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Antimicrobial Agents and Chemotherapy, June 2003, p. 1867-1874, Vol. 47, No. 6
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.6.1867-1874.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Antimicrobial Resistance in Respiratory Tract Streptococcus pneumoniae Isolates: Results of the Canadian Respiratory Organism Susceptibility Study, 1997 to 2002

George G. Zhanel,1,2,3 Lorraine Palatnick,3 Kimberly A. Nichol,1,3 Tracy Bellyou,3 Don E. Low,4 and Daryl J. Hoban1,3*

Department of Medical Microbiology, Faculty of Medicine, University of Manitoba,1 Departments of Medicine,2 Clinical Microbiology, Health Sciences Centre, Winnipeg, Manitoba,3 Mount Sinai Hospital, Toronto, Ontario, Canada4

Received 6 September 2002/ Returned for modification 23 January 2003/ Accepted 26 February 2003


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ABSTRACT
 
A total of 6,991 unique patient isolates of Streptococcus pneumoniae were collected from October 1997 to June 2002 from 25 medical centers in 9 of the 10 Canadian provinces. Among these isolates, 20.2% were penicillin nonsusceptible, with 14.6% being penicillin intermediate (MIC, 0.12 to 1 µg/ml) and 5.6% being penicillin resistant (MIC, ≥2 µg/ml). The proportion of high-level penicillin-resistant S. pneumoniae isolates increased from 2.4 to 13.8% over the last 3 years of the study, and the proportion of multidrug-resistant S. pneumoniae isolates increased from 2.7 to 8.8% over the 5-year period. Resistant rates (intermediate and resistant) among non-ß-lactam agents were as follows: macrolides, 9.6 to 9.9%; clindamycin, 3.8%; doxycycline, 5.5%; chloramphenicol, 3.9%; and trimethoprim-sulfamethoxazole, 19.0%. Rates of resistance to non-ß-lactam agents were higher among penicillin-resistant strains than among penicillin-susceptible strains. No resistance to vancomycin or linezolid was observed; however, 0.1% intermediate resistance to quinupristin-dalfopristin was observed. The rate of macrolide resistance (intermediate and resistant) increased from 7.9 to 11.1% over the 5 years. For the fluoroquinolones, the order of activity based on the MICs at which 50% of isolates are inhibited (MIC50s) and the MIC90s was gemifloxacin > clinafloxacin > trovafloxacin > moxifloxacin > grepafloxacin > gatifloxacin > levofloxacin > ciprofloxacin. The investigational compounds ABT-773 (MIC90, 0.008 µg/ml), ABT-492 (MIC90, 0.015 µg/ml), GAR-936 (tigecycline; MIC90, 0.06 µg/ml), and BMS284756 (garenoxacin; MIC90, 0.06 µg/ml) displayed excellent activities. Despite decreases in the rates of antibiotic consumption in Canada over the 5-year period, the rates of both high-level penicillin-resistant and multidrug-resistant S. pneumoniae isolates are increasing in Canada.


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INTRODUCTION
 
Streptococcus pneumoniae is a leading cause of morbidity and mortality worldwide (1, 14, 27, 32). It is the most common cause of community-acquired pneumonia, bacterial meningitis, and acute otitis media (2, 5, 10, 13, 25, 27, 32). Initially, all S. pneumoniae isolates were exquisitely susceptible to penicillin (MICs, ≤0.06 µg/ml) and ß-lactams served as the treatment of choice for S. pneumoniae infections (2, 24, 27, 35). Beginning in the 1960s, however, resistance to penicillin and other agents began to be reported (2, 19, 24, 27). Reports of an increase in the prevalence of infections attributed to drug-resistant pneumococci appeared from a wide geographic area during the 1980s and, in particular, have appeared during the past 5 years, suggesting that drug resistance is spreading rapidly (1, 6, 11, 17, 21, 24, 30, 33, 34, 36, 37). Today, drug-resistant S. pneumoniae is recognized worldwide (16). In North America, recent surveys have shown an increase in the prevalence of resistance to penicillins from less than 5% before 1989 to more than 50% in 1999 (6, 11, 17, 23, 33, 34, 36, 37). In the United States in 1999 and 2000, of all S. pneumoniae isolates tested, 12.7% were intermediately resistant to penicillin (MICs, 0.12 to 1 µg/ml), while 21.5% were highly penicillin resistant (MICs, ≥2 µg/ml) (11). During 1997 in Canada, 14.8 and 6.4% of respiratory tract isolates of S. pneumoniae (n = 1,180) were penicillin intermediate and penicillin resistant, respectively (37). Most important and alarming is the finding that pneumococcal strains which are not susceptible (intermediate or resistant) to penicillin are more likely than penicillin-susceptible strains to be concomitantly resistant to other classes of antibiotics, including macrolides (6, 11, 17, 20, 33, 34, 36, 37).

The present report describes the results of the ongoing annual Canadian Respiratory Organism Susceptibility Study (CROSS) (37). This study included isolates from 25 medical centers from all regions of Canada participating from 1997 to 2002 inclusive. Use of isolates over a 5-year study period allows the evaluation of resistance rates over time.


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MATERIALS AND METHODS
 
Between October 1997 and June 2002 a total of 6,991 unique patient S. pneumoniae isolates were collected from 25 medical centers in major population centers in 9 of the 10 provinces in Canada. Each study site was asked to collect and submit each year 100 S. pneumoniae isolates (from respiratory tract specimens only, one per patient) deemed significant by that study site. Isolate inclusion in this study was not dependent on patient age. All organisms were identified as S. pneumoniae at each site by the criteria used at the local site, and at the reference site, where indicated, the organisms were further identified by standard methodologies such as Gram staining characteristics, optochin disk testing, bile solubility, and colony characteristics on growth medium. At the study sites, the isolates were subcultured on 5% sheep blood agar plates and incubated for 24 h at 35°C in 5 to 10% CO2 (37). Amies semisolid transport medium containing charcoal (Difco Laboratories, Detroit, Mich.) was then inoculated with the isolate and sent to the coordinating laboratory (Health Sciences Centre, Winnipeg, Manitoba, Canada), where the isolates were subcultured on 5% sheep blood agar and stocked in skim milk at -70°C.

Thirty-five antimicrobial agents (penicillin, amoxicillin-clavulanate, cefuroxime, cefprozil, cefixime, cefaclor, cefotaxime, ceftriaxone, imipenem, meropenem, erythromycin, azithromycin, clarithromycin, clindamycin, tetracycline, doxycycline, chloramphenicol, trimethoprim-sulfamethoxazole [TMP-SMX], vancomycin, quinupristin-dalfopristin, ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, trovafloxacin, gemifloxacin, grepafloxacin, clinafloxacin, linezolid, telithromycin, ABT-773, ABT-492, ertapenem, BMS284756 [garenoxacin], GAR-936 [tigecycline]) were obtained as laboratory-grade powders from their respective manufacturers. Stock solutions were prepared and dilutions were made by the National Committee for Clinical Laboratory Standards (NCCLS) M7-A5 method (28). Following two subcultures from frozen stocks, the MICs of the antimicrobial agents for the isolates were determined by the NCCLS M7-A5 approved broth microdilution method (28, 29). Briefly, for the S. pneumoniae isolates, 96-well custom-designed microtiter plates containing doubling antibiotic dilutions in 100 µl of cation-adjusted Mueller-Hinton broth plus lysed horse blood (2 to 5%; vol/vol) per well were inoculated to achieve a final concentration of approximately 5 x 105 CFU/ml, and the plates were incubated in ambient air for 24 h prior to reading of the results. Colony counts were determined periodically to confirm the inocula. Quality control was performed every 2 weeks by using the following quality control organisms from the American Type Culture Collection (ATCC): S. pneumoniae ATCC 49619, Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853.


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RESULTS
 
The demographics of the patients whose isolates were included in CROSS are described in Table 1. The numbers of S. pneumoniae isolates recovered from respiratory sources varied from 1,180 to 1,593 per year over the 5-year study period. In each year of the study, ≥90% of S. pneumoniae isolates were isolated from sputum specimens, bronchoalveolar lavage specimens, or endotracheal secretions. Approximately 54 and 46% of the isolates submitted were obtained from inpatients and outpatients, respectively, and approximately 40 and 60% of the isolates submitted were from females and males, respectively. The breakdowns of the S. pneumoniae isolates submitted by age group were approximately 20% from individuals ≤16 years of age, 40% from individuals 17 to 64 years of age, and 40% from individuals ≥65 years of age. Table 1 indicates that the demographics of the patients from whom isolates were recovered did not change over the 5-year study period.


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  		TABLE 1. Isolation of S. pneumoniae isolates from 1997 to 2002 by specimen source, service, gender, and age

The in vitro activities of 35 antibiotics against 6,991 S. pneumoniae isolates are presented in Table 2. Only the new breakpoints of amoxicillin-clavulanate, as well as those of cephalosporins such as cefuroxime, cefprozil, cefaclor, cefotaxime, and ceftriaxone, for S. pneumoniae were used (29). Among the collection of 6,991 S. pneumoniae isolates, 20.2% were penicillin nonsusceptible, with 14.6% being penicillin intermediate (MICs, 0.12 to 1 µg/ml) and 5.6% being penicillin resistant (MICs, ≥2 µg/ml) (Table 2). Rates of resistance to amoxicillin-clavulanate were low among the penicillin-intermediate and -resistant isolates (0.8 and 0.1%, respectively). The activities of expanded-spectrum cephalosporins on the basis of the MICs at which 90% of isolates are inhibited (MIC90s) were as follows: cefuroxime = cefprozil > cefixime > cefaclor. On the basis of the breakpoints, the lowest percentages of intermediate resistance and resistance occurred with cefprozil and cefuroxime (Table 2). Among all S. pneumoniae isolates tested, rates of intermediate and high-level resistance to broad-spectrum cephalosporins were 0.2 and 0.1%, respectively, for cefotaxime and 0.1 and 0%, respectively, for ceftriaxone. For carbapenems, imipenem demonstrated greater activity than meropenem, on the basis of the MIC90s.


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  		TABLE 2. In vitro activities of antibiotics against 6,991 S. pneumoniae isolatesa

When isolates were grouped according to penicillin susceptibility, the highest rates of resistance to all ß-lactam and ß-lactam-like agents including penicillins, cephalosporins, and carbapenems occurred among the penicillin-resistant strains. As can be seen in Table 3, the rates of penicillin resistance, both intermediate and high-level resistance, varied from 16.1 to 24.0% throughout the 5-year study. It appears that in the first 3 years, from 1997 to 1999 inclusive, there was a decrease in the rate of penicillin resistance; however, from 1999 to 2002 inclusive, there was not only an increase in the rate of penicillin resistance but also an increase in the rate of high-level penicillin resistance from 2.4 to 13.8% (P = 0.001) (Table 3).


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  		TABLE 3. Antibiotic resistance among S. pneumoniae isolates from 1997 to 2002

The rates of amoxicillin-clavulanate resistance (breakpoints for intermediate resistance and resistance, 4 and ≥8 µg/ml, respectively) were maintained at a low level, varying from 0 to 1% over the study period. The rates of resistance to cefuroxime, a representative expanded-spectrum cephalosporin, ranged from 8.3 to 10.5% (Table 3) and did not change over the 5-year study period. Table 4 shows that the impact of service, gender, and age group on the prevalence of penicillin-intermediate and penicillin-resistant S. pneumoniae isolates was minimal. As well, the impact of service, gender, and age group on resistance to cephalosporins such as cefuroxime was limited. Table 5 describes the MIC distributions of penicillin over the 5-year study period. As can be observed, there appears to have been a rightward shift (a shift to higher MICs) in the distribution of the penicillin MICs over the last 3 years of the study (1999 to 2002); however, no isolates for which penicillin MICs were >8 µg/ml were found. The distributions of the MICs of amoxicillin-clavulanate are described in Table 5. No rightward shift in amoxicillin-clavulante MICs occurred. For cefuroxime, the MIC distribution data showed that the MICs were ≤0.25 µg/ml for the majority of isolates, with a few strains with high-level resistance (MICs, 16 and ≥32 µg/ml) being reported. No rightward shift in the cefuroxime MIC distribution was observed.


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  		TABLE 4. Rates of recovery of S. pneumoniae isolates with intermediate and high levels of antibiotic resistance by service, gender, and agea


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  		TABLE 5. Distribution of MICs of selected antibiotics for the S. pneumoniae isolates tested

Three macrolides were examined over the 5 years of the study, including erythromycin, clarithromycin, and azithromycin. Even though the NCCLS breakpoints differ (29) for each macrolide, when the percentages of intermediate and fully resistant isolates are added, the rates of resistance to all macrolides were similar (approximately 10%) (Table 2). The rates of resistance to macrolides were the lowest among the penicillin-susceptible strains (approximately 4 to 5%), but this increased to 20 to 25% among the penicillin-intermediate strains and to approximately 40 to 50% among the penicillin-resistant strains (Table 2). As described in Table 3, in Canada the rates of resistance (intermediate and resistant) to clarithromycin, a representative macrolide, increased from 7.9 to 11.1% over the 5-year study period. The rates of resistance to macrolides were not influenced by service, gender, or age group (Table 4). When the distributions of the MICs of the macrolides are analyzed, it is clear that the MICs were ≤0.03 µg/ml for the majority of strains. However, greater than 60% of macrolide-resistant strains (clarithromycin MICs, ≥1 µg/ml) appeared to demonstrate a macrolide resistance phenotype (M phenotype; macrolide MICs of 1 to 16 µg/ml and susceptibility to clindamycin), whereas approximately 40% of strains demonstrated a macrolide, lincosamide, and streptogramin B resistance phenotype (MLSB phenotype; macrolide MICs of ≥32 µg/ml and resistance to clindamycin). It should be stated that, on the basis of the MIC distributions, the incidences of the M and MLSB phenotypes did not change over the 5-year study period (Table 5).

The rates of resistance (intermediate and resistant) to other antimicrobials were as follows: clindamycin, 3.8%; doxycycline, 5.5%; chloramphenicol, 3.9%; TMP-SMX, 19.0%; vancomycin, 0%; quinupristin-dalfopristin, 0.1%; and linezolid, 0%. The rates of resistance to ß-lactam agents (penicillins and cephalosporins), as well as carbapenems, macrolides, clindamycin, tetracyclines such as doxycycline, chloramphenicol, and TMP-SMX increased as the penicillin resistance changed from penicillin intermediate to penicillin resistant (Table 2). No resistance to vancomycin and linezolid was noted among the penicillin-resistant strains. Among the fluoroquinolones, the order of activity based on the MIC50s and MIC90s was gemifloxacin > clinafloxacin > trovafloxacin > moxifloxacin > grepafloxacin > gatifloxacin > levofloxacin > ciprofloxacin. The rates of resistance to the fluoroquinolones were the highest among the penicillin-resistant strains (Table 2). As described in Table 3, the rate of resistance to fluoroquinolones, with levofloxacin used as a representative fluoroquinolone, varied from 0.5 to 1.1%. The rate of resistance to levofloxacin was higher for isolates from inpatients, those from females, and those from patients ≥65 years of age (Table 4). The distribution of the levofloxacin MICs suggested that the MICs were 0.5 and 1.0 µg/ml for the majority of isolates, and no rightward shift in the MIC distribution occurred over the 5-year study period. The investigational fluoroquinolones BMS284756 (garenoxacin) and ABT-492 both demonstrated excellent activities against the S. pneumoniae isolates, with MIC90s of 0.06 and 0.015 µg/ml, respectively (Table 2). Two investigational ketolides, telithromycin and ABT-773, were studied. The MIC90s of telithromycin and ABT-773 were 0.015 and 0.008 µg/ml, respectively. The MIC90s of both ketolides increased for penicillin-intermediate and penicillin-resistant S. pneumoniae isolates relative to those for penicillin-susceptible strains. An investigational glycylcycline, GAR-936 (tigecycline), demonstrated excellent activities against penicillin-susceptible as well as penicillin-resistant S. pneumoniae isolates, with MIC90s of 0.06 µg/ml (Table 2).

Table 3 describes the incidence of a multidrug resistance phenotype over the 5-year study period. The multidrug resistance phenotype was defined as resistance to three or more classes of antimicrobials, including ß-lactams, macrolides, tetracyclines, TMP-SMX, and fluoroquinolones. The proportions of isolates with the multidrug resistance phenotype increased in every year of the study, from 2.7% in 1997-1998 to 8.8% in 2001-2002 (P < 0.001) (Table 3).

Table 6 compares the rates of resistance to penicillin, macrolides (clarithromycin), and fluoroquinolones (levofloxacin) by province or region of Canada. The major observation was that considerable variation occurred both within and between each province or region in a given year. However, general trends were observed. Consistently, the highest rates of penicillin nonsusceptibility were observed in western Canada (e.g., Saskatchewan), while the lowest rates of penicillin resistance occurred in the Maritime provinces (Table 6). Macrolide resistance tended to be lowest in British Columbia and Manitoba and highest in Quebec. The rate of fluoroquinolone resistance was observed to be low (~1%) in all parts of the country.


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  		TABLE 6. Rates of resistance to selected antimicrobials by province or region, 1997 to 2002a


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DISCUSSION
 
CROSS is an ongoing longitudinal surveillance program that studies the incidence of antibiotic resistance in respiratory pathogens across all regions of Canada (37). Thus, it represents a unique opportunity to compare rates of antibiotic resistance among isolates from various geographically distributed medical centers, among isolates from patients with different demographic profiles, and by antimicrobial class. From 1997 to 2002, the same 25 medical centers participated in the study during all 5 years of the study. Each year large numbers (1,180 to 1,593) of respiratory tract S. pneumoniae isolates were isolated and collected during the same time of year (during the winter months). Over the 5-year study period, the study demographics remained constant, in that the specimen type was primarily sputum specimens, bronchoalveolar lavage specimens, and endotracheal secretions. The breakdown of the isolates by service was approximately 54% inpatient and 46% outpatient. The breakdown of the isolates by gender was approximately 40% female and 60% male, and the breakdown of the isolates by age was approximately 20% from those ≤16 years of age, 40% from those 17 to 64 years of age, and 40% from those >65 years of age (Tables 1 and 4).

This study found that the rate of penicillin resistance (intermediate and resistant) did not significantly change over the 5-year period and ranged from 21.2% in 1997-1998 to 24.0% in 2001-2002. However, in the last 3 years of the study a dramatic increase in the proportion of isolates with high-level penicillin resistance (MICs, ≥2 µg/ml), which increased from 2.4% in 1999-2000 to 13.8% in 2001-2002, occurred (P = 0.001) (Table 3). The same observation has been made previously (11, 36). For the majority of these highly penicillin resistant isolates, the penicillin MICs were 2 to 4 µg/ml; however, for some strains the penicillin MICs were 8 µg/ml (Table 5). This is particularly worrisome, as high-level penicillin-resistant strains may be more likely to be associated not only with cross-resistance to other antimicrobial classes but also with failure with ß-lactams (2, 24).

As would be expected, when the isolates were grouped by penicillin susceptibility categories, the rates of resistance to all ß-lactams, including penicillins, cephalosporins, and carbapenems, increased in parallel with increasing penicillin resistance. This is not surprising, as penicillin resistance in S. pneumoniae is the result of alterations in penicillin binding proteins, and all ß-lactam and ß-lactam like agents bind at least to some extent to the same penicillin binding proteins (3, 7, 9, 12, 15).

Rates of resistance (intermediate and resistant) to non-ß-lactam agents were approximately 3.8% for clindamycin, 5.5% for doxycycline, 3.9% for chloramphenicol, and 19.0% for TMP-SMX; and these rates did not change over the 5-year study period (Tables 2 and 3). The rates of resistance to all non-ß-lactam antibiotics were consistently higher among the penicillin-intermediate and penicillin-resistant S. pneumoniae isolates than among their penicillin-susceptible counterparts. Vancomycin and linezolid consistently showed excellent activities, and no resistance was observed. Macrolide resistance, as depicted for clarithromycin, a representative macrolide, increased significantly over the 5-year study period, from 7.9% in 1997-1998 to 11.1% in 2001-2002 (Table 3). The phenotypic expression of macrolide resistance was consistent with both efflux-based (M phenotype) and target-based (MSLB phenotype) resistance (11, 38, 39). We previously reported that the M phenotype predominates over the MLSB phenotype, as determined by PCR (18). Other North American studies have also concluded that the M phenotype predominates (11, 17, 33, 34, 36, 37). Unlike other investigators (13, 19), we have not observed a rightward shift in the MIC distribution, with higher MICs for isolates with the efflux-based phenotype observed over time. The investigational ketolides telithromycin and ABT-773 (38) demonstrated excellent activities against penicillin-susceptible and penicillin-nonsusceptible S. pneumoniae isolates, with MIC90s of 0.015 and 0.008 µg/ml, respectively (Table 2). It should be noted, however, that the ketolide MICs were elevated for some penicillin-nonsusceptible isolates. The investigational glycylcycline GAR-936 (tigecycline) demonstrated excellent activities against penicillin-susceptible as well as penicillin-nonsusceptible S. pneumoniae isolates, with MIC90s of 0.06 µg/ml (Table 2).

The activities of fluoroquinolones, as measured by the MIC90s (which are given in parentheses), were gemifloxacin (0.03 µg/ml) > clinafloxacin (0.06 µg/ml) > trovafloxacin (0.12 µg/ml) > grepafloxacin (0.25 µg/ml) = moxifloxacin (0.25 µg/ml) > gatifloxacin (0.5 µg/ml) > levofloxacin (1 µg/ml) > ciprofloxacin (2 µg/ml) (Table 2). This order of fluoroquinolone activity has been reported previously (40). The investigational fluoroquinolones ABT-492 and BMS284756 (garenoxacin) also demonstrated excellent activities against S. pneumoniae, with MIC90s of 0.015 and 0.06 µg/ml, respectively (Table 2). As displayed in Table 3, the rates of resistance (intermediate and resistant) to fluoroquinolones, as depicted by levofloxacin, continues to range from 0.5 to 1.1% among isolates in Canada. Thus, following the observation of Chen et al. (8) of increasing ciprofloxacin resistance in Canada and globally (4, 16, 22, 26, 31, 40), the use of new fluoroquinolones such as gatifloxacin, levofloxacin, and moxifloxacin has not led to date to a rapid escalation in the rates of resistance to the new fluoroquinolone agents in Canada. We have not observed a rightward shift in the distributions of the MICs of the new fluoroquinolones such as levofloxacin (Table 5); however, these MIC frequency distributions need to be continuously monitored over time, especially among isolates from inpatients and elderly individuals, to alert clinicians and researchers to any increasing shift in fluoroquinolone MICs. For levofloxacin-resistant isolates (MICs, ≥8 µg/ml), the corresponding ciprofloxacin MICs were 16 to 64 µg/ml, the gatifloxacin MICs were 2 to 16 µg/ml, the moxifloxacin MICs were 1 to 16 µg/ml, the gemifloxacin MICs were 0.12 to 4 µg/ml, the ABT-492 MICs were 0.06 to 0.5 µg/ml, and the BMS284756 (garenoxacin) MICs were 0.25 to 8 µg/ml (data not shown). It should be mentioned that isolates with high-level fluoroquinolone resistance, as depicted by levofloxacin MICs of ≥8 µg/ml, were frequently resistant to penicillin as well as non-ß-lactam agents.

We have demonstrated in this multiyear surveillance study that although the proportions of penicillin-resistant (intermediate and resistant) S. pneumoniae isolates remained relatively stable, the rate of high-level penicillin resistance increased, as did the rate of multidrug resistance (Table 3). In fact, the proportions of S. pneumoniae isolates with the multidrug resistance phenotype increased from 2.7% in 1997-1998 to 8.8% in 2001-2002 (P < 0.001). The increase in the proportions of S. pneumoniae isolates with the multidrug-resistant phenotype has previously been shown by Doern et al. (11) as well as Whitney et al. (36). One potential explanation for the increase in high-level penicillin resistance and multidrug resistance is the continuous proliferation of a few "fit" clones that are high-level penicillin resistant and/or multidrug resistant. This has been reported in the United States and continues to evolve (9, 11). Doern et al. (11) have suggested that 9 to 10 major clones of penicillin-resistant S. pneumoniae isolates exist in the United States and comprise 70 to 80% of penicillin-resistant S. pneumoniae isolates. We believe that these same fit clones exist in Canada and appear to be proliferating (data not shown). We hypothesize that the rapid dissemination of high-level penicillin-resistant and multidrug-resistant S. pneumoniae isolates in Canada is continuing due to the rapid proliferation of these fit clones.

The influence of patient demographics on S. pneumoniae has been shown in Table 4. In brief, we observed that inpatient or outpatient service had little impact on resistance, nor did gender. However, we did observe a higher incidence of fluoroquinolone resistance among isolates from inpatients and subjects ages ≥65 years. It remains essential to monitor the evolution of fluoroquinolone resistance in this patient population.

In conclusion, the rate of antimicrobial resistance among S. pneumoniae isolates in Canada continues to grow. Over the last 3 years we have observed the rapid evolution of highly penicillin-resistant as well as multidrug-resistant S. pneumoniae isolates. As well, the rate of macrolide resistance continues to grow, but the rate of resistance to the new fluoroquinolones appears to be stable at approximately 0.5 to 1%.


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ACKNOWLEDGMENTS
 
CROSS surveillance sites and investigators were as follows: Victoria General Hospital, Victoria, British Columbia, P. Kibsey; Vancouver Hospital, Vancouver, British Columbia, D. L. Roscoe; Calgary Lab Services, Calgary, Alberta, D. Church; University of Alberta Hospitals, Edmonton, Alberta, R. P. Rennie; Regina General Hospital, Regina, Saskatchewan, E. Thomas; Royal University Hospital, Saskatoon, Saskatchewan, J. M. Blondeau; St. Boniface Hospital, Winnipeg, Manitoba, G. K. M. Harding; Health Sciences Centre, Winnipeg, Manitoba, D. J. Hoban and G. G. Zhanel; St. Joseph's Hospital, Hamilton, Ontario, D. Groves; Hamilton Health Sciences Centre, Hamilton, Ontario, F. Smaill; McMaster, Hamilton, Ontario, M. Loeb; Mount Sinai Hospital, Toronto, Ontario, D. Low; London Health Sciences Centre, London, Ontario, Z. Hussain; Ottawa General Hospital, Ottawa, Ontario, K. Ramotar; Children's Hospital of Eastern Ontario, Ottawa, Ontario, F. Chan; Montreal Children's Hospital, Montreal, Quebec, J. McDonald; Montreal Jewish General Hospital, Montreal, Quebec, A. Dascal; Maisonneuve-Rosemont, Montreal, Quebec, M. Laverdiere; Montreal General Hospital, Montreal, Quebec, V. Loo; Hotel-Dieu of Montreal, Montreal, Quebec, M. Poisson; Universitaire de Sante de l'Estrie, Sherbrooke, Quebec, J. Dubois; South East Health Care Corp., Moncton, New Brunswick, M. Kuhn; St. John Regional, St. John, New Brunswick, G. Hardy and Y. Yaschuk; Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, K. Forward and R. Davidson; and Queen Elizabeth Hospital, Charlottetown, Price Edward Island, L. Abbott.

We thank M. Wegrzyn for expert secretarial assistance. Funding for the CROSS study was provided in part by Abbott Laboratories Ltd., Astra Zeneca, Aventis Pharma, Bayer Inc., Bristol-Myers Squibb Pharmaceutical Group, GlaxoSmithKline, Janssen-Ortho Inc., Merck Frosst Canada & Co., Pharmacia Upjohn, Pfizer, and Wyeth.


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FOOTNOTES
 
* Corresponding author. Mailing address: Clinical Microbiology, Health Sciences Centre, MS673-820 Sherbrook St., Winnipeg, Manitoba R3A 1R9, Canada. Phone: (204) 787-1191. Fax: (204) 787-4699. E-mail: dhoban{at}hsc.mb.ca. Back


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Antimicrobial Agents and Chemotherapy, June 2003, p. 1867-1874, Vol. 47, No. 6
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.6.1867-1874.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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