33 - 151 Pneumococcal Infections

151 Pneumococcal Infections

French GL: Antimicrobial resistance and healthcare-associated infec­ tions, in Hospital Epidemiology and Infection Control, 4th ed. GC Mayhall (ed). Philadelphia, Lippincott Williams & Wilkins, 2012, pp. 1297–1310. Rice LB: Mechanisms of resistance and clinical relevance of resistance to β-lactams, glycopeptides, and fluoroquinolones. Mayo Clin Proc 87:198, 2012. Silver LL, Bush K (eds): Antibiotics and Antibiotic Resistance. Cold Spring Harbor Perspectives in Medicine. New York, Cold Spring Harbor Laboratory Press, 2016. Section 5 Diseases Caused by

Gram-Positive Bacteria David Goldblatt, Katherine L. O’Brien

Pneumococcal

Infections In the late nineteenth century, pairs of micrococci were first recog­ nized in the blood of rabbits injected with human saliva by both Louis Pasteur, working in France, and George Sternberg, an American army physician. The important role of these micrococci in human disease was not appreciated at that time. By 1886, when the organism was designated “pneumokokkus” and Diplococcus pneumoniae, it had been isolated by many independent investigators, and its role in the etiol­ ogy of pneumonia was well known. In the 1930s, pneumonia was the third leading cause of death in the United States (after heart disease and cancer) and was responsible for ~7% of all deaths both in the United States and in Europe. While pneumonia was caused by a host of pathogens, lobar pneumonia—a pattern more likely to be caused by the pneumococcus—accounted for approximately one-half of all pneu­ monia deaths in the United States in 1929. In 1974, the organism was reclassified as Streptococcus pneumoniae. ■ ■MICROBIOLOGY Etiologic Agent  Pneumococci are spherical gram-positive bacteria of the genus Streptococcus. Within this genus, cell division occurs along a single axis, and bacteria grow in chains or pairs—hence the name Streptococcus, from the Greek streptos, meaning “twisted,” and kokkos, meaning “berry.” At least 22 streptococcal species are recognized and are divided further into groups based on their hemolytic properties. S. pneumoniae belongs to the α-hemolytic group that characteristically produces a greenish color on blood agar because of the reduction of iron in hemoglobin (Fig. 151-1). The bacteria are fastidious and grow best in 5% CO2 but require a source of catalase (e.g., blood) for growth on agar plates, where they develop mucoid (smooth/shiny) colonies. Pneumococci without a capsule produce colonies with a rough surface. Unlike that of other α-hemolytic streptococci, their growth is inhibited in the presence of optochin (ethylhydrocupreine hydrochloride), and they are bile soluble. In common with other gram-positive bacteria, pneumococci have a cell membrane beneath a cell wall, which in turn is covered by a polysaccharide capsule. Pneumococci are divided into serogroups or serotypes based on capsular polysaccharide structure, as distinguished with rabbit polyclonal antisera; capsules swell in the presence of spe­ cific antiserum (the Quellung reaction). The most recently discovered serotypes—6C, 6D, 6F, 6G, 6H, 10D, 11E, 20A, 20B, and 35D—have been identified with monoclonal antibodies and by serologic, genetic, and biochemical means. The currently recognized 100 serotypes fall

FIGURE 151-1  Pneumococci growing on blood agar, illustrating α hemolysis and optochin sensitivity (zone around optochin disk). Inset: Gram’s stain, illustrating gram-positive diplococci. (Photographs courtesy of Paul Turner, University of Oxford, United Kingdom.) CHAPTER 151 into 21 serogroups, and each serogroup contains two to eight serotypes with closely related capsules. Detailed genetic analysis of the locus cod­ ing for the polysaccharide capsule, the cps locus, continues to reveal putative novel capsular polysaccharides, variants within existing sero­ groups that are designated with an “X.” In the absence of type-specific antibody, the capsule protects the bacteria from phagocytosis by host cells and is arguably the most important determinant of pneumococcal virulence. Unencapsulated variants are occasionally identified in cases of invasive pneumococcal disease; however, when their genotype is assessed, they often contain capsular genes. Thus it is likely that they were encapsulated in vivo and have stopped producing capsule during the laboratory steps of pathogen isolation. Pneumococcal Infections Virulence Factors  Within the cytoplasm, cell membrane, and cell wall, many molecules that may play a role in pneumococcal pathogenesis and virulence have been identified (Fig. 151-2). These proteins are often involved in direct interactions with host tissues or in concealment of the bacterial surface from host defense mechanisms. Pneumolysin (PLY) is a secreted cytotoxin thought to result in cytolysis of cells and tissues, and LytA enhances pathogenesis. A number of cell wall proteins interfere with the complement pathway, thus inhibiting complement deposition and preventing lysis and/or opsonophagocyto­ sis. The pneumococcal H inhibitor (Hic) impedes the formation of C3 convertase, while pneumococcal surface protein C (PspC), also known as choline-binding protein A (CbpA), binds factor H and is thought to accelerate the breakdown of C3. PspA and CbpA inhibit the deposition of or degrade C3b. To avoid clearance by the mucus, pneumococci utilize the matrix metalloprotease ZmpA, which cleaves mucosal IgA to evade complement activation, preventing agglutination and thus clearance by the mucociliary flow. The numerous pneumococcal proteins thought to be involved in adhesion include pneumococcal surface adhesin A (PsaA) and the exoglycosidases such as neuraminidase (NanA), β-galactosidase (BgaA), and β-N-Acetylglucosaminidase (StrH), which deglycosylate host glycoproteins releasing sugars as a nutrient source and expos­ ing hidden receptors for adhesion. Once through the epithelial bar­ rier, pneumococci utilize PLY and mannose receptor C type lectin 1 (MRC-1/CD206) on the surface of dendritic cells and macrophages to enter cells, where they may survive intracellularly in vacuoles thus

Pneumolysin: secreted cytolytic/cytotoxic protein; activates complement and stimulates proinflammatory cytokines Polysaccharide capsule: prevents complement binding; therefore antiphagocytic, target for protective antibody Pneumococcal surface protein A: interferes with complement deposition by blocking alternative complement pathway activation Pneumococcal surface protein C (choline-binding protein A): principal pneumococcal adhesion molecule Pneumococcal iron acquisition A and iron uptake A: lipoprotein components of iron ABC transporters, essential for iron uptake PspA PspC/ CbpA IgA1 protease: degrades human IgA1 PiaA and PiuA CbpG Hyal PsaA Pneumolysin Phosphorylcholine Autolysin PBP Enolase PART 5 Infectious Diseases Histidine triad Neuraminidase (NanA, NanB) Cell membrane Polysaccharide capsule Cell wall FIGURE 151-2  Schematic diagram of the pneumococcal cell surface, with key antigens and their roles highlighted. facilitating spread. To outcompete the other co-colonizing bacteria, the pneumococcus produces bacteriocins called pneumocins that medi­ ate intraspecific competition. Some of the antigens mentioned above are potential vaccine candidates (see “Prevention,” below). Biofilm production by pneumococci is now well recognized and is likely to be an important mechanism aiding survival of pneumococci in the upper respiratory tract and contributing to local disease manifestations such as otitis media. Although the capsule surrounding the cell wall of S. pneumoniae is the basis for categorization by serotype, the disease potential of a sero­ type is also related to the genetic composition of the strain. Molecular genotyping and epidemiology are therefore essential. Conventionally, multilocus sequence typing (MLST) was the gold-standard technique for epidemiologic analyses due to its simplicity and effectiveness. Alleles at seven loci are sequenced, compared with all of the known alleles at that locus and a unique sequence type (ST) assigned using the pneumococcal MLST website (pubmlst.org/organisms/streptococcus-

pneumoniae/). With the advent of high-throughput and relatively inexpensive sequencing techniques, whole-genome sequencing has facilitated even more precise molecular epidemiology: enhanced genomic epidemiology can be performed using ribosomal MLST (rMLST; >50 ribosomal genes) or core genome MLST (cgMLST; >1300 core genes) with assignment via the PubMLST website, while k-mer–based methods fully exploit core and accessory genomic variation (Pop­ PUNK, github.com/bacpop/PopPUNK) to assign Global Pneumococcal Sequence Clusters (GPSCs) via the Global Pneumococcal Sequencing project website (pneumogen.net). Twenty-three years after the first pneumococcal genome was sequenced, >50,000 pneumococcal genomes are now available on pub­ lic nucleotide sequence databases. There are two curated pneumococ­ cal genome databases: the PubMLST Pneumococcal Genome Library contains ~33,000 curated, published, assembled genomes and isolate

Choline-binding protein G: cleaves host extracellular matrix, aiding adhesion Pneumococcal surface antigen A: metal-binding lipoprotein (Zn and Mn); may have a role in adhesion Hyaluronate lyase: degrades hyaluronan and chondroitin sulfate in extracellular matrix Binds to platelet-activating factor receptor on human epithelial cells Releases peptidoglycan, teichoic acid, pneumolysin, and other intracellular contents on autolysis Penicillin-binding proteins: catalyze polymerization of glycan chains and transpeptidation of pentapeptidic moieties within structure of peptidoglycan Neuraminidase: contributes to adherence; removes sialic acids on host glycopeptides and mucin to expose binding sites Binds to fibronectin in host tissues PhtA, B, D, E: cell-surface exposed proteins, unknown function Pili: on cell surface; inhibit phagocytosis, promote invasion Pili provenance data (pubmlst.org/organisms/streptococcus-pneumoniae/pgl/), and the GPS Database Monocle Dataviewer, which contains ~21,000 high-quality genomes with epidemiologic data (www.pneumogen

.net/gps/gps-database-overview/). These databases are publicly avail­ able and free to access. Over the past decade, web applications such as Pathogenwatch (pathogen.watch/) have provided a user-friendly platform to enable fast and reliable analysis of pneumococcal genome data without the requirement for bioinformatic expertise. Users can simply drag and drop genome data into a browser to obtain details such as serotype, genotype (including GPSC and MLST), and antimi­ crobial resistance profiles. In recent years, genome sequence analyses have made major contributions to the understanding of pneumococcal molecular epidemiology, biology, diversity, pathogenicity, and vaccine impact. ■ ■EPIDEMIOLOGY (See also “Global Health,” below.) Pneumococcal infections remain a significant global cause of morbidity and death, particularly among children and the elderly. Rapid and dramatic changes in the epide­ miology of this disease during the past 20 years in several developed countries followed the licensure and routine childhood administration of pneumococcal polysaccharide–protein conjugate vaccine (PCV). With PCV introduction in low- and middle-income countries (LMIC), additional profound changes in pneumococcal ecology and disease epidemiology are occurring. The disease burden and serotype distribu­ tion in the PCV era are influenced not only by the reduction in disease caused by serotypes included in PCV but also by serotype replacement as a result of reductions in vaccine serotypes, concomitant secular trends in pneumococcal strains unrelated to vaccine use, the impact of antibiotic use on pneumococcal strain ecology, and surveillance system attributes that can themselves affect analysis of epidemiologic features of pneumococcal strains and disease.

Serotype Distribution  Not all pneumococcal serotypes are equally likely to cause disease; observed serotype distributions vary by age category, disease syndrome, and geography. Geographic differences may be driven by variations in the relative prevalence of syndromes caus­ ing disease rather than by true serotype distribution differences, as cer­ tain serotypes are more common causes of some syndromes than others (e.g., pneumonia and meningitis). Most data on serotype distribution come from pediatric invasive pneumococcal disease (IPD, defined as infection of a normally sterile site); much less information on global or regional serotype distributions is available for disease in adults. In the era before PCV use, five to seven serotypes caused >60% of IPD cases among children <5 years of age in most parts of the world; seven sero­ types (1, 5, 6A, 6B, 14, 19F, and 23F) accounted for ~60% of such cases in all areas of the world, but in any given region these seven serotypes may not all rank as the most common disease strains. Some serotypes (e.g., types 1 and 5) not only tend to cause disease in areas with a high disease burden but also cause waves of disease in lower-burden areas (e.g., Europe) or outbreaks (e.g., in military barracks; meningitis in sub-Saharan Africa). The widespread use of pneumococcal conjugate vaccines has significantly altered serotype-specific epidemiology, with some of the serotypes identified above now causing little invasive disease in countries with mature vaccine programs and emerging sero­ types, not prominent in the pre–conjugate vaccine era, appearing as important causes of invasive disease. These include serotypes such as 15BC, 22F, 10A, 23B, 12F, 15A, and 8 while some serotypes included in PCVs such as 3 and 19A continue to cause IPD. Nasopharyngeal Carriage  Pneumococci are intermittent inhabit­ ants of the healthy human nasopharynx and are transmitted by respi­ ratory droplets. In children, pneumococcal nasopharyngeal ecology varies by geographic region, socioeconomic status, climate, degree of crowding, and particularly intensity of exposure to other children, with children in day-care settings having higher rates of colonization. In developed-world settings, children serve as the major vectors of pneu­ mococcal transmission. By 1 year of age, ~50% of children have had at least one episode of pneumococcal colonization. Cross-sectional prev­ alence data show rates of pneumococcal carriage ranging from 20% to 50% among children <5 years of age and from 5% to 15% among young and middle-aged adults; Fig. 151-3 shows relevant data from the United Kingdom. Data on colonization rates among healthy elderly individuals are limited. In LMICs, pneumococcal acquisition occurs much earlier, sometimes within the first few days after birth, and nearly all infants have had at least one episode of colonization by 2 months of age. Cross-sectional studies show that up to the age of 5 years, 70–90% of children carry S. pneumoniae in the nasopharynx, and a significant proportion of adults (sometimes >40%) also are colonized. Their high rates of colonization make adults an important source of transmission and may affect community transmission dynamics. 50% 60% 70% 80% 90% 100% Age in years: 0–2 3–4 5–17 18+ Carriage prevalence 0% 10% 20% 30% 40% January February March April May June October November December Swabbing month FIGURE 151-3  Prevalence of pneumococcal carriage in adults and children resident in the United Kingdom who had nasopharyngeal swabs collected monthly for 10 months (no seasonal trend; t test trend, >.05). (Data adapted from D Goldblatt et al: J Infect Dis 192:387, 2005.)

Cases/100,000 population

<1

Age group (years) 5–17 18–34 35–49 50–64

65 FIGURE 151-4  Rates of invasive pneumococcal disease before the introduction of pneumococcal conjugate vaccine, by age group: United States, 1998. (Source: CDC, Active Bacterial Core Surveillance/Emerging Infectious Program Network, 2000. Data adapted from MMWR 49[RR-9], 2000.) Invasive Disease and Pneumonia  IPD develops when S. pneu­ moniae invades the bloodstream and seeds other organs or directly reaches the cerebrospinal fluid (CSF) by local extension. Pneumonia may follow aspiration of pneumococci, although only 10–30% of pneu­ mococcal pneumonia cases are associated with a positive blood culture (and thus contribute to the measured burden of IPD). The substantial variation of IPD rates with age is illustrated by data from the United States for 1998–1999, a period prior to PCV introduction. Rates of IPD were highest among children <2 years of age and among adults ≥65 years of age (188 and 60 cases/100,000, respectively; Fig. 151-4). Since the introduction of PCV, IPD rates among infants and children in the

United States have fallen by >75%, a decrease driven by the near elimina­ tion of vaccine-serotype IPD. A similar impact of PCV on vaccine-sero­ type IPD rates has been consistently observed in countries where PCV has been introduced into the routine pediatric vaccination schedule. However, the magnitudes of change in the non-vaccine-serotype IPD rate in various countries have been heterogeneous; the interpretation of this heterogeneity is a complex issue. In the United States, Canada, and Australia, rates of non-vaccine-serotype IPD have increased but the magnitude of the increase is generally small relative to the substantial reductions in vaccine-serotype IPD. In contrast, in other settings (e.g., Alaska Native communities and adults in the United Kingdom), the reduction in vaccine-serotype IPD has been offset by notable increases in rates of disease caused by non-vaccine serotypes. Explanations for the heterogeneity of findings include replacement disease resulting from vaccine pressure, changes in clinical case investigation, secular trends unrelated to PCV use, antibiotic pressure selecting for resistant organ­ isms, changes in surveillance or reporting systems, rapidity of PCV introduction, and inclusion of a catch-up campaign. Serotype replace­ ment in IPD follows the use of PCV7, PCV10, and PCV13, but the magnitude of this phenomenon may be small relative to the reduction in disease from vaccine serotypes in vaccinated populations. In adults in the UK, however, where rates of IPD due to vaccine serotypes fell following PCV introduction, the increase in IPD secondary to non- vaccine sero­ types is eroding the original impact of PCV. Furthermore, not all vaccine serotypes have declined and persistent disease due to serotypes 3 and 19A in particular has been noted in many settings. CHAPTER 151 Pneumococcal Infections Pneumonia is the most common of the serious pneumococcal dis­ ease syndromes and poses special challenges from a clinical and public health perspective. Most cases of pneumococcal pneumonia are not associated with bacteremia, and in these cases a definitive etiologic diagnosis is difficult or impossible. As a result, estimates of disease bur­ den focus primarily on IPD rates and fail to include the major portion of the burden of serious pneumococcal disease. Among children, PCV trials designed to collect efficacy data on syndrome-based outcomes (e.g., radiographically confirmed pneumonia, clinically diagnosed pneumonia) have revealed the burden of culture-negative pneumococ­ cal pneumonia. These trials have provided the means to infer that only ~5–20% of pneumococcal pneumonia cases result in bacteremia. An important randomized controlled trial of PCV among the elderly in July

the Netherlands (the CAPiTA trial) has revealed the small fraction of adult pneumococcal pneumonia patients who also have bacteremia. Use of high-quality sputum specimens and, in the case of adults with a low likelihood of colonization absent disease, urine antigen detec­ tion both contribute to the diagnosis of nonbacteremic pneumococcal pneumonia. Furthermore, accruing evidence continues to indicate that pneumococcal pneumonia events are often the result of co-infection with viral or other bacterial pathogens. Thus a pneumonia case result­ ing from a pulmonary infection with a single pathogen is probably an uncommon event; rather, most cases of pneumonia likely result from the sequential or contemporaneous co-infection of a host with multiple pathogens, often both viruses and bacteria.

The case–fatality ratios (CFRs) for pneumococcal pneumonia and IPD vary by age, underlying medical condition, and access to care. In addition, the CFR for pneumococcal pneumonia varies with the severity of disease at presentation (rather than according to whether the pneu­ monia episode is associated with bacteremia) and with the patient’s age (from <5% among hospitalized patients 18–44 years old to >12% among those >65 years old, even when appropriate and timely management is available). Notably, the likelihood of death in the first 24 h of hospital­ ization did not change substantially with the introduction of antibiotics; this surprising observation highlights the fact that the pathophysiology of severe pneumococcal pneumonia among adults reflects a rapidly progressive cascade of events that often unfolds irrespective of antibiotic administration. Management in an intensive care unit can provide criti­ cal support for the patient through the acute period, with lower CFRs, while antibiotics address the underlying infection. Rates of pneumococcal disease vary by season, with higher rates in colder than in warmer months in temperate climates; by sex, with males more often affected than females; and by risk group, with risk factors including underlying medical conditions, behavioral issues (e.g., smoking), and ethnic group. In the United States, some Native American populations (including Alaska Natives) and African Americans have higher rates of disease than the general population; the increased risk is probably attributable to socioeconomic conditions and the prev­ alence of underlying risk factors for pneumococcal disease. Medical conditions that increase the risk of pneumococcal infection are listed in Table 151-1. Outbreaks of disease are well recognized in crowded settings with susceptible individuals, such as infant day-care facilities, military barracks, and nursing homes. Furthermore, there is a clear association between preceding viral respiratory disease (especially but not exclusively influenza) and risk of secondary pneumococcal infec­ tions. The significant role of pneumococcal pneumonia in the morbid­ ity and mortality associated with seasonal and pandemic influenza is increasingly well recognized. PART 5 Infectious Diseases Antibiotic Resistance  Reduced pneumococcal susceptibility to penicillin was first noted in 1967, but not until the 1990s did reduced antibiotic susceptibility emerge as a significant clinical and public health issue, with an increasing prevalence of pneumococcal isolates resistant to single or multiple classes of antibiotics and a rising absolute magnitude of minimal inhibitory concentrations (MICs). Strains with reduced susceptibility to penicillin G, cefotaxime, ceftriaxone, mac­ rolides, and other antibiotics are now found worldwide and account for a significant proportion of disease-causing strains in many loca­ tions, especially among children. Vancomycin resistance has not yet been observed in clinical pneumococcal strains. Lack of antimicrobial susceptibility is clearly related to a subset of serotypes, many of which disproportionately cause disease among children. Resistance pheno­ types are based on a diverse array of mutational events and inter- and intraspecies gene-transfer phenomena carried out by several types of mobile genetic elements, with consequent dissemination of success­ ful resistant clones. The vicious cycle of antibiotic exposure, selection of resistant organisms in the nasopharynx, and transmission of these organisms within the community, leading to difficult-to-treat infec­ tions and increased antibiotic exposure, has been interrupted to some extent by the introduction and routine use of PCV. The clinical impli­ cations of pneumococcal antimicrobial nonsusceptibility are addressed in “Treatment,” below.

TABLE 151-1  Clinical Risk Groups for Pneumococcal Infection CLINICAL RISK GROUP EXAMPLES Asplenia or splenic dysfunction Sickle cell disease and other hemoglobinopathies, celiac disease Chronic respiratory disease Chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis, interstitial lung fibrosis, pneumoconiosis, bronchopulmonary dysplasia, aspiration risk, neuromuscular disease (e.g., cerebral palsy), severe asthma Chronic heart disease Ischemic heart disease, congenital heart disease, hypertension with cardiac complications, chronic heart failure Chronic kidney disease Nephrotic syndrome, chronic renal failure, renal transplantation Chronic liver disease Cirrhosis, biliary atresia, chronic hepatitis Diabetes mellitus Diabetes mellitus requiring insulin or oral hypoglycemic drugs Immunocompromise/ immunosuppression HIV infection, primary immunodeficiency (including B cell, T cell, complement, and some phagocytic disorders), leukemia, lymphoma, Hodgkin’s disease, multiple myeloma, generalized malignancy, chemotherapy, organ or bone marrow transplantation, systemic glucocorticoid treatment for >1 month at a dose equivalent to ≥20 mg/d (children, ≥1 mg/kg per day) Cochlear implants … Cerebrospinal fluid leaks … Miscellaneous Infancy and old age; prior hospitalization; alcoholism; malnutrition; cigarette smoking; day-care center attendance; residence in military training camps, prisons, homeless shelters Note: Groups for whom pneumococcal vaccines are recommended by the Advisory Committee on Immunization Practices can be found at www.cdc.gov/vaccines/ schedules/. ■ ■PATHOGENESIS Pneumococci colonize the human nasopharynx from an early age; colonization acquisition events are generally described as asymptom­ atic, but evidence exists to associate acquisition with mild respira­ tory symptoms, especially in the very young. Bacteria survive in the nasopharynx protected by a variety of factors, including their bacterial capsule and the formation of a biofilm. From the nasopharynx, the bacteria spread either via the bloodstream to distant sites (e.g., brain, joint, bones, peritoneal cavity) or locally to mucosal surfaces where they can cause otitis media or pneumonia. Direct spread from the nasopharynx to the central nervous system (CNS) can occur in rare cases of skull-base fracture, although most cases of pneumococcal meningitis are secondary to hematogenous spread. The pneumococcus is not a static bacterium; rather, it modifies its expression of capsule in adaptation to the external environment. In the nasopharynx, the pneumococcus downregulates capsular expression, averting protective immunologic mechanisms that recognize capsule; rough colonies are the phenotype on culture. Upon invasion by traversal of the epithelium, the pneumococcus upregulates its capsular expression, transforming its appearance on culture to smooth colonies—a change illustrating the dynamic nature of the organism in response to the local environ­ ment. Pneumococci can cause disease in almost any organ or part of the body; however, otitis media, pneumonia, bacteremia, and menin­ gitis are most common. Colonization is a relatively frequent event, yet disease is rare. In the nasopharynx, pneumococci survive in mucus secreted by epithelial cells and in a biofilm they create, where they can avoid local immune factors such as leukocytes and complement. The mucus itself is a component of local defense mechanisms, and the flow of mucus (driven in part by cilia in what is known as the mucociliary escalator) effects mechanical clearance of pneumococci. While many colonization episodes are of short duration, longitudinal studies in adults and children have revealed persistent colonization with a spe­ cific serotype over many months. Colonization eventually results in

the development of capsule- and protein-specific serum IgG antibod­ ies, which are thought to play a role in mediating clearance of bacteria from the nasopharynx. IgG antibodies to surface-exposed cell-wall or secreted proteins also appear in the circulation in an age-dependent fashion or after colonization; these antibodies are likely to have a disease-modifying and/or protective role. Recent acquisition of a new colonizing serotype is more likely to be associated with subsequent invasion, presumably as a result of the absence of type-specific immu­ nity. Intercurrent viral infections make the host more susceptible to pneumococcal colonization, and pneumococcal disease in a colonized individual often follows perturbation of the nasopharyngeal mucosa by such infections. Local cytokine production after a viral infection is thought to upregulate adhesion factors in the respiratory epithelium, allowing pneumococci to adhere via a variety of surface adhesin mol­ ecules, including PsaA, PspA, CbpA, PspC, Hyl, pneumolysin, and the neuraminidases (Fig. 151-2). Adhesion coupled with inflammation induced by pneumococcal factors such as peptidoglycans and teichoic acids results in invasion. It is the inflammation induced by various

bacterium-derived factors that is responsible for the pathology associated with pneumococcal infection. Pneumococcal cell wall–derived teichoic acids and peptidoglycans induce a variety of cytokines, including the proinflammatory cytokines interleukin (IL) 1, IL-6, and tumor necrosis factor, and activate complement via the alternative pathway. Polymor­ phonuclear leukocytes are thus attracted, and an intense inflammatory response is initiated. Pneumolysin also is important in local pathology, inducing proinflammatory cytokine production by local monocytes. The pneumococcal capsule, consisting of polysaccharides with anti­ phagocytic properties (i.e., the capacity to resist complement deposi­ tion in the absence of type-specific antibody), plays an important role in pathogenesis. While most capsular types can cause human disease, certain capsular types are more commonly isolated from sites of infec­ tion. The reason for the dominance of some serotypes over others in IPD is unclear. ■ ■HOST DEFENSE MECHANISMS Innate Immunity  As described above, intact respiratory epithelium and a host of nonspecific or innate immune factors (e.g., mucus, splenic function, complement, neutrophils, and macrophages) constitute the first line of defense against pneumococci. Physical factors such as the cough reflex and the mucociliary escalator are important in clearing bacteria from the lungs. Immunologic factors are critical as well: C-reactive protein (CRP) binds phosphorylcholine in the pneumococcal

cell wall, inducing complement activation and leading to bacterial clear­ ance; Toll-like receptor 2 (TLR2) recognizes pneumococcal-derived lipoproteins. In animal models, the absence of host TLR2 leads to more severe infection and impaired clearance of nasopharyngeal colonization. TLR4 appears to be necessary for the proinflammatory effect of pneumo­ lysin on macrophages. The importance of TLR recognition is underlined by descriptions of an inherited deficiency of human IL-1 receptor– associated kinase 4 (IRAK-4) that manifests as an unusual susceptibility to infection with bacteria, including S. pneumoniae. IRAK-4 is essential for the normal functioning of several TLRs. Other factors that interfere with these nonspecific mechanisms (e.g., viral infections, cystic fibrosis, bronchiectasis, complement deficiency, chronic obstructive pulmonary disease) all predispose to the development of pneumococcal pneumonia. Patients who lack a spleen or have abnormal splenic function (e.g., per­ sons with sickle cell disease) are at high risk of developing overwhelming pneumococcal disease. Acquired Immunity  Acquired immunity induced following colo­ nization or through exposure to cross-reactive antigens rests largely on the development of serum IgG antibody specific for the pneumococcal capsular polysaccharide. Nearly all polysaccharides are T cell–independent antigens; B cells can make antibodies to such antigens without

T cell help. However, in children <1–2 years old, such B cell responses are poorly developed. This delayed ontogeny of capsule-specific IgG in young children is associated with susceptibility to pneumococcal infec­ tion (Fig. 151-4). The extremely high risk of pneumococcal infection in the absence of serum immunoglobulin (i.e., in conditions such as

agammaglobulinemia) highlights the important role of capsular anti­ body in protection against disease. Each serotype’s capsule is chemically distinct, even though for some serotypes the chemical distinction from another type may be a minor one; thus immunity tends to be serotype specific, although some cross-immunity exists. For example, conjugate vaccine–induced antibodies to serotype 6B prevent infection due to serotype 6A but not 6C; cross-protection against serotype 6C requires the administration of vaccines containing 6A. Antibodies to surfaceexposed or secreted pneumococcal proteins (such as pneumolysin, PsaA, and PspA) also appear in the circulation with increasing age of the host and are likely to contribute to protection. Data from murine models suggest that CD4+ T cells may play a role in preventing pneu­ mococcal colonization and disease, and experimental data derived from humans suggest that IL-17-secreting CD4+ T cells may be relevant.

APPROACH TO THE PATIENT Pneumococcal Infections There is no pathognomonic presentation of pneumococcal disease; patients may present with one or more clinical syndromes (e.g., pneumonia, meningitis, sepsis). S. pneumoniae can infect nearly any body tissue, manifesting as disease ranging in severity from mild and self-limited to life-threatening. The differential diagnosis of common clinical syndromes such as pneumonia, otitis media, fever of unknown origin, and meningitis should always include pneumococcal infection. A microbiologically confirmed diagnosis is made in only a minority of pneumococcal cases since, in most circumstances (and especially in pneumonia and otitis media), fluid from the site of infection is not available for etiologic determina­ tion, and infection of body fluids distant from the site of infection (e.g., blood in the case of pneumonia) occurs in only a minority of true pneumococcal cases. Empirical therapy that includes appropri­ ate treatment for S. pneumoniae is often indicated. CHAPTER 151 Algorithms for assessment and management of ill children (Inte­ grated Management of Childhood Illness; IMCI) have been devel­ oped for use in the developing world or in other settings where evaluation by a trained physician may not be feasible. No such algorithms for the management of adults with suspected disease exist. Children who present with signs associated with increased risk of serious disease, such as an inability to drink, convulsions, lethargy, and severe malnutrition, are categorized as having very severe disease without further evaluation by the community health care worker; are given antibiotics; and are immediately referred to a hospital for diagnosis and management. Children who present with cough and tachypnea (the latter defined according to specific age strata) are further stratified into severity categories based on the presence or absence of lower chest wall indrawing and are managed accordingly either with antibiotics alone or with antibiotics and referral to a hospital facility. Children with cough but no tachypnea are categorized as having a nonpneumonia respiratory illness. Pneumococcal Infections ■ ■CLINICAL MANIFESTATIONS The clinical manifestations of pneumococcal disease depend on the site of infection and the duration of illness. Clinical syndromes are classified as noninvasive (e.g., otitis media) or invasive (e.g., bacteremic pneumonia, meningitis) according to whether a normally sterile site is infected. The pathogenesis of noninvasive illness involves contiguous spread from the nasopharynx or skin; invasive disease involves infec­ tion of a normally sterile body fluid or follows bacteremia. Regardless of the mechanism, all pneumococcal infections result from nasopha­ ryngeal acquisition of the organism. Pneumonia  Pneumonia is the most common serious pneumo­ coccal syndrome and is considered invasive when associated with a positive blood culture. Whether to categorize nonbacteremic pneumo­ coccal pneumonia as invasive or noninvasive remains debatable. Pneumococcal pneumonia can present as a mild community-acquired infection at one extreme and as a life-threatening disease requiring intubation and intensive support at the other.

PRESENTING MANIFESTATIONS  The presentation of pneumococcal pneumonia does not reliably distinguish it from pneumonia of other etiologies. In a subset of cases, pneumococcal pneumonia is recognized at the outset as associated with a viral upper respiratory infection and is characterized by the abrupt onset of cough and dyspnea accompanied by fever, shaking chills, and myalgias. The cough evolves from nonpu­ rulent to productive of sputum that is purulent and sometimes tinged with blood. Patients may describe stabbing pleuritic chest pain and sig­ nificant dyspnea indicating involvement of the parietal pleura. Among the elderly, the presenting clinical symptoms may be less specific, with confusion or malaise but without fever or cough. In such cases, a high index of suspicion is required because failure to treat pneumococcal pneumonia promptly in an elderly patient is likely to result in rapid evolution of the infection, with increased severity, morbidity, and risk of death.

FINDINGS ON PHYSICAL EXAMINATION    The clinical signs associ­ ated with pneumococcal pneumonia among adults include tachypnea (defined as >20 breaths/min) and tachycardia, hypotension in severe cases, and fever in most cases (although not in all elderly patients). Respiratory signs are varied, including dullness to percussion in areas of the chest with significant consolidation, crackles on auscultation, reduced expansion of the chest in some cases as a result of splinting to reduce pain, bronchial breathing in a minority of cases, pleural rub in occasional cases, and cyanosis in cases with significant hypoxemia. Among infants with severe pneumonia, chest wall indrawing and nasal flaring are common. Nonrespiratory findings can include upper abdominal pain if the diaphragmatic pleura is involved as well as men­ tal status changes, particularly confusion in elderly patients. PART 5 Infectious Diseases DIFFERENTIAL DIAGNOSIS  The differential diagnosis of pneumococ­ cal pneumonia includes cardiac conditions such as myocardial infarc­ tion and heart failure with atypical pulmonary edema; pulmonary conditions such as atelectasis; and pneumonia caused by viral patho­ gens, mycoplasmas, Haemophilus influenzae, Klebsiella pneumoniae, Staphylococcus aureus, Legionella, or (in HIV-infected and otherwise immunocompromised hosts) Pneumocystis jirovecii. In cases with abdominal symptoms, the differential diagnosis includes cholecystitis, appendicitis, perforated peptic ulcer disease, and subphrenic abscesses. The challenge in cases with abdominal symptoms is to remember to include pneumococcal pneumonia—a nonabdominal process—in the differential diagnosis. DIAGNOSIS    Some authorities advocate treating uncomplicated, nonsevere, community-acquired pneumonia without determining the microbiologic etiology, given that this information is unlikely to alter clinical management. However, efforts to identify the cause of pneu­ monia are important when the disease is more severe and when the diagnosis of pneumonia is not clearly established. The gold standard for etiologic diagnosis of pneumococcal pneumonia is pathologic examination of lung tissue. In lieu of that procedure, evidence of an infiltrate on chest radiography warrants a diagnosis of pneumonia. However, cases of pneumonia without radiographic evidence do occur. An infiltrate can be absent either early in the course of the illness or with dehydration; upon rehydration, an infiltrate usually appears. The radiographic appearance of pneumococcal pneumonia is varied; it classically consists of lobar or segmental consolidation (Fig. 151-5) but in some cases is patchy. More than one lobe is involved in ~30% of cases. Consolidation may be associated with a small pleural effusion or empyema in complicated cases. In children, “round pneumonia,” a distinctly spherical consolidation on chest radiography, is associated with a pneumococcal etiology. Round pneumonia is uncommon in adults. S. pneumoniae is not the only cause of such lesions; other causes, especially cancer, should be considered. Blood drawn from patients with suspected pneumococcal pneu­ monia can be used for supportive or definitive diagnostic tests. Blood cultures are positive for pneumococci in a minority (<30%) of cases of pneumococcal pneumonia, as evidenced especially by vaccine clinical trials, which provide an independent method to reveal the contribu­ tion of the pneumococcus to pneumonia cases. Nonspecific findings

FIGURE 151-5  Chest radiograph depicting classic lobar pneumococcal pneumonia in the right lower lobe of an elderly patient’s lung. include an elevated polymorphonuclear leukocyte count (>15,000/μL in most cases and upward of 40,000/μL in some), leukopenia in <10% of cases (a poor prognostic sign associated with a fatal outcome), and elevated values in liver function tests (e.g., both conjugated and unconjugated hyperbilirubinemia). Anemia, low serum albumin levels, hyponatremia, and elevated serum creatinine levels are all found in ~20–30% of patients. Urinary pneumococcal antigen assays, based on identifying a ubiq­ uitous common cell wall polysaccharide, have facilitated etiologic diag­ nosis, but the application of the results is confounded by the fact that nasopharyngeal colonization with the pneumococcus, in the absence of disease, also results in a positive test. In adults, therefore, a positive pneumococcal urinary antigen test has a predictive value for etiologic attribution of pneumonia because the prevalence of pneumococcal nasopharyngeal colonization is relatively low, although the sensitivity of the assay is modest. In communities, particularly those in low-

income countries, where colonization rates among adults are high, urine antigen assays may be less useful. The same issue holds for chil­ dren, in whom a positive urinary antigen test is usually uninformative for etiologic attribution of their pneumonia illness because coloniza­ tion rates are generally high. A recent advance is the development of quantitative serotype-specific urinary antigen detection assays for up to 24 pneumococcal antigens; their application for adults and children holds promise, especially in detecting serotypes that are rarely identi­ fied in asymptomatic carriage (e.g., serotype 1), even among children. Most cases of pneumococcal pneumonia in adults are diagnosed by Gram’s staining and culture of sputum. The utility of a sputum specimen is directly related to its quality and the patient’s antibiotic treatment status. COMPLICATIONS    Empyema is the most common focal complica­ tion of pneumococcal pneumonia, occurring in <5% of cases. When fluid in the pleural space is accompanied by fever and leukocytosis (even low-grade) after 4–5 days of appropriate antibiotic treatment for pneumococcal pneumonia, empyema should be considered. Para­ pneumonic effusions are more common than empyema, representing a self-limited inflammatory response to pneumonia. Pleural fluid with frank pus, bacteria (detected by microscopic examination), or a pH of ≤7.1 indicates empyema and demands aggressive and complete drain­ age, usually through chest tube insertion.

Meningitis  Pneumococcal meningitis usually presents as a pyo­ genic condition that is clinically indistinguishable from meningitis of other bacterial etiologies. Meningitis can be the primary presenting pneumococcal syndrome or a complication of other conditions such as skull fracture, otitis media, bacteremia, or mastoiditis. Now that

H. influenzae type b vaccine is routinely used in children, S. pneumoniae and Neisseria meningitidis are the most common bacterial causes of meningitis in both adults and children. Pyogenic meningitis, including that due to S. pneumoniae, is associated clinically with findings that include severe, generalized, gradual-onset headache, fever, and nausea as well as specific CNS manifestations such as stiff neck, photophobia, seizures, and confusion. Clinical signs include a toxic appearance, altered consciousness, bradycardia, and hypertension indicative of increased intracranial pressure. A small proportion of adult patients have Kernig’s or Brudzinski’s sign or cranial nerve palsies (particularly of the third and sixth cranial nerves). A definitive diagnosis of pneumococcal meningitis rests on the examination of CSF for (1) evidence of turbidity (visual inspection); (2) elevated protein level, elevated white blood cell count, and reduced glucose concentration (quantitative measurement); and (3) specific identification of the etiologic agent (culture, Gram’s staining, antigen testing, or polymerase chain reaction [PCR]). A blood culture positive for S. pneumoniae in conjunction with clinical manifestations of men­ ingitis also is considered confirmatory. As discussed in “Pneumonia,” above, detection of pneumococcal antigen in urine is considered highly specific among adults because of the low prevalence of nasopharyngeal colonization in this age group. The mortality rate for pneumococcal meningitis is ~20%. In addi­ tion, up to 50% of survivors experience acute or chronic complications, including deafness, hydrocephalus, and mental retardation in children and diffuse brain swelling, subarachnoid bleeding, hydrocephalus, cerebrovascular complications, and hearing loss in adults. Other Invasive Syndromes  S. pneumoniae can cause other inva­ sive syndromes involving virtually any body site. These syndromes include primary bacteremia without other sites of infection (bactere­ mia without a source; occult bacteremia), osteomyelitis, septic arthritis, endocarditis, pericarditis, and peritonitis. The essential diagnostic approach is collection of fluid from the site of infection by sterile technique and examination by Gram’s staining, culture, and—when relevant—capsular antigen assay or PCR. Hemolytic-uremic syndrome can complicate invasive pneumococcal disease. Noninvasive Syndromes  The major noninvasive syndromes caused by S. pneumoniae are sinusitis, bacterial bronchitis, and otitis media; the latter is the most common pneumococcal syndrome and most often affects young children. The manifestations of otitis media include the acute onset of severe pain, fever, deafness, and tinnitus, most frequently in the setting of a recent upper respiratory tract infec­ tion. Clinical signs include a red, swollen, often bulging tympanic membrane with reduced movement on insufflation or tympanography. Redness of the tympanic membrane is not sufficient for the diagnosis of otitis media. Pneumococcal sinusitis is also a complication of upper respiratory tract infections and presents with facial pain, congestion, fever, and— in many cases—persistent nighttime cough. A definitive diagnosis is made by aspiration and culture of sinus material; however, presumptive treatment is most commonly initiated after application of a strict set of clinical diagnostic criteria. Pneumococcal bronchitis is usually seen in the context of pre-existing lung conditions such as bronchiectasis or chronic obstructive pulmonary disease (COPD) and may be caused by nontypeable strains. TREATMENT Pneumococcal Infections Historically, the activity of penicillin against pneumococci made parenteral penicillin G the drug of choice for disease caused by susceptible organisms, including community-acquired pneumonia.

Today, parenteral β-lactam drugs such as ampicillin, cefotaxime, ceftriaxone, and cefuroxime are often used as first-line agents for community-acquired infections. Macrolides and cephalosporins are alternatives for penicillin-allergic patients. While agents such as clindamycin, tetracycline, and trimethoprim-sulfamethoxazole exhibit some activity against pneumococci, resistance to these agents is frequently encountered in different parts of the world.

Penicillin-resistant pneumococci were first described in the mid1960s, at which point tetracycline- and macrolide-resistant strains had already been reported. Multidrug-resistant strains were first described in the 1970s, but it was during the 1990s that pneumo­ coccal drug resistance reached pandemic proportions. The use of antibiotics selects for resistant pneumococci, and strains resistant to β-lactam agents and to multiple drugs are now found all over the world. The emergence of high rates of macrolide and fluoro­ quinolone resistance also has been described. Drug-resistant pneu­ mococci are considered a serious threat by the Centers for Disease Control and Prevention. The molecular basis of penicillin resistance in S. pneumoniae is the alteration of penicillin-binding protein (PBP) genes by transfor­ mation and horizontal transfer of DNA from related streptococcal species. Such alteration of PBPs results in lower affinity for penicil­ lins. Depending on the specific PBP(s) and the number of PBPs altered, the level of resistance ranges from intermediate to high. For many years, penicillin susceptibility breakpoints have been defined by MICs as follows: susceptible, ≤0.06 μg/mL and resistant, ≥2.0 μg/mL. However, in vitro results often were not predictive of the response of a patient to treatment for pneumococcal diseases other than meningitis. Revised recommendations have been based on the penicillin G breakpoints established in 2008 by the Clinical and Laboratory Standards Institute. For IV treatment of meningitis with at least 24 million units per day in 8 divided doses, the suscep­ tibility breakpoint remains ≤0.06 μg/mL, and MICs of ≥0.12 μg/mL indicate resistance. For IV treatment of nonmeningeal infections with 12 million units per day in 6 divided doses, the breakpoints are ≤2 μg/mL for susceptible organisms and ≥8 μg/mL for resistant organisms; a dosage of 18–24 million units per day is recommended for strains with MICs in the intermediate category. CHAPTER 151 Pneumococcal Infections Although guidelines for antibiotic therapy should be driven in part by local patterns of resistance, guidelines from national organizations in many countries (e.g., the Infectious Diseases Society of America/ American Thoracic Society, the British Thoracic Society, the European Respiratory Society) lay out evidence-based approaches. The following guidelines for the treatment of individual sepsis syn­ dromes are based on those advocated by the American Academy of Pediatrics Red Book and updated in 2023. MENINGITIS LIKELY OR PROVEN TO BE DUE

TO S. PNEUMONIAE In areas of the world with an increased prevalence of resistant pneumococci, first-line therapy for persons ≥1 month of age is a combination of vancomycin (adults, 30–60 mg/kg per day; infants and children, 60 mg/kg per day) and cefotaxime (adults, 8–12 g/d in 4–6 divided doses; children, 225–300 mg/kg per day in 1 dose or 2 divided doses) or ceftriaxone (adults, 4 g/d in 1 dose or 2 divided doses; children, 100 mg/kg per day in 1 dose or 2 divided doses). In low-prevalence areas and where the patient has not recently traveled, vancomycin is not included in first-line therapy. If children are hypersensitive to β-lactam agents (penicillins and cephalosporins), rifampin (adults, 600 mg/d; children, 20 mg/d in 1 dose or 2 divided doses) can be substituted for cefotaxime or ceftriaxone and added as a second agent. A repeat lumbar puncture should be considered after 48 h if the organism is not susceptible to penicillin and information on cephalosporin sensitivity is not yet available, if the patient’s clinical condition does not improve or deteriorates, or if dexamethasone has been administered interfering with the ability to interpret clinical responses in the deteriorating patient. When antibiotic sensitivity data become available, treat­ ment should be modified accordingly. If the isolate is sensitive

to penicillin, vancomycin can be discontinued and penicillin can replace the cephalosporin, or cefotaxime or ceftriaxone can be con­ tinued alone. If the isolate displays any resistance to penicillin but is susceptible to the cephalosporins, vancomycin can be discontinued and cefotaxime or ceftriaxone continued. If the isolate exhibits any resistance to penicillin and is not susceptible to cefotaxime and ceftriaxone, vancomycin and high-dose cefotaxime or ceftriaxone can be continued and rifampin may be added. Data support the use of corticosteroids in high-income countries but do not appear to have a beneficial effect in low-income countries. This discrepancy in the efficacy of corticosteroids may be related to differences in availability of appropriate and timely medical care. Glucocorticoids significantly reduce rates of mortality, severe hearing loss, and neurologic sequelae in adults and should be administered to those with community-acquired bacterial meningitis. If dexamethasone is given to either adults or children, it should be administered before or in conjunction with the first antibiotic dose.

SEPSIS (EXCLUDING MENINGITIS) In previously well children with noncritical illness, therapy with a recommended antibiotic should be instigated at the usually rec­ ommended dosages: ampicillin 200 mg/kg/day (doses 6 h apart), cefotaxime, 75–225 mg/kg/day (doses 8 h apart), ceftriaxone, 50–75 mg/kg/day (doses 12–24 h apart) or penicillin G, 250,000–400,000 units/kg per day (in divided doses 4–6 h apart). For critically ill children, including those who have myocarditis or multilobular pneumonia with hypoxia or hypotension, vancomycin may be added if the isolate may possibly be resistant to β-lactam drugs, with its use reviewed once susceptibility data become available. If the organism is resistant to β-lactam agents, therapy should be modi­ fied on the basis of clinical response and susceptibility to other anti­ biotics. Clindamycin or vancomycin can be used as a first-line agent for children with severe β-lactam hypersensitivity, but vancomycin should not be continued if the organism is shown to be sensitive to other non-β-lactam antibiotics. PART 5 Infectious Diseases For outpatient management, oral amoxicillin (45–90 mg/kg/ day, doses 8 h apart) provides effective treatment for virtually all cases of pneumococcal pneumonia. Cephalosporins, which are far more expensive, offer no advantages over amoxicillin. Levofloxacin (500–750 mg/d as a single dose) and moxifloxacin (400 mg/d as a single dose) also are highly likely to be effective in the United States except in patients who come from closed populations where these drugs are used widely or who have themselves been treated recently with a quinolone. Clindamycin (600–1200 mg/d every 6 h) is effec­ tive in 90% of cases and azithromycin (500 mg on day 1 followed by 250–500 mg/d) or clarithromycin (500–750 mg/d as a single dose) in 80% of cases. Treatment failure resulting in bacteremic disease due to macrolide-resistant isolates has been amply documented in patients given azithromycin empirically. As noted above, rates of resistance to all these antibiotics are relatively low in some countries and much higher in others; high-dose amoxicillin remains the best option worldwide. The optimal duration of treatment for pneumococcal pneu­ monia is uncertain, but its continuation for at least 5 days once the patient becomes afebrile appears to be a prudent approach— although in adults, 5 days in total will usually suffice. Cases with a second focus of infection (e.g., empyema or septic arthritis) require longer therapy. ACUTE OTITIS MEDIA Amoxicillin (80–90 mg/kg per day) is recommended for infants <6 months of age and those 6–23 months of age with bilateral dis­ ease. Observation and symptom-based treatment without antibiot­ ics are advocated for nonsevere illness and an uncertain diagnosis in children 6 months to 2 years of age and nonsevere illness (even if the diagnosis seems certain) in children >2 years of age. Although the optimal duration of therapy has not been conclusively estab­ lished, a 10-day course is recommended for younger children and for children with severe disease at any age. For children >6 years

old who have mild or moderate disease, a course of 5–7 days is considered adequate. Patients whose illness fails to respond should be reassessed at 48–72 h. If acute otitis media is confirmed and anti­ biotic treatment has not been started, administration of amoxicillin should be commenced. If antibiotic therapy fails, a change is indi­ cated. Failure to respond to second-line antibiotics (such as highdose amoxicillin-clavulanate) as well indicates that myringotomy or tympanocentesis may need to be undertaken in order to obtain samples for culture. The above recommendations can also be followed for the treat­ ment of sinusitis. Detailed information on the further management of these conditions in children has been published by the American Academy of Pediatrics, the American Academy of Family Physi­ cians, the Pediatric Infectious Diseases Society, and the Infectious Diseases Society of America. ■ ■PREVENTION Measures to prevent pneumococcal disease include vaccination against S. pneumoniae and influenza viruses, reduction of comorbidities that increase the risk of pneumococcal disease, and prevention of antibiotic overuse, which fuels pneumococcal resistance. Capsular Polysaccharide Vaccines  The 23-valent pneumococ­ cal polysaccharide vaccine (PPSV23), containing 25 μg of each capsular polysaccharide, has been licensed for use since 1983. Recommenda­ tions for its use vary by country with an age-based recommendation for those ≥65 years of age most commonly found. However, the utility of PPSV23 is likely to be limited in the future as more countries introduce the newly licensed (2021) extended-valency pneumococcal conjugate vaccines (see “Polysaccharide–Protein Conjugate Vaccines,” below). The effectiveness of PPSV23 against IPD, pneumococcal pneu­ monia, all-cause pneumonia, and death is controversial, with wide variation in observations. The many published meta-analyses of PPSV efficacy have often reached opposing conclusions with regard to a given clinical entity. Generally, observational studies cite greater effec­ tiveness than do controlled clinical trials. The consensus is that PPSV is effective against IPD but is less effective against nonbacteremic pneu­ mococcal pneumonia. However, the results of some published trials, observational studies, and meta-analyses contradict this view. Effec­ tiveness is often lower in the elderly and in immunodeficient patients whose condition is associated with reduced antibody responses to vaccines than in younger, healthier populations. When PPSV is effec­ tive, the duration of protection following a single dose of vaccine is estimated to be ~5 years. Even in the setting of routine pneumococcal conjugate vaccination of infants (which indirectly protects adults from vaccine-serotype strains), disease caused by serotypes not represented in the conjugate vaccine continues to be a significant burden among adults. Polysaccharide–Protein Conjugate Vaccines  Infants and young children respond poorly to PPSV, which contains T cell–independent antigens. Consequently, another class of pneumococcal vaccines, the PCVs, were developed specifically for infants and young children. The first product, a 7-valent PCV, was licensed in 2000 in the United States and two PCV products—containing 10 and 13 serotypes, respectively— were licensed in 2009 and 2010, respectively. The serotypes included in these original PCV formulations were important causes of IPD and antibiotic resistance among young children. Randomized controlled trials and real-world evidence accumulated following their widespread use have demonstrated a high degree of efficacy of PCVs against vaccine-serotype IPD as well as efficacy against pneumonia, otitis media, nasopharyngeal colonization, and all-cause mortality. PCVs are recommended by the World Health Organization for inclusion in routine childhood immunization schedules worldwide, especially in countries with high infant mortality rates. To date 146 countries (75%) have PCV in their National Immunization program, 15 are planning introduction, and 33 have no national decision. In 2021, two new PCVs were licensed for adults: a 15-valent pneumococcal conjugate vaccine, VAXNEUVANCE (Merck), and a