Staphylococcus aureus

Capsule and Cell Wall

Many clinical S. aureus isolates have a polysaccharide capsule, although the role of capsule in invasive human disease remains unclear. Although two capsular serotypes (5 and 8) predominate in collections of encapsulated clinical isolates, unencapsulated strains of S. aureus also frequently cause invasive disease, including the epidemic MRSA clone, USA300. ^, The unclear role of capsules in human staphylococcal infection is reinforced by the failure of two S. aureus vaccine candidates targeting the type 5 and 8 polysaccharide capsules to meet primary clinical endpoints.

The cell wall of S. aureus is composed of peptidoglycan, capsular polysaccharide (when present), ribitol teichoic acid, lipoteichoic acid, and many surface proteins, including protein A, which binds to the Fc region of the immunoglobulin G (IgG) molecule ( Fig. 115.1 ). ^, Binding of IgG antibodies to the staphylococcal cell surface in this nonphysiologic manner interferes with the opsonization and phagocytosis of S. aureus and suppresses the effective formation of memory B-lymphocyte responses.

Surface Proteins

Many proteins found on the surface of S. aureus have been implicated in pathogenesis ( Fig. 115.1 ). Adherence of S. aureus to mammalian extracellular matrix components is mediated by a family of adhesins, the microbial surface components that recognize adhesive matrix molecules (MSCRAMMs). Coagulase, found on the bacterial cell surface and in its environment, binds to host prothrombin and catalyzes the formation of fibrin from fibrinogen. The A and B clumping factors are cell surface proteins that bind to fibrinogen, producing the typical clusters of staphylococci when mixed with plasma. Coagulase and the clumping factors breach host defenses by causing localized clotting; the clumping factors also may aid adherence to traumatized skin, endothelial structures, and foreign surfaces. Recognition of the role of S. aureus clumping factors has prompted investigation into their potential use as vaccine antigens.

Metal ions are essential nutrients for S. aureus replication and survival in the host. The iron-regulated surface determinant (Isd) system, which includes a surface receptor for human hemoglobin, IsdB, is essential for pathogenesis in multiple in vivo models, ^, though a vaccine targeting IsdB failed to demonstrate benefit. Uptake of additional cations such as magnesium and zinc is also essential for S. aureus survival in the host, and the manganese transporter MntABC system has been explored as a potential target for vaccine-based interventions. ^,

Toxins

The virulence of S. aureus is due to a combination of variously elaborated proteins, including the α, β, γ, and δ hemolysins (also called toxins), leukocidins, proteases, lipase, deoxyribonuclease, a fatty acid–modifying enzyme, and hyaluronidase. The most extensively studied of the exotoxins is α-hemolysin (Hla), a pore-forming toxin with a high tropism toward erythrocytes which, along with LukED and HlgAB, promotes S. aureus growth by providing access to host hemoglobin and, therefore, iron. Hla-mediated endothelial lysis leads to vascular permeability and exacerbation of sepsis in murine models, and this permeability may allow S. aureus dissemination from the bloodstream into host tissue. Serologic studies indicate that Hla is expressed during pediatric infections, including pneumonia and bacteremia ; therefore, its potential use as a vaccine target is currently in development.

Phagocytes are critical for human host defense against S. aureus , and patients with neutrophil defects have a severe burden of staphylococcal disease. The bi-component leukocidins (e.g., LukAB, LukED, and Panton-Valentine leukocidin [PVL]) are lytic to host phagocytes via pore formation in the target cell membrane. Many of the leukocidins are highly lytic to human cells but only weakly toxic to murine cells, and this species-specific disparity in receptor binding and cellular lysis has likely led to an underestimation of the importance of these toxins for human disease. The potential clinical importance of the leukocidin family of toxins is underscored by their expression during natural human infection. LukAB in particular is known to be expressed during invasive pediatric disease, ^, and the leukocidins are under investigation as potential targets of intervention against S. aureus , particularly for the amelioration or prevention of invasive disease and bloodstream infections.

S. aureus causes a variety of toxin-mediated clinical syndromes, including staphylococcal scalded skin syndrome (SSSS), toxic shock syndrome (TSS), and staphylococcal food poisoning. These clinical syndromes are all caused by the action of exotoxins and enterotoxins. Exfoliative toxins A (ETA) and B (ETB) cleave the glycoprotein desmoglein 1, promoting the spread of S. aureus under the stratum corneum ^, and resulting in blistering of the superficial epidermis, which is characteristic of SSSS and bullous impetigo ( Fig. 115.2 ). Toxic shock syndrome toxin-1 (TSST-1) and staphylococcal enterotoxins B (SEB) and C (SEC) have been implicated in most cases of TSS. These toxins have superantigen activity; that is, they stimulate T lymphocytes nonspecifically, resulting in cytokine release and clinical toxic shock. At a skin or mucosal port of entry, TSST-1 can interfere with the release of inflammatory mediators locally, which may account for a surprisingly benign appearance at the local infective site. An expanding family of enterotoxins has been implicated in staphylococcal food poisoning, but the most frequently implicated molecule is enterotoxin A (SEA).

Genetic Basis and Regulation of Pathogenicity Factors and Antimicrobial Resistance

The genome of S. aureus has a circular chromosome of about 2.8 million base pairs. While genes for many housekeeping functions are highly conserved, clinical strains of S. aureus also possess multiple mobile genetic elements, such as plasmids, transposons, prophages, and pathogenicity islands, many of which encode virulence factors or determinants of antibiotic resistance. These factors represent a subset of a large class of accessory gene products (including surface proteins, exotoxins, and other enzymes) that provide one or more advantages in particular environments, although these accessory products are not required for growth and cell division.

S. aureus has evolved a remarkable network of regulatory mechanisms that control subsets of genes that are upregulated or downregulated under certain growth and environmental conditions. The most extensively studied is the agr locus with its two-component signal transduction system and its effector RNAIII molecule. The agr locus upregulates genes that encode capsular polysaccharides, α-δ toxins, two-component synergohymenotropic toxins, enterotoxins, exfoliatins, and proteases; agr expression downregulates other genes, such as those that encode MSCRAMMs, other adhesins, and protein A. This regulation of virulence gene expression offers pathogenic advantages to S. aureus; in early stages of growth (exponential phase), surface-expressed proteins are preferentially upregulated, while in later stages of growth (stationary phase), once the population of staphylococci is established, surface-expressed (and thus immunologically exposed) proteins are downregulated and secreted virulence factors that aid in nutrient acquisition and immune evasion are upregulated. Other two-component signal transduction systems implicated in pathogenesis include saeRS , srrAB , arlSR , and lytRS as well as protein systems that bind deoxyribonucleic acid (DNA), such as sarA and its regulatory homologues. Taken together, these quorum sensing systems afford S. aureus a versatile environmental response system and confer the capacity to respond to a myriad of environmental stimuli, such as electrolyte concentrations, subinhibitory concentrations of protein synthesis inhibitors, acidic pH, oxygen tension, or conditions in which essential nutrients (e.g., amino acids) are limited.

S. aureus can overcome environmental antibiotic pressure through the acquisition and transmission of resistance genes from other, usually less pathogenic, species and strains of the same species. Resistance to β-lactam antibiotics (e.g., penicillins, cephalosporins, and carbapenems) is one example. The β-lactam antibiotics bind to S. aureus penicillin-binding proteins (PBPs), thereby inhibiting cell wall synthesis. Resistance to penicillin was documented almost immediately after the medication’s introduction into clinical practice in the 1940s. It is mediated by the elaboration of a plasmid-based β-lactamase. Almost all clinical isolates of S. aureus elaborate this enzyme, rendering antibiotics susceptible to β-lactamase hydrolysis clinically ineffective.

The development of β-lactamase–resistant semisynthetic penicillins temporarily overcame this widely prevalent clinical problem. However, some strains became resistant to semisynthetic compounds by acquiring mecA, a gene encoding PBP2a, a peptidoglycan-synthesizing enzyme that has decreased affinity for β-lactam antibiotics. ^, These resistant strains are called MRSA and are responsible for nosocomial outbreaks and for the current community-based MRSA epidemic. MRSA strains are resistant to all β-lactams except ceftaroline.

The mecA resistance gene is located on a mobile genetic element called the staphylococcal chromosome cassette mec (SCC mec ), which is present in all MRSA isolates, with occasional exceptions. SCC mec contains a mec complex, comprised of mecA and its variably present mec1 and mecR1 regulatory genes, and a ccr complex, comprised of genes that mediate insertion and excision of SCC mec from the genome. Currently, 12 SCC mec elements have been sequenced or partially characterized. In the US, mobile elements SCC mec types I to III generally are found in healthcare-associated MRSA (HA-MRSA) isolates, and SCC mec types IV and V generally are found in community-associated MRSA (CA-MRSA) isolates, although these distinctions have blurred over the last 2 decades.

Although the mechanism of the movement of SCC mec elements from strain to strain is unknown, the large size of types I to III is believed to limit easy transfer of the elements. Types IV and V elements, however, are small and mobile. Types IV and V have been found in multiple S. aureus genetic backgrounds, which supports the hypothesis that they are readily transferred from strain to strain. To date, types VI through XII have been identified in only a limited number of strains.

Colonization

Humans and other mammals are the natural reservoirs for S. aureus. Asymptomatic colonization is frequent in humans, and traditionally the anterior nares were thought to be a predominant site. However, the skin, nails, oropharynx, axillae, perineum, gastrointestinal tract, and vagina are also common sites of colonization. Colonization rates range from 25% to 50%; higher rates are found in children, people with dermatologic conditions (e.g., eczema), those who perform needle injections frequently (e.g., intravenous [IV] drug abusers), those with indwelling intravascular devices (e.g., patients receiving dialysis), and healthcare personnel (HCP). Even higher rates have been documented with the use of highly sensitive detection methods, leading some to speculate that colonization may be universal. Most individuals experience intermittent colonization, although as many as 20% of individuals may be persistently colonized and 10% may be relatively resistant to colonization with S. aureus. Traditionally, nasal S. aureus carriage has been a risk factor in developing an infection, although most colonized individuals do not do so. Site of colonization may play a role in risk of infection; for example, children with recurrent furunculosis involving the lower extremities are more likely to experience gastrointestinal colonization.

Healthcare-Associated Infections

S. aureus can develop resistance to all classes of antimicrobial agents. The first MRSA strain was reported less than a year after the introduction of semisynthetic penicillins in the early 1960s, even though these penicillins were active against β-lactamase–producing, methicillin-susceptible S. aureus (MSSA). Multidrug-resistant HA-MRSA strains spread worldwide in hospital settings. The National Healthcare Safety Network (NHSN) (formerly the National Nosocomial Infections Surveillance System), an agency of the Centers for Disease Control and Prevention (CDC), has reported S. aureus as a major pathogen of HAIs. In 2003, MRSA accounted for 64% of nosocomial S. aureus isolates in intensive care units (ICUs) in US hospitals, an increase from 36% in 1992. From January 2006 to October 2007, S. aureus was the second most common cause of HAI, exceeded only by coagulase-negative staphylococci (CoNS).

In pediatric ICUs in the US, S. aureus is the major nosocomial pathogen in a variety of clinical situations, accounting for 9% of HA bloodstream infections (HA-BSIs), 17% of cases of HA pneumonia, and 20% of surgical site infections. Current patterns of HA-MRSA isolates reveal decreasing rates of isolation and decreasing resistance to non–β-lactam antibiotics; this suggests a shift in nosocomial MRSA epidemiology, probably reflecting the movement of “biologically fit” CA-MRSA isolates into the hospital. ^,

Community-Associated MRSA Infections

Prevalent MRSA infection outside the healthcare setting was first reported in 1982 in Detroit, Michigan, among IV drug users. This and subsequent reports of CA-MRSA were associated with risk factors for infection similar to those for HA-MRSA, including IV drug use, recent hospitalization or surgery, presence of indwelling catheters or devices, dialysis, or residence in a longterm care facility. In the late 1990s, CA-MRSA infections emerged, occurring predominantly in children with no identifiable predisposing MRSA risk factor and commonly resulting in skin and soft tissue infections (SSTIs). Some serious infections required hospitalization or were fatal. The number and geographic distribution of CA-MRSA infections grew substantially over a decade. Strong evidence supports the de novo rise of MRSA in the community, rather than movement of HA-MRSA into the community. ^,

A CA-MRSA infection can be defined as one that occurs in an outpatient or that develops within 72 hours of admission to the hospital in a patient without any of the factors used to define risk for HA-MRSA: recent hospitalization or surgery, prolonged antibiotic therapy, underlying chronic disease, indwelling catheter or other device, healthcare contact, or residence in a longterm facility. Molecular definitions also have been used to distinguish HA-MRSA from CA-MRSA strains. Outbreaks of CA-MRSA infections have been reported in group childcare settings, ^, sports teams, ^, correctional facilities, ^, and military units, ^, which suggests that close contact and suboptimal hygiene practices play a role in the spread of infection.

CA-MRSA isolates also can be distinguished from HA-MRSA by their lack of multidrug resistance. Most CA-MRSA isolates are susceptible to clindamycin, trimethoprim-sulfamethoxazole (TMP-SMX), and doxycycline, whereas HA-MRSA isolates usually are resistant to these agents. Multilocus sequence typing, SCC mec typing, and pulsed-field gel electrophoresis have elucidated important differences between HA-MRSA and CA-MRSA isolates. In the US, HA-MRSA isolates usually contain SCC mec type II and genes that mediate resistance to several non–β-lactam antibiotics. In contrast, CA-MRSA isolates usually contain SCC mec type IV or type V and lack non–β-lactam antibiotic resistance genes. Even among CA-MRSA isolates, however, determinants of non–β-lactam agent resistance can be found elsewhere in the cell, such as on plasmids or in the chromosome. For example, erythromycin resistance is common among both HA-MRSA and CA-MRSA strains and can be mediated by a variety of phenotypic and genetic mechanisms. When the erm gene that commonly mediates erythromycin resistance is present, a constitutive or inducible macrolide-lincosamide-streptogramin B (MLS _B ) phenotype (discussed later in the chapter) is conferred. ^,

Another difference between CA-MRSA and HA-MRSA isolates is their repertoire of toxin genes. The most striking examples are the lukS-PV and lukF-PV genes that encode for PVL and are transferred from strain to strain by an as yet unknown mechanism. These toxin genes have been associated with MSSA and MRSA strains that cause SSTIs, necrotizing pneumonia, and empyema. Most circulating CA-MRSA organisms in the US belong to a genetic lineage called USA300 (from a nomenclature scheme based on pulsed-field gel electrophoretic pattern). These organisms contain an island of foreign DNA called the arginine catabolic mobile element (ACME)–encoded arc cluster. The role of ACME is the subject of controversy, but it is thought to confer an improved survival advantage on skin and spermidine susceptibility.

Vancomycin-Intermediate S. aureus and Vancomycin-Resistant S. aureus Infections

S. aureus isolates with decreased susceptibility to vancomycin also emerged in the late 1990s. These vancomycin-intermediate S. aureus (VISA) strains, defined as having a minimal inhibitory concentration (MIC) of vancomycin >2 μg/mL, typically have been isolated from patients with underlying medical conditions in whom vancomycin therapy has failed; ^, these strains usually also are resistant to teicoplanin (a glycopeptide not licensed in the US). Therefore, the term glycopeptide-intermediately susceptible S. aureus (GISA) may be more appropriate. In 2002, the first high-level vancomycin-resistant S. aureus (VRSA) strain was reported (MIC of vancomycin >16 μg/mL); this isolate apparently acquired the vanA vancomycin resistance genes from Enterococcus organisms. To date, 13 VRSA isolates have been reported in the US, and all strains evaluated have carried the vanA gene.

Skin and Soft Tissue Infections

Impetigo

S. aureus is a major cause of cutaneous infections; the most superficial is impetigo, which begins as a small, tender, erythematous papule. Often the integument has been interrupted, such as by an insect bite, eczema, or a minor abrasion. Bullous impetigo is a specific S. aureus manifestation in which transparent bullae rupture easily, exposing a moist base surrounded by a thin rim of scale ( Fig. 115.3 ). Bullous impetigo is mediated by the production of ETA and ETB. ^,

Several studies have demonstrated the superiority of topical or systemic antibiotics over simple cleansing for the treatment of impetigo. For uncomplicated singular sites of impetigo in children outside the neonatal period, topical mupirocin can be appropriate. Mupirocin ointment should be applied 3 times daily for 7–10 days. Retapamulin is licensed for topical therapy for children ≥9 months of age who have impetigo caused by Streptococcus pyogenes or MSSA (but not MRSA). Systemic (oral or parenteral) antimicrobial therapy should be considered for bullous or widespread impetigo. Because of the high prevalence of MRSA, a culture should be performed before the initiation of systemic therapy in most patients.

Abscess

S. aureus commonly causes superficial abscesses of the skin, including furuncles, boils, folliculitis, and hidradenitis. When the lesion is associated with a hair shaft, the term furuncle is often used (see Fig. 67.12 ). Rupture yields a purulent discharge. A carbuncle is a larger lesion formed by the coalescence of furuncles. With most small skin abscesses, the symptoms are local (e.g., pain, warmth, and erythema), although fever can be present. Systemic signs can accompany larger lesions. In the neonate, a cutaneous abscess can progress rapidly to BSI and clinical sepsis.

S. aureus is the leading cause of breast abscess in infants, which commonly occurs within the first 3 weeks of life ( Fig. 115.4 ). The abscess usually is unilateral and accompanied by erythema and induration. Occasionally fever, leukocytosis, or BSI can occur. Isolation of the pathogen from the abscess drainage aids management.

Incision and drainage with local cleansing are essential components of the management of abscesses. ^, Recent randomized, placebo-controlled trials have indicated that antimicrobial therapy (e.g., TMP-SMX or clindamycin) is superior to drainage alone even for small abscesses (<5 cm). ^, A course of 7–10 days of therapy appears most appropriate. Systemic antibiotic treatment is particularly important for neonates and patients with severe or extensive disease, rapid progression of associated cellulitis, systemic illness, associated comorbidity or immunosuppression, abscess in an area difficult to drain (e.g., face, genitalia, or hand), or associated phlebitis.

Recurring MRSA SSTIs are common and pose a management challenge. Underlying skin conditions (e.g., eczema or diaper dermatitis) should be managed aggressively, and careful hand and nail hygiene may help reduce recurrences. Though burdensome to families, attempts to decolonize a patient using nasal mupirocin plus topical application of an antiseptic (e.g., chlorhexidine or dilute bleach baths) may be of benefit. Recent data suggest that targeted decolonization of family members with a prior year history of SSTI may be as effective as household-wide measures. Consideration of congenital or acquired immunodeficiency may be warranted in patients with recurrent disease, especially if the response to therapy is slow or healing occurs with remarkable scarring.

Ocular Infections

S. aureus is an important cause of purulent conjunctivitis. The organism can be visualized by Gram stain or isolated from purulent discharge. Conjunctivitis usually resolves without treatment, although topical ophthalmic antimicrobial agents frequently are used. S. aureus is the most frequently recognized cause of a stye or a hordeolum, an infection of the sebaceous gland or the eyelash follicle, respectively. Use of a topical antimicrobial agent may prevent the spread of infection to adjacent hair follicles, but frequent application of warm compresses usually suffices for treatment.

Preseptal (periorbital) cellulitis can result from extension of sinusitis or from autoinoculation of skin flora after a break in the skin due to local trauma, an insect bite, an abscess, or impetigo ( Fig. 115.5 ). S. aureus is the leading cause of skin lesion–related preseptal cellulitis. Because of the elasticity and thinness of the skin in and around the eyelid, the clinical presentation can be dramatic, with a rapid onset of lid swelling, erythema, and tenderness. Low-grade fever and leukocytosis can be present, although typically the child does not appear systemically ill. Visual acuity is not affected, and movement of the globe (which is not proptotic) is not painful or limited. Treatment of preseptal cellulitis usually is initiated parenterally; oral therapy can be substituted after a clinical response has been demonstrated.

S. aureus is presumed to be the leading cause of orbital (postseptal) cellulitis after surgical or accidental trauma to the orbit, and it can be responsible for orbital cellulitis that complicates sinusitis. Patients or parents note a red, swollen “eye”; physical examination reveals one or more of the following: decreased or painful movement of the globe, impaired visual acuity, chemosis, or proptosis. Complicating cavernous sinus thrombosis should be suspected if the patient has abnormal neurologic findings. Treatment requires confirmation of the pathogen and antimicrobial susceptibility. CT helps distinguish between orbital phlegmon, subperiosteal abscess, and orbital abscess; staphylococci are more often associated with abscesses. These diagnoses mandate assessment for surgical drainage in addition to IV antibiotics. An extended course of antimicrobial therapy is given parenterally.

S. aureus endophthalmitis is an uncommon infection in children and usually follows ocular surgery or penetrating trauma to the globe . Symptoms include blurred vision, redness, pain, lid swelling, and the presence of a hypopyon. Systemic signs or fever and lethargy often are present. Treatment includes antibiotics, both given parenterally and instilled directly into the vitreal cavity, and vitrectomy. Visual outcomes are poor.

Invasive Infections