Diseases
S. aureus causes abscesses (Figure 1), various pyogenic infections (e.g., endocarditis, septic arthritis, and osteomyelitis), gastroenteritis, scalded-skin syndrome, and toxic shock syndrome. It is one of the most common causes of hospital-acquired pneumonia, septicemia, and surgical-wound infections. It is an important cause of skin and soft tissue infections (SSTIs), such as folliculitis (Figure2), purulent soft tissue infections (abscesses), and impetigo (Figure 3). It is a common cause of bacterial conjunctivitis.
Fig1. Abscess on foot. Note central raised area of whitish pus surrounded by erythema. An abscess is the classic lesion caused by Staphylococcus aureus. (Reproduced with permission from Wolff K, Johnson R: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 6th ed. New York, NY: McGraw Hill; 2009.)
Fig2. Folliculitis. Note the multiple, small pustules on the chin and neck. Staphylococcus aureus is the most common cause of folliculitis. (Reproduced with permission from Wolff K, Goldsmith LA, Katz SI, et al: Fitzpatrick’s Dermatology in General Medicine, 7th ed. New York, NY: McGraw Hill; 2008.)
Fig3. Impetigo. Lesions of impetigo are crops of vesicles with a “honey-colored” crust. Impetigo is caused by either Staphylococcus aureus or Streptococcus pyogenes. (Reproduced with permission from Wolff K, Johnson R: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 6th ed. New York, NY: McGraw Hill; 2009.)
Important Properties
Staphylococci are spherical gram-positive cocci arranged in irregular grapelike clusters (Figure 4). All staphylococci produce catalase, whereas no streptococci do (catalase degrades H2O2 into O2 and H2O). Catalase is an important virulence fac tor. Bacteria that make catalase can survive the killing effect of H2O2 within neutrophils.
Fig4. Staphylococcus aureus—Gram stain. Arrows point to two “grapelike” clusters of gram-positive cocci. Arrowhead points to neutrophil with pink segmented nuclei. (Used with permission from Professor Shirley Lowe, University of California, San Francisco School of Medicine.)
Three species of staphylococci are important human pathogens: S. aureus, Staphylococcus epidermidis, and Staphylococcus saprophyticus (Table 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 (Figure5). 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.
Table1. Staphylococci of Medical Importance
Fig5. Coagulase test. Upper tube inoculated with Staphylococcus aureus; lower tube inoculated with Staphylococcus epidermidis. Arrow points to clotted plasma formed by coagulase produced by S. aureus. (Used with permission from Professor Shirley Lowe, University of California, San Francisco School of Medicine.)
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 (PBPs) 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 Staphylococcus aureus (MRSA). MRSA causes both healthcare acquired and community-acquired infections. MRSA accounts for more than 50% of S. aureus strains isolated from hospital patients in the United States and is also very commonly seen in the community but at a slightly lower frequency. 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 immunoglobulin (Ig) G. 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.
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.
Pathogenesis
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 mast cells, which stimulates the enteric nervous system via the vagus nerve 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. 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 SSTI 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 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.
Table2. Important Features of Pathogenesis by Staphylococci
Staphylococcus aureus: Pyogenic Diseases
(1) SSTIs are very common. These include abscess (see Figure 1), impetigo (see Figure 3), furuncles, carbuncles, paronychia, cellulitis, folliculitis (see Figure 2), necrotizing fasciitis, hidradenitis suppurativa, conjunctivitis, eyelid infections (blepharitis and hordeolum), and postpartum breast infections (mastitis). Note that MRSA is also an important cause of surgical site in the hospital. 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.
(2) 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.)
(3) 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.
(4) 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 hardware (e.g., prosthetic joints or cardiac pacemakers) are installed.
(5) 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. Conjunctivitis typically presents with unilateral burning eye pain, hyperemia of the conjunctiva, and a purulent discharge. The organism is trans mitted 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.
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; hypo tension; 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 6). Bullous impetigo is caused by localized production of exfoliatin by S. aureus.
Fig6. Bullous impetigo. Blue arrow points to one of several vesicles that will coalesce to form bullae, the characteristic lesion of bullous impetigo. (Reproduced with permission from Kang S, Amagai M, Bruckner AL, et al: Fitzpatrick’s Dermatology in General Medicine, 9th ed. New York, NY: McGraw Hill; 2019.)
Laboratory Diagnosis
Smears from staphylococcal lesions reveal gram-positive cocci in grapelike clusters (see Figure4). Cultures of S. aureus typically yield golden-yellow colonies that are usually β-hemolytic. S. aureus is coagulase positive (see Figure 5). 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.
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]) although studies have shown that the addition of antibiotics can further enhance cure rate. 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 by virtue of altered PBPs. These resistant strains of S. aureus are often abbreviated MRSA, respectively. Such organ isms can produce sizable outbreaks of disease, especially in hospitals.
Vancomycin and daptomycin can be effective intravenous options for patients with severe MRSA infections, although daptomycin is not active in the lungs so not used for pneumonia. 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, although Ceftaroline fosamil is the first β-lactam drug useful for the treatment of MRSA infections as it can bind to the altered penicillin-binding protein of MRSA.
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 the treatment of impetigo caused by S. aureus but not useful for deeper types of skin infections. 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.
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, but is difficult to eliminate completely. Cefazolin is often used perioperatively to prevent staphylococcal surgical-wound infections.
