Abstract
Among 1,011 recently isolated Streptococcus pyogenes isolates from 10 Central and Eastern European centers, the MICs at which 50% of isolates are inhibited (MIC50s) and the MIC90s were as follows: for telithromycin, 0.03 and 0.06 μg/ml, respectively; for erythromycin, azithromycin, and clarithromycin, 0.06 to 0.125 and 1 to 8 μg/ml, respectively; and for clindamycin, 0.125 and 0.125 μg/ml, respectively. Erythromycin resistance occurred in 12.3% of strains. Erm(A) [subclass erm(TR)] was most commonly encountered (60.5%), followed by mef(A) (23.4%) and erm(B) (14.5%). At <0.5 μg/ml, telithromycin was active against 98.5% of the strains tested.
Streptococcus pyogenes strains continue to be penicillin susceptible, but erythromycin resistance has increasingly been reported. A recent Canadian study (10) has documented that 2.1% of S. pyogenes strains collected in 1997 were macrolide resistant. Significant rates of erythromycin resistance have been reported in many countries including Finland, Sweden, Spain, France, and Italy (1, 3, 6, 8, 11, 12, 16, 18, 20, 21, 24). In the United States, it has been assumed that the rate of erythromycin resistance is low (14, 15). However, a recent study has reported erythromycin resistance rates of 32% among isolates from specimens from patients with invasive disease and 9% among isolates from cultures of throat swab specimens isolated between 1994 and 1995 in the San Francisco, California, area (25).
For S. pyogenes isolates from most areas tested, macrolide resistance is mediated by the mef(A) gene (23), making the isolates resistant to 14- and 15-membered-ring macrolides but susceptible to 16-membered-ring macrolides and clindamycin. Erm(A) [subclass erm(TR)] has also been described (21); strains containing erm(A) are usually inducibly resistant to 14- and 15-membered-ring macrolides but are susceptible to 16-membered-ring macrolides and lincosamides. The erm(B) gene has also been described, with strains that contain this gene being resistant to macrolides and lincosamide (6, 10, 11, 16).
Telithromycin is a ketolide (9, 13, 19) with low MICs for erythromycin-susceptible and -resistant S. pyogenes strains except those carrying erm(B). To understand macrolide susceptibility in areas where high rates of drug-resistant pneumococcci have been described, Central and Eastern Europe (2), we tested the activities of telithromycin, erythromycin, azithromycin, clarithromycin, and clindamycin against 1,011 isolates of S. pyogenes. Levofloxacin was tested as the representative fluoroquinolone.
Strains were consecutively obtained from clinical isolates recovered during 1999 and 2000 and were screened by the bacitracin disk method. Organisms were frozen at all collection sites except Warsaw (where swabs in Amies transport medium were used) and were transported on dry ice to Hershey Medical Center, where they were stored frozen in double-strength skim milk (Difco Laboratories, Detroit, Mich.) at −70°C until use. The identities of the organisms were confirmed by colonial morphology, bacitracin testing, beta-hemolysis, and, in some cases (e.g., Romanian urine isolates), serogrouping.
MICs were determined by the agar dilution methods used in our laboratory on Mueller-Hinton agar (BBL Microbiology Systems, Cockeysville, Md.) with 5% sheep blood (9, 19); the plates were incubated in air (5). The breakpoints were those approved by the National Committee for Clinical Laboratory Standards for S. pneumoniae (17) for all drugs except telithromycin, for which breakpoints of 0.5 and 2.0 μg/ml were used. Macrolide-resistant strains were tested by PCR for the presence of erm(B), mef(A), and erm(A) genes as described previously (21-23). Clindamycin MICs were not high for some erythromycin-resistant strains that were positive for the erm(B) or the erm(A) gene (4, 7, 23). These and all other erythromycin-resistant strains were screened for the presence of inducible resistance by double-disk diffusion (5).
Patient ages varied between <2 and >60 years, with the age group with the highest rate of infection being children ages 2 to 10 years in all countries except Romania (where most organisms were detected in those ages 11 to 20 years). Among all 1,011 S. pyogenes isolates tested, 826 (81.7%) were isolated from throat swab cultures, 119 (11.8%) were isolated from wounds or pus, and 32 (3.1%) were isolated from blood. In Romania 20 strains were urine isolates. No further information was available for those 20 strains. Isolates were predominantly recovered from throat swab cultures in each country except Lithuania, where S. pyogenes was recovered predominantly from pus and wounds.
Overall, the telithromycin MICs at which 50% of isolates are inhibited (MIC50s) and MIC90s were 0.03 and 0.06 μg/ml, respectively (Table 1). The MIC90s for the other drugs tested were as follows: erythromycin, 2 μg/ml; azithromycin, 8 μg/ml; clarithromycin, 1 μg/ml; and clindamycin, 0.125 μg/ml. Macrolide MIC90s were the highest for isolates from Croatia and the Slovak Republic: ≥4 μg/ml for erythromycin, clarithromycin, and azithromycin. All strains were penicillin G susceptible (MICs, ≤0.03 μg/ml). The levofloxacin MIC90 was 2 μg/ml.
TABLE 1.
MIC50s and MIC90s for the S. pyogenes tested by agar dilution
| Country | MIC50/MIC90 (μg/ml)
|
||||||
|---|---|---|---|---|---|---|---|
| Penicillin G | Telithromycin | Erythromycin | Azithromycin | Clarithromycin | Clindamycin | Levofloxacin | |
| Slovak Republic | 0.016/0.016 | 0.06/0.5 | 0.125/8.0 | 0.25/8.0 | 0.06/8.0 | 0.125/0.25 | 0.5/2.0 |
| Romania | ≤0.008/0.016 | 0.03/0.06 | 0.06/0.125 | 0.125/0.25 | 0.06/0.125 | 0.125/0.125 | 1.0/1.0 |
| Hungary | 0.016/0.016 | 0.06/0.06 | 0.06/0.125 | 0.125/0.25 | 0.06/0.06 | 0.125/0.125 | 1.0/2.0 |
| Lithunania | 0.016/0.016 | 0.03/0.06 | 0.06/0.125 | 0.25/0.25 | 0.06/0.06 | 0.125/0.125 | 1.0/2.0 |
| Slovenia | 0.016/0.016 | 0.03/0.06 | 0.06/2.0 | 0.125/16.0 | 0.06/2.0 | 0.125/0.125 | 0.5/1.0 |
| Czech Republic | 0.016/0.016 | 0.06/0.125 | 0.125/0.125 | 0.125/0.25 | 0.06/0.125 | 0.125/0.125 | 1.0/2.0 |
| Latvia | 0.016/0.016 | 0.03/0.06 | 0.06/0.125 | 0.125/0.5 | 0.06/0.125 | 0.125/0.25 | 0.5/1.0 |
| Bulgaria | 0.016/0.016 | 0.03/0.06 | 0.06/2.0 | 0.25/8.0 | 0.06/1.0 | 0.125/0.25 | 0.5/1.0 |
| Poland | ≤0.008/0.016 | 0.03/0.06 | 0.06/2.0 | 0.125/8.0 | 0.03/1.0 | 0.125/0.125 | 0.5/1.0 |
| Croatia | 0.016/0.016 | 0.03/0.125 | 0.06/8.0 | 0.125/16.0 | 0.06/4.0 | 0.125/0.25 | 1.0/2.0 |
| All strains | 0.016/0.016 | 0.03/0.06 | 0.06/2.0 | 0.125/8.0 | 0.06/1.0 | 0.125/0.125 | 1.0/2.0 |
The overall rates of susceptibility to telithromycin at 0.5 and 2 μg/ml were 98.5 and 98.9%, respectively (Table 2). For the macrolides and azalides, isolates from Hungary had the highest susceptibility rates (94.8%) and isolates from Croatia and Bulgaria had the lowest susceptibility rates (approximately 82%). All S. pyogenes isolates from Slovenia were susceptible to clindamycin, while the lowest susceptibility rate was for isolates from Bulgaria (90.6%). All isolates from Bulgaria, the Czech Republic, Latvia, Poland, and Slovenia were susceptible to levofloxacin. The highest prevalence of levofloxacin-intermediate S. pyogenes was found in Lithuania (10.2%).
TABLE 2.
Rates of susceptibility to S. pyogenes
| Country | % Susceptible
|
|||||
|---|---|---|---|---|---|---|
| Telithro- mycina | Erythro- mycin | Azithro- mycin | Clarithro- mycin | Clinda- mycin | Levo- floxacin | |
| Slovak Republic | 96.0/97.0 | 83.3 | 82.3 | 84.3 | 96.0 | 97.0 |
| Romania | 99.0/99.0 | 90.2 | 90.2 | 90.2 | 99.0 | 99.0 |
| Hungary | 97.9/98.9 | 94.8 | 94.8 | 94.8 | 97.9 | 97.9 |
| Lithunania | 100/100 | 89.8 | 89.8 | 89.8 | 96.9 | 89.8 |
| Slovenia | 100/100 | 87.2 | 86.2 | 87.2 | 100 | 100 |
| Czech Republic | 100/100 | 92.3 | 92.3 | 92.3 | 98.0 | 100 |
| Latvia | 100/100 | 91.0 | 91.0 | 91.0 | 98.0 | 100 |
| Bulgaria | 100/100 | 82.2 | 82.2 | 82.2 | 90.6 | 100 |
| Poland | 95.9/95.9 | 83.6 | 83.6 | 83.6 | 93.8 | 100 |
| Croatia | 95.9/97.9 | 81.8 | 81.8 | 82.8 | 95.9 | 94.9 |
| All strains | 98.5/98.9 | 87.7 | 87.5 | 87.8 | 97.3 | 98.0 |
For telithromycin, values are for breakpoints for telithromycin susceptibility at ≤0.5/≤2.0 μg/ml.
The incidence of macrolide-resistant strains and the mechanisms of resistance are shown in Table 3. The prevalence of macrolide-resistant S. pyogenes was <10% in the Czech Republic (7.7%), Hungary (5.2%), Latvia (9.0%), and Romania (9.7%). One hundred twenty-four strains (12.3%) were macrolide resistant, and erm(A) was found in 75 (60.5%) strains. Twenty-nine strains (23.4%) had mef(A); the largest number of mef(A) strains was found in the Slovak Republic, with 9 of 17 (52.9%) macrolide-resistant strains having mef(A), while no strains with mef(A) were found in the Czech Republic, Latvia, Lithuania, Poland, or Slovenia. Eighteen resistant strains (14.5%) had erm(B) and were found in Croatia, Hungary, Poland, Romania, and the Slovak Republic. The largest number of isolates with erm(B) was found in Croatia, with 6 of 18 (33.3%) macrolide-resistant strains having erm(B).
TABLE 3.
Incidence of macrolide resistance and mechanisms of resistance for isolates from 10 centers
| Country | No. (%) of macrolide-resistant S. pyogenes strains | No. of strains with the following gene:
|
|||
|---|---|---|---|---|---|
| Erm(B) | Erm(A) | Mef(A) | Other | ||
| Slovak Republic | 17 (16.7) | 4 | 3 | 9 | 1 |
| Romania | 10 (9.7) | 1 | 1 | 8 | 0 |
| Hungary | 5 (5.2) | 2 | 2 | 1 | 0 |
| Lithunania | 10 (10.1) | 0 | 10 | 0 | 0 |
| Slovenia | 13 (12.7) | 0 | 13 | 0 | 0 |
| Czech Republic | 8 (7.7) | 0 | 8 | 0 | 0 |
| Latvia | 9 (9.0) | 0 | 9 | 0 | 0 |
| Bulgaria | 18 (16.8) | 0 | 12 | 6 | 0 |
| Poland | 16 (16.3) | 5 | 11 | 0 | 0 |
| Croatia | 18 (18.2) | 6 | 6 | 5 | 1 |
| Total | 124 (12.3) | 18 | 75 | 29 | 2 |
The correlation between the MIC distribution and the mechanism of resistance in S. pyogenes is shown in Table 4. The MIC50 and the MIC90 of telithromycin for erm(A) strains were 0.06 and 0.06 μg/ml, respectively. Most erm(B) strains (11) had constitutive resistance, and the MIC90s of all macrolides were >64 μg/ml for these strains; six strains from Croatia with erm(B) genes had inducible resistance, with azithromycin, clarithromycin, and erythromycin MIC50s of >64 μg/ml, while the clindamycin MIC50 was 0.25 μg/ml and the telithromycin MIC50 was 2 μg/ml. The MIC90 of telithromycin for strains with mef(A) was 0.5 μg/ml. For two strains from Croatia and the Slovak Republic, the erythromycin MICs were lower (0.125 and 0.5 μg/ml, respectively), but the azithromycin MICs were high (2 and 8 μg/ml, respectively) and the strains had no discernible macrolide resistance mechanisms.
TABLE 4.
MIC distribution by mechanism of resistance in S. pyogenes
| Drug resistance genea | MIC (μg/ml)
|
||
|---|---|---|---|
| Range | 50% | 90% | |
| Telithromycin | |||
| erm(B)C (n =12) | 0.125->64 | 16 | >64 |
| erm(B)I (n = 6) | 0.125-4 | 2 | |
| erm(A)C (n = 3) | 0.03-0.125 | 0.06 | |
| erm(A)I (n = 72) | 0.004-0.125 | 0.06 | 0.06 |
| mef(A) (n = 29) | 0.25-0.5 | 0.5 | 0.5 |
| Others (n = 2) | 0.125 | 0.125 | |
| Total (n = 124) | 0.004->64 | 0.06 | 16 |
| Azithromycin | |||
| erm(B)C (n = 12) | >64 | >64 | >64 |
| erm(B)I (n = 6) | >64 | >64 | |
| erm(A)C (n = 3) | 4->64 | >64 | |
| erm(A)I (n = 72) | 4->64 | 16 | 64 |
| mef(A) (n = 29) | 4-16 | 8 | 8 |
| Others (n = 2) | 2-8 | 8 | |
| Total (n = 124) | 2->64 | 16 | >64 |
| Erythromycin | |||
| erm(B)C (n = 12) | 64->64 | >64 | >64 |
| erm(B)I (n = 6) | >64 | >64 | |
| erm(A)C (n = 3) | 2->64 | 64 | |
| erm(A)I (n = 72) | 1->64 | 4 | 8 |
| mef(A) (n = 29) | 4-16 | 8 | 16 |
| Others (n = 2) | 0.125-0.5 | 0.5 | |
| Total (n = 124) | 0.125->64 | 4 | >64 |
| Clarithromycin | |||
| erm(B)C (n = 12) | 16->64 | >64 | >64 |
| erm(B)I (n = 6) | >64 | >64 | |
| erm(A)C (n = 3) | 0.5-32 | 16 | |
| erm(A)I (n = 72) | 1->64 | 2 | 4 |
| mef(A) (n = 29) | 2-8 | 4 | 8 |
| Others (n = 2) | 0.125-0.25 | 0.25 | |
| Total (n = 124) | 0.125->64 | 2 | >64 |
| Clindamycin | |||
| erm(B)C (n = 12) | 8->64 | >64 | >64 |
| erm(B)I (n = 6) | 0.125-0.25 | 0.25 | |
| erm(A)C (n = 3) | 2->64 | >64 | |
| erm(A)I (n = 72) | 0.06-1 | 0.25 | 0.5 |
| mef(A) (n = 29) | 0.06-0.25 | 0.125 | 0.125 |
| Others (n = 2) | 0.06-2 | 2 | |
| Total (n = 124) | 0.06->64 | 0.125 | >64 |
I, inducible; C, constitutive.
Taking into consideration the heterogeneity of sample origins, the prevalence of macrolide-resistant S. pyogenes strains was 12.3%, varying from 5.2 to 18.2%. Most erythromycin-resistant S. pyogenes strains had erm(A) and most had inducible resistance. These strains were cross resistant to azithromycin, erythromycin, and clarithromycin. All strains with mef(A) were clindamycin susceptible (6, 10, 16). No strain had more than one macrolide resistance mechanism. Two strains from Croatia and the Slovak Republic (Tables 3 and 4), for which azithromycin MICs were higher (2 to 8 μg/ml) but for which erythromycin MICs were lower (0.125 to 0.5 μg/ml), did not have the erm(A), erm(B), or mef(E) gene (23); we are working to determine their mechanisms of resistance. Telithromycin MICs were lower (0.004 to 0.5 μg/ml) than those of macrolides and azalides (0.5 to >64 μg/ml) for S. pyogenes strains with erm(A) or mef(A); however, the telithromycin MIC50 and MIC90 were higher (16 and >64 μg/ml, respectively) for erm(B) strains (5).
In summary, telithromycin had excellent in vitro activity against S. pyogenes isolates with the exception of isolates with erm(B). However, the presence of erm(B) is not a common mechanism of resistance in S. pyogenes strains from most countries. The prevalence of erythromycin resistance in Croatia, Poland, and the Slovak Republic was higher than that in other countries. Our findings point to the potential use of telithromycin in the treatment of S. pyogenes infections.
Acknowledgments
This study was supported by a grant from Aventis, Romainville, France.
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