JAC Advance Access published online on January 24, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm525
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Increasing telithromycin resistance among Streptococcus pyogenes in Europe
1 Department of Pathology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242-1009, USA 2 Instituto Valenciano Microbio, Masia El Romeral, Betera, Valencia 46117, Spain 3 Laboratory of Microbiology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium
* Corresponding author. Tel: +1-319-356-2990; Fax: +1-319-356-4916; E-mail: sandra-richter{at}uiowa.edu
Received 17 August 2007; returned 1 December 2007; revised 22 October 2007; accepted 11 December 2007
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Abstract |
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Objectives: To assess changes in macrolide and ketolide resistance among Streptococcus pyogenes in Europe and to examine the relationship of resistance to antimicrobial usage.
Methods: Clinical S. pyogenes isolates were collected from Denmark, Finland, France, Germany, Italy, Netherlands, Norway, Spain, Sweden, UK, Croatia, Hungary, Poland, Slovak Republic and Slovenia during 2002–03 (n = 2165) and 2004–05 (n = 2333). Resistance to telithromycin (MIC 
2) and erythromycin (MIC 0.5) was determined by CLSI broth microdilution. Changes in resistance over time and the relationship of resistance to antimicrobial use (European Surveillance of Antimicrobial Consumption data) were assessed. Telithromycin-resistant isolates were characterized by PFGE to determine genetic relatedness and by PCR to detect mef(A), erm(A) and erm(B).
Results: The erythromycin resistance rate during 2004–05 (11.6%) was similar to 2002–03 (10.4%). The proportion of macrolide-resistant isolates with the constitutive MLSB phenotype increased from 29.3% (2002–03) to 45.7% (2004–05). Telithromycin resistance increased from 1.8% in 2002–03 to 5.2% in 2004–05. For Western Europe, associations of telithromycin and erythromycin resistance, respectively, were found with azithromycin use (R2 = 0.52 and 0.60), clarithromycin use (R2 = 0.76 and 0.85) and total macrolide/lincosamide use (R2 = 0.75 and 0.69). For Eastern Europe, associations of antimicrobial use with resistance were not apparent. The 162 telithromycin-resistant isolates comprised 42 PFGE patterns with 68.5% in eight major PFGE groups. The erm(B) gene was detected in 155 of the 162 telithromycin-resistant isolates.
Conclusions: Significant increases in telithromycin resistance occurred from 2002–03 to 2004–05 in Europe. Macrolide use appears to be a factor in the emergence of ketolide resistance among S. pyogenes in Western Europe.
Key Words: group A streptococci , ketolides , macrolides
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Introduction |
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Macrolides provide an alternative for treating β-lactam allergic patients with a Streptococcus pyogenes infection. However, the usefulness of this class of drugs against S. pyogenes is limited in European and Asian countries with high rates of macrolide resistance.1–5
Macrolides inhibit protein synthesis by binding to 23S rRNA (domain V) of the 50S bacterial ribosome subunit.6 The majority of S. pyogenes that are macrolide-resistant contain an erm gene encoding methylation of the ribosomal target or mef(A) causing efflux of the antimicrobial agent.7–9 Isolates with the mef(A) gene have the M phenotype: low to moderate resistance to 14- and 15-membered macrolides, but are susceptible to 16-membered macrolides, lincosamides and streptogramin B.7 The erm gene confers macrolide, lincosamide and streptogramin B resistance [constitutive MLSB (cMLSB) phenotype—usually erm(B)] or may require macrolide exposure for clindamycin resistance to become apparent [inducible MLSB (iMLSB) phenotype—usually erm(A)].8,9 Mutations in 23S rRNA and ribosomal proteins have occasionally been associated with macrolide resistance in S. pyogenes.10–12
Ketolides are a new class of antimicrobials derived from erythromycin with 10-fold greater ribosomal binding affinity due to secondary interaction with domain II.13 The first available ketolide, telithromycin, is an effective therapy for macrolide-resistant Streptococcus pneumoniae, but has variable activity against S. pyogenes isolates with cMLSB phenotype expression.14–16 The overall prevalence of ketolide resistance in the S. pyogenes population has been relatively low.17,18
The purpose of this study was to assess changes in macrolide and ketolide resistance rates among S. pyogenes clinical isolates from Europe. The second goal was to determine the relationship of macrolide and ketolide resistance to antimicrobial usage in Europe. Telithromycin-resistant isolates were further characterized by PFGE to determine genetic relatedness and by PCR to detect macrolide resistance genotypes.
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Isolates
Clinically significant S. pyogenes isolates from unique patients were obtained from 65 medical centres in 15 countries (Denmark, Finland, France, Germany, Italy, Netherlands, Norway, Spain, Sweden, UK, Croatia, Hungary, Poland, Slovak Republic and Slovenia) during 2002–03 (n = 2165) and 2004–05 (n = 2333). Forty-four medical centres contributed isolates during both study periods. The susceptibility profiles of the 2002–03 isolates were reported previously.1 Data regarding identification methods used by participating laboratories were not collected. The identification of the isolates was confirmed in the central laboratory by colony morphology, β-haemolysis and a positive PYR test followed by storage at –70°C.19
Susceptibility testing was performed using the CLSI broth microdilution method in Mueller–Hinton broth supplemented with 3% lysed horse blood.20 The antimicrobial agents tested were azithromycin, cefdinir, clarithromycin, clindamycin, erythromycin, levofloxacin, penicillin and telithromycin. CLSI MIC breakpoints for ‘Streptococcus spp. other than S. pneumoniae’ were applied.21 The CLSI interpretive criteria for S. pneumoniae were used for cefdinir and telithromycin.21 S. pneumoniae ATCC 49619 was used for quality control.
The relationship of erythromycin and telithromycin resistance in 2004–05 to outpatient antimicrobial use in 2002–03 [European Surveillance of Antimicrobial Consumption (ESAC) data] was assessed by linear regression analysis. The ESAC project applies the Anatomic Therapeutic Chemical classification system with measurement by the defined daily dose (DDD) unit (endorsed by the World Health Organization) per 1000 inhabitants per day. Detailed descriptions of the ESAC project have been published previously.22–24
Macrolide resistance phenotype
The double disc diffusion D-zone test was performed on telithromycin-resistant isolates with a clindamycin MIC 
0.5 mg/L (susceptible or intermediate) using 15 µg erythromycin and 2 µg clindamycin discs according to CLSI guidelines (12 mm apart).21 Blunting of the inhibition zone around the clindamycin disc adjacent to the erythromycin disc was interpreted as the iMLSB phenotype. Clindamycin-susceptible isolates with no blunting were assigned the M phenotype. Resistance to erythromycin and clindamycin was considered the cMLSB phenotype.
A multiplex PCR for erm(A), erm(B) and mef(A) was performed on all telithromycin-resistant isolates as previously described.25–27 Isolates with negative PCR results were analysed for mutations in domain V of 23S rRNA genes according to published methods.10,12,28
Pulsed-field gel electrophoresis
Telithromycin-resistant isolates were characterized by PFGE after DNA digestion with ApaI (New England Biolabs) using CHEF-DR II (Bio-Rad) at 14°C and 200 V for 23 h (initial forward time, 1 s; final forward time, 17 s). Ethidium bromide stained gels were analysed using BionumericsTM software (Applied Maths, Kortrijk, Belgium). The dendrogram was constructed using the unweighted pair group method with arithmetic averages and the DICE coefficient (1.0% optimization, 1.0% position tolerance). Isolates were assigned to the same PFGE pattern if their profile differed by three bands or less (similarity coefficient of 84% on the dendrogram).29
The 
2 test with Yates’ correction was used to evaluate the significance of dichotomous values. Only P values <0.05 were considered significant.
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The types of specimens yielding S. pyogenes isolates in 2002–03 (n = 2165) and 2004–05 (n = 2333) were similar: throat (67%, 64%), skin and soft tissue (21%, 20%), upper respiratory tract (6%, 6%), blood cultures/sterile site (4%, 6%) and other (2%, 4%). The age distribution of the patients for the two periods was 0–5 (19%, 24%), 6–20 (26%, 33%), 21–64 (27%, 35%),
65 years (5%, 6%) and unknown (23%, 2%).
During the 2004–05 period, resistance (intermediate category included) was detected to azithromycin (11.6%), clarithromycin (11.4%), clindamycin (5.4%), erythromycin (11.6%), levofloxacin (0.1%, intermediate only) and telithromycin (5.3%). The 2004–05 erythromycin resistance rate (MIC 0.5 mg/L) of 11.6% was similar to the 2002–03 rate of 10.4% (Table 1). However, there was a shift towards higher erythromycin MICs with an 8-fold increase in MIC90 from 1 mg/L in 2002–03 to 8 mg/L in 2004–05. Only two countries had a significant increase in erythromycin resistance: Sweden (1.1% to 5.2%, P = 0.04) and Slovak Republic (20.6% to 40.9%, P = 0.02) (Table 2).
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The proportion of erythromycin-resistant isolates with the cMLSB phenotype (erythromycin- and clindamycin-resistant) in Europe increased from 29.3% in 2002–03 to 45.7% in 2004–05 (P = 0.0003) (Table 3). This trend was seen in Western (22.4% to 36.3% cMLSB phenotype) and Eastern Europe (45.4% to 64.8% cMLSB phenotype).
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The telithromycin resistance rate (MIC
2 mg/L, includes intermediate category) in Europe increased from 1.8% in 2002–03 to 5.2% in 2004–05 (Table 4). The significant change in telithromycin resistance rates was evident in Western (from 1.9% to 4.5%) and Eastern Europe (from 1.7% to 6.7%) (P < 0.0001). The 15 isolates with a telithromycin MIC 32 mg/L were all from the 2004–05 surveillance period. Four countries had significant increases in telithromycin resistance (Table 2): Italy (3.7% to 10.1%, P = 0.009), Croatia (2.1% to 11.8%, P = 0.02), Slovak Republic (0% to 36.4%, P < 0.0001) and Slovenia (3% to 12.3%, P = 0.03).
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All 162 telithromycin-resistant isolates (both time periods) were high-level erythromycin resistant (MIC
64 mg/L) and 90.7% were also clindamycin resistant (cMLSB phenotype) (Table 5). D-zone testing performed on the 15 telithromycin-resistant isolates with a clindamycin MIC 0.5 mg/L revealed an iMLSB phenotype. From 2002–03 to 2004–05, the overall prevalence of telithromycin resistance among cMLSB phenotype isolates increased from 55.4% to 91% (P < 0.0001)—a trend evident in Western (68.6% to 95.4%) and Eastern Europe (40% to 86%) (Table 3). The telithromycin-susceptible isolates with a cMLSB phenotype had MICs ranging from 0.03 to 1 mg/L with 0.06 mg/L as the modal MIC.
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For Western Europe, there was a significant association between rates of erythromycin resistance in 2004–05 with azithromycin usage (R2 = 0.606), clarithromycin usage (R2 = 0.8526) and total macrolide/lincosamide usage (R2 = 0.6993) in 2002–03 (Figure 1). For Western Europe, significant associations of telithromycin resistance in 2004–05 with azithromycin usage (R2 = 0.5294), clarithromycin usage (R2 = 0.7645) and total macrolide/lincosamide usage (R2 = 0.754) in 2002–03 were also evident (Figure 2).
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For Eastern Europe, no significant association between antimicrobial use and resistance with S. pyogenes was found (R2 < 0.5; consumption data are given in Table 2).
The 162 telithromycin-resistant isolates represented 42 different PFGE patterns with 68.5% of the isolates in eight major PFGE clones (A–H) containing six or more isolates (Table 6). The predominant PFGE pattern (A) included 40 isolates, primarily from Eastern Europe and the 2004–05 period. The 29 isolates comprising PFGE B were recovered almost exclusively from Western Europe (96.6%) during 2004–05 (72.4%).
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The predominant macrolide resistance genotype detected among the 162 telithromycin-resistant isolates was erm(B) (n = 155, 95.7%) and included the 15 isolates with iMLSB phenotypes (Table 5). The mef(A) gene was also detected in two of the isolates with erm(B). Seven telithromycin-resistant isolates were negative for erm(B), erm(A) and mef(A) genes. A 23S rRNA A2058T mutation was detected in two of these isolates. Both isolates with the A2058T mutation were from Croatia, but had unrelated PFGE profiles (unique and PFGE H).
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In 2004–05, the prevalence of macrolide resistance in individual countries was highly variable ranging from 0% in the Netherlands to 40.9% in the Slovak Republic (Table 2). The overall erythromycin resistance rate for Europe increased only slightly between 2002–03 and 2004–05 (10.4% to 11.6%). However, the macrolide resistance rates in two countries (Sweden and Slovak Republic) were significantly higher in 2004–05 than in 2002–03. Three countries had the highest levels of erythromycin resistance during both time periods: Spain (23.1% and 18.4%), Italy (24.8% and 31.3%) and Slovak Republic (20.6% and 40.9%). An unfortunate reduction in Slovak Republic participating centres from two (2002–03, 97 isolates) to one (2004–05, 44 isolates) limited the strength of the Slovak Republic data from the latter time period. The prevalence of macrolide resistance reported by Nagai et al.18 in the Slovak Republic during 1999–2000 was lower (16.7% of 102 isolates). A 2004 surveillance study reported a similar level of erythromycin resistance (21.7%) in Spain.30 Earlier studies in Italy documented macrolide resistance rates of 28.1% in 1995,31 31% in 1998–994 and 35.8% in 2000.32
In the current study, the proportion of erythromycin-resistant isolates with the cMLSB phenotype in Europe increased from 29.3% to 45.7% in 2004–05—a rate similar to Korea during 1998–2003 (42.1%).33 A 1999–2000 Central and Eastern European study documented a much lower rate of cMLSB phenotype (12.1%) among erythromycin-resistant S. pyogenes.18 In 2004, a significant increase in cMLSB phenotype to 30.5% of the macrolide-resistant isolates was noted in Spain.30
The overall telithromycin resistance rate of 5.2% in the current study was a significant increase from the 2002–03 rate of 1.8%. In 2004–05, there were four countries with telithromycin resistance rates above 10% (Italy, 10.1%; Croatia, 11.8%; Slovenia, 12.3%; and Slovak Republic, 36.4%)—a sharp contrast to 2003–04 when the telithromycin resistance rate for each individual country was <4%. A 1999–2000 study reported telithromycin resistance rates (4 mg/L) of 2.1% in Croatia, 0% in Slovenia and 3% in the Slovak Republic.18
The presence of erm(B) in the majority of telithromycin-resistant S. pyogenes isolates (95.7%) in this study is consistent with observations made by others.16,17,27,34,35 However, the low telithromycin MICs for virtually all S. pneumoniae and at least some erm(B)-positive S. pyogenes isolates suggest additional factors are needed to confer telithromycin resistance. For example, a 1999–2003 Belgium study described macrolide-resistant S. pyogenes isolates with the cMLSB phenotype which had telithromycin MICs ranging from 0.0075 to 32 mg/L with an MIC50 of 1 mg/L; only 10% of isolates with erm(B) had telithromycin MICs 4 mg/L.36 In our study, the proportion of cMLSB phenotype isolates with a telithromycin MIC 2 mg/L increased from 55.4% (36 of 65) in 2002–03 to 91% (111 of 122) in 2004–05. Thus, the cMLSB phenotype became more predictive of telithromycin resistance over time. This same trend was observed in Spain in 2004: 88.6% of cMLSB phenotype S. pyogenes isolates had telithromycin MICs 4 mg/L.30
The erm genes encode methylation of the A2058 nucleotide of 23S rRNA where macrolide and ketolide antibiotics bind susceptible strains. There is a variation among erm genes—they may monomethylate or dimethylate the A2058 position.37 Using mass spectrometry, Douthwaite et al.38 demonstrated correlation of telithromycin resistance with degree of methylation by erm(B): isolates with fully dimethylated A2058 had the highest telithromycin MICs while a large proportion of rRNA in ketolide-susceptible strains was monomethylated. Incubation of ketolide-susceptible erm(B) strains with erythromycin (0.5 mg/L) increased the degree of dimethylation and telithromycin MICs.38 An H118R (A677G) mutation has been detected in the erm(B)-coding region by two independent investigators in 12 telithromycin-resistant S. pyogenes isolates.17,36 Mutations in erm(B) may increase the degree of rRNA dimethylation at A2058 or alter methylase specificity to allow methylation of additional telithromycin binding sites.36
Of the seven telithromycin-resistant isolates without erm(B), two unrelated strains from Croatia had 23S rRNA A2058T mutations that have been previously associated with macrolide resistance in pneumococci.39 The A2058G 23S rRNA mutations that have been reported in macrolide-resistant10,11 and telithromycin-resistant S. pyogenes27,40 were not detected.
The significant associations found for erythromycin resistance in 2004–05 with macrolide use in 2002–03 in Western Europe have also been reported in Finland,41 Spain42 and Italy.43 A more direct link between antibiotic use and the emergence of resistance has been demonstrated by a randomized, double-blind study that found an increased proportion of macrolide-resistant streptococci colonizing the pharynx of volunteers after azithromycin or clarithromycin treatment in comparison to placebo.44 The association between macrolide use and telithromycin resistance is not surprising given the increased rRNA dimethylation at A2058 and decreased ketolide susceptibility demonstrated in vitro for S. pyogenes strains after exposure to subinhibitory concentrations of erythromycin.38 The lack of significant association between macrolide use and our 2004–05 resistance data for Eastern Europe is likely due to the lower number of isolates collected from those countries. The substantial number of countries without any consumption of telithromycin as documented by EUCAST (Table 2) hindered our ability to assess the potential association between telithromycin use and resistance.
In conclusion, we found significant increases in telithromycin resistance among S. pyogenes in Europe from 2002–03 to 2004–05. Although the macrolide-resistance rate was stable, the prevalence of cMLSB phenotype strains and telithromycin resistance in this population has increased over time. Correlation of antibiotic use with resistance rates in Western Europe supports macrolide use as a factor in the emergence of ketolide resistance. The presence of predominant clones among the telithromycin-resistant S. pyogenes population suggests clonal expansion is also contributing to the observed increase in ketolide resistance.
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This study was supported by a grant from Abbott Laboratories, Inc. (Abbott Park, IL, USA) awarded to G. V. D.
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G. V. D. has received research funding from Abbott Laboratories, Bayer Pharmaceuticals, Cubist and AstraZeneca. He has been on the speakers’ bureau for Abbott Laboratories, Bayer Pharmaceuticals, Cubist, AstraZeneca, Pfizer, GlaxoSmithKline, Aventis and Roche. S. S. R. has received research funding from Becton–Dickinson and Pfizer. All other authors: none to declare.
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Presented in part at the Forty-sixth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, 2006 (abstract C2-1291).
We thank the following individuals for providing the isolates of S. pyogenes characterized in this study: Croatia (2 centres): Arjana Tambic Andrasevic, Klinika za infektivne bolesti, Zagreb; Vinco Zoranic, Zavod za javno, Zdravstvo Zupanije, Splitsko-dalmatinske, Split; Denmark (2): Bettina Lundgren, Hvidovre University Hospital, Hvidovre; Neils Norskov-Lauritsen, Klinisk Mikrobiologisk Afdeling, Aarhus (2004–05 only); Finland (2): Martii Vaara, Helsinki University Central Hospital Diagnostic Laboratories, Helsinki; Markku Koskela, Oulu University Hospital Microbiological Laboratory, Oulu (2004–05 only); France (8): Micheline Roussel-Delvallez, CHRU Lille-Hospital Calmette, Lille (2002–03 only); Thierry Fosse, Hospital de L’Archet, Nice; Henri Dabernat, Hospital de Purpan, Toulouse; Henri Drugeon, Laboratoire de Bacteriologie, Hotel Dieu, Nantes; Claude-James Soussy, Hospital Henri Mondor, Creteil; Roland Leclercq, Hospital Cote de Nacre, Caen (2004–05 only); Monique Chomarat, Centre Hospitalier Lyon Sud, Pierre-Benite (2004–05 only); Marie-Cecile Ploy, Hospital Universitaire Dupuytren, Limoges (2004–05 only); Germany (5): Bernd Wiedermann, Pharmazeutische Mikrobiologie der Universitat Bonn, Bonn (2002–03 only); Guido Funke, Gartner and Colleagues Laboratories, Weingarten; Arne Rodloff, Mikrobiologie Infektionsepidemiologie der Universitat Leipzig, Leipzig; Rene Reinert, Institute for Medical Microbiology, RWTH Aachen, Aachen; Michael Kresken, Gesellschaft fur klinisch-microbiologische Forschung und Kommunikation mbH, Bonn; Hungary (8): Miklos Fuzi, National Center for Epidemiology, Budapest (2002–03 only); Lenke Szikra, ANTSZ Fejer megyei, Szekesfehervar; Maria Kalman, ANTSZ CsongraD EGYE, Szeged; Ferrenc Lakatos, ANTSZ Vas megye, Szombathely; Károly Csiszár, ANTSZ Nograd Megye, Salgotarjan (2002–03 only); Erzsébet Puskas, Public Health Service, Miskolc (2002–03 only); Sandor Penzes, ÁNTSZ of Heves County, Eger; Zoltan Lajos, ANTSZ Fovarosi Intezete, Budapest Vaci (2004–05 only); Italy (6): Schito Giancarlo, Institute of Microbiology, Medical School, University of Genoa, Genoa; Gianna Tempera, Department of Microbiological Science, University of Catania, Catania; Giovanni Fadda, Institute Microbiology, Catholic University Sacro Cuore, Roma; Maria Antonieta Tufano, Department of Microbiology Clinical Bacteriology, University of Naples, Napoli; Pierluigi Nicoletti, Azienda Ospedaliera Careggi, Piastra dei Servizi, Firenze; Roberto Mattina, Institute of Medical Microbiology, University of Milano, Milano (2002–03 only); Netherlands (5): R. de Groot, Sophie Children’s Hospital, Rotterdam (2002–03 only); J. H. Sloos, Medical Center Alkamaar, Alkamaar; J. H. T. Wagenvoort, Atrium Medical Centre, Heerlen; Andreas Voss, University Medical Center, Nijmegen; Ellen Stobberingh, University Hospital Maastricht, Maastricht (2002–03 only); Norway (2): Arnfinn Sundsfjord, University Hospital of North-Norway, Tromso; Harleen Grewal, Haukeland University Hospital, Bergen; Poland (6): Jan Patzer, Zaklad Mikrobiologii I Immunologii, Klinicznej, Instytut Pomnik, Warszawa; Andrzej Kasprowicz, Centrum Badan Mikrobiologic znych I Autoszczwepio nek Sp.Zo.o., Krakow (2002–03 only); Waleria Hryniewicz, Centralne Laboratorium, Surowic I Szczepionek, Warszawa; Ryszard Prosiecki, Samodzielny Publiczny ZOZ, Zaklad Mikrobiologii, Sanok (2002–03 only); Stefania Giedrys-Kalemba, Pomeranian Medical University, Szczecin (2002–03 only); Tomasz Koziol, Wojewodzki Szpotal Specjalistyczny nr.3, Rybnic (2004–05 only); Slovak Republic (2): Leon Langsadl, NUTaRCH, Bratislava (2002–03 only); Anna Purgelova, NsP F. D. Roosevelt, Banska Bystrica; Slovenia (2): Katja Seme, Institute of Microbiology and Immunology, Ljubljana; Barbara Zdolsek, Institute of Public Health, Celje; Spain (6): Francesco Marco, Hospital Clinic i Provincial, Barcelona; Carlos Fernandez Mazarrasa and Luis Martinez, Hospital Universitario Marqués de Valdecilla, Santander; Manuel de la Rosa Fraile, Hospital Universitario Virgen de las Nieves, Granada; Miguel Gobernado Serrano, Hospital Universitari La Fe, Valencia; Emilio Bouza Santiago, Hospital General Universitario Gregorio Maranón, Madrid; Javier Aznar Martin, Hospital Virgen del Rocío, Sevilla (2002–03 only); Sweden (4): Carl Erik Nord, Huddinge University Hospital, Stockholm; Arne Forsgren, University Hospital MAS, Malmo; Gunnar Kahlmeter, Klinisk Mikrobiologi, Vaxjo; Lennart E. Nilsson, Linkoping Universitet, Linkoping; UK (5): Alasdair MacGowan, Southmead Hospital, Bristol; Peter Hawkey, Public Health Laboratory, Heartlands Hospital, Birmingham; Richard Wise, City Hospital Trust, Birmingham; Derek Brown, Clinical Microbiology and Public Health Laboratory, Addenbrooke’s Hospital, Cambridge; Gary French, St Thomas’ Hospital, London (2002–03 only).
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