AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Background

Streptococcus pneumoniae is a gram-positive, catalase-negative cocci 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, it remains the most common cause of community-acquired pneumonia (CAP), bacterial meningitis, bacteremia, and otitis media. S pneumoniae infection is also an important cause of sinusitis, septic arthritis, osteomyelitis, peritonitis, and endocarditis and an infrequent cause of other less common diseases.

Pathophysiology

Adherence and invasion
 
S pneumoniae is an example of a typical extracellular bacterial pathogen. Pathogenicity requires adherence to host cells, along with the ability to replicate and to escape clearance and/or phagocytosis. The organism must then gain access to areas where it can manifest infection, either via direct extension or lymphatic or hematogenous spread.

The rates of pneumococcal colonization in healthy children and adults provide information about the success of adherence and replication of the pneumococcus. After colonization, organisms may gain access to areas of the upper and/or lower respiratory tracts (sinuses, bronchi, eustachian tubes) by direct extension. Under normal conditions in a healthy host, anatomic and ciliary clearance mechanisms prevent clinical infection. However, clearance may be inhibited by chronic (smoking, allergies, bronchitis) or acute (viral infection, allergies) factors, which can lead to infection. Alternatively, pneumococci may reach normally sterile areas, such as the blood, peritoneum, cerebrospinal fluid, or joint fluid, by hematogenous spread after mucosal invasion. In the absence of previously acquired serotype-specific antibodies (see below), clinically apparent infection is likely to occur.

Capsule
 
Other than some isolates associated with conjunctivitis outbreaks, essentially all clinical isolates of S pneumoniae are encapsulated. Repeating oligosaccharides that make up the capsule of an individual bacterial isolate are transported to the cell surface, where they bind tightly with the cell-wall polysaccharides. Based on antigenic differences within these capsular polysaccharides, 90 serotypes of S pneumoniae have been identified. 
 
The virulence of each organism is determined in part by the makeup and amount of capsule present. In a pneumococcus-naive host (or in the absence of antibody to pneumococcal capsule) host-cell phagocytosis is severely limited because of the inhibition of phagocytosis and the inhibition of the activation of the classic complement pathway. 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 types. 

There are 2 recognized numbering systems based on pneumococcal serotypes. In the American system, the serotypes were numbered in order of discovery, with lower numbers corresponding to serotypes that more frequently cause clinical disease, meaning that they were identified earlier. The Danish numbering system is based on grouping of serotypes with similar antigenicity and is more widely accepted and used worldwide. Today, serotyping provides important epidemiological information, especially with the increasingly widespread use of vaccination, but rarely provides timely clinical information.

The Quellung reaction is demonstrated by combining sera of previously immunized animals with capsular antigen. Agglutination causes capsule refractility and the ability to observe the capsule microscopically.

Toxins and other virulence factors
 
Pneumococcal isolates produce few toxins; however, all serotypes produce pneumolysin, which is an important virulence factor that acts as a cytotoxin and activates the complement system. In addition, pneumolysin causes a release of tumor necrosis factor-alpha and interleukin-1.

Other potential virulence factors include cell surface proteins such as surface protein A and surface adhesin A and enzymes such as autolysin, neuraminidase, and hyaluronidase. The contributions of these substances to pneumococcal virulence are being studied extensively, and some are being investigated as potential vaccine constituents.

Complement activation 
 
Much of the clinical severity of pneumococcal disease is due to 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.^{1, 2, 3} 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.

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.

Noninvasive disease

In adults admitted to the hospital for pneumonia treatment, S pneumoniae remains the most common organism isolated. Annual rates of pneumonia proven to be caused by S pneumoniae infection in the United States are estimated to be around 175,000; however, this number is likely a gross underestimate, as a definite cause is not determined in most cases of pneumonia treated each year. 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. The most common cause of death due to pneumococcal disease throughout the world is pneumonia.

S pneumoniae infection is estimated to cause over 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.^{4, 3}

Invasive disease

Invasive pneumococcal disease is estimated to cause more than 50,000 cases of bacteremia and 3,000-5,000 cases of meningitis annually. Death due to invasive disease is estimated to be 6,000 persons annually, with more than half of these in adults with specific risk factors (age, immunosuppression) for severe disease. Such risk factors are an indication for vaccination.^{4, 3}

International

Despite the worldwide importance of disease due to S pneumoniae infection, very little information is available on the extent of pneumococcal disease, particularly in developing countries.

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 pneumococcus infection is responsible for more than one million of the 2.6 million annual deaths due to acute respiratory infection in children younger than 5 years.

Estimates of pneumococcal disease in Gambian children show high rates of infection in the first year of life (≥500 per 100,000 children).⁵ 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.⁵

In Europe, children younger than 2 years constitute the population most at risk for pneumococcal infection, with rates decreasing as persons age. The overall incidence of invasive disease is estimated to be somewhat lower in Europe (35.8 per 100,000 persons in England vs 45.3 per 100,000 persons in Finland 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.⁵

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.⁶

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 from pneumococcal disease are high; however, further studies are greatly needed.⁷

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.⁸ 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.⁹

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.²

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.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

History

After successful colonization, S pneumoniae can cause a wide range of clinical disease. By direct extension from the nasopharynx, S pneumoniae infection can manifest as otitis media, sinusitis, tracheobronchitis, bronchitis, and pneumonia. By 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 include the following:

• High-risk age groups
• • 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.
• Immunodeficiencies: Conditions that cause immunodeficiency, including HIV infection, malignancy, diabetes mellitus, absence of the spleen, humoral immunity defects, complement deficiencies, and neutrophil dysfunction, are associated with an increased risk of disease.
• Conditions associated with decreased pulmonary clearance functions: These include asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), viral infections, and active/passive cigarette smoke exposure.
• Presentation in the late fall to early spring: Pneumococcal infections peak in late fall to early spring in the Northern Hemisphere.

Physical

Clinical signs and symptoms and physical examination findings alone often fail to distinguish S pneumoniae disease from those caused by other pathogens.

Diseases Due To Direct Extension

• Bacterial conjunctivitis is commonly more 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 suggested or showed that S pneumoniae otitis media is usually accompanied by fever and pain and that the fever is higher than in otitis media caused by other common bacterial pathogens.²
• Pneumococcal disease is less likely to resolve spontaneously.
• Eustachian tube congestion caused by a preceding viral infection is common. 
• 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 of otitis media.

Sinusitis

• As in otitis media, 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 sinusitis is usually preceded by a viral infection, leading to sinus mucosal swelling and ostia obstruction. This is followed by the development of a purulent discharge and cough.
• Malodorous breath and worsening cough due to postnasal drip are often noted at night.

Acute exacerbations of chronic bronchitis

• 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, cold symptoms, and dyspnea may indicate a viral cause.¹⁰

Pneumonia

• Classic pneumococcal pneumonia often develops in older children and adults. It is often preceded by a viral illness that is followed by an acute onset of high fever—often with rigors, productive cough, pleural pain, dyspnea, tachypnea, tachycardia, sweats, malaise, and fatigue.
• Patients typically appear ill and may have an anxious appearance. On careful physical examination, crackles can be heard in most patients. About half of all patients exhibit dullness to percussion, and splinting due to pain may be seen. Signs of effusion may be found on examination and include dullness to percussion at the bases and diaphragmatic motion that is decreased from that expected in light of the patient's tachypnea.
• In children (particularly school-aged and younger children), the potential manifestations of pneumonia are broad and often nonspecific. These may include nonspecific, mild respiratory symptoms, with or without a cough on initial presentation, high fever, abdominal pain, abdominal distention, anorexia, emesis (often suggesting a primary gastrointestinal disease, and meningeal signs due to meningeal irritation with upper lobe pneumonias.
• In elderly patients with pneumococcal pneumonia, tachypnea may be the primary presenting sign, and their temperature elevations may be mild or absent.
• The most common complication of pneumococcal pneumonia is pleural effusion. 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, with only 2% of these patients meeting criteria for true empyema. S pneumoniae infection, as well as S aureus infection, remains a common cause of pediatric empyema.^{2, 3, 11}

Invasive Disease

• As a cause of meningitis, S pneumoniae usually invades the meninges via the bloodstream. Recent studies have shown that this is most likely due to pneumococcal adherence to up-regulated platelet-activating factor on vascular endothelial meningeal surfaces.
• S pneumoniae can also directly invade the meninges after basilar skull fractures or other trauma that compromises the dura and is the most common cause of recurrent bacterial meningitis in these patients.
• 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 non-acutely after hours to days of developing signs and symptoms. Presenting signs and symptoms may be nonspecific and include fever, irritability, emesis, lethargy, anorexia, and malaise.
• Neurologic signs and symptoms are usually prominent and may include mental-status changes, delirium, lethargy, nuchal rigidity with positive Brudzinski and Kernig signs, cranial nerve palsies, and other focal neurological deficits.
• A bulging fontanelle and poor feeding may be seen infants.
• Elderly patients may present with more indolent signs, including increasing lethargy, nonresponsiveness, or coma.
• Twenty to 25% of patients with pneumococcal meningitis experience seizures.
• Bacteremia may or may not be found when blood cultures are obtained.
• Prolonged or secondary fevers are not uncommon but do not usually affect outcomes.
• Complications of pneumococcal meningitis include hearing loss (up to half of patients), seizures, learning disabilities, mental difficulties, and palsies. 
• Pneumococcal meningitis carries a greater risk of death and significant neurological disabilities than does meningitis of other common bacterial causes (eg, Haemophilus influenzae type B [Hib] and Neisseria meningitidis).^{2, 3, 11}

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 in these children since the widespread use of the Hib vaccine. 
• In adult patients, pneumococcal bacteremia is much more likely to be associated with another focal infection such as pneumonia, meningitis, or sinusitis.
• Signs, symptoms, and physical examination findings are usually nonspecific in patients with occult bacteremia due to pneumococcal infection.
• In most patients, fever develops within 24 hours of positive culture findings, with higher temperatures more often associated with the development of occult bacteremia.
• A peripheral WBC count greater than 15,000 cells/μL is associated with the presence of occult bacteremia.
• Bacteremia is less likely in patients with fever and signs or symptoms of focal infection (eg, otitis media or a viral syndrome).
• Most cases of occult bacteremia spontaneously resolve.
• Complications develop in an estimated 10% of patients with occult bacteremia and 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.^{3, 2} 

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, similar to rates of osteomyelitis sequelae caused by other organisms.
  • 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.¹²
• • Patients with prostheses or rheumatic fever are at increased risk for joint disease.

Soft tissue infections

• Although uncommon, S pneumoniae infection can cause of mild to serious soft tissue infections, including cellulitis, myositis, periorbital cellulitis, and abscess.
• 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.{Ref2}

Peritonitis

• 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 and other immunocompromising diseases.
• In adults, primary peritonitis is usually associated with cirrhosis.
• Females with severe pelvic inflammatory disease 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 with right lower quadrant abdominal pain are often initially investigated 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.
• 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. 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.

Predisposing conditions to pneumococcal infection are broad and often overlapping, including the following:

• Exposure
• • Cigarette smoke
  • Alcohol
  • Glucocorticosteroids
  • Cold
  • Stress
  • Prior respiratory infections (including influenza)
  • Daycare attendance
  • Homeless shelters
  • Military training
  • Prisons
  • Malnutrition
  • Lack of exposure to breast milk
• Defects in clearance of pneumococci from the blood
• • Congenital asplenia
  • Splenectomy
  • Autosplenectomy due to sickle cell disease
• Defects in clearance from sinopulmonary tissue or inflammatory conditions
• • Asthma
  • COPD
  • Cigarette smoking
  • Influenza/respiratory viral infections
• Defective antibody formation
• • Primary
  • • Congenital agammaglobulinemia
    • Common variable hypogammaglobulinemia
    • Selective immunoglobulin G (IgG) subclass deficiency
  • Secondary
  • • Lymphoma
    • Chronic lymphocytic leukemia
    • Multiple myeloma
    • HIV infection
• Defective complement (primary or secondary): Absent or decreased amounts of C1, C2, C3 or C4
• Abnormalities in polymorphonuclear leukocytes
• • Decreased levels associated with cyclic neutropenia, drug-induced neutropenia, or aplastic anemia
  • Decreased function caused by conditions such as alcoholism, cirrhosis, diabetes mellitus, renal insufficiency, and steroid therapy
• Other
• • Age (children <2 y and elderly persons)
  • Fatigue
  • Chronic disease
  • Hospitalization³

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

Lab Studies

• In any patient in whom a pneumococcal infection is suspected, Gram stain and culture should be performed using appropriate specimens, when possible, including one or more of the following:
• • Blood
  • Cerebrospinal fluid (CSF)
  • Sputum
  • Pleural fluid or lung aspirate
  • Joint fluid
  • Bone
  • Other abscess or tissue specimens
• 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 on all cultures with growth of S pneumoniae.
• 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).

Noninvasive Infections

• Many patients with pneumonia are treated presumptively with antibiotics to include coverage of S pneumoniae. When possible, sputum cultures should be obtained in patients with pneumonia. This can be accomplished via expectoration (in adults), collection of endotracheal specimens, or bronchoalveolar lavage (BAL).
• 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 provides good evidence for pneumococcus.
• When large effusions or empyema is present, attempts should be made to obtain pleural fluid for Gram stain and culture.
• Blood cultures should be obtained in hospitalized patients with pneumonia; in pneumococcal pneumonia, blood cultures are positive in an estimated 10% of children and up to 25% of adults.
• 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.
• Neutrophil levels, CRP levels, and ESR are all often elevated.

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. An abnormally low WBC count may indicate severe disease and a poor prognosis.
• The ESR and CRP level are typically elevated in patients with invasive pneumococcal disease.
• The development of a polymerase chain reaction (PCR) assay for S pneumoniae with sufficient sensitivity and specificity is underway.

Meningitis

• CSF findings are typical of those found in bacterial meningitis and usually include the following:
• • Elevated opening pressure
  • Elevated WBC count (1000-5000 cells/μL) and elevated neutrophil level (>80%)
  • Elevated protein level (>100 mg/dL)
  • Decreased glucose level (<40 mg/dL; <50% of simultaneous blood glucose)
• Positive Gram stain and culture results in most patients with pneumococcal meningitis who did not receive antibiotics in the 4-6 hours prior to lumbar puncture.
• Rapid antigen tests (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. CSF obtained from patients pretreated with antibiotics may be an exception.
• 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.
• Microbiological laboratories should follow established guidelines regarding inoculum size and media (Mueller-Hinton agar with sheep, horse, or lysed horse red blood cells).
• Susceptibilities can be determined using the minimal inhibitory concentration (MIC) or using disk diffusion techniques, such as the E-test.
• The National Committee for Clinical Laboratory Standards (NCCLS) has defined S pneumoniae susceptibility as follows:
• • Penicillin
  • • Susceptible: MIC is less than or equal to 0.06 µg/mL.
    • Intermediate: MIC is between 0.12 and 1 µg/mL.
    • Resistant: MIC is greater than or equal to 2 µg/mL.
  • Cefotaxime/ceftriaxone
  • • Susceptible (non-CNS/CNS): MIC is less than or equal to 1 or 0.5 µg/mL, respectively.
    • Intermediate (non-CNS/CNS): MIC is 2 or 1 µg/mL, respectively.
    • Resistant (non-CNS/CNS): MIC is greater than or equal to 4 or 2 µg/mL, respectively.
• 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 those with pneumonia.
  • Early in the disease process, the chest radiography findings may appear normal
  • 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, pneumatoceles, and, rarely, abscesses.
  • Cavitation is not a feature of S pneumoniae pneumonia and should prompt investigation for other pathogens.
• 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.
  • Sinus CT scanning may provide information about the presence and extent of sinus disease. Positive findings include opacification and/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 observe 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 infection involvement.

Other Tests

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

Procedures

• Middle ear fluid aspiration
• Pleural fluid aspiration
• Chest tube thoracostomy or catheter placement
• Video-assisted thoracoscopy (VATS) or pleural decortication
• Lumbar puncture
• Joint fluid aspiration and/or wash-out of joint space
• Bone biopsy
• Soft tissue/muscle biopsy

Histologic Findings

See Causes.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

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.

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 mildly ill presentations to febrile pneumonia to respiratory distress requiring ICU-level care. Factors such as age, types 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 deciding the need for and level of hospitalization. 

Hospitalized patients should usually be treated with parenteral antibiotics in addition to medications for pulmonary symptoms, pain medications, intravenous fluids, and/or parenteral or enteral nutrition, oxygen, and other indicated medications, as needed.

Meningitis

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

The use of steroids 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.¹³

Steroids should be considered prior to antibiotic therapy in children aged 6 weeks and older with possible pneumococcal meningitis.¹⁴

Intravenous fluids, parenteral/enteral nutrition, and other medications should be used as indicated in certain patients.

Bacteremia and sepsis

Patients with pneumococcal bacteremia should be treated with appropriate antibiotics.

Children who undergo a workup to rule out sepsis (or serious bacterial illness) but who are not treated initially with antibiotics and whose cultures subsequently grow S pneumoniae are often asymptomatic and have negative repeat blood culture findings at follow-up.

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.

Other infections

Patients with cardiac, skin/soft-tissue, bone, and/or joint infections with S pneumoniae should usually be admitted to the hospital for observation, intravenous antibiotic therapy, and expedition of further workup and evaluation for location and extent of disease.

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.
• In patients with suspected septic arthritis or osteomyelitis, appropriate specimens should be obtained for Gram stain, cell count, histology, and/or culture.
• Patients with recurrent or chronic otitis media, periorbital or orbital cellulitis, or facial cellulitis may require surgical intervention.

Consultations

• An infectious disease specialist should be consulted in all cases of sepsis, meningitis, complicated pneumonia, spontaneous bacterial peritonitis, osteomyelitis, septic arthritis, and infection with resistant isolates.
• A surgeon should be consulted in cases of complicated pneumonia or complicated soft-tissue infections.
• An orthopedic specialist should be consulted in cases of septic arthritis or osteomyelitis.
• A neurosurgeon should be consulted in cases of recurrent meningitis.
• A pulmonologist should be consulted in cases of complicated pneumonia.
• Consultation with an otolaryngologist may be needed in cases of recurrent otitis media.
• An otolaryngologist and/or an ophthalmologist should be consulted in cases of periorbital and/or orbital cellulitis.
• A cardiologist should be consulted in all cases of endocarditis or pericarditis.

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• Multimedia
• References

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 Centers for Disease Control and Prevention (CDC), as well as many state health departments, maintain a population-based surveillance system (called the Active Bacterial Core Surveillance system) that investigates the epidemiology and susceptibility patterns of invasive pneumococcal infections in the United States. In 2004, 21.4% of all isolates obtained showed intermediate or resistant susceptibility patterns to penicillin (up from 20% in 2003).¹⁵ 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.^{16, 17} Resistance rates are generally higher in most European countries, as well as in Hong Kong and Thailand.¹⁸

Unlike many common bacterial organisms, the method of resistance of pneumococcus to penicillin and cephalosporins is through alteration in the cell wall penicillin-binding proteins (PBPs). By altering these sites (where the antibiotics bind), the antibiotic affinity is decreased, subsequently decreasing the susceptibilities. This type of resistance can be overcome if the serum or site levels of the antibiotic exceed the minimum inhibitory concentration (MIC) of the organism for 40-50% of the dosing interval.

Penicillin-resistant pneumococci are often also resistant to multiple other classes of antibiotics, including other penicillins, 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 transposon, that encodes resistance to multiple antibiotics.

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

No vancomycin-resistant pneumococcal isolates have been reported to date. The phenomenon of tolerance (survival but not growth in the presence of a given antibiotic) has been observed, but its clinical relevance is unknown.

In the United States, most pneumococcal isolates remain susceptible to fluoroquinolones. In certain countries and specific populations in whom the use of fluoroquinolones is more prevalent (eg, nursing homes), an increase in resistance has been seen.^{2, 3, 11}

• Children
• • In children with CAP treated as outpatients, amoxicillin or amoxicillin-clavulanate at dosages used for the treatment of otitis media are recommended. In school-aged children (>5 y), the addition of a macrolide for coverage of atypical organisms is advised.
  • In children ill enough to warrant hospitalization, the use of penicillin, ampicillin-sulbactam, or ceftriaxone is usually appropriate, and decisions for therapy should account for local resistance patterns.
  • 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.¹¹
• Adults
• • The Infectious Disease Society of America (IDSA) guidelines recommend the initial use of a macrolide (or doxycycline) for outpatient therapy of previously healthy adults with no specific risk factors for resistant S pneumoniae infection.
• • In adult patients with underlying chronic disease, immunosuppression (including asplenia or that caused by immunosuppressive therapies), recent use of antibiotics (the preceding 3 mo), or other specific risk factors for resistant organisms (eg, residence in an area with high rates of resistant pneumococcus), the IDSA guidelines recommend use of either (1) a respiratory fluoroquinolone (moxifloxacin, gemifloxacin, levofloxacin) or (2) a beta-lactam antibiotic (high-dose amoxicillin, amoxicillin-clavulanate, or, alternatively, a second- or third-generation cephalosporin) plus a macrolide (or doxycycline).
  • For inpatient treatment of adult pneumonia on a medical ward, treatment recommendations are as above for outpatient treatment of patients with comorbid conditions.
  • For inpatient treatment of adult patients who require ICU care, recommendations are for a beta-lactam antibiotic plus a macrolide or a fluoroquinolone.¹⁹

Drug Category: Antibiotics

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).

Typical doses of penicillin provide more than adequate serum and body fluid concentrations for susceptible organisms (usually even with intermediate-susceptible strains), and many studies have shown similar outcomes in patients with penicillin-resistant versus penicillin-susceptible pneumococcal isolates treated with appropriate doses of beta-lactam antibiotics. Levels of CSF penetration are also therapeutic, although, in most cases, vancomycin should be used in addition to a beta-lactam antibiotic until isolate susceptibilities can be determined given the increasing rate of penicillin-resistant strains of S pneumoniae.

Cephalosporins, which are also beta-lactam antibiotics, inhibit pneumococcus in the same way as penicillins and are resisted in the same manner (alteration in the cell wall PBPs). First-generation cephalosporins provide similar coverage in the treatment of penicillin-susceptible strains, although many of them have higher MICs. Most strains of pneumococcus that are not susceptible to penicillin also have some resistance to third-generation cephalosporins, although some may still be susceptible, depending on the particular PBPs affected. 

In most cases, macrolides have activity against penicillin-susceptible strains of S pneumoniae. However, half or more of pneumococcal strains that have intermediate resistance or that are resistant to penicillin are also resistant to macrolides. Most macrolide-resistant isolates of S pneumoniae may derive their resistance through an efflux pump mechanism, which may be overcome with levels of drug that exceed the MIC for sufficient periods. Macrolides have CSF penetration and should not be used to treatment meningitis.

Most pneumococcal isolates in the United States remain susceptible to certain fluoroquinolones, including moxifloxacin (most effective), levofloxacin, gatifloxacin, and gemifloxacin. Ciprofloxacin and ofloxacin have limited activity against pneumococcal infections. Fluoroquinolones provide broad-spectrum treatment for CAP and achieve excellent serum drug levels and tissue penetration. Specific populations in whom the use of fluoroquinolones is traditionally increased (eg, residents of nursing homes) have shown increased levels of pneumococcal resistance to fluoroquinolones, and their empiric use in respiratory infections should also be tempered by the concern for rapid development of resistance to this class by many organisms.
 
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, and it is the drug of choice (with a third-generation cephalosporin) in the treatment of pneumococcal meningitis. 

The increased 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. 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.