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Antimicrob Agents Chemother. Oct 1999; 43(10): 2504–2509.
PMCID: PMC89508
Note

Prevalence of Antimicrobial Resistance in Respiratory Tract Isolates of Streptococcus pneumoniae: Results of a Canadian National Surveillance Study

George G. Zhanel,1,2,3,4 James A. Karlowsky,1,2,4 Lorraine Palatnick,3 Laverne Vercaigne,2 Donald E. Low,5, The Canadian Respiratory Infection Study Group, and Daryl J. Hoban1,4,*

Abstract

From October 1997 to November 1998, 1,180 respiratory tract isolates of Streptococcus pneumoniae were collected from 18 medical centers in 9 of the 10 Canadian provinces. Penicillin-intermediate and -resistant isolates occurred at rates of 14.8 and 6.4%, respectively, and these rates varied considerably by geographic region. Trimethoprim-sulfamethoxazole, tetracycline, and macrolide rates of nonsusceptibility were 12.2, 10.6, and 8.0 to 9.3%, respectively. The most potent agents studied were newer fluoroquinolones.

In Canada, penicillin-resistant and multidrug-resistant (MDR) pneumococci were rarely isolated until the mid-1990s (11). Three Canadian studies performed in the 1970s and 1980s reported Streptococcus pneumoniae penicillin resistance rates of 2.4, 1.3, and 1.5% in the provinces of Alberta, Quebec, and Ontario, respectively (2, 5, 6). However, only penicillin-intermediate (MIC, 0.12 to 1 μg/ml) isolates were detected in these studies; penicillin-resistant (MIC, ≥2 μg/ml) isolates were not identified. In 1993 to 1994, increasing penicillin resistance was reported in southern Ontario (10). More recently, two Canadian national surveys yielded similar results in assessing the prevalence of penicillin resistance in S. pneumoniae (1, 11). First, between October 1994 and August 1995, 8.4 and 3.3% of isolates from 39 Canadian laboratories were reported to be penicillin intermediate and resistant, respectively (11). Similarly, Davidson and coworkers subsequently reported a significant increase in the isolation of penicillin-intermediate and -resistant S. pneumoniae, from 6.4 to 8.9% and from 2.1 to 4.4%, respectively, during two collection periods, September 1994 to May 1995 and September to December 1996 (1). The purpose of the present study was to perform a 1997-1998 Canadian national survey to determine if the prevalence of penicillin resistance among respiratory tract isolates of S. pneumoniae has continued to increase and to determine the activity of clinically available and investigational antimicrobial agents against these isolates.

Between October 1997 and November 1998, a total of 1,180 unique patient isolates of S. pneumoniae were collected from 18 medical centers in major population centers in 9 of the 10 Canadian provinces. Isolates, one per patient, were collected from respiratory tract specimens only. Isolate inclusion in the study was not dependent upon patient age. Isolates were identified by conventional methodology (9) and deemed to be significant respiratory pathogens by individual laboratory protocols. At study sites, isolates were subcultured on 5% sheep blood agar plates and incubated for 24 h at 35°C in 5 to 10% CO2. 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 isolates were subcultured on 5% sheep blood agar and stocked in skim milk at −70°C. Antimicrobial agents 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-A4 method (7). Following two subcultures from frozen stock, the MICs of the antimicrobial agents for the isolates were determined by the NCCLS M7-A4 approved broth microdilution method (7).

Of the 1,180 clinical isolates of S. pneumoniae collected in this study, 78.8% were susceptible to penicillin (MIC, ≤0.06 μg/ml), 14.8% were penicillin intermediate (MIC, 0.12 to 1 μg/ml), and 6.4% were penicillin resistant (MIC, ≥2 μg/ml). The prevalence of penicillin-resistant S. pneumoniae varied by geographical location in Canada. In the three eastern Canadian provinces studied (New Brunswick, Nova Scotia, and Prince Edward Island), ≤5% of isolates were penicillin nonsusceptible. The rates of penicillin-intermediate-isolate and penicillin-resistant-isolate recovery varied from 3 to 4.5% and from 0 to 1.5%, respectively. The prevalence of penicillin-resistant S. pneumoniae was higher in Ontario and Quebec (central Canadian provinces) than in the eastern provinces. Ontario and Quebec isolates demonstrated penicillin nonsusceptibility rates of 22.5 and 24.4%, respectively. Quebec demonstrated higher rates of penicillin-intermediate-isolate recovery (19.7 versus 9.2%) and lower rates of penicillin-resistant-isolate recovery (4.7 versus 13.3%) than Ontario. The highest rates of nonsusceptibility to penicillin, ranging from 22.5 to 34.6%, were found in isolates collected in the western Canadian provinces (Manitoba, Saskatchewan, Alberta, and British Columbia). Penicillin-intermediate-isolate and penicillin-resistant-isolate recovery rates varied from 15.0 to 22.3% and from 6.3 to 12.3%, respectively, in the western provinces.

The in vitro activities of 23 antimicrobial agents against S. pneumoniae are listed in Table Table1.1. Among these agents, amoxicillin demonstrated activity similar to that of penicillin. Of the cephalosporins tested, the rank order of in vitro activity, based upon MICs at which 90% of the isolates were inhibited (MIC90s), was cefotaxime > cefprozil > cefuroxime = cefixime > cefaclor = loracarbef. Relative fluoroquinolone activities against S. pneumoniae, based upon MIC90s, were moxifloxacin = trovafloxacin > grepafloxacin > levofloxacin > ciprofloxacin. The recovery of fluoroquinolone-resistant isolates was very infrequent (≤0.3%).

TABLE 1
In vitro antimicrobial agent activities against 1,180 isolates of S. pneumoniae collected from across Canada between October 1997 and November 1998

The activities of antimicrobial agents against S. pneumoniae isolates, categorized by penicillin susceptibility, are summarized in Table Table2.2. Overall, penicillin-susceptible S. pneumoniae isolates were also susceptible to the majority of the other antimicrobial agents. For all β-lactams, with the exception of cefaclor, penicillin-susceptible S. pneumoniae isolates demonstrated 99 to 100% susceptibility. Based upon NCCLS-approved breakpoints (8), cefotaxime was the most active β-lactam against penicillin-intermediate isolates. Cefaclor, cefprozil, cefixime, and cefuroxime did not possess activity (<5% of the isolates were susceptible) against penicillin-resistant S. pneumoniae, while 60.5% of isolates remained susceptible to cefotaxime. Overall, based upon NCCLS-approved breakpoints (percent resistance) (8), the rank order of cephalosporin activity against penicillin-susceptible, -intermediate, and -resistant isolates was cefotaxime ≥ cefprozil ≥ cefuroxime > cefixime > cefaclor (Table (Table2).2). The highest rates of susceptibility of S. pneumoniae were obtained with the fluoroquinolones, with no apparent differences in activity when the isolates were stratified into penicillin-susceptible, -intermediate, and -resistant groups. More than 95% of the penicillin-susceptible S. pneumoniae isolates were also susceptible to all the macrolides that were tested. However, only 78.9 to 85.9% of the penicillin-intermediate isolates and 57.9 to 66.1% of the penicillin-resistant isolates were macrolide susceptible. The rank order of activity for the macrolides tested, based upon NCCLS-approved breakpoints (8), was azithromycin > clarithromycin > erythromycin. Susceptibility to chloramphenicol, tetracycline, and trimethoprim-sulfamethoxazole (SXT) (ratio, 1:19) decreased with increasing resistance to penicillin. Only 55.2 and 13.2% of the penicillin-resistant isolates were susceptible to tetracycline and SXT, respectively. Vancomycin-resistant isolates were not identified. Based upon recent NCCLS-approved breakpoints, 99.3% of the S. pneumoniae isolates were susceptible to quinupristin-dalfopristin (8). Table Table33 depicts the MIC distributions of the antimicrobial agents for the penicillin-susceptible, -intermediate, and -resistant isolates.

TABLE 2
Cross-resistance of 1,180 S. pneumoniae isolates to penicillin and other antimicrobial agents
TABLE 3
MIC distribution of antimicrobial agents for isolates of S. pneumoniae

The presence of an MDR phenotype, defined as resistance to penicillin and two or more non-β-lactam agents, such as macrolides, SXT, or tetracyclines, correlated with penicillin resistance. For the penicillin-intermediate isolates, 17.1% (30 of 175) were MDR and 7.4% (13 of 175) were cross-resistant to both macrolides and tetracycline. For the penicillin-resistant isolates, 36.8% (28 of 76) were MDR and 27.6% (21 of 76) were cross-resistant to both macrolides and tetracycline. For penicillin-susceptible isolates, only 0.8% (7 of 929) demonstrated cross-resistance to two or more classes of agents.

This study has demonstrated that the rate of penicillin nonsusceptibility in the S. pneumoniae isolates from across Canada that were tested in 1997 to 1998 was 21.2%. The prevalence of both penicillin-intermediate and -resistant pneumococci approximately doubled in Canada between the periods of 1994 to 1996 (1, 11) and 1997 to 1998. Although resistance was detected in all regions of the country, the prevalence of resistance was highest in western Canada and lowest in eastern Canada. The lower prevalence of penicillin-nonsusceptible S. pneumoniae isolates in the eastern provinces remains unexplained; however, these data are consistent with previous Canadian studies (1, 5, 6, 11). We are unaware of any unique antimicrobial agent prescribing patterns, population sampling differences, or alternative infection control stewardships in the eastern provinces.

The rates of resistance to cephalosporins have also increased throughout Canada, compared with the 1994 to 1995 (11) and 1995 to 1996 (1) surveys. As reported in previous studies, cefotaxime was the most active cephalosporin against S. pneumoniae that was studied (3, 4). Our data demonstrated that of the cephalosporins tested, only cefuroxime, cefprozil, and cefotaxime retain sufficient in vitro activity to be considered for empiric management of respiratory tract infections known or suspected to be caused by S. pneumoniae. The prevalence of S. pneumoniae resistance to macrolides also increased in Canada between the periods of 1994 to 1996 (1, 11) and 1997 to 1998, with resistance rates now ranging from 5.8 to 8.1% of isolates. All macrolides demonstrated excellent activity against penicillin-susceptible isolates, good activity against penicillin-intermediate isolates, and variable activity (57.9 to 66.1% of the isolates were susceptible) against penicillin-resistant isolates. The activity of SXT against S. pneumoniae continues to decrease in Canada (1, 2, 5, 6, 11), with 77.6% of the penicillin-resistant isolates demonstrating SXT cross-resistance. The most potent agents identified in this study were the fluoroquinolones, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin, which were active against the penicillin-susceptible, -intermediate, and -resistant isolates of S. pneumoniae.

Penicillin susceptibility of S. pneumoniae is an important marker for the presence or absence of an MDR phenotype. The MDR phenotype very rarely occurred in penicillin-susceptible isolates but was, however, present in 17.1 and 36.8% of penicillin-intermediate and -resistant isolates, respectively. In addition, penicillin-intermediate and -resistant isolates were cross-resistant to oral cephalosporins, such as cefuroxime, at rates of 26.0 and 96.0%, respectively. Thus, for a patient infected with penicillin-resistant S. pneumoniae, one should assume cross-resistance to oral cephalosporins and a high likelihood (~40%) of additional cross-resistance to macrolides, tetracycline, and/or SXT.

In conclusion, the combined rate of penicillin-intermediate-isolate and penicillin-resistant-isolate recovery in a Canada-wide surveillance study in 1997 to 1998 was 21.2%. The prevalence of both penicillin-intermediate and -resistant S. pneumoniae approximately doubled in Canada between the periods of 1994 to 1996 (1, 11) and 1997 to 1998. The rapid increase in the isolation of penicillin-intermediate, penicillin-resistant, and MDR S. pneumoniae in Canada will require an alteration of the empiric treatment guidelines for both community acquired respiratory infections, such as pneumonia, acute exacerbations of chronic bronchitis, sinusitis, and otitis media, as well as the treatment of hospitalized patients.

Acknowledgments

We gratefully acknowledge the financial support of Glaxo-Wellcome and Janssen-Ortho.

We thank M. Wegrzyn for expert secretarial service.

Appendix

Other members of the Canadian Respiratory Infection Study Group included P. Kibsey, Victoria General Hospital, Victoria, and D. Roscoe, Vancouver Hospital, Vancouver, British Columbia; A. Gibb, Calgary Laboratory Services, Calgary, and R. Rennie, University of Alberta Hospitals, Edmonton, Alberta; E. Thomas, Regina General Hospital, Regina, and J. Blondeau, Royal University Hospital, Saskatoon, Saskatchewan; G. Harding, St. Boniface General Hospital, Winnipeg, Manitoba; D. Groves, St. Joseph’s Hospital, and F. Smaill, Hamilton Health Sciences Centre, Hamilton, and Z. Hussain, London Health Sciences Centre, London, Ontario; J. Dubois, Universitaire de Sante de l’Estrie, Sherbrooke, and M. Laverdiere, Maisonneuve-Rosemont, and V. Loo, Montreal General Hospital, Montreal, Quebec; M. Kuhn, South-East Health Care Corporation, Moncton, New Brunswick; K. Forward, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia; and L. Abbott, Queen Elizabeth Hospital, Charlottetown, Prince Edward Island.

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