Chapter 280. Pneumococcal Infections

Sandra R. Arnold; P. Joan Chesney

Pneumococcal Infections: Introduction

Streptococcus pneumoniae, Staphylococcus aureus, and group A Streptococcus pyogenes are the three most important bacterial pathogens causing infections in otherwise well children. In 2005 it was estimated that S pneumoniae caused 700,000 to 1 million deaths in children younger than 5 years of age. Most of these children lived in developing countries.1

There are 90 immunologically and chemically distinct capsular polysaccharides that determine virulence. Based on antigenic similarities, the 90 types have been grouped into 45 serotypes. Relatively few serotypes cause most disease, which has lead to development of polyvalent vaccines.2

S pneumoniae can cause infection in almost any tissue or organ. The vast majority of infections in children occur in the middle ear, sinuses, lungs, meninges, and bloodstream. In 2000, the Food and Drug Administration approved and the Advisory Committee on Immunization Practices recommended the heptavalent pneumococcal conjugate vaccine (PCV7) for routine use in infants and young children as a primary series at 2, 4, and 6 months of age and a booster dose at 12 to 15 months of age.3 This vaccine has had an impressive effect on the incidence of invasive pneumococcal disease in vaccine recipients and the general population (see Chapter 244).

Epidemiology

Recent nasopharyngeal colonization with a new serotype almost always precedes infection.4,5 Colonization rates are highest in infants and preschool children, where they may be as high as 35%.4 Children may carry different serotypes at different times but are almost always colonized by those limited serotypes responsible for infections in this age group.2 Carriage rates are lower in older children (40–50%) and in adults (5–30%).6,7 PCV7 includes the 7 most common serotypes causing colonization and infection in children (4, 6B, 9V, 14, 18C, 19F, and 23F). These serotypes and the cross-reactive serotypes (6A, 9A, 9L, 18B, 18F) caused 86% of cases of bacteremia, 83% of cases of meningitis, and 65% of cases of acute otitis media in children younger than 6 years.3 These serotypes also accounted for more than 80% of penicillin-resistant colonizing serotypes.8

PCV7 was licensed for use in the prevention of invasive pneumococcal disease (a positive culture from a normally sterile body site, eg, meningitis and bacteremia) in infants and toddlers. In the Northern California Kaiser Permanente Vaccine Study among 37,686 infants, vaccine efficacy was 97.4% compared with placebo for vaccine serotype invasive pneumococcal disease.9 In the same study population, episodes of pneumonia with an abnormal chest radiograph with consolidation or empyema were reduced by 17.7%. In a separate study population, vaccine efficacy for otitis media was demonstrated but to a more modest degree (6% for all cases of otitis media, 34% for culture-confirmed pneumococcal episodes, and 57% for otitis media caused by the pneumococcal serotypes contained in the vaccine).10

Since the release of PCV, the rates of colonization and invasive pneumococcal disease due to vaccine serotypes have steadily declined, with the most dramatic effect seen in age 2 years or younger group. The overall rate of colonization in children has remained steady secondary to the increase in colonization by nonvaccine serotypes.11-16 Based upon active surveillance by the Centers for Disease Control and Prevention, overall invasive pneumococcal disease rate among children aged 5 years or younger was 77% lower in 2005 (approximately 13,000 fewer cases) compared with 1998 to 1999.17 In addition, secondary to indirect effects of PCV7 herd immunity,18 disease incidence dropped by 18% in the 65 years or older age group.19,20 The decline in invasive pneumococcal disease is attributable to a decline in disease caused by vaccine serotypes. As with pneumococcal colonization, these gains have been somewhat offset by increases in disease secondary to nonvaccine serotypes.19,21-27 The emergence of serotype 19A causing invasive pneumococcal disease and complicated otitis media has elicited concerns as a substantial proportion of these isolates have been found to be multidrug resistant.28,29

Prior to the release of PVC7, the incidence of penicillin-resistant and multidrug-resistant strains had increased dramatically through the late 1990s and was as high as 35% in many parts of the United States.8 Between 1999 and 2004, the incidence of resistant strains in invasive pneumococcal disease fell by 81% in children under 2 years of age and by approximately 50% across all age groups due to a reduction in disease caused by antibiotic-resistant vaccine serotypes30,31; however, in the same time period, infections due to multidrug-resistant serotypes increased.32 The likely mechanisms by which PCV7 has had this impact on antibiotic resistance are (1) interruption of transmission of vaccine serotype antibiotic-resistant strains by blocking acquisition of these strains and (2) overall reduction in antibiotic use accompanying the reduction in invasive and noninvasive pneumococcal infections.33,34 It should be noted that despite improvements in the antibiotic profile of pneumococcal infections, antibiotic resistance will continue to increase with the emergence of antibiotic-resistant serotypes not contained in the vaccine and persistence of resistant vaccine serotypes that have undergone capsular switching. In addition, continued inappropriate use of antibiotics for viral infections will provide a suitable ecology for these changes to occur.

Pathophysiology and Genetics

Virulence of the Organism

Invasive pneumococcal disease is preceded by colonization of the nasopharynx, the organism having been acquired through respiratory droplet spread from a colonized individual. A variety of virulence factors promote colonization of the nasopharynx, including capsular polysaccharides of the cell wall.35 Subsequent infection can occur by bacterial aspiration into the lower respiratory tract or spread to the middle ear or sinuses.36 Adherence at these sites may be enhanced by the presence of viral respiratory pathogens resulting in exposed muscosal receptors.37,38Inflammatory response to toxic bacterial cell wall components and other virulence factors result in accumulation of fluid, cells, and cytokines, leading to symptomatology.36 Bacteremia and meningitis occur when colonizing bacteria gain access to the bloodstream, penetrating the epithelial barrier of the nasopharynx.

Host Immunity

Local and circulating antibody and an intact complement pathway are the most important factors mediating the outcome of S pneumoniae invasive pneumococcal disease. Circulating antibody may be acquired as the result of maternal transmission (neonates), nasopharyngeal colonization, immunization or infection. Individuals who have had no previous contact with a virulent strain and therefore have no serotype-specific circulating antibody are at risk for developing infection. Serotype specific or cross-reactive antibody adheres to the capsule, which results in capsular swelling and “stickiness” enhancing opsonization and phagocytosis by neutrophils. Without antibody attached to the organism, these cells are unable to phagocytose the organisms, which can reproduce unhindered. Infants under 2 years of age are at high risk for invasive pneumococcal disease as they are unable to produce anticapsular antibody after infection or following immunization with purified polysaccharide vaccine.

Populations at Risk

Children in daycare centers have an increased risk, presumably as a result of the spread of and colonization by virulent serotypes. Children who are not breastfed are also at higher risk. The risk of invasive pneumococcal disease is increased approximately twofold to fourfold for and American Indians, Alaskan natives, and African American have an increased risk.27,39-41 Significant narrowing or elimination of these racial/ethnic disparities in invasive pneumococcal disease incidence has been documented with the use of PCV7.12,42,43

Increased risk for invasive pneumococcal disease also occurs among children with immunodeficiency,44 including defects in humoral immunity; HIV infection44; asplenia or splenic dysfunction,45 including sickle hemoglobinopathies46; and recently described defects of the innate immune system (see Chapters 187 and 188). Other populations at risk include children with cancer, central nervous system disorders or craniofacial anomalies, congenital heart disease, asthma,50 chronic kidney disease (especially nephrotic syndrome), liver disease, recent trauma, burns or near drowning.41 children who have received cochlear implants, particularly those with a positioner, are at increased risk for pneumococcal meningitis.51,52

Clinical Manifestations

In the pre-PCV7 era, S pneumoniae was the predominant organism causing occult bacteremia (92% of cases).53 In the postvaccine era, this entity has virtually disappeared.54,55

In children beyond the neonatal period, S pneumoniae is the leading bacterial cause of pneumonia in the United States, causing 70% of cases that involve respiratory bacteria (see Chapter 240).56 In infants and young children, bronchopneumonia with scattered distribution of parenchymal consolidation is commonly seen on x-rays. In older children and adults, lobar consolidation is more common. Other radiographic findings can include pleural fluid, lung abscess(es) resulting from necrosis, and, infrequently, pneumatoceles. Symptoms may range from mild fever and nonspecific respiratory symptoms with or without cough to high fever with toxicity and severe respiratory impairment. In infants and toddlers, fever, vomiting, abdominal distension, and pain may suggest appendicitis. The classic clinical presentation in older children and adults, following a viral prodrome, is the abrupt onset of high fever with chills, dyspnea, and cough with rust-colored sputum. Patients with right upper lobe pneumonia can have nuchal rigidity suggestive of meningitis. Forty percent of cases of bacterial pneumonia are associated with parapneumonic effusions, (inflammatory fluid collection adjacent to a pneumonic process). Pneumonia rates have declined in the PCV7 era,57,58 but reports of complicated parapneumonic effusion or empyema (fibrinopurulent exudate) increased before and after PCV7 with nonvaccine serotype 1 S pneumoniae as the predominant pathogen.27,59-62

Local spread from the colonized nasopharynx may result in acute otitis media, sinusitis, conjunctivitis, and periorbital or buccal cellulitis. Other important but uncommon infections resulting from metastatic seeding following S pneumoniae bacteremia are meningitis, acute bacterial endocarditis, pericarditis, pyogenic arthritis, osteomyelitis, and cellulitis. All of these infections are covered in more detail in other chapters. In children with defective humoral immunity, functional, or anatomic asplenia, and/or complement defects, fulminant septicemia occurs with S pneumoniae.45 Pneumococcal peritonitis may be uniquely seen in children with nephrotic syndrome.64

Diagnostic Evaluation

Pneumococcal infections can only be diagnosed with certainty if the organism is isolated from a normally sterile site, such as blood; cerebrospinal fluid; joint, pleural, pericardial, or middle ear fluid; or a bone or abscess aspirate. Every attempt should be made to obtain these cultures before starting antibiotics in order to document the etiology and perform antimicrobial susceptibility testing.

Nasopharngeal cultures are of no value as almost all young children are colonized with S pneumoniae at some time. Lower respiratory tract secretions obtained by tracheal aspirate or bronchoalveolar lavage or needle aspirate of infected lung tissue are valuable but rarely justified.

Rapid antigen tests for S pneumoniae have been of limited value for rapid diagnosis, but with better sensitivity hold promise for the future. Latex agglutination, enzyme immunoassay, immunochromatic, and polymerase chain reaction assays in general are as effective as Gram stains.65,66 Inflammatory markers such as leukocytes, elevated ESR, and CRP are frequently associated with invasive pneumococcal disease but are not specific for invasive pneumococcal disease and should never be used to restrict antibiotics to cover S pneumoniae alone.

Treatment

Penicillin and all β-lactam drugs act on S pneumoniae by inhibiting the activity of transpeptidase enzymes (also called penicillin-binding proteins), which build the peptidoglycan lattice or scaffolding of the cell wall. Through the process of transformation, S pneumoniae acquired mutated penicillin-binding proteins from other resistant streptococcal species (see Chapter 222). Changes have resulted in a slow but steady increase the minimal inhibitory concentrations for β-lactam antibiotics.67 Multidrug resistance occurs in penicillin-resistant pneumococci and includes resistance to cefotaxime, macrolides, trimethoprim-sulfamethoxazole, chloramphenicol, tetracycline, and increasingly, to clindamycin and the fluoroquinolones.8,68,69 Vancomycin is the only drug to which no strains have yet become resistant. Resistant strains may spread from person to person, throughout communities and across international borders.

The definition of antimicrobial susceptibility is based upon achievable levels of the antibiotic at the site of infection and varies by antibiotic. Recently, changes have been made to the susceptibility break points for penicillin and cefotaxime (eTable 280.1).

eTable 280.1 Break Points for StreptococcusPneumoniae Susceptibility to Penicillin and Third-Generation Cephalosporins (in μG/Ml)

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eTable 280.1 Break Points for StreptococcusPneumoniae Susceptibility to Penicillin and Third-Generation Cephalosporins (in μG/Ml)

Susceptible

Intermediate

Resistant

Penicillin

⩽ 2*

⩾ 8

Cefotaxime/ceftriaxone (meningeal)

⩽ 0.5

⩾ 2

Cefotaxime/ceftriaxone (nonmeningeal)

⩽ 2

⩾ 4

The breakpoint for penicillin susceptibility in meningitis remains ⩽ 0.06 μg/mL.

All patients with suspected bacterial meningitis should be treated initially with vancomycin at 60 mg/kg and cefotaxime at 200 to 300 mg/kg until susceptibilities of the organism are available. Ceftriaxone at 100 mg/kg per day is an acceptable substitute for cefotaxime. After susceptibilities are available, antibiotic modifications can be made. For susceptible organisms, aqueous penicillin G, 250,000 U/kg per day divided every 4 hours, is an appropriate regimen. Therapy is usually continued for 10 days, but may extend for longer periods. The use of dexamethasone as adjunctive therapy for bacterial meningitis remains unresolved (see Chapter 231).70,71 Results from a meta-analysis of clinical trials of steroids in meningitis, including cases of pneumococcal meningitis, suggest a benefit in the prevention of hearing loss if steroids are given before or concomitantly with antibiotics.72

For nonmeningeal invasive pneumococcal disease in the immunocompetent host, empiric use of vancomycin is not generally indicated because treatment failures are rare with penicillins and cephalosporins for bacteremia and pneumonia. Plasma levels of recommended agents, including the β-lactam antibiotics, are well in excess of the minimum inhibitory concentration of even the highly resistant strains isolated thus far.73,74 No clear therapeutic failures have yet been reported for nonmeningeal invasive infections when recommended doses of systemic β-lactam agents are used in patients with normal host defenses. Less experience is available for patients with fulminant and potentially life-threatening invasive infections, particularly in immunocompromised hosts. In patients with fulminant and potentially life-threatening invasive infections, particularly in immunocompromised hosts, the addition of vancomycin to the usual regimen for an invasive, nonmeningeal infection may be justified, providing the vancomycin is discontinued after susceptibilities reveal that therapy with β-lactam agents should be successful. Treatment failures with the use of newer macrolides and fluoroquinolones (the latter in adults) to treat bacteremia and pneumonia due to nonsusceptible strains have been reported75,76; thus, empiric monotherapy with these agents for community-acquired pneumonia should take into account the antibiotic-resistance patterns and the severity of illness. Linezolid was licensed for the treatment of gram-positive community-acquired and nosocomial pneumonia in children in 2002 and is a treatment option for suspected or confirmed multidrug-resistant pneumococcal pneumonia; it may be most useful when infection (either primary or coinfection) with methicillin-resistant S aureus cannot be excluded (see Chapter 240).77

High doses of amoxicillin (80–90 mg/kg/day) remains the drug of choice for otitis media caused by S pneumoniae,78,79 (see Chapter 243).

Complications

Pneumococcal meningitis has a case fatality rate of 5% to 10% in developed countries.71,80,81 Hearing loss is the most common neurologic sequela occurring in up to 10% of infections; other neurologic sequelae occur with less frequency, ranging from mild to severe.72,80,82 Fulminant pneumococcal sepsis is unusual but can occur, especially among immunocompromised or asplenic individuals. Pneumococcal pneumonia may be complicated by pleural effusion or empyema necessitating a chest tube or surgical procedure to hasten resolution. Mastoiditis is an uncommon complication of otitis media that may be complicated by meningitis or brain abscess. Increased incidence of mastoiditis may occur with decreased frequency of otitis media treatment although this is still unclear.83,84 Invasive pneumococcal infections may be rarely be complicated by hemolytic uremic syndrome.85

Prevention

The 23-valent pneumococcal capsular polysaccharide vaccine licensed in 1977 covers 90% of the serotypes causing invasive pneumococcal disease in the United States. This vaccine elicits type-specific antibody responses in children older than 5 years of age and adults, but not for children younger than 2 years of age (see Chapter 244).3,86

Serotype replacement with nonvaccine serotypes in colonization and invasive pneumococcal disease has occurred.New pneumococcal conjugate vaccines containing capsular polysaccharide from additional serotypes (1, 3, 5, and 7F) currently being studied should expand coverage for both invasive and noninvasive pneumococcal disease and improve coverage for invasive pneumococcal disease in developing countries where these serotypes cause more invasive disease.87,88 The development of novel pneumococcal vaccines are based on pneumococcal proteins that contribute to virulence and are common to all serotypes. Several candidate protein vaccine antigens have been identified and tested, with the most promising being a combination of pneumolysin, pneumococcal surface protein A, and choline-binding protein A (eFig. 280.1).35

eFigure 280.1.

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Changes in incidence rate* of invasive pneumococcal disease (IPD) among children aged 5 years and younger before and after introduction of 7-valent pneumococcal conjugate vaccine (PCV7), by age and year. Active Bacterial Core surveillance, 8 states, 1998–2005.

References

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