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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 5  |  Issue : 1  |  Page : 3-7

Topical antibacterials: Current concepts and advances


1 Department of Skin and STD, Karnataka Institute of Medical Sciences, Hubballi, Karnataka, India
2 Department of Dermatology, Venereology and Leprosy, Yenepoya Medical College, Mangalore, Karnataka, India

Date of Submission14-Aug-2019
Date of Decision27-Jan-2020
Date of Acceptance25-Feb-2020
Date of Web Publication08-Jul-2020

Correspondence Address:
Dr. Spandana Prakash Hegde
Department of Dermatology, Venereology and Leprosy, Yenepoya Medical College, Deralakatte, Mangalore - 575 018, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bjhs.bjhs_37_19

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  Abstract 


Skin and mucosa act as a barrier against the entry of microbial agents, but loss of integrity of the skin weakens the host defense mechanisms and antimicrobials appear to play a role. Antibiotics have come a long way from penicillin which was accidentally discovered by Alexander Fleming when experimenting on influenza virus to the latest unnamed molecules. Recent topical antibiotics include retapamulin, nadifloxacin, dapsone, ozenoxacin, REP8839, and BAL19403. This article summarizes the current scientific information on newer topical antibiotics available along with overview of other old antibiotics, their indications in various fields, advantages of topical over oral antibiotics, available formulations, side effects, and precautions to be followed so as to minimize the emergence of drug resistance. Indiscriminate use of topical antibiotics is an important contributor for the development of bacterial resistance and should be curbed and they should be judiciously used. There is no ideal topical antibiotic, and clinicians must be watchful to identify the various patterns of antibiotic resistance.

Keywords: Mupirocin, retapamulin, topical antibacterials


How to cite this article:
Krishna S, Hegde SP, Shenoy MM. Topical antibacterials: Current concepts and advances. BLDE Univ J Health Sci 2020;5:3-7

How to cite this URL:
Krishna S, Hegde SP, Shenoy MM. Topical antibacterials: Current concepts and advances. BLDE Univ J Health Sci [serial online] 2020 [cited 2020 Aug 11];5:3-7. Available from: http://www.bldeujournalhs.in/text.asp?2020/5/1/3/289197



Skin being an external organ, often has a disadvantage of being subjected to the microbial insult from the external environment. Other organs such as the eyes, external ear, nasal mucosa, throat, genitourinary mucosa, and certain other parts are also affected in a similar manner because of their proximity to the external environment. When infection sets in and the primary defense of our body is not able to curtail it, the role of anti-infective agents appears. Antibiotics are used commonly in systemic forms, but when these organ systems are affected, topical anti-infectives are also used. The ability to use a topical antibiotic can be considered as an advantage in these situations.

Topical antibiotics are being widely used and are the subject of clinical relevance. Topical antibiotics are routinely prescribed in day-to-day clinical practice by dermatologists, surgeons, family physicians, ophthalmologists, and otorhinolaryngologists for a wide variety of ailments. The recent years have seen a surge in the number of antibiotics belonging to various families being licensed for topical use.[1] Antibiotics are defined as the subgroup of anti-infective agents that are derived from bacterial sources and are used to treat infections caused by bacteria.[2]


  Historical Background Top


Throughout history, man has had to contend with dermal wounds. In the ancient times, crude remedies for wounds were extracted from various plants, minerals, and animal sources.[3] The earliest evidence of topical wound therapy was found as inscriptions on clay tablets documented in approximately 2500 BC in Mesopotamia. In 1928, a Scottish biologist named Sir Alexander Fleming, while conducting experiments on influenza virus, made an observation that a common fungus, Penicillium notatum, had destroyed bacteria in a Staphylococcus aureus culture plate. He then named it as penicillin.[4] The 20th century saw the emergence of numerous newer antibiotics with increased specificity which led to a transformation in clinical therapy and decline of several older remedies.[5]


  Classification Top


Topical antibiotics can be classified according to the mechanism of action as follows:[2],[6]

  • Cell wall synthesis inhibitors – bacitracin, polymyxin B, and mupirocin
  • Ribosome function inhibitors – neomycin, tetracycline, meclocycline, erythromycin, clindamycin, chloramphenicol, and fusidic acid
  • Sulfa drugs – silver sulfadiazine and mafenide acetate
  • Miscellaneous – Gramicidin, clioquinol, and nitrofurazone.



  Newer Antibiotics Top


Mupirocin

Mupirocin (formerly called pseudomonic acid) is a natural crotonic acid derivative extracted from a strain of Pseudomonas fluorescens. It is available as 2% ointment in polyethylene glycol or as 2% cream in mineral oil. It is classified as pregnancy category B drug. It is approved by the Food and Drug Administration (FDA) for the treatment of impetigo and secondarily infected traumatic skin lesions due to S. aureus and Streptococcus pyogenes. It is highly effective against Gram-positive staphylococci and streptococci. It inhibits the synthesis of bacterial protein by binding reversibly to bacterial isoleucyl tRNA synthetase.[7],[8] Intranasal mupirocin has proven efficacious in the elimination of staphylococci and methicillin-resistant Staphylococcus aureus (MRSA) from chronic carriers.[9]

REP8839

The emergence of mupirocin-resistant S. aureus necessitates the need for new agents. REP8839 is a novel methionyl-tRNA synthetase inhibitor. It has demonstrated potent bacteriostatic activity against S. aureus and other Gram-positive bacteria of clinical significance. It exhibits little activity against Gram-negative bacteria.[10]

Retapamulin

It belongs to a class of the naturally occurring pleuromutilin produced by Clitophilus scyphoides, an edible mushroom. Its distinctive mechanism of action involves inhibition of bacterial protein synthesis through an interaction at a binding site on the 50S subunit of the bacterial ribosome.[8],[11],[12] It is available as 1% ointment. Retapamulin is FDA approved for the treatment of impetigo, and it has bacteriostatic activity against S. aureus and S. pyogenes.[13]

Indolmycin

Topical indolmycin is bacteriostatic with good antistaphylococcal activity. It has shown encouraging results in the treatment of MRSA strains which are resistant to mupirocin and fusidic acid. It is known to exhibit goodin vitro activity against methicillin-sensitive S. aureus, MRSA, as well as vancomycin-intermediate S. aureus.[14]

Nadifloxacin

Nadifloxacin is a potent topical quinolone with a broad spectrum of antimicrobial activity. It is an approved topical agent for the treatment of acne vulgaris and skin infections. It is available as 1% cream. Quinolones exhibit bactericidal activity by inhibiting the bacterial DNA gyrase or the topoisomerase four enzymes. Nadifloxacin has broad-spectrum activity against Gram-positive bacteria, including coagulase-negative staphylococci and  Propionibacterium acnes Scientific Name Search am-negative bacteria such as Pseudomonas aeruginosa and  Escherichia More Details coli.[15] The safety and bacteriological efficacy of 1% cream of nadifloxacin was comparable to 2% cream of erythromycin as per a study conducted over 12 weeks.[16]

Ozenoxacin

Ozenoxacin is a novel nonfluorinated quinolone. It acts by selective inhibition of DNA replication. Ozenoxacin 1% cream has been used in the treatment of impetigo. Ozenoxacin has demonstrated potent bactericidal activity against the common Gram-positive organisms including MRSA, mupirocin, fusidic acid, and ciprofloxacin-resistant strains of S. aureus.[17],[18] The activity of ozenoxacin against quinolone-resistant strains may be due to its increased inhibitory activity than other quinolones for the enzymes essential for the transcription and replication of bacterial DNA, i.e., DNA gyrase and topoisomerase IV.[17]

Rifalazil

Rifalazil are modified rifamycins with a distinct planar benzoxazine ring.[19] The intracellular levels of rifalazil are higher due to their increased capability of tissue penetration. The problem of the development of resistance to rifampin is an issue of concern with the topical usage of this class of drugs.[2]

Fusidic acid

Fusidic acid, belonging to fusidanes, has a structural similarity to corticosteroids but is devoid of the steroid-like effects. It is a derivative of the fungus Fusidium coccineum. Fusidic acid interferes with the synthesis of bacterial proteins. The property of its high penetrability results in a higher drug concentration at the infection site. It has excellent activity against S. aureus.[20] Fusidic acid is often recommended as thefirst line of therapy in superficial skin infections and infected eczema.[21]

BAL19403

BAL19403 is a novel macrolide antibiotic which demonstrates very goodin vitro activity against propionibacteria, including erythromycin as well as clindamycin-resistant strains.[22]

Dapsone

Dapsone, a sulfone, was initially used in the treatment of leprosy.[23] Dapsone has the advantage of having a strong anti-inflammatory property in addition to its antimicrobial activity. However, the systemic toxicity caused by dapsone led to a decline in its use for severe inflammatory acne. A topical gel formulation of 5% dapsone is approved for the treatment of mild-to-moderate acne.[24]


  Combination Topical Antibiotics Top


The combination of various topical antibiotics is used for broad-spectrum antimicrobial coverage. A combination of neomycin, polymyxin B sulfate, and bacitracin zinc (Neosporin) are effective against S. aureus, Streptococcus pneumoniae, E. Coli,  Neisseria More Details, and P. aeruginosa.[25] However, the antibacterial coverage provided by the combination is inadequate and has an increased risk of allergic sensitization to neomycin.[2]

Topical antibiotics are also combined with pharmacologically diverse compounds such as topical steroids and topical antifungals. This is primarily meant for the management of the mixed and eczematous infections. However, such uses should be discouraged.


  Advantages Top


The advantages of topical therapy over oral therapy include:[2],[8],[26],[27]

  • Reduced risk of systemic side effects and toxicity
  • Avoidance of usage of systemic antibiotic
  • Delivery of the antibiotic in high concentration at the desired site.



  Indications Top


  • Localized cutaneous bacterial infections, such as impetigo and other superficial pyodermas
  • Localized infected eczemas and other dermatological diseases
  • Elimination of staphylococcal nasal carriage
  • Therapy of eye and external ear infections
  • Other dermatoses such as acne vulgaris and rosacea
  • Postoperatively to surgical wound sites and stomas as prophylaxis against infection
  • Superficial wounds following minor trauma, cuts, insect bites, burns, and simple surgical procedures
  • In chronic wounds such as leg ulcers, often based on culture and sensitivity.[1],[2],[27]



  Precautions Top


  • Topical medications should be applied to the entire affected area, in a quantity that readily absorbs, ideally twice daily
  • The affected site has to be treated with a thin layer of the topical preparation. The “fingertip unit” may be used as the standard application method
  • The topical medication should be massaged thoroughly and gently onto the skin
  • When topical antibiotics are used in combination with topical corticosteroids, the signs of underlying allergic reaction or infections may be masked
  • Adverse effects are common with topical medications but they usually cause application site reactions.[2],[27]



  Adverse Effects Top


The commonly reported adverse effects of topical antibacterials include itching or burning sensation. They infrequently require medical assistance unless they are severe which is rare.[2] Specific side effects of each topical antibacterial are mentioned in [Table 1].[2]
Table 1: Common adverse effects of topical antibacterials

Click here to view



  Hurdles Top


Resistance to topical antibiotics is a major concern, and cross-resistance can exist among commonly used antibiotics.[26] The mechanism of the development of resistance to various topical antibiotics is given in [Table 2].[8],[10],[27],[28],[29],[30],[31] To overcome the hurdle of resistance, topical antibiotics should be used only for short periods of time and only as directed. The application of topical antibiotics on large areas of skin or on open wounds should be discouraged.[2],[27]
Table 2: Mechanism of the development of drug resistance to various topical antibiotics

Click here to view



  Conclusion Top


Topical antibiotics are extensively used in all fields for diverse indications, and they offer an array of advantages over the oral antibiotics. The injudicious usage of topical antibiotics can cause an alteration in the inherent microbiologic environment of the skin leading to emergence of resistant pathogens. However, with proper precautions taken during prescribing the antibiotics, problems of resistance can also be overcome. The availability of newer antibiotics such as mupirocin, retapamulin, and nadifloxacin is a boon which can be used as a tool against the microbial agents.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Eady EA, Cove JH. Topical antibiotic therapy: Current status and future prospects. Drugs Exp Clin Res 1990;16:423-33.  Back to cited text no. 1
    
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Dai T, Huang YY, Sharma SK, Hashmi JT, Kurup DB, Hamblin MR. Topical antimicrobials for burn wound infections. Recent Pat Antiinfect Drug Discov 2010;5:124-51.  Back to cited text no. 6
    
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Bonner MW, James WD. Topical antibiotics. In: Goldsmith LA, Katzsi SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff AK, editors. Fitzpatrick's Dermatology in General Medicine. 8th ed. USA: McGraw Hill; 2012. p. 2673-6.  Back to cited text no. 9
    
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Critchley IA, Young CL, Stone KC, Ochsner UA, Guiles J, Tarasow T, et al. Antibacterial activity of REP8839, a new antibiotic for topical use. Antimicrob Agents Chemother 2005;49:4247-52.  Back to cited text no. 10
    
11.
Parish LC, Parish JL. Retapamulin: A new topical antibiotic for the treatment of uncomplicated skin infections. Drugs Today (Barc) 2008;44:91-102.  Back to cited text no. 11
    
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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. 12
    
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Dhingra D, Parakh A, Ramachandran S. Retapamulin: A newer topical antibiotic. J Postgrad Med 2013;59:127-30.  Back to cited text no. 13
    
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Hurdle JG, O'Neill AJ, Chopra I. Anti-staphylococcal activity of indolmycin, a potential topical agent for control of staphylococcal infections. J Antimicrob Chemother 2004;54:549-52.  Back to cited text no. 14
    
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Vasani RJ, Medhekar SV. Topical 2% mupirocin versus 2% fusidic acid versus 1% nadifloxacin cream in the treatment of superficial bacterial infections of the skin. Indian J Drugs Dermatol 2015;1:16-8.  Back to cited text no. 15
  [Full text]  
16.
Jacobs MR, Appelbaum PC. Nadifloxacin: A quinolone for topical treatment of skin infections and potential for systemic use of its active isomer, WCK 771. Expert Opin Pharmacother 2006;7:1957-66.  Back to cited text no. 16
    
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Rosen T, Albareda N, Rosenberg N, Alonso FG, Roth S, Zsolt I, et al. Efficacy and safety of ozenoxacin cream for treatment of adult and pediatric patients with impetigo: A randomized clinical trial. JAMA Dermatol 2018;154:806-13.  Back to cited text no. 17
    
18.
Vila J, Hebert AA, Torrelo A, López Y, Tato M, García-Castillo M, et al. Ozenoxacin: A review of preclinical and clinical efficacy. Expert Rev Anti Infect Ther 2019;17:159-68.  Back to cited text no. 18
    
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Rothstein DM, Farquhar RS, Sirokman K, Sondergaard KL, Hazlett C, Doye AA, et al. Efficacy of novel rifamycin derivatives against rifamycin-sensitive and resistant Staphylococcus aureus isolates in murine models of infection. Antimicrob Agents Chemother 2006;50:3658-64.  Back to cited text no. 19
    
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Wilkinson JD. Fusidic acid in dermatology. Br J Dermatol 1998;139 Suppl 53:37-40.  Back to cited text no. 20
    
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Abeck D, Mempel M. Staphylococcus aureus colonization in atopic dermatitis and its therapeutic implications. Br J Dermatol 1998;139 Suppl 53:13-6.  Back to cited text no. 21
    
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Heller S, Kellenberger L, Shapiro S. Antipropionibacterial activity of BAL19403, a novel macrolide antibiotic. Antimicrob Agents Chemother 2007;51:1956-61.  Back to cited text no. 22
    
23.
Wolf R, Matz H, Orion E, Tuzun B, Tuzun Y. Dapsone. Dermatol Online J 2002;8:2.  Back to cited text no. 23
    
24.
Draelos ZD, Carter E, Maloney JM, Elewski B, Poulin Y, Lynde C, et al. Two randomized studies demonstrate the efficacy and safety of dapsone gel, 5% for the treatment of acne vulgaris. J Am Acad Dermatol 2007;56:439.e1-10.  Back to cited text no. 24
    
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Jones RN, Li Q, Kohut B, Biedenbach DJ, Bell J, Turnidge JD. Contemporary antimicrobial activity of triple antibiotic ointment: A multiphased study of recent clinical isolates in the United States and Australia. Diagn Microbiol Infect Dis 2006;54:63-71.  Back to cited text no. 25
    
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Amirthalingam S, Yi KS, Ching LT, Mun NY. Topical antibacterials and global challenges on resistance development. Trop J Pharm Res 2015;14:919-24.  Back to cited text no. 26
    
27.
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28.
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29.
McNeil JC, Hulten KG, Kaplan SL, Mason EO. Decreased susceptibilities to retapamulin, mupirocin, and chlorhexidine among Staphylococcus aureus isolates causing skin and soft tissue infections in otherwise healthy children. Antimicrob Agents Chemother 2014;58:2878-83.  Back to cited text no. 29
    
30.
Oizumi N, Kawabata S, Hirao M, Watanabe K, Okuno S, Fujiwara T, et al. Relationship between mutations in the DNA gyrase and topoisomerase IV genes and nadifloxacin resistance in clinically isolated quinolone-resistant Staphylococcus aureus. J Infect Chemother 2001;7:191-4.  Back to cited text no. 30
    
31.
Nakase K, Sakuma Y, Nakaminami H, Noguchi N. Emergence of fluoroquinolone-resistant propionibacterium acnes caused by amino acid substitutions of DNA gyrase but not DNA topoisomerase IV. Anaerobe 2016;42:166-71.  Back to cited text no. 31
    



 
 
    Tables

  [Table 1], [Table 2]



 

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  In this article
Abstract
Historical Backg...
Classification
Newer Antibiotics
Combination Topi...
Advantages
Indications
Precautions
Adverse Effects
Hurdles
Conclusion
References
Article Tables

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