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Staphylococcal Infections

Staphylococcal Infections

Franklin D. Lowy

Staphylococcus aureus, the most virulent of the many staphylococcal species, has demonstrated its versatility by remaining a major cause of morbidity and mortality despite the availability of numerous effective antistaphylococcal antibiotics. S. aureus is a pluripotent pathogen, causing disease through both toxin-mediated and non-toxin-mediated mechanisms. This organism is responsible for both nosocomial and community-based infections that range from relatively minor skin and soft tissue infections to life-threatening systemic infections.

The “other” staphylococci, collectively designated coagulase-negative staphylococci (CoNS), are considerably less virulent than S. aureus but remain important pathogens in selected clinical settings. These include but are not limited to infections associated with prosthetic devices.

MICROBIOLOGY AND TAXONOMY

The 33 staphylococcal species (with additional staphylococcal species under review) are pathogenic members of the family Micrococcaceae. A simple strategy for identification of the more clinically important species is outlined in. Automated diagnostic systems as well as kits are available for biochemical characterization of all the staphylococcal species. 16S ribosomal RNA analysis has proved a reliable method for distinguishing among species. With few exceptions, S. aureus is distinguished from other staphylococcal species by its production of coagulase, a surface enzyme that converts fibrinogen to fibrin. Most other clinically relevant staphylococci are coagulase-negative. S. aureus also ferments mannitol, is positive for protein A, and produces DNase. On blood agar plates, S. aureus tends to form golden β-hemolytic colonies; in contrast, CoNS produce white nonhemolytic colonies.

Staphylococci are gram-positive cocci that form grapelike clusters on Gram's stain. They are catalase-positive (unlike streptococcal species), nonmotile, aerobic, and facultatively anaerobic. These hardy organisms are capable of prolonged survival on environmental surfaces in varying conditions.

Determining whether multiple isolates (especially of CoNS) from a particular patient are the same or different is often an important factor in distinguishing contaminants from genuine pathogens. Determining whether multiple isolates from different patients are the same or different is relevant when there is concern that a nosocomial outbreak may have been due to a common point source (e.g., a contaminated medical instrument). Biochemical tests, often performed in conjunction with antimicrobial susceptibility testing, have been used as a relatively simple means of distinguishing among staphylococcal species or strains. More discriminating molecular typing techniques, such as pulsed-field gel electrophoresis, have also been used for this purpose.

S. AUREUS INFECTIONS

EPIDEMIOLOGY

S. aureus is a part of the normal human flora. The anterior nares is the most frequent site of human colonization, although the skin (especially when damaged), vagina, axilla, perineum, and oropharynx may also be colonized. Approximately 25 to 50% of healthy persons may be persistently or transiently colonized with S. aureus. The rate of colonization is higher among insulin-dependent diabetics, HIV-infected patients, injection drug users, patients undergoing hemodialysis, and individuals with skin damage. Sites of colonization serve as a reservoir of strains for future S. aureus infections, and persons colonized with S. aureus are at greater risk of subsequent infection (with their colonizing strain) than are uncolonized individuals.

Overall, S. aureus is a leading cause of nosocomial infections. It is the most common cause of surgical wound infections and is second only to CoNS as a cause of primary bacteremia. Increasingly, nosocomial isolates are resistant to multiple drugs. In the community, S. aureus remains an important cause of skin and soft tissue infections, respiratory infections, and (among injection drug users) infective endocarditis. As the number of patients receiving home infusion therapy increases, so does the number of community-acquired staphylococcal infections.

Several reports have described community-acquired infections (in both rural and urban settings) caused by methicillin-resistant S. aureus (MRSA) in individuals with no prior medical exposure. In contrast to hospital-acquired MRSA strains, these community isolates have remained susceptible to many non-β-lactam antibiotics. Of concern has been the apparent capacity of community-acquired MRSA strains to cause serious disease in immunocompetent individuals. This ability may be due to the presence of different toxin-producing genes in these strains as well as the use of β-lactam agents for empirical treatment of patients infected with these strains.

Most individuals who develop S. aureus infections do so with their own colonizing strains. However, S. aureus may also be acquired from other people or from environmental exposures. Transmission most frequently results from transient colonization of the hands of hospital personnel, who then transfer strains from one patient to another. Spread of staphylococci in aerosols of respiratory or nasal secretions from heavily colonized individuals has also been reported.

PATHOGENESIS

General Concepts

S. aureus is a pyogenic pathogen known for its capacity to induce abscess formation at sites of both local and metastatic infections. This classic pathologic response to S. aureus defines the framework within which the infection will progress. The bacteria elicit an inflammatory response characterized by an initial intense polymorphonuclear leukocyte (PMN) response and the subsequent infiltration of macrophages and fibroblasts. Either the host cellular response (including the deposition of fibrin and collagen) contains the infection, or infection spreads to the adjoining tissue or the bloodstream.

In toxin-mediated staphylococcal disease, the clinical infection is not invariably present. For example, once toxin has been elaborated into food, staphylococcal food poisoning can develop in the absence of viable bacteria. In the staphylococcal toxic shock syndrome (TSS), conditions that allow elaboration of toxin at sites of colonization (e.g., the presence of a superabsorbent tampon) are sufficient for initiation of clinical illness.

The S. aureus Genome

The entire genome has been sequenced for several strains of S. aureus. Among the interesting revelations are the following: (1) There is a high degree of nucleotide sequence similarity among the different strains. (2) A relatively large amount of genetic information is acquired by horizontal transfer from other bacterial species. (3) S. aureus contains a number of unique “pathogenicity” or “genomic” islands. These islands are mobile genetic elements that contain clusters of enterotoxin and exotoxin genes or antimicrobial resistance determinants. (4) Among the genes contained in these islands are those carrying mecA, the gene responsible for methicillin resistance. These methicillin resistance–containing islands have been designated staphylococcal cassette chromosomes (SCCmec) and range in size from ~20 to 60 kb. To date, four SCCmecs have been identified. The type 4 SCCmec has been associated with the community-acquired MRSA strains that have been responsible for numerous outbreaks.

Regulation of Virulence Gene Expression

In both toxin-mediated and non-toxin-mediated diseases due to S. aureus, the expression of virulence determinants associated with infection is dependent on a series of regulatory genes [e.g., accessory gene regulator (agr) and staphylococcal accessory regulator (sar)] that coordinately control the expression of the virulence genes. The regulatory gene agr is part of a quorum-sensing signal transduction pathway that senses and responds to bacterial density. Staphylococcal surface proteins are synthesized during the bacterial exponential growth phase in vitro. In contrast, secreted proteins, such as α toxin, the enterotoxins, and assorted enzymes, are released during the postexponential growth phase.

It has been hypothesized that these regulatory genes serve a similar function in vivo. Successful invasion requires the sequential expression of these different bacterial elements. Bacterial adhesins are needed to initiate colonization of host tissue surfaces. The subsequent release of various enzymes enables the colony to obtain nutritional support and permits bacteria to spread to adjacent tissues. Studies using mutant strains with these regulatory genes inactivated show reduced virulence in several animal models of S. aureus infection.

Pathogenesis of Invasive S. aureus Infection

Staphylococci are opportunists. For these organisms to invade the host and cause infection, some or all of the following steps are necessary: inoculation and local colonization of tissue surfaces, invasion, evasion of the host response, and metastatic spread. The initiation of staphylococcal infection requires a breach in cutaneous or mucosal barriers. Colonizing strains or strains transferred from other individuals are inoculated into damaged skin, a wound, or the bloodstream. Except under these circumstances, staphylococci generally persist as harmless commensals.

In S. aureus infections, recurrences develop relatively frequently, apparently because of the capacity of these pathogens to survive, to persist in a quiescent state in various tissues, and then to cause recrudescent infections when suitable conditions arise.

Nasal Colonization

The anterior nares are the principal site of staphylococcal colonization in humans. Surprisingly little is known about the biology of this colonization process. It appears to involve the attachment of S. aureus to both nasal mucin and keratinized epithelial cells of the anterior nares. Other factors that may contribute to colonization include the influence of other resident nasal flora and their bacterial density, nasal mucosal damage (e.g., that resulting from inhalational drug use), the antimicrobial properties of nasal secretions, and host genetic factors [e.g., human leukocyte antigen (HLA) type].

Inoculation and Colonization of Tissue Surfaces

Staphylococci may be introduced into tissue as a result of minor abrasions, administration of medications such as insulin, or establishment of intravenous access with catheters. After their introduction into a tissue site, bacteria replicate and colonize the host tissue surface. A family of structurally related S. aureus surface proteins referred to as MSCRAMMs (microbial surface components recognizing adhesive matrix molecules) plays an important role as a mediator of adherence to these sites. MSCRAMMs such as fibronectin-binding protein, clumping factor, and collagen-binding protein enable the bacteria to colonize different tissue surfaces; these proteins contribute to the pathogenesis of invasive infections such as endocarditis and arthritis by facilitating the adherence of S. aureus to surfaces with exposed fibronectin, fibrinogen, or collagen.

Although CoNS are classically known for their ability to elaborate a biofilm and colonize prosthetic devices, S. aureus also possesses the genes responsible for biofilm formation—the intercellular adhesion (ica) locus. Binding to these devices often involves staphylococcal adherence to serum constituents that have coated the device surface. As a result, S. aureus is frequently isolated from biomedical-device infections.

Invasion

After colonization, staphylococci replicate at the initial site of infection, elaborating enzymes that include serine proteases, hyaluronidases, thermonucleases, and lipases. These enzymes facilitate bacterial survival and local spread across tissue surfaces, although their precise role in infections is still not well defined. The lipases may also facilitate survival in lipid-rich areas such as the hair follicles, where S. aureus infections are often initiated. The S. aureus toxin Panton-Valentine leukocidin is cytolytic to PMNs, macrophages, and monocytes. Strains elaborating this toxin have been epidemiologically linked with cutaneous infections such as furuncles and carbuncles as well as with serious pulmonary infections in adolescents.

Constitutional findings may result from either localized or systemic infections. The cell wall—consisting of alternating N-acetyl muramic acid and N-acetyl glucosamine units in combination with an additional cell wall component, lipoteichoic acid—can initiate an inflammatory response that includes the sepsis syndrome. Staphylococcal α toxin, which causes pore formation in various eukaryotic cells, can also initiate an inflammatory response with findings suggestive of sepsis.

Evasion of Host Defense Mechanisms

Evasion of host defense mechanisms is critical to invasion. Staphylococci possess an antiphagocytic polysaccharide microcapsule. Most human S. aureus infections are due to capsular types 5 and 8. The S. aureus capsule also appears to play an important role in the induction of abscess formation. The capsular polysaccharides are characterized by a zwitterionic charge pattern (the presence of both negatively and positively charged molecules) that is critical to abscess formation. Protein A, an MSCRAMM unique to S. aureus, acts as an Fc receptor. This protein can bind the Fc portion of IgG subclasses 1, 2, and 4, preventing opsonophagocytosis by PMNs.

An additional mechanism of S. aureus evasion of the host response is its capacity for intracellular survival. Both professional and nonprofessional phagocytes are capable of internalizing staphylococci. Staphylococcal internalization by endothelial cells provides a sanctuary that protects bacteria against the host's defenses. It also results in cellular changes, such as the expression of integrins and Fc receptors and the release of cytokines. These cellular changes may contribute to systemic manifestations of disease, including sepsis and vasculitis.

The intracellular environment favors the phenotypic expression of S. aureus small-colony variants. These menadione and hemin auxotrophic mutants are generally deficient in α toxin and are able to persist within endothelial cells. Small-colony variants are often selected after aminoglycoside therapy and are more commonly found in sites of persistent infections (e.g., chronic bone infections) and in respiratory secretions from patients with cystic fibrosis. These variants represent another mechanism for prolonged staphylococcal survival that may enhance the likelihood of recurrences. Finally, S. aureus can survive within PMNs and may use these cells to spread and to seed other tissue sites.

Host Response to S. aureus Infection

The primary host response to S. aureus infection is the PMN. PMNs are attracted to sites of infection by bacterial components such as formylated peptides or peptidoglycan. These cells are also attracted by the cytokines tumor necrosis factor (TNF) and interleukins (ILs) 1 and 6, which are released by activated macrophages and endothelial cells.

Although most individuals have antistaphylococcal antibodies, it is not clear that the antibody levels are qualitatively or quantitatively sufficient to protect against infection. Anticapsular and anti-MSCRAMM antibodies facilitate opsonization in vitro and have been protective against infection in several animal models.

Groups at Increased Risk of Infection

Some diseases appear to entail multiple risk factors for S. aureus infection; diabetes, for example, entails an increased rate of colonization with S. aureus, the use of injectable insulin, and the possibility of impaired leukocyte function. Individuals with congenital or acquired qualitative or quantitative defects in PMNs are at increased risk of S. aureus infections; these include neutropenic patients (e.g., those receiving chemotherapeutic agents), individuals with defective intracellular killing of staphylococci (e.g., chronic granulomatous disease), and persons with Job's syndrome or Chédiak-Higashi syndrome. Other groups at risk include individuals with abnormalities of the skin (e.g., eczema) and those with prosthetic devices.

Pathogenesis of Toxin-Mediated Disease

S. aureus produces three types of toxin: cytotoxins (discussed above), pyrogenic-toxin superantigens, and exfoliative toxins. Both epidemiologic and animal data suggest that the presence of antitoxin antibodies is protective against illness in TSS, staphylococcal food poisoning, and staphylococcal scalded-skin syndrome (SSSS). Illness develops after synthesis and absorption of the toxin followed by the toxin-initiated host response.

Enterotoxin and Toxic Shock Syndrome Toxin 1 (TSST-1)

The pyrogenic toxin superantigens are a family of small-molecular-size, structurally similar proteins that are responsible for two diseases: TSS and food poisoning. TSS results from the ability of enterotoxins and TSST-1 to function as T cell mitogens. In the normal process of antigen presentation, the antigen is first processed within the cell, and peptides are then presented in the major histocompatibility complex (MHC) class II groove, initiating a measured T cell response. In contrast, enterotoxins bind directly to the invariant region of MHC—outside the MHC class II groove. The enterotoxins can then bind T cell receptors via the vβ chain, resulting in a dramatic overexpansion of T cell clones (up to 20% of the total T cell population).

As a result of this T cell expansion, there is the equivalent of a “cytokine storm,” with the release of inflammatory mediators that include interferon (IFN) γ, IL-1, IL-6, TNF-α, and TNF-β. The result is a multisystem disease that produces a constellation of findings, including myalgias, fever, rash, and hypotension. These findings mimic those found in endotoxin shock; however, the pathogenic mechanisms differ. It has been hypothesized that a contributing factor to TSS is the release of endotoxin from the gastrointestinal tract, which may synergistically enhance the effects of the toxin.

A different region of the enterotoxin molecule is responsible for the symptoms of food poisoning. The enterotoxins are heat stable and can survive conditions that kill the bacteria. Illness results from the ingestion of preformed toxin. As a result, the incubation period is short (1 to 6 h). The toxin stimulates the vagus nerve and the vomiting center of the brain. It also appears to stimulate intestinal peristaltic activity.

Exfoliative Toxins and the Staphylococcal Scalded-Skin Syndrome

The exfoliative toxins are responsible for SSSS. The toxins that produce disease in humans have been divided into two serotypes: ETA and ETB. These toxins disrupt the desmosomes that link adjoining cells. Although the mechanism of this disruption remains uncertain, studies suggest that the toxins possess serine protease activity, which—through as-yet-undefined mechanisms—triggers exfoliation. The result is a split in the epidermis at the granular level, and this event is responsible for the superficial desquamation of the skin that typifies this illness.

DIAGNOSIS

S. aureus infections are readily diagnosed by Gram's stain and microscopic examination of abscess contents or of infected tissue. Staphylococci appear as large gram-positive cocci that are present singly, in pairs, or in clusters. Routine culture of infected material usually yields positive results, and blood cultures are sometimes positive even when infections are localized to extravascular sites. Polymerase chain reaction (PCR)–based assays have been applied to the rapid diagnosis of S. aureus infection and are increasingly being used in clinical microbiology laboratories. To date, serologic assays have not proved useful for the diagnosis of staphylococcal infections. Determining whether patients with documented S. aureus bacteremia also have infective endocarditis or a metastatic focus of infection remains a diagnostic challenge.

CLINICAL SYNDROMES

Skin and Soft Tissue Infections

S. aureus causes a variety of cutaneous infections. Common predisposing factors include skin diseases, damage to the skin (e.g., insect bites, minor trauma), injections (e.g., in diabetes, injection drug use), and poor personal hygiene. These infections are characterized by the formation of pus-containing blisters, which often begin in hair follicles and spread to adjoining tissues. Folliculitis is a superficial infection that involves the hair follicle, with a central area of purulence (pus) surrounded by induration and erythema. Furuncles (boils) are more extensive, painful lesions that tend to occur in hairy, moist regions of the body and extend from the hair follicle to become a true abscess with an area of central purulence. Carbuncles are most often located in the lower neck and are even more severe and painful, resulting from the coalescence of other lesions that extend to a deeper layer of the subcutaneous tissue. In general, furuncles and carbuncles are readily apparent, with pus often expressible or discharging from the abscess.

Mastitis develops in 1 to 3% of nursing mothers. The infection, which generally presents within 2 to 3 weeks after delivery, is characterized by findings that range from cellulitis to abscess formation. Systemic signs, such as fever and chills, are often present in more severe cases.

Other cutaneous S. aureus infections include impetigo, cellulitis, and hidradenitis suppurativa (recurrent follicular infections in regions such as the axilla). S. aureus is also one of the most common causes of surgical wound infection.

Musculoskeletal Infections

S. aureus is among the most common causes of bone infections—both those resulting from hematogenous dissemination and those arising from contiguous spread from a soft tissue site.

Hematogenous osteomyelitis in children most often involves the long bones. Infections present with fever and bone pain or with a child's reluctance to bear weight. The white blood cell count and erythrocyte sedimentation rate are often elevated. Blood cultures are positive in ~50% of cases. When necessary, bone biopsies for culture and histopathologic examination are usually diagnostic. Routine x-rays may be normal for up to 14 days after the onset of symptoms. ^99mTc-phosphonate scanning often detects early evidence of infection. Magnetic resonance imaging (MRI) is more sensitive than other techniques in establishing a radiologic diagnosis.

In adults, hematogenous osteomyelitis involving the long bones is less common. However, vertebral osteomyelitis is among the more common clinical presentations. These infections are most often seen in patients with endocarditis, those undergoing hemodialysis, diabetics, and injection drug users. Vertebral bone infections may present with intense back pain and fever but may also be clinically occult, presenting with chronic back pain and low-grade fever. S. aureus is the most common cause of epidural abscess, a complication that can result in neurologic compromise. Patients complain of difficulty voiding or walking and of radicular pain in addition to the symptoms associated with their osteomyelitis. Surgical intervention in this setting often constitutes a medical emergency. MRI most reliably establishes the diagnosis.

Bone infections that result from contiguous spread tend to develop from soft tissue infections, such as those associated with diabetic or vascular ulcers, surgery, or trauma. Exposure of bone, a draining fistulous tract, failure to heal, or continued drainage suggests involvement of underlying bone. Bone involvement is established by bone culture and histopathologic examination. Contamination of culture material from adjacent tissue can make the diagnosis of osteomyelitis difficult in the absence of pathologic confirmation. In addition, it is sometimes difficult to distinguish radiologically between osteomyelitis and overlying soft tissue infection with underlying osteitis.

S. aureus is the most common cause of septic arthritis in children. This infection is rapidly progressive and may be associated with extensive joint destruction if left untreated. It presents with intense pain on motion of the affected joint, swelling, and fever. Aspiration of the joint reveals turbid fluid, with >50,000 PMNs/µL and gram-positive cocci in clusters on Gram's stain. In adults, arthritis may result from trauma, surgery, or hematogenous dissemination. The most commonly involved joints include the knees, shoulders, hips, and phalanges. Infection frequently develops in joints previously damaged by osteoarthritis or rheumatoid arthritis. Iatrogenic infections resulting from aspiration or injection of agents into the joint also occur. In these settings, the patient experiences increased pain and swelling in the involved joint in association with fever.

Pyomyositis is an unusual infection of skeletal muscles that is seen primarily in tropical climates. In addition to occurring in seriously immunocompromised patients, it has recently been reported in HIV-infected individuals. Pyomyositis presents with fever, swelling, and pain overlying the involved muscle. Aspiration of fluid from the involved tissue reveals pus containing numerous white blood cells and gram-positive bacteria in clusters. Although a history of trauma may be associated with the infection, its pathogenesis is poorly understood.

Respiratory Tract Infections

Respiratory tract infections caused by S. aureus occur in selected clinical settings. S. aureus is a cause of serious infections in newborns and infants; these infections present with shortness of breath, fever, and respiratory failure. Chest x-ray may reveal pneumatoceles (shaggy, thin-walled cavities). Pneumothorax and empyema are recognized complications of this type of infection.

In adults, nosocomial S. aureus pulmonary infections are commonly seen in intubated patients on intensive care units. The clinical presentation is no different from that encountered in pulmonary infections of other bacterial etiologies. Patients produce increased volumes of purulent sputum and develop respiratory distress, fever, and new pulmonary infiltrates. Distinguishing bacterial pneumonia from other causes of respiratory failure or new pulmonary infiltrates in critically ill patients is often difficult and relies on a constellation of clinical, radiologic, and laboratory findings.

Community-acquired respiratory tract infections due to S. aureus are most commonly seen as postviral infections or as a result of septic pulmonary emboli (e.g., in injection drug users). Influenza is the most common cause of the former type of presentation. Patients may present with fever, bloody sputum production, and midlung field pneumatoceles or multiple, patchy pulmonary infiltrates. Diagnosis is made by sputum Gram's stain and culture. Blood cultures, although useful, are usually negative.

Bacteremia, Sepsis, and Infective Endocarditis

S. aureus bacteremia may be complicated by sepsis, endocarditis, vasculitis, or metastatic seeding (establishment of suppurative collections at other tissue sites). The frequency of metastatic seeding during bacteremia has been estimated to be as high as 31%. Among the more commonly seeded tissue sites are bones, joints, kidneys, and lungs.

Recognition that these complications have developed is often difficult if clinical and laboratory diagnostic methods alone are used. Comorbid conditions that are frequently seen in association with S. aureus bacteremia and that increase the risk of complications include diabetes, HIV infection, and renal insufficiency. Other host factors associated with an increased risk of complications include presentation with community-acquired S. aureus bacteremia (except in injection drug users), lack of an identifiable primary focus, and presence of prosthetic devices.

Clinically, S. aureus sepsis presents in a manner similar to that documented for sepsis due to other bacteria. The well-described progression of hemodynamic changes—beginning with respiratory alkalosis and clinical findings of hypotension and fever—is commonly seen. The microbiologic diagnosis is established by positive blood cultures.

The overall incidence of S. aureus endocarditis has increased over the past 20 years. Depending on the series, S. aureus now accounts for 25 to 35% of all cases of bacterial endocarditis. This increase is due, at least in part, to the increased use of intravascular devices; the incidence of infective endocarditis among patients with S. aureus bacteremia and intravascular catheters was 25% when studied with transesophageal echocardiography. Other factors associated with an increased risk of endocarditis are injection drug use, hemodialysis, the presence of intravascular prosthetic devices, and immunosuppression. Despite the availability of effective antibiotics, mortality from these infections continues to range from 20 to 40%, depending on both the host and the nature of the infection. Complications of S. aureus endocarditis include cardiac valvular insufficiency, peripheral emboli, metastatic seeding, and central nervous system involvement. S. aureus brain abscess is a recognized complication of left-sided endocarditis.

S. aureus endocarditis is encountered in four clinical settings: (1) right-sided endocarditis in association with injection drug use, (2) left-sided native-valve endocarditis, (3) prosthetic-valve endocarditis, and (4) nosocomial endocarditis. In each of these settings, the diagnosis is established by recognition of clinical stigmata suggestive of endocarditis. These findings include cardiac manifestations such as new or changing cardiac valvular murmurs; cutaneous evidence of endocarditis such as vasculitic lesions, Osler's nodes, or Janeway lesions; evidence of embolic disease; and a history suggesting a risk for S. aureus bacteremia. In the absence of antecedent antibiotic therapy, blood cultures are almost uniformly positive. Transthoracic echocardiography, while less sensitive than transesophageal echocardiography, is less invasive and often establishes the presence of valvular vegetations.

Acute right-sided tricuspid valvular S. aureus endocarditis is most often seen in injection drug users. The classic presentation includes a high fever, a toxic clinical appearance, pleuritic chest pain, and the production of purulent (sometimes bloody) sputum. Chest x-rays reveal evidence of septic pulmonary emboli (small, peripheral, circular lesions that may cavitate with time). A high percentage of the affected patients have no history of antecedent valvular damage. At the outset of their illness, patients may present with fever alone, without cardiac or other localizing findings. As a result, a high index of clinical suspicion is essential to the diagnosis.

Individuals with antecedent cardiac valvular damage more commonly present with left-sided native-valve endocarditis involving the previously affected valve. These patients tend to be older than those with right-sided endocarditis, their prognosis is worse, and their incidence of complications (including peripheral emboli, cardiac decompensation, and metastatic seeding) is higher.

S. aureus is one of the more common causes of prosthetic-valve endocarditis. This infection is especially fulminant in the early postoperative period and is associated with a high mortality rate. In most instances, medical therapy alone is not sufficient and urgent valve replacement is necessary. Patients are prone to develop valvular insufficiency or myocardial abscesses originating from the region of valve implantation.

The increased frequency of nosocomial endocarditis (15 to 30% of cases, depending on the study) reflects in part the increased use of intravascular devices. This form of endocarditis is most commonly caused by S. aureus; because patients often are critically ill, are receiving antibiotics for various other indications, and have comorbid conditions, the diagnosis is not easily recognized.

Urinary Tract Infections

Urinary tract infections are infrequently caused by S. aureus. In contrast with that of most other urinary pathogens, the presence of S. aureus in the urine is suggestive of hematogenous dissemination. Ascending S. aureus infections occasionally result from instrumentation of the genitourinary tract.

Prosthetic Device–Related Infections

S. aureus accounts for a large proportion of prosthetic device–related infections. These infections often involve intravascular catheters, prosthetic valves, orthopedic devices, peritoneal or intraventricular catheters, and vascular grafts. Recently, S. aureus isolates have also been responsible for a sizable proportion of infections of left-ventricular-assist devices. In contrast with the more indolent presentation of CoNS infections, S. aureus device-related infections often present more acutely, with both localized and systemic manifestations. The latter infections also tend to be more rapidly progressive. It is relatively common for a pyogenic collection to be present at the device site. Aspiration of these collections and performance of blood cultures are important components in establishing a diagnosis. S. aureus infections tend to occur more commonly in the early postimplantation period unless the device is used for access (e.g., intravascular or hemodialysis catheters). In the latter instance, infections can occur as long as the device is used. As in most prosthetic-device infections, successful therapy usually involves removal of the device. Left in place, the device is a potential nidus for either persistent or recurrent infections.

Toxin-Mediated Diseases

Toxic Shock Syndrome

TSS was first recognized as a disease in children in 1978. The disease gained national attention in the early 1980s, when a nationwide outbreak occurred among young, otherwise healthy, menstruating women. Epidemiologic investigation demonstrated that these cases were strongly associated with menstruation and the use of a highly absorbent tampon that had recently been introduced to the market. Subsequent studies established the role of TSST-1 in these illnesses. Withdrawal of the tampon from the market resulted in a rapid decline in the incidence of this disease. However, menstrual and nonmenstrual cases continue to be reported.

The clinical presentation is similar in menstrual and nonmenstrual TSS, although the nature of the risk clearly differs. Evidence of a clinical S. aureus infection is not a prerequisite for the development of the illness. TSS results from the elaboration of an enterotoxin or the structurally related enterotoxin-like TSST-1. More than 90% of menstrual cases are caused by TSST-1, whereas a high percentage of nonmenstrual cases are caused by enterotoxins.

TSS begins with relatively nonspecific flulike symptoms. In menstrual cases, the onset usually comes 2 or 3 days after the start of menstruation. Patients present with fever, hypotension, and erythroderma of variable intensity. Mucosal involvement is common (e.g., conjunctival hyperemia). The illness can rapidly progress to symptoms that include vomiting, diarrhea, confusion, myalgias, and abdominal pain. These symptoms reflect the multisystemic nature of the disease, with involvement of the liver, kidneys, gastrointestinal tract, and/or central nervous system. Desquamation of the skin occurs during convalescence, usually 1 or 2 weeks after the onset of illness. Laboratory findings may include azotemia, leukocytosis, hypoalbuminemia, thrombocytopenia, and liver function abnormalities.

Diagnosis of TSS still depends on the presence of a constellation of findings rather than on one specific finding (Table 2). Part of the case definition is the absence of laboratory evidence of other illnesses that are often included in the differential (e.g., Rocky Mountain spotted fever, rubeola, leptospirosis). Other diagnoses to be considered are drug toxicities, viral exanthems, sepsis, and Kawasaki disease. Illness occurs only in persons who lack antibody to TSST-1. Recurrences are possible if antibody fails to develop after the illness.

Food Poisoning

S. aureus is among the most common causes of food-borne outbreaks of infection in the United States. S. aureus food poisoning results from the inoculation of toxin-producing S. aureus into food by colonized food handlers. Toxin is then elaborated in such growth-promoting food as custards, potato salad, or processed meats. Even if the bacteria are killed by warming, the heat-stable toxin is not destroyed. The onset of illness is rapid and explosive, occurring within 1 to 6 h of ingestion. The illness is characterized by nausea and vomiting, although diarrhea, hypotension, and dehydration may also occur. The differential diagnosis includes diarrhea of other etiologies, especially that caused by similar toxins (e.g., the toxins elaborated by Bacillus cereus). The rapidity of onset, the absence of fever, and the epidemic nature of the presentation arouse suspicion regarding this diagnosis. Symptoms generally resolve within 8 to 10 h. The diagnosis can be established by the demonstration of bacteria or the documentation of enterotoxin in the implicated food. Treatment is entirely supportive.

Staphylococcal Scalded-Skin Syndrome

SSSS most often affects newborns and children. The illness may vary from localized blister formation to exfoliation of much of the skin surface. The skin is usually fragile and often tender, with thin-walled, fluid-filled bullae. Gentle pressure results in rupture of the lesions, leaving denuded underlying skin .

The mucous membranes are usually spared. In more generalized infection, there are often constitutional symptoms, including fever, lethargy, and irritability with poor feeding. Significant amounts of fluid can be lost in more extensive cases. Illness usually follows localized infection at one of a number of possible sites. SSSS is much less common among adults but can follow infections caused by exfoliative toxin–producing strains.

PREVENTION

Prevention of the spread of S. aureus infections in the hospital setting involves hand washing and careful attention to appropriate isolation procedures. Through strict isolation practices, some Scandinavian countries have been remarkably successful at preventing the introduction and dissemination of MRSA in hospitals. Other countries, such as the United States and Great Britain, have been less successful.

The use of topical antimicrobial agents (e.g., mupirocin) to eliminate nasal colonization with S. aureus and to prevent subsequent infection has been investigated in a number of clinical settings. Elimination of nasal carriage of S. aureus has reduced the incidence of infections among patients undergoing hemodialysis and peritoneal dialysis. A randomized, placebo-controlled study attempted to reduce rates of wound infection among patients undergoing surgery with the prophylactic application of topical mupirocin to the nares. The results failed to demonstrate an overall benefit from the use of mupirocin but did suggest that the incidence of infections might be reduced if the use of mupirocin were limited to patients nasally colonized with S. aureus.

The ability of a capsular polysaccharide–protein conjugate vaccine to prevent staphylococcal infections in hemodialysis patients was studied. The results, while inconclusive, did show promise. Other potential vaccine candidates, including those incorporating the ligand-binding domains of several MSCRAMMs, are also under investigation.

COAGULASE-NEGATIVE STAPHYLOCOCCAL INFECTIONS

CoNS, although considerably less virulent than S. aureus, are among the most common causes of prosthetic-device infections. Approximately half of the 32 identified CoNS species have been associated with human infections. Of these species, S. epidermidis is the most common human pathogen overall; this component of the normal human flora is found on the skin (where it is the most abundant bacterial species) as well as in the oropharynx and vagina. S. saprophyticus, a novobiocin-resistant species, is a pathogen in urinary tract infections.

PATHOGENESIS

Among CoNS, S. epidermidis is the species most commonly associated with prosthetic-device infections. Infection is a two-step process, with initial adhesion to the device followed by colonization. S. epidermidis is uniquely adapted to colonize these devices by its capacity to elaborate the extracellular polysaccharide (slime) that facilitates formation of a protective biofilm on the device surface.

Implanted prosthetic material is often coated with host serum or tissue constituents such as fibrinogen or fibronectin. These molecules serve as potential bridging ligands, facilitating bacterial attachment to the device surface. The surface-associated staphylococcal enzyme autolysin (AtlE) may play a role in attachment to either modified or unmodified prosthetic surfaces. In addition to AtlE, other surface molecules, such as fibrinogen-binding protein and cell wall teichoic acid, appear to mediate adherence to fibrinogen and fibronectin, respectively. The polysaccharide intercellular adhesin facilitates subsequent staphylococcal colonization and accumulation on the device surface. The genes responsible for synthesis of this polysaccharide (the ica genes) are also present in S. aureus, although their role in the two species may differ. In S. epidermidis, the ica genes are more commonly found in strains associated with device infections than in strains associated with colonization of mucosal surfaces. Biofilm appears to act as a barrier protecting bacteria from host defense mechanisms as well as from antibiotics, while providing a suitable environment for bacterial survival.

Two additional staphylococcal species, S. lugdunensis and S. schleiferi, produce more serious infections (native-valve endocarditis and osteomyelitis) than do other CoNS. The basis for this enhanced virulence is not known, although both species appear to share more virulence determinants with S. aureus (e.g., clumping factor and lipase) than do other CoNS.

The capacity of S. saprophyticus to cause urinary tract infections in young women appears to be related to its enhanced capacity to adhere to uroepithelial cells. A 160-kDa hemagglutinin/adhesin may contribute to this affinity.

DIAGNOSIS

While the detection of CoNS at sites of infection or in the bloodstream is not difficult by standard microbiologic culture methods, interpretation of these results is frequently problematic. Since these organisms are present in large numbers on the skin, they often contaminate cultures. It has been estimated that only 10 to 25% of blood cultures positive for CoNS reflect true bacteremia. Similar problems arise with cultures of other sites. Among the clinical findings suggestive of true bacteremia are fever, evidence of local infection (e.g., erythema or purulent drainage at the intravenous catheter site), leukocytosis, and systemic signs of sepsis. Laboratory findings suggestive of true bacteremia include multiple positive cultures of the same strain (i.e., the same species with the same antibiogram or a closely related DNA fingerprint) from separate cultures, growth of the strain within 48 h, and bacterial growth in both aerobic and anaerobic bottles.

CLINICAL SYNDROMES

CoNS cause diverse prosthetic device–related infections, including those that involve prosthetic cardiac valves and joints, vascular grafts, intravascular devices, and central nervous system shunts. In all of these settings, the clinical presentation is similar. The signs of localized infection are often subtle, the rate of disease progression is slow, and the systemic findings are often limited. Signs of infection such as purulent drainage, pain at the site, or loosening of prosthetic implants are sometimes evident. Fever is frequently but not always present, and there may be mild leukocytosis.

Infections that are not associated with prosthetic devices are infrequent, although native-valve endocarditis due to CoNS has accounted for ~5% of cases in some reviews. S. lugdunensis appears to be a more aggressive pathogen in this setting, causing greater mortality and rapid valvular destruction with abscess formation.

TREATMENT

General Principles of Therapy

In addition to the selection of appropriate antimicrobial therapy for staphylococcal infections, surgical incision and drainage of all suppurative collections are necessary. Prosthetic-device infections are unlikely to be successfully managed unless the device is removed. In the limited number of situations in which removal is not possible or the infection is due to CoNS, an initial attempt at medical therapy without device removal may be warranted. Because of the well-recognized risk of complications associated with S. aureus bacteremia, therapy is generally prolonged (4 to 8 weeks) unless the patient is identified as being one of the small percentage of individuals who are at low risk for complications—e.g., immunocompetent patients and patients whose S. aureus infection is associated with a removable focus (such as an intravenous catheter) and whose device is promptly removed.

Duration of Antimicrobial Therapy

Debate continues regarding the duration of therapy for bacteremic S. aureus infections. No carefully controlled, prospective study has addressed this question. A meta-analysis reviewing studies relevant to this issue concluded that insufficient information was currently available to determine which patients were candidates for short-course therapy (2 weeks rather than 4 to 8 weeks).

Among the findings associated with an increased risk of complicated bacteremia are persistently positive blood cultures 48 to 96 h after institution of therapy, acquisition of the infection in the community, a removable focus of infection (i.e., intravascular catheters) that is not removed, and cutaneous or embolic manifestations of infection. In those immunocompetent patients for whom short-course therapy is planned, a transesophageal echocardiogram to rule out endocarditis is warranted since neither clinical nor laboratory findings are adequate to detect cardiac involvement. In addition, an aggressive radiologic investigation to identify potential metastatic collections is indicated. All symptomatic sites need to be carefully evaluated.

Choice of Antimicrobial Agents

The choice of antimicrobial agents to treat both coagulase-positive staphylococcal and CoNS infections has become increasingly problematic because of the prevalence of multidrug-resistant strains. Data collected by the Centers for Disease Control and Prevention from intensive care units in the United States (1988 to 1998) show a dramatic increase in the number of isolates that are now susceptible only to vancomycin. This trend is even more apparent with CoNS: more than 80% of nosocomial isolates are resistant to methicillin, and these MRSA strains are usually resistant to most other antibiotics as well. Because the selection of antimicrobial agents for the treatment of S. aureus infections is similar to that for CoNS infections, treatment options for these pathogens are discussed together and are summarized in Table 3.

As a result of the widespread dissemination of plasmids containing the enzyme penicillinase, few strains of staphylococci (<5%) remain susceptible to penicillin. However, against susceptible strains, penicillin remains the drug of choice. Penicillin-resistant isolates are treated with semisynthetic penicillinase-resistant penicillins (SPRPs) such as oxacillin or nafcillin. Methicillin, the first of the SPRPs, is now used infrequently. Cephalosporins are alternative therapeutic agents for these infections. Second- and third-generation cephalosporins do not have a therapeutic advantage over first-generation cephalosporins for the treatment of staphylococcal infections. The carbapenem imipenem has excellent activity against methicillin-sensitive S. aureus (MSSA) but not MRSA.

The isolation of MRSA was reported within 1 year of the introduction of methicillin. The prevalence of MRSA has since increased steadily. In many hospitals, 40 to 50% of S. aureus isolates are now resistant to methicillin. Resistance to methicillin indicates resistance to all SPRPs as well as all cephalosporins. Many MRSA isolates are also resistant to other antimicrobial families, including aminoglycosides, quinolones, and macrolides.

Production of a novel penicillin-binding protein (PBP 2a or 2′) is responsible for methicillin resistance. This protein is synthesized by the mecA gene, which (as stated above) is part of a large mobile genetic element—a pathogenicity or genomic island—called the staphylococcal cassette chromosome (SCCmec). It is hypothesized that acquisition of this genetic material resulted from horizontal transfer from a related staphylococcal species, such as S. sciuri. Phenotypic expression of methicillin resistance may be constitutive (i.e., expressed in all organisms in a population) or heterogeneous (i.e., displayed by only a proportion of the total organism population). Detection of methicillin resistance in the clinical microbiology laboratory can be difficult if the strain expresses heterogeneous resistance. Therefore, susceptibility studies are routinely performed at reduced temperatures (30° to 35°C for 24 h), with increased concentrations of salt in the medium to enhance the expression of resistance. In addition to PCR-based techniques, a number of rapid methods for the detection of methicillin resistance have recently been developed.

Vancomycin is the drug of choice for the treatment of methicillin-resistant staphylococcal infections. Because it is less bactericidal than the β-lactams, it should be used only after careful consideration in patients with a history of β-lactam allergies. In 1997, an S. aureus strain with reduced susceptibility to vancomycin (VISA) was reported from Japan. Subsequently, additional clinical isolates of VISA were reported from geographically disparate locations. These strains were all resistant to methicillin and many other antimicrobial agents. The VISA strains appear to evolve (under vancomycin selective pressure) from strains that are susceptible to vancomycin but are heterogeneous, with a small proportion of the bacterial population expressing the resistance phenotype. The mechanism of VISA resistance is uncertain but appears to be an abnormal cell wall, which was first noted by electron microscopy. Vancomycin is trapped by the abnormal peptidoglycan cross-linking and is unable to gain access to its target site.

In 2002, the first clinical isolate of fully vancomycin-resistant S. aureus was reported. Resistance in this and one subsequently reported clinical isolate was due to the presence of vanA, the gene responsible for expression of vancomycin resistance in enterococci. This observation suggested that resistance was acquired as a result of horizontal conjugal transfer from a vancomycin-resistant strain of Enterococcus faecalis. The patients had both MRSA and vancomycin-resistant enterococci cultured from sites of infection. The isolates remained susceptible to chloramphenicol, linezolid, minocycline, quinupristin/dalfopristin, and trimethoprim-sulfamethoxazole (TMP-SMX). The vanA gene is responsible for the synthesis of the dipeptide D-Ala-D-Lac in place of D-Ala-D-Ala. Vancomycin is not able to bind to the altered peptide.

Alternatives to the β-lactams and vancomycin have less antistaphylococcal activity. Although the quinolones have reasonable in vitro activity against staphylococci, the frequency of fluoroquinolone resistance has increased progressively, especially among methicillin-resistant isolates. Methicillin-susceptible staphylococci have remained more susceptible to the fluoroquinolones than have methicillin-resistant strains. Of particular concern in methicillin-resistant strains is the possible emergence of quinolone resistance during therapy. Resistance to the quinolones is most commonly chromosomal and results from mutations of the topoisomerase IV or DNA gyrase genes, although multidrug efflux pumps may also contribute. While the newer quinolones exhibit increased in vitro activity against staphylococci, it is uncertain whether this increase translates into enhanced in vivo activity. Other antibiotics such as minocycline and TMP-SMX have been successfully used to treat methicillin-resistant staphylococcal infections in the face of vancomycin toxicity or intolerance.

Among the newer antistaphylococcal agents, the parenteral streptogramin quinupristin/dalfopristin displays bactericidal activity against all staphylococci, including VISA strains. This drug has been used successfully to treat serious MRSA infections. In cases of erythromycin or clindamycin resistance, it is bacteriostatic against staphylococci.

Linezolid—the first member of a new drug family, the oxazolidinones—is bacteriostatic against staphylococci, has been well tolerated, and offers the advantage of comparable bioavailability after oral or parenteral administration. Cross-resistance with other inhibitors of protein synthesis has not been reported. Resistance to linezolid has been limited, although at least one resistant clinical isolate has been reported. The efficacy of linezolid in the treatment of deep-seated infections such as osteomyelitis has not yet been established. There are currently insufficient data on the efficacy of either quinupristin/dalfopristin or linezolid for the treatment of infective endocarditis. Daptomycin, a new parenteral bactericidal agent with antistaphylococcal activity, was recently approved for the treatment of complicated skin infections. This drug disrupts the cytoplasmic membrane. Oritavancin, a new glycopeptide, is undergoing clinical trials.

Combinations of antistaphylococcal agents are sometimes used to enhance bactericidal activity in the treatment of serious infections such as endocarditis or osteomyelitis. In selected instances (e.g., right-sided endocarditis), drug combinations are also used to shorten the duration of therapy. Among the antimicrobial agents used in combinations are rifampin, aminoglycosides (e.g., gentamicin), and fusidic acid (which is not readily available in the United States). While these agents are not effective singly because of the frequent emergence of resistance, they have proved useful in combination with other agents because of their bactericidal activity against staphylococci.

In vitro studies have demonstrated synergy against staphylococci with the following combinations: (1) β-lactams and aminoglycosides; (2) vancomycin and gentamicin; (3) vancomycin, gentamicin, and rifampin (against CoNS); and (4) vancomycin and rifampin. In several instances, these in vitro observations have been supported by studies using the experimental animal model of endocarditis.

Antimicrobial Therapy for Selected Settings

For uncomplicated skin and soft tissue infections, the use of oral antistaphylococcal agents is usually successful. For other infections, parenteral therapy is indicated.

S. aureus endocarditis is usually an acute, life-threatening infection. Thus blood cultures need to be obtained promptly and followed by the immediate institution of empirical antimicrobial therapy. For S. aureus native-valve endocarditis, a combination of antimicrobial agents is often used. In a large prospective study, an SPRP combined with an aminoglycoside did not alter the clinical outcome but did reduce the duration of S. aureus bacteremia. As a result, many clinicians begin therapy for life-threatening infections with a 3- to 5-day course of a β-lactam and an aminoglycoside (gentamicin, 1 mg/kg intravenously every 8 h). If a MRSA strain is isolated, vancomycin (30 mg/kg every 24 h, given in two equal doses up to a total of 2 g) is recommended. Patients are treated for 4 to 6 weeks, depending on the clinical response.

In prosthetic-valve endocarditis, surgery in addition to antibiotic therapy is often necessary. The combination of a β-lactam agent—or, if the isolate is β-lactam resistant, vancomycin (30 mg/kg every 24 h, given in two equal doses up to a total of 2 g)—with an aminoglycoside (gentamicin, 1 mg/kg intravenously every 8 h) and rifampin (300 mg orally every 8 h) is recommended. This combination is used to avoid the possible emergence of rifampin resistance during therapy if only two drugs are used.

For hematogenous osteomyelitis or septic arthritis in children, a 4-week course of therapy is usually adequate. In adults, treatment is often more prolonged. For chronic forms of osteomyelitis, surgical debridement is necessary in combination with antimicrobial therapy. For joint infections, a critical component of therapy is the repeated aspiration or arthroscopy of the affected joint to prevent damage from leukocytes. The combination of rifampin with ciprofloxacin has been used successfully to treat prosthetic-joint infections, especially when the device cannot be removed. The efficacy of this combination may reflect the enhanced activity against staphylococci in biofilms as well as the attainment of effective intracellular concentrations.

The choice of empirical therapy for staphylococcal infections depends in part on susceptibility data for the local geographic area. Increasingly, vancomycin (in combination with an aminoglycoside or rifampin for serious infections) is the drug of choice for both community- and hospital-acquired infections.

Therapy for Toxic Shock Syndrome

Supportive therapy with reversal of hypotension is the mainstay of therapy for TSS. Both fluids and pressors may be necessary. Tampons or other packing material should be promptly removed. The role of antibiotics is less clear. Some investigators recommend a combination of clindamycin and a semisynthetic penicillin. Clindamycin is advocated because, as a protein synthesis inhibitor, it reduces toxin synthesis in vitro. A semisynthetic penicillin is suggested to eliminate any potential focus of infection as well as to eradicate persistent carriage that might increase the likelihood of recurrent illness. Anecdotal reports document the successful use of intravenous immunoglobulin to treat TSS. The role of glucocorticoids in the treatment of this disease is uncertain at present.

Therapy for Other Toxin-Mediated Diseases

Therapy for staphylococcal food poisoning is entirely supportive. For SSSS, antistaphylococcal therapy targets the primary site of infection.

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