Effects of New Penicillin Susceptibility Breakpoints for Streptococcus pneumoniae --- United States, 2006--2007

Streptococcus pneumoniae (pneumococcus) is a common cause of pneumonia and meningitis in the United States. Antimicrobial resistance, which can result in pneumococcal infection treatment failure, is identified by measuring the minimum inhibitory concentration (MIC) of an antimicrobial that will inhibit pneumococcal growth. Breakpoints are MICs that define infections as susceptible (treatable), intermediate (possibly treatable with higher doses), and resistant (not treatable) to certain antimicrobials. In January 2008, after a reevaluation that included more recent clinical studies, the Clinical and Laboratory Standards Institute (CLSI) published new S. pneumoniae breakpoints for penicillin (the preferred antimicrobial for susceptible S. pneumoniae infections). To assess the potential effects of the new breakpoints on susceptibility categorization, CDC applied them to MICs of invasive pneumococcal disease (IPD) isolates collected by the Active Bacterial Core surveillance (ABCs) system* at sites in 10 states during 2006--2007. This report summarizes the results of that analysis, which found that the percentage of IPD nonmeningitis S. pneumoniae isolates categorized as susceptible, intermediate, and resistant to penicillin changed from 74.7%, 15.0%, and 10.3% under the former breakpoints to 93.2%, 5.6%, and 1.2%, respectively, under the new breakpoints. Microbiology laboratories should be aware of the new breakpoints to interpret pneumococcal susceptibility accurately, and clinicians should be aware of the breakpoints to prescribe antimicrobials appropriately for pneumococcal infections. State and local health departments also should be aware of the new breakpoints because they might result in a decrease in the number of reported cases of penicillin-resistant pneumococcus.

Antimicrobial susceptibility breakpoints are established based on 1) the pharmacokinetic and pharmacodynamic properties of an antimicrobial agent and 2) data correlating individual MIC results with patient outcomes. Under the former criteria, susceptible, intermediate, and resistant MIC breakpoints for penicillin were <0.06, 0.12--1, and >2 µg/mL, respectively, for all pneumococcal isolates, regardless of clinical syndrome or route of penicillin administration. Those breakpoints remain unchanged for patients without meningitis who can be treated with oral penicillin (e.g., for outpatient pneumonia). However, for patients without meningitis who are treated with intravenous penicillin, the new breakpoints are <2, 4, and >8 µg/mL, respectively. In addition, isolates from patients with meningitis are now categorized as either susceptible or resistant, with intravenous penicillin breakpoints of <0.06 or >0.12 µg/mL, respectively (Table). Because the blood-brain barrier limits penetration of penicillin into the cerebrospinal fluid (CSF), no intermediate category for meningitis exists.

To conduct this analysis, cases of IPD were identified through ABCs. Cases of IPD were defined by isolation of S. pneumoniae from a normally sterile site, such as blood or CSF. S. pneumoniae infections in persons with noninvasive isolates (e.g., from sputum) were not considered IPD cases. Cases were categorized as meningitis or nonmeningitis based on medical record review (e.g., clinical presentation) and source of the isolate. If a case was classified as meningitis on the basis of the patient's clinical presentation but pneumococcus was isolated from blood rather than CSF, the new meningitis breakpoints were applied to the blood isolate (1). Isolates were tested for susceptibility at reference laboratories, using CLSI methods (1). Because 88% of persons with nonmeningitis IPD are hospitalized and oral penicillin is not used for treatment of hospitalized persons with IPD, the oral penicillin route was not considered in this analysis, and only the new intravenous penicillin breakpoints were applied to the MICs.

During 2006--2007, ABCs identified 7,903 cases of IPD. Isolates were available for 6,845 (87%) cases. Of the available isolates, 6,423 (94%) were associated with nonmeningitis syndromes, and 422 (6%) were associated with meningitis. Among isolates from patients without meningitis, the number of penicillin-susceptible isolates increased from 4,797 (74.7%) under the former breakpoints to 5,989 (93.2%) using the new breakpoints for intravenous treatment (Figure 1). The number of isolates associated with nonmeningitis syndromes with intermediate susceptibility to penicillin decreased from 962 (15.0%) under the former breakpoints to 357 (5.6%) under the new intravenous breakpoints; the number of penicillin-resistant isolates decreased from 664 (10.3%) under the former breakpoints to 77 (1.2%) under the new intravenous breakpoints.

The number of penicillin-susceptible isolates associated with meningitis remained unchanged at 306 (73%). All isolates associated with meningitis that had been categorized under the former breakpoints as having intermediate susceptibility to penicillin were recategorized as penicillin resistant under the new breakpoints, increasing the number of resistant isolates from 45 (10.7%) to 116 (27.5%) (Figure 2).

Reported by: A Reingold, MD, California Emerging Infections Program, Oakland, California. K Gershman, MD, Colorado Dept of Public Health and Environment. J Hadler, MD, Emerging Infections Program, Connecticut Dept of Public Health. MM Farley, MD, Georgia Emerging Infections Program, Veterans Affairs Medical Center and Emory Univ School of Medicine, Atlanta, Georgia. L Harrison, MD, Maryland Emerging Infections Program, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. A Glennen, PhD, R Lynfield, MD, L Lesher, MPH, Minnesota Dept of Health. J Baumbach, MD, New Mexico Dept of Health. GL Smith, Monroe County Dept of Public Health, Rochester, New York. A Thomas, MD, Oregon Public Health Div. WS Schaffner, MD, Tennessee Dept of Health. J Jorgensen, PhD, Univ of Texas Health Science Center at San Antonio. B Beall, PhD, CG Whitney, MD, M Moore, MD, Div of Bacterial Diseases, National Center for Immunization and Respiratory Diseases; M Deutscher, MD, EIS Officer, CDC.

Editorial Note:

The new susceptibility breakpoints for S. pneumoniae, published by CLSI in January 2008, were the result of a reevaluation that showed clinical response to penicillin was being preserved in clinical studies of pneumococcal infection, despite reduced susceptibility response in vitro. CLSI took a similar approach in 2003, when third-generation cephalosporin breakpoints for S. pneumoniae were redefined for isolates from patients with and without meningitis (2). The former penicillin breakpoints for S. pneumoniae were based on attainable concentrations of penicillin in CSF and the MIC at which meningitis treatment was thought to fail. However, published studies evaluating penicillin as monotherapy for treatment during the first 48 hours of nonmeningitis pneumococcal infections have not shown increased case-fatality rates associated with penicillin MICs <2 µg/mL (3--5). These studies provide evidence that that the former CLSI breakpoints for penicillin underestimated the clinical utility of that agent for intravenous therapy of nonmeningitis pneumococcal infections.

Because most antimicrobial reports from clinical laboratories have included only one set of susceptibility breakpoints, the use of multiple sets of breakpoints has the potential to cause confusion among clinicians. Some patients with clinical signs and symptoms of pneumococcal meningitis have negative cultures from CSF but positive cultures from blood. Therefore, CLSI recommends that both sets of breakpoints for intravenous therapy (i.e., for meningitis and nonmeningitis syndromes) be reported for all pneumococcal isolates not collected from CSF (1). Professional society guidelines state that, after patients have received empiric therapy and culture and susceptibility results are available, penicillin should be used to treat infections caused by penicillin-susceptible S. pneumoniae (6). Clinicians should review all susceptibility results, decide which set of breakpoints to use, based on the patient's clinical presentation and the planned route of drug administration, and then decide whether penicillin or some other antimicrobial is most appropriate for treatment. If a third-generation cephalosporin is considered as an alternative for treatment, clinicians also should evaluate both susceptibility breakpoints provided for third-generation cephalosporins (2). Clinical laboratory reports should include sufficient information regarding the susceptibility results, so that clinicians can apply the appropriate breakpoints to their patients.

Use of narrow-spectrum agents, such as penicillin, is encouraged to prevent the spread of antimicrobial-resistant S. pneumoniae and also the spread of methicillin-resistant Staphylococcus aureus and Clostridium difficile, which can result from use of broader-spectrum antimicrobials (7,8). The changes in penicillin breakpoints for S. pneumoniae have the potential to allow clinicians to increase use of penicillin to treat penicillin-susceptible nonmeningitis pneumococcal infections, instead of using broader-spectrum antimicrobials.

Some state and local health departments conduct surveillance for antimicrobial-resistant pneumococcal infections. Because of the breakpoint changes described in this report, those health departments might observe decreases in reported cases of antimicrobial-resistant IPD during 2008. Health departments should take these breakpoint changes into consideration when interpreting trends in antimicrobial resistance.

References

1. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; eighteenth informational supplement. CLSI document M100-S18. Wayne, PA: Clinical and Laboratory Standards Institute; 2008.
2. CDC. Effect of new susceptibility breakpoints on reporting of resistance in Streptococcus pneumoniae---United States, 2003. MMWR 2004;53:152--4.
3. Pallares R, Linares J, Vadillo M, et al. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med 1995;333:474--80.
4. Yu VL, Chiou CC, Feldman C, et al. An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome. Clin Infect Dis 2003;37:230--7.
5. Song JH, Jung SI, Ki HK, et al. Clinical outcomes of pneumococcal pneumonia caused by antibiotic-resistant strains in Asian countries: a study by the Asian Network for Surveillance of Resistant Pathogens. Clin Infect Dis 2004;38:1570--8.
6. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44:S27--72.
7. Schneider-Lindner V, Delaney JA, Dial S, Dascal A, Suissa S. Antimicrobial drugs and community-acquired methicillin-resistant Staphylococcus aureus, United Kingdom. Emerg Infect Dis 2007;13:994--1000.
8. Baxter R, Ray GT, Fireman BH. Case-control study of antibiotic use and subsequent Clostridium difficile-associated diarrhea in hospitalized patients. Infect Control Hosp Epidemiol 2008;29:44--50.

* ABCs is a collaboration between CDC, state health departments, and universities and conducts active, population-based, laboratory-based surveillance for invasive bacterial diseases in all or parts of 10 states. Additional information is available at http://www.cdc.gov/ncidod/dbmd/abcs/index.htm.

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Date last reviewed: 12/17/2008