Chapter 175. General Considerations of Bacterial Diseases

The microbes that live on or in the human body are collectively referred to as the human microbiome. Some microbes of the human microbiome cause disease and others do not (commensals). The skin microbiome is a complex and diverse population of organisms that includes many bacteria, both commensals and pathogenic. The Human Microbiome Project includes recent work using metagenomic sequencing that describes the skin microbiome in previously inconceivable detail. The effects of multiple factors, including sebum secretion, body location, lipid content, pH, and sweat production significantly influence the growth of bacteria on the skin.1 The effects of skin diseases such as psoriasis also dictate the composition of the skin microbiome.2 It is clear there are many more bacteria normally living on our skin than previously imagined. Understanding the factors that contribute to healthy skin and skin disease will lead to improved treatment and prevention of skin infections and perhaps many noninfectious skin diseases.

The relationship of bacteria and the skin may be considered in four major categories1: (1) primary skin infections,2 (2) secondary infection of a primary skin disease (e.g., infected atopic dermatitis),3 (3) the skin lesions as manifestations of primary infection in some other organ system, usually the blood, and4 (4) reactive skin conditions resulting from bacterial infection elsewhere (e.g., erythema nodosum due to streptococcal pharyngitis). Thus, the balance of host immunity and the growth of the skin bacteria determine the disease state of the skin. Controlling a disease state, like atopic dermatitis, clearly reduces the number of skin infections that arise in the broken skin barrier. Conversely, controlling skin infections with dilute bleach baths and mupirocin ointment can lead to decreased atopic dermatitis flare as well.3

When considering the patient, it is important to remember that not all skin infections are suppurative but may present as reactive responses (e.g., erythema nodosum). Equally important, not all suppurative skin problems are primary skin infections (e.g., hidradenitis suppurativa). Notably, many erythematous skin lesions are not infectious at all (e.g., stasis dermatitis). The importance of the skin as a mirror of systemic infection cannot be overemphasized, especially when classic clinical findings are distorted as in immunocompromised patients. The timely recognition of the cutaneous clues of bacteremia may prevent the rapid spread of life-threatening infections due to organisms such as Pseudomonas aeruginosa, Vibrio vulnificus, Salmonella typhi, Staphylococcus aureus, and Neisseria meningitidis.

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.

Portal of Entry

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

Antimicrobial Peptides

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.

The discovery of specific bacteria as the cause of skin infections has led, in most cases, to classification of skin diseases based on the pathogenic bacteria rather than by morphology. In many cases, however, the infectious agent will be identified by culture, and the results not known for at least 1 day. In addition, impetigo (see Chapter 176), cellulitis, and necrotizing fasciitis (see Chapter 179) are three examples where multiple pathogens are capable of causing the same clinical pattern and require treatment decision based on the most likely pathogens. Therefore, morphologic classification of skin lesions is still important and can guide initial diagnostic testing and empiric antibiotic treatment. To this end, the classification of skin findings caused by bacterial infections as1 primary infections (pyodermas),2 secondary infections,3 cutaneous manifestations of systemic bacterial disease, and4 reactive conditions resulting from distant infection, seems warranted. Primary bacterial infections are produced by the invasion of ostensibly normal skin by a single species of pathogenic bacteria. In such infections, there is usually no doubt as to the primary etiologic role of the specific agent in the pathogenesis of the lesion. Treatment aimed at the bacterial pathogen almost universally results in cure of the lesion. Impetigo, erysipelas, and furunculosis (see Chapter 176) are familiar examples of primary cutaneous infections. In contrast, secondary infections develop in areas of already damaged skin. Although the bacteria present did not produce the underlying skin disorder, their proliferation and subsequent invasion of surrounding areas may aggravate and prolong the disease. Such secondary infection may occur when the integrity of the skin has been broken, or the local immune milieu is altered by the primary skin condition, allowing infection by bacteria. In contrast to the primary infections, the secondary infections at times show a mixture of organisms on culture, and not infrequently, it is impossible to determine which, if any, play the major role. It is important to know in which conditions recovery of a bacterial pathogen is important, and in which it is less predictable of response to antibiotic treatment. In flares of atopic dermatitis (see Chapter 14), decreasing the numbers of S. aureus on the skin surface with antibiotics is often associated with improvement of the dermatitis. In contrast, even experts in the field disagree on the significance of culturing bacterial “pathogens” from chronic leg ulcers. In the case of secondary infections, the morphology of the primary skin disease may be minimally altered, and the presence of an exacerbating bacterial pathogen may only be suspected by poor response to treatment or an otherwise unexplained flare of the condition.

Direct Examination of Aspirates and Biopsies

Identification of bacteria from skin lesions may provide important information as to the cause of cutaneous infections. Although not practical in many settings, examination of a Gram-stained smear of material from a suspected skin infection can guide decisions on early antibiotic therapy before a cultural diagnosis is made. For these reasons, bacteriologic investigation is an important part of the initial evaluation of patients with skin lesions and includes1 appropriate sampling,2 interpretation of Gram-stained smears, and3 use of selective growth media for culturing.

Gram staining provides a very rapid method of examining a sample for number and type of bacteria, as well as for the character of the inflammatory exudate in sterile pustules. Obtaining an appropriate specimen for microscopic study and culture requires care to avoid contamination. Bacterial cultures from cellulitis and erysipelas are generally unrewarding. Aspirates or biopsies from the advancing edge of cellulitis yielded positive cultures in an average of 16% of patients.26 Although not routinely performed, findings on needle aspiration, when positive, can provide an immediate useful guide to therapy. If sterile saline is injected into a lesion for diagnostic culture, solutions without bacteriostatic additives should be employed. In circumstances in which no data are available from needle aspiration, a surgical biopsy may yield information that is life saving. In the bioterrorism-associated outbreak of anthrax infections in the United States, rapid specific diagnosis of cutaneous disease was accomplished by punch biopsy of an erythematous, indurated plaque and tissue Gram stain demonstrated Gram-positive rods, confirmed as B. anthracis by immunohistochemical analysis (see Chapter 183).27 Local lesions of the skin and subcutaneous tissues in immunocompromised patients should always be biopsied if aspiration fails to define a pathogen. Encouraging results have been reported in patients with suspected necrotizing fasciitis (see Chapter 179) who had biopsies done to confirm the diagnosis early in the course of this devastating infection.28

Other Diagnostic Procedures

Fluorescent Antibody

The practical use of this procedure in bacterial diseases of the skin is currently of limited applicability. Spirochetes can be demonstrated (by the direct or indirect techniques) in chancres, (see Chapter 200). N. gonorrhoeae, Actinomyces israelii, Legionella sp., Francisella tularensis, B. anthracis, and Y. pestis have been identified by this rapid direct fluorescent antibody staining method. Its greatest use is in the specific diagnosis of uncommon but serious infections.29

Other Immunologic Methods

A variety of serologic tests may be helpful in the diagnosis of bacterial infections of the skin. These tests are particularly important in conditions where the cutaneous manifestations are secondary to systemic disease (e.g., “rose spots” of typhoid fever). Bartonella infections are routinely diagnosed in this manner.

Polymerase Chain Reaction

Polymerase chain reaction (PCR) technology can be applied to diagnosis of material obtained on skin punch biopsy of lesional tissue or aspirates from a vesiculobullous lesion just as it has been used in diagnosis of infection in body fluids (cerebrospinal fluid, pleural fluid, blood). Appropriate precautions to exclude contamination during the acquisition of the specimen must be taken. The use of this procedure is most helpful when one particular rare bacterial species is being considered, and appropriate primers are available. Such was the case in a patient with a cutaneous lesion during the bioterrorism-induced anthrax outbreak.25,29

(See Chapter 230)

The selection of the appropriate antibiotic should be made initially on the basis of the appearance of the skin lesion, the characteristics of any systemic illness, and a Gram-stained smear of material from a lesion, if available. Culture results and susceptibility testing of the isolated pathogen(s) are usually available within 24–48 hours. Additional epidemiologic factors (current hospitalization or residence in a nursing home, recent antibiotic use, neutropenia, and immune status) should be considered in the choice of initial antimicrobial therapy. Also, it is important to make the choice based on the latest data from the local area and from frequently updated sources in view of the rapidly changing patterns of antimicrobial resistance of various bacterial species. The use of computerized decision support, infectious disease reference systems, best-practice guidelines, or pharmacologic databases should be considered when choosing empiric therapy for bacterial infections.

Dosage: Methods of Administration—Excretion

Primary cutaneous infections of mild to moderate severity can be treated with local measures, topical drugs, oral antibiotics, or by a combination of these methods. Extensive infections of the skin, with or without systemic manifestations, should be vigorously treated with parenteral antibiotics in adequate dosages. In the immunocompromised host, parenteral treatment of cutaneous infections is virtually always recommended.

A number of factors must be considered in administering antibiotics: oral treatment may be limited by absorption and gastrointestinal disturbances; hypotension and extensive skin disease can prohibit the intramuscular route; and the proper drug selected may be suitable for administration only by a specific route. The metabolism profile of a given antibiotic should always be considered to avoid underdosing or toxic accumulation in the face of specific organ malfunction (e.g., hepatic or renal impairment).

Toxicity

The toxicity of antibiotics should be considered on an individual basis but some problems are applicable to all antibiotics. Hypersensitivity reactions are relatively common and can include skin rashes, fever, or more severe manifestations such as acute anaphylaxis or exfoliative erythrodermas. The penicillins and sulfonamides are particularly likely to produce these problems. Questions regarding previous drug allergy should be asked whenever any antibiotic is to be administered. All antibiotics can alter the indigenous flora, especially broad-spectrum agents such as the cephalosporins. Gastrointestinal disturbances and oral mucous membrane lesions are the major problems encountered with alteration of the flora. There are numerous other potential drug reactions (renal, hematologic, hepatic, nervous system) to antibiotics that may represent acceptable risks if the reasons for use of these drugs are compelling. It is the physician's responsibility to be aware of the usual and unusual manifestations of toxicity of any of the antibiotics used and to be alert to possible novel effects in individual patients. The use of electronic medical records with physician alerting systems will help improve these potential negative outcomes.

Antibiotic Resistance

Transferable resistance to multiple antibiotics has emerged as a widespread problem. The mechanisms of acquired resistance can occur in several ways.30 Foreign DNA containing an antibiotic resistance gene can be transferred by (a) horizontal gene transfer into a recipient by several paths; (b) cell-to-cell conjugation; (c) transformation by naked DNA plasmid or linear fragments released by dead cells; or (d) phage-mediated transduction. Antimicrobial resistance can also arise by de novo mutation. Efforts should be made to minimize the overuse of antibiotics and to use agents with the narrowest spectrum of antimicrobial coverage when appropriate.

Topical Antibacterial Agents

(See Chapter 218)

Topical antibacterial agents are frequently used to prevent, as well as to suppress, bacterial growth in open lesions and surgical wounds. In the case of sutured dermatologic wounds, topical antibiotics are often no better than petrolatum and have limited effect in reducing wound infections.31 Additionally, topical neomycin and bacitracin commonly precipitate contact dermatitis and should be avoided. Contact dermatitis is especially common when these topical antibiotics are applied to venous insufficiency leg ulcers.

Among the most useful topical antibacterial agents are acetic acid (1%–5% for Pseudomonas nail and toe web infections, gentamicin (0.17% cream) may be useful in selected patients when mixed Gram-negative bacteria require local suppression (e.g., Erosio interdigitalis blastomycetica) and mupirocin (2% cream or ointment) with antibacterial activity against various streptococci and S. aureus. A number of broad-spectrum antiseptics are also available for topical use. Povidone-iodine (Betadine) is effective against most Gram-positive and Gram-negative bacteria but does not persist in the skin to provide a residual action. Chlorhexidine gluconate (4% solution) combines broad antibacterial properties with prolonged action. An alcoholic preparation is especially effective, is not appreciably absorbed into the blood, and generally is not irritating to the skin. These broad-spectrum antiseptics can be used prophylactically or to treat local wounds and superficially infected dermatoses.

The author thanks Timothy G. Berger, MD, for his excellent work on this chapter in the previous edition.