Fusidic acid in dermatology: an updated review

ARTICLE

Auteur(s) : Helmut Schöfer, Lene Simonsen

¹Dept. of Dermatovenereology, University Hospital der J. W. Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany
²Medical Affairs, LEO Pharma, Ballerup, Denmark

accepté le 23 Juillet 2009

Fusidic acid (Fucidin^®; LEO Pharma, Ballerup, Denmark) has been available as an antibiotic for use in dermatology for many years: as tablets since 1962, a suspension since 1963, an ointment since 1965, and a cream since 1982. It has proved valuable in the treatment of primary and secondary skin infections, particularly those caused by Staphylococcus aureus. Its usefulness is further increased by the availability of combination formulations: fusidic acid/hydrocortisone ointment (Fucidin^® H) since 1967, fusidic acid/betamethasone cream (Fucicort^® cream) since 1987 for the treatment of infected eczema, and a new lipid-rich formulation of fusidic acid/betamethasone cream (Fucicort^® Lipid), introduced in 2007 for the treatment of infected eczema lesions where a more lipid-rich formulation is preferred by doctors or patients.

This review provides an overview of the available evidence for the clinical effectiveness of fusidic acid in dermatology, as well as new information on changing resistance patterns. The review is restricted to dermatology; ophthalmological use of fusidic acid, and use of the intravenous formulation for serious systemic infections are not covered. In addition, it should be noted that availability of the different formulations mentioned varies by country. The term “fusidic acid” is used to cover both fusidic acid (constituent of the cream) and sodium fusidate (constituent of the ointment and the tablets), as the active principle (fusidate) is the same for both compounds following absorption.

Selection of studies for inclusion

Properties of fusidic acid

Administration of oral fusidic acid has also been shown to achieve high concentrations in plasma [6], serum, blister fluid [7], burn crusts [8], and interstitial dermal fluid [9].

In vitro, fusidic acid has high activity against S. aureus, including methicillin-resistant strains (MRSA), and S. epidermidis (table 1) [10-13]. It is also active against some Corynebacterium species, and is indicated for use in the treatment of mild to moderately severe primary and secondary skin and soft tissue infections (SSTIs) caused by sensitive organisms (which in clinical practice are most often S. aureus).
Table 1 Minimum inhibitory concentration (MIC) values for fusidic acid for common pathogens in skin infections

Studies on efficacy and safety

Systemic formulations

Patients enrolled in these studies were generally suffering from any of a number of primary or secondary skin infections, including abscesses/furuncles, impetigo, acute paronychia, and superficial wound infections. The duration of treatment was 5 or 10 days. Response was defined in most studies as cure or improvement, as assessed by the investigator; the precise definition of response is given in each publication. Some studies compared the effects of different doses of fusidic acid [15-17]. With doses above 250 mg twice daily (BID), cure rates did not increase greatly, and there were more adverse events at the higher doses [15, 17]. The most common side effects with systemic fusidic acid are gastrointestinal events such as nausea and diarrhoea. These are reported to occur at a frequency of between > 1% and < 10% [15, 17, 22, 23]. All other adverse events were reported at a frequency of < 1% [22, 23]. The recommended dosing in most countries is 250 mg BID.

In the studies comparing fusidic acid with flucloxacillin, pristinamycin, ciprofloxacin, and erythromycin, response rates were similar with fusidic acid and the comparator. Tolerability of fusidic acid was either similar to the comparator [18-20] or significantly better, primarily because of fewer gastrointestinal adverse events [1, 16, 21]. In general, systemic fusidic acid has good tolerability, with few and minor side effects [24].

Five studies also examined bacteriological efficacy, defined as eradication of the pre-treatment pathogen or no swab being taken at the end of treatment because no pathological material was present. In each case, bacteriological efficacy was high and similar for fusidic acid and the comparator: 87% and 91%, 94% and 97%, and 85% and 83%, respectively, in three studies in which staphylococci were the most common infecting organisms; but streptococci were also isolated from some patients and were included in the bacteriological assessments [18, 19, 21]. The remaining two studies reported efficacy against S. aureus as 96% and 97% for fusidic acid and erythromycin, respectively [20], and efficacy against all isolated staphylococci as 92%, 100%, and 97% for fusidic acid 500 mg/day, fusidic acid 1 g/day, and pristinamycin 2 g/day, respectively [16].

Oral fusidic acid is also available in a suspension formulation suitable for paediatric use. In a recent study of fusidic acid suspension in 411 children aged 1-12 years with SSTIs, 91% of those treated with 20 mg/kg/day given in two divided doses and 89% of those treated with 50 mg/kg/day given in three divided doses were cured [25]. The lower-dose regimen had significantly better tolerability (p = 0.025), due to fewer gastrointestinal side effects. Bacteriological efficacy was demonstrated in 100% and 99% of children, respectively.

In clinical practice, the systemic formulations of fusidic acid are usually used when patients have extensive disease, deeper infections, or evidence of systemic spread of disease or septicaemia, or when topical therapy cannot be used for some reason. Oral fusidic acid is not available in some countries (e.g. Germany, where it serves as a reserve antibiotic).
Table 2 Studies of fusidic acid tablets in patients with skin and soft tissue infections

Topical formulations (plain fusidic acid)

As can be seen in table 3, in general, fusidic acid had similar clinical and bacteriological efficacy to the comparators in all of the studies. Some advantages of fusidic acid were apparent. In one study, healing time was significantly more rapid with topical fusidic acid than with oral antibiotics (p < 0.01) [38]. Fusidic acid ointment was clinically as effective as mupirocin ointment in all of the studies comparing these two agents. However, patients considered fusidic acid ointment more acceptable, primarily because of the greasiness of mupirocin ointment [41]. Patients also preferred fusidic acid cream to mupirocin ointment [29].

With respect to impetigo, more patients responded to fusidic acid than to neomycin/bacitracin combination cream (p < 0.01), and after 7 days, 69% of patients using fusidic acid were healed, versus 47% using neomycin/bacitracin [39]. A Cochrane review has concluded that there is good evidence that topical fusidic acid is equally, or more, effective than oral antibiotics for patients with limited impetigo [46]. Similarly, the authors of a recent systematic review concluded that fusidic acid and mupirocin are equally effective, and recommended the use of a topical agent for 7 days in limited impetigo, noting also that topical antibiotics have better tolerability and may achieve better compliance compared with oral antibiotics [47]. In clinical practice, mupirocin is often reserved to eradicate nasal carriage of MRSA [48-51]. A new antibiotic, retapamulin, which has recently been approved in the USA and Europe for use in impetigo due to S. aureus (methicillin-susceptible isolates only) or S. pyogenes, was not available when the reviews were conducted. In a comparative study, retapamulin and fusidic acid showed similar efficacy in impetigo, and there were fewer drug-related adverse events with fusidic acid (one adverse event reported in 172 subjects) than with retapamulin (14 adverse events reported in 345 subjects) [45].

The adverse events most commonly noted with topical antibiotics relate to the induction of hypersensitivity, resulting in local irritation or sensitization. Clinical experience over many years of use has been that plain topical fusidic acid formulations have low sensitizing potential, and few and mild side effects. A recent safety overview of published and unpublished studies and postmarketing surveillance data has confirmed the good tolerability of these formulations [52].

Specific studies confirm the low allergenic potential of fusidic acid. A study in the UK showed a low incidence of positive patch test reactions to fusidic acid (0.3%, compared with 3.6% for neomycin and 0.7% for clioquinol), and no increase in the frequency of allergic reactions to fusidic acid since the early 1980s, despite increasing use [53]. Patch testing data from Germany showed a low incidence of allergic reactions to fusidic acid (0% among atopic individuals and 1.76% among non-atopic individuals) [54]. More recently, the prevalence of positive reactions to patch tests in the general German population was estimated to be 2.2% for neomycin, 3.2% for gentamicin, and 0.8% for fusidic acid [55].

Although adverse drug reactions are rare with fusidic acid, occasional cases of skin reactions, and in particular application site reactions, have been reported [106-110]. According to the authors of these case reports, the allergenic potential of sodium fusidate is low, and sensitisation can be favoured by chronic inflammatory states, especially if associated with stasis dermatitis, as in leg ulcers [106]. A recent case report described the first known case of a generalised urticaria following simultaneous oral and topical fusidic acid [111].
Table 3 Studies on healing rates and times with fusidic acid cream (a) and ointment (b) in skin and soft tissue infections

Use of fusidic acid-steroid combinations in infected atopic eczema

Fusidic acid is available in some countries in cream formulations that include 1% hydrocortisone acetate (Fucidin^® H) or 0.1% betamethasone 17-valerate (Fucicort^®/Fucibet^®). A new formulation of fusidic acid and betamethasone in a lipid cream (Fucicort^® Lipid/Fucibet^® Lipid) has recently been developed to provide an alternative treatment for patients with infected eczema in whom the existing combination cream does not provide an adequate moisturizing effect.

The fusidic acid-hydrocortisone combination was more effective than fusidic acid alone (n = 68) in achieving a combined clinical-bacteriological endpoint, and more effective than hydrocortisone alone in a subset of patients with pathogens at baseline (n = 73) [60]. The fusidic acid-betamethasone combination was compared with betamethasone alone by using each therapy on the left or right side of the body in patients with atopic dermatitis, contact dermatitis, or psoriasis, in a double-blind study [61]. The two treatments had similar overall efficacy, but investigator assessment of the efficacy of therapy on each side showed a significant preference for combination treatment (p < 0.05).

A number of studies have confirmed the efficacy of these combinations in infected eczema (table 4) [62-67]. In all of these studies, the fusidic acid-steroid combination was shown to have similar or superior clinical and bacteriological efficacy compared to other combination products. In one study, significantly more patients rated the cosmetic acceptability as “good” for fusidic acid-betamethasone than for clioquinol-betamethasone [66].

It is worth mentioning the recent study in which fusidic acid–betamethasone cream was compared with the new lipid cream formulation [67]. This study had several strengths: it was double-blinded, the diagnosis of clinically infected atopic eczema was based on strict criteria, and patients were representative of a wide spectrum of out-patients with this condition. Finally, the various different endpoints that were examined (percentage reduction in total severity score, investigators’ assessment of efficacy, patients’ assessment of efficacy, bacteriological response) all showed similar high efficacy for the cream and the lipid cream formulations.

A safety overview of published and unpublished studies and postmarketing surveillance data has shown that, as with plain fusidic acid, fusidic acid-steroid combination products have few and mild side effects [68].
Table 4 Comparative trials of fusidic acid/corticosteroid combination preparations in infected eczema

Resistance

A concern amongst microbiologists is the potential development of drug resistance with extensive use of topical fusidic acid. Resistance is due to either chromosomal or plasmid-mediated resistance. Chromosomal resistance appears readily in vitro at a frequency of 10^-6 to 10^-11, depending on the concentration of fusidic acid used [70]. The selected variants typically have minimum inhibitory concentration (MIC) values ranging from 8 mg/L to more than 256 mg/L [71]. This chromosomal resistance is due to modification of elongation factor G (the site of action of fusidic acid) by one or several point mutations. Such variants have been detected in clinical settings [71, 72]; they appear to be defective, because they grow more slowly than the parent strain and have a lower pathogenicity [71, 73, 74]. Furthermore, those mutants revert to full susceptibility when fusidic acid is absent from the medium [75].

Plasmid-mediated resistance to fusidic acid has been called “naturally occurring resistance” as it is detectable in isolates from patients never exposed to the drug [75]. This resistance may be linked to resistance to heavy metals and to other antibiotic resistances, including penicillinase production [76]. These strains are pathogenic and grow normally. However, as the plasmid may be unstable, some resistant colonies revert to fusidic acid susceptibility [75].

Recent analyses of clinical isolates have shown that a single gene (fusB) from the plasmid is capable of conferring resistance to fusidic acid in S. aureus and that this gene is now inserted into the chromosome of some epidemic strains [72]. In addition, chromosomal genes (fusB) encoding proteins with about 45% similarity to FusB have been identified [112]. These strains do not have a modified elongation factor G, nor do they deactivate fusidic acid enzymatically. The fusB and fusC genes code for a protein that binds directly to elongation factor G, thereby preventing interference in protein synthesis by fusidic acid [77, 112].

Thus, resistance of S. aureus to fusidic acid may arise from one of at least three different resistance classes: the FusA class (mutation of elongation factor G), FusB class (plasmid-mediated resistance), and FusC class (chromosomal fusC gene) [112].

The prevalence of resistance to fusidic acid was reviewed by Turnidge [78]. In general, up to the mid-1980s, studies on S. aureus bacteraemia showed a low-level resistance of 0-2.3% to fusidic acid. Later studies showed rates of resistance up to 6.4% in hospital patients [79]. Numerous contradictory studies can be found in the literature, some with higher rates of resistance for bacterial strains that have been isolated from SSTIs. The resistance level to fusidic acid might have been overestimated in these studies, as the cultures were generally taken from patients who did not respond to therapy [80].

In Scandinavia, the UK, and Ireland, increased levels of resistance have been observed. This was primarily due the spread of a clone in impetigo patients, which seems to have peaked and is now declining [81-83]. The rest of Europe has levels of resistance below 10% [84-86]. Resistance of MRSA to topical fusidic acid has remained at a low level in Germany (3.4% in 1998, 2.4% in 2002) [87]. However, it should also be noted that, in recent years, new MRSA strains have spread in the community, presumably arising from several diverse genetic backgrounds in several countries [88]. These MRSA strains, referred to as community-associated MRSA (CA-MRSA), were isolated e.g. in North America (ST USA300), Central Europe (ST080, ST398), Australia, and New Zealand. CA-MRSA are considered to be more virulent than other MRSA strains due to their production of Panton-Valentine leukocidin, and other toxins. Those strains can be resistant to specific antibiotics; for fusidic acid, resistance is due to the far-1 gene [89, 90]. In severe clinical infections (deep necrotizing abscesses) S. aureus diagnostics should include PCR for the lukF/lukS gene (coding for Panton-Valentine leukocidin) and the far-1 gene (coding for fusidic acid resistance).

Resistance levels to fusidic acid did not change between 1988 and 1994 in Australia [91], and there was no trend to increasing fusidic acid resistance at a Canadian hospital from 1999 to 2005 [92].

Some reports have suggested that extensive use of topical antibiotics, including mupirocin and fusidic acid, against S. aureus infections, particularly for prolonged periods, is linked with increased occurrence of resistance [93, 94]. There is general consensus that short-term therapy, for periods of no more than 2 weeks at a time, avoids the risk of resistance emerging [59, 95-97]. This suggestion was reinforced by results from the recent study on the efficacy of the new fusidic acid-betamethasone lipid cream (n = 629), in which a prospective evaluation of the emergence of resistance was performed. S. aureus isolates with resistance or intermediate resistance to fusidic acid were seen in 2.3% of the patients who applied fusidic acid, and 1.9% of those given the vehicle only [67].

Guideline recommendations

The joint European/American allergy/immunology guidelines recommend topical fusidic acid for mild and localized secondary infection in atopic eczema [105]. In order to avoid resistance development, such use should be restricted to periods of about 2 weeks.

Conclusion

Acknowledgements

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