Chapter 15: Gram-Positive Cocci

There are two medically important genera of gram-positive cocci: Staphylococcus and Streptococcus. Two of the most important human pathogens, Staphylococcus aureus and Streptococcus pyogenes, are described in this chapter. Staphylococci and streptococci are nonmotile and do not form spores.

Both staphylococci and streptococci are gram-positive cocci, but they are differentiated by two main criteria:

1. Microscopically, staphylococci appear in grapelike clusters, whereas streptococci are in chains.

2. Biochemically, staphylococci produce catalase (i.e., they degrade hydrogen peroxide), whereas streptococci do not.

Additional information regarding the clinical aspects of infections caused by the organisms in this chapter is provided in Part IX entitled Infectious Diseases beginning Chapter 70.

1. Staphylococcus aureus

Diseases

S. aureus causes abscesses (Figure 15–1), various pyogenic infections (e.g., endocarditis, septic arthritis, and osteomyelitis), food poisoning, scalded skin syndrome (Figure 15–2), and toxic shock syndrome. It is one of the most common causes of hospital-acquired pneumonia, septicemia, and surgical-wound infections, including the site of insertion of cardiac pacemakers. It is an important cause of skin and soft tissue infections, such as folliculitis (Figure 15–3), cellulitis, and impetigo (Figure 15–4). It is a common cause of bacterial conjunctivitis.

Methicillin-resistant S. aureus (MRSA) is the most common cause of skin abscesses in the United States. MRSA is also an important cause of pneumonia, necrotizing fasciitis, and sepsis in immunocompetent patients. S. aureus, especially MRSA, is the most common cause of infections in users of intravenous drugs.

Kawasaki syndrome is a disease of unknown etiology that may be caused by certain strains of S. aureus.

Important Properties

Staphylococci are spherical gram-positive cocci arranged in irregular grapelike clusters (Figure 15–5). All staphylococci produce catalase, whereas no streptococci do (catalase degrades H₂O₂ into O₂ and H₂O). Catalase is an important virulence factor. Bacteria that make catalase can survive the killing effect of H₂O₂ within neutrophils.

Three species of staphylococci are important human pathogens: S. aureus, Staphylococcus epidermidis, and Staphylococcus saprophyticus (Table 15–1). Of these three, S. aureus is by far the most common and causes the most serious infections. S. aureus is distinguished from the others primarily by coagulase production (Figure 15–6). Coagulase is an enzyme that causes plasma to clot by activating prothrombin to form thrombin. Thrombin then catalyzes the activation of fibrinogen to form the fibrin clot. S. epidermidis and S. saprophyticus are often referred to as coagulase-negative staphylococci and are described in the section below.

S. aureus produces a pigment called staphyloxanthin, which imparts a golden color to its colonies. This pigment enhances the pathogenicity of the organism by inactivating the microbicidal effect of superoxides and other reactive oxygen species within neutrophils. S. epidermidis does not synthesize this pigment and produces white colonies. The virulence of S. epidermidis is significantly less than that of S. aureus.

Two other characteristics further distinguish these species, namely, S. aureus usually ferments mannitol and hemolyzes red blood cells, whereas S. epidermidis and S. saprophyticus do not. Hemolysis of red cells by hemolysins produced by S. aureus is the source of iron required for growth of the organism. The iron in hemoglobin is recovered by the bacteria and utilized in the synthesis of cytochrome enzymes used to produce energy.

More than 90% of S. aureus strains contain plasmids that encode β-lactamase, the enzyme that degrades many, but not all, penicillins. β-Lactamase–resistant penicillins such as nafcillin are used to treat infections caused by those strains of S. aureus.

Note, however, that many strains of S. aureus are resistant to the β-lactamase–resistant penicillins, such as methicillin and nafcillin, by virtue of changes in the penicillin-binding proteins (PBP) in their cell membrane. Genes on the bacterial chromosome called mecA genes encode these altered PBPs. The most important of these PBPs is PBP2a that can perform its transpeptidase function but does not bind penicillins.

These strains are commonly known as methicillin-resistant S. aureus (MRSA) or nafcillin-resistant S. aureus (NRSA). MRSA causes both healthcare-acquired (HCA-MRSA) and community-acquired (CA-MRSA) infections. MRSA currently accounts for more than 50% of S. aureus strains isolated from hospital patients in the United States. CA-MRSA is a very common cause of community-acquired staphylococcal infections. Almost all strains of CA-MRSA produce P-V leukocidin (see later), whereas relatively few strains of HCA-MRSA do so. The most common strain of MRSA in the United States is the USA300 strain.

Strains of S. aureus with intermediate resistance to vancomycin (VISA) and with full resistance to vancomycin (VRSA) have also been detected. The cassette of genes that encodes vancomycin resistance in S. aureus is the same as the cassette that provides vancomycin resistance in enterococci. These genes are located in a transposon on a plasmid and encode the enzymes that substitute D-lactate for D-alanine in the peptidoglycan.

S. aureus has several important cell wall components and antigens:

1. Protein A is the major protein in the cell wall. It is an important virulence factor because it binds to the Fc portion of IgG. The Fc part is occupied and is not free to bind to the Fc receptor on neutrophils and macrophages, so phagocytosis of S. aureus by those cells does not occur. The coagulase-negative staphylococci do not produce protein A.

2. Teichoic acids are polymers of ribitol phosphate. They mediate adherence of the staphylococci to mucosal cells. Lipoteichoic acids play a role in the induction of septic shock by inducing cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) from macrophages (see the discussion of septic shock in the Endotoxin section of Chapter 7).

3. Polysaccharide capsule is also an important virulence factor. There are 11 serotypes based on the antigenicity of the capsular polysaccharide, but types 5 and 8 cause 85% of infections. Some strains of S. aureus are coated with a small amount of polysaccharide capsule, called a microcapsule. The capsule is poorly immunogenic, which has made producing an effective vaccine difficult.

4. Surface receptors for specific staphylococcal bacteriophages permit the “phage typing” of strains for epidemiologic purposes. Teichoic acids make up part of these receptors.

5. The peptidoglycan of S. aureus has endotoxin-like properties (i.e., it can stimulate macrophages to produce cytokines and can activate the complement and coagulation cascades). This explains the ability of S. aureus to cause the clinical findings of septic shock yet not possess endotoxin.

Transmission

Humans are the reservoir for staphylococci. The nose is the main site of colonization of S. aureus, and approximately 30% of people are colonized at any one time. People who are chronic carriers of S. aureus in their nose have an increased risk of skin infections caused by S. aureus.

The skin, especially of hospital personnel and patients, is also a common site of S. aureus colonization. Hand contact is an important mode of transmission, and handwashing decreases transmission.

S. aureus is also found in the vagina of approximately 5% of women, which predisposes them to toxic shock syndrome. Additional sources of staphylococcal infection are shedding from human lesions and fomites such as towels and clothing contaminated by these lesions.

Disease caused by S. aureus is favored by a heavily contaminated environment (e.g., family members with boils) and a compromised immune system. Reduced humoral immunity, including low levels of antibody, complement, or neutrophils, especially predisposes to staphylococcal infections.

Diabetes is a major predisposing factor to infections by S. aureus. S. aureus, especially MRSA, is the most common cause of infections in users of intravenous drugs. Patients with chronic granulomatous disease (CGD), a disease characterized by a defect in the ability of neutrophils to kill bacteria, are especially prone to S. aureus infections (see Chapter 68).

Pathogenesis

Staphylococcus aureus

S. aureus causes disease both by producing toxins and by inducing pyogenic (pus-producing) inflammation. The typical lesion of S. aureus pyogenic infection is an abscess. Abscesses undergo central necrosis and usually drain pus to the outside (e.g., furuncles and boils), but organisms may disseminate via the bloodstream as well. Foreign bodies, such as sutures and intravenous catheters, are important predisposing factors to infection by S. aureus.

Coagulase is an important virulence factor in the formation of an abscess. It causes formation of a fibrin clot that walls off the bacteria and prevents access of neutrophils to the site of infection.

Several important toxins and enzymes are produced by S. aureus. The three clinically important exotoxins are enterotoxin, toxic shock syndrome toxin, and exfoliatin.

1. Enterotoxin causes food poisoning characterized by prominent vomiting and watery, nonbloody diarrhea. It acts as a superantigen within the gastrointestinal tract to stimulate the release of large amounts of IL-1 and IL-2 from macrophages and helper T cells, respectively. The prominent vomiting is caused by serotonin (5-hydroxytryptamine) released from enterochromaffin cells, which stimulate the enteric nervous system to activate the vomiting center in the brain. Enterotoxin is fairly heat-resistant and is therefore usually not inactivated by brief cooking. It is resistant to stomach acid and to enzymes in the stomach and jejunum. There are six immunologic types of enterotoxin, types A–F.

2. Toxic shock syndrome toxin (TSST) causes toxic shock, especially in tampon-using menstruating women or in individuals with wound infections. Toxic shock also occurs in patients with nasal packing used to stop bleeding from the nose. TSST is produced locally by S. aureus in the vagina, nose, or other infected site. The toxin enters the bloodstream, causing a toxemia. Blood cultures typically do not grow S. aureus.

   TSST is a superantigen and causes toxic shock by stimulating the release of large amounts of IL-1, IL-2, and TNF (see the discussions of exotoxins in Chapter 7 and superantigens in Chapter 60). Approximately 5% to 25% of isolates of S. aureus carry the gene for TSST. Toxic shock occurs in people who do not have antibody against TSST.

3. Exfoliatin causes “scalded skin” syndrome in young children. It is “epidermolytic” and acts as a protease that cleaves desmoglein in desmosomes, leading to the separation of the epidermis at the granular cell layer. Localized production of exfoliatin by S. aureus results in bullous impetigo.

4. Several exotoxins can kill leukocytes (leukocidins) and cause necrosis of tissues in vivo. Of these, the two most important are alpha toxin and P-V leukocidin. Alpha toxin causes marked necrosis of the skin and hemolysis. The cytotoxic effect of alpha toxin is attributed to the formation of holes in the cell membrane and the consequent loss of low-molecular-weight substances from the damaged cell.

   P-V leukocidin is a pore-forming toxin that kills cells, especially white blood cells, by damaging cell membranes. The two subunits of the toxin assemble in the cell membrane to form a pore through which cell contents leak out. The gene-encoding P-V leukocidin is located on a lysogenic phage. P-V leukocidin is an important virulence factor for CA-MRSA and plays a role in the severe skin and soft tissue infection caused by this organism. A severe necrotizing pneumonia is also caused by strains of S. aureus that produce P-V leukocidin. Approximately 2% of clinical isolates of S. aureus produce P-V leukocidin.

5. The enzymes include coagulase, fibrinolysin, hyaluronidase, proteases, nucleases, and lipases. Coagulase, by clotting plasma, serves to wall off the infected site, thereby retarding the migration of neutrophils into the site. Staphylokinase is a fibrinolysin that can lyse thrombi.

Unlike S. aureus, coagulase-negative staphylococci do not produce exotoxins. Thus, they do not cause food poisoning or toxic shock syndrome. They do, however, cause pyogenic infections (see later).

Clinical Findings

The important clinical manifestations caused by S. aureus can be divided into two groups: pyogenic (pus-producing) and toxin-mediated (Table 15–2). S. aureus is a major cause of skin, soft tissue, bone, joint, lung, heart, and kidney pyogenic infections. Pyogenic diseases are the first group described, and toxin-mediated diseases are the second group.

Staphylococcus aureus: Pyogenic Diseases

1. Skin and soft tissue infections are very common. These include abscess (see Figure 15–1), impetigo (see Figure 15–4), furuncles, carbuncles (Figure 15–7), paronychia, cellulitis, folliculitis (see Figure 15–3), necrotizing fasciitis (Figure 77–10), hidradenitis suppurativa, conjunctivitis, eyelid infections (blepharitis and hordeolum), and postpartum breast infections (mastitis). Lymphangitis can occur, especially on the forearm associated with an infection on the hand.

   Severe necrotizing skin and soft tissue infections (SSTI) are caused by MRSA strains that produce P-V leukocidin. These infections are typically community-acquired rather than hospital-acquired. In the United States, CA-MRSA strains are the most common cause of skin and soft tissue infections. These CA-MRSA strains are an especially common cause of infection among the homeless and intravenous drug users. Athletes who engage in close personal contact such as wrestlers and football players are also at risk.

   Note that MRSA are also an important cause of SSTI in the hospital. HCA-MRSA cause approximately 50% of all nosocomial S. aureus infections. Molecular analysis reveals that the CA-MRSA strains are different from the HCA-MRSA strains.

2. Septicemia (sepsis) can originate from any localized lesion, especially wound infection, or as a result of intravenous drug abuse. Sepsis caused by S. aureus has clinical features similar to those of sepsis caused by certain gram-negative bacteria, such as Neisseria meningitidis (see Chapter 16).

3. Endocarditis may occur on normal or prosthetic heart valves, especially right-sided endocarditis (tricuspid valve) in intravenous drug users. (Prosthetic valve endocarditis is often caused by S. epidermidis.)

4. Osteomyelitis and septic arthritis may arise either by hematogenous spread from a distant infected focus or be introduced locally at a wound site. S. aureus is a very common cause of these diseases, especially in children.

5. S. aureus is the most common cause of postsurgical wound infections, which are an important cause of morbidity and mortality in hospitals. For example, S. aureus and S. epidermidis are the most common causes of infections at the site where cardiac pacemakers are installed.

6. Pneumonia can occur in postoperative patients or following viral respiratory infection, especially influenza. Staphylococcal pneumonia often leads to empyema or lung abscess. In many hospitals, it is the most common cause of nosocomial pneumonia in general and especially of ventilator-associated pneumonia in intensive care units. CA-MRSA causes a severe necrotizing pneumonia.

7. Conjunctivitis typically presents with unilateral burning eye pain, hyperemia of the conjunctiva, and a purulent discharge. The organism is transmitted to the eye by contaminated fingers. S. aureus is the most common cause overall, but Streptococcus pneumoniae and Haemophilus influenzae are more common in children. Gonococcal and nongonococcal (caused by Chlamydia trachomatis) conjunctivitis is acquired by infants during passage through the birth canal.

8. Abscesses can occur in any organ when S. aureus circulates in the bloodstream (bacteremia). These abscesses are often called “metastatic abscesses” because they occur by the spread of bacteria from the original site of infection, often in the skin.

Staphylococcus aureus: Toxin-Mediated Diseases

1. Food poisoning (gastroenteritis) is caused by ingestion of enterotoxin, which is preformed in foods and hence has a short incubation period (1–8 hours). In staphylococcal food poisoning, vomiting is typically more prominent than diarrhea.

2. Toxic shock syndrome is characterized by fever; hypotension; a diffuse, macular, sunburn-like rash that goes on to desquamate; and involvement of three or more of the following organs: liver, kidney, gastrointestinal tract, central nervous system, muscle, or blood.

3. Scalded skin syndrome is characterized by fever, large bullae, and an erythematous macular rash. The rash looks like a burn, hence the name “scalded-skin.” Large areas of skin slough, serous fluid exudes, and electrolyte imbalance can occur. Hair and nails can be lost. Recovery usually occurs within 7 to 10 days. This syndrome occurs most often in young children.

4. Bullous impetigo is characterized by vesicles containing clear fluid that coalesce to form bullae (Figure 15–8). Bullous impetigo is caused by localized production of exfoliatin by S. aureus.

Staphylococcus aureus: Kawasaki Disease

Kawasaki disease (KD) is a disease of unknown etiology that is discussed here because several of its features resemble toxic shock syndrome caused by the superantigens of S. aureus (and S. pyogenes). KD is a vasculitis involving small- and medium-size arteries, especially the coronary arteries. It is the most common cause of acquired heart disease in children in the United States.

Clinically, KD is characterized by a high fever of at least 5 days in duration; bilateral nonpurulent conjunctivitis; lesions of the lips and oral mucosa (e.g., strawberry tongue, edema of the lips, and erythema of the oropharynx); cervical lymphadenopathy; a diffuse erythematous, maculopapular rash; and erythema and edema of the hands and feet that often ends with desquamation.

The most characteristic clinical finding of KD is cardiac involvement, especially myocarditis, arrhythmias, and regurgitation involving the mitral or aortic valves. The main cause of morbidity and mortality in KD is aneurysm of the coronary arteries.

KD is much more common in children of Asian ancestry, leading to speculation that certain major histocompatibility complex (MHC) alleles may predispose to the disease. It is a disease of children younger than 5 years, often occurring in mini-outbreaks. It occurs worldwide but is much more common in Japan.

There is no definitive diagnostic laboratory test for KD. Effective therapy consists of high-dose intravenous immune globulins (IVIG) plus high-dose aspirin, which promptly reduce the fever and other symptoms and, most importantly, significantly reduce the occurrence of aneurysms.

Laboratory Diagnosis

Smears from staphylococcal lesions reveal gram-positive cocci in grapelike clusters (see Figure 15–5). Cultures of S. aureus typically yield golden-yellow colonies that are usually β-hemolytic. S. aureus is coagulase-positive (see Figure 15–6). Mannitol-salt agar is a commonly used screening device for S. aureus. S. aureus ferments mannitol, which lowers the pH, causing the agar to turn yellow, whereas S. epidermidis does not ferment mannitol and the agar remains pink.

In toxic shock syndrome, isolation of S. aureus is not required to make a diagnosis as long as the clinical criteria are met. Laboratory findings that support a diagnosis of toxic shock syndrome include the isolation of a TSST-producing strain of S. aureus and development of antibodies to the toxin during convalescence, although the latter is not useful for diagnosis during the acute disease.

For epidemiologic purposes, S. aureus can be subdivided into subgroups based on the susceptibility of the clinical isolate to lysis by a variety of bacteriophages. A person carrying S. aureus of the same phage group as that which caused the outbreak may be the source of the infections.

Treatment

Drainage (spontaneous or surgical) is the cornerstone of abscess treatment. Incision and drainage (I&D) is often sufficient treatment for a skin abscess (e.g., furuncle [boil]). Antibiotics are not necessary in most cases. However, if signs of systemic infection are seen, antibiotics, such as oral trimethoprim-sulfa or intravenous vancomycin are recommended (see Chapter 77). Previous infection provides only partial immunity to reinfection.

In the United States, 90% or more of S. aureus strains are resistant to penicillin G. Most of these strains produce β-lactamase. Such organisms can be treated with β-lactamase–resistant penicillins (e.g., nafcillin or cloxacillin), some cephalosporins, or vancomycin. Treatment with a combination of a β-lactamase–sensitive penicillin (e.g., amoxicillin) and a β-lactamase inhibitor (e.g., clavulanic acid) is also useful.

Approximately 20% of S. aureus strains are methicillin-resistant or nafcillin-resistant by virtue of altered penicillin-binding proteins. These resistant strains of S. aureus are often abbreviated MRSA or NRSA, respectively. Such organisms can produce sizable outbreaks of disease, especially in hospitals.

The drug of choice for these staphylococci is vancomycin, to which gentamicin is sometimes added. Daptomycin is also useful. Trimethoprim-sulfamethoxazole or clindamycin can be used to treat non–life-threatening infections caused by these organisms. Note that MRSA strains are resistant to almost all β-lactam drugs, including both penicillins and cephalosporins. Ceftaroline fosamil is the first β-lactam drug useful for the treatment of MRSA infections.

Strains of S. aureus with intermediate resistance to vancomycin (VISA strains) and with complete resistance to vancomycin (VRSA strains) have been isolated from patients. These strains are typically methicillin-/nafcillin-resistant as well, which makes them very difficult to treat. Daptomycin (Cubicin) can be used to treat infections by these organisms. Quinupristin-dalfopristin (Synercid) is another useful choice.

The treatment of toxic shock syndrome involves correction of the shock by using fluids, pressor drugs, and inotropic drugs; administration of a β-lactamase–resistant penicillin such as nafcillin; and removal of the tampon or debridement of the infected site as needed. Pooled serum globulins, which contain antibodies against TSST, may be useful.

Mupirocin is very effective as a topical antibiotic in skin infections caused by S. aureus. It has also been used to reduce nasal carriage of the organism in hospital personnel and in patients with recurrent staphylococcal infections. A topical skin antiseptic, such as chlorhexidine, can be added to mupirocin.

Some strains of staphylococci exhibit tolerance (i.e., they can be inhibited by antibiotics but are not killed). (That is, the ratio of minimum bactericidal concentration [MBC] to minimum inhibitory concentration [MIC] is very high.) Tolerance may result from failure of the drugs to inactivate inhibitors of autolytic enzymes that degrade the organism. Tolerant organisms should be treated with drug combinations (see Chapter 10).

Prevention

There is no vaccine against staphylococci. Cleanliness, frequent handwashing, and aseptic management of lesions help to control spread of S. aureus. Persistent colonization of the nose by S. aureus can be reduced by intranasal mupirocin or by oral antibiotics, such as ciprofloxacin or trimethoprim-sulfamethoxazole, but is difficult to eliminate completely. Shedders may have to be removed from high-risk areas (e.g., operating rooms and newborn nurseries). Cefazolin is often used perioperatively to prevent staphylococcal surgical-wound infections.

2. Coagulase-negative staphylococci (Staphylococcus epidermidis & Staphylococcus saprophyticus)

Diseases

S. epidermidis causes prosthetic valve endocarditis and prosthetic joint infections. It is the most common cause of central nervous system shunt infections and an important cause of sepsis in newborns. S. saprophyticus causes urinary tract infections, especially cystitis.

Important Properties

Staphylococci are spherical gram-positive cocci arranged in irregular grapelike clusters (see Figure 15–5). All staphylococci produce catalase, whereas no streptococci do (catalase degrades H₂O₂ into O₂ and H₂O). Catalase is an important virulence factor. Bacteria that make catalase can survive the killing effect of H₂O₂ within neutrophils.

S. epidermidis and S. saprophyticus are often referred to as coagulase-negative staphylococci. Coagulase is an enzyme that causes plasma to clot by activating prothrombin to form thrombin. Thrombin then catalyzes the activation of fibrinogen to form the fibrin clot (see Figure 15-6).

S. epidermidis and S. saprophyticus do not synthesize staphyloxanthin and produces white colonies. The virulence of these organisms is significantly less than that of S. aureus, a property that is, in part, attributed to their failure to produce staphyloxanthin. They also do not produce protein A, an important virulence factor made by S. aureus.

Two other characteristics further distinguish these species, namely, S. aureus usually ferments mannitol and hemolyzes red blood cells, whereas S. epidermidis and S. saprophyticus do not.

Transmission

Humans are the reservoir for staphylococci. S. epidermidis is found primarily on the human skin and can enter the bloodstream at the site of intravenous catheters that penetrate through the skin. S. saprophyticus is found primarily on the mucosa of the genital tract in young women and from that site can ascend into the urinary bladder to cause urinary tract infections.

S. epidermidis infections are almost always hospital-acquired, whereas S. saprophyticus infections are almost always community-acquired.

Pathogenesis

Unlike S. aureus, the two coagulase-negative staphylococci do not produce exotoxins. Thus, they do not cause food poisoning or toxic shock syndrome. They do, however, cause pyogenic infections. For example, S. epidermidis is a prominent cause of pyogenic infections on prosthetic implants such as heart valves and hip joints, and S. saprophyticus causes pyogenic urinary tract infections, especially cystitis.

Strains of S. epidermidis that produce a glycocalyx are more likely to adhere to prosthetic implant materials and therefore are more likely to infect these implants than strains that do not produce a glycocalyx. Hospital personnel are a major reservoir for antibiotic-resistant strains of S. epidermidis.

Clinical Findings

S. epidermidis is part of the normal human flora on the skin and mucous membranes but can enter the bloodstream (bacteremia) and cause metastatic infections, especially at the site of implants. It commonly infects intravenous catheters and prosthetic implants (e.g., prosthetic heart valves [endocarditis], vascular grafts, and prosthetic joints [arthritis or osteomyelitis]) (see Table 15–2). S. epidermidis is also a major cause of sepsis in neonates and of peritonitis in patients with renal failure who are undergoing peritoneal dialysis through an indwelling catheter. It is the most common bacterium to cause cerebrospinal fluid shunt infections.

S. saprophyticus causes urinary tract infections, particularly in sexually active young women. Most women with this infection have had sexual intercourse within the previous 24 hours. This organism is second to Escherichia coli as a cause of community-acquired urinary tract infections in young women.

Staphylococcus lugdunensis is a relatively uncommon coagulase-negative staphylococcus that causes prosthetic valve endocarditis and skin infections.

Laboratory Diagnosis

Smears from staphylococcal lesions reveal gram-positive cocci in grapelike clusters (see Figure 15–5). Cultures of coagulase-negative staphylococci typically yield white colonies that are nonhemolytic. The two coagulase-negative staphylococci are differentiated by their reaction to the antibiotic novobiocin: S. epidermidis is sensitive, whereas S. saprophyticus is resistant. There are no serologic or skin tests used for the diagnosis of any staphylococcal infection.

Treatment

S. epidermidis is highly antibiotic resistant. Most strains produce β-lactamase but are sensitive to β-lactamase–resistant drugs such as nafcillin. These are called methicillin-sensitive strains (MSSE). Some strains are methicillin/nafcillin-resistant (MRSE) due to altered penicillin-binding proteins. The drug of choice for MRSE is vancomycin, to which either rifampin or an aminoglycoside can be added. Removal of the catheter or other device is often necessary. S. saprophyticus urinary tract infections can be treated with trimethoprim-sulfamethoxazole or a quinolone, such as ciprofloxacin.

Prevention

There is no vaccine against the coagulase-negative staphylococci. Prompt removal of intravenous catheters reduces the rick of infections caused by S. epidermidis.

Streptococci of medical importance are listed in Table 15–3. All but one of these streptococci are discussed in this section; S. pneumoniae is discussed separately at the end of this chapter because it is so important.

Diseases

Streptococci cause a wide variety of infections. S. pyogenes (group A Streptococcus) is the leading bacterial cause of pharyngitis (Figure 15–9) and cellulitis (Figure 15–10). It is an important cause of impetigo (see Figure 15–4), erysipelas, necrotizing fasciitis, scarlet fever, and streptococcal toxic shock syndrome. It is also the inciting factor of two important immunologic diseases, namely, rheumatic fever and acute glomerulonephritis. Streptococcus agalactiae (group B Streptococcus) is the leading cause of neonatal sepsis and meningitis. Enterococcus faecalis is an important cause of hospital-acquired urinary tract infections and endocarditis. Viridans group streptococci are the most common cause of endocarditis (Figure 15–11). Streptococcus bovis (also known as Streptococcus gallolyticus) is an uncommon cause of endocarditis.

Important Properties

Streptococci are spherical gram-positive cocci arranged in chains or pairs (Figure 15–12). All streptococci are catalase-negative, whereas staphylococci are catalase-positive (see Table 15–3).

One of the most important characteristics for identification of streptococci is the type of hemolysis (Figure 15–13).

1. α-Hemolytic streptococci form a green zone around their colonies as a result of incomplete lysis of red blood cells in the agar. The green color is formed when hydrogen peroxide produced by the bacteria oxidizes hemoglobin (red color) to biliverdin (green color).

2. β-Hemolytic streptococci form a clear zone around their colonies because complete lysis of the red cells occurs. β-Hemolysis is due to the production of enzymes (hemolysins) called streptolysin O and streptolysin S (see “Pathogenesis” later).

3. Some streptococci are nonhemolytic (γ-hemolysis).

There are two important antigens of β-hemolytic streptococci:

1. C carbohydrate determines the group of β-hemolytic streptococci. It is located in the cell wall, and its specificity is determined by an amino sugar. For example, group A β-hemolytic streptococci (S. pyogenes) are distinguished from group B β-hemolytic streptococci (S. agalactiae) because they have a different C carbohydrate.

2. M protein is the most important virulence factor of S. pyogenes. It protrudes from the outer surface of the cell and blocks phagocytosis (i.e., it is antiphagocytic). It inactivates C3b, a component of complement that opsonizes the bacteria prior to phagocytosis (see Chapter 63). Strains of S. pyogenes that do not produce M protein are nonpathogenic.

M protein also determines the type of group A β-hemolytic streptococci. There are approximately 100 serotypes based on the M protein, which explains why multiple infections with S. pyogenes can occur. Antibody to M protein provides type-specific immunity.

Strains of S. pyogenes that produce certain M protein types are rheumatogenic (i.e., cause primarily rheumatic fever), whereas strains of S. pyogenes that produce other M protein types are nephritogenic (i.e., cause primarily acute glomerulonephritis). Although M protein is the main antiphagocytic component of S. pyogenes, the organism also has a polysaccharide capsule that plays a role in retarding phagocytosis.

Classification of Streptococci

β-Hemolytic Streptococci

These are arranged into groups A–U (known as Lancefield groups) on the basis of antigenic differences in C carbohydrate. In the clinical laboratory, the group is determined by precipitin tests with specific antisera or by immunofluorescence.

Group A streptococci (S. pyogenes) are one of the most important human pathogens. They are the most frequent bacterial cause of pharyngitis and a very common cause of skin infections. They adhere to pharyngeal epithelium via pili composed of lipoteichoic acid and M protein. Many strains have a hyaluronic acid capsule that is antiphagocytic. The growth of S. pyogenes on agar plates in the laboratory is inhibited by the antibiotic bacitracin, an important diagnostic criterion (Figure 15–14).

Group B streptococci (S. agalactiae) colonize the genital tract of some women and can cause neonatal meningitis and sepsis. They are usually bacitracin-resistant. They hydrolyze (break down) hippurate, an important diagnostic criterion.

Group D streptococci include enterococci (e.g., E. faecalis and Enterococcus faecium) and nonenterococci (e.g., S. bovis). Enterococci are members of the normal flora of the colon and are noted for their ability to cause urinary, biliary, and cardiovascular infections. They are very hardy organisms; they can grow in hypertonic (6.5%) saline or in bile and are not killed by penicillin G. As a result, a synergistic combination of penicillin and an aminoglycoside (e.g., gentamicin) is required to kill enterococci. Vancomycin can also be used, but vancomycin-resistant enterococci (VRE) have emerged and become an important and much feared cause of life-threatening nosocomial infections. More strains of E. faecium are vancomycin-resistant than are strains of E. faecalis.

Nonenterococcal group D streptococci, such as S. bovis, can cause similar infections but are much less hardy organisms (e.g., they are inhibited by 6.5% NaCl and killed by penicillin G). Note that the hemolytic reaction of group D streptococci is variable: most are α-hemolytic, but some are β-hemolytic, and others are nonhemolytic.

Groups C, E, F, G, H, and K–U streptococci infrequently cause human disease.

Non–β-Hemolytic Streptococci

Some streptococci produce no hemolysis; others produce α-hemolysis. The principal α-hemolytic organisms are S. pneumoniae (pneumococci) and the viridans group of streptococci (e.g., Streptococcus mitis, Streptococcus sanguinis, and Streptococcus mutans). Pneumococci and viridans streptococci are distinguished in the clinical laboratory by two main criteria: (1) the growth of pneumococci is inhibited by optochin, whereas the growth of viridans streptococci is not inhibited; and (2) colonies of pneumococci dissolve when exposed to bile (bile-soluble), whereas colonies of viridans streptococci do not dissolve.

Viridans streptococci are part of the normal flora of the human pharynx and intermittently reach the bloodstream to cause infective endocarditis. S. mutans synthesizes polysaccharides (dextrans) that are found in dental plaque and lead to dental caries. Streptococcus intermedius and Streptococcus anginosus (also known as the S. anginosus-milleri group) are usually α-hemolytic or nonhemolytic, but some isolates are β-hemolytic. They are found primarily in the mouth and colon.

Peptostreptococci

These grow under anaerobic or microaerophilic conditions and produce variable hemolysis. Peptostreptococci are members of the normal flora of the gut, mouth, and female genital tract and participate in mixed anaerobic infections. The term mixed anaerobic infections refers to the fact that these infections are caused by multiple bacteria, some of which are anaerobes and others are facultatives. For example, peptostreptococci and viridans streptococci, both members of the oral flora, are often found in brain abscesses following dental surgery. Peptostreptococcus magnus and Peptostreptococcus anaerobius are the species frequently isolated from clinical specimens.

Transmission

Most streptococci are part of the normal flora of the human throat, skin, and intestines but produce disease when they gain access to tissues or blood. Viridans streptococci and S. pneumoniae are found chiefly in the oropharynx; S. pyogenes is found on the skin and in the oropharynx in small numbers; S. agalactiae occurs in the vagina and colon; and both the enterococci and anaerobic streptococci are located in the colon.

Pathogenesis

Group A streptococci (S. pyogenes) cause disease by three mechanisms: (1) pyogenic inflammation, which is induced locally at the site of the organisms in tissue; (2) exotoxin production, which can cause widespread systemic symptoms in areas of the body where there are no organisms; and (3) immunologic, which occurs when antibody against a component of the organism cross-reacts with normal tissue or forms immune complexes that damage normal tissue (see the section on poststreptococcal diseases later in the chapter). The immunologic reactions cause inflammation (e.g., the inflamed joints of rheumatic fever), but there are no organisms in the lesions (Table 15–4).

The M protein of S. pyogenes is its most important antiphagocytic factor, but its capsule, composed of hyaluronic acid, is also antiphagocytic. Antibodies are not formed against the capsule because hyaluronic acid is a normal component of the body and humans are tolerant to it.

Group A streptococci produce four important enzymes related to pathogenesis:

1. Hyaluronidase degrades hyaluronic acid, which is the ground substance of subcutaneous tissue. Hyaluronidase is known as spreading factor because it facilitates the rapid spread of S. pyogenes in skin infections (cellulitis).

2. Streptokinase (fibrinolysin) activates plasminogen to form plasmin, which dissolves fibrin in clots, thrombi, and emboli. It can be used to lyse thrombi in the coronary arteries of heart attack patients.

3. DNase (streptodornase) degrades DNA in exudates or necrotic tissue. Antibody to DNase B develops during pyoderma; this can be used for diagnostic purposes. Streptokinase–streptodornase mixtures applied as a skin test give a positive reaction in most adults, indicating normal cell-mediated immunity.

4. IgG degrading enzyme is a protease that specifically cleaves IgG heavy chains. This prevents opsonization and complement activation thereby enhancing the virulence of the organism.

In addition, group A streptococci produce five important toxins and hemolysins:

1. Erythrogenic toxin causes the rash of scarlet fever. Its mechanism of action is similar to that of the TSST of S. aureus (i.e., it acts as a superantigen; see S. aureus, earlier, and Chapter 58). It is produced only by certain strains of S. pyogenes lysogenized by a bacteriophage carrying the gene for the toxin. The injection of a skin test dose of erythrogenic toxin (Dick test) gives a positive result in persons lacking antitoxin (i.e., susceptible persons).

2. Streptolysin O is a hemolysin that is inactivated by oxidation (oxygen-labile). It causes β-hemolysis only when colonies grow under the surface of a blood agar plate. It is antigenic, and antibody to it (ASO) develops after group A streptococcal infections. The titer of ASO antibody can be important in the diagnosis of rheumatic fever.

3. Streptolysin S is a hemolysin that is not inactivated by oxygen (oxygen-stable). It is not antigenic but is responsible for β-hemolysis when colonies grow on the surface of a blood agar plate.

4. Pyrogenic exotoxin A is the toxin responsible for most cases of streptococcal toxic shock syndrome. It has the same mode of action as does staphylococcal TSST (i.e., it is a superantigen that causes the release of large amounts of cytokines from helper T cells and macrophages; see Gram-Negative Bacteria and Memory T Cells).

5. Exotoxin B is a protease that rapidly destroys tissue and is produced in large amounts by the strains of S. pyogenes, the so-called “flesh-eating” streptococci that cause necrotizing fasciitis.

Pathogenesis by group B streptococci (S. agalactiae) is based on the ability of the organism to induce an inflammatory response. However, unlike S. pyogenes, no cytotoxic enzymes or exotoxins have been described, and there is no evidence for any immunologically induced disease. Group B streptococci have a polysaccharide capsule that is antiphagocytic, and anticapsular antibody is protective.

Pathogenesis by S. pneumoniae and the viridans streptococci is uncertain, as no exotoxins or tissue-destructive enzymes have been demonstrated. The main virulence factor of S. pneumoniae is its antiphagocytic polysaccharide capsule. Many of the strains of viridans streptococci that cause endocarditis produce a glycocalyx that enables the organism to adhere to the heart valve.

Clinical Findings

S. pyogenes causes three types of diseases: (1) pyogenic diseases such as pharyngitis and cellulitis, (2) toxigenic diseases such as scarlet fever and toxic shock syndrome, and (3) immunologic diseases such as rheumatic fever and acute glomerulonephritis (AGN). (See next section on poststreptococcal diseases.)

S. pyogenes (group A Streptococcus) is the most common bacterial cause of pharyngitis (sore throat). Streptococcal pharyngitis (strep throat) is characterized by throat pain and fever. On examination, an inflamed throat and tonsils, often with a yellowish exudate, are found, accompanied by tender cervical lymph nodes. If untreated, spontaneous recovery often occurs in 10 days, but rheumatic fever may occur (see next section on poststreptococcal diseases). Untreated pharyngitis may extend to the middle ear (otitis media), the sinuses (sinusitis), the mastoids (mastoiditis), or the meninges (meningitis). Continuing inability to swallow may indicate a peritonsillar or retropharyngeal abscess.

If the infecting streptococci produce erythrogenic toxin and the host lacks antitoxin, scarlet fever may result. A “strawberry” tongue is a characteristic lesion seen in scarlet fever. S. pyogenes also causes another toxin-mediated disease, streptococcal toxic shock syndrome, which has clinical findings similar to those of staphylococcal toxic shock syndrome (see Transmission). However, streptococcal toxic shock syndrome typically has a recognizable site of pyogenic inflammation and blood cultures are often positive, whereas staphylococcal toxic shock syndrome typically has neither a site of pyogenic inflammation nor positive blood cultures.

Group A streptococci cause skin and soft tissue infections, such as cellulitis, erysipelas (Figure 15–15), necrotizing fasciitis (streptococcal gangrene), and impetigo (see Figure 15–4).

Necrotizing fasciitis is often called the “flesh-eating” disease. In addition to S. pyogenes, Clostridium perfringens and MRSA are important causes. The clinical aspects of necrotizing fasciitis are described in Chapter 77.

Impetigo, a form of pyoderma, is a superficial skin infection characterized by “honey-colored” crusted lesions. Lymphangitis can occur, especially on the forearm associated with an infection on the hand.

Group A streptococci also cause endometritis (puerperal fever), a serious infection of pregnant women, and sepsis. Immune-mediated poststreptococcal AGN can also occur, especially following skin infections caused by certain M protein types of S. pyogenes.

Group B streptococci cause neonatal sepsis and meningitis. The main predisposing factor is prolonged (longer than 18 hours) rupture of the membranes in women who are colonized with the organism. Children born prior to 37 weeks of gestation have a greatly increased risk of disease. Also, children whose mothers lack antibody to group B streptococci and who consequently are born without transplacentally acquired IgG have a high rate of neonatal sepsis caused by this organism. Group B streptococci are an important cause of neonatal pneumonia as well.

Although most group B streptococcal infections are in neonates, this organism also causes infections such as pneumonia, endocarditis, arthritis, cellulitis, and osteomyelitis in adults. Postpartum endometritis also occurs. Diabetes is the main predisposing factor for adult group B streptococcal infections.

Viridans streptococci (e.g., S. mutans, S. sanguinis, S. salivarius, and S. mitis) are the most common cause of infective endocarditis. They enter the bloodstream (bacteremia) from the oropharynx, typically after dental surgery. Signs of endocarditis are fever, heart murmur, anemia, and embolic events such as splinter hemorrhages, subconjunctival petechial hemorrhages, and Janeway lesions. The heart murmur is caused by vegetations on the heart valve (see Figure 15–11). It is 100% fatal unless effectively treated with antimicrobial agents. About 10% of endocarditis cases are caused by enterococci, but any organism causing bacteremia may settle on deformed valves. At least three blood cultures are necessary to ensure recovery of the organism in more than 90% of cases.

Viridans streptococci, especially S. anginosus, S. milleri, and S. intermedius, also cause brain abscesses, often in combination with mouth anaerobes (a mixed aerobic–anaerobic infection). Dental surgery is an important predisposing factor to brain abscess because it provides a portal for the viridans streptococci and the anaerobes in the mouth to enter the bloodstream (bacteremia) and spread to the brain. Viridans streptococci are involved in mixed aerobic–anaerobic infections in other areas of the body as well (e.g., lung abscesses and abdominal abscesses, including liver abscesses).

Enterococci cause urinary tract infections, especially in hospitalized patients. Indwelling urinary catheters and urinary tract instrumentation are important predisposing factors. Enterococci also cause endocarditis, particularly in patients who have undergone gastrointestinal or urinary tract surgery or instrumentation. They also cause intra-abdominal and pelvic infections, typically in combination with anaerobes. S. bovis, a nonenterococcal group D Streptococcus, causes endocarditis, especially in patients with carcinoma of the colon. This association is so strong that patients with S. bovis, bacteremia, or endocarditis should be investigated for the presence of colonic carcinoma.

Peptostreptococci are one of the most common bacteria found in brain, lung, abdominal, and pelvic abscesses.

Poststreptococcal (Nonsuppurative) Diseases

These are disorders in which a local infection with group A streptococci is followed weeks later by inflammation in an organ that was not infected by the streptococci. The inflammation is caused by an immunologic (antibody) response to streptococcal M proteins that cross-react with human tissues. Some strains of S. pyogenes bearing certain M proteins are nephritogenic and cause AGN, and other strains bearing different M proteins are rheumatogenic and cause acute rheumatic fever. Note that these diseases appear several weeks after the actual infection because that is the length of time it takes to produce sufficient antibodies.

Acute Glomerulonephritis

AGN typically occurs 2 to 3 weeks after skin infection by certain group A streptococcal types in children (e.g., M protein type 49 causes AGN most frequently). AGN is more frequent after skin infections than after pharyngitis. The most striking clinical features are hypertension, edema of the face (especially periorbital edema) and ankles, and “smoky” urine (due to red cells in the urine). Most patients recover completely. Reinfection with streptococci rarely leads to recurrence of glomerulonephritis.

The disease is initiated by antigen–antibody complexes on the glomerular basement membrane. Complement is activated and C5a attracts neutrophils that secrete enzymes that damage the endothelium of the glomerular capillaries. It can be prevented by early eradication of nephritogenic streptococci from skin colonization sites but not by administration of penicillin after the onset of symptoms.

Acute Rheumatic Fever

Approximately 2 weeks after a group A streptococcal infection—usually pharyngitis—rheumatic fever, characterized by fever, migratory polyarthritis, and carditis, may develop. The carditis damages myocardial and endocardial tissue, especially the mitral and aortic valves, resulting in vegetations on the valves. Uncontrollable, spasmodic movements of the limbs or face (chorea) may also occur. ASO titers and the erythrocyte sedimentation rate are elevated. Note that group A streptococcal skin infections do not cause rheumatic fever. Most cases of pharyngitis caused by group A streptococci occur in children age 5 to 15 years, and hence rheumatic fever occurs in that age group.

Rheumatic fever is due to an immunologic cross-reaction between antibodies formed against M proteins of S. pyogenes and proteins on the surface of joint, heart, and brain tissue. It is an autoimmune disease greatly exacerbated by recurrent streptococcal infections. If streptococcal infections are treated within 8 days of onset, rheumatic fever is usually prevented. After a heart-damaging attack of rheumatic fever, reinfection must be prevented by long-term prophylaxis.

In the United States, less than 0.5% of group A streptococcal infections lead to rheumatic fever, but in developing tropical countries, the rate is higher than 5%. Rheumatic heart disease remains a significant global health burden.

Laboratory Diagnosis

Microbiologic

Gram-stained smears are useless in streptococcal pharyngitis because viridans streptococci are members of the normal flora and cannot be visually distinguished from the pathogenic S. pyogenes. However, stained smears from skin lesions or wounds that reveal streptococci are diagnostic. Cultures of swabs from the pharynx or lesion on blood agar plates show small, translucent β-hemolytic colonies in 18 to 48 hours. If inhibited by bacitracin disk, they are likely to be group A streptococci (see Figure 15–14).

Group B streptococci are characterized by their ability to hydrolyze hippurate and by the production of a protein that causes enhanced hemolysis on sheep blood agar when combined with β-hemolysin of S. aureus (CAMP test). Group D streptococci hydrolyze esculin in the presence of bile (i.e., they produce a black pigment on bile-esculin agar). The group D organisms are further subdivided: the enterococci grow in hypertonic (6.5%) NaCl, whereas the nonenterococci do not.

Although cultures remain the gold standard for the diagnosis of streptococcal pharyngitis, a problem exists because the results of culturing are not available for at least 18 hours, and it is beneficial to know while the patient is in the office whether antibiotics should be prescribed. For this reason, rapid tests that provide a diagnosis in approximately 10 minutes were developed.

The rapid test detects bacterial antigens in a throat swab specimen. In the test, specific antigens from the group A streptococci are extracted from the throat swab with certain enzymes and are reacted with antibody to these antigens bound to latex particles. Agglutination of the colored latex particles occurs if group A streptococci are present in the throat swab. The specificity of these tests is high, but the sensitivity is low (i.e., false-negative results can occur). If the test result is negative but the clinical suspicion of streptococcal pharyngitis is high, a culture should be done.

A rapid test is also available for the detection of group B streptococci in vaginal and rectal samples. This PCR-based assay detects the DNA of the organism, and results can be obtained in approximately 1 hour.

Viridans group streptococci form α-hemolytic colonies on blood agar and must be distinguished from S. pneumoniae (pneumococci), which is also α-hemolytic. Viridans group streptococci are resistant to lysis by bile and will grow in the presence of optochin, whereas pneumococci will not. The various viridans group streptococci are classified into species by using a variety of biochemical tests.

Serologic

ASO titers are high soon after group A streptococcal infections. In patients suspected of having rheumatic fever, an elevated ASO titer is typically used as evidence of previous infection because throat culture results are often negative at the time the patient presents with rheumatic fever. Titers of anti–DNase B are high in group A streptococcal skin infections and serve as an indicator of previous streptococcal infection in patients suspected of having AGN.

Treatment

Group A streptococcal infections can be treated with either penicillin G or amoxicillin, but neither rheumatic fever nor AGN patients benefit from penicillin treatment after the onset of the two diseases. In mild group A streptococcal infections, oral penicillin V can be used. In penicillin-allergic patients, erythromycin or one of its long-acting derivatives (e.g., azithromycin) can be used. However, erythromycin-resistant strains of S. pyogenes have emerged that may limit the effectiveness of the macrolide class of drugs in the treatment of streptococcal pharyngitis. Clindamycin can also be used in penicillin-allergic patients. Streptococcal pyogenes is not resistant to penicillins.

Invasive group A streptococcal infections such as necrotizing fasciitis and streptococcal toxic shock syndrome can be treated with a combination of clindamycin and intravenous immunoglobulins.

Endocarditis caused by most viridans streptococci is curable using prolonged penicillin treatment. However, enterococcal endocarditis can be eradicated only by a penicillin or vancomycin combined with an aminoglycoside.

Enterococci resistant to multiple drugs (e.g., penicillins, aminoglycosides, and vancomycin) have emerged. Resistance to vancomycin in enterococci is mediated by a cassette of genes that encode the enzymes that substitute D-lactate for D-alanine in the peptidoglycan. The same set of genes encodes vancomycin resistance in S. aureus.

VREs are now an important cause of nosocomial infections; there is no reliable antibiotic therapy for these organisms. At present, two drugs are being used to treat infections caused by VRE: linezolid (Zyvox) and daptomycin (Cubicin).

Nonenterococcal group D streptococci (e.g., S. bovis) are not highly resistant and can be treated with penicillin G.

The drug of choice for group B streptococcal infections is either penicillin G or ampicillin. Some strains may require higher doses of penicillin G or a combination of penicillin G and an aminoglycoside to eradicate the organism. Peptostreptococci can be treated with penicillin G.

Prevention

Rheumatic fever can be prevented by prompt treatment of group A streptococcal pharyngitis with penicillin G or oral penicillin V. Prevention of streptococcal infections (usually with benzathine penicillin once each month for several years) in persons who have had rheumatic fever is important to prevent recurrence of the disease. There is no evidence that patients who have had AGN require a similar penicillin prophylaxis.

In patients with damaged heart valves who undergo invasive dental procedures, endocarditis caused by viridans streptococci can be prevented by using amoxicillin perioperatively. To avoid unnecessary use of antibiotics, it is recommended to give amoxicillin prophylaxis only to patients who have the highest risk of severe consequences from endocarditis (e.g., those with prosthetic heart valves or with previous infective endocarditis) and who are undergoing high-risk dental procedures, such as manipulation of gingival tissue. It is no longer recommended that patients undergoing gastrointestinal or genitourinary tract procedures receive prophylaxis.

The incidence of neonatal sepsis caused by group B streptococci can be reduced by a two-pronged approach: (1) All pregnant women at 35 to 37 weeks of gestation should be screened by doing vaginal and rectal cultures. If cultures are positive, then penicillin G (or ampicillin) should be administered intravenously at the time of delivery. (2) If the patient has not had cultures done, then penicillin G (or ampicillin) should be administered intravenously at the time of delivery to women who have not delivered within 18 hours after rupture of membranes, or whose labor begins before 37 weeks of gestation, or who have a fever at the time of labor. If the patient is allergic to penicillin, either cefazolin or vancomycin can be used.

Oral ampicillin given to women who are vaginal carriers of group B streptococci does not eradicate the organism. Rapid screening tests for group B streptococcal antigens in vaginal specimens can be insensitive, and neonates born of antigen-negative women have, nevertheless, been diagnosed with neonatal sepsis. Note, also, that as group B streptococcal infections have declined as a result of these prophylactic measures, neonatal infections caused by E. coli have increased.

There are no vaccines available against any of the streptococci except S. pneumoniae (see following section).

Diseases

S. pneumoniae causes pneumonia, bacteremia, meningitis, and infections of the upper respiratory tract such as otitis media, mastoiditis, and sinusitis. Pneumococci are the most common cause of community-acquired pneumonia, meningitis, sepsis in splenectomized individuals, otitis media, and sinusitis. They are a common cause of conjunctivitis, especially in children. Note that S. pneumoniae is also known as the pneumococcus (plural, pneumococci).

Important Properties

Pneumococci are gram-positive lancet-shaped cocci arranged in pairs (diplococci) or short chains (Figure 15–16). (The term lancet-shaped means that the diplococci are oval with somewhat pointed ends rather than being round.) On blood agar, they produce α-hemolysis. In contrast to viridans streptococci, they are lysed by bile or deoxycholate, and their growth is inhibited by optochin (Figure 15–17).

Pneumococci possess polysaccharide capsules that have 91 antigenically distinct types (serotypes) based on the different sugars in the polysaccharide. With type-specific antiserum, capsules swell (quellung reaction), and this can be used to identify the type. Capsules are virulence factors (i.e., they interfere with phagocytosis and favor invasiveness). Specific antibody to the capsule opsonizes the organism, facilitates phagocytosis, and promotes resistance. Such antibody develops in humans as a result either of infection (asymptomatic or clinical) or of administration of polysaccharide vaccine. Capsular polysaccharide elicits primarily a β-cell (i.e., T-independent) response.

Another important surface component of S. pneumoniae is a teichoic acid in the cell wall called C-substance (also known as C-polysaccharide). It is medically important not for itself, but because it reacts with a normal serum protein made by the liver called C-reactive protein (CRP). CRP is an “acute-phase” protein that is elevated as much as 1000-fold in acute inflammation. CRP is not an antibody (which are γ-globulins) but rather a β-globulin. (Plasma contains α-, β-, and γ-globulins.) Note that CRP is a nonspecific indicator of inflammation and is elevated in response to the presence of many organisms, not just S. pneumoniae. Clinically, CRP in human serum is measured in the laboratory by its reaction with the carbohydrate of S. pneumoniae. The medical importance of CRP is that an elevated CRP appears to be a better predictor of heart attack risk than an elevated cholesterol level.

Transmission

Humans are the natural hosts for pneumococci; there is no animal reservoir. Because a proportion (5%–50%) of the healthy population harbors virulent organisms in the oropharynx, pneumococcal infections are not considered to be communicable. Resistance is high in healthy young people, and disease results most often when predisposing factors (see following discussion) are present.

Pathogenesis

The most important virulence factor is the capsular polysaccharide, and anticapsular antibody is protective. Lipoteichoic acid, which activates complement and induces inflammatory cytokine production, contributes to the inflammatory response and to the septic shock syndrome that occurs in some immunocompromised patients. Pneumolysin, the hemolysin that causes α-hemolysis, may also contribute to pathogenesis.

Pneumococci produce IgA protease that enhances the organism’s ability to colonize the mucosa of the upper respiratory tract by cleaving IgA. Pneumococci multiply in tissues and cause inflammation. When they reach alveoli, there is outpouring of fluid and red and white blood cells, resulting in consolidation of the lung. During recovery, pneumococci are phagocytized, mononuclear cells ingest debris, and the consolidation resolves.

Factors that lower resistance and predispose persons to pneumococcal infection include (1) alcohol or drug intoxication or other cerebral impairment that can depress the cough reflex and increase aspiration of secretions; (2) abnormality of the respiratory tract (e.g., viral infections), pooling of mucus, bronchial obstruction, and respiratory tract injury caused by irritants (which disturb the integrity and movement of the mucociliary blanket); (3) abnormal circulatory dynamics (e.g., pulmonary congestion and heart failure); (4) splenectomy; and (5) certain chronic diseases such as sickle cell anemia and nephrosis. Patients with sickle cell anemia auto-infarct their spleen, become functionally asplenic, and are predisposed to pneumococcal sepsis. Trauma to the head that causes leakage of spinal fluid through the nose predisposes to pneumococcal meningitis.

Clinical Findings

Pneumonia often begins with a sudden chill, fever, cough, and pleuritic pain. Sputum is a red or brown “rusty” color. Bacteremia occurs in 15% to 25% of cases. Spontaneous recovery may begin in 5 to 10 days and is accompanied by development of anticapsular antibodies. Pneumococci are a prominent cause of otitis media, sinusitis, mastoiditis, conjunctivitis, purulent bronchitis, pericarditis, bacterial meningitis, and sepsis. Pneumococci are the leading cause of sepsis in patients without a functional spleen.

Laboratory Diagnosis

In sputum, pneumococci are seen as lancet-shaped gram-positive diplococci in Gram-stained smears (see Figure 15–15). They can also be detected by using the quellung reaction with multitype antiserum. On blood agar, pneumococci form small α-hemolytic colonies. The colonies are bile-soluble (i.e., are lysed by bile), and growth is inhibited by optochin (see Figure 15–16).

Blood cultures are positive in 15% to 25% of pneumococcal infections. Culture of cerebrospinal fluid is usually positive in meningitis. Rapid diagnosis of pneumococcal meningitis can be made by detecting its capsular polysaccharide in spinal fluid using the latex agglutination test. A rapid test that detects urinary antigen is also available for the diagnosis of pneumococcal pneumonia and bacteremia. The urinary antigen is the C polysaccharide (also known as the C substance), not the capsular polysaccharide. Because of the increasing numbers of strains resistant to penicillin, antibiotic sensitivity tests must be done on organisms isolated from serious infections.

Treatment

Most pneumococci are susceptible to penicillins and erythromycin, although a significant resistance to penicillins has emerged (see next paragraph). In severe pneumococcal infections, penicillin G is the drug of choice, whereas in mild pneumococcal infections, oral penicillin V can be used. A fluoroquinolone with good antipneumococcal activity, such as levofloxacin, can also be used. In penicillin-allergic patients, erythromycin or one of its long-acting derivatives (e.g., azithromycin) can be used.

In the United States, about 25% of isolates exhibit low-level resistance to penicillin, primarily as a result of changes in penicillin-binding proteins. An increasing percentage of isolates, ranging from 15% to 35% depending on location, show high-level resistance, which is attributed to multiple changes in penicillin-binding proteins. They do not produce β-lactamase. Vancomycin is the drug of choice for the penicillin-resistant pneumococci, especially for severely ill patients. Ceftriaxone or levofloxacin can be used for less severely ill patients. However, strains of pneumococci tolerant to vancomycin have emerged. (Tolerance to antibiotics is described on Penicillins and Specific Mechanisms of Resistance.) Strains of pneumococci resistant to multiple drugs, especially azithromycin, have also emerged.

Prevention

Despite the efficacy of antimicrobial drug treatment, the mortality rate of pneumococcal infections is high in immunocompromised (especially splenectomized) patients and children under the age of 5 years. Such persons should be immunized with the 13-valent pneumococcal conjugate vaccine (Prevnar 13). The immunogen in this vaccine is the pneumococcal polysaccharide of the 13 most prevalent serotypes conjugated (coupled) to a carrier protein (diphtheria toxoid). The unconjugated 23-valent pneumococcal vaccine (Pneumovax 23) should be given to healthy individuals age 50 years or older.

These vaccines are safe and effective and provide long-lasting (at least 5 years) protection. Immunization of children reduces the incidence of pneumococcal disease in adults because children are the main source of the organism for adults and immunization reduces the carrier rate in children.

A booster dose is recommended for (1) people older than 65 years who received the vaccine more than 5 years ago and who were younger than 65 years when they received the vaccine, and (2) people between the ages of 2 and 64 years who are asplenic, infected with human immunodeficiency virus (HIV), receiving cancer chemotherapy, or receiving immunosuppressive drugs to prevent transplant rejection.

A potential problem regarding the use of the pneumococcal vaccine is that of serotype replacement. Will the vaccine reduce the incidence of disease caused by the serotypes in the vaccine but not the overall incidence of pneumococcal disease because other serotypes that are not in the vaccine will now cause disease? In fact, an increase in invasive pneumococcal disease caused by serotype 19A, which was not in the previously used 7-valent vaccine, occurred. This led to the production of the current conjugate vaccine containing 13 serotypes, including 19A.