Staphylococcus aureus

Sta. aureus causes disease both by producing toxins and by inducing pyogenic inflammation. The typical lesion of Sta. aureus infection is an abscess. Abscesses undergo central necrosis and usually drain 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 Sta. aureus.

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

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 interleukin-1 (IL-1) and interleukin-2 (IL-2) from macrophages and helper T cells, respectively. The prominent vomiting appears to be caused by cytokines released from the lymphoid 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.

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 Sta. aureus in the vagina, nose, or other infected site. The toxin enters the bloodstream, causing a toxemia. Blood cultures typically do not grow Sta. aureus.

TSST is a superantigen and causes toxic shock by stimulating the release of large amounts of IL-1, IL-2, and tumor necrosis factor (TNF) (see the discussions of exotoxins in Chapter 7 and superantigens in Chapter 58). Approximately 5% to 25% of isolates of Sta. aureus carry the gene for TSST. Toxic shock occurs in people who do not have antibody against TSST.

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.

Several toxins can kill leukocytes (leukocidins) and cause necrosis of tissues in vivo. Of these, one of the most important is alpha toxin, which 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, a second important toxin, 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.

The importance of P-V leukocidin as a virulence factor is indicated by the severe skin and soft tissue infection caused by MRSA strains that produce this leukocidin. A severe necrotizing pneumonia is also caused by strains of Sta. aureus that produce P-V leukocidin. Approximately 2% of clinical isolates of Sta. aureus produce P-V leukocidin.

The enzymes include coagulase, fibrinolysin, hyaluro-nidase, 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.

Staphylococcus epidermidis & Staphylococcus saprophyticus

Unlike Sta. aureus, these 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, Sta. epidermidis is a prominent cause of pyogenic infections on prosthetic implants such as heart valves and hip joints.

Clinical Findings

The important clinical manifestations caused by Sta. aureus can be divided into two groups: pyogenic and toxin-mediated (Table 15–2). Sta. aureus is a major cause of skin, soft tissue, bone, joint, lung, heart, and kidney infections.
Staphylococcus aureus: Pyogenic Diseases

Skin infections are very common. These include impetigo, furuncles, carbuncles, paronychia, cellulitis, folliculitis, hydradenitis 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 are caused by MRSA strains that produce P-V leukocidin. These infections are typically community-acquired rather than hospital-acquired. These community-acquired, methicillin-resistant strains of Sta. aureus (CA-MRSA) are a 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 hospital-acquired MRSA (HA-MRSA) causes approximately 50% of all nosocomial Sta. aureus infections. Molecular analysis reveals that the CA-MRSA strains are different from the HA-MRSA strains.

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

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 Sta. epidermidis.)

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

Postsurgical wound infections are an important cause of morbidity and mortality in hospitals. Sta. aureus is the most common cause.

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.

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. Sta. aureus is the most common cause overall but Streptococcus pneumoniae and Haemophilus influenzae are more common in children. Gonococcal and non-gonococcal (caused by Chlamydia trachomatis) conjunctivitis is acquired by infants during passage through the birth canal.

Abscesses can occur in any organ when the organism circulates in the bloodstream (bacteremia). These abscesses are often called "metastatic abscesses" because they occur by the spread of bacteria from the original site.

Staphylococcus aureus: Toxin-Mediated Diseases

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.

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.

Scalded-skin syndrome is characterized by fever, large bullae, and an erythematous macular rash. Large areas of skin slough, serous fluid exudes, and electrolyte imbalance can occur. Hair and nails can be lost. Recovery usually occurs within 7–10 days. This syndrome occurs most often in young children.

Staphylococcus aureus: Kawasaki Syndrome

Kawasaki syndrome (KS) is a disease of unknown etiology that is discussed here because several of its features resemble toxic shock syndrome caused by the superantigens of Sta. aureus (and Str. pyogenes). KS is a vasculitis involving small and medium-size arteries, especially the coronary arteries.

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

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

KS 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 of age, often occurring in minioutbreaks. It occurs worldwide but is much more common in Japan.

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

Staphylococcus epidermidis & Staphylococcus saprophyticus

There are two coagulase-negative staphylococci of medical importance: Sta. epidermidis and Sta. saprophyticus. Sta. epidermidis infections are almost always hospital-acquired, whereas Sta. saprophyticus infections are almost always community-acquired.

Sta. 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) (Table 15–2). Sta. 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.

Strains of Sta. 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 Sta. epidermidis.

Sta. 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.

Laboratory Diagnosis

Smears from staphylococcal lesions reveal gram-positive cocci in grapelike clusters. Cultures of Sta. aureus typically yield golden-yellow colonies that are usually -hemolytic. Sta. aureus is coagulase-positive. Mannitol-salt agar is a commonly used screening device for Sta. aureus. Cultures of coagulase-negative staphylococci typically yield white colonies that are nonhemolytic. The two coagulase-negative staphylococci are distinguished by their reaction to the antibiotic novobiocin: Sta. epidermidis is sensitive, whereas Sta. saprophyticus is resistant. There are no serologic or skin tests used for the diagnosis of any acute staphylococcal infection.

In toxic shock syndrome, isolation of Sta. 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 Sta. aureus and development of antibodies to the toxin during convalescence, although the latter is not useful for diagnosis during the acute disease.

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

Treatment

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

Approximately 20% of Sta. aureus strains are methicillin-resistant or nafcillin-resistant by virtue of altered penicillin-binding proteins. These resistant strains of Sta. 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 these MRSA strains are resistant to all -lactam drugs, including both penicillins and cephalosporins.

Strains of Sta. 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 -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 Sta. aureus. It has also been used to reduce nasal carriage of the organism in hospital personnel and in patients with recurrent staphylococcal infections.

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).

Drainage (spontaneous or surgical) is the cornerstone of abscess treatment. Previous infection provides only partial immunity to reinfection.

Sta. epidermidis is highly antibiotic resistant. Most strains produce -lactamase and many are methicillin-/nafcillin-resistant due to altered penicillin-binding proteins. The drug of choice is vancomycin, to which either rifampin or an aminoglycoside can be added. Removal of the catheter or other device is often necessary. Sta. saprophyticus urinary tract infections can be treated with a quinolone, such as norfloxacin, or with trimethoprim-sulfamethoxazole.