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Chapter 8: Future perspectives

The present study indicates that further studies in the following areas are relevant: future consumption of macrolide antibiotics in relation to erythromycin-resistance development in S. aureus; why is the Danish population protected against the spread of imported methicillin-resistant S. aureus; the importance of coagulasenegative staphylococci as reservoirs of resistance genes; and furthermore, more detailed genetic studies of the ermA and ermC genes, their mode of spread and their naturally occurring mutants; and finally, characterization of the genes involved in non-erm containing erythromycin-resistant S. aureus. As resistance to pristinamycin was found in human isolates of coagulase-negative staphylococci, it would be interesting to evaluate whether the usage of streptogramins for animal feed supplementation plays a role for development of resistance. The decline of erythromycin consumption in the late 1980s led to a blunting of the rise in erythromycin-resistant S. aureus seen since 1983 in S. aureus. However, the selective pressure exerted by macrolide consumption on the staphylococcal population in Denmark is increasing again, and the introduction of new macrolide compounds has fuelled the upward spiral of consumption leading to increasing macrolide resistance. The continued surveillance of phage type patterns in S. aureus shows that Denmark is currently able to keep imported methicillin-resistant S. aureus from spreading. The continued Danish efforts to keep imported methicillin-resistant strains from spreading are important. This is achieved by the restrictive antibiotic usage policy of Danish hospitals and in general practice. In general practice increased microbiological service to facilitate rapid diagnosis and educational programmes must be used to curb the efforts of the industries to sell broad spectrum drugs when narrow-spectrum drugs still suffice. The ermC gene seems to have superseded ermA as the Danish erythromycin-resistance gene of importance in S. aureus and is today the most important gene responsible for erythromycin-resistance in coagulase-negative staphylococci. It will be interesting to follow the prevalence of ermA in the future. The msrA gene is very often found as the cause of erythromycinresistance in coagulase-negative staphylococci and may be spreading to S. aureus. In Denmark the level of erythromycin-resistance is more than ten times higher in coagulase-negative staphylococci than in S. aureus. No explanation for this difference is known. Possibly it reflects the fact that all persons are colonized with coagulase-negative staphylococci but only about 30% with S. aureus. This gives a more continuous antibiotic pressure on coagulase-negative staphylococci, when erythromycin is used for treatment of infectious diseases. Working with Southern blotting has been time-consuming, but has yielded interesting information on the prevalence of resistance genes. The introduction of PCR techniques might open for screening of large materials on a more reasonable time scale. With appropriate primers it would also be possible to create and subsequently sequence a PCR product containing the insertion site of ermA in the S. aureus chromosome, giving more data on the insert sites in strains with two and three inserts. More information on insert sites is interesting, as Tn544 has a primary insertion site with affinity to the mecA gene. In S. uureus with two or more ermA inserts sequencing of Tn.544 DNA might also elucidate if these inserts represent infection with two transposons or if transposition of the original insert of Tn544 by cointegrate formation occurred at a later date. Transposition by cointegrate formation has been suggested by phenotypical data in our studies. Although ermC mainly expressed an inducible phenotype in a 2.5 kb plasmid, about 10% of the strains had constitutive resistance. In some cases this could be explained by deletions in the leader peptide but some strains must have had smaller deletions/mutations as