Epidemiological differences between the UK and Ireland versus France in Staphylococcus aureus isolates resistant to fusidic acid from community-acquired skin and soft tissue infections.

OBJECTIVES: To characterize the epidemiology of Staphylococcus aureus isolates resistant to fusidic acid isolated from patients with skin and soft tissue infections (SSTIs) in France, the UK and Ireland. METHODS: One hundred and thirty-six S. aureus isolates with an MIC of fusidic acid above 1 mg/L were isolated during the EPISA study from patients more than 2 years old attending their general practitioners for SSTIs. All isolates were related to clonal complex by a combination of PFGE, spa typing and multilocus sequence typing. The presence of toxin genes and of the fusB determinant was monitored to characterize each represented clonal complex. RESULTS: Eight different clonal complexes were identified. CC121 constituted the majority of the isolates from Ireland and the UK but was not represented in France. Among the other clonal complexes, CC8 and CC5 were the most common in the three countries, although the number of French isolates was limited. CC121 was the only clonal complex significantly associated with a skin infection, namely impetigo (P < 0.05). Toxin genes were present in CC121 and CC80. The fusB determinant was also detected in the same clonal complexes. Enterotoxins were found in four clonal complexes (CC1, CC5, CC8 and CC22). CONCLUSIONS: The impetigo clone (CC121: ST123) was present in the majority of S. aureus isolates from the UK and Ireland but was not detected in France. This strain was associated with impetigo, exfoliative toxins and the fusB determinant. No other clonal complex appeared to be dominant in other types of skin infections.

Characterization of the epidemic European fusidic acid-resistant impetigo clone of Staphylococcus aureus.

Resistance to the antibiotic fusidic acid in European strains of Staphylococcus aureus causing impetigo has increased in recent years. This increase appears to have resulted from clonal expansion of a strain we have designated the epidemic European fusidic acid-resistant impetigo clone (EEFIC), which carries the fusidic acid resistance determinant fusB on its chromosome. To understand better the properties of the EEFIC responsible for its success, we have performed detailed phenotypic and genotypic characterization of this clone. Molecular typing revealed the EEFIC to be ST123, spa type t171, and agr type IV and therefore unrelated to earlier prevalent fusB(+) strains found in the United Kingdom. EEFIC strains exhibited resistance to fusidic acid, penicillin, and, in some cases, erythromycin, which are all used in the treatment of impetigo. PCR analysis of the EEFIC and complete DNA sequencing of the 39.3 Kb plasmid it harbors identified genes encoding several toxins previously implicated in impetigo (exfoliative toxins A and B and EDIN-C). The location of fusB was mapped on the chromosome and found to be associated with a novel 16.6-kb genomic island integrated downstream of groEL. Although this element is related to classical staphylococcal pathogenicity islands, it does not encode any known virulence factors and consequently has been designated SaRI(fusB) (for "S. aureus resistance island carrying fusB").

Genetic basis of resistance to fusidic acid in staphylococci.

Resistance to fusidic acid in Staphylococcus aureus often results from acquisition of the fusB determinant or from mutations in the gene (fusA) that encodes the drug target (elongation factor G). We now report further studies on the genetic basis of resistance to this antibiotic in the staphylococci. Two staphylococcal genes that encode proteins exhibiting ca. 45% identity with FusB conferred resistance to fusidic acid in S. aureus. One of these genes (designated fusC) was subsequently detected in all fusidic acid-resistant clinical strains of S. aureus tested that did not carry fusB or mutations in fusA, and in strains of S. intermedius. The other gene (designated fusD) is carried by S. saprophyticus, explaining the inherent resistance of this species to fusidic acid. Fusidic acid-resistant strains of S. lugdunensis harbored fusB. Thus, resistance to fusidic acid in clinical isolates of S. aureus and other staphylococcal species frequently results from expression of FusB-type proteins.

Synthesis and conformational analysis of fusidic acid side chain derivatives in relation to antibacterial activity.

Novel fusidic acid type antibiotics having flexible side chains are described. Saturation of the double bond between C-17 and C-20 of fusidic acid produces four stereoisomers differing in the configuration at C-17 and C-20. The structure-activity relationship of the stereoisomers was studied using computer-assisted analyses of low-energy conformations and crystallographic data. Only one of the four stereoisomers showed potent antibiotic activity comparable with that of fusidic acid, whereas the other three stereoisomers retained little or no activity. The orientation of the side chain is crucial, and there is only a limited space for bioactive side chain conformations. This investigation demonstrates the essential role of the side chain conformations in relation to antibacterial activity and contradicts earlier assumptions that the Delta17(20) bond is an essential feature in the molecule.