Abstract
One hundred and seven clinical isolates of Streptococcus pyogenes, 80 susceptible to macrolides and 27 resistant to erythromycin A (MIC >0.5 μg/ml), were examined. The erythromycin A-lincomycin double-disk test assigned 7 resistant strains to the M-phenotype, 8 to the inducible macrolide, lincosamide, and streptogramin B resistance (iMLSB) phenotype, and 12 to the constitutive MLSB resistance (cMLSB) phenotype. MICs of erythromycin A, clarithromycin, azithromycin, roxithromycin, and clindamycin were determined by a broth microdilution method. MICs of telithromycin were determined by three different methods (broth microdilution, agar dilution, and E-test methods) in an ambient air atmosphere and in a 5 to 6% CO2 atmosphere. Erythromycin A resistance genes were investigated by PCR in the 27 erythromycin A-resistant isolates. MICs of erythromycin A and clindamycin showed six groups of resistant strains, groups A to F. iMLSB strains (A, B, and D groups) are characterized by two distinct patterns of resistance correlated with genotypic results. A- and B-group strains were moderately resistant to 14- and 15-membered ring macrolides and highly susceptible to telithromycin. All A- and B-group isolates harbored erm TR gene, D-group strains, highly resistant to macrolides and intermediately resistant to telithromycin (MICs, 1 to 16 μg/ml), were all characterized by having the ermB gene. All M-phenotype isolates (C group), resistant to 14- and 15-membered ring macrolides and susceptible to clindamycin and telithromycin, harbored the mefA gene. All cMLSB strains (E and F groups) with high level of resistance to macrolides, lincosamide, and telithromycin had the ermB gene. The effect of 5 to 6% CO2 was remarkable on resistant strains, by increasing MICs of telithromycin from 1 to 6 twofold dilutions against D-E- and F-group isolates.
Target site modification was the major mechanism of streptococcal resistance to erythromycin A until the 1990s. N-6 dimethylation of specific adenine residues in 23S rRNA confers cross-resistance to macrolides, lincosamides, and streptogramin B (the so-called MLSB phenotype) (8, 18). MLSB resistance can be expressed constitutively (cMLSB phenotype) or inducibly (iMLSB phenotype) (6, 8, 19). In staphylococci, 14- and 15-membered ring macrolides are inducers, whereas 16-membered ring macrolides and lincosamides are not (8). Conversely, streptococci show cross-resistance to MLSB antibiotics.
For streptococci, MLSB resistance is commonly mediated by two classes of methylase genes: the ermB gene and the recently described ermTR gene (8, 13). The erm determinants of streptococci are usually located on the chromosome. In the early 1990s, a new resistance pattern (called the M phenotype) was described in Streptococcus pyogenes and Streptococcus pneumoniae (9, 14, 15). Strains harboring this phenotype were resistant only to 14- and 15-membered ring macrolides. This new resistance pattern is mediated by an efflux system encoded by a novel gene, mefA (2), which encodes a membrane protein responsible for this efflux resistance pattern.
Ketolides, a new class of erythromycin A semisynthetic derivatives, have recently been introduced. This class is derived from erythromycin A with a 3-keto function instead of the l-cladinose moiety (1, 4). One of the ketolides, telithromycin, is active against most gram-positive bacteria.
The present study evaluated the activity of telithromycin in comparison with macrolides against erythromycin A-susceptible and -resistant strains of S. pyogenes. The influence of methodological factors, e.g., CO2, broth, and agar methods, as well as the E-test was evaluated. Erythromycin A resistance genes (ermB, ermTR, and mefA) were investigated by PCR and compared with patterns of susceptibility to MLSB antibiotics in S. pyogenes.
MATERIALS AND METHODS
Bacterial strains.
The activity of telithromycin was tested against 107 clinical isolates of S. pyogenes, 80 strains susceptible and 27 strains resistant (MIC, >0.5 μg/ml) to erythromycin A. Ninety-seven strains were isolated in various hospitals in France, and 10 erythromycin A-resistant strains were from Italy.
Antibiotics.
The antibiotics used were erythromycin A, clarithromycin, azithromycin, roxithromycin, and telithromycin (Hoechst Marion Roussel, Romainville, France) and clindamycin (Sigma Chemical Co., St. Louis, Mo.).
Classification of resistance.
Erythromycin A resistance was classified on the basis of a double-disk test with erythromycin A (30 μg) and lincomycin (15 μg) disks (Sanofi-Diagnostics Pasteur, Marne-la-Coquette, France). The disks were placed 20 mm apart on Mueller-Hinton agar (BioMérieux, La Balme-les-Grottes, France) supplemented with 5% whole horse blood. The susceptibility test was determined by the agar diffusion method, with an inoculum size of 107 CFU/ml according to the recommendations of the Comité de l'antibiogramme de la Société Française de Microbiologie (3). After 18 h of incubation at 37°C in 5 to 6% CO2, blunting of the lincomycin inhibition zone proximal to the erythromycin A disk indicated inducible resistance (iMLSB). Absence of a significant inhibition zone around the two disks was regarded as constitutive resistance (cMLSB). Susceptibility to lincomycin with no blunting of the inhibition zone around the lincomycin disk indicated the M phenotype.
MIC determination.
The MICs of all antibiotics tested were determined by a broth microdilution method, whereas those of telithromycin were ascertained by three different methods (broth microdilution, agar dilution, and E-test methods).
(i) Broth microdilution method.
The MICs were determined with Mueller-Hinton broth (BioMérieux) supplemented with 3% lysed horse blood as test medium. The antibiotics were tested at final concentrations (prepared from twofold dilutions) ranging from 0.0019 to 32 μg/ml. The inoculum size was 106 CFU/ml. The plates were incubated for 18 h at 37°C in ambient air. The MICs of telithromycin were determined in ambient air and in a 5 to 6% CO2 atmosphere. After overnight culture, the lowest concentration of the drug in which bacterial growth was not observed was regarded as the MIC.
(ii) Agar dilution method.
The MICs of telithromycin were determined with Mueller-Hinton agar (BioMérieux) supplemented with 5% whole sheep blood as test medium. A series of twofold agar dilutions (0.0019 to 32 μg/ml) of each antibacterial was prepared, and the bacterial suspension (6 × 106 CFU/ml) was inoculated using a microinoculator (2 × 104 CFU/spot). One series of plates was incubated in ambient air, and another was incubated in a 5 to 6% CO2 atmosphere. The MICs were determined after overnight culture at 37°C.
(iii) E-test MICs.
Testing was performed using Mueller-Hinton agar with 5% whole sheep blood (BioMérieux) inoculated with bacteria grown overnight and diluted to a 0.5 McFarland suspension in Mueller-Hinton broth. E-tests for telithromycin were applied to agar plates, as recommended by the manufacturer. Plates were incubated for 18 h in a 5 to 6% CO2 atmosphere and in ambient air. E-test MICs were read as the intersection of the ellipse of growth inhibition with the strip.
Detection of erythromycin A resistance genes.
S. pyogenes DNA was extracted by a cell lysis method using lysozyme and mutanolysin (12, 13). The DNA was dissolved in 50 μl of TE buffer (10 mM Tris-HCl [pH 8.3], 1 mM EDTA), and 5 μl of the solution was used as a template in PCRs.
ermB and mefA genes were detected by PCR using the oligonucleotides primer pairs reported by Sutcliffe et al. (16), which gave the expected PCR products of 639 and 345 bp, respectively (16). For detection of the ermTR gene, primers TR1 and TR2 (5′-ATAACCGGCAAGGAGAAGGT-3′ and 5′-GTGAAAATATGCTCGTGGCAC-3′, respectively), designed on the basis of the ermTR sequence (GenBank accession number AF002716), provided specific PCR products of 540 bp. The PCR mixture was prepared with a magnesium concentration of 3 mM for the ermB and ermTR primer sets and 3.5 mM for the mefA primer set. Amplification and electrophoresis of PCR products were performed following described procedures (16).
RESULTS
Strains susceptible to erythromycin A.
The MICs of three 14-membered ring macrolides (erythromycin A, clarithromycin, and roxithromycin) and one 15-membered ring macrolide (azithromycin) were compared as well as those of clindamycin. The MIC modes and ranges are indicated in Table 1. MIC distribution was homogeneous (MIC range, 0.003 to 0.25 μg/ml). The MIC mode is 0.03 μg/ml for erythromycin A, clarithromycin, and clindamycin; 0.06 μg/ml for roxithromycin; and 0.125 μg/ml for azithromycin.
TABLE 1.
Modes and ranges of MICs for susceptible S. pyogenes strains
| Antibiotic and method | Atmosphere | MIC (μg/ml)
|
|
|---|---|---|---|
| Mode | Range | ||
| Erythromycin A | 0.03 | 0.003–0.25 | |
| Azithromycin | 0.125 | 0.015–0.25 | |
| Clarithromycin | 0.03 | 0.007–0.0125 | |
| Roxithromycin | 0.06 | 0.015–0.25 | |
| Clindamycin | 0.03 | 0.015–0.125 | |
| Telithromycin | |||
| Dilution (broth) | Ambient air | 0.015 | 0.003–0.06 |
| 5–6% CO2 | 0.03 | 0.015–0.125 | |
| Dilution (agar) | Ambient air | 0.015 | 0.003–0.06 |
| 5–6% CO2 | 0.03 | 0.015–0.125 | |
| E-test | Ambient air | 0.023 | 0.008–0.064 |
| 5–6% CO2 | 0.047 | 0.032–0.19 | |
Strains resistant to erythromycin A.
The 27 strains resistant to erythromycin A were classified on the basis of the erythromycin A-lincomycin double-disk test. Eight strains were assigned to the iMLSB phenotype, and seven strains were assigned to the M phenotype. Twelve strains without a susceptibility zone around the erythromycin A and lincomycin disks were considered as having a cMLSB phenotype (Table 2). The MICs of erythromycin A and clindamycin determined six groups of resistant strains (groups A to F) (Table 2).
TABLE 2.
MIC ranges of macrolides for resistant S. pyogenes strainsa
| Antibiotic | MIC (μg/ml) or MIC range for group:
|
|||||
|---|---|---|---|---|---|---|
| A (2 strains) | B (1 strain) | C (7 strains) | D (5 strains) | Eb (5 strains) | Fb (7 strains) | |
| Erythromycin A | 1–2 | 2 | 4–8 | >32 | >32 | >32 |
| Azithromycin | 4 | 8 | 4–16 | >32 | >32 | >32 |
| Clarithromycin | 0.25–0.5 | 0.5 | 4–8 | >32 | >32 | >32 |
| Roxithromycin | 2–4 | 4 | 8–32 | >32 | >32 | >32 |
| Clindamycin | 0.03–0.06 | >32 | 0.0–0.12 | 0.12–0.25 | >32 | >32 |
Resistance phenotypes for strains in groups A to F were iMLSB, iMLSB, M, cMLSB, cMLSB, and cMLSB, respectively; resistance genes for strains in these groups were ermTR, ermTR, mefA, ermB, ermB, and ermB, respectively.
E and F groups were separated on the basis of susceptibility to telithromycin.
The eight isolates of the iMLSB phenotype were classified in the A, B, and D groups. The A group comprised two strains isolated in France. They were characterized by low-level resistance to 14- and 15-membered ring macrolides (MIC range, 0.25 to 4 μg/ml) and susceptibility to clindamycin (MIC range, 0.03 to 0.06 μg/ml). The B group was limited to one French strain. The strain differed from the A group strains by a high-level resistance to clindamycin (MIC, >32 μg/ml). The D group consisted of five inductible strains, all isolated in Italy. Homogeneous susceptibility patterns were observed, showing high-level of resistance to 14- and 15-membered ring macrolides (MIC, >32 μg/ml) and susceptibility to clindamycin (MIC range, 0.125 to 0.25 μg/ml).
The seven isolates of the M phenotype belonged to the C group (Table 2). Two were isolated in France and five were isolated in Italy. All seven strains were resistant to the 14- and 15-membered ring macrolides (MIC range, 4 to 32 μg/ml) and susceptible to clindamycin (MIC range, 0.03 to 0.12 μg/ml).
The 12 strains assigned to the cMLSB, phenotype were divided into two groups, E and F, depending on their susceptibilities to telithromycin. All 12 isolates were highly resistant to 14- and 15-membered ring macrolides (MICs, >32 μg/ml) and clindamycin.
Activity of telithromycin against S. pyogenes.
For strains susceptible to erythromycin A, MIC distribution was homogeneous (MIC mode, 0.015 μg/ml). The MICs of telithromycin were only 1 twofold dilution higher by the E-test method than the dilution method (MIC modes 0.023 μg/ml and 0.015 μg/ml respectively). The MICs of telithromycin increased by 1 twofold dilution for plates incubated in 5 to 6% CO2 (Table 1).
For strains resistant to erythromycin A, the MICs of telithromycin were scattered, ranging from <0.015 to >32 μg/ml (Table 3). As in the case of susceptible strains, the MICs were ≤0.12 μg/ml for A- and B-group strains. There was a twofold increase in MIC after incubation in 5 to 6% CO2. The MICs for C-group isolates (MIC range, 0.25 to 2 μg/ml) showed no increase for the broth dilution method and a twofold increase for the agar dilution and the E-test methods, after incubation in 5 to 6% CO2. The five strains assigned to the D group were more resistant to telithromycin. The MICs increased two- to fourfold after incubation in 5 to 6% CO2 (MIC range without CO2, 1 to 4 μg/ml; MICs with 5 to 6% CO2, 16 μg/ml). Heterogeneous resistance was observed by the E-test method. E-group strains were more highly resistant after incubation in 5 to 6% CO2 than without CO2 (MIC range, 16 to >32 μg/ml versus 0.25 to 12 μg/ml, respectively). For isolates of the F group, high-level resistance to telithromycin was recorded irrespective of 5 to 6% CO2 atmosphere (MIC range, 4 to >32 μg/ml).
TABLE 3.
MIC ranges of telithromycin for resistant S. pyogenes strainsa
| Method | Atmosphere | MIC (μg/ml) or MIC range of telithromycin for group:
|
|||||
|---|---|---|---|---|---|---|---|
| A (2 strains) | B (1 strain) | C (7 strains) | D (5 strains) | E (5 strains) | F (7 strains) | ||
| Broth dilution | Aerobic | 0.015 | 0.03 | 0.5–1 | 1–2 | 2–4 | 4–16 |
| CO2 | 0.03 | 0.06 | 0.25–1 | 16 | 16–32 | 16 –>32 | |
| Agar dilution | Aerobic | 0.007–0.01 | 0.03 | 0.25–1 | 4 | 0.25 | 16 |
| CO2 | 0.007–0.03 | 0.125 | 1–2 | 16 | 16–32 | 32 –>32 | |
| E-test | Aerobic | 0.023 | 0.06 | 0.38–1.57 | 64 | 2–12 | >32 |
| CO2 | 0.06–0.09 | 0.12 | 1–2 | 64 | >32 | >32 | |
Resistance phenotypes and resistance genes for groups A to F are listed in footnote a of Table 2.
Erythromycin A resistance genes.
The presence of the erythromycin A resistance genes was investigated by PCR in the 27 resistant strains (Tables 2 and 3). All M-phenotype strains (C group) had the mefA gene, and all cMLSB phenotype isolates had the ermB gene, whereas iMLSB strains had either the ermB or the ermTR gene (the ermTR gene in A- and B-group isolates and the ermB gene in D-group strains). The mefA gene was not found in isolates of iMLSB and cMLSB phenotypes.
DISCUSSION
Methylation of ribosomal target and active efflux of erythromycin A are the two most important factors involved in the resistance of streptococci to macrolides. In fact, clarithromycin, azithromycin, and roxithromycin are incapable of overcoming MLSB resistance. HMR 3004, a ketolide, demonstrated good in vitro activity against Streptococcus sp. and S. pneumoniae isolates, even those resistant to erythromycin A by efflux or MLSB mechanisms (4), which is consistent with its noninduction of resistance to MLSB (1).
Our findings show homogeneous susceptibility patterns for S. pyogenes isolates and indicate that telithromycin is more active than erythromycin A, clarithromycin, azithromycin, and roxithromycin (one twofold dilution) against 80 erythromycin A-susceptible strains. Comparable results have been reported for telithromycin against beta-hemolytic streptococci in a recent study (20).
However, different susceptibility patterns were observed in the erythromycin A-resistant isolates. iMLSB strains (A, B, and D groups) were characterized by two distinct resistance patterns. Strains from the A and B groups showed low-level resistance to 14- and 15-membered ring macrolides and susceptibility to telithromycin. These isolates were more susceptible to telithromycin than to clarithromycin. D-group strains showed high-level resistance to 14- and 15-membered ring macrolides and susceptibility to low-level resistance to telithromycin. iMLSB strains possessed ermB or ermTR genes, but in the panel of strains tested these two methylase determinants were not found together. The mefA gene was not found in iMLSB strains, contrary to observations in a recent Finnish study (7). Giovanetti et al. described two determinants in some iMLSB S. pyogenes strains, i.e., mefA and ermB or mefA and ermTR genes (5). Our results showed that there is a correlation between genotypic profile and phenotype susceptibility patterns: iMLSB strains with low-level resistance to 14- and 15-membered ring macrolides and susceptibility to telithromycin possessed the ermTR gene, and those highly resistant to macrolides and intermediate or resistant to telithromycin all had the ermB gene. The same arrangement was observed among Italian iMLSB S. pyogenes isolates tested against HMR 3004 (5). In our study, 10 of the 15 iMLS strains came from Italy. However, Kataja et al. (7) found that iMLSB isolates of S. pyogenes all possessed the ermTR gene but not the ermB gene (7). Finnish strains were characterized by low-level resistance to 14- and 15-membered ring macrolides and could be inserted in our A and B groups.
An iMLSB strain from the B group was resistant to both 14- and 15-membered ring macrolides and clindamycin and remained highly susceptible to telithromycin. In a recent study, Rosato et al. (10) described Streptococcus and Enterococcus strains highly resistant to erythromycin A and lincomycin, due to inducible expression of MLSB resistance. The isolates included S. pneumoniae, Streptococcus agalactiae, Enterococcus faecalis, and E. faecium. In the study of Giovanetti et al. (5), all iMLSB S. pyogenes isolates were susceptible to clindamycin without induction (5). Our findings indicate that at least one S. pyogenes-inducible strain (group B, ermTR) was also highly resistant to lincosamides, although the mecanisms involved were not elucidated. Mutations have been described in the regulatory region located upstream of the ermB gene (11). The regulatory region of the ermTR (present in the B-group strain) has not yet been investigated. Mutational sequences in II or V 23S rRNA domains could contribute to erythromycin A resistance but have not been searched for in S. pyogenes isolates (17).
M-type strains (C group) remained susceptible to telithromycin, and all had the mefA gene. A recent study reported that telithromycin is also active against Streptococcus mitis and Streptococcus oralis harboring an efflux mechanism of resistance to erythromycin A (T. Ono, F. Aikawa, Y. Murakami, and Y. Miyake, Abstr. 39th Intersci. Conf. Antimicrob. Agents Chemother. (abstr. 1245, p. 258, 1999). cMLSB strains (E and F groups) showed high-level resistance to 14- and 15-membered ring macrolides and telithromycin (MIC range, 0.25 to >32 μg/ml), and all possessed the ermB gene. The MICs of telithromycin for S. pneumoniae strains resistant to erythromycin A and clindamycin were lower (20).
The MICs of telithromycin were in the same range, irrespective of the method used. D-group strains showed heterogeneous resistance, with MICs up to 64 μg/ml by the E-test method.
The role of 5 to 6% CO2 differed between the groups of susceptibility patterns. The MICs of telithromycin for strains susceptible or intermediate to erythromycin A (A and B groups) were unchanged when 5 to 6% CO2 was added to the atmosphere. The influence of 5 to 6% CO2 atmosphere was dramatic for erythromycin A-resistant strains. The MICs of telithromycin increased from 1 to 6 twofold dilutions against D-E- and F-group isolates possessing the ermB gene. An increase in methylase production in the presence of CO2 could be one explanation, although this possibility was not experimentally evaluated. Growth limitation may also account for the low MIC range for S. pyogenes strains in ambient air.
It may be concluded that telithromycin is active against susceptible and moderately erythromycin A-resistant S. pyogenes strains and that this activity is conserved against strains resistant by efflux. Telithromycin does not overcome the macrolide resistance of highly resistant strains.
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