CHAPTER 18  STAPHYLOCOCCUS AND RELATED GRAM-POSITIVE COCCI   171

Coagulase-Negative Staphylococci • Organisms can survive on dry surfaces for Diagnosis

long periods
Trigger Words • As with S. aureus infections
• Person-to-person spread through direct
Opportunistic, slime layer, subacute contact or exposure to contaminated
Treatment, Prevention, and Control
fomites, although most infections are with
Biology and Virulence the patient’s own organisms • The antibiotics of choice are oxacillin (or
• Patients are at risk when a foreign body is other penicillinase-resistant penicillin) or
• Catalase-positive, coagulase-negative,
present vancomycin for oxacillin-resistant strains
gram-positive cocci arranged in clusters
• The organisms are ubiquitous, so there are • Removal of the foreign body is often
• Relatively avirulent, although production of a
no geographic or seasonal limitations required for successful treatment
“slime” layer can allow adherence to foreign
• Prompt treatment for endocarditis or shunt
bodies (e.g., catheters, grafts, prosthetic
Diseases infections is necessary to prevent further
valves and joints, shunts) and protection
tissue damage or immune complex
from phagocytosis and antibiotics • Infections include subacute endocarditis, formation
infections of foreign bodies, and urinary
Epidemiology tract infections
• Normal human flora on skin and mucosal
surfaces

T he gram-positive cocci are a heterogeneous collection of

bacteria. Features they have in common are their spheri-
cal shape, their Gram-stain reaction, and an absence of
endospores. The presence or absence of catalase, an enzyme
that converts hydrogen peroxide into water and oxygen, is
used to subdivide the various genera. The most important
aerobic catalase-positive genus is Staphylococcus (discussed
in this chapter), and the most important aerobic catalase-
negative genera, Streptococcus and Enterococcus, are dis-
cussed in the next chapter.
Staphylococci are gram-positive cocci that grow in a char-
acteristic pattern resembling a cluster of grapes (Figure 18-1
and Table 18-1), although organisms in clinical specimens
may also appear as single cells, pairs, or short chains. Most
staphylococci are large, 0.5 to 1.5 µm in diameter, and able
to grow and potentially produce disease in a variety of
conditions—aerobic and anaerobic atmosphere, in the pres-
ence of a high concentration of salt (e.g., 10% sodium chlo-
ride), and at temperatures ranging from 18° C to 40° C. The FIGURE 18-1  Gram stain of Staphylococcus in a blood culture.
genus currently consists of 49 species and 27 subspecies,
many of which are found on the skin and mucous mem-
branes of humans. Some species have very specific niches ous for producing serious infections in hospitalized patients
where they are commonly found. For example, Staphylococ- and outside the hospital in previously healthy children and
cus aureus colonizes the anterior nares, Staphylococcus capitis adults. S. aureus colonies can have a yellow or gold color as
is found where sebaceous glands are present (e.g., forehead), the result of the carotenoid pigments that form during their
and Staphylococcus haemolyticus and Staphylococcus hominis growth, hence the species name. It is also the most common
are found in areas where apocrine glands are present (e.g., species in humans that produces the enzyme coagulase, and
axilla). Staphylococci are important pathogens in humans, therefore this property is a useful diagnostic test. When a
causing opportunistic infections and a wide spectrum of colony of S. aureus is suspended in plasma, coagulase binds
life-threatening systemic diseases, including infections of the to a serum factor and this complex converts fibrinogen to
skin, soft tissues, bones, and urinary tract (Table 18-2). The fibrin, resulting in formation of a clot. Most other staphylo-
species most commonly associated with human diseases coccal species do not produce coagulase and are referred to
are S. aureus (the most virulent and best-known member of collectively as coagulase-negative staphylococci. This is a
the genus), Staphylococcus epidermidis, S. haemolyticus, useful distinction because the coagulase-negative staphylo-
Staphylococcus lugdunensis, and Staphylococcus sapro- cocci are less virulent and primarily cause opportunistic
phyticus. Methicillin-resistant S. aureus (MRSA) is notori- infections.
172   MEDICAL MICROBIOLOGY

important antibiotics. Half of the cell wall by weight is pep-

Table 18-1  Important Staphylococci
tidoglycan, consisting of layers of glycan chains built with
Organism Historical Derivation 10 to 12 alternating subunits of N-acetylmuramic acid and
Staphylococcus staphylé, bunch of grapes; coccus, grain or berry N-acetylglucosamine. Oligopeptide side chains are attached
(grapelike cocci) to the N-acetylmuramic acid subunits and are then cross-
linked with peptide bridges. Unlike gram-negative bacteria,
S. aureus aureus, golden (golden or yellow) the peptidoglycan layer in gram-positive organisms consists
S. epidermidis epidermidis, outer skin (of the epidermis or outer of many cross-linked layers, which makes the cell wall more
skin) rigid. The enzymes that catalyze construction of the pepti-
doglycan layer are called penicillin-binding proteins
S. lugdunensis Lugdunum, Latin name for Lyon, France, where the
because these are the targets of penicillins and other β-lactam
organism was first isolated
antibiotics. Bacterial resistance to methicillin and related
S. saprophyticus sapros, putrid; phyton, plant (saprophytic or growing penicillins and cephalosporins is mediated by acquisition of
on dead tissues) a gene (mecA) that codes for a novel penicillin-binding
protein, PBP2a, that has a low affinity for methicillin and
related penicillins and cephalosporins (refer to Treatment,
Prevention, and Control for additional details). The mecA
Table 18-2  Common Staphylococcus Species and gene is located on the staphylococcal cassette chromosome
Their Diseases mec (SCCmec), and multiple gene sequences of this cassette
Organism Diseases are described. This information is relevant because MRSA
strains, previously restricted to hospital-acquired infections,
S. aureus Toxin mediated (food poisoning, scalded skin
are now present in the community and responsible for the
syndrome, toxic shock syndrome), cutaneous
majority of staphylococcal infections. Although the hospital
(carbuncles, folliculitis, furuncles, impetigo, wound
and community strains were initially distinct, movement
infections), other (bacteremia, endocarditis,
into and out of the hospital is now common, making control
pneumonia, empyema, osteomyelitis, septic arthritis)
of hospital-acquired infections more difficult.
S. epidermidis Bacteremia; endocarditis; surgical wounds; urinary The peptidoglycan has endotoxin-like activity, stimulat-
tract infections; opportunistic infections of catheters, ing the production of endogenous pyrogens, activation of
shunts, prosthetic devices, and peritoneal dialysates complement, production of interleukin (IL)-1 from mono-
S. saprophyticus Urinary tract infections, opportunistic infections cytes, and aggregation of PMNs (a process responsible for
abscess formation).
S. lugdunensis Endocarditis, arthritis, bacteremia, opportunistic
infections, urinary tract infections Teichoic Acids and Lipoteichoic Acids
S. haemolyticus Bacteremia, endocarditis, bone and joint infections, Teichoic acids are the other major component of the
urinary tract infections, wound infections, cell wall. Teichoic acids are species-specific, phosphate-
opportunistic infections containing polymers that are bound covalently to N-
acetylmuramic acid residues of the peptidoglycan layer or to
the lipids in the cytoplasmic membrane (lipoteichoic acids).
Although the teichoic acids are poor immunogens, a specific
• Physiology and Structure antibody response is stimulated when they are bound to
peptidoglycan. Although the production of antibodies was
Capsule and Slime Layer used initially as a marker of S. aureus infection, this insensi-
The outermost layer of the cell wall of many staphylococci is tive test has been abandoned in recent years.
covered with a polysaccharide capsule. Eleven capsular
serotypes have been identified in S. aureus. Serotypes 1 and Surface Adhesion Proteins
2 are associated with very thick capsules and mucoid- A large collection of surface proteins have been identified
appearing colonies but are rarely associated with human in S. aureus that are important virulence factors because
disease. In contrast, serotypes 5 and 8 are associated with they adhere to host matrix proteins bound to host tissues
the majority of infections in humans. The capsule protects (e.g., fibronectin, fibrinogen, elastin, collagen). Most of
the bacteria by inhibiting phagocytosis of the organisms by these surface adhesion proteins are covalently bound to the
polymorphonuclear leukocytes (PMNs). A loose-bound, cell wall peptidoglycan in staphylococci and have been
water-soluble film (slime layer or biofilm) consisting of designated MSCRAMM (microbial surface components
monosaccharides, proteins, and small peptides is produced recognizing adhesive matrix molecules) proteins. The
by most staphylococci in varying amounts. This extracellular nomenclature for the individual proteins is confusing; for
substance binds the bacteria to tissues and foreign bodies example, staphylococcal protein A (spa) binds to the Fc
such as catheters, grafts, prosthetic valves and joints, and receptor of immunoglobulin (Ig)G1, IgG2, and IgG4;
shunts and is particularly important for the survival of rela- fibronectin-binding protein A binds fibronectin as the name
tively avirulent coagulase-negative staphylococci. indicates; and S. aureus surface protein A has an undeter-
mined function. The best characterized MSCRAMM pro-
Peptidoglycan and Associated Enzymes teins are staphylococcal protein A, fibronectin-binding
An understanding of the structure of the gram-positive bac- proteins A and B, and clumping factor proteins A and B. The
terial cell wall is important because this is the target of many clumping factor proteins (also called coagulase) bind
 CHAPTER 18  STAPHYLOCOCCUS AND RELATED GRAM-POSITIVE COCCI   173

fibrinogen and convert it to insoluble fibrin, causing the

Table 18-3  Staphylococcus aureus Virulence Factors
staphylococci to clump or aggregate. Detection of these pro-
teins is the primary identification test for S. aureus. Two Virulence Factors Biological Effects
MSCRAMM proteins, S. aureus surface proteins G and H, Structural Components
have been associated with invasive disease.
Capsule Inhibits chemotaxis and phagocytosis; inhibits
Cytoplasmic Membrane proliferation of mononuclear cells
The cytoplasmic membrane is made up of a complex of Slime layer Facilitates adherence to foreign bodies
proteins, lipids, and a small amount of carbohydrates. It
Peptidoglycan Provides osmotic stability; stimulates production of
serves as an osmotic barrier for the cell and provides an
endogenous pyrogen (endotoxin-like activity);
anchorage for the cellular biosynthetic and respiratory
leukocyte chemoattractant (abscess formation);
enzymes.
inhibits phagocytosis
Teichoic acid Binds to fibronectin
• Pathogenesis and Immunity Protein A Inhibits antibody-mediated clearance by binding
IgG1, IgG2, and IgG4 Fc receptors; leukocyte
The ability of staphylococci to cause disease depends on chemoattractant; anticomplementary
the ability of the bacteria to evade immune clearance,
produce surface proteins that mediate adherence of the Toxins
bacteria to host tissues during colonization, and produce Cytotoxins Toxic for many cells, including erythrocytes,
disease through the elaboration of specific toxins and hydro- fibroblasts, leukocytes, macrophages, and platelets
lytic enzymes leading to tissue destruction (Table 18-3). Exfoliative toxins Serine proteases that split the intercellular bridges
These properties—immunologic evasion, adherence, tissue (ETA, ETB) in the stratum granulosum epidermis
destruction—are common to most pathogenic organisms.
Enterotoxins (A-E, Superantigens (stimulate proliferation of T cells and
Regulation of Virulence Genes G-I) release of cytokines); stimulate release of
Expression of virulence factors in staphylococci is under the inflammatory mediators in mast cells, increasing
complex control of the agr (accessory gene regulator) intestinal peristalsis and fluid loss, as well as
operon. This quorum-sensing (bacterial density) control nausea and vomiting
system allows expression of adhesion proteins and promotes Toxic shock Superantigen (stimulates proliferation of T cells and
tissue colonization when the density of bacteria is low, and syndrome toxin-1 release of cytokines); produces leakage or cellular
tissue invasion and production of hydrolytic enzymes and destruction of endothelial cells
toxins when the density is high. The operon encodes autoin-
ducer peptides (AIP1-4) that bind to cell surface receptors Enzymes
and regulate protein expression based on the population Coagulase Converts fibrinogen to fibrin
density. The innate immune regulation of bacterial virulence Hyaluronidase Hydrolyzes hyaluronic acids in connective tissue,
is mediated by apolipoprotein B, the major structural protein promoting spread of staphylococci in tissue
of very low- and low-density lipoproteins (VLDL, LDL),
which binds to AIPs and suppresses agr signaling. Thus, Fibrinolysin Dissolves fibrin clots
under optimal conditions, the bacterial density is maintained Lipases Hydrolyze lipids
at a low concentration, providing the benefits of immune
Nucleases Hydrolyze DNA
stimulation by colonizing staphylococci without the conse-
quences of tissue invasion and destruction.

Defenses Against Innate Immunity (A and B), numerous enterotoxins (A to E, G to X, plus

Opsonins (IgG, complement factor C3) in serum bind to multiple variants), and toxic shock syndrome toxin-1 (TSST-
encapsulated staphylococci, but the capsule protects the bac- 1). The cytolytic toxins have been described as hemolysins,
teria by inhibiting phagocytosis of the organisms by PMNs; but this is a misnomer because the activities of the first four
however, in the presence of specific antibodies directed toxins are not restricted solely to red blood cells, and P-V
against the staphylococci, increased C3 is bound to the bac- leukocidin is unable to lyse erythrocytes. Cytotoxins can lyse
teria and leads to phagocytosis. The extracellular slime layer neutrophils, resulting in the release of lysosomal enzymes
also interferes with phagocytosis of bacteria. The ability of that subsequently damage surrounding tissues. One cyto-
protein A to bind immunoglobulins effectively prevents toxin, P-V leukocidin, has been linked with severe pulmo-
antibody-mediated immune clearance of the S. aureus. Addi- nary and cutaneous infections.
tionally, extracellular protein A can bind antibodies and Exfoliative toxin A, the enterotoxins, and TSST-1 belong
form immune complexes, with the subsequent consumption to a class of polypeptides known as superantigens. These
of the complement. toxins bind to class II major histocompatibility complex
(MHC II) molecules on macrophages, which in turn interact
Staphylococcal Toxins with the variable regions of the β subunit of specific T-cell
S. aureus produces many toxins, including five cytolytic or receptors (VβTCR). This results in a massive release of cyto-
membrane-damaging toxins (alpha, beta, delta, gamma, and kines by both macrophages (IL-1β and tumor necrosis factor
Panton-Valentine [P-V] leukocidin), two exfoliative toxins [TNF]-α) and T cells (IL-2, interferon [IFN]-γ, and TNF-β).
174   MEDICAL MICROBIOLOGY

Release of TNF-α and TNF-β is associated with hypotension serine proteases that split desmoglein-1, a member of a
and shock, and fever is associated with IL-1β release. family of cell adhesion structures (desmosomes) responsible
for forming the intercellular bridges in the stratum granulo-
Cytotoxins sum epidermis. The toxins are not associated with cytolysis
Alpha toxin, which can be encoded on both the bacterial or inflammation, so neither staphylococci nor leukocytes are
chromosome and a plasmid, is a 33,000-Da polypeptide pro- typically present in the involved layer of the epidermis (this
duced by most strains of S. aureus that cause human disease. is an important diagnostic clue). After exposure of the epi-
The toxin disrupts the smooth muscle in blood vessels and dermis to the toxin, protective neutralizing antibodies
is toxic to many types of cells, including erythrocytes, leu- develop, leading to resolution of the toxic process. SSSS is
kocytes, hepatocytes, and platelets. Alpha toxin binds to the seen mostly in young children and only rarely in older chil-
cell surface, aggregates into a heptamer (7 toxin molecules) dren and adults.
forming a 1- to 2-nm pore, and allows the rapid efflux of K+
and influx of Na+, Ca2+, and other small molecules, which Enterotoxins
leads to osmotic swelling and cell lysis. Alpha toxin is Numerous distinct staphylococcal enterotoxins (A to X)
believed to be an important mediator of tissue damage in have been identified, with enterotoxin A most commonly
staphylococcal disease. associated with food poisoning. Enterotoxins C and D are
Beta toxin, also called sphingomyelinase C, is a 35,000- found in contaminated milk products, and enterotoxin B
Da heat-labile protein produced by most strains of S. aureus causes staphylococcal pseudomembranous enterocolitis. Less
responsible for disease in humans and animals. This enzyme is known about the prevalence or clinical importance of the
has a specificity for sphingomyelin and lysophosphatidyl- other enterotoxins. The enterotoxins are designed perfectly
choline and is toxic to a variety of cells, including erythro- for causing foodborne disease—stable to heating at 100° C for
cytes, fibroblasts, leukocytes, and macrophages. It catalyzes 30 minutes and resistant to hydrolysis by gastric and jejunal
the hydrolysis of membrane phospholipids in susceptible enzymes. Thus, once a food product has been contaminated
cells, with lysis proportional to the concentration of sphin- with enterotoxin-producing staphylococci and the toxins
gomyelin exposed on the cell surface. This is believed to be have been produced, neither mild reheating of the food nor
responsible for the differences in species susceptibility to the exposure to gastric acids will be protective. These toxins are
toxin. The effect on erythrocytes occurs primarily at low produced by 30% to 50% of all S. aureus strains. The precise
temperatures, so this toxin may be less efficient than other mechanism of toxin activity is not understood. These toxins
hemolysins. are superantigens capable of inducing nonspecific activation
Delta toxin is a 3000-Da polypeptide produced by almost of T cells and massive cytokine release. Characteristic histo-
all S. aureus strains and other staphylococci (e.g., S. epider- logic changes in the stomach and jejunum include infiltration
midis, S. haemolyticus). The toxin has a wide spectrum of of neutrophils into the epithelium and underlying lamina
cytolytic activity, affecting erythrocytes, many other mam- propria, with loss of the brush border in the jejunum. Stimula-
malian cells, and intracellular membrane structures. This tion of release of inflammatory mediators from mast cells is
relatively nonspecific membrane toxicity is consistent with believed to be responsible for the emesis that is characteristic
the belief that the toxin acts as a surfactant, disrupting cel- of staphylococcal food poisoning.
lular membranes by means of a detergent-like action.
Gamma toxin (made by almost all S. aureus strains) and Toxic Shock Syndrome Toxin-1
P-V leukocidin are bicomponent toxins composed of two TSST-1 is a 22,000-Da heat- and proteolysis-resistant, chro-
polypeptide chains: the S (slow-eluting proteins) component mosomally mediated exotoxin. It is estimated that 90% of S.
and F (fast-eluting proteins) component. Three S proteins aureus strains responsible for menstruation-associated toxic
(HlgA [hemolysin gamma A], HlgC, LukS-PV) and two F shock syndrome (TSS) and half of the strains responsible for
proteins (HlgB, LukF-PV) have been identified. Bacteria other forms of TSS produce TSST-1. Enterotoxin B and
capable of producing both toxins can encode all these pro- (rarely) enterotoxin C are responsible for approximately half
teins, with the potential for producing six distinct toxins. All the cases of nonmenstruation-associated TSS. Expression of
six toxins can lyse neutrophils and macrophages, whereas TSST-1 in vitro requires an elevated oxygen concentration
the greatest hemolytic activity is associated with HlgA/HlgB, and neutral pH. This is likely the reason TSS is relatively
HlgC/HlgB, and HlgA/LukF-PV. The PV leukocidin toxin uncommon compared with the incidence of S. aureus wound
(LukS-PV/LukF-PV) is leukotoxic but has no hemolytic infections (a setting where the environment of an abscess is
activity. Cell lysis by the gamma and PV leukocidin toxins is relatively anaerobic and acidic). TSST-1 is a superantigen
mediated by pore formation, with subsequent increased per- that stimulates release of cytokines, producing leakage of
meability to cations and osmotic instability. endothelial cells at low concentrations and a cytotoxic effect
to the cells at high concentrations. The ability of TSST-1 to
Exfoliative Toxins penetrate mucosal barriers, even though the infection
Staphylococcal scalded skin syndrome (SSSS), a spectrum remains localized in the vagina or at the site of a wound, is
of diseases characterized by exfoliative dermatitis, is medi- responsible for the systemic effects of TSS. Death in patients
ated by exfoliative toxins. The prevalence of toxin production with TSS is caused by hypovolemic shock leading to multi-
in S. aureus strains varies geographically but is generally less organ failure.
than 5%. Two distinct forms of exfoliative toxin (ETA and
ETB) have been identified, and either can produce disease. Staphylococcal Enzymes
ETA is heat stable and the gene is phage associated, whereas S. aureus strains possess two forms of coagulase: bound and
ETB is heat labile and located on a plasmid. The toxins are free. Coagulase bound to the staphylococcal cell wall can
 CHAPTER 18  STAPHYLOCOCCUS AND RELATED GRAM-POSITIVE COCCI   175

directly convert fibrinogen to insoluble fibrin and cause dramatic change was observed in 2003 when new strains of
the staphylococci to clump. The cell-free coagulase accom- MRSA were reported to be responsible for outbreaks of
plishes the same result by reacting with a globulin plasma community-acquired cutaneous infections and severe pneu-
factor (coagulase-reacting factor) to form staphylothrom- monia. Interestingly, the strains were not related to strains
bin, a thrombin-like factor. This factor catalyzes the conver- circulating in hospitals, and strains isolated in each country
sion of fibrinogen to insoluble fibrin. The role of coagulase were genetically unique. Unfortunately, the community
in the pathogenesis of disease is speculative, but coagulase strains have moved into hospitals in the last decade, compli-
may cause the formation of a fibrin layer around a staphylo- cating control measures previously established. Hospitalized
coccal abscess, thus localizing the infection and protecting patients are now susceptible to infections caused by strains
the organisms from phagocytosis. Some other species of they were colonized with in the community as well as strains
staphylococci produce coagulase, but these are primarily acquired in the hospital.
animal pathogens and uncommonly recovered in human
infections.
Staphylococci produce a variety of other enzymes that • Clinical Diseases (Box 18-1)
hydrolyze host tissue components and aid in bacterial spread.
Hyaluronidase hydrolyzes hyaluronic acids, present in the Staphylococcus aureus
acellular matrix of connective tissue. Fibrinolysin, also S. aureus causes disease through production of toxins or
called staphylokinase, can dissolve fibrin clots. All strains of through direct invasion and destruction of tissue. The clini-
S. aureus and more than 30% of the strains of coagulase- cal manifestations of some staphylococcal diseases are almost
negative Staphylococcus produce several different lipases exclusively the result of toxin activity (e.g., staphylococcal
that hydrolyze lipids and ensure survival of staphylococci in scalded skin syndrome, staphylococcal food poisoning, and
the sebaceous areas of the body. S. aureus also produces a toxic shock syndrome), whereas other diseases result from
thermostable nuclease that can hydrolyze viscous DNA. proliferation of the organisms, leading to abscess formation
and tissue destruction (e.g., cutaneous infections, endocar-
ditis, pneumonia, empyema, osteomyelitis, septic arthritis)
• Epidemiology (Figure 18-2). In the presence of a foreign body (e.g., splinter,
catheter, shunt, prosthetic valve or joint), significantly fewer
Staphylococci are ubiquitous. All persons have coagulase- staphylococci are necessary to establish disease. Likewise,
negative staphylococci on their skin, and transient coloni­ patients with congenital diseases associated with an impaired
zation of moist skinfolds with S. aureus is common. chemotactic or phagocytic response (e.g., Job syndrome,
Colonization of the umbilical stump, skin, and perineal area Wiskott-Aldrich syndrome, chronic granulomatous disease)
of neonates with S. aureus is common. S. aureus and are more susceptible to staphylococcal diseases.
coagulase-negative staphylococci are also found in the oro-
pharynx, gastrointestinal tract, and urogenital tract. Short- Staphylococcal Scalded Skin Syndrome (SSSS)
term or persistent S. aureus carriage in older children and In 1878, Gottfried Ritter von Rittershain described 297
adults is more common in the anterior nasopharynx than infants younger than 1 month old who had bullous exfolia-
in the oropharynx. Approximately 15% of normal healthy tive dermatitis. The disease he described, now called Ritter’s
adults are persistent nasopharyngeal carriers of S. aureus, disease or SSSS, is characterized by the abrupt onset of a
with a higher incidence reported for hospitalized patients, localized perioral erythema (redness and inflammation
medical personnel, persons with eczematous skin diseases, around the mouth) that spreads over the entire body within
and those who regularly use needles, either illicitly (e.g., drug 2 days. Slight pressure displaces the skin (a positive Nikolsky
abusers) or for medical reasons (e.g., patients with insulin- sign), and large bullae or cutaneous blisters form soon
dependent diabetes, patients receiving allergy injections, or thereafter, followed by desquamation of the epithelium
those undergoing hemodialysis). Adherence of the organism (Figure 18-3). The blisters contain clear fluid but no organ-
to the mucosal epithelium is regulated by the staphylococcal isms or leukocytes, a finding consistent with the fact that the
cell surface adhesins. disease is caused by the bacterial toxin. The epithelium
Because staphylococci are found on the skin and in the becomes intact again within 7 to 10 days, when antibodies
nasopharynx, shedding of the bacteria is common and is against the toxin appear. Scarring does not occur, because
responsible for many hospital-acquired infections. Staphylo- only the top layer of epidermis is sloughed. This is a disease
cocci are susceptible to high temperatures and disinfectants primarily of neonates and young children, with the mortality
and antiseptic solutions; however, the organisms can survive rate less than 5%. When death does occur, it is a result of
on dry surfaces for long periods. The organisms can be trans- secondary bacterial infection of the denuded skin areas.
ferred to a susceptible person either through direct contact Infections in adults usually occur in immunocompromised
or through contact with fomites (e.g., contaminated clothing, hosts or patients with renal disease, and mortality is as high
bed linens). Therefore, medical personnel must use proper as 60%.
hand-washing techniques to prevent transfer of staphylo- Bullous impetigo is a localized form of SSSS. In this
cocci from themselves to patients or among patients. syndrome, specific strains of toxin-producing S. aureus (e.g.,
Beginning in the 1980s, strains of MRSA spread rapidly phage type 71) are associated with formation of superficial
in susceptible hospitalized patients, dramatically changing skin blisters (Figure 18-4). Unlike patients with the dissemi-
the therapy available for preventing and treating staphylo- nated manifestations of SSSS, patients with bullous impetigo
coccal infections. Although MRSA infections were relatively have localized blisters that are culture positive. The erythema
uncommon among healthy individuals in the community, a does not extend beyond the borders of the blister, and the
176   MEDICAL MICROBIOLOGY

Box 18-1  Staphylococcal Diseases: Clinical Summaries

Endocarditis
Staphylococcus aureus 4 + Blood (S. aureus)
Toxin-Mediated Diseases 4 + Blood (other species)
Scalded skin syndrome: Disseminated desquamation of epithelium in
Staphylococcal
infants; blisters with no organisms or leukocytes
scalded skin syndrome
Food poisoning: After consumption of food contaminated with heat- 4 + Nasopharynx
stable enterotoxin, rapid onset of severe vomiting, diarrhea, and 1 + Skin
abdominal cramping, with resolution within 24 hours 1 + Blood
Toxic shock: multisystem intoxication characterized initially by fever, Pneumonia
hypotension, and a diffuse, macular, erythematous rash; high mortality 3 + Sputum
without prompt antibiotic therapy and elimination of the focus of 2 + Blood
infection
Staphylococcal
Suppurative Infections food poisoning
Impetigo: localized cutaneous infection characterized by pus-filled vesicle 3 + Food
on an erythematous base 1 + Feces
Folliculitis: impetigo involving hair follicles Catheter
Furuncles or boils: large, painful, pus-filled cutaneous nodules infections
Carbuncles: Coalescence of furuncles with extension into subcutaneous 4 + Blood
4 + Catheter tip
tissues and evidence of systemic disease (fever, chills, bacteremia)
Bacteremia and endocarditis: Spread of bacteria into the blood from Toxic shock syndrome
4 + Vagina/wound
a focus of infection; endocarditis characterized by damage to the
1 + Blood
endothelial lining of the heart
Pneumonia and empyema: Consolidation and abscess formation in the Cutaneous infections
(impetigo, folliculitis, furuncle,
lungs; seen in the very young and elderly and in patients with underly- carbuncle)
ing or recent pulmonary disease; a severe form of necrotizing pneu- 4 + Skin
monia with septic shock and high mortality is now recognized 2 + Blood
Osteomyelitis: Destruction of bones, particularly the metaphyseal area Septic arthritis
of long bones 4 + Synovial fluid
Septic arthritis: Painful erythematous joint with collection of purulent 3 + Blood
material in the joint space
Coagulase-Negative Staphylococcus Species
Wound infections: Characterized by erythema and pus at the site of a
traumatic or surgical wound; infections with foreign bodies can be
caused by S. aureus and coagulase-negative staphylococci
Urinary tract infections: Dysuria and pyuria in young sexually active FIGURE 18-2  Staphylococcal diseases. Isolation of staphylococci
women (S. saprophyticus), in patients with urinary catheters (other from sites of infection. 1+, Less than 10% positive cultures; 2+, 10%
coagulase-negative staphylococci), or following seeding of the urinary to 50% positive cultures; 3+, 50% to 90% positive cultures; 4+, more
tract by bacteremia (S. aureus) than 90% positive cultures.
Catheter and shunt infections: Chronic inflammatory response to bac-
teria coating a catheter or shunt (most commonly with coagulase-
negative staphylococci)
Prosthetic device infections: Chronic infection of device characterized
by localized pain and mechanical failure of the device (most commonly
with coagulase-negative staphylococci)

Nikolsky sign is not present. The disease occurs primarily in

infants and young children and is highly communicable.

Staphylococcal Food Poisoning

(Clinical Case 18-1)
Staphylococcal food poisoning, one of the most common
foodborne illnesses, is an intoxication rather than an infec-
tion. Disease is caused by bacterial toxin present in food
rather than from a direct effect of the organisms on the
patient. The most commonly contaminated foods are pro-
cessed meats such as ham and salted pork, custard-filled FIGURE 18-3  Staphylococcal scalded skin syndrome. (From
pastries, potato salad, and ice cream. Growth of S. aureus Mandell G, Bennett J, Dolin R: Principles and practice of infectious
in salted meats is consistent with the ability of this organ- disease, ed 6, Philadelphia, 2005, Churchill Livingstone.)
 CHAPTER 18  STAPHYLOCOCCUS AND RELATED GRAM-POSITIVE COCCI   177

nated hand), the food must remain at room temperature or

warmer for the organisms to grow and release the toxin.
The contaminated food will not appear or taste tainted.
Subsequent heating of the food will kill the bacteria but not
inactivate the heat-stable toxin.
After ingestion of contaminated food, the onset of disease
is abrupt and rapid, with a mean incubation period of 4
hours, which again is consistent with a disease mediated by
preformed toxin. Further toxin is not produced by ingested
staphylococci, so the disease has a rapid course, with symp-
toms generally lasting less than 24 hours. Severe vomiting,
diarrhea, and abdominal pain or nausea are characteristic of
staphylococcal food poisoning. Sweating and headache may
occur, but fever is not seen. The diarrhea is watery and non-
bloody, and dehydration may result from the considerable
fluid loss.
The toxin-producing organisms can be cultured from the
contaminated food if the organisms are not killed during
food preparation. The enterotoxins are heat-stable, so con-
taminated food can be tested for toxins at a public health
facility; however, these tests are rarely performed.
FIGURE 18-4  Bullous impetigo, a localized form of staphylococcal Treatment is for relief of abdominal cramping and diar-
scalded skin syndrome. (From Emond RT, Rowland HAK, Welsby rhea and for fluid replacement. Antibiotic therapy is not
P: Colour atlas of infectious diseases, ed 3, London, 1995, Wolfe.) indicated; as already noted, the disease is mediated by pre-
formed toxin, not by replicating organisms. Neutralizing
antibodies to the toxin can be protective, and limited cross-
protection occurs among the different enterotoxins. Short-
Clinical Case 18-1  Staphylococcal Food Poisoning lived immunity means that second episodes of staphylococcal
food poisoning can occur, particularly with serologically dis-
A report published in the Centers for Disease Control and Prevention’s tinct enterotoxins.
Morbidity and Mortality Weekly Report (MMWR 46:1189–1191, 1997) Certain strains of S. aureus can also cause enterocolitis,
illustrates many important features of staphylococcal food poisoning. A which is manifested clinically by watery diarrhea, abdominal
total of 18 persons attending a retirement party became ill approximately cramps, and fever. The majority of strains producing this
3 to 4 hours after eating. The most common symptoms were nausea disease produce both enterotoxin A and the bicomponent
(94%), vomiting (89%), and diarrhea (72%). Relatively few individuals had leukotoxin LukE/LukD. Enterocolitis occurs primarily in
fever or headache (11%). The symptoms lasted a median of 24 hours. The patients who have received broad-spectrum antibiotics that
illness was associated with eating ham at the party. A sample of the suppress the normal colonic flora and permit the growth of
cooked ham was positive for staphylococcal enterotoxin type A. A food S. aureus. The diagnosis of staphylococcal enterocolitis can
preparer had cooked the ham at home, transported it to her workplace be confirmed only after more common causes of infection
and sliced it while it was still hot, and then refrigerated the ham in a large have been excluded (e.g., Clostridium difficile colitis). Abun-
plastic container covered with foil. The ham was served cold the next day. dant staphylococci are typically present in the stool of
Cooking the ham would kill any contaminating S. aureus, so it is likely the affected patients, and the normal gram-negative bacteria are
ham was contaminated after it was cooked. The delays involved in refrig- absent. Fecal leukocytes are observed, and white plaques
erating the ham and the fact it was stored in a single container allowed with ulceration are seen on the colonic mucosa.
the organism to proliferate and produce enterotoxin. Type A toxin is the
most common toxin associated with human disease. The rapid onset and Toxic Shock Syndrome
short duration of nausea, vomiting, and diarrhea is typical of this disease. (TSS; Clinical Case 18-2)
Care must be used to avoid contamination of salted meats such as ham The first outbreak of this disease occurred in 1928 in Aus-
because reheating the food at a later time will not inactivate the heat- tralia, where the disease developed in 21 children, 12 of
stable toxin. whom died after an injection with an S. aureus–contaminated
vaccine. Fifty years later, J.K. Todd observed what he called
toxic shock syndrome in seven children with systemic
ism to grow in the presence of high salt concentrations. disease, and the first reports of TSS in menstruating women
Unlike many other forms of food poisoning in which an were published in the summer of 1980. These reports were
animal reservoir is important, staphylococcal food poison- followed by a dramatic increase in the incidence of TSS,
ing results from contamination of the food by a human particularly in women. Subsequently, it was discovered that
carrier. Although contamination can be prevented by not TSST-1–producing strains of S. aureus could multiply rapidly
allowing individuals with an obvious staphylococcal skin in hyperabsorbent tampons and release toxin. After the
infection to prepare food, approximately half of the infec- recall of these tampons, the incidence of disease—particularly
tions originate from carriers with asymptomatic nasopha- in menstruating women—decreased rapidly. At present,
ryngeal colonization. After the staphylococci have been fewer than 100 cases of TSS are reported annually in the
introduced into the food (through a sneeze or contami- United States. Although it was originally reported that
178   MEDICAL MICROBIOLOGY

Clinical Case 18-2  Staphylococcal Toxic

Shock Syndrome

Todd and associates (Lancet 2:1116–1118, 1978) were the first investiga-
tors to describe a pediatric disease they called “toxic shock syndrome”
(TSS). This patient illustrates the clinical course of the disease. A 15-year-
old girl was admitted to the hospital with a 2-day history of pharyngitis
and vaginitis associated with vomiting and watery diarrhea. She was febrile
and hypotensive on admission, with a diffuse erythematous rash over her
entire body. Laboratory tests were consistent with acidosis, oliguria, and
disseminated intravascular coagulation with severe thrombocytopenia. Her
chest radiograph showed bilateral infiltrates suggestive of “shock lung.”
She was admitted to the hospital intensive care unit, where she was
stabilized and improved gradually over a 17-day period. On the third day,
fine desquamation started on her face, trunk, and extremities and pro-
gressed to peeling of the palms and soles by the 14th day. All cultures
were negative except from the throat and vagina, from which Staphylococ-
cus aureus was isolated. This case illustrates the initial presentation of
TSS, the multiorgan toxicity, and the protracted period of recovery.

FIGURE 18-6  Pustular impetigo. Note the vesicles at different

stages of development, including pus-filled vesicles on an erythem-
atous base and dry, crusted lesions. (From Emond RT, Rowland
HAK, Welsby P: Colour atlas of infectious diseases, ed 3, London,
1995, Wolfe.)

was primarily associated with overwhelming Neisseria men-

ingitidis infections.
As the etiology and epidemiology of this disease have
become better understood, the initially high-fatality rate has
been decreased to approximately 5%. Unless the patient is
specifically treated with an effective antibiotic, however, the
risk of recurrent disease is as high as 65%. Serologic studies
have demonstrated that more than 90% of adults have anti-
bodies to TSST-1; however, more than 50% of patients with
TSS fail to develop protective antibodies after their disease
resolves. These unprotected patients are at significant risk for
recurrent disease.

Cutaneous Infections
Localized pyogenic staphylococcal infections include
FIGURE 18-5  Toxic shock syndrome. A case of fatal infection with impetigo, folliculitis, furuncles, and carbuncles. Impetigo, a
cutaneous and soft-tissue involvement is shown. superficial infection that mostly affects young children,
occurs primarily on the face and limbs. Initially, a small
macule (flattened red spot) is seen, and then a pus-filled
coagulase-negative staphylococci could cause TSS, it is now vesicle (pustule) on an erythematous base develops. Crusting
believed that this disease is restricted to S. aureus. occurs after the pustule ruptures. Multiple vesicles at differ-
The disease is initiated with the localized growth of toxin- ent stages of development are common, owing to the second-
producing strains of S. aureus in the vagina or a wound, ary spread of the infection to adjacent skin sites (Figure
followed by release of the toxin into blood. Toxin production 18-6). Impetigo is usually caused by S. aureus, although
requires an aerobic atmosphere and neutral pH. Clinical group A streptococci, either alone or with S. aureus, are
manifestations start abruptly and include fever, hypotension, responsible for 20% of cases.
and a diffuse, macular, erythematous rash. Multiple organ Folliculitis is a pyogenic infection in the hair follicles.
systems (e.g., central nervous, gastrointestinal, hematologic, The base of the follicle is raised and reddened, and there is
hepatic, musculature, renal) are also involved, and the entire a small collection of pus beneath the epidermal surface. If
skin, including the palms and soles, desquamates (Figure this occurs at the base of the eyelid, it is called a stye. Furun-
18-5). A particularly virulent form of toxic shock syndrome cles (boils), an extension of folliculitis, are large, painful,
is purpura fulminans. This disease is characterized by large raised nodules that have an underlying collection of dead
purpuric skin lesion, fever, hypotension, and disseminated and necrotic tissue. These can drain spontaneously or after
intravascular coagulation. Previously, purpura fulminans surgical incision.
 CHAPTER 18  STAPHYLOCOCCUS AND RELATED GRAM-POSITIVE COCCI   179

associated with dissemination to other body sites, including

the heart.
Acute endocarditis caused by S. aureus is a serious
disease, with a mortality rate approaching 50%. Although
patients with S. aureus endocarditis may initially have non-
specific influenza-like symptoms, their condition can dete-
riorate rapidly and include disruption of cardiac output and
peripheral evidence of septic embolization. Unless appropri-
ate medical and surgical intervention is instituted immedi-
ately, the patient’s prognosis is poor. An exception to this is
S. aureus endocarditis in parenteral drug abusers, whose
disease normally involves the right side of the heart (tricus-
pid valve) rather than the left. The initial symptoms may be
mild, but fever, chills, and pleuritic chest pain caused by
pulmonary emboli are generally present. Clinical cure of the
endocarditis is the rule, although it is common for complica-
FIGURE 18-7  Staphylococcus aureus carbuncle. This carbuncle
tions to occur as the result of secondary spread of the infec-
developed on the buttock over a 7- to 10-day period and required
tion to other organs.
surgical drainage plus antibiotic therapy. (From Cohen J, Powderly
WG, Opal SM: Infectious diseases, ed 3, Philadelphia, 2010, Mosby.) Pneumonia and Empyema
S. aureus respiratory disease can develop after the aspiration
of oral secretions or from the hematogenous spread of the
Carbuncles occur when furuncles coalesce and extend to organism from a distant site. Aspiration pneumonia is seen
the deeper subcutaneous tissue (Figure 18-7). Multiple sinus primarily in the very young, the elderly, and patients with
tracts are usually present. Unlike patients with folliculitis and cystic fibrosis, influenza, chronic obstructive pulmonary
furuncles, patients with carbuncles have chills and fevers, disease, and bronchiectasis. The clinical and radiographic
indicating the systemic spread of staphylococci via bactere- presentations of the pneumonia are not unique. Radio-
mia to other tissues. graphic examination reveals the presence of patchy infiltrates
Staphylococcal wound infections can also occur in with consolidation or abscesses, the latter consistent with the
patients after a surgical procedure or after trauma, with organism’s ability to secrete cytotoxic toxins and enzymes
organisms colonizing the skin introduced into the wound. and to form localized abscesses. Hematogenous pneumonia
The staphylococci are generally not able to establish an infec- is common for patients with bacteremia or endocarditis.
tion in an immunocompetent person unless a foreign body Community-acquired MRSA is responsible for a severe form
(e.g., stitches, a splinter, dirt) is present in the wound. Infec- of necrotizing pneumonia with massive hemoptysis, septic
tions are characterized by edema, erythema, pain, and an shock, and a high mortality rate. Although this disease is
accumulation of purulent material. The infection can be reported most commonly in children and young adults, it is
easily managed if the wound is reopened, the foreign matter not restricted to these age groups.
removed, and the purulence drained. If signs such as fever Empyema occurs in 10% of patients with pneumonia,
and malaise are observed or if the wound does not clear in and S. aureus is responsible for a third of all cases. Because
response to localized management, antibiotic therapy the organism can become consolidated in loculated areas,
directed against S. aureus is indicated. drainage of the purulent material is sometimes difficult.
With the spread of MRSA strains in the community,
these organisms are now the most common cause of skin and Osteomyelitis and Septic Arthritis
soft-tissue infections in patients presenting to U.S. hospital S. aureus osteomyelitis can result from hematogenous dis-
emergency departments. This problem is complicated by the semination to bone, or it can be a secondary infection result-
fact that the majority of these patients are initially treated ing from trauma or the extension of disease from an adjacent
with a penicillin, cephalosporin, or other equally ineffective area. Hematogenous spread in children generally results
antibiotic. from a cutaneous staphylococcal infection and usually
involves the metaphyseal area of long bones, a highly vascu-
Bacteremia and Endocarditis larized area of bony growth. This infection is characterized
(Clinical Case 18-3) by the sudden onset of localized pain over the involved bone
S. aureus is a common cause of bacteremia. Although bac- and by high fever. Blood cultures are positive in approxi-
teremias caused by most other organisms originate from an mately 50% of cases.
identifiable focus of infection (e.g., infection of the lungs, The hematogenous osteomyelitis seen in adults com-
urinary tract, gastrointestinal tract), the initial foci of infec- monly occurs in the form of vertebral osteomyelitis and
tion in approximately a third of patients with S. aureus bac- rarely in the form of an infection of the long bones. Intense
teremias are not known. Most likely, the infection spreads to back pain with fever is the initial symptom. Radiographic
the blood from an innocuous-appearing skin infection. evidence of osteomyelitis in children and adults is not seen
More than 50% of the cases of S. aureus bacteremia are until 2 to 3 weeks after the initial symptoms appear. A Brodie
acquired in the hospital after a surgical procedure or result abscess is a sequestered focus of staphylococcal osteomyeli-
from continued use of a contaminated intravascular catheter. tis that arises in the metaphyseal area of a long bone and
S. aureus bacteremias, particularly prolonged episodes, are occurs only in adults. The staphylococcal osteomyelitis that
180   MEDICAL MICROBIOLOGY

Clinical Case 18-3  Staphylococcus aureus Clinical Case 18-4  Staphylococcus lugdunensis
Endocarditis Endocarditis
Chen and Li (N Engl J Med 355:e27, 2006) described a 21-year-old Seenivasan and Yu (Eur J Clin Microbiol Infect Dis 22:489–491, 2003)
woman with a history of intravenous drug abuse, HIV, and a CD4 count of described a typical report of native valve endocarditis caused by
400 cells/mm3 who developed endocarditis caused by S. aureus. The S. lugdunensis, a coagulase-negative Staphylococcus with a predilection
patient had a 1-week history of fever, chest pain, and hemoptysis. Physical for causing endocarditis. The 36-year-old woman was an active cocaine
exam revealed a 3/6 pansystolic murmur and rhonchi in both lung fields. user who presented with an acute onset of weakness in the right extremi-
Multiple bilateral cavitary lesions were observed by chest radiography, and ties. She reported fever with chills, malaise, and shortness of breath over
cultures of blood and sputum were positive for methicillin-susceptible S. the preceding 10 weeks. Upon admission to the hospital, she had tachy-
aureus. The patient was treated with oxacillin for 6 weeks, with resolution cardia, hypotension, a temperature of 39° C, a pansystolic murmur, and
of the endocarditis and pulmonary abscesses. This case illustrated the right-sided hemiparesis. A computed tomography scan of the brain
acute onset of S. aureus endocarditis, risk factors of intravenous drug revealed a large infarct in the left basal ganglia. Four sets of blood cul-
abuse, and the frequency of complications caused by septic emboli. tures were positive with S. lugdunensis. The isolate was penicillin resistant
and susceptible to all other tested antibiotics. Because the patient had a
penicillin allergy, treatment was initiated with vancomycin and gentamicin.
The patient became afebrile at 3 days, and subsequent blood cultures
occurs after trauma or a surgical procedure is generally were negative. Gentamicin was discontinued after 1 week, and the patient
accompanied by inflammation and purulent drainage from received a total of 6 weeks of therapy with vancomycin. Over the next 7
the wound or the sinus tract overlying the infected bone. months, the patient developed progressive mitral regurgitation that neces-
Because the staphylococcal infection may be restricted to the sitated mitral valve replacement. S. lugdunensis is more virulent com-
wound, isolation of the organism from this site is not con- pared with other coagulase-negative staphylococci, causing disease most
clusive evidence of bony involvement. With appropriate anti- commonly in native heart valves and with secondary complications
biotic therapy and surgery, the cure rate for staphylococcal (e.g., a brain infarct caused by septic emboli) more frequently reported.
osteomyelitis is excellent. Persistent bacteremia is characteristic of intravascular infections such as
S. aureus is the primary cause of septic arthritis in young endocarditis.
children and in adults who are receiving intraarticular injec-
tions or who have mechanically abnormal joints. Secondary
involvement of multiple joints is indicative of hematogenous Catheter and Shunt Infections
spread from a localized focus. S. aureus is replaced by Neis- More than 50% of all infections of catheters and shunts are
seria gonorrhoeae as the most common cause of septic arthri- caused by coagulase-negative staphylococci. These infections
tis in sexually active persons. Staphylococcal arthritis is have become a major medical problem because long-dwelling
characterized by a painful erythematous joint, with purulent catheters and shunts are used commonly for the medical
material obtained on aspiration. Infection is usually demon- management of critically ill patients. The coagulase-negative
strated in the large joints (e.g., shoulder, knee, hip, elbow). staphylococci are particularly well adapted for causing these
The prognosis in children is excellent, but in adults it depends infections, because they can produce a polysaccharide slime
on the nature of the underlying disease and the occurrence that bonds them to catheters and shunts and protects them
of any secondary infectious complications. from antibiotics and inflammatory cells. A persistent bacter­
emia is generally observed in patients with infections of
Staphylococcus epidermidis and Other shunts and catheters, because the organisms have continual
Coagulase-Negative Staphylococci access to the blood. Immune complex–mediated glomerulo-
Endocarditis (Clinical Case 18-4) nephritis occurs in patients with long-standing disease.
S. epidermidis, S. lugdunensis, and related coagulase-negative
staphylococci can infect prosthetic and, less commonly, Prosthetic Joint Infections
native heart valves. Infections of native valves are believed to Infections of artificial joints, particularly the hip, can be
result from the inoculation of organisms onto a damaged caused by coagulase-negative staphylococci. The patient
heart valve (e.g., a congenital malformation, damage result- usually experiences only localized pain and mechanical
ing from rheumatic heart disease). S. lugdunensis is the failure of the joint. Systemic signs such as fever and leuko-
staphylococcal species most commonly associated with cytosis are not prominent, and blood cultures are usually
native valve endocarditis, although this disease is more com- negative. Treatment consists of joint replacement and anti-
monly caused by streptococci. In contrast, staphylococci are microbial therapy. The risk of reinfection of the new joint is
a major cause of endocarditis of artificial valves. The organ- considerably increased in such patients.
isms are introduced at the time of valve replacement, and the
infection characteristically has an indolent course, with clin- Urinary Tract Infections
ical signs and symptoms not developing for as long as 1 year S. saprophyticus has a predilection for causing urinary tract
after the procedure. Although the heart valve can be infected, infections in young, sexually active women and is rarely
more commonly the infection occurs at the site where the responsible for infections in other patients. It is also infre-
valve is sewn to the heart tissue. Thus infection with abscess quently found as an asymptomatic colonizer of the urinary
formation can lead to separation of the valve at the suture tract. Infected women usually have dysuria (pain on urina-
line and to mechanical heart failure. The prognosis is guarded tion), pyuria (pus in urine), and numerous organisms in the
for patients who have this infection, and prompt medical and urine. Typically, patients respond rapidly to antibiotics, and
surgical management is critical. reinfection is uncommon.
 CHAPTER 18  STAPHYLOCOCCUS AND RELATED GRAM-POSITIVE COCCI   181

• Laboratory Diagnosis
Microscopy
Staphylococci are gram-positive cocci that form clusters
when grown on agar media but commonly appear as single
cells or small groups of organisms in clinical specimens.
Successful detection of organisms in a clinical specimen
depends on the type of infection (e.g., abscess, bacteremia,
impetigo) and the quality of the material submitted for anal-
ysis. If the clinician scrapes the base of the abscess with a
swab or curette, then an abundance of organisms should be
observed in the Gram-stained specimen. Aspirated pus or
superficial specimens collected with swabs consist primarily
of necrotic material with relatively few organisms, so these
specimens are not as useful. Relatively few organisms are FIGURE 18-8  Staphylococcus aureus grown on a sheep blood agar
generally present in the blood of bacteremic patients (an plate. Note the colonies are large and β-hemolytic.
average of <1 organism per milliliter of blood), so blood
specimens should be cultured, but blood examined by Gram
stain is not useful. Staphylococci are seen in the nasopharynx Identification
of patients with SSSS and in the vagina of patients with TSS, Relatively simple biochemical tests (e.g., positive reactions
but these staphylococci cannot be distinguished from the for coagulase, protein A, heat-stable nuclease, and mannitol
organisms that normally colonize these sites. Diagnosis of fermentation) can be used to identify S. aureus. Colonies
these diseases is made by the clinical presentation of the resembling S. aureus are identified in most laboratories by
patient, with isolation of S. aureus in culture confirmatory. mixing a suspension of organisms with a drop of plasma and
Staphylococci are implicated in food poisoning by the clini- observing clumping of the organisms (positive coagulase
cal presentation of the patient (e.g., rapid onset of vomiting test). Alternatively, plasma placed in a test tube can be inocu-
and abdominal cramps) and a history of specific food inges- lated with the organism and examined at 4 and 24 hours for
tion (e.g., salted ham). Gram stains of the food or patient formation of a clot (positive tube coagulase test). Identifica-
stool specimens are generally not useful. tion of the coagulase-negative staphylococci is more complex,
traditionally requiring the use of commercial identification
Nucleic Acid–Based Tests systems or detection of species-specific genes by nucleic acid
Commercial nucleic acid amplification tests are available for sequencing techniques. More recently mass spectrometry
the direct detection and identification of S. aureus in clinical has been used to identify these bacteria, as well as many
specimens. Whereas the earlier versions of these tests other species of organisms, with a high level of accuracy and
required manual extraction of bacterial DNA and testing rapid time to results (generally identified in minutes). His-
multiple specimens in large batches, integrated processing of torically, the analysis of genomic DNA by pulsed-field gel
specimens (extraction, gene amplification, target detection) electrophoresis or similar technique was the most commonly
is now performed on highly automated platforms with dis- used method for characterizing isolates at the subspecies
posable reagent strips or cartridges. These tests are useful for levels; however, whole genome sequencing is rapidly becom-
the detection of methicillin-sensitive S. aureus (MSSA) and ing the preferred tool for subtyping organisms for epidemio-
MRSA in wound specimens and screening nasal specimens logic studies.
for carriage of these bacteria.
Antibody Detection
Culture Antibodies to cell wall teichoic acids are present in many
Clinical specimens should be inoculated onto nutritionally patients with long-standing S. aureus infections. However,
enriched agar media supplemented with sheep blood. Staphy- this test has been discontinued in most hospitals because it
lococci grow rapidly on nonselective media incubated aerobi- is less sensitive than culture and nucleic acid–based tests.
cally or anaerobically, with large, smooth colonies seen within
24 hours (Figure 18-8). As noted earlier, S. aureus colonies will
gradually turn yellow, particularly when the cultures are incu- • Treatment, Prevention, and Control
bated at room temperature. Almost all isolates of S. aureus and
some strains of coagulase-negative staphylococci produce Staphylococci quickly developed drug resistance after peni-
hemolysis on sheep blood agar. The hemolysis is caused by cillin was introduced, and today less than 10% of the strains
cytotoxins, particularly alpha toxin. If there is a mixture of are susceptible to this antibiotic. This resistance is mediated
organisms in the specimen (e.g., wound or respiratory speci- by penicillinase (β-lactamase specific for penicillins), which
men), S. aureus can be isolated selectively on a variety of special hydrolyzes the β-lactam ring of penicillin. Because of the
media including chromogenic agar (where S. aureus colonies problems with penicillin-resistant staphylococci, semisyn-
are a characteristic color) or mannitol-salt agar, which is sup- thetic penicillins resistant to β-lactamase hydrolysis (e.g.,
plemented with mannitol (fermented by S. aureus but not by methicillin, nafcillin, oxacillin, dicloxacillin) were devel-
most other staphylococci) and 7.5% sodium chloride (inhibits oped. Unfortunately, staphylococci developed resistance to
the growth of most other organisms). these antibiotics as well. Currently, the majority of S. aureus
182   MEDICAL MICROBIOLOGY

responsible for hospital- and community-acquired infec- can also be difficult to control because asymptomatic naso-
tions are resistant to these semisynthetic penicillins, and pharyngeal carriage is the most common source of these
these MRSA strains are resistant to all β-lactam antibiotics organisms.
(i.e., penicillins, cephalosporins, carbapenems). Not all bac-
teria in a resistant population may express their resistance in
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splinter, stitches) is present in the wound. Proper cleansing Srinivasan A, Dick JD, Perl TM: Vancomycin resistance in staphylococci,
Clin Microbiol Rev 15:430–438, 2002.
of the wound and application of an appropriate disinfectant Stanley J, Amagai M: Pemphigus, bullous impetigo, and the staphylococcal
(e.g., germicidal soap, iodine solution, hexachlorophene) scalded-skin syndrome, N Engl J Med 355:1800–1810, 2006.
will prevent most infections in healthy individuals. Tang Y, Stratton C: Staphylococcus aureus: an old pathogen with new
The spread of staphylococci from person to person is weapons, Clin Lab Med 30:179–208, 2010.
Uhlemann AC, Otto M, Lowy FD, et al: Evolution of community- and
more difficult to prevent. An example of this is surgical healthcare-associated methicillin-resistant Staphylococcus aureus, Infect
wound infections, which can be caused by relatively few Genet Evol 21:563–574, 2014.
organisms, because foreign bodies and devitalized tissue Vandenesch F, Lina G, Henry T: Staphylococcus aureus hemolysins,
may be present. Although it is unrealistic to sterilize operat- bi-component leukocidins, and cytolytic peptides: a redundant arsenal
ing room personnel and the environment, the risk of con- of membrane-damaging virulence factors? Front Cell Infect Microbiol
2:12, 2012.
tamination during an operative procedure can be minimized Zhu W, Murray PR, Huskins WC, et al: Dissemination of an Enterococcus
through proper hand washing and the covering of exposed Inc18-Like vanA plasmid associated with vancomycin-resistant Staphy-
skin surfaces. The spread of methicillin-resistant organisms lococcus aureus, Antimicrob Agents Chemother 54:4314–4320, 2010.
 CHAPTER 18  STAPHYLOCOCCUS AND RELATED GRAM-POSITIVE COCCI   182.e1

Case Study and Questions 2. Staphylococcal diseases can be subdivided into two
An 18-year-old man fell on his knee while playing basketball. categories: localized pyogenic infections and dissemi-
The knee was painful, but the overlying skin was unbroken. nated toxin-mediated infections. Cutaneous infections
The knee was swollen and remained painful the next day, so (e.g., impetigo, folliculitis, furuncles, carbuncles), wound
he was taken to the local emergency department. Clear fluid infections, endocarditis, pneumonia, empyema, osteomy-
was aspirated from the knee, and the physician prescribed elitis, and septic arthritis are examples of localized pyo-
symptomatic treatment. Two days later, the swelling returned, genic infections. Each is characterized by localized tissue
the pain increased, and erythema developed over the knee. destruction and abscess formation. SSSS, TSS, and staph-
Because the patient also felt systemically ill and had an oral ylococcal food poisoning are examples of toxin-mediated
temperature of 38.8° C, he returned to the emergency depart- infections. Each is characterized by disseminated symp-
ment. Aspiration of the knee yielded cloudy fluid, and cul- toms and an absence of purulence.
tures of the fluid and blood were positive for Staphylococcus 3. S. aureus produces a variety of potent toxins. The dissemi-
aureus. nated toxin-mediated diseases are characterized by pro-
1. Name two possible sources of this organism. duction of a specific toxin or group of toxins that spread
2. Staphylococci cause a variety of diseases, including cutane- systemically in the blood and are responsible for the clini-
ous infections, endocarditis, food poisoning, SSSS, and TSS. cal symptoms: SSSS, exfoliative toxins (ETA, ETB); TSS,
How do the clinical symptoms of these diseases differ from TSST-1; and food poisoning, enterotoxins (A-R). Five
the infection in this patient? Which of these diseases are groups of cytolytic toxins are responsible for the tissue
intoxications? destruction characteristic of pyogenic staphylococcal
3. What toxins have been implicated in staphylococcal dis- infections: alpha toxin, beta toxin (sphingomyelinase C),
eases? Which staphylococcal enzymes have been proposed delta toxin, gamma toxins (5 different bicomponent
as virulence factors? toxins), and P-V leukocidin toxin. P-V leukocidin is asso-
4. Which structures in the staphylococcal cell and which ciated with fulminant wound and pulmonary infections.
toxins protect the bacterium from phagocytosis? A variety of staphylococcal enzymes have also been impli-
5. What is the antibiotic of choice for treating staphylococcal cated in disease, including coagulases (bound and free),
infections? (Give two examples.) catalase, hyaluronidase, fibrinolysin (staphylokinase),
lipases, nuclease, and β-lactamases.
4. Staphylococci are protected from phagocytosis by their
Answers capsule; a loosely bound slime layer consisting of mono-
1. This patient has septic arthritis caused by S. aureus. The saccharides, proteins, and small peptides; and protein A.
organism could have been introduced into the joint either 5. Effective treatment of staphylococcal infections requires
by direct extension from the skin surface, by hematoge- drainage of purulent collections and effective antibiotics.
nous spread, or when the synovial fluid was originally Because resistance to antibiotics is common, antimicro-
aspirated. Although transient bacteremia with S. aureus bial susceptibility tests must be performed. Almost 90%
can occur, this is very uncommon. Therefore, without of staphylococci produce β-lactamases, so penicillin G is
evidence of a S. aureus infection at another site (e.g., ineffective. β-Lactamase–resistant penicillins (e.g., meth-
endocarditis), the most likely source of this organism is icillin, oxacillin, nafcillin, dicloxacillin) are effective and
direct extension from the skin surface. Even though the considered the drugs of choice if the antibiotics are active
skin surface appeared to be unbroken, localized trauma against the bacteria. If resistance is determined (com-
of this nature can introduce organisms into the deeper monplace in many hospitals), vancomycin should be used
skin tissues. Alternatively, bacteria on the skin surface to treat serious staphylococcal infections.
could have been introduced into the joint when the accu-
mulated fluid was originally aspirated.
 CHAPTER 19  STREPTOCOCCUS AND ENTEROCOCCUS    183
CHAPTER

19  
STREPTOCOCCUS AND
ENTEROCOCCUS

An 8-year-old boy presented to his pediatrician with a low-grade fever and a diffuse erythematous rash over
his chest, which developed 2 days after he complained of a painful sore throat. An exudate was present over
the tonsillar area of the throat and covered his tongue. The clinical diagnosis of scarlet fever was confirmed
by positive antigen test for group A Streptococcus from a throat specimen. The genera Streptococcus and
Enterococcus include a large number of species capable of causing a wide spectrum of diseases.
1. What sites of the human body are normally colonized with Streptococcus pyogenes, Streptococcus agalactiae,
and Streptococcus pneumoniae? How does this relate to infections caused by these bacteria?
2. The viridans streptococci (i.e., α-hemolytic and nonhemolytic streptococci) are subdivided into five groups. What
are the groups and the specific diseases associated with each group?
3. Enterococci, like many other bacteria, can cause urinary tract infections but primarily in hospitalized patients.
What characteristics of this bacterium are responsible for the predilection for disease in this population?
4. What biochemical properties are used to separate enterococci from the staphylococci and streptococci?
Answers to these questions are available on StudentConsult.com.

• SUMMARIES  CLINICALLY SIGNIFICANT ORGANISMS

Streptococcus pyogenes (Group A) • Pharyngitis and soft-tissue infections Diagnosis

Trigger Words typically caused by strains with different M • Microscopy is useful in soft-tissue infections
proteins but not pharyngitis or nonsuppurative
Group A, pharyngitis, pyoderma, rheumatic • Person-to-person spread by respiratory
fever, glomerulonephritis complications
droplets (pharyngitis) or through • Direct tests for the group A antigen are useful
breaks in skin after direct contact with for the diagnosis of streptococcal pharyngitis
Biology and Virulence infected person, fomite, or arthropod • Isolates identified by catalase (negative),
• Rapidly growing gram-positive cocci vector positive PYR (L-pyrrolidonyl arylamidase)
arranged in chains; group-specific • Individuals at higher risk for disease include reaction, susceptibility to bacitracin, and
carbohydrate (A antigen) and type-specific children 5 to 15 years old (pharyngitis); presence of group-specific antigen (group A
proteins (M protein) in cell wall children 2 to 5 years old with poor personal antigen)
• Virulence determined by ability to avoid hygiene (pyoderma); patients with • Antistreptolysin O test is useful for
phagocytosis (mediated primarily by soft-tissue infection (streptococcal toxic confirming rheumatic fever or
capsule, M and M-like proteins, C5a shock syndrome); patients with prior glomerulonephritis associated with
peptidase), adhere to and invade host cells streptococcal pharyngitis (rheumatic fever, streptococcal pharyngitis; anti-DNase B test
(M protein, lipoteichoic acid, F protein), and glomerulonephritis) or soft-tissue infection should be performed for glomerulonephritis
produce toxins (streptococcal pyrogenic (glomerulonephritis) associated with pharyngitis or soft-tissue
exotoxins, streptolysin S, streptolysin O, infections
streptokinase, DNases) Diseases
• Responsible for suppurative diseases Treatment, Prevention, and Control
Epidemiology (pharyngitis, soft-tissue infections, • Penicillin V or amoxicillin used to treat
• Transient colonization in upper respiratory streptococcal toxic shock) and pharyngitis; oral cephalosporin or macrolide
tract and skin surface, with disease caused nonsuppurative diseases (rheumatic fever, for penicillin-allergic patients; intravenous
by recently acquired strains (before glomerulonephritis) penicillin plus clindamycin used for systemic
protective antibodies are produced) infections

183
 CHAPTER 19  STREPTOCOCCUS AND ENTEROCOCCUS    183.e1

Answers
1. S. pyogenes colonizes the oropharynx and skin surface
and causes pharyngitis, skin and soft-tissue infections,
and nonsuppurative infections (rheumatic fever, glomer-
ulonephritis); S. agalactiae colonizes the female genital
tract and causes neonatal infections, as well as infections
in pregnant women and older adults; S. pneumoniae colo-
nizes the oropharynx and causes pneumonia, sinusitis,
otitis media, and meningitis.
2. Anginosus group—abscess formation; mitis group—
septicemia in neutropenic patients and endocarditis; sali-
varius group—endocarditis; mutans group—dental
caries; bovis group—bacteremia associated with gastroin-
testinal cancer and meningitis.
3. The bacteria are resistant to many commonly used anti-
biotics (oxacillin, cephalosporins, aminoglycosides, van-
comycin), so infections are most commonly seen in
patients hospitalized for prolonged periods and receiving
broad-spectrum antibiotics.
4. Staphylococci are catalase positive in contrast with strep-
tococci and enterococci; enterococci are PYR positive,
whereas most streptococci (except S. pyogenes) are PYR
negative. The microscopic morphology of enterococci
(gram-positive cocci in pairs) is also a distinguishing
feature (staphylococci are in clusters, and most strepto-
cocci are in long chains).
184   MEDICAL MICROBIOLOGY

• Oropharyngeal carriage occurring after Diagnosis Epidemiology

treatment can be re-treated; treatment is • Microscopy useful for meningitis • Most infections are caused by endogenous
not indicated for prolonged asymptomatic (cerebrospinal fluid), pneumonia (lower spread from the colonized nasopharynx or
carriage, because antibiotics disrupt normal respiratory secretions), and wound oropharynx to distal site (e.g., lungs,
protective flora infections (exudates) sinuses, ears, blood, meninges); person-to-
• Starting antibiotic therapy within 10 days in • Antigen tests are less sensitive than person spread through infectious droplets is
patients with pharyngitis prevents rheumatic microscopy and should not be used rare
fever • Culture most sensitive test; a selective broth • Colonization is highest in young children
• For glomerulonephritis, no specific antibiotic (i.e., LIM) is needed for optimal detection of and their contacts
treatment or prophylaxis is indicated vaginal carriage • Individuals with antecedent viral respiratory
• For patients with a history of rheumatic • Polymerase chain reaction–based assays to tract disease or other conditions that
fever, antibiotic prophylaxis is required detect vaginal carriage in pregnant women interfere with bacterial clearance from
before procedures (e.g., dental) that can are commercially available; currently require respiratory tract are at increased risk for
induce bacteremias leading to endocarditis use of enrichment broth for optimum pulmonary disease
sensitivity • Children and the elderly are at greatest risk
Streptococcus agalactiae (Group B) • Isolates identified by demonstration of for meningitis
Trigger Words group-specific cell wall carbohydrate or • People with hematologic disorder (e.g.,
positive nucleic acid amplification test malignancy, sickle cell disease) or functional
Group B, neonatal disease, screening pregnant
asplenia are at risk for fulminant sepsis
women
Treatment, Prevention, and Control • Although the organism is ubiquitous,
disease is more common in cool months
Biology and Virulence • Penicillin G is the drug of choice; empirical
therapy with broad-spectrum antibiotics
• Rapidly growing gram-positive cocci Diagnosis
(broad-spectrum cephalosporin plus
arranged in chains; group-specific
aminoglycoside) used until specific • Microscopy is highly sensitive, as is culture,
carbohydrate (B antigen) and type-specific
pathogen identified; combination of unless the patient has been treated with
capsular carbohydrates (Ia, Ib, II-VIII)
penicillin and aminoglycoside is used in antibiotics
• Virulence determined primarily by ability to
patients with serious infections; a • Antigen tests for pneumococcal C
avoid phagocytosis (mediated by capsule)
cephalosporin or vancomycin is used for polysaccharide are sensitive with
patients allergic to penicillin cerebrospinal fluid (meningitis) but not with
Epidemiology
• For high-risk babies, penicillin is given at urine (meningitis, pneumonia, other
• Asymptomatic colonization of the upper least 4 hours before delivery infections)
respiratory tract and genitourinary tract • No vaccine is currently available • Nucleic acid–based tests are not commonly
• Early-onset disease acquired by neonates used for diagnosis
from mother during pregnancy or at time of Streptococcus pneumoniae • Culture requires use of enriched-nutrient
birth media (e.g., sheep blood agar); organism
• Neonates are at higher risk for infection if Trigger Words
highly susceptible to many antibiotics, so
(1) there is premature rupture of Diplococci, capsule, pneumonia, meningitis, culture can be negative in partially treated
membranes, prolonged labor, preterm birth, vaccine patients
or disseminated maternal group B • Isolates identified by catalase (negative),
streptococcal disease, and (2) mother is Biology and Virulence susceptibility to optochin, and solubility in bile
without type-specific antibodies and has low • Elongated gram-positive cocci arranged
complement levels in pairs (diplococci) and short chains; Treatment, Prevention, and Control
• Women with genital colonization are at risk cell wall includes teichoic acid rich in • Penicillin is the drug of choice for
for postpartum disease phosphorylcholine (C polysaccharide), susceptible strains, although resistance is
• Men and nonpregnant women with diabetes which is required for the activity of an increasingly common
mellitus, cancer, or alcoholism are at autolytic enzyme, amidase • Vancomycin combined with ceftriaxone is
increased risk for disease • Virulence determined by ability to colonize used for empirical therapy; monotherapy
• No seasonal incidence oropharynx (surface protein adhesions), with a cephalosporin, fluoroquinolone, or
spread into normally sterile tissues vancomycin can be used in patients with
Diseases (pneumolysin, immunoglobulin [Ig]A susceptible isolates
• Responsible for neonatal disease (early- protease), stimulate local inflammatory • Immunization with 13-valent conjugated
onset and late-onset disease with response (teichoic acid, peptidoglycan vaccine is recommended for all children
meningitis, pneumonia, bacteremia), fragments, pneumolysin), and evade younger than 2 years; a 23-valent
infections in pregnant women (endometritis, phagocytic killing (polysaccharide polysaccharide vaccine is recommended for
wound infections, urinary tract infections), capsule) adults at risk for disease
and other adults (bacteremia, pneumonia, • Responsible for pneumonia, sinusitis and
bone and joint infections, skin and otitis media, meningitis, and bacteremia
soft-tissue infections)
 CHAPTER 19  STREPTOCOCCUS AND ENTEROCOCCUS    185

Enterococcus • Most infections endogenous (from patient’s Treatment, Prevention, and Control
bacterial flora); some caused by patient-to-
Trigger Words • Therapy for serious infections requires
patient spread combination of an aminoglycoside with a
Diplococci, gastrointestinal carriage, drug- • Patients at increased risk include those cell wall–active antibiotic (penicillin,
resistant, urinary tract infections, peritonitis hospitalized for prolonged periods and ampicillin, or vancomycin); newer agents
treated with broad-spectrum antibiotics used for antibiotic-resistant bacteria include
Biology and Virulence (particularly cephalosporins, to which linezolid, daptomycin, tigecycline, and
• Gram-positive cocci arranged in pairs and enterococci are naturally resistant) quinupristin/dalfopristin
short chains (morphologically similar to • Antibiotic resistance to each of these drugs
Streptococcus pneumoniae) Diseases is becoming increasingly common, and
• Cell wall with group-specific antigen (group • Diseases include urinary tract infections, infections with many isolates (particularly
D glycerol teichoic acid) peritonitis (usually polymicrobic), wound Enterococcus faecium) are not treatable
• Virulence mediated by ability to adhere to infections, and bacteremia with or without with any antibiotics
host surfaces and form biofilms and by endocarditis • Prevention and control of infections require
antibiotic resistance careful restriction of antibiotic use and
Diagnosis implementation of appropriate infection-
Epidemiology control practices
• Grows readily on common nonselective
• Colonizes the gastrointestinal tracts of media; differentiated from related organisms
humans and animals; spreads to other by simple tests (catalase negative,
mucosal surfaces if broad-spectrum L-pyrrolidonyl arylamidase–positive, resistant
antibiotics eliminate the normal bacterial to bile and optochin)
population
• Cell wall structure typical of gram-positive
bacteria, which allows survival on
environmental surfaces for prolonged periods

T he genera Streptococcus and Enterococcus are a diverse

collection of gram-positive cocci typically arranged in
pairs or chains (in contrast to the clusters formed by Staphy-
the α-hemolytic and γ-hemolytic streptococci, which are
classified by biochemical testing. The latter group is referred
to collectively as viridans streptococci, a name derived from
lococcus) (Table 19-1). Most species are facultative anaer- viridis (Latin for “green”), referring to the green pigment
obes, and some grow only in an atmosphere enhanced with formed by the partial hemolysis of blood agar.
carbon dioxide (capnophilic growth). Their nutritional Rebecca Lancefield developed the serologic classification
requirements are complex, necessitating the use of blood- or scheme in 1933. β-Hemolytic strains possess group-specific
serum-enriched media for isolation. Carbohydrates are fer- cell wall antigens, most of which are carbohydrates. These
mented, resulting in the production of lactic acid, and unlike antigens can be readily detected by immunologic assays and
Staphylococcus species, streptococci and enterococci are cat- have been useful for the rapid identification of some impor-
alase negative. The number of genera of catalase-negative, tant streptococcal pathogens. For example, one disease
gram-positive cocci that are recognized as human pathogens caused by Streptococcus pyogenes (classified as group A Strep-
continues to increase; however, Streptococcus and Enterococ- tococcus in the Lancefield typing scheme) is streptococcal
cus are the genera most frequently isolated and most com- pharyngitis (“strep throat”). The group antigen for this
monly responsible for human disease. The other genera are organism can be detected directly from throat swab speci-
relatively uncommon and are listed in Table 19-2 but are not mens by a variety of rapid immunoassays and is a commonly
discussed further. used diagnostic test in hospital and physician office labora-
The classification of more than 100 species within the tories. The Lancefield typing scheme is primarily used today
genus Streptococcus is complicated because three different for only a few species of streptococci (e.g., those classified in
overlapping schemes are used: (1) serologic properties: groups A, B, C, F, and G; Table 19-3).
Lancefield groupings (originally A to W); (2) hemolytic The enterococci (“enteric cocci”) were previously classi-
patterns: complete (beta [β]) hemolysis, incomplete (alpha fied as group D streptococci because they share the group
[α]) hemolysis, and no (gamma [γ]) hemolysis; and (3) bio- D cell wall antigen, a glycerol teichoic acid, with other strep-
chemical (physiologic) properties. Although this is an tococci. In 1984, the enterococci were reclassified into the
oversimplification, it is practical to think that the strepto- new genus Enterococcus, and there are currently 54 species
cocci are divided into two groups: (1) the β-hemolytic strep- in this genus; however, relatively few species are important
tococci, which are classified by Lancefield grouping, and (2) human pathogens. The most commonly isolated and
186   MEDICAL MICROBIOLOGY

Table 19-1  Important Streptococci and Enterococci Table 19-2  Catalase-Negative, Gram-Positive Cocci and
Their Diseases
Organism Historical Derivation
Organism Diseases
Streptococcus streptus, pliant; coccus, grain or berry (a pliant berry or
coccus; refers to the appearance of long, flexible Abiotrophia Bacteremia, endocarditis (native and prosthetic valves),
chains of cocci) nosocomial brain abscesses and meningitis, eye
infections
S. agalactiae agalactia, want of milk (original isolate [called
S. mastitidis] was responsible for bovine mastitis) Aerococcus Bacteremia, endocarditis, urinary tract infections
S. anginosus anginosus, pertaining to angina Enterococcus Bacteremia, endocarditis, urinary tract infections,
peritonitis, wound infections
S. constellatus constellatus, studded with stars (original isolate
embedded in agar with smaller colonies surrounding Granulicatella Bacteremia, endocarditis (native and prosthetic valves),
the large colony; satellite formation does not occur eye infections
around colonies on the surface of an agar plate) Lactococcus Bacteremia in immunocompromised patients,
S. dysgalactiae dys, ill, hard; galactia, pertaining to milk (loss of milk endocarditis (native and prosthetic valves), urinary tract
secretion; isolates associated with bovine mastitis) infections, osteomyelitis
S. gallolyticus gallatum, gallate; lyticus, to loosen (able to digest or Leuconostoc Opportunistic infections, including bacteremia, wound
hydrolyze methyl gallate) infections, central nervous system infections, and
peritonitis
S. intermedius intermedius, intermediate (initial confusion about
whether this was an aerobic or an anaerobic Pediococcus Opportunistic infections, including bacteremia in severely
bacterium) immunocompromised patients
S. mitis mitis, mild (incorrectly thought to cause mild infections) Streptococcus Refer to Tables 19-3 and 19-4
S. mutans mutans, changing (cocci that may appear rodlike,
particularly when initially isolated in culture)
S. pneumoniae pneumon, the lungs (causes pneumonia) Table 19-3  Classification of Common β-Hemolytic
Streptococci
S. pyogenes pyus, pus; gennaio, beget or producing (pus producing;
Group Representative Diseases
typically associated with formation of pus in wounds)
Species
S. salivarius salivarius, salivary (found in the mouth in saliva)
A S. pyogenes Pharyngitis, skin and soft-tissue infections,
Enterococcus enteron, intestine; coccus, berry (intestinal coccus) bacteremia, rheumatic fever, acute
E. faecalis faecalis, relating to feces glomerulonephritis

E. faecium faecium, of feces S. anginosus group Abscesses

E. gallinarum gallinarum, of hens (original source was intestines of B S. agalactiae Neonatal disease, endometritis, wound
domestic fowl) infections, urinary tract infections,
bacteremia, pneumonia, skin and
E. casseliflavus casseli, Kassel’s; flavus, yellow (Kassel’s yellow) soft-tissue infections
C S. dysgalactiae Pharyngitis, acute glomerulonephritis

clinically important species are Enterococcus faecalis and F, G S. anginosus group Abscesses
Enterococcus faecium. Enterococcus gallinarum and Entero- S. dysgalactiae Pharyngitis, acute glomerulonephritis
coccus casseliflavus are also common colonizers of the
human intestinal tract and are important because these
species are inherently vancomycin resistant.
The viridans streptococci are subdivided into five clini- common cause of bacterial pharyngitis, the notoriety of S.
cally distinct groups (Table 19-4). Some species of the viri- pyogenes, popularly called “flesh-eating” bacteria, results
dans streptococci can be β-hemolytic as well as α-hemolytic from life-threatening myonecrosis caused by this organism.
and nonhemolytic, which unfortunately has resulted in clas-
sifying these bacteria by both their Lancefield grouping and Physiology and Structure
as viridans streptococci. Although the classification of the Isolates of S. pyogenes are spherical cocci, 1 to 2 µm in
streptococci is somewhat confusing, clinical disease is well diameter, arranged in short chains in clinical specimens and
defined for individual species, which will be the emphasis for longer chains when grown in liquid media (Figure 19-1).
the remainder of this chapter. Growth is optimal on enriched-blood agar media but is
inhibited if the medium contains a high concentration
of glucose. After 24 hours of incubation, 1- to 2-mm
• Streptococcus pyogenes white colonies with large zones of β-hemolysis are observed
(Figure 19-2).
S. pyogenes causes a variety of suppurative and nonsuppura- The antigenic structure of S. pyogenes has been exten-
tive diseases (Box 19-1). Although this organism is the most sively studied. The basic structural framework of the cell wall
 CHAPTER 19  STREPTOCOCCUS AND ENTEROCOCCUS    187

Table 19-4  Classification of Viridans Group of

Streptococcus
Group Representative Species Diseases
Anginosus S. anginosus, Abscesses in brain, oropharynx,
S. constellatus, or peritoneal cavity
S. intermedius
Mitis S. mitis, Subacute endocarditis; sepsis in
S. pneumoniae, neutropenic patients;
S. oralis pneumonia; meningitis
Mutans S. mutans, S. sobrinus Dental caries; bacteremia
Salivarius S. salivarius Bacteremia; endocarditis
Bovis S. gallolyticus subsp. Bacteremia associated with
gallolyticus, subsp. gastrointestinal cancer (subsp.
pasteurianus gallolyticus); meningitis (subsp.
pasteurianus) FIGURE 19-1  Gram stain of Streptococcus pyogenes.
Ungrouped S. suis Meningitis; bacteremia;
streptococcal toxic shock
syndrome

Box 19-1  Streptococcal and Enterococcal Diseases: Clinical Summaries

Streptococcus pyogenes (Group A) Other β-Hemolytic Streptococci

Suppurative Infections Abscess formation in deep tissues: associated with S. anginosus group
Pharyngitis: reddened pharynx with exudates generally present; cervical Pharyngitis: associated with S. dysgalactiae; disease resembles
lymphadenopathy can be prominent that caused by S. pyogenes; can be complicated with acute
Scarlet fever: diffuse erythematous rash beginning on the chest and glomerulonephritis
spreading to the extremities; complication of streptococcal pharyngitis
Viridans Streptococci
Pyoderma: localized skin infection with vesicles progressing to pustules;
Abscess formation in deep tissues: associated with S. anginosus group
no evidence of systemic disease
Septicemia in neutropenic patients: associated with S. mitis group
Erysipelas: localized skin infection with pain, inflammation, lymph node
Subacute endocarditis: associated with S. mitis and S. salivarius groups
enlargement, and systemic symptoms
Dental caries: associated with S. mutans group
Cellulitis: infection of the skin that involves the subcutaneous tissues
Malignancies of gastrointestinal tract: associated with S. bovis group
Necrotizing fasciitis: deep infection of skin that involves destruction of
(S. gallolyticus subsp. gallolyticus)
muscle and fat layers
Streptococcal toxic shock syndrome: multiorgan systemic infection Meningitis: associated with S. gallolyticus subsp. pasteurianus, S. suis,
resembling staphylococcal toxic shock syndrome; however, most and S. mitis group
patients are bacteremic and with evidence of fasciitis
Streptococcus pneumoniae
Other suppurative diseases: variety of other infections recognized includ-
Pneumonia: acute onset with severe chills and sustained fever; productive
ing puerperal sepsis, lymphangitis, and pneumonia
cough with blood-tinged sputum; lobar consolidation
Nonsuppurative Infections Meningitis: severe infection involving the meninges, with headache, fever,
Rheumatic fever: characterized by inflammatory changes of the heart and sepsis; high mortality and severe neurologic deficits in survivors
(pancarditis), joints (arthralgias to arthritis), blood vessels, and subcuta- Bacteremia: more common in patients with meningitis than with pneumo-
neous tissues nia, otitis, media, or sinusitis; overwhelming sepsis in asplenic patients
Acute glomerulonephritis: acute inflammation of the renal glomeruli with
Enterococcus faecalis and Enterococcus faecium
edema, hypertension, hematuria, and proteinuria
Urinary tract infection: dysuria and pyuria, most commonly in hospitalized
Streptococcus agalactiae (Group B) patients with an indwelling urinary catheter and receiving broad-
Early-onset neonatal disease: within 7 days of birth, infected newborns spectrum cephalosporin antibiotics
develop signs and symptoms of pneumonia, meningitis, and sepsis Peritonitis: abdominal swelling and tenderness after abdominal trauma or
Late-onset neonatal disease: more than 1 week after birth, neonates surgery; patients typically are acutely ill and febrile and have positive
develop signs and symptoms of bacteremia with meningitis blood cultures; typically a polymicrobic infection
Infections in pregnant women: most often present as postpartum endo- Bacteremia: associated with either a localized infection or endocarditis
metritis, wound infections, and urinary tract infections; bacteremia and Endocarditis: infection of the heart endothelium or valves; associated with
disseminated complications may occur persistent bacteremia; can present acutely or chronically
Infections in other adult patients: most common diseases include bac-
teremia, pneumonia, bone and joint infections, and skin and soft-tissue
infections
188   MEDICAL MICROBIOLOGY

Pathogenesis and Immunity

The virulence of group A streptococci is determined by the
ability of the bacteria to avoid opsonization and phagocyto-
sis, adhere to and invade host cells, and produce a variety of
toxins and enzymes.

Initial Host-Parasite Interactions

S. pyogenes has multiple mechanisms for avoiding opso-
nization and phagocytosis. The hyaluronic acid capsule is
a poor immunogen and interferes with phagocytosis. The
M proteins also interfere with phagocytosis by blocking the
binding of the complement component C3b, an important
mediator of phagocytosis. C3b may also be degraded by
factor H, which binds to the cell surface of the M protein.
M-like proteins resemble M proteins in structure and are
under the same regulatory control. These proteins interfere
with phagocytosis by binding either the Fc fragment of
FIGURE 19-2  Streptococcus pyogenes (group A) typically appears antibodies or fibronectin, which blocks activation of com-
as small colonies with a large zone of hemolysis. plement by the alternate pathway and reduces the amount
of bound C3b. Finally, S. pyogenes has C5a peptidase on
the surface. This serine protease inactivates C5a, a che-
is the peptidoglycan layer, which is similar in composition moattractant of neutrophils and mononuclear phagocytes,
to that found in other gram-positive bacteria. Within the and protects the bacteria from early clearance from infected
cell wall are group-specific and type-specific antigens. tissues.
The group-specific carbohydrate that constitutes approxi- Many different bacterial antigens have been demonstrated
mately 10% of the dry weight of the cell (Lancefield group to mediate adherence to host cells, with lipoteichoic
A antigen) is a dimer of N-acetylglucosamine and rham- acid, M proteins, and F protein the most important. The
nose. This antigen is used to classify group A streptococci initial adherence is a weak interaction between lipoteichoic
and distinguish them from other streptococcal groups. acid and fatty acid binding sites on fibronectin and epithelial
M protein is the major type-specific protein associated with cells. Subsequent adherence involves M protein, F protein,
virulent strains. It consists of two polypeptide chains com- and other adhesins that interact with specific host cell
plexed in an alpha helix. The protein is anchored in the receptors.
cytoplasmic membrane, extends through the cell wall, and S. pyogenes can invade into epithelial cells, a process that
protrudes above the cell surface. The carboxyl terminus, is mediated by M protein and F protein and other bacterial
which is anchored in the cytoplasmic membrane, and the antigens. This internalization is believed to be important for
portion of the molecule in the cell wall are highly conserved maintenance of persistent infections (e.g., recurrent strepto-
(by amino acid sequence) among all group A streptococci. coccal pharyngitis) and invasion into deep tissues.
The amino terminus, which extends above the cell surface,
is responsible for the antigenic differences observed among Toxins and Enzymes
the unique serotypes of M proteins. M proteins are subdi- The streptococcal pyrogenic exotoxins (Spe), originally
vided into class I and class II molecules. The class I M pro- called erythrogenic toxins, are produced by lysogenic strains
teins share exposed antigens, whereas the class II M proteins of streptococci and are similar to the toxin produced in
do not have exposed shared antigens. Although strains with Corynebacterium diphtheriae. Four immunologically distinct
both classes of antigens can cause suppurative infections and heat-labile toxins (SpeA, SpeB, SpeC, and SpeF) have been
glomerulonephritis, only bacteria with class I (exposed described in S. pyogenes and in rare strains of groups C and
shared antigen) M proteins cause rheumatic fever. The epi- G streptococci. The toxins act as superantigens, interacting
demiologic classification of S. pyogenes is based on sequence with both macrophages and helper T cells, with the enhanced
analysis of the emm gene that encodes the M proteins. release of proinflammatory cytokines. This family of exotox-
Other important components in the cell wall of S. pyo- ins is believed responsible for many of the clinical manifesta-
genes include M-like surface proteins, lipoteichoic acid, tions of severe streptococcal diseases, including necrotizing
and F protein. A complex of more than 20 genes that com- fasciitis and streptococcal toxic shock syndrome, as well as
prise the emm gene superfamily encode the M-like proteins the rash observed in patients with scarlet fever. It is unclear
as well as the M proteins and immunoglobulin-binding pro- whether the rash results from the direct effect of the toxin
teins. Lipoteichoic acid and F protein facilitate binding of on the capillary bed or, more likely, is secondary to a hyper-
host cells by complexing with fibronectin, which is present sensitivity reaction.
on the host cell surface. Streptolysin S is an oxygen-stable, nonimmunogenic,
Some strains of S. pyogenes have an outer hyaluronic acid cell-bound hemolysin that can lyse erythrocytes, leukocytes,
capsule that is antigenically indistinguishable from hyal- and platelets. It can also stimulate the release of lysosomal
uronic acid in mammalian connective tissues. Because the contents after engulfment, with subsequent death of the
capsule can protect the bacteria from phagocytic clearance, phagocytic cell. Streptolysin S is produced in the presence of
encapsulated strains are more likely to be responsible for serum (the S indicates serum stable) and is responsible for
severe systemic infections. the characteristic β-hemolysis seen on blood agar media.
 CHAPTER 19  STREPTOCOCCUS AND ENTEROCOCCUS    189

Streptolysin O is an oxygen-labile hemolysin capable of Clinical Diseases

lysing erythrocytes, leukocytes, platelets, and cultured cells.
This hemolysin is antigenically related to oxygen-labile Suppurative Streptococcal Disease
toxins produced by Streptococcus pneumoniae, Clostridium Pharyngitis
tetani, Clostridium perfringens, Bacillus cereus, and Listeria Pharyngitis generally develops 2 to 4 days after exposure to
monocytogenes. Antibodies are readily formed against strep- the pathogen, with an abrupt onset of sore throat, fever,
tolysin O (antistreptolysin O [ASO] antibodies), a feature malaise, and headache. The posterior pharynx can appear
differentiating it from streptolysin S, and are useful for docu- erythematous with an exudate, and cervical lymphadenopa-
menting recent group A streptococcal infection (ASO test). thy can be prominent. Despite these clinical signs and symp-
Streptolysin O is irreversibly inhibited by cholesterol in skin toms, differentiating streptococcal pharyngitis from viral
lipids, so patients with cutaneous infections do not develop pharyngitis is difficult. An accurate diagnosis can be made
ASO antibodies. only with specific laboratory tests.
At least two forms of streptokinase (A and B) have been Scarlet fever is a complication of streptococcal pharyn-
described. These enzymes mediate the cleavage of plasmino- gitis that occurs when the infecting strain is lysogenized by
gen, releasing the protease plasmin that, in turn, cleaves a bacteriophage that mediates production of a pyrogenic
fibrin and fibrinogen. Thus these enzymes can lyse blood exotoxin. Within 1 to 2 days after the initial clinical symp-
clots and fibrin deposits and facilitate the rapid spread of S. toms of pharyngitis develop, a diffuse erythematous rash
pyogenes in infected tissues. Antibodies directed against initially appears on the upper chest and then spreads to the
these enzymes (anti-streptokinase antibodies) are a useful extremities. The area around the mouth is generally spared
marker for infection. (circumoral pallor), as are the palms and soles. A yellowish-
Four immunologically distinct deoxyribonucleases white coating initially covers the tongue and is later shed,
(DNases A to D) have been identified. These enzymes are revealing a red, raw surface beneath (“strawberry tongue”).
not cytolytic but can depolymerize free deoxyribonucleic The rash, which blanches when pressed, is best seen on the
acid (DNA) present in pus. This process reduces the viscosity abdomen and in skinfolds (Pastia lines). The rash disappears
of the abscess material and facilitates spread of the organ- over the next 5 to 7 days and is followed by desquamation
isms. Antibodies developed against DNase B are an impor- of the superficial skin layer. Suppurative complications of
tant marker of S. pyogenes infections (anti-DNase B test), streptococcal pharyngitis (e.g., peritonsillar and retropha-
particularly for patients with cutaneous infections, because ryngeal abscesses) are rare since the advent of antimicrobial
they fail to make antibodies against streptolysin O (see pre- therapy.
ceding text).
Pyoderma
Epidemiology Pyoderma (impetigo) is a confined, purulent (“pyo”) infec-
The Centers for Disease Control and Prevention (CDC) has tion of the skin (“derma”) that primarily affects exposed areas
estimated that at least 10 million cases of noninvasive disease (i.e., face, arms, legs). Infection begins when the skin is colo-
occur annually, with pharyngitis and pyoderma the most nized with S. pyogenes after direct contact with an infected
common infections. Group A streptococci can colonize the person or fomites. The organism is introduced into the sub-
oropharynx of healthy children and young adults in the cutaneous tissues through a break in the skin (e.g., scratch,
absence of clinical disease. However, isolation of S. pyogenes insect bite). Vesicles develop, progressing to pustules (pus-
in a patient with pharyngitis is generally considered signifi- filled vesicles), and then rupture and crust over. The regional
cant. Asymptomatic colonization with S. pyogenes is tran- lymph nodes can become enlarged, but systemic signs of
sient, regulated by the person’s ability to mount specific infection (e.g., fever, sepsis, involvement of other organs) are
immunity to the M protein of the colonizing strain and the uncommon. Secondary dermal spread of the infection
presence of competitive organisms in the oropharynx. caused by scratching is typical.
Untreated patients produce antibodies against the specific Pyoderma is seen primarily during the warm, moist
bacterial M protein that can result in long-lived immunity; months in young children with poor personal hygiene.
however, this antibody response is diminished in treated Although S. pyogenes is responsible for most streptococcal
patients. skin infections, groups C and G streptococci have also been
In general, S. pyogenes disease is caused by recently implicated. Staphylococcus aureus is also commonly present
acquired strains that can establish an infection of the pharynx in the lesions. The strains of streptococci that cause skin
or skin before specific antibodies are produced or competi- infections differ from those that cause pharyngitis, although
tive organisms are able to proliferate. Pharyngitis caused by pyoderma serotypes can colonize the pharynx and establish
S. pyogenes is primarily a disease of children between the a persistent carriage state.
ages of 5 and 15 years, but infants and adults are also sus-
ceptible. The pathogen is spread from person to person Erysipelas
through respiratory droplets. Crowding, such as in class- Erysipelas (erythros, “red”; pella, “skin”) is an acute infection
rooms and day-care facilities, increases the opportunity for of the skin. Patients experience localized pain, inflammation
the organism to spread, particularly during the winter (erythema, warmth), lymph node enlargement, and systemic
months. Soft-tissue infections (i.e., pyoderma, erysipelas, signs (chills, fever, leukocytosis). The involved skin area is
cellulitis, fasciitis) are typically preceded by initial skin colo- typically raised and distinctly differentiated from the unin-
nization with group A streptococci, after which the organ- volved skin (Figure 19-3). Erysipelas occurs most commonly
isms are introduced into the superficial or deep tissues in young children or older adults, historically on the face but
through a break in the skin. now more commonly on the legs, and usually is preceded by
190   MEDICAL MICROBIOLOGY

infections of the respiratory tract or skin with S. pyogenes spreads along the fascial planes, and is characterized by an
(less commonly with group C or G streptococci). extensive destruction of muscle and fat (Figure 19-4). The
organism (referred to by the news media as “flesh-eating
Cellulitis bacteria”) is introduced into the tissue through a break in the
Unlike erysipelas, cellulitis typically involves both the skin skin (e.g., minor cut or trauma, vesicular viral infection,
and deeper subcutaneous tissues, and the distinction between burn, surgery). Initially, there is evidence of cellulitis, after
infected and noninfected skin is not as clear. As in erysipelas, which bullae form and gangrene (tissue necrosis associated
local inflammation and systemic signs are observed. Precise with obstructed blood flow) and systemic symptoms develop.
identification of the offending organism is necessary because Toxicity, multiorgan failure, and death are the hallmarks of
many different organisms can cause cellulitis. this disease; thus prompt medical intervention is necessary
to save the patient. Unlike cellulitis, which can be treated
Necrotizing Fasciitis with antibiotic therapy, fasciitis must also be treated aggres-
Necrotizing fasciitis (also called streptococcal gangrene) is sively with surgical debridement of infected tissue.
an infection that occurs deep in the subcutaneous tissue,
Streptococcal Toxic Shock Syndrome
(Clinical Case 19-1)
Although the incidence of severe S. pyogenes disease declined
steadily after the advent of antibiotics, this trend changed
dramatically in the late 1980s, when infections characterized
by multisystem toxicity were reported. Patients with this syn-
drome initially experience soft-tissue inflammation at the
site of the infection, pain, and nonspecific symptoms such as
fever, chills, malaise, nausea, vomiting, and diarrhea. The
pain intensifies as the disease progresses to shock and organ
failure (e.g., kidney, lungs, liver, heart)—features similar to
those of staphylococcal toxic shock syndrome. However, in
contrast with staphylococcal disease, most patients with
streptococcal disease are bacteremic, and many have necro-
tizing fasciitis.
Although people of all age groups are susceptible to strep-
tococcal toxic shock syndrome, increased risk for disease is
observed for patients with human immunodeficiency virus
(HIV) infection, cancer, diabetes mellitus, heart or pulmo-
nary disease, and varicella-zoster virus infection, as well as
intravenous drug abusers and those who abuse alcohol. The
strains of S. pyogenes responsible for this syndrome differ
from the strains causing pharyngitis in that most of the former
FIGURE 19-3  Acute stage of erysipelas of the leg. Note the ery- are M serotypes 1 or 3 and many have prominent mucopoly-
thema in the involved area and bullae formation. (From Emond RT, saccharide hyaluronic acid capsules (mucoid strains). The
Rowland HAK, Welsby P: Colour atlas of infectious diseases, ed 3, production of pyrogenic exotoxins, particularly SpeA and
London, 1995, Wolfe.) SpeC, is also a prominent feature of these organisms.

A B

FIGURE 19-4  Necrotizing fasciitis caused by Streptococcus pyogenes. The patient presented with a 3-day history of malaise, diffuse myalgia,
and low-grade fever. Over 3 hours, the pain became excruciating and was localized to the calf. A, Note the two small, purple bullae over
the calf (arrows). B, Extensive necrotizing fasciitis was present on surgical exploration. The patient died despite aggressive surgical and
medical management. (From Cohen J, Powderly WG, Opal SM: Infectious diseases, ed 3, Philadelphia, 2010, Mosby.)
 CHAPTER 19  STREPTOCOCCUS AND ENTEROCOCCUS    191

antigenic site are responsible for rheumatic fever. In addi-

Clinical Case 19-1  Streptococcal Toxic
Shock Syndrome
tion, rheumatic fever is associated with streptococcal phar-
yngitis but not cutaneous streptococcal infections. As would
Streptococcal toxic shock syndrome is a frightening, deadly infection. This be expected, the epidemiologic characteristics of the disease
is illustrated by a patient reported by Cone and associates in 1987 (N Engl mimic those of streptococcal pharyngitis. It is most common
J Med 317:146–149, 1987). The patient was a 46-year-old man who was in young school-age children, with no male or female predi-
scratched on his forearm by his German shepherd dog and then reopened lection, and occurs primarily during the cooler months of
the wound while at work the next day. The following evening, he developed the fall or winter. The disease occurs most commonly in
a low-grade fever, chills, backache, and myalgia. When he presented to patients with severe streptococcal pharyngitis; however, as
the local emergency department, minimal erythema and a thin serous many as one third of patients have asymptomatic or mild
discharge were noted at the wound site. Cultures of the wound and blood infection. Rheumatogenic strains induce a vigorous antibody
were collected, and intravenous antibiotics were started. Within 10 hours, response in all patients with pharyngitis. Rheumatic fever
the patient became confused and hypotensive. He was transferred to the can recur with a subsequent streptococcal infection if anti-
intensive care unit. Because the erythema over the wound had spread and biotic prophylaxis is not used. The risk for recurrence
multiple bullae formed on the wound surface, the patient was taken to decreases with time.
surgery, where yellowish fluid in the muscle tissues was drained. Cultures Because no specific diagnostic test can identify patients
from the surgical site, as well as the original wound cultures, grew Strep- with rheumatic fever, the diagnosis is made on the basis of
tococcus pyogenes. Following surgical debridement, the patient continued clinical findings and documented evidence of a recent S.
to decline, with the development of abnormal liver function, renal failure, pyogenes infection, such as (1) positive throat culture or spe-
pulmonary distress, and cardiac abnormalities. The patient developed cific nucleic acid–based test, (2) detection of the group A
persistent hypotension and died 3 days after admission to the hospital. antigen in a throat swab, or (3) an elevation of ASO, anti-
The fulminant progression of this disease and multiorgan failure underlines DNase B, or anti-hyaluronidase antibodies. The absence of
the need for aggressive medical intervention. an elevated or rising antibody titer would be strong evidence
against rheumatic fever.
Acute Glomerulonephritis
Other Suppurative Diseases The second nonsuppurative complication of streptococcal
S. pyogenes has been associated with a variety of other sup- disease is glomerulonephritis, which is characterized by
purative infections, including puerperal sepsis, lymphangi- acute inflammation of the renal glomeruli with edema,
tis, and pneumonia. Although these infections are still seen, hypertension, hematuria, and proteinuria. Specific nephrito-
they became less common after the introduction of antibiotic genic strains of group A streptococci are associated with this
therapy. disease. In contrast with rheumatic fever, acute glomerulo-
nephritis is a sequela of both pharyngeal and pyodermal
Bacteremia streptococcal infections; however, the nephrogenic M sero-
S. pyogenes is one of the most common β-hemolytic strepto- types differ for the two primary diseases. The epidemiologic
cocci isolated in blood cultures. Patients with localized characteristics of the disease are similar to those of the initial
infections (e.g., pharyngitis, pyoderma, erysipelas) rarely are streptococcal infection. Diagnosis is determined on the basis
bacteremic, but blood cultures are positive in most patients of the clinical presentation and the finding of evidence of a
with necrotizing fasciitis or toxic shock syndrome. The mor- recent S. pyogenes infection. Young patients generally have
tality in this population of patients approaches 40% in coun- an uneventful recovery, but the long-term prognosis for
tries with a sophisticated medical infrastructure and is much adults is unclear. Progressive irreversible loss of renal func-
higher in resource-limited countries. tion has been observed in adults.
Nonsuppurative Streptococcal Disease Laboratory Diagnosis
Rheumatic Fever Microscopy
Rheumatic fever is a nonsuppurative complication of S. Gram stains of affected tissue can be used to make a rapid
pyogenes pharyngitis. It is characterized by inflammatory preliminary diagnosis of S. pyogenes soft-tissue infections or
changes involving the heart, joints, blood vessels, and sub- pyoderma. Because streptococci are not observed in Gram
cutaneous tissues. Involvement of the heart manifests as a stains of uninfected skin, the finding of gram-positive cocci
pancarditis (endocarditis, pericarditis, myocarditis) and is in pairs and chains in association with leukocytes is impor-
often associated with subcutaneous nodules. Chronic pro- tant. In contrast, many species of streptococci are part of the
gressive damage to the heart valves may occur. Joint mani- normal oropharyngeal flora, so observation of streptococci
festations can range from arthralgias to frank arthritis, with in a respiratory specimen from a patient with pharyngitis has
multiple joints involved in a migratory pattern (i.e., involve- no diagnostic significance.
ment shifts from one joint to another).
The incidence of rheumatic fever in the United States has Antigen Detection
decreased from a peak of more than 10,000 cases per year A variety of immunologic tests using antibodies that react
reported in 1961 to 112 cases reported in 1994 (the last year with the group-specific carbohydrate in the bacterial cell wall
of mandatory reporting). In contrast, disease in developing can be used to detect group A streptococci directly in throat
countries is much more common, with an estimated 100 swabs. These tests are rapid, inexpensive, and specific.
cases per 100,000 children per year. Specific class I M protein Antigen tests are not used for cutaneous or nonsuppurative
types (e.g., types 1, 3, 5, 6, and 18) with an exposed shared diseases.
192   MEDICAL MICROBIOLOGY

Nucleic Acid–Based Tests with streptococcal pyoderma (see previous discussion).

Commercial nucleic acid probe assay and nucleic acid ampli- The production of antibodies against other streptococcal
fication assays are available for the detection of S. pyogenes enzymes, particularly DNase B, has been documented in
in pharyngeal specimens. Probe assays are less sensitive than patients with either streptococcal pyoderma or pharyngitis.
culture, but amplification assays are as sensitive as culture The anti-DNase B test should be performed if streptococcal
and are the test of choice where available. glomerulonephritis is suspected.

Culture Treatment, Prevention, and Control

Despite the difficulty of collecting throat swab specimens S. pyogenes is very sensitive to penicillin, so oral penicillin V
from children, specimens must be obtained from the poste- or amoxicillin can be used to treat streptococcal pharyngitis.
rior oropharynx (e.g., tonsils). Fewer bacteria are present in For penicillin-allergic patients, an oral cephalosporin or
the anterior areas of the mouth, and because the mouth macrolide may be used. The combined use of intravenous
(particularly saliva) is colonized with bacteria that inhibit penicillin with a protein synthesis–inhibiting antibiotic (e.g.,
the growth of S. pyogenes, contamination of even a properly clindamycin) is recommended for severe systemic infec-
collected specimen may obscure or suppress the growth of tions. Resistance or poor clinical response has limited the
S. pyogenes. The recovery of S. pyogenes from patients with usefulness of the tetracyclines and sulfonamides, and resis-
impetigo is not a problem. The crusted top of the lesion is tance to erythromycin and the newer macrolides (e.g.,
raised, and the purulent material and base of the lesion are azithromycin, clarithromycin) is increasing in frequency.
cultured. Culture specimens should not be obtained from Drainage and aggressive surgical debridement must be
open draining skin pustules, because they might be superin- promptly initiated in patients with serious soft-tissue
fected with staphylococci. Organisms are readily recovered infections.
in the tissues and blood cultures obtained from patients with Persistent oropharyngeal carriage of S. pyogenes can occur
necrotizing fasciitis; however, relatively few organisms may after a complete course of therapy. This state may stem from
be present in the skin of patients with erysipelas or cellulitis. poor compliance with the prescribed course of therapy, rein-
As mentioned previously, streptococci have fastidious growth fection with a new strain, or persistent carriage in a seques-
requirements and growth on the plates may be delayed, so tered focus. Because penicillin resistance has not been
prolonged incubation (2 to 3 days) should be used before a observed in patients with oropharyngeal carriage, penicillin
culture is considered negative. can be given for an additional course of treatment. If carriage
persists, re-treatment is not indicated, because prolonged
Identification antibiotic therapy can disrupt the normal bacterial flora.
Group A streptococci are identified definitively through the Antibiotic therapy in patients with pharyngitis speeds the
demonstration of the group-specific carbohydrate, a tech- relief of symptoms and, if initiated within 10 days of the
nique that was not practical until the introduction of direct initial clinical disease, prevents rheumatic fever. Antibiotic
antigen detection tests. Differentiation of S. pyogenes from therapy does not appear to influence the progression to acute
other species of streptococci with the group-specific A glomerulonephritis.
antigen can be determined by their susceptibility to bacitra- Patients with a history of rheumatic fever require long-
cin or the presence of the enzyme L-pyrrolidonyl arylami- term antibiotic prophylaxis to prevent recurrence of the
dase (PYR). Susceptibility to bacitracin is determined by disease. Because damage to the heart valve predisposes these
placing a disk saturated with bacitracin onto a plate inocu- patients to endocarditis, they also require antibiotic prophy-
lated with group A streptococci; after overnight incubation, laxis before they undergo procedures that can induce tran-
strains inhibited by bacitracin are considered group A strep- sient bacteremias (e.g., dental procedures). Specific antibiotic
tococci. The PYR test measures hydrolysis l-pyrrolindonyl- therapy does not alter the course of acute glomerulonephri-
β-naphthylamide, releasing β-naphthylamine, which, in the tis, and prophylactic therapy is not indicated because recur-
presence of p-dimethylaminocinnamaldehyde, forms a red rent disease is not observed in these patients.
compound. The advantage of this specific test is that it takes
less than 1 minute to determine whether the reaction is
positive (S. pyogenes) or negative (all other streptococci). • Streptococcus agalactiae
Enterococci are PYR positive but do not react with group A
antisera. S. agalactiae is the only species that has the group B antigen.
This organism was first recognized as a cause of puerperal
Antibody Detection sepsis. Although this disease is now relatively uncommon,
Patients with S. pyogenes disease produce antibodies to spe- S. agalactiae has become better known as an important cause
cific streptococcal enzymes. Although antibodies against the of septicemia, pneumonia, and meningitis in newborn
M protein are produced and are important for maintaining children, as well as a cause of serious disease in adults (see
immunity, these type-specific antibodies appear late in the Box 19-1).
clinical course of the disease and are not useful for diagnosis.
In contrast, the measurement of antibodies against strepto- Physiology and Structure
lysin O (ASO test) is useful for confirming rheumatic fever Group B streptococci are gram-positive cocci (0.6 to 1.2 µm)
or acute glomerulonephritis resulting from a recent strepto- that form short chains in clinical specimens and longer
coccal pharyngeal infection. These antibodies appear 3 to 4 chains in culture, features that make them indistinguishable
weeks after the initial exposure to the organism and then on Gram stain from S. pyogenes. They grow well on nutri-
persist. An elevated ASO titer is not observed in patients tionally enriched media and, in contrast with the colonies of
 CHAPTER 19  STREPTOCOCCUS AND ENTEROCOCCUS    193

S. pyogenes, the colonies of S. agalactiae are large with a Colonization with subsequent development of disease in
narrow zone of β-hemolysis. Some strains (1% to 2%) are the neonate can occur in utero, at birth, or during the first
nonhemolytic, although their prevalence may be underesti- few months of life. S. agalactiae is the most common cause
mated because nonhemolytic strains are not commonly of bacterial septicemia and meningitis in newborns. The use
screened for the group B antigen. of intrapartum antibiotic prophylaxis is responsible for a
Strains of S. agalactiae can be characterized on the basis dramatic decline in neonatal disease—from approximately
of three serologic markers: (1) the group-specific cell wall 8000 infections in 1993 to 1800 infections in 2002.
polysaccharide B antigen (Lancefield grouping antigen); (2) The risk of invasive disease in adults is greater in pregnant
nine type-specific capsular polysaccharides (Ia, Ib, and II women than in men and nonpregnant women. Urinary tract
to VIII); and (3) surface proteins (the most common is the infections, amnionitis, endometritis, and wound infections
c antigen). The type-specific polysaccharides are important are the most common manifestations in pregnant women.
epidemiologic markers, with serotypes Ia, Ib, II, III, and V Infections in men and nonpregnant women are primarily
most commonly associated with colonization and disease. skin and soft-tissue infections, bacteremia, urosepsis (urinary
Knowledge of the specific serotypes associated with disease tract infection with bacteremia), and pneumonia. Condi-
and of shifting patterns of serotype prevalence is important tions that predispose to the development of disease in non-
for vaccine development. pregnant adults include diabetes mellitus, chronic liver or
renal disease, cancer, and HIV infection.
Pathogenesis and Immunity
The most important virulence factor of S. agalactiae is the Clinical Diseases
polysaccharide capsule that interferes with phagocytosis Early-Onset Neonatal Disease
until the patient develops type-specific antibodies. Anti- Clinical symptoms of group B streptococcal disease acquired
bodies against the type-specific capsular antigens are pro- in utero or at birth develop during the first week of life.
tective, a factor that partly explains the predilection of this Early-onset disease, characterized by bacteremia, pneumo-
organism for neonates. In the absence of maternal antibod- nia, or meningitis, is indistinguishable from sepsis caused
ies, the neonate is at risk for disease. In addition, genital by other organisms. Because pulmonary involvement is
colonization with group B streptococci has been associated observed in most infants and meningeal involvement may
with increased risk of premature delivery, and premature be initially inapparent, examination of cerebrospinal fluid
infants are at greater risk of disease. Functional classical (CSF) is required for all infected children. The mortality rate
and alternative complement pathways are required for has decreased to less than 5% because of rapid diagnosis and
killing group B streptococci, particularly types Ia, III, and better supportive care; however, 15% to 30% of infants who
V. As a result, there is a greater likelihood of systemic survive meningitis have severe neurologic sequelae, includ-
spread of the organism in colonized premature infants with ing blindness, deafness, and mental retardation.
physiologically low complement levels or for infants in
whom the receptors for complement, or for the Fc fragment Late-Onset Neonatal Disease
of immunoglobulin (Ig)G antibodies, are not exposed on (Clinical Case 19-2)
neutrophils. It has also been found that the type-specific Late-onset disease is acquired from an exogenous source
capsular polysaccharides of types Ia, Ib, and II streptococci (e.g., mother, another infant) and develops between 1 week
have a terminal residue of sialic acid. Sialic acid can inhibit and 3 months of age. The predominant manifestation is bac-
activation of the alternative complement pathway, thus teremia with meningitis, which resembles disease caused by
interfering with the phagocytosis of these strains of group B other bacteria. Although the mortality rate is low (e.g., 3%),
streptococci. neurologic complications are common in children with
meningitis (e.g., 25% to 50%).
Epidemiology
Group B streptococci colonize the lower gastrointestinal
tract and the genitourinary tract. Transient vaginal carriage
has been observed in 10% to 30% of pregnant women, Clinical Case 19-2  Group B Streptococcal Disease in
although the observed incidence depends on the time during a Neonate
the gestation period when the sampling is done and the The following is a description of late-onset group B streptococcal disease
culture techniques used. in a neonate (Hammersen et al: Eur J Pediatr 126:189–197, 1977). An
Approximately 60% of infants born to colonized mothers infant male weighing 3400 grams was delivered spontaneously at term.
become colonized with their mothers’ organisms. The likeli- Physical examinations of the infant were normal during the first week of
hood of colonization at birth is higher when the mother is life; however, the child started feeding irregularly during the second week.
colonized with large numbers of bacteria. Other associations On day 13, the baby was admitted to the hospital with generalized sei-
for neonatal colonization are premature delivery, prolonged zures. A small amount of cloudy cerebrospinal fluid was collected by
membrane rupture, and intrapartum fever. Disease in infants lumbar puncture, and Streptococcus agalactiae serotype III was isolated
younger than 7 days of age is called early-onset disease; from culture. Despite prompt initiation of therapy, the baby developed
disease appearing between 1 week and 3 months of life is hydrocephalus, necessitating implantation of an atrioventricular shunt. The
considered late-onset disease. The serotypes most com- infant was discharged at age 3.5 months with retardation of psychomotor
monly associated with early-onset disease are Ia (35% to development. This patient illustrates neonatal meningitis caused by the
40%), III (30%), and V (15%). Serotype III is responsible for most commonly implicated serotype of group B streptococci in late-onset
most late-onset disease. Serotypes Ia and V are the most disease and the complications associated with this infection.
common in adult disease.
194   MEDICAL MICROBIOLOGY

Infections in Pregnant Women macrolides, clindamycin, and tetracyclines is common, so

Postpartum endometritis, wound infection, and urinary these drugs should not be selected unless demonstrated to
tract infections occur in women during and immediately be active in vitro.
after pregnancy. Because childbearing women are generally In an effort to prevent neonatal disease, it is recom-
in good health, the prognosis is excellent for those who mended that all pregnant women should be screened for
receive appropriate therapy. Secondary complications of bac- colonization with group B streptococci at 35 to 37 weeks’
teremia such as endocarditis, meningitis, and osteomyelitis gestation (refer to the following CDC document for addi-
are rare. tional information: www.cdc.gov/groupbstrep/guidelines/
index.html). Chemoprophylaxis should be used for all
Infections in Men and Nonpregnant Women women who are either colonized or at high risk. A pregnant
Compared with pregnant women who acquire group B strep- woman is considered to be at high risk to give birth to a baby
tococcal infection, men and nonpregnant women with group with invasive group B disease if she has previously given
B streptococcal infections are generally older and have debil- birth to an infant with the disease or risk factors for the
itating underlying conditions. The most common presenta- disease are present at birth. These risk factors are (1) intra-
tions are bacteremia, pneumonia, bone and joint infections, partum temperature of at least 38° C, (2) membrane rupture
and skin and soft-tissue infections. Because these patients at least 18 hours before delivery, and (3) vaginal or rectal
often have compromised immunity, mortality is higher in culture positive for organisms at 35 to 37 weeks’ gestation.
this population. Intravenous penicillin G or ampicillin administered at least
4 hours before delivery is recommended; cefazolin is used
Laboratory Diagnosis for penicillin-allergic women or clindamycin (if susceptible)
Antigen Detection or vancomycin for mothers at high risk for anaphylaxis. This
Tests for the direct detection of group B streptococci in uro- approach ensures high protective antibiotic levels in the
genital specimens are available but are too insensitive to be infant’s circulatory system at the time of birth.
used to screen mothers and predict which newborns are at Because newborn disease is associated with decreased
increased risk for acquiring neonatal disease. Likewise, the circulating antibodies in the mother, efforts have been
antigen tests are too insensitive (<30%) to be used with CSF. directed at developing a polyvalent vaccine against serotypes
A Gram stain of CSF has much better sensitivity and should Ia, Ib, II, III, and V. The capsular polysaccharides are poor
be used. immunogens; however, complexing them with tetanus toxoid
has improved the immunogenicity of the vaccine. Trials with
Nucleic Acid–Based Tests this polyvalent vaccine demonstrated that protective levels
Polymerase chain reaction (PCR)–based nucleic acid ampli- of antibodies are induced in animal models; however, no
fication assays are approved by the U.S. Food and Drug licensed vaccine is currently available.
Administration (FDA) for rectal/vaginal swabs from preg-
nant women. The tests are relatively insensitive, so testing
must be performed using a selective enrichment broth (e.g., • Other β-Hemolytic Streptococci
Lim broth) rather than directly with the clinical specimen.
Among the other β-hemolytic streptococci, groups C, F, and
Culture G are most commonly associated with human disease.
Group B streptococci readily grow on a nutritionally enriched Organisms of particular importance are the Streptococcus
medium, producing large colonies after 24 hours of incuba- anginosus group (includes S. anginosus, Streptococcus constel-
tion; however, β-hemolysis may be difficult to detect or latus, and Streptococcus intermedius) and Streptococcus dys-
absent, posing a problem in the detection of the organism galactiae. β-Hemolytic members of the S. anginosus group
when other organisms are present in the culture (e.g., vaginal can possess the group A, C, F, or G polysaccharide antigen
culture). Thus use of a selective enrichment broth medium (or not have any group-specific antigen), and S. dysgalactiae
with antibiotics added to suppress the growth of other organ- can have either the group C or G antigen. It should be noted
isms (e.g., LIM broth with colistin and nalidixic acid) fol- that an individual isolate possesses only one group antigen.
lowed by subculture to nonselective media such as a blood Isolates of the S. anginosus group grow as small colonies
agar plate is currently recommended by the CDC for the (requiring 2 days of incubation) with a narrow zone of
detection of group B streptococci in women between weeks β-hemolysis (Figure 19-5A). These species are primarily
35 and 37 of pregnancy. associated with abscess formation and not pharyngitis, in
contrast with the other group A Streptococcus, S. pyogenes.
Identification S. dysgalactiae produces large colonies with a large zone
Isolates of S. agalactiae are identified definitively by the dem- of β-hemolysis on blood agar media (see Figure 19-5B),
onstration of the group-specific cell wall carbohydrate. resembling S. pyogenes. Additionally, S. dysgalactiae causes
pharyngitis, which is sometimes complicated by acute glo-
Treatment, Prevention, and Control merulonephritis but never rheumatic fever.
Group B streptococci are susceptible to penicillin, which is
the drug of choice. Because other bacteria can be responsible
for neonatal disease (e.g., S. pneumoniae, Listeria, gram- • Viridans Streptococci
negative rods), broad-spectrum therapy should be selected
for empirical therapy. A cephalosporin or vancomycin The viridans group of streptococci is a heterogeneous
can be used in penicillin-allergic patients. Resistance to collection of α-hemolytic and nonhemolytic streptococci
 CHAPTER 19  STREPTOCOCCUS AND ENTEROCOCCUS    195

A B

FIGURE 19-5  Group C Streptococcus. A, S. anginosus, small-colony species. B, S. dysgalactiae, large-colony species.

(Figure 19-6). Many species and subspecies have been identi-

fied, and most are classified into five subgroups. This clas-
sification scheme is clinically important because many of the
species in the five subgroups are responsible for specific dis-
eases (see Table 19-4). Some members of the viridans strep-
tococci (e.g., S. anginosus group) can have β-hemolytic
strains with the group-specific cell wall polysaccharides
(thus contributing to the confusing taxonomy of this genus).
In addition, S. pneumoniae is a member of the Streptococcus
mitis subgroup, although most physicians and microbiolo-
gists do not think of S. pneumoniae as viridans streptococci;
it will be discussed separately in this chapter.
The viridans streptococci colonize the oropharynx, gas-
trointestinal tract, and genitourinary tract. Similar to most A
other streptococci, viridans species are nutritionally fastidi-
ous, requiring complex media supplemented with blood
products and, frequently, an incubation atmosphere with 5%
to 10% carbon dioxide.
Although most viridans streptococci are highly suscep-
tible to penicillin, with minimum inhibitory concentrations
(MICs) of less than 0.1 µg/ml, moderately resistant (penicil-
lin MIC of 0.2 to 2 µg/ml) and highly resistant (MIC >2 µg/
ml) streptococci have become common in the S. mitis group.
Infections with isolates that are moderately resistant can gen-
erally be treated with a combination of penicillin and an
aminoglycoside; however, alternative antibiotics such as a
broad-spectrum cephalosporin or vancomycin must be used
to treat serious infections.

• Streptococcus pneumoniae B

S. pneumoniae was isolated independently by Pasteur and FIGURE 19-6  Streptococcus mitis. A, Gram stain from blood
Steinberg more than 100 years ago. Since that time, research culture. B, α-Hemolytic colonies.
with this organism has led to a greater understanding of
molecular genetics, antibiotic resistance, and vaccine-related
immunoprophylaxis. Unfortunately, pneumococcal disease gram-negative. Colonial morphology varies, with colonies of
is still a leading cause of morbidity and mortality. encapsulated strains generally large (1 to 3 mm in diameter
on blood agar; smaller on chocolatized or heated blood
Physiology and Structure agar), round, and mucoid, and colonies of nonencapsulated
The pneumococcus is an encapsulated gram-positive coccus. strains smaller and flat. All colonies undergo autolysis with
The cells are 0.5 to 1.2 µm in diameter, oval, and arranged aging—that is, the central portion of the colony dissolves,
in pairs (commonly referred to as diplococci) or short chains leaving a dimpled appearance. Colonies appear α-hemolytic
(Figure 19-7). Older cells decolorize readily and can stain on blood agar if incubated aerobically and may be β-hemolytic
196   MEDICAL MICROBIOLOGY

ride precipitates a serum globulin fraction (C-reactive

protein [CRP]) in the presence of calcium. CRP is present
in low concentrations in healthy people but in elevated con-
centrations in patients with acute inflammatory diseases
(hence, monitoring levels of CRP is used to predict inflam-
mation). The teichoic acid bound to lipids in the bacterial
cytoplasmic membrane is called the F antigen because it can
cross-react with the Forssman surface antigens on mamma-
lian cells. Both forms of teichoic acid are associated with
phosphorylcholine residues. Phosphorylcholine is unique
to the cell wall of S. pneumoniae and plays an important
regulatory role in cell wall hydrolysis. Phosphorylcholine
must be present for activity of the pneumococcal autolysin,
amidase, during cell division.

Pathogenesis and Immunity

Although S. pneumoniae has been extensively studied, much
remains to be learned about the pathogenesis of pneumococ-
cal disease. The disease manifestations are caused primarily
by the host response to infection rather than the production
FIGURE 19-7  Gram stain of Streptococcus pneumoniae. of organism-specific toxic factors. However, an understand-
ing of how S. pneumoniae colonizes the oropharynx, spreads
into normally sterile tissues, stimulates a localized inflam-
if grown anaerobically. The α-hemolytic appearance results matory response, and evades being killed by phagocytic cells
from production of pneumolysin, an enzyme that degrades is crucial.
hemoglobin, producing a green product.
The organism has fastidious nutritional requirements and Colonization and Migration
can grow only on enriched media supplemented with blood S. pneumoniae is a human pathogen that colonizes the oro-
products. S. pneumoniae can ferment carbohydrates, pro- pharynx and then, in specific situations, is able to spread to
ducing lactic acid as the primary metabolic byproduct. S. the lungs, paranasal sinuses, or middle ear. It can also be
pneumoniae grows poorly in media with high glucose con- transported in the blood to distal sites such as the brain. The
centrations because lactic acid rapidly reaches toxic levels in initial colonization of the oropharynx is mediated by the
such preparations. Similar to all streptococci, the organism binding of the bacteria to epithelial cells by means of surface
lacks catalase. Unless an exogenous source of catalase is pro- protein adhesins. Subsequent migration of the organism to
vided (e.g., from blood), the accumulation of hydrogen per- the lower respiratory tract can be prevented if the bacteria
oxide inhibits the growth of S. pneumoniae, as observed on are enveloped in mucus and removed from the airways by
chocolatized blood agar. the action of ciliated epithelial cells. The bacteria counteract
Virulent strains of S. pneumoniae are covered with a this envelopment by producing secretory IgA protease and
complex polysaccharide capsule. The capsular polysaccha- pneumolysin. Secretory IgA traps bacteria in mucus by
rides have been used for the serologic classification of strains; binding the bacteria to mucin with the Fc region of the anti-
currently, 94 serotypes are recognized. Purified capsular body. The bacterial IgA protease prevents this interaction.
polysaccharides from the most commonly isolated serotypes Pneumolysin, a cytotoxin similar to the streptolysin O in
are used in a polyvalent vaccine. Individual strains of S. S. pyogenes, binds cholesterol in the host cell membrane and
pneumoniae can switch capsular serotypes through genomic creates pores. This activity can destroy the ciliated epithelial
recombination and point mutations in the capsular genes. cells and phagocytic cells.
Recombination is also associated with acquisition of genes
encoding penicillin resistance, so use of vaccines or antibi- Tissue Destruction
otic therapy can facilitate the selection and dissemination of A characteristic of pneumococcal infections is the mobi­
new capsular serotypes. lization of inflammatory cells to the focus of infection.
The peptidoglycan layer of the cell wall of the pneumo- Pneumococcal teichoic acid, peptidoglycan fragments, and
coccus is typical of gram-positive cocci. Attached to alternat- pneumolysin mediate the process. Teichoic acid and the
ing subunits of N-acetylglucosamine and N-acetylmuramic peptidoglycan fragments activate the alternative comple-
acid are oligopeptide chains, which, in turn, are cross-linked ment pathway, producing C5a, which mediates the inflam-
by pentaglycine bridges. The other major component of the matory process. This activity is augmented by the bacterial
cell wall is teichoic acid. Two forms of teichoic acid exist in enzyme amidase, which enhances release of the cell wall
the pneumococcal cell wall, one exposed on the cell surface components. Pneumolysin activates the classic complement
and a similar structure covalently bound to the plasma mem- pathway, resulting in the production of C3a and C5a. In turn,
brane lipids. The exposed teichoic acid is linked to the pep- cytokines such as interleukin (IL)-1 and tumor necrosis
tidoglycan layer and extends through the overlying capsule. factor (TNF)-α are produced by the activated leukocytes,
This species-specific structure, called the C polysaccharide, leading to the further migration of inflammatory cells to the
is unrelated to the group-specific carbohydrate observed by site of infection, fever, tissue damage, and other signs char-
Lancefield in β-hemolytic streptococci. The C polysaccha- acteristic of pneumococcal infection. The production of
 CHAPTER 19  STREPTOCOCCUS AND ENTEROCOCCUS    197

hydrogen peroxide by S. pneumoniae can also lead to tissue spread on airborne droplets from one person to another in
damage caused by reactive oxygen intermediates. a closed population, epidemics are rare. Disease occurs when
Finally, phosphorylcholine present in the bacterial cell the natural defense mechanisms (e.g., epiglottal reflex, trap-
wall can bind to receptors for platelet-activating factor that ping of bacteria by the mucus-producing cells lining the
are expressed on the surface of endothelial cells, leukocytes, bronchus, removal of organisms by the ciliated respiratory
platelets, and tissue cells, such as those in the lungs and epithelium, and cough reflex) are circumvented, permitting
meninges. By binding these receptors, the bacteria can enter organisms colonizing the oropharynx to gain access to the
the cells, where they are protected from opsonization and lungs. Pneumococcal disease is most commonly associated
phagocytosis, and pass into sequestered areas, such as blood with an antecedent viral respiratory disease, such as influ-
and the central nervous system. This activity facilitates the enza, or with other conditions that interfere with bacterial
spread of disease. clearance, such as chronic pulmonary disease, alcoholism,
congestive heart failure, diabetes mellitus, chronic renal
Phagocytic Survival disease, and splenic dysfunction or splenectomy.
S. pneumoniae survives phagocytosis because of the anti-
phagocytic protection afforded by its capsule and the Clinical Diseases
pneumolysin-mediated suppression of the phagocytic cell Pneumonia (Clinical Case 19-3)
oxidative burst, which is required for intracellular killing. Pneumococcal pneumonia develops when the bacteria mul-
The virulence of S. pneumoniae is a direct result of this tiply in the alveolar spaces. After aspiration, the bacteria
capsule. Encapsulated (smooth) strains can cause disease in grow rapidly in the nutrient-rich edema fluid. Erythrocytes
humans and experimental animals, whereas nonencapsu- leaking from congested capillaries accumulate in the alveoli,
lated (rough) strains are avirulent. Antibodies directed followed by the neutrophils, and then the alveolar macro-
against the type-specific capsular polysaccharides protect phages. Resolution occurs when specific anticapsular anti-
against disease caused by immunologically related strains, so bodies develop, facilitating phagocytosis of the organism and
capsular switching allows a strain to avoid immune clear- microbial killing.
ance. The capsular polysaccharides are soluble and have been The onset of the clinical manifestations of pneumococcal
called specific soluble substances. Free polysaccharides can pneumonia is abrupt, consisting of a severe shaking chill and
protect viable organisms from phagocytosis by binding with sustained fever of 39° C to 41° C. The patient often has
opsonic antibodies. symptoms of a viral respiratory tract infection 1 to 3 days
before the onset. Most patients have a productive cough with
Epidemiology blood-tinged sputum, and they commonly have chest pain
S. pneumoniae is a common inhabitant of the throat and (pleurisy). Because the disease is associated with aspiration,
nasopharynx in healthy people, with colonization more it is generally localized in the lower lobes of the lungs (hence
common in children than in adults and more common in the name lobar pneumonia; Figure 19-8). However, chil-
adults living in a household with children. Colonization ini- dren and the elderly can have a more generalized broncho-
tially occurs at approximately 6 months of age. Subsequently, pneumonia. Patients usually recover rapidly after the
the child is transiently colonized with other serotypes of the initiation of appropriate antimicrobial therapy, with com-
organism. The duration of carriage decreases with each suc- plete radiologic resolution in 2 to 3 weeks.
cessive serotype carried, in part because of the development The overall mortality rate is 5%, although the likelihood
of serotype-specific immunity. Although new serotypes are of death is influenced by the serotype of the organism and
acquired throughout the year, the incidence of carriage and the age and underlying disease of the patient. The mortality
associated disease is highest during the cool months. The rate is considerably higher in patients with disease caused by
strains of pneumococci that cause disease are the same as
those associated with carriage.
Pneumococcal disease occurs when organisms colonizing
the nasopharynx and oropharynx spread to the lungs (pneu- Clinical Case 19-3  Streptococcus pneumoniae
monia), paranasal sinuses (sinusitis), ears (otitis media), or Pneumonia
meninges (meningitis). Spread of S. pneumoniae in blood to Costa and associates (Am J Hematol 77:277–281, 2004) described a
other body sites can occur with all of these diseases. It is 68-year-old woman who was in good health until 3 days before hospital-
recognized that some serotypes have a higher predilection ization. She developed fever, chills, increased weakness, and a productive
for invasive pneumococcal disease. cough with pleuritic chest pain. On admission, she was febrile, had
Although the introduction of vaccines for pediatric and an elevated pulse and respiration rate, and was in moderate respiratory
adult populations has reduced the incidence of disease caused distress. Initial laboratory values showed leucopenia, anemia, and acute
by S. pneumoniae, the organism is still a common cause of renal failure. Chest radiograph demonstrated infiltrates in the right and
bacterial pneumonia acquired outside the hospital, meningi- left lower lobes, with pleural effusions. Therapy with a fluoroquinolone
tis, otitis media and sinusitis, and bacteremia. Disease is most was initiated, and blood and respiratory cultures were positive for
common in children and the elderly with low levels of protec- S. pneumoniae. Additional tests (serum and urine protein electrophoresis)
tive antibodies directed against the pneumococcal capsular revealed the patient had multiple myeloma. The patient’s infection resolved
polysaccharides. The World Health Organization (WHO) with a 14-day course of antibiotics. This patient illustrates the typical
estimates that more than 200,000 children younger than age picture of pneumococcal lobar pneumonia and the increased susceptibility
5 years die each year of pneumococcal pneumonia. to infection in patients with defects in their ability to clear encapsulated
Pneumonia occurs when the endogenous oral organisms organisms.
are aspirated into the lower airways. Although strains can
198   MEDICAL MICROBIOLOGY

meningitis. In contrast, bacteria are generally not present in

the blood of patients with sinusitis or otitis media. Endocar-
ditis can occur in patients with normal or previously damaged
heart valves. Destruction of valve tissue is common.
Laboratory Diagnosis
Microscopy
Gram stain of sputum specimens is a rapid way to diagnose
pneumococcal pneumonia and meningitis. The organisms
characteristically appear as elongated pairs of gram-positive
cocci surrounded by an unstained capsule; however, they
may also appear to be gram negative because they tend not
to stain well (particularly in older cultures). In addition, their
morphology may be distorted in a patient receiving antibi-
otic therapy. A Gram stain consistent with S. pneumoniae can
be confirmed with the quellung (German for “swelling”)
reaction. In this test, polyvalent anticapsular antibodies are
mixed with the bacteria, and then the mixture is examined
FIGURE 19-8  Dense consolidation of left lower lobe in patient with microscopically. A greater refractiveness around the bacteria
pneumonia caused by Streptococcus pneumoniae. (From Mandell G, is a positive reaction for S. pneumoniae. An alternative test
Bennett J, Dolin R: Principles and practice of infectious diseases, is to mix a drop of bile with a suspension of bacteria. Bile
ed 8, Philadelphia, 2015, Elsevier.) will dissolve S. pneumoniae and no organisms will be seen
in the Gram stain.

S. pneumoniae type 3, as well as in elderly patients and Antigen Detection

patients with documented bacteremia. Patients with splenic Pneumococcal C polysaccharide is excreted in urine and
dysfunction or splenectomy can also have severe pneumo- can be detected using a commercially prepared immunoas-
coccal disease because of decreased bacterial clearance from say. Maximum sensitivity requires that the urine be concen-
the blood and the defective production of early antibodies. trated by ultrafiltration before it is assayed. Sensitivity has
In these patients, disease can be associated with a fulminant been reported to be 70% in patients with bacteremic pneu-
course and high mortality rate. mococcal pneumonia; however, specificity can be low, par-
Abscesses do not commonly form in patients with ticularly in pediatric patients. For this reason, the test is not
pneumococcal pneumonia, except in those infected with recommended for children with suspected infections. The
specific serotypes (e.g., serotype 3). Pleural effusions are test has a sensitivity approaching 100% for patients with
seen in approximately 25% of patients with pneumococcal pneumococcal meningitis if CSF is tested; however, the test
pneumonia, and empyema (purulent effusion) is a rare has poor sensitivity and specificity if urine is tested in these
complication. patients.
Sinusitis and Otitis Media Nucleic Acid–Based Tests
S. pneumoniae is a common cause of acute infections of the PCR assays have been developed for identification of S. pneu-
paranasal sinuses and ear. The disease is usually preceded by moniae isolates in clinical specimens such as CSF but are not
a viral infection of the upper respiratory tract, after which widely used.
polymorphonuclear neutrophils (leukocytes) (PMNs) infil-
trate and obstruct the sinuses and ear canal. Middle ear Culture
infection (otitis media) is primarily seen in young children, Sputum specimens should be inoculated onto an enriched
but bacterial sinusitis can occur in patients of all ages. nutrient medium supplemented with blood. S. pneumoniae
is recovered in the sputum cultures from only half of the
Meningitis patients who have pneumonia, because the organism has
S. pneumoniae can spread into the central nervous system fastidious nutritional requirements and is rapidly overgrown
after bacteremia, infections of the ear or sinuses, or head by contaminating oral bacteria. Selective media have been
trauma that causes a communication between the subarach- used with some success to isolate the organism from sputum
noid space and the nasopharynx. Although pneumococcal specimens, but it takes some technical skill to distinguish S.
meningitis is relatively uncommon in neonates, S. pneu- pneumoniae from the other α-hemolytic streptococci that
moniae is now a leading cause of disease in children and are often present in the specimen. An aspirate must be
adults. Mortality and severe neurologic deficits are 4 to 20 obtained from the sinus or middle ear for the organism
times more common in patients with meningitis caused by responsible for sinusitis or otitis to be diagnosed definitively.
S. pneumoniae than in those with meningitis resulting from Specimens taken from the nasopharynx or outer ear should
other organisms. not be cultured. It is not difficult to isolate S. pneumoniae
from specimens of CSF if antibiotic therapy has not been
Bacteremia initiated before the specimen is collected; however, as many
Bacteremia occurs in 25% to 30% of patients with pneumo- as half of infected patients who have received even a single
coccal pneumonia and in more than 80% of patients with dose of antibiotics will have negative cultures.
 CHAPTER 19  STREPTOCOCCUS AND ENTEROCOCCUS    199

Identification because the prevalent serotypes are not represented in the

Isolates of S. pneumoniae are lysed rapidly when the autoly- vaccines. Additionally, although the 23-valent vaccine is
sins are activated after exposure to bile (bile solubility test). immunogenic in normal adults and immunity is long lived,
Thus the organism can be identified by placing a drop of bile the vaccine is less effective in some patients at high risk for
on an isolated colony. Most colonies of S. pneumoniae are pneumococcal disease, including: (1) patients with asplenia,
dissolved within a few minutes, whereas other α-hemolytic sickle cell disease, hematologic malignancy, and HIV infec-
streptococci remain unchanged. S. pneumoniae can also be tion; (2) patients who have undergone renal transplant; and
identified by its susceptibility to optochin (ethylhydrocupre- (3) the elderly.
ine dihydrochloride). The isolate is streaked onto a blood
agar plate and a disk saturated with optochin is placed in the
middle of the inoculum. A zone of inhibited bacterial growth • Enterococcus
is seen around the disk after overnight incubation. Addi-
tional biochemical, serologic, or molecular diagnostic tests Physiology and Structure
can be performed for a definitive identification. The enterococci are gram-positive cocci, typically arranged
in pairs and short chains (Figure 19-9). The microscopic
Treatment, Prevention, and Control morphology of these isolates cannot be differentiated reliably
Historically penicillin was the treatment of choice for pneu- from that of S. pneumoniae. The cocci grow both aerobically
mococcal disease; however, in 1977, researchers in South and anaerobically in a broad temperature range (10° C to
Africa reported isolates of S. pneumoniae that were resistant 45° C), in a wide pH range (4.6 to 9.9), and in the presence
to multiple antibiotics, including penicillin. Although high- of high concentrations of sodium chloride (NaCl) and bile
level resistance to penicillin (MIC of at least 2 µg/ml) was salts. Thus there are very few clinical conditions that inhibit
relatively uncommon, this situation changed dramatically the growth of enterococci. Glucose is fermented with l-lactic
beginning in 1990. Now resistance to penicillin is observed acid as the predominant end product (enterococci are com-
for as many as half of the strains isolated in the United States monly referred to as lactic acid bacteria). After 24 hours
and in other countries. Resistance to penicillins is associated of incubation, colonies on enriched sheep blood agar are
with a decreased affinity of the antibiotic for the penicillin- large and can appear nonhemolytic, α-hemolytic, or, rarely,
binding proteins present in the bacterial cell wall, and β-hemolytic.
patients infected with resistant bacteria have an increased
risk of an adverse outcome. Resistance to macrolides (e.g., Pathogenesis and Immunity
erythromycin), tetracyclines, and to a lesser extent cephalo- Although enterococci do not possess the broad range of
sporins (e.g., ceftriaxone) has also become commonplace. virulence factors found in staphylococci or streptococci, life-
Thus, for serious pneumococcal infections, treatment with a threatening disease with antibiotic-resistant strains has
combination of antibiotics is recommended until in vitro become a serious problem in hospitalized patients. Virulence
susceptibility results are available. Vancomycin combined is mediated by two general properties: (1) ability to adhere
with ceftriaxone is used commonly for empirical treatment, to tissues and form biofilms and (2) antibiotic resistance. A
followed by monotherapy with an effective cephalosporin, number of factors have been described that mediate adher-
fluoroquinolone, or vancomycin. ence and biofilm formation, including surface proteins,
Efforts to prevent or control the disease have focused on membrane glycolipids, gelatinase, and pili. In addition, the
the development of effective anticapsular vaccines. A 23- enterococci either are inherently resistant to many com-
valent pneumococcal polysaccharide vaccine (with 23 monly used antibiotics (e.g., oxacillin, cephalosporins) or
different capsular polysaccharides) is recommended for chil-
dren older than 2 years and adults. Polysaccharides are
T-independent antigens, stimulating mature B lymphocytes
but not T lymphocytes. Very young children respond poorly
to T-independent antigens, so these polysaccharide vaccines
are ineffective for this population. In contrast, conjugation
of polysaccharides to proteins stimulates a T-helper cell
response, resulting in a strong primary response among
infants and effective booster response when reimmunized.
This approach of using conjugated vaccines for pediatric
immunizations has also been used for other neonatal patho-
gens, such as Haemophilus influenzae. Immunization with
the 13-valent conjugated pneumococcal vaccine is cur-
rently recommended for infants younger than 2 years.
Whereas a single dose of the 23-valent vaccine is generally
effective, a series of four doses (at 2, 4, 6, and 12 to 15
months) is recommended for the 13-valent conjugated
vaccine. The effectiveness of these vaccines is determined by
the prevalent serotypes of S. pneumoniae responsible for
invasive disease in the population. Whereas these vaccines
are generally effective in the United States and European FIGURE 19-9  Gram stain of blood culture with Enterococcus
populations, they are less effective in developing countries faecalis.
200   MEDICAL MICROBIOLOGY

have acquired resistance genes (e.g., to aminoglycosides,

Clinical Case 19-4  Enterococcal Endocarditis
vancomycin). Clearance of enterococci from blood and
tissues is mediated by the rapid influx of neutrophils and Zimmer and associates (Clin Infect Dis 37:e29–e30, 2003) described the
opsonization of the bacteria, so patients who are immuno- epidemiology of enterococcal infections and the difficulties in treating a
compromised are particularly susceptible to enterococcal patient with endocarditis. The patient was a 40-year-old man with hepatitis
infections. C, hypertension, and end-stage renal disease who developed fevers and
chills during hemodialysis. In the 2 months before this episode, he was
Epidemiology treated with ampicillin, levofloxacin, and gentamicin for group B strepto-
As their name implies, enterococci are enteric bacteria that coccal endocarditis. Cultures performed during the hemodialysis grew
are commonly recovered in feces collected from humans and Enterococcus faecalis resistant to levofloxacin and gentamicin. Because
from a variety of animals. E. faecalis is found in the large the patient had an allergic reaction to ampicillin, he was treated with
intestine in high concentrations (e.g., 105 to 107 organisms linezolid. Echocardiography showed vegetation on the mitral and tricuspid
per gram of feces) and in the genitourinary tract. The distri- valves. Over a 3-week period, the patient’s cardiac output deteriorated, so
bution of E. faecium is similar to that of E. faecalis but is the patient was desensitized to ampicillin and therapy was switched to
found in lower concentrations. Significant risk factors for ampicillin and streptomycin. After 25 days of hospitalization, the patient’s
enterococcal infections include use of urinary or intravascu- damaged heart valves were replaced, and therapy was extended for an
lar catheters, prolonged hospitalization, and use of broad- additional 6 weeks. Thus use of broad-spectrum antibiotics predisposed
spectrum antibiotics, particularly antibiotics that are this patient with previously damaged heart valves to endocarditis caused
inherently inactive against enterococci. by Enterococcus, and treatment was complicated by resistance of the
The prevalence of the many other enterococcal species is isolate to many commonly used antibiotics.
unknown, although they are believed to colonize the intes-
tines in small numbers. Two species that are commonly
recovered in the human intestines are E. gallinarum and E.
casseliflavus. These relatively avirulent species are important Phenotypic properties (e.g., pigment production, motility),
because, although they are rarely associated with human biochemical tests, and nucleic acid sequencing are necessary
disease, they are inherently resistant to vancomycin and can to differentiate among E. faecalis, E. faecium, and the other
be confused with the more important species, E. faecalis and Enterococcus species, but this topic is beyond the scope of
E. faecium. this text.

Clinical Diseases (See Box 19-1) Treatment, Prevention, and Control

Enterococci are important pathogens, particularly in hospi- Antimicrobial therapy for enterococcal infections is compli-
talized patients; indeed, enterococci are one of the most cated because most antibiotics are not bactericidal at clini-
common causes of infections acquired in the hospital (noso- cally relevant concentrations. Therapy for serious infections
comial infection). The urinary tract is the most common has traditionally consisted of the synergistic combination of
site of enterococcal infections, and infections are frequently an aminoglycoside and a cell wall–active antibiotic (e.g.,
associated with urinary catheterization or instrumentation. ampicillin, vancomycin). However, some cell wall antibiotics
These infections may be asymptomatic, uncomplicated cys- have no activity against enterococci (e.g., nafcillin, oxacillin,
titis, or cystitis associated with pyelonephritis. Peritoneal cephalosporins), ampicillin and penicillin are generally inef-
infections are typically polymicrobic (i.e., associated with fective against E. faecium, and vancomycin resistance (par-
other aerobic and anaerobic bacteria) and associated with ticularly in E. faecium) is commonplace. In addition, more
leakage of intestinal bacteria either from trauma or due to than 25% of enterococci are resistant to the aminoglycosides,
disease that compromises the intestinal lining. Enterococci and resistance to aminoglycosides and vancomycin is par-
recovered in the blood may either be dissemination from a ticularly troublesome because it is mediated by plasmids and
localized infection of the urinary tract, the peritoneum, or a can be transferred to other bacteria.
wound or represent primary infection of the endocardium Newer antibiotics have been developed that can treat
(endocarditis). Endocarditis is a particularly serious infec- enterococci resistant to ampicillin, vancomycin, or the
tion because many enterococci are resistant to most com- aminoglycosides. They include linezolid, daptomycin, tigecy-
monly used antibiotics (Clinical Case 19-4). cline, and quinupristin/dalfopristin. Unfortunately, resis-
tance to linezolid is steadily increasing, and quinupristin/
Laboratory Diagnosis dalfopristin is not active against E. faecalis (the most com-
Enterococci grow readily on nonselective media such as monly isolated enterococcal species). Enterococci susceptible
blood agar and chocolate agar. Although enterococci may to ampicillin and resistant to aminoglycosides can be treated
resemble S. pneumoniae on Gram-stained specimens, the with ampicillin plus daptomycin, imipenem, or linezolid.
organisms can be readily differentiated on the basis of simple Enterococci resistant to ampicillin and susceptible to amino-
biochemical reactions. For example, enterococci are resistant glycosides can be treated with an aminoglycoside combined
to optochin (S. pneumoniae is susceptible), do not dissolve with vancomycin (if active), linezolid, or daptomycin. If the
when exposed to bile (S. pneumoniae is dissolved), and isolate is resistant to both ampicillin and aminoglycosides,
produce l-pyrrolidonyl arylamidase (PYR) (the only Strep- then treatment can include daptomycin, linezolid, or vanco-
tococcus that is PYR positive is Streptococcus pyogenes). The mycin combined with another active agent.
PYR test is a commonly performed “5-minute spot” test. It is difficult to prevent and control enterococcal infec-
Catalase-negative, PYR-positive cocci arranged in pairs and tions. Careful restriction of antibiotic usage and the imple-
short chains can be presumptively identified as enterococci. mentation of appropriate infection-control practices (e.g.,
 CHAPTER 19  STREPTOCOCCUS AND ENTEROCOCCUS    201

isolation of infected patients, use of gowns and gloves by Johansson L, Thulin P, Low DE, et al: Getting under the skin: the immuno-
anyone in contact with patients) can reduce the risk of colo- pathogenesis of Streptococcus pyogenes deep tissue infections, Clin Infect
Dis 51:58–65, 2010.
nization with these bacteria, but the complete elimination of Johnson DR, Kurlan R, Leckman J, et al: The human immune response to
infections is unlikely. Additionally, it is extremely difficult to streptococcal extracellular antigens: clinical, diagnostic, and potential
eradicate a vancomycin-resistant strain of E. faecium or E. pathogenetic implications, Clin Infect Dis 50:481–490, 2010.
faecalis once a patient is colonized. Kanjanabuch T, Kittikowit W, Eiam-Ong S: An update on acute postinfec-
tious glomerulonephritis worldwide, Nat Rev Nephrol 5:259–269, 2009.
Krzysciak W, Pluskwa KK, Jurczak A, et al: The pathogenicity of the Strep-
tococcus genus, Eur J Clin Microbiol Infect Dis 32:1361–1376, 2013.
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 CHAPTER 19  STREPTOCOCCUS AND ENTEROCOCCUS    201.e1

Case Study and Questions pyoderma, erysipelas, cellulites, necrotizing fasciitis, lym-
A 62-year-old man with a history of chronic obstructive phangitis, and pneumonia. Nonsuppurative diseases
pulmonary disease (COPD) came to the emergency depart- include rheumatic fever and acute glomerulonephritis. S.
ment because of a fever of 40° C, chills, nausea, vomiting, agalactiae (group B Streptococcus) is an important patho-
and hypotension. The patient also produced tenacious yel- gen in neonates, causing early-onset disease (bacteremia,
lowish sputum that had increased in quantity over the pre- pneumonia, meningitis) and late-onset disease (bactere-
ceding 3 days. His respiratory rate was 18 breaths/min, and mia, meningitis). S. agalactiae also causes disease in preg-
his blood pressure was 94/52 mm Hg. Chest radiographic nant women, most commonly urinary tract infections but
examination showed extensive infiltrates in the left lower also endocarditis, meningitis, and osteomyelitis. Elderly
lung that involved both the lower lobe and the lingula. Mul- men and women are also susceptible to disease presenting
tiple blood cultures and culture of the sputum yielded S. as pneumonia, bone and joint infections, and skin and
pneumoniae. The isolate was susceptible to cefazolin, vanco- soft-tissue infections. S. dysgalactiae is most commonly
mycin, and erythromycin but resistant to penicillin. associated with pharyngitis, which is occasionally com-
1. What predisposing condition made this patient more sus- plicated by acute glomerulonephritis (but not rheumatic
ceptible to pneumonia and bacteremia caused by S. pneu- fever as in the case of S. pyogenes). S. anginosus causes
moniae? What other populations of patients are susceptible abscesses in deep tissues, and the viridans streptococci
to these infections? What other infections does this organ- cause a variety of diseases, most commonly subacute bac-
ism cause, and what populations are most susceptible? terial endocarditis, dental caries, and abscess formation.
2. What is the mechanism most likely responsible for this 4. The major virulence factor of S. pneumoniae is the capsule,
isolate’s resistance to penicillin? which provides antiphagocytic protection. Protein adhe­
3. What infections are caused by S. pyogenes, S. agalactiae, sins on the surface of the bacteria facilitate colonization
S. anginosus, S. dysgalactiae, and viridans streptococci? of the oropharynx by binding to epithelial cells. Phos-
4. What are the major virulence factors of S. pneumoniae, S. phorylcholine, present in the bacterial cell wall, binds to
pyogenes, and S. agalactiae? the surface of a variety of cells (endothelial, leukocytes,
5. S. pyogenes can cause streptococcal toxic shock syndrome. platelets) and allows entry into these cells, where the bac-
How does this disease differ from the disease produced by teria are protected from opsonization and phagocytosis.
staphylococci? Teichoic acid, peptidoglycan fragments, and pneumoly-
6. What two nonsuppurative diseases can develop after local- sin stimulate the inflammatory response, leading to
ized S. pyogenes disease? abscess formation. S. pyogenes has a large array of viru-
lence factors. Bacterial antigens (e.g., lipoteichoic acid, M
proteins, F protein) mediate adherence to host cells. M
Answers proteins also function to avoid opsonization and phago-
1. Disease caused by S. pneumoniae is most common in cytosis of the bacteria. The bacteria also produce a variety
young children and the elderly, populations that are of toxins and cytolytic enzymes, including pyogenic exo-
unable to mount protective antibodies against the pneu- toxins, streptolysins (S and O), streptokinases (A and B),
mococcal capsules. Additionally, patients with underly- deoxyribonucleases (A to D), C5a peptidase, and hyal-
ing pulmonary disease, such as COPD in this patient, or uronidase. S. agalactiae primarily produces disease in
an antecedent viral respiratory infection that compro- hosts that are unable to mount an anticapsular antibody
mises the protective clearance of the ciliated respiratory response (neonates, elderly). The role of hydrolytic
epithelium, are susceptible to pneumonia caused by this enzymes (e.g., deoxyribonucleases, hyaluronidase, neur-
organism. Other infections caused by S. pneumoniae aminidase, proteases, hemolysins) is unknown.
include otitis media (primarily in young children), sinus- 5. Streptococcal toxic shock is defined as any S. pyogenes
itis (all age groups), meningitis (all age groups but pri- infection associated with sudden onset of shock and
marily in the young and elderly), and bacteremia (usually organ failure (including renal impairment, coagulopa-
secondary to pneumonia or meningitis). Patients with thies, liver involvement, pulmonary disease, soft-tissue
conditions that interfere with bacterial clearance, such as necrosis, generalized erythematous rash). In contrast
alcoholism, asplenia, congestive heart disease, diabetes with staphylococcal toxic shock, which is mediated by
mellitus, and chronic renal disease, are at increased risk toxic shock syndrome toxin-1 (TSST-1), streptococcal
for disseminated disease. disease is characterized by the presence of bacteria in the
2. S. pneumoniae is able to acquire, by transformation blood and involved tissues.
(exchange of DNA between bacteria), DNA encoding 6. Rheumatic fever and acute glomerulonephritis are com-
altered penicillin-binding proteins (e.g., PBP2x, PBP2b, plications of S. pyogenes disease. Rheumatic fever is asso-
PBP1a). These new PBPs make the bacteria less suscep- ciated with streptococcal pharyngitis but not cutaneous
tible to penicillins and some cephalosporins. infections. Acute glomerulonephritis is associated with
3. S. pyogenes (group A Streptococcus) causes both suppura- both pharyngeal and pyodermal infections, but the
tive and nonsuppurative diseases. It is the most common specific strains responsible for the complication are
cause of bacterial pharyngitis and the systemic complica- different.
tion of scarlet fever. Other suppurative diseases include