streptococcus pneumoniae: Revisión


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Descripcion del neumococo basado en el clasico libro de Infectología, Mandel.

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streptococcus pneumoniae: Revisión

  1. 1. Mandell: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed. Streptococcus pneumoniae DANIEL M. MUSHER* * All material in this chapter is in the public domain, with the exception of any borrowed figures or tables. Long recognized as a major cause of pneumonia, meningitis, sinusitis, and otitis media, Streptococcus pneumoniae is an important bacterial pathogen in humans; it is a less frequent cause of endocarditis, septic arthritis, and peritonitis and an uncommon cause of a variety of other infectious diseases. History A brief review of the history of S. pneumoniae, also known as pneumococcus, documents the important role of this organism in the history of microbiology.[1-3] In 1881, the organism was identified concurrently in the Old and New Worlds; Pasteur, in France named it Microbe septicemique du salive, and Sternberg, in the United States, called it Micrococcus pasteuri. By the late 1880s, the term pneumococcus was generally used because this bacterium had come to be recognized as the most common cause of lobar pneumonia. The name Diplococcus pneumoniae was assigned in 1926 because of its appearance in Gram-stained sputum, and in 1974 the organism was renamed once again, this time as Streptococcus pneumoniae, because of its morphology during growth in liquid medium. S. pneumoniae was the first organism to be shown to behave as what is now regarded as a prototypic extracellular bacterial pathogen. In the absence of antibody, this bacterium resists phagocytosis and replicates extracellularly in mammalian tissues. In the early 1890s, Felix and Georg Klemperer showed that immunization with killed pneumococci protected animals against subsequent pneumococcal challenge and, furthermore, that protection could be transferred by infusing serum (―humoral‖ substance) from immunized mice into naive recipients. Subsequently, serum from persons who had recovered from pneumococcal pneumonia was found to confer the same degree of protection. The basis for this immunity was shown by Neufeld and Rimpau to be the presence of factor(s) in serum that facilitated ingestion by white blood cells (WBCs), a process that these investigators called opsonization, derived from the Greek word for preparing food. These observations provided the basis for what we now call humoral immunity. Serotypes were also recognized after observing that injection of killed organisms into a rabbit stimulated the production of serum antibody that agglutinated and caused capsular swelling of the immunizing strain, as well as some, but not all other pneumococcal isolates. Early in the 20th century, three serotypes were distinguished, called serotypes 1, 2, and 3; all other pneumococci were called group 4. In the first decade of the 20th century, Maynard, Lister, Wright, and others applied the concepts of humoral immunity to the problem of epidemic lobar pneumonia that each year affected as many as 1 in 10 African miners.[1,4] Inoculation of killed pneumococci caused a substantial reduction in the incidence of pneumonia. In the 1920s, Heidelberger and Avery[5] demonstrated that the protective antibody was reactive with surface capsular polysaccharides. Felton[6] prepared the first purified pneumococcal capsular polysaccharides for immunization of human subjects, and a preparation of type 1 polysaccharide was used to abort an epidemic of pneumonia at a state hospital in Massachusetts in the winter of 1937-1938.[7] Taken together, these studies showed that a specific bacterial polysaccharide antigen could be used to stimulate humoral antibodies that conferred protection against epidemic human infection. Further confirmation was provided during World War II, when MacLeod and colleagues[8] found that vaccinating military recruits with capsular material from four serotypes of S. pneumoniae
  2. 2. greatly reduced the incidence of pneumonia caused by serotypes in the vaccine, but not by other pneumococcal serotypes. S. pneumoniae also played a central role in the discovery of DNA. Experiments done by Griffith[9] in the 1920s had shown that intraperitoneal injection of live unencapsulated (mutant) pneumococci, together with heat-killed encapsulated pneumococci, into mice led to the emergence of viable, encapsulated bacteria; he called this process transformation. This observation remained unexplained until the 1940s, when Avery and associates[10] provided conclusive evidence that these mutants had recovered the capacity to produce capsule by taking up DNA from killed virulent organisms—in other words, that DNA is responsible for the observed transformation and is, in fact, the genetic material that encodes for phenotype. Microbiology S. pneumoniae is a gram-positive coccus that replicates in chains in liquid medium. The organism is catalase-negative but generates H2O2 via a flavoenzyme system, and therefore grows better in the presence of a source of catalase such as red blood cells. Pneumococci produce pneumolysin (formerly called α-hemolysin), which breaks down hemoglobin into a green pigment; as a result, pneumococcal colonies are surrounded by a green zone during growth on blood agar plates. This property is still termed α-hemolysis, although properly speaking it should not be, because lysis of red blood cells is not responsible. This point becomes readily apparent when one observes the greenish yellow color that appears around colonies of S. pneumoniae during growth on chocolate agar, a medium in which red blood cells were already lysed during preparation. Growth of pneumococci is inhibited by ethyl hydrocupreine (Optochin), and the organisms are lysed by bile salts. Thus, pneumococci are identified in the microbiology laboratory by four reactions: (1) α-hemolysis of blood agar; (2) catalase negativity; (3) susceptibility to Optochin; and (4) solubility in bile salts. Some pneumococci are Optochin-resistant, [11] and a newly recognized species, Streptococcus pseudopneumoniae, which is associated with exacerbation of chronic obstructive pulmonary disease (COPD) or pneumonia, is Optochin-susceptible during growth in room air at 37? C but Optochin-resistant when grown in the presence of increased CO2. [12] These factors have led to greater reliance on the use of bile solubility for definitive identification. A highly reliable probe that detects rRNA sequences unique to S. pneumoniae is also commercially available. Anatomy and Physiology Peptidoglycan and teichoic acid are the principal constituents of the pneumococcal cell wall[13] (Fig. 200-1). Peptidoglycan consists of long chains of alternating N-acetyl-D-glucosamine and N-acetylmuramic acid, from which extend chains of four to six amino acids called stem peptides. Stem peptides are cross-linked by pentaglycine bridges, which provides substantial strength to the cell wall. Teichoic acid, a carbohydrate polymer that contains phosphorylcholine, is covalently linked to the peptidoglycan on the outermost surface of the bacterial wall and protrudes into the capsule. This teichoic acid, together with tightly adherent fragments of peptidoglycan, makes up C-polysaccharide, a substance that is present in all pneumococci and is otherwise detected only in a few species of viridans streptococci. C- polysaccharide reacts with proteins that appear in the blood stream in inflammatory conditions (called acute-phase reactants or C-reactive proteins). Many proteins are expressed on the pneumococcal cell surface. Of particular importance in pathogenesis of disease are those that bind to choline, including pneumococcal surface proteins A and C, pneumococcal surface adhesin (choline-binding protein) A, choline-binding protein C, and proteins involved in competence, all of which will be discussed later in this chapter because of their potential role in pathogenicity. The characteristic three-layered cell membrane consists of lipid and teichoic acid and is called F antigen because of cross-reactivity with Forssman antigens.
  3. 3. Figure 200-1 Representation of the cell membrane, cell wall, and capsule of Streptococcus pneumoniae. Within the cell wall, M = N-acetylmuramic acid and G = N-acetyl-D-glucosamine. The stem peptides and the cross-linked pentaglycine bridges that extend from the long M-G-M- G chains are not shown. Cell wall (C−) polysaccharide consists of teichoic acid with peptidoglycan and phosphorylcholine (not shown). F antigen is the lipid–teichoic acid moiety in the cell membrane that extends into the cell wall. Almost every clinical isolate of S. pneumoniae contains an external capsule; unencapsulated isolates have mainly been implicated in outbreaks of conjunctivitis.[14] Capsules[15] (see Fig. 200-1) are made up of repeating oligosaccharides that are synthesized within the cytoplasm, polymerized, and transported to the bacterial surface by cell membrane transferases. These polysaccharides are covalently bound to peptidoglycan and C-polysaccharide, which explains the difficulty of separating capsular from cell wall polysaccharide. Genetic control of this complex set of events has been elucidated for some serotypes; for example, a cassette of 15 genes that functions as a single transcriptional unit is responsible for encapsulation in serogroup 19.[16] Ninety-one serotypes of S. pneumoniae have been identified on the basis of antigenic differences in their capsular polysaccharides. Among the genes that encode capsule production, some are specific for individual polysaccharides, whereas others are conserved among almost all pneumococci and even some other streptococci.[17] Immunization of rabbits with a pneumococcus of a specific capsular type stimulates the appearance of antibodies that cause agglutination and microscopic demonstrability of the capsule; in the latter reaction, called the Quellung reaction, antibody renders the capsule refractile and therefore more readily visible, which visibility is often, but erroneously, referred to as capsular swelling. Because serum antibody is the basis for identifying these types of pneumococcus, they are called serotypes. In the American numbering system, serotypes are numbered from 1 to 91 in the order in which they were identified. The more widely accepted Danish numbering system distinguishes 46 serogroups, with the groups containing antigenically related serotypes. For example, Danish serogroup 19 includes serotypes 19F, 19A, 19B, and 19C (the letter F indicates the first member of the group to be identified, followed by A, B, and C), which in the American system would be serotypes 19, 57, 58, and 59, respectively. Serotypes that most frequently cause human disease were the earliest to be identified and assigned numbers, which explains why the lower numbered serotypes are more likely to be implicated in human infection. Serotyping was clinically relevant in the 1930s, when antisera were administered for therapy, and is of great interest from epidemiologic and public health standpoints today, especially as new vaccines are being developed, but has little relevance for the clinician in an individual case of pneumococcal infection. An important property of S. pneumoniae is its capacity, as part of its quorum-sensing mechanism, to express a competence-sensing protein and internalize DNA from other pneumococci or from other bacterial species.[18] This transfer of genetic information to pneumococci is called transformation, and it enables pneumococci to acquire new traits—for example, the ability to make a different capsular polysaccharide. Transformation of capsular types occurs under experimental conditions but, more importantly, also occurs during colonization or infection of humans.[19-21] Epidemiology As with many other microorganisms, S. pneumoniae finds its ecologic niche in colonizing the nasopharynx. On a single occasion, appropriate culturing yields pneumococci in 5% to 10% of healthy adults and 20% to 40% of healthy children. With repeated attempts at culture, the percentage increases in all age groups, rising to 40 to 60% or greater[22] in toddlers and young children in daycare. For reasons that remain unclear, the rate of colonization is seasonal, with
  4. 4. an increase in the midwinter period, although pneumococci can be recovered from healthy children and adults throughout the year. A careful prospective study in infants in the United States[23] has shown that the first pneumococcus to colonize an infant is generally acquired at around 6 months of age and can be detected for a mean of about 4 months. In contrast, infants from select populations, such as native Americans, aboriginal Australians, or disadvantaged members of developed societies,[24] are more likely to be colonized, and with high numbers of pneumococci, even within the first few weeks of life. In adults, an individual serotype persists for shorter periods, usually 2 to 4 weeks,[25] but sometimes much longer.[1] Population-based studies carried out in different parts of the world have shown that the overall rate of invasive pneumococcal disease, defined as the isolation of S. pneumoniae from a normally sterile site such as blood, pleural fluid, or cerebrospinal fluid (CSF), is about 15/100,000 persons/year.[26] This figure reflects extensive data obtained before the widespread use of conjugate pneumococcal vaccine in infants and toddlers; the incidence has been reduced substantially in countries in which this vaccine is used. Furthermore, this number reflects the averaging of rates of disease in different age groups and populations. Invasive pneumococcal disease is relatively common in newborns and infants up to 2 years of age and much less in teenage children and young adults, again increasing in adults older than 65 years[27,28] (Fig. 200-2); for example, in South Carolina before conjugate pneumococcal vaccine was used,[28] the incidence was 160, 5, and 70/100,000 persons, respectively, among infants, young adults, and those 70 years of age or older. Interestingly, although the overall incidence of pneumococcal infection in the population is vastly reduced when compared with the preantibiotic era, this relationship to age has not changed. In certain populations, including African Americans,[29] Native Americans[30] (especially Alaskans[31] ), and Australian Aboriginals,[32] the incidence may be up to 10-fold greater, although it is unclear to what extent genetic or environmental factors are responsible (Table 200-1).[33] Most cases of pneumococcal bacteremia in adults are caused by pneumonia, and probably three to four cases of nonbacteremic pneumonia occur for every case of bacteremic pneumonia, thus leading to estimates of 25 cases of pneumococcal pneumonia/100,000 young adults and 280/100,000 older adults each year. Because of lack of confirmation, the true incidence may be several times greater. By contrast, in the preantibiotic era, about 700 cases of pneumonia occurred in 100,000 young adults each year.[1] Figure 200-2 Relationship between pneumococcal bacteremia and age is shown for two studies, widely separated in time. A, Data published in the preantibiotic era. B, Includes data from South Carolina obtained in 1986 and 1987.[30] Interestingly, the shape of the curve is remarkably similar to that in A, although the vertical axis in the lower curve shows a vastly reduced incidence when compared with that in the upper one. More recent studies continue to confirm these earlier findings. (A adapted from Heffron R. Pneumonia: With Special Reference to Pneumococcus Lobar Pneumonia. TABLE 200-1 -- Invasive Pneumococcal Disease in U.S. Racial Groups* Group Age (yr) 18-64 ≧65 White 10 57 Black 44 82 Navajo 56 190 Adapted from Watt JP, O’Brien KL, Benin AL, et al. Invasive pneumococcal disease among Navajo adults, 1989-1998. Clin Infect Dis. 2004;38:496-501. * Data are presented as rates/100,000 persons/year for 1989-1998 (before licensing of conjugate pneumococcal
  5. 5. vaccination). These results reflect the impact of genetic and environmental factors.[33] The occurrence of pneumococcal otitis media[34,35] or bacteremia[36,37] is related to season, perhaps because of the association with viral respiratory illnesses. A November through April clustering with a clear peak in February was apparent for otitis media in the study of Gray and Dillon.[23] In Houston, Texas, invasive disease in children occurred mainly during September through May, thus coinciding with the school year and sparing the summer months, but with no clear midwinter peak (Fig. 200-3). In contrast, invasive disease in adults clearly reaches a peak in the middle of winter, inversely related to ambient temperature and directly associated with the peak of viral respiratory disease.[36,37] Figure 200-3 Invasive pneumococcal disease. Each bar shows the number of cases of invasive pneumococcal disease at four tertiary care hospitals (adult and pediatric) in Houston during a 2-week period. A fall, winter, and early spring predominance is noted. The line graph[36] is the number of specimens from patients thought to have a viral syndrome, obtained by a consortium of physicians in cooperation with the Influenza Research Center of the Baylor College of Medicine, Houston. Pneumococci are transmitted from one individual to another as a result of close contact,[38] but infection is generally not regarded as contagious because so many factors intervene between acquisition of the organism (colonization) and development of disease. Daycare centers are very likely to be places for spread of these organisms in toddlers.[39-41] In adults, close crowded living conditions such as in military camps,[42] prisons,[43] shelters for the homeless,[44] and nursing homes,[45] are associated with epidemics, but contact in schools or in the workplace is generally not.[38] The common feature for outbreaks is that in addition to crowding and close contact, the population has some additional feature(s) that contribute(s) to susceptibility to infection such as fatigue, malnutrition, or intercurrent viral infection. Pathogenetic Mechanisms To cause disease, pneumococci, like other extracellular bacterial pathogens, must adhere to mammalian cells; replicate in situ; be carried to, replicate in, and fail to be cleared from anatomic areas that are normally free of them, escape phagocytosis; and damage tissue by causing inflammation and/or producing substances that directly damage cells. Many of these reactions are governed at a molecular level by bacterial and host properties.[46-48] Unlike certain other organisms such as Streptococcus pyogenes, which produce a variety of tissue- damaging substances, S. pneumoniae produces few toxins, of which pneumolysin is the principal one. Rather, this organism causes disease because of its capacity to an intense inflammatory response. In most organs—for example, the lungs, middle ear, and central nervous system—this inflammatory response is the disease. ADHERENCE, COLONIZATION, INVASION The prevalence of pneumococcal colonization attests to the adaptational success of this organism in adhering to mammalian cells and replicating in the nasopharynx. S. pneumoniae attaches to human pharyngeal cells through a variety of mechanisms involving the specific interaction of bacterial surface adhesins (e.g., pneumococcal surface antigen A, choline- binding proteins) and epithelial cell receptors such as platelet-activating factor.[49] Rhinovirus infection, for example, is followed by increased adherence of pneumococci to cultured human tracheal cells, and this reaction is inhibited by blocking platelet activating factor.[50]
  6. 6. Pneumococci also become invasive as a result of the interaction with platelet-activating factor on the surface of epithelial cells.[51] Epithelial cell glycoconjugates containing the disaccharide GlcNAcb1-4Gal[52] or asialo-GM glycolipid[53] are other possible binding sites. Phase variation of pneumococci may also play a role. On culture in vitro, a mixed population of transparent and opaque colonies can be identified. Organisms from transparent colonies have greatly increased quantities of phosphorylcholine and choline binding protein A, which contribute to their capacity to adhere to mammalian cells.[54] When an opaque colony is inoculated intranasally into an experimental animal, only those organisms that make transparent colonies persist. In contrast, intraperitoneal inoculation of opaque colonies may be lethal, whereas transparent colonies are less likely to be lethal; increased capsule production by opaque forms may in part be responsible. The recently demonstrated adhesin PsrP does not affect nasopharyngeal colonization but is necessary for pneumococci to adhere to and persist in the lungs of mice after tracheal challenge; antibody to this protein protects mice against challenge with S. pneumoniae serotype 4.[55] Once nasopharyngeal colonization has taken place, infection may result if the organisms are carried into cavities from which they are not readily cleared. Under normal circumstances, when bacteria find their way into eustachian tubes, sinuses, or bronchi, clearance mechanisms, chiefly ciliary action, lead to their rapid removal. If allergy or coexisting viral infection, for example, has caused edema that obstructs the opening of the eustachian tube into the pharynx or the ostium of a paranasal sinus, clinically recognizable infection may result. Similarly, damage to ciliated bronchial cells or increased production of mucus, whether chronic (e.g., from cigarette smoking or occupational exposure) or acute (e.g., from influenza or some other viral infection), may prevent the clearance of inhaled or aspirated organisms and lead to infection. In some cases, pneumococci also act as invasive organisms, penetrating mucosal barriers. This is thought to occur because choline-binding protein A interacts with polymeric immunoglobulin receptors on the surface of epithelial and mucosal cells,[56] with subsequent endocytosis, transport through the cell, and release through the inner cell membrane. If pneumococci are released into the bloodstream, they may invade the central nervous system by interacting with the receptor for platelet-activating factor,[57] which has been upregulated by inflammatory events. It is not certain whether the site of invasion in the brain is the choroid plexus or endothelial cells.[58] capsule and aVOIDANCE OF PHAGOCYTOSIS S. pneumoniae causes disease because it is able to avoid ingestion and killing by host phagocytic cells. In an immunologically naive host, specifically in the absence of anticapsular antibody, pneumococci are poorly ingested and killed by the host's professional phagocytes, polymorphonuclear leukocytes (PMNs), and macrophages. Capsule plays a central role in preventing phagocytosis. Interruption of capsule production in S. pneumoniae type 3 renders the organism essentially avirulent, with the lethal dose in mice shifted from 2–3 to >3 ? 107 colony-forming units.[59] Possible contributing mechanisms include (1) the absence of receptors on phagocytic cells that recognize capsular polysaccharides, (2) the presence of electrochemical forces that repel phagocytic cells, (3) the masking of antibody to cell wall constituents and C3b that may have fixed to the cell wall but beneath the capsule, and (4) the inactivation of complement.[60] A close relationship has been observed between the absolute amount of capsule produced and the virulence of pneumococcal strains, as well as between the amount of anticapsular antibody infused into mice and the level of protection against challenge with each of several serotypes of S. pneumoniae.[61] PspA prevents deposition and activation of C3b by interfering with complement factor B[62,63] and PspC blocks activation of the complement cascade by binding complement factor H.[64] These effects are attenuated or blocked by antibody to these surface-expressed proteins.
  7. 7. noncapsular VIRULENCE FACTORS As noted, noncapsular protein constituents, including pneumolysin, surface proteins, and autolysin, contribute to the pathogenesis of pneumococcal disease. Genetically engineered mutants that lack the ability to produce one or more of these substances have generally been shown to have diminished virulence, and immunization with the purified substance has stimulated the production of antibodies that confer protection in experimental animals (Table 200-2). It needs to be emphasized, however, that despite the current interest in these and other protein constituents of S. pneumoniae,[65,66] at the time of this writing (April, 2009), only indirect evidence of a protective effect of antibody to any of these substances has been found in humans. TABLE 200-2 -- Role of Pneumococcal Constituents as Virulence Factors* Pneumococcal Constituent Mechanism Strength of Evidence as Virulence Factor Antibody Prevents Disease[†] Mutants Lack Virulence Capsular polysaccharide Prevents phagocytosis; activates complement 4+ 4+ Cell wall polysaccharide Stimulates inflammation by strongly activating complement and stimulating release of cytokines 0 ND Pneumolysin Cytotoxic; activates complement, cytokines 2-3+ 2-3+ PspA Inhibits phagocytosis by blocking activation and deposition of complement on bacterial surface 2+ 2+ PspC Inhibits phagocytosis by binding complement factor H 1-2+ 1-2+ PsaA Mediates adherence 1-2+ 1-2+ Autolysin Causes bacterial disintegration; releases components 1+ 2+ Neuraminidase Possibly mediates adherence 0-1+ 0-1+ ND, not done; Psa, pneumococcal surface adhesin; Psp, pneumococcal surface protein. * The grading system is subjective and indicates (on a scale of 1+ to 4+) the stringency and importance of the demonstrated effect. For discussion and references, see the text. † Animal models only, except capsular polysaccharides. All serotypes of S. pneumoniae produce pneumolysin, a thiol-activated toxin that inserts into the lipid bilayer of cell membranes via its interaction with cholesterol. Pneumolysin is cytotoxic for phagocytic and respiratory epithelial cells and causes inflammation by activating complement and inducing the production of tumor necrosis factor-α and interleukin-1 (IL- 1).[67,68] Injection of pneumolysin into rat lung causes all the histologic findings of pneumonia,[69]
  8. 8. and immunization of mice with this substance before pneumococcal infection[70] or challenge with genetically engineered pneumococci that do not produce it[71] is associated with a significant reduction in virulence. Different regions of the pneumolysin molecule are responsible for cytotoxic and complement activity properties, and studies using strains with defined point mutations have shown that the cytotoxic activity is dominant in causing disease after intraperitoneal but not necessarily after intranasal challenge of mice.[72] When human macrophages are infected in vitro, altered expression can be demonstrated in a large number of genes; in the great majority, observed alterations specifically reflect the response to pneumolysin.[73] Human antibody to pneumolysin increases after pneumococcal pneumonia; the presence of this antibody is associated with a decreased likelihood of bacteremic infection, and it protects mice against pneumococcal challenge.[74] Proteins on the pneumococcal surface that bind to choline residues may mediate attachment to and penetration of mammalian cells, especially if these cells have been upregulated by prior cytokine exposure.[57] Pneumococcal surface protein A is present on the surface of almost all pneumococci and exerts an antiphagocytic force, perhaps by blocking deposition of complement.[75] Despite some antigenic variability, antibody raised against pneumococcal surface protein A protects experimental animals to a greater or lesser extent against challenge with the same or different strain,[76] and genetically engineered mutants that lack it have reduced virulence for mice.[77] Human antibody to this protein protects mice against pneumococcal infection[78] and may protect humans against pneumococcal colonization.[79] This substance is a major constituent of a vaccine that is currently in development (see later). Pneumococcal surface adhesin A, a surface-expressed permease, is universally present in S. pneumoniae. This protein shows very little antigenic variability. Antibody to it reduces pneumococcal colonization of the nasopharynx in mice,[80] perhaps by blocking attachment[81] ; this antibody may also be associated with a reduced risk of otitis media.[82] It may be involved in colonization of the nasopharynx, but it appears to contribute to virulence in other, as yet undetermined ways. Autolysin[71] disrupts the bacterial wall at the site of attachment of stem proteins. In nature, this enzyme contributes to cell wall remodeling. In infection, it probably contributes to disease by releasing peptidoglycan components that more vigorously activate complement, as well as substances (e.g., pneumolysin) to which the tissues of the infected host might otherwise not be exposed. As with other putative virulence factors, strains that lack autolysin are less virulent in experimental animals, and antibody to autolysin is modestly protective.[83] Pneumococci produce neuraminidase, which may contribute to bacterial adherence and colonization by cleaving sialic acid on mucous membrane surfaces and exposing GlcNAc-Gal, to which S. pneumoniae adheres more readily. Immunization of mice with neuraminidase has also provided modest protection against parenteral pneumococcal challenge, perhaps suggesting a role in virulence other than inhibition of colonization. All pneumococci also produce hyaluronidase, but a role in pathogenesis has not been clearly demonstrated. Innate Immunity to Pneumococcus Natural immune mechanisms are those that require no prior exposure to an infecting organism to exert their protective effect. This section discusses activation of complement, the pattern recognition receptors on human cells, and B-1 cells. Nonimmunologic mechanisms that protect against pneumococcal infection, such as glottal reflex and ciliary activity of bronchial epithelial cells, are discussed later, under host mechanisms of defense. ACTIVATION OF COMPLEMENT The cell wall of S. pneumoniae, including both teichoic acid and peptidoglycan constituents, activates complement by the alternative pathway. [84,85] Injection of either of these substances into the subarachnoid space causes an inflammatory reaction that has the characteristics of bacterial meningitis, although the kinetics vary with the substance injected. [85] C-reactive protein may also play an active part. [86] Polysaccharide capsule in addition appears to activate
  9. 9. the alternative pathway in vitro, [87,88] albeit to a somewhat lesser extent. The classic pathway is activated by almost universally present antibody to cell wall polysaccharides, even in the absence of anticapsular antibody. [88] To the extent that complement is fixed on bacterial surfaces and is accessible to phagocytic cells, such activation may be protective. Polymorphisms in the complement receptor on phagocytic cells are associated with a greater likelihood of having bacteremic pneumococcal infection. [89] Complement activation is associated with the release of C5a so that, whether or not complement is fixed on the bacterial surface, C5a, a potent attractant for PMNs, is released to the surrounding medium. Thus, an intense inflammatory response fueled by vigorous activation of both the alternative and classic complement pathways accompanies pneumococcal infection of an immunologically naive host. OTHER INNATE MECHANISMS Pathogen recognition receptors on the surface of mammalian cells play a major role in innate immunity. [48] Peptidoglycan and lipoteichoic acid interact with CD14, stimulating Toll-like receptor 2, [90,91] and pneumolysin interacts with Toll-like receptor 4 to induce nuclear factor kappa B (NF-κB). [92] The result could be regarded as a two-edged sword. These stimuli facilitate uptake of pneumococci in the absence of antibody to any of its constituents. [93] At the same time, they stimulate a vigorous inflammatory response by upregulating production of inflammatory cytokines IL-1, IL-6, and TNF-α, thereby contributing to pneumococcal disease that is largely a result of inflammation and is often severe in direct proportion to the intensity of the inflammatory response. A C-type lectin, SIGN-R1, expressed by macrophages, specifically interacts with some capsular polysaccharides, facilitating ingestion of pneumococci. [94] Serum proteins that react with cell wall polysaccharide (C-reactive protein) might play a modest role in protection by activating complement and exerting an opsonizing effect. [86] A recently recognized line of B-1a cells make IgM antibody to polysaccharides without regard to prior exposure to bacteria [95] ; this natural antibody, present in germ-free mice, provides some protection against pneumococcal challenge. [48,96] Finally, a host deficiency of serum mannose- binding lectin may reduce innate immune responses and contribute to lethal infection in humans. [97] Immunologically Specific Mechanisms of Immunity ANTIBODY TO PNEUMOCOCCAL CAPSULE Ample evidence has shown that in humans, anticapsular antibody is protective against pneumococcal infection, with little or no evidence to date to support a role for antibody to other bacterial constituents: (1) antibody to capsule appears in the bloodstream 5 to 8 days after the onset of infection, which is when that fever spontaneously resolves in the absence of treatment [1] ; (2) in the preantibiotic era, administration of serum that contained type-specific antibody was moderately effective in treating pneumococcal pneumonia [98] ; and (3) various assays all seem to show greatly increased uptake and killing of pneumococci in vitro in the presence of anticapsular antibody. [27,99,100] In contrast, except for indirect data suggesting an association between antibody to pneumolysin [74] or pneumococcal surface adhesin a, [82] there are few data in humans to support a protective role for antibody to other substances. Epidemiologic evidence supports the notion that immune mechanisms other than antibody to capsule are responsible for protection in the population. [101] It is important to note, however, that in the preantibiotic era, some proportion of patients recovered from pneumococcal pneumonia without producing measurable amounts of anticapsular antibody. Furthermore, some adults lack the capacity to make antibody to most pneumococcal capsules, [102] yet live long and healthy lives free of pneumococcal disease. Although IgG antibody to capsular polysaccharides, as measured by enzyme-linked immunosorbent assay (ELISA), generally predicts protection of experimental animals and opsonophagocytosis activity in vitro, such is not uniformly the case. Older adults [103,104] or
  10. 10. those admitted for pneumococcal pneumonia [105] may have relatively high levels of anticapsular antibody, but the antibody may not opsonize pneumococci for phagocytosis or protect mice against experimental challenge. The precise reason for the lack of protection is not known; perhaps the IgG antibody is relatively less avid for capsular material. Significant differences in kappa and lambda gene usage have been shown in older versus younger subjects. [104] Thus, when present, anticapsular antibody is regarded as a generally good, but not ideal, surrogate marker of immunity. The converse—namely, that the absence of such antibody indicates a relative degree of susceptibility—is probably true, even though many other factors (e.g., innate immunity, antibody to other pneumococcal constituents, general level of health, host receptors for pneumococcal constituents) enter into protection against pneumococcal disease. PREVALENCE OF ANTICAPSULAR ANTIBODY In the late 1980s, before the introduction of a pediatric pneumococcal vaccine, a sensitive and specific ELISA technique [106,107] showed that the great majority of 19-year-old military recruits lack antibody to most pneumococcal serotypes [108] ; the average subject had type-specific anticapsular IgG to only 15% of commonly infecting serotypes. Around this same time (which also preceded wide-scale pneumococcal vaccination of adults) the average working adult or older man was likely to have antibody to no more than one third of common pneumococcal serotypes. To the extent that immunity is greatly enhanced by the presence of anticapsular antibody, these data suggest that unvaccinated healthy adults of all ages tend to be susceptible to most serotypes of S. pneumoniae that commonly cause infection. EMERGENCE OF ANTIBODY DURING COLONIZATION OR SUBCLINICAL INFECTION Pneumococcal colonization stimulates production of anticapsular antibody. Studies of families carried out in the preantibiotic era [109] and of infants and toddlers in the 1970s [23] suggested that the acquisition of antibody also follows colonization. Serotype-specific antibody developed within 30 days in about two thirds of military personnel who became colonized during an outbreak of pneumococcal pneumonia. [108] After pneumococcal infection, antibody to the infecting serotype, as measured in older studies by agglutination in vitro or mouse protection, appears in the serum of adults in about two thirds of cases with some variability, depending on the serotype. [110] In children, the rate of appearance of antibody may be lower, [111-113] but these studies need to be repeated with ELISA. The reason(s) for the failure of detectable levels of antibody to develop after infection remain unclear. One explanation is a genetically mediated incapacity to recognize as foreign the relevant capsular polysaccharide and, therefore, to make antibody to it. [102] Failure to switch to IgG synthesis or to make certain IgG subclasses may also be implicated. [114] COLONIZATION AND IMMUNITY The best explanation for the low incidence of pneumococcal disease despite the relatively high rate of colonization and the low prevalence of detectable antipneumococcal antibody in the adult population is that antibody to the capsular polysaccharide of a colonizing organism is likely to appear before infection. However, in those who aspirate pharyngeal contents or who have diminished mechanisms of lower airway clearance, exposure to a high inoculum of organisms is more likely to occur before antibody is produced. Of course, those individuals who have a diminished capacity to form antibody remain susceptible as long as they are colonized, which explains the high rate of pneumococcal pneumonia in patients with multiple myeloma, acquired immunodeficiency syndrome (AIDS), and other such conditions. THE SPLEEN IN DEFENSE OF PNEUMOCOCCAL INFECTION
  11. 11. The principal organ that clears unopsonized pneumococci from the bloodstream is the spleen. [115,116] Experiments in human subjects have shown that highly opsonized particles are removed from the circulation by the liver but, with decreasing opsonization, the spleen increasingly assumes the role of clearance. [117] Presumably, the slow passage of blood through the spleen and prolonged contact time with reticuloendothelial cells in the cords of Billroth and the splenic sinuses allow for the relatively less efficient removal of nonopsonized particles through natural immune mechanisms (see earlier). [118] Overwhelming pneumococcal infection occurs in children and adults from whom the spleen has been removed or does not function normally. The heralding event in an outbreak of pneumococcal pneumonia in a metropolitan [43] prison was the rapid septic death of two prisoners, both of whom had previously undergone splenectomy. Pneumococcal disease progressed so rapidly in these cases that pneumonia was not initially detectable clinically or even with certainty by chest radiographs, although it was seen at autopsy. The 100-fold increase in the incidence of pneumococcal bacteremia or meningitis in children with sickle cell disease is probably caused by splenic dysfunction, although other factors such as complement abnormalities may also contribute. [115,119] Factors that Predispose to Pneumococcal Infection S. pneumoniae is a prototypic extracellular bacterial pathogen; host defenses against infection rely heavily on the interaction between humoral factors such as antibody and complement and phagocytic cells, specifically PMNs. A representative listing of conditions that affect the immunologic capacity of the host and predispose to pneumococcal infection is shown in Table 200-3. Specific conditions associated with pneumococcal pneumonia are shown in Table 200- 4. TABLE 200-3 -- Conditions That Predispose to Pneumococcal Infection Defective antibody formation Primary Congenital agammaglobulinemia Common variable (acquired) hypogammaglobulinemia Selective IgG subclass deficiency Secondary Multiple myeloma Chronic lymphocytic leukemia Lymphoma HIV infection Defective complement (primary or secondary) Decreased or absent C1, C2, C3, C4 Insufficient numbers of PMNs Primary Cyclic neutropenia Secondary Drug-induced neutropenia
  12. 12. Aplastic anemia Poorly functioning PMNs Alcoholism Cirrhosis of the liver Diabetes mellitus Glucocorticosteroid treatment Renal insufficiency Poorly avid receptors for FCγII (R131 allele) Defective clearance of pneumococcal bacteremia Primary Congenital asplenia, hyposplenia Secondary Splenectomy Sickle cell disease (autosplenectomy) Multifactorial and/or uncertain Infancy and aging Glucocorticosteroid treatment Malnutrition Cirrhosis of the liver Renal insufficiency Diabetes mellitus Alcoholism Chronic disease, hospitalization Fatigue Stress Cold exposure Excess likelihood of exposure Daycare centers Military training camps Prisons Shelters for the homeless Prior respiratory infection Influenza Other Inflammatory condition Cigarette smoking
  13. 13. Asthma COPD COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus; PMNs, polymorphonuclear leukocytes. TABLE 200-4 -- Factors Predisposing Adults to Invasive Pneumococcal Disease* Predisposing Factor All Invasive Pneumococ cal Infection (Sweden)[28] All Community -Acquired Pneumonia (Pittsburgh )[113] Pneumococ cal Bacteremic Meningitis (Israel)[115] Bacteremic Pneumococ cal Pneumonia (Ohio)[116] Nonbactere mic Pneumococ cal Pneumonia (Houston)[11 4] Bacteremic Pneumococ cal Pneumonia (Houston)[11 4] Alcoholism 32 33 NL 11 35 58 Cigarette smoking 40 55 NL 56 67 69 Chronic lung disease 17 31 19 28 58 42 Congestive heart failure NL 13 35 16 17 27 Diabetes mellitus 6 13 15 18 12 11 Malignancy 12 29 NL 26 17 25 Kidney disease 1 7 13 4 4 2 Liver disease 2 5 6 NL 21 23 Immunosuppres sion NL 36 36 NL 24 32 Recent hospitalization NL NL NL NL 37 35 No underlying disease 21 31 22 10 0 0 NL, not listed. * With the exception of ―no underlying disease,‖ the finding of low numbers in some studies and much higher ones in others suggests the possibility of incomplete availability of data in the former. In the Swedish study,[27] 20% of patients with meningitis had prior head injury. Defective antibody formation, whether congenital or acquired, has the greatest impact on susceptibility to pneumococcal infection. Bruton's original description of congenital agammaglobulinemia stressed the prominence of S. pneumoniae as an infecting agent.
  14. 14. Pneumococcus is also a major cause of serious infection in acquired agammaglobulinemia (common variable immunodeficiency)[120] and perhaps in IgG subclass deficiency[121] as well; subtle defects may also be responsible.[114] Homozygous expression of the R131 allele of the FCγII receptor on PMNs, a receptor that binds the Fc of IgG2 only poorly, or absence of the mannose-binding protein may be associated with susceptibility to pneumococcal bacteremia.[122] The incidence of invasive pneumococcal disease (isolation of S. pneumoniae from a normally sterile site) in adults is about 9/100,000 in healthy subjects—51 in diabetes, 63 in chronic lung disease, 94 in chronic heart disease, and 100 in alcohol abuse. The incidence rises further to 300 in patients with solid cancer, 423 in HIV/AIDS, and 503 in hematologic malignancies.[123] Pneumococcus continues to be the most common bacterial pathogen to infect persons who have multiple myeloma, lymphoma, or chronic lymphocytic leukemia, before chemotherapy and hospitalization tip the balance toward gram-negative infections.[124] In these conditions, as well as in HIV infection, there are probably immunologic defects at several points in the host defense, but defective antibody production predominates in the predisposition to pneumococcal infection. Just to place these numbers in perspective, if three to four nonbacteremic cases of pneumonia occur for each invasive (bacteremic) case, almost 1 in 25 HIV-infected persons may be expected to have pneumococcal pneumonia in a given year. Some authorities have recommended that bacteremic pneumonia or unusual pneumococcal infections in young adults[125,126] should trigger a search for HIV infection. Of the many possible defects in complement, only those factors required to generate C3b are associated with pneumococcal infection. Because pneumococci are not killed by serum, the host response is unaffected by defects in C6, C7, C8, or C9, which result in decreased membrane attack complexes. In contrast, deficiencies in C1, C2, and C4, whether congenital or acquired, are expected to be associated with increased susceptibility to pneumococcal infection, although cases documenting the association are reported only rarely.[127] Neutropenia of whatever cause is associated with S. pneumoniae infection although, somewhat surprisingly, leukocyte adhesion deficiency syndrome (Mac-1 deficiency) is generally not.[128] One study[129] has shown that at the time of initial hospitalization for acute leukemia, patients are more likely to have infection caused by more ordinary gram-positive pathogenic bacteria, probably analogous to the pretreatment situation in multiple myeloma.[124] Defective bacterial killing by PMNs as seen in chronic granulomatous disease does not predispose to infection with S. pneumoniae; the absence of catalase renders this organism susceptible to the interaction between its endogenous H2O2 and myeloperoxidase and the halide present in PMNs. The susceptibility of older adults to pneumococcal pneumonia is multifactorial, reflecting senescence of the immune system because of diminished production of immunoglobulins (or production of poorly functional ones), impaired response to cytokines, and general debilitation caused by weakening of the gag reflex, malnutrition, and the presence of other diseases. The effect of alcoholism is also multifactorial and involves lifestyle (e.g., cold exposure, malnutrition), suppression of the gag reflex, and possibly deleterious effects on PMN function, although in most cases these alterations have been difficult to attribute to the effect of alcohol alone.[130,131] Heffron[1] has cited studies from the preantibiotic era showing a 30% to 50% incidence of alcohol abuse in patients with pneumococcal pneumonia. More recent studies have continued to find about one third of such patients to have alcoholic-related disease.[27,132,133] A disproportionately high number of patients with pneumococcal infection have diabetes mellitus,[27,132-135] a condition in which PMN chemotaxis is reduced[136] and phagocytic function is defective.[137] Anemia (hemoglobin lower than 10 g/dL) was detected in one third of a series of patients with pneumococcal pneumonia.[133] Many chronic diseases are associated with pneumococcal pneumonia by virtue of an association with pneumonia of whatever cause, which suggests that the predisposition is a
  15. 15. general one rather than being specific for S. pneumoniae. Pneumococcal pneumonia follows hospitalization for all causes[138] and has even been observed as a nosocomial infection.[139] Other factors such as cold exposure, stress, and fatigue[21] may predispose to pneumococcal pneumonia by unknown mechanisms. As noted, prior respiratory viral infection, especially that caused by influenza virus, plays a prominent role in predisposing to pneumococcal infection.[36,37,140,141] Upregulation of surface receptors during viral infection may enhance pneumococcal adherence[142] and invasion. Bacteria are certainly less well cleared from the airways because of viral-induced damage. Pneumococcal disease is greatly increased in people with altered pulmonary clearance, such as those who have chronic bronchitis, asthma, or COPD. Only fairly recently has a study supported clinical observations to associate cigarette smoking with susceptibility to pneumonia.[143] It is an interesting sign of the times that Heffron's classic treatise[1] on pneumococcus, published in 1939, had a section on inhalation of ―noxious substances,‖ yet did not mention cigarette smoking. In the United States, invasive pneumococcal disease is more common in certain ethnic groups (e.g., African Americans and Navajo Indians[30] ); this prevalence is thought to reflect genetic and environmental factors.[33] Clinical Syndromes S. pneumoniae causes infection of the middle ear, sinuses, trachea, bronchi, and lungs by direct spread of organisms from the nasopharyngeal site of colonization and causes infection of the central nervous system, heart valves, bones, joints by hematogenous spread; the peritoneal cavity may be infected by either route (Fig. 200-4). Infection of pleura or peritoneal cavity and of the central nervous system may occur by direct extension or by hematogenous spread. In any individual case, the route of infection cannot usually be determined. Bacteremia that occurs without an apparent source or focus of infection is called primary bacteremia. In a population-based study of adults in Israel,[144] pneumonia was present in 71% of cases of pneumococcal bacteremia, meningitis was present in 8%, and otitis media or sinusitis in 4%; bacteremia was regarded as primary in 18%. Primary bacteremia has always been more common in children than adults; when therapy has been withheld, a focus of infection has often become apparent. Figure 200-4 Relationship of exposure to development of pneumococcal disease. This is a schematic representation of events that take place between the initial response to pneumococci and eventual development of disease. OTITIS MEDIA Almost every study of acute otitis media in which material from the middle ear has been cultured has shown S. pneumoniae to be the most common isolate or second only to nontypeable Haemophilus influenzae; Moraxella (Branhamella) catarrhalis is usually a distant third.[145] In these studies, which were usually carried out in children aged 6 months to 4 years and were completed before widespread use of pneumococcal conjugate vaccine, S. pneumoniae was implicated in about 40% to 50% of cases in which a causative agent was isolated or in 30% to 40% of all cases. Pneumococcus is the most prevalent pathogen in otitis media in adults as well.[146] Prior infection by a respiratory virus is thought to play a major contributory role by causing congestion of the opening to the eustachian tube. Prospective longitudinal studies[23,34,147] have shown that when pneumococcal otitis media follows fairly closely after colonization by a new serotype, although most cases of colonization occur without disease. The traditional predominant role of serotypes 6, 14, 19F, and 23F as
  16. 16. colonizing and infecting organisms in unvaccinated children may be related to more avid adherence to mammalian cells; important changes that have resulted from widespread use of the conjugate pneumococcal vaccine are discussed later SINUSITIS Acute purulent sinusitis is caused by the same organisms as acute otitis media; thus, S. pneumoniae dominates or is second to H. influenzae. [148] The pathogenesis of infection is also similar, with a prominent predisposing role for congestion of the mucosal membranes caused by viral infection, atmospheric pollutants, or allergens. Accumulation of fluid in the paranasal sinus cavities, even during simple colds, [149] provides a medium for bacterial proliferation and subsequent acute sinus infection. MENINGITIS Except during an epidemic of meningococcal infection, S. pneumoniae is the most common cause of bacterial meningitis in adults. [150] In countries that have implemented effective vaccination programs for H. influenzae type b, pneumococcus has become the most common sporadic cause of meningitis in children older than 6 months as well. Meningitis may result from direct extension from the sinuses or middle ear or from bacteremia. [58,151] Favoring the former possibility are the association between acute otitis media or sinusitis and infection of the central nervous system, and the well-documented role of S. pneumoniae as the most common cause of recurrent bacterial meningitis associated with head trauma, CSF leak, or a break in the integrity of the dura. [152] Favoring the latter is the high association of pneumococcal pneumonia or bacteremia without a known focus with subsequent meningitis. In addition, an autopsy study of the temporal bones of children who died of bacterial meningitis [153] showed no evidence for extension from the middle ear, which supports the possibility that even when it follows otitis media, meningitis may develop as a result of bacteremia. Although hematogenous spread to the choroid plexus was originally thought to be the pathogenesis in most cases of pneumococcal meningitis, it is now believed that infection upregulates platelet-activating factor on vascular endothelial surfaces in the meninges, and that pneumococci adhere and are internalized by this mechanism. [52] Extension through lymphatics may also contribute. [154] Communication through the cochlear aqueduct between the inner ear and the subarachnoid space may explain deafness, a common complication in patients with hematogenous bacterial meningitis. [154,155] Once pneumococci appear in the meninges or subarachnoid space, the capabilities to escape phagocytosis and produce inflammation are central to the disease process. As noted, intracisternal injection of cell wall constituents in rabbits, principally peptidoglycan and, to a lesser extent, teichoic acid, causes the CSF abnormalities of bacterial meningitis, presumably through various mediators, including C5a, tumor necrosis factor, IL-1, IL-6, and other active inflammatory peptides. [59,157] Although interaction with Toll-like receptors 2 and 4 may provide some protection, this interaction clearly stimulates further inflammation. [157] No distinctive clinical or laboratory features of pneumococcal meningitis enable the physician to suspect S. pneumoniae over any other causative agent. Using current laboratory techniques for centrifugation of specimens, examination of a Gram-stained specimen of CSF provides the correct diagnosis in almost all cases, [158] unless 3 to 6 hours have passed since the administration of an effective antibiotic, in which case the number of bacteria may be greatly decreased. Immunologic detection of pneumococcal capsular material (―bacterial antigen‖) generally does not add information beyond what is determined by Gram stain, [159] although nuclear probes are likely to be developed in the near future to help in this situation. ACUTE EXACERBATION OF CHRONIC BRONCHITIS
  17. 17. Careful microbiologic observation [160,161] has confirmed the clinical impression that S. pneumoniae is second to H. influenzae as a common cause of exacerbation in patients who have chronic bronchitis. The converse also applies, namely, that a clinically recognizable exacerbation of the chronic disease is highly associated with acquisition of a new pneumococcal strain. [162] PNEUMONIA Pathogenesis If potentially protective mechanisms fail to prevent both the access of pneumococci to the alveoli and their subsequent replication, pneumonia results. Bacteria proliferate in alveolar spaces and spread via the alveolar septa; in these sites, they activate complement, generate cytokine production, and upregulate receptors on vascular endothelial surfaces. Exudative fluid and WBCs accumulate in the septa and alveoli and extend to uninvolved areas through the pores of Kohn. This filling of alveoli with microorganisms and inflammatory exudate defines the presence of pneumonia; a clinical diagnosis is made when fluid accumulation is great enough to allow it to be seen radiographically as a nonlucent region of ―infiltration‖ or ―consolidation.‖ Predisposing Factors In a prospective study of pneumococcal pneumonia, [133] almost all patients had two or more predisposing conditions such as cigarette smoking, chronic obstructive pulmonary disease, alcohol abuse, neurologic disease (e.g., cerebrovascular accident [CVA], seizures, and dementia), malignancy, liver disease (e.g., hepatitis and/or cirrhosis), recent IV drug use, congestive heart failure, diabetes mellitus, or HIV infection. One third of patients had been discharged from a hospital within the preceding 6 months. The wintertime increase in adult pneumococcal pneumonia and the striking association with viral infections in children and adults has long been noted. [36,42,163,164] Symptoms and Physical Findings Cough, fatigue, fever, chills, sweats, and shortness of breath are the most frequent symptoms of pneumonia; these are all more prominent in younger than in older patients. [165,166] Patients with pneumococcal pneumonia usually appear ill and have a grayish, anxious appearance that differs from that of persons with viral or mycoplasmal pneumonia. The temperature may be elevated to 102? to 103? F, the pulse to 90 to 110 beats/min, and the respiratory rate to more than 20/min. Older patients may have only a slight temperature elevation or be afebrile but are more likely to have an increased respiratory rate. [165] The absence of fever in proven pneumococcal pneumonia is associated with increased morbidity and mortality, as is (especially) hypothermia. Physical examination may reveal diminished respiratory excursion (splinting) on the affected side because of pain. Dullness to percussion is present in about half of cases. Crackling sounds are heard on careful auscultation in almost all cases, but in patients who have chronic lung disease, it is often difficult to be certain that such sounds signify the presence of pneumonia. Increased fremitus is often overlooked, but is very useful in detecting pneumonia. Bronchial or tubular breath sounds may be heard if consolidation is present. Flatness to percussion at the lung base and an inability to detect the expected degree of diaphragmatic motion based on the patient's respiratory excursion suggest the presence of pleural fluid. Unless all the vital signs are normal, which substantially reduces the likelihood of pneumonia, no set of physical findings can reliably replace the chest x-ray in diagnosing the presence or absence of pneumonia. [167] The finding of a heart murmur raises concern about endocarditis, a
  18. 18. rare but serious complication. Confusion, obtundation, or especially neck stiffness suggest the presence of meningitis. Radiographic Findings In most cases of pneumococcal pneumonia, chest radiography reveals an area of infiltration involving one or more segments within a single lobe. [133] Air space consolidation is detected radiographically in most cases, and is more frequent in bacteremic cases; an air bronchogram, which reflects especially dense air space consolidation, highly correlates with bacteremia. [133,168] Rarely, S. pneumoniae infection causes a lung abscess. [169] As emphasized earlier, pneumococci do not produce highly toxic tissue-damaging substances. Thus, abscesses do not generally occur, even at a microscopic level and, if an abscess is seen, concurrent anaerobic infection or an anatomic abnormality such as bronchial obstruction, cancer, or pulmonary infarction should be suspected. Although pleural effusion may be found in 40% of patients with pneumococcal pneumonia by careful search, only 10% have sufficient amounts of fluid to aspirate, and in only a minority of these, perhaps 2% of the total, is empyema present. [170] General Laboratory Findings Twenty-five percent of patients with pneumococcal pneumonia have a hemoglobin level of 10 mg/dL or lower. [133] Although most have leukocytosis (WBC count > 12,000/mm 3 ), a substantial proportion may have a normal WBC count, at least at the time of admission. A WBC count lower than 6000/mm 3 occurs in 5% to 10% of persons hospitalized for pneumococcal pneumonia and indicates a very poor prognosis. [171] Bone marrow suppression is responsible, resulting from overwhelming infection, sometimes with further contribution by ethanol. [172] The low serum albumin level that often is present may result from malnutrition— and therefore indicate a predisposing condition—or reflect catabolism and fluid shifts that are manifestations of sepsis. [133] The serum bilirubin level may be increased to 3 to 4 mg/dL; the pathogenesis of this abnormality is multifactorial, with hypoxia, hepatic inflammation, and breakdown of red blood cells in the lung all thought to contribute. Levels of lactate dehydrogenase may be elevated. The likelihood that underlying disease is present must always be considered when evaluating abnormal laboratory findings. Laboratory abnormalities in empyema are reviewed in Chapter 65. Diagnostic Microbiology The causative role of the pneumococcus in a patient who has pneumonia is strongly suggested by microscopic demonstration of large numbers of PMNs, very few epithelial cells, and numerous, slightly elongated gram-positive cocci in pairs and chains in Gram-stained sputum (Fig. 200-5). If accepted terminology is strictly followed, a presumptive diagnosis of pneumococcal pneumonia is then made if S. pneumoniae is identified by sputum culture and the diagnosis is proved if S. pneumoniae is identified by blood culture. The argument that the diagnosis is never certain unless the blood culture is also positive is overly restrictive because, even in the preantibiotic era, only about 25% of patients with pneumococcal pneumonia had detectable bacteremia. [1] Ways of interpreting results of blood and sputum culture are shown in Table 200-5. Figure 200-5 Gram-stained sputum from patient with pneumococcal pneumonia (?1000). Shown are many polymorphonuclear neutrophils and no epithelial cells, with large numbers of slightly elongated, gram-positive cocci in pairs and chains indicative of Streptococcus pneumoniae. A clear area surrounding bacteria indicates the capsule.
  19. 19. TABLE 200-5 -- Microscopic Examination and Culture of Sputum for Pneumococci Gram Stain Sputum Culture Blood Culture Comment + + + Generally regarded as conclusive diagnosis of invasive pneumococcal disease (pneumonia), but does not exclude contribution by a contributing cause (e.g., influenza virus infection or lung cancer) + + − Good evidence for nonbacteremic pneumococcal pneumonia if a clinical syndrome suggesting pneumonia is present, microscopic examination of Gram-stained sputum is characteristic (see Fig. 200- 5), and culture shows strongly predominant growth of pneumococci with no other likely pathogenic bacteria + or − − + With symptoms and signs of pneumonia and an infiltrate on the chest radiograph, these findings are generally taken to indicate invasive pneumococcal pneumonia, even if organisms are not found in sputum. + − − In the presence of the appropriate clinical syndrome, still remains suggestive of pneumococcal pneumonia because organisms can be missed on culture as a result of sampling error and overgrowth of streptococci from saliva. − + − Less suggestive of pneumococcal disease. Pneumococci can be isolated by culture of sputum from persons who are colonized. However, especially in patients already treated with antibiotics, the positive culture may be the only supporting evidence for diagnosis of nonbacteremic pneumococcal pneumonia. − − − Does not support a diagnosis of pneumococcal pneumonia Attempts to make a diagnosis based on an inadequate sputum specimen [173-175] are largely responsible for studies claiming that microscopic examination and culture of sputum are not reliable. To be reliable, the sputum sample should contain material that on microscopic examination reveals areas with hundreds of WBCs and few epithelial cells at low-power magnification (100?) and at least 10 to 20 WBCs with no epithelial cells under 1000? magnification. At this higher magnification, pneumococci are generally present in large numbers (more than 25/field; see Fig. 200-5), although occasionally as few as 1 to 2 may be seen per field. If sufficient numbers of inflammatory cells are not present, relevant material has not been obtained; if many epithelial cells are detected, the finding of bacteria cannot be trusted to reflect what is present in the bronchi or lungs. A good-quality sputum specimen is far more likely to be obtained by a physician, who best understands its central role in establishing an etiologic diagnosis and determining therapy, than by ancillary personnel, who
  20. 20. may not. In our studies, [176] we have found that if patients who cannot provide any specimen or an adequate specimen are excluded, Gram stain and culture identify pneumococci in more than two thirds of cases. With further exclusion of patients who have received antibiotics for 24 hours or longer, Gram stain and culture each are more than 85% likely to reveal pneumococci in expectorated sputum of patients with pneumococcal pneumonia. When a patient who has pneumonia cannot initially provide an expectorated specimen, the potential problems of empirical therapy should be balanced against the time and trouble that it may take to obtain one (e.g., by nasotracheal suction or hydration, or by having the patient breathe humidified air or hypertonic saline mist). Undue delay (e.g., beyond 6 to 8 hours) should be avoided because it has been shown in large series of cases to be associated with a worse outcome; nevertheless, I believe that many individual patients receive deficient care because the causative organism has not been identified. The recommendation that an antibiotic must be given within 4 hours of a patient's arrival at an emergency room has been recently withdrawn. [177] Other diagnostic techniques focus on the detection of antigen or antibody. In general, if the sputum is not of sufficiently good quality that the Gram stain is positive, other tests such as coagglutination, antigen detection, or polymerase chain reaction that look for pneumococci in the sputum are not helpful because they are confounded by the potential problem of detecting carriage rather than infection. Pneumococcal cell wall polysaccharide is detected in urine in about 80% of patients with bacteremic pneumococcal pneumonia and a slightly lower percentage of those with pneumococcal bacteremia without pneumonia, or pneumococcal pneumonia without bacteremia. Less than 10% of adults without pneumococcal pneumonia also may have a positive test. [178,179] A strongly positive test in the clinical setting of pneumonia is now regarded as diagnostic of pneumococcal pneumonia in adults. [177] In children, the test is positive with pharyngeal colonization and is not useful diagnostically. [180] Complications Empyema, the most common complication of pneumococcal pneumonia in the preantibiotic era, occurred in about 5% of cases and remains the most common today, with an incidence of approximately 2%. [170] As noted, pleural fluid appears in a substantial proportion of cases of pneumonia but is usually reactive. When bacteria reach the pleural space, either hematogenously or as a result of extension of the pneumonia to the visceral pleura with spread via lymphatics, empyema results. Persistence of fever, even if low grade, and leukocytosis after 4 to 5 days of appropriate antibiotic treatment of pneumococcal pneumonia is suggestive of empyema; this diagnosis is even more likely if the radiograph shows persistence of pleural fluid. The presence of frank pus in the pleural space, a positive Gram stain, or fluid with a pH of 7.1 or lower are all indications for aggressive and complete drainage with repeated needle aspiration or prompt insertion of a chest tube. If no response is seen, immediate removal of infected material by pleuroscopy or open thoracotomy is indicated. [181] One study of medical empyema caused by all organisms found that mortality exceeded 30% in two hospitals in which the therapeutic approach was not aggressive but was less than 10% in a third hospital where it was. [182] We have recently noted an important set of noninfectious complications of pneumococcal pneumonia. [183] In a series of 170 veterans hospitalized for this disease, 33 (19.4%) had at least one major cardiac complication, including 12 (7%) with acute myocardial infarction (MI; of these, 2 also had arrhythmia and 5 had new-onset or worsening congestive heart failure [CHF]), 8 (5%) with new-onset atrial fibrillation or ventricular tachycardia that was transient in every case, and 13 (8%) with newly diagnosed or worsening CHF, without MI or new arrhythmias. Mechanisms for these cardiac events include the following: (1) increased local inflammatory response in vulnerable plaques in coronary arteries with rupture and infarction [184] ; (2) decreased oxygen supply because of ventilation-perfusion mismatch; and (3)
  21. 21. increased demand on the heart related to the response to fever in the presence of shunting in the lungs. OTHER INFECTIOUS SYNDROMES S. pneumoniae can be implicated in a wide variety of infectious states. Isolated or epidemic conjunctivitis may occur, caused (somewhat surprisingly) by unencapsulated pneumococci, essentially the only condition in which unencapsulated pneumococci play a role. [185,186] A case of pneumococcal endocarditis [187] is seen once or twice per decade at a large tertiary care hospital in the United States; 14 cases were identified in Denmark (population, 5 million) in a 10-year period. [188] Alcoholic dependence is common, most infections involve previously normal heart valves, and the disease tends to be rapidly progressive and severe. [187-189] Purulent pericarditis [190] caused by pneumococcus has also become exceedingly rare, whether it occurs as a separate entity or together with endocarditis. Pneumococcal peritonitis occurs by hematogenous or local inoculation of the peritoneal cavity. [191] In patients who have preexisting ascites, pneumococci reach the peritoneum and replicate in the peritoneal fluid, generally in the absence of a documented source of infection elsewhere. Local inoculation occurs in women when pneumococci are carried to the peritoneal cavity via the female reproductive tract, with or without clinically recognizable infection (e.g., salpingitis), or as a result of bowel perforation. Pneumococcal infections of the female reproductive organs [192-194] may occur, with or without peritonitis. Septic arthritis occurs spontaneously in a natural or prosthetic joint or as a complication of rheumatoid arthritis. [195-197] Multiple joints are involved in less than 25% of cases, [198] and the functional outcome is often bad. Osteomyelitis in adults tends to involve the vertebral bones. [199] Epidural and brain abscesses are rarely described. [200] Soft tissue infections [201,202] occur, especially in persons who have connective tissue diseases or HIV infection. Bacteremic pneumococcal cellulitis generally occurs in patients who have severe underlying diseases, and a respiratory focus is often apparent. [203] Finally, the appearance of unusual pneumococcal infections in a young adult might suggest that tests for HIV infection be undertaken. [125] Antibiotic Susceptibility Until the mid-1970s, pneumococci were inhibited or killed by readily achievable levels of almost all relevant antibiotics. This remarkable susceptibility allowed for a somewhat cavalier approach to diagnosing and treating otitis, sinusitis, and pneumonia, an approach that has unfortunately not changed, despite the fact that in the past 2 decades, pneumococci have become more resistant to penicillin and other antibiotics. The subject of pneumococcal resistance to penicillin is complicated because the definitions have changed and the susceptibility patterns have evolved. [204] Until the time that pneumococcal resistance was first recognized (importantly, this was in cases of meningitis), no one had ever bothered to apply a definition of susceptibility. Based on the historical knowledge that all isolates had previously been susceptible to ≦0.06 ?g/mL, isolates with a minimal inhibitory concentration (MIC) of 0.06 ?g/mL (levels readily achievable in CSF with maximum doses of penicillin) were called penicillin-susceptible. Isolates with an MIC ≥ 0.12 to 1.0 ?g/mL (levels between 0.5 and 1.0 ?g/mL are achieved in some patients) were said to have reduced susceptibility or intermediate resistance, whereas those with an MIC > 1.0 ?g/mL were defined as resistant. However, with generally administered doses of IV penicillin, levels achieved in interstitial fluid and in the lungs are far in excess of those achieved in CSF and well above 1 to 2 ?g/mL for most of the treatment period. In 2008, the definitions of susceptibility to penicillin changed to reflect the site of infection and the route of therapy. [205] For infections other than those of the CNS, which are treated with parenteral penicillin, susceptibility, intermediate resistance, and resistance to penicillin are now defined as an MIC ≦ 2, 4, and ≥8 ?g/mL, respectively, for infections other than those of the CNS. If oral penicillin is to be used, the old definitions apply, reflecting the substantially lower tissue levels
  22. 22. achievable with that therapy. Most importantly, in cases of meninqitis, organisms with an MIC ≦ 0.06 ?g/mL are susceptible; those with an MIC ≥ 0.12 ?g/mL are regarded as resistant. Similar approaches and definitions have been developed to define susceptibility to amoxicillin, ceftriaxone, and other β-lactam antibiotics. For example, MICs for susceptibility, intermediate resistance, and resistance to amoxicillin are defined simply as ≦2, 4, and ≥8 ?g/mL, respectively, reflecting the concept that no physician would use oral therapy to treat a CNS infection. For ceftriaxone, there are separate definitions for CNS and non-CNS infections. It is essential to understand these changes in definitions before reading the medical literature on this subject published from 1985 through 2007. Current rates of resistance to these and other antimicrobials are presented in the following section (―Prevalence of Resistance‖) and summarized in Table 200-6. TABLE 200-6 -- Definitions of Susceptibility of Pneumococci to Representative β-Lactam Antibiotics* Antibiotic Susceptible Intermediate Resistant Penicillin (oral) ≥0.06 0.12-1 ≥2 Penicillin (parenteral) Non-CNS infection ≤2 4 ≥8 CNS infection ≤0.06 ≥0.12 Amoxicillin [†] Non-CNS ≤2 4 ≥8 Ceftriaxone or cefotaxime Non-CNS infection ≤1 2 ≥4 CNS infection ≤0.5 1 ≥2 CNS, central nervous system. * Distinguishing between isolates from patients in whom the CNS is or is not involved, according to definitions of the National Committee for Clinical and Laboratory Standards. † In the case of amoxicillin, no definition is made for CNS infection under the assumption that physicians would not use an oral antibiotic to treat patients for meningitis; parenteral amoxicillin is not available in the United States.
  23. 23. Penicillin inhibits the replication of S. pneumoniae by binding enzymes needed to synthesize peptidoglycan, including higher molecular weight transpeptidases and a lower molecular weight carboxypeptidase. The binding is covalent, and a serine ester–linked, enzymatically nonactive penicilloyl complex is formed. The reaction with penicillin is used to recognize these enzymes by two general methods: incubating with radiolabeled penicillin, followed by electrophoresis and autoradiography, or incubating with nonlabeled penicillin, followed by electrophoresis and immunoblotting with radiolabeled antipenicilloyl antibody. Six such enzymes have been identified—1A, 1B, 2A, 2B, 2X, and 3. In fully susceptible isolates of S. pneumoniae, these six enzymes, which are also called penicillin-binding proteins (PBPs), are identifiable after incubation with low concentrations of penicillin. Resistant isolates have PBPs with decreased affinity for penicillin in a very approximate proportion to the degree of resistance. Changes in the genes that encode these enzymes, with relatively minor alterations in the amino acids at essential loci, [206] may result in the decreased affinity. Alterations in PBP 2B are more likely to account for low-level resistance, whereas mutations in PBP 2X have been associated with high-level resistance. [207] Pneumococci have become resistant by acquiring genetic material from other bacteria with which they coexist in close proximity. In fact, the altered sequence in the gene for PBP 2B in many penicillin-resistant isolates appears to have originated in Streptococcus mitis. [208] The unique capacity of S. pneumoniae to acquire genetic material by transformation is a major determinant of this process. Extensive diversity among isolates [209] or within the transpeptide- encoding region of the pneumococcal genome [207,210] indicates that many discrete mutational events have occurred, some of which reflect acquisition and others, rearrangement of DNA. Alterations in several PBPs may eventually appear within an individual isolate, and a mosaic array of PBPs results. Nevertheless, the major source of resistance worldwide has been the geographic spread of a few clones that seem to have special capability to spread and colonize. [211] One well-documented example was the importation into, and rapid spread throughout Iceland of a strain that was prevalent in Spain during the 1992 Olympics. [212] In the United States, the dominant factor in the emergence of antibiotic-resistant pneumococci has been human-to-human spread of relatively few clonal groups that harbor resistance determinants to multiple classes of antibiotics. [213] These same clones seem to have spread worldwide and may be found, for example, in Korea or Thailand, as well as in Europe. [214] Geographic spread is greatly facilitated by antibiotic pressure, which explains why many of the widespread colonizing clones exhibit antibiotic resistance. A prominent site for this selection is daycare centers. Point prevalence studies in the United States have shown that at any given time, a remarkably high proportion of children in daycare are receiving antibiotics. These conditions (1) suppress susceptible flora, thereby creating a niche for resistant organisms; (2) spare antibiotic-resistant pneumococci; (3) increase the prevalence of antibiotic-resistant viridans streptococci, thus setting the stage for further transformation of pneumococci to antibiotic resistance; and (4) provide close contact among small children, which allows for the spread of organisms. Other situations characterized by close contact and excessive antibiotic use, such as nursing homes, may also serve as breeding grounds for these organisms. Resistance to penicillin is only the tip of the iceberg. Resistance results from acquisition of a cassette of genetic elements that encode resistance to other antibiotics as well. Many penicillin-resistant strains have alterations in PBPs, especially PBP 2X and 1A, [210] that also render them resistant to third-generation cephalosporins, such as cefotaxime or ceftriaxone. Even low-level increases in MICs for penicillin that still define strains as sensitive are associated with resistance to other widely used antibiotics, including the macrolides, trimethoprim-sulfamethoxazole, tetracyclines, and, to a lesser extent, the quinolones (see Table 200-6). An understanding of macrolide resistance is important clinically. Macrolides insert into a pocket of the 23S subunit of the 50S ribosome, specifically by attaching at domain V of the peptidyl transferase loop, thereby blocking protein assembly. In doing so, these drugs are bactericidal for Streptococcus pneumoniae. (The mechanism for killing of pneumococci is
  24. 24. complex; macrolides are generally regarded as bacteriostatic drugs against gram-positive pathogens such as Staphylococcus aureus, but are bactericidal against pneumococcus.) Acquisition of genetic material, designated erm(B) or mef(A), often together with genes that encode penicillin resistance, may lead to resistance: 1. erm(B) encodes methylation of a base in domain V of the 23S rRNA (A2058). This methylation essentially blocks the ribosomal pocket; because the macrolide no longer fits into the pocket, increasing its concentration has little effect, and high-level resistance results (≥64 ?g/mL). 2. mef(A) encodes an efflux pump that excludes macrolides. High antibiotic concentrations might be expected to overcome the pump, forcing enough antibiotic into the bacterium to exert an antibacterial effect. This resistance is at a lower level (usually ≦16 ?g/mL) and, at a sufficient dosage, a macrolide might be expected to be effective. The debate about whether such resistance is clinically meaningful [215] is based on the fact that most macrolide-resistant isolates in the United States have mef(A), and that present doses of macrolides may be effective despite the in vitro finding that an isolate is resistant. Other mutations are responsible for resistance in a small percentage of isolates, causing other base substitutions in domain V or altering protein sequences within or adjacent to the macrolide binding site, especially involving ribosomal proteins L4 and L22. [216] Prevalence of Resistance Because the medical literature from 1985 to 2006 used definitions that have now been changed, levels of pneumococcal resistance to β-lactam antibiotics appeared to be much higher than they actually were. Extrapolating from earlier studies, in the United States at present, in treating non-CNS infections caused by S. pneumoniae, about 65% of isolates appear to be susceptible to penicillin given orally, 17% are of intermediate resistance, and 17% are resistant (see Table 200-6). [217-220] About 93% of all pneumococci are susceptible to penicillin given parenterally or amoxicillin given orally, 5% are intermediate, and 2% are resistant. [220] In cases of meningitis, 65% or organisms are susceptible to penicillin and 35% are resistant (no intermediate resistance is defined). For ceftriaxone, in non-CNS infections, 97% of organisms are susceptible, 2% are intermediate, and 1% resistant; in CNS infections, these percentages are 90%, 7%, and 3%, respectively. [221] Isolates from invasive infection are generally more likely to be antibiotic-susceptible than those from otitis media or nasopharyngeal colonization. Variations occur from city to city and within segments of the population or even within institutions in a single city, so the actual likelihood that a patient will be infected with a resistant strain varies greatly. Rates of resistance are higher in most European countries, with the notable exception of the Netherlands and Germany, where accepted standards of practice strictly limit antibiotic usage, [222] especially among very young children, and are even higher in Korea, Hong Kong, and Thailand, where antibiotic usage is uncontrolled. [223] Pneumococci with low MICs for penicillin remain susceptible to most other antibiotics. In contrast, as resistance to penicillin increases, organisms are progressively more likely to exhibit resistance to other commonly used antibiotics [219] (Table 200-7). At present, in the United States, about 25% of all pneumococci are resistant to macrolides, 10% to clindamycin, 30% to trimethoprim-sulfamethoxazole, 18% to doxycycline, and 2% to the newer quinolones, [224] again varying with the site of isolation and the geographic region. One third of macrolide-resistant strains have erm(B) and are also resistant to clindamycin. In Europe, a higher proportion of pneumococci show some level of macrolide resistance, and erm(B) is
  25. 25. responsible in most isolates. Rates of resistance are lower in Canada than in the United States and higher in the Far East than in Europe. In general, more than 98% of isolates remain susceptible to fluoroquinolones, probably because these drugs are not used to treat children. In Canada, an increase in resistance has paralleled increased quinolone use [225] and, in high-usage locales, such as chest clinics [226] or nursing homes, [227] the rate of resistance may exceed 5%. Resistance to vancomycin, the oxazolidinones (linezolid), the ketolides (e.g., telithromycin and cethromycin), or the glycylcyclines (e.g., tigecycline) has not yet been documented. TABLE 200-7 -- Likelihood (%) of In Vivo Susceptibility of Pneumococcus to Antibiotic Indicated* Antibiotic Likelihood Penicillin (parenteral), ampicillin, piperacillin 93 [†] Amoxicillin 93 [†] Cefuroxime, cefpodoxime, cefdinir 85 [†] Cefotaxime, ceftriaxone, cefepime 97 [†] Imipenem, meropenem, ertapenem 95 Azithromycin, clarithromycin 85 [‡] Clindamycin 93 Telithromycin 100 Trimethoprim-sulfamethoxazole 65 Doxycycline 82 Vancomycin 100 Quinolones [?] 98 * When causing a non-CNS infection such as pneumonia (see text). This is my estimate of the likelihood (%) of a bacteriologic response during treatment with customary doses, based on numerous approximations discussed in the text, as well as by Musher and colleagues. 204 This is not the same as in vitro susceptibility, which is defined by a committee of the National Committee for Clinical and Laboratory Standards (NCCLS), nor is it the same as the likelihood of producing a curve in vivo, which depends in part on bacterial susceptibility but also on other factors, such as the status of the host and the severity of the infection.
  26. 26. † With high doses of these drugs, almost all pneumococci are expected to be susceptible. ‡ This number reflects a balance between the 25% rate of resistance in vitro and clinical experience, which has documented some failures but shows a generally high rate of response. At the time of this writing (November 2008), the precise relationship between in vitro resistance and in vivo failure is still uncertain. ? Quinolones = levofloxacin, moxifloxacin. Treatment The basic principles of treating pneumococcal infection are similar to those for treating other infections: (1) administer an antibiotic that provides a level sufficient to inhibit or kill the infecting organism; (2) continue treatment at least until the host is able to complete the curing and healing processes; (3) drain infections of closed spaces if necessary; (4) know what response to expect; and (5) be prepared to reevaluate if this response is not observed. These basic principles having been stated, the reader will discover that their application is by no means simple. A few selected factors include the following: (1) for most diseases caused by pneumococcus, when therapy is begun, the causative agent is unknown and, in many cases, no microbiologic studies will be done to reveal it; (2) even if S. pneumoniae is believed to be causative, antibiotic susceptibility is not known when treatment is begun; (3) for many common infections, the appropriate duration of therapy has not been established by scientific study; (4) in otitis media and sinusitis, the most common infections caused by S. pneumoniae, drainage is not usually done; and (5) many physicians do not clearly understand what response to expect after treatment has begun. OTITIS MEDIA In 1998, the Otitis Media Working Group of the Centers for Disease Control and Prevention [145] recommended amoxicillin, 30 mg/kg, three times daily, to treat children with otitis media. The group reasoned that (1) S. pneumoniae is the most common identifiable cause of this infection and the one associated with the greatest morbidity; (2) penicillin-susceptible and intermediately resistant pneumococci are likely to respond better to this treatment than to any other; and (3) no other oral therapy is likely to be more effective for resistant pneumococci. The American Academy of Pediatrics has subsequently recommended watchful waiting for children older than 2 years unless severe pain or high fever are present, [228] and these recommendations seem appropriate for adults, as well. Amoxicillin–clavulanic acid, a fluoroquinolone, or ceftriaxone can be used if amoxicillin alone fails. In the absence of a perforated tympanic membrane or some other complication, therapy need not be given for more than 5 days. [229] SINUSITIS Because the pathogenesis and causative organisms of acute sinusitis are essentially identical to those of otitis media, the same therapeutic considerations apply. Guidelines have been carefully crafted, and treatment has been related to antibiotic susceptibility patterns, as outlined earlier. [230] Once again, the physician is left with the essential problem of empirical therapy, not knowing whether S. pneumoniae is present or, if it is present, whether it is susceptible or resistant to the selected therapy. Amoxicillin is regarded as first-line therapy, with a likely beneficial effect in 80% to 90% of cases; amoxicillin–clavulanic acid, with a slightly higher likelihood of success because of efficacy against β-lactamase–producing H. influenzae, is the backup in cases of failure. [230] Unlike children, for whom quinolones have not been approved, adults can be treated with this class of drugs. Ceftriaxone is the fall-back
  27. 27. choice, and a failure after this antibiotic has been tried is likely to require referral to an otolaryngologist. PNEUMONIA Outpatient Therapy This section will generally be confined to the selection of therapy for pneumonia caused by S. pneumoniae because the broader question of treatment of pneumonia is covered in Chapter 64. Some redundancy is, however, necessary. In outpatients, an attempt is generally not made to establish an etiologic diagnosis; when such attempts are made, S. pneumoniae is the predominant agent, accounting for more than half of cases in which a bacterium is cultured and more than one third in which a diagnosis is made (or suspected) by bacteriologic or serologic means. The response generally appears to be excellent, irrespective of the therapy chosen; specifically, penicillins with or without β-lactamase inhibitors, macrolides, doxycycline, or a newer fluoroquinolone all seem to be equally effective,[177] although attention has been called to clinical failures when macrolides are used to treat outpatient pneumonia caused by macrolide-resistant pneumococci.[231] When patients are stratified by risk groups,[232] the mortality reported (without regard to cause) is negligible in most patients who do not require hospitalization. To treat outpatients for pneumonia, the Infectious Disease Society of America[233] recommends, in no particular order, the use of a macrolide, doxycycline, amoxicillin (with or without clavulanic acid), or a quinolone. There is no certainty of cure in infectious disease practice, and, in my opinion, the cautious physician would do well to try to make the correct diagnosis by microbiologic means. When this cannot be done, patients should be advised of this fact; the physician should keep in close touch with them for the first few days rather than feel content in having ―covered‖ them with empirical antibiotic therapy. Inpatient Therapy The importance of the decision to hospitalize or even to admit directly to intensive care cannot be overemphasized. Published guidelines[177] should generally be used, although not followed slavishly. Stratification in accord with recommendations by the Pneumonia Outcomes Research Team[232] should be used to help decide whether hospitalization is needed although, if the physician is in doubt, he or she should hospitalize the patient, at least for the initiation of therapy. The remainder of this section deals with selection of an antibiotic to treat pneumococcal pneumonia. Pneumococcal pneumonia caused by organisms that are susceptible or intermediately resistant to penicillin responds to treatment with penicillin, 1 million units IV every 4 hours, ampicillin, 1 g every 6 hours, or ceftriaxone, 1 g every 24 hours.[234] The principal concern is whether pneumonia caused by those relatively uncommon pneumococci that are resistant by present definitions responds to such therapy, and also whether the use of higher doses of β- lactam antibiotics or the addition of vancomycin or a fluoroquinolone in such instances seems appropriate. Patients who are treated for pneumococcal pneumonia with an effective antibiotic generally have substantially reduced fever and feel much better within 48 hours. Based on all the foregoing considerations, if a patient has responded to treatment with a β-lactam antibiotic, this therapy should be continued, even if the antibiotic susceptibility test shows that the causative organism is resistant. If, however, a clear response is not observed and the organism is resistant, therapy should be changed in accordance with susceptibility testing results. A large prospective study[235] has appeared to show that mortality from severe pneumococcal pneumonia is lower in patients who receive two antibiotics (usually a β-lactam
  28. 28. and a macrolide) than in those who receive only one (usually a β-lactam). The mortality in the monotherapy arm was excessively high by any standard, even by comparison with data from the early antibiotic era. The authors of that study proposed a role for the anti-inflammatory effect of the macrolide, which was most often the second antibiotic. A more recent prospective study[236] that compared a fluoroquinolone with or without the addition of ceftriaxone has shown no difference. I continue to treat pneumococcal pneumonia with a β-lactam antibiotic. The optimal duration of therapy for pneumococcal pneumonia is uncertain. Pneumococci are not readily detected in sputum microscopically by culture more than 24 hours after the administration of an effective antibiotic.[175] A small-scale study in the 1950s showed that a single dose of procaine penicillin, which maintains an effective antimicrobial level for as long as 24 hours, could cure otherwise healthy young adults of pneumococcal pneumonia. Experience obtained early in the antibiotic era showed that 5 to 7 days of therapy sufficed. Nevertheless, the tendency of the medical profession has been to prolong therapy and, in the absence of data to prove additional benefit, most physicians now treat pneumonia for 10 to 14 days. The inclination to prolong therapy entails the risk of emergence of antibiotic-resistant organisms and the onset of complications such as Clostridium difficile infection. Three to 5 days of close observation with parenteral therapy for pneumococcal pneumonia and a final few days of oral treatment, in all totaling 7 to 8 days and not exceeding 3 days after a febrile patient has defervesced (temperature lower than 99? F), may be the best approach. Failure of the patient to defervesce within 3 to 5 days should stimulate a review of the organism's antibiotic susceptibility, as well as a search for a loculated infection such as empyema. MENINGITIS Pneumococcal meningitis has been treated with 12 to 24 million units of penicillin every 24 hours or 1 to 2 g ceftriaxone every 12 hours. Either regimen is effective against antibiotic- susceptible S. pneumoniae; pharmacokinetic considerations and achievable CSF levels favor the use of ceftriaxone. During treatment of resistant strains, β-lactam antibiotics are likely not to achieve therapeutic levels in CSF. This explains why, until susceptibility results are reported, vancomycin is recommended along with the β-lactam antibiotic—the β-lactam because it crosses the blood-brain barrier more reliably and most isolates are susceptible, and the vancomycin because of its potential efficacy against β-lactam-resistant strains. In patients who have major penicillin and cephalosporin allergies, vancomycin can be used; in such cases, addition of a carbapenem should be considered. Some anecdotal reports have claimed a better outcome when rifampin is added to a β-lactam antibiotic in the treatment of pneumococcal meningitis. In experimental animals, the addition of rifampin to ceftriaxone [237] or vancomycin [238] has not been beneficial, except in the presence of concomitant glucocorticosteroid administration, which may diminish CNS penetration of the antibiotics. Our systematic study in vitro has shown indifference or antagonism when rifampin is added to β-lactam drugs. [239] Although some authorities [156] recommend that rifampin be added when steroids are given together with a third-generation cephalosporin, I believe that the available data do not justify this practice. A study in adults [240] has found, as had been previously shown in children, that addition of dexamethasone, 10 mg four times daily, leads to a distinctly better outcome in pneumococcal meningitis. I use this approach in my practice, although two more recent studies have not confirmed these results. Because of the possibility that steroids may diminish the penetration of antibiotics into the CNS, [241-243] patients receiving these agents should be observed particularly closely; repeat spinal taps may be needed to document abatement of CSF abnormalities, especially if there is any suggestion of a delayed clinical response. Steroid administration should not be continued beyond the recommended 4 days MISCELLANEOUS