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Antimicrobial Agents and Chemotherapy, September 2004, p . 3594-3597, Vol . 48, No . 9 A Fusidic Acid-Resistant Epidemic Strain of Staphylococcus aureus Carries the fusB Determinant, whereas fusA Mutations Are Prevalent in Other Resistant IsolatesAlexander J . O'Neill,1 Anders R . Larsen,2 Anne S . Henriksen,3 and Ian Chopra1* Antimicrobial Research Centre and School of Biochemistry and Microbiology, University of Leeds, Leeds, United Kingdom,1 Department of Research & Development, Statens Serum Institut, Copenhagen,2 LEO Pharma, Ballerup, Denmark3 Received 9 December 2003/ Returned for modification 3 March 2004/ Accepted 30 April 2004
Recently, fusidic acid-resistant epidemic strains of S . aureus causing impetigo bullosa were reported in Sweden and Norway (11, 16) . In this paper we demonstrate that resistant strains reported in these Scandinavian outbreaks are clonally related and exist in other European countries . Furthermore, we found that this clonotype carries the fusB resistance determinant . In contrast, fusidic acid resistance arising in nonepidemic strains was attributed, in several cases, to mutations in fusA . Clinical S . aureus isolates in which the genetic basis of fusidic acid resistance was established are listed in Table 1 . In addition to representatives of epidemic fusidic acid-resistant strains from Scandinavia and Ireland, resistant strains collected during a comparative phase III study (FCF0001 INT) and from a dermatology unit in Harrogate, United Kingdom (strain designations with an H prefix) (13), were examined . Detection of fusA mutations in these strains was performed by PCR amplification and sequencing, as previously described (10) . The fusB determinant was detected by Southern hybridization (14) with the Alkphos Direct kit (Amersham Biosciences, Amersham, United Kingdom) using the entire fusB gene (A . J . O'Neill and I . Chopra, Abstr . 42nd Intersci . Conf . Antimicrob . Agents Chemother., abstr . 1064, 2002) as a probe . Further isolates were screened by PCR amplification of a 292-bp fragment of the fusB gene using oligonucleotide primers FB(iii) (5'-ATTCAATCGGAAACCTATAATGATA) and FB(iv) (5'-TTATATATTTCCGATTTGATGCAAG) . Using an annealing temperature of 60°C, it was established that these primers generated an amplicon only from strains known to carry fusB (data not shown) .
Other Fusr strains belonging to this clonotype from dermatology patients in Harrogate, United Kingdom (13), were tested for the presence of fusB by PCR . A 292-bp amplicon was generated from strains belonging to the epidemic clonotype (Fig . 1; strains with the prefix H), indicating the presence of fusB (data not shown) . The genetic basis of fusidic acid resistance was also examined in nonepidemic isolates recovered from patients undergoing topical fusidic acid treatment for atopic dermatitis . In instances where fusidic acid resistance arose during treatment, both initial (fusidic acid-susceptible) and final (fusidic acid-resistant) isolates were examined . One nonepidemic strain (CS642) carried fusB (Fig . 2) and exhibited low-level resistance (Table 1) . As for the epidemic strains, fusB appeared to be chromosomally located in strain CS642 . Higher-level fusidic acid resistance (MIC > 12 µg/ml) in the nonepidemic strains resulted exclusively from nucleotide substitutions in fusA (Table 1) . In addition, two low-level Fusr strains (CS1116 and CS957) were also resistant as a result of mutation in EF-G (Table 1) . All mutations identified in EF-G save one (A71T) have previously been shown to confer fusidic acid resistance or to participate in compensatory adaptation to the costs of fusidic acid resistance (8, 10) . Since an alternative Fusr substitution at the A71 locus (A71V) has been described (8), the A71T mutation discussed above is likely to confer resistance to fusidic acid . Several mutations (P404L, G451V, and G452S) previously identified only in Fusr strains derived in vitro (8, 10) were detected here for the first time in clinical S . aureus isolates (Table 1) . In four nonepidemic strains exhibiting relatively low-level resistance (CS992, CS730, CS808, and CS866), neither fusB nor polymorphic variations in fusA were detected . This suggests that while mutations in fusA and possession of fusB are common routes to fusidic acid resistance in clinical isolates, other mechanisms may also exist . In conclusion, we have demonstrated that several fusidic acid-resistant clinical isolates of S . aureus recovered from patients with impetigo bullosa in European countries represent a clonal epidemic strain carrying the fusB determinant on the chromosome . Mutations in fusA were identified in nonepidemic fusidic acid-resistant strains, but such mutations were not identified in the clonal epidemic strain . The factors favoring dissemination of the epidemic clonal strain have yet to be identified .
We thank J . Ravenscroft, Y . Tveten, and G . Kahlmeter for provision of strains and A . M . Moita for technical assistance .
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4 µg/ml) (Table 
