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USMLE – Staphylococcus

Staphylococcus aureus causes abscesses, various pyogenic infections (eg, endocarditis and osteomyelitis), food poisoning, and toxic shock syndrome. It is one of the most common causes of hospital-acquired pneumonia, septicemia, and surgical-wound infections. Staphylococcus epidermidis can cause endocarditis and prosthetic joint infections. Staphylococcus saprophyticus causes urinary tract infections.

Important Properties
Staphylococci are spherical gram-positive cocci arranged in irregular grapelike clusters. All staphylococci produce catalase, whereas no streptococci do (catalase degrades H2O2 into 02 and H2O). Catalase is an important virulence factor because H2O2 is microbicidal and its degradation limits the ability of neutrophils to kill.

Three species of staphylococci are human pathogens: S aureus, S epidermidis, and S saprophyticus. Of the three, S aureus is by far the most important. S aureus is distinguished from the others primarily by coagulase production (coagulase is an enzyme that causes plasma to clot by activating prothrombin). Furthermore, S aureus usually ferments mannitol and hemolyzes red blood cells, whereas the others do not. S epidermidis and S saprophyticus are often referred to as coagulase negative staphylococci.

More than 90% of S aureus strains contain plasmids that encode beta-lactamase, the enzyme that degrades many, but not all, penicillins. Some strains of S aureus are resistant to the beta-lactamase-resistant penicillins, such as methicillin and nafcillin, by virtue of changes in the penicillin-binding protein in their cell membrane. These strains are commonly known as methicillin-resistant S aureus (MRSA) or nafcillin-resistant S aureus (NRSA). Rare strains called vancomycin-intermediate S aureus (VISA), with reduced sensitivity to vancomycin, have emerged.

S aureus has several important cell wall components and antigens.

Protein A is the major protein in the cell wall. It is an important virulence factor because it binds to the Fe portion of IgG at the complement-binding site, thereby preventing the activation of complement. As a consequence, no C3b is produced, and the opsonization and phagocytosis of the organisms are greatly reduced. Protein A is used in certain tests in the clinical laboratory because it binds to IgG and forms a “coagglutinate” with antigen-antibody complexes. The coagulase-negative staphylococci do not produce protein A.

Teichoic acids are polymers of ribitol phosphate. They mediate adherence of the staphylococci to mucosal cells. Antibodies to teichoic acids develop in certain staphylococcal infections. eg, endocarditis.

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

Most strains of S aureus are coated with a small amount of polysaccharide capsule (microcapsule) that is antiphagocytic. There are 11 serotypes based on antigenicity of the capsular polysaccharide.

The peptidoglycan of S aureus has endotoxin-like properties; ie, 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.

Staphylococci are found primarily in the normal human flora. S epidermidis is regularly present on normal skin and mucous membranes. S aureus is most often found in the nose and sometimes on the skin, especially in hospital staff and patients. Additional sources of staphylococcal infection are shedding from human lesions and fomites contaminated by these lesions. Disease production is favored by a heavily contaminated environment (eg, family members with boils) and a compromised immune system. Low levels of antibody, complement, or neutrophils especially predispose to staphylococcal infections.

S aureus causes disease both by producing toxins and by multiplying in tissue and causing inflammation. The typical lesion of S aureus infection is an abscess. Abscesses undergo central necrosis and usually drain to the outside (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.

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

Enterotoxin causes 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. It is fairly heat-resistant and therefore is usually not inactivated by brief cooking. 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 a superantigen and causes toxic shock by stimulating the release of large amounts of IL-1, 1L-2, and tumor necrosis factor (TNF). Approximately 5-25% of isolates of S 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 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, 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.

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.

S epidermidis and S saprophyticus
Unlike S aureus, these two coagulase-negative staphylococci do not produce exotoxins. Thus, they do not cause food poisoning or toxic shock syndrome. They can, however, cause pyogenic infections by eliciting a neutrophilic response. For example, S 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 S aureus can be divided into two groups: inflammatory and toxin-mediated. S aureus is a major cause of skin, soft tissue, bone, joint, lung, heart, and kidney infections. In the following list, the first six are inflammatory in origin, whereas the last three are toxin-mediated.

S aureus: Inflammatory
Skin infections, including impetigo, furuncles, carbuncles, paronychia, cellulitis, surgical wound infections, eyelid infections (blepharitis), and postpartum breast infections (mastitis).

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.

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

Osteomyelitis and arthritis, either hematogenous or traumatic; it is a very common cause of osteomyelitis and arthritis, especially in children.

Pneumonia in postoperative patients or following viral respiratory infection, especially influenza (staphylococcal pneumonia often leads to empyema).

Abscesses (metastatic) in any organ, after bacteremia.

S aureus: Toxin-Mediated
Food poisoning (characterized by vomiting being more prominent than diarrhea) caused by ingestion of enterotoxin, which is preformed in foods and hence has a short incubation period (1-8 hours);

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

Scalded skin syndrome, in which the superficial layers of the epidermis slough in response to the presence of exfoliatin.

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

S epidermidis is part of the normal human flora on the skin and mucous membranes but can cause infections of intravenous catheters and prosthetic implants, eg. heart valves, vascular grafts, and joints. 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. 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.

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 E 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 S aureus typically yield golden-yellow colonies that are usually beta-hemolytic. S aureus is coagulase-positive. Mannitol-salt agar is a commonly used screening device for S 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: S epidermidis is sensitive, whereas S saprophyticus is resistant. There are no generally useful serologic or skin tests. In toxic shock syndrome, isolation of S aureus is not required to make a diagnosis as long as the clinical criteria are met.

In the United States, 90% or more of S aureus strains are resistant to penicillin G. Most strains produce beta-lactamase under control of transmissible plasmids. Such organisms can be treated with beta-lactamase-resistant penicillins, eg, nafcillin or cloxacillin, some cephalosporins, or vancomycin. Treatment with a combination of a beta-lactamase-sensitive penicillin, eg, amoxicillin, and a beta-lactamase inhibitor, eg, clavulanic acid, is also useful. Approximately 20% of S aureus strains are “methicillin-resistant” (or “nafcillin-resistant”) by virtue of altered penicillin-binding proteins. 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. Strains of S aureus with intermediate resistance (so-called VISA strains) and with complete resistance to vancomycin have been isolated from patients. These strains are typically methicillin/nafcillin-resistant as well, which makes them very difficult to treat. A combination of two streptogramins, quinupristin-dalfopristin (Synercid), has been shown to be effective, but Synercid is available only as an investigational drug at this time. Streptogramins inhibit bacterial protein synthesis in a manner similar to macrolides but are bactericidal for S aureus.

The treatment of toxic shock syndrome involves correction of the shock using fluids, pressor drugs, and inotropic drugs; administration of a beta-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 also has 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; ie, they can be inhibited by antibiotics but are not killed (the ratio of MBC to 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.

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

S epidermidis is highly antibiotic resistant. Most strains produce beta-lactamase and many are methicilin/nafcillin-resistant. 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. S saprophyticus urinary tract infections can be treated with a quinolone, such as norfloxacin, or with trimethoprim/sulfamethoxazole.

There is no effective immunization with toxoids or bacterial vaccines. Cleanliness, frequent hand-washing 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, eg, operating rooms and newborn nurseries. Cefazolin is often used perioperatively to prevent staphylococcal surgical wound infections.

Lillian Thompson By Lillian Thompson

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