Pneumococcal Infections (Streptococcus pneumoniae)

Back

Practice Essentials

Pneumococcal infections are caused by Streptococcus pneumoniae, a gram-positive, catalase-negative organism commonly referred to as pneumococcus. S pneumoniae is the most common cause of community-acquired pneumonia (CAP), bacterial meningitis, bacteremia, and otitis media, as well as an important cause of sinusitis, septic arthritis, osteomyelitis, peritonitis, and endocarditis. Complications of each of these diagnoses are common. See the image below. Clinical signs and symptoms and physical examination findings alone cannot distinguish S pneumoniae disease from infections caused by other pathogens.



View Image

Empyema caused by Streptococcus pneumoniae. Anteroposterior film. Courtesy of R. Duperval, MD.

Epidemiology

S pneumoniae can cause a wide variety of clinical symptoms owing to its ability to cause disease by either direct extension from the nasopharynx into surrounding anatomic structures or vascular invasion with hematogenous spread. Features that should prompt the clinician to consider pneumococcal infection include the following:

Conditions that may develop by direct extension of S pneumoniae from the nasopharynx include the following:

Conditions that may result from vascular invasion and hematogenous spread of S pneumoniae include the following:

See Clinical Presentation for more detail.

Diagnosis

If a pneumococcal infection is suspected or considered, Gram stain and culture of appropriate specimens should be obtained, when possible. Potential specimens may include 1 or more of the following:

All S pneumoniae isolates, regardless of the isolation site, should be tested for susceptibility to penicillin and cefotaxime or ceftriaxone. Susceptibilities based on the type of specimen (CSF versus other) were defined by the Clinical and Laboratory Institute (CLSI) in 2008.[1, 2]

Nonspecific laboratory tests that may support the diagnosis include the following:

Imaging studies that may be helpful include the following:

Other modalities that may help define the extent of infection include the following:

See Workup for more detail.

Management

Antibiotics are the mainstay of therapy. Treatments for specific infections may include the following:

Additional treatment measures that may be helpful for particular conditions are as follows:

Measures for preventing pneumococcal infection include the following:

See Treatment and Medication for more detail.

Background

S pneumoniae is a gram-positive, catalase-negative coccus that has remained an extremely important human bacterial pathogen since its initial recognition in the late 1800s. The term pneumococcus gained widespread use by the late 1880s, when it was recognized as the most common cause of bacterial lobar pneumonia.

Worldwide, S pneumoniae remains the most common bacterial cause of community-acquired pneumonia (CAP). However, a recent study involving state-of-the-art diagnostic techniques for bacterial, viral, and fungal infections indicated that a specific pathogen was detected in only 38% of CAP cases. Of these cases, one or more viruses were retrieved in 23% of cases and bacteria in 11%. A combination of bacterial and viral pathogens was seen in 3%. Fungal and mycobacterial organisms accounted for 1%. Human rhinoviruses were isolated in 9% of cases and influenza virus in 6%. S pneumoniae remained the most common cause of bacterial CAP, at 5% of patients.[4]

S pneumoniae is a common cause of bacterial meningitis, bacteremia, and otitis media. S pneumoniae infection is also an important cause of sinusitis, septic arthritis, osteomyelitis, peritonitis, and endocarditis. Worldwide in 2000, 14.5 million estimated episodes of invasive pneumococcal disease were reported in children younger than 5 years, which correlates to more than 800,000 estimated deaths (11% of all deaths in this age group).[5]

Pneumococcal vaccination, particularly routine childhood pneumococcal conjugate vaccine (PCV; introduced in the United States in 2000), has led to decreased rates of invasive pneumococcal infections (>90%) caused by pneumococcal serotypes covered by the vaccine, as well as overall decreased rates of invasive disease (45% overall; 75% in children < 5 years). In addition, herd immunity has led to decreased rates of disease in older children and adults.[6, 7, 8]

Surveillance data following introduction and widespread uptake of 7-valent PCV (PCV7) immunization showed an astounding reduction in invasive disease of 100% in children younger than 5 years in the United States (94% in all ages) when considering disease caused by serotypes contained in PCV7.[5]

Many subsequent studies have shown increased rates of invasive and noninvasive disease caused by serotypes not covered by the vaccine, including serotypes 15, 19A, and 33F. An analysis of over 700 cases of invasive disease in completely immunized children (PCV7) showed that 96% were due to nonvaccine serotypes. An additional 6 serotypes accounted for almost two thirds of invasive infections in this age group.

An analysis of 653 invasive pneumococcal infections in the Spanish population before and after the implementation of PCV7 immunization showed an increased incidence of invasive disease in the postvaccine period, which was primarily due to nonvaccine serotypes and was associated with higher rates of complications, such as septic shock. Similar studies in the United States and other European countries have shown similar results, introducing the concept of replacement disease and its effects.

Serotype 19A has received the most attention, not only because of increased disease rates associated with this serotype, but also owing to its association with increased drug resistance. Increased rates of invasive disease with such serotypes caused the overall rates of invasive disease to remain somewhat steady starting in 2002, although these rates remain greatly reduced from rates prior to introduction of the conjugate vaccine.

For these reasons, work on the development of a vaccine containing additional serotypes continued. A 13-valent PCV (PCV13) was approved by the US Food and Drug Administration (FDA) on February 24, 2010 with the hope that its induced T-cell–dependent immune response would have increased efficacy in children and elderly persons. This potential benefit has yet to be demonstrated in elderly individuals.[6, 9, 10, 11, 12, 13, 14, 15, 8, 16, 17, 18, 5, 19, 20]

The 23-valent polysaccharide vaccine is more effective in decreasing pneumococcal bacteremia than pneumonia. As a result, mortality rates have decreased. Ongoing surveillance will help determine the effects of widespread routine immunization with PCV13 and its expanded serotype coverage on pneumococcal disease in children and adults.

In January 2013, the FDA approved PCV13 for the prevention of invasive pneumococcal disease in children and adolescents between 6 and 17 years of age.[21] In February 2013, the CDC's Advisory Committee on Immunization Practices (ACIP) voted for the use of the vaccine in children with immunodeficiencies. The panel recommends routine use of a single dose of PCV13 for children aged 6-18 years who have an immunocompromising condition (eg, sickle cell disease or HIV infection) and have not previously received the vaccine.[22]

Despite an overall decreased incidence of otitis media caused by serotypes covered by vaccination since the introduction of the conjugate pneumococcal vaccine, an increase in rates of disease caused by serotypes not covered by the vaccine has occurred, as well as an increase in rates of diseases caused by vaccine-covered serotypes in incompletely immunized children. The incidence of otitis media caused by serotype 19F has remained steady. Overall health care utilization for otitis media has decreased, as has the incidence of recurrent otitis media in some populations and studies.[7, 23, 24, 25]

Pathophysiology

Capsule

The capsule is composed of polysaccharides that cover the cell wall, which is made up of peptidoglycan and teichoic acid, characterizing the classic gram positive structure; It acts as the principal antiphagocytic and protective element that prevents access of the leukocytes to the underlying cell wall elements. The capsular polysaccharides have served as means of serotyping and identifying these organisms. The Quellung reaction is the criterion standard method for pneumococcal capsular serotyping. More than 9 serotypes of S pneumoniae have been identified; currently, serotypes 6, 14, 18, 19, and 23 are the most prevalent agents that cause infections. Serotyping provides important epidemiological information, especially with the widespread use of vaccination, but rarely provides timely clinical information.

The virulence of each organism is determined in part by two distinct states: opaque and transparent colony types that influence the capacity to evade host defenses. The nasopharynx is predominantly colonized by the transparent phenotype. Conversely, the opaque type predominates in lung, CNS, and bloodstream infections; it has increased capsular polysaccharide and produces more biofilm.[26] In addition, in vitro and in vivo studies of clinical isolates have shown that pneumococci have the ability to obtain DNA from other pneumococci (or other bacteria) via transformation, allowing them to switch to serotypically distinct capsular type.

Adherence and Invasion

S pneumoniae is an extracellular bacterial pathogen that can adhere avidly to the respiratory epithelium and mucus. It exhibits different surface proteins that recognize and attach to human cells. Pneumococcal surface protein C (PspC) binds to the poly-Ig receptor on epithelial cells, pneumococcal surface antigen A (PsaA) binds to E-cadherin on epithelial cells, pneumococcal adhesion and virulence factor A (PavA) binds to fibronectin, and enolase (Eno) binds to plasminogen that may bridge binding to host cells. Phospho-cholines interact with the receptor for platelet-activating on activated epithelial cells. Capsule, pneumolysin, and the ABC transporter Ami have also been implicated in adherence.[27] S pneumoniae produces biofilm after binding to host cells. Biofilm production is regulated by external factors, such as temperature.

Invasion is promoted by phospho-cholines. After interacting with the PAF receptor, it is inserted into the host cell via endocytosis, causing translocation of bacteria through the endothelium. This is particularly important for translocation over the blood-brain barrier during meningitis development. Bacteria surface coat is changed via gene expression to avoid host defenses and complete translocation. Invasion is also mediated by adhesins and pneumolysin; pneumolysin is a cytotoxin that induces apoptosis of epithelial cells by membrane pore formation, resulting in access to subendothelium. Intraalveolar replication of pneumococci, penetration into the interstitium, and dissemination into the bloodstream are among other functions of pneumolysin.[28]

Much of the clinical severity of pneumococcal disease results from the activation of the complement pathways and cytokine release, which induce a significant inflammatory response. S pneumoniae cell wall components, along with the pneumococcal capsule, activate the alternative complement pathway; antibodies to the cell wall polysaccharides activate the classic complement pathway. Cell wall proteins, autolysin, and DNA released from bacterial breakdown all contribute to the production of cytokines, inducing further inflammation.

Frequency

United States

Colonization

S pneumoniae remains an important pathogen in large part because of its ability to first colonize the nasopharynx efficiently. Studies performed in the United States prior to universal vaccination recommendations have shown average carriage rates of 40%-50% in healthy children and 20%-30% in healthy adults. Factors such as age, daycare attendance, composition of household, immune status, antibiotic use, and others obviously affect these numbers.[29, 30, 31] With the implementation of childhood vaccination with the heptavalent conjugate vaccine for S pneumoniae, the colonization rates have decreased in children receiving the vaccine and in adults and other children in their household because of the phenomenon of herd immunity.

Most individuals who are colonized with S pneumoniae carry only a single serotype at any given time; the duration of colonization varies and depends on specific serotype and host characteristics. Invasive disease is usually related to recent acquisition of a new serotype. However, in most healthy hosts, colonization is not associated with symptoms or disease but allows for the continued presence of S pneumoniae within the population, allowing for prolonged low-level transmission among contacts.

S pneumoniae infection is the most common cause of CAP, bacterial meningitis, bacteremia, and otitis media in the United States. There is a clear seasonality, with infections peaking in the fall and winter months.[32]

Noninvasive disease

Pneumococcal colonization allows for spread of organisms into the adjacent paranasal sinuses, middle ear, and/or tracheobronchial tree down to the lower respiratory tract. This spread results in specific clinical syndromes (sinusitis, otitis media, bronchitis, pneumonia) related to the noninvasive spread of the organisms.

Worldwide, the most common cause of death due to pneumococcal disease is pneumonia. In adults admitted to the hospital in the United States for pneumonia treatment, S pneumoniae remains the most common organism isolated. Until 2000, 100,000-135,000 patients were hospitalized for pneumonia proven to be caused by S pneumoniae infection in the United States annually. These numbers are likely a gross underestimate, as a definite cause is not determined in most cases of pneumonia treated each year. In addition, the actual rates are also likely decreasing owing to implementation of pneumococcal conjugate vaccination.[33]

S pneumoniae infection is an important cause of bacterial co-infection in patients with influenza and can increase the morbidity and mortality in these patients. This has been emphasized recently by the increased number of cases of invasive pneumococcal disease seen in association with increased rates of hospitalizations for influenza during the 2009 H1N1 influenza A pandemic.[34] Postmortem lung specimens from patients who died of H1N1 influenza A from May to August of 2009 were examined for evidence of concomitant bacterial infection. Twenty-nine percent of the specimens showed evidence of bacterial co-infection, with almost half of these being S pneumoniae.[35]

S pneumoniae infection is estimated to cause over 6-7 million cases of otitis media annually in the United States. These numbers have likely decreased somewhat with the advent of universal vaccinations; however, S pneumoniae infection remains the most common cause of otitis media.[36, 31]

Invasive disease

Statistics regarding invasive pneumococcal disease in the United States are based on active surveillance using the Centers for Disease Control and Prevention (CDC) Active Bacterial Core Surveillance (ABC) system. Calculations for 2010 estimated 39,750 (12.9 cases per 100,000 population) cases of invasive disease nationally, with 4,000 (1.3 cases per 100,000 population) estimated deaths. (Comparable 2008 data showed 44,000 (14.5 cases per 100,000 population) episodes of invasive disease with 4,500 (1.5 cases per 100,000 population) deaths.[6]

Children younger than 5 years and adults older than 65 years are 2 identified age groups in whom rates of disease and death are increased. In 2010, rates of pneumococcal invasive disease in these groups were estimated to be 19 per 100,000 population and 36 per 100,000 population, respectively. This compares with rates of 20.2 and 40.4 in 2008, 21.8 and 39.2 in 2007, and 23.2 and 43.3 in 2002, respectively. More than half of deaths due to invasive pneumococcal disease occur in adults with specific risk factors (age, immunosuppression) for severe disease. Such risk factors are an indication for vaccination.[6, 37]

International

Despite the worldwide importance of disease due to S pneumoniae infection, very little information is available on the extent of pneumococcal disease in developing countries. A review of the available literature does show an increase in reports of incidence, prevalence, complications, and vaccine effects in many areas of Europe, Asia, and Australia.

Children

In developing countries, pneumococcus remains the most common and important disease-causing organism in infants. Although exact numbers are difficult to obtain, it is estimated that pneumococcal infections are responsible for more than one million of the 2.6 million annual deaths due to acute respiratory infection in children younger than 5 years. Case fatality rates associated with invasive disease vary widely but can approach and surpass 50% and are greatest in patients with meningitis; one quarter to more than one half of those who survive develop long-term sequelae of infection.[36, 38]

Estimates of pneumococcal disease in Gambian children show high rates of infection in the first year of life (≥500 per 100,000 children).[39] Latin American studies also show a particularly high risk in infants younger than 6 months, and children in southern India have higher rates of colonization at younger ages compared with US children, according to US clinical studies. Some particular populations, such as indigenous Australians and minority Israeli persons, also have disproportionately higher rates of disease, similar to the native Alaskan and native Indian populations in the United States, although determining the role of socioeconomic factors in the higher incidence of disease in these populations is difficult.[39]

In Europe, children younger than 2 years constitute the population most at risk for pneumococcal infection, with rates decreasing with age. The overall incidence of invasive disease is estimated to be somewhat lower in Europe (14 per 100,000 persons in Germany vs 35.8 per 100,000 persons in England vs 45.3 per 100,000 persons in Finland vs 90 per 100,000 persons in Spain vs 235 per 100,000 persons in the United States), although many have postulated that this may be due in part to the more liberal blood-culture collection practices in the American health care system.[39, 36]

Adults

Even fewer data are available on the worldwide incidence of pneumococcal disease in adults. As in the United States, the most common cause of CAP in Europe is S pneumoniae infection, affecting approximately 100 per 100,000 adults each year. Overall rates of febrile bacteremia and meningitis are also similar, (15–19 per 100,000 adults and 1–2 per 100,000 adults, respectively), with the risk for these diseases increased in elderly and infant populations.[40]

Because no population-based data on pneumococcal disease in adults in developing countries are available, estimates of disease burden are based on small clinical studies, vaccine trials, extrapolation from data in developed countries, and studies of persons at high risk for disease. The information gleaned from these sources suggests that the incidence of and mortality rates associated with pneumococcal disease are high, with HIV-positive populations exhibiting particularly high rates of infection. Further studies are greatly needed.[41, 36]

Mortality/Morbidity

Although exact rates are difficult to determine, the World Health Organization (WHO) estimates that, worldwide, 1.6 million deaths were caused by pneumococcal disease in 2005, with 700,000 to 1 million of these occurring in children younger than 5 years.[42] Even in patients in developed countries, invasive pneumococcal disease carries a high mortality rate—an average of 10-20% in adults with pneumococcal pneumonia, with much higher rates in those with risk factors for disease.[43, 44]

Race

In the United States, invasive pneumococcal disease is more common in native Alaskans, Navajo and Apache Indians, and African Americans than in other ethnic groups. Some studies have shown this difference persists even when the results are controlled for socioeconomic factors, and the reasons for this discrepancy among certain populations are unclear.[30]

Sex

Most clinical studies of pneumococcal disease show a slight male predilection for disease; the reason for this is unclear.

Age

Children younger than 2 years carry the highest burden of S pneumoniae disease worldwide. In developed countries, the incidence is highest in those aged 6 months to 1 year, while, in developing countries, the disease is particularly common in children younger than 6 months.

Adults older than 55-65 years are the next most commonly affected age group worldwide.

Immunosuppressed persons of any age are at a higher risk for pneumococcal disease.

Prognosis

Pneumococcal conjunctivitis, otitis media, and sinusitis in developed countries where appropriate antibiotics are available usually carry an excellent prognosis; potential complications are listed above (see Complications).

The prognosis of pneumococcal pneumonia depends largely on underlying factors, including age, immunosuppression, availability of antibiotics, and extent of lung involvement. It appears that most adults (mean age, 64.6 years) who survive invasive pneumococcal pneumonia lose a mean 9.9 years of longevity.[45]

The prognosis of pneumococcal meningitis is also related in part to host factors. Most studies have shown that morbidity rates in otherwise healthy US children with meningitis are usually less than 10%; however, neurological sequelae are common.

Patient Education

All parents should be advised of the recommendations for universal childhood immunization with the pneumococcal conjugate vaccine.

Patients with medical conditions that place them at an increased risk for serious or invasive S pneumoniae disease should be educated about their condition, the potential presenting signs and symptoms of pneumococcal infection, and the need to obtain medical care promptly upon any concern for possible infection. These patients should also be educated about the benefits of the pneumococcal polysaccharide vaccine and should be encouraged to receive it.

History

After successful colonization, S pneumoniae can cause a wide variety of clinical symptoms. By direct extension from the nasopharynx, S pneumoniae infection can spread and then manifest as otitis media, sinusitis, tracheobronchitis, bronchitis, and pneumonia. By invasion and hematogenous spread, S pneumoniae infection can cause primary bacteremia, meningitis, osteomyelitis, pericarditis, endocarditis, myositis, septic arthritis, and peritonitis.

Factors that should prompt consideration of pneumococcal disease in patients with the above conditions are discussed below.

Predisposing factors

Children younger than 5 years, particularly aged 2 years or younger, are at an increased risk of disease. In addition, absence of breastfeeding, exposure to cigarette smoke, daycare attendance, and lack of immunization with the pneumococcal conjugate vaccine further increase the risk of disease. Adults older than 55-65 years are also at an increased risk of disease.

Conditions that cause immune deficits, including HIV infection, malignancy, diabetes mellitus, functional or anatomic asplenia, humoral immunity defects, complement deficiencies, and neutrophil dysfunction, are associated with an increased risk of disease. Conditions associated with decreased pulmonary clearance, such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), viral infections, and active/passive cigarette smoke exposure, also predispose to infection.

Diseases Due to Direct Extension

Conjunctivitis

Bacterial conjunctivitis is more likely to be bilateral and purulent than viral conjunctivitis.

S pneumoniae is found in up to one third of patients with bacterial conjunctivitis; the rate of isolates that are not susceptible to penicillin is increasing.

Otitis media

S pneumoniae is the most commonly isolated bacterial pathogen from children and adults with otitis media. Several early studies demonstrated that otitis media due to S pneumoniae is usually accompanied by fever and pain; the fever associated with pneumococcal otitis media tends to be higher than that caused by other common bacterial pathogens.[30] Pneumococcal disease is less likely to resolve spontaneously.

Increasing antibiotic resistance has led to decreased effectiveness of the antibiotics that were once used most commonly to treat otitis media. S pneumoniae infection is the most common cause of mastoiditis, a complication of otitis media that was more common in the pre-antibiotic era; this complication is now more commonly associated with untreated or improperly treated cases.

Sinusitis

S pneumoniae is the most commonly isolated bacterial organism from patients with acute sinusitis. Acute sinusitis manifestations may vary depending on the age of the patient and the developmental status of individual sinuses. In children younger than 5 years, infection is usually limited to the ethmoid and maxillary sinuses. Acute bacterial sinusitis is usually preceded by a viral upper respiratory infection that leads to mucosal edema, resulting in ostia obstruction. This is followed by the development of a purulent nasal discharge and cough. Halitosis and worsening cough at night due to postnasal drip are often noted.

Acute exacerbations of chronic bronchitis (AECB)

Acute exacerbations of chronic bronchitis manifest as a change from baseline chronic symptoms. Symptoms include shortness of breath, increased production and/or purulence of sputum, increased sputum tenacity, and cough.

An estimated 80% of cases of acute exacerbations of chronic bronchitis are caused by infection, with about one half of those caused by aerobic bacteria, of which S pneumoniae is the most commonly isolated organism.

Symptoms such as sore throat, rhinorrhea, nasal congestion, and dyspnea may indicate a viral cause.[46]

Pneumonia

Classic pneumococcal pneumonia often develops in older children and adults. Sometimes preceded by a viral illness, there is acute onset of high fever, rigors, productive cough, pleuritic chest pain, dyspnea, tachypnea, tachycardia, malaise, and fatigue. Patients typically appear ill and may appear anxious. On physical examination, rales can be heard in most patients. About half of all patients exhibit dullness to percussion, and splinting due to pain may be seen.

In children (particularly school-aged and younger children), the potential manifestations of pneumonia are broad and often nonspecific, including mild respiratory symptoms, with or without a cough on initial presentation; tachypnea, dyspnea, and splinting; high fever; abdominal pain and/or distention; anorexia; emesis (often suggesting a primary gastrointestinal disease); meningeal signs due to meningeal irritation with right upper lobe pneumonias; or chest pain due to pleural irritation.

In elderly patients with pneumococcal pneumonia, tachypnea may be the primary presenting sign. Temperature elevations may be mild or absent.

S pneumoniae is also the most common cause of CAP in HIV-infected patients.

The most common complication of pneumococcal pneumonia is pleural effusion. In patients with concomitant parapneumonic effusion or empyema, physical examination may reveal dullness to percussion, decreased breath sounds, and decreased tactile fremitus at the bases. Although up to 40% of patients with pneumococcal pneumonia may have pleural effusion, only an estimated 10% of these patients have enough fluid to aspirate; of these, only 2% meet the diagnostic criteria for empyema.[30, 31, 47]

Invasive Disease

Meningitis

As a cause of meningitis, S pneumoniae usually invades the meninges via the bloodstream. Although there are multiple possible mechanisms by which this pathogen may cross the blood-brain barrier (BBB), it is likely that multiple factors must act in concert to allow for establishment of infection in the CNS. Transcytosis through meningeal vascular endothelial cells, which are key components of the blood brain barrier, is mediated by pneumococcal adherence to platelet-activating factor receptors. Lastly, by directly invading the meninges after basilar skull fracture or other trauma that compromises the dura, S pneumoniae is the most common cause of recurrent bacterial meningitis following such head trauma.

In countries with routine vaccination policies, S pneumoniae infection is the most common cause of sporadic bacterial meningitis in both children and adults.

Most patients with pneumococcal meningitis present with nonspecific signs and symptoms, including fever, irritability, emesis, lethargy, anorexia, and malaise. Neurologic signs and symptoms, including mental status changes, delirium, lethargy, nuchal rigidity with positive Brudzinski and Kernig signs, cranial nerve palsies, and other focal neurological deficits, are usually prominent. A bulging fontanelle and poor feeding may be seen infants. Twenty to 25% of patients of any age with pneumococcal meningitis experience seizures.

Complications of pneumococcal meningitis include hearing loss, seizures, learning disabilities, mental difficulties, and cranial nerve palsies. In a study from Denmark, 240 patients who survived pneumococcal meningitis were examined using audiometry.[48] More than half (54%) had a hearing deficit, with 39% of these not suspected of hearing loss at the time of hospital discharge. Of the 240 study participants, 14% demonstrated profound hearing loss—7% unilateral and 7% bilateral. Significant risk factors for hearing loss included advanced age, the presence of comorbidity, and higher severity of meningitis. Audiometry should be considered in all patients who survive pneumococcal meningitis.

Pneumococcal meningitis carries a greater risk of death and significant neurological sequelae than does meningitis of other bacterial causes (eg, Haemophilus influenzae type B [Hib], Neisseria meningitidis).[30, 31, 47]

Bacteremia

Bacteremia is the most common manifestation of invasive pneumococcal disease. Most cases are primary bacteremia and are found in children younger than 2 years. It is estimated that S pneumoniae infection has been the cause of 90% of occult bacteremia (bacteremia without a source) cases since the widespread use of the Hib vaccine, although the overall incidence has been decreasing since the institution of routine pneumococcal immunization in infants.[49, 50]

In adult patients, pneumococcal bacteremia is much more likely to be associated with another focus of infection, such as pneumonia or meningitis.

Signs, symptoms, and physical examination findings are usually nonspecific in patients with occult pneumococcal bacteremia. In most patients, fever develops within 24 hours of positive culture findings. A peripheral WBC count greater than 15,000 cells/μL is associated with the presence of occult bacteremia.

Complications, which develop in an estimated 10% of patients with occult bacteremia, include meningitis, osteomyelitis, pneumonia, soft tissue and joint infections, and sepsis. Patients with higher WBC counts and fever, those who have not undergone prior antibiotic therapy, and children younger than 20 months are at a higher risk for persistent bacteremia or the development of focal infection.[31, 30]

Joint and bone infections

S pneumoniae infection is an uncommon cause of osteomyelitis and septic arthritis, causing approximately 4% and 20% of cases in children, respectively.

Septic arthritis: Pneumococcal septic arthritis usually manifests as painful, swollen, and hot joints. The ankles and knees are most commonly involved, and one or more joints may be affected. Blood or synovial cultures usually grow S pneumoniae. Up to half of patients with pneumococcal septic arthritis have concomitant osteomyelitis.

Osteomyelitis: The femur and humerus are most often involved in cases of pneumococcal osteomyelitis in children; the vertebral bones are often involved in adult patients. Up to 20% of patients with pneumococcal osteomyelitis develop long-term sequelae, a figure similar to that of rates of osteomyelitis of other causes. One clinical study performed by the Pediatric Multicenter Pneumococcal Surveillance Study Group (PMPSSG) showed that more than 40% of patients with joint and bone pneumococcal infections had associated bacteremia.[51] Patients with joint prostheses or rheumatic fever are at increased risk for joint disease.

Soft tissue infections

Although uncommon, S pneumoniae infection can be a cause of mild-to-serious soft tissue infections, including cellulitis, myositis, periorbital cellulitis, and abscess, particularly in some immunocompromised hosts (eg, those with SLE). Most patients have WBC counts greater than 15,000 cells/μL and elevated temperatures. Physical findings are related to the site of infection and usually include redness, warmth, and tenderness of the involved area. Movement may be limited by pain and/or swelling. The incidence of soft tissue infections is increased in persons with HIV infection or underlying connective tissue disease; however, most affected individuals are otherwise healthy and respond well to antibiotic therapy.[30]

Peritonitis

Overall, primary peritonitis (peritonitis caused by the spread of organisms via blood or lymph to the peritoneal cavity) is rare, accounting for less than 20% of peritonitis cases.

S pneumoniae is the most commonly isolated organism in patients with primary peritonitis. Primary peritonitis in children is usually associated with underlying conditions such as nephrotic syndrome or other immunocompromising diseases. In adults, primary peritonitis is usually associated with cirrhosis.

Females with severe pelvic inflammatory disease due to S pneumoniae infection may develop peritonitis. In such cases, organisms may gain access to the peritoneum via the fallopian tubes from the female genital tract. This is the only invasive disease caused by S pneumoniae infection that is more common in females. Other persons at risk for peritonitis include persons with gastrointestinal injury, ulcers, or malignancy.

Presenting symptoms of peritonitis include abdominal pain, anorexia, emesis, diarrhea, and fever. Children may present atypically with right lower quadrant abdominal pain that may be mistaken for appendicitis.

Cardiac infections

In the antibiotic era, pneumococcal cardiac infections are rare.

Endocarditis: Involvement of native aortic and mitral valves are most common; infection can lead to valve destruction, heart failure, and embolization. Presenting signs and symptoms are typical of those seen in other causes of endocarditis and include fever, new or changing murmurs, muscle and/or joint pains, sweating, fatigue, anorexia, and skin findings. In alcoholics, may be part of the triad of endocarditis, pneumonia, and meningitis.

Pericarditis: Prior to the widespread use of antibiotics, S pneumoniae infection was the most common cause of purulent pericarditis in children; now, infection in childhood is extremely rare, and nearly all cases of pneumococcal pericarditis occur in adults. Symptoms, signs, and examination findings may include chest and/or pleuritic pain; radiating pain to the neck, abdomen, shoulder, or back; orthopnea; dry cough; extremity swelling; anxiety; fatigue; fever; pericardial rub; and muffled heart sounds.

Causes

S pneumoniae is an encapsulated, gram-positive, catalase-negative cocci that grows as a facultative anaerobe. These organisms often appear on Gram stain as lancet-shaped diplococci that grow in chains (see image below). On blood and chocolate agar plates, a green zone (alpha-hemolysis; due to the breakdown of hemoglobin by pneumolysin) surrounds the colonies. Other identifying properties include sensitivity to optochin (which distinguishes it from other alpha-hemolytic streptococci) and bile solubility.



View Image

Sputum Gram stain from a patient with a pneumococcal pneumonia. Note the numerous polymorphonuclear neutrophils and gram-positive, lancet-shaped diplo....

Predisposing conditions to pneumococcal infection are broad and often overlap; they include the following:

Laboratory Studies

If a pneumococcal infection is suspected or considered, Gram stain and culture of appropriate specimens should be obtained, when possible. Potential specimens may include one or more of the following:

Specimens should be obtained prior to the initiation of antibiotic therapy and inoculated directly into blood-culture bottles, when possible.

Antibiotic susceptibilities should be obtained routinely on all cultures with growth of S pneumoniae. Note that MIC breakpoints are different depending on the specimen type.

Other laboratory values that may be helpful in diagnosis and treatment include a complete blood cell (CBC) count and differential, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP).

In children who do not produce sputum and in adults with a nonproductive cough, the diagnosis may be made based on urine antigen testing for S pneumoniae. As with urinary antigen testing for Legionella, antigenuria may not be present in early infection or in patients without bacteremia, but, if present, may persist after clinical resolution of infection. Evaluation of sputum via a combination of culture, Gram stain, and pneumococcal antigen was found to be the most useful way of achieving an etiologic diagnosis of community-acquired pneumonia. In the absence of sputum, urinary antigen has been found to be the best diagnostic approach. The role of fiberoptic bronchoscopy is best established in the absence of adequate sputum for culture or when the patient is not responding to current therapy.[54] The pneumococcal urinary antigen assay may augment the standard diagnostic methods of blood culture and sputum culture, as it provides rapid results.[3] It is unable to provide antimicrobial susceptibility data, so it does not supplant traditional culture methods.

Noninvasive Infections

Conjunctivitis, otitis media, sinusitis

Laboratory work is not usually obtained in patients with conjunctivitis, otitis media, or sinusitis unless they have unusually high fevers or have an extremely ill appearance. If specimens are obtained, they should be sent for Gram stain and culture and susceptibility. In these cases, isolation of S pneumoniae should be considered a strong indication for pathogenicity and treatment.[55]

Pneumonia

Many patients with pneumonia are treated empirically. Antibiotics used in these cases should include those that cover S pneumoniae. In severe, unusual, or complicated cases or those that require hospitalization, an attempt to obtain sputum cultures should be made.[56] An acceptable sputum sample is indicated by the presence of few epithelial cells and many polymorphonuclear neutrophils (a ratio of 1:10-20). The presence of many gram-positive cocci in pairs and chains on Gram stain of sputum provides good evidence for pneumococcus. When large effusions/empyema is present, pleural fluid should be obtained for Gram stain and culture.

The yield of blood cultures in pneumonia is relatively low. The most common bacteria isolated is S pneumoniae. Blood cultures are not indicated in all hospitalized patients with CAP, but they should be obtained in patients with severe pneumonia, immunocompromise (alcohol abuse, leukopenic, liver disease, asplenia, HIV infection), and in outpatient therapy failure.[3]

Most patients with pneumococcal pneumonia have significant leukocytosis (>12,000 cells/μL), and up to one fourth have a hemoglobin level of 10 mg/dL or less.

A small study by Casado Flores et al evaluated a rapid immunochromatographic test for detection of the pneumococcal antigen, C polysaccharide antigen, in children with pleural effusion.[57] The positive predictive value was 96%, and the sensitivity and specificity were high. In this study, the immunochromatographic test made identification of the pneumococcal origin of effusion easy.

Invasive Infections

In most patients with invasive pneumococcal infections, the WBC count is elevated (>12,000 cells/μL) and there is a predominance of neutrophils. However, the WBC count may be normal, especially early in the disease process. Conversely, leukopenia may indicate severe disease and is a poor prognostic sign. The ESR and CRP level are typically elevated.

The development of polymerase chain reaction (PCR) assays for S pneumoniae with sufficient sensitivity and specificity is being widely investigated. Successful commercial assays may prove to be clinically useful but are not yet commercially available.

Meningitis

CSF findings are typical of those found in bacterial meningitis and usually include the following:

Most patients with pneumococcal meningitis who do not receive antibiotics in the 4-6 hours prior to lumbar puncture will have positive results on Gram stain and/or culture.

Rapid antigen tests (eg, latex agglutination or enzyme immunosorbent assays) can be performed on CSF (as well as sputum and urine) but rarely provide information beyond what is obtained with Gram stain and culture unless antibiotics were administered to the patient prior to performing the lumbar puncture.

Blood culture results are positive in up to 90% of patients.

Bacteremia

The WBC count may be elevated, and blood cultures are positive for growth of S pneumoniae.

Other invasive infections

The WBC count, neutrophil level, CRP level, and ESR are often elevated in patients with bone, joint, soft tissue, cardiac, and other invasive infections. Specimens of appropriate material may yield positive Gram stain findings and/or culture growth. Blood cultures are frequently positive and should be obtained when possible. In females with peritonitis, vaginal swab cultures should be obtained in addition to blood and peritoneal cultures.

Culture and Susceptibility

Antimicrobial susceptibility testing should be performed on all isolates of S pneumoniae, regardless of the isolation site, because of the increasing prevalence of intermediately susceptible and resistant isolates. All isolates should be tested for susceptibility to penicillin and either cefotaxime or ceftriaxone. In addition, CSF isolates should be tested for susceptibility to vancomycin and meropenem. CSF isolates that are found to be nonsusceptible to penicillin should also be tested for susceptibility to rifampin.

Microbiology laboratories should follow established guidelines regarding inoculum size and media (Mueller-Hinton agar with sheep, horse, or lysed horse red blood cells). Isolates from patients with invasive disease should undergo testing with quantitative minimal inhibitory concentration (MIC) techniques (eg, broth microdilution, antibiotic gradient strips).

The Clinical and Laboratory Institute (CLSI) (2010) has defined S pneumoniae susceptibility as follows[1, 2] :

Strains with intermediate or resistant susceptibility patterns should be considered nonsusceptible and alternate therapy used.

Imaging Studies

Chest radiography

Chest radiography should be performed in most patients with evidence of invasive pneumococcal infection and in those with pneumococcal pneumonia. The typical chest radiography finding in adolescents and adults with pneumococcal pneumonia is lobar consolidation. Infants and young children with pneumococcal pneumonia more often have a pattern of scattered parenchymal consolidation and bronchopneumonia. Other chest radiography findings may include air bronchograms, pleural effusions/empyema, pneumatoceles, and, rarely, abscesses. Cavitation is not a feature of S pneumoniae pneumonia and, if present, should prompt investigation for other pathogens.



View Image

Lobar consolidation with pneumococcal pneumonia. Posteroanterior film. Courtesy of R. Duperval, MD.



View Image

Lobar consolidation with pneumococcal pneumonia. Lateral film. Courtesy of R. Duperval, MD.



View Image

Empyema caused by Streptococcus pneumoniae. Anteroposterior film. Courtesy of R. Duperval, MD.

Ultrasonography/CT scanning

Chest ultrasonography or chest CT scanning may be obtained to provide information on the presence and/or extent of pleural effusion/empyema and parenchymal disease. Studies investigating the diagnostic utility of lung ultrasonography to diagnose pneumonia have also been promising.[58]

Sinus CT scanning may provide information about the presence and extent of sinus disease. Positive findings include opacification or air-fluid levels.

Facial CT scanning should be obtained in patients with periorbital or orbital cellulitis to look for evidence of soft tissue swelling, bony involvement, cranial nerve impingement, or proptosis.

MRI/CT scanning

MRI or CT scanning of affected bones or joints should be obtained to evaluate for evidence of joint destruction, periosteal elevation, or a mass.

An MRI of the brain may be obtained in patients with meningitis to determine the location and extent of involvement but is not required by Infectious Disease Society of America (IDSA) guidelines.

Other Tests

Echocardiography should be performed in patients in whom endocarditis is suspected.

Procedures

See the list below:

Histologic Findings

See Causes.

Medical Care

Conjunctivitis, otitis media, sinusitis, bronchitis, and tracheobronchitis

Most patients with conjunctivitis, otitis media, sinusitis, bronchitis, and tracheobronchitis due to S pneumoniae infection can be treated on an outpatient basis with appropriate antibiotics. Compliance and follow-up should be ensured.

Infants and elderly patients, as well as those with immunodeficiencies, underlying disease, or signs of severe disease, should be treated more aggressively and hospitalized when indicated.

Pneumonia

Presenting signs and symptoms widely vary in patients with pneumococcal pneumonia, from mild illness to severe pneumonia to respiratory distress requiring ICU-level care. Factors such as age, type of symptoms, duration of symptoms, underlying and/or chronic illness, compliance with treatment, appropriate home care and potential for worsening disease must be considered in determining the need for and level of hospitalization. There are several scoring systems to appropriately triage patients with pneumonia and decide level of care.[59, 60, 61, 62, 63, 64, 65]

Most hospitalized patients should be treated with parenteral antibiotics in addition to medications for pulmonary symptoms, pain medications, intravenous fluids and/or parenteral or enteral nutrition, oxygen, and additional medications, as indicated on an individual basis.[66, 67, 68, 69, 70]

Diabetes appears to be the only underlying condition that by itself worsened mortality in ICU patients with invasive pneumococcal disease.[71]

Meningitis

Patients with S pneumoniae meningitis should be admitted to the hospital and treated with parenteral antibiotics.

The use of systemic steroids within 15 minutes of initiating infusion of antibiotics in adult patients with bacterial meningitis is usually recommended with caution, as they may decrease CSF antibiotic concentration; patients with meningitis treated with steroids should be monitored closely.[72]

Steroids can be considered prior to antibiotic therapy in children aged 6 weeks and older with possible pneumococcal meningitis. If used, they should be given before or at the time of the first dose of antibiotics.[7]

Intravenous fluids, parenteral/enteral nutrition, and other medications should be used as indicated in appropriate clinical instances.

Bacteremia and sepsis

Patients with pneumococcal bacteremia should be treated with appropriate antibiotics and supportive care.

Repeat blood cultures should always be obtained in patients with S pneumoniae bacteremia.

Patients with signs or symptoms of sepsis should be admitted to the hospital and treated aggressively with antibiotics and other medical therapies, as indicated.

Surgical Care

Patients with complicated pneumonia may require a chest tube for drainage of pleural fluid; VATS or decortication may be required in more severe cases or in those with empyema.

In patients with suspected septic arthritis or osteomyelitis, synovial fluid or bone tissue should be obtained for Gram stain, cell count, histology, and culture.

Patients with recurrent or chronic otitis media, periorbital or orbital cellulitis, or facial cellulitis may require surgical intervention.

Prevention

Behavior modification and risk factors

Cigarette smoking and passive cigarette smoke exposure have been linked to an increased risk for invasive pneumococcal disease in healthy adults; thus, smoking cessation should be encouraged. Optimal nutrition and living conditions may decrease the risk for pneumococcal disease. Breastfeeding of infants should also be encouraged, as the rates of invasive pneumococcal infection is lower in breastfed infants. Daycare attendance is associated with acquisition, carriage (of susceptible and drug-resistant strains), infection, and outbreaks of pneumococcal disease in proportion to the number of attendees.

Immunization

Until February 2010, two pneumococcal vaccines were available for use in the prevention of pneumococcal disease. On February 24, 2010, the FDA approved the use of PCV13 vaccine for use in children aged 2-71 months, and its use replaces PCV7.[17, 73, 74, 75, 76, 77, 78, 79]

The capsular polysaccharide vaccine (PPSV23), licensed in 1977, contains capsular antigens from the 23 serotypes of S pneumoniae that cause most of the infections in the United States. After vaccination with the polysaccharide vaccine, persons aged 5 years and older develop type-specific protective antibodies. Polysaccharide vaccines produce antibodies primarily through T-cell–independent methods. Because these systems are not fully developed in young children, children younger than 2 years have a poor response to these types of vaccines.[70] In some elderly persons and persons of all ages with immunosuppressive conditions, the immunogenicity is similarly poor. No anamnestic response occurs with revaccination, and the duration of immunity with the polysaccharide vaccine is unknown. Neither a decrease in pneumococcal carriage rates or protection of unimmunized persons due to herd immunity has been documented after immunization using the polysaccharide vaccine.

A 13-valent pneumococcal conjugate vaccine (PVC13) was licensed for use in 2010 and includes antigens from the capsules of 13 pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F). When this vaccine was introduced in 2010, it replaced PCV7. The additional 6 serotypes accounted for the majority of pneumococcal isolates that caused invasive disease since the introduction of PCV7 in 2000.[16]

Pneumococcal conjugate vaccines link capsular polysaccharides to a conjugate (diphtheroid) carrier protein. Responses to these antigens are developed using T-cell–dependent mechanisms. These antibodies induce immunologic memory, reduce carriage rates of pneumococcal vaccine-serotype isolates, and provide indirect protection to unimmunized persons via herd immunity.

Table 1. Routine Vaccination With Pneumococcal Vaccines[80, 81, 78]



View Table

See Table

The Advisory Committee on Immunization Practices (ACIP) recommends that the pneumococcal vaccine (PPSV23) be given to high-risk children (children aged 2-6 y should complete the recommended doses of PCV13 before PPSV23 is given).

Table 2. Vaccination of High-Risk Children Aged 2-18 Years With Pneumococcal Polyvalent Vaccine 23-Valent[82]



View Table

See Table

Additionally, in August 2014, the ACIP published updated recommendations for pneumococcal vaccination of high-risk adults. The committee now recommends routine use of PCV13 in sequence with the previously recommended PPSV23. High-risk adults who have not previously received either pneumococcal vaccine should be given 1 dose of PCV13 followed a minimum of 8 weeks later by 1 dose of PPSV23. In patients who have previously received PPSV23, 1 dose of PCV13 should be administered a minimum of 1 year following the last PPSV23 dose. If the last PPSV23 dose was given prior to age 65 years and at least 1 year prior, PCV13 should be administered followed 6-12 months later by another PPSV23 dose.[83]

Table 3. Vaccination of High-Risk Adults Aged 19 Years or Older With Pneumococcal Vaccines[83]



View Table

See Table

The duration of protection is probably 5-10 years but may vary widely. Revaccination is recommended in certain populations, including the following:

A study showed that, in elderly patients with chronic illness, dual vaccination with pneumococcal polysaccharide vaccine and influenza vaccine led to decreased complications related to respiratory, cardiovascular, and cerebrovascular diseases.[84] A reduction in hospitalizations, critical illness, and death was also noted in these patients.

Recommendations for universal vaccination in all children aged 59 months and younger in the United States are now in place. In addition, PCV13 use is recommended in children aged 60-71 months with underlying medical conditions placing them at increased risk for pneumococcal disease and its complications. Health care providers considering vaccination should refer to the ACIP guidelines and the American Academy of Pediatrics policy statement on recommendations for immunization of children against pneumococcal disease, outlined as follows[73] :

A single supplemental dose of PCV13 is recommended for all children in the following groups who were previously fully immunized with PCV7:

High-risk patients include those with sickle cell disease or hemoglobinopathies, asplenia (congenital or functional), HIV infection, cochlear implants, those of Alaskan Native descent (and of some American Indian populations) who are younger than 2 years, immunocompromising conditions (congenital immune deficiencies), chronic cardiac or pulmonary illness, diabetes mellitus, chronic renal insufficiency (including nephrotic syndrome), diseases requiring immunosuppressive or radiation therapy, and/or CSF leaks.[7]

Table 4. Recommended Schedule for Doses of PCV13, Including Catch-up Immunizations in Previously Unimmunized and Partially Immunized Children[7]



View Table

See Table

Many clinical investigations have shown the positive impact of the pneumococcal conjugate vaccine on invasive and noninvasive disease in children, as well as the reduction in nasopharyngeal carriage of vaccine serotypes.[85, 86]

The increasing vaccination rates in children and resultant herd immunity coupled with the increased number of serotypes, even with a possible inferior immune response of the polysaccharide vaccine, make this question relevant.

Further Inpatient Care

Pneumonia

Patients with pneumococcal pneumonia who do not respond or respond slower than usual to initial treatment should undergo follow-up chest radiography. Worsening disease and/or the presence of a pleural effusion may indicate the need for consultation with a pulmonologist, an infectious disease specialist, and/or a surgeon for further intervention. Oral therapy can be initiated when patients have clinically improved and become afebrile. Repeat chest radiography should be performed 4-8 weeks after therapy is completed to ensure resolution of disease. Chest radiography findings may remain abnormal for weeks to months, particularly following severe disease or complicated pneumonias.

Bacteremia

In hospitalized patients with pneumococcal bacteremia, follow-up blood cultures should be obtained until culture results are negative.

Meningitis

A repeat lumbar puncture should be considered after 48 hours of therapy in the following circumstances:

Patients with pneumococcal meningitis should receive the entire course of antibiotic therapy parenterally.

Other invasive infections

Purulent pneumococcal pericarditis and endocarditis are serious diseases and should be treated aggressively with appropriate courses of parenteral antibiotics.

Blood cultures should be obtained until multiple negative sets are documented. Repeat chest radiography, echocardiography, and other imaging tests may be repeated as recommended to monitor disease resolution.

Patients with osteomyelitis and joint infections caused by S pneumoniae infection should be monitored closely for a decrease in pain and inflammatory markers and improved use of the affected limb or joint. Failure to improve should prompt re-evaluation of the area via aspiration, washout, biopsy, or repeat imaging.

Medication Summary

Antibiotics are the mainstay of treatment in S pneumoniae infections. Until the 1970s, essentially all pneumococcal isolates were sensitive to easily achievable levels of most commonly used antibiotics, including penicillins, macrolides, clindamycin, cephalosporins, rifampin, vancomycin, and trimethoprim-sulfamethoxazole. Beginning in the 1990s, many pneumococcal isolates in the United States showed decreased susceptibility to penicillin and other commonly used antibiotics. Continued increases in these isolates have led to the need for re-establishment of susceptibility standards.

As of 2007, isolates of drug-resistant S pneumoniae have become increasingly common worldwide. The CDC, as well as many state health departments, maintain a population-based surveillance system (the ABC system) that investigates the epidemiology and susceptibility patterns of invasive pneumococcal infections in the United States. In 2010, only 10.6% of all isolates obtained showed intermediate or resistant susceptibility patterns to penicillin (down from 24.8% in 2008; 25.6% in 2007).[6] The prevalence of resistance varies greatly among countries, states, counties, and within populations in particular cities and may be as high as 30%-40% in some locations.[87, 88] Resistance rates are generally higher in most European countries, as well as in Hong Kong and Thailand.[89, 90]

The mechanism of pneumococcal resistance to penicillin and cephalosporins is through alteration in the molecular cell wall targets, penicillin-binding proteins (PBPs). Mutations that alter the PBPs result in decreased affinity for binding to these agents, rendering them less effective. This type of resistance can be overcome if the antibiotic concentration at the site of infection exceeds the MIC of the organism for 40%-50% of the dosing interval.

Penicillin-resistant pneumococci are often resistant to multiple additional classes of antibiotics, including other penicillin derivatives, cephalosporins, sulfonamides, trimethoprim-sulfamethoxazole (through amino acid changes), macrolides (through methylation or via an efflux pump), quinolones (through decreased permeability, efflux pumps, and alteration of enzymes), and chloramphenicol (through inactivating enzymes). Resistance is obtained as part of a cassette of genetic information, or a transposon, that encodes resistance to multiple antibiotics.

Resistance rates of pneumococcal isolates in the United States to trimethoprim-sulfamethoxazole, tetracycline, and the macrolides are relatively high. Some isolates (< 10% in the United States) that are resistant to macrolides are also resistant to clindamycin.

Vancomycin-resistant pneumococcal isolates have not been reported in the United States. The phenomenon of tolerance (survival but not growth in the presence of a given antibiotic) has been observed, but its clinical relevance is unknown. Any strain with an in vitro MIC greater than 1 µg/mL to vancomycin should be immediately reported to the state health department and arrangements made for confirmatory testing at the CDC.

In the United States, most pneumococcal isolates remain susceptible to fluoroquinolones. In certain countries and specific populations in whom the use of "respiratory fluoroquinolones" is more prevalent (eg, nursing homes), an increase in resistance to these agents has been seen.[30, 31, 47]

Otitis media

The guideline produced by the American Academies of Pediatrics and Family Practitioners for the treatment of otitis media recommends first-line treatment of most patients with amoxicillin 80-90 mg/kg/day.

Patients who do not improve within 48-72 hours should be re-evaluated and their antibiotics switched to amoxicillin-clavulanate or a second- or third-generation oral cephalosporin, although highly resistant pneumococci may require treatment with parenteral ceftriaxone in order to achieve adequate serum levels of antibiotics.

Sinusitis

The typical pathogens that cause sinusitis mimic those of otitis media; therefore, initial therapeutic recommendations are similar. In adult allergic patients and in adults who do not respond to initial therapy, fluoroquinolones provide appropriate coverage. In this clinical situation, this class of antibiotics is not approved for children.

Pneumonia

Most patients treated for community-acquired pneumonia (CAP) are treated as outpatients, and the etiological agent is rarely identified. Clinical studies have shown that, when etiological agents are sought, S pneumoniae is the predominating agent found when a bacterial organism is isolated.

In August of 2011, the IDSA released new Clinical Practice Guidelines (CPG) for the treatment for CAP in infants and children. The first line antibiotic recommended is amoxicillin (90 mg/kg/day in 2 doses or 45 mg/kg/day in 3 doses) for previously healthy, appropriately immunized infants, preschool children, school-aged children, and adolescents with mild-to-moderate CAP suspected to be of bacterial origin.

In fully immunized, previously healthy children and adolescents ill enough to warrant hospitalization, ampicillin or penicillin G is recommended for first-line treatment when specific local epidemiology does not show evidence of high-level resistance to penicillin. In critically ill or immunocompromised children in whom pneumococcal pneumonia is suspected or possible, vancomycin and a broad-spectrum cephalosporin should be used until or unless organism susceptibilities are available.

The updated guidelines recommend treatment with a third-generation parenteral cephalosporin (ceftriaxone or cefotaxime) for children who are incompletely immunized or live in an area where local susceptibility data show the presence of penicillin resistance, as well as in those children with life-threatening infection and/or complications (to include empyema). In general, non–beta-lactam agents such as vancomycin have proven more effective than third-generation cephalosporins for treatment of pneumococcal pneumonia given the amount of resistance in this country.[91]

The 2007 IDSA guidelines recommend the initial use of a macrolide (alternative, doxycycline [level 3 evidence]) for outpatient therapy of CAP in previously healthy adults with no specific risk factors for drug-resistant S pneumoniae infection.[92] Risk factors include antibiotic use in the preceding 3 months, chronic cardiac/renal/liver/lung disease, immunosuppression (including asplenia, diabetes mellitus, HIV infection, and immunosuppressive therapy), or residence in a region with high rates of drug-resistant pneumococcus. For patients with these risk factors, as well as any adult patient requiring hospital admission, the IDSA guidelines recommend use of either (1) a respiratory fluoroquinolone (ie, moxifloxacin, levofloxacin) or (2) combination therapy with beta-lactam antibiotic (high-dose amoxicillin, amoxicillin-clavulanate, or, alternatively, a second- or third-generation cephalosporin) plus a macrolide. The recommendation in non–critically ill adults admitted with CAP is being called into question by a recent study of non–critically ill hospitalized patients with CAP, which demonstrated noninferiority of beta-lactam monotherapy to both combination therapy (beta-lactam plus macrolide) or fluoroquinolone monotherapy when comparing 90-day mortality rates.[93]

Meningitis

The recommended initial therapy of presumed bacterial meningitis in children is with vancomycin plus ceftriaxone or cefotaxime at meningeal doses. A beta-lactam (penicillin or, more likely, ceftriaxone or cefotaxime [for CSF penetration]) ± vancomycin (adequate CSF levels).

For the treatment of pneumococcal meningitis in children who are allergic to beta-lactams, a combination of vancomycin and rifampin should be considered. Monotherapy with vancomycin should not be attempted, as it is difficult to achieve sustained adequate bactericidal concentrations of vancomycin in the CSF. Monotherapy with rifampin should also not be attempted owing to the high potential for rapid development of resistance in this setting.

In patients infected with rifampin-sensitive pneumococcal isolates, the addition of rifampin should be considered after 48 hours if (1) the clinical condition has worsened despite treatment with vancomycin and cefotaxime/ceftriaxone, (2) repeat lumbar puncture repeatedly yields positive culture results, and/or (3) the isolate displays an MIC to cefotaxime/ceftriaxone of ≥4 µg/mL.

The recommendations for treatment of bacterial meningitis in adults are similar to those in children.

Cefotaxime (Claforan)

Clinical Context:  Third-generation cephalosporin with broad gram-negative spectrum, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. Arrests bacterial cell wall synthesis by binding to one or more of the PBPs, in turn inhibiting bacterial growth. Safety profile is more favorable than aminoglycosides. DOC for meningitis (all ages), inpatient treatment of pneumonia, bacteremia, and other invasive infections.

Penicillin G (Pfizerpen)

Clinical Context:  DOC for severe infections, including meningitis attributed to susceptible strains of S pneumoniae. DOC for severe infections, excluding meningitis attributed to strains of S pneumoniae with intermediate susceptibility to penicillin.

Amoxicillin (Moxatag)

Clinical Context:  Has better absorption than penicillin VK and administration is q8h instead of q6h. For minor infections, some authorities advocate administration q12h. Probably most active of the penicillins for non–penicillin-susceptible S pneumoniae.

Ampicillin

Clinical Context:  No advantage over penicillin G in the treatment of pneumococcal infections. Bactericidal activity against susceptible organisms. Alternative to amoxicillin when unable to take medication orally.

Cefazolin

Clinical Context:  Alternative choice for parenteral treatment of pneumococcal infection outside CNS. Best beta-lactam for IM administration. Poor capacity to cross blood-brain barrier precludes use for treatment of meningitis.

Ceftriaxone (Rocephin)

Clinical Context:  May be used to treat pneumococci that have reduced susceptibility to penicillin. Generally not preferred for infections caused by high-level penicillin-resistance pneumococci. For empiric treatment of meningitis, use in conjunction with vancomycin or rifampin.

Azithromycin (Zithromax)

Clinical Context:  Generally better tolerated than erythromycin. Because of long half-life, treatment duration is reduced. Should not be used for meningitis owing to poor CSF penetration.

Vancomycin

Clinical Context:  Always active against strains of S pneumoniae. DOC for the treatment of meningitis caused by non–penicillin-susceptible S pneumoniae. Has suboptimal capability to cross blood-brain barrier and should be administered with cefotaxime or ceftriaxone for the treatment of meningitis. In adults, glucocorticoids may decrease penetration of vancomycin in the CNS; avoid this medication unless specific indications exist. Vancomycin is frequently the preferred drug for the treatment of severe penicillin-resistant pneumococcal infections outside the CNS and for patients with an IgE-type allergy to penicillin. Only IV administration is effective.

The maintenance dose can be estimated using the following formula: 150 + 15 times the creatinine clearance in mL/min = mg of vancomycin to be administered daily.

Clindamycin (Cleocin)

Clinical Context:  Lincosamide for treatment of serious skin and soft-tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Meropenem (Merrem IV)

Clinical Context:  A carbapenem antibiotic alternative for patients allergic to penicillin with meningitis or other severe invasive infections (good CSF penetration). Has been used successfully in patients with meningitis caused by penicillin-resistant pneumococci.

Linezolid (Zyvox)

Clinical Context:  Prevents formation of functional 70S initiation complex, which is essential for bacterial translation process. Bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci. Used as alternative in patients allergic to vancomycin and for treatment of vancomycin-resistant enterococci.

Ceftaroline (Teflaro)

Clinical Context:  Appears to be effective in vitro against pneumococcal isolates. A study in US medical centers from 2009 through 2012 that evaluated multidrug-resistant S pneumoniae (not susceptible to penicillin, ceftriaxone, erythromycin, tetracycline, trimethoprim-sulfamethoxazole, and levofloxacin) showed that ceftaroline was 16 times more potent than ceftriaxone.[93]

Tigecycline (Tygacil)

Clinical Context:  A glycylcycline antibiotic that is structurally similar to tetracycline antibiotics. Inhibits bacterial protein translation by binding to 30S ribosomal subunit and blocks entry of amino-acyl tRNA molecules in ribosome A site. Indicated for complicated skin and skin structure infections caused by E coli, E faecalis (vancomycin-susceptible isolates only), S aureus (methicillin-susceptible and methicillin-resistant isolates), S agalactiae, S anginosus group (includes S anginosus, S intermedius, and S constellatus), S pyogenes, and B fragilis.

Trimethoprim/sulfamethoxazole (Bactrim, Bactrim DS, Sulfatrim Pediatric)

Clinical Context:  Sulfamethoxazole and trimethoprim is a sulfonamide derivative antibiotic. This agent inhibits bacterial synthesis of dihydrofolic acid by competing with paraaminobenzoic acid, thereby inhibiting folic acid synthesis and resulting in inhibition of bacterial growth.

Levofloxacin (Levaquin)

Clinical Context:  Levofloxacin is rapidly becoming a popular choice in pneumonia; this agent is a fluoroquinolone used to treat CAP caused by S aureus, S pneumoniae (including penicillin-resistant strains), H influenzae, H parainfluenzae, Klebsiella pneumoniae, M catarrhalis, C pneumoniae, Legionella pneumophila, or M pneumoniae.

Levofloxacin is the L stereoisomer of the D/L parent compound ofloxacin, the D form being inactive. It has good monotherapy with extended coverage against Pseudomonas species and excellent activity against pneumococcus. Levofloxacin acts by inhibition of DNA gyrase activity. The oral form has a bioavailability that is reportedly 99%.

The 750-mg dose is as well tolerated as the 500-mg dose, and it is more effective. Other fluoroquinolones with activity against S pneumoniae may be useful and include moxifloxacin, gatifloxacin, and gemifloxacin.

Moxifloxacin (Avelox, Moxifloxacin Systemic)

Clinical Context:  Moxifloxacin is a fluoroquinolone that inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription. Use caution in prolonged therapy, and perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic). Note that superinfections may occur with prolonged or repeated antibiotic therapy, and fluoroquinolones have induced seizures in patients with CNS disorders and caused tendinitis or tendon rupture.

Gemifloxacin (Factive)

Clinical Context:  Gemifloxacin is a fluoroquinolone that inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication, DNA repair, recombination, transposition, and transcription.

Clarithromycin (Biaxin, Biaxin XL)

Clinical Context:  Clarithromycin is another initial drug of choice that is used in otherwise uncomplicated pneumonia. It is used to treat CAP caused by H influenzae, M pneumoniae, S pneumoniae, M catarrhalis, H parainfluenzae, or C pneumoniae (TWAR strain). Clarithromycin appears to cause more GI symptoms (eg, gastric upset, metallic taste) than azithromycin.

This agent is a semisynthetic macrolide antibiotic that reversibly binds to the P site of the 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl t-RNA from ribosomes, causing bacterial growth inhibition.

Class Summary

Penicillin and its derivatives are inexpensive effective antibiotics for treating pneumococcal infections when they are used against susceptible isolates. Penicillins can be administered orally or parenterally and work by inhibiting cell wall synthesis. Penicillin G is the parenteral drug of choice for susceptible S pneumoniae infections, and other parenteral beta-lactams do not provide additional or improved coverage (nor do beta-lactamase inhibitor combinations).

Cephalosporins' mechanism of action and modes of resistance are the same as for all other beta-lactams. First-generation cephalosporins provide similar coverage in the treatment of penicillin-susceptible strains, although many of them have higher MICs.

In most cases, macrolides have activity against penicillin-susceptible strains of S pneumoniae. However, between 1998 and 2011, resistance rates have increased to an estimated 25%-45% in the United States.[94]

Macrolides have poor CSF penetration and should not be used to treatment meningitis.72Hawser SP. Activity of tigecycline against Streptococcus pneumoniae, an important causative pathogen of community-acquired pneumonia (CAP). J Infect.

Most pneumococcal isolates in the United States remain susceptible to respiratory fluoroquinolones. In the United States, less than 1% of S pneumoniae isolates are resistant to levofloxacin, moxifloxacin, or gemifloxacin.[95] Ciprofloxacin and ofloxacin have limited activity against pneumococcal infections. Fluoroquinolones achieve excellent serum drug levels and tissue penetration. Specific populations in whom the use of fluoroquinolones is traditionally increased (eg, nursing home residents) have shown increased rates of pneumococcal resistance to fluoroquinolones, serving as a reminder that consideration of their empiric use in uncomplicated respiratory infections should be tempered by concern for the promotion of further antimicrobial resistance.

Vancomycin is the only glycopeptide antibiotic that has demonstrated effectiveness against pneumococcal infections. To date, no clinical or in vitro evidence of pneumococcal resistance to vancomycin has been reported in the United States, and it is the drug of choice (with a third-generation cephalosporin) in the treatment of penicillin-resistant pneumococcal meningitis.

The increasing number of pneumococcal isolates resistant to trimethoprim-sulfamethoxazole precludes its use unless susceptibilities are known and beta-lactam use is contraindicated.

Clindamycin may also be used to treat nonmeningeal S pneumoniae infections. Approximately 5%-10% of S pneumoniae strains in the United States are resistant to clindamycin.[26] As such, clindamycin should be used only after susceptibility testing has confirmed activity on clinical isolates. Penicillin or macrolide resistance may also be associated with clindamycin resistance in individual isolates.

Carbapenems are also effective against S pneumoniae but should be reserved for specific cases given their broad coverage and the potential for development of resistance by multiple organisms.

Pneumococcal vaccine 13-valent (Prevnar 13)

Clinical Context:  Capsular polysaccharide vaccine against 13 strains of S pneumoniae, conjugated to nontoxic diphtheria protein, including serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F.

Pneumococcal vaccine polyvalent (Pneumovax 23)

Clinical Context:  S pneumoniae capsular antigens stimulate active immune response, resulting in production of endogenously produced antibodies. The 23 serotypes contained in the vaccine include : 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F.

Class Summary

Pneumococcal vaccines are recommended as part of routine prophylaxis in young children (aged < 5 y) and adults aged 65 y or older. These vaccines are also recommended for individuals who are immunocompromised (eg, HIV, cancer, renal disease) or have functional or anatomic asplenia, cerebrospinal fluid leaks, or cochlear implants.

What are pneumococcal infections?Which clinical features suggest pneumococcal infection?Which conditions result from direct extension of pneumococcal infection?Which conditions result from vascular invasion and hematogenous spread of pneumococcal infection?How is pneumococcal infection diagnosed?Which nonspecific lab tests may support the diagnosis of pneumococcal infection?Which imaging studies may be helpful in the diagnosis of pneumococcal infection?Which tests are performed to determine the extent of pneumococcal infection?How are specific pneumococcal infections treated?How are pneumococcal infections prevented?What are pneumococcal infections?What is the role of the bacterial capsule in the pathophysiology of pneumococcal infection?What is the role of adherence and invasion in the pathophysiology of pneumococcal infection?How does S pneumoniae colonization affect the incidence of pneumococcal infection in the US?What is the prevalence of noninvasive pneumococcal infection in the US?What is the prevalence of invasive pneumococcal infection in the US?What is the global prevalence of pneumococcal infection?What is the prevalence of pneumococcal infection in children?What is the prevalence of pneumococcal infection in adults?What are the mortality rates for pneumococcal infections?What are the racial predilections of pneumococcal infection?What are sexual predilections of pneumococcal infection?Which age groups have the highest prevalence of pneumococcal infection?What is the prognosis of pneumococcal infection?What should be included in patient information about pneumococcal infection?Which clinical history findings are characteristic of pneumococcal infection?Which clinical history findings are characteristic of pneumococcal conjunctivitis?Which clinical history findings are characteristic of pneumococcal otitis media?Which clinical history findings are characteristic of pneumococcal sinusitis?Which clinical history findings are characteristic of pneumococcal infection- related acute exacerbations of chronic bronchitis (AECB)?Which clinical history findings are characteristic of pneumococcal pneumonia?Which clinical history findings are characteristic of pneumococcal meningitis?Which clinical history findings are characteristic of pneumococcal bacteremia?Which clinical history findings are characteristic of pneumococcal infection in the joints or bones?Which clinical history findings are characteristic of soft tissue pneumococcal infection?Which clinical history findings are characteristic of pneumococcal peritonitis?Which clinical history findings are characteristic of pneumococcal cardiac infection?What causes pneumococcal infection?Which exposures increase the risk for pneumococcal infection?What is the role of splenic abnormalities in the etiology of pneumococcal infection?Which inflammatory conditions increase the risk for pneumococcal infection?Which defective antibody formations increase the risk for pneumococcal infection?Which polymorphonuclear leukocytes abnormalities increase the risk for pneumococcal infection?What are the risk factors for pneumococcal infection?What are the differential diagnoses for Pneumococcal Infections (Streptococcus pneumoniae)?What is the role of Gram stain and culture in the workup of pneumococcal infection?In addition to cultures, which lab tests are performed in the workup of pneumococcal infection?What is the role of lab tests in the diagnosis of pneumococcal conjunctivitis, otitis media, and sinusitis?What is included in the workup of pneumococcal pneumonia?How are invasive pneumococcal infections diagnosed?What is the role of lab testing in the diagnosis of pneumococcal meningitis?How is pneumococcal bacteremia diagnosed?What is the role of lab testing in the diagnosis of invasive pneumococcal infections?What is the role of culture and susceptibility testing in the workup of pneumococcal infections?What are the CLSI definitions of S pneumoniae susceptibility?What is the role of chest radiography in the workup of pneumococcal infection?What are the roles of ultrasonography, CT scanning, and MRI in the workup of pneumococcal infection?What is the role of echocardiography in the workup of pneumococcal infection?Which clinical procedures may be performed in the workup of pneumococcal infection?How are pneumococcal-related conjunctivitis, otitis media, sinusitis, bronchitis, and tracheobronchitis treated?How is pneumococcal pneumonia treated?How is pneumococcal meningitis treated?How are pneumococcal bacteremia and sepsis treated?What is the role of surgery in the treatment of pneumococcal infection?How is the risk for pneumococcal infection reduced?How are pneumococcal infections prevented?When is revaccination against pneumococcal infections indicated?What are the ACIP and AAP recommendations for immunization of children against pneumococcal infection?How is pneumococcal infection prevented in high-risk patients?What is included in inpatient care for pneumococcal pneumonia?How are hospitalized patients with pneumococcal bacteremia monitored?How are hospitalized patients with pneumococcal meningitis monitored during treatment?What is included in inpatient care for invasive pneumococcal infections?What is the role of medications in the treatment of pneumococcal infection?Which medications in the drug class Vaccines are used in the treatment of Pneumococcal Infections (Streptococcus pneumoniae)?Which medications in the drug class Antibiotics are used in the treatment of Pneumococcal Infections (Streptococcus pneumoniae)?

Author

Claudia Antonieta Nieves Prado, MD, Resident Physician, Department of Internal Medicine, Albert Einstein Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Sarah Perloff, DO, FACP, Director, Antibiotic Stewardship Program, Associate Program Director, Internal Medicine Residency, Program Director, Infectious Diseases Fellowship, Einstein Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Aaron Glatt, MD, Chairman, Department of Medicine, Chief, Division of Infectious Diseases, Hospital Epidemiologist, South Nassau Communities Hospital

Disclosure: Nothing to disclose.

Chief Editor

John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance

Disclosure: Nothing to disclose.

Additional Contributors

Dawn F Muench, MD, Assistant Professor of Pediatrics, F Edward Herbert School of Medicine, Uniformed Services University of the Health Sciences; Clinical Assistant Professor of Pediatrics, University of Washington School of Medicine, Seattle, WA; Pediatric Infectious Disease Physician, Department of Pediatrics, Madigan Army Medical Center

Disclosure: Nothing to disclose.

Michael Rajnik, MD, Associate Professor, Department of Pediatrics, Program Director, Pediatric Infectious Disease Fellowship Program, Uniformed Services University of the Health Sciences

Disclosure: Nothing to disclose.

Thomas E Herchline, MD, Professor of Medicine, Wright State University, Boonshoft School of Medicine; Medical Consultant, Public Health, Dayton and Montgomery County (Ohio) Tuberculosis Clinic

Disclosure: Nothing to disclose.

References

  1. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: 18th Informational Supplement. 2008.
  2. Centers for Disease Control and Prevention. Effects of new penicillin susceptibility breakpoints for Streptococcus pneumoniae- United States, 2006-2007. 2008. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5750a2.htm
  3. [Guideline] Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007 Mar 1. 44 Suppl 2:S27-72. [View Abstract]
  4. Jain S, Self WH, Wunderink RG, Fakhran S, Balk R, Bramley AM. Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults. N Engl J Med. 2015 Jul 30. 373 (5):415-27. [View Abstract]
  5. O'Brien KL, Wolfson LJ, Watt JP, et al. Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates. Lancet. 2009 Sep 12. 374(9693):893-902. [View Abstract]
  6. Active Bacterial Core Surveillance (ABCs) Report; Emerging Infections Program Network; Streptococcus pneumoniae. 2010;
  7. Committee on Infectious Diseases; American Academy of Pediatrics. Pneumococcal Infections. Pickering LK, Baker CJ, Long SS, McMillan JA. Red Book 2009 Report of the Committee on Infectious Diseases. 28th. American Academy of Pediatrics; 2009. 525-335.
  8. Centers for Disease Control and Prevention (CDC). Invasive pneumococcal disease in children 5 years after conjugate vaccine introduction--eight states, 1998-2005. MMWR Morb Mortal Wkly Rep. 2008 Feb 15. 57(6):144-8. [View Abstract]
  9. Hsu KK, Shea KM, Stevenson AE, Pelton SI,. Changing Serotypes Causing Childhood Invasive Pneumococcal Disease: Massachusetts, 2001-2007. Pediatr Infect Dis J. 2009 Nov 21. [View Abstract]
  10. Singleton RJ, Hennessy TW, Bulkow LR, Hammitt LL, Zulz T, Hurlburt DA. Invasive pneumococcal disease caused by nonvaccine serotypes among alaska native children with high levels of 7-valent pneumococcal conjugate vaccine coverage. JAMA. 2007 Apr 25. 297(16):1784-92. [View Abstract]
  11. Ongkasuwan J, Valdez TA, Hulten KG, Mason EO Jr, Kaplan SL. Pneumococcal mastoiditis in children and the emergence of multidrug-resistant serotype 19A isolates. Pediatrics. 2008 Jul. 122(1):34-9. [View Abstract]
  12. Eiland LS. Increasing Prevalence of Pneumococcal Serotype 19A Among US Children. Journal of Pharmacy Practice. 2008. 21(5):356-62.
  13. Singleton RJ, Hennessy TW, Bulkow LR, Hammitt LL, Zulz T, Hurlburt DA, et al. Invasive pneumococcal disease caused by nonvaccine serotypes among alaska native children with high levels of 7-valent pneumococcal conjugate vaccine coverage. JAMA. 2007 Apr 25. 297(16):1784-92. [View Abstract]
  14. McNeil JC, Hulten KG, Mason EO Jr, Kaplan SL. Serotype 19A is the Most Common Streptococcus pneumoniae Isolate in Children With Chronic Sinusitis. Pediatr Infect Dis J. 2009 Sep. 28(9):766-8. [View Abstract]
  15. Pilishvili T, Lexau C, Farley MM, Hadler J, Harrison LH, Bennett NM, et al. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis. 201(1). 2010 Jan 1:32-41. [View Abstract]
  16. Centers for Disease Control and Prevention (CDC). Invasive pneumococcal disease in young children before licensure of 13-valent pneumococcal conjugate vaccine - United States, 2007. MMWR Morb Mortal Wkly Rep. 2010 Mar 12. 59(9):253-7. [View Abstract]
  17. Centers for Disease Control and Prevention (CDC). Licensure of a 13-valent pneumococcal conjugate vaccine (PCV13) and recommendations for use among children - Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep. 2010 Mar 12. 59(9):258-61. [View Abstract]
  18. American Academy of Pediatrics, Committee on Infectious Diseases. Recommendations for the Prevention of Streptococcus pneumoniae Infections in Infants and Children: Use of 13-Valent Pneumococcal Conjugate Vaccine (PCV13) and Pneumococcal Polysaccharide Vaccine (PPSV23). Pediatrics. July 1, 2010. 126:186 -190.
  19. Burgos J, Falcó V, Borrego A, Sordé R, et al. Impact of the emergence of non-vaccine pneumococcal serotypes on the clinical presentation and outcome of adults with invasive pneumococcal pneumonia. Clin Microbiol Infect. 2012 Apr 16. [View Abstract]
  20. Gubbins PO, Li C. The Influence of Influenza and Pneumococcal Vaccines on Community-Acquired Pneumonia (CAP) Outcomes Among Elderly Patients. Curr Infect Dis Rep. 2015 Dec. 17 (12):49. [View Abstract]
  21. Hede K. FDA extends pneumococcal vaccine use to older children. Medscape Medical News. January 29, 2013. Available at http://www.medscape.com/viewarticle/778454. Accessed: February 11, 2013.
  22. Tucker ME. CDC Panel Endorses PCV13 Use in Immunocompromised Children. Available at http://www.medscape.com/viewarticle/779664. Accessed: February 28, 2013.
  23. McEllistrem MC, Adams JM, Patel K, Mendelsohn AB, Kaplan SL, Bradley JS, et al. Acute otitis media due to penicillin-nonsusceptible Streptococcus pneumoniae before and after the introduction of the pneumococcal conjugate vaccine. Clin Infect Dis. 2005 Jun 15. 40(12):1738-44. [View Abstract]
  24. Poehling KA, Szilagyi PG, Grijalva CG, Martin SW, LaFleur B, Mitchel E, et al. Reduction of frequent otitis media and pressure-equalizing tube insertions in children after introduction of pneumococcal conjugate vaccine. Pediatrics. 2007 Apr. 119(4):707-15. [View Abstract]
  25. Poehling KA, Lafleur BJ, Szilagyi PG, Edwards KM, Mitchel E, Barth R, et al. Population-based impact of pneumococcal conjugate vaccine in young children. Pediatrics. 2004 Sep. 114(3):755-61. [View Abstract]
  26. Henriques-Normark B, Tuomanen EI. The pneumococcus: epidemiology, microbiology, and pathogenesis. Cold Spring Harb Perspect Med. 2013 Jul 1. 3 (7):[View Abstract]
  27. Kadioglu A, Weiser JN, Paton JC, Andrew PW. The role of Streptococcus pneumoniae virulence factors in host respiratory colonization and disease. Nat Rev Microbiol. 2008 Apr. 6 (4):288-301. [View Abstract]
  28. Rubins JB, Charboneau D, Paton JC, Mitchell TJ, Andrew PW, Janoff EN. Dual function of pneumolysin in the early pathogenesis of murine pneumococcal pneumonia. J Clin Invest. 1995 Jan. 95 (1):142-50. [View Abstract]
  29. Ghaffar F, Friedland IR, McCracken GH Jr. Dynamics of nasopharyngeal colonization by Streptococcus pneumoniae. Pediatr Infect Dis J. 1999 Jul. 18(7):638-46. [View Abstract]
  30. Dagan R, Greenberg D, Jacobs MR. Pneumococcal Infections. Feigin RD, Cherry JD, Demmler GJ, Kaplan SL. Textbook of Pediatric Infectious Diseases. 5th. Philadelphia, Pennsylvania: Saunders (Elsevier Science); 2004. 1: 1204-1258/90.
  31. Musher DM. Streptococcus pneumoniae. Mandell GL, Bennett JE, Dolin R. Principles and Practice of Infectious Diseases. 6th. Philadelphia, Pennsylvania: Elsevier, Churchill Livingstone; 2005. 2: 197.
  32. Lynch JP 3rd, Zhanel GG. Streptococcus pneumoniae: epidemiology and risk factors, evolution of antimicrobial resistance, and impact of vaccines. Curr Opin Pulm Med. 2010 May. 16(3):217-25. [View Abstract]
  33. CDC. Streptococcus pneumoniae Disease. CDC.gov. Available at http://www.cdc.gov/ncidod/dbmd/diseaseinfo/streppneum_t.htm. Accessed: December 5, 2009.
  34. CDC. 2009 H1N1 Pandemic Update: Pneumococcal Vaccination Recommended to Help Prevent Secondary Infections. CDC. November 16, 2009. Available at http://www.cdc.gov/H1N1flu/HAN/111609.htm
  35. Centers for Disease Control and Prevention (CDC). Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1) - United States, May-August 2009. MMWR Morb Mortal Wkly Rep. 2009 Oct 2. 58(38):1071-4. [View Abstract]
  36. WHO Initiative for Vaccine Research Division. Acute Respiratory Infections, Streptococcus pneumoniae. World Health Organization (WHO).
  37. National Center for Immunization and Respiratory Diseases / Division of Bacterial Diseases. ABCs Report: Streptococcus pneumoniae, PROVISIONAL 2008Active Bacterial Core Surveillance (ABCs): Emerging Infections Program Network. CDC. 1 September 2009. Available at http://www.cdc.gov/abcs/survreports/spneu08.htm
  38. Goetghebuer T, West TE, Wermenbol V, Cadbury AL, Milligan P, Lloyd-Evans N, et al. Outcome of meningitis caused by Streptococcus pneumoniae and Haemophilus influenzae type b in children in The Gambia. Trop Med Int Health. 2000 Mar. 5(3):207-13. [View Abstract]
  39. Eskola J, Black S, Shinefield H. Pneumococcal conjugate vaccines. Plotkin SA, Orenstein WA, eds. Vaccines. 4th ed. Philadelphia, PA: Elsevier Inc; 2004. 23.
  40. Scott JA. The preventable burden of pneumococcal disease in the developing world. Vaccine. 2007 Mar 22. 25(13):2398-405. [View Abstract]
  41. Fedson DS, Scott JA. The burden of pneumococcal disease among adults in developed and developing countries: what is and is not known. Vaccine. 1999 Jul 30. 17 Suppl 1:S11-8. [View Abstract]
  42. World Health Organization. Weekly Epidemiological Record. March/2007. Available at http://www.who.int/wer
  43. WHO.INT; Immunization, Vaccines and Biologicals Division. Pneumococcal Vaccines. WHO.INT. Available at http://www.who.int/vaccines/en/pneumococcus.shtml. Accessed: April 2003.
  44. Rudan I, Campbell H. The deadly toll of S pneumoniae and H influenzae type b. Lancet. 2009 Sep 12. 374(9693):854-6. [View Abstract]
  45. Ajayi OO, Norton NB, Gress TW, Stanek RJ, Mufson MA. Three Decades of Follow-up of Adults After Recovery From Invasive Pneumococcal Pneumonia. Am J Med Sci. 2017 May. 353 (5):445-451. [View Abstract]
  46. [Guideline] Brunton S, Carmichael BP, Colgan R, Feeney AS, Fendrick AM, Quintiliani R, et al. Acute exacerbation of chronic bronchitis: a primary care consensus guideline. Am J Manag Care. 2004 Oct. 10(10):689-96. [View Abstract]
  47. Peter G, Klein JO. Streptococcus pneumoniae. Long SS, Pickering LK, Prober CG, eds. Principles and Practices of Pediatric Infectious Diseases. 2nd ed. Philadelphia, PA: Churchill Livingstone (Elsevier); 2002. 739-746/131.
  48. Worsoe L, Caye-Thomasen P, Brandt CT, Thomsen J, Ostergaard C. Factors associated with the occurrence of hearing loss after pneumococcal meningitis. Clin Infect Dis. 2010 Oct 15. 51(8):917-24. [View Abstract]
  49. Waddle E, Jhaveri R. Outcomes of febrile children without localising signs after pneumococcal conjugate vaccine. Arch Dis Child. 2009 Feb. 94(2):144-7. [View Abstract]
  50. Stoll ML, Rubin LG. Incidence of occult bacteremia among highly febrile young children in the era of the pneumococcal conjugate vaccine: a study from a Children's Hospital Emergency Department and Urgent Care Center. Arch Pediatr Adolesc Med. 2004 Jul. 158(7):671-5. [View Abstract]
  51. Bradley JS, Kaplan SL, Tan TQ, Barson WJ, Arditi M, Schutze GE, et al. Pediatric pneumococcal bone and joint infections. The Pediatric Multicenter Pneumococcal Surveillance Study Group (PMPSSG). Pediatrics. 1998 Dec. 102(6):1376-82. [View Abstract]
  52. Simons M, Scott-Sheldon LAJ, Risech-Neyman Y, Moss SF, Ludvigsson JF, Green PHR. Celiac Disease and Increased Risk of Pneumococcal Infection: A Systematic Review and Meta-Analysis. Am J Med. 2018 Jan. 131 (1):83-89. [View Abstract]
  53. Schurder J, Goulenok T, Jouenne R, Dossier A, Van Gysel D, Papo T, et al. Pneumococcal infection in patients with systemic lupus erythematosus. Joint Bone Spine. 2017 May 18. [View Abstract]
  54. van der Eerden MM, Vlaspolder F, de Graaff CS, Groot T, Jansen HM, Boersma WG. Value of intensive diagnostic microbiological investigation in low- and high-risk patients with community-acquired pneumonia. Eur J Clin Microbiol Infect Dis. 2005 Apr. 24 (4):241-9. [View Abstract]
  55. American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Clinical Practice Guideline: Diagnosis and management of acute otitis media. Pediatrics. 2004 May. 113(5):1451-65. [View Abstract]
  56. Anevlavis S, Petroglou N, Tzavaras A, Maltezos E, Pneumatikos I, Froudarakis M, et al. A prospective study of the diagnostic utility of sputum Gram stain in pneumonia. J Infect. 2009 Aug. 59(2):83-9. [View Abstract]
  57. Casado Flores J, Nieto Moro M, Berrón S, Jiménez R, Casal J. Usefulness of pneumococcal antigen detection in pleural effusion for the rapid diagnosis of infection by Streptococcus pneumoniae. Eur J Pediatr. 2010 May. 169(5):581-4. [View Abstract]
  58. Chavez MA, Shams N, Ellington LE, Naithani N, Gilman RH, Steinhoff MC, et al. Lung ultrasound for the diagnosis of pneumonia in adults: a systematic review and meta-analysis. Respir Res. 2014 Apr 23. 15:50. [View Abstract]
  59. Cunha BA. Pneumonia Essentials. 2nd ed. Sudbury, MA: Jones & Bartlett, Publishers; 2010.
  60. Fung HB, Monteagudo-Chu MO. Community-acquired pneumonia in the elderly. Am J Geriatr Pharmacother. 2010 Feb. 8(1):47-62. [View Abstract]
  61. Johnstone J. Review: pneumococcal vaccination is not effective for preventing pneumonia, bacteraemia, bronchitis, or mortality. Evid Based Med. 2009 Aug. 14(4):109. [View Abstract]
  62. Johnstone J, Eurich DT, Minhas JK, Marrie TJ, Majumdar SR. Impact of the pneumococcal vaccine on long-term morbidity and mortality of adults at high risk for pneumonia. Clin Infect Dis. 2010 Jul 1. 51(1):15-22. [View Abstract]
  63. Luján M, Gallego M, Belmonte Y, Fontanals D, Vallès J, Lisboa T, et al. Influence of pneumococcal serotype group on outcome in adults with bacteremic pneumonia. Eur Respir J. 2010 Feb 11. [View Abstract]
  64. Donowitz GR, Mandell GL. Acute pneumonia. Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone; 2000. 717-43.
  65. Madeddu G, Fois AG, Pirina P, Mura MS. Pneumococcal pneumonia: clinical features, diagnosis and management in HIV-infected and HIV noninfected patients. Curr Opin Pulm Med. 2009 May. 15(3):236-42. [View Abstract]
  66. Austrian R. Pneumococcal pneumonia. Diagnostic, epidemiologic, therapeutic and prophylactic considerations. 1986. Chest. 2009 Nov. 136(5 Suppl):e30. [View Abstract]
  67. Clifford V, Tebruegge M, Vandeleur M, Curtis N. Question 3: can pneumonia caused by penicillin-resistant Streptococcus pneumoniae be treated with penicillin?. Arch Dis Child. 2010 Jan. 95(1):73-7. [View Abstract]
  68. Cunha BA. Clinical relevance of penicillin-resistant Streptococcus pneumoniae. Semin Respir Infect. 2002 Sep. 17(3):204-14. [View Abstract]
  69. Garnacho-Montero J, García-Cabrera E, Diaz-Martín A, Lepe-Jiménez JA, Iraurgi-Arcarazo P, Jiménez-Alvarez R, et al. Determinants of outcome in patients with bacteraemic pneumococcal pneumonia: importance of early adequate treatment. Scand J Infect Dis. 2010 Mar. 42(3):185-92. [View Abstract]
  70. van der Poll T, Opal SM. Pathogenesis, treatment, and prevention of pneumococcal pneumonia. Lancet. 2009 Oct 31. 374(9700):1543-56. [View Abstract]
  71. Garrouste-Orgeas M, Azoulay E, Ruckly S, Schwebel C, de Montmollin E, Bedos JP, et al. Diabetes was the only comorbid condition associated with mortality of invasive pneumococcal infection in ICU patients: a multicenter observational study from the Outcomerea research group. Infection. 2018 Jul 4. [View Abstract]
  72. van de Beek D, de Gans J, McIntyre P, Prasad K. Steroids in adults with acute bacterial meningitis: a systematic review. Lancet Infect Dis. 2004 Mar. 4(3):139-43. [View Abstract]
  73. [Guideline] American Academy of Pediatrics Committee on Infectious Diseases. Recommendations for the prevention of Streptococcus pneumoniae infections in infants and children: use of 13-valent pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide vaccine (PPSV23). Pediatrics. 2010 Jul. 126(1):186-90. [View Abstract]
  74. [Guideline] Advisory Committee on Immunization Practices (ACIP). Preventing pneumococcal disease among infants and young children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2000 Oct 6. 49:1-35. [View Abstract]
  75. [Guideline] Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP). Updated recommendation from the Advisory Committee on Immunization Practices (ACIP) for use of 7-valent pneumococcal conjugate vaccine (PCV7) in children aged 24-59 months who are not completely vaccinated. MMWR Morb Mortal Wkly Rep. 2008 Apr 4. 57(13):343-4. [View Abstract]
  76. Domínguez A, Izquierdo C, Salleras L, Ruiz L, Sousa D, Bayas JM, et al. Effectiveness of the pneumococcal polysaccharide vaccine in Preventing Pneumonia in the elderly. Eur Respir J. 2010 Jan 14. [View Abstract]
  77. Grijalva CG, Poehling KA, Nuorti JP, Zhu Y, Martin SW, Edwards KM, et al. National impact of universal childhood immunization with pneumococcal conjugate vaccine on outpatient medical care visits in the United States. Pediatrics. 2006 Sep. 118(3):865-73. [View Abstract]
  78. Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices. Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). MMWR Morb Mortal Wkly Rep. 2010 Sep 3. 59(34):1102-6. [View Abstract]
  79. Rinta-Kokko H, Dagan R, Givon-Lavi N, Auranen K. Estimation of vaccine efficacy against acquisition of pneumococcal carriage. Vaccine. 2009 Jun 12. 27(29):3831-7. [View Abstract]
  80. Centers for Disease Control and Prevention (CDC). Recommended Adult Immunization Schedule – United States, 2012 MMWR 2012 feb 3;61(4):66-72.
  81. Recommended immunization schedules for persons aged 0 through 18 Years — United States, 2012. MMWR Morb Mortal Wkly Rep. 2012 Feb 10. 61(5):1-4. [View Abstract]
  82. Nuorti JP, Whitney CG. Prevention of pneumococcal disease among infants and children - use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine - recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010 Dec 10. 59:1-18. [View Abstract]
  83. Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine for Adults with Immunocompromising Conditions: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2012 Oct 12. 61:816-9. [View Abstract]
  84. Hung IF, Leung AY, Chu DW, Leung D, Cheung T, Chan CK. Prevention of acute myocardial infarction and stroke among elderly persons by dual pneumococcal and influenza vaccination: a prospective cohort study. Clin Infect Dis. 2010 Nov 1. 51(9):1007-16. [View Abstract]
  85. Black SB, Shinefield HR, Hansen J, Elvin L, Laufer D, Malinoski F. Postlicensure evaluation of the effectiveness of seven valent pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2001 Dec. 20(12):1105-7. [View Abstract]
  86. Kaplan SL, Mason EO Jr, Wald ER, Schutze GE, Bradley JS, Tan TQ, et al. Decrease of invasive pneumococcal infections in children among 8 children's hospitals in the United States after the introduction of the 7-valent pneumococcal conjugate vaccine. Pediatrics. 2004 Mar. 113(3 Pt 1):443-9. [View Abstract]
  87. Karlowsky JA, Thornsberry C, Jones ME, Evangelista AT, Critchley IA, Sahm DF. Factors associated with relative rates of antimicrobial resistance among Streptococcus pneumoniae in the United States: results from the TRUST Surveillance Program (1998-2002). Clin Infect Dis. 2003 Apr 15. 36(8):963-70. [View Abstract]
  88. Whitney CG, Farley MM, Hadler J, Harrison LH, Lexau C, Reingold A, et al. Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States. N Engl J Med. 2000 Dec 28. 343(26):1917-24. [View Abstract]
  89. Song JH, Jung SI, Ko KS, Kim NY, Son JS, Chang HH, et al. High prevalence of antimicrobial resistance among clinical Streptococcus pneumoniae isolates in Asia (an ANSORP study). Antimicrob Agents Chemother. 2004 Jun. 48(6):2101-7. [View Abstract]
  90. Cunha BA. Effective antibiotic-resistance control strategies. Lancet. 2001 Apr 28. 357(9265):1307-8. [View Abstract]
  91. Bradley JS, Byington CL, Shah SS, et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011 Oct. 53(7):e25-76. [View Abstract]
  92. Shea KW, Cunha BA, Ueno Y, Abumustafa F, Qadri SM. Doxycycline activity against Streptococcus pneumoniae. Chest. 1995 Dec. 108(6):1775-6. [View Abstract]
  93. Postma DF, van Werkhoven CH, van Elden LJ, Thijsen SF, Hoepelman AI, Kluytmans JA, et al. Antibiotic treatment strategies for community-acquired pneumonia in adults. N Engl J Med. 2015 Apr 2. 372 (14):1312-23. [View Abstract]
  94. Jones RN, Sader HS, Mendes RE, Flamm RK. Update on antimicrobial susceptibility trends among Streptococcus pneumoniae in the United States: report of ceftaroline activity from the SENTRY Antimicrobial Surveillance Program (1998-2011). Diagn Microbiol Infect Dis. 2013 Jan. 75 (1):107-9. [View Abstract]
  95. Jones RN, Jacobs MR, Sader HS. Evolving trends in Streptococcus pneumoniae resistance: implications for therapy of community-acquired bacterial pneumonia. Int J Antimicrob Agents. 2010 Sep. 36 (3):197-204. [View Abstract]
  96. Reuters Health Information. U.S. advisory panel recommends Prevnar 13 vaccine for elderly. Medscape Medical News. August 14, 2014.
  97. Bonten M, Bolkenbaas M, Huijts S, et al. Community Acquired Pneumonia Immunization Trial in Adults (CAPiTA). Abstract no. 0541. Pneumonia 2014;3:95. Available at https://pneumonia.org.au/public/journals/22/PublicFolder/ABSTRACTBOOKMASTERforwebupdated20-3-14.pdf
  98. Tomczyk S, Bennett NM, Stoecker C, Gierke R, Moore MR, Whitney CG, et al. Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among Adults Aged =65 Years: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2014 Sep 19. 63(37):822-5. [View Abstract]
  99. Mitchell AM, Mitchell TJ. Streptococcus pneumoniae: virulence factors and variation. Clin Microbiol Infect. 2010 May. 16(5):411-8. [View Abstract]
  100. Hawser SP. Activity of tigecycline against Streptococcus pneumoniae, an important causative pathogen of community-acquired pneumonia (CAP). J Infect. 2010 Apr. 60(4):306-8. [View Abstract]
  101. Grau I, Pallares R, Tubau F, Schulze MH, Llopis F, Podzamczer D, et al. Epidemiologic changes in bacteremic pneumococcal disease in patients with human immunodeficiency virus in the era of highly active antiretroviral therapy. Arch Intern Med. 2005 Jul 11. 165(13):1533-40. [View Abstract]
  102. Park SY, Van Beneden CA, Pilishvili T, Martin M, Facklam RR, Whitney CG. Invasive pneumococcal infections among vaccinated children in the United States. J Pediatr. 2010 Mar. 156(3):478-483.e2. [View Abstract]
  103. Pilishvili T, Lexau C, Farley MM, et al. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis. 2010 Jan 1. 201(1):32-41. [View Abstract]
  104. Ray GT, Pelton SI, Klugman KP, Strutton DR, Moore MR. Cost-effectiveness of pneumococcal conjugate vaccine: an update after 7 years of use in the United States. Vaccine. 2009 Nov 5. 27(47):6483-94. [View Abstract]
  105. Flamm RK, Sader HS, Farrell DJ, Jones RN. Antimicrobial activity of ceftaroline tested against drug-resistant subsets of Streptococcus pneumoniae from U.S. medical centers. Antimicrob Agents Chemother. 2014. 58 (4):2468-71. [View Abstract]
  106. Brooks LRK, Mias GI. Streptococcus pneumoniae's Virulence and Host Immunity: Aging, Diagnostics, and Prevention. Front Immunol. 2018. 9:1366. [View Abstract]

Empyema caused by Streptococcus pneumoniae. Anteroposterior film. Courtesy of R. Duperval, MD.

Sputum Gram stain from a patient with a pneumococcal pneumonia. Note the numerous polymorphonuclear neutrophils and gram-positive, lancet-shaped diplococci. Courtesy of C. Sinave, MD, personal collection.

Lobar consolidation with pneumococcal pneumonia. Posteroanterior film. Courtesy of R. Duperval, MD.

Lobar consolidation with pneumococcal pneumonia. Lateral film. Courtesy of R. Duperval, MD.

Empyema caused by Streptococcus pneumoniae. Anteroposterior film. Courtesy of R. Duperval, MD.

Sputum Gram stain from a patient with a pneumococcal pneumonia. Note the numerous polymorphonuclear neutrophils and gram-positive, lancet-shaped diplococci. Courtesy of C. Sinave, MD, personal collection.

Lobar consolidation with pneumococcal pneumonia. Posteroanterior film. Courtesy of R. Duperval, MD.

Lobar consolidation with pneumococcal pneumonia. Lateral film. Courtesy of R. Duperval, MD.

Empyema caused by Streptococcus pneumoniae. Anteroposterior film. Courtesy of R. Duperval, MD.

Purpura due to pneumococcal sepsis in a 39-year-old man who underwent a splenectomy 20 years earlier. Courtesy of Thomas Herchline, MD, Wright State University, Dayton, Ohio.

Population Vaccine
Children aged 6 weeks through 5 years: 0.5 mL IM; series of 4 doses at ages 2, 4, 6, and 12-15 months (catch-up schedule through age 5 y)Pneumococcal conjugate vaccine 13-valent (Prevnar 13)
Adults ≥50 years*: 0.5 mL IM as a single dosePneumococcal conjugate vaccine 13-valent (Prevnar 13, PCV13)
Adults >65 years*†: 0.5 mL IMPneumococcal polyvalent vaccine 23-valent (PPSV23); 6-12 mo after PCV13
*Although PCV13 is licensed by the FDA for individuals aged ≥50 y, ACIP recommends routine vaccination with both PCV13 plus PPSV23 for individuals aged ≥65 y.



†Those who received PPSV23 before age 65 years for any indication should receive another dose of the vaccine at age 65 years or later if at least 5 years have passed since their previous dose.



Pediatric Risk Group Condition
ImmunocompetentChronic heart disease (particularly cyanotic congenital heart disease and cardiac failure)



Chronic lung disease (including asthma if treated with high-dose corticosteroids)



Diabetes mellitus



Cerebrospinal fluid leaks



Cochlear implant



Functional or anatomic aspleniaSickle cell disease and other hemoglobinopathies



Congenital or acquired asplenia or splenic dysfunction



Immunocompromising conditionsHIV infection



Chronic renal failure and nephrotic syndrome



Immunosuppressive drugs or radiation therapy, malignant neoplasms, leukemias, lymphomas, Hodgkin disease, solid organ transplantation



Congenital immunodeficiency



Risk Group Condition PCV13 PPSV23 Revaccinate With PPSV23 5 Years After First Dose
Immunocompetent individualsChronic heart disease*   
Chronic lung disease†   
Diabetes mellitus   
Cerebrospinal fluid leaksxx 
Cochlear implantxx 
Alcoholism x 
Chronic liver disease, cirrhosis x 
Functional or anatomic aspleniaSickle cell disease and other hemoglobinopathiesxxx
Congenital or acquired aspleniaxxx
Immunocompromised individualsCongenital or acquired immunodeficiencyxxx
HIV infectionxxx
Chronic renal failurexxx
Nephrotic syndromexxx
Leukemiaxxx
Lymphomaxxx
Hodgkin diseasexxx
Generalized malignancyxxx
Iatrogenic immunosuppression‡xxx
Solid organ transplantxxx
Multiple myelomaxxx
*Congestive heart failure and cardiomyopathies, excluding hypertension.



†Including chronic obstructive pulmonary disease, emphysema, and asthma.



‡Diseases requiring treatment with immunosuppressive drugs, including long-term systemic corticosteroids and radiation therapy.



Age at Examination (mo) Immunization History Recommended Regimen*
2-60 doses3 doses, 2 mo apart; fourth dose at age 12-15 mo
 1 dose2 doses, 2 mo apart; fourth dose at age 12-15 mo
 2 doses1 dose, 2 mo after the most recent dose; fourth dose at age 12-15 mo
7-110 doses2 doses, 2 mo apart; third dose at age 12 mo
 1 or 2 doses before age 7 mo1 dose at age 7-11 mo, with another dose at age 12-15 mo (≥2 mo later)
12-230 doses2 doses, ≥2 mo apart
 1 dose at < 12 mo2 doses, ≥2 mo apart
 1 dose at ≥12 mo1 dose, ≥2 mo after the most recent dose
 2 or 3 doses at < 12 mo1 dose, ≥2 mo after the most recent dose
24-71[75]   
Healthy children



(24-59mo)



Any incomplete schedule1 dose, ≥2 mo after the most recent dose†
Children at high



risk‡ (24-71 mo)



Any incomplete schedule of < 3 doses2 doses, one ≥2 mo after the most recent dose and another dose ≥2 mo later
 Any incomplete schedule of 3 doses1 dose, ≥2 mo after the most recent dose
*In children immunized before age 12 mo, the minimum interval between doses is 4 weeks. Doses administered at age 12 months or later should be administered at least 8 weeks apart.



† Providers should administer a single dose to all healthy children aged 24-59 mo with any incomplete schedule.



‡Children with sickle cell disease, asplenia, chronic heart or lung disease, diabetes mellitus, CSF leak, cochlear implant, HIV infection, or another immunocompromising condition. PPV23 is also indicated (see below).