ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Sept. 2002, p. 3106–3107 0066-4804/02/$04.00⫹0 DOI: 10.1128/AAC.46.9.3106–3107.2002 Copyright © 2002, American Society for Microbiology. All Rights Reserved.
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Relationship between Antibiotic Resistance in Streptococcus pneumoniae and That in Haemophilus influenzae: Evidence for Common Selective Pressure ity testing by NCCLS broth microdilution using NCCLS 1999 interpretive criteria (10). Relationships between the proportion of resistant isolates in each country to individual antimicrobial agents were tested by measuring the correlation coefficient (r) using a t test analysis. Antimicrobial susceptibility of S. pneumoniae and H. influenzae to all agents tested is shown (Fig. 1). Among S. pneumoniae organisms, considerable variations in resistance to -lactams, macrolides, and SXT were detected between countries, especially in Eastern regions of the world. Levofloxacin resistance by S. pneumoniae was rare in most countries (except China, 3.3%, and Hong Kong, 8.0%) and undetected in H. influenzae. Ampicillin and SXT resistance among H. influenzae varied considerably by country, with high rates of resistance detected in the same regions as those with higher resistance rates among pneumococci (Fig. 1). An interspecies comparison of the proportion of penicillinresistant S. pneumoniae and ampicillin-resistant H. influenzae by country demonstrated a highly significant relationship (r ⫽
We report data from a recent international surveillance study noting significant interspecies relationships between resistance in Streptococcus pneumoniae and Haemophilus influenzae, both common causative agents of respiratory tract infections (3). Previous studies have shown geographic variation in the prevalence of -lactam and trimethoprim-sulfamethoxazole (SXT) resistance among S. pneumoniae and H. influenzae (6, 7, 13–16), which may be attributed to differences in antibiotic consumption and infection control practices between countries (2). Interspecies relationships of resistance prevalence are not commonly reported. During 1999 to 2000, 5,015 S. pneumoniae and 4,846 H. influenzae isolates were prospectively collected from hospital laboratories in China (three sites), Hong Kong (two sites), South Korea (four sites), Thailand (four sites), France (nine sites), Germany (eight sites), Ireland (one site), Italy (six sites), Spain (six sites), the United Kingdom (seven sites), South Africa (eight sites), Brazil (six sites), and Mexico (five sites). Isolates were submitted to Focus Technologies (Herndon, Va.) for antimicrobial susceptibil-
FIG. 1. Incidence of resistance to different antimicrobials tested against S. pneumoniae and H. influenzae isolates by country, utilizing NCCLS (10) interpretative criteria. In order by country, the numbers of S. pneumoniae and H. influenzae isolates and the percentage that was H. influenzae -lactamase positive were as follows: Brazil (448, 274/10.6%), China (214, 198/10.6%), France (547, 454/5.6%), Germany (560, 639/6.9%), Hong Kong (175, 178/27.5%), Ireland (17, 37/10.8%), Italy (491, 521/10.6%), Mexico (271, 226/17.7%), South Africa (701, 627/7.3%), South Korea (351, 272/60.7%), Spain (492, 559/20.9%), Thailand (206, 305/45.5%), and the United Kingdom (542, 556/11.3%). 3106
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LETTERS TO THE EDITOR
0.928; P ⬍ 0.001). A significant interspecific relationship (r ⫽ 0.714; P ⬍ 0.01) was also recorded for SXT resistance. No significant interspecific relationships (P ⬎ 0.05) were found for resistance to amoxicillin-clavulanate, cefuroxime, clarithromycin, or levofloxacin. The interspecific relationship observed for -lactam and SXT resistance has not been reported previously. -Lactam resistance in S. pneumoniae and H. influenzae is conferred by unrelated mechanisms; respectively, penicillin-binding protein alterations and expression of TEM-1 or ROB-1 -lactamases (4, 8, 9). S. pneumoniae resistance to SXT is chromosome encoded by mutations in folA (11) and sulA (1). In H. influenzae, mutations in the chromosome-encoded folH have been shown to encode trimethoprim resistance (5, 12), while sulfamethoxazole resistance is likely chromosome encoded through a sulA analogue. As such the relationship between resistance in these species suggests a response to a common selective pressure with increases in resistance likely driven independently of each other, either by acquisition of a resistance mechanism or through clonal expansion of resistant isolates, a phenomenon well documented in S. pneumoniae but not in H. influenzae. No interspecies correlation between the incidences of clarithromycin, cefuroxime, or levofloxacin resistance was observed. These observations are presumably despite exposure to the same antibiotic selective pressure. The relationship between resistance in these species provides evidence that antibiotic usage drives resistance and suggests that attempts to control the emergence of resistance in S. pneumoniae through prudent antibiotic consumption or improved infection control may impact on resistance prevalence in H. influenzae and perhaps other species. Surveillance of antibiotic consumption and infection control practices is necessary to further explore this phenomenon. (This work was previously presented in part at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada [A. M. Staples, C. Thornsberry, I. A. Critchley, K. S. Murfitt, D. F. Sahm, and M. E. Jones, Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. C-1221, 2000].) This work was supported by Daiichi Pharmaceuticals Co. Ltd. (Tokyo, Japan). We extend our gratitude to all hospital laboratory participants around the world, without whose cooperation such studies would not be possible. REFERENCES 1. Adrian, P. V., and K. P. Klugman. 1997. Mutations in the dihydrofolate reductase gene of trimethoprim-resistant isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 41:2406–2413. 2. Austin, D. J., K. G. Kristinsson, and R. M. Anderson. 1999. The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance. Proc. Natl. Acad. Sci. USA 96:1152–1156. 3. Bartlett, J. G., and L. M. Mundy. 1995. Community-acquired pneumonia. N. Engl. J. Med. 333:1619–1624.
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4. Daum, R. S., M. Murphey-Corb, E. Shapira, and S. Dipp. 1988. Epidemiology of rob -lactamase among ampicillin-resistant Haemophilus influenzae isolates in the United States. J. Infect. Dis. 157:450–455. 5. de Groot, R., M. Sluijter, A. de Bruyn, J. Campos, W. H. Goessens, A. Smith, and P. W. Hermans. 1996. Genetic characterization of trimethoprim resistance in Haemophilus influenzae. Antimicrob. Agents Chemother. 40:2131– 2136. 6. Felmingham, D., R. N. Gru ¨neberg, and the Alexander Project Group. 2000. The Alexander Project 1996–1997: latest susceptibility data from this international study of bacterial pathogens from community-acquired lower respiratory tract infections. J. Antimicrob. Chemother. 45:191–203. 7. Jones, M. E., A. M. Staples, I. Critchley, C. Thornsberry, P. Heinze, H. D. Engler, and D. F. Sahm. 2000. Benchmarking the in vitro activity of moxifloxacin against recent clinical isolates of Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae. A European multi-centre study. Diagn. Microbiol. Infect. Dis. 37:201–211. 8. Jorgenson, J. H. 1992. Update on the mechanisms and prevalence of antimicrobial resistance in Haemophilus influenzae. Clin. Infect. Dis. 14:1119– 1123. 9. Livermore, D. M. 1995. -Lactamases in laboratory and clinical practice. Clin. Microbiol. Rev. 8:557–584. 10. NCCLS. 1999. Performance standards for antimicrobial susceptibility testing, eighth informational supplement. Approved standard, document M100-S8. NCCLS, Wayne, Pa. 11. Padayachee, T., and K. P. Klugman. 1999. Novel expansions of the gene encoding dihydropteroate synthase in trimethoprim-sulfamethoxazole-resistant Streptococcus pneumoniae. Antimicrob. Agents Chemother. 43:2225– 2230. 12. Powell, M., Y. Hu, and D. M. Livermore. 1991. Resistance to trimethoprim in Haemophilus influenzae. Infection 19:174–177. 13. Richard, M. P., A. Aguado, R. Mattina, R. Marre, and the SPAR Study Group. 1998. Sensitivity to sparfloxacin and other antibiotics of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis strains isolated from adults with community-acquired lower respiratory tract infections: a European multicentre study. J. Antimicrob. Chemother. 41:207–214. 14. Sahm, D. F., M. E. Jones, M. L. Hickey, D. R. Diakun, S. Mani, and C. Thornsberry. 2000. Resistance surveillance of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis isolated in Asia and Europe, 1997–1998. J. Antimicrob. Chemother. 45:457–466. 15. Thornsberry, C., M. E. Jones, M. Hickey, Y. Mauriz, J. Kahn, and D. F. Sahm. 1999. Resistance surveillance of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in the United States, 1997– 1998. J. Antimcrob. Chemother. 44:749–759. 16. Thornsberry, C., and D. F. Sahm. 2000. Antimicrobial resistance in respiratory tract pathogens: results of an international surveillance study. Chemotherapy 46(Suppl. 1):15–23.
Mark E. Jones* Focus Technologies Hilversum, The Netherlands James A. Karlowsky Rene´e Blosser-Middleton Ian Critchley Clyde Thornsberry Daniel F. Sahm Focus Technologies Herndon, VA *Phone: 31-35-6257290 Fax: 31-35-6257287 E-mail:
[email protected].
