Topical antibacterial and antiviral agents: prescribing and resistance

THERAPY FOCUS Topical antibacterial and antiviral agents: prescribing and resistance STEVE CHAPLIN This article describes the current prescribing patterns for topical antibacterial and antiviral preparations in primary care and the factors to consider when choosing a treatment, including the evidence for antimicrobial resistance. Topical formulations for infections of the skin (eg impetigo, furunculosis, infected eczema), eye (eg uncomplicated conjunctivitis) and ear (eg acute otitis externa) have long been popular in primary care. Their use has been slowly increasing for several years, reaching 4.7 million prescriptions in 2015 at a cost of 23.6 million. 1 As Figure 1 shows, almost half of this prescribing is for the treatment of eye infections, about which there is little dispute, but around one-third is for antibacterials that are also available systemically (fusidic acid and metronidazole) something that raises fears about the development of resistance. Concern has also been expressed about the use of topical antibiotics for acne, which include clindamycin and erythromycin, and for which 1.2 million prescriptions were dispensed in 2015 at a cost of about 16 million. Is NHS England devoting significant resources on treatments that may be exacerbating the problem of antibiotic resistance? for eye infection for skin also used systemically for ear infections 0 500 1000 1500 2000 chloramphenicol 1748 fusidic acid 333 ciprofloxacin 81 ofloxacin 42 gentamicin 37 levofloxacin 9 azithromycin 2 dibromo/propamidine isetionate 2 tobramycin 1 fusidic acid/sodium fusidate 1146 metronidazole 303 framycetin/dexamethasone 369 clioquinol/flumetasone 191 acetic acid 60 chloramphenicol 3 ciprofloxacin 1 Prescribing overview The antibacterial and antiviral agents available for topical treatment include 26 anti-infective agents and 38 formulations (see Tables 1 4). There is some overlap but most agents occur in only one category. Several, however, are also used orally and/ or parenterally. To highlight the risk of increasing resistance, the BNF defines a separate group of antibiotics that are not used systemically (mupirocin, neomycin, polymyxins, retapamulin) as preferable for topical use. Based on statistics for primary care prescribing in England in 2015, 1 the volume of prescribing of these agents is small compared with two agents also used orally fusidic acid (1.1 million prescriptions) and metronidazole (300,000). Only mupirocin (as a generic and Bactroban cream/ointment) tops the 100,000 mark (see Figure 2). Another formulation of mupirocin (Bactroban Nasal Ointment) is used to eliminate staphylococci from the nasal septum but much less so than the less expensive neomycin/chlorhexidine (Naseptin) (90,000 vs 448,000 prescriptions). Antivirals for skin infections for skin only used topically Antivirals for eye infections aciclovir 217 penciclovir 3 mupirocin 111 polymyxins 13 retapamulin 1.7 neomycin 0.1 ganciclovir 19 aciclovir 13 Figure 1. Comparison of prescribing volume in primary care: topical antibacterial and antiviral preparations, England 2015 1 (numbers are thousands of prescriptions) Prescriber July 2016 29

metronidazole fusidic acid/ sodium fusidate retapamulin polymyxins neomycin mupirocin framycetin/ dexamethasone/ gramicidin clioquinol/ flumetasone ciprofloxacin chloramphenicol acetic acid 0 200 400 600 800 1000 1200 Figure 2. Topical antibacterial preparations for skin infections: prescribing volume in primary care, England 2015 1 0 50 100 150 200 250 300 350 400 Figure 4. Topical antibacterial preparations for ear infections: prescribing volume in primary care, England 2015 1 tobramycin ofloxacin levofloxacin gentamicin fusidic acid dibromo/propamidine isetionate ciprofloxacin chloramphenicol azithromycin 0 500 1000 1500 2000 Figure 3. Topical antibacterial preparations for eye infections: prescribing volume in primary care, England 2015 1 Chloramphenicol dominates prescribing for eye infections, accounting for 78 per cent of volume (see Figure 3) and about one-third of costs. Fusidic acid is the next most frequently prescribed agent (15 per cent of volume) but it accounts for 59 per cent of costs in this category (compared with 33 per cent for chloramphenicol). Combined formulations containing a corticosteroid dominate prescribing for ear infections (see Figure 4). Together, two preparations (framycetin/dexamethasone/gramicidin and clioquinol/flumetasone) account for 90 per cent of volume and 88 per cent of cost in this category. Topical treatments are preferred to oral agents for mild to moderate acne and the most frequently prescribed contain antibiotics (see Figure 5). Benzoyl peroxide/clindamycin (33 per cent of volume), clindamycin (9 per cent) and erythromycin (25 per cent) together account for two-thirds of the 16 million spent in this category. Compared with 2010, prescribing of erythromycin and clindamycin has declined by 20 25 per cent erythromycin clindamycin and tretinoin clindamycin benzoyl peroxide/ clindamycin 0 100 200 300 400 500 600 Figure 5. Topical antibacterial preparations for acne: prescribing volume in primary care, England 2015 1 whereas that of benzoyl peroxide/clindamycin has increased by 30 per cent. There are relatively few prescriptions for topical antivirals (see Figure 1), presumably reflecting a greater probability of treating viral eye infections in secondary care and the availability of over-the-counter products for cold sores. Ganciclovir is favoured over aciclovir for herpetic eye infection (19,000 vs 13,000 prescriptions) but aciclovir dominates prescribing for skin infection (217,000 prescriptions vs 3000 for penciclovir). Topical preparations and resistance Concern about the risk of resistance associated with the use of topical antibiotics has long been sufficient to limit their use, though it is hard to find evidence that the risk of resistance would be lower if the antibiotic was given orally instead. The implication is that it may be better not to prescribe an antibiotic at all, bearing in mind that the indication in question is a relatively minor condition that might improve without treatment. Skin infections There is little doubt that use of topical antibiotics to treat skin infections is associated with an increase in resistance. In New 30 Prescriber July 2016

Topical antimicrobials l THERAPY FOCUS Zealand, for example, the prevalence of fusidic acid resistance in one community increased from 17 per cent in 1999 to 29 per cent in 2013, a period in which dispensing rates increased four-fold. 2 During the same period, dispensing of mupirocin declined slightly and the prevalence of resistance decreased from 28 to 11 per cent. In a second example, mupirocin resistance increased from less than 3 per cent to 65 per cent over a four-year period when it was used to control methicillin-resistant Staphylococcus aureus (MRSA) in a hospital setting. 3 Prior exposure has been identified as a risk factor for resistance to fusidic acid 4 and mupirocin, 5 and reducing topical prescribing of fusidic acid is associated with a fall in resistance. 6 The same is true for antibiotic treatment of acne, leading to the recommendation that antibiotic monotherapy should be avoided in preference to co-prescription with benzoyl peroxide or tretinoin, even for oral antibiotics. 7,8 This advice has already influenced prescribing practice in primary care. 1 Resistance to topical antibiotics can develop secondary to other treatment: one analysis of clinical isolates from children with skin and soft tissue infections found that reduced susceptibility of Sta. aureus to retapamulin or mupirocin was associated with recurrent infection and greater prior exposure to antibiotics. 9 The emergence of resistance due to the use of topical fusidic acid has important implications for antimicrobial stewardship: one UK study has shown that fusidic acid resistance among strains of MRSA acquired in the community also Antibacterial Formulation Dose Cost* Mupirocin 2% cream 3 times daily for up to 10 days 5.26/15g 2% nasal ointment 2 3 times daily; clearance normally after 5 7 days 2% ointment 2 3 times daily for up to 10 days Neomycin** 0.5% cream up to 3 times daily; short-term use only 3.89/3g 4.38/15g 2.17/15g Polymyxin b sulfate/ bacitracin zinc ointment 10,000/500 units per gram at least twice daily 3.26/4g 4.62/20g Retapamulin 1% ointment twice daily for 5 days 7.89/5g Fusidic acid 2% cream 3 4 times daily; if covered, less frequent application may be effective 1.92/15g 3.59/30g 2% ointment 2.23/15g 3.79/30g Fusidic acid, hydrocortisone acetate 2%/1% cream twice daily, normally for up to 2 weeks 5.02/30g 10.04/60g Metronidazole gel, cream 0.75% twice daily for 6 12 weeks 4.47/15g 6.60-12.00/30g 9.88-22.63/40g Clindamycin 1% solution (contains alcohol) twice daily 4.34/30ml 7.23/50ml 1% gel 8.66/30g Erythromycin 2% solution (contains alcohol) 7.69/50ml 40mg/30ml solution (contains alcohol) 7.71/30ml 16.68/90ml **Not considered first choice but use may be justifiable in certain circumstances Table 1. Topical antibacterial preparations skin infections Prescriber July 2016 31

Antibacterial Formulation Dose Cost * Chloramphenicol 5%, 10% drops 2 3 drops 2 3 times daily 57.90/10ml (5%) 20.99/10ml (10%) Clioquinol/flumetasone pivalate 1%/0.02% drops 2 3 drops twice daily for 7 10 days (adults and children >2 years) 1.76/7.5ml Dexamethasone sodium metasulfobenzoate/framycetin sulfate/gramicidin** 0.05%/0.5%/0.005% drops 2 3 drops 3 4 times daily 7.50/10ml Neomycin/dexamethasone/ glacial acetic acid 3250 units per ml/0.1%/ 2% spray One metered spray 3 times daily (adults and children >2 years) 3.27/5ml Neomycin/betamethasone sodium phosphate 0.5%/0.1% drops 2 3 drops 3 4 times daily 2.39/10ml Gentamicin 0.3% drops 2 3 drops 4 5 times daily including at bedtime Gentamicin/hydrocortisone 0.3%/1% drops 2 4 drops 4 5 times daily including at bedtime 2.13/10ml 4.76/10ml **Not considered first choice but use may be justifiable in certain circumstances Table 2. Topical antibacterial preparations otitis externa encodes for beta-lactam resistance, 10 raising the possibility of increasing resistance to valuable antibiotics. There is, however, a clinical case for prescribing topical agents. In 2012, a Cochrane review of the treatment of impetigo concluded: There is good evidence that topical mupirocin and topical fusidic acid are equally, or more, effective than oral treatment [with clearance rates about two-fold higher]. Due to the lack of studies in people with extensive impetigo, it is unclear if oral antibiotics are superior to topical antibiotics in this group. Fusidic acid and mupirocin are of similar efficacy. 11 This evidence is reflected in guidance from Public Health England. 12 When treating impetigo, for example, it recommends oral antibiotics for extensive, severe or bullous impetigo; it explicitly aims to limit the risk of resistance by recommending topical antibiotics only for very localised lesions and reserving mupirocin to treat infection by MRSA. Furthermore, topical treatment should be limited to five days duration. The same is true for visibly infected eczema, but cellulitis and actively infected leg ulcers should be treated orally. Eye infections The question of possible bacterial resistance in acute blepharitis or conjunctivitis has not received much attention in recent years. Most cases of acute conjunctivitis are self-limiting; a topical antibiotic (chloramphenicol or, second-line, fusidic acid) is recommended only for severe infection, 12 even though there is evidence that treatment speeds the resolution of symptoms and infection. 13 It may be difficult to determine the clinical impact of resistance in the treatment of acute conjunctivitis in the absence of microbiological confirmation of the diagnosis: failure of standard therapy could be explained by an allergic or viral cause. It has been shown that widespread ocular use of antibiotics (in this case, a trachoma control programme with azithromycin and tetracycline) may be associated with increased prevalence of resistance among nasopharyngeal isolates of streptococci. 14 This lends support to the notion that community exposure to antibiotics raises the local prevalence of organisms resistant to them. Ear infections A recent review found no strong direct evidence to support the use of topical antibiotics in children with acute otitis media and ear discharge caused by spontaneous perforation of the eardrum, 15 supporting current advice that antibiotics should be prescribed orally for otitis media in young children and when signs and symptoms are severe. 12 A combination of an antibiotic and a corticosteroid is recommended as second-line therapy in the treatment of acute otitis externa, for which bacterial resistance does not appear to be an active concern. 16,17 Acetic acid is the drug of first choice precisely because it is not associated with resistance. 12 A systematic review found no evidence that topical antibiotics used to treat ear infections are associated with a significant risk of resistance, 18 but the possibility cannot be dismissed because microbial susceptibility differs between preparations 19 and may increase over time. 20 There is no evidence of differences in efficacy between the treatment options for otitis externa; the risk of resistance is therefore 32 Prescriber July 2016

one among several factors that should be considered when choosing between them. 21 Viral infections Resistance to aciclovir is rare among immunocompetent people, with reported rates below one per cent, 22 but identifying treatment failure is probably difficult given the small benefit it offers in treating a cold sore and the extensive unsupervised use in the community. By contrast, resistant herpes simplex virus (HSV) has been reported among patients with uveitis or keratitis. For example, the prevalence of aciclovir resistance among patients attending a specialist centre for the treatment of herpetic keratitis due to HSV-1 virus was 6.4 per cent. 23 Of the 11 patients with resistant virus, four were using topical therapy (36 per cent) compared with 21 of 162 patients with aciclovir-sensitive HSV-1 (13 per cent). A second study reported a prevalence of aciclovir resistance of 14 per cent among 212 patients with keratitis or keratouveitis who were treated locally or systemically. 24 It is not clear from this evidence whether local rather than systemic administration was a factor in promoting resistance. Choosing topical or oral administration The choice of topical or oral administration depends on clinical factors and the pros and cons need to be weighed for each patient. Current recommendations follow the principle that infections potentially posing a greater risk for example, if the patient is a young child, the infection is spreading or symptoms are more severe should be treated orally. 12 The choice is less clear when the infection may be self-limiting or is causing a nuisance rather than a problem, in which case the best option may be not to prescribe anything. The factors in favour of topical administration are primarily about lowering the risks of treatment to the patient, such as limiting systemic exposure and reducing the risk of systemic adverse effects. But topical administration is not without risk: Antibacterial Formulation Dosage Cost* Azithromycin 1.5% single-use drops One drop twice daily for 3 days 6.99 for 6 x 250mg Chloramphenicol 0.5% drops (single and multi-dose) 2 drops every 3 hours 10.99 for 20 x 0.5ml 1.45 1.65/10ml 1% ointment Every 3 hours 1.08 1.79/4g Ciprofloxacin 0.3% drops 1 2 drops 4 times a day (2-hourly for first 2 days if severe); continue for up to 21 days 0.3% ointment 1.25cm 3 times daily for 2 days, then twice daily for a further 5 days or longer at physician s discretion 4.70/5ml 5.22/3.5g Fusidic acid 1% drops 1 drop twice daily 2.69/5g Gentamicin 0.3% drops 1 or 2 drops up to 6 times daily (every 15 20 minutes initially in severe infection) 2.13/10ml Levofloxacin 0.5% drops (single and multi-dose) 2-hourly up to 8 times daily for first 2 days then 4 times daily for 3 days (adults and children >1 year) 6.95/5ml 17.95 30 x 0.5ml Moxifloxacin 0.5% drops 1 drop 3 times daily usually for 7 8 days 9.80/5ml Ofloxacin 0.3% drops Every 2 4 hours for 2 days then 4 times daily for up to 10 days (adults and children >1 year) 2.17/5ml Propamidine isetionate 0.1% drops Up to 4 times daily 2.80 3.26/10ml 0.15% ointment 1 2 times daily 2.92 3.49/5g Tobramycin 0.3% drops Twice daily for 6 8 days Severe infection: 4 times daily on first day then twice daily for 5 7 days (adults and children >1 year) 4.74/5ml Table 3. Topical antibacterial preparations eye infections 34 Prescriber July 2016

Topical antimicrobials l THERAPY FOCUS Antiviral Formulation Indication Dosage Cost * Aciclovir 5% cream Treatment of herpes simplex virus infections of the skin including initial and recurrent genital herpes and herpes labialis 4-hourly (5 times daily) for 5 10 days, starting at first sign 1.40 4.63/2g 7.00 13.96/10g 3% eye ointment Treatment of herpes simplex keratitis 1cm 4-hourly (5 times daily), continue for 3 days after healing Ganciclovir 0.15% gel Treatment of acute herpetic keratitis One drop 5 times a day until complete corneal re-epithelialisation then 3 times daily for 7 days after healing, usually up to 21 days 9.34/5g 19.99/5g Penciclovir 1% cream Treatment of herpes simplex virus infections of the lips and face (herpes labialis) in adults) and children >12 years 2-hourly during waking hours, (approximately 8 times a day) for 4 days 5 7 approx. (OTC) Table 4. Topical antiviral preparations it can be associated with local adverse effects, eg dermatitis with neomycin or the excipient propylene glycol, and absorption may be sufficient to cause serious toxicity, eg ototoxicity with aminoglycosides in a child with a perforated eardrum. However, there is no good evidence that chloramphenicol administered in eye drops causes aplastic anaemia. 25 There are also practical issues. Topical application is logical when the site of infection is readily accessible, as is the case with conjunctivitis, but less so if there is a physical barrier to achieving a high concentration of the antibiotic, as with some skin infections. Good adherence cannot be assumed topical administration may sometimes be easier (for example, a child may more readily accept a cream applied by a parent than swallowing a capsule or suspension) or harder (poor manual dexterity may make it difficult to use eye drops). Dose frequency may also be problematic, particularly for topical antivirals. Public Health England s guidance on the management of infection in primary care does not favour the use of topical antibacterial agents, advising GPs to avoid widespread use of topical antibiotics (especially those agents also available as systemic preparations, eg fusidic acid). 12 NICE has now incorporated this recommendation into its quality standard for the prevention and control of infection as part of antimicrobial stewardship. 26 This is likely to form part of the requirement for commissioned services and to be used to measure GPs prescribing performance. Summary Topical antibiotics and antivirals remain popular in primary care but guidance aimed at improving prescribing quality limits their role to less serious infections, sometimes as second-line therapy, and discourages widespread use. The primary motivation for this is to limit the spread of resistance, though the evidence for this risk seems well established only for skin infections. Whether topical therapy offers advantages depends on individual patient need. References 1. Health and Social Care Information Centre. Prescription Cost Analysis. England 2015. April 2016. 2. Williamson DA, et al. High usage of topical fusidic acid and rapid clonal expansion of fusidic acid-resistant Staphylococcus aureus: a cautionary tale. Clin Infect Dis 2014;59:1451 4. 3. Miller MA, et al. Development of mupirocin resistance among methicillin-resistant Staphylococcus aureus after widespread use of nasal mupirocin ointment. Infect Control Hosp Epidemiol 1996;17:811 3. 4. Heng YK, et al. Staphylococcus aureus and topical fusidic acid use: results of a clinical audit on antimicrobial resistance. Int J Dermatol 2013;52:876 81. 5. Antonov NK, et al. High prevalence of mupirocin resistance in Staphylococcus aureus isolates from a pediatric population. Antimicrob Agents Chemother 2015;59:3350 6. 6. Wylie G, et al. Effect of withdrawing topical fusidic acid on Staphylococcus aureus resistance rates. Scot Med J 2011;56:10-1. 7. Dreno B, et al. Antibiotic stewardship in dermatology: limiting antibiotic use in acne. Eur J Dermatol 2014;24:330 4. 8. Walsh TR, et al. Systematic review of antibiotic resistance in acne: an increasing topical and oral threat. Lancet Infect Dis 2016;16:e23 33. 9. McNeil JC, et al. 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. 10. Ellington MJ, et al. Emergent and evolving antimicrobial resistance cassettes in community-associated fusidic acid and meticillin-resistant Staphylococcus aureus. Int J Antimicrob Agents 2015;45:477 84. 11. 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9:CD001211. 14. Gaynor BD, et al. Topical ocular antibiotics induce bacterial resistance at extraocular sites. Br J Ophthalmol 2005;89:1097 9. 15. Venekamp RP, et al. Are topical antibiotics an alternative to oral antibiotics for children with acute otitis media and ear discharge? BMJ 2016;352:i308. 16. Schaefer P, Baugh RF. Acute otitis externa: an update. Am Fam Physician 2012;86:1055 61. 17. NICE. Clinical Knowledge Summaries. Acute diffuse otitis externa (initial management). July 2015. (http://cks.nice.org.uk/otitis-externa#!scenariorecommendation:2) 18. Weber PC, et al. The development of antibiotic resistant organisms with the use of ototopical medications. Otolaryngol Head Neck Surg 2004;130:S89 94. 19. Dohar JE, et al. Differences in bacteriologic treatment failures in acute otitis externa between ciprofloxacin/dexamethasone and neomycin/polymyxin B/hydrocortisone: results of a combined analysis. Curr Med Res Opin 2009;25:287 91. 20. Cantrell HF, et al. Declining susceptibility to neomycin and polymyxin B of pathogens recovered in otitis externa clinical trials. South Med J 2004;97:465 71. 21. Kaushik V, et al. Interventions for acute otitis externa. Cochrane Database Syst Rev 2010;Issue 1:CD004740. 22. Cunningham A, et al. Current management and recommendations for access to antiviral therapy of herpes labialis. J Clin Virol 2012;53: 6 11. 23. Duan R, et al. Acyclovir-resistant corneal HSV-1 isolates from patients with herpetic keratitis. J Infect Dis 2008;198:659 63. 24. Hlinomazová Z, et al. The treatment of HSV1 ocular infections using quantitative real-time PCR results. Acta Ophthalmol 2012;90:456 60. 25. Wiholm BE, et al. Relation of aplastic anaemia to use of chloramphenicol eye drops in two international case-control studies. BMJ 1998;316:666. 26. NICE. Infection prevention and control. QS61. April 2014. Declaration of interests None to declare. Steve Chaplin is a pharmacist who specialises in writing on therapeutics 36 Prescriber July 2016