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Emergence of Penicillin-Resistant Streptococcus pneumoniae -- Southern Ontario, Canada, 1993-1994

Streptococcus pneumoniae is a leading cause of infectious disease-related illness and death in the United States, accounting for an estimated 3000 cases of meningitis, 50,000 cases of bacteremia, 500,000 cases of pneumonia, and 7 million cases of acute otitis media each year (1). Penicillin has been the antibiotic of choice for the treatment of infections caused by S. pneumoniae; since the mid-1980s, the prevalence of penicillin-resistant S. pneumoniae has increased substantially worldwide (2-4). In Canada, a strain of pneumococcus with reduced susceptibility to penicillin was first reported in 1974 (5); based on surveys during 1977-1990, rates of resistance to penicillin were 2.4%, 1.5%, and 1.3% in the provinces of Alberta, Ontario, and Quebec, respectively (6-8). To determine whether the prevalence of penicillin resistance had increased among pneumococcal isolates, investigators from the University of Toronto tested the susceptibility of strains collected from a Toronto hospital and from a surrounding region in southern Ontario during June-December 1993 and March-June 1994. This report summarizes the results of this investigation.

During the study period, all nonduplicate S. pneumoniae isolates were obtained from a private community-based laboratory providing services to physicians, clinics, and nursing homes in metropolitan Toronto, and from patients assessed in the emergency department of a tertiary-care teaching hospital in Toronto. In vitro susceptibility testing was conducted by a broth microdilution procedure in accordance with interpretive standards of the U.S. National Committee for Clinical Laboratory Standards (NCCLS) (9). An intermediate level of resistance to penicillin was defined as a minimal inhibitory concentration (MIC) of 0.1-1.0 ug/mL; high-level resistance was defined as an MIC greater than or equal to 2.0 ug/mL.

A total of 202 isolates (196 from noninvasive sites {i.e., sputum}) of S. pneumoniae were tested, including 122 isolates obtained from the private laboratory and 80 from the hospital emergency department. Of the 202 isolates, 16 (7.9%) were penicillin-resistant -- including four with high-level resistance; 11 had been obtained from eye, ear, or sputum samples from children (eight of 68 aged less than 5 years) in outpatient settings and five from sputum, blood, cerebrospinal fluid, and eye samples from adults in the emergency department.

Penicillin-susceptible strains generally were susceptible to other antimicrobial agents. However, high proportions of penicillin-resistant S. pneumoniae isolates were resistant to tetracycline (63%; MIC greater than or equal to 8 ug/mL), trimethoprim/sulfamethoxazole (56%; MIC greater than or equal to 4 ug/mL), erythromycin (50%; MIC greater than or equal to 4 ug/mL), and cefuroxime (38%; MIC greater than or equal to 2 ug/mL). High-level resistance to ceftriaxone (MIC greater than or equal to 2 ug/mL) occurred in four (25%) of 16 penicillin-resistant isolates; high-level resistance to penicillin was present in three of the four isolates resistant to ceftriaxone. All isolates were susceptible to vancomycin and imipenem. Serotypes of the penicillin-resistant pneumococci tested in the Canadian Streptococcal Reference Laboratory (Edmonton, Alberta) were 19F (five isolates), 9V (two), 23F (two), and one each of 6A, 6B, and 19A; four were non-typeable. Reported by: AE Simor, MD, L Louie, J Goodfellow, M Louie, MD, Dept of Microbiology, Sunnybrook Health Science Centre, Univ of Toronto; Med-Chem Laboratories, Toronto, Ontario, Canada. Adult Vaccine Preventable Disease Br, and Child Vaccine Preventable Disease Br, Div of Epidemiology and Surveillance, National Immunization Program; Nosocomial Pathogens Laboratory Br, Hospital Infections Program, and Childhood and Respiratory Diseases Br, Div of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: The findings in this report suggest an increased prevalence of penicillin-resistant S. pneumoniae in metropolitan Toronto compared with that in a similar study in Toronto in 1988 (1.5% {8}). By selecting all pneumococcal isolates from a large outpatient reference laboratory and hospital emergency department in metropolitan Toronto (97% of which were obtained from noninvasive sites), the study provided an indication of the antimicrobial resistance patterns among pneumococci circulating in the community and reflects a trend of emerging pneumococcal drug resistance in North America and other countries (2-4). For example, in the United States during 1987-1992, the prevalence of high-level resistance to penicillin increased more than 60-fold, from 0.02% to 1.3% in pneumococcal isolates collected from sentinel sites (3). The proportion of pneumococcal isolates resistant to penicillin has ranged from 2% to 26% in selected communities in the United States, indicating substantial geographic variability in prevalence of penicillin resistance (3,4; CDC, unpublished data, 1995).

In communities where pneumococci resistant to extended-spectrum cephalosporins have been identified, antimicrobial regimens for treatment of life-threatening pneumococcal infection should initially include vancomycin until the results of susceptibility testing are available. Although the selection of antimicrobials should be guided by the region-specific prevalence of drug-resistant S. pneumoniae (DRSP), the incidence of this problem is unknown for most regions of the country, and community-specific surveillance is needed to determine the incidence of resistance to antimicrobial drugs (e.g., penicillin and extended-spectrum cephalosporins) and to inform clinicians to enable selection of optimal antimicrobials.

Appropriate interpretive standards for antimicrobial susceptibility testing of S. pneumoniae isolates have been updated by the NCCLS (9,10). All pneumococcal isolates from normally sterile sites should be screened for penicillin resistance using an NCCLS-approved method. Oxacillin disk diffusion is a cost-effective and sensitive method for screening; susceptible isolates have a zone size of greater than or equal to 20 mm. Nonsusceptible isolates should have MICs determined for penicillin, an extended-spectrum cephalosporin, chloramphenicol, vancomycin, and other clinically indicated drugs. MICs should be determined using approved methods such as broth microdilution, agar disk diffusion, and antimicrobial gradient strips. Automated in vitro methods are not recommended for determining pneumococcal susceptibility.

The emergence of DRSP underscores the need for strategies to monitor, prevent, and control DRSP infections. Because inappropriate empiric or prophylactic therapy facilitates the occurrence of pneumococcal antimicrobial resistance, prevention and control of DRSP infections should include efforts to promote judicious antimicrobial prescribing practices among clinicians. In addition, these efforts should promote adherence to the recommendations of the Advisory Committee on Immunization Practices that the 23-valent pneumococcal polysaccharide capsular vaccine be administered to persons aged greater than or equal to 2 years with medical conditions increasing their risk for serious pneumococcal infection and to all persons aged greater than or equal to 65 years. Current pneumococcal vaccination levels are low; for example, in a 1993 survey, only 27% of persons aged greater than or equal to 65 years reported having been vaccinated (CDC, unpublished data, 1995). There is no commercially available vaccine for children aged less than 2 years; however, clinical trials are in progress to assess immunogenicity and efficacy of protein conjugate pneumococcal polysaccharide vaccines in young children.

To address the factors contributing to increased resistance and to identify methods for prevention and control of DRSP in the United States, in June 1994, CDC convened a working group comprising public health practitioners, clinical laboratory professionals, health-care providers, and representatives of professional societies. This group has developed a strategy with objectives to 1) establish DRSP as a nationally reportable condition, 2) promote appropriate NCCLS interpretive standards for pneumococcal antimicrobial susceptibility testing, 3) develop an electronic laboratory-based surveillance system to detect invasive DRSP infections and other laboratory-reportable conditions, 4) establish a group of clinicians and public-health officials to form consensus treatment recommendations for pneumococcal infections based on interpretations of antimicrobial resistance data, and 5) promote pneumococcal vaccination and judicious antimicrobial drug use. The goal of this strategy is to minimize complications of DRSP infection, including increased and prolonged illness, long-term sequelae of infection, health-care expenditures, and death. Information about activities of the DRSP Working Group can be obtained through the Childhood and Respiratory Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, CDC, Mailstop C-09, Atlanta, GA 30333; Internet address drsp@ciddbd1.em.cdc.gov.

References

  1. Reichler MR, Allphin AA, Breiman RF, et al. The spread of multiply-resistant Streptococcus pneumoniae at a day care center in Ohio. J Infect Dis 1992;166:1346-53.

  2. Applebaum PC. Antimicrobial resistance in Streptococcus pneumoniae: an overview. Clin Infect Dis 1992;15:77-83.

  3. Breiman RF, Butler JC, Tenover FC, Elliott JA, Facklam RR. Emergence of drug resistant pneumococcal infections in the United States. JAMA 1994;271:1831-5.

  4. CDC. Drug-resistant Streptococcus pneumoniae -- Kentucky and Tennessee, 1993. MMWR 1994; 43:23-5,31.

  5. Dixon JMS. Pneumococcus with increased resistance to penicillin. Lancet 1974;2:474.

  6. Dixon JMS, Lipinski AE, Graham MEP. Detection and prevalence of pneumococci with increased resistance to penicillin. Can Med Assoc J 1977;117:1159-61.

  7. Jette LP, Lamothe F, and the Pneumococcus Study Group. Surveillance of invasive Streptococcus pneumoniae infection in Quebec, Canada, from 1984 to 1986: serotype distribution, antimicrobial susceptibility, and clinical characteristics. J Clin Microbiol 1989;27:1-5.

  8. Mazzulli T, Simor AE, Jaeger R, Fuller S, Low DE. Comparative in vitro activities of several new fluoroquinolones and beta-lactam antimicrobial agents against community isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 1990;34:467-9.

  9. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing {Fifth informational supplement}. Villanova, Pennsylvania: National Committee for Clinical Laboratory Standards, 1994; NCCLS document no. M100-S5.

  10. Jorgensen JH, Swenson JM, Tenover FC, Ferraro MJ, Hindler JA, Murray PR. Development of interpretive criteria and quality control limits for broth microdilution and disk diffusion antimicrobial susceptibility testing of Streptococcus pneumoniae. J Clin Microbiol 1994;32:2448-59.




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