ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 2004, p. 1882–1884 0066-4804/04/$08.00⫹0 DOI: 10.1128/AAC.48.5.1882–1884.2004 Copyright © 2004, American Society for Microbiology. All Rights Reserved.
Vol. 48, No. 5
Activities of Telithromycin against 13,874 Streptococcus pneumoniae Isolates Collected between 1999 and 2003 David J. Farrell* and David Felmingham GR Micro Limited, London, United Kingdom Received 15 October 2003/Returned for modification 6 December 2003/Accepted 20 January 2004
Telithromycin MICs for 13,874 Streptococcus pneumoniae isolates collected in the first 3 years of the global PROTEKT study (1999 to 2003) were studied. There was no change in the distribution of telithromycin MICs over this period, even in countries where telithromycin is in use. The telithromycin MICs for 10 isolates (0.07%) were >4 g/ml, and these 10 isolates contained erm(B); there was no evidence of reproducible clonal spread between centers.
(GR Micro Limited, London, United Kingdom). The EU breakpoints for telithromycin follow: susceptibility, ⱕ0.5 g/ ml; intermediate susceptibility, 1 g/ml; and resistance, 2 g/ ml. NCCLS breakpoints of 1 g/ml for susceptible, 2 g/ml for intermediate, and ⱖ4 g/ml for resistant have been approved but not yet published (NCCLS SAST meeting minutes, January 2003). Multilocus sequence typing (MLST), pulsed-field gel electrophoresis, and serotyping were performed as described previously (3). The distribution of telithromycin and erythromycin MICs shows no evidence of drift over the first 3 years of the study (Table 1). If the EU breakpoint is used, 13,766 of 13,874 (99.2%) of isolates were susceptible to telithromycin. If the NCCLS breakpoint is used, 13,853 of 13,874 (99.8%) of isolates were susceptible, with only 10 isolates falling into the resistant category with a MIC of ⱖ4 g/ml. All 10 of the telithromycin-resistant isolates were positive for the erm(B) methylase gene. In total, 2,736 isolates were erm(B) positive and the mode, MIC50 (MIC at which 50% of the isolates tested are inhibited), and MIC90 did not increase over the 3 years (year 1, 0.03, 0.03, and 0.5 g/ml, respectively; year 2, 0.03, 0.03, and 0.25 g/ml, respectively; year 3, 0.015, 0.03, and 0.25 g/ml, respectively). The 99.2% telithromycin susceptibility rate, using the EU breakpoint (ⱕ0.5 g/ml), differs from the 85.0% susceptibility rate presented in the Taiwanese study (8). The Taiwanese study did not present MIC distributions for the various antimicrobial agents tested. This information is critical in assessing possible methodological errors (e.g., drifts in mode MICs compared to previous reports) and important in determining relative resistance in an antimicrobial, such as telithromycin, undergoing breakpoint assessment. Hsueh et al. reported that the telithromycin MICs ranged from 1 to 2 g/ml for 15% of the isolates but did not provide further detail (8). Since the NCCLS breakpoint is 1 g/ml, their reported susceptibility rate of telithromycin could vary from 84 to 99%, depending on the number of isolates for which the telithromycin MICs were 1 g/ml. In a recent study using 291 S. pneumoniae isolates collected from eight centers in Taiwan between 2000 and 2003, 99% were inhibited by ⱕ0.5 g of telithromycin per ml and 100% were inhibited by ⱕ1 g of telithromycin per ml (C. Janus, K. W. Yu, Y. C. Chuang, W. C. Ko, C. M. Lee, M. H.
The ketolide telithromycin has demonstrated high in vitro activity and clinical and bacteriological efficacy against Streptococcus pneumoniae isolates causing community-acquired respiratory tract disease, including macrolide-resistant, penicillin-resistant, and multiresistant strains (1, 6, 7). Telithromycin has also demonstrated high activity against clinical isolates of macrolide-resistant strains of S. pneumoniae with efflux, methylase, combined efflux and methylase, or ribosomal mutations as the mechanisms of resistance (3, 4). Recently, a high prevalence of telithromycin resistance was reported in clinical isolates of S. pneumoniae in Taiwan (8). The telithromycin MICs for 16% of 936 clinical isolates were found to be ⱖ1 g/ml, which is of concern given that telithromycin is not yet available in Taiwan. Telithromycin is marketed in 39 countries worldwide, including the European Union (EU). It has been launched in Germany (October 2001), Italy, Spain and Mexico (January 2002), Brazil (March 2002), and France (August 2002) with ⬎4 million units sold to date (R. Nieman [Aventis], personal communication). The PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) study is an international (112 centers in 33 countries), longitudinal, antibacterial resistance surveillance study, which was initiated in late 1999 to monitor the spread of resistance among bacterial pathogens isolated from community-acquired respiratory tract infections worldwide. The PROTEKT study includes isolates from all of the countries in which telithromycin has been launched. In light of the report from Taiwan and the increasing use of telithromycin, it would be prudent to analyze and present telithromycin activity data from the first 3 complete years of the PROTEKT study. A total of 13,874 isolates were collected from patients with community-acquired respiratory tract infections. The design and methodology of the PROTEKT study have been described previously (5). Briefly, MICs were determined using the National Committee for Clinical Laboratory Standards (NCCLS) broth microdilution method in a central reference laboratory * Corresponding author. Mailing address: Medical and Molecular Microbiology, GR Micro Limited, 7-9 William Rd., London NW1 3ER, United Kingdom. Phone: 44 (0)20 73887320. Fax: 44 (0) 20 73887324. E-mail:
[email protected]. 1882
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TABLE 1. Distribution of telithromycin and erythromycin MICs in 13,874 isolates of S. pneumoniae isolated from the global PROTEKT antimicrobial surveillance studies from 1999 to 2003 No. of isolates (%) 1999–2001 (n ⫽ 3,372)
MIC (g/ml)
0.002 0.004 0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 ⬎64
2000–2002 (n ⫽ 4,256)
2001–2003 (n ⫽ 6,246)
Telithromycin
Erythromycin
Telithromycin
Erythromycin
Telithromycin
Erythromycin
2 (0.06) 14 (0.42) 1,383 (41.01) 1,045 (30.99) 215 (6.38) 256 (7.59) 163 (4.83) 151 (4.48) 119 (3.53) 21 (0.62) 1 (0.03) 1 (0.03) 1 (0.03) 0 0 0 0
0 0 0 0 216 (6.41) 1,993 (59.10) 89 (2.64) 22 (0.65) 7 (0.21) 17 (0.50) 67 (1.99) 147 (4.36) 89 (2.64) 47 (1.39) 13 (0.39) 57 (1.69) 608 (18.03)
2 (0.05) 37 (0.87) 1,620 (38.06) 1,443 (33.91) 327 (7.68) 329 (7.73) 191 (4.49) 185 (4.35) 88 (2.07) 30 (0.70) 2 (0.05) 1 (0.02) 1 (0.02) 0 0 0 0
0 0 0 0 554 (13.02) 2,262 (53.15) 39 (0.92) 4 (0.09) 6 (0.14) 44 (1.03) 148 (3.48) 91 (2.14) 98 (2.30) 53 (1.25) 3 (0.07) 5 (0.12) 949 (22.30)
4 (0.06) 54 (0.86) 2,532 (40.54) 1,806 (28.91) 414 (6.63) 573 (9.17) 315 (5.04) 252 (4.03) 246 (3.94) 36 (0.58) 8 (0.13) 5 (0.08) 1 (0.02) 0 0 0 0
0 0 0 0 525 (8.41) 3,350 (53.63) 83 (1.33) 15 (0.24) 8 (0.13) 43 (0.69) 249 (3.99) 258 (4.13) 133 (2.13) 50 (0.80) 13 (0.21) 4 (0.06) 1,515 (24.26)
Lee, J. J. Lu, J. M. Shih, L. S. Wang, and H. B. Drugeon, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. E-1529, 2003). In the same study, it was demonstrated that the MIC of telithromycin rises when measured in CO2. Again, these results differ from those reported by Hsueh et al. (8), who used agar dilution. This method of testing is not recommended for S. pneumoniae by the NCCLS, because S. pneumoniae often requires CO2 for growth. It has been demonstrated that the agar dilution method increases telithromycin MICs compared to the reference microdilution method even when tested in air (2). Isolates P1501016 and P2501025 had the same serotype, MLST, and genotype and were isolated from the same center in France in year 1 and year 2, respectively, but not in year 3 (Table 2). Isolates P1530023 (isolated in Italy in year 1) and P3502040 (isolated in France in year 3) also appeared to be clonally related; however, no similar isolate was found in year
2. Isolate P3650074 also appeared to be related to these last two isolates (same serotype and MLST) but had a very different pulsed-field gel electrophoresis pattern, suggesting independent mutations rather than clonal spread. Also, the telithromycin MICs for only 2 of the 2,764 S. pneumoniae isolates tested to date in year 4 of the PROTEKT study were found to be ⱖ4 g/ml (both 8 g/ml). Both of the telithromycin-resistant isolates are from different centers than those previously reported. In Germany, where patient exposure to telithromycin has been the greatest and the longest, of the 1,641 isolates collected during 2003 from 11 centers, there were no isolates for which the MIC was ⱖ4 g/ml. The lack of reproducible resistance and shift in MIC distribution are encouraging for the longevity of telithromycin, especially considering that by year 4 many patients in Europe have been exposed to this drug. However, as with any antimicrobial, the development of resistance needs to be carefully
TABLE 2. Epidemiology of S. pneumoniae isolates for which the telithromycin MIC was ⱖ4 g/ml in the first 3 years of the PROTEKT study Serotype
Yr 1 P1501016
23F
81
4
4
2
4
4
1
1
A
4
14
143
7
5
10
18
6
8
1
B
Yr 2 P2501025 P2553008
23F 14
81 Unknown
4 7
4 11
2 10
4 1
4 6
1 8
1 58 (97.3%)
Yr 3 P3533199 P3503022 P3502040 P3084055 P3083069 P3650074
9V 6A 14 6B 23F 14
169 327 143 902n 242 143
7 1 7 2 15 7
11 5 5 13 29 5
10 7 10 2 4 10
1 12 18 1 21 18
6 10 6 6 30 6
8 1 8 121 1 8
14 14 1 121 14 1
P1530023
a
Sequence type
Locus sequence type
Yr and isolate
aroE gdh gki recP spi
PFGE, pulsed-field gel electrophoresis.
xpt
ddL
PFGE Telithromycin typea MIC (g/ml)
Country
Centre
Age (yr)
Sex
Source
France
501
76
Male
8
Italy
530
37
Male
Bronchoalveolar lavage Ear
A C
4 8
France Spain
501 553
72 2
Male Female
Sputum Ear
D E B F G H
4 4 4 4 4 8
Italy France France Japan Japan Hungary
533 503 502 84 83 650
Unknown 83 60 61 2 3
Unknown Male Male Female Male Female
Unknown Blood Blood Sputum Nasopharynx Sinus
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ANTIMICROB. AGENTS CHEMOTHER.
monitored. The PROTEKT study is the first global antimicrobial surveillance study to routinely test for phenotypes, genotypes, and serotypes and hence provides a valuable tool in rapidly assessing the development of resistance. It is imperative to continue the ongoing PROTEKT study to assess the evolution of MIC shifts over time in countries where telithromycin is marketed. We used the Multi Locus Sequence Typing website (http://www.mlst .net) developed by Man-Suen Chan and David Aanensen and funded by the Wellcome Trust. Aventis is acknowledged for their financial support of the PROTEKT study. We are grateful to our colleagues worldwide for supplying bacterial isolates as part of the PROTEKT study and the GR Micro PROTEKT team who performed the MIC, serotype, and genotype determinations.
3.
4.
5. 6.
7.
REFERENCES 1. Bozdogan, B., P. C. Appelbaum, L. M. Kelly, D. B. Hoellman, A. TambicAndrasevic, L. Drukalska, W. Hryniewicz, H. Hupkova, M. R. Jacobs, J. Kolman, M. Konkoly-Thege, J. Miciuleviciene, M. Pana, L. Setchanova, J. Trupl, and P. Urbaskova. 2003. Activity of telithromycin and seven other agents against 1034 pediatric Streptococcus pneumoniae isolates from ten central and eastern European centers. Clin. Microbiol. Infect. 9:653–661. 2. Davies, T. A., L. M. Kelly, M. R. Jacobs, and P. C. Appelbaum. 2000. Anti-
8.
pneumococcal activity of telithromycin by agar dilution, microdilution, E test, and disk diffusion methodologies. J. Clin. Microbiol. 38:1444–1448. Farrell, D. J., S. Douthwaite, I. Morrissey, S. Bakker, J. Poehlsgaard, L. Jakobsen, and D. Felmingham. 2003. Macrolide resistance by ribosomal mutation in clinical isolates of Streptococcus pneumoniae from the PROTEKT 1999–2000 study. Antimicrob. Agents Chemother. 47:1777–1783. Farrell, D. J., I. Morrissey, S. Bakker, and D. Felmingham. 2002. Molecular characterization of macrolide resistance mechanisms among Streptococcus pneumoniae and Streptococcus pyogenes isolated from the PROTEKT 1999– 2000 study. J. Antimicrob. Chemother. 50(Suppl. S1):39–47. Felmingham, D. 2002. The need for antimicrobial resistance surveillance. J. Antimicrob. Chemother. 50:1–7. Felmingham, D., R. R. Reinert, Y. Hirakata, and A. Rodloff. 2002. Increasing prevalence of antimicrobial resistance among isolates of Streptococcus pneumoniae from the PROTEKT surveillance study, and comparative in vitro activity of the ketolide, telithromycin. J. Antimicrob. Chemother. 50(Suppl. S1):25–37. Fogarty, C. M., S. Kohno, P. Buchanan, M. Aubier, and M. Baz. 2003. Community-acquired respiratory tract infections caused by resistant pneumococci: clinical and bacteriological efficacy of the ketolide telithromycin. J. Antimicrob. Chemother. 51:947–955. Hsueh, P.-R., L.-J. Teng, T.-L. Wu, D. Yang, W.-K. Huang, J.-M. Shyr, Y.-C. Chuang, J.-H. Wan, J.-J. Yan, J.-J. Lu, J.-J. Wu, W.-C. Ko, F.-Y. Chang, Y.-C. Yang, Y.-J. Lau, Y.-C. Liu, C.-M. Lee, H.-S. Leu, C.-Y. Liu, and K.-T. Luh. 2003. Telithromycin- and fluoroquinolone-resistant Streptococcus pneumoniae in Taiwan with high prevalence of resistance to macrolides and -lactams: SMART program 2001 data. Antimicrob. Agents Chemother. 47:2145–2151.
