1188 PART 5 Infectious Diseases

the affected joint to prevent damage from leukocytes. The combination of rifampin with ciprofloxacin has been used successfully

to treat or suppress prosthetic-joint infections, especially when the

device cannot be removed. The efficacy of this combination may

reflect enhanced activity against staphylococci in biofilms as well as

the attainment of effective intracellular concentrations.

Skin and Soft Tissue Infections The increase in SSTIs caused by

CA-MRSA has drawn attention to the need for initiation of appropriate empirical therapy. Even small abscesses appear to benefit

from antibiotic therapy in addition to incision and drainage. Antibiotics are selected depending on local antibiotic susceptibility data;

a number of oral agents have been used to treat these infections,

including clindamycin, trimethoprim-sulfamethoxazole, doxycycline, linezolid, and tedizolid. Parenteral therapy is reserved for

more complicated infections.

Toxic Shock Syndrome Treatment of shock is the mainstay of

therapy for TSS. Both fluids and pressors may be necessary. Tampons or other packing material should be promptly removed. Some

investigators recommend therapy with a combination of clindamycin and a semisynthetic penicillin or (if the isolate is resistant to

methicillin) vancomycin. Clindamycin is advocated because, as a

protein synthesis inhibitor, it reduces toxin production. Linezolid

also appears to be effective. A semisynthetic penicillin or a glycopeptide is recommended to eliminate any potential focus of infection as well as to eradicate persistent carriage that might increase

the possibility of recurrence. Intravenous immunoglobulin to treat

TSS is of uncertain benefit. Glucocorticoids are not recommended

for the treatment of this disease.

Other Toxin-Mediated Diseases Therapy for staphylococcal food

poisoning is entirely supportive. For SSSS, antistaphylococcal therapy targets the primary site of infection.

NONTRADITIONAL APPROACHES TO

ANTI-STAPHYLOCOCCAL THERAPY

In addition to the development of new antibiotics, new and nontraditional approaches to therapy are currently being investigated.

These include the use of phages or phage-derived peptides, as well

as probiotics and anti-virulence strategies that target selected virulence determinants.

■ PREVENTION

Primary prevention of S. aureus infections in the hospital setting

involves hand washing and careful attention to appropriate isolation

procedures. Through careful screening for MRSA carriage and strict

isolation practices, several Scandinavian countries have been remarkably successful at preventing the introduction and dissemination of

MRSA in hospitals.

Decolonization strategies, using both universal and targeted

approaches with topical agents (e.g., mupirocin) to eliminate nasal

colonization and/or chlorhexidine to eliminate colonization of additional body sites with S. aureus, have been successful in some clinical

settings where the risk of infection is high (e.g., intensive care units).

An analysis of clinical trials suggests that decolonization can reduce the

incidence of postsurgical infections among people nasally colonized

with S. aureus. The risk of recurrent admissions among patients with

S. aureus bacteremia following discharge is high (approximately 22%

within 30 days). Decolonization following discharge with mupirocin

and chlorhexidine can lower the incidence of recurrent infections.

“Bundling” (the application of selected medical interventions in a

sequence of prescribed steps) has reduced rates of nosocomial infections related to procedures such as the insertion of intravenous catheters, in which staphylococci are among the most common pathogens

(see Table 142-1). A number of immunization strategies to prevent S.

aureus infections—both active (e.g., capsular polysaccharide–protein

conjugate vaccine) and passive (e.g., clumping factor antibody)—have

been investigated. However, to date, none has been successful for either

prophylaxis or therapy in clinical trials.

Strategies to prevent recurrent S. aureus infections in the community

have had limited success. Decolonization with intranasal mupirocin

and chlorhexidine washes of the infected individual and the additional

decolonization of household members combined with environmental

cleaning of surfaces and personal items have all been studied. For individuals with extensive skin disease and recurrent infections, the use

of bleach baths (e.g., one-half cup of household bleach in a half-filled

bathtub) 15 minutes three times weekly may be useful.

■ FURTHER READING

Becker K et al: Coagulase-negative staphylococci. Clin Microbiol Rev

27:870, 2014.

DeLeo FR et al: Community-associated methicillin-resistant Staphylococcus aureus. Lancet 375:1557, 2010.

Huang SS et al: Decolonization to reduce post discharge infection risk

among MRSA carriers. N Engl J Med 380:638, 2019.

Kullar R et al: When sepsis persists: A review of MRSA bacteraemia

salvage therapy. J Antimicrob Chemother 71:576, 2016.

Lee AS et al: Methicillin-resistant Staphylococcus aureus. Nat Rev Dis

Primers 4:18033:1, 2018.

Thwaites GE et al: Adjunctive rifampicin for Staphylococcus aureus

bacteraemia (ARREST): A multicentre, randomised, double-blind,

placebo-controlled trial. Lancet 391:668, 2018.

Tong SY et al: Staphylococcus aureus infections: Epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol

Rev 28:603, 2015.

Many varieties of streptococci are found as part of the normal flora

colonizing the human respiratory, gastrointestinal, and genitourinary

tracts. Several species are important causes of human disease. Group

A Streptococcus (GAS, Streptococcus pyogenes) is responsible for streptococcal pharyngitis, one of the most common bacterial infections of

school-age children, and for the postinfectious syndromes of acute

rheumatic fever (ARF) and poststreptococcal glomerulonephritis

(PSGN). Group B Streptococcus (GBS, Streptococcus agalactiae) is the

leading cause of bacterial sepsis and meningitis in newborns and a

major cause of endometritis and fever in parturient women. Viridans

streptococci are the most common cause of bacterial endocarditis.

Enterococci, which are morphologically similar to streptococci, are

now considered a separate genus on the basis of DNA homology studies. Thus, the species previously designated as Streptococcus faecalis

and Streptococcus faecium have been renamed Enterococcus faecalis

and Enterococcus faecium, respectively. The enterococci are discussed

in Chap. 149.

Streptococci are gram-positive, spherical to ovoid bacteria that

characteristically form chains when grown in liquid media. Most

streptococci that cause human infections are facultative anaerobes,

although some are strict anaerobes. Streptococci are relatively fastidious organisms, requiring enriched media for growth in the laboratory.

Clinicians and clinical microbiologists identify streptococci by several

classification systems, including hemolytic pattern, Lancefield group,

species name, and common or trivial name. Many streptococci associated with human infection produce a zone of complete (β) hemolysis

around the bacterial colony when cultured on blood agar. The βhemolytic streptococci that form large (≥0.5-mm) colonies on blood

agar can be classified by the Lancefield system, a serologic grouping

based on the reaction of specific antisera with bacterial cell-wall

carbohydrate antigens. With rare exceptions, organisms belonging

to Lancefield groups A, B, C, and G are all β-hemolytic, and each

148 Streptococcal Infections

Michael R. Wessels

1189CHAPTER 148 Streptococcal Infections

is associated with characteristic patterns of human infection. Other

streptococci produce a zone of partial (α) hemolysis, often imparting

a greenish appearance to the agar. These α-hemolytic streptococci are

further identified by biochemical testing and include Streptococcus

pneumoniae (Chap. 146), an important cause of pneumonia, meningitis, and other infections, and the several species referred to collectively

as the viridans streptococci, which are part of the normal oral flora and

are important agents of subacute bacterial endocarditis. Finally, some

streptococci are nonhemolytic, a pattern sometimes called γ hemolysis.

Among the organisms classified serologically as group D streptococci,

the enterococci are assigned to a distinct genus (Chap. 149). The classification of the major streptococcal groups causing human infections

is outlined in Table 148-1.

GROUP A STREPTOCOCCI

Lancefield group A consists of a single species, S. pyogenes. As its

species name implies, this organism is associated with a variety of

suppurative infections. In addition, GAS can trigger the postinfectious

syndromes of ARF (which is uniquely associated with S. pyogenes

infection; Chap. 359) and PSGN (Chap. 314).

Worldwide, GAS infections and their postinfectious sequelae (primarily ARF and rheumatic heart disease) account for an estimated

500,000 deaths per year. Although data are incomplete, the incidence

of all forms of GAS infection and that of rheumatic heart disease are

thought to be tenfold higher in resource-limited countries than in

developed countries (Fig. 148-1).

TABLE 148-1 Classification of Streptococci

LANCEFIELD

GROUP REPRESENTATIVE SPECIES HEMOLYTIC PATTERN TYPICAL INFECTIONS

A S. pyogenes β Pharyngitis, impetigo, cellulitis, scarlet fever

B S. agalactiae β Neonatal sepsis and meningitis, puerperal infection, urinary

tract infection, diabetic ulcer infection, endocarditis

C, G S. dysgalactiae subsp. equisimilis β Cellulitis, bacteremia, endocarditis

D Enterococcia

: E. faecalis, E. faecium Usually nonhemolytic Urinary tract infection, nosocomial bacteremia, endocarditis

Nonenterococci: S. gallolyticus (formerly S. bovis) Usually nonhemolytic Bacteremia, endocarditis

Variable or

nongroupable

Viridans streptococci: S. sanguis, S. mitis α Endocarditis, dental abscess, brain abscess

Intermedius or milleri group: S. intermedius,

S. anginosus, S. constellatus

Variable Brain abscess, visceral abscess

Anaerobic streptococcib

: Peptostreptococcus magnus Usually nonhemolytic Sinusitis, pneumonia, empyema, brain abscess, liver abscess

a

See Chap. 149. b

See Chap. 177.

■ PATHOGENESIS

GAS elaborates a number of cell-surface components and extracellular products important in both the pathogenesis of infection and

the human immune response. The cell wall contains a carbohydrate

antigen that may be released by acid treatment. The reaction of such

acid extracts with group A–specific antiserum is the basis for definitive

identification of a streptococcal strain as S. pyogenes. Rarely, the group

A antigen may be present on isolates of S. dysgalactiae ssp. equisimilis,

which usually express the group C or G antigen (see “Streptococci

of Groups C and G,” below). The major surface protein of GAS is M

protein, which is the basis for the serotyping of strains with specific

antisera. The M protein molecules are fibrillar structures anchored in

the cell wall of the organism that extend as hairlike projections away

from the cell surface. The amino acid sequence of the distal or aminoterminal portion of the M protein molecule is variable, accounting for

the antigenic variation of the different M types, while more proximal

regions of the protein are relatively conserved. Traditional M-typing by

serologic methods has been largely supplanted by a newer technique

for assignment of M type to GAS isolates by use of the polymerase

chain reaction to amplify the variable region of the emm gene, which

encodes M protein. DNA sequence analysis of the amplified gene segment can be compared with an extensive database (developed at the

Centers for Disease Control and Prevention [CDC]) for assignment of

emm type. Use of emm typing has increased the number of identified

emm types to more than 200. This method eliminates the need for

typing sera, which are available in only a few reference laboratories.

0.3

Presence of rheumatic heart disease (cases per 1000)

0.8 1.8

1.0 1.3

2.2 5.7

3.5

FIGURE 148-1 Prevalence of rheumatic heart disease in children 5–14 years old. The circles within Australia and New Zealand represent indigenous populations (and also

Pacific Islanders in New Zealand). (Reproduced with permission from JR Carapetis et al: The global burden of group A streptococcal diseases. Lancet Infect Dis 5:685, 2005.)

1190 PART 5 Infectious Diseases

The presence of M protein on a GAS isolate correlates with its capacity

to resist phagocytic killing in fresh human blood. This phenomenon

appears to be due, at least in part, to the binding of plasma fibrinogen

to M protein molecules on the streptococcal surface, which interferes

with complement activation and deposition of opsonic complement

fragments on the bacterial cell. This resistance to phagocytosis may

be overcome by M protein–specific antibodies; thus, individuals with

antibodies to a given M type acquired as a result of prior infection are

protected against subsequent infection with organisms of the same M

type but not against that with different M types.

GAS also elaborates, to varying degrees, a polysaccharide capsule

composed of hyaluronic acid. While most clinical isolates of GAS

produce a hyaluronic acid capsule, strains of M type 4 or 22 lack a

capsule, as do some isolates of M type 89. The fact that acapsular

strains have been associated with pharyngitis and invasive infection

implies that the capsule is not essential for virulence. The production

of large amounts of capsule by certain strains imparts a characteristic

mucoid appearance to the colonies. The capsular polysaccharide plays

an important role in protecting GAS from ingestion and killing by

phagocytes. In contrast to M protein, the hyaluronic acid capsule is a

weak immunogen, and antibodies to hyaluronate have not been shown

to be important in protective immunity. The presumed explanation is

the apparent structural identity between streptococcal hyaluronic acid

and the hyaluronic acid of mammalian connective tissues. The capsular

polysaccharide may also play a role in GAS colonization of the pharynx

by binding to CD44, a hyaluronic acid–binding protein expressed on

human pharyngeal epithelial cells.

GAS produces a large number of extracellular products that may be

important in local and systemic toxicity and in the spread of infection

through tissues. These products include streptolysins S and O, toxins

that damage cell membranes and account for the hemolysis produced

by the organisms; streptokinase; DNAses; SpyCEP, a serine protease

that cleaves and inactivates the chemoattractant cytokine interleukin

8, thereby inhibiting neutrophil recruitment to the site of infection;

and several pyrogenic exotoxins. Previously known as erythrogenic

toxins, the pyrogenic exotoxins cause the rash of scarlet fever. Since the

mid-1980s, pyrogenic exotoxin–producing strains of GAS have been

linked to unusually severe invasive infections, including necrotizing

fasciitis and the streptococcal toxic shock syndrome (TSS). Several

extracellular products stimulate specific antibody responses useful for

serodiagnosis of recent streptococcal infection. Tests for antibodies to

streptolysin O and DNase B are used most commonly for detection of

preceding streptococcal infection in cases of suspected ARF or PSGN.

■ CLINICAL MANIFESTATIONS

Pharyngitis Although seen in patients of all ages, GAS pharyngitis is

one of the most common bacterial infections of childhood, accounting

for 20–40% of all cases of exudative pharyngitis in children; it is rare

among those under the age of 3. Younger children may manifest streptococcal infection with a syndrome of fever, malaise, and lymphadenopathy without exudative pharyngitis. Infection is acquired through contact

with another individual carrying the organism. Respiratory droplets are

the usual mechanism of spread, although other routes, including foodborne outbreaks, have been well described. The incubation period is

1–4 days. Symptoms include sore throat, fever and chills, malaise, and

sometimes abdominal complaints and vomiting, particularly in children.

Both symptoms and signs are quite variable, ranging from mild throat

discomfort with minimal physical findings to high fever and severe sore

throat associated with intense erythema and swelling of the pharyngeal

mucosa and the presence of purulent exudate over the posterior pharyngeal wall and tonsillar pillars. Enlarged, tender anterior cervical lymph

nodes commonly accompany exudative pharyngitis.

The differential diagnosis of streptococcal pharyngitis includes the

many other bacterial and viral etiologies (Table 148-2). Streptococcal

infection is an unlikely cause when symptoms and signs suggestive of viral infection are prominent (conjunctivitis, coryza, cough,

hoarseness, or discrete ulcerative lesions of the buccal or pharyngeal

mucosa). Because of the range of clinical presentations of streptococcal

pharyngitis and the large number of other agents that can produce the

same clinical picture, diagnosis of streptococcal pharyngitis on clinical

grounds alone is not reliable. The throat culture remains the diagnostic

gold standard. Culture of a throat specimen that is properly collected

(i.e., by vigorous rubbing of a sterile swab over both tonsillar pillars)

and properly processed is the most sensitive and specific means of

definitive diagnosis. A rapid diagnostic test for latex agglutination or

enzyme immunoassay of swab specimens is a useful adjunct to throat

culture. While precise figures on sensitivity and specificity vary, rapid

diagnostic tests generally are >95% specific. Thus, a positive result

can be relied upon for definitive diagnosis and eliminates the need for

throat culture. In settings in which the incidence of rheumatic fever

is low, a confirmatory throat culture is not recommended for routine

evaluation of most adults with a negative rapid test. However, because

rapid diagnostic tests are less sensitive than throat culture (relative

sensitivity in comparative studies, 70–90%), a negative result should be

confirmed by throat culture for individuals at higher risk such as those

with a history of rheumatic fever or immunocompromise or a family

member with such a history; patients living in congregate settings of

young adults such as dormitories or military facilities where the incidence of GAS pharyngitis may be elevated; individuals with household

exposure to someone with proven GAS infection; and those living in

an area in which rheumatic fever is endemic.

TREATMENT

GAS Pharyngitis

In the usual course of uncomplicated streptococcal pharyngitis,

symptoms resolve after 3–5 days. The course is shortened little by

treatment, which is given primarily to prevent suppurative complications and ARF. Prevention of ARF depends on eradication of

the organism from the pharynx, not simply on resolution of symptoms, and requires 10 days of penicillin treatment (Table 148-3).

A first-generation cephalosporin, such as cephalexin or cefadroxil,

TABLE 148-2 Infectious Etiologies of Acute Pharyngitis

ORGANISM ASSOCIATED CLINICAL SYNDROME(S)

Viruses

Rhinovirus Common cold

Coronavirus Common cold, COVID-19

Adenovirus Pharyngoconjunctival fever

Influenza virus Influenza

Parainfluenza virus Cold, croup

Coxsackievirus Herpangina, hand-foot-and-mouth disease

Herpes simplex virus Gingivostomatitis (primary infection)

Epstein-Barr virus Infectious mononucleosis

Cytomegalovirus Mononucleosis-like syndrome

HIV Acute (primary) infection syndrome

Bacteria

Group A streptococci Pharyngitis, scarlet fever

Group C or G streptococci Pharyngitis

Mixed anaerobes Vincent’s angina

Arcanobacterium haemolyticum Pharyngitis, scarlatiniform rash

Neisseria gonorrhoeae Pharyngitis

Treponema pallidum Secondary syphilis

Francisella tularensis Pharyngeal tularemia

Corynebacterium diphtheriae Diphtheria

Yersinia enterocolitica Pharyngitis, enterocolitis

Yersinia pestis Plague

Chlamydiae

Chlamydia pneumoniae Bronchitis, pneumonia

Chlamydia psittaci Psittacosis

Mycoplasmas

Mycoplasma pneumoniae Bronchitis, pneumonia

1191CHAPTER 148 Streptococcal Infections

may be substituted for penicillin in cases of penicillin allergy if the

nature of the allergy is not an immediate hypersensitivity reaction

(anaphylaxis or urticaria) or another potentially life-threatening

manifestation (e.g., severe rash and fever).

Alternative agents are erythromycin and azithromycin. Azithromycin offers the advantages of better gastrointestinal tolerability,

once-daily dosing, and a 5-day treatment course. Resistance to erythromycin and other macrolides is common among isolates from

several countries, including Spain, Italy, Finland, Japan, and Korea.

Macrolide resistance may be becoming more prevalent elsewhere

with the increasing use of this class of antibiotics. In areas with

resistance rates exceeding 5–10%, macrolides should be avoided

unless results of susceptibility testing are known.

Follow-up culture after treatment is no longer routinely recommended but may be warranted in selected cases, such as those

involving patients or families with frequent streptococcal infections

or those occurring in situations in which the risk of ARF is thought

to be high (e.g., when cases of ARF have recently been reported in

the community).

Complications Suppurative complications of streptococcal pharyngitis have become uncommon with the widespread use of antibiotics for most symptomatic cases. These complications result from

the spread of infection from the pharyngeal mucosa to deeper tissues

by direct extension or by the hematogenous or lymphatic route and

may include cervical lymphadenitis, peritonsillar or retropharyngeal

abscess, sinusitis, otitis media, meningitis, bacteremia, endocarditis,

and pneumonia. Local complications, such as peritonsillar or parapharyngeal abscess formation, should be considered in a patient with

unusually severe or prolonged symptoms or localized pain associated

with high fever and a toxic appearance. Nonsuppurative complications

include ARF (Chap. 358) and PSGN (Chap. 314), both of which are

thought to result from immune responses to streptococcal infection.

Penicillin treatment of streptococcal pharyngitis reduces the likelihood

of ARF but not that of PSGN.

BACTERIOLOGIC TREATMENT FAILURE

AND THE ASYMPTOMATIC CARRIER STATE

Surveillance cultures have shown that up to 20% of individuals in certain

populations may have asymptomatic pharyngeal colonization with GAS.

There are no definitive guidelines for management of these asymptomatic carriers or of asymptomatic patients who still have a positive

throat culture after a full course of treatment for symptomatic pharyngitis. A reasonable course of action is to give a single 10-day course of

penicillin for symptomatic pharyngitis and, if positive cultures persist,

not to re-treat unless symptoms recur. Studies of the natural history of

streptococcal carriage and infection have shown that the risk both of

developing ARF and of transmitting infection to others is substantially

lower among asymptomatic carriers than among individuals with symptomatic pharyngitis. Therefore, aggressive attempts to eradicate carriage

probably are not justified under most circumstances. An exception is

the situation in which an asymptomatic carrier is a potential source of

infection to others. Outbreaks of food-borne infection and nosocomial

puerperal infection have been traced to asymptomatic carriers who may

harbor the organisms in the throat, vagina, or anus or on the skin.

TREATMENT

Asymptomatic Pharyngeal Colonization with GAS

When a carrier is transmitting infection to others, attempts to eradicate carriage are warranted. Data are limited on the best regimen

to clear GAS after penicillin alone has failed. Regimens reported to

have efficacy superior to that of penicillin alone for eradication of carriage include (1) a first-generation cephalosporin such as cephalexin

(30 mg/kg; 500 mg maximum) twice daily for 10 days or (2) oral clindamycin (7 mg/kg; 300 mg maximum) three times daily for 10 days. A

10-day course of oral vancomycin (250 mg four times daily) and rifampin (600 mg twice daily) has eradicated rectal colonization. Single-dose

azithromycin (20 mg/kg; 1000 mg maximum) has been used for mass

prophylaxis/eradication of colonization in outbreak situations.

Scarlet Fever Scarlet fever consists of streptococcal infection,

usually pharyngitis, accompanied by a characteristic rash (Fig. 148-2).

The rash arises from the effects of one of several toxins, currently

designated streptococcal pyrogenic exotoxins and previously known as

erythrogenic or scarlet fever toxins. In the past, scarlet fever was thought

to reflect infection of an individual lacking toxin-specific immunity

with a toxin-producing strain of GAS. Susceptibility to scarlet fever

was correlated with results of the Dick test, in which a small amount

of erythrogenic toxin injected intradermally produced local erythema

in susceptible individuals but elicited no reaction in those with specific

immunity. Subsequent studies have suggested that development of the

scarlet fever rash may reflect a hypersensitivity reaction requiring prior

exposure to the toxin. For reasons that are not clear, scarlet fever has

become less common in recent years, although large outbreaks have

TABLE 148-3 Treatment of Group A Streptococcal Infections

INFECTION TREATMENTa

Pharyngitis Benzathine penicillin G (1.2 mU IM) or penicillin V

(250 mg PO tid or 500 mg PO bid) × 10 days

(Children <27 kg: Benzathine penicillin G [600,000 units

IM] or penicillin V [250 mg PO bid or tid] × 10 days)

Impetigo Same as pharyngitis

Erysipelas/cellulitis Severe: Penicillin G (1–2 mU IV q4h)

Mild to moderate: Procaine penicillin (1.2 mU IM bid)

Necrotizing fasciitis/

myositis

Surgical debridement plus penicillin G (2–4 mU IV q4h)

plus clindamycinb

 (600–900 mg IV q8h)

Pneumonia/empyema Penicillin G (2–4 mU IV q4h) plus drainage of empyema

Streptococcal toxic

shock syndrome

Penicillin G (2–4 mU IV q4h) plus clindamycinb

(600–900 mg IV q8h) plus IV immunoglobulinb

 (2 g/kg as

a single dose)

a

Penicillin allergy: A first-generation cephalosporin, such as cephalexin or

cefadroxil, may be substituted for penicillin in cases of penicillin allergy if the

nature of the allergy is not an immediate hypersensitivity reaction (anaphylaxis or

urticaria) or another potentially life-threatening manifestation (e.g., severe rash and

fever). Alternative agents for oral therapy are erythromycin (10 mg/kg PO qid, up to

a maximum of 250 mg per dose) and azithromycin (a 5-day course at a dose of

12 mg/kg once daily, up to a maximum of 500 mg/d). Vancomycin is an alternative for

parenteral therapy. b

Efficacy unproven, but recommended by several experts. See

text for discussion.

FIGURE 148-2 Scarlet fever exanthem. Finely punctate erythema has become

confluent (scarlatiniform); petechiae can occur and have a linear configuration

within the exanthem in body folds (Pastia’s lines). (From TB Fitzpatrick, RA Johnson,

K Wolff: Color Atlas and Synopsis of Clinical Dermatology, 4th ed, New York,

McGraw-Hill, 2001, with permission.)

1192 PART 5 Infectious Diseases

occurred recently in China and the United Kingdom. The symptoms of

scarlet fever are the same as those of pharyngitis alone. The rash typically begins on the first or second day of illness over the upper trunk,

spreading to involve the extremities but sparing the palms and soles.

The rash is made up of minute papules, giving a characteristic “sandpaper” feel to the skin. Associated findings include circumoral pallor,

“strawberry tongue” (enlarged papillae on a coated tongue, which later

may become denuded), and accentuation of the rash in skinfolds (Pastia’s lines). Subsidence of the rash in 6–9 days is followed after several

days by desquamation of the palms and soles. The differential diagnosis

of scarlet fever includes other causes of fever and generalized rash,

such as measles and other viral exanthems, Kawasaki disease, TSS, and

systemic allergic reactions (e.g., drug eruptions).

Skin and Soft Tissue Infections GAS—and occasionally other

streptococcal species—can cause a variety of infections involving the

skin, subcutaneous tissues, muscles, and fascia. While several clinical

syndromes offer a useful means for classification of these infections,

not all cases fit exactly into one category. The classic syndromes are

general guides to predicting the level of tissue involvement in a particular patient, the probable clinical course, and the likelihood that surgical

intervention or aggressive life support will be required.

IMPETIGO (PYODERMA)

Impetigo, a superficial infection of the skin, is caused primarily by

GAS and occasionally by other streptococci or Staphylococcus aureus.

Impetigo is seen most often in young children, tends to occur during

warmer months, and is more common in semitropical or tropical

climates than in cooler regions. Infection is more common among

children living under conditions of poor hygiene. Prospective studies

have shown that colonization of unbroken skin with GAS precedes

clinical infection. Minor trauma, such as a scratch or an insect bite,

may then serve to inoculate organisms into the skin. Impetigo is best

prevented, therefore, by attention to adequate hygiene. The usual sites

of involvement are the face (particularly around the nose and mouth)

and the legs, although lesions may occur at other locations. Individual lesions begin as red papules, which evolve quickly into vesicular

and then pustular lesions that break down and coalesce to form characteristic honeycomb-like crusts (Fig. 148-3). Lesions generally are

not painful, and patients do not appear ill. Fever is not a feature of

impetigo and, if present, suggests either infection extending to deeper

tissues or another diagnosis. The classic presentation of impetigo usually poses little diagnostic difficulty. Cultures of impetiginous lesions

often yield S. aureus as well as GAS. In almost all cases, streptococci

are isolated initially, and staphylococci appear later, presumably as

secondary colonizing flora. In the past, penicillin was nearly always

effective against these infections. However, an increasing frequency

of penicillin treatment failure suggests that S. aureus may have

become more prominent as a cause of impetigo. Bullous impetigo

due to S. aureus is distinguished from typical streptococcal infection

by more extensive, bullous lesions that break down and leave thin

paper-like crusts instead of the thick amber crusts of streptococcal

impetigo. Other skin lesions that may be confused with impetigo

include herpetic lesions—either those of orolabial herpes simplex

or those of chickenpox or zoster. Herpetic lesions can generally be

distinguished by their appearance as more discrete, grouped vesicles

and by a positive Tzanck test or by herpes simplex virus- or varicellazoster virus-specific PCR. In difficult cases, cultures of vesicular fluid

should yield GAS (or Staphylococcus aureus) in impetigo and the

responsible virus in herpesvirus infections.

TREATMENT

Streptococcal Impetigo

Treatment of streptococcal impetigo is the same as that for streptococcal pharyngitis. In view of evidence that S. aureus has become

a relatively frequent cause of impetigo, empirical regimens should

cover both streptococci and S. aureus. For example, either dicloxacillin or cephalexin can be given at a dose of 250 mg four times

daily for 10 days. Topical mupirocin ointment also is effective.

Culture may be indicated to rule out methicillin-resistant S. aureus,

especially if the response to empirical treatment is unsatisfactory. In

most areas of the world, ARF is not a sequela to streptococcal skin

infections, although PSGN may follow either skin or throat infection. The reason for this difference is not known. One hypothesis

is that the immune response necessary for development of ARF

occurs only after infection of the pharyngeal mucosa. In addition,

the strains of GAS that cause pharyngitis are generally of different

M protein types than those associated with skin infections; thus

the strains that cause pharyngitis may have rheumatogenic potential, while the skin-infecting strains may not. An exception to this

general rule may occur among indigenous people in northern

Australia and in certain Pacific island groups. Acute rheumatic

fever and rheumatic heart disease are prevalent in these populations

as is streptococcal impetigo/pyoderma, but not pharyngitis. This

epidemiologic pattern has led investigators to suggest that skin

infection may trigger acute rheumatic fever in this setting.

CELLULITIS

Inoculation of organisms into the skin may lead to cellulitis: infection

involving the skin and subcutaneous tissues. The portal of entry may

be a traumatic or surgical wound, an insect bite, or any other break in

skin integrity. Often, no entry site is apparent. One form of streptococcal cellulitis, erysipelas, is characterized by a bright red appearance

of the involved skin, which forms a plateau sharply demarcated from

surrounding normal skin (Fig. 148-4). The lesion is warm to the

touch, may be tender, and appears shiny and swollen. The skin often

has a peau d’orange texture, which is thought to reflect involvement of

superficial lymphatics; superficial blebs or bullae may form, usually

2–3 days after onset. The lesion typically develops over a few hours

and is associated with fever and chills. Erysipelas tends to occur on

the malar area of the face (often with extension over the bridge of the

nose to the contralateral malar region) or on the lower extremities.

After one episode, recurrence at the same site—sometimes years

later—is not uncommon. Classic cases of erysipelas, with typical

features, are almost always due to β-hemolytic streptococci, usually

GAS and occasionally group C or G. Often, however, the appearance

of streptococcal cellulitis is not sufficiently distinctive to permit a

specific diagnosis on clinical grounds. The anatomic area involved

may not be typical for erysipelas, the lesion may be less intensely red

than usual and may fade into surrounding skin, and/or the patient

FIGURE 148-3 Impetigo is a superficial streptococcal or Staphylococcus aureus

infection consisting of honey-colored crusts and erythematous weeping erosions.

Occasionally, bullous lesions may be seen. (Courtesy of Mary Spraker, MD; with

permission.)

1193CHAPTER 148 Streptococcal Infections

may appear only mildly ill. In such cases, it is prudent to broaden the

spectrum of empirical antimicrobial therapy to include other pathogens, particularly S. aureus, that can produce cellulitis with the same

appearance. Staphylococcal infection should be suspected if cellulitis

develops around a wound or an ulcer.

Streptococcal cellulitis tends to develop at anatomic sites in which

normal lymphatic drainage has been disrupted, such as sites of prior

cellulitis, the arm ipsilateral to a mastectomy and axillary lymph node

dissection, a lower extremity previously involved in deep venous

thrombosis or chronic lymphedema, or the leg from which a saphenous

vein has been harvested for coronary artery bypass grafting. The

organism may enter via a dermal breach some distance from the

eventual site of clinical cellulitis. For example, some patients with

recurrent leg cellulitis following saphenous vein removal stop having

recurrent episodes only after treatment of tinea pedis on the affected

extremity. Fissures in the skin presumably serve as a portal of entry for

streptococci, which then produce infection more proximally in the leg

at the site of previous injury. Streptococcal cellulitis may also involve

recent surgical wounds. GAS is among the few bacterial pathogens that

typically produce signs of wound infection and surrounding cellulitis

within the first 24 h after surgery. These wound infections are usually

associated with a thin exudate and may spread rapidly, either as cellulitis in the skin and subcutaneous tissue or as a deeper tissue infection

(see below). Streptococcal wound infection or localized cellulitis may

also be associated with lymphangitis, manifested by red streaks extending proximally along superficial lymphatics from the infection site.

TREATMENT

Streptococcal Cellulitis

See Table 148-3 and Chap. 129.

DEEP SOFT-TISSUE INFECTIONS

Necrotizing fasciitis (hemolytic streptococcal gangrene) involves the superficial and/or deep fascia investing the muscles of an extremity or the

trunk. The source of the infection is either the skin, with organisms

introduced into tissue through trauma (sometimes trivial), or the bowel

flora, with organisms released during abdominal surgery or from an

occult enteric source, such as a diverticular or appendiceal abscess. The

inoculation site may be inapparent and is often some distance from the

site of clinical involvement; e.g., the introduction of organisms via minor

trauma to the hand may be associated with clinical infection of the

tissues overlying the shoulder or chest. Cases associated with the bowel

flora are usually polymicrobial, involving a mixture of anaerobic bacteria

(such as Bacteroides fragilis or anaerobic streptococci) and facultative

organisms (usually gram-negative bacilli). Cases unrelated to contamination from bowel organisms are most commonly caused by GAS alone

or in combination with other organisms (most often S. aureus). Overall,

GAS is implicated in ~60% of cases of necrotizing fasciitis. The onset of

symptoms is usually quite acute and is marked by severe pain at the site

of involvement, malaise, fever, chills, and a toxic appearance. The physical findings, particularly early on, may not be striking, with only minimal

erythema of the overlying skin. Pain and tenderness are usually severe.

In contrast, in more superficial cellulitis, the skin appearance is more

abnormal, but pain and tenderness are only mild or moderate. As the

infection progresses (often over several hours), the severity and extent

of symptoms worsen, and skin changes become more evident, with the

appearance of dusky or mottled erythema and edema. The marked tenderness of the involved area may evolve into anesthesia as the spreading

inflammatory process produces infarction of cutaneous nerves.

Although myositis is more commonly due to S. aureus infection,

GAS occasionally produces abscesses in skeletal muscles (streptococcal

myositis), with little or no involvement of the surrounding fascia or

overlying skin. The presentation is usually subacute, but a fulminant

form has been described in association with severe systemic toxicity,

bacteremia, and a high mortality rate. The fulminant form may reflect

the same basic disease process seen in necrotizing fasciitis, but with the

necrotizing inflammatory process extending into the muscles themselves rather than remaining limited to the fascial layers.

TREATMENT

Deep Soft-Tissue Streptococcal Infections

Once necrotizing fasciitis is suspected, early surgical exploration is

both diagnostically and therapeutically indicated. Surgery reveals

necrosis and inflammatory fluid tracking along the fascial planes

above and between muscle groups, without involvement of the

muscles themselves. The process usually extends beyond the area of

clinical involvement, and extensive debridement is required. Drainage and debridement are central to the management of necrotizing

fasciitis; antibiotic treatment is a useful adjunct (Table 148-3), but

surgery is life-saving. Treatment for streptococcal myositis consists

of surgical drainage—usually by an open procedure that permits

evaluation of the extent of infection and ensures adequate debridement of involved tissues—and high-dose penicillin (Table 148-3).

Pneumonia and Empyema GAS is an occasional cause of pneumonia, generally in previously healthy individuals. The onset of symptoms

may be abrupt or gradual. Pleuritic chest pain, fever, chills, and dyspnea

are the characteristic manifestations. Cough is usually present but may

not be prominent. Approximately one-half of patients with GAS pneumonia have an accompanying pleural effusion. In contrast to the sterile

parapneumonic effusions typical of pneumococcal pneumonia, those

complicating streptococcal pneumonia are almost always infected. The

empyema fluid is usually visible by chest radiography on initial presentation, and its volume may increase rapidly. These pleural collections should

be drained early, as they tend to become loculated rapidly, resulting in a

chronic fibrotic reaction that may require thoracotomy for removal.

Bacteremia, Puerperal Sepsis, and Streptococcal Toxic Shock

Syndrome In adults, GAS bacteremia is usually associated with an

identifiable local infection, whereas children may have bacteremia

without an associated focal infection. Bacteremia occurs rarely with

otherwise uncomplicated pharyngitis, occasionally with cellulitis or

pneumonia, and relatively frequently with necrotizing fasciitis. Bacteremia without an identified source raises the possibility of endocarditis,

an occult abscess, or osteomyelitis. A variety of focal infections may

arise secondarily from streptococcal bacteremia, including endocarditis, meningitis, septic arthritis, osteomyelitis, peritonitis, and visceral

abscesses. GAS is occasionally implicated in infectious complications

FIGURE 148-4 Erysipelas is a streptococcal infection of the superficial dermis and

consists of well-demarcated, erythematous, edematous, warm plaques.

1194 PART 5 Infectious Diseases

TABLE 148-4 Proposed Case Definition for Streptococcal Toxic Shock

Syndromea

I. Isolation of group A streptococci (Streptococcus pyogenes)

A. From a normally sterile site

B. From a nonsterile site

II. Clinical signs of severity

A. Hypotension and

B. ≥2 of the following signs

1. Renal impairment

2. Coagulopathy

3. Liver function impairment

4. Adult respiratory distress syndrome

5. A generalized erythematous macular rash that may desquamate

6. Soft tissue necrosis, including necrotizing fasciitis or myositis; or

gangrene

a

An illness fulfilling criteria IA, IIA, and IIB is defined as a definite case. An illness

fulfilling criteria IB, IIA, and IIB is defined as a probable case if no other etiology for

the illness is identified.

Source: Modified from Working Group on Severe Streptococcal Infections: JAMA

269:390, 1993.

of childbirth, usually endometritis and associated bacteremia. In the

preantibiotic era, puerperal sepsis was commonly caused by GAS; currently, it is more often caused by GBS. Several nosocomial outbreaks of

puerperal GAS infection have been traced to an asymptomatic carrier,

usually someone present at delivery. The site of carriage may be the

skin, throat, anus, or vagina.

Beginning in the late 1980s, several reports described patients with

GAS infections associated with shock and multisystem organ failure.

This syndrome was called streptococcal toxic shock syndrome (TSS)

because it shares certain features with staphylococcal TSS. In 1993, a

case definition for streptococcal TSS was formulated (Table 148-4).

The general features of the illness include fever, hypotension, renal

impairment, and respiratory distress syndrome. Various types of rash

have been described, but rash usually does not develop. Laboratory

abnormalities include a marked shift to the left in the white blood cell

differential, with many immature granulocytes; hypocalcemia; hypoalbuminemia; and thrombocytopenia, which usually becomes more

pronounced on the second or third day of illness. In contrast to patients

with staphylococcal TSS, the majority with streptococcal TSS are bacteremic. The most common associated infection is a soft tissue infection—

necrotizing fasciitis, myositis, or cellulitis—although a variety of other

associated local infections have been described, including pneumonia,

peritonitis, osteomyelitis, and myometritis. Streptococcal TSS is associated with a mortality rate of ≥30%, with most deaths secondary to

shock and respiratory failure. Because of its rapidly progressive and

lethal course, early recognition of the syndrome is essential. Patients

should receive aggressive supportive care (fluid resuscitation, pressors,

and mechanical ventilation) in addition to antimicrobial therapy and,

in cases associated with necrotizing fasciitis, should undergo surgical

debridement. Exactly why certain patients develop this fulminant syndrome is not known. Early studies of the streptococcal strains isolated

from these patients demonstrated a strong association with the production of pyrogenic exotoxin A. This association has been inconsistent in

subsequent case series. Pyrogenic exotoxin A and several other streptococcal exotoxins act as superantigens to trigger release of inflammatory

cytokines from T lymphocytes. Fever, shock, and organ dysfunction

in streptococcal TSS may reflect, in part, the systemic effects of

superantigen-mediated cytokine release.

TREATMENT

Streptococcal Toxic Shock Syndrome

In light of the possible role of pyrogenic exotoxins or other streptococcal toxins in streptococcal TSS, treatment with clindamycin has been

advocated by some authorities (Table 148-3), who argue that, through

its direct action on protein synthesis, clindamycin is more effective in

rapidly terminating toxin production than is penicillin—a cell-wall

agent. Support for this view comes from studies of an experimental

model of streptococcal myositis, in which mice given clindamycin

had a higher rate of survival than those given penicillin. Comparable data on the treatment of human infections are not available,

although retrospective analysis has suggested a better outcome

when patients with invasive soft-tissue infection are treated with

clindamycin rather than with cell wall–active antibiotics. Although

clindamycin resistance in GAS is uncommon among U.S. isolates

(<2%), resistance rates as high as 23% have been documented in

Finland. Thus, if clindamycin is used for initial treatment of a critically ill patient, penicillin should be given as well until the antibiotic

susceptibility of the streptococcal isolate is known. IV immunoglobulin has been used as adjunctive therapy for streptococcal TSS

(Table 148-3). Pooled immunoglobulin preparations contain antibodies capable of neutralizing the effects of streptococcal toxins.

Anecdotal reports and case series have suggested favorable clinical

responses to IV immunoglobulin, but no adequately powered, prospective, controlled trials have been reported. A meta-analysis of

five studies of streptococcal TSS patients treated with clindamycin

found that IVIG use was associated with a reduction in mortality

rate from 33.7% to 15.7%.

■ PREVENTION

No vaccine against GAS is commercially available. A formulation that consists of recombinant peptides containing epitopes of 26 M-protein types has

undergone phase 1 and 2 testing in volunteers. Early results indicate that

the vaccine is well tolerated and elicits type-specific antibody responses.

Vaccines based on a conserved region of M protein or on a mixture of

other conserved GAS protein antigens are in earlier stages of development.

Household contacts of individuals with invasive GAS infection (e.g.,

bacteremia, necrotizing fasciitis, or streptococcal TSS) are at greater

risk of invasive infection than the general population. Asymptomatic

pharyngeal colonization with GAS has been detected in up to 25% of

persons with >4 h/d of same-room exposure to an index case. However,

the CDC does not recommend antibiotic prophylaxis routinely for

contacts of patients with invasive disease because such an approach (if

effective) would require treatment of hundreds of contacts to prevent

a single case. Prophylaxis may be considered for contacts of unusually

severe cases or for individuals at increased risk for invasive infection.

STREPTOCOCCI OF GROUPS C AND G

Group C and group G streptococci are β-hemolytic bacteria that

occasionally cause human infections similar to those caused by GAS.

Strains that form small colonies on blood agar (<0.5 mm) are generally

members of the Streptococcus milleri group (Streptococcus intermedius,

Streptococcus anginosus; see “Viridans Streptococci,” below). Largecolony group C and G streptococci of human origin are now considered a single species, Streptococcus dysgalactiae subspecies equisimilis.

These organisms have been associated with pharyngitis, cellulitis and

soft tissue infections, pneumonia, bacteremia, endocarditis, and septic

arthritis. Puerperal sepsis, meningitis, epidural abscess, intraabdominal abscess, urinary tract infection, and neonatal sepsis also have been

reported. Group C or G streptococcal bacteremia most often affects

elderly or chronically ill patients and, in the absence of obvious local

infection, is likely to reflect endocarditis. Septic arthritis, sometimes

involving multiple joints, may complicate endocarditis or develop in

its absence. Distinct streptococcal species of Lancefield group C cause

infections in domesticated animals, especially horses and cattle; some

human infections are acquired through contact with animals or consumption of unpasteurized milk. These zoonotic organisms include

Streptococcus equi subspecies zooepidemicus and S. equi subspecies equi.

TREATMENT

Group C or G Streptococcal Infection

Penicillin is the drug of choice for treatment of group C or G streptococcal infections. Antibiotic treatment is the same as for similar

syndromes due to GAS (Table 148-3). Patients with bacteremia or

1195CHAPTER 148 Streptococcal Infections

septic arthritis should receive IV penicillin (2–4 mU every 4 h). All

group C and G streptococci are sensitive to penicillin; nearly all are

inhibited in vitro by concentrations of ≤0.03 μg/mL. Occasional

isolates exhibit tolerance: although inhibited by low concentrations

of penicillin, they are killed only by significantly higher concentrations. The clinical significance of tolerance is unknown. Because of

the poor clinical response of some patients to penicillin alone, the

addition of gentamicin (1 mg/kg every 8 h for patients with normal

renal function) is recommended by some authorities for treatment

of endocarditis or septic arthritis due to group C or G streptococci;

however, combination therapy has not been shown to be superior

to penicillin treatment alone. Patients with joint infections often

require repeated aspiration or open drainage and debridement for

cure; the response to treatment may be slow, particularly in debilitated patients and those with involvement of multiple joints. Infection of prosthetic joints almost always requires prosthesis removal

in addition to antibiotic therapy.

GROUP B STREPTOCOCCI

Identified first as a cause of mastitis in cows, streptococci belonging

to Lancefield group B have since been recognized as a major cause of

sepsis and meningitis in human neonates. GBS is also a frequent cause

of peripartum fever in women and an occasional cause of serious infection in nonpregnant adults. Since the widespread institution of prenatal

screening for GBS in the 1990s, the incidence of neonatal infection per

1000 live births has fallen from ~2–3 cases to ~0.6 case. During the

same period, GBS infection in adults with underlying chronic illnesses

has become more common; adults now account for a larger proportion of invasive GBS infections than do newborns. Lancefield group B

consists of a single species, S. agalactiae, which is definitively identified

with specific antiserum to the group B cell wall–associated carbohydrate antigen. A streptococcal isolate can be classified presumptively as

GBS on the basis of biochemical tests, including hydrolysis of sodium

hippurate (in which 99% of isolates are positive), hydrolysis of bile

esculin (in which 99–100% are negative), bacitracin susceptibility (in

which 92% are resistant), and production of CAMP factor (in which

98–100% are positive). CAMP factor is a phospholipase produced by

GBS that causes synergistic hemolysis with β lysin produced by certain

strains of S. aureus. Its presence can be demonstrated by cross-streaking

of the test isolate and an appropriate staphylococcal strain on a blood

agar plate. GBS organisms causing human infections are encapsulated

by one of ten antigenically distinct polysaccharides. The capsular polysaccharide is an important virulence factor. Antibodies to the capsular

polysaccharide afford protection against GBS of the same (but not of a

different) capsular type.

■ INFECTION IN NEONATES

Two general types of GBS infection in infants are defined by the age

of the patient at presentation. Early-onset infections occur within the

first week of life, with a median age of 20 h at onset. Approximately

half of these infants have signs of GBS disease at birth. The infection

is acquired during or shortly before birth from the colonized maternal

genital tract. Surveillance studies have shown that 5–40% of women

are vaginal or rectal carriers of GBS. Approximately 50% of infants

delivered vaginally by carrier mothers become colonized, although

only 1–2% develop clinically evident infection. Prematurity, prolonged

labor, obstetric complications, and maternal fever are risk factors for

early-onset infection. The presentation of early-onset infection is the

same as that of other forms of neonatal sepsis. Typical findings include

respiratory distress, lethargy, and hypotension. Essentially all infants

with early-onset disease are bacteremic, one-third to one-half have

pneumonia and/or respiratory distress syndrome, and one-third have

meningitis.

Late-onset infections occur in infants 1 week to 3 months old and,

in rare instances, in older infants (mean age at onset, 3–4 weeks). The

infecting organism may be acquired during delivery (as in early-onset

cases) or during later contact with a colonized mother, nursery personnel, or another source. Meningitis is the most common manifestation

of late-onset infection and in most cases is associated with a strain of

capsular type III. Infants present with fever, lethargy or irritability, poor

feeding, and seizures. The various other types of late-onset infection

include bacteremia without an identified source, osteomyelitis, septic

arthritis, and facial cellulitis associated with submandibular or preauricular adenitis.

TREATMENT

Group B Streptococcal Infection in Neonates

Penicillin is the agent of choice for all GBS infections. Empirical

broad-spectrum therapy for suspected bacterial sepsis, consisting

of ampicillin and gentamicin, is generally administered until culture

results become available. If cultures yield GBS, many pediatricians

continue to administer gentamicin, along with ampicillin or penicillin, for a few days until clinical improvement becomes evident.

Infants with bacteremia or soft tissue infection should receive penicillin at a dosage of 200,000 units/kg per day in divided doses. For

meningitis, infants ≤7 days of age should receive 250,000–450,000

units/kg per day in three divided doses; infants >7 days of age

should receive 450,000–500,000 units/kg per day in four divided

doses. Meningitis should be treated for at least 14 days because of

the risk of relapse with shorter courses.

Prevention The incidence of GBS infection is unusually high

among infants of women with risk factors: preterm delivery, early rupture of membranes (>24 h before delivery), prolonged labor, fever, or

chorioamnionitis. Because the usual source of the organisms infecting

a neonate is the mother’s birth canal, efforts have been made to prevent GBS infections by the identification of high-risk carrier mothers

and their treatment with various forms of antibiotic prophylaxis or

immunoprophylaxis. Prophylactic administration of ampicillin or

penicillin to such patients during delivery reduces the risk of infection

in the newborn. This approach has been hampered by logistical difficulties in identifying colonized women before delivery; the results of

vaginal cultures early in pregnancy are poor predictors of carrier status

at delivery. The CDC recommends screening for anogenital colonization at 35–37 weeks of pregnancy by a swab culture of the lower vagina

and anorectum; intrapartum chemoprophylaxis is recommended for

culture-positive women and for women who, regardless of culture

status, have previously given birth to an infant with GBS infection or

have a history of GBS bacteriuria during pregnancy. Women whose

culture status is unknown and who develop premature labor (<37

weeks), prolonged rupture of membranes (>18 h), or intrapartum

fever or who have a positive intrapartum nucleic acid amplification

test for GBS also should receive intrapartum chemoprophylaxis. The

recommended regimen for chemoprophylaxis is a loading dose of 5

million units of penicillin G followed by 2.5 million units every 4 h

until delivery. Cefazolin is an alternative for women with a history

of penicillin allergy who are thought not to be at high risk for anaphylaxis. For women with a history of immediate hypersensitivity,

clindamycin may be substituted, but only if the colonizing isolate has

been demonstrated to be susceptible. If susceptibility testing results

are not available or indicate resistance, vancomycin should be used in

this situation.

Treatment of all pregnant women who are colonized or have risk factors for neonatal infection will result in exposure of up to one-third of

pregnant women and newborns to antibiotics, with the attendant risks

of allergic reactions and selection for resistant organisms. Although

still in the developmental stages, a GBS vaccine may ultimately offer a

better solution to prevention. Because transplacental passage of maternal antibodies produces protective antibody levels in newborns, efforts

are underway to develop a vaccine against GBS that can be given to

childbearing-age women before or during pregnancy. Results of phase

1 clinical trials of GBS capsular polysaccharide–protein conjugate vaccines suggest that a multivalent conjugate vaccine would be safe and

highly immunogenic.

1196 PART 5 Infectious Diseases

■ INFECTION IN ADULTS

The majority of GBS infections in otherwise healthy adults are related

to pregnancy and parturition. Peripartum fever, the most common

manifestation, is sometimes accompanied by symptoms and signs of

endometritis or chorioamnionitis (abdominal distention and uterine

or adnexal tenderness). Blood and vaginal swab cultures are often positive. Bacteremia is usually transitory but occasionally results in meningitis or endocarditis. Infections in adults that are not associated with

the peripartum period generally involve individuals who are elderly

or have an underlying chronic illness, such as diabetes mellitus or a

malignancy. Among the infections that develop with some frequency

in adults are cellulitis and soft tissue infection (including infected

diabetic skin ulcers), urinary tract infection, pneumonia, endocarditis, and septic arthritis. Other reported infections include meningitis,

osteomyelitis, and intraabdominal or pelvic abscesses. Relapse or

recurrence of invasive infection weeks to months after a first episode is

documented in ~4% of cases.

TREATMENT

Group B Streptococcal Infection in Adults

GBS is less sensitive to penicillin than GAS, requiring somewhat

higher doses. Adults with serious localized infections (pneumonia,

pyelonephritis, abscess) should receive doses of ~12 million units of

penicillin G daily; patients with endocarditis or meningitis should

receive 18–24 million units per day in divided doses. Vancomycin is

an acceptable alternative for penicillin-allergic patients.

NONENTEROCOCCAL GROUP D

STREPTOCOCCI

The main nonenterococcal group D streptococci that cause human

infections were previously considered a single species, Streptococcus

bovis. The organisms encompassed by S. bovis have been reclassified

into two species, each of which has two subspecies: Streptococcus gallolyticus subspecies gallolyticus, S. gallolyticus subspecies pasteurianus,

Streptococcus infantarius subspecies infantarius, and S. infantarius

subspecies coli. Endocarditis caused by these organisms is often associated with neoplasms of the gastrointestinal tract—most frequently,

a colon carcinoma or polyp—but is also reported in association with

other bowel lesions. When occult gastrointestinal lesions are carefully

sought, abnormalities are found in >60% of patients with endocarditis

due to S. gallolyticus or S. infantarius. In contrast to the enterococci,

nonenterococcal group D streptococci like these organisms are reliably

killed by penicillin as a single agent, and penicillin is the agent of choice

for the infections they cause.

VIRIDANS AND OTHER STREPTOCOCCI

■ VIRIDANS STREPTOCOCCI

Consisting of multiple species of α-hemolytic streptococci, the viridans

streptococci are a heterogeneous group of organisms that are important agents of bacterial endocarditis (Chap. 128). Several species of

viridans streptococci, including Streptococcus salivarius, Streptococcus

mitis, Streptococcus sanguis, and Streptococcus mutans, are part of the

normal flora of the mouth, where they live in close association with

the teeth and gingiva. Some species contribute to the development of

dental caries.

Previously known as Streptococcus morbillorum, Gemella morbillorum has been placed in a separate genus, along with Gemella haemolysans, on the basis of genetic-relatedness studies. These species

resemble viridans streptococci with respect to habitat in the human

host and associated infections.

The transient viridans streptococcal bacteremia induced by eating,

toothbrushing, flossing, and other sources of minor trauma, together

with adherence to biologic surfaces, is thought to account for the predilection of these organisms to cause endocarditis (see Fig. 128-1).

Viridans streptococci are also isolated, often as part of a mixed flora,

from sites of sinusitis, brain abscess, and liver abscess.

Viridans streptococcal bacteremia occurs relatively frequently in

neutropenic patients, particularly after bone marrow transplantation

or high-dose chemotherapy for cancer. Some of these patients develop

a sepsis syndrome with high fever and shock. Risk factors for viridans

streptococcal bacteremia include chemotherapy with high-dose cytosine arabinoside, prior treatment with trimethoprim-sulfamethoxazole

or a fluoroquinolone, treatment with antacids or histamine antagonists,

mucositis, and profound neutropenia.

The S. milleri group (also referred to as the S. intermedius or

S. anginosus group) includes three species that cause human disease:

S. intermedius, S. anginosus, and Streptococcus constellatus. These

organisms are often considered viridans streptococci, although they

differ somewhat from other viridans streptococci in both their hemolytic pattern (they may be α-, β-, or nonhemolytic) and the disease

syndromes they cause. This group commonly produces suppurative

infections, particularly abscesses of brain and abdominal viscera, and

infections related to the oral cavity or respiratory tract, such as peritonsillar abscess, lung abscess, and empyema.

TREATMENT

Infection with Viridans Streptococci

Isolates from neutropenic patients with bacteremia are often resistant to penicillin; thus these patients should be treated presumptively with vancomycin until the results of susceptibility testing

become available. Viridans streptococci isolated in other clinical

settings usually are sensitive to penicillin. Susceptibility testing

should be performed to guide treatment of serious infections.

■ ABIOTROPHIA AND GRANULICATELLA SPECIES

(NUTRITIONALLY VARIANT STREPTOCOCCI)

Occasional isolates cultured from the blood of patients with endocarditis fail to grow when subcultured on solid media. These nutritionally variant streptococci require supplemental thiol compounds

or active forms of vitamin B6

 (pyridoxal or pyridoxamine) for growth

in the laboratory. The nutritionally variant streptococci are generally

grouped with the viridans streptococci because they cause similar

types of infections. However, they have been reclassified on the basis of

16S ribosomal RNA sequence comparisons into two separate genera:

Abiotrophia, with a single species (Abiotrophia defectiva), and Granulicatella, with three species associated with human infection (Granulicatella adiacens, Granulicatella para-adiacens, and Granulicatella

elegans).

TREATMENT

Infection with Nutritionally Variant Streptococci

Treatment failure and relapse appear to be more common in cases

of endocarditis due to nutritionally variant streptococci than in

those due to the usual viridans streptococci. Thus, the addition of

gentamicin (1 mg/kg every 8 h for patients with normal renal function) to the penicillin regimen is recommended for endocarditis

due to the nutritionally variant organisms.

■ OTHER STREPTOCOCCI

Streptococcus suis is an important pathogen in swine and has been

reported to cause meningitis in humans, usually in individuals with

occupational exposure to pigs. S. suis has been reported to be the

most common cause of bacterial meningitis in Vietnam, and it has

been responsible for outbreaks in China. Strains of S. suis associated

with human infections have generally reacted with Lancefield group

R typing serum and sometimes with group D typing serum as well.

Isolates may be α- or β-hemolytic and are sensitive to penicillin. Streptococcus iniae, a pathogen of fish, has been associated with infections

in humans who have handled live or freshly killed fish. Cellulitis of the

hand is the most common form of human infection, although bacteremia and endocarditis have been reported. Anaerobic streptococci, or

1197CHAPTER 149 Enterococcal Infections

peptostreptococci, are part of the normal flora of the oral cavity, bowel,

and vagina. Infections caused by the anaerobic streptococci are discussed in Chap. 177.

■ FURTHER READING

Bruckner L, Gigliotti F: Viridans group streptococcal infections

among children with cancer and the importance of emerging antibiotic resistance. Semin Pediatr Infect Dis 17:153, 2006.

Parks T et al: Polyspecific intravenous immunoglobulin in

clindamycin-treated patients with streptococcal toxic shock syndrome: A systematic review and meta-analysis. Clin Infect Dis

67:1434, 2018.

Raabe V, Shane A: Group B Streptococcus (Streptococcus agalactiae),

in Gram-Positive Pathogens, 3rd ed, Fischetti V et al (eds). Washington, DC, ASM Press, 2019, pp 228–238.

Shulman ST et al: Clinical practice guideline for the diagnosis and

management of group A streptococcal pharyngitis: 2012 update by

the Infectious Diseases Society of America. Clin Infect Dis 55:1279,

2012.

Stevens DL, Bryant AE: Necrotizing soft tissue infections. N Engl J

Med 377:2253, 2017.

Enterococci have been recognized as potential human pathogens for

well over a century, but only in recent years have these organisms

acquired prominence as important causes of nosocomial infections.

The ability of enterococci to survive and/or disseminate in the hospital

environment and to acquire antibiotic resistance determinants makes

the treatment of some enterococcal infections in critically ill patients

a difficult challenge. Enterococci were first mentioned in the French

literature in 1899; the “entérocoque” was found in the human gastrointestinal tract. The first pathologic description of an enterococcal

infection dates to the same year. A clinical isolate from a patient who

died as a consequence of endocarditis was initially designated Micrococcus zymogenes, was later named Streptococcus faecalis subspecies

zymogenes, and would now be classified as Enterococcus faecalis. The

ability of this isolate to cause severe disease in both rabbits and mice

illustrated its potential lethality in the appropriate settings.

■ MICROBIOLOGY AND TAXONOMY

Enterococci are gram-positive organisms. In clinical specimens, they are

usually observed as single cells, diplococci, or short chains (Fig. 149-1),

although long chains are noted with some strains. Enterococci were

originally classified as streptococci because organisms of the two genera share many morphologic and phenotypic characteristics, including

a generally negative catalase reaction. Only DNA hybridization studies

and later 16S rRNA sequencing clearly demonstrated that enterococci

should be grouped as a genus distinct from the streptococci. Unlike the

majority of streptococci, enterococci hydrolyze esculin in the presence

of 40% bile salts and grow at high salt concentrations (e.g., 6.5%) and

at high temperatures (46°C). Enterococci are usually reported by the

clinical laboratory to be nonhemolytic on the basis of their inability to

lyse the ovine or bovine red blood cells (RBCs) commonly used in agar

plates; however, some strains of E. faecalis do lyse RBCs from humans,

horses, and rabbits due to the presence of an acquired hemolysin/

cytolysin gene. The majority of clinically relevant enterococcal species

hydrolyze pyrrolidonyl-β-naphthylamide (PYR); this characteristic is

helpful in differentiating enterococci from organisms of the Streptococcus gallolyticus group (formerly known as S. bovis, which includes

149 Enterococcal Infections

William R. Miller, Cesar A. Arias,

Barbara E. Murray

FIGURE 149-1 Gram’s stain of cultured blood from a patient with enterococcal

bacteremia. Oval gram-positive bacterial cells are arranged as diplococci and short

chains. (Courtesy of Audrey Wanger, PhD.)

S. gallolyticus, S. pasteurianus, and S. infantarius) and from Leuconostoc

species. Although many species of enterococci have been isolated from

human infections, the overwhelming majority of cases are caused by

two species, E. faecalis and E. faecium. Less frequently isolated species

include Enterococcus gallinarum, E. durans, E. hirae, and E. avium.

■ PATHOGENESIS

Enterococci are normal inhabitants of the large bowel of human adults,

although they usually make up <1% of the culturable intestinal microbiota. In the healthy human host, enterococci are typical symbionts that

coexist with other gastrointestinal bacteria; in fact, the utility of certain

enterococcal strains as probiotics in the treatment of diarrhea suggests

their possible role in maintaining the homeostatic equilibrium of the

bowel. These commensals play a role in colonization resistance, or the

ability of a healthy gastrointestinal microbiota to impede the establishment of a population of drug-resistant bacteria such as vancomycinresistant enterococci (VRE). Colonization resistance arises from a

complex set of metabolic and immunologic interactions between the

host, pathogen, and intestinal microbiota, many of which are disrupted

in hospitalized or chronically ill patients.

Several studies have shown that a higher level of gastrointestinal

colonization is a critical factor in the pathogenesis of enterococcal

infections. However, the mechanisms by which enterococci successfully colonize the bowel and gain access to the lymphatics and/or

bloodstream remain incompletely understood. Physical factors, such

as stomach pH and the mucin layer on the interior of the intestinal

lumen, provide a barrier and limit pathogen access to the intestinal

epithelium. In the hospital setting, administration of medications that

suppress stomach acid secretion, or degradation of the mucin layer by

gut commensals during periods of decreased oral intake, can disrupt

these protective layers.

One of the most important factors that promotes increased gastrointestinal colonization by enterococci is the administration of antimicrobial agents since enterococci are intrinsically resistant to a variety

of commonly used antibacterial drugs. In particular, antibiotics that

are excreted in the bile and have broad-spectrum activity (e.g., certain

cephalosporins that target gram-negative bacteria or anaerobes) are

usually associated with the recovery of higher numbers of enterococci

from feces. However, the increased colonization by hospital-associated

1198 PART 5 Infectious Diseases

strains of E. faecium in the presence of antimicrobial agents appears

to be due to more than the simple filling of a “biological niche” after

the eradication of competing components of the microbiota. Studies

of colonization dynamics in mouse intestines suggest the importance

of secreted compounds with bactericidal activity against VRE in preventing domination of the intestinal tract. These include host-derived

antimicrobial peptides produced by the innate immune system (such as

the lectin RegIIIγ) and compounds such as lantibiotics or bacteriocins

produced by members of the microbiota itself. Activation of Toll-like

receptors by lipopolysaccharide (an important component of the

gram-negative cell envelope) leads, in mice, to increased production

of RegIIIγ, and loss of this stimulation by antibiotic-induced disruptions of commensal gram-negative bacteria impairs clearance of VRE

from the intestines. Similarly, antimicrobial lantibiotics produced by

commensal bacteria (such as Blautia producta) are active against VRE

in vitro, but this organism may require a cooperative partnership with

other members of the microbiota to effectively provide colonization

resistance. Disruption of these partnerships by antibiotic administration can lead to an environment where VRE can flourish. Another factor that may contribute to enterococcal survival in the gastrointestinal

tract is the production of bacteriocins (molecules that kill competing

bacteria). Strains of E. faecalis harboring pheromone-producing plasmids that code for bacteriocins are capable of outcompeting enterococci lacking such plasmids. Furthermore, in vivo transfer of these

plasmids occurs by conjugation, enhancing the survival of the recipients. In the absence of antibiotics, hospital-associated lineages of E.

faecium seem to be less adapted for survival in the gastrointestinal tract

than are commensal E. faecium strains. Studies examining the rate of

carriage of VRE in patients after discharge from the hospital document

a median time to clearance between 2 and 4 months in patients without

ongoing risk factors, such as continued antibiotic use, residence in a

long-term care facility, or need for hemodialysis.

Several vertebrate, worm, and insect models have been developed to

study the role of possible pathogenic determinants in both E. faecalis

and E. faecium. Three main groups of virulence factors may increase

the ability of enterococci to colonize the gastrointestinal tract and/or

cause disease. The first group, enterococcal secreted factors, are molecules released outside the bacterial cell that contribute to the process

of infection. The best studied of these molecules include enterococcal

hemolysin/cytolysin and two enterococcal proteases (gelatinase and

serine protease). Enterococcal cytolysin is a heterodimeric toxin produced by some strains of E. faecalis that is capable of lysing human

(as well as equine but not ovine) RBCs as well as polymorphonuclear

leukocytes and macrophages. E. faecalis gelatinase and serine protease

are thought to mediate virulence by several mechanisms, including the

degradation of host tissues and the modification of critical components

of the immune system. Mutants lacking the genes corresponding to

these proteins are highly attenuated in experimental animal models of

peritonitis, endocarditis, and endophthalmitis.

A second group of virulence factors, enterococcal surface components, includes adhesins and is thought to contribute to bacterial

attachment to extracellular matrix molecules in the human host.

Several molecules on the surface of enterococci have been characterized and shown to play a role in the pathogenesis of enterococcal

infections. Among the characterized adhesins is aggregation substance

of E. faecalis, which mediates the attachment of bacterial cells to each

other, thereby facilitating conjugative plasmid exchange. Several lines

of evidence indicate that aggregation substance and enterococcal

cytolysin act synergistically to increase the virulence potential of E.

faecalis strains in experimental endocarditis. The surface protein

adhesin of collagen of E. faecalis (Ace) and its E. faecium homologue

(Acm) are microbial surface components adhering to matrix molecules

(MSCRAMMs); they recognize adhesive matrix molecules involved in

bacterial attachment to host proteins such as collagen, fibronectin, and

fibrinogen. Both Ace and Acm are collagen adhesins that are important

in the pathogenesis of experimental endocarditis. Pili of gram-positive

bacteria are important mediators of attachment to and invasion of

host tissues and are considered potential targets for immunotherapy.

Both E. faecalis and E. faecium have surface pili. Mutants of E. faecalis

lacking pili are attenuated in biofilm production, experimental endocarditis, and urinary tract infections (UTIs). Other surface proteins

that share structural homology with MSCRAMMs and appear to play a

role in enterococcal attachment to the host and in virulence include the

E. faecalis surface protein Esp and its E. faecium homologue Espfm, the

second collagen adhesin of E. faecium (Scm), the surface proteins of E.

faecium (Fms), SgrA (which binds to components of the basal lamina),

and EcbA (which binds to collagen type V). Additional surface components apparently associated with pathogenicity include the Erl protein (a protein from the WxL family) and polysaccharides, which are

thought to interfere with phagocytosis of the organism by host immune

cells. Some E. faecalis strains appear to harbor at least three distinct

classes of capsular polysaccharide; some of these polysaccharides play a

role in virulence and are potential targets for immunotherapy. Teichoic

acids on the enterococcal surface appear to be immunogenic, and

antibodies to these molecules are protective in some animal models.

The third group of virulence factors has not been well characterized but includes the E. faecalis stress protein Gls24, which has been

associated with enterococcal resistance to bile salts and appears to

be important in the pathogenesis of endocarditis, and the hylEfmcontaining plasmids of E. faecium, which are transferable between

strains and increase gastrointestinal colonization by E. faecium. In

mouse peritonitis, acquisition of these plasmids increased the lethality

of a commensal strain of E. faecium and enhanced colonization of the

uroepithelium. A gene encoding a regulator of oxidative stress (AsrR)

has been identified as an important virulence factor of E. faecium.

■ EPIDEMIOLOGY

According to data collected from 2015 to 2017 by the National Healthcare Safety Network of the Centers for Disease Control and Prevention,

enterococci are the second most common isolates (after staphylococci)

from hospital-associated infections in the United States. Although E.

faecalis remains the predominant species recovered from nosocomial

infections, the isolation of E. faecium has increased substantially in the

past 20 years and accounts for approximately one-third of all enterococcal infections identified to the species level. This point is important,

since E. faecium is by far the most resistant and challenging enterococcal species to treat. More than 90% of E. faecium isolates are resistant

to ampicillin (historically the most effective β-lactam agent against

enterococci), while ampicillin resistance in E. faecalis is uncommon.

Vancomycin resistance in E. faecium isolates ranges from 83% in acute

care hospitals in the United States to up to 93% in long-term care facilities. Resistance to vancomycin in E. faecalis isolates is less common,

with a higher incidence in device-associated infections (7.2%) than

surgical-site infections (3.4%).

The dynamics of enterococcal transmission and dissemination

in the hospital environment have been extensively studied, with a

focus on VRE. These studies have revealed that VRE colonization

of the gastrointestinal tract is a critical step in the development of

enterococcal disease and that a substantial proportion of patients colonized with VRE remain colonized for prolonged periods (sometimes

>1 year) and are more likely than patients without VRE colonization

to develop an Enterococcus-related illness (e.g., bacteremia). Important

factors associated with VRE colonization and persistence in the gut

include prolonged hospitalization; long courses of antibiotic therapy;

hospitalization in long-term care facilities, surgical units, and/or

intensive care units; organ transplantation; renal failure (particularly

in patients undergoing hemodialysis) and/or diabetes; high APACHE

(Acute Physiology and Chronic Health Evaluation) scores; and physical

proximity to patients infected or colonized with VRE or these patients’

rooms. Once a patient becomes colonized with VRE, several key factors are involved in the organisms’ dissemination in the hospital environment. VRE can survive exposure to heat and certain disinfectants

and have been found on numerous inanimate objects in the hospital,

including bed rails, medical equipment, doorknobs, gloves, telephones,

and computer keyboards. Thus, health care workers and the environment play pivotal roles in enterococcal transmission from patient to

patient, and infection control measures are crucial in breaking the

chain of transmission. Moreover, two meta-analyses have found that,