35 - 153 Streptococcal Infections

153 Streptococcal Infections

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 indi­ viduals 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) for 15 minutes three times weekly may be useful.

■ ■FURTHER READING Becker K et al: Coagulase-negative staphylococci. Clin Microbiol Rev 27:870, 2014. Cheung GYC et al: Pathogenicity and virulence of Staphylococcus aureus. Virulence 12:547, 2021. DeLeo FR et al: Community-associated methicillin-resistant Staphylo­ coccus aureus. Lancet 375:1557, 2010. Holland TL et al: Ceftobiprole for treatment of complicated Staphylo­ coccus aureus bacteremia. N Engl J Med 389:1390, 2023. Lee AS et al: Methicillin-resistant Staphylococcus aureus. Nat Rev Dis Primers 4:18033:1, 2018. Minter DJ et al: Contemporary management of Staphylococcus aureus bacteremia—Controversies in clinical practice. Clin Infect Dis 77:e57, 2023. Rose W et al: Current paradigms of combination therapy in methicillinresistant Staphylococcus aureus (MRSA) bacteremia: Does it work, which combination, and for which patients? Clin Infect Dis 73:2353, 2021. Siciliano V et al: Difficult-to-treat pathogens: A review on the man­ agement of multidrug- resistant Staphylococcus epidermidis. Life 13:1126, 2023. Tong SY et al: Staphylococcus aureus infections: Epidemiology, patho­ PART 5 Infectious Diseases physiology, clinical manifestations, and management. Clin Microbiol Rev 28:603, 2015. Michael R. Wessels

Streptococcal Infections 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 infec­ tions of school-age children, and for the postinfectious syndromes of TABLE 153-1  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 aSee Chap. 154. bSee Chap. 182.

acute rheumatic fever (ARF) and poststreptococcal glomerulonephri­ tis (PSGN). Group B Streptococcus (GBS; Streptococcus agalactiae) is a leading cause of bacterial sepsis and meningitis in newborns and a major cause of endometritis and fever in parturient women. Viridans streptococci are a common cause of bacterial endocarditis. Enterococci, which are morphologically similar to streptococci, are now con­ sidered 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. 154. Streptococci are gram-positive, spherical to ovoid bacteria that characteristically form chains when grown in liquid media. Most strep­ tococci that cause human infections are facultative anaerobes, although some are strict anaerobes. Streptococci are relatively fastidious organ­ isms, requiring enriched media for growth in the laboratory. Clinicians and clinical microbiologists identify streptococci by several classifica­ tion 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 β-hemolytic 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 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. 151), an important cause of pneumonia, meningitis, and other infec­ tions, 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 entero­ cocci are assigned to a distinct genus (Chap. 154). The classification of the major streptococcal groups causing human infections is outlined in Table 153-1. GROUP A STREPTOCOCCI Lancefield group A consists of a single species, S. pyogenes. As its spe­ cies name implies, this organism is associated with a variety of sup­ purative infections. In addition, GAS can trigger the postinfectious syndromes of ARF (which is uniquely associated with S. pyogenes infection; Chap. 371) and PSGN (Chap. 326). Worldwide, GAS infections and their postinfectious sequelae (pri­ marily 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

Presence of rheumatic heart disease (cases per 1000) 0.3 0.8 1.8 FIGURE 153-1  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.) developed countries (Fig. 153-1). As has been observed with infections due to other pathogens associated with the human respiratory tract, the incidence of streptococcal pharyngitis and of invasive GAS infection fell during 2020–2022 in association with COVID-19-related social distancing restrictions. A rebound in GAS infection has been observed in many countries beginning in the last quarter of 2022. Unusually high rates of invasive GAS infections in both children and adults were reported in 2023 and 2024 from centers in Europe and the United States. Prominent among these cases have been severe pneumonia and empy­ ema, sometimes as a co-infection with influenza or another respiratory virus, as well as necrotizing soft tissue infections and streptococcal toxic shock. A GAS strain designated M1UK first emerged in the United Kingdom in association with an upsurge in scarlet fever and has since been implicated as a dominant strain in invasive GAS infec­ tions in the United Kingdom and other European countries. Multiple other lineages of GAS have been identified in invasive infections else­ where in Europe and around the world. ■ ■PATHOGENESIS GAS elaborates a number of cell-surface components and extracel­ lular 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 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 seg­ ment 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.

1.0 1.3 3.5 2.2 5.7 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 infection with different M types. CHAPTER 153 Streptococcal Infections 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 asso­ ciated 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 hyal­ uronate 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 con­ nective 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 infec­ tion 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, includ­ ing 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 pharyn­ gitis is one of the most common bacterial infections of childhood, accounting for 20–40% of all cases of exudative pharyngitis in chil­ dren; 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. Respi­ ratory droplets are the usual mechanism of spread, although other routes, including food-borne 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 variable, rang­ ing 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 exu­ date 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 153-2). Streptococ­ cal infection is an unlikely cause when symptoms and signs sugges­ tive 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 PART 5 Infectious Diseases TABLE 153-2  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

definitive diagnosis. A rapid diagnostic test for latex agglutination or enzyme immunoassay of swab specimens is a useful adjunct to throat culture. Rapid diagnostic tests typically have a specificity of >95%. 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 recom­ mended 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 immunocompro­ mise or a family member with such a history; patients living in congre­ gate 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. National or professional organization guidelines in some countries with a very low incidence of ARF recommend symptomatic treatment for patients with mild symptoms and restricting diagnostic testing and/or anti­ biotic treatment to those with suggestive clinical features (e.g., fever, tonsillar swelling or exudate, tender anterior cervical adenopathy, and/ or absence of cough) or special risk factors. 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 compli­ cations 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 153-3). A firstgeneration 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 (anaphy­ laxis or urticaria) or another potentially life-threatening manifesta­ tion (e.g., severe rash and fever). Alternative agents are erythromycin and azithromycin. Azithro­ mycin 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 TABLE 153-3  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 immunoglobulin (2 g/kg as a single dose) aPenicillin 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. bLinezolid (600 mg IV q12h) may be substituted for isolates resistant to clindamycin. See text for discussion.

elsewhere with the increasing use of this class of antibiotics. Data from the CDC and the Active Bacterial Core surveillance program indicate a rise in macrolide resistance among invasive GAS isolates in the United States to >30% since 2021. 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 not 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 phar­ yngitis have become uncommon with the widespread use of antibiot­ ics 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 para­ pharyngeal 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. 370) and PSGN (Chap. 326), 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 cul­ tures 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 indi­ viduals with symptomatic pharyngitis. Therefore, aggressive attempts to eradicate carriage probably are not justified under most circum­ stances. 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 erad­ icate 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 maxi­ mum) has been used for mass prophylaxis/eradication of coloniza­ tion in outbreak situations. In vitro susceptibility to clindamycin or azithromycin should be confirmed before prescribing either of these antibiotics for eradication of colonization.

FIGURE 153-2  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.) CHAPTER 153 Scarlet Fever  Scarlet fever consists of streptococcal infection, usually pharyngitis, accompanied by a characteristic rash (Fig. 153-2). 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 occurred recently in China and the United Kingdom. The symptoms of scarlet fever are the same as those of pharyngitis alone. The rash typi­ cally 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 “sand­ paper” 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 skin folds (Pas­ tia’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, toxic shock syndrome, and systemic allergic reactions (e.g., drug eruptions). Streptococcal Infections 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 syn­ dromes offer a useful means for classification of these infections, not all cases fit exactly into one category. The classic syndromes are gen­ eral 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

FIGURE 153-3  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.) 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. 153-3). Lesions generally are not painful, and patients do not appear ill. Fever is not a feature of impetigo and, if present, suggests either infection extend­ ing 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, penicil­ lin 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 strep­ tococcal 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 gener­ ally be distinguished by their appearance as more discrete, grouped vesicles and by a positive Tzanck test or by herpes simplex virus- or varicella-zoster virus-specific PCR. In difficult cases, cultures of vesicular fluid should yield GAS (or Staphylococcus aureus) in impe­ tigo and the responsible virus in herpesvirus infections. PART 5 Infectious Diseases TREATMENT Streptococcal Impetigo Treatment of streptococcal impetigo is the same as that for strepto­ coccal 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 dicloxa­ cillin 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 infec­ tion. 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 gen­ eral 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 epide­ miologic 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 strep­ tococcal cellulitis, erysipelas, is characterized by a bright red appear­ ance of the involved skin, which forms a plateau sharply demarcated from surrounding normal skin (Fig. 153-4). 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 extremi­ ties. 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 may appear only mildly ill. In such cases, it is prudent to broaden the spectrum of empirical antimicrobial therapy to include other patho­ gens, particularly S. aureus, that can produce cellulitis with the same FIGURE 153-4  Erysipelas is a streptococcal infection of the superficial dermis and consists of well-demarcated, erythematous, edematous, warm plaques.

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 saphe­ nous 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 may 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 sur­ rounding 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, mani­ fested by red streaks extending proximally along superficial lymphat­ ics from the infection site. TREATMENT Streptococcal Cellulitis See Table 153-3 and Chap. 134. 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 organ­ isms 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 anaero­ bic 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 pro­ gresses (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 inflam­ matory 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 them­ selves 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. Drain­ age and debridement are central to the management of necrotizing fasciitis; antibiotic treatment is a critical adjunct (Table 153-3), 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 debride­ ment of involved tissues—and high-dose penicillin (Table 153-3). Infection models in animals and multiple retrospective clinical studies support the addition of clindamycin to the antibiotic treat­ ment regimen for severe GAS necrotizing soft tissue infections. In vitro and animal models suggest that the growth of GAS slows after the organism reaches a high density in infected tissues and that penicillin and other beta-lactam antibiotics have reduced efficacy under these circumstances as they target cell wall biosynthesis. By contrast, protein synthesis inhibitors retain activity regardless of growth phase of the bacteria. If the infecting strain is not known to be susceptible to clindamycin, linezolid is an alternative. Pneumonia and Empyema  GAS is an occasional cause of pneu­ monia, generally in previously healthy individuals. The onset of symp­ toms 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 pneu­ monia, 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 thora­ cotomy 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. Bacte­ remia 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 endocardi­ tis, meningitis, septic arthritis, osteomyelitis, peritonitis, and visceral abscesses. GAS is occasionally implicated in infectious complications of childbirth, usually endometritis and associated bacteremia. In the preantibiotic era, puerperal sepsis was commonly caused by GAS; cur­ rently, 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. CHAPTER 153 Streptococcal Infections 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. A case definition for streptococcal TSS was formulated in 1993 and updated in 2010 (Table 153-4). 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 usu­ ally becomes more pronounced on the second or third day of illness.

TABLE 153-4  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 aAn 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 Streptococcal Toxic Shock Syndrome (STSS) (Streptococcus pyogenes) 2010 Case Definition: Centers for Disease Control and Prevention (https:// ndc.services.cdc.gov/case-definitions/streptococcal-toxic-shock-syndrome-2010/). 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 addi­ tion 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 superanti­ gens 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. PART 5 Infectious Diseases TREATMENT Streptococcal Toxic Shock Syndrome High-dose penicillin is the agent of choice for streptococcal TSS. For empiric treatment of sepsis before the etiology is known, a broad-spectrum antibiotic regimen should include an agent with excellent activity against GAS such as an extended-spectrum peni­ cillin, cephalosporin, or a carbapenem. In light of the possible role of pyrogenic exotoxins or other streptococcal toxins in streptococ­ cal TSS, adjunctive treatment with clindamycin has been advocated by some authorities (Table 153-3), 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. As discussed previously (see “Treatment of Deep Soft Tis­ sue Streptococcal Infections,” above), 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 and streptococcal TSS are treated with clindamycin rather than with cell wall–active antibiotics alone. As clindamycin resistance occurs in 30% or more of invasive GAS isolates in the United States and many other countries, susceptibility to clindamy­ cin should not be assumed in the absence of in vitro testing of the

infecting strain. Linezolid is an appropriate alternative in the setting of clindamycin resistance or unknown susceptibility. IV immuno­ globulin also has been used as adjunctive therapy for streptococcal TSS (Table 153-3). Pooled immunoglobulin preparations contain antibodies capable of neutralizing the effects of streptococcal toxins and may have opsonic activity against GAS. Intravenous immu­ noglobulin (IVIG) also has immunomodulatory properties, which may mitigate the pathophysiologic effects of inflammatory cyto­ kines. Anecdotal reports and case series have suggested favorable clinical responses to IVIG, 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 anti­ body 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). Large-colony group C and G streptococci of human origin are now considered a single species, Streptococcus dysgalactiae subspecies equisimilis (SDSE). Genomic studies have demonstrated extensive overlap between the genomes of SDSE and GAS and evidence of cross-species recombina­ tion. These organisms have been associated with pharyngitis, cellulitis and soft tissue infections, pneumonia, bacteremia, endocarditis, and septic arthritis. Puerperal sepsis, meningitis, epidural abscess, intraab­ dominal abscess, urinary tract infection, and neonatal sepsis also have been reported. SDSE bacteremia most often affects elderly or chroni­ cally 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 domes­ ticated animals, especially horses and cattle; some human infections are acquired through contact with animals or consumption of unpasteur­ ized milk. These zoonotic organisms include Streptococcus equi subspe­ cies 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 strep­ tococcal infections. Antibiotic treatment is the same as for similar syndromes due to GAS (Table 153-3). Patients with bacteremia or 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 concentra­ tions. 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 debili­ tated patients and those with involvement of multiple joints. Infec­ tion 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 infec­ tion 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 propor­ tion 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 carbohy­ drate 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 crossstreaking of the test isolate and an appropriate staphylococcal strain on a blood agar plate. GBS organisms causing human infections are encapsulated by 1 of 10 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 person­ nel, 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 preau­ ricular 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 peni­ cillin, for a few days until clinical improvement becomes evident. Infants with bacteremia or soft tissue infection should receive peni­ cillin 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 d 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 chorio­ amnionitis. Because the usual source of the organisms infecting a neo­ nate 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 immunopro­ phylaxis. 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 previ­ ously 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 penicil­ lin 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 substi­ tuted, 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. CHAPTER 153 Streptococcal Infections Treatment of all pregnant women who are colonized or have risk fac­ tors 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 mater­ nal 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 vac­ cines suggest that a multivalent conjugate vaccine would be safe and highly immunogenic. ■ ■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 posi­ tive. Bacteremia is usually transitory but occasionally results in men­ ingitis 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, endocardi­ tis, 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 divided 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. Van­ comycin 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 gal­ lolyticus subspecies gallolyticus, S. gallolyticus subspecies pasteurianus, Streptococcus infantarius subspecies infantarius, and S. infantarius subspecies coli. Endocarditis caused by these organisms is often associ­ ated 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. PART 5 Infectious Diseases 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 impor­ tant agents of bacterial endocarditis (Chap. 133). 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 morbillo­ rum has been placed in a separate genus, along with Gemella haemoly­ sans, 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 pre­ dilection of these organisms to cause endocarditis (see Fig. 133-1). 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 viri­ dans streptococcal bacteremia include chemotherapy with high-dose

cytosine arabinoside, prior treatment with trimethoprim-sulfamethox­ azole 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 organ­ isms are often considered viridans streptococci, although they differ somewhat from other viridans streptococci in their small colony size on solid medium (they typically form colonies <0.5 mm in diameter), 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, sinusitis and complications such as orbital cellulitis, subdural and epidural abscess, and cerebral venous sinus thrombosis, lung abscess, and empyema. TREATMENT Infection with Viridans Streptococci Isolates from neutropenic patients with bacteremia are often resis­ tant to penicillin; thus, these patients should be treated presump­ tively 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 endocar­ ditis fail to grow when subcultured on solid media. These nutrition­ ally 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 Granuli­ catella, with three species associated with human infection (Granulica­ tella 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 func­ tion) 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 typ­ ing 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 pepto­ streptococci, are part of the normal flora of the oral cavity, bowel, and vagina. Infections caused by the anaerobic streptococci are discussed in Chap. 182.