Chapter 1

25
Streptococci and Enterococci

Scarlet fever awes me, and is above my aim.

I leave it to the professional and graduated
homicides.
—Sydney Smith, 1833

B
acteria of the genus Streptococcus are Gram-positive cocci typically arranged in
chains. In addition to relatively harmless members of the oropharyngeal flora, the
genus includes three of the most important pathogens of humans. The group A strep-
tococcus (S pyogenes) is the cause of “strep throat,” which can lead to scarlet fever, rheumatic
fever, and rheumatic heart disease; the ability of some strains to cause catastrophic deep
tissue infections led British tabloids to apply the gory label “flesh-eating bacteria.” The group B
streptococcus (S agalactiae) is the most common cause of sepsis in newborns and the pneu-
mococcus (S pneumoniae) a leading cause of both pneumonia and meningitis in persons
of all ages.

STREPTOCOCCI

Group Characteristics
Streptococci stain readily with common dyes, demonstrating that coccal cells are generally
smaller and more ovoid in shape than staphylococci. They are usually arranged in chains
with oval cells touching end to end, because they divide in one plane and tend to remain Oval cells arranged in chains end
attached (Figure 25–1). Length may vary from a single pair to continuous chains of over to end
30 cells, depending on the species and growth conditions. Medically important streptococci
are not acid-fast, do not form spores, and are nonmotile. Some members form capsules
composed of polysaccharide complexes or hyaluronic acid.
Streptococci grow best in enriched media under aerobic or anaerobic conditions (fac-
ultative). Sheep blood agar is preferred because it satisfies the growth requirements and β-Hemolysis is clear
also serves as an indicator for patterns of hemolysis. The colonies are small, ranging from
pinpoint size to 2 mm in diameter, and they may be surrounded by a zone where the eryth- α-Hemolysis shows greening of
rocytes suspended in agar have been hemolyzed. When the zone is clear, this state is called blood agar
a-hemolysis (Figure 25–2). When the zone is hazy with a green discoloration of the agar,
it is called `-hemolysis. Streptococci are metabolically active, attacking a variety of car- Catalase-negative
bohydrates, proteins, and amino acids. Glucose fermentation yields mostly lactic acid. In
contrast to staphylococci, streptococci are catalase-negative.

447
448 PART III Pathogenic Bacteria

FIGURE 25–1. Group A

streptococcus (GAS) Gram stain.
Note the oval cocci chaining end to end
(arrow). (Image contributed by Professor
Shirley Lowe, University of California,
San Francisco School of Medicine, with
permission.)

CLASSIFICATION
At the turn of the 20th century, a classification based on hemolysis and biochemical tests
was sufficient to associate some streptococcal species with infections in humans and ani-
mals. Rebecca Lancefield, who demonstrated carbohydrate antigens in cell wall extracts of
Lancefield antigens are cell wall the β-hemolytic streptococci, put this taxonomy on a sounder basis. Her studies formed a
carbohydrates classification by serogroups (eg, A, B, C), each of which is generally correlated with one of
the previously established species. Later it was discovered that some nonhemolytic strepto-
Presence of Lancefield antigens cocci had the same cell wall antigens. Over the years it has become clear that possession of
defines the pyogenic streptococci one of the Lancefield antigens defines a particularly virulent segment of the streptococcal
genus regardless of hemolytic patterns. These are called the pyogenic streptococci, and in
medical circles they are now better known by their Lancefield letter than the older species
name. Pediatricians instantly recognize GBS as an acronym for group B streptococcus, but
may be confused by use of the proper name, Streptococcus agalactiae (Table 25–1).
For practical purposes, the type of hemolysis and certain biochemical reactions remain
Hemolysis is a practical guide to valuable for the initial recognition and presumptive classification of streptococci, and as an
classification indication of what subsequent taxonomic tests to perform. Thus, β-hemolysis indicates that
the strain has one of the Lancefield group antigens, but some Lancefield-positive strains or
Only pyogenic streptococci are groups may be α-hemolytic or even nonhemolytic. The streptococci are considered here as
β-hemolytic follows: (1) pyogenic streptococci (Lancefield groups); (2) pneumococci; and (3) viridans
and other streptococci (Table 25–1).

MM Pyogenic Streptococci
Of the many Lancefield groups, the ones most frequently isolated from humans are A, B, C,
Groups A and B streptococci are F, and G. Of these, groups A (S pyogenes) and B (S agalactiae) are the most common causes
the most common causes of disease of serious disease. The group D carbohydrate is found in the genus Enterococcus, which
used to be classified among the streptococci.

MM Pneumococci
This category contains a single species, S pneumoniae, commonly called the pneumococcus. Its
distinctive feature is the presence of a capsule composed of polysaccharide polymers that vary

FIGURE 25–2. a-Hemolysis.

Colonies of group A streptococci
(GAS) on sheep blood agar plates are
surrounded by a zone of complete
clearing of the RBCs suspended in the
agar. (Reproduced with permission from
Nester EW: Microbiology: A Human
Perspective, 6th edition. 2009.)
 STREPTOCOCCI AND ENTEROCOCCI CHAPTER 25 449

TABLE 25–1 Classification of Streptococci and Enterococci

MAJOR ANTIGENS/STRUCTURES
COMMON LANCEFIELD SURFACE VIRULENCE
GROUP/SPECIES TERM HEMOLYSIS CELL WALL PROTEIN CAPSULE FACTORS DISEASE
Streptococci
Pyogenic
Streptococcus Group A strep β A M protein Hyaluronic acid M protein, Strep throat,
pyogenes (GAS) (100+) lipoteichoic impetigo, pyogenic
acid, StrepSAgs, infections,
streptolysin O, toxic shock,
streptokinase rheumatic fever,
glomerulonephritis
S agalactiae Group B strep β, – B – Sialic acid (9) Capsule Neonatal sepsis,
(GBS) meningitis, pyogenic
infections
S equi β C – – StrepSAg genes Pyogenic infections
S bovis –, α D – – – Pyogenic infections
Other species β, α, – E-W – – – Pyogenic infections
Pneumococcus
S pneumoniae Pneumococcus α – Choline- Polysaccharide Capsule, Pneumonia,
binding (90+) pneumolysin, meningitis, otitis
protein neuraminidase media, pyogenic
infections
Viridans and
Nonhemolytic
S sanguis α – – – – Low virulence,
endocarditis
S salivarius α Low virulence,
endocarditis
S mutans α – – Dental caries
Other species α, – – – – – Low virulence,
endocarditis
Enterococci
Enterococcus Enterococcus –, α D – – – Urinary tract,
faecalis pyogenic infections
E faecium Enterococcus –, α D – – – Urinary tract,
pyogenic infections
Other species –, α D, – – – – Urinary tract,
pyogenic infections

in antigenic specificity. More than 90 capsular immunotypes have been defined. Although the Pneumococci have an antigenic
pneumococcal cell wall shares some common antigens with other streptococci, it does not polysaccharide capsule
possess any of the Lancefield group antigens. Streptococcus pneumoniae is α-hemolytic.

MM Viridans and Other Streptococci

Viridans streptococci are α-hemolytic and lack both the group carbohydrate antigens of
the pyogenic streptococci and the capsular polysaccharides of the pneumococcus. The term
encompasses several species, including S salivarius and S mitis. Viridans streptococci are
members of the resident oral flora of humans. They rarely demonstrate invasive qualities. A Viridans and nonhemolytic species
variety of other streptococci may be encountered, which lack the features of the pyogenic lack Lancefield antigens or capsules
streptococci or pneumococci; these would be classified with the viridans group, except that
they are not α-hemolytic. Such strains are usually assigned descriptive terms such as non-
hemolytic streptococci or microaerophilic streptococci. They have been less thoroughly
studied, but generally have the same biologic behavior as the viridans streptococci.
450 PART III Pathogenic Bacteria

Group A Streptococci (Streptococcus pyogenes)

BACTERIOLOGY

MORPHOLOGY AND GROWTH

Group A streptococci (GAS) typically appear in purulent lesions or broth cultures as spher-
ical or ovoid cells in chains of short to medium length (4-10 cells). On blood agar plates,
colonies are usually compact, small, and surrounded by a 2 to 3 mm zone of β-hemolysis
Streptolysin O or S cause
(Figure 25–2), which is easily seen and sharply demarcated. β-Hemolysis is caused by either
β-hemolysis
of two hemolysins, streptolysin S and the oxygen-labile streptolysin O, both of which are
produced by most group A strains. Strains that lack streptolysin S are β-hemolytic only
Aerobically, only S is active
under anaerobic conditions, because the remaining streptolysin O is not active in the
presence of oxygen. This feature is of practical importance, because such strains would be
missed in clinical laboratories if cultures were incubated only aerobically.

STRUCTURE
The structure of GAS is illustrated in Figure 25–3. The cell wall is built on a peptidoglycan
matrix that provides rigidity, as in other Gram-positive bacteria. Within this matrix lies
Wall contains group antigen
the group carbohydrate antigen, which by definition is present in all GAS. A number of
with multiple surface molecules
other molecules such as M protein and lipoteichoic acid (LTA) are attached to the cell wall,
extending beyond
but extend beyond, often in association with, the hair-like pili. Group A streptococci are
divided into more than 100 serotypes based on antigenic differences in the M protein.

MM M Protein
The M protein itself is a fibrillar coiled-coil molecule (Figure 25–4) with structural homol-
Coiled-coil structure is similar to ogy to myosin. Its carboxy terminus is rooted in the peptidoglycan of the cell wall, and the
myosin amino-terminal regions extend out from the surface. The specificity of the multiple sero-
types of M protein is determined by variations in the amino sequence of the amino-terminal
portion of the molecule. Because of its exposed location, this part of the M protein is also

Epithelial cell
Surface
fibronectin
Protein F

M protein
Protein F Lipoteichoic acid

Pili Pilus
Hyaluronic acid Lipoteichoic acid
M protein
Peptidoglycan
Cell wall
Lancefield
carbohydrate

Cell membrane

FIGURE 25–3. Antigenic structure of GAS and adhesion to an epithelial cell. The
location of peptidoglycan and Lancefield carbohydrate antigens in the cell wall is shown in the
diagram. M protein and lipoteichoic acid are associated with the cell surface and the pili. Lipoteichoic
acid and protein F mediate binding to fibronectin on the host surface.
 STREPTOCOCCI AND ENTEROCOCCI CHAPTER 25 451

Variable

Rheumatogenic
epitopes

Conserved

Type 1 Type 2 Type 3 Type 4

FIGURE 25–4. M protein. The coiled-coil structure of M protein is shown for four hypothetical
serotypes. The most variable parts of the molecule are oriented to the outside and provide the
antiphagocytic effect and serologic specificity for each type. The conserved portions are rooted in
the cell wall and are homologous in structure. All four types contain epitopes that may stimulate the
cross-reactive immune reactions seen in rheumatic fever.

the most available to immune surveillance. The middle part of the molecule is less variable,
and some carboxy-terminal regions are conserved across many M types. There is increasing Antigenicity and function differ in
evidence that some of the many known biologic functions of M protein can be assigned to domains of the molecule
specific domains of the molecule. This includes both antigenicity and the capacity to bind
other molecules such as fibrinogen, serum factor H, and immunoglobulins. There are more 100+ M protein serotypes exist
than 100 immunotypes of M protein, which are the basis of a subtyping system for GAS.

MM Other Surface Molecules

A number of surface proteins have been described on the basis of their similarity with
M protein or some unique binding capacity. Of these, a fibronectin-binding protein F and
LTA are both exposed on the streptococcal surface (Figure 25–3) and play a role in patho- Protein F and LTA bind fibronectin
genesis. An IgG-binding protein has the capacity to bind the Fc portion of antibodies in
much the same way as staphylococcal protein A. In principle, this could interfere with opso- Hyaluronic acid capsule may be
nization by creating a covering of antibody molecules on the streptococcal surface that are present
facing the “wrong way.” Many GAS have a nonantigenic hyaluronic acid capsule. Although
this capsule has been shown to be antiphagocytic, its role in disease is clouded by the fact
that strains which lack it are still fully virulent.

EXTRACELLULAR PRODUCTS
MM Streptolysin O
Streptolysin O is a pore-forming cytotoxin, lysing leukocytes, tissue cells, and platelets. The Streptolysin O is pore-forming and
toxin inserts directly into the cell membrane of host cells, forming transmembrane pores in antigenic
452 PART III Pathogenic Bacteria

a manner similar to complement and staphylococcal α-toxin. Streptolysin O is antigenic,

and the quantitation of antibodies against it is the basis of a standard serologic test called
antistreptolysin O (ASO).

MM Streptococcal Superantigen Toxins

Just as with Staphylococcus aureus, approximately 10% of GAS produce one of a family
of exotoxins whose major biologic effect is through the superantigen (SAg) mechanism
(Figure 22–7). Over many decades, these toxins have been assigned a number of names
StrepSAgs are produced by some linked to their association with scarlet fever (erythrogenic toxin) and with streptococcal
strains toxic shock (streptococcal pyrogenic exotoxins [Spe]). As with S aureus, there are several
antigenically distinct proteins (SpeA, SpeB, and so on). Because the staphylococcal and
StrepSAgs and StaphSAgs are streptococcal SAgs have similar amino acid structure and biologic activity, in this book they
superantigens are called StaphSAgs and StrepSAgs. StrepSAgs have multiple effects, including fever, rash
(scarlet fever), T-cell proliferation, B-lymphocyte suppression, and heightened sensitivity
to endotoxin. Most of these actions are due to cytokine release through the superantigen
mechanism. At least one StrepSAg (SpeB) also has direct enzymatic activity digesting tissue
and extracellular matrix proteins.

MM Other Extracellular Products

Most strains of GAS produce a number of other extracellular products including streptoki-
C5a peptidase degrades nase, hyaluronidase, nucleases, and a C5a peptidase. The C5a peptidase is an enzyme that
complement degrades complement component C5a, the main factor that attracts phagocytes to sites of
complement deposition. The enzymatic actions of the others likely play some role in tissue
Streptokinase converts injury or spread, but no specific roles have been defined. Some are antigenic and have been
plasminogen to plasmin the basis of serologic tests. Streptokinase causes lysis of fibrin clots through conversion of
plasminogen in normal plasma to the protease plasmin.

GROUP A STREPTOCOCCAL DISEASE

CLINICAL CAPSULE

Group A streptococci are the cause of “strep throat,” an acute inflammation of the
pharynx and tonsils that includes fever and painful swallowing. Skin and soft tissue
infections range from the tiny skin pustules called impetigo to a severe toxic and
invasive disease that can be fatal in a matter of days. In addition to acute infections, GAS
are responsible for inflammatory diseases that are not direct infections but represent
states in which the immune response to streptococcal antigens causes injury to host
tissues. Acute rheumatic fever is a prolonged febrile inflammation of connective tissues,
which recurs after each subsequent streptococcal pharyngitis. Repeated episodes
cause permanent scarring of the heart valves. Acute glomerulonephritis is an insidious
disease with hypertension, hematuria, proteinuria, and edema due to inflammation of
the renal glomerulus.

EPIDEMIOLOGY
MM Pharyngitis
Group A streptococci are the most common bacterial cause of pharyngitis in school-
age children 5 to 15 years of age. Transmission is person-to-person from the large
Most common bacterial cause of droplets produced by infected persons during coughing, sneezing, or even conversation
sore throat (Figure 25–5). This droplet transmission is most efficient at the short distances (2-5 feet)
at which social interactions commonly take place in families and schools, particularly
in fall and winter months. Asymptomatic carriers (<1%) may also be the source of GAS,
 STREPTOCOCCI AND ENTEROCOCCI CHAPTER 25 453

Group A Streptococcus

Strep throat

Impetigo

Streptococcal
toxic shock
syndrome

Cellulitis

Group A Streptococci
Streptococcal
Superantigen toxin (StrepSAg)

FIGURE 25–5. GAS disease overview. The primary sources of infection are respiratory droplets
or direct contact with the skin. Impetigo results from minor trauma such as insect bites in skin transiently
colonized with GAS. In streptococcal toxic shock, StrepSAgs producing GAS in a superficial lesion
spread into the bloodstream. Note both toxin and bacteria are circulating.

particularly if colonized in the nose as well as the throat. Although GAS survive for some Droplets spread over short
time in dried secretions, environmental sources and fomites are not important means of distances from throat and nasal
spread. Unless the condition is treated, the organisms persist for 1 to 4 weeks after symp- sites
toms have disappeared.

MM Impetigo
Impetigo occurs when transient skin colonization with GAS is combined with minor trauma
such as insect bites. The tiny skin pustules are spread locally by scratching and to others Skin colonization plus trauma leads
by direct contact or shared fomites such as towels. Impetigo is most common in summer to impetigo
months when insects bite and when the general level of hygiene is low. The M protein types
of GAS most commonly associated with impetigo are different from those causing respira-
tory infection.

MM Wound and Puerperal Infections

Group A streptococci, once a leading cause of postoperative wound and puerperal infec-
tions, retain this potential, but the conditions favoring these diseases are now less common
in developed countries. As with staphylococci, transmission from patient-to-patient is by
454 PART III Pathogenic Bacteria

Hospital outbreaks are linked to the hands of physicians or other medical attendants who fail to follow recommended hand-
carriers washing practices. Organisms may be transferred from another patient or may come from
the healthcare workers themselves.

MM Streptococcal Toxic Shock Syndrome

Since the late 1980s, a severe invasive form of GAS soft tissue infection appeared with
increased frequency worldwide. Rapid progression to death in only a few days occurred in
STSS may be fatal in healthy previously healthy persons, including Muppet creator Jim Henson of Sesame Street fame.
persons The outstanding features of these infections are their multiorgan involvement, suggesting
a toxin and rapid invasiveness with spread to the bloodstream and distant organs. Soft-tissue
Strains produce StrepSAgs necrosis and streptococcal gangrenous myositis can rapidly ensure without the trauma
associated with clostridial gas gangrene (Chapter 29). The toxic features together with the
discovery that almost all the isolates produce StrepSAgs have caused this syndrome to be
labeled streptococcal toxic shock syndrome (STSS).

MM Poststreptococcal Sequelae
The association between GAS and the inflammatory disease acute rheumatic fever (ARF)
is based on epidemiologic studies linking GAS pharyngitis, the clinical features of rheu-
matic fever, and heightened immune responses to streptococcal products. ARF does not
ARF follows respiratory, not skin, follow skin or other nonrespiratory infection with GAS. Although some M types are more
infection “rheumatogenic,” it is not practical to define risk in advance. The general approach is that
recurrences of ARF can be triggered by infection with any GAS. Injury to the heart caused
Rheumatic heart disease is by recurrences of ARF leads to rheumatic heart disease, a major cause of heart disease
produced by recurrent ARF worldwide. Although ARF has declined in developed countries, resurgence in the form of
small regional outbreaks began in the late 1980s. These outbreaks involved children of a
higher socioeconomic status than that previously associated with ARF and a shift in preva-
lent M types. The underlying basis of the resurgence is unknown. In contrast, ARF is ram-
pant in many developing countries, particularly in Africa, the Middle East, India, and South
America.
Glomerulonephritis follows Poststreptococcal glomerulonephritis may follow either respiratory or cutaneous GAS
respiratory or skin infection infection and involves only certain “nephritogenic” strains. It is more common in temperate
climates where insect bites lead to impetigo. The average latent period between infection
Only nephritogenic strains are and glomerulonephritis is 10 days from a respiratory infection, but generally about 3 weeks
involved from a skin infection. Nephritogenic strains are limited to a few M types and seem to have
declined in recent years.

PATHOGENESIS
MM Acute Infections
As with other pathogens, adherence to mucosal surfaces is a crucial step in initiating dis-
Surface molecules binding to ease (Figure 25–6). Along with pili, a dozen specific adhesins have been described that
fibronectin is important first step facilitate the ability of the GAS to adhere to epithelial cells of the nasopharynx and/or skin.
Of these, the most important are M protein, LTA, and protein F. In the nasopharynx, all
M protein supports nasopharyngeal three appear to be involved in mediating attachment to the fatty acid binding sites in the
cell adherence glycoprotein fibronectin covering the epithelial cell surface. The role of M protein in the
pharynx is not direct, but it appears to function as an anchor for LTA, which is essential for
it to reach its binding site (Figure 25–3).
However, M protein appears to be direct and dominant in binding to the skin through
M protein and protein F are its ability to interact with subcorneal keratinocytes, the most numerous cell type in cutane-
involved in keratinocyte binding ous tissue. This adherence takes place at domains of the M protein that bind to receptors
on the keratinocyte surface. Protein F is also involved primarily in adherence to antigen-
Expression is environmentally presenting Langerhans cells. Expression of M protein and protein F is regulated in response
regulated to environmental conditions (O2, CO2), which could play a role in establishing the microbe
or in relation to the immune response.
Clinical evidence makes it clear that GAS have the capacity to be highly invasive. The
events following attachment that trigger invasion are only starting to be understood. It
appears that M protein, protein F, and other fibronectin-binding proteins are required for
 STREPTOCOCCI AND ENTEROCOCCI CHAPTER 25 455

FIGURE 25–6. GAS is shown

attaching to the cell membrane of a
human oral epithelial cell (E). Note the
hair-like pili (arrows), which mediate the
attachment. As in Figure 23–3, both
M protein and lipoteichoic acid are
associated with the pili. (Reproduced
with permission from Beachey EH,
Ofek I. J Exp Med 1976;143:764.)

the invasion of nonprofessional phagocytes. There is also evidence that StrepSAg genes are
linked to invasiveness. The invasion itself involves integrin receptors and is accompanied Multiple factors involved in invasion
by cytoskeleton rearrangements, but the molecular events do not yet make a coherent story.
After the initial events of attachment and invasion, the concerted activity of the M protein,
immunoglobulin-binding proteins, and the C5a peptidase play the key roles in allowing
the streptococcal infection to continue (Figure 25–7). M protein plays an essential role in Antiphagocytic M protein binds
GAS resistance to phagocytosis because of the ability of domains of the molecule to bind factor H
serum factor H. This leads to a diminished availability of alternative pathway-generated
complement component C3b for deposition on the streptococcal surface in the same man- Surface C3b deposition is
ner as polysaccharide capsules (Figure 22–4). In the presence of M type-specific antibody, diminished
classical pathway opsonophagocytosis proceeds, and the streptococci are rapidly killed.

Streptolysin O

Streptolysin O
Streptokinase

C5a peptidase

Hyaluronidase

PMNs

Bacteria

FIGURE 25–7. GAS disease, cellular view. The cellular events are similar to that of Staphylococcus
aureus (see Figure 24–4). Streptolysin O is a pore-forming toxin, and there are many extracellular
products. A difference is that although S aureus tends to be localized, GAS tend to spread diffusely,
as shown in the cell on the right. This may be due to hyaluronidase (spreading factor) or resistance
to phagocytosis. Below the cells, factor H binding is mediating GAS escaping the polymorphonuclear
neutrophils (PMNs).
456 PART III Pathogenic Bacteria

C5a peptidase blocks phagocyte As a second antiphagocytic mechanism, the C5a peptidase inactivates C5a and thus blocks
chemotaxis chemotaxis of polymorphonuclear neutrophils (PMNs) and other phagocytes to the site of
infection.
The precise role of other bacterial factors in the pathogenesis of acute infection is uncer-
tain, but the combined effect of streptokinase, DNAase, and hyaluronidase may prevent
Other virulence factors contribute effective localization of the infection, whereas the streptolysins produce tissue injury and
to spread and injury are toxic to phagocytic cells. Antibodies against these components are formed in the course
of streptococcal infection but are not known to be protective.
In STSS, as with staphylococcal toxic shock syndrome, the findings of shock, renal
impairment, coagulopathy, and rash seem to be explained by the massive cytokine release
Superantigenicity of StrepSAgs stimulated by the superantigenicity of the StrepSAgs. Exotoxin production, however, does
contributes to STSS not explain the enhanced invasiveness of GAS, which is an added feature of STSS compared
to its staphylococcal counterpart. Although the enzymatic activity of some StrepSAgs have
Invasive component is unexplained been linked to invasiveness, the underlying mechanisms are unclear. One theory is that
STSS may be due to the horizontal transfer of StrepSAg genes to GAS clones with enhanced
invasive potential, a deadly combination.

MM Poststreptococcal Sequelae
Acute Rheumatic Fever
Of the many theories advanced to explain the role of GAS in ARF, an autoimmune mech-
anism related to antigenic similarities between streptococci antigens and human tissues
ARF is an autoimmune state has the most experimental support. Streptococcal pharyngitis patients who develop ARF
induced by streptococcal infection have higher levels of antistreptococcal and autoreactive antibodies than those who do not.
Some of these antibodies have been shown to react with both heart tissue and streptococcal
antigens.
The antigen stimulating these antibodies is most probably M protein, but the group A
carbohydrate is also a possibility. There is similarity between the structure of regions of the
M protein and myosin, and M protein fragments have been shown to stimulate antibodies
that bind to human heart sarcolemma membranes, cardiac myosin, synovium, and articular
Antibodies react with sarcolemma,
cartilage. Acute rheumatic fever is a prime example of the molecular mimicry mechanism
myosin, synovium by molecular
of Type II autoimmune hypersensitivity (Chapter 2). Immunochemical studies of M protein
mimicry
are now directed at locating the epitopes in the large M protein molecule, which stimulate
protective antibody (anti-factor H binding sites) and those that stimulate anti-self antibod-
Cross-reactive and protective
ies. There is evidence these domains are in different locations in the M protein coiled coil
M protein domains differ
(Figure 25–4). If they can be separated, there is hope for an M protein-based vaccine that
does not cause the very disease (ARF) it is designed to prevent. A further complication
with this approach is establishing the consistency of these relationships among the many
M types.
Patients with ARF also show enhanced TH1 responses to streptococcal antigens. Cyto-
toxic T lymphocytes may be stimulated by M protein, and cytotoxic lymphocytes have
Cell-mediated immunity responses been observed in the blood of patients with ARF. A cellular reaction pattern consisting of
include cytotoxic lymphocytes lymphocytes and macrophages aggregated around fibrinoid deposits is found in human
hearts. This lesion, called the Aschoff body (Figure 25–8), is considered characteristic of
rheumatic carditis.
Genetic factors are probably also important in ARF because only a small percentage of
individuals infected with GAS develop the disease. Attack rates have been highest among
Alloantigens are associated with those of lower socioeconomic status and vary among those of different racial origins. The
hyperreactivity to streptococci gene for an alloantigen found on the surface of B lymphocytes occurs four to five times
more frequently in patients with rheumatic fever than in the general population. This fur-
ther suggests a genetic predisposition to hyperreactivity to streptococcal products.

Acute Glomerulonephritis
The renal injury of acute glomerulonephritis is caused by deposition in the glomerulus
Autoimmune reactions to of antigen–antibody complexes with complement activation and consequent inflamma-
M protein or streptokinase are tion. This is a type III hypersensitivity (Chapter 2). The M proteins of some nephritogenic
implicated strains have been shown to share antigenic determinants with glomeruli, which suggests an
autoimmune mechanism similar to rheumatic fever. Streptokinase has also been implicated
both through molecular mimicry and through its plasminogen activation capacity.
 STREPTOCOCCI AND ENTEROCOCCI CHAPTER 25 457

FIGURE 25–8. Aschoff nodule.

Reacting lymphocytes and large
mononuclear cells in myocardium
demonstrate a cellular component to
the immune reaction in rheumatic fever.
(Reproduced with permission from
Connor DH, Chandler FW, Schwartz
DQ, et al: Pathology of ­Infectious
Diseases. Stamford CT: Appleton &
Lange, 1997.)

IMMUNITY
It has long been known that an antibody directed against M protein is protective for subse-
quent GAS infections. This protection, however, is only for subsequent infection with strains
of the same M type. This is called type-specific immunity. This protective IgG is directed Type-specific IgG reverses
against factor H-binding epitopes in the amino-terminal regions of the molecule and antiphagocytic effect of M protein
reverses the antiphagocytic effect of M protein. Streptococci opsonized with type-specific
antibody bind complement C3b by the classical pathway, facilitating phagocyte recognition. Repeated infections and ARF are
There is evidence that mucosal IgA is also important in blocking adherence, whereas the due to many M types
IgG is able to protect against invasion. Unfortunately, because there are over 100 M types,
repeated infections with new M types occur. Eventually, immunity to the common M types is
acquired and infections become less common in adults. In ARF patients, it is the hyperreac-
tion seen in each episode that produces the lesions associated with rheumatic heart disease.

GROUP A STREPTOCOCCAL INFECTIONS:

CLINICAL ASPECTS

MANIFESTATIONS
MM Streptococcal Pharyngitis
Although it may occur at any age, streptococcal pharyngitis occurs most frequently between
the ages of 5 and 15 years. The illness is characterized by acute sore throat, malaise, fever, Sore throat, fever, malaise
and headache. Infection typically involves the tonsillar pillars, uvula, and soft palate, which
become red, swollen, and covered with a yellow-white exudate. The cervical lymph nodes Overlaps with viral pharyngitis
that drain this area may also become swollen and tender. This clinical syndrome overlaps
with viral pharyngitis taking place at the same age.
GAS pharyngitis is usually self-limiting. Typically, the fever is gone by the third to fifth
day, and other manifestations subside within 1 week. Occasionally, the infection spreads
locally to produce peritonsillar or retropharyngeal abscesses, otitis media, suppurative cervi- Spread beyond the pharynx now
cal adenitis, and acute sinusitis. Rarely, more extensive spread occurs, producing meningitis, uncommon
pneumonia, or bacteremia with metastatic infection in distant organs. In the preantibiotic
era, these suppurative complications were responsible for a mortality rate of 1% to 3% after
acute streptococcal pharyngitis. Such complications are much less common now, and fatal
infections are rare.

MM Impetigo
The primary lesion of streptococcal impetigo is a small (up to 1 cm) vesicle surrounded by
an area of erythema. The vesicle enlarges over a period of days, becomes pustular, and even-
tually breaks to form a yellow crust. The lesions usually appear in 2- to 5-year-old children Exposed skin of 2- to 5-year-old
on exposed body surfaces, typically the face and lower extremities. Multiple lesions may children
coalesce to form deeper ulcerated areas. Although S aureus produces a clinically distinct
bullous form of impetigo, it can also cause vesicular lesions resembling streptococcal impe- Tiny pustules may combine to form
tigo. Both pathogens are isolated from some cases. ulcers
458 PART III Pathogenic Bacteria

FIGURE 25–9. Streptococcal

erysipelas. The diffuse erythema and
swelling in the face of this woman are
characteristic of GAS cellulitis at any
site. (Reproduced with permission from
Connor DH, Chandler FW, Schwartz
DQ, et al: Pathology of ­Infectious
Diseases. Stamford CT: Appleton &
Lange, 1997.)

MM Erysipelas
Erysipelas is a distinct form of streptococcal infection of the skin and subcutaneous tis-
Spreading erythema of dermal sues, primarily affecting the dermis. It is characterized by a spreading area of erythema and
tissues edema with rapidly advancing, well-demarcated edges, pain, and systemic manifestations,
including fever and lymphadenopathy. Infection usually occurs on the face (Figure 25–9),
and a previous history of streptococcal sore throat is common.

MM Puerperal Infection
Infection of the endometrium at or near delivery is a life-threatening form of GAS infec-
GAS causes virulent form of tion. Fortunately, it is now relatively rare, but in the 19th century, the clinical findings of
puerperal fever “childbed fever” were characteristic and common enough to provide the first clues to the
transmission of bacterial infections in hospitals (Chapter 3). Other organisms can cause
puerperal fever, but this form is the most likely to produce a rapidly progressive infection.

MM Disease Associated with Streptococcal Superantigen Toxins

Scarlet Fever
Infection with strains that elaborate any of the StrepSAgs may superimpose the signs of
scarlet fever on a patient with streptococcal pharyngitis. In scarlet fever, the buccal mucosa,
temples, and cheeks are deep red, except for a pale area around the mouth and nose (cir-
Scarlet fever is strep throat with a cumoral pallor). Punctate hemorrhages appear on the hard and soft palates, and the tongue
characteristic rash becomes covered with a yellow-white exudate through which the red papillae are promi-
nent (strawberry tongue). A diffuse red “sandpaper” rash appears on the second day of ill-
ness, spreading from the upper chest to the trunk and extremities. Circulating antibody to
the toxin neutralizes these effects. For unknown reasons, scarlet fever is both less frequent
and less severe than early in the 20th century.

Streptococcal Toxic Shock Syndrome

Streptococcal toxic shock syndrome may begin at the site of any GAS infection even at the
site of seemingly minor trauma. The systemic illness starts with vague myalgia, chills, and
STSS is a rapidly progressive severe pain at the infected site. Most commonly, this is in the skin and soft tissues and leads
multisystem disease to necrotizing fasciitis and myonecrosis. The striking nature of this progression when it
involves the extremities is the basis of the label “flesh-eating bacteria.” STSS continues with
 STREPTOCOCCI AND ENTEROCOCCI CHAPTER 25 459

nausea, vomiting, and diarrhea followed by hypotension, shock, and organ failure. The out-
standing laboratory findings are a lymphocytosis; impaired renal function (azotemia); and, Shock, azotemia, and bacteremia
in over half the cases, bacteremia. Some patients are in irreversible shock by the time they are common
reach a medical facility. Many survivors have been left as multiple amputees as the result of
metastatic spread of the streptococci.

MM Poststreptococcal Sequelae
Acute Rheumatic Fever
Acute rheumatic fever is a nonsuppurative inflammatory disease characterized by fever, car-
ditis, subcutaneous nodules, chorea, and migratory polyarthritis. The diagnosis is based on
a set of primarily clinical findings (Jones Criteria) recommended by the American Heart Fever, carditis, nodules, and
Association. Evidence of a previous GAS infection is included in these criteria, but there is polyarthritis are clinical criteria
no test which is diagnostic of ARF. Cardiac enlargement, valvular murmurs, and effusions
are seen clinically and reflect endocardial, myocardial, and epicardial damage, which can No test is diagnostic
lead to heart failure. Attacks typically begin 3 weeks (range 1-5 weeks) after an attack of
GAS pharyngitis and, in the absence of antiinflammatory therapy, last 2 to 3 months.
ARF also has a predilection for recurrence with subsequent streptococcal infections as
new M types are encountered. The first attack usually occurs between the ages of 5 and New M types trigger recurrences
15 years. The risk of recurrent attacks after subsequent GAS infection continues into adult
life and then decreases. Repeated attacks lead to progressive damage to the endocardium Recurrences lead to rheumatic
and heart valves, with scarring and valvular stenosis or incompetence (rheumatic heart heart disease
disease).

Acute Glomerulonephritis
Poststreptococcal glomerulonephritis is primarily a disease of childhood that begins 1 to
4 weeks after streptococcal pharyngitis and 3 to 6 weeks after skin infection. It is character-
ized clinically by edema, hypertension, hematuria, proteinuria, and decreased serum com- Children develop a nephritis, which
plement levels. Pathologically, there are diffuse proliferative lesions of the glomeruli. The slowly resolves
clinical course is usually benign, with spontaneous healing over weeks to months. Occa-
sionally, a progressive course leads to renal failure and death.

DIAGNOSIS
Although the clinical features of streptococcal pharyngitis are fairly typical, there is
enough overlap with viral pharyngitis that a culture of the posterior pharynx and tonsils is
required for diagnosis. A direct Gram-stained smear of the throat is not helpful because of
the other streptococci in the pharyngeal flora. However, smears from normally sterile sites Throat culture followed by
usually demonstrate streptococci. Sheep blood agar plates incubated anaerobically give the Lancefield grouping is definitive
best yield because they favor the demonstration of β-hemolysis (see streptolysins earlier
in chapter). β-Hemolytic colonies are identified by Lancefield grouping using immuno- Bacitracin susceptibility predicts
fluorescence or agglutination methods. In smaller laboratories, an indirect method based group A
on the exquisite susceptibility of GAS to bacitracin and the relative resistance of strains of
other groups may be used for presumptive separation of group A strains from the others
(Table 25–2).
Detection of group A antigen extracted directly from throat swabs is now available in
a wide variety of kits marketed for use in physicians’ offices. These methods are rapid and
specific, but are at best only 90% sensitive compared with culture. Given the importance of Group A antigen test is rapid and
the detection of group A streptococci in the prevention of ARF (it is the reason physicians specific but not sensitive
culture sore throats), missing 10% or more of cases is not tolerable. Patients with a positive
direct antigen test may be treated without culture, but the American Academy of Pediat-
rics recommends that negative results must be confirmed by culture before withholding
treatment.
Several serologic tests have been developed to aid in the diagnosis of poststreptococcal
sequelae by providing evidence of a previous GAS infection. They include the ASO, anti- ASO antibodies document previous
DNAase B, and some tests that combine multiple antigens. High titers of ASO are usually infection in suspect ARF
found in sera of patients with rheumatic fever, so that test is used most widely.
460 PART III Pathogenic Bacteria

TABLE 25–2  sual Hemolytic, Biochemical, and Cultural Reactions of Common

U
Streptococci and Enterococcia
SUSCEPTIBILITY TO
BILE/
BILE ESCULIN
BACITRACIN OPTOCHIN SOLUBILITY REACTIONb PYR
Streptococci
β-Hemolytic
Lancefield group A + – – – +
 Lancefield groups B, – – – – –
C, F, G
α-Hemolytic
S pneumoniae – + + – –
Viridans group – – – – –
Nonhemolytic – – – – –
Enterococci – – – + +

PYR, pyrrolidonyl arylamidase test.

a
All are tests commonly substituted for serologic identification in clinical laboratories.
b
Tests for the ability to grow in bile and reduce esculin.

TREATMENT
Group A streptococci are highly susceptible to penicillin G, the antimicrobial of choice.
Concentrations as low as 0.01 μg/mL have a bactericidal effect, and penicillin resistance is
so far unknown. Numerous other antimicrobials are also active, including other β-lactams
GAS remain susceptible to and macrolides, but not aminoglycosides. Patients allergic to penicillin are usually treated
penicillin with erythromycin or azithromycin, and impetigo is often treated with erythromycin to
cover the prospect of S aureus involvement. Adequate treatment of streptococcal pharyn-
Treatment of pharyngitis within gitis within 10 days of onset prevents rheumatic fever by removing the antigenic stimulus;
10 days prevents ARF its effect on the duration of the pharyngitis is not dramatic because of the short course of
the natural infection. Treatment of the acute infection may not prevent the development of
acute glomerulonephritis.

PREVENTION
Penicillin prophylaxis with long-acting preparations is used to prevent recurrences of ARF
during the most susceptible ages (5-15 years). Patients with a history of rheumatic fever or
Prophylactic penicillin prevents ARF known rheumatic heart disease receive antimicrobial prophylaxis while undergoing pro-
recurrences cedures known to cause transient bacteremia, such as dental extraction. Multivalent vac-
cines using M protein epitopes that are not cross-reactive to self are in clinical trials with
encouraging results.

GROUP B STREPTOCOCCI (STREPTOCOCCUS AGALACTIAE)

BACTERIOLOGY

Group B streptococci (GBS) produce short chains and diplococcal pairs of spherical or
ovoid Gram-positive cells. Colonies are larger and β-hemolysis due to a pore-forming cyto-
Nine capsular types contain lysin (β-hemolysin) is less distinct than with GAS and may even be absent. In addition to
sialic acid the Lancefield B antigen, GBS produce polysaccharide capsules of nine antigenic types
(Ia, Ib, II–VIII), all of which contain sialic acid in the form of terminal side chain residues.
Pili and surface proteins are also present.
 STREPTOCOCCI AND ENTEROCOCCI CHAPTER 25 461

GROUP B STREPTOCOCCAL DISEASE

CLINICAL CAPSULE

The typical GBS case is a newborn in the first few days of life who is not doing well.
Fever, lethargy, poor feeding, and respiratory distress are the most common features.
Localizing findings are usually lacking, and the diagnosis is revealed only by isolation
of GBS from blood or cerebrospinal fluid. The mortality rate is high even when
appropriate antibiotics are used.

EPIDEMIOLOGY
Group B streptococci are the leading cause of sepsis and meningitis in the first few days of
life. The organism is resident in the gastrointestinal tract, with secondary spread to other
sites, the most important of which is the vagina. Group B streptococci can be found in the
lower gastrointestinal and vaginal flora of 10% to 40% of women. During pregnancy and Neonatal sepsis is acquired from
childbirth, these organisms may gain access to the amniotic fluid or colonize the newborn mother’s vaginal flora
as it passes through the birth canal (Figure 25–10). Group B streptococci produce disease
in approximately 2% of these encounters. The risk is much higher when factors are present Ruptured membranes and
that decrease the infant’s innate resistance (prematurity) or increase the chances of trans- prematurity increase risk
mission such as rupture of the amniotic membranes for 18 hours or more before delivery.
Some infants are healthy at birth but develop sepsis 1 to 3 months later. It is not known
whether the organism in these “late-onset” cases was acquired from the mother, in the nurs-
ery, or in the community after leaving the hospital.

Pneumococcus and GBS

Pneumococcal
pneumonia

Pneumococcal FIGURE 25–10. GBS and

GBS Neonatal
meningitis pneumococcal disease overview.
sepsis
Streptococcus pneumoniae is aspirated
from the normal orophyaryngeal
Vagina flora to the lung where it produces
pneumonia. Bacteremic spread can infect
other sites particularly the brain where
meningitis is produced. GBS vaginal
colonization during pregnancy leads to
Streptococcus pneumoniae (pneumococcus) infection of the fetus either in the uterus
Group B streptococcus (GBS) or during childbirth.
462 PART III Pathogenic Bacteria

PATHOGENESIS
Group B streptococci disease requires the proper combination of organism and host factors.
The GBS capsule is the major organism factor. For the initial stages of infection, pili and a
number of surface exposed proteins that attach to fibronectin and extracellular matrix pro-
Capsule binds factor H teins have been identified. The sialic acid moiety of the capsule has been shown to bind serum
factor H, which in turn accelerates degradation of C3b before it can be effectively deposited on
C3b deposition is disrupted the surface of the organism. This makes alternative pathway-mediated mechanisms of opso-
nophagocytosis relatively ineffective (Figure 22–4). Thus, complement-mediated phagocyte
Transplacental IgG is protective recognition requires specific antibody and the classical pathway. Newborns have this antibody
only if they receive it from their mother as transplacental IgG. Those who lack the protective
“cover” of antibody specific to the type of GBS they encounter must rely on alternative path-
way mechanisms, a situation in which the GBS has an advantage over less virulent organisms.
Group B streptococci have also been shown to produce a peptidase that inactivates C5a, the
major chemoattractant of PMNs (polymorphonuclear leukocytes). This may correlate with
the observation that serious neonatal infections often show a paucity of infiltrating PMNs.
The pore-forming cytolysin may contribute to tissue-destructive elements of invasive disease.

IMMUNITY
Antibody is protective against GBS disease, but as with group A streptococcal M protein,
the antibody must be specific to the infecting type of GBS. Fortunately, there are only nine
Type-specific anticapsular antibody types, and type III produces the majority of early and late-onset cases. Antibody is acquired
is protective by GBS infection, and specific IgG may be transmitted transplacentally to the fetus, provid-
ing protection in the perinatal period. In the presence of type-specific antibody, classical
pathway C3b deposition, phagocyte recognition, and killing proceed normally.

GROUP B STREPTOCOCCI: CLINICAL ASPECTS

MANIFESTATIONS
The clinical findings of poor feeding, irritability, lethargy, jaundice, respiratory distress, and
Nonspecific findings evolve to hypotension are nonspecific and similar to those found in other serious infections in the
pneumonia and meningitis neonatal period. Fever is sometimes absent, and infants may even be hypothermic. Pneumo-
nia is common, and meningitis is present in 5% to 10% of cases. Most infections have GBS
Disease onset is early (first circulating in the bloodstream without localizing findings. The disease onset is typically in
few days) or late (1-3 months) the first few days of life, and signs of infection are present at birth in almost 50% of cases.
The late-onset (1-3 month) cases have similar findings, but are more likely to have meningitis
and focal infections in the bones and joints. Even with increased awareness and improved
supportive therapy, the mortality rate for early-onset GBS infection still approaches 10%.
Group B streptococci infections in adults are uncommon and fall into two groups. The
first group comprises peripartum chorioamnionitis and bacteremia, the mother’s side of
Maternal and other adult infections the neonatal syndrome. Other infections include pneumonia and a variety of skin and soft
can be serious tissue infections similar to those produced by other pyogenic streptococci. Although adult
GBS infections may be serious, they are usually not fatal unless patients are immunocom-
promised. Group B streptococci infections are not associated with rheumatic fever or acute
glomerulonephritis.

DIAGNOSIS
The laboratory diagnosis of GBS infection is by culture of blood, cerebrospinal fluid, or
other appropriate specimen. Definitive identification involves serologic determination of
Specialized culture required to the Lancefield group by the same methods used for GAS. Maximal detection of vaginal col-
detect vaginal colonization onization in pregnant women requires procedures utilizing selective media and enrichment
broths. These must be separately established in the laboratory, since they are used for no
other purpose. Methods for direct detection of GBS antigen in vaginal specimens have been
evaluated, but their sensitivity is far too low for use in the diagnosis of neonatal infection.
 STREPTOCOCCI AND ENTEROCOCCI CHAPTER 25 463

TREATMENT
Group B streptococci are susceptible to the same antimicrobials as group A organisms. Penicil-
lin is the treatment of choice and there is no known resistance to β-lactam agents. However, in Penicillin is primary antibiotic
the initial stage, neonatal infections are often initially treated with combinations of penicillin
(or ampicillin) and an aminoglycoside because of known synergism and the possibility of other
bacterial agents. Once GBS is confirmed, therapy can be completed with penicillin alone.

PREVENTION
Strategies for the prevention of neonatal GBS disease are focused on reducing contact of
the newborn with the organism. In colonized women, attempts to eradicate the carrier state
have not been successful, but intrapartum (during labor) antimicrobial prophylaxis with
intravenous penicillin has been shown to reduce transmission and disease. It is now rec-
ommended by expert obstetric and perinatology groups that all newborns at risk receive
such prophylaxis. Risk is defined by the presence of vaginal or rectal GBS in a culture taken Intrapartum IV penicillin
during the third trimester (35-37 weeks). Thus, all expectant mothers must be screened by prophylaxis is protective
selective culture (see Diagnosis) and intrapartum prophylaxis administered to all found
culture-positive. An alternative risk-based approach (eg, prematurity, prolonged membrane Third-trimester culture
rupture, and fever) is easier for obstetricians to apply, but has now been discarded as much determines risk
less effective in preventing GBS disease. Implementation of these screening and prophylaxis
procedures was followed by a dramatic decrease (>70%) in neonatal early-onset GBS dis-
ease. For women who present in labor without culture results, a risk-based assessment is all
that can be used to decide whether to administer prophylaxis. Prevention by immunization
with purified GBS capsular polysaccharide has been shown to be feasible, and considerable
effort is now being directed at the development of a vaccine.

Other Pyogenic Streptococci

The other pyogenic streptococci occasionally produce various respiratory, skin, wound, soft
tissue, and genital infections, which may resemble those caused by group A and B strep-
All are virulent but uncommon
tococci. Although a few foodborne outbreaks of pharyngitis have been linked to groups
C and G streptococci, their role as a cause of everyday sore throats is not established. These
None associated with immunologic
streptococci are susceptible to penicillin, and infections are managed in a manner similar to
sequelae
that with deep tissue infections caused by group A and B strains. None of the non-group A
pyogenic streptococci have been associated with poststreptococcal sequelae.

Streptococcus pneumoniae

BACTERIOLOGY

Streptococcus pneumoniae (pneumococci) are Gram-positive, oval cocci typically arranged

end to end in pairs (diplococcus), giving the cells a bullet shape (Figure 25–11). On blood
agar, pneumococci produce round, glistening 0.5 to 2.0 mm colonies surrounded by a zone
of α-hemolysis. Both colonies and broth cultures have a tendency to undergo autolysis Colonies are α-hemolytic
because of their susceptibility to peroxides produced during growth and the action of auto-
lysins, a family of pneumococcal enzymes that degrade peptidoglycan. Accelerating the
autolytic process with bile salts is the basis of the bile solubility test that separates pneumo-
cocci from other α-hemolytic streptococci.
The distinguishing structural feature of the pneumococcus is its capsule (Figure 25-12).
All virulent strains have surface capsules, composed of high-molecular-weight polysaccharide
polymers that are complex mixtures of monosaccharides, oligosaccharides, and sometimes Capsule has 90+ serotypes
other components. The exact makeup of the polymer is unique and distinctly antigenic for each
of more than 90 serotypes. Pneumococcal cell wall structure is similar to that of other strepto- Choline-binding proteins attach
cocci, and a variety of surface proteins are rooted in the peptidoglycan extending outward into to cells
the capsule. One group of these, the choline-binding proteins, is able to bind to both pneu-
mococcal cell wall cholines and carbohydrates that are present on the surface of epithelial cells.
464 PART III Pathogenic Bacteria

FIGURE 25–11. Streptococcus

pneumoniae in sputum of patient with
pneumonia. Note the marked tendency
to form oval diplococci (arrows). The
clear halos around the pairs a due to
the capsule which does not stain by
the Gram method. (Image contributed
by Professor Shirley Lowe, University
of California, San Francisco School of
Medicine, with permission.)

EXTRACELLULAR PRODUCTS
All pneumococci produce pneumolysin, which is a member of the family of transmem-
brane pore-forming toxins that includes staphylococcal α toxin, S pyogenes streptolysin
O, and others. The pneumococcus does not secrete pneumolysin, but it is released on lysis of
Pneumolysin forms pores after
the organisms augmented by autolysins. Pneumolysin has a number of other effects, includ-
release by autolysins
ing its ability to stimulate cytokines and disrupt the cilia of human respiratory epithelial cells.
Pneumococci also produce a neuraminidase, which cleaves sialic acid that is present in host
mucin, glycolipids, and glycoproteins.

PNEUMOCOCCAL DISEASE

CLINICAL CAPSULE

The most common form of infection with Streptococcus pneumoniae is pneumonia,

which begins with fever and a shaking chill followed by signs that localize the disease
to the lung. These include difficulty breathing and cough with production of purulent
sputum, sometimes containing blood. The pneumonia typically fills part or all of a lobe
of the lung with inflammatory cells, and the bacteria may spread to the bloodstream
and thus other organs. The most important of the latter is the central nervous system,
where seeding with pneumococci leads to acute purulent meningitis. Pneumococci are
also a leading cause of otitis media the “hot ear” of childhood.

Bacterium
FIGURE 25–12. Pneumococcal
capsule. In this test, live Streptococcus
pneumoniae have been mixed with Swollen capsule
antibody specific to the capsular
polysaccharide. The opsonizing
antibody defines the capsule, which
appears “swollen” when compared
with preparations without antibody.
(Reproduced with permission from
Willey JM: Prescott, Harley, & Klein’s
Microbiology, 7th edition. McGraw-Hill,
2008.)
 STREPTOCOCCI AND ENTEROCOCCI CHAPTER 25 465

EPIDEMIOLOGY
Streptococcus pneumoniae is a leading cause of pneumonia, acute purulent meningitis, bac-
teremia, and other invasive infections. In the United States, it is responsible for an estimated
3000 cases of meningitis, 50 000 cases of bacteremia, and 500 000 cases of pneumonia each
Pneumonia is common
year. Worldwide, more than 5 million children die every year from pneumococcal disease.
Streptococcus pneumoniae is also the most common cause of otitis media, a virtually univer-
Young and old are most affected
sal disease of childhood with millions of cases every year. Pneumococcal infections occur
throughout life, but are most common in the very young (<2 years) and in the elderly
(>60 years). Alcoholism, diabetes mellitus, chronic renal disease, asplenia, and some malig-
nancies are associated with more frequent and serious pneumococcal infection.
Infections are derived from colonization of the nasopharynx, where pneumococci can be
Respiratory colonization is
found in 5% to 40% of healthy persons depending on age, season, and other factors. The
common
highest rates are among children in the winter. Respiratory secretions containing pneumo-
cocci may be transmitted from person-to-person by direct contact or from the microaerosols
Microaerosols transmit person-to-
created by coughing and sneezing in close quarters. Such conditions are favored by crowded
person
living conditions, particularly when colonized persons are mixed with susceptible ones, as in
child care centers, recruitment barracks, and prisons. As with other bacterial pneumonias,
viral respiratory infection and underlying chronic disease are important predisposing factors.
Surveillance data show that just over 20 of the 90 pneumococcal serotypes produce dis-
ease more often than the others. There is also a variation among types in the age and geo-
graphic distribution of cases. These differences are presumably due to enhanced virulence Some serotypes are more common
factors in these types, but the specific reasons are not known. These features do not influ-
ence the medical management of individual cases but are important in devising prevention
strategies such as immunization (see following text).

PATHOGENESIS
Pneumococcal adherence to nasopharyngeal cells involves multiple factors. The primary
relationship is the bridging effect of the choline-binding proteins’ attachment to cell wall
cholines and carbohydrates covering or exposed on the surface of host epithelial cells. This
binding may be aided by the exposure of additional receptors by neuraminidase digestion,
viral infection, or pneumolysin-stimulated cytokine activation of host cells. Aspiration of Aspiration of colonizing bacteria
respiratory secretions containing these pneumococci is the initial step leading to pneu- starts the disease process
monia (Figure 25–13). This must be a common event. Normally, aspirated organisms are
cleared rapidly by the defense mechanisms of the lower respiratory tract, including the Impaired clearance mechanisms
cough and epiglottic reflexes; the mucociliary “blanket”; and phagocytosis by alveolar mac- enhance susceptibility
rophages. Host factors that impair the combined efficiency of these defenses allow pneu-
mococci to reach the alveoli and multiply there. These include chronic pulmonary diseases;
damage to bronchial epithelium from smoking or air pollution; and respiratory dysfunction
from alcoholic intoxication, narcotics, anesthesia, and trauma.
When organisms reach the alveolus, pneumococcal virulence factors operate in two
stages. The first stage is early in infection, when the capsule and some surface proteins
of intact organisms act to block phagocytosis. This allows the organisms to multiply and

FIGURE 25–13. Pneumococcal

pneumonia. In this histologic view
of infected lung, note that the alveoli
are filled with neutrophils. Also note
that the alveolar septa are relatively
intact despite the high level of cellular
infiltrate. The stain used here does not
demonstrate the pneumococci, which
would be much smaller than the cells at
this magnification.
466 PART III Pathogenic Bacteria

Capsule interferes with spread despite an acute inflammatory response. The second stage occurs when organisms
phagocytosis begin to disintegrate and release a number of factors either synthesized by the pneumococ-
cus or part of its structure, thus causing injury. These include pneumolysin, autolysin, and
Pneumolysin causes injury components of the cell wall.

MM Capsule
The polysaccharide capsule of S pneumoniae is the major determinant of virulence. Unen-
capsulated mutants do not produce disease in humans or laboratory animals. Like the GBS
Unencapsulated pneumococci are capsule, pneumococcal polysaccharide interferes with effective deposition of complement
avirulent on the organism’s surface and thus phagocyte recognition and engulfment. This property is
particularly important in the absence of specific antibody, when alternative pathway is the
Alternate pathway C3b deposition primary means for C3b-mediated opsonization. In addition to the capsule, some of the sur-
blocked by capsule face choline-binding proteins may participate in this antiphagocytic effect by binding the
serum factor H. When antibody specific to the capsular polysaccharide appears, classical
pathway opsonophagocytosis proceeds efficiently.

MM Pneumolysin
Some of the clinical features seen in the course of pneumococcal infections are not explain-
able by the capsule alone. These include the dramatic abrupt onset, toxicity, fulminant
Pneumolysin disrupts cells and cilia
course, and disseminated intravascular coagulation seen in some cases. Pneumolysin’s toxic-
ity for pulmonary endothelial cells and direct effect on cilia contributes to the disruption of
Lysis required to release from
the endothelial barrier and facilitates the access of pneumococci to the alveoli and eventually
bacterial cell
their spread beyond into the bloodstream. Pneumolysin also has direct effects on phago-
cytes and suppresses host inflammatory and immune functions. Because pneumolysin is not
actively secreted outside the bacterial cell, the action of the autolysins is required to release it.
The combined effects of pneumococcal and host factors produce a pneumonia, which
PMNs and red blood cells progresses through a series of stages. Initial alveolar multiplication produces a profuse out-
consolidate alveoli pouring of serous edema fluid, which is then followed by an influx of PMNs and erythrocytes
(Figure 25–13). By the second or third day of illness, the lung segment has increased three-
Lesions resolve without structural to fourfold in weight through accumulation of this cellular, hemorrhagic fluid typically in a
damage single lobe of the lung. In the consolidated alveoli, neutrophils predominate initially, but once
actively growing, pneumococci are no longer present, macrophages replace the granulocytes,
and resolution of the lesion ensues. A remarkable feature of pneumococcal pneumonia is the
lack of structural damage to the lung, which usually leads to complete resolution on recovery.

IMMUNITY
Immunity to S pneumoniae infection is provided by antibody directed against the specific
Immunity is specific to capsular pneumococcal capsular type. When antibody binds to the capsular surface, C3b is deposited
type by classical pathway mechanisms, and phagocytosis can proceed. Because the number of
serotypes is large, complete immunity through natural experience is not realistic, which is
Antibody leads to classical pathway why pneumococcal infections occur throughout life. Infections are most often seen in the
complement deposition very young, when immunologic experience is minimal, and in the elderly, when immunity
begins to wane and risk factors are more common. Recently, experience with pneumococ-
Capsule switching changes capsule cal vaccines has unmasked a phenomenon called capsule switching in which the antigenic
antigenicity makeup of the capsule changes. This is felt to be due to in vivo transformation and recom-
bination with external DNA. We should not be too surprised at this since the discovery of
DNA as the keeper of the genetic code was through experiments transforming pneumococci.

PNEUMOCOCCAL DISEASE: CLINICAL ASPECTS

MANIFESTATIONS
MM Pneumococcal Pneumonia
Pneumococcal pneumonia begins abruptly with a shaking chill and high fever. Cough with
production of sputum pink to rusty in color (indicating the presence of red blood cells), and
pleuritic chest pain are common. Physical findings usually indicate pulmonary consolidation.
 STREPTOCOCCI AND ENTEROCOCCI CHAPTER 25 467

Children and young adults typically demonstrate a lobular or lobar consolidation on chest Shaking chill is followed by bloody
radiography, whereas older patients may show a less localized bronchial distribution of the sputum
infiltrates. Without therapy, sustained fever, pleuritic pain, and productive cough continue
until a “crisis” occurs 5 to 10 days after onset of the disease. The crisis involves a sudden Lung consolidation is typically lobar
decrease in temperature and improvement in the patient’s condition. It is associated with
effective levels of opsonizing antibody reaching the lesion. Although infection may occur
at any age, the incidence and mortality of pneumococcal pneumonia increase sharply after
50 years.

MM Pneumococcal Meningitis
Streptococcus pneumoniae is one of the three leading causes of acute bacterial meningitis.
The signs and symptoms are similar to those produced by other bacteria. Acute purulent
meningitis may follow pneumococcal pneumonia or infection at another site or may appear Sequelae are slightly higher than
with no apparent antecedent infection. It may also develop after trauma involving the skull. other meningeal pathogens
The mortality and frequency of sequelae are slightly higher with pneumococcal meningitis
than with other forms of pyogenic meningitis.

MM Other Infections
Pneumococci are common causes of sinusitis and otitis media. The latter frequently occurs
in children in association with viral infection. Chronic infection of the mastoid or respi-
ratory sinus sometimes extends to the subarachnoid space to cause meningitis. Pneumo-
cocci may also cause endocarditis, arthritis, and peritonitis, usually in association with Sinusitis and otitis media are
bacteremia. Patients with ascites caused by diseases such as cirrhosis and nephritis may common
develop spontaneous pneumococcal peritonitis. Pneumococci do not cause pharyngitis or
tonsillitis.

DIAGNOSIS
Gram smears of material from sputum and other sites of pneumococcal infection typically
show Gram-positive, lancet-shaped diplococci (Figure 25–11). Sputum collection may be Sputum quality complicates
difficult, however, and specimens contaminated with respiratory flora are useless for diag- diagnosis
nosis. Other types of lower respiratory specimens may be needed for diagnosis. Streptococ-
cus pneumoniae grows well overnight on blood agar medium and is usually distinguished Optochin or bile solubility
from viridans streptococci by susceptibility to the synthetic chemical ethylhydrocupreine distinguish from viridans
(optochin) or by a bile solubility (Table 25–2). Bacteremia is common in pneumococcal streptococci
pneumonia and meningitis, and blood cultures are valuable supplements to cultures of local
fluids or exudates. Detection of pneumococcal capsular antigen in body fluids is possible
but valuable primarily when cultures are negative.

TREATMENT
For decades pneumococci were uniformly susceptible to penicillin at concentrations lower
than 0.1 μg/mL. In the late 1960s, this began to change, and strains with decreased suscep-
tibility to all β-lactams began to emerge. These strains have penicillin minimal inhibitory
concentrations (MICs) of 0.12 to 8.0 μg/mL and are associated with treatment failures in
cases of pneumonia and meningitis. The resistance is not absolute and can be overcome Altered transpeptidases decrease
with increased dosage, depending on the MIC and the site of infection. The mechanism penicillin susceptibility
involves alterations in the β-lactam target, the transpeptidase penicillin-binding proteins
(PBPs) that cross-link peptidoglycan in cell wall synthesis. Resistant strains have mutations
in one or more of these transpeptidases, which cause decreased affinity for penicillin and
other β-lactams. Penicillinase is not produced. Resistance rates now exceed 10% in most
locales and may be greater than 40% in some areas. Resistance to erythromycin is increas-
ing and is more likely with penicillin-resistant strains.
Antibiotic selection differs with the site of the infection and whether it is to be carried out
in an inpatient or outpatient setting. Penicillin is still effective for susceptible strains, but the
uncertainty has caused a shift toward third-generation cephalosporins (ceftriaxone, cefo-
taxime) for primary treatment. Even though penicillin-resistant strains also have decreased
468 PART III Pathogenic Bacteria

susceptibility to cephalosporins, the pharmacologic features of these agents make it easier to

achieve blood levels higher than the MIC. Penicillin-resistant strains (MIC > 2.0 µg/mL)
for patients without meningitis are treated with fluoroquinolones, clindamycin, or an active
third-generation cephalosporin. Patients with meningitis caused by pneumococci with a
Pneumococcal resistance criteria penicillin MIC > 0.06 µg/mL require high doses of an active third-generation cephalosporin
are different for meningitis and plus vancomycin unless the cephalosporin MIC is ≤ 0.5 µg/mL. The therapeutic response
nonmeningitis isolates to treatment of pneumococcal pneumonia is often dramatic. Reduction in fever, respiratory
rate, and cough can occur in 12 to 24 hours but may occur gradually over several days. Chest
radiography may yield normal results only after several weeks.

PREVENTION
Two pneumococcal vaccines prepared from capsular polysaccharide are now available. The
first pneumococcal polysaccharide vaccine (PPV), available since 1977, contains purified
polysaccharide extracted from the 23 serotypes of S pneumoniae most commonly isolated
from invasive disease. It shares the T-cell-independent characteristics of other polysaccha-
ride immunogens and is recommended for use only in those older than 2 years. In 2000,
23-valent PPV is T-cell independent
a pneumococcal conjugate vaccine (PCV) was introduced in which polysaccharide was
conjugated with protein. This vaccine stimulates T-dependent TH2 responses and is effec-
13-valent PCV stimulates TH2 in
tive beginning at 2 months of age. In 2010 the original 7-valent vaccine was replaced by
children
a 13-valent (PCV13) conjugate vaccine and is the standard for childhood immunization.
Because of its broader coverage, the 23-valent PPV is recommended after age 2 except for
immunocompromised children under 5, who should still receive PCV. The phenomenon
of capsule switching (see Immunity above) is of concern as a mechanism for evading these
vaccines. That is, a significant antigenic change in any of the serotypes covered by either
vaccine could be the basis of failure to protect.

MM Viridans and Nonhemolytic Streptococci

The viridans group comprises all α-hemolytic streptococci that remain after the criteria
for defining pyogenic streptococci and pneumococci have been applied. Characteristically
members of the resident flora of the oral and nasopharyngeal cavities, they have the basic
Most α-hemolytic species are bacteriologic features of streptococci but lack the specific antigens, toxins, and virulence of
normal respiratory flora the other groups. Although the viridans group includes many species (Table 25–2), they are
usually not completely identified in clinical practice because there is little difference among
them in medical significance.
Although their virulence is very low, viridans strains can cause disease when they are
protected from host defenses. The prime example is subacute bacterial endocarditis. In this
disease, viridans streptococci reach previously damaged heart valves as a result of transient
bacteremia associated with manipulations, such as tooth extraction, which disturb their
Low-virulence species may cause usual habitat. Protected by fibrin and platelets, they multiply on the valve, causing local and
bacterial endocarditis systemic disease that is fatal if untreated. Extracellular production of glucans, complex poly-
saccharide polymers, may enhance their attachment to cardiac valves in a manner similar to
Glucan production enhances the pathogenesis of dental caries by S mutans (see Chapter 41). The clinical course of viridans
attachment streptococcal endocarditis is subacute, with slow progression over weeks or months. It is
effectively treated with penicillin, but uniformly fatal if untreated. The disease is particularly
associated with valves damaged by recurrent rheumatic fever. The decline in the occurrence
of rheumatic heart disease has reduced the incidence of this particular type of endocarditis.

ENTEROCOCCI

BACTERIOLOGY
Former streptococci possess
Until genomic studies dictated their separation into the genus Enterococcus, the entero-
group D antigen
cocci were classified as streptococci. Indeed, the most common enterococcal species share
 STREPTOCOCCI AND ENTEROCOCCI CHAPTER 25 469

the bacteriologic characteristics previously described for pyogenic streptococci, including

presence of the Lancefield group D antigen. The term “enterococcus” derives from their
presence in the intestinal tract and the many biochemical and cultural features that reflect
that habitat. These include the ability to grow in the presence of high concentrations of bile Intestinal inhabitants resist action
salts and sodium chloride. Most enterococci produce nonhemolytic or α-hemolytic colo- of bile salts
nies that are larger than those of most streptococci. A dozen species are recognized based
on biochemical and cultural reactions (Table 25–2) of which Enterococcus faecalis and E
faecium are the most common.

ENTEROCOCCAL DISEASE

CLINICAL CAPSULE

Enterococci cause infection almost exclusively in hospitalized patients with trauma,

abdominal surgery, or compromised defenses.The primary sites are the urinary tract and
soft tissue sites adjacent to the intestinal flora where enterococcal species are resident.
The infections themselves are often low grade and have no unique clinical features.

EPIDEMIOLOGY
Enterococci are part of the resident intestinal flora. Although they are capable of produc-
ing disease in many settings, the hospital environment is where a substantial increase has
occurred in the last two decades. Patients with extensive abdominal surgery, transplan-
tation, or indwelling devices or those who are undergoing procedures such as peritoneal Endogenous infection is associated
dialysis are at greatest risk. Prolonged hospital stays and prior antimicrobial therapy, par- with medical procedures
ticularly with vancomycin, cephalosporins, or aminoglycosides, are also risk factors. Most
infections are acquired from the endogenous flora but spread between patients has been
documented. From 10% to 15% of all nosocomial urinary tract, intra-abdominal, and
bloodstream infections are due to enterococci.

PATHOGENESIS
Enterococci are a significant cause of disease in specialized hospital settings, but they are
not highly virulent. On their own, they do not produce fulminant disease and in wound
and soft tissue infections are usually mixed with other members of the intestinal flora.
Virulence factors unknown
Some have even doubted their significance when isolated together with more virulent
members of the Enterobacteriaceae or Bacteroides fragilis. Enterococcus faecalis has been
Persist in the face of stress
shown to form biofilms sticking to medical devices and possess surface proteins adherent
to urinary epithelium but as a whole classical virulence factors are lacking. More than
anything, enterococci seem to be very effective at withstanding environmental and anti-
microbial agent stresses.

ENTEROCOCCAL DISEASE: CLINICAL ASPECTS

MANIFESTATIONS
Enterococci cause opportunistic urinary tract infections (UTIs) and occasionally wound
and soft tissue infections, in much the same fashion as members of the Enterobacteria-
ceae. Infections are often associated with urinary tract manipulations, malignancies, bili- UTIs and soft tissue infections are
ary tract disease, and gastrointestinal disorders. Vascular or peritoneal catheters are often most common
points of entry. Respiratory tract infections are rare. There is sometimes an associated
470 PART III Pathogenic Bacteria

bacteremia, which can result in the development of endocarditis on previously damaged

cardiac valves.

TREATMENT
The outstanding feature of the enterococci is their high and increasing levels of resis-
tance to antimicrobial agents. Their inherent relative resistance to most β-lactams, com-
plete resistance to all cephalosporins, and high-level resistance to aminoglycosides can be
Inherent resistance is enhanced by
viewed as a kind of virulence factor in the hospital environment where these agents are
altered PBPs
widely used. Enterococci also have particularly efficient means of acquiring plasmid and
transposon resistance genes from themselves and other species. All enterococci require
4 to 16 μg/mL of penicillin for inhibition owing to decreased affinity of their PBPs for all
β-lactams. Higher levels of resistance have been increasing, especially in E faecium, owing
to altered PBPs. Ampicillin remains the most consistently active agent against E faecalis.
Enterococci share with streptococci a resistance to aminoglycosides based on failure of
the antibiotic to be actively transported into the cell. Despite this, many strains of entero-
Synergy between penicillin and cocci are inhibited and rapidly killed by low concentrations of penicillin when combined
aminoglycosides is based on access with an aminoglycoside. Under these conditions, the action of penicillin on the cell wall
to ribosomes allows the aminoglycoside to enter the cell, where it can then act at its ribosomal site. Some
strains show high-level resistance to aminoglycosides based on mutations at the ribosomal
binding site or the presence of aminoglycoside-inactivating enzymes. These strains do not
demonstrate synergistic effects with penicillin.
Recently, resistance to vancomycin, the antibiotic most used for ampicillin-resistant
Vancomycin resistance is emerging strains has emerged. Vancomycin resistance is due to a subtle change in peptidoglycan
threat precursors, which are generated by ligases that modify the terminal amino acids of cross-
linking side chains at the point where β-lactams bind. The modifications decrease the bind-
Ligases modify peptidoglycan side ing affinity for penicillins 1000-fold without a detectable loss in peptidoglycan strength.
chains Although hospitals vary, the average rate of resistance in enterococci isolated from intensive
care units is around 20%. Enterococci are consistently resistant to sulfonamides and often
resistant to tetracyclines and erythromycin.
Ampicillin remains the agent of choice for most UTIs and minor soft tissue infections.
Ampicillin or combinations of More severe infections, particularly endocarditis, are usually treated with combinations of a
antimicrobials are used penicillin and aminoglycoside. Vancomycin is used for ampicillin-resistant strains in com-
bination with other agents, as guided by susceptibility testing. If the strain is vancomycin
resistant, linezolid is an alternative.

SO RE T H ROAT, MUR MUR , A ND PA I NF U L S WO L L E N J O IN T S

An 8-year-old boy presented with a 1-day history of fever (39°C), associated with
painful swelling of the right wrist and left knee. The patient had a sore throat 2 weeks
before the present illness, which was treated with salicylates. No cultures were obtained.
The last medical history was essentially negative, and the boy had no history of drug
allergy, weight loss, rash, dyspnea, or illness in siblings.
PHYSICAL EXAMINATION: Temperature (39°C), blood pressure 120/80 mm
Hg, pulse 110/min, respirations 28/min. The patient was ill-appearing. He avoided
movement of the right wrist and left knee, which were swollen, red, hot, and tender. He
had a moderately injected oropharynx without exudate and an enlarged right cervical
lymph node estimated to be 1 × 1 cm. The precordium was active and, a systolic thrill
could be felt. Auscultation of the heart revealed a heart rate of 120/min, normal heart
sounds, and a grade III/VI holosystolic murmur over the apex not transmitting toward
the axilla. Lungs were clear No rush or hepatosplenomegaly was present, and the
neurologic examination was normal.
 STREPTOCOCCI AND ENTEROCOCCI CHAPTER 25 471

L ABORATORY DATA :
Hemoglobin 12 g, Hct 37%, WBC 16 500/mm3
Sedimentation rate 90 mm/h
Urinalysis: Normal
Serology: Antistreptolysin 0 (ASO) titer 666Todd units (normal <200)
Chest X-ray: Normal (no cardiomegaly)
Throat culture: Negative for group A β-hemolytic streptococci
Blood culture: Negative
Electrocardiogram: Essentially normal except for mild ST depression and nonspecific
T-wave changes on V6
Aspirate from left knee: 3 mL of yellow and turbid fluid
WBCs: 3000/mm3 mainly polymorphonuclear leukocytes
Gram stain: Negative
Culture : No growth

QUESTIONS
MM This patient’s condition is most probably a case of:
A. Strep throat
B. Scarlet fever
C. Streptococcal toxic shock
D. Rheumatic fever
E. Poststreptococcal glomerulonephritis
MM This boy’s joint and cardiac findings are due to:
A. Circulating streptococcal pyrogenic exotoxin
B. Circulating streptolysin O
C. Antibody directed against M protein
D. Antibody directed against streptolysin O (ASO)
E. Circulating group A streptococci
MM The illness could have been prevented by:
A. Penicillin treatment of the sore throat
B. Penicillin treatment at the onset of joint pain
C. Aspirin at any point
D. Streptococcal vaccine in infancy
E. There is no prevention
MM The etiology of the sore throat would have been best determined by:
A. ASO titer
B. Throat culture
C. Throat antigen detection