Relationship between antibiotic resistance in Streptococcus pneumoniae and that in Haemophilus influenzae: evidence for common selective pressure.

Abstract

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 β-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 susceptibility 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. ​(Fig.1).1). Among S. pneumoniae organisms, considerable variations in resistance to β-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. ​(Fig.11). 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 ... An interspecies comparison of the proportion of penicillin-resistant S. pneumoniae and ampicillin-resistant H. influenzae by country demonstrated a highly significant relationship (r = 0.928; P 0.05) were found for resistance to amoxicillin-clavulanate, cefuroxime, clarithromycin, or levofloxacin. The interspecific relationship observed for β-lactam and SXT resistance has not been reported previously. β-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 β-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].)