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FOCUS
Year : 2010  |  Volume : 76  |  Issue : 1  |  Page : 77-79

Retapamulin: A novel topical antibiotic


Department of Pharmacology, K.S. Hegde Medical Academy, Mangalore, Karnataka, India

Date of Web Publication6-Jan-2010

Correspondence Address:
H Nagabushan
Vin Manor, Right 2nd cross,Valancia Mangalore, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0378-6323.58693

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How to cite this article:
Nagabushan H. Retapamulin: A novel topical antibiotic. Indian J Dermatol Venereol Leprol 2010;76:77-9

How to cite this URL:
Nagabushan H. Retapamulin: A novel topical antibiotic. Indian J Dermatol Venereol Leprol [serial online] 2010 [cited 2018 Jul 21];76:77-9. Available from: http://www.ijdvl.com/text.asp?2010/76/1/77/58693



  Introduction Top


Skin infections are a common reason for patients to seek attention from dermatologists. The most common bacteria found in skin and soft tissue infections (SSTI) include the gram-positive organisms Staphylococcus aureus (55.2%), β- hemolytic Streptococci (5.0%), and Coagulase- negative Staphylococci (4.9%). Most of these bacteria causing SSTI have become resistant to the leading topical antimicrobials used in clinical practice. Antibiotics with a novel mechanism of action are needed to address the rising resistance to established classes of both systemic and topical agents. Resistance has already developed to two of the most commonly used topical antibiotics, fusidic acid and mupirocin. [1] Retapamulin, a novel topical antibacterial agent, will probably replace the use of mupirocin and fusidic acid. [2] It was approved by FDA, in 2007, for topical treatment of impetigo. [3] European Medicines Agency approved this drug also for infected wounds caused by S. pyogenes and methicillin susceptible S. aureus. [4]

Synthesis

Retapamulin is a derivative of the naturally occurring pleuromutilin, produced by Pleurotus mutilins (now called Clitopilus scyphoides), an edible mushroom. [5] Pleuromutilin was discovered in 1951, but it was not until the early 1970s that its potential for use as an antimicrobial was more fully recognized. Other agents in this class (tiamulin and valnemulin) have been developed as veterinary antibiotics. These drugs have a common tricyclic mutilin core, a C21 keto group, essential for antimicrobial activity and various substituents at its C14, most of which are extensions of diverse chemical nature. Retapamulin is a C14-sulfanyl-acetate derivative of pleuromutilin [Figure 1].


  Mechanism of Action Top


The pleuromutilin class has a unique mode of action which involves inhibition of bacterial protein synthesis at the level of bacterial 50s ribosome. [1] It binds to domain V of 23s rRNA, inhibits ribosomal peptidyl transferase activity and partially inhibits the binding of the initiator tRNA substrate to the ribosomal P-site. [7] The ribosomal binding site for pleuromutilin overlaps with that for chloramphenicol and puromycin, hence both drugs compete with retapamulin for the binding site. [8]

Antimicrobial spectrum

Retapamulin is effective against gram-positive and some gram-negative organisms. It includes Streptococcus pyogenes, Streptococcus agalactiae, b-hemolytic streptococci, Streptococci viridans, Staphylococcus aureus, Coagulase-negative staphylococci, Propionibacterium spp (including P acnes), Prevotella spp, Porphyromonas spp, Fusobacterium spp, Bacteroides and Clostridium.

It is a bacteriostatic drug, but may be bactericidal at high concentration. The minimum bactericidal concentration (MBC) is 1000 times higher than the minimum inhibitory concentration (MIC).The MIC against S. aureus is between 0.03 and 0.25 mcg/ml and for S. pyogenes it is between 0.008 and 0.03 mcg/ml. [9] It has substantial post antibiotic effect (PAE) against S. aureus and S. pyogenes, which may contribute to the efficacy observed after twice daily application of 1% ointment. [10]

However, retapamulin showed minimal or no activity against enterococci and gram-negative bacilli. It is active against B. fragilis but less active against other members of the B. fragilis group, especially B. thetaiotaomicron.

It is as potent as Co-amoxiclav, imipenem, metronidazole and clindamycin against Prevotella spp, Porphyromonas spp and Fusobacterium spp. It is also more active than clindamycin, metronidazole and ceftriaxone against anerobic gram- positive cocci. [11]

Most importantly, it maintains its activity against organisms that are resistant to a number of antimicrobials including methicillin, erythromycin, fusidic acid, mupirocin, azithromycin and levofloxacin.

Pharmacokinetics

Bioavailability is low. Hence systemic exposure is minimal following topical application to intact or abraded skin. It is 94% protein bound and metabolized in liver by monooxygenation and N-demethylation to numerous metabolites. The main enzyme responsible for metabolism in liver microsome is CYP3A4.

Side effects

The most common adverse effect is pruritus at the application site. [12] Others are blisters, burning, redness, swelling, headache, diarrhea, eczema and oozing at the site where the ointment is applied. Retapamulin is classified as pregnancy category B; however, there have been no adequate human studies in this population group.

Drug resistance

Retapamulin has demonstrated excellent activity in vitro against S. aureus, irrespective of their level of resistance to other antimicrobials. [13] One study has shown that bacterial resistance in vitro is through two mechanisms: Mutation in protein L3 close to the peptidyl transferase center and the development of drug efflux mechanisms. [14] Mutation in L3 is a multi-step process which appears to be slow to emerge. Evidences from multiple-step and single-step studies also suggest that retapamulin has a low potential to select for resistant mutants in S. pyogenes and S. aureus. Retapamulin had the lowest rate of spontaneous mutations by single step passaging and the lowest parent and selected mutant MICs by multi step passaging among all drugs tested for all S. aureus strains and three S. pyogenes strains which yielded resistant clones. [15] Another study showed a stepwise reduction in pleuromutilin susceptibility occurring concurrently with stepwise acquisition of mutations in rplC. [16] A potential clinical threat of cross-resistance in the antibiotics that targets the ribosomal peptidyl transferase center (PTC) is the multidrug resistance phenotype mediated by the cfr rRNA methyltransferase. This gene encodes a methyltransferase that modifies the PTC nucleotide A2503, and is responsible for resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin antibiotics. [17]

Dosage and administration

A thin layer of retapamulin should be applied to the affected area (up to 100 cm 2 in total area in adults or 2% total body surface area in pediatric patients aged nine months or older) twice daily for five days. The treated area may be covered with a sterile bandage or gauze dressing if desired.

Drug interactions

Drug interactions are less due to low systemic exposure following topical application. Dosage adjustments are unnecessary when co-administered with CYP3A4 inhibitors such as ketoconazole.

Indications

It is used in adults and children over nine months of age for topical treatment of impetigo and infected wounds caused by S. pyogenes and methicillin susceptible S. aureus (MSSA). [3],[4]


  Conclusions Top


Retapamulin, a novel pleuromutilin derivative, could probably provide a valuable therapeutic option for the management of skin and soft tissue infections caused by S. pyogenes and S. aureus resistant to the most commonly used topical antibiotics.

 
  References Top

1.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. 1      
2.Gelmetti C. Local antibiotics in dermatology. Dermatol Ther 2008;21:187-95.  Back to cited text no. 2      
3.Food and Drug Administration, 2007. FDA News Release.FDA Approves Antibiotic Ointment for Children and Adults. Food and Drug Administration, Washington, DC . Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108888.htm [last accessed on 2009 Jun 28].  Back to cited text no. 3      
4.European Medicines Agency. 2007 Altargo: Summary of product characteristics. European Medicines Agency, London, United Kingdom. Available from: http://www.emea.europa.eu/humandocs/PDFs/EPAR/altargo/H-757-PI-en.pdf. [last assessed on 2009 Jun 28].  Back to cited text no. 4      
5.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. 5      
6.Ross JE, Jones RN. Quality control guidelines for susceptibility testing of retapamulin (SB-275833) by reference and standardized methods. J Clin Microbiol 2005;43:6212-3.  Back to cited text no. 6      
7.Yan K, Madden L, Choudhry AE, Voigt CS, Copeland RA, Gontarek RR. Biochemical characterization of the interactions of the novel pleuromutilin derivative retapamulin with bacterial ribosomes. Antimicrob Agents Chemother 2006;50 : 3875-81.  Back to cited text no. 7      
8.Hoegenaur G. The mode of action of pleuromutilin derivatives. Eur J Biochem 1975;52:93-8.  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.Rittenhouse S, Biswas S, Broskey J, McCloskey L, Moore T, Vasey S, et al. Selection of retapamulin, a novel pleuromutilin for topical use. Antimicrob Agents Chemother 2006;50 : 3882-5.  Back to cited text no. 10      
11.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. 11      
12.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. 12      
13.Woodford N, Afzal-Shah 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. 13      
14.Bψsling J, Poulsen SM, Vester B, Long KS. Resistance to the Peptidyl Transferase Inhibitor Tiamulin Caused by Mutation of Ribosomal Protein L3. Antimicrob Agents Chemother 2003;47:2892-6.  Back to cited text no. 14      
15.Kosowska-Shick K, Clark C, Credito K, McGhee P, Dewasse B, Bogdanovich T, 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 2006;50:765-9.  Back to cited text no. 15      
16.Gentry DR, Rittenhouse SF, McCloskey L, Holmes DJ. 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 2007;51:2048-52.  Back to cited text no. 16      
17.Giessing AM, Jensen SS, Rasmussen A. Hansen LH, Gondela A, Long K, et al. Identification of 8-methyladenosine as the modification catalyzed by the radical SAM methyltransferase Cfr that confers antibiotic resistence in bacteria. RNA 2009;15:327-36.  Back to cited text no. 17      


    Figures

  [Figure 1]

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