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Infectious DiseasesPneumococcal Disease in Adults: Prevention and Management CMEChristopher J. Lettieri, MD; Jacob F. Collen, MD

This article is a CME-certified activity. To earn credit for this activity visit:

http://cme.medscape.com/viewarticle/714701This activity is supported by an independent educational grant from Wyeth.

Co-sponsored by the Duke University School of Medicine, the National Foundation for Infectious Diseases, and Medscape, LLC.

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Pneumococcal Disease in Adults: Prevention and Management

This article is a CME certified activity. To earn credit for this activity visit:

http://cme.medscape.com/viewarticle/714701 This activity is supported by an independent educational grant from Wyeth.

CMEReleased:01/20/2010;Validforcreditthrough01/20/2011

TargetAudience

This activity is intended for infectious disease specialists who are uniquely qualified to initiate preventive measures and appropriate treatment regimens, inform the debates over areas of uncertainty and controversy, and provide expert guidance to generalists and other clinicians who provide care for this patient population.

Goal

The goal of this activity is to address the following gaps:

• Gap in performance: Results of a recent survey on adult vaccination practices show that nearly 50% of healthcare providers did not use the Advisory Committee on Immunization Practices (ACIP) recommendations to guide their practice. • Gap in competence: The presentation of pneumococcal pneumonia varies greatly, and many patients do not have “classic” features, such as fever. Many manifestations of pneumococcal infection can quickly lead to dire consequences. Clinicians must be alert to all aspects of patient history and be prepared to employ optimal and rapid diagnostic testing.

AuthorsandDisclosures

Christopher J. Lettieri, MDAssociate Professor of Medicine, Uniformed Services University of Health Sciences, Bethesda, Maryland; Director, Sleep Medicine/Pulmonary, Critical Care, and Sleep Medicines, Walter Reed Army Medical Center, Washington, DCDisclosure: Christopher J. Lettieri, MD, has disclosed no relevant financial relationships.

Jacob F. Collen, MDTeaching Fellow in Medicine, Uniformed Services University of the Health Services, Bethesda, Maryland; Fellow, Pulmonary and Criti-cal Care Medicine, Walter Reed Army Medical Center, Washington, D.C.Disclosure: Jacob F. Collen, MD, has disclosed no relevant financial relationships.

Editor(s)

Susan L. Smith, MN, PhDScientific Director, MedscapeCMEDisclosure: Susan L. Smith, MN, PhD, has disclosed no relevant financial relationships.

Reviewer(s)

Susan J. Rehm, MDMedical Director, National Foundation for Infectious Diseases, Bethesda, Maryland; Vice Chair, Department of Infectious Disease, Cleveland Clinic, Cleveland, OhioDisclosure: Susan J. Rehm, MD, has disclosed the following relevant financial relationships:Received grants for clinical research from: Cubist PharmaceuticalsServed as an advisory board member for: Pfizer Inc. Served as a speaker or member of a speakers bureau for: Cubist Pharmaceuticals

Lauren Ero, MSDirector, Continuing Medical Education, National Foundation for Infectious Diseases, Bethesda, MarylandLauren Ero has disclosed no relevant financial relationships.

http://cme.medscape.com/viewarticle/714701

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CMEReviewer(s)

Katherine Grichnik, MDAssociate Dean, Office of CME, Duke University School of Medicine, Durham, North CarolinaDisclosure: Katherine Grichnik, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Hyperspectral Imaging Owns stock, stock options, or bonds from: Digital Dermatology; Malachyte Corporation

LearningObjectives

Upon completion of this activity, learners should be able to:

1. Summarize data supporting current clinical practice guideline recommendations for the prevention of pneumococcal disease

2. Advise others in regard to the safety and efficacy data on current and emerging therapies for the prevention of pneumococcal disease, as well as the changing epidemiology of Streptococcus pneumoniae and implications for practice

3. Judiciously use, and promote judicious use of, antimicrobials for the treatment of pneumococcal disease

CreditsAvailable

Physicians - maximum of 1.50 AMA PRA Category 1 Credit(s)™ All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation.

Physicians should only claim credit commensurate with the extent of their participation in the activity.

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Duke School of Medicine requires CME faculty (authors) to disclose to attendees when products or procedures being discussed are off-label, unlabeled, experimental, and/or investigational (not FDA approved); and any limitations on the information that is presented, such as data that are preliminary or that represent ongoing research, interim analyses, and/or unsupported opinion. Faculty may/will discuss information about pharmaceutical agents that is outside of US Food and Drug Administration approved labeling. This information is intended solely for continuing medical education and is not intended to promote off-label use of these medications. If you have questions, contact the medical affairs department of the manufacturer for the most recent prescribing information.

StaffandContentValidationReviewerDisclosure

The staff involved with this activity and any content validation reviewers of this activity have reported no relevant financial relationships with commercial interests.

ResolutionofConflictsofInterest

In accordance with the ACCME Standards for Commercial Support of CME, the Duke University School of Medicine implemented mechanisms, prior to the planning and implementation of this CME activity, to identify and resolve conflicts of interest for all individuals in a position to control content of this CME activity.

Disclaimer

The information provided at this CME activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition.

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Streptococcus pneumoniae

Streptococcus pneumoniae, also known as pneumococcus, is a formidable foe in the battle against infectious diseases. Discovered over 100 years ago, S pneumoniae is a significant cause of morbidity and mortality worldwide.[1] S pneumoniae is an encapsulated organism with > 90 known serotypes on its capsule’s surface. However, relatively few (approximately 30) of these serotypes are known to cause clinical disease.[1] Serotype distribution varies by geographic region; thus, the rates of specific serotypes are vari-able between different countries and continents. Data on serotype distribution also vary according to the time of year when the data were collected and the isolation site of bacteria. Some pneumococci are more likely to cause lower respiratory tract infections vs meningitis or other forms of invasive disease.[2]

S pneumoniae is a gram-positive, alpha-hemolytic, anaerobic diplococcus (Figure 1). The polysaccharide capsule of S pneumoniae has been considered the primary virulence factor because nonencapsulated bacteria are essentially harmless compared with the same encapsulated strain. Recent studies, however, have suggested that certain pneumococcal proteins on the surface of S pneumoniae may also be important virulence factors in the pathogenesis of infection and disease, and potentially for the development of new vaccines. These virulence factors are described in detail elsewhere.[3,4] These proteins and enzymes enable S pneumoniae to evade host defenses and cause invasive disease by concealing and protecting the bacterial surface from host immune defenses and interacting with host tissues to facilitate bacterial colonization (ie, of the nasopharynx); adherence (ie, to the respiratory epithelium); and ultimately pulmonary and extrapulmonary dissemination, bacteremia, and systemic disease.[3,5]

Figure 1. Under a high magnification of 20,000x, this colorized scanning electron micrograph revealed a small clustered group of gram-positive, beta-hemolytic group C Streptococcus species bacteria.This image is in the public domain and thus free of any copyright restrictions. Photo credit: Janice Haney Carr.

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Pneumonia

Bacteremia

Meningitis

An active cigarette smoker

A passive cigarette smoker (exposed to secondhand smoke)

Someone who quit cigarette smoking 8 years ago

A tobacco chewer

Very familiar

Somewhat familiar

Not familiar

Patient with diabetes

Patient who is alcoholic

Patient with renal cell carcinoma

Patient with chronic myeloid leukemia

Clinical Factors Points

Confusion 1

Blood urea nitrogen > 19 mg/dL 1

Respiratory rate ≥ 30 breaths per minute 1

Systolic blood pressure < 90 mm Hg 1

or Diastolic blood pressure ≤ 60 mm Hg

Age ≥ 65 years 1

Total score 5

Site of Care Recommendations[a]

Outpatient For oreviously healthy patient and no use of antimicrobials within 3 months:Setting - A macrolide - Doxycycline

Patient with presence of comorbidities or antimicrobials within 3 months: - Respiratory �uoroquinolone: 750 mg of moxi�oxacin, gemi�oxacin, and levo�oxacin - Beta-lactam (high-dose amoxicillin preferred) plus a macrolide

Note: If high rate of “high-level” macrolide-resistant S pneumoniae, consider use of alternative agents listed above.

Hospital (not in Respiratory �uoroquinolone (moxi�oxacin, 400 mg once daily; levo�oxacin, 750 mg onceICU) daily) Beta-lactam plus a macrolide

Note: Antibiotics, including alternative agents, should be chosen on the basis of pror antimicrobial use as indicated.

Hospital (in A beta-lactam (cefotaxime, ceftriaxone, ampicillin/sulbactam) plus either azithromycin or aICU) respiratory �uoroquinolone Note: For penicillin-allergic patients, a respiratory �uoroquinolone and aztreonam are recommended. Special considerations include Pseudomonas and CA-MRSA.

Disease Category Cases/1000,000 Persons Fold Increase

Healthy adults 9 0

Diabetes 51 5.8

Chronic lung disease 63 7.1

Chronic heart disease 94 10.6

Alcoholism 100 11.3

Solid cancers 300 34.1

HIV/AIDS 423 48.1

Hematologic cancers 503 57.1

Criteria De�ning Characteristics

Age > 60 years

History of central nervous system disease Mass lesion Cerebrovascular accident Focal infection

History of seizure (≤ 1 week prior to presentation) Delay lumbar puncture for 30 minutes after seizure

Abnormal neurologic examination Altered level of consciousness Inability to correctly answer 2 consecutive questions Inability to follow 2 consecutive commands Gaze palsy Abnormal visual �elds Facial palsy Arm or leg drift Abnormal speech or language

Immunocompromising conditions HIV/AIDS latrogenic (medication) Cancer Transplantation

30 days

60 days

90 days

120 days

Streptococcus pneumoniae Identi�ed Identi�ed by Gram Stain

Recommended Therapy Alternative Therapy

Vancomycin plus a third-generation cephalosporin[a,b] Meropenem, �uoroquinolone[c]

Isolated Streptococcus pneumoniae and Susceptibility Testing

Standard Therapy Alternative Therapy

Penicillin MIC Penicillin MIC<0.1 μg/mL penicillin G or ampicillin < 0.1 μg/mL third-generation0.1-1.0 μg/mL[b] third-generation cephalosporin[a] cephalosporin[a]

≥ 2.0 μg/mL vancomycin plus a third-generation cephalosporin[a,c] chloramphenicol 0.1-1.0 μg/mL cefepime, meropenemCefotaxime or vancomycin plus a third-ceftriaxone generation ≥ 2.0 μg/mL �uoroquinolone[d]

cephalosporinMIC Cefotaxime, �uoroquinolone,[d]

≥ 1.0 μg/mL or ceftriaxone MIC ≥ 1.0 μg/mL

Standard Susceptibility Category Minimum Inhibitory Concentration μg/mL

Susceptible[a] Intermediate[b] Resistant[c]

Former (all clinical syndromes and penicillin administration ≤ 0.06 0.12-1.0 > 2routes)

New (by clinical syndromes and penicillin administration

- Meningitis, intravenous penicillin ≤ 0.06 - ≥ 0.12

- Nonmeningitis, intravenous penicillin ≤ 2 4 ≥ 8

- Nonmeningitis, oral penicillin ≤ 0.06 0.12-1.0 >2

Streptococcus Preferred Antimicrobial Alternative Antimicrobialpneumoniae

Penicillin- Penicillin G, amoxicillin - Macrolidesnonresistant - Oral cephalosporins (cefuroxime(MIC < 2 μg/mL) cefprozil, cefdinir, cefditoren) - Parenteral cephalosporins (cefuroxime, ceftriaxone, cefotaxime) - Clindamycin - Clindamycin - Doxyxycline - Respiratory �uoroquinolone

Penicillin-resistant Agents chosen on the basis of susceptibility, - Vancomycin(MIC ≥ 2 μg/mL) including cefotaxime, ceftriaxone, and respiratory - Linezolid �uoroquinolone - High-dose amoxicillin (3 g/day with penicillin MIC ≤ 4 mg/mL)

Tetanus, diphtheria,pertussis (Td/Tdap)

Td boosterevery 10 yr

3 doses(females)

Human papillomavirus(HPV)

Varicella 2 doses

1 doses

1 dose

2 doses

3 doses

1 dose

1 dose annually

1 or 2 doses

1 or more doses

1 or 2 doses

Zoster

Measles, mumps,rubella (MMR)

Pneumococcal(polysaccharide)

Hepatitis A

Hepatitis B

Meningococcal

In�uenza

Substitute 1-time dose of Tdap for Td booster; thenboost with Td every 10 yr

Vaccine Age group 19-26 yr 27-49 yr 50-59 yr 60-64 yr ≥ 65 yr

NOTE: The above recommendations must be read along with the published footnotes: CDC. MMWR. 2009;57:Q1-Q4.

TheBurdenofDisease

S pneumoniae is the most common cause of a number of noninvasive (bacterial sinusitis,[6] otitis media [7 million cases and 12 mil-lion office visits each year],[6] and community-acquired pneumonia [CAP]) and invasive (bacteremia, meningitis) disease states.[7] In the United States, S pneumoniae is responsible for a significant burden of disease:

• 500,000 cases of pneumonia; • 50,000 cases of bacteremia (of which 60%-87% are associated with pneumonia[3]); • 3000 cases of meningitis; and • 40,000 deaths annually.[2,3]

Worldwide, approximately 1.6 million people die from pneumococcal disease annually. Most of these deaths occur in infants and children, and most die from pneumonia.[7]

Which of the following conditions would you consider to be invasive pneumococcal disease (IPD)? (select all that apply)

Pneumococcal Pneumonia

S pneumoniae is responsible for 25%-30% of the 500,000 cases/year of bacterial pneumonia in the United States,[2] with a case-fatality rate of 5%-7%.[3] S pneumoniae is also the most frequent organism isolated in patients with chronic obstructive pulmonary disease presenting with pneumonia or acute exacerbation.[8] S pneumoniae is the causative pathogen in 50% of hospital admis-sions for CAP and hospital-acquired pneumonia.[8,9] Twenty percent of all cases of pneumococcal pneumonia are bacteremic, with mortality rates of up to 50% in the elderly and hospital care costs of approximately $2 billion annually.[2] CAP is the sixth leading cause of death and the most common cause of death due to infection in the United States.[3,10]

IPD

Since the 1990s, the prevalence of IPD has increased,[4,11] In addition to bacteremia and meningitis, common complications of pneumonia include parapneumonic effusion, empyema, necrosis, and bacteremia.[1] This trend has been accompanied by longer duration of illness, greater supplemental oxygen requirement, increased number of antibiotic days, and increased hospital length of stay.[1] The cause of this trend is 2-fold. First, due to genetic heterogeneity and genomic plasticity, S pneumoniae has been able to adapt to vaccines and develop resistance to antibiotics.[12] Second, the number of patients who are immunocompromised due to aging, medical therapies, and underlying disease continues to increase. Of note, the elderly[4,13,14]; solid organ transplant and hematopoietic stem cell transplant recipients[15]; and those with HIV,[16] hyposplenism,[17] or underlying pulmonary disease are at an increased risk for S pneumoniae infections.

Pathogenesis of Disease: Pneumonia, Bacteremia, and Meningitis

The pathogenesis of pneumococcal pneumonia originates in the nasopharynx and follows a typical series of events that ultimate-ly lead to invasive disease. Before S pneumoniae can cause disease, it must colonize. The reservoir for colonization in humans is the nasopharynx, which is colonized with S pneumoniae shortly after birth. Fifteen percent of children are colonized with pneumo-cocci by the time they reach 6 months of age, and 40% are colonized by the time they reach 19 months.[18] Bacterial colonization of the nasopharynx (Figure 2) is followed by adherence of pneumococci to epithelial cells in the nasopharynx and evasion of opso-nophagocytosis.


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Figure 2. Nasal colonization by Streptococcus pneumoniae. Progression of nasal colonization of BALB/c mice with a serotype 23F pneumococcal isolate. The images a-d show the progression of infection over a 2-week period (from 30 minutes to 14 days [x40 magnification]). Bacteria (shown in red) were detected with serotype-specific antisera. Mouse tissue was stained with DAPI (4’,6-diamidino-2-phenylindole; blue). The inset in c shows neutrophils stained (shown in green) with an antibody to murine Ly6-G.Images courtesy of A. Roche, University of Pennsylvania, USA.Reprinted by permission from Macmillan Publishers Ltd: Kadioglu A, et al. Nature Reviews Microbiology. 2008;6(4):288-301.

Impaired mucociliary clearance facilitates entrapment of bacteria in mucus and development of a biofilm, which promotes further adherence and limits antimicrobial efficacy, allowing local spread that can lead to sinusitis and/or otitis media. Pulmonary aspiration of this biofilm results in adherence to the bronchial epithelium and alveoli, and virulence factors enable penetration of S pneumoniae into the respiratory interstitium (leading to pneumonia) and bloodstream invasion (leading to bacteremia). This is often precipitated by viral infections, which is why the prevalence of IPD is higher during the winter months in the northern hemisphere.

The pathogenesis of pneumococcal meningitis is similar and begins with nasopharyngeal colonization, followed by hematoge-nous or contiguous spread to the meninges. Bacterial invasion of the meninges is followed by replication within the subarachnoid space, leading to an inflammatory response that facilitates further bacterial penetration.[19]

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Pneumonia

Bacteremia

Meningitis




A tobacco chewer

Very familiar

Somewhat familiar

Not familiar






Confusion 1





Age ≥ 65 years 1

Total score 5









Healthy adults 9 0

Diabetes 51 5.8



Alcoholism 100 11.3


HIV/AIDS 423 48.1



Age > 60 years





30 days

60 days

90 days

120 days






















3 doses(females)


Varicella 2 doses

1 doses

1 dose

2 doses

3 doses

1 dose

1 dose annually

1 or 2 doses

1 or more doses

1 or 2 doses

Zoster



Hepatitis A

Hepatitis B

Meningococcal

In�uenza




Pneumonia

Bacteremia

Meningitis




A tobacco chewer

Very familiar

Somewhat familiar

Not familiar






Confusion 1





Age ≥ 65 years 1

Total score 5









Healthy adults 9 0

Diabetes 51 5.8



Alcoholism 100 11.3


HIV/AIDS 423 48.1



Age > 60 years





30 days

60 days

90 days

120 days






















3 doses(females)


Varicella 2 doses

1 doses

1 dose

2 doses

3 doses

1 dose

1 dose annually

1 or 2 doses

1 or more doses

1 or 2 doses

Zoster



Hepatitis A

Hepatitis B

Meningococcal

In�uenza




TheChangingEpidemiologyof S pneumoniae

Pneumococcal vaccines were developed as a strategy to control colonization. The changing epidemiology and increasing viru-lence of S pneumoniae has been largely driven by the widespread implementation of pneumococcal vaccination programs. In 1983, the 23-valent polysaccharide vaccine (PPSV23) became available, but it is an antibody-dependent vaccine, and it is not immunogenic enough to be effective for those at most risk -- children aged < 2 years. Therefore, its benefit has been a reduction in visceral and bacteremic disease, but not pneumonia.[20]

How familiar are you with the phenomenon of herd immunity?

A milestone in the epidemiology of S pneumoniae began in 2000 with the introduction of the 7-valent protein conjugate vaccine (PCV7) that targets the 7 most common serotypes responsible for IPD, which also carry the major burden of antimicrobial resis-tance. This vaccine stimulates T cells; thus, the immune response to it is more prolonged. PCV7 is 100% effective in preventing IPD in children,[21] and creates the potential for herd immunity. Herd immunity occurs when vaccination of a portion of persons in a population (the herd) provides protection to unvaccinated persons in the population, thus making it more difficult to transmit and maintain a chain of infection. The higher the proportion of vaccinated persons, the lower is the likelihood that an unvaccinated person will come into contact with an infected person. Disease transmission is blocked when a critical portion of the population has been vaccinated.

The success of PCV7 eliminated the 7 most common serotypes, creating a niche for other serotypes to become established, repop-ulate, and cause invasive disease. Consequently, there has been an increase in colonization and IPD from serotypes that are not covered by vaccines. This replacement phenomenon has led to the introduction of new serotypes that do not have to compete with vaccine serotypes.[12] For example, the 19F serotype was included in PCV7, but the 19A serotype was not. Responding to the immune-selective pressure of PCV7, the pneumococcus replaced the 19F serotype with the 19A serotype. This is called capsular switching.[22] As pneumococci continue to spread from children to adults, 19A is now colonizing not only children, but also their parents, grandparents, and other adults. The 19A serotype (a nonvaccine serotype) is now predominant in children and adults,[23,24] and there is great concern about 19A because of its multidrug resistance.[25]

Which of the following patients would you consider to be at greatest risk for IPD?


Pg.9

AdultRiskFactorsforPneumococcalDisease

S pneumoniae is a leading pathogen responsible for infection and disease in all age groups and populations. Rates of disease are higher among young children, the elderly, those who are immunocompromised as well as those with underlying chronic illnesses.[3,4,26,27] Chronic disease is especially important, increasing the risk for IPD up to 57-fold, as shown in Table 1.

Table 1. Influence of Chronic Illness on the Incidence of Invasive Pneumococcal Disease in Adults[27]

Old Age

With advancing age, immune function diminishes and the annual incidence of pneumonia increases. The elderly are dispropor-tionately affected by S pneumoniae, with 61.5 cases/100,000 patients per year among those aged ≥ 65 years.[9] Pneumonia occurs in 1 in 20 persons aged ≥ 85 years annually, and compared with nonelderly persons, there is a 6-fold increase in the annual rate of pneumonia among those aged > 90 years.[13] Similarly, the case-fatality rate is also higher among the elderly compared with those aged ≤ 65 years, with death occurring in 20.6% of those aged > 80 years.[9] Specific risk factors for pneumonia in the elderly are nu-merous: smoking; habitual contact with young children; abrupt changes in environmental temperature; underlying cardiopulmo-nary disease; prior episodes of pneumonia, aspiration, or neurologic dysfunction; poor oral hygiene; malnutrition; poor glycemic control; use of antipsychotic agents; treatment with proton-pump inhibitors; and use of medications that interfere with immune function.[14] Elderly people are also more likely to have drug-resistant S pneumoniae (DRSP) infections.[14]

Chronic Pulmonary Disease

Individuals with chronic pulmonary disease are at particular risk for pneumococcal infections. Asthma, which affects 16 million adults in the United States, has emerged as an especially important risk factor for IPD. Talbot and colleagues[28] conducted a study in individuals aged 2-49 years who were identified through the Tennessee Medicare program via a pneumococcal disease surveil-lance program. Individuals with mild asthma had a 2.3-fold increased risk for IPD compared with those who do not have asthma, and those with severe asthma had a 4.2-fold increased risk for IPD. Approximately 10%-15% of chronic obstructive pulmonary disease exacerbations are due to S pneumoniae. The cause is multifactorial: chronic smoking; increased mucous production; impaired mucociliary clearance; chronic airway inflammation; the use of oral and inhaled corticosteroids; and malnutrition.[29,30]

Pneumonia

Bacteremia

Meningitis




A tobacco chewer

Very familiar

Somewhat familiar

Not familiar






Confusion 1





Age ≥ 65 years 1

Total score 5









Healthy adults 9 0

Diabetes 51 5.8



Alcoholism 100 11.3


HIV/AIDS 423 48.1



Age > 60 years





30 days

60 days

90 days

120 days






















3 doses(females)


Varicella 2 doses

1 doses

1 dose

2 doses

3 doses

1 dose

1 dose annually

1 or 2 doses

1 or more doses

1 or 2 doses

Zoster



Hepatitis A

Hepatitis B

Meningococcal

In�uenza




Pg.10


Pneumonia

Bacteremia

Meningitis




A tobacco chewer

Very familiar

Somewhat familiar

Not familiar






Confusion 1





Age ≥ 65 years 1

Total score 5









Healthy adults 9 0

Diabetes 51 5.8



Alcoholism 100 11.3


HIV/AIDS 423 48.1



Age > 60 years





30 days

60 days

90 days

120 days






















3 doses(females)


Varicella 2 doses

1 doses

1 dose

2 doses

3 doses

1 dose

1 dose annually

1 or 2 doses

1 or more doses

1 or 2 doses

Zoster



Hepatitis A

Hepatitis B

Meningococcal

In�uenza




Which of the following persons would you consider to be at increased risk for IPD? (select all that apply)

Cigarette Smoking

Twenty percent of adult Americans smoke cigarettes. Cigarette smoking is the strongest independent risk factor for IPD among otherwise healthy, nonelderly adults.[31] The adjusted attributable risk for IPD is 51% for active cigarette smoking (exceeding all other risk factors for IPD) and 17% for passive smoking. The number of cigarettes that one smokes daily and the cumulative smok-ing history in pack-years correlate with the risk for IPD. Of note, former smokers remain at an increased risk of developing IPD for about 10 years after they quit smoking. Although their risk declines over time, it takes about 10 years for lung damage in smokers to repair and return to a healthy baseline state.

Smoking creates structural changes in the respiratory tract and impairs the immune response, making respiratory infections more likely to occur. Specifically, cigarette smoke increases mucous production, impairs mucociliary clearance, and disrupts normal respiratory epithelium. These changes enhance bacterial adherence, which facilitates nasopharyngeal colonization.[4] In addition, cigarette smoking can lead to reduced humoral immunity, cellular immunity, immunoglobulin levels, and ultimately an impaired immune response to infectious antigens. As such, both upper and lower respiratory tract infections, especially those caused by S pneumoniae, are significantly more common among smokers.[4]

Immunocompromising Conditions

Immunosuppressive medications commonly used for treatment and management of a number of conditions (ie, solid organ transplant, hematopoietic stem cell transplant, malignancies, and connective tissue diseases) diminish humoral and cellular im-munity, and have dramatically increased the size of the population that is susceptible to serious infections from encapsulated bac-teria, particularly S pneumoniae. S pneumoniae is the most common cause of CAP in persons with HIV and AIDS, and hyposplenism or asplenia (functional or anatomic) increases the risk for infections caused by encapsulated bacteria, most commonly Haemophi-lus influenzae and S pneumoniae. [17]

Homelessness

Homeless persons are at a significantly increased risk for S pneumoniae infections and related complications due to malnutrition, tobacco abuse, alcohol dependence, and intravenous drug use -- all of which have been shown to increase the risk for S pneumoniae infection. The incidence of pneumococcal infection was found to be 273/100,000 persons per year among the homeless, compared with only 9/100,000 in the general population.[32] IPD was also more common and occurred in a younger age group (aged 46 years vs aged 65 years in the general population). Likewise, the incidence of recurrent infection is 5-fold higher among the homeless.


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DiagnosingPneumococcalCAP

Pneumococcal pneumonia is diagnosed on the basis of radiographic and clinical findings. Individual clinical signs or symptoms are poor predictors of pneumonia, but when they occur together (eg, cough, fever, tachycardia, and/or rales and bronchial breath sounds over the involved segment), the probability of pneumonia increases.[26,33] The diagnosis can be made on the basis of isolated findings on chest x-ray, such as lobar infiltrate (Figure 3), and the presence of one of the following:

• Fever (oral temperature > 38°C) or hypothermia (oral temperature < 35°C); or

• White blood cell count > 10,000/mm3 with 10% bands.

Figure 3. Chest x-ray shows right upper lobe pneumonia with loculated parapneumonic effusion.

Patients may also present with a cough productive of rust-colored sputum. Additional laboratory investigations, such as a complete blood count, metabolic panel, coagulation profile, and urinalysis, may provide information about disease severity and comorbid conditions.

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Microbiological Assessment

Microbiological assessment entails evaluation of sputum cultures, blood cultures, and urinary streptococcal antigen level, but these tests have limited use in the outpatient setting. Recommendations for microbiological assessment in patients with suspected CAP include blood cultures, expectorated sputum cultures, and urinary antigen test for Legionella and pneumococcus for patients admitted to the hospital with severe CAP, and those with pertinent risk factors, including hemodynamic or respiratory instability, leukopenia, alcohol abuse, chronic severe liver disease, asplenia, pleural effusions, or cavitary infiltrates.[26] When possible, blood cultures should be performed prior to the administration of antibiotics, and sputum specimens must be of good quality in order to be useful.

A quality sputum sample is one that is collected before antibiotics are administered and:

• Is visibly purulent; • Has < 10 squamous and > 25 polymorphonuclear epithelial cells/low-power field; and • Is transported to the laboratory in < 2 hours after being obtained.

A sputum sample from an endotracheal aspirate is required for intubated patients.

The urinary streptococcal antigen detects S pneumoniae C-polysaccharide in the organism’s the cell wall. Urinary antigen testing for Legionella and pneumococcus is particularly useful in patients with HIV,[34] but it is not a good test for children because of the high rate of false-positive test results in this population.

ManagementofCAP

Optimal management of the patient with CAP is based on disease severity, local bacterial susceptibility and resistance patterns, and appropriate pharmacokinetic and pharmacodynamic targets for bacterial eradication.[35] Validated mortality prediction tools can also be used for objective risk assessment to determine the most appropriate site of care (inpatient or outpatient setting).[36] Two mortality prediction tools are commonly used for this purpose: (1) the PORT (Pneumonia Outcomes Research Team) Severity Index (PSI)[37] and (2) the CURB-65 (Confusion, Urea concentration, Respiratory rate, Blood pressure, and age > 65) prediction rule.[38,39] Both account for clinical variables and are predictive of 30-day mortality. The PSI relies on numerous variables, such as age, leukocytosis, fever, comorbid conditions, and institutionalization for risk stratification. Although predictive, it is significantly more cumbersome than the CURB-65 (Confusion, Urea, > 7 mmol/L, Respiratory rate > 30/minute, Blood pressure < 90 mmHg systolic or ≤ 60 mmHg diastolic, Age > 65 years), which utilizes data that are easy to obtain.[38]

Patients with a CURB-65 score ≥ 2 should be considered for hospital admission (Table 2). In addition, hospitalization should be considered in patients with preexisting conditions that potentially compromise their safety in home care, who have hypoxemia, are unable to take oral medications, or have psychosocial factors that could have a negative impact on effective treatment. As the CURB-65 score increases from 1 to 5, the mortality risk increases from 2.7% to > 27%.[40]

Table 2. CURB-65 Prediction Criteria

CURB-65 = Confusion, Urea concentration, Respiratory rate, Blood pressure, and age > 65

Pneumonia

Bacteremia

Meningitis




A tobacco chewer

Very familiar

Somewhat familiar

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Confusion 1





Age ≥ 65 years 1

Total score 5









Healthy adults 9 0

Diabetes 51 5.8



Alcoholism 100 11.3


HIV/AIDS 423 48.1



Age > 60 years





30 days

60 days

90 days

120 days






















3 doses(females)


Varicella 2 doses

1 doses

1 dose

2 doses

3 doses

1 dose

1 dose annually

1 or 2 doses

1 or more doses

1 or 2 doses

Zoster



Hepatitis A

Hepatitis B

Meningococcal

In�uenza





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CAP-related death, particularly in the elderly, is often due to respiratory failure and hemodynamic instability. The PORT and CURB-65 scores have poor sensitivity for predicting the need for respiratory or vasopressor support.[12] The PSI, PORT, and CURB-65 tools have limited predictive ability in patients with severe CAP.[41] A more sensitive scoring system for predicting the need for intensive respiratory or vasopressor support is SMART-COP (Systolic blood pressure, Multilobar chest radiography involvement, Albumin level, Respiratory rate, Tachycardia, Confusion, Oxygenation, and arterial pH)[41] SMART-COP is a simple, practical tool that can be used by clinicians at the point of care for accurately predicting CAP severity and the need for intensive respiratory or vasopressor support.

TreatingPneumococcalPneumonia

Recommendations from the Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) provide guidance for optimal management of CAP.[26] S pneumoniae is the most common cause of CAP, regardless of the severity, but causative organ-isms depend on the patient care setting (community or hospital) in which pneumonia is acquired. This information should be used by clinicians as guidance for selection of pathogen-directed therapy. In addition, antibiotic selection should take into account local patterns of drug resistance and comorbid conditions that may affect outcomes. Inappropriate antibiotic selection can lead to infections that are more difficult to treat, treatment failure, IPD, and antibiotic resistance.[35] The IDSA/ATS guidelines for the empirical treatment of CAP consider the clinical site of care and the potential organisms typically associated with those sites of care (Table 3).

Table 3. Recommendations for Empirical Treatment of Community-Acquired Pneumonia [26]

CA-MRSA = community-acquired methicillin-resistant Staphylococcus aureus; ICU = intensive care unit [a]Refer to the full-text guideline for strength and level of evidence assigned to each recommendation. In general, the duration of therapy is at least 5 days, provided that the patient is clinically stable and afebrile for 48-72 hours.[26,34] Given that no pathogen is identified in 40%-70% of cases of CAP, the empirical regimen given should be broad enough in spectrum to cover pneumococcus and atypical organisms.[42] The choice of antibiotic should also be guided by local resistance patterns because DRSP is common.

Pneumonia

Bacteremia

Meningitis




A tobacco chewer

Very familiar

Somewhat familiar

Not familiar






Confusion 1





Age ≥ 65 years 1

Total score 5









Healthy adults 9 0

Diabetes 51 5.8



Alcoholism 100 11.3


HIV/AIDS 423 48.1



Age > 60 years





30 days

60 days

90 days

120 days






















3 doses(females)


Varicella 2 doses

1 doses

1 dose

2 doses

3 doses

1 dose

1 dose annually

1 or 2 doses

1 or more doses

1 or 2 doses

Zoster



Hepatitis A

Hepatitis B

Meningococcal

In�uenza




Pg.14


PneumococcalMeningitis

Meningitis should be considered a potential diagnosis in any patient with evidence of infection (ie, fever or leukocytosis) and altered mental status or signs of meningeal irritation. Acute bacterial meningitis is a neurologic emergency, and any diagnostic measures taken prior to the administration of antibiotics should be done expeditiously.[43] In acute bacterial meningitis, especially if due to S pneumoniae, meningeal irritation can develop within hours. Symptoms commonly include neck stiffness, headache, photophobia, and altered level of consciousness.

Diagnosis of meningitis requires examination of the cerebrospinal fluid (CSF).[19,43] Lumbar puncture to obtain CSF for analysis and culture can be safely performed in the absence of increased intracranial pressure. The CSF cell count with a differential count can help differentiate bacterial from aseptic meningitis. CSF in the patient with bacterial meningitis typically shows a neutrophil predominance, whereas CSF in the patient with aseptic or viral meningitis typically shows a lymphocyte predominance. Gram stain of the CSF provides the information to make a timely and accurate diagnosis in the majority of cases (Figure 4).

Figure 4. Gram stain of cerebrospinal fluid. Streptococcus pneumoniae with large number of gram-positive diplococcic present.Credit: World Health Organization (WHO): http://www.who.int/csr/resources/publications/meningitis/whocdscsredc997fig.pdf

Ideally, CSF studies and blood cultures are obtained prior to administration of antibiotics. However, empirical therapy should be initiated if there are any delays in obtaining the CSF specimens for analysis. A computed tomographic (CT) scan of the head should be performed prior to lumbar puncture if there are signs of increased intracranial pressure to avoid the risk for uncal herniation.[43] Indications for obtaining a CT scan of the head prior to performing a lumbar puncture are listed in Table 4.


Pg.15

Table 4. Criteria for Computed Tomography of the Head Prior to Lumbar Puncture[43]

Additional tests that can be used to assist in making the diagnosis of meningitis include[43,44]:

• Latex agglutination of CSF for rapid identification of S pneumoniae antigen;

• Polymerase chain reaction of CSF and serum when antibiotics have already been given and the culture or Gram stain yield is compromised;

• The in vitro immunochromatographic test for rapid detection of S pneumoniae antigen in urine specimens in patients with pneumonia and for differentiating bacterial from viral meningitis;

• CSF lactate level > 4.2 mmol/L for differentiating bacterial from viral meningitis; and

• A CSF procalcitonin level > 0.2 ng/L for differentiating bacterial from viral meningitis.

The Gram stain and CSF culture should be negative after 24 hours of appropriate therapy.[45]

A repeat lumbar puncture for evaluation of the CSF should be considered in patients not responding after 48 hours of appropriate therapy.

Pneumonia

Bacteremia

Meningitis




A tobacco chewer

Very familiar

Somewhat familiar

Not familiar






Confusion 1





Age ≥ 65 years 1

Total score 5









Healthy adults 9 0

Diabetes 51 5.8



Alcoholism 100 11.3


HIV/AIDS 423 48.1



Age > 60 years





30 days

60 days

90 days

120 days






















3 doses(females)


Varicella 2 doses

1 doses

1 dose

2 doses

3 doses

1 dose

1 dose annually

1 or 2 doses

1 or more doses

1 or 2 doses

Zoster



Hepatitis A

Hepatitis B

Meningococcal

In�uenza




Pg.16


TreatingPneumococcalMeningitis

Meningitis is a neurologic emergency. Treatment should be initiated at the first suspicion of the diagnosis. The initial priority is to determine whether a CT scan of the head should be performed prior to performing a lumbar puncture for obtaining a CSF specimen, as previously discussed. If a CT scan is not indicated, then blood cultures and lumbar puncture should be performed immediately, followed by initiation of empirical antibiotic therapy per published guidelines. If a CT scan is indicated, blood cultures should be drawn, followed by antibiotic therapy and corticosteroids (if indicated). If the head CT scan is negative, a lumbar puncture should be performed and treatment should continue.[43]

Corticosteroid Therapy

Corticosteroid (dexamethasone 0.15 mg/kg every 6 hours for the first 2-4 days of treatment) should be administered 10-20 minutes prior to (or at least concomitant with) the first dose of antibiotic in patients with suspected or confirmed S pneumoniae-related acute bacterial meningitis.[43] Dexamethasone should be discontinued if the culture report is negative for S pneumoniae. A concern with corticosteroid use in patients with DRSP infection being treated with vancomycin is that the anti-inflammatory effects of corticosteroids may limit penetration of vancomycin into the subarachnoid space. If this is a concern, it is reasonable to add rifampin to the empirical coverage.[43]

Antibiotic Therapy

Bacterial meningitis can be treated with a number of effective antibiotics. It is important that treatment be initiated early in the course of the disease. Recommendations for antimicrobial therapy in adults with S pneumoniae as the presumptive pathogen identified by Gram stain, and empirical therapy that is based on isolation of S pneumoniae and susceptibility testing are listed in Tables 5 and 6. Antibiotic therapy for S pneumoniae should be administered for 10-14 days. It is safe to begin outpatient therapy when the patient has received inpatient therapy for at least 6 days, has been afebrile for 24-48 hours, demonstrates no neurologic dysfunction, is clinically stable, shows overall improvement, and meets other discharge criteria.[43]

Table 5. Empirical Antimicrobial Therapy Recommendations for Meningitis[43]

[a]Ceftriaxone or cefotaxime[b]Some experts would add rifampin if dexamethasone is also given.[c]Gatifloxacin or moxifloxacin

Pneumonia

Bacteremia

Meningitis




A tobacco chewer

Very familiar

Somewhat familiar

Not familiar






Confusion 1





Age ≥ 65 years 1

Total score 5









Healthy adults 9 0

Diabetes 51 5.8



Alcoholism 100 11.3


HIV/AIDS 423 48.1



Age > 60 years





30 days

60 days

90 days

120 days






















3 doses(females)


Varicella 2 doses

1 doses

1 dose

2 doses

3 doses

1 dose

1 dose annually

1 or 2 doses

1 or more doses

1 or 2 doses

Zoster



Hepatitis A

Hepatitis B

Meningococcal

In�uenza





Pg.17

Pneumonia

Bacteremia

Meningitis




A tobacco chewer

Very familiar

Somewhat familiar

Not familiar






Confusion 1





Age ≥ 65 years 1

Total score 5









Healthy adults 9 0

Diabetes 51 5.8



Alcoholism 100 11.3


HIV/AIDS 423 48.1



Age > 60 years





30 days

60 days

90 days

120 days






















3 doses(females)


Varicella 2 doses

1 doses

1 dose

2 doses

3 doses

1 dose

1 dose annually

1 or 2 doses

1 or more doses

1 or 2 doses

Zoster



Hepatitis A

Hepatitis B

Meningococcal

In�uenza




Table 6. Specific Antimicrobial Therapy Recommendations for Meningitis[43]

MIC = minimum inhibitory concentration [a]Ceftriaxone or cefotaxime[b]Ceftriaxone/cefotaxime-susceptible isolates[c]Consider addition of rifampin if the MIC of ceftriaxone is > 2 µg/mL.[d]Gatifloxacin or moxifloxacin

Which of the following time periods for previous antibiotic use is recognized as a risk factor for subsequent DRSP?

AntimicrobialResistance

DRSP has become increasingly common since the mid-1990s. Risk factors for DRSP include[14,26]:

• Antimicrobial use within the past 90 days; • Extremes of age; • Underlying illness or chronic disease; • Nosocomial and nursing home acquisition; • Epidemiologic and geographic association; • Institutionalization; • Community or household exposure; and • Clonal dissemination in crowded environments.

Any antibiotic use within the past 90 days, in particular, is a significant predictor for DRSP and should influence how we prescribe antibiotics.[26] Therefore, if you are treating a patient who has been on an antibiotic within the last 3 months, regardless of the type of infection or antibiotic, the current infection is likely to be resistant to the antibiotic used to treat the prior infection. Therefore, it is important to prescribe an antibiotic in a different class from the antibiotic used to treat the prior infection.

Pneumonia

Bacteremia

Meningitis




A tobacco chewer

Very familiar

Somewhat familiar

Not familiar






Confusion 1





Age ≥ 65 years 1

Total score 5









Healthy adults 9 0

Diabetes 51 5.8



Alcoholism 100 11.3


HIV/AIDS 423 48.1



Age > 60 years





30 days

60 days

90 days

120 days






















3 doses(females)


Varicella 2 doses

1 doses

1 dose

2 doses

3 doses

1 dose

1 dose annually

1 or 2 doses

1 or more doses

1 or 2 doses

Zoster



Hepatitis A

Hepatitis B

Meningococcal

In�uenza




Pg.18


Minimum Inhibitory Concentration

Antimicrobial resistance for S pneumoniae is established by measuring the minimum inhibitory concentration (MIC) of an antimicrobial agent (ie, penicillin) that will inhibit pneumococcal growth. MIC breakpoints for penicillin, the preferred antimicrobial agent for susceptible S pneumoniae infections, are used to describe infections as susceptible (treatable), intermediate (possibly treatable with higher doses), or resistant (not treatable) to certain antimicrobial agents. In the United States, most DRSP is considered intermediate, and most commonly used therapies are still effective. Thus, intermediate resistance does not have an impact on outcome.

In 2008, the Clinical and Laboratory Standards Institute and the US Food and Drug Administration changed their breakpoints for S pneumoniae pneumonia to make them more clinically relevant (Table 7). With the new breakpoints, the rate of S pneumoniae nonmeningeal isolates in the US Centers for Disease Control and Prevention (CDC) 2006-2007 Active Bacterial Core Surveillance database susceptible to penicillin increased from 74.4% to 93.2%.[46] For meningeal isolates, a penicillin MIC of ≤ 0.06 µg/mL is considered susceptible, and a penicillin MIC of ≥ 0.12 µg/mL is considered resistant. Recommendations for antimicrobial therapy that have been based on MIC breakpoints are listed in Table 8.

Table 7. Former and New Breakpoints for Streptococcus pneumoniae Pneumonia

[a]Susceptible implies that isolates are inhibited by the usually achievable concentrations of antimicrobial agent when the recommended dosage is used for the site of infection.[b]Intermediate includes isolates with antimicrobial minimal inhibitory concentrations that approach usually attainable blood and tissue levels, and for which response rates may be lower than for susceptible isolates.[c]Resistant implies that isolates are not inhibited by the usually achievable concentrations of the agent with normal dosage schedules, and/or that demonstrate zone diameters that fall in the range where specific microbial resistance mechanisms are likely. From Centers for Disease Control and Prevention (CDC).[46]

Pneumonia

Bacteremia

Meningitis




A tobacco chewer

Very familiar

Somewhat familiar

Not familiar






Confusion 1





Age ≥ 65 years 1

Total score 5









Healthy adults 9 0

Diabetes 51 5.8



Alcoholism 100 11.3


HIV/AIDS 423 48.1



Age > 60 years





30 days

60 days

90 days

120 days






















3 doses(females)


Varicella 2 doses

1 doses

1 dose

2 doses

3 doses

1 dose

1 dose annually

1 or 2 doses

1 or more doses

1 or 2 doses

Zoster



Hepatitis A

Hepatitis B

Meningococcal

In�uenza





Pg.19

Table 8. Recommendations for Specific Antimicrobial Therapy[26]

MIC = minimal inhibitory concentration

PreventionofPneumococcalDiseaseinAdults

Prevention of IPD in adults depends on multiple efforts and factors, including epidemiologic surveillance (described elsewhere in detail by the CDC[47]), widespread implementation of vaccination programs, overcoming patient and healthcare provider barriers to vaccination uptake, access to medical care for at-risk populations, behavior modification for patients with high-risk behaviors (eg, smoking), and adherence to standard guidelines for diagnosis and management of disease.

Vaccine Strategies PPSV23 became available in 1983, but it is antibody dependent and not immunogenic enough to be effective for those at most risk, namely, children under the age of 2 years. The benefit realized from the polysaccharide vaccine was reduction of visceral and bacteremic disease, but not necessarily pneumonia. In contrast, the T-cell-dependent PCV7, directed against the 7 most common serotypes responsible for invasive disease, is nearly 100% efficacious in preventing IPD.[20] As previously discussed, prevention of infection and disease in children translates into a lesser disease burden in adults.

The second strategy for protection against IPD in adults is vaccination with PPSV23. This strategy is recommended by the CDC, the American College of Physicians, the American Academy of Family Physicians, and the American College of Obstetricians and Gynecologists.[48] PPSV23 has mistakenly been referred to as the “pneumonia vaccine.” Although it is 60%-70% effective in preventing IPD,[2] PPSV23 is less effective in protecting against other types of pneumococcal infections, particularly against all-cause pneumonia and all-cause mortality.[49,50]

Immunizing Persons at High Risk Vaccination with PPSV23 is recommended for all immunocompetent persons aged ≥ 65 years (Figure 5).[27] The CDC’s Advisory Committee on Immunization Practices (ACIP) also makes recommendations for high-risk persons aged < 65 years. Persons aged 2-64 years who are at increased risk for pneumococcal disease or its complications if they become infected, including those with chronic illness, functional or anatomic asplenia, conditions associated with reduced immunologic function, and those living in special environments or social settings, should be vaccinated.[27]

Pneumonia

Bacteremia

Meningitis




A tobacco chewer

Very familiar

Somewhat familiar

Not familiar






Confusion 1





Age ≥ 65 years 1

Total score 5









Healthy adults 9 0

Diabetes 51 5.8



Alcoholism 100 11.3


HIV/AIDS 423 48.1



Age > 60 years





30 days

60 days

90 days

120 days






















3 doses(females)


Varicella 2 doses

1 doses

1 dose

2 doses

3 doses

1 dose

1 dose annually

1 or 2 doses

1 or more doses

1 or 2 doses

Zoster



Hepatitis A

Hepatitis B

Meningococcal

In�uenza




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Figure 5. Recommended adult immunization schedule by vaccine and age group -- United States, 2009.

In October 2008, the ACIP revised its recommendations for the use of PPSV23 for the prevention of IPD to include adults who currently smoke cigarettes and adults who have asthma. The recommendations are that persons aged 19-64 years:

• Who smoke cigarettes should receive a single dose of PPSV23 and smoking cessation counseling; and/or • Who have asthma should receive a single dose of PPSV23.[51]

The reader is encouraged to refer to additional resources on pneumococcal disease in adults.[52,53]

Summary

IPD represents a significant burden to the healthcare community. Widespread vaccination programs have led to a reduction in invasive disease through protection of vaccinated populations and herd immunity, but efficacy is limited by the increase in replacement serotypes and DRSP. Although continued vaccine developments offer hope, it is increasingly important to focus on preventive methods, appropriate medical care and education for at-risk populations, careful epidemiologic tracking of disease, and strict adherence to standard treatment guidelines.

Pneumonia

Bacteremia

Meningitis




A tobacco chewer

Very familiar

Somewhat familiar

Not familiar






Confusion 1





Age ≥ 65 years 1

Total score 5









Healthy adults 9 0

Diabetes 51 5.8



Alcoholism 100 11.3


HIV/AIDS 423 48.1



Age > 60 years





30 days

60 days

90 days

120 days






















3 doses(females)


Varicella 2 doses

1 doses

1 dose

2 doses

3 doses

1 dose

1 dose annually

1 or 2 doses

1 or more doses

1 or 2 doses

Zoster



Hepatitis A

Hepatitis B

Meningococcal

In�uenza





Pg.21

ThisarticleisaCMEcertifiedactivity.Toearncreditforthisactivityvisit:http://cme.medscape.com/viewarticle/714701

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40. Ebell MH. Outpatient vs. inpatient treatment of community acquired pneumonia. Fam Pract Manag. 2006;13:41-44.

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45. van de Beek D, de Gans J, Tunkel AR, et al. Community-acquired bacterial meningitis in adults. N Engl J Med. 2006;354:44-53. 46. Centers for Disease Control and Prevention (CDC). Effects of new penicillin susceptibility breakpoints for Streptococcus pneumoniae -- United States, 2006-2007. MMWR Morb Mortal Wkly Rep. 2008;57:1353-1355.

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The Duke University School of Medicine designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.Estimated time to complete: 1.5 hours

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Infectious Diseases - Medscapeimg.medscape.com/.../714/701/ID-PrintMonogr-CU-Lettieri-Pneumoco… · Received grants for clinical research from: Cubist Pharmaceuticals Served as an