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February 16, 1996 / Vol. 45 / No. RR-1 Defining the Public Health Impact
Streptococcus pneumoniae :
Report of a Working Group
Public Health Service
Centers for Disease Control and Prevention (CDC) Atlanta, Georgia 30333 The MMWR series of publications is published by the Epidemiology Program Office,Centers for Disease Control and Prevention (CDC), Public Health Service, U.S. Depart-ment of Health and Human Services, Atlanta, GA 30333.
Centers for Disease Control and Prevention. Defining the public health impact ofdrug-resistant Streptococcus pneumoniae : report of a working group. MMWR1996;45(No. RR-1):[inclusive page numbers].
Centers for Disease Control and Prevention . David Satcher, M.D., Ph.D.
The material in this report was prepared for publication by: National Center for Infectious Diseases. James M. Hughes, M.D.
Division of Bacterial and Mycotic Diseases . Mitchell L. Cohen, M.D.
The production of this report as an MMWR serial publication was coordinated in: Epidemiology Program Office. Stephen B. Thacker, M.D., M.Sc.
Richard A. Goodman, M.D., M.P.H.
Editor, MMWR Series Scientific Information and Communications Program Recommendations and Reports. Suzanne M. Hewitt, M.P.A.
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Vol. 45 / No. RR-1
February 16, 1996
Drug-Resistant Streptococcus pneumoniae Working Group
Guthrie Birkhead, M.D.
Daniel Jernigan, M.D., M.P.H.
New York State Department of Health Centers for Disease Control Council of State and Territorial James Jorgensen, M.D.
Robert Breiman, M.D.
National Committee for Clinical Centers for Disease Control David Klein, M.D.
Jay Butler, M.D.
National Institute of Allergy Centers for Disease Control National Institutes of Health Matthew Cartter, M.D.
Thomas O'Brien, M.D.
Connecticut Department of World Health Organization Public Health and Addiction Services Collaborating Center for Martin Cetron, M.D. (Chair)Centers for Disease Control Benjamin Schwartz, M.D.
Centers for Disease Control Joan Chesney, M.D.
American Academy of Pediatrics Albert Sheldon, Jr., Ph.D.
Food and Drug AdministrationRockville, MD William Craig, M.D.
Infectious Disease Society of America Kenneth Spitalny, M.D.
New Jersey State Department of HealthTrenton, NJ Robert Gaynes, M.D.
Centers for Disease Control Fred Tenover, Ph.D.
Centers for Disease Control Mary Gilchrist, Ph.D.
American Society for Microbiology Ralph Timperi, M.P.H.
Association of State and Territorial Public Health Laboratory Directors Richard Hoffman, M.D.
Colorado Department of Public Health and Council of State and Territorial EpidemiologistsDenver, CO Vol. 45 / No. RR-1
The following CDC staff members prepared this report: Daniel B. Jernigan, M.D., M.P.H.
Martin S. Cetron, M.D.
Robert F. Breiman, M.D.
Division of Bacterial and Mycotic Diseases National Center for Infectious Diseases Vol. 45 / No. RR-1
Defining the Public Health Impact of
Report of a Working Group
Streptococcus pneumoniae is a leading cause of morbidity and mortality in the United States, resulting each year in an estimated 3,000 cases of meningitis,50,000 cases of bacteremia, 500,000 cases of pneumonia, and 7,000,000 cases ofotitis media. As with most respiratory pathogens, rapid, sensitive, and specificdiagnostic tests are not available; thus, early in the course of illness, diagnosisof S. pneumoniae infection is usually presumptive, and the choice of antimicro-bial therapy is nearly always empiric. In the past, isolates of S. pneumoniaewere uniformly susceptible to penicillin; however, penicillin-resistant andmultidrug-resistant strains have begun to emerge in the United States and arewidespread in some communities. The full impact of the problem is unknownbecause infection with drug-resistant S. pneumoniae (DRSP) is not a reportablecondition for most of the United States. To develop a strategy for minimizing theimpact of DRSP, in June 1994, CDC convened a working group of public healthpractitioners, clinical laboratorians, health-care providers, and representativesof key professional societies. This report describes the three goals developed bythe working group that address surveillance, epidemiologic investigation, andprevention and control of DRSP, and the objectives for each goal.
Streptococcus pneumoniae infections are among the leading causes worldwide of illness and death for young children, persons who have underlying debilitatingmedical conditions, and the elderly (1 ). Each year in the United States, pneumococ-cal disease is estimated to account for 3,000 cases of meningitis, 50,000 cases ofbacteremia, 500,000 cases of pneumonia, and 7,000,000 cases of otitis media (2 ).
Case-fatality rates vary by age and underlying illnesses of patients; however, case-fatality rates for some high-risk patients have been reported to be >40% for bactere-mia and 55% for meningitis, despite appropriate antimicrobial therapy (3 ). A vaccinefor the 23 most common serotypes of S. pneumoniae has been available since theearly 1980s. The Advisory Committee on Immunization Practices (ACIP) recommendsthat the vaccine be administered to persons ≥2 years of age who have certain under-lying medical conditions associated with increased risk for pneumococcal disease andits complications and to all persons ≥65 years of age (3). However, despite its availabil-ity, the vaccine is underutilized. As of 1993, data from CDC's National Health InterviewSurvey indicated that only 27% of persons ≥65 years of age had been vaccinated (4 ).
In the past, S. pneumoniae was almost uniformly susceptible to penicillin, allowing most physicians to treat persons who had severe infections with penicillin alone with-out testing for resistance. Since the 1960s, however, resistance to penicillin and otherantimicrobial agents has spread rapidly and was first reported in Australia in 1967, inNew Guinea in 1969, in South Africa in 1977, and in many other countries throughout February 16, 1996
Africa, Asia, and Europe (5,6 ). In the United States, high-level resistance to penicillinhas increased substantially in the last decade. Investigations of outbreaks by CDChave revealed that resistance to penicillin varies by region; in some areas of theUnited States, as many as 30% of pneumococcal isolates are resistant to penicillin(7,8 ). Also, the incidence of drug-resistant infections can change rapidly (9 ). A smalleryet substantial percentage of isolates is also resistant to multiple (i.e., two or more)antimicrobial drugs; some are susceptible only to vancomycin. Within communities,the proportion of pneumococcal illnesses caused by drug-resistant S. pneumoniae(DRSP) among children may be markedly different from that among adults.
Therapy for invasive pneumococcal disease and for milder illnesses (e.g., otitis me- dia) remains empiric because rapid, sensitive, and specific diagnostic tests are notavailable. Although the choice of antimicrobial agents for empiric therapy should beguided by the regional prevalence of DRSP, the prevalence of resistance to penicillin isunknown for most areas of the United States because DRSP infection has not been areportable condition. Consequently, for these infections, therapy often consists ofprescribing antimicrobial drugs that are either not necessary or are too broad. Inap-propriate empiric or prophylactic use of antimicrobial drugs contributes to thedevelopment of DRSP.
Rapid emergence of resistance to antimicrobial drugs among other bacteria also has been documented. This trend of waning susceptibility has fostered public con-cern, as reported in nationally syndicated magazines and recently published books(10,11 ). Treating patients who have resistant organisms often requires both pro-longed hospitalization and the use of expensive alternative antimicrobial drugs. Newdrugs to combat drug-resistant pathogens are being developed but may not be readilyavailable (12 ).
In the United States, prolonged hospitalization and the use of more expensive an- timicrobial agents have increased the cost of treating resistant infections, which isestimated to range from $100 million to $30 billion per year (13 ). Many of these issueswere addressed in a 1992 report by the Institute of Medicine, Emerging Infections:Microbial Threats to Health in the United States, which emphasized the need for im-proved surveillance and control of pathogens that are resistant to antimicrobial drugs(14 ). Although as of December 1995, 13 states and one city health department havemade mandatory the reporting of DRSP, no coordinated national effort has been initi-ated previously to address this problem.
The spread of DRSP presents a challenge to clinicians, laboratorians, and public health practitioners to identify and implement prevention and control methods tominimize the complications of DRSP infections (e.g., greater duration and severity ofillness, health-care expenses, and mortality). In June 1994, a CDC-convened workinggroup of public health practitioners, clinical laboratorians, health-care providers, andrepresentatives of key professional societies identified the development of a nation-wide laboratory-based surveillance system as the essential first step in a strategy ofsurveillance, investigation, prevention, and control of DRSP. The strategy is intendedto be flexible and may change as a result of data obtained during initial phases ofits implementation and from new studies. This report describes the three goalsdeveloped by the working group—surveillance, epidemiologic investigation, and pre-vention and control of DRSP—and the objectives for each goal.
Vol. 45 / No. RR-1
Goal I. Surveillance: define and monitor the prevalence and
geographic distribution of DRSP and rapidly recognize the
emergence of new patterns of resistance.

The incidence of penicillin-resistant S. pneumoniae has increased in certain senti- nel sites in the United States (1 ). These sites detected a 60-fold increase in high-levelresistance to penicillin among isolates from several large hospitals located primarilyin urban areas; however, these data are not representative of many communities inother parts of the country. Resistance to antimicrobial drugs appears to vary amongcommunities and even among hospitals in the same city. Prevention or controlprograms designed to address increasing and variable resistance to antimicrobialdrugs should include surveillance to detect levels of resistance specific to differentcommunities.
Objective A. Establish nationwide mandatory reporting of DRSP.
Concern about increasing resistance to antimicrobial agents has prompted 13 state health departments (Arkansas, Colorado, Connecticut, Georgia, Michigan, Minnesota,Missouri, New Hampshire, New Jersey, New York, North Carolina, Ohio, and SouthCarolina) and the New York City Health Department to institute regulations requiringlaboratories to report DRSP isolates from certain anatomic sites (e.g., cerebrospinalfluid [CSF] and blood). To ensure that such a surveillance system has maximumparticipation and more nationally representative data, a nationwide requirement forreporting DRSP isolates is needed.
In late 1994, the DRSP working group submitted a proposal to the Council of State and Territorial Epidemiologists (CSTE) that required all states to report invasiveinfections caused by DRSP. This proposal was approved by CSTE in January 1995(15 ). Although regulatory authority for reporting nationally notifiable diseases residesat the state level, approval by CSTE provides a basis for state health officials to en-courage their state legislators to adopt the measure. Objective B. Improve the detection of DRSP in laboratories by promoting
appropriate interpretive standards for identification and susceptibility
testing of S. pneumoniae.

On the basis of National Committee for Clinical Laboratory Standards (NCCLS) in- terpretive standards, all isolates of S. pneumoniae from usually sterile sites should betested for penicillin resistance (16 ). Pneumococcal resistance to penicillin can bescreened initially by using a 1 µg oxacillin disk; penicillin resistance is consideredprobable with oxacillin zone size ≤19 mm. The screening approach is highly sensitive(99%) and specific (80%–90%) and should detect almost all isolates resistant to peni-cillin and extended-spectrum cephalosporins (e.g., ceftriaxone or cefotaxime). Isolatesfound to be nonsusceptible by oxacillin disk should then be subjected to quantitativeMIC testing against penicillin, an extended-spectrum cephalosporin, chloramphenicol,vancomycin, and other drugs clinically indicated to treat the patient. MIC testing February 16, 1996
should be performed by using methods determined by NCCLS to be valid and reliable(e.g., broth microdilution, agar dilution, disk diffusion, or antimicrobial gradientstrips).
A recent CDC survey of laboratories providing service to large academic pediatric centers indicated that 85% of these laboratories were screening pneumococcal iso-lates for penicillin resistance by using a 1 µg oxacillin disk, a method recommended byNCCLS (CDC, unpublished data). Data from a statewide survey performed by the Colo-rado State Department of Health demonstrated that of 78 laboratories surveyed,57 (73%) were using oxacillin screening for S. pneumoniae isolates for penicillinsusceptibility; 29 (37%) were screening all isolates. A survey from the New York CityDepartment of Health demonstrated that 68% of hospital and commercial laboratoriesin New York City screened with oxacillin testing, either all isolates or all sterile siteisolates. The degree to which smaller hospital laboratories in other areas of the coun-try adhere to the NCCLS interpretive standards for pneumococcal testing is less wellknown. Many laboratories also are in periods of transition while implementing meth-ods newly approved by NCCLS, such as changes in interpretive breakpoints (e.g., zonediameters) and recommendations against the use of automated methods of minimalinhibitory concentration (MIC) susceptibility testing for S. pneumoniae (17,18 ).
The current mechanism for disseminating information from NCCLS to laborato- ries should be augmented to reach the majority of laboratorians and health-careproviders. Thus, distribution should be expanded by publishing NCCLS's current rec-ommendations on routine testing and reporting of S. pneumoniae and interpretativestandards in publications likely to be received by laboratorians and health-care provid-ers (Tables 1–3). In addition, the working group has asked selected researchers tosubmit letters to appropriate laboratory-oriented publications encouraging theprompt institution of NCCLS interpretive standards for pneumococcal testing. Thepublished recommendations should stress prompt adherence to NCCLS interpretivestandards and promote the use of appropriate methods for MIC testing.
The interpretive standards are included in this report to disseminate the most current recommendations concerning MIC interpretive breakpoints (Tables 1–3). Addi-tionally, the CDC electronic surveillance module for capturing DRSP prevalence data(DRSP-PHLIS [Public Health Laboratory Information System], v. 3.1) has incorporatedthe 1994 NCCLS interpretive breakpoints into the computer menu to assist users ofthis surveillance system with consistent interpretation of MIC data. Clinical laboratori-ans who suspect a pneumococcal isolate to be nonsusceptible to vancomycin shoulda) verify the results, b) save the isolate, and c) report the confirmed results to therespective state health department and to CDC (Childhood and Respiratory DiseasesBranch, Division of Bacterial and Mycotic Diseases, National Center for InfectiousDiseases).
Objective C. Develop an electronic, laboratory-based surveillance system
capable of reporting DRSP and other conditions.

Surveillance for pneumococcal disease has been limited in the past. Since 1979, CDC has been actively monitoring trends in invasive pneumococcal disease at13 sentinel sites nationwide. In addition, CDC-funded, population-based surveillanceprojects have been under development since October 1994 to monitor pneumococcaldisease at selected locations in several states (i.e., California, Connecticut, Georgia, Vol. 45 / No. RR-1
Maryland, Minnesota, Oregon, Tennessee, and Texas). Researchers at academicmedical centers have gathered data on DRSP and other antimicrobial-resistantorganisms such as methicillin-resistant Staphylococcus aureus (MRSA) andvancomycin-resistant enterococcus (VRE). Although these activities have yielded use-ful information regarding the incidence of DRSP, they reflect the levels of resistancespecific to those sites. Geographic variation in resistance to antimicrobial drugsamong communities and among hospitals in the same community is common.
Population-based laboratory surveillance is necessary to reflect accurately local geographic and temporal trends in DRSP. The surveillance system should capture datafrom as many laboratories as possible within each community. These data must beaggregated, analyzed, and reported to local health-care providers in a timely manner.
Clinicians need DRSP prevalence data specific to their community to select appropri-ate antimicrobial agents when empirically treating persons who have pneumococcalinfections. For example, in communities that have a high incidence of DRSP, personswho have life-threatening infections might receive therapy with vancomycin in combi-nation with an extended-spectrum cephalosporin until results of CSF or blood culturesare known. Additionally, in areas known to have low levels of pneumococci resis-tant to extended-spectrum cephalosporins, empiric vancomycin use can be avoided,thereby reducing overuse of an important antimicrobial drug. Rapid increasesin pneumococcal resistance patterns have occurred over a short time in many TABLE 1. Suggested groupings of approved antimicrobial agents* that should be
considered for routine testing and reporting of Streptococcus pneumoniae by clinical
microbiology laboratories†

Group A: Primary test and report Group B: Primary test, report selectively Group C: Supplemental, report selectively *Approved by the Food and Drug Administration.
† Adapted with permission from the National Committee for Clinical Laboratory Standards (NCCLS). Performance standards for antimicrobial susceptibility testing (fifth informationalsupplement). Villanova, PA: NCCLS, 1994; NCCLS document vol. 14, no. 16, M100-S5, M7-A3,Table 1A.
§ Only results of testing with penicillin, chloramphenicol, vancomycin, and cefotaxime or ceftriaxone (if tested by a dilution method as outlined in NCCLS document M7 of the fifthinformational supplement vol. 14. no. 16, 1994) should be reported routinely with blood andCSF isolates of S. pneumoniae recovered from patients who have life-threatening infections(e.g., meningitis and bacteremia).
¶ Susceptibility and resistance to azithromycin and clarithromycin can be predicted by suscep- tibility testing of erythromycin.
NOTE: Selection of the most appropriate antimicrobial agents to test and report is a decisionbest made by each clinical laboratory in consultation with infectious disease practitioners, thepharmacy, and the pharmacy and infection-control committees of the medical staff. Theantimicrobial agents listed above in each grouping have, during in vitro tests, demonstratedacceptable efficacy. Considerations in the assignment of agents to Groups A, B, and C includeclinical efficacy, prevalence of resistance, minimizing emergence of resistance, cost, and currentconsensus recommendations for first choice and alternative drugs. Tests on selected agentsmay be useful for infection control.
February 16, 1996
communities; therefore, recommendations regarding empiric therapy must be basedon the most recent data available. Public health practitioners also will benefit from knowledge of communitywide trends in pneumococcal resistance. For example, if such practitioners identify areaswithin their jurisdictions with high levels of resistance requiring more immediate con-trol measures, efforts can then be directed toward increasing vaccine use in thesecommunities to prevent illness in persons who are at high risk for pneumococcal ill-ness. These vaccination efforts should be part of a broader campaign to increasevaccine use in general. Laboratory surveillance for invasive pneumococcal isolatesand their susceptibility patterns can be used also to monitor changes in pneumococcal TABLE 2. Zone diameter interpretive standards and equivalent minimum inhibitory
concentration (MIC) breakpoints for Streptococcus pneumoniae*

(nearest whole mm)
Resistant Intermediate Susceptible
(oxacillin disk)** * Adapted with permission from the National Committee for Clinical Laboratory Standards (NCCLS). Performance standards for antimicrobial susceptibility testing (fifth informationalsupplement). Villanova, PA: NCCLS, 1994; NCCLS document vol. 14. no. 16, M100-S5, M2-A5,Table 2C.
†These zone diameter standards apply only to tests performed by using Mueller-Hinton agar supplemented with 5% sheep blood.
§These values represent MIC breakpoints used in determining approximate zone size interpretive criteria. They relate to MICs determined by M7 methodology. Equivalent MICbreakpoints relate to tests performed by broth microdilution using cation-adjustedMueller-Hinton Broth with 2%–5% lysed horse blood.
¶ Zone diameters and MIC breakpoints are considered tentative for 1995.
** Isolates of pneumococci with oxacillin zone sizes of ≥20 mm are susceptible (MIC ≤0.06 µg/mL) to penicillin and can be considered susceptible to ampicillin, amoxicillin,amoxicillin/clavulanic acid, ampicillin/sulbactam, cefaclor, cefepime, cefetamet, cefixime,cefotaxime, cefprozil, ceftibuten, ceftriaxone, cefuroxime, cefpodoxime, ceftizoxime,imipenem, and loracarbef for approved indications, and these agents need not be tested.
A penicillin MIC should be determined on isolates of S. pneumoniae with oxacillin zonesizes of ≤19 mm. The disk test does not distinguish penicillin intermediate strains (i.e.,MICs=0.12–1.0 µg/mL) from strains that are penicillin-resistant (i.e., MICs ≥2.0 µg/mL).
Reliable disk diffusion tests for cefotaxime and ceftriaxone do not yet exist; their in vitroactivity is best assessed by using an MIC method.
††The absence of resistant strains precludes defining any results categories other than susceptible. If clinical laboratorians suspect a pneumococcal isolate to be nonsusceptibleto vancomycin, they should 1) verify the reports, 2) save the isolate, and 3) report theconfirmed result to the respective state health department and to CDC.
Vol. 45 / No. RR-1
incidence after the introduction of protein conjugate pneumococcal vaccines that arenow being developed for use in children and adults.
To decrease the burden (e.g., time, staffing, and other resources) to laboratory per- sonnel, any system for laboratory-based reporting should use existing computerizeddata that might be already stored electronically in a laboratory information system(LIS). In addition, reporting software should be flexible enough to receive and managedata for multiple laboratory-reportable conditions (e.g., Haemophilus influenzae typeB and Neisseria meningitidis).
A laboratory-based surveillance system developed for DRSP should use electronic data management and transfer methods when appropriate and allow for feedback ofinformation to the laboratory, state and local health departments, CDC, and health-care professionals (Figure 1). The software and the methods of data transfer chosen TABLE 3. Minimum inhibitory concentration (MIC) interpretive standards (µg/mL) for
Streptococcus pneumoniae*†

Cefuroxime axetil (oral) * Adapted with permission from the National Committee for Clinical Laboratory Standards (NCCLS). Performance standards for antimicrobial susceptibility testing (fifth informationalsupplement). Villanova, PA: NCCLS, 1994; NCCLS document vol. 14. no. 16, M100-S5, M7-A3,Table 2C.
†These interpretive standards are applicable to only broth microdilution susceptibility tests with S. pneumoniae using cation-adjusted Mueller-Hinton broth with 2%–5% lysed horseblood.
§When recovered from patients who have meningitis, strains in the intermediate category may require therapy with maximum doses of the drug.
¶ A pneumococcal isolate that is susceptible to penicillin can be considered susceptible to amoxicillin, amoxicillin/clavulanic acid, ampicillin, ampicillin/sulbactam, cefaclor, cefepime,cefetamet, cefixime, cefotaxime, cefprozil, ceftibuten, ceftriaxone, cefuroxime, cefpodoxime,ceftizoxime, imipenem, and loracarbef for approved indications. Testing of these agents(except cefepime, cefotaxime, ceftriaxone, or cefuroxime axetil) against penicillin-intermediate or penicillin-resistant isolates is not recommended. Currently, reliableinterpretive criteria for these agents are not available. Physicians should be informed thatclinical response rates with these agents may be lower in strains that are not susceptibleto penicillin.
** The absence of resistant strains precludes defining any results categories other than susceptible. If clinical laboratorians suspect a pneumococcal isolate to be nonsusceptibleto vancomycin, they should 1) verify the results, 2) save the isolate, and 3) report theconfirmed result to the respective state health department and to CDC.
February 16, 1996
for electronic reporting should be expandable and standardized and should allow forreporting conditions other than DRSP. A proposed electronic, laboratory-based sys-tem is described in this report (Appendix).
Goal II. Investigation: improve the understanding of the
epidemiology and clinical impact of DRSP.

Objective A. Identify risk factors for development of resistance to
antimicrobial drugs by conducting epidemiologic investigations in
communities that have unusually high or low levels of DRSP.

Levels of pneumococcal antimicrobial resistance can vary among communities.
Identifying regions that have unusually high or low levels of resistance, as well asidentifying outbreaks caused by resistant strains, will assist investigators in moreaccurately characterizing the epidemiology of DRSP and in developing methods toprevent and control the complications of DRSP-related illness. Molecular methods willbe employed to track epidemiologically the spread of highly resistant strains and togain further understanding of mechanisms of resistance to antimicrobial drugs. Byfocusing on communities that have unusually high levels of resistance to antimicro-bial drugs, investigators can evaluate risk factors that promote the development ofantimicrobial resistance. CDC and state and local health departments also should FIGURE 1. Flow of information through an electronic, laboratory-based surveillance
system — United States, 1995

Minimum Inhibitory Concentration exported Laboratory State Health Department Vol. 45 / No. RR-1
focus investigations on communities with low levels of resistance to antimicrobialdrugs to identify factors that have deterred the increase of antimicrobial resistanceand to implement programs for preventing the spread of DRSP. Comparing communi-ties with high and low levels of resistance can help to identify risk factors forantimicrobial resistance. Studies are currently being conducted in several cities toidentify risk factors for development of DRSP and for increased morbidity from theseinfections.
Objective B. Determine outcome and treatment costs of DRSP infections
and formulate recommendations for changing empiric antimicrobial
therapy on the basis of community-specific levels of resistance to
antimicrobial drugs.

CDC studies are under way to determine the cost of treatment and outcome of in- vasive DRSP infections. This information will be used to develop models that publichealth officials at the state and local levels can use to determine thresholds for recom-mending changes in antimicrobial therapy.
Because initial therapy for pneumococcal infection is usually empiric, the selection of antimicrobial agents should be guided by the regional prevalence of DRSP. Surveil-lance for DRSP will provide data on community-specific levels of resistance. Thesedata can be useful in deciding when to change empiric therapy. Although no consen-sus exists for this decision making, many factors (e.g., outcome of infection, cost oftreating infection, susceptibility of the population, and access to medical care) may beimportant for determining a threshold at which empiric therapy should be changed.
Through the process of decision analysis, these factors can be incorporated intoa model that can be used for determining the community-specific proportion ofresistant pneumococcal isolates at which a change in empiric therapy should be rec-ommended to clinicians in the community.
Objective C. Investigate the transmission of antimicrobial-resistant
pneumococci through studies of nasopharyngeal colonization.

Several factors have been associated with the emergence of DRSP, most notably attendance in child day care centers and frequent use of antimicrobial drugs. Becausemany earlier studies of pneumococcal transmission were performed before wide-spread emergence of penicillin resistance, the relevance of these findings for DRSP isnot clear, and several issues regarding the transmission of DRSP remain to be exam-ined. Identifying these key factors for transmission will help to improve preventionand control strategies.
To determine the association of nasopharyngeal carriage of DRSP with develop- ment of invasive DRSP infection, several studies recently have been initiated inGeorgia, Maryland, and Texas. The studies are intended to provide information onpatterns of resistance and proportions of DRSP nasopharyngeal isolates in thecommunity and their relation to invasive DRSP isolates identified during community-wide surveillance. If isolates identified through nasopharyngeal cultures arerepresentative of isolates that cause invasive disease, surveillance of DRSP by usingnasopharyngeal cultures may be useful in areas where laboratory-based surveillanceis not possible. For small population areas, long periods of time may be required toobtain sufficient numbers of cases of invasive pneumococcal isolates before precise February 16, 1996
estimates of DRSP prevalence can be obtained. In these communities, surveillance byusing nasopharyngeal cultures might provide a more rapid estimate of the prevalenceof DRSP.
Goal III. Prevention and control: minimize complications of
DRSP infections through prevention and control of DRSP

Objective A. Improve vaccination use nationally, targeting areas most likely
to benefit from intervention (e.g., regions with high levels of resistance to
antimicrobial drugs or communities of persons at highest risk for infection).

A vaccine for the 23 most common serotypes of S. pneumoniae is available, yet underutilized. Healthy People 2000 objectives target the vaccination of 60% of personsat risk for pneumococcal illness by the year 2000 (19 ). As of 1993, data from theNational Health Interview Survey indicated that only 27% of persons ≥65 years of agehad been vaccinated (4 ). Reasons for insufficient use of the vaccine differ; however,vaccine use increases when efforts are made to raise awareness and promote thebenefits of vaccination. Communities with high levels of antimicrobial resistance andpersons at highest risk for infection will benefit from targeted campaigns to increaserates of vaccination. The 23-valent pneumococcal vaccine is not adequately immuno-genic in young children; thus, it is not recommended for use in children <2 years ofage, a population at high risk for acute pneumococcal otitis media, bacteremia, andmeningitis.
In conjunction with state health departments and the Health Care Financing Ad- ministration, CDC is developing and expanding programs to promote the use ofpneumococcal vaccine. By using data obtained from surveillance for DRSP, state andlocal health departments can target areas of high-level pneumococcal antimicrobialresistance for increased vaccination. Promotions for vaccination among the generalpublic and for targeted groups can be disseminated through media releases, medicalsocieties, infection-control practitioners, and health-care providers (e.g., health main-tenance organizations, hospitals, and health clinics).
An effective pneumococcal protein-conjugate vaccine prescribed at least for all children <2 years of age would be the most effective means of preventing pneumococ-cal illness in children; however, conjugate vaccines are still being developed andevaluated. If effective, approved vaccines will likely not be available for several years.
As surveillance for DRSP improves, the prevalence of antimicrobial resistance mayreach levels sufficiently high to warrant changes in the current recommendations forpneumococcal polysaccharide vaccine use. Such necessary changes may includereexamining the definition of persons at high risk for pneumococcal infection to in-crease vaccine use (e.g., by children in day care centers).
Objective B. Promote the judicious use of antimicrobial agents.
Increased use of antimicrobial drugs encourages the spread of resistance and in- creases the prevalence of drug-resistant strains. Data from hospital-based studiesindicate an association between increased rates of use of antimicrobial agents andresistant nosocomial infections (20 ); data from studies associating rates of use of Vol. 45 / No. RR-1
antimicrobial agents and resistance on a district or national scale indicate a similarassociation (21,22 ). In addition, multiple case-control studies have indicated thatprevious use of antimicrobial drugs is a substantial risk factor for infection with a re-sistant pathogen (2,23 ).
Most antimicrobial drugs are administered for treatment of outpatient infections. In 1992, in the United States, an estimated 110 million courses of antimicrobial therapywere prescribed by office-based physicians—a 28% increase over the number pre-scribed in 1980 (24 ). Rates of use of antimicrobial agents for children <15 years of agewere approximately three times greater than those for other age groups. In 1990, com-mon respiratory infections, upper respiratory tract infection, bronchitis, sinusitis, andpharyngitis were the five leading diagnoses resulting in prescriptions for antimicrobialdrugs.
Although appropriate antimicrobial-drug use has unquestioned benefit, often these agents are used inappropriately by physicians and the public. The following practicesof physicians may contribute to inappropriate use of antimicrobial drugs: Providing antibacterial drugs to treat viral infections. In 1992, upper respiratory
tract infections were the second leading indication for outpatient use of antibacterialdrugs (24 ). Studies have demonstrated that antibacterial therapy for nonspecificupper respiratory infections does not benefit patients because these infections have aviral etiology but does increase the likelihood that resistant organisms will beselected.
Using inadequate diagnostic criteria for infections that might have a bacterial eti-
ology. Patients who have a cough and nasal discharge frequently are diagnosed as
having bronchitis and sinusitis—the third and fifth leading diagnoses resulting in out-
patient antimicrobial use (24 ). However, the specificity of these diagnoses for an
infection that truly requires treatment will be low unless appropriate criteria are used
in making the diagnosis. Establishing age-appropriate standards for diagnosing these
conditions would assist physicians in deciding which patients require antimicrobial
therapy and which patients can be sent home with appropriate follow-up and no
antimicrobial drugs. For pharyngitis—the fourth leading diagnosis—standards for di-
agnosis already have been established by the Committee on Infectious Diseases of the
American Academy of Pediatrics (24,25 ); however, these guidelines frequently are not
followed (26 ).
Prescribing expensive, broad-spectrum agents that are unnecessary, determining
improper dose and duration of therapy, and not following established recommenda-
tions for chemoprophylaxis.
Although amoxicillin remains an effective first-line
therapy for most children who have otitis media, data from a recent study among
children in a managed-care organization demonstrated that during 1993–1994,
24% and 17% of children with otitis media had been treated with cephalosporins and
combination agents, respectively (CDC, unpublished data). Drugs used for otitis media
prophylaxis included cephalosporins as well as the recommended agents amoxicillin
and sulfisoxazole (25 ).
Reasons for overuse of antimicrobial drugs are manifold. Physicians may be uncer- tain regarding the optimal approach to diagnosis and the best therapy for anindividual patient, particularly in a community where antimicrobial resistance alreadyis present. Practices concerning the use of antimicrobial drugs may also be affected byphysicians' concerns regarding not treating infections potentially caused by bacteria February 16, 1996
and the possibility of subsequent lawsuits from untoward outcomes. Patients andparents contribute to the misuse of antimicrobial drugs by pressuring physicians toprovide treatment. Developing effective strategies to improve antimicrobial use willrequire the recognition that the physician and the patient (or the patient's parent[s])are partners in health care and that information must be provided to both groups.
These strategies should ensure that bacterial infections are appropriately treated interms of health outcome and cost, while preserving the usefulness of antimicrobialagents in treating future disease.
Beginning in 1995, CDC, in collaboration with professional societies, managed-care organizations, and other groups, initiated projects to a) evaluate current knowledge,attitudes, and behaviors of physicians and the public regarding use of antimicrobialagents; b) develop standards for diagnosis, therapy, and prophylaxis of common out-patient respiratory tract infections; c) develop educational materials for providers andpatients/parents by promoting appropriate diagnostic methods and judicious antimi-crobial use; and d) evaluate the impact of these interventions. Although changingbehaviors regarding the use of antimicrobial drugs will require a long-term, multifac-eted strategy, these projects will be an important first step in reaching Objective B. Objective C. Establish rational treatment guidelines for use by physicians
treating presumptive pneumococcal infections.

Relevant clinical interpretations of data pertaining to antimicrobial resistance obtained through the proposed surveillance system should be communicated toclinicians treating patients who have presumed pneumococcal illness. Physicians incommunities that have high levels of antimicrobial resistance should be informedof appropriate empiric choices of antimicrobial agents. Those in areas that have lowlevels resistance also should be informed so that unnecessary drug combinations orinappropriately broad regimens are not used. This information, which constitutes thefeedback arm of the surveillance system, should be easily accessible to public healthofficials and provided regularly to clinicians. To establish treatment guidelines, persons from the DRSP working group, profes- sional societies, academic institutions, state health agencies, and CDC will examineavailable data and work to develop recommendations that represent a rational ap-proach to antimicrobial therapy in the context of increasing antimicrobial resistance.
These guidelines should be used to assist state and local health departments in rec-ommending appropriate empiric antimicrobial regimens and vaccination strategiesbased on susceptibility trends in their jurisdictions. Medical societies, communicable-disease newsletters, hospitals, and managed-care organizations may be usefulresources for sharing information. Because rapid changes in resistance levels can oc-cur, surveillance data and recommendations should be communicated to clinicianseither monthly or bimonthly.
Objective D. Periodically publish national and regional trends in
pneumococcal antimicrobial resistance.

Data from the proposed surveillance system will be received at CDC from various state health departments as described previously in Goal I, Objective C. These datawill be analyzed to develop a national profile of DRSP incidence showing geographicpatterns of pneumococcal resistance. The results of data analyses will be used by Vol. 45 / No. RR-1
health-care providers, public health officials, and managed-care organizations todevelop policies regarding DRSP and to develop treatment guidelines. These data alsomay give manufacturers of antimicrobial drugs more accurate descriptions of the an-timicrobial susceptibilities of drugs used to treat pneumococcal infections.
Early in the implementation of the surveillance system, CDC will publish DRSP inci- dence data quarterly in the MMWR (weekly) indicating individual state totals andnational trends. The data also will be disseminated periodically in appropriate jour-nals. New regulations from the Food and Drug Administration may require packageinserts for antimicrobial drugs to contain information on antimicrobial susceptibilityobtained from national surveillance databases.
The DRSP working group's strategy for surveillance, investigation, prevention, and control of infections caused by DRSP has focused on implementation of a laboratory-based, electronic surveillance system for reporting invasive DRSP infections,increased pneumococcal vaccination, and promotions of judicious use of antimicro-bial drugs. Data received through the surveillance system will be used to determinecommunity-specific levels of pneumococcal antimicrobial resistance. This informationwill be made available to health-care providers and clinicians to promote appropriateuse of antimicrobial drugs and increased vaccine use. The intended outcome of thesurveillance system is to control the spread of DRSP and to minimize complications ofDRSP infection (e.g., greater duration and severity of illness, long-term sequelae,health-care expenditures, and mortality). The strategy is intended to be flexible andmay change on the basis of information obtained during initial phases of its imple-mentation and on results of new studies.
1. Breiman RF, Butler JC, Tenover FC, Elliott JA, Facklam RR. Emergence of drug-resistant pneu- mococcal infections in the United States. JAMA 1994;271:1831–5.
2. 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.
3. CDC. Pneumococcal polysaccharide vaccine. MMWR 1989;38:64–7,68–77.
4. CDC. Influenza and pneumococcal vaccination coverage levels among persons aged ≥65 years—United States, 1973–1993. MMWR 1995;44:506–7,513–5.
5. Caputo GM, Appelbaum PC, Liu HH. Infections due to penicillin-resistant pneumococci: clinical, epidemiologic, and microbiologic features. Arch Intern Med 1993;153:1301–7.
6. Jacobs MR, Koornhof HJ, Robins-Browne RM, et al. Emergence of multiply resistant pneu- mococci. N Engl J Med 1978;299:735–40.
7. Duchin JS, Breiman RF, Diamond A, et al. High prevalence of multidrug-resistant Streptococcus pneumonia among children in a rural Kentucky community. Pediatr Infect Dis J 1995;14:745–50.
8. CDC. Prevalence of penicillin-resistant Streptococcus pneumoniae —Connecticut, 1992–1993.
MMWR 1994;43:216–7, 223.
9. Block SL, Harrison CJ, Hedrick JA, et al. Penicillin-resistant Streptococcal pneumoniae in acute otitis media: risk factors, susceptibility patterns, and antimicrobial management. Pediatr InfectDis J 1995;14:751–9.
10. Revenge of the killer microbes: losing the war against infectious disease. Time 1994; 11. Garrett L. The coming plague: newly emerging diseases in a world out of balance. New York: Farrar, Straus, and Giroux, 1994:411.
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12. Service RF. Antibiotics that resist resistance. Science 1995;270:724–7.
13. Phelps CE. Bug/drug resistance: sometimes less is more. Med Care 1989;27:194–203.
14. Institute of Medicine. Emerging infections: microbial threats to health in the United States.
Washington, DC: National Academy Press, 1992:92–4.
15. CDC. National surveillance for infectious diseases, 1995. MMWR 1995;44:737–9.
16. National Committee for Clinical Laboratory Standards. Performance standards for antimicro- bial susceptibility testing. Villanova, PA: National Committee for Clinical Laboratory Standards,1994;14(16).
17. 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 diffusionantimicrobial susceptibility testing of Streptococcus pneumoniae. J Clin Microbiol 1994;32:2448–59. 18. National Committee for Clinical Laboratory Standards. Performance standards for antimicro- bial susceptibility testing (5th informational supplement). Villanova, PA: National Committeefor Clinical Laboratory Standards, 1994; NCCLS document no. M100–S5.
19. Public Health Service. Healthy people 2000: national health promotion and disease prevention objectives. Washington, DC: US Department of Health and Human Services, Public HealthService, 1991; DHHS publication no.(PHS) 91–50213. 20. McGowan JE. Antimicrobial resistance in hospital organisms and its relation to antibiotic use.
Rev Infect Dis 1983;5:1033–48.
21. Baquero F, Martinez-Beltran J, Loza E. A review of antibiotic resistance patterns of Strepto- coccus pneumoniae in Europe. J Antimicrob Chemother 1991;28(suppl C):31–8.
22. Seppälä H, Klaukka T, Lehtonen R, Nenonen E, the Finnish Study Group for Antimicrobial Resistance, Huovinen P. Outpatient use of erythromycin: link to increased erythromycin re-sistance in Group A streptococci. Clin Infect Dis 1995;21:1378–85.
23. Radetsky MS, Istre GR, Johansen TL, et al. Multiply resistant pneumococcus causing men- ingitis: its epidemiology within a day care center. Lancet 1981;2:771–3.
24. McCaig LF, Hughes JM. Trends in antimicrobial drug prescribing among office-based physi- cians in the United States. JAMA 1995;273:214–9.
25. American Academy of Pediatrics. Group A streptococcal infections. In: Peter G, ed. 1994 Red book: report of the Committee on Infectious Diseases, 23rd ed. Elk Grove Village, IL: AmericanAcademy of Pediatrics, 1994:430–9, 521.
26. Schwartz B, Fries S, Fitzgibbon AM, Lipman H. Pediatricians' diagnostic approach to pharyngi- tis and impact of CLIA 1988 on office diagnostic tests. JAMA 1994;271:234–8.
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February 16, 1996
Appendix: Laboratory-Based Surveillance System
I. Components and operation of the laboratory-based
The proposed surveillance system is intended to monitor only invasive pneu-mococcal infections and their antimicrobial susceptibility patterns. For thissystem, invasive pneumococcal infection refers only to meningitis and bac-teremia identified by isolation of S. pneumoniae from cerebrospinal fluid (CSF)or blood, respectively. The system is not intended to monitor isolates obtainedfrom respiratory secretions. Although information from respiratory isolatesmay be useful, the large number of sputum specimens routinely collected frompatients who have pneumonia would likely overwhelm a surveillance systeminitially. Addition of surveillance for respiratory isolates might be considered inthe future, depending upon ease of implementing surveillance, available re-sources, and expected utility. The following definitions have been approved bythe Council of State and Territorial Epidemiologists (CSTE) for drug-resistantStreptococcus pneumoniae (DRSP) surveillance: 1. Confirmed case A confirmed case of invasive DRSP is defined as either meningitis or bactere-mia in which S. pneumoniae cultured from CSF or blood is identified asnonsusceptible (using National Committee for Clinical Laboratory Standards[NCCLS] methods and breakpoints) to antimicrobial drugs currently ap-proved for treating pneumococcal infections.
When oxacillin disk screening is the only antimicrobial susceptibility methodused, the antimicrobial susceptibility profile cannot be definitely determined.
For these instances, a probable case definition is needed.
To obtain data from laboratories that perform only oxacillin screening, aprobable case definition has been made. A probable case of invasive DRSPis defined as either meningitis or bacteremia in which S. pneumoniaecultured from CSF or blood is identified as nonsusceptible by oxacillinscreening (i.e., zone size ≤19 mm) and no further antimicrobial susceptibilitytesting has been performed.
B. Reporting
Laboratories will be required to report probable or confirmed cases of DRSPto their state health departments in a line-listed manner to include the pa-tient's date of birth or age, the anatomic site of specimen collection, the date of Vol. 45 / No. RR-1
specimen collection, the antimicrobial susceptibility pattern, and unique iden-tifiers for the laboratory and the specimen. The patient's first and last namealso will be required at the state level; however, CDC will not have personalidentifiers. Measures will be taken to protect sensitive health information. Cur-rent reporting software supports the capability to encrypt names, allowingpersonal identifiers to be removed. Having the encrypted name along withlaboratory and specimen identifiers allows duplicate reports to be identified. Toreduce duplicate reporting of isolates from the same episode of clinical illness,isolates from the same patient will not be added to the surveillance database ifthe specimen submission date is within 10 days of a previous report.
To determine the incidence and prevalence of DRSP, the total number ofinvasive site isolates tested (i.e., denominator data) must be determined. De-nominator data will be essential for providing relevant clinical information tophysicians and other health-care providers (see Goal III, Objectives C and D).
For laboratories with computerized data management, all invasive site isolatescan be reported in the same manner as previously described. Laboratoriesunable to provide data easily in this manner should report aggregate denomi-nator data monthly; data would include the total number of invasive siteisolates tested by age group (<6 years of age, 6–17 years, and ≥18 years of age)and anatomic collection site (i.e., CSF or blood).
The data being collected for surveillance may be readily available from thecomputerized records of many laboratories. This information may be importedfrom laboratory computer files into a currently available standardized databaseformat, which may be either transmitted electronically or sent by maileddiskette to the state health departments and subsequently to CDC. Ideally,computerized laboratories would be able to provide data output in Health LevelSeven (HL7) standard format, or in a compatible standard format, for transmis-sion to the state health department, where the data could be retrieved bycompatible software. HL7 is being used increasingly as a standard for codingand electronically transmitting hospital and laboratory data, and its continueduse as a standard should be encouraged by CDC, CSTE, and Association ofState and Territorial Public Health Laboratory Directors (ASTPHLD). These HL7standards and specifications should be made readily available to laboratoryinformation systems (LIS) vendors and large national reference laboratories.
Initially, the system would be piloted in selected cities. Ultimately, it is intendedto be a comprehensive, population-based system for U.S. laboratories certifiedin accordance with the Clinical Laboratories Improvement Amendment (CLIA)of 1988, including hospital laboratories, commercial laboratories, and statepublic health laboratories.
C. Data management and dissemination
Data will be stored in three locations: the laboratory data repository, statehealth departments, and CDC. State-specific information regarding DRSPprevalence will be maintained at the respective state health departments and February 16, 1996
will be used to provide regular feedback of regional data to hospitals, laborato-ries, and clinicians (see Goal III, Objective C). Data merged from multiplelaboratories will be periodically transmitted electronically to state healthdepartments and CDC. These data will be compiled to determine DRSP preva-lence data by state and to provide a quarterly national summary report (seeGoal III, Objective D). State health departments will have the ability to restrictcertain data fields, such as personal identifiers, before sending data to CDC.
The quarterly results of the merged surveillance information will be publishedin journals accessible to laboratorians and clinicians. Data presented in agraphic format will reflect regional variations and temporal changes.
II. Phases of implementation
The surveillance system will be implemented in four phases: pilot, addition oflaboratories in the pilot community, expansion to other laboratories, and nation-wide laboratory participation.
A. Phase 1. Pilot study
Two laboratories in New Jersey (one in Camden County and one in MiddlesexCounty) have been identified for participation. These counties are the site of avaccine demonstration study currently being conducted with CDC assistance.
Both laboratories provide services to large academic centers and have agreedto participate in the pilot phase of the implementation of the surveillancesystem. These and other laboratories in New Jersey have been participatingin surveillance of methicillin-resistant Staphylococcus aureus (MRSA),vancomycin-resistant enterococcus (VRE), and DRSP through a traditional sur-veillance mechanism that uses paper report forms. Implementing the pilotphase in New Jersey allows for introduction of electronic reporting in an envi-ronment where reporting is already required and familiar to laboratories.
A review of the computer capabilities and laboratory practices of the two par-ticipating laboratories was performed in early January 1995. Initial site visitswere made to introduce the hospitals to the electronic surveillance system.
During a trial period after the initiation of the pilot, data will be collected andelectronically transmitted to the state health department. Software will beavailable at the state level for analysis and for transmission to CDC. After thedata are transmitted to CDC at the end of the first month of collection, the sys-tem will be evaluated and improved.
B. Phase 2. Addition of laboratories in the pilot community
In Phase 2, laboratories in the same counties as the two pilot laboratories willbe added to the surveillance system. Phase 2 should begin approximately90 days after initiation of Phase 1. Laboratories will be evaluated for participa-tion in the following manner: Vol. 45 / No. RR-1
1. Laboratory survey Through a mailed questionnaire, laboratories in the pilot area will besurveyed to determine the methods used for susceptibility testing of pneu-mococcal isolates and to determine the level of computer capability in thelaboratory.
2. Assessment of laboratories Laboratories capable of participation in the pilot should meet the followingcriteria: • Perform pneumococcal susceptibility testing by using NCCLS interpre- • Enter and report laboratory data by using computers,• Have a laboratory software package capable of being translated to a database software through downloaded ASCII text, Health Level 7standard format, or a comparable standard format, • Have a personal computer (at least a 386 processor) with a modem (≥2400 bps), capable of running PHLIS (Public Health Laboratory Infor-mation System) version 3.1, and • Have personnel available and willing to implement the pilot study.
Laboratories meeting the criteria will be involved in Phase 2. Those laborato-ries not yet capable of electronic reporting will be encouraged to enhancetheir present system to participate in later phases. In the two pilot sites,19 laboratories are expected to participate.
3. Implementation and evaluation Data from the participating laboratories will be transmitted to the statehealth department at least once a month. At the end of each 30-day period,the state health department will transmit the data to CDC. The system will beevaluated and improved.
C. Phase 3. Expansion of surveillance to other laboratories
During Phase 3, laboratories in communities that have ongoing population-based pneumococcal studies will be enrolled. These studies may beCDC-sponsored emerging infections programs or other surveillance projects.
Implementing surveillance in communities that have ongoing studies will en-able comparisons to be made between the new, electronic, laboratory-basedsurveillance and the present standard for surveillance. Four to seven statesare expected to have communities participating. When the surveillance is es-tablished within those communities with ongoing pneumococcal studies,expansion to include all laboratories within the state will begin. Implementa-tion of Phase 3 is expected by late 1996.
February 16, 1996
D. Phase 4. Nationwide laboratory participation
Laboratories will be added to the surveillance system, with an estimated par-ticipation of 70% of clinical laboratories nationwide by 1998. Expansion of thesurveillance system to include other laboratory-reportable illnesses is ex-pected. The system proposed in the strategy is intended to utilize software anddata transmission standards to allow coordination with other systems for re-porting.
III. System attributes
The proposed surveillance system is intended to simplify data reporting by usinginformation that is currently being collected in many laboratories. The system isflexible because the software used to manage and transmit the data will be ableto accommodate other laboratory reportable diseases in the future. The systemfacilitates timely feedback to the laboratories and health departments because in-cidence of DRSP can be determined using the software both in the laboratory andin the health department. IV. Utility
The surveillance system is intended to provide public health officials, clinicians,and health-care providers with data that can be used to prevent and control DRSPinfections. In addition, the DRSP surveillance system is intended to be a model forthe introduction of electronic, laboratory-based reporting of communicable dis-eases. Inherent in the implementation and maintenance of the surveillancesystem is the ability to change the components or the focus of surveillance torespond to results of new studies and emerging problems. Given the dynamicnature of DRSP, predicting the rate at which resistance to antimicrobial drugs willincrease communitywide and nationwide is difficult. Surveillance may be scaledback and performed at selected sites when geographic and temporal variations inDRSP incidence are no longer apparent.
The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control
and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis
for paper copy. To receive an electronic copy on Friday of each week, send an e-mail message to
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. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing
Office, Washington, DC 20402; telephone (202) 512-1800.

Data in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments.
The reporting week concludes at close of business on Friday; compiled data on a national basis are officially
released to the public on the following Friday. Address inquiries about the MMWR Series, including material
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All material in the MMWR Series is in the public domain and may be used and reprinted without
permission; citation as to source, however, is appreciated.
U.S. Government Printing Office: 1996-733-175/27038 Region IV


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CUSTOMER SOLUTIONS NEXIUM CUSTOMER SOLUTIONS "El Centro Virtual de Experiencias de Internacionalización" (The On-line Centre for International Business Cases) is the result of the collaboration of the Spanish Institute for Foreign Trade ICEX and AEEDE, the Spanish Association of Business Schools , which includes eleven leading Business Schools. The aim of this project is to promote the internationalisation of Spanish SMEs,

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