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Activity of telithromycin compared with seven other agents against 1039 Streptococcus pyogenes pediatric isolates from ten centers in central and eastern Europe

2003; Elsevier BV; Volume: 9; Issue: 7 Linguagem: Inglês

10.1046/j.1469-0691.2003.00598.x

1469-0691

Bülent Bozdoğan, Peter C. Appelbaum, Linda M. Kelly, Dianne B. Hoellman, Arjana Tambić-Andrašević, Liga Drukalska, Waleria Hryniewicz, Helena Hupková, Michael R. Jacobs, Jana Kolman, Marianne Konkoly-Thege, Jolanta Miciulevičienė, Marina Pană, Lena Setchanova, J. Trupl, P Urbášková,

Antimicrobial Resistance in Staphylococcus

In total, 1039 pediatric Streptococcus pyogenes isolates from Bulgaria, Croatia, the Czech Republic, Hungary, Latvia, Lithuania, Poland, Romania, Slovakia and Slovenia were studied. All strains were susceptible to penicillin G, levofloxacin, and quinupristin–dalfopristin, 91–100% to telithromycin, and 82–100% to erythromycin, azithromycin, and clarithromycin, and 90–100% to clindamycin. Macrolide resistance occurred mainly in Slovakia (25%), the Czech Republic (17.3%), and Croatia (15.8%). Overall, 9.7% of S. pyogenes isolates were erythromycin resistant due to erm(B)- or erm(A)-encoded methylases (72.3%) or to a mef(A)-encoded efflux pump (25.7%). One strain had alterations of both 23S rRNA (A2058G Escherichia coli numbering) and ribosomal protein L22 (G95D). In total, 1039 pediatric Streptococcus pyogenes isolates from Bulgaria, Croatia, the Czech Republic, Hungary, Latvia, Lithuania, Poland, Romania, Slovakia and Slovenia were studied. All strains were susceptible to penicillin G, levofloxacin, and quinupristin–dalfopristin, 91–100% to telithromycin, and 82–100% to erythromycin, azithromycin, and clarithromycin, and 90–100% to clindamycin. Macrolide resistance occurred mainly in Slovakia (25%), the Czech Republic (17.3%), and Croatia (15.8%). Overall, 9.7% of S. pyogenes isolates were erythromycin resistant due to erm(B)- or erm(A)-encoded methylases (72.3%) or to a mef(A)-encoded efflux pump (25.7%). One strain had alterations of both 23S rRNA (A2058G Escherichia coli numbering) and ribosomal protein L22 (G95D). Streptococcus pyogenes is a significant cause of morbidity and mortality in humans, as well as being the leading cause of bacterial pharyngitis. S. pyogenes has been increasingly implicated in serious and sometimes systemic life-threatening infections in recent years. Although these strains have retained their penicillin G susceptibility, macrolide resistance has been increasingly reported in recent years [1Perez-Trallero E Fernandez-Mazarrasa C Garcia-Rey C et al.Antimicrobial susceptibilities of 1,684 Streptococcus pneumoniae and 2,039 Streptococcus pyogenes isolates and their ecological relationships: results of a 1-year (1998–1999) multicenter surveillance study in Spain.Antimicrob Agents Chemother. 2001; 45: 3334-3340Crossref PubMed Scopus (214) Google Scholar, 2Cornaglia G Ligozzi M Mazzariol A et al.Resistance of Streptococcus pyogenes to erythromycin and related antibiotics in Italy.Clin Infect Dis. 1998; 27: S87-S92Crossref PubMed Scopus (92) Google Scholar, 3Jasir A Schalén C Survey of macrolide resistance phenotypes in Swedish clinical isolates of Streptococcus pyogenes.J Antimicrob Chemother. 1998; 41: 135-137Crossref PubMed Scopus (42) Google Scholar]. A recent study from Spain [1Perez-Trallero E Fernandez-Mazarrasa C Garcia-Rey C et al.Antimicrobial susceptibilities of 1,684 Streptococcus pneumoniae and 2,039 Streptococcus pyogenes isolates and their ecological relationships: results of a 1-year (1998–1999) multicenter surveillance study in Spain.Antimicrob Agents Chemother. 2001; 45: 3334-3340Crossref PubMed Scopus (214) Google Scholar] has reported erythromycin resistance in 20% of S. pyogenes strains, while the incidence of these strains increased 2–20-fold from 1993 to 1995 in Italy, and was >30% in five of the 14 centers participating in the study [2Cornaglia G Ligozzi M Mazzariol A et al.Resistance of Streptococcus pyogenes to erythromycin and related antibiotics in Italy.Clin Infect Dis. 1998; 27: S87-S92Crossref PubMed Scopus (92) Google Scholar]. In Sweden, a recent retrospective study has documented macrolide resistance in a collection of strains isolated between 1980 and 1985 [3Jasir A Schalén C Survey of macrolide resistance phenotypes in Swedish clinical isolates of Streptococcus pyogenes.J Antimicrob Chemother. 1998; 41: 135-137Crossref PubMed Scopus (42) Google Scholar]. Macrolide resistance in S. pyogenes is usually mediated by erm(A)-encoded methylases [4Seppälä H Skurnik M Soini H Roberts MC Huovinen P A novel erythromycin resistance methylase gene (ermTR) in Streptococcus pyogenes.Antimicrob Agents Chemother. 1998; 42: 257-262Crossref PubMed Scopus (13) Google Scholar] or a mef(A)-encoded efflux pump [5Clancy J Petitpas J Dib-Hajj F et al.Molecular cloning and functional analysis of a novel macrolide-resistance determinant, mef(A), from Streptococcus pyogenes.Mol Microbiol. 1996; 22: 867-879Crossref PubMed Scopus (298) Google Scholar]. Macrolide resistance with erm(B) is also encountered. Telithromycin is a new ketolide which has been shown to have low MICs against both macrolidesusceptible and -resistant pneumococcal strains [6Ednie L Spangler SK Jacobs MR Appelbaum PC Susceptibilities of 228 penicillin- and erythromycin-susceptible and -resistant pneumococci to RU 64004, a new ketolide, compared with susceptibilities to 16 other agents.Antimicrob Agents Chemother. 1997; 41: 1033-1036Crossref PubMed Google Scholar, 7Pankuch GA Visalli MA Jacobs MR Appelbaum PC Susceptibilities of penicillin- and erythromycin-susceptible and -resistant pneumococci to HMR 3647 (RU 66647), a new ketolide, compared with susceptibilities to 17 other agents.Antimicrob Agents Chemother. 1998; 42: 624-630PubMed Google Scholar]. In S. pyogenes, the activity of telithromycin expands to most macrolide-resistant strains, except for those carrying erm(B) [8Nagai K Appelbaum PC Davies TA et al.Susceptibility to telithromycin in 1,011 Streptococcus pyogenes isolates from 10 central and eastern European countries.Antimicrob Agents Chemother. 2002; 46: 546-549Crossref PubMed Scopus (42) Google Scholar]. In many central and eastern European countries, high rates of macrolide resistance in S. pyogenes have already been documented in the general population [8Nagai K Appelbaum PC Davies TA et al.Susceptibility to telithromycin in 1,011 Streptococcus pyogenes isolates from 10 central and eastern European countries.Antimicrob Agents Chemother. 2002; 46: 546-549Crossref PubMed Scopus (42) Google Scholar, 9Appelbaum PC Gladkova C Hryniewicz W et al.Carriage of antibiotic-resistant Streptococcus pneumoniae by children in eastern and central Europe—a multicenter study with use of standardized methods.Clin Infect Dis. 1996; 23: 712-717Crossref PubMed Scopus (71) Google Scholar]. As the reservoir of S. pyogenes is children, we tested the activity of telithromycin compared with penicillin G, erythromycin, azithromycin, clarithromycin, clindamycin, quinupristin–dalfopristin and levofloxacin against 1039 S. pyogenes isolates from pediatric patients in ten centers in ten central and eastern European countries during 2000–2001. Identification of strains was by bacitracin susceptibility, β-hemolysis, and, where necessary, latex agglutination (Diagnostic Products Corporation, Los Angeles, CA, USA). Susceptibility testing was performed on Mueller–Hinton agar (BBL Microbiology Systems, Cockeysville, MD, USA) supplemented with 5% sheep blood as described previously [7Pankuch GA Visalli MA Jacobs MR Appelbaum PC Susceptibilities of penicillin- and erythromycin-susceptible and -resistant pneumococci to HMR 3647 (RU 66647), a new ketolide, compared with susceptibilities to 17 other agents.Antimicrob Agents Chemother. 1998; 42: 624-630PubMed Google Scholar, 8Nagai K Appelbaum PC Davies TA et al.Susceptibility to telithromycin in 1,011 Streptococcus pyogenes isolates from 10 central and eastern European countries.Antimicrob Agents Chemother. 2002; 46: 546-549Crossref PubMed Scopus (42) Google Scholar]. NCCLS breakpoints for S. pneumoniae were used [10National Committee for Clinical Laboratory Standards Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 5th edn. NCCLS Document M7-A5. NCCLS, Villanova, PA2000Google Scholar], except for telithromycin, where a preliminary breakpoint of ≤0.5 mg/L was used [11Soussy CJ Goldstein F Bryskier A et al.Telithromycin (TEL): assessment of susceptibility testing. [abstract 321].Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, 2000Google Scholar]. Antimicrobials were obtained from Aventis-Pharma, Anti-infectives, Romainville, France. All macrolide-resistant strains were screened for the presence of erm(B), erm(A) and mef(A) by PCR, according to previously reported methodology [8Nagai K Appelbaum PC Davies TA et al.Susceptibility to telithromycin in 1,011 Streptococcus pyogenes isolates from 10 central and eastern European countries.Antimicrob Agents Chemother. 2002; 46: 546-549Crossref PubMed Scopus (42) Google Scholar]. Macrolide-resistant strains that did not have erm or mef were tested for the mutations in domain V of 23S rRNA, and in ribosomal proteins L4 and L22 [8Nagai K Appelbaum PC Davies TA et al.Susceptibility to telithromycin in 1,011 Streptococcus pyogenes isolates from 10 central and eastern European countries.Antimicrob Agents Chemother. 2002; 46: 546-549Crossref PubMed Scopus (42) Google Scholar]. The ability to induce the expression of resistance was determined by the double-disk test method using erythromycin and clindamycin disks [12Seppälä H Nissinen A Yu Q Huovinen P Three different phenotypes of erythromycin-resistant Streptococcus pyogenes in Finland.J Antimicrob Chemother. 1993; 32: 885-891Crossref PubMed Scopus (277) Google Scholar]. To determine the clonality of resistance in S. pyogenes, pulsed-field gel electrophoresis (PFGE) with a CHEF DR III apparatus (Bio-Rad Laboratories, Hercules, CA, USA) was performed on selected isolates as described previously [13Nagai K Davies TA Pankuch GA Dewasse BE Appelbaum PC Resistance to clinafloxacin, ciprofloxacin, and trovafloxacin in Streptococcus pneumoniae.Antimicrob Agents Chemother. 2000; 44: 2740-2746Crossref PubMed Scopus (45) Google Scholar]. Interpretation of the interrelationships of PFGE patterns was done by use of the criteria of Tenover et al. [14Tenover FC Arberit RD Goering RV et al.Interpreting chromosomal DNA restriction patterns produced by pulse-field gel electrophoresis: criteria for bacterial strain typing.J Clin Microbiol. 1995; 33: 2223-2239Google Scholar]. S. pyogenes isolates were from patients aged 15 days to 15 years. Most strains were isolated from the throats (89%) of children with pharyngitis. All strains were susceptible to penicillin G, quinupristin–dalfopristin, and levofloxacin. Of all strains, 90.2% were susceptible to erythromycin and azithromycin, 90.3% to clarithromycin, and 97.4% to clindamycin. Rates of susceptibility to telithromycin were higher than rates of susceptibility to macrolides; 96.3% of isolates were susceptible to telithromycin (Table 1). Among the antimicrobials tested, penicillin had the lowest MIC90 values, followed by telithromycin, clindamycin, quinupristin–dalfopristin, levofloxacin, erythromycin, and azithromycin (Table 1).Table 1Comparative agar dilution MICs and rates of susceptibility to telithromycin and seven comparator agents for Streptococcus pyogenesMIC50/MIC90 (mg/L) (% of susceptibility rate)aSusceptible at breakpoints of ≤0.25 mg/L (erythromycin, clarithromycin, clindamycin), ≤0.5 mg/L (azithromycin, telithromycin), ≤1 mg/L (quinupristin–dalfopristin), ≤2 mg/L (levofloxacin), ≤0.06 mg/L (penicillin G).Center (n)TelithromycinPenicillin GErythromycinAzithromycinClarithromycinClindamycinQuinupristin–dalfopristinLevofloxacinBulgaria (100)0.03/0.06 (96)0.008/0.016 (100)0.06/0.06 (95)0.125/0.25 (95)0.06/0.06 (95)0.06/0.125 (99)0.25/0.25 (100)1/1 (100)Croatia (101)0.03/0.125 (98)≤0.016/0.016 (100)0.06/4 (84.2)0.25/4 (84.2)0.06/4 (84.2)0.125/0.125 (100)0.25/0.5 (100)0.5/1 (100)Czech Republic (98)0.03/0.25 (91.8)≤0.008/0.016 (100)0.06/>64 (82.7)0.25/>64 (82.7)0.06/>64 (82.7)0.06/0.125 (90.8)0.25/0.5 (100)0.5/1 (100)Hungary (119)0.03/0.125 (94.1)≤0.008/0.016 (100)0.06/0.125 (93.3)0.125/0.25 (93.3)0.06/0.06 (93.3)0.125/0.125 (93.3)0.12/0.5 (100)1/1 (100)Latvia (102)0.03/0.03 (100)≤0.008/0.016 (100)0.06/0.06 (99)0.125/0.25 (99)0.03/0.06 (99)0.06/0.125 (100)0.25/0.25 (100)1/1 (100)Lithuania (92)0.03/0.06 (98.9)≤0.016/0.016 (100)0.06/0.06 (91.3)0.125/0.25 (91.3)0.06/0.06 (91.3)0.125/0.125 (98.9)0.25/0.5 (100)1/1 (100)Poland (104)0.03/0.06 (100)≤0.008/0.016 (100)0.06/0.06 (99)0.125/0.25 (99)0.06/0.06 (99)0.125/0.125 (100)0.25/0.5 (100)0.5/2 (100)Romania (98)0.03/0.06 (99)0.016/0.016 (100)0.06/0.125 (91.8)0.25/0.5 (91.8)0.06/0.125 (91.8)0.06/0.125 (99)0.25/1 (100)0.5/1 (100)Slovakia (120)0.03/0.25 (98.3)0.016/0.016 (100)0.06/8 (91.7)0.125/32 (91.7)0.06/4 (91.7)0.125/0.25 (95)0.25/0.5 (100)0.5/1 (100)Slovenia (107)0.03/0.06 (100)0.016/0.016 (100)0.06/0.125 (92.5)0.125/0.25 (92.5)0.06/0.125 (93.5)0.06/0.125 (99.1)0.25/0.25 (100)0.5/1 (100)Total (1039)0.03/0.06 (96.3)0.016/0.016 (100)0.06/4 (90.2)0.125/4 (90.2)0.06/2 (90.3)0.06/0.125 (97.4)0.25/0.5 (100)1/1 (100)a Susceptible at breakpoints of ≤0.25 mg/L (erythromycin, clarithromycin, clindamycin), ≤0.5 mg/L (azithromycin, telithromycin), ≤1 mg/L (quinupristin–dalfopristin), ≤2 mg/L (levofloxacin), ≤0.06 mg/L (penicillin G). Open table in a new tab Ribosomal methylation was the most prevalent resistance mechanism (Table 2). Of 73 macrolide-resistant strains with methylase, 53 (72.6%) contained erm(A) and 20 (27.4%) erm(B). The expression of methylases was constitutive in 16 of 20 strains with erm(B) and in five of 53 strains with erm(A) by double-disk test. In Hungary and the Czech Republic, six and eight strains, respectively, had constitutive erm(B). These strains were resistant to telithromycin (4–32 mg/L). The clonality of these strains was determined by PFGE. Two patterns were identified in the eight Prague strains (two type A and six type B). Six strains from Budapest with erm(B) had similar PFGE patterns. Among strains with constitutive or inducible erm(A), only one isolate was resistant to telithromycin (8 mg/L). Twenty-six macrolide-resistant strains contained mef(A) efflux genes. Croatia and Bulgaria were the only locations with predominance of the efflux resistance mechanism (Table 2).Table 2Mechanisms of macrolide resistance in Streptococcus pyogenesNo. of macrolide strains with specified mechanismCenter (n)erm(B)erm(A)mef(A)Ribosomal mutationaRibosomal mutant has mutation both in 23S rRNA (A2058G) and in ribosomal protein L22 (G95D).UnknownbNo erm or mef gene, and mutations in studied portion of 23S rRNA and in ribosomal proteins L4 and L22 are detected.Total (%)cPrevalence of resistant strain among strains tested.Bulgaria (100)235 (5)Croatia (101)25916 (15.8)Czech Republic (98)88117 (17.3)Hungary (119)6117 (6.7)Latvia (100)11 (2)Lithuania (92)178 (8.6)Poland (104)11 (0.9)Romania (98)14218 (9.0)Slovakia (120)2181030 (25)Slovenia (107)617 (6.5)Total (1039)20 (19.8%)dPrevalence of resistance mechanism among macrolide-resistant strains.53 (52.5%)dPrevalence of resistance mechanism among macrolide-resistant strains.26 (25.7%)dPrevalence of resistance mechanism among macrolide-resistant strains.1 (1%)dPrevalence of resistance mechanism among macrolide-resistant strains.1 (1%)dPrevalence of resistance mechanism among macrolide-resistant strains.101 (9.7)a Ribosomal mutant has mutation both in 23S rRNA (A2058G) and in ribosomal protein L22 (G95D).b No erm or mef gene, and mutations in studied portion of 23S rRNA and in ribosomal proteins L4 and L22 are detected.c Prevalence of resistant strain among strains tested.d Prevalence of resistance mechanism among macrolide-resistant strains. Open table in a new tab Two strains did not contain erm or mef. One of these strains, HMC2621 from Hungary, had mutations in both 23S ribosomal RNA by A→G substitution at position 2058 (Escherichia coli numbering) and in ribosomal protein L22 by G95D substitution. The MICs of this strain for telithromycin, erythromycin, azithromycin, clarithromycin and clindamycin were 2, >64, >64, >64 and 8 mg/L, respectively. The other strain, HMC1711 from Romania, did not have mutations in ribosomal proteins L4 and L22 or in studied portions of 23S rRNA. The MICs for telithromycin, erythromycin, azithromycin, clarithromycin and clindamycin were 0.016, 0.5, 2, 0.5 and 0.06 mg/L, respectively (Table 3). The macrolide resistance mechanism of this strain is currently under investigation.Table 3MICs according to the mechanism of resistance in 101 macrolide-resistant Streptococcus pyogenes strainsMIC (mg/L)AntimicrobialResistance mechanism (n)RangeMIC50MIC90Telithromycinerm(B) (20)2–32832erm(A) (53)<0.008–80.060.125mef(A) (26)0.125–0.50.50.5Ribosomal mutant (1)aRibosomal mutant has mutations in both 23S rRNA (A2058G) and ribosomal protein L22 (G95D).2––Unknown (1)bNo erm or mef gene, and mutations in studied portion of 23S rRNA, and in ribosomal proteins L4 and L22, are detected.0.016––All strains (101) 64>64>64erm(A) (53)2 to >6432>64mef(A) (26)882–16Ribosomal mutant (1)aRibosomal mutant has mutations in both 23S rRNA (A2058G) and ribosomal protein L22 (G95D).>64––Unknown (1)bNo erm or mef gene, and mutations in studied portion of 23S rRNA, and in ribosomal proteins L4 and L22, are detected.2––All strains (101)2 to >6416>64Erythromycin Aerm(B) (20)>64>64>64erm(A) (53)0.5 to >644>64mef(A) (26)4–16816Ribosomal mutant (1)aRibosomal mutant has mutations in both 23S rRNA (A2058G) and ribosomal protein L22 (G95D).>64––Unknown (1)bNo erm or mef gene, and mutations in studied portion of 23S rRNA, and in ribosomal proteins L4 and L22, are detected.1––All strains (101)1 to >648>64Clarithromycinerm(B) (20)>64>64>64erm(A) (53)0.5 to >642>64mef(A) (26)4–848Ribosomal mutant (1)aRibosomal mutant has mutations in both 23S rRNA (A2058G) and ribosomal protein L22 (G95D).>64––Unknown (1)bNo erm or mef gene, and mutations in studied portion of 23S rRNA, and in ribosomal proteins L4 and L22, are detected.0.5––All strains (101)0.5 to >644>64Clindamycinerm(B) (20)0.125 to >64>64>64erm(A) (53)0.06 to >640.1250.5mef(A) (26)0.03–0.1250.060.125Ribosomal mutant (1)aRibosomal mutant has mutations in both 23S rRNA (A2058G) and ribosomal protein L22 (G95D).8––Unknown (1)bNo erm or mef gene, and mutations in studied portion of 23S rRNA, and in ribosomal proteins L4 and L22, are detected.0.06––All strains (101)0.03 to >640.125>64a Ribosomal mutant has mutations in both 23S rRNA (A2058G) and ribosomal protein L22 (G95D).b No erm or mef gene, and mutations in studied portion of 23S rRNA, and in ribosomal proteins L4 and L22, are detected. Open table in a new tab The prevalence of macrolide resistance was 9.7% among pediatric S. pyogenes isolates from eastern European centers (Table 2). In Slovakia (25%), the Czech Republic (17.3%) and Croatia (15.8%), macrolide resistance was high. A high prevalence of macrolide resistance has also previously been reported in Greece (38%) [15Syrogiannopoulos GA Grivea IN Fitoussi F et al.High prevalence of erythromycin resistance of Streptococcus pyogenes in Greek children.Pediatr Infect Dis J. 2001; 20: 863-868Crossref PubMed Scopus (40) Google Scholar] and in Spain (20%) [1Perez-Trallero E Fernandez-Mazarrasa C Garcia-Rey C et al.Antimicrobial susceptibilities of 1,684 Streptococcus pneumoniae and 2,039 Streptococcus pyogenes isolates and their ecological relationships: results of a 1-year (1998–1999) multicenter surveillance study in Spain.Antimicrob Agents Chemother. 2001; 45: 3334-3340Crossref PubMed Scopus (214) Google Scholar]. Nagai et al. have reported a macrolide resistance rate of 12.3% among S. pyogenes strains from the general population of central and eastern European countries [8Nagai K Appelbaum PC Davies TA et al.Susceptibility to telithromycin in 1,011 Streptococcus pyogenes isolates from 10 central and eastern European countries.Antimicrob Agents Chemother. 2002; 46: 546-549Crossref PubMed Scopus (42) Google Scholar], which is higher than the prevalence in pediatric isolates in the present study (9.7%). Macrolide resistance rates of S. pyogenes isolates from pediatric patients were higher than in the general population only in the Czech Republic, Slovak Republic, and Hungary. In Poland, the incidence of macrolide resistance of the strains from pediatric patients (0.9%) was 16-fold lower than in the general population (16.3%). Analysis of PFGE patterns of the resistant strains from the general population showed the presence of one erm(A) clone (six of 12 strains) and one erm(B) clone (four of four strains). Among pediatric S. pyogenes isolates from central and eastern European countries, erm(A)-encoded methylase was the most frequent macrolide resistance mechanism. In Croatia and Bulgaria, an mef(A)-encoded efflux mechanism was the most prevalent mechanism, as in Greece [15Syrogiannopoulos GA Grivea IN Fitoussi F et al.High prevalence of erythromycin resistance of Streptococcus pyogenes in Greek children.Pediatr Infect Dis J. 2001; 20: 863-868Crossref PubMed Scopus (40) Google Scholar], Spain [16Alós JI Aracil B Oteo J Torres C Gómez-Garcés JL High prevalence of erythromycin-resistant, clindamycin/miocamycin-susceptible (M phenotype) Streptococcus pyogenes: results of a Spanish multicentre study in 1998.J Antimicrob Chemother. 2000; 45: 605-609Crossref PubMed Scopus (56) Google Scholar], and Italy [17Giovanetti E Montanari MP Mingoia M Varaldo PE Phenotypes and genotypes of erythromycin-resistant Streptococcus pyogenes strains in Italy and heterogeneity of inducibly resistant strains.Antimicrob Agents Chemother. 1999; 43: 1935-1940PubMed Google Scholar]. In Hungary and the Czech Republic, constitutive expression of macrolide resistance due to erm(B) was the most important resistance mechanism, as has already been reported in France [18Bingen E Fitoussi F Doit C et al.Resistance to macrolides in Streptococcus pyogenes in France in pediatric patients.Antimicrob Agents Chemother. 2000; 44: 1453-1457Crossref PubMed Scopus (107) Google Scholar]. In this study, we report on S. pyogenes HMC2621 from Hungary, resistant to macrolides, with mutations both in 23S rRNA and in ribosomal protein L22. Macrolide resistance by alteration of 23S rRNA and ribosomal protein L4 has already been reported from the Slovak Republic and Croatia [19Malbruny B Nagai K Coquemont M et al.Resistance to macrolides in clinical isolates of Streptococcus pyogenes due to ribosomal mutations.J Antimicrob Chemother. 2002; 49: 935-939Crossref PubMed Scopus (70) Google Scholar]. These latter mutants had low levels of resistance to macrolides, and were susceptible to telithromycin and clindamycin. In contrast, S. pyogenes HMC2621 was highly resistant to erythromycin, azithromycin, and clarithromycin, and had a low level of resistance to telithromycin (2 mg/L) and clindamycin (8 mg/L). All strains tested were susceptible to penicillin G, levofloxacin, and quinupristin–dalfopristin. Telithromycin had superior in vitro activity to that of the macrolides tested, and similar in vitro activity to that of clindamycin. All strains, except those with the constitutive expression of methylases and a ribosomal mutant, were susceptible to telithromycin. If the prevalence of erm(B) strains does not increase, telithromycin therefore has potential for the empirical treatment of infections, particularly in penicillin-allergic patients in whom S. pyogenes plays a role. This study was partially presented at ICAAC 2001, Chicago, and was supported by a grant from Aventis-Pharma, Romainville, France.