P-Haemolytic streptococci of Lancefield groups A, B, C and G remain exquisitely sensitive to penicillin and other P-lactams, but resistance to sulphonamides and tetracyclines has been recognised since the Second World War. Penicillin has, therefore, always been the drug of choice for most infections caused by P-haemolytic streptococci, but macrolide compounds, including erythromycin, clarithromycin, roxithromycin and azithromycin, have been good alternatives in penicillin-allergic patients.
In striking contrast to erythromycin no increase in penicillin resistance has been observed in vitro among clinical isolates of P-haemolytic streptococci, in particular GAS. Penicillin tolerance, however, amongst GAS, defined as an increased mean bactericidal concentration (MBC) : minimum inhibitory concentration (MIC) ratio (usually >16), has been reported at a higher frequency in patients who were clinical treatment failures than in those successfully treated for pharyngitis (Holm 2000). The presence of P-lactamase-producing bacteria in the throat has been assumed to be another significant factor in the high failure rate of penicillin V therapy. Although many P-lactamase-producing bacteria are not pathogenic to this particular niche, they can act as indirect pathogens through their capacity to inactivate penicillin V administered to eliminate P-haemolytic streptococci.
Macrolide resistance amongst GAS has increased between the 1990s and early 2000s in many countries (Seppala etal. 1992; Cornaglia etal. 1998; Garcia-Rey etal. 2002). The resistance is caused by two different mechanisms: target-site modification (Weisblum 1985) and active drug efflux (Sutcliffe, Tait-Kamradt and Wondrack 1996). Target-site modification is mediated by a methylase enzyme that reduces binding of macrolides, lincosamides and streptogramin B antibiotics (MLSB resistance) to their target site in the bacterial ribosome, giving rise to the constitutive (CR) and inducible (IR) MLSb resistance phenotypes (Weisblum 1985). Another phenotype called noninducible (NI) conferring low-level resistance to erythromycin (MIC <16mg/L) and to other 14- or 15-membered compounds but sensitive to the 16-membered macrolides has also been described (Seppala etal. 1993). This phenotype is invariably susceptible to clindamycin and has been designated as NI because of an efflux mechanism.
Since the identification of plasmid-mediated MLS resistance in the Streptococcus sp. in the early 1970s it has been shown that conjugation is the most common dissemination mode of resistance. Transduction may also contribute to the spread of antibiotic resistance amongst GAS but has not been reported for other streptococci (Courvalin, Carlier and Chabbert 1972). Transposon-mediated MLS resistance in GAS has been described, and chromosomally integrated resistance genes of presumed plasmid origin have been found in many plasmid-free strains (Le Bouguenec, de Cespedes and Horaud 1990).
The genes encoding the methylases have been designated erm (erythromycin ribosome methylation). The methylases of the various species have been characterised at the molecular level and are subdivided into several classes, named by letters (Levy etal. 1999). In GAS the so-called ermB (ermAM) gene is among the most common, found to be present in 31% of 143 macrolide-resistant GAS lower respiratory tract infection strains obtained from 25 countries participating in the Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin (PROTEKT) study during 1999-2000 (Farrell et al. 2002). A closely related gene, ermTR (ermA) (Seppala etal. 1998), was found in 23% of these isolates, whilst mefA, the resistance gene due to macrolide efflux (Levy et al. 1999), was detected in 46% of these strains.
The increase in erythromycin resistance amongst GAS has been shown to be caused by isolates with the M phenotype, known to be associated with active efflux (Tait-Kamradt etal. 1997). The increase in the prevalence of erythromycin-resistant GAS carrying the ermA, ermB and/or mefA genes has been the subject of many recent reports (Giovanetti etal. 1999; Kataja, Huovinen and Seppala 2000; Leclercq 2002). In contrast, less work has been undertaken to characterise the mechanism of tetracycline resistance amongst P-haemolytic streptococci. For GAS, only the tetM gene has been the commonly identified gene. Other streptococcal species that carry the tet(O) gene, which codes for another tetracycline resistance ribosomal protection protein, or the tet(K) and the tet(L) genes, which code for efflux-mediated tetracyc-line resistance, have also been identified (Chopra and Roberts 2001).
Current estimates of macrolide resistance in GAS strains within Europe show some variation, from 1.8% in a collection of invasive and noninvasive strains from Denmark (Statens Serum Institut, Danish Veterinary and Food Administration, Danish Medicines Agency and Danish Institute for Food and Veterinary Research 2004), 4% of bacteraemic strains in the United Kingdom (HPA 2004b) to 20% of noninvasive strains from across Spain (Perez-Trallero etal. 2001). In a mixed collection of GAS strains obtained from Russia 11% were found to be erythromycin resistant (Kozlov etal. 2002). Among the P-haemolytic streptococcal strains collected as part of the SENTRY worldwide antimicrobial susceptibility monitoring programme between 1997 and 2000, 10% of European isolates from invasive and noninvasive disease were found to be erythromycin resistant and 11% of strains collected from Asia-Pacific region, 19% from North American and only 3% from Latin American exhibited erythromycin resistance (Gordon etal. 2002).
Rifampicin is a particularly active agent against Gram-positive bacteria and mycobacteria. There have been few reports about the susceptibility of S. pyogenes to rifampicin; however, resistance has been estimated to be approximately 0.3% amongst isolates from Spain. Resistance is caused by an alteration of one or more regions of the target site, the P-subunit of RNA polymerase. Most of the mutations associated with rifampicin resistance are located in a segment in the centre of the rpoB gene cluster (Herrera etal. 2002).
Was this article helpful?