The development and evolution of bacterial infection involve three major factors1: (1) the portal of entry and skin barrier function,2 (2) the host defenses and inflammatory response to microbial invasion, and3 (3) the pathogenic properties of the organism.
Normal intact pediatric and adult skin is relatively resistant to infection and most skin infections occur when there is disruption of the skin barrier. Maceration, shaving, chronic wounds, excoriation of pruritic insect bites, and disruption of the epidermal barrier by other pathogens are some of the ways bacteria can breach the skin barrier. For example, skin trauma, interdigital maceration, or tinea pedis can be predisposing factors for lower leg cellulitis in an otherwise healthy person without venous incompetence or a leg ulcer.4
The character of the cutaneous inflammatory response to bacteria will be influenced by how the organisms reach the involved area. Local inflammation and suppuration commonly accompany direct bacterial infection of the skin. In septicemia, the vascular wall is often the primary site of skin involvement; hemorrhage, or thrombosis with infarction is the initial manifestation leading to ulceration or eschar. Certain bacteria can produce bacteremia or distant lesions without evoking an obvious inflammatory response at the portal of entry [e.g., Yersinia pestis, Streptobacillus moniliformis (rat-bite fever)], even in a healthy host. Occasionally, a devastating Streptococcus pyogenes septicemia has followed closely on an innocuous pinprick or abrasion that has not induced a significant local lesion.
Natural Resistance of the Skin
The normal skin of healthy individuals is highly resistant to invasion by the wide variety of bacteria to which it is constantly exposed. It is difficult to produce localized infections such as impetigo, furunculosis, or cellulitis, if the integument is intact.5 Pathogenic organisms such as S. pyogenes (group A streptococcus, GAS) and S. aureus produce characteristic lesions of cellulitis and furunculosis in hosts with normal defenses usually because there is a disruption of the normal skin barrier. The presence of a silk suture reduces by a factor of 10,000, in the case of S. aureus, the number of organisms needed to produce an abscess in the human skin.6
Bacteria are unable to penetrate the keratinized layers of normal skin and, when applied to the surface, rapidly decrease in number. Maceration and occlusion, which result in increased pH, higher carbon dioxide content, and higher epidermal water content, result in dramatic increases in bacterial flora.7 Some bacteria, such as those that are Gram negative, can only be found in such sites, suggesting that normal skin conditions prevent them from colonizing the skin. The relative dryness of normal skin specifically contributes to the marked limitation of growth of bacteria, especially Gram-negative bacilli.
Lipids found on the skin surface also may have antibacterial properties.8,9 Reduction of skin surface lipids with topical solvents prolongs the survival time of S. aureus on the skin. The free fatty acids, and linoleic and linolenic acids, are more inhibitory for S. aureus than for coagulase-negative staphylococci, a component of the normal skin flora. Sphingosine, glucosylceramides, and cis-6-hexadeconic acid have been demonstrated to have antimicrobial activity against S. aureus. Bacterial interference (the suppressive effect of one bacterial species on colonization by another) exerts a major influence on the overall composition of the skin flora.
The organisms that characteristically survive and multiply in various ecologic niches of the skin constitute the “normal cutaneous flora.” As an example, the distribution of different species of coagulase-negative staphylococci varies among different anatomic areas, and their relative numbers can depend on age. In adults, Staphylococcus epidermidis is the principal staphylococcal species isolated from the scalp, face, chest, and axilla. In a study of the skin microbiome of healthy adults, over 98% of skin bacteria belonged to four phyla: (1) Actinobacteria (51.8%), (2) Firmicutes (24.4%), (3) Proteobacteria (16.5%), and (4) Bacteroidetes (6.3%). Although 205 genera were identified on only 20 individuals, three were associated with more than 62% of the sequences: (1) Corynebacteria (22.8%; Actinobacteria), (2) Propionibacteria (23.0%; Actinobacteria), and (3) Staphylococci (16.8%; Firmicutes).10
Human skin contains a wide range of proteins with inherent antimicrobial properties. These antimicrobial peptides (AMPs) are expressed on the skin surface as well as in eccrine sweat and saliva.11 Activated keratinocytes produce AMPs. The AMPs produced in keratinocytes are delivered to the skin surface in the lamellar bodies, and their appearance on the skin surface is closely tied to the production of normal skin stratum corneum lipids (see Chapter 47). These small proteins have as a characteristic physical property: the presence of an amphipathic organization, with one portion being cationic and capable of binding to microbial membranes, and another being hydrophobic allowing for insertion into the bacterial lipid membrane. The insertion into the membrane results in membrane disruption and microbial death. The second principle of AMPs is that they are processed after release by enzymes on the skin surface, resulting in multiple peptides each with different activities and different targets. The third principle of AMPs is that they not only kill microbes directly, but they are also potent activators of the host immune response. There are dozens of AMPs with activity on the human skin.12 The two major AMPs studied to date on the skin are (1) the cathelicidins (LL-37) and (2) the defensins. The marked decrease of these molecules on the inflamed skin of patients with atopic dermatitis may be related to the susceptibility of atopic patients to infections with S. aureus, herpes simplex virus, and vaccinia virus.13 T-helper 2 cytokines specifically suppress the production of these AMPs, a possible explanation for why psoriatic skin has normal or elevated AMP content and is less susceptible to bacterial and viral infections.14
Specific Features of Host Inflammatory Response to Cutaneous Infection
The adaptive immune system, which requires the development of targeted cells and antibodies, is highly effective in protecting humans from infection once the effector cells and antibodies have been produced. However, this takes days, and bacteria replicate and invade in hours. The discovery of the “innate” immune system explains the ability of organisms to mount an effective and targeted immune response to microbes before the adaptive immune system comes into play (see Chapter 10). The innate immune system is present in plants, invertebrates, and vertebrates. This system relies on a series of pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPS) that are not present on “self”.15 Binding of the PRRs to the PAMPs results in opsonization and activation of the complement system as well as induction of inflammatory signaling pathways. This process involves at least three PRRs1: (1) the AMPs discussed in Antimicrobial Peptides,2 (2) Toll-like receptors (TLRs), and3 (3) the complement system. These three systems engage bacteria once they enter the skin and, by intercommunication and by signaling neutrophils and other immune cells, are vital in bringing to the site of infection the cells required to destroy the pathogen.
TLRs are a repertoire of pattern recognition receptors (see Chapter 10).16 They occur on cell membranes and recognize certain exogenous ligands that are unique to invading microorganisms and not found in the host. They play a prominent role as primary sensors for invading pathogens. For instance, TLR2 recognizes the peptidoglycan on the surface of Gram-positive bacteria, TLR4 recognizes the lipopolysaccharide on Gram-negative bacteria, and TLR5 recognizes flagellin, unique to flagellated bacteria. These structural elements of the invading organism are essential for its pathogenicity and therefore are hard to eliminate on an evolutionary basis. The TLRs not only engage the invader, but they also orchestrate what type of immune response is generated for that specific pathogen. TLRs do this by instructing antigen-presenting cells that have engaged the organism to secrete appropriate cytokines to generate the desired immunologic milieu and eventual adaptive immune response (see Chapter 10). Alternative downstream signaling pathways can result in different immune responses from engagement of the identical TLRs.
Complement (see Chapter 37) is activated when mannin-binding lectin binds to carbohydrate patterns on bacteria and activates C2 and C4.17 Activation of C3 liberates C3a and C3b. C3b on membranes leads to opsonization and enhanced phagocytosis. In addition, the cleavage of C5 leads to C5a, a potent activator of neutrophils and a stimulator of proinflammatory cytokines, including interleukin 1 (IL-1) and IL-8. The “membrane attack complex” is formed by completion of the complement cascade and kills invading microbes. Not surprisingly, complement components also modulate the immune system, and alter TLR stimulation of some activation pathways. Through an extensive repertoire of outcome options, the human host has the ability to develop an organism-specific response to a wide variety of infectious agents that the host has not previously encountered. In addition, the innate immune system through complement and TLR orchestrates the adaptive immune system to appropriately respond to the invading microbe. This elaborate innate immune response explains the variety of rather distinctive clinical responses to various bacterial infections that have been described. The infectious agent, the anatomic site of the infection, and the attendant inflammatory response pattern create the clinical lesion.
Pathogenicity of the Microorganism
To effectively invade a host, the microbe must initially gain access. S. aureus uses teichoic acid and other surface proteins that promote adherence to the nasal mucosa. The bacteria are then available to contaminate any breaches in the skin, binding to fibronectin in wounds. The disease-producing capacity of bacteria is termed virulence. The genetic material encoding virulence factors and toxins are carried on mobile genetic elements called pathogenicity islands. Bacteriophages carry genetic elements from one bacterium to the next (Panton–Valentine leukocidin for example). Panton–Valentine leukocidin is a cytotoxin directed against human immune cells. It is associated with deep-seated and more inflammatory furunculosis, and now has been correlated with methicillin resistant S. aureus (MRSA). Importantly, up to 37% of patients with purulent CA-MRSA infections are colonized at another anatomical location with the organism.18 In addition, many bacterial species contain DNA elements within their own genome that specifically are designed to escape, inactivate, or suppress the host's innate immune response, especially by resisting killing by neutrophils and excreted products. These gene products that respond to the host's immune attack are usually composed of a two-protein interaction cascade involving a sensor and a response protein. This is called a two-component gene regulatory system. In the case of S. aureus, numerous specific substances target each element of the innate immune attack by the host. Staphylokinase (SAK) inactivates defensins. Aureolysin A cleaves LL-37. The oatA gene encodes a membrane protein that imparts lysozyme resistance. S. aureus is catalase positive, and the yellow pigment of S. aureus (carotenoids) protects it from oxidative killing by neutrophils. SAK also activates plasminogen to plasmin. Surface plasmin cleaves C3b and immunoglobulin G, removing important opsonin molecules from the bacterial surface. Chemotaxis inhibitory protein of S. aureus binds to C5a blocking neutrophil activation. Staphylococcal complement inhibitor binds to C3 convertase on the bacterial surface preventing it from cleaving C3 and activating the complement cascade. SAKS, chemotaxis inhibitory protein of S. aureus, and staphylococcal complement inhibitor are carried on the same pathogenicity islands.19–22
Although it is useful to distinguish between disease caused by toxins and those caused by direct invasion and virulence factors, most bacterial infections result from the combination of the invasive and toxigenic properties of the organism. Examples in which locally secreted toxins are instrumental in creating the characteristic lesions are infections with S. aureus (bullous impetigo), Corynebacterium diphtheriae, and Bacillus anthracis (see Chapter 177). Systemic manifestations of toxin secretion are seen in staphylococcal scalded skin syndrome and tetanus. In the case of Clostridium perfringens, elaboration of a variety of extracellular toxins and enzymes (α-toxin or lecithinase, proteases, collagenases) appears to play an important role in the rapidly spreading skin lesions and the systemic manifestations of clostridial myonecrosis (see Chapter 179). S. pyogenes, specifically GAS, also contains numerous genes that help it evade the innate immune system. These include those within the genome, such as the M protein, which prevents phagocytosis by neutrophils, and those transmitted on prophages such as exotoxin A. The production of DNase SdaD2 protects GAS from extracellular killing by neutrophils in neutrophil extracellular traps and is important in skin infections. Tissue invasion and systemic spread are enhanced by streptokinase. GAS streptokinase is active only against human plasminogen, which may be critical in restricting GAS infection to humans. The proclivity of streptococcus to share the genetic material containing these virulence factors across strains has blurred the restrictions of streptococcal types to certain disease patterns. Now, for instance, in some regions, group G streptococcus is a major cause of pharyngitis and contains the same virulence genes that gave GAS the ability to cause this condition.23,24
Gram-negative bacteria (Escherichia coli, S. typhi, N. meningitidis, Neisseria gonorrhoeae, Brucella melitensis, and others) contain endotoxin, or complex phospholipid-polysaccharide macromolecules (LPS), as an integral part of the bacterial cell envelope (see Chapter 180). Endotoxins, unlike exotoxins, are released only upon breakdown of the bacterial cell. Their toxicity appears to be linked principally to the lipid fraction, whereas their antigenic determinants reside with the polysaccharide component. Much is now known of the mechanisms by which LPS exerts its biologic effects in systemic infections due to Gram-negative bacteria or in major localized infections that may also be capable of producing the sepsis syndrome. The effects are both toxic and immunologic. The two cytokines most important in the toxic and proinflammatory effects of LPS are produced by LPS-activated macrophages: (1) tumor necrosis factor (TNF-α) and (2) IL-1. TNF-α initiates a proinflammatory cytokine cascade (see Chapter 11). TNF-α activates the coagulation system through its effects on vascular endothelium, and decreases blood pressure and tissue perfusion by reducing myocardial contractility and by relaxing smooth muscle. High circulating levels of TNF-α are demonstrable in patients with meningococcemia and other forms of severe sepsis.25 Infusion of high concentrations of purified TNF-α alone can produce shock and death. The ability of LPS, through TNF-α production, to induce leukocyte adherence to capillary endothelium and to induce fibrin deposition has been suggested as the basis for development of the hemorrhagic necrotic skin lesions (with or without direct bacterial invasion) that sometimes occur during the course of Gram-negative bacteremias and particularly in meningococcemia. Purpura fulminans develops in 10%–20% of cases of marked meningococcal sepsis, and severe cases may develop thrombosis of large vessels with infarction of digits (see Chapters 144 and 180).
Changing Patterns of Bacterial Infections of the Skin
Three factors have resulted in an increase in the prevalence and virulence of bacterial infections. First, new pathogens such as Bartonella spp. that were not previously known to cause human disease were discovered (see Chapter 182). Second, bacteria themselves have become more difficult to treat via the acquisition of virulence factors and antibiotic resistance. Third, there is an ever increasing number of immunocompromised patients due to increasing numbers of the elderly and debilitated, the human immunodeficiency virus-infected, and the iatrogenically immunosuppressed. In addition to the usual pathogens, a variety of “nonpathogenic” members of the cutaneous microbiome are capable of producing disease in debilitated patients and in individuals with altered humoral or cellular defenses. For example, ecthyma gangrenosum due to local or systemic destructive invasion of the skin by Pseudomonas aeruginosa is seen virtually always in the setting of neutropenia (see Chapter 179). In the immunocompetent host, a transient and self-healing folliculitis (“hot-tub folliculitis) is caused by the same organism. Bartonella henselae causes cat-scratch disease, a self-healing disorder in the immunocompetent host (see Chapter 182). In patients with advanced AIDS (CD4 <50), B. henselae leads to bacillary angiomatosis and systemic involvement that is fatal without treatment (see Chapters 182 and 198).
Influence of Hypersensitivity to Bacterial Antigens on Inflammatory Reaction in Skin
The ability of bacteria to induce immunologic events on the part of the host explains certain syndromes. The flares of atopic dermatitis induced by S. aureus may be due to shifts in cytokine profile in the lesions induced by the bacterial infection. Similarly, streptococcal infection of the pharynx can induce an immunologic response that triggers guttate psoriasis via activation of the immune system.
Neutrophilic Conditions as a Cutaneous Response to Systemic Infection
Inflammatory changes in and about small blood vessels in the skin may occur in a variety of bacteremic infections in the absence of obvious localization of bacteria at these sites. The papular and petechial lesions of chronic meningococcemia, and at times in disseminated gonococcal infection (see Chapters 180 and 205), and the development of leukocytoclastic vasculitis following adequate treatment of endocarditis (probably induced by circulating immune complexes) are examples. The lesions of Sweet syndrome (see Chapter 32) and early erythema nodosum (see Chapter 70) can have prominent tissue neutrophilia, even though the initiating infection (e.g., streptococcal pharyngitis) is distant. The Osler nodes and petechiae of subacute bacterial endocarditis, caused by viridans streptococci, probably provide the best examples of this association of small-vessel vasculitis with bacteremia (see Chapter 181). Histologically, these lesions are more suggestive of vasculitis than of emboli. The occasional development of such lesions in profusion, localized to the lower extremities, supports the concept of cutaneous vascular inflammation rather than embolization.