Chapter 21

Learning Objectives

• Describe the major anatomical features of the skin and eyes

• Compare and contrast the microbiomes of various body sites, such as the hands, back, feet, and eyes

• Explain how microorganisms overcome defenses of skin and eyes in order to cause infection

• Describe general signs and symptoms of disease associated with infections of the skin and eyes

Human skin is an important part of the innate immune system. In addition to serving a wide range of other functions, the skin serves as an important barrier to microbial invasion. Not only is it a physical barrier to penetration of deeper tissues by potential pathogens, but it also provides an inhospitable environment for the growth of many pathogens. In this section, we will provide a brief overview of the anatomy and normal microbiota of the skin and eyes, along with general symptoms associated with skin and eye infections.

Layers of the Skin

Human skin is made up of several layers and sublayers. The two main layers are the epidermis and the dermis. These layers cover a third layer of tissue called the hypodermis, which consists of fibrous and adipose connective tissue (Figure 21.2).

The epidermis is the outermost layer of the skin, and it is relatively thin. The exterior surface of the epidermis, called the stratum corneum, primarily consists of dead skin cells. This layer of dead cells limits direct contact between the outside world and live cells. The stratum corneum is rich in keratin, a tough, fibrous protein that is also found in hair and nails. Keratin helps make the outer surface of the skin relatively tough and waterproof. It also helps to keep the surface of the skin dry, which reduces microbial growth. However, some microbes are still able to live on the surface of the skin, and some of these can be shed with dead skin cells in the process of desquamation, which is the shedding and peeling of skin that occurs as a normal process but that may be accelerated when infection is present.

Beneath the epidermis lies a thicker skin layer called the dermis. The dermis contains connective tissue and embedded structures such as blood vessels, nerves, and muscles. Structures called hair follicles (from which hair grows) are located within the dermis, even though much of their structure consists of epidermal tissue. The dermis also contains the two major types of glands found in human skin: sweat glands (tubular glands that produce sweat) and sebaceous glands (which are associated with hair follicles and produce sebum, a lipid-rich substance containing proteins and minerals).

Perspiration (sweat) provides some moisture to the epidermis, which can increase the potential for microbial growth. For this reason, more microbes are found on the regions of the skin that produce the most sweat, such as the skin of the underarms and groin. However, in addition to water, sweat also contains substances that inhibit microbial growth, such as salts, lysozyme, and antimicrobial peptides. Sebum also serves to protect the skin and reduce water loss. Although some of the lipids and fatty acids in sebum inhibit microbial growth, sebum contains compounds that provide nutrition for certain microbes.

Figure 21.2 (a) A micrograph of a section through human skin shows the epidermis and dermis. (b) The major layers of human skin are the epidermis, dermis, and hypodermis. (credit b: modification of work by National Cancer Institute)

• How does desquamation help with preventing infections?

Normal Microbiota of the Skin

The skin is home to a wide variety of normal microbiota, consisting of commensal organisms that derive nutrition from skin cells and secretions such as sweat and sebum. The normal microbiota of skin tends to inhibit transient- microbe colonization by producing antimicrobial substances and outcompeting other microbes that land on the surface of the skin. This helps to protect the skin from pathogenic infection.

The skin’s properties differ from one region of the body to another, as does the composition of the skin’s microbiota. The availability of nutrients and moisture partly dictates which microorganisms will thrive in a particular region of the skin. Relatively moist skin, such as that of the nares (nostrils) and underarms, has a much different microbiota than the dryer skin on the arms, legs, hands, and top of the feet. Some areas of the skin have higher densities of sebaceous glands. These sebum-rich areas, which include the back, the folds at the side of the nose, and the back of the neck, harbor distinct microbial communities that are less diverse than those found on other parts of the body.

Different types of bacteria dominate the dry, moist, and sebum-rich regions of the skin. The most abundant microbes typically found in the dry and sebaceous regions are Betaproteobacteria and Propionibacteria, respectively. In the moist regions, Corynebacterium and Staphylococcus are most commonly found (Figure 21.3). Viruses and fungi are also found on the skin, with Malassezia being the most common type of fungus found as part of the normal microbiota. The role and populations of viruses in the microbiota, known as viromes, are still not well understood, and there are limitations to the techniques used to identify them. However, Circoviridae, Papillomaviridae, and Polyomaviridae appear to be the most common residents in the healthy skin virome.^[1][2][3]

Figure 21.3 The normal microbiota varies on different regions of the skin, especially in dry versus moist areas. The figure shows the major organisms commonly found in different locations of a healthy individual’s skin and external mucosa. Note that there is significant variation among individuals. (credit: modification of work by National Human Genome Research Institute)

• What are the four most common bacteria that are part of the normal skin microbiota?

1. Belkaid, Y., and J.A. Segre. “Dialogue Between Skin Microbiota and Immunity,” Science 346 (2014) 6212:954–959.

2. Foulongne, Vincent, et al. “Human Skin Microbiota: High Diversity of DNA Viruses Identified on the Human Skin by High Throughput Sequencing.” PLoS ONE (2012) 7(6): e38499. doi: 10.1371/journal.pone.0038499.

3. Robinson, C.M., and J.K. Pfeiffer. “Viruses and the Microbiota.” Annual Review of Virology (2014) 1:55–59. doi: 10.1146/annurev- virology-031413-085550.

Infections of the Skin

While the microbiota of the skin can play a protective role, it can also cause harm in certain cases. Often, an opportunistic pathogen residing in the skin microbiota of one individual may be transmitted to another individual more susceptible to an infection. For example, methicillin-resistant Staphylococcus aureus (MRSA) can often take up residence in the nares of health care workers and hospital patients; though harmless on intact, healthy skin, MRSA can cause infections if introduced into other parts of the body, as might occur during surgery or via a post-surgical incision or wound. This is one reason why clean surgical sites are so important.

Injury or damage to the skin can allow microbes to enter deeper tissues, where nutrients are more abundant and the environment is more conducive to bacterial growth. Wound infections are common after a puncture or laceration that damages the physical barrier of the skin. Microbes may infect structures in the dermis, such as hair follicles and glands, causing a localized infection, or they may reach the bloodstream, which can lead to a systemic infection.

In some cases, infectious microbes can cause a variety of rashes or lesions that differ in their physical characteristics. These rashes can be the result of inflammation reactions or direct responses to toxins produced by the microbes. Table 21.1 lists some of the medical terminology used to describe skin lesions and rashes based on their characteristics; Figure 21.4 and Figure 21.5 illustrate some of the various types of skin lesions. It is important to note that many different diseases can lead to skin conditions of very similar appearance; thus the terms used in the table are generally not exclusive to a particular type of infection or disease.

Some Medical Terms Associated with Skin Lesions and Rashes

Table 21.1

Figure 21.4 (a) Acne is a bacterial infection of the skin that manifests as a rash of inflamed hair follicles (folliculitis). The large whitehead near the center of the cheek is an infected hair follicle that has become purulent (or suppurative), leading to the formation of a furuncle. (b) An abscess is a pus-filled lesion. (credit b: modification of work by Bruce Blaus)

Figure 21.5 Numerous causes can lead to skin lesions of various types, some of which are very similar in appearance. (credit: modification of work by Bruce Blaus)

• How can asymptomatic health care workers transmit bacteria such as MRSA to patients?

Anatomy and Microbiota of the Eye

Although the eye and skin have distinct anatomy, they are both in direct contact with the external environment. An important component of the eye is the nasolacrimal drainage system, which serves as a conduit for the fluid of the eye, called tears. Tears flow from the external eye to the nasal cavity by the lacrimal apparatus, which is composed of

the structures involved in tear production (Figure 21.6). The lacrimal gland, above the eye, secretes tears to keep the eye moist. There are two small openings, one on the inside edge of the upper eyelid and one on the inside edge of the lower eyelid, near the nose. Each of these openings is called a lacrimal punctum. Together, these lacrimal puncta collect tears from the eye that are then conveyed through lacrimal ducts to a reservoir for tears called the lacrimal sac, also known as the dacrocyst or tear sac.

From the sac, tear fluid flows via a nasolacrimal duct to the inner nose. Each nasolacrimal duct is located underneath the skin and passes through the bones of the face into the nose. Chemicals in tears, such as defensins, lactoferrin, and lysozyme, help to prevent colonization by pathogens. In addition, mucins facilitate removal of microbes from the surface of the eye.

Figure 21.6 The lacrimal apparatus includes the structures of the eye associated with tear production and drainage. (credit: modification of work by “Evidence Based Medical Educator Inc.”/YouTube)

The surfaces of the eyeball and inner eyelid are mucous membranes called conjunctiva. The normal conjunctival microbiota has not been well characterized, but does exist. One small study (part of the Ocular Microbiome project) found twelve genera that were consistently present in the conjunctiva.^[4] These microbes are thought to help defend the membranes against pathogens. However, it is still unclear which microbes may be transient and which may form a stable microbiota.^[5]

Use of contact lenses can cause changes in the normal microbiota of the conjunctiva by introducing another surface into the natural anatomy of the eye. Research is currently underway to better understand how contact lenses may impact the normal microbiota and contribute to eye disease.

The watery material inside of the eyeball is called the vitreous humor. Unlike the conjunctiva, it is protected from contact with the environment and is almost always sterile, with no normal microbiota ( Figure 21.7).

4. Abelson, M.B., Lane, K., and Slocum, C.. “The Secrets of Ocular Microbiomes.” Review of Ophthalmology June 8, 2015. http://www.reviewofophthalmology.com/content/t/ocular_disease/c/55178. Accessed Sept 14, 2016.

5. Shaikh-Lesko, R. “Visualizing the Ocular Microbiome.” The Scientist May 12, 2014. http://www.the-scientist.com/?articles.view/ articleNo/39945/title/Visualizing-the-Ocular-Microbiome. Accessed Sept 14, 2016.

Figure 21.7 Some microbes live on the conjunctiva of the human eye, but the vitreous humor is sterile.

Infections of the Eye

The conjunctiva is a frequent site of infection of the eye; like other mucous membranes, it is also a common portal of entry for pathogens. Inflammation of the conjunctiva is called conjunctivitis, although it is commonly known as pinkeye because of the pink appearance in the eye. Infections of deeper structures, beneath the cornea, are less common (Figure 21.8). Conjunctivitis occurs in multiple forms. It may be acute or chronic. Acute purulent conjunctivitis is associated with pus formation, while acute hemorrhagic conjunctivitis is associated with bleeding in the conjunctiva. The term blepharitis refers to an inflammation of the eyelids, while keratitis refers to an inflammation of the cornea (Figure 21.8); keratoconjunctivitis is an inflammation of both the cornea and the conjunctiva, and dacryocystitis is an inflammation of the lacrimal sac that can often occur when a nasolacrimal duct is blocked.

Figure 21.8 (a) Conjunctivitis is inflammation of the conjunctiva. (b) Blepharitis is inflammation of the eyelids. (c) Keratitis is inflammation of the cornea. (credit a: modification of work by Lopez-Prats MJ, Sanz Marco E, Hidalgo- Mora JJ, Garcia-Delpech S, Diaz-Llopis M; credit b, c: modification of work by Centers for Disease Control and Prevention)

Infections leading to conjunctivitis, blepharitis, keratoconjunctivitis, or dacryocystitis may be caused by bacteria or viruses, but allergens, pollutants, or chemicals can also irritate the eye and cause inflammation of various structures. Viral infection is a more likely cause of conjunctivitis in cases with symptoms such as fever and watery discharge that occurs with upper respiratory infection and itchy eyes. Table 21.2 summarizes some common forms of conjunctivitis and blepharitis.

Types of Conjunctivities and Blepharitis

Table 21.2

• How does the lacrimal apparatus help to prevent eye infections?

Learning Objectives

• Identify the most common bacterial pathogens that cause infections of the skin and eyes

• Compare the major characteristics of specific bacterial diseases affecting the skin and eyes

Despite the skin’s protective functions, infections are common. Gram-positive Staphylococcus spp. and Streptococcus spp. are responsible for many of the most common skin infections. However, many skin conditions are not strictly associated with a single pathogen. Opportunistic pathogens of many types may infect skin wounds, and individual cases with identical symptoms may result from different pathogens or combinations of pathogens.

In this section, we will examine some of the most important bacterial infections of the skin and eyes and discuss how biofilms can contribute to and exacerbate such infections. Key features of bacterial skin and eye infections are also summarized in the Disease Profile boxes throughout this section.

Staphylococcal Infections of the Skin

Staphylococcus species are commonly found on the skin, with S. epidermidis and S. hominis being prevalent in the normal microbiota. S. aureus is also commonly found in the nasal passages and on healthy skin, but pathogenic strains are often the cause of a broad range of infections of the skin and other body systems.

S. aureus is quite contagious. It is spread easily through skin-to-skin contact, and because many people are chronic nasal carriers (asymptomatic individuals who carry S. aureus in their nares), the bacteria can easily be transferred from the nose to the hands and then to fomites or other individuals. Because it is so contagious, S. aureus is prevalent in most community settings. This prevalence is particularly problematic in hospitals, where antibiotic- resistant strains of the bacteria may be present, and where immunocompromised patients may be more susceptible to infection. Resistant strains include methicillin-resistant S. aureus (MRSA), which can be acquired through health- care settings (hospital-acquired MRSA, or HA-MRSA) or in the community (community-acquired MRSA, or CA- MRSA). Hospital patients often arrive at health-care facilities already colonized with antibiotic-resistant strains of S. aureus that can be transferred to health-care providers and other patients. Some hospitals have attempted to detect these individuals in order to institute prophylactic measures, but they have had mixed success (see Eye on Ethics: Screening Patients for MRSA).

When a staphylococcal infection develops, choice of medication is important. As discussed above, many staphylococci (such as MRSA) are resistant to some or many antibiotics. Thus, antibiotic sensitivity is measured to identify the most suitable antibiotic. However, even before receiving the results of sensitivity analysis, suspected S. aureus infections are often initially treated with drugs known to be effective against MRSA, such as trimethoprim- sulfamethoxazole (TMP/SMZ), clindamycin, a tetracycline (doxycycline or minocycline), or linezolid.

The pathogenicity of staphylococcal infections is often enhanced by characteristic chemicals secreted by some strains. Staphylococcal virulence factors include hemolysins called staphylolysins, which are cytotoxic for many types of cells, including skin cells and white blood cells. Virulent strains of S. aureus are also coagulase-positive, meaning they produce coagulase, a plasma-clotting protein that is involved in abscess formation. They may also produce leukocidins, which kill white blood cells and can contribute to the production of pus and Protein A, which inhibits phagocytosis by binding to the constant region of antibodies. Some virulent strains of S. aureus also produce other toxins, such as toxic shock syndrome toxin-1 (see Virulence Factors of Bacterial and Viral Pathogens).

To confirm the causative agent of a suspected staphylococcal skin infection, samples from the wound are cultured. Under the microscope, gram-positive Staphylococcus species have cellular arrangements that form grapelike clusters; when grown on blood agar, colonies have a unique pigmentation ranging from opaque white to cream. A catalase test is used to distinguish Staphylococcus from Streptococcus, which is also a genus of gram-positive cocci and a common cause of skin infections. Staphylococcus species are catalase-positive while Streptococcus species are catalase-negative.

Other tests are performed on samples from the wound in order to distinguish coagulase-positive species of Staphylococcus (CoPS) such as S. aureus from common coagulase-negative species (CoNS) such as S. epidermidis. Although CoNS are less likely than CoPS to cause human disease, they can cause infections when they enter the body, as can sometimes occur via catheters, indwelling medical devices, and wounds. Passive agglutination testing can be used to distinguish CoPS from CoNS. If the sample is coagulase-positive, the sample is generally presumed to contain S. aureus. Additional genetic testing would be necessary to identify the particular strain of S. aureus.

Another way to distinguish CoPS from CoNS is by culturing the sample on mannitol salt agar (MSA). Staphylococcus species readily grow on this medium because they are tolerant of the high concentration of sodium chloride (7.5% NaCl). However, CoPS such as S. aureus ferment mannitol (which will be evident on a MSA plate), whereas CoNS such as S. epidermidis do not ferment mannitol but can be distinguished by the fermentation of other sugars such as lactose, malonate, and raffinose (Figure 21.9).

Figure 21.9 (a) A mannitol salt agar plate is used to distinguish different species of staphylococci. In this plate, S. aureus is on the left and S. epidermidis is in the right. Because S. aureus is capable of fermenting mannitol, it produces acids that cause the color to change to yellow. (b) This scanning electron micrograph shows the characteristic grapelike clusters of S. aureus. (credit a: modification of work by “ScienceProfOnline”/YouTube; credit b: modification of work by Centers for Disease Control and Prevention)

Eye on Ethics

Streptococcal Infections of the Skin

Streptococcus are gram-positive cocci with a microscopic morphology that resembles chains of bacteria. Colonies are typically small (1–2 mm in diameter), translucent, entire edge, with a slightly raised elevation that can be either nonhemolytic, alpha-hemolytic, or beta-hemolytic when grown on blood agar (Figure 21.13). Additionally, they are facultative anaerobes that are catalase-negative.

Figure 21.13 Streptococcus pyogenes forms chains of cocci. (credit: modification of work by Centers for Disease Control and Prevention)

The genus Streptococcus includes important pathogens that are categorized in serological Lancefield groups based on the distinguishing characteristics of their surface carbohydrates. The most clinically important streptococcal species in humans is S. pyogenes, also known as group A streptococcus (GAS). S. pyogenes produces a variety of extracellular enzymes, including streptolysins O and S, hyaluronidase, and streptokinase. These enzymes can aid in transmission and contribute to the inflammatory response.^[6] S. pyogenes also produces a capsule and M protein, a streptococcal cell wall protein. These virulence factors help the bacteria to avoid phagocytosis while provoking a substantial immune response that contributes to symptoms associated with streptococcal infections.

S. pyogenes causes a wide variety of diseases not only in the skin, but in other organ systems as well. Examples of diseases elsewhere in the body include pharyngitis and scarlet fever, which will be covered in later chapters.

6. Starr, C.R. and Engelberg N.C. “Role of Hyaluronidase in Subcutaneous Spread and Growth of Group A Streptococcus.” Infection and Immunity 2006(7:1): 40–48. doi: 10.1128/IAI.74.1.40-48.2006.

Acne

One of the most ubiquitous skin conditions is acne. Acne afflicts nearly 80% of teenagers and young adults, but it can be found in individuals of all ages. Higher incidence among adolescents is due to hormonal changes that can result in overproduction of sebum.

Acne occurs when hair follicles become clogged by shed skin cells and sebum, causing non-inflammatory lesions called comedones. Comedones (singular “comedo”) can take the form of whitehead and blackhead pimples. Whiteheads are covered by skin, whereas blackhead pimples are not; the black color occurs when lipids in the clogged follicle become exposed to the air and oxidize (Figure 21.18).

Figure 21.18 (a) Acne is characterized by whitehead and blackhead comedones that result from clogged hair follicles. (b) Blackheads, visible as black spots on the skin, have a dark appearance due to the oxidation of lipids in sebum via exposure to the air. (credit a: modification of work by Bruce Blaus)

Often comedones lead to infection by Propionibacterium acnes, a gram-positive, non-spore-forming, aerotolerant anaerobic bacillus found on skin that consumes components of sebum. P. acnes secretes enzymes that damage the hair follicle, causing inflammatory lesions that may include papules, pustules, nodules, or pseudocysts, depending on their size and severity.

Treatment of acne depends on the severity of the case. There are multiple ways to grade acne severity, but three levels are usually considered based on the number of comedones, the number of inflammatory lesions, and the types of lesions. Mild acne is treated with topical agents that may include salicylic acid (which helps to remove old skin cells) or retinoids (which have multiple mechanisms, including the reduction of inflammation). Moderate acne may be treated with antibiotics (erythromycin, clindamycin), acne creams (e.g., benzoyl peroxide), and hormones. Severe acne may require treatment using strong medications such as isotretinoin (a retinoid that reduces oil buildup, among other effects, but that also has serious side effects such as photosensitivity). Other treatments, such as phototherapy and laser therapy to kill bacteria and possibly reduce oil production, are also sometimes used.

• What is the role of Propionibacterium acnes in causing acne?

Anthrax

The zoonotic disease anthrax is caused by Bacillus anthracis, a gram-positive, endospore-forming, facultative anaerobe. Anthrax mainly affects animals such as sheep, goats, cattle, and deer, but can be found in humans as well. Sometimes called wool sorter’s disease, it is often transmitted to humans through contact with infected animals or animal products, such as wool or hides. However, exposure to B. anthracis can occur by other means, as the endospores are widespread in soils and can survive for long periods of time, sometimes for hundreds of years.

The vast majority of anthrax cases (95–99%) occur when anthrax endospores enter the body through abrasions of the skin.^[8] This form of the disease is called cutaneous anthrax. It is characterized by the formation of a nodule on the skin; the cells within the nodule die, forming a black eschar, a mass of dead skin tissue (Figure 21.19). The localized infection can eventually lead to bacteremia and septicemia. If untreated, cutaneous anthrax can cause death in 20% of patients.^[9] Once in the skin tissues, B. anthracis endospores germinate and produce a capsule, which prevents the bacteria from being phagocytized, and two binary exotoxins that cause edema and tissue damage. The first of the two exotoxins consists of a combination of protective antigen (PA) and an enzymatic lethal factor (LF), forming lethal toxin (LeTX). The second consists of protective antigen (PA) and an edema factor (EF), forming edema toxin (EdTX).

8. Shadomy, S.V., Traxler, R.M., and Marston, C.K. “Infectious Diseases Related to Travel: Anthrax” 2015. Centers for Disease Control and Prevention. http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/anthrax. Accessed Sept 14, 2016.

9. US FDA. “Anthrax.” 2015. http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ucm061751.htm. Accessed Sept 14, 2016.

Figure 21.19 (a) Cutaneous anthrax is an infection of the skin by B. anthracis, which produces tissue-damaging exotoxins. Dead tissues accumulating in this nodule have produced a small black eschar. (b) Colonies of B. anthracis grown on sheep’s blood agar. (credit a, b: modification of work by Centers for Disease Control and Prevention)

Less commonly, anthrax infections can be initiated through other portals of entry such as the digestive tract (gastrointestinal anthrax) or respiratory tract (pulmonary anthrax or inhalation anthrax). Typically, cases of noncutaneous anthrax are more difficult to treat than the cutaneous form. The mortality rate for gastrointestinal anthrax can be up to 40%, even with treatment. Inhalation anthrax, which occurs when anthrax spores are inhaled, initially causes influenza-like symptoms, but mortality rates are approximately 45% in treated individuals and 85% in those not treated. A relatively new form of the disease, injection anthrax, has been reported in Europe in intravenous drug users; it occurs when drugs are contaminated with B. anthracis. Patients with injection anthrax show signs and symptoms of severe soft tissue infection that differ clinically from cutaneous anthrax. This often delays diagnosis and treatment, and leads to a high mortality rate.^[10]

B. anthracis colonies on blood agar have a rough texture and serrated edges that eventually form an undulating band (Figure 21.19). Broad spectrum antibiotics such as penicillin, erythromycin, and tetracycline are often effective treatments.

Unfortunately, B. anthracis has been used as a biological weapon and remains on the United Nations’ list of potential agents of bioterrorism.^[11] Over a period of several months in 2001, a number of letters were mailed to members of the news media and the United States Congress. As a result, 11 individuals developed cutaneous anthrax and another 11 developed inhalation anthrax. Those infected included recipients of the letters, postal workers, and two other individuals. Five of those infected with pulmonary anthrax died. The anthrax spores had been carefully prepared to aerosolize, showing that the perpetrator had a high level of expertise in microbiology.^[12]

A vaccine is available to protect individuals from anthrax. However, unlike most routine vaccines, the current anthrax vaccine is unique in both its formulation and the protocols dictating who receives it.^[13] The vaccine is administered through five intramuscular injections over a period of 18 months, followed by annual boosters. The US Food and Drug Administration (FDA) has only approved administration of the vaccine prior to exposure for at-risk adults, such as individuals who work with anthrax in a laboratory, some individuals who handle animals or animal products (e.g., some veterinarians), and some members of the United States military. The vaccine protects against cutaneous and

10. Berger, T., Kassirer, M., and Aran, A.A.. “Injectional Anthrax—New Presentation of an Old Disease.” Euro Surveillance 19 (2014) 32. http://www.ncbi.nlm.nih.gov/pubmed/25139073. Accessed Sept 14, 2016.

11. United Nations Office at Geneva. “What Are Biological and Toxin Weapons?” http://www.unog.ch/ 80256EE600585943/%28httpPages%29/29B727532FECBE96C12571860035A6DB?. Accessed Sept 14, 2016.

12. Federal Bureau of Investigation. “Famous Cases and Criminals: Amerithrax or Anthrax Investigation.” https://www.fbi.gov/history/ famous-cases/amerithrax-or-anthrax-investigation. Accessed Sept 14, 2016.

13. Centers for Disease Control and Prevention. “Anthrax: Medical Care: Prevention: Antibiotics.” http://www.cdc.gov/anthrax/medical- care/prevention.html. Accessed Sept 14, 2016.

inhalation anthrax using cell-free filtrates of microaerophilic cultures of an avirulent, nonencapsulated strain of B. anthracis.^[14] The FDA has not approved the vaccine for routine use after exposure to anthrax, but if there were ever an anthrax emergency in the United States, patients could be given anthrax vaccine after exposure to help prevent disease.

• What is the characteristic feature of a cutaneous anthrax infection?

14. Emergent Biosolutions. AVA (BioThrax) vaccine package insert (Draft). Nov 2015. http://www.fda.gov/downloads/ biologicsbloodvaccines/bloodbloodproducts/approvedproducts/licensedproductsblas/ucm074923.pdf.

Figure 21.20

Bacterial Conjunctivitis

Like the skin, the surface of the eye comes in contact with the outside world and is somewhat prone to infection by bacteria in the environment. Bacterial conjunctivitis (pinkeye) is a condition characterized by inflammation of the conjunctiva, often accompanied by a discharge of sticky fluid (described as acute purulent conjunctivitis) (Figure 21.21). Conjunctivitis can affect one eye or both, and it usually does not affect vision permanently. Bacterial conjunctivitis is most commonly caused by Haemophilus influenzae, but can also be caused by other species such as Moraxella catarrhalis, S. pneumoniae, and S. aureus. The causative agent may be identified using bacterial cultures, Gram stain, and diagnostic biochemical, antigenic, or nucleic acid profile tests of the isolated pathogen. Bacterial conjunctivitis is very contagious, being transmitted via secretions from infected individuals, but it is also self-limiting.

Bacterial conjunctivitis usually resolves in a few days, but topical antibiotics are sometimes prescribed. Because this condition is so contagious, medical attention is recommended whenever it is suspected. Individuals who use contact lenses should discontinue their use when conjunctivitis is suspected. Certain symptoms, such as blurred vision, eye pain, and light sensitivity, can be associated with serious conditions and require medical attention.

Figure 21.21 Acute, purulent, bacterial conjunctivitis causes swelling and redness in the conjunctiva, the membrane lining the whites of the eyes and the inner eyelids. It is often accompanied by a yellow, green, or white discharge, which can dry and become encrusted on the eyelashes. (credit: “Tanalai”/Wikimedia Commons)

Trachoma

Trachoma, or granular conjunctivitis, is a common cause of preventable blindness that is rare in the United States but widespread in developing countries, especially in Africa and Asia. The condition is caused by the same species that causes neonatal inclusion conjunctivitis in infants, Chlamydia trachomatis. C. trachomatis can be transmitted easily through fomites such as contaminated towels, bed linens, and clothing and also by direct contact with infected individuals. C. trachomatis can also be spread by flies that transfer infected mucous containing C. trachomatis from one human to another.

Infection by C. trachomatis causes chronic conjunctivitis, which leads to the formation of necrotic follicles and scarring in the upper eyelid. The scars turn the eyelashes inward (a condition known as trichiasis) and mechanical abrasion of the cornea leads to blindness (Figure 21.23). Antibiotics such as azithromycin are effective in treating trachoma, and outcomes are good when the disease is treated promptly. In areas where this disease is common, large public health efforts are focused on reducing transmission by teaching people how to avoid the risks of the infection.

Figure 21.23 (a) If trachoma is not treated early with antibiotics, scarring on the eyelid can lead to trichiasis, a condition in which the eyelashes turn inward. (b) Trichiasis leads to blindness if not corrected by surgery, as shown here. (credit b: modification of work by Otis Historical Archives National Museum of Health & Medicine)

• Why is trachoma rare in the United States?

Bacterial Keratitis

Keratitis can have many causes, but bacterial keratitis is most frequently caused by Staphylococcus epidermidis and/ or Pseudomonas aeruginosa. Contact lens users are particularly at risk for such an infection because S. epidermidis and P. aeruginosa both adhere well to the surface of the lenses. Risk of infection can be greatly reduced by proper care of contact lenses and avoiding wearing lenses overnight. Because the infection can quickly lead to blindness, prompt and aggressive treatment with antibiotics is important. The causative agent may be identified using bacterial cultures, Gram stain, and diagnostic biochemical, antigenic, or nucleic acid profile tests of the isolated pathogen.

• Why are contact lens wearers at greater risk for developing keratitis?

Biofilms and Infections of the Skin and Eyes

When treating bacterial infections of the skin and eyes, it is important to consider that few such infections can be attributed to a single pathogen. While biofilms may develop in other parts of the body, they are especially relevant to skin infections (such as those caused by S. aureus or P. aeruginosa) because of their prevalence in chronic skin wounds. Biofilms develop when bacteria (and sometimes fungi) attach to a surface and produce extracellular polymeric substances (EPS) in which cells of multiple organisms may be embedded. When a biofilm develops on a wound, it may interfere with the natural healing process as well as diagnosis and treatment.

Because biofilms vary in composition and are difficult to replicate in the lab, they are still not thoroughly understood. The extracellular matrix of a biofilm consists of polymers such as polysaccharides, extracellular DNA, proteins, and lipids, but the exact makeup varies. The organisms living within the extracellular matrix may include familiar pathogens as well as other bacteria that do not grow well in cultures (such as numerous obligate anaerobes). This presents challenges when culturing samples from infections that involve a biofilm. Because only some species grow in vitro, the culture may contain only a subset of the bacterial species involved in the infection.

Biofilms confer many advantages to the resident bacteria. For example, biofilms can facilitate attachment to surfaces on or in the host organism (such as wounds), inhibit phagocytosis, prevent the invasion of neutrophils, and sequester host antibodies. Additionally, biofilms can provide a level of antibiotic resistance not found in the isolated cells and colonies that are typical of laboratory cultures. The extracellular matrix provides a physical barrier to antibiotics, shielding the target cells from exposure. Moreover, cells within a biofilm may differentiate to create subpopulations of dormant cells called persister cells. Nutrient limitations deep within a biofilm add another level of resistance, as stress responses can slow metabolism and increase drug resistance.

Learning Objectives

• Identify the most common viruses associated with infections of the skin and eyes

• Compare the major characteristics of specific viral diseases affecting the skin and eyes

Until recently, it was thought that the normal microbiota of the body consisted primarily of bacteria and some fungi. However, in addition to bacteria, the skin is colonized by viruses, and recent studies suggest that Papillomaviridae, Polyomaviridae and Circoviridae also contribute to the normal skin microbiota. However, some viruses associated with skin are pathogenic, and these viruses can cause diseases with a wide variety of presentations.

Numerous types of viral infections cause rashes or lesions on the skin; however, in many cases these skin conditions result from infections that originate in other body systems. In this chapter, we will limit the discussion to viral skin

infections that use the skin as a portal of entry. Later chapters will discuss viral infections such as chickenpox, measles, and rubella—diseases that cause skin rashes but invade the body through portals of entry other than the skin.

Papillomas

Papillomas (warts) are the expression of common skin infections by human papillomavirus (HPV) and are transmitted by direct contact. There are many types of HPV, and they lead to a variety of different presentations, such as common warts, plantar warts, flat warts, and filiform warts. HPV can also cause sexually-transmitted genital warts, which will be discussed in Urogenital System Infections. Vaccination is available for some strains of HPV.

Common warts tend to develop on fingers, the backs of hands, and around nails in areas with broken skin. In contrast, plantar warts (also called foot warts) develop on the sole of the foot and can grow inwards, causing pain and pressure during walking. Flat warts can develop anywhere on the body, are often numerous, and are relatively smooth and small compared with other wart types. Filiform warts are long, threadlike warts that grow quickly.

In some cases, the immune system may be strong enough to prevent warts from forming or to eradicate established warts. However, treatment of established warts is typically required. There are many available treatments for warts, and their effectiveness varies. Common warts can be frozen off with liquid nitrogen. Topical applications of salicylic acid may also be effective. Other options are electrosurgery (burning), curettage (cutting), excision, painting with cantharidin (which causes the wart to die so it can more easily be removed), laser treatments, treatment with bleomycin, chemical peels, and immunotherapy (Figure 21.25).

Figure 21.25 Warts can vary in shape and in location. (a) Multiple plantar warts have grown on this toe. (b) A filiform wart has grown on this eyelid.

Oral Herpes

Another common skin virus is herpes simplex virus (HSV). HSV has historically been divided into two types, HSV-1 and HSV-2. HSV-1 is typically transmitted by direct oral contact between individuals, and is usually associated with oral herpes. HSV-2 is usually transmitted sexually and is typically associated with genital herpes. However, both HSV-1 and HSV-2 are capable of infecting any mucous membrane, and the incidence of genital HSV-1 and oral HSV-2 infections has been increasing in recent years. In this chapter, we will limit our discussion to infections caused by HSV-1; HSV-2 and genital herpes will be discussed in Urogenital System Infections.

Infection by HSV-1 commonly manifests as cold sores or fever blisters, usually on or around the lips (Figure 21.26). HSV-1 is highly contagious, with some studies suggesting that up to 65% of the US population is infected; however, many infected individuals are asymptomatic.^[15] Moreover, the virus can be latent for long periods, residing in the trigeminal nerve ganglia between recurring bouts of symptoms. Recurrence can be triggered by stress or

environmental conditions (systemic or affecting the skin). When lesions are present, they may blister, break open, and crust. The virus can be spread through direct contact, even when a patient is asymptomatic.

While the lips, mouth, and face are the most common sites for HSV-1 infections, lesions can spread to other areas of the body. Wrestlers and other athletes involved in contact sports may develop lesions on the neck, shoulders, and trunk. This condition is often called herpes gladiatorum. Herpes lesions that develop on the fingers are often called herpetic whitlow.

HSV-1 infections are commonly diagnosed from their appearance, although laboratory testing can confirm the diagnosis. There is no cure, but antiviral medications such as acyclovir, penciclovir, famciclovir, and valacyclovir are used to reduce symptoms and risk of transmission. Topical medications, such as creams with n-docosanol and penciclovir, can also be used to reduce symptoms such as itching, burning, and tingling.

Figure 21.26 This cold sore was caused by HSV-1. (credit: Centers for Disease Control and Prevention)

• What are the most common sites for the appearance of herpetic lesions?

Roseola and Fifth Disease

The viral diseases roseola and fifth disease are somewhat similar in terms of their presentation, but they are caused by different viruses. Roseola, sometimes called roseola infantum or exanthem subitum (“sudden rash”), is a mild viral infection usually caused by human herpesvirus-6 (HHV-6) and occasionally by HHV-7. It is spread via direct contact with the saliva or respiratory secretions of an infected individual, often through droplet aerosols. Roseola is very common in children, with symptoms including a runny nose, a sore throat, and a cough, along with (or followed by) a high fever (39.4 ºC). About three to five days after the fever subsides, a rash may begin to appear on the chest and abdomen. The rash, which does not cause discomfort, initially forms characteristic macules that are flat or papules that are firm and slightly raised; some macules or papules may be surrounded by a white ring. The rash may eventually spread to the neck and arms, and sometimes continues to spread to the face and legs. The diagnosis is generally made based upon observation of the symptoms. However, it is possible to perform serological tests to confirm the diagnosis. While treatment may be recommended to control the fever, the disease usually resolves without treatment within a week after the fever develops. For individuals at particular risk, such as those who are immunocompromised, the antiviral medication ganciclovir may be used.

Fifth disease (also known as erythema infectiosum) is another common, highly contagious illness that causes a distinct rash that is critical to diagnosis. Fifth disease is caused by parvovirus B19, and is transmitted by contact

15. Wald, A., and Corey, L. “Persistence in the Population: Epidemiology, Transmission.” In: A. Arvin, G. Campadelli-Fiume, E. Mocarski et al. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press, 2007. http://www.ncbi.nlm.nih.gov/books/NBK47447/. Accessed Sept 14, 2016.

with respiratory secretions from an infected individual. Infection is more common in children than adults. While approximately 20% of individuals will be asymptomatic during infection,^[16] others will exhibit cold-like symptoms (headache, fever, and upset stomach) during the early stages when the illness is most infectious. Several days later, a distinct red facial rash appears, often called “slapped cheek” rash (Figure 21.27). Within a few days, a second rash may appear on the arms, legs, chest, back, or buttocks. The rash may come and go for several weeks, but usually disappears within seven to twenty-one days, gradually becoming lacy in appearance as it recedes.

In children, the disease usually resolves on its own without medical treatment beyond symptom relief as needed. Adults may experience different and possibly more serious symptoms. Many adults with fifth disease do not develop any rash, but may experience joint pain and swelling that lasts several weeks or months. Immunocompromised individuals can develop severe anemia and may need blood transfusions or immune globulin injections. While the rash is the most important component of diagnosis (especially in children), the symptoms of fifth disease are not always consistent. Serological testing can be conducted for confirmation.

Figure 21.27 (a) Roseola, a mild viral infection common in young children, generally begins with symptoms similar to a cold, followed by a pink, patchy rash that starts on the trunk and spreads outward. (b) Fifth disease exhibits similar symptoms in children, except for the distinctive “slapped cheek” rash that originates on the face.

• Identify at least one similarity and one difference between roseola and fifth disease.

Viral Conjunctivitis

Like bacterial conjunctivitis viral infections of the eye can cause inflammation of the conjunctiva and discharge from the eye. However, viral conjunctivitis tends to produce a discharge that is more watery than the thick discharge associated with bacterial conjunctivitis. The infection is contagious and can easily spread from one eye to the other or to other individuals through contact with eye discharge.

16. Centers for Disease Control and Prevention. “Fifth Disease.” http://www.cdc.gov/parvovirusb19/fifth-disease.html. Accessed Sept 14, 2016.

Viral conjunctivitis is commonly associated with colds caused by adenoviruses; however, other viruses can also cause conjunctivitis. If the causative agent is uncertain, eye discharge can be tested to aid in diagnosis. Antibiotic treatment of viral conjunctivitis is ineffective, and symptoms usually resolve without treatment within a week or two.

Learning Objectives

• Identify the most common fungal pathogens associated with cutaneous and subcutaneous mycoses

• Compare the major characteristics of specific fungal diseases affecting the skin

Many fungal infections of the skin involve fungi that are found in the normal skin microbiota. Some of these fungi can cause infection when they gain entry through a wound; others mainly cause opportunistic infections in immunocompromised patients. Other fungal pathogens primarily cause infection in unusually moist environments that promote fungal growth; for example, sweaty shoes, communal showers, and locker rooms provide excellent breeding grounds that promote the growth and transmission of fungal pathogens.

Fungal infections, also called mycoses, can be divided into classes based on their invasiveness. Mycoses that cause superficial infections of the epidermis, hair, and nails, are called cutaneous mycoses. Mycoses that penetrate the epidermis and the dermis to infect deeper tissues are called subcutaneous mycoses. Mycoses that spread throughout the body are called systemic mycoses.

Tineas

A group of cutaneous mycoses called tineas are caused by dermatophytes, fungal molds that require keratin, a protein found in skin, hair, and nails, for growth. There are three genera of dermatophytes, all of which can cause cutaneous mycoses: Trichophyton, Epidermophyton, and Microsporum. Tineas on most areas of the body are generally called ringworm, but tineas in specific locations may have distinctive names and symptoms (see Table

3. and Figure 21.29). Keep in mind that these names—even though they are Latinized—refer to locations on the body, not causative organisms. Tineas can be caused by different dermatophytes in most areas of the body.

Some Common Tineas and Location on the Body

Table 21.3

Figure 21.29 Tineas are superficial cutaneous mycoses and are common. (a) Tinea barbae (barber’s itch) occurs on the lower face. (b) Tinea pedis (athlete’s foot) occurs on the feet, causing itching, burning, and dry, cracked skin between the toes. (c) A close-up view of tinea corporis (ringworm) caused by Trichophyton mentagrophytes. (credit a, c: modification of work by Centers for Disease Control and Prevention; credit b: modification of work by Al Hasan M, Fitzgerald SM, Saoudian M, Krishnaswamy G)

Dermatophytes are commonly found in the environment and in soils and are frequently transferred to the skin via contact with other humans and animals. Fungal spores can also spread on hair. Many dermatophytes grow well in moist, dark environments. For example, tinea pedis (athlete’s foot) commonly spreads in public showers, and the causative fungi grow well in the dark, moist confines of sweaty shoes and socks. Likewise, tinea cruris (jock itch) often spreads in communal living environments and thrives in warm, moist undergarments.

Tineas on the body (tinea corporis) often produce lesions that grow radially and heal towards the center. This causes the formation of a red ring, leading to the misleading name of ringworm recall the Clinical Focus case in The Eukaryotes of Microbiology.

Several approaches may be used to diagnose tineas. A Wood’s lamp (also called a black lamp) with a wavelength of 365 nm is often used. When directed on a tinea, the ultraviolet light emitted from the Wood’s lamp causes the fungal elements (spores and hyphae) to fluoresce. Direct microscopic evaluation of specimens from skin scrapings, hair, or nails can also be used to detect fungi. Generally, these specimens are prepared in a wet mount using a potassium hydroxide solution (10%–20% aqueous KOH), which dissolves the keratin in hair, nails, and skin cells to

allow for visualization of the hyphae and fungal spores. The specimens may be grown on Sabouraud dextrose CC (chloramphenicol/cyclohexamide), a selective agar that supports dermatophyte growth while inhibiting the growth of bacteria and saprophytic fungi (Figure 21.30). Macroscopic colony morphology is often used to initially identify the genus of the dermatophyte; identification can be further confirmed by visualizing the microscopic morphology using either a slide culture or a sticky tape prep stained with lactophenol cotton blue.

Various antifungal treatments can be effective against tineas. Allylamine ointments that include terbinafine are commonly used; miconazole and clotrimazole are also available for topical treatment, and griseofulvin is used orally.

Figure 21.30 To diagnose tineas, the dermatophytes may be grown on a Sabouraud dextrose CC agar plate. This culture contains a strain of Trichophyton rubrum, one of the most common causes of tineas on various parts of the body. (credit: Centers for Disease Control and Prevention)

• Why are tineas, caused by fungal molds, often called ringworm?

Cutaneous Aspergillosis

Another cause of cutaneous mycoses is Aspergillus, a genus consisting of molds of many different species, some of which cause a condition called aspergillosis. Primary cutaneous aspergillosis, in which the infection begins in the skin, is rare but does occur. More common is secondary cutaneous aspergillosis, in which the infection begins in the respiratory system and disseminates systemically. Both primary and secondary cutaneous aspergillosis result in distinctive eschars that form at the site or sites of infection (Figure 21.31). Pulmonary aspergillosis will be discussed more thoroughly in Respiratory Mycoses).

Figure 21.31 (a) Eschar on a patient with secondary cutaneous aspergillosis. (b) Micrograph showing a conidiophore of Aspergillus. (credit a: modification of work by Santiago M, Martinez JH, Palermo C, Figueroa C, Torres O, Trinidad R, Gonzalez E, Miranda Mde L, Garcia M, Villamarzo G; credit b: modification of work by U.S. Department of Health and Human Services)

Primary cutaneous aspergillosis usually occurs at the site of an injury and is most often caused by Aspergillus fumigatus or Aspergillus flavus. It is usually reported in patients who have had an injury while working in an agricultural or outdoor environment. However, opportunistic infections can also occur in health-care settings, often at the site of intravenous catheters, venipuncture wounds, or in association with burns, surgical wounds, or occlusive dressing. After candidiasis, aspergillosis is the second most common hospital-acquired fungal infection and often occurs in immunocompromised patients, who are more vulnerable to opportunistic infections.

Cutaneous aspergillosis is diagnosed using patient history, culturing, histopathology using a skin biopsy. Treatment involves the use of antifungal medications such as voriconazole (preferred for invasive aspergillosis), itraconazole, and amphotericin B if itraconazole is not effective. For immunosuppressed individuals or burn patients, medication may be used and surgical or immunotherapy treatments may be needed.

• Identify the sources of infection for primary and secondary cutaneous aspergillosis.

Candidiasis of the Skin and Nails

Candida albicans and other yeasts in the genus Candida can cause skin infections referred to as cutaneous candidiasis. Candida spp. are sometimes responsible for intertrigo, a general term for a rash that occurs in a skin fold, or other localized rashes on the skin. Candida can also infect the nails, causing them to become yellow and harden (Figure 21.32).

Figure 21.32 (a) This red, itchy rash is the result of cutaneous candidiasis, an opportunistic infection of the skin caused by the yeast Candida albicans. (b) Fungal infections of the nail (tinea unguium) can be caused by dermatophytes or Candida spp. The nail becomes yellow, brittle, and prone to breaking. This condition is relatively common among adults. (c) C. albicans growing on Sabouraud dextrose agar. (credit a: modification of work by U.S. Department of Veterans Affairs; credit c: modification of work by Centers for Disease Control and Prevention)

Candidiasis of the skin and nails is diagnosed through clinical observation and through culture, Gram stain, and KOH wet mounts. Susceptibility testing for anti-fungal agents can also be done. Cutaneous candidiasis can be treated with topical or systemic azole antifungal medications. Because candidiasis can become invasive, patients suffering from HIV/AIDS, cancer, or other conditions that compromise the immune system may benefit from preventive treatment. Azoles, such as clotrimazole, econazole, fluconazole, ketoconazole, and miconazole; nystatin; terbinafine; and naftifine may be used for treatment. Long-term treatment with medications such as itraconazole or ketoconazole may be used for chronic infections. Repeat infections often occur, but this risk can be reduced by carefully following treatment recommendations, avoiding excessive moisture, maintaining good health, practicing good hygiene, and having appropriate clothing (including footwear).

Candida also causes infections in other parts of the body besides the skin. These include vaginal yeast infections (see Fungal Infections of the Reproductive System) and oral thrush (see Microbial Diseases of the Mouth and Oral Cavity).

• What are the signs and symptoms of candidiasis of the skin and nails?

Sporotrichosis

Whereas cutaneous mycoses are superficial, subcutaneous mycoses can spread from the skin to deeper tissues. In temperate regions, the most common subcutaneous mycosis is a condition called sporotrichosis, caused by the fungus Sporothrix schenkii and commonly known as rose gardener’s disease or rose thorn disease (recall Case in Point: Every Rose Has Its Thorn). Sporotrichosis is often contracted after working with soil, plants, or timber, as the fungus can gain entry through a small wound such as a thorn-prick or splinter. Sporotrichosis can generally be avoided by wearing gloves and protective clothing while gardening and promptly cleaning and disinfecting any wounds sustained during outdoor activities.

Sporothrix infections initially present as small ulcers in the skin, but the fungus can spread to the lymphatic system and sometimes beyond. When the infection spreads, nodules appear, become necrotic, and may ulcerate. As more lymph nodes become affected, abscesses and ulceration may develop over a larger area (often on one arm or hand). In severe cases, the infection may spread more widely throughout the body, although this is relatively uncommon.

Sporothrix infection can be diagnosed based upon histologic examination of the affected tissue. Its macroscopic morphology can be observed by culturing the mold on potato dextrose agar, and its microscopic morphology can be observed by staining a slide culture with lactophenol cotton blue. Treatment with itraconazole is generally recommended.

• Describe the progression of a Sporothrix schenkii infection.

Learning Objectives

• Identify two parasites that commonly cause infections of the skin and eyes

• Identify the major characteristics of specific parasitic diseases affecting the skin and eyes

Many parasitic protozoans and helminths use the skin or eyes as a portal of entry. Some may physically burrow into the skin or the mucosa of the eye; others breach the skin barrier by means of an insect bite. Still others take advantage of a wound to bypass the skin barrier and enter the body, much like other opportunistic pathogens. Although many parasites enter the body through the skin, in this chapter we will limit our discussion to those for which the skin or eyes are the primary site of infection. Parasites that enter through the skin but travel to a different site of infection will be covered in other chapters. In addition, we will limit our discussion to microscopic parasitic infections of the skin and eyes. Macroscopic parasites such as lice, scabies, mites, and ticks are beyond the scope of this text.

Acanthamoeba Infections

Acanthamoeba is a genus of free-living protozoan amoebae that are common in soils and unchlorinated bodies of fresh water. (This is one reason why some swimming pools are treated with chlorine.) The genus contains a few parasitic species, some of which can cause infections of the eyes, skin, and nervous system. Such infections can sometimes travel and affect other body systems. Skin infections may manifest as abscesses, ulcers, and nodules. When acanthamoebae infect the eye, causing inflammation of the cornea, the condition is called Acanthamoeba keratitis. Figure 21.34 illustrates the Acanthamoeba life cycle and various modes of infection.

While Acanthamoeba keratitis is initially mild, it can lead to severe corneal damage, vision impairment, or even blindness if left untreated. Similar to eye infections involving P. aeruginosa, Acanthamoeba poses a much greater risk to wearers of contact lenses because the amoeba can thrive in the space between contact lenses and the cornea. Prevention through proper contact lens care is important. Lenses should always be properly disinfected prior to use, and should never be worn while swimming or using a hot tub.

Acanthamoeba can also enter the body through other pathways, including skin wounds and the respiratory tract. It usually does not cause disease except in immunocompromised individuals; however, in rare cases, the infection can spread to the nervous system, resulting in a usually fatal condition called granulomatous amoebic encephalitis (GAE) (see Fungal and Parasitic Diseases of the Nervous System). Disseminated infections, lesions, and Acanthamoeba keratitis can be diagnosed by observing symptoms and examining patient samples under the microscope to view the parasite. Skin biopsies may be used.

Acanthamoeba keratitis is difficult to treat, and prompt treatment is necessary to prevent the condition from progressing. The condition generally requires three to four weeks of intensive treatment to resolve. Common treatments include topical antiseptics (e.g., polyhexamethylene biguanide, chlorhexidine, or both), sometimes with painkillers or corticosteroids (although the latter are controversial because they suppress the immune system, which can worsen the infection). Azoles are sometimes prescribed as well. Advanced cases of keratitis may require a corneal transplant to prevent blindness.

Figure 21.34 Acanthamoeba spp. are waterborne parasites very common in unchlorinated aqueous environments. As shown in this life cycle, Acanthamoeba cysts and trophozoites are both capable of entering the body through various routes, causing infections of the eye, skin, and central nervous system. (credit: modification of work by Centers for Disease Control and Prevention)

Figure 21.35 (a) An Acanthamoeba cyst. (b) An Acanthamoeba trophozoite (c) The eye of a patient with Acanthamoeba keratitis. The fluorescent color, which is due to sodium fluorescein application, highlights significant damage to the cornea and vascularization of the surrounding conjunctiva. (credit a: modification of work by Centers for Disease Control and Prevention; credit b, c: modification of work by Jacob Lorenzo-Morales, Naveed A Kahn and Julia Walochnik)

• How are Acanthamoeba infections acquired?

Loiasis

The helminth Loa loa, also known as the African eye worm, is a nematode that can cause loiasis, a disease endemic to West and Central Africa (Figure 21.36). The disease does not occur outside that region except when carried by travelers. There is evidence that individual genetic differences affect susceptibility to developing loiasis after infection by the Loa loa worm. Even in areas in which Loa loa worms are common, the disease is generally found in less than 30% of the population.^[17] It has been suggested that travelers who spend time in the region may be somewhat more susceptible to developing symptoms than the native population, and the presentation of infection may differ.^[18]

The parasite is spread by deerflies (genus Chrysops), which can ingest the larvae from an infected human via a blood meal (Figure 21.36). When the deerfly bites other humans, it deposits the larvae into their bloodstreams. After about five months in the human body, some larvae develop into adult worms, which can grow to several centimeters in length and live for years in the subcutaneous tissue of the host.

The name “eye worm” alludes to the visible migration of worms across the conjunctiva of the eye. Adult worms live in the subcutaneous tissues and can travel at about 1 cm per hour. They can often be observed when migrating through the eye, and sometimes under the skin; in fact, this is generally how the disease is diagnosed. It is also possible to test for antibodies, but the presence of antibodies does not necessarily indicate a current infection; it only means that the individual was exposed at some time. Some patients are asymptomatic, but in others the migrating worms can cause fever and areas of allergic inflammation known as Calabar swellings. Worms migrating through the conjunctiva can cause temporary eye pain and itching, but generally there is no lasting damage to the eye. Some patients experience a range of other symptoms, such as widespread itching, hives, and joint and muscle pain.

Worms can be surgically removed from the eye or the skin, but this treatment only relieves discomfort; it does not cure the infection, which involves many worms. The preferred treatment is diethylcarbamazine, but this medication produces severe side effects in some individuals, such as brain inflammation and possible death in patients with heavy infections. Albendazole is also sometimes used if diethylcarbamazine is not appropriate or not successful. If left untreated for many years, loiasis can damage the kidneys, heart, and lungs, though these symptoms are rare.

17. Garcia, A.. et al. “Genetic Epidemiology of Host Predisposition Microfilaraemia in Human Loiasis.” Tropical Medicine and International Health 4 (1999) 8:565–74. http://www.ncbi.nlm.nih.gov/pubmed/10499080. Accessed Sept 14, 2016.

18. Spinello, A., et al. “Imported Loa loa Filariasis: Three Cases and a Review of Cases Reported in Non-Endemic Countries in the Past 25 Years.” International Journal of Infectious Disease 16 (2012) 9: e649–e662. DOI: http://dx.doi.org/10.1016/j.ijid.2012.05.1023.

Figure 21.36 This Loa loa worm, measuring about 55 mm long, was extracted from the conjunctiva of a patient with loiasis. The Loa loa has a complex life cycle. Biting deerflies native to the rain forests of Central and West Africa transmit the larvae between humans. (credit a: modification of work by Eballe AO, Epée E, Koki G, Owono D, Mvogo

CE, Bella AL; credit b: modification of work by NIAID; credit c: modification of work by Centers for Disease Control and Prevention)

• Describe the most common way to diagnose loiasis.

Summary

1. Anatomy and Normal Microbiota of the Skin and Eyes

   • Human skin consists of two main layers, the epidermis and dermis, which are situated on top of the

hypodermis, a layer of connective tissue.

• The skin is an effective physical barrier against microbial invasion.

• The skin’s relatively dry environment and normal microbiota discourage colonization by transient microbes.

• The skin’s normal microbiota varies from one region of the body to another.

• The conjunctiva of the eye is a frequent site for microbial infection, but deeper eye infections are less common; multiple types of conjunctivitis exist.

2. Bacterial Infections of the Skin and Eyes

   • Staphylococcus and Streptococcus cause many different types of skin infections, many of which occur when bacteria breach the skin barrier through a cut or wound.

   • S. aureus are frequently associated with purulent skin infections that manifest as folliculitis, furuncles, or

carbuncles. S. aureus is also a leading cause of staphylococcal scalded skin syndrome (SSSS).

• S. aureus is generally drug resistant and current MRSA strains are resistant to a wide range of antibiotics.

• Community-acquired and hospital-acquired staphyloccocal infections are an ongoing problem because many people are asymptomatic carriers.

• Group A streptococci (GAS), S. pyogenes, is often responsible for cases of cellulitis, erysipelas, and

erythema nosodum. GAS are also one of many possible causes of necrotizing fasciitis.

• P. aeruginosa is often responsible for infections of the skin and eyes, including wound and burn infections,

hot tub rash, otitis externa, and bacterial keratitis.

• Acne is a common skin condition that can become more inflammatory when Propionibacterium acnes infects hair follicles and pores clogged with dead skin cells and sebum.

• Cutaneous anthrax occurs when Bacillus anthracis breaches the skin barrier. The infection results in a localized black eschar on skin. Anthrax can be fatal if B. anthracis spreads to the bloodstream.

• Common bacterial conjunctivitis is often caused by Haemophilus influenzae and usually resolves on its own in a few days. More serious forms of conjunctivitis include gonococcal ophthalmia neonatorum, inclusion conjunctivitis (chlamydial), and trachoma, all of which can lead to blindness if untreated.

• Keratitis is frequently caused by Staphylococcus epidermidis and/or Pseudomonas aeruginosa, especially among contact lens users, and can lead to blindness.

• Biofilms complicate the treatment of wound and eye infections because pathogens living in biofilms can be difficult to treat and eliminate.

3. Viral Infections of the Skin and Eyes

   • Papillomas (warts) are caused by human papillomaviruses.

   • Herpes simplex virus (especially HSV-1) mainly causes oral herpes, but lesions can appear on other areas of the skin and mucous membranes.

   • Roseola and fifth disease are common viral illnesses that cause skin rashes; roseola is caused by HHV-6 and HHV-7 while fifth disease is caused by parvovirus 19.

   • Viral conjunctivitis is often caused by adenoviruses and may be associated with the common cold. Herpes keratitis is caused by herpesviruses that spread to the eye.

4. Mycoses of the Skin

   • Mycoses can be cutaneous, subcutaneous, or systemic.

   • Common cutaneous mycoses include tineas caused by dermatophytes of the genera Trichophyton, Epidermophyton, and Microsporum. Tinea corporis is called ringworm. Tineas on other parts of the body have names associated with the affected body part.

   • Aspergillosis is a fungal disease caused by molds of the genus Aspergillus. Primary cutaneous aspergillosis enters through a break in the skin, such as the site of an injury or a surgical wound; it is a common hospital- acquired infection. In secondary cutaneous aspergillosis, the fungus enters via the respiratory system and disseminates systemically, manifesting in lesions on the skin.

   • The most common subcutaneous mycosis is sporotrichosis (rose gardener’s disease), caused by Sporothrix schenkii.

• Yeasts of the genus Candida can cause opportunistic infections of the skin called candidiasis, producing

intertrigo, localized rashes, or yellowing of the nails.

5. Protozoan and Helminthic Infections of the Skin and Eyes

   • The protozoan Acanthamoeba and the helminth Loa loa are two parasites that can breach the skin barrier, causing infections of the skin and eyes.

   • Acanthamoeba keratitis is a parasitic infection of the eye that often results from improper disinfection of contact lenses or swimming while wearing contact lenses.

   • Loiasis, or eye worm, is a disease endemic to Africa that is caused by parasitic worms that infect the subcutaneous tissue of the skin and eyes. It is transmitted by deerfly vectors.

Review Questions

Multiple Choice

1. glands produce a lipid-rich substance that contains proteins and minerals and protects the skin.

   1. Sweat

   2. Mammary

   3. Sebaceous

   4. Endocrine

2. Which layer of skin contains living cells, is vascularized, and lies directly above the hypodermis?

   5. the stratum corneum

   6. the dermis

   7. the epidermis

   8. the conjunctiva

3. Staphylococcus aureus is most often associated with being

   9. coagulase-positive.

   10. coagulase-negative.

   11. catalase-negative.

   12. gram-negative

4. M protein is produced by

   13. Pseudomonas aeruginosa

   14. Staphylococcus aureus

   15. Propionibacterium acnes

   16. Streptococcus pyogenes

5. is a major cause of preventable blindness that can be reduced through improved sanitation.

   17. Ophthalmia neonatorum

   18. Keratitis

   19. Trachoma

   20. Cutaneous anthrax

6. Which species is frequently associated with nosocomial infections transmitted via medical devices inserted into the body?

   21. Staphylococcus epidermidis

   22. Streptococcus pyogenes

   23. Proproniobacterium acnes

   24. Bacillus anthracis

7. Warts are caused by

   25. human papillomavirus.

   26. herpes simplex virus.

   27. adenoviruses.

   28. parvovirus B19.

8. Which of these viruses can spread to the eye to cause a form of keratitis?

   29. human papillomavirus

   30. herpes simplex virus 1

   31. parvovirus 19

   32. circoviruses

9. Cold sores are associated with:

   33. human papillomavirus

   34. roseola

   35. herpes simplex viruses

   36. human herpesvirus 6

10. Which disease is usually self-limiting but is most commonly treated with ganciclovir if medical treatment is needed?

    37. roseola

    38. oral herpes

    39. papillomas

    40. viral conjunctivitis

11. Adenoviruses can cause:

    41. viral conjunctivitis

    42. herpetic conjunctivitis

    43. papillomas

    44. oral herpes

12. is a superficial fungal infection found on the head.

    45. Tinea cruris

    46. Tinea capitis

    47. Tinea pedis

    48. Tinea corporis

13. For what purpose would a health-care professional use a Wood’s lamp for a suspected case of ringworm?

    49. to prevent the rash from spreading

    50. to kill the fungus

    51. to visualize the fungus

    52. to examine the fungus microscopically

14. Sabouraud dextrose agar CC is selective for:

    53. all fungi

    54. non-saprophytic fungi

    55. bacteria

    56. viruses

15. The first-line recommended treatment for sporotrichosis is:

    57. itraconazole

    58. clindamycin

    59. amphotericin

    60. nystatin

16. Which of the following is most likely to cause an

Acanthamoeba infection?

61. swimming in a lake while wearing contact lenses

62. being bitten by deerflies in Central Africa

63. living environments in a college dormitory with communal showers

64. participating in a contact sport such as wrestling

17. The parasitic Loa loa worm can cause great pain when it:

    65. moves through the bloodstream

    66. exits through the skin of the foot

    67. travels through the conjunctiva

    68. enters the digestive tract

18. A patient tests positive for Loa loa antibodies. What does this test indicate?

    69. The individual was exposed to Loa loa at some point.

    70. The individual is currently suffering from loiasis.

    71. The individual has never been exposed to Loa loa.

    72. The individual is immunosuppressed.

Fill in the Blank

20. The is the outermost layer of the epidermis.

19. 
    is commonly treated with a combination of chlorhexidine and polyhexamethylene biguanide.

    73. Acanthamoeba keratitis

    74. Sporotrichosis

    75. Candidiasis

    76. Loiasis

21. The mucous membrane that covers the surface of the eyeball and inner eyelid is called the .

22. A purulent wound produces .

23. Human herpesvirus 6 is the causative agent of .

24. The most common subcutaneous mycosis in temperate regions is .

25. Eye worm is another name for .

26. The is the part of the eye that is damaged due to Acanthamoeba keratitis.

Short Answer

27. What is the role of keratin in the skin?

28. What are two ways in which tears help to prevent microbial colonization?

29. Which label indicates a sweat gland?

Figure 21.38 (credit: modification of work by National Cancer Institute)

30. How are leukocidins associated with pus production?

31. What is a good first test to distinguish streptococcal infections from staphylococcal infections?

32. Compare and contrast bacterial and viral conjunctivitis.

33. What yeasts commonly cause opportunistic infections?

Critical Thinking

34. Explain why it is important to understand the normal microbiota of the skin.

35. Besides the presence or absence of ulceration, how do acute ulcerative and nonulcerative blepharitis differ?

36. What steps might you recommend to a patient for reducing the risk of developing a fungal infection of the toenails?

37. Why might a traveler to a region with Loa loa worm have a greater risk of serious infection compared with people who live in the region?

38. What preventative actions might you recommend to a patient traveling to a region where loiasis is endemic?