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

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. †
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. 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. 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