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Antimicrob Agents Chemother. Jan 2006; 50(1): 256–261.
PMCID: PMC1346824

Resistance to Erythromycin and Telithromycin in Streptococcus pyogenes Isolates Obtained between 1999 and 2002 from Greek Children with Tonsillopharyngitis: Phenotypic and Genotypic Analysis

Abstract

Since the late 1990s, the prevalence of erythromycin-resistant Streptococcus pyogenes has significantly increased in several European countries. Between January 1999 and December 2002, 1,577 isolates of S. pyogenes were recovered from children with tonsillopharyngitis living in various areas of Western Greece. Erythromycin resistance was observed in 379 (24%) of the 1,577 isolates. All erythromycin-resistant strains along with 153 randomly selected erythromycin-susceptible S. pyogenes isolates were tested for their antimicrobial susceptibility, resistance phenotypes, and genotypes. Representative isolates underwent emm gene sequence typing. Isolates with reduced susceptibility to telithromycin (MIC, ≥2 μg/ml) were studied for multilocus sequence type, L22, L4, and 23S rRNA mutations. Of the total 379 erythromycin-resistant isolates, 193 (50.9%) harbored the mef(A) gene, 163 (43%) erm(A), 1 (0.3%) mef(A) plus erm(A), and 22 (5.8%) the erm(B) gene. Among the erythromycin-susceptible isolates, emm 1 (25%), emm 2 (12.5%), and emm 77 (12.5%) predominated. Furthermore, among the erythromycin-resistant isolates, emm 4 (30.6%), emm 28 (22.2%), and emm 77 (12.5%) prevailed. Resistance to telithromycin was observed in 22 (5.8%) of the erythromycin-resistant isolates. Sixteen (72.7%) of the 22 isolates appeared to be clonally related, since all of them belonged to emm type 28 and multilocus sequence type 52. One of the well-known mutations (T2166C) in 23S rRNA, as well as a new one (T2136C), was detected in erythromycin- and telithromycin-resistant isolates. High incidence of macrolide resistance and clonal spread of telithromycin resistance were the characteristics of the Greek S. pyogenes isolates obtained from 1999 to 2002.

Streptococcus pyogenes is the most common bacterial agent implicated in acute tonsillopharyngitis and can also cause a variety of skin and soft tissue infections and severe invasive disease (20). Macrolides constitute the alternative choice for the treatment of streptococcal tonsillopharyngitis and other respiratory tract infections, valuable especially in patients allergic to β-lactams.

Since the late 1990s, resistance to erythromycin and other 14- and 15-membered ring macrolides has been increasingly detected in S. pyogenes in several European countries (1, 10, 16) and other parts of the world, such as Korea (24). The main known mechanisms of macrolide resistance in S. pyogenes are a 14- and 15-membered ring macrolide-specific efflux mechanism (M phenotype) (21), encoded by the mef(A) gene (6), as well as the modification of the ribosomal target by a methylase encoded by the erm(B) (26) or the erm(TR) gene (18); the latter is currently referred to as erm(A) or erm(A), subclass erm(TR) gene (17). Methylation results in reduced binding of and coresistance to 14-, 15-, and 16-membered ring macrolide, lincosamide, and streptogramin B (MLS) antibiotics. Methylase can be expressed either constitutively (cMLS phenotype) or inducibly (iMLS phenotype). Three subtypes of the iMLS macrolide resistance phenotype have been distinguished: iMLS-A, iMLS-B, and iMLS-C (10). Susceptibility to 16-membered ring macrolides was of particular importance in distinguishing these three subtypes. The iMLS-A subtype was characterized by high-level constitutive resistance to 16-membered ring macrolides. In contrast, the iMLS-B and iMLS-C strains were susceptible to the 16-membered ring macrolide josamycin, but after induction they became high-level and low-level resistant, respectively.

Apart from the above, in a few clinical isolates of S. pyogenes, macrolide resistance has been attributed to changes clustered in a highly conserved sequence of L4 (2, 12) and in nucleotide residues of domain V of 23S rRNA (11, 12), which have a key role in macrolide binding (25).

Telithromycin is a ketolide developed specifically for the treatment of community-acquired respiratory tract infections. Some of the constitutively resistant erm(B)-positive S. pyogenes isolates were found to be telithromycin resistant, although telithromycin retains activity against strains possessing the other macrolide resistance genotypes, such as erm(A) and mef(A) (10, 16).

The aim of the present study was to investigate in pharyngeal S. pyogenes isolates recovered from Greek children with acute tonsillopharyngitis over a 4-year study period (i) the phenotypes and genotypes of erythromycin-resistant isolates, (ii) the predominant emm types in erythromycin-susceptible and -resistant isolates, (iii) the in vitro activity of telithromycin in comparison with that of other antibiotics used for the treatment of respiratory tract infections, and (iv) the molecular characteristics of isolates with reduced susceptibility to telithromycin.

(This research was presented in part at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Ill., abstr. C2-73, 2003, and the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C., abstr. C2-799, 2004.)

MATERIALS AND METHODS

Subjects and specimens.

Between January 1999 and December 2002, S. pyogenes isolates were recovered from children with tonsillopharyngitis living in Western Greece. Isolates were recovered in various areas of the prefectures of Preveza, Etoloakarnania, Achaia, Ilia, and Messinia. The study population consisted of children between 2 and 16 years of age, with signs and symptoms of acute tonsillopharyngitis confirmed by a positive throat culture for S. pyogenes. The study was performed in collaboration with 14 practicing pediatricians, who participate in our working group, the Hellenic Antibiotic-Resistant Respiratory Pathogens (HARP) Study Group. From November 2000 through December 2002, these pediatricians enrolled children with tonsillopharyngitis on clinical studies of different treatment regimens (G. A. Syrogiannopoulos, I. N. Grivea, N. G. Beratis, and the HARP Study Group, 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. G-436, 2002; G. A. Syrogiannopoulos, I. N. Grivea, D. Kritikou, and the HARP Study Group, 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. G-1547, 2003). One S. pyogenes isolate from each child was included in the study. Throat cultures were performed at the Laboratory of the Division of Pediatric Infectious Disease of the University of Patras.

Isolates were identified as S. pyogenes by colony morphology, β-hemolysis on sheep blood agar, and Lancefield grouping by using a commercially available agglutination technique (Slidex, Streptokit; bioMérieux, Marcy l'Etoile, France) and by using the pyrrolidonyl-arylamidase test.

S. pyogenes isolates were screened for susceptibility to erythromycin by both the disk diffusion method and the Etest method (AB Biodisk, Sweden). All the erythromycin-resistant and randomly sampled erythromycin-susceptible (n = 153) S. pyogenes isolates were studied for their antimicrobial susceptibility. MIC testing was performed by using the broth microdilution method as recommended by CLSI (formerly the National Committee for Clinical Laboratory Standards [NCCLS]) (13). Commercially manufactured microtiter plates (Micronaut-S; Merlin Diagnostics, Bornheim, Germany) containing penicillin G, amoxicillin, cefotaxime, erythromycin, clindamycin, telithromycin, tetracycline, gatifloxacin, ciprofloxacin, vancomycin, and teicoplanin and cation-adjusted Mueller-Hinton broth (Oxoid, Wesel, Germany) plus 5% lysed horse blood (Oxoid) were used. The final inoculum was 5 × 105 CFU/ml (equivalent to a 0.5 McFarland standard). MICs were determined after incubation at 35°C for 24 h in ambient air. S. pneumoniae strain ATCC 49619 was used as a control strain. Current NCCLS interpretive criteria were used to define antimicrobial resistance (14). For telithromycin, S. pneumoniae breakpoints of ≤1 and ≥4 μg/ml were used for sensitivity and resistance, respectively.

Determination of macrolide resistance phenotype.

The macrolide resistance phenotypes and their subtypes were determined on the basis of the pattern of susceptibility to erythromycin and clindamycin and confirmed by the triple-disk (erythromycin plus clindamycin and josamycin) test. The triple-disk test was set up to facilitate the laboratory discrimination of the 3 subtypes (iMLS-A, iMLS-B, and iMLS-C) of the iMLS macrolide resistance phenotype, as described previously (10).

Macrolide resistance determinants.

S. pyogenes isolates showing resistance to erythromycin were tested by PCR for the presence of erm(A), erm(B), or mef(A) macrolide resistance determinants (3). Isolates with reduced susceptibility to telithromycin (MIC, ≥2 μg/ml) were further analyzed for mutations in 23S rRNA and ribosomal proteins L4 and L22. Nucleotide sequences for 23S rRNA and L4 and L22 ribosomal proteins in Escherichia coli and S. pneumoniae were obtained from the Institute for Genome Research website (http://www.tigr.org). Specific oligonucleotide primers were designed from these sequences. Primer sequences and conditions for PCR amplifications were those described by Canu et al. (4). The following primers were used: for rplV (L22), 5′-GCAGACGACAAGAAAACACG-3′ and 5′-GCCGACACGCATACCAATTG-3′; for rplD (L4), (i) 5′-AAAGGTAACGTACCAGGTGC-3′ and 5′-GCGTGGTGGTGGTGT TG-3′ and (ii) 5′-CACGAGTGTCAACTTCAAATAC-3′ and 5′-GAGCGTCTACAGCTACG-3′; for rrl (23S rRNA domain II), 5′-CGGCGAGTTACGATTATGATGC-3′ and 5′-CTCTAATGTCGACGCTAGCC-3′; and for rrl (23S rRNA domain V), (i) 5′-CTGTCTCAACGAGAGACTC-3′ and 5′-CTTAGACTCCTACCTATCC-3′ and (ii) 5′-GTATAAGGGAGCTTGACTG-3′ and 5′-GGGTTTCACACTTAGATG-3′. Since better discrimination between mutated alleles was obtained for denatured DNA fragments between 150 and 500 bp, portions of the rrl gene (domains II and V of 23S rRNA), the entire rplV gene and two overlapping fragments of the L4 gene (rplD) were amplified. The three fragments amplified from rrl, two for domain V and one for domain II, included bases that are essential for the development of erythromycin resistance: G2057, A2058, A2062, G2505, C2611, and A752 (4).

Quinolone resistance determinants.

Isolates with reduced susceptibility to ciprofloxacin were tested by PCR for the presence of mutations in the GyrA subunit of the DNA gyrase and/or the ParC subunit of topoisomerase IV.

emm types of S. pyogenes isolates.

A randomly selected sample of 104 erythromycin-susceptible and -resistant S. pyogenes isolates were studied for their emm type according to the method of Podbielski et al. (15). Similarity searching was performed by using the N-terminal hypervariable region of the M gene based on the latest information from the Centers for Disease Control and Prevention website (http://www.cdc.gov/ncidod/-biotech/strep/strains/emmtypes.html). S. pyogenes CS101 (emm 49) was used as a reference strain.

Multilocus sequence typing.

Telithromycin-resistant isolates were analyzed by multilocus sequence typing as described by Enright et al. (8).

Statistical analysis.

The standard chi-square test was used for comparison of proportions between groups of isolates, employing Yates' continuity correction in 2 by 2 tables. In the event of low expected frequencies, exact P values were obtained from SPSS version 11 (SPSS Inc., Chicago, Ill). A two-tailed P value of ≤0.05 was considered significant.

RESULTS

Between January 1999 and December 2002, 1,577 consecutive clinical strains of S. pyogenes were isolated from children with tonsillopharyngitis living in Western Greece. S. pyogenes infections were mainly seen among children 5 to 10 years of age (64% of cases). The distribution of isolates during the study period was the following: 70 in 1999, 200 in 2000, 823 in 2001, and 484 in 2002.

Resistance to erythromycin was found in 379 (24%) of these 1,577 isolates. Out of a total of 379 erythromycin-resistant isolates, 50.9% had the M phenotype, 0.5% the iMLS-A, 9% had the iMLS-B, 34% the iMLS-C, and finally 5.6% had the cMLS phenotype (Table (Table1).1). There was phenotype and genotype agreement in >99% of the erythromycin-resistant isolates. The 379 tested erythromycin-resistant isolates harbored the mef(A) (50.9%), erm(A) (43%), mef(A) plus erm(A) (0.3%), or erm(B) (5.8%) gene (Table (Table22).

TABLE 1.
Year of recovery and macrolide resistance phenotypes of the 379 erythromycin-resistant isolates
TABLE 2.
Macrolide resistance phenotypes of the 379 erythromycin-resistant isolates

The antimicrobial susceptibility results for the 153 randomly sampled erythromycin-susceptible and the 379 erythromycin-resistant isolates are presented in Table Table3.3. One isolate, not included in the table, had intermediate resistance to erythromycin. The molecular analysis of this isolate did not reveal the presence of any macrolide resistance determinant. The highest rates of reduced susceptibility to tetracycline were noted among isolates harboring the erm(A) gene and expressing the iMLS-B (38.2%) and iMLS-C (53.1%) subtypes.

TABLE 3.
Antimicrobial susceptibility of erythromycin-susceptible and erythromycin-resistant S. pyogenes isolates with different resistance genotypes

In addition txxxo the antimicrobial agents presented in Table Table3,3, good activity against all isolates was seen with cefotaxime (MICs, ≤0.016 μg/ml), vancomycin (MICs, 0.125 to 0.5 μg/ml), and teicoplanin (MICs, ≤0.03 to 0.25 μg/ml). Among the S. pyogenes isolates tested, one had relatively reduced susceptibility to ciprofloxacin (MIC = 2 μg/ml) and 22 were telithromycin resistant.

All the isolates that showed the cMLS phenotype and harbored the erm(B) gene had high-level resistance to erythromycin and clindamycin (MICs, ≥32 μg/ml), except one isolate that had an erythromycin MIC of 2 μg/ml and clindamycin MIC of ≥32 μg/ml, but was susceptible to telithromycin (MIC, 0.06 μg/ml).

emm types of S. pyogenes isolates.

Three emm types, 1, 2, and 77, accounted for 50% of the 32 typed erythromycin-susceptible isolates (Table (Table4).4). Among the 72 typed erythromycin-resistant isolates, emm 4 (30.6%), emm 28 (22.2%), and emm 77 (12.5%) predominated. emm types 4, 12, 75, and 1 accounted for 86.2% of the mef(A)-positive isolates.

TABLE 4.
emm type distribution in 32 erythromycin-susceptible and 72 erythromycin-resistant S. pyogenes isolates with different macrolide resistance genotypes

emm type 1 accounted for 8 (25%) of the 32 erythromycin-susceptible isolates and 4 (5.6%) of the 72 erythromycin-resistant strains (P = 0.007). emm type 4 accounted for 2 (6.2%) of the 32 erythromycin-susceptible isolates and 22 (30.6%) of the 72 erythromycin-resistant strains (P = 0.006). emm type 28 was not observed in any of the erythromycin-susceptible isolates compared to 16 (22.2%) of the 72 erythromycin-resistant strains (P = 0.002).

Telithromycin-resistant isolates.

In 18 of the 22 telithromycin-resistant isolates, one point mutation was detected in the 23S rRNA (Table (Table5).5). Specifically, a T2136C mutation was present in 15 isolates and a T2166C mutation in three. Sixteen (72.7%) of the 22 isolates showed an identical multilocus sequence type (ST 52) and emm type (emm 28), indicating clonal relatedness of most of the isolates. These 16 isolates were recovered in different areas of the prefecture of Etoloakarnania over a 16-month period.

TABLE 5.
Characteristics of the 22 telithromycin-resistant S. pyogenes isolates

Isolate with relatively reduced susceptibility to ciprofloxacin.

The isolate with the relatively reduced susceptibility to ciprofloxacin had the wild type of the GyrA subunit of the DNA gyrase, whereas a mutation was found in the ParC subunit of topoisomerase IV. Specifically, in regions of the ParC, which determine quinolone resistance, a TCC(S)-79-GCC(A) mutation was detected.

DISCUSSION

Prospectively collecting pediatric tonsillopharyngitis isolates, we were able to create a quite large collection of clinical S. pyogenes isolates from Western Greece over a 4-year period, from 1999 to 2002. One-fourth (24%) of the 1,577 Greek isolates were erythromycin resistant. In Athens, Greece, 15.2% of the S. pyogenes isolates recovered between August 1996 and July 1997 and 23.9% of those isolated between October 1997 and September 1998 were erythromycin resistant (19, 23).

In this study, the M phenotype was encountered in 50.9% of the erythromycin-resistant isolates. Throughout the 4-year study period, the predominant subtype of the iMLS phenotype was iMLS-C. In the present collection, only two isolates exhibited the iMLS-A subtype; one isolate harbored the erm(A) and the other one the erm(B) gene. Both of the isolates with the iMLS-A subtype have been found to show constitutive resistance to the 16-membered ring macrolide miocamycin (MIC > 16 μg/ml) (G. A. Syrogiannopoulos, B. Bozdogan, I. N. Grivea, L. Ednie, G. D. Katopodis, D. Kritikou, N. G. Beratis, and P. C. Appelbaum, 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. C2-1984, 2002).

Resistance to tetracycline appears to be common in the erythromycin-resistant S. pyogenes strains (9, 10). Among the Greek S. pyogenes isolates obtained from 1999 to 2002, variable rates of resistance to tetracycline were associated with the carriage of different macrolide resistance determinants. The highest rate (49.7%) of reduced susceptibility to tetracycline was noted among the isolates carrying the erm(A) gene, whereas the lowest (1.5%) was in strains harboring the mef(A) gene. Concomitant resistance to erythromycin and tetracycline has been attributed to the presence in the same transposon of mef(A), erm(A), or erm(B) gene as well as tet(M) or tet(O) gene encoding resistance to tetracycline (5, 9).

Our study showed that the erythromycin-resistant isolates belonged to a limited number of emm types. emm types 4, 12, 75, and 1 accounted for 86.2% of mef(A)-positive erythromycin-resistant S. pyogenes isolates. The same types accounted for 68.2%, 77.1%, and 100% of mef(A)-positive erythromycin-resistant S. pyogenes isolates in Italy, North America, and France, respectively (1, 7, 22). In the present study, emm type 28 was found to be predominant among the erm(B)-positive erythromycin-resistant S. pyogenes isolates. The same type accounted for 50% and 70% of erm(B)-positive erythromycin-resistant S. pyogenes isolates in North America and France, respectively (1, 22).

Our findings indicate that over the last few years in Western Greece, 5.8% of erythromycin-resistant S. pyogenes isolates had exhibited resistance to telithromycin. In addition, it should be noted that 72.7% of the telithromycin-resistant S. pyogenes isolates belonged to a single emm type (emm 28) and multilocus sequence type (ST 52), conferring clonal relatedness of isolates.

Sequencing data of telithromycin-resistant isolates showed unique results. In 18 of the 22 isolates one point mutation was detected in the 23S rRNA. Specifically, in 15 isolates a T2136C mutation was detected and in 3 isolates, a T2166C mutation was detected. The T2136C is a new mutation, whereas the T2166C mutation has been described in telithromycin-resistant S. pyogenes isolates recovered in Germany (16). The relevance between these mutations and the development of macrolide resistance in S. pyogenes needs to be confirmed by further transformation experiments. Most information available today is based on in vitro selection studies showing that certain structures involving domains II and V of 23S rRNA participate in the binding of macrolides (4). In clinical isolates, most of the point mutations were identical to those found in in vitro selection studies, but new mutations were also observed (11, 12, 16). The A2058G and A2058U substitutions confer the highest level of MLS resistance (11, 12).

In summary, 24% of the 1,577 S. pyogenes isolates recovered in Western Greece from 1999 to 2002 were erythromycin resistant. Moreover, 5.8% of the erythromycin-resistant isolates also had resistance to telithromycin. The erythromycin- and telithromycin-resistant isolates showed one of the well-known mutations in the 23S rRNA, but they also exhibited a new mutation in the 23S rRNA. Finally, it should be noted that the Greek S. pyogenes isolates were characterized by the clonal spread of telithromycin resistance.

Acknowledgments

We acknowledge the investigators in Greece who enrolled patients: Garyfalia Chioti, Kalamata; Georgia Danasi-Loukopoulou, Nafpaktos; Panagiotis Fakos, Patras; Ekaterini Ifanti, Egio; Anthi Kakogianni, Patras; Kyriaki Kotsioni, Amaliada; Elias Mamalis, Agrinio; Christos Mitselos, Pyrgos; Constantinos Panagopoulos, Patras; Dimitrios Papalabrou, Patras; Irini Papanagiotou, Agrinio; Eugenia Passa, Preveza; Ioannis Psaras, Egio; and Alexandros Tzortzinis, Gargaliani. We also acknowledge Nelli Neuberger for excellent technical assistance and Denise Chryssanthopoulou for reviewing the manuscript.

This study was supported in part by a grant from the German Ministry of Health (Bundesminister für Gesundheit).

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