Topical antibacterial and antiviral agents: prescribing and resistance

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?

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Figure 1. Comparison of prescribing volume in primary care: topical antibacterial and antiviral preparations, England 20151 (numbers are thousands of prescriptions)

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.

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Table 1. Topical antibacterial preparations – skin infections

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Table 2. Topical antibacterial preparations – otitis externa

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Table 3. Topical antibacterial preparations – eye infections

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Table 4. Topical antiviral preparations

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).

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Figure 2. Topical antibacterial preparations for skin infections: prescribing volume in primary care, England 20151

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).

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Figure 3. Topical antibacterial preparations for eye infections: prescribing volume in primary care, England 20151

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.

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Figure 4. Topical antibacterial preparations for ear infections: prescribing volume in primary care, England 20151

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 whereas that of benzoyl peroxide/clindamycin has increased by 30 per cent.

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Figure 5. Topical antibacterial preparations for acne: prescribing volume in primary care, England 20151

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 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 acid4 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 encodes for betalactam 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 preparations19 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 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: 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.

Declaration of interests

None to declare.

Steve Chaplin is a pharmacist who specialises in writing on therapeutics

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. Koning S, et al. Interventions for impetigo. Cochrane Database of Systematic Reviews 2012;Issue 1:CD003261.
12. Public Health England. Management of infection guidance for pri­mary care for consultation and local adaptation. May 2016.
13. Sheikh A, et al. Antibiotics versus placebo for acute bacterial conjunctivitis. Cochrane Database of Systematic Reviews 2012;Issue 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.

Topical antibacterial and antiviral agents: prescribing and resistance

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