A supplement to : Addressing Treatment Adelaide A. Hebert, MD Challenges and Burden The UTHealth McGovern Medical School-Houston of Disease Houston, Texas Introduction Review of Impetigo Linda F. Impetigo, a very common bacterial Impetigo affects the epidermal skin Stein Gold, MD , is a moving target. Over layer with either nonbullous or bul- Henry Ford Health the past few decades there has been lous presentation. Approximately 70% System a shift in the associated bacteriology of all impetigo cases present as the Detroit, Michigan and resistance patterns, making the nonbullous form, which largely affects choice of best treatment more difficult preschool and school-aged children without the benefit of culture and sen- (ages 2-6 years), though all ages can sitivity guidance.1 Evidence that Staph- experience this contagious infection. ylococcus aureus (S. aureus) strains and Impetigo is predominantly caused by S. streptococcal species are developing aureus or pyogenes (S. Author Disclosures resistance to typical first-line topical pyogenes), sometimes referred to as Dr. Hebert: treatments is mounting.2-4 Emergence of group A beta-hemolytic streptococcus Research: Cassiopea, Cutanea, Mupirocin resistance has been reported (GABHS).9,10 Risk of infection increases Dermira, Galderma, GlaxoSmithKline, in several recent studies.5 Methicillin- in populations where hygiene is poor, Leo, Medimetrics, Novan, Pfizer, resistant S. aureus (MRSA) is also a or where there is inadequate access to Sienna, Valeant. All monies paid to growing concern in the community set- housing, health care, and other resourc- The UTHealth McGovern Medical School-Houston, Houston, Texas. ting. Oral penicillin and are es. Primary infection occurs in intact no longer viable treatment options and skin. Secondary infection occurs fol- Honoraria: Amgen, Cassiopea, resistance is emerging against clinda- lowing excoriation of scabies or insect Cutanea, Novan, Pfizer, Valeant mycin, cephalexin, and linezolid, lead- bites, and/or in the presence of comor- Data safety monitoring Boards (with ing to the potential for more expensive bid conditions such as atopic dermati- honoraria): Bausch, GlaxoSmithKline, and intensive therapies.2,6,7 tis (eczema) and . Nonbullous Sanofi Regeneron While often described as “self limit- impetigo is characterized by the pres- Dr. Stein Gold: ing,” treatment of impetigo is gener- ence of small pustules that form a Advisor: Cutanea ally advised as this disorder is highly yellow-gold crust located around the This supplement is sponsored by contagious, often requiring isolation nose and mouth as well as on extrem- from school, work, or social activities. ities; it is usually not associated with A multitude of blistering skin disorders systemic symptoms such as fever.6,7,9 S. complicate the differential diagnosis aureus has become more prominent as with no good immediate diagnostic the causative agent in the nonbullous This content was prepared by the tests.7 Additional concerns over disease form, though in more tropical locations specialized content division of progression to more serious problems and indigenous peoples S. pyogenes is Frontline Medical Communications, 7,11 publishers of Dermatology News. put primary caregivers on a precarious still of concern. The bullous form is tipping point, balancing the need for exclusively caused by S. aureus, which Copyright © 2019 Frontline Medical a quick and effective treatment with produces toxins that cause larger su- Communications Inc. All rights reserved. No part of this publication good antibiotic stewardship. Current perficial bullae filled with yellow fluid. may be reproduced or transmitted in treatments include a new topical anti- These occur on the trunk and inter- any form, by any means, without prior biotic, ozenoxacin (Xepi), retapamulin triginous skin of extremeties, mostly in written permission of the Publisher. (Altabax), and the old topical treat- diapered regions of children younger Frontline Medical Communications ments such as mupirocin and fusid- than 2 years of age.6,7,9 Inc. will not assume responsibility ic acid (not available in the United Globally, impetigo has been estimated for damages, loss, or claims of States), which are still widely used as to affect over 100 million people at any any kind arising from or related to first-line therapies. This, coupled with a one time and ranks within the top 50 the information contained in this recent study highlighting the need for burden-inducing disease states.3,12 In the publication, including any claims improved proficiency in impetigo rec- United States, approximately 3 million related to the products, drugs, or 13 services mentioned herein. The ognition, warrants a refresher to ensure cases occur annually. Heat, humid- opinions expressed in this supplement diagnosis and empiric treatment of the ity, and prior skin trauma are pre- do not necessarily reflect the views of infection is well understood by those disposing factors, and as such there the Publisher. on the front lines.7,8 can be seasonal variation favoring warmer weather and exposure to insect outside of the United States, vary great- clothing in hot water (60°C/140°F), and bites.3,7 Incidence rates have been not- ly among studies and demonstrate the keeping fingernails short can help miti- ed to vary over the course of several importance of knowing local resistance gate the spread of bacteria.7,9,19 Natural years, and children with atopic derma- patterns.3 Overall resistance rates to the remedies, such as tea tree oil and Manu- titis are at greater risk for infection.3 commonly prescribed topical antibiot- ka honey have been used with anecdot- Placing a dollar value on the overall ics are reportedly as high as 81%.15 As al success, but are not well studied and burden is difficult as costs of treatment resistance is known to increase health may not satisfy daycare requirements.6,7 constitute only a portion of the total costs due to hospitalization and the Access to readily available disinfec- encumbrance. Lesions in either form need for more expensive and intensive tants and over-the-counter (OTC) top- are highly contagious and require that treatment, this is considered a major ical antibiotics may entice individuals the affected individual be kept from threat to public health.6 or families to self treat. Topical antisep- school or work. Families are impacted Proper diagnosis adds to the diffi- tics are not well studied as comparator when parents must care for infected culty of treatment choice, with both agents, and there is little evidence to children, or when cross-contamination family/caregivers and medical person- support routine use for primary ther- results in the need to treat more than 1 nel potentially attributing skin blisters apy over topical antibiotics.6,7,10 While individual.3,6 Though less severe cases to other causes. Nonbullous impetigo certain alcohol-based hand cleansers,* will self resolve after 4 weeks, treat- may be mistaken as atopic dermatitis, hydrogen peroxide, povidone-iodine, ment is recommended to hasten re- contact dermatitis, scabies, herpes sim- and chlorhexidine solutions are not covery time or prevent progression plex, or varicella zoster virus, and not shown to cause resistance and may to more severe disease and spread to be prescribed the appropriate treat- therefore be used concomitantly, there others. Poststreptococcal glomerulo- ment. The bullous form may be misin- is still the need to consider their overall nephritis and rheumatic heart disease terpreted as insect bites, tinea corporis, environmental impact, and the Dutch have become less common with the eczema, contact dermatitis, or a drug College of General Practitioner’s guide- shift toward S. aureus as the causative eruption.7,8,16 A 2015 survey of pedia- lines recommend they be avoided.3,4,10 pathogen, though glomerulonephritis tricians at Johns Hopkins University Bacitracin is available in combination can occur in up to 5% of nonbullous found that only 31.9% were able to cor- with polymixin B and/or neomycin OTC cases in areas where impetigo is highly rectly diagnose , and in the United States, and while this OTC prevalent.6,7,10 Antibiotic treatment has though most chose mupirocin as first- product appears to have good labora- not been proven to reduce the inci- line therapy for localized infections, tory data to support its effectiveness dence of glomerulonephritis.7,9 31.3% chose bacitracin, which is not against Gram-positive bacteria, it has Despite the pressure to treat impeti- recommended in either form of impeti- not stood the test of clinical applica- go, clinicians may also feel sanctioned go as a first- or second-line treatment.8 bility and is feared to not effectively to limit antibiotic use in the face of While skin swabs may not be help- eradicate bacteria.1,10 Additionally, it is growing microbial resistance.3,6,7 Anton- ful in determining empiric treatment, implicated in severe contact allergic ov et al reported that 31.3% of all S. cultures should be obtained if MRSA reactions in people both with and with- aureus isolates collected from children is suspected, and serologic tests can out preexisting conditions.4 seen in a predominantly outpatient set- help determine poststreptococcal glo- Most recent reviews indicate that ting in New York City were resistant merulonephritis or herpes simplex vi- there is no significant data to rec- to mupirocin, and that prior mupirocin rus (HSV).7,9,10,17 Differentiation between ommend one topical antibiotic over use was strongly correlated.14 McNeil impetigo and herpes gladiatorum is of another, or to recommend oral ther- et al documented that up to 10% of in particular importance with athletes of apy over topical, and there remains vitro S. aureus isolates from healthy, close-contact sports to ensure early variations across countries on thera- community-based children in the Hous- effective treatment and to avoid trans- py standards.3,7 The topical antibiotics ton area displayed resistance to topical mission.17,18 Of note, many of the di- mupirocin, , or retapamu- antibiotics, including MRSA. MRSA ac- agnoses listed above may be primary lin have been recommended as initial counted for over 60% of isolates from disease states with impetigo as a sec- treatment choices for smaller bullae or children with chronic conditions like ondary superinfection, and follow-up localized nonbullous lesions.9 One trial eczema. In those with recurrent infec- studies for immune-based skin diseases in nonbullous impetigo compared re- tion, 14.7% of isolates were mupirocin- may be needed in refractory cases.9,17,18 tapamulin to fusidic acid, but no signif- resistant and included cross-resistance icant difference was found.1 The most with , while 9.5% showed re- Treatment common problems associated with sistance to retapamulin, including some Given the high potential for exposure topical agents are application site reac- that were cross-resistant to linezolid in daycare and preschool settings, the tion (irritation), and difficulty in appli- and daptomycin, augmenting concern best line of defense is to incorporate cation to certain areas, such as eyelids, that topical treatments may impart good hygiene measures into the daily mouth, or inaccessible areas.7,10 Advan- resistance to systemic antibiotics.2,4 If lives of children. Proper hand-washing tages of topical agents over systemic S. pyogenes is considered a likely patho- techniques are important and should be include delivery of higher concentra- gen, known resistance of streptococcus conducted frequently throughout the tions to the infection site for a poten- to macrolides and mupirocin factor into day. Should there be an outbreak, avoid- tially more rapid onset, greater patient the decision to treat.7 S. aureus resis- ing contact with lesions, regular bathing compliance, and avoidance of systemic tance rates to fusidic acid, widely used with soap and water, washing linens and side effects.4 Topicals can be used for

*Those agents that contained triclosan did show bacterial resistance over time.

2 \\ Impetigo: Addressing Treatment Challenges and Burden of Disease TABLE. Review of topical antibiotics used in impetigo19-23 Drug Name, Generic (US Trade Name/Year Indication/Antibacterial Common Adverse of FDA approval) Dose Activity Events/Issues Ozenoxacin (Xepi™) 1% cream BID • The topical treatment of impetigo due to S. • Rosacea and December 2017 for 5 days; NTE aureus or S. pyogenes in adult and pediatric seborrheic coverage of patients 2 months of age and older. dermatitis 100cm2 in adults, • Inhibits bacterial DNA replication enzymes, • Safety in patients and 2% of total DNA gyrase A, and topoisomerase IV. younger than 2 body surface in • Bactericidal. months has not pediatrics aged • Activity against MRSA. been established. 2-12 years • No contraindications. • Limited total application Retapamulin 1% ointment BID • For use in adults and pediatric patients • Application site (Altabax®) for 5 days; NTE aged 9 months and older for the topical irritation April 2007 coverage of treatment of impetigo (up to 100 cm2 in • Safety in patients 100 cm2 in total area in adults or 2% total body surface younger than 9 adults, and 2% area in pediatric patients aged 9 months months has not of total body or older) due to S. aureus (methicillin- been established. surface in susceptible isolates only) or S. pyogenes. • Limited total pediatrics • Inhibits peptidyl transfer, blocks P-site application interactions, and prevents the normal formation of active 50S ribosomal subunits. • Bacteriostatic. Mupirocin 2% cream or • Topical treatment of impetigo due to • Eye irritation (Bactroban®) ointment susceptible isolates of S. aureus and S. • Local irritation December 1987 (w/PEG),* TID pyogenes. • Risk of PEG Generic available for up to 10 days • RNA synthetase inhibitor. absorption • Bacteriostatic at MIC. Fusidic Acid/Sodium 2% cream/ • For use in the treatment of primary and • Application site pain Fusidate 2% ointment secondary skin infections caused by and mild irritation Not approved in the TID-QID sensitive strains of S. aureus, Streptococcus • More frequent United States spp, and minutissimum. application, though Infections may include: impetigo contagiosa, TID adequate when erythrasma, and secondary skin infections dressing applied such as infected wounds and infected burns. • Interferes with amino acid transfer from aminoacyl-tRNA to protein on the ribosomes. • Bacteriostatic or bactericidal depending on inoculum size. Abbreviations: BID, 2 times daily; DNA, deoxyribonucleic acid; IV, intravenous; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; NTE, not to exceed; P-site, peptidyl; PEG, polyethylene glycol; QID, 4 times daily; RNA, ribonucleic acid; S, Svedberg unit; spp, species; TID, 3 times daily. *non-PEG nasal formulation available

5 to 14 days, however a retrospective acid resistance is suspected, however that 4 hours after a single application, study of Dutch primary care found that, it is not approved for MRSA.1,6,7 The ozenoxacin achieved bactericidal ac- on average, practitioners prescribed a table summarizes important prescrib- tivity (killed the bacteria) at very low second antibiotic after just 7 days, in- ing information for the topical agents. concentrations, with favorable activity dicating that more studies are needed With concerns over emerging resis- against MRSA and quinolone-resistant to determine the appropriate length of tance to the above topical agents, a strains of S. aureus, compared to the 24 time in evaluating the effectiveness of new antibiotic with a differing mecha- hours it took for mupirocin, retapamu- first-line therapy.3 Mupirocin has been nism of action, even compared to oth- lin, and fusidic acid to reach bacterio- the most common initial choice in the ers within its quinolone class, has been static activity (only inhibits the growth United States, while fusidic acid may added to the arsenal. Ozenoxacin is a of bacteria). Because of its dual-target be a front-runner in other countries; nonfluorinated quinolone for impeti- mechanism of action and rapid bacte- retapamulin is usually reserved as an go treatment in patients 2 months of ricidal activity, ozenoxacin has shown alternative when mupirocin or fusidic age and older.19 In vitro studies found very low probability to induce sponta-

A supplement to DERMATOLOGY NEWS \\ 3 neous bacterial resistance. In two phase cline class, and quinolones that cov- and in considering the role of patient 3 clinical trials, ozenoxacin demonstrat- er Gram-positive organisms are best if compliance and preference.1,4,6 As such, ed superior clinical success rates over MRSA is suspected.7,10 Trimethoprim/ patients should be instructed to wash vehicle after 5 days of twice-daily treat- sulfamethoxazole treats MSSA and away crusted skin gently with soap and ment (pooled analysis 88.5% vs 78.2%, MRSA, but is ineffective againstS. pyo- water prior to topical application. Also respectively [P<.0001]).24 Ozenoxacin genes.7 Oral antibiotics have generally important is that the patient not return demonstrated negligible systemic ab- more egregious side effect profiles than to daycare, school, sports, or work un- sorption, and only 1 patient out of 362 topicals, like diarrhea, anaphylaxis, pho- til the lesions have cleared or antibi- assessed for safety in phase 3 trials tosensitivity, arthropathies/tendonop- otics have been consistently used for reported worsening preexistent rosa- athies, or pseudomembranous colitis; 24 hours.9,10,13,25 Patients should addition- cea and seborrheic dermatitis.19 It is additionally, they either need carefully ally be instructed on proper storage thought defluorination has contributed calculated dosing, or should be avoided and to discard unused medications to the lack of photoreactivity and skin in children altogether (, flu- (both topical and oral) after therapy is sensitization found with ozenoxacin, oroquinolones).1,7 As these often are tak- complete. and that S. aureus efflux mechanisms en for 7 or more days, compliance and Systemic therapy should be reserved do not impact its ability to reach high storage difficulties may be an issue.6,7 for extensive disease and second-line intracellular concentrations more rap- therapy.1,7 While oral antibiotics are idly than other quinolones.15 Conclusion frequently used after perceived top- Oral antibiotics should be reserved In addressing skin infections, it is import- ical treatment failure, the release of for use on severe wide-spread impeti- ant that general practitioners and pedi- the novel topical quinolone approved go, when resistance patterns to topical atricians, as well as extension caregivers for impetigo, ozenoxacin, may prompt treatments is known, or when topical such as physician assistants and nurse comparative studies and a review of treatments have failed.6 Only penicil- practitioners, become well acquainted practice guidelines within the next few lins that are immune to beta-lactamase, with the proper differential diagnosis years.13 Overall, prescribers need to such as dicloxacillin or amoxicillin/ of impetigo and the local microbiology weigh the quickest onset of action (to clavulanate, should be considered for resistance patterns.4,6,8 Early treatment ensure the patient can return to work S. pyogenes and methicillin-sensitive is recommended given the contagious or school), tolerability, compliance, and S. aureus (MSSA). No single generation nature of impetigo and the need to the shortest duration of therapy cou- of cephalosporins has proven more ef- prevent escalation to more costly care. pled with pathogen-targeted treatment fective over another, but cephalexin is Topical antibiotics are the best initial to ensure success while minimizing the widely used. Clindamycin, the tetracy- choice for good antibiotic stewardship risk of resistance.

References 1. Edge R, Argáez C. Topical Antibiotics for 8. Simkin DJ, Grossberg AL, Cohen BA. cy. Expert Review of Anti-infective Therapy. Impetigo: A Review of the Clinical Effec- Bullous impetigo rapid diagnostic and Published online: 11 Feb 2019. tiveness and Guidelines. Ottawa (ON). Ca- therapeutic quiz: a model for assessing 16. Ahmed S, Bromberek E, Borhart J. Exag- nadian Agency for Drugs and Technologies basic dermatology knowledge of prima- gerated arthropod bite: a case report and in Health. (2017). Available at: https://www. ry care providers. Pediatr Dermatol. 2016; review of the mimics. Clin Pract Cases Emerg ncbi.nlm.nih.gov/books/NBK447580/pdf/ 33(6):627-631. Med. 2018;2(1):58-60. Bookshelf_NBK447580.pdf. Accessed April 9. Nardi NM, Schaefer TJ. Impetigo. NCBI 17. Micali G, Lacarrubba F. Eczema Herpeticum. 16, 2019. Bookshelf. A service of the National Library N Engl J Med. 2017;377:e9. 2. McNeil JC, Hulten KG, Kaplan SL, Mason of Medicine, National Institutes of Health. 18. Saleh D, Sharma D. Herpes, Simplex, Type 1. OE. Decreased susceptibilities to retapam- StatPearls [Internet]. Treasure Island (FL): StatPearls. Last Update: October 27, 2018. ulin, mupirocin, and chlorhexidine among StatPearls Publishing; 2018 Jan. Last Up- Accessed 1/24/2019. Treasure Island (FL): Staphylococcus aureus isolates causing date: October 27, 2018. Copyright ©2018, StatPearls Publishing; 2018. skin and soft tissue infections in otherwise StatPearls Publishing LLC. 19. Xepi™(ozenoxacin) [package insert]. Wayne, healthy children. Antimicrob Agents Chemo- 10. Pereira LB. Impetigo – review. An Bras Der- PA: Cutanea Life Sciences, Inc.; 2019. ther. 2014;58(5):2878-2883. matol. 2014;89(2):293-299. 20. Altabax®(retapamulin) [package insert]. 3. Loadsman MEN, Verheij TJM, van der Velden 11. Allmon A, Deane K, Martin KL. Common Research Triangle Park, NC: GlaxoSmithKline; AW. Impetigo incidence and treatment: a skin rashes in children. Am Fam Physician. 2012. retrospective study of Dutch routine primary 2015;92(3):211-216. 21. Mupirocin ointment [package insert]. North care data. [published online ahead of print] 12. Hay RJ, Johns NE, Williams HC, et al. The Wales, PA: Teva Pharmaceuticals USA, Inc.; Fam Pract. October 19, 2018. global burden of skin disease in 2010: an 2017. 4. Williamson DA, Carter GP, Howden BP. Cur- analysis of the prevalence and impact of 22. Bactroban®(mupirocin) [package insert]. rent and emerging topical antibacterials and skin conditions. J Invest Dermatol. 2014; Research Triangle Park, NC: GlaxoSmith- antiseptics: agents, action, and resistance pat- 134(6):1527-1534. Kline; 2017. terns. Clin Microbiol Rev. 2017;30(3):827-860. 13. How to Treat Impetigo and Control This 23. Fucidin®(fusidic acid/sodium fusidate) 5. Poovelikunnel T, Gethin G, Humphreys H. Common Skin Infection. FDA Consumer Up- [package insert]. Thornhill, Ontario: Leo Mupirocin resistance: clinical implications dates website. https://www.fda.gov/ForCon- Pharma Inc.; 2008. and potential alternatives for the eradica- sumers/ConsumerUpdates/ucm048837.htm 24. Hebert AA, Albareda N, Rosen T, et al. topi- tion of MRSA. J Antimicrob Chemother. Last updated: November 1, 2016. Accessed cal antibacterial agent for treatment of adult 2015;70(10):2681-2692. March 5, 2019. and pediatric patients with impetigo: pooled 6. D’Cunha NM, Peterson GM, Baby KE, Thom- 14. Antonov NK, Garzon MC, Morel KD, et al. analysis of phase 3 clinical trials. J Drugs as J. Impetigo: a need for new therapies in a High prevalence of mupirocin resistance in Dermatol. 2018;17(10):1051-1057. world of increasing antimicrobial resistance. Staphylococcus aureus isolates from a pedi- 25. Impetigo: Overview. Created: February 14, J Clin Pharm Ther. 2018;43(1):150-153. atric population. Antimicrob Agents Chemo- 2006; Last Update: August 24, 2017; Next 7. Hartman-Adams H, Banvard C, Juckett G. ther. 2015;59(6):3350-3356. update: 2020. IQWiG (Institute for Quality Impetigo: diagnosis and treatment. Am Fam 15. Vila J, Hebert AA, Torrelo A, et al. Ozenoxa- and Efficiency in Health Care) Bookshelf ID: Physician. 2014;90(4):229-235. cin: a review of preclinical and clinical effica- NBK27953.

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