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Background: An increase in erythromycin resistance rates among group A streptococci has been reported in some European countries. These bacteria, long thought to be extracellular pathogens, can be efficiently internalised by, and survive within, human cells of respiratory-tract origin. Macrolide antibiotics enter eukaryotic cells, whereas beta-lactams are essentially confined to the extracellular fluid. A protein encoded by gene prtF1 is required for efficient entry of group A streptococci into epithelial cells. We investigated isolates of group A streptococci from children with pharyngitis in Italy for the presence of prtF1 and cell-invasion efficiency., Methods: We investigated 74 erythromycin-resistant and 52 erythromycin-susceptible isolates collected throughout Italy in 1997-98 from children with pharyngitis. Erythromycin-resistance phenotypes (constitutive, inducible, and M) were assessed by the triple-disc test and resistance determinants (ermB, ermTR, and mefA) by PCR. All strains were examined for the presence of prtF1 by PCR and for their ability to enter cultured human respiratory cells., Findings: The proportion of prtF1-positive strains was significantly higher among erythromycin-resistant than susceptible strains (66 [89%] vs 11 [21%]; difference 68% [95% CI 52-84]). All erythromycin-resistant strains without prtF1 were of the M phenotype. The proportion of highly cell-invasive isolates (invasion efficiency >10%) was significantly higher among erythromycin-resistant than among susceptible strains (59 [80%] vs five [10%]; difference 70% [57-83])., Interpretations: The unsuspected association between erythromycin resistance and cell invasiveness in group A streptococci raises serious concern. Strains combining erythromycin resistance and ability to enter human respiratory-tract cells may be able to escape both beta-lactams by virtue of intracellular location and macrolides by virtue of resistance.