :: Formulation Top


It is available as 10 mg retapamulin/1 g of ointment in 5, 10, 15, and 30 g tubes.


 :: Adverse Drug Reactions Top


Retapamulin treatment has not been seen to be associated with any major side effects. The most common treatment related adverse effect noted is application site irritation. [9] There have been few reports of patients developing contact dermatitis secondary to application of retapamulin; however, in all these patients the dermatitis responded to discontinuation of retapamulin. [10]


 :: Studies Top


Clinical studies

Retapamulin has been compared in in vitro microbiological studies and clinical randomized controlled trials (RCT) with placebo, other topical antibiotics, and oral drugs such as cephalexin for treatment of impetigo in children >9 months of age. The clinical studies are summarized in [Table 2] and in vitro studies in [Table 3].
Table 2: Clinical studies on retapamulin

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Table 3: In vitro studies comparing retapamulin with other antibiotics

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Retapamulin (5 days) has been compared with oral antibiotics such as oral cephalexin (10 days) for treatment of secondarily infected dermatitis. [11] (clinical efficacy/microbiologic success: Retapamulin 85.9%/87.2% versus oral cephalexin 89.7%/91.8%) and secondarily infected traumatic lesions (SITLs) (Clinical success: Retapamulin 89.5%; oral cephalexin 91.9%) and has been found to be non-inferior to cephalexin. [12]

Retapamulin has also been found to be non-inferior to fusidic acid in a large multicentric non-inferiority blinded RCT with similar clinical and bacteriological response rates: retapamulin (99.1%, 99.2%) and fusidic acid (94%, 93%) (P≤0.022). [13] There have been no comparative clinical studies with any other topical antibiotic such as mupirocin. When compared to a placebo in a double blind randomized trial retapamulin was found to be superior (success rate 85.6% vs. 52.1%, P>0.0001). [14] In a recent single center open labeled pilot study from USA Kircik evaluated the efficacy and tolerability of retapamulin for the treatment of infected atopic dermatitis. Application of retapamulin produced a mean 8.1-point reduction from baseline in the mean Skin Infection Rating Scale score with the majority of subjects achieved clinical cure. [15] Given its efficacy and good tolerability retapamulin 1% ointment needs to be further evaluated for this indication.

Microbiologic studies

Retapamulin has shown significant in vitro activity against methicillin sensitive staphylococcus aureus and MRSA. Retapamulin has been compared to mupirocin, oxacillin, and erythromycin resistant strains of S. aureus and has shown consistent minimum inhibiting concentration (MIC) required to inhibit 90% of isolates MIC 90 of 0.06 μg/ml. [16] Significant in vitro activity of retapamulin has also been shown against S. aureus resistant to fusidic acid. [17] Favorable activity of retapamulin has also been recorded against MRSA (MIC 90 -0.12 μg/ml), but not against MRSA harbouring cfr gene, which expresses methyl transferase and also confers cross resistance to lincosamides. [18] Retapamulin has shown comparable in vitro activity against S. pyogenes as well. [19] When compared against S. pyogenes with other topical antibiotics, retapamulin showed the highest intrinsic activity with MIC 90 ranging from ≤0.015 μg/ml to 0.12 μg/ml. [20]


 :: Conclusions Top


Retapamulin appears to be a promising drug for treatment of impetigo and other SITLs resulting due to S. aureus and S. pyogenes. The drug with its novel site of action, topical formulation, and shorter duration of action and less frequent dosing will help to ensure compliance and also prevent the development of resistance to antibacterial agents. The drug is safe and has poor systemic absorption. Retapamulin is a convenient and safe therapeutic option for the treatment of impetigo and SITLs for all age groups including children.

 
 :: References Top

1.Ladhani S, Garbash M. Staphylococcal skin infections in children: Rational drug therapy recommendations. Paediatr Drugs 2005;7:77-102.  Back to cited text no. 1
    
2.Nagabushan H. Retapamulin: A novel topical antibiotic. Indian J Dermatol Venereol Leprol 2010;76:77-9.  Back to cited text no. 2
    
3.Jacobs MR. Retapamulin: A semisynthetic pleuromutilin compound for topical treatment of skin infections in adults and children. Future Microbiol 2007;2:591-600.  Back to cited text no. 3
    
4.Shawar R, Scangarella-Oman N, Dalessandro M, Breton J, Twynholm M, Li G, et al. Topical retapamulin in the management of infected traumatic skin lesions. Ther Clin Risk Manag 2009;5:41-9.  Back to cited text no. 4
    
5.Weinberg JM, Tyring SK. Retapamulin: An antibacterial with a novel mode of action in an age of emerging resistance to staphylococcus aureus. J Drugs Dermatol 2010;9:1198-204.  Back to cited text no. 5
    
6.Gelmetti C. Local antibiotics in dermatology. Dermatol Ther 2008;21:187-95.  Back to cited text no. 6
    
7.Odou MF, Muller C, Calvet L, Dubreuil L. In vitro activity against anaerobes of retapamulin, a new topical antibiotic for treatment of skin infections. J Antimicrob Chemother 2007;59:646-51.  Back to cited text no. 7
    
8.Yang LP, Keam SJ. Retapamulin: A review of its use in the management of impetigo and other uncomplicated superficial skin infections. Drugs 2008;68:855-73.  Back to cited text no. 8
    
9.Yang LP, Keam SJ. Spotlight on retapamulin in impetigo and other uncomplicated superficial skin infections. Am J Clin Dermatol 2008;9:411-3.  Back to cited text no. 9
    
10.Warshaw EM, Toby Mathias CG, Baker DR. Allergic contact dermatitis from retapamulin ointment. Dermatitis 2009;20:220-1.  Back to cited text no. 10
    
11.Parish LC, Jorizzo JL, Breton JJ, Hirman JW, Scangarella NE, Shawar RM, 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 2006;55:1003-13.  Back to cited text no. 11
    
12.Free A, Roth E, Dalessandro M, Hiram J, Scangarella N, Shawar R, 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 2006;5:224-32.  Back to cited text no. 12
    
13.Oranje AP, Chosidow O, Sacchidanand S, Todd G, Singh K, Scangarella N, et al. Topical retapamulin ointment, 1%, versus sodium fusidate ointment, 2%, for impetigo: A randomized, observer-blinded, noninferiority study. Dermatology 2007;215:331-40.  Back to cited text no. 13
    
14.Koning S, van der Wouden JC, Chosidow O, Twynholm M, Singh KP, Scangarella N, et al. Efficacy and safety of retapamulin ointment as treatment of impetigo: Randomized double-blind multicentre placebo-controlled trial. Br J Dermatol 2008;158:1077-82.  Back to cited text no. 14
    
15.Kircik LH. Efficacy and tolerability of retapamulin 1% ointment for the treatment of infected atopic dermatitis: A pilot study. J Drugs Dermatol 2012;11:858-60.  Back to cited text no. 15
    
16.Jones RN, Fritsche TR, Sader HS, Ross JE. Activity of retapamulin (SB-275833), a novel pleuromutilin, against selected resistant gram-positive cocci. Antimicrob Agents Chemother 2006;50:2583-6.  Back to cited text no. 16
    
17.Woodford N, Afzal-Shah M, Warner M, Livermore DM. In vitro activity of retapamulin against staphylococcus aureus isolates resistant to fusidic acid and mupirocin. J Antimicrob Chemother 2008;62:766-8.  Back to cited text no. 17
    
18.Candel FJ, Morales G, Picazo JJ. In vitro activity of retapamulin against linezolid and methicillin-resistant staphylococcus aureus isolates. Rev Esp Quimioter 2011;24:127-30.  Back to cited text no. 18
    
19.Traczewski MM, Brown SD. Proposed MIC and disk diffusion microbiological cutoffs and spectrum of activity of retapamulin, a novel topical antimicrobial agent. Antimicrob Agents Chemother 2008;52:3863-7.  Back to cited text no. 19
    
20.Pérez-Trallero E, Tamayo E, Montes M, García-Arenzana JM, Iriarte V. In vitro activities of retapamulin and 16 other antimicrobial agents against recently obtained Streptococcus pyogenes isolates. Antimicrob Agents Chemother 2011;55:2406-8  Back to cited text no. 20
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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