TABLE 1. Gram-Positive Cocci Genera

The backbone of a bacterial cell wall is peptidoglycan, which is composed of layers of polysaccharide chains that are linked by short peptides. The alternating sugars in the peptidoglycan are N-acetylmuramic acid and N-acetylglucosamine. The peptidoglycan has important biologic properties: it elicits the production of interleukin-1 from human monocytes, induces a local Swartzmann reaction, is capable of attracting polymorphonuclear neutrophils (PMNs), has endotoxin-like activity, activates complement, and elicits the production of opsonic antibodies.¹ The cell wall of gram-positive bacteria is very thick compared with the gramnegative peptidoglycan layer and consists of layer upon layer of molecules, accounting for 50% to 60% of the total dry weight of the cell wall. Much of the remaining cell wall material is a special polysaccharide called teichoic acid, which is interwoven in the peptidoglycan matrix permeating the cell wall and appearing on the surface of the organism. Some of the teichoic acids have a lipid attached (lipoteichoic acid), which is embedded in the cytoplasmic membrane. Different strains and species of gram-positive bacteria differ in teichoic acid structure and in surface proteins.

The cross-linking of polysaccharide chains by way of peptides results in a very rigid cell wall. The cell wall protects the organism from lysis under harsh osmotic conditions and aids in attachment of the bacteria to mucosal cell receptor sites. Many Staphylococcus aureus strains and other grampositive bacteria are coated with an external polysaccharide capsule that can be released during focal infection.²

Gram-positive cocci of ophthalmic importance are members of the genera Staphylococcus, Streptococcus, and Enterococcus. Because most infections are acute and associated with a chemoattraction for PMNs, the pathogenic cocci are often referred to as pyogenic cocci.

Members of the genus Staphylococcus occur singly, in pairs, or in grapelike clusters. They are nonmotile, are non-spore-forming, and are usually unencapsulated or have limited capsule formation. Most are facultative anaerobes with more rapid and abundant growth under aerobic conditions. They are among the hardiest non-spore-forming bacteria, and they can survive many nonphysiologic environmental conditions. Staphylococci are widespread in nature, with heavy concentration on the skin, skin glands, and mucous membranes. Staphylococci are ubiquitous human parasites, and their chief sources of infection include shedding human lesions, fomites contaminated from such lesions, and from the human respiratory tract and skin. Many neonates, and most children and adults, will become intermittently colonized by Staphylococcus aureus. Contact spread of infection has assumed added importance in hospitals, where a large proportion of the staff and patients carry antibiotic-resistant staphylococci in the nose or on the skin. Physicians, nurses, and hospital ward attendants may be nasopharyngeal carriers in a higher percentage of cases (50%, 70%, and 90%, respectively) than the general population (33%).⁴ Approximately 20% of adults are chronically colonized, and another 10% to 20% are transiently colonized at a given time. These rates are even higher for drug users and patients with chronic skin diseases or renal disease requiring hemodialysis.⁵ This carrier state can serve as a reservoir for the infection of hospitalized patients, although most carriers do not disseminate the organism and are not a risk to others. In hospitals, the areas at highest risk for severe staphylococci infections are the newborn nursery, intensive care units, operating rooms, and cancer chemotherapy wards.

The increased use of intravenous access devices and invasive procedures has been a factor in the changing spectrum of Staphylococcus aureus infections.⁶ Infection occurs when bacteria colonize the skin around the catheter entry site, propagate along the track of the catheter, and enter the vascular compartment. Attachment of Staphylococcus aureus to traumatized or disrupted skin, to foreign surfaces, and to endothelial structures involves interaction with at least five different proteins (fibrinogen, fibronectin, laminin, thrombospondin, and possibly collagen IV). Staphylococci species found most often as pathogens include Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus haemolyticus.

The coagulase-positive species, Staphylococcus aureus, is a significant opportunistic pathogen with major morbidity and mortality as a nosocomial organism.^7,8 All other human species are collectively referred to as the coagulase-negative staphylococci. The capsule is a cell wall surface structure that is well documented as a virulence factor for staphylococci. Certain strains of Staphylococcus aureus produce a polysaccharide capsule that helps to protect it from phagocytosis by PMNs. The mechanism by which the capsule mediates resistance to phagocytosis appears to involve interference with recognition of the opsonins that bind to the cell wall underneath the capsule by rendering the opsonins inaccessible for recognition by phagocytic cells. Staphylococcus aureus incorporates covalently into its outer peptidoglycan layer a protein with a molecular weight of 42,000 d, protein A, which binds to the Fc terminal of all human immunoglobulin G subclasses except IgG3. Protein A prevents antibody-mediated phagocytosis by PMNs. In the bloodstream, aggregates of IgG bound to protein A on staphylococcal surfaces will fix complement, causing complement-mediated tissue damage to the host.

The initial stage in infection is adherence to the host, which is accomplished by specific interaction of the staphylococcal adhesin (lipoteichoic acid) with the host epithelial cell receptor (fibronectin).⁵ Staphylococcus aureus produces a number of enzymes and toxins that, along with the invasive properties of the strain, contribute to its pathophysiology. The prototype of a staphylococcal lesion is a focal abscess with some of the disease patterns associated with toxin production. Staphylococcus aureus produces the enzymes catalase, coagulase, phosphatase, thermostable deoxyribonuclease and ribonuclease, lipase, gelatinase, protease, and fibrolysin (Table 2). Catalase production differentiates staphylococci from streptococci. Coagulase coats the surface of staphylococci with fibrin and may prevent phagocytosis. It also circumvents the normal plasma clotting cascade. Hyaluronidase may facilitate spread of infection through the tissues. The alpha, beta, gamma, and delta toxins act on red and white blood cell and platelet membranes of some species and on sphingomyelin, vascular smooth muscle, or other membranes. Many Staphylococcus aureus strains produce a leukocidin that increases the permeability of leukocytes to cations and subsequently leads to swelling and rounding up of the cells; the membranes of cytoplasmic granules fuse with the cytoplasmic membrane of the cell, causing release of the cytoplasmic granules and cell disruption. The rigid cell wall elicits production of interleukin-1 and opsonic antibodies by monocytes. It can be a chemoattractant for polymorphonuclear leukocytes, have an endotoxin-like activity, produce a localized Swartzmann phenomenon, and activate complement.

TABLE 2. Toxins and Enzymes of Gram-Positive Organisms

Lysozyme is secreted by some strains of staphylococci, primarily coagulase-positive strains. It has the ability to lyse certain bacteria by acting as a muramidase to cleave portions of the bacterial cell wall, especially micrococci. It may digest debris from cell walls of bacteria killed in other ways and thereby facilitate clearing of debris from clinical lesions.

Other important toxins of Staphylococcus aureus include enterotoxins, exfoliative toxins, and the toxins associated with toxic shock syndrome. These are all included within a recognized class of immune system modulators, the superantigens. These superantigens bind major histocompatibility complex II molecules, stimulating T cells independently of other mediators, and subsequently cause systemic effects, including the release of cytokines such as interleukin-2, gamma interferon, and tumor necrosis factors.⁹ Staphylococcus aureus produces at least six different enterotoxins, some of which are implicated in food poisoning and antibiotic-induced pseudomembranous colitis. The exfoliative toxin causes the staphylococcal scalded skin syndrome, which cleaves the middle layers of the epidermis, allowing the surface skin to peel.

Food poisoning is often attributed to staphylococcal enterotoxin, although the bacterium is usually not isolated from the patient. A community-acquired disease of potentially serious consequence, toxic shock syndrome, has also been attributed to infection or colonization with Staphylococcus aureus. This is associated with strains that secrete a specific superantigen exotoxin that stimulates T cells and is also a potent inducer of tumor necrosis factor and the cytokine interleukin-1.³ This is a systemic disease characterized by fever, hypotension, and multiorgan involvement but negative blood cultures.¹⁰ Although most cases have occurred in menstruating young females who are vaginal carriers of Staphylococcus aureus, other sites, including abscesses or wounds, may harbor the toxinproducing organisms.

Staphylococcus aureus infections are often acute and pyogenic with spread to surrounding tissues or to metastatic sites by means of a bacteremia. Some of the skin infections caused by Staphylococcus aureus include furuncles, cellulitis, impetigo, scalded skin syndrome, and postoperative wound infections. Other major infections caused by Staphylococcus aureus include bacteremia, pneumonia, osteomyelitis, acute endocarditis, myocarditis, pericarditis, cervicitis, cerebritis, meningitis, and abscesses of the muscle, urogenital tract, central nervous system, and various intra-abdominal organs (Table 3).

TABLE 3. Major Disease Associations With Gram-Positive Cocci

The coagulase-negative Staphylococcus species constitute a major component of the normal microflora in humans. Although the coagulase-negative staphylococci do not produce the number of extracellular products that Staphylococcus aureus does, many species produce hemolysins, and some may possess an antiphagocytic capsule. It is occasionally important to identify the individual species of coagulase-negative staphylococci involved in an infection because of clinical, economical, and therapeutic implications; laboratory tests have been developed to differentiate among these staphylococci.

Infection with Staphylococcus epidermidis has been increasing. This increase correlates with the use of prosthetic and indwelling devices and the growing number of immunocompromised patients in hospitals.^11,12 Staphylococcus epidermidis has been isolated from hospital-acquired bacteremia, osteomyelitis cardiac valve and cardiotomy infections, cerebrovascular fluid shunts, prosthetic joints, and orthopedic devices. It also has been isolated during ambulatory peritoneal dialysis. Staphylococcus saprophyticus is an opportunistic pathogen in human urinary tract infections and in urethritis. Staphylococcus haemolyticus also has been associated with a variety of clinical infections, many with underlying immune diseases or intravascular manipulations. Because the coagulase-negative bacteria are a major cause of foreign-body infections, there may be a polysaccharide adhesion to biomaterials that initiates a biofilm formation.¹¹ The production of a biofilm can mediate bacterial adherence and correlates with pathogenicity.¹³ The slime inhibits the polymorphonuclear cell response to chemotactic substances and stimulates these cells to degranulate, thus reducing the uptake and killing of bacteria.

Micrococci occur mostly in pairs or clusters and are obligate aerobes. Distinction is made between staphylococcus and micrococcus based on DNA, cell wall differences, and a host of clinical laboratory tests.³ Micrococcus also is found in the same locations as staphylococci, but they are much less virulent than the staphylococci. The predominant species found in humans includes M. luteus, M. roseus and M. varians.³ Micrococci are saprophytes that colonize the skin, mucosa, and oropharynx. They can be opportunistic pathogens in immunocompromised patients. M. luteus has been implicated as the causative agent in intracranial abscesses, septic arthritis, endocarditis, and meningitis.

Species of stomatococcus have been recovered from compromised patients, particularly drug abusers, as the cause of endocarditis and septicemia.¹⁴ They are known as “sticky staph” because their capsules can adhere to the agar.

Lancefield and co-workers developed a technique for differentiating the streptococci based on serologic groups A through O on the basis of the antigenic characteristics of a cell-wall carbohydrate called the C substance. More than 90% of streptococcal disease in humans is caused by Group A β-hemolytic streptococci. These β-hemolytic isolates with Lancefield group A, C, or G antigen can be subdivided into two groups: large-colony and small-colony formers. Large-colony forming group A (Streptococcus pyogenes), C, and G strains are “pyogenic” streptococci replete with a variety of effective virulence mechanisms.^15,16 The smallcolony forming β-hemolytic strains are members of the Streptococcus milleri group that are usually much less pathogenic.¹⁷ Among the non-β-hemolytic streptococcal strains, alpha-reacting isolates can be separated into Streptococcus pneumoniae and the viridans division, which is composed of a number of species groups. The nutritionally variant streptococci, previously thought to be nutritional mutants of viridans strains, have been shown to constitute a separate group of streptococcal species.¹⁸ Organisms previously thought to be anaerobic streptococci have been shown to be unrelated to members of the genus Streptococcus.¹⁹

Streptococci are usually found as parasites of humans. Some streptococci function as virulent pathogens while other strains live as avirulent commensals. Streptococci colonize the skin and mucous membranes, and they can be isolated as part of the normal flora of the alimentary, respiratory, and genital tract.

The β-hemolytic Lancefield Group A streptococci (Streptococcus pyogenes) are significant pathogens related to numerous virulence factors. These factors include M protein, lipoteichoic acid, enzymes, and toxins that allow it to cause a wide array of serious infections (e.g., pharyngitis, respiratory infection, skin and soft tissue infections [impetigo, erysipelas], endocarditis, meningitis, puerperal sepsis, and arthritis).¹⁵ Toxin-producing strains can cause scarlet fever or toxic shock-like syndromes. Sequelae of pharyngitis can include spread to contiguous tissue or bacteremia. Streptococcus pyogenes produces various extracellular products and toxins that enhance virulence. Erythrogenic toxin, elaborated by scarlet fever-associated strains, is responsible for the characteristic rash. Group A streptococci produce deoxyribonuclease, hyaluronidase, streptokinase, NADase, and proteinases. Streptokinase is a fibrinolysin that transforms plasminogen into plasmin and digests fibrin. It is used pharmacologically to dissolve emboli and thromboses. Streptodornase depolymerizes DNA and is used pharmacologically for enzymatic debridement. Hyaluronidase splits hyaluronic acid and elicits specific antibodies in the serum. The two hemolysins, streptolysin O and streptolysin S, can lyse human and other erythrocytes, as well as the cell membranes of polymorphonuclear cells, platelets, and other cells. Antistreptolysin O serum titer suggests recent infection. It is also implicated in the pathogenesis of rheumatic fever. Three potent pyrogenic exotoxins can induce fever and encourage development of acute respiratory distress syndrome, renal failure, and tissue necrosis.¹⁶ They can cause an erythrogenic rash and toxic shock. In primary streptococcal infections the infecting strain is often capable of spreading to surrounding tissue because of various extracellular products, including hyaluronidase, proteinase, streptokinase, and nucleases.

The streptococcal cell wall contains proteins (M, T, and R antigens), carbohydrates (group-specific), and peptidoglycans. M protein is a filamentous macromolecule that exists as a stable dimer with an alpha-helical coiled structure; it is anchored to the cell membrane, traverses, and then penetrates the cell wall. Hairlike pili project through the capsule of group A streptococci. The pili consist partly of M protein and are covered by lipoteichoic acid. The cell wall lipoteichoic acids serve to effect adherence of the organism to host cell respiratory epithelium, which is an essential initial step that is necessary for the start of infection. The M protein is the major virulence factor of the bacteria; some of the streptococcal pyrogenic exotoxins and some M antigens can act as activators of T-cells and systemic immunomodulators. The T protein provides a system of serotyping strains that cannot be typed by their M protein. T protein is often used for identification of streptococcal strains isolated from patients with impetigo. Both the hyaluronic acid capsule and cell wall M protein serve to prevent phagocytosis. Mucoid strains possess a large hyaluronic acid capsule that acts to inhibit phagocytosis.

Nonsuppurative sequelae of streptococcal infection include rheumatic fever and acute glomerulonephritis. Although the pathogenesis of these nonsuppurative diseases is not entirely clarified, they are probably autoimmune phenomena with cross-reactive antibodies originally directed against streptococcal cell membranes (C substance) binding to myosin in human heart muscle cells and other cross-reactive antibodies binding to components of the glomerular basement membrane. An alternative view is that these conditions are caused by streptococcal toxins acting as superantigens due to release of immune cytokines.²⁰ Acute rheumatic fever occurs only after upper respiratory tract infection dependent on host factors, such as histocompatibility-linked antigen type, immunoglobin secretory status, and immune responsiveness and factors of the organism (e.g., adherence mechanisms and cell wall carbohydrate components). Glomerulonephritis occurs after pharyngitis or after suppurative skin infection caused by a limited number of serotypes. These serotypes are defined by the existence of antisera against the M protein component of the cell wall. A recent upsurge in serious invasive group A streptococcal disease is a public health concern.¹⁶ This disease can strike otherwise healthy adults with minimal focus of disease and can be community acquired; nearly half the patients may die.

β-Hemolytic streptococci with Lancefield Group B antigen (Streptococcus agalactiae) are a frequent cause of serious neonatal infection characterized by sepsis and meningitis in up to 3.7 per 1000 live births.²¹ Their normal carriage site is in the oral cavity, intestinal tract, or vagina. The colonization of group B streptococci in pregnant women usually occurs through the gastrointestinal tract. In immunosuppressed patients, it is associated with endocarditis, pneumonia, and pyelonephritis; in others, it is associated with joint infection, osteomyelitis, and wound infection.

Other β-hemolytic streptococci that are not Group A or B usually belong to Group C or G; they cause a wide range of rare but serious infections such as bacteremia, endocarditis, meningitis, septic arthritis, as well as infections of the respiratory tract and skin. Other small β-hemolytic strains may be nongroupable and are usually identified as Streptococcus milleri. These organisms are usually commensal, but they can be involved in urogenital tract infections, abscesses, and other purulent soft tissue infections.

Streptococcus pneumoniae is an important agent of community-acquired pneumonia that may be accompanied by bacteremia.²² This diplococcus is a common inhabitant of the oropharynx and makes interpretation of expectorated sputum difficult. It is an exclusively human pathogen, spread from person to person by aerosols. Other pneumococcal infections include otitis media, sinusitis, meningitis, and endocarditis. The pneumococci are facultative anaerobes and are fastidious in their cultural requirements. The organisms are surrounded by an antiphagocytic capsule composed of polysaccharide antigens that are useful in strain typing (more than 80 types are described). The capsular polysaccharide is the primary virulence factor, but the pathogenesis of serious infection is related to the inflammatory responses to pneumococcal cell wall components (teichoic acid and peptidoglycan) and other proteins. Pneumococci cause disease in the presence of predisposing host conditions, often a preceding viral respiratory tract infection. The capsular polysaccharide plays a key role in allowing the establishment of infection by resisting phagocytosis; antibody to the capsular antigen is protective against pneumonia. Streptococcus pneumoniae produces several other factors that may play a role in virulence, including pneumolysin O, an oxygen-sensitive toxin that is cytolytic for cells, and neuraminidase, an enzyme that degrades surface structures of host tissue. The cell walls of pneumococci contain C substance, a teichoic acid that reacts with a certain serum protein, resulting in the activation of some nonspecific host immune responses.

The viridans species of Streptococcus is derived from the Latin word “viridis,” meaning “green,” because many members of this group are α-hemolytic and produce a “green” discoloration in blood agar.²³ Strains of viridans streptococci are normal inhabitants of the oral cavity, gastrointestinal tract, and female genital tract. They do not react with Lancefield grouping sera. They are not usually primary pathogens but act as opportunistic challengers to the host. Viridans streptococci are considered to be bacteria of low virulence because they possess no endotoxin and secrete little exotoxins. They are frequent contaminants in blood cultures and have also been associated with subacute bacterial endocarditis, especially in patients with damaged or prosthetic valves. They can also be pathogens in neutropenic patients. The amount of dextran produced by a streptococcal strain correlates with its ability to adhere to cardiac valves. These strains are also associated with brain abscess, perioral abscess, aspiration, liver abscess, and other suppurative infections, often in combination with other bacterial species or anaerobes. There are seven species: Streptococcus anginosus, Streptococcus bovis variants, Streptococcus mitis, Streptococcus mutans, Streptococcus salivarius, Streptococcus sanguis, and Streptococcus vestibularis. Some species of viridans streptococci produce extracellular enzymes and toxins similar to those produced by β-hemolytic streptococci. Gingival disease and dental manipulations, including dental prophylaxis, are often predisposing factors in the development of endocarditis. Streptococcus mutans has been definitively established as a major cause of dental carries and is also a cause of endocarditis. Extracellular polysaccharides, called dextrans, serve as attachment mediators for tooth surfaces as well as heart valves.

Streptococcus bovis, a group D streptococcus, can be associated with malignancies of the gastrointestinal tract, endocarditis, or meningitis. The presence of Streptococcus bovis bacteremia, with or without endocarditis, is almost always indicative of a loss of integrity of the gastrointestinal mucosa and frequently indicates a colon malignancy.²⁴

The nutritionally variant streptococci are normal residents of the oral cavity but have been identified as agents of endocarditis as well as ophthalmic infections.²⁵ There are two separate species, Streptococcus defectivus and Streptococcus adjacens.¹⁸ Nutritionally variant streptococci require vitamin B₆, or pyridoxal, for growth on agar. Staphylococcus aureus can provide the necessary growth factors for development of satelliting colonies of the streptococci in a zone surrounding the staphylococcus. The exact taxonomic relationship between nutritionally variant streptococci and viridans streptococci is uncertain.

Peptostreptococcus consists of many species that grow only under anaerobic or microaerophilic conditions. Most are nonhemolytic. They are part of the normal flora of the mouth, upper respiratory tract, bowel, and female genital tract. They often participate with many other bacterial species in mixed anaerobic infections in the abdomen, pelvis, lung, or brain. These anaerobic cocci are phylogenically distinct and are covered in a separate chapter.

Enterococci are ubiquitous in nature, surviving under harsh conditions, and this makes establishing clinical significance difficult. There is an increasing trend in their clinical significance.²⁶ Enterococci are the second or third most common etiologic agents of nosocomial infection in the Unites States, especially in association with medical devices. Enterococci are often involved in urinary tract infections, usually in patients with structural abnormalities. Intra-abdominal or pelvic wound infections are commonly encountered,²⁷ as is bacteremia caused by this organism. Enterococci are estimated to cause between 5% and 20% of bacterial endocarditis cases, with E. faecalis being the most commonly encountered enterococcus.²⁶ Surperinfection with enterococci, including bacteremia, is a relatively common occurrence in patients being treated with a third-generation cephalosporin because they are resistant to these agents as well as to penicillin.

In general, staphylococci produce localized abscesses. Staphylococci are also the most common secondary invaders in many conditions, including dacryocystitis, trachoma, pemphigus, keratomalacia, and viral superinfections. Both Staphylococcus aureus and Staphylococcus epidermidis are a frequent cause of nosocomial infections. These two organisms are responsible for infections with implanted medical devices²⁸ correlated with the specific polysaccharide intercellular adhesin production by some strains²⁹ of Staphylococcus epidermidis and by the fibronectin-binding protein adhesins of Staphylococcus aureus.^30,31 Staphylococcus epidermidis has the ability to produce a biofilm slime, which promotes the colonization of smooth surfaces.³² Dextran production in oral streptococci has been shown to correlate with both the capacity to produce dental caries and the ability to cause bacterial endocarditis.³³

Streptococci can produce a number of severe serious diseases with invasive spreading properties that are correlated with the secretion of a number of toxins and enzymes. The pyogenic process for streptococci appears in the form of a cellulitis rather than as the localized abscess typical of staphylococcal infections. Streptococcus pneumoniae causes serious ocular infection by invasiveness and multiplication but does not produce significant toxins. Because Streptococcus pneumoniae or other gram-positive organisms are often present in the normal flora, any ocular injury may lead to severe purulent infection. The characteristic pathology of pneumococcal infections is marked edema and fibrinous exudate, often with an explosive onset. The membrane-active toxins alpha of Staphylococcus aureus³⁴ and pneumolysin of Streptococcus pneumoniae³⁵ contribute to the virulence of each of these bacteria for corneal disease and probably endophthalmitis. The toxin cytolysin produced by E. faecalis has been shown to be responsible for the severe destructive endophthalmitis characteristic of this organism.³⁶

Many gram-positive bacteria display several adhesins on fimbriae (pili) and nonfimbriated structures that recognize carbohydrates on host cells or alternatively enhance protein-protein interactions. The adherence of Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa to injured corneal epithelium is significantly higher than that in other bacteria.³⁷ The degree of binding also depends on epithelial cell factors, as evidenced by the greater affinity of Staphylococcus aureus to the nasal mucosa of carriers compared with noncarriers. The presence of M protein or lipoteichoic acid in Streptococcus pyogenes correlates with increased adherence to epithelial cells. In the cornea, damaged epithelium is particularly susceptible to bacterial adherence, and it is the epithelial edge rather than the bare stroma to which bacteria adhere. Exopolysaccharide formation by some organisms results in local immunosuppressive effects, interfering with phagocytosis. The bacterial exotoxins can cause severe stromal destruction. Coagulase-positive strains of staphylococci are the most pathogenic and elaborate other extracellular enzymes, such as staphylokinase, lipase, hyaluronidase, DNAase, coagulase, and lysozyme. Staphylococcus epidermidis also produces a potentially destructive toxin to the cornea.³⁸ Other virulence factors produced by Staphylococcus aureus and Staphylococcus epidermidis include lipoteichoic acid as well as other components of their capsule. Streptococcal toxins include streptolysin O and S, erythrogenic toxin, and the enzymes hyaluronidase, streptodornase, streptokinase, and collagenase. Pneumococci can proliferate in the presence of neutrophils because peptidoglycan and M protein inhibit opsonization, impair complement activation, and reduce leukocyte migration.

Antibiotic resistance, especially to the grampositive cocci, is an emerging clinical problem. Most Staphylococcus aureus are resistant to penicillin, and multidrug resistance is now quite common. Forty percent of nosocomial infection cases in the United States are caused by methicillin-resistant Staphylococcus aureus. Sixty percent of coagulase-negative staphylococci are methicillin resistant. Penicillin-resistant Streptococcus pneumoniae represents 40% of Streptococcus pneumoniae in some communities, with many multiresistant. Vancomycin-resistant Enterococcus represents 16% of enterococci in intensive care units, and many are also resistant to newer agents, including teicoplanin. Fluoroquinolone resistance is increasing among streptococci, enterococci, and staphylococci.

Many of these antibiotic resistance problems are related to excessive, inappropriate, and extended antimicrobial prescribing patterns that have led to the emergence of resistance. The failure to use basic infection control measures has increased the dissemination of resistant strains in hospitals. National guidelines for antibiotic use have not worked because medicine is practiced according to local standards and is not nationally driven. Hospital leadership is necessary to combat this trend by enforcing and policing the recommendations of infectious disease experts. Strategic goals and processes have the potential to slow down antibiotic resistance patterns.

SKIN DISEASE

Folliculitis can be divided by its clinical manifestations into superficial and deep staphylococcal infections. The superficial form, called Bockhart's impetigo, is common in children, whereas the deep form, called sycosis barbae, is seen almost exclusively in men. In Bockhart's impetigo, the focal or clustered lesions are small superficial follicular pustules that are yellowish in color and have a thin rim of erythema. Common locations for these lesions are the scalp, back, and extremities. Sycosis barbae is characterized by pustules, papules, and nodules in the beard area.

Crusted impetigo is a pustule that ruptures to a thickly crusted dermatitis of exposed skin areas. It usually occurs in children and has a tendency to develop in endemic foci during the warm, humid summer months. Amber serous fluid exudes from the erosion. Impetigo may develop secondarily around pre-existing varicella or herpes simplex lesions of the eyelids. This infection is caused by Streptococcus pyogenes, Staphylococcus aureus, or both, so therapy must address both organisms. The vesicopustule is under the corium and contains numerous neutrophils and a few acantholytic cells and gram-positive cocci. The upper dermis is involved with a moderately dense mixed-cell infiltrate.

Bullous impetigo is a localized form of the staphylococcal scalded skin syndrome. It is characterized by fragile, flaccid bullae that can rupture to form thinly crusted lesions. The bulla fluid can be clear or cloudy and up to 3 cm in diameter. Regional lymphadenopathy is uncommon. It is an endemic disease with a propensity to occur in epidemics, especially in neonates or children, and is less common than impetigo. It represents a localized form of Staphylococcus aureus infection with the focal effect of an epidermolytic toxin. Rarely, Streptococcus pyogenes causes a similar process.³⁹ The toxin disrupts intercellular attachments of cells in the granular layer of human epidermis.⁴⁰ The cleavage plane for the bulla lies in the subcorneal or granular region. There is a mixed perivascular and interstitial infiltrate in the upper dermis.

Ecthyma is characterized by an ulceration of the skin covered by a dirty-appearing crust. The ulcers are painful and chronic. They occur commonly on the lower extremities and were seen in American infantrymen in Vietnam. They very rarely involve the lids or periorbita. The initial lesion is a vesicle with an erythematous base that erodes through the epidermis to form a shallow dermal ulcer.⁴¹ The ulcer enlarges over several days with a margin that is indurated, raised, and erythematous. Histopathology reveals an ulcer with nonspecific features and numerous neutrophils both in the dermis and in the serous exudate on the ulcer floor. It is primarily an Streptococcus pyogenes infection with secondary Staphylococcus aureus colonization. Ecthyma heals with scarring that can lead to significant lid deformities.

Erysipelas (St. Anthony's fire) is a distinctive streptococcal infection of the dermis with prominent lymphatic involvement. It presents as a painful, red, spreading, hot plaque that is sharply demarcated from surrounding skin. The lids may be dramatically swollen. This form of infection can invade the soft tissues of the orbit, resulting in chemosis, mild proptosis, and limitation of ocular movement.^42,43 The surface may be covered by small vesicles or pustules. Systemic symptoms of fever and chills can occur for days before the dermatitis is visible. It most commonly occurs on the face or legs. Diabetes and alcohol abuse are common associations.⁴⁴ Some cases have no apparent portal of entry of the organism. Tender preauricular lymph nodes are present, and the lymph tissue may be a source of spread. Streptococcus pyogenes is the most common etiologic agent, although it is cultured only 40% of the time. Combining culture, direct immunofluorescence, and serologic studies increases the evidence for a streptococcal etiology.⁴⁵ Blood cultures are positive in less than 10% of cases.⁴⁴ Complications of the acute infection include septicemia, abscesses, necrotizing fasciitis, and cavernous sinus thrombosis. The papillary dermis shows prominent edema, which may progress to subepithelial blister formation. Lymphatics and capillaries are dilated. There is a sparse infiltrate of predominantly neutrophils throughout the dermis.

Preseptal cellulitis can progress to necrotizing fasciitis, gas gangrene of the subcutaneous tissue, vascular thrombosis, and necrosis of the overlying eyelid skin. There may be necrosis (gangrene) of the preseptal and tarsal skin, with eschar formation and purulent discharge. The most common pathogens are group A streptococci, although Haemophilus influenzae, P. aeruginosa, and Clostridium species have been involved. Several reports suggest that the incidence of invasive group A streptococcal infections, including toxic shock syndrome and necrotizing fasciitis, is increasing.⁴⁶ Although initial reports found healthy young adults at increased risk, more recently identified risk factors include HIV infection, cancer, diabetes, alcohol abuse, and chickenpox⁴⁶; the mortality rate is 15% overall. There is a shift to a greater frequency of M serotypes associated with greater virulence.⁴⁷ There is a substantial risk of transmission in households and health care institutions, although the precise mode of transmission remains unknown.

Cellulitis is an infectious and inflammatory condition of the skin and subcutaneous tissues. Because both the dermis and the subcutis are involved, the sharply defined margin of erysipelas is not present, but erythema, heat, swelling, induration, and tenderness are still present. Cellulitis occurs most commonly on the legs, but approximately 10% of cases occur on the face.⁴⁸ The disease affects predominantly men. The bacterial etiology has been difficult to establish, but combined culture, direct immunofluorescence, and serologic studies are most commonly positive for Streptococcus pyogenes in extremity cellulitis.⁴⁵ The facial involvement is usually a disease of childhood, with additional involvement of H. influenzae or Streptococcus pneumoniae.⁴⁰ Preseptal cellulitis presents with periorbital swelling, eyelid edema, erythema, and localized tenderness but without orbital involvement. It can occur after localized trauma, insect bites, impetigo, erysipelas, or acute hordeolum, or by arterial and venous communications from otitis and paranasal sinus infections. Post-traumatic preseptal cellulitis occurs after puncture wounds, lacerations, or blunt trauma, with the main pathogens being Staphylococcus aureus and Streptococcus pyogenes. In young children, H. influenzae type b and Streptococcus pneumoniae are the most common causes of preseptal cellulitis without antecedent skin infection or trauma and are thought to spread from the upper respiratory tract, sinuses, or middle ear to the preseptal space.⁴⁹

EYELID MARGIN DISEASE

The eyelid margin equivalent of folliculitis is the external hordeolum (stye). It represents an Staphylococcus aureus infection of the glands of Zeis or Moll at the base of the hair follicle. An internal hordeolum is an acute infection involving the meibomian glands. An acute hordeolum can progress to a perifolliculitis, which resembles a furuncle, a cutaneous abscess centered around a solitary follicle with associated pain and induration and a shiny, bright red area. Spontaneous drainage may occur. The pathology shows typical changes of folliculitis with neutrophils and an abscess and variable destruction of the hair follicle.

Staphylococcal blepharitis is a common cause of anterior eyelid, ocular surface, and corneal inflammation. The eyelids in staphylococcal blepharitis are inflamed with moderate erythema and edema, and there are hard, brittle, fibrinous scales at the base of the lashes. Collarettes are formed by fibrin exudation of the ulcerated skin at the base of the lash. Poliosis (white lashes), madarosis (loss of lashes), tylosis (irregularity of the lid margin), and broken and misdirected lashes may be present and are related to damage to the hair follicles. External and internal hordeolums are seen as an extension of the staphylococcal infection.

The normal eyelids are colonized by Staphylococcus aureus and Staphylococcus epidermidis approximately 10% and 95% of the time, respectively. In patients with staphylococcal disease, Staphylococcus aureus has been isolated approximately 47% of the time, with Staphylococcus epidermidis, Propionibacterium acnes, and Corynebacterium species present in higher than normal quantities.^50,51 Others have reported similar quantitative cultures and biotypes of Staphylococcus epidermidis in patients with and without blepharitis.⁵² No consistent difference is evident in the strains of these organisms to explain the clinical condition. Colonization of the lids with Staphylococcus aureus occurs intermittently in the normal host but is excessive in the atopic patient and in patients with acute folliculitis. The lid inflammatory reaction in chronic staphylococcal blepharitis may be related to a combination of factors, including actual infection and other variables, such as toxins,⁵³ lipases (splitting meibomian triglycerides to toxic fatty acids),⁵⁴ and delayed-type hypersensitivity.⁵⁵

Filtrates prepared from patients with staphylococcal blepharitis caused by Staphylococcus aureus and Staphylococcus epidermidis have produced toxigenic conjunctivitis in normal eyes.³⁸ There are several candidates for this response, including exfoliative toxin, toxic shock syndrome toxin, and the beta, gamma, and delta toxins or the lipases. The lipases are sterol and fatty wax esters that may alter the viscosity and surface tension of the tear film and ocular flora.⁵⁶ Some investigators have not found the staphylococcal toxins to be significant factors in causing blepharitis.⁵³ Enhanced cell-mediated immunity to Staphylococcus aureus has been found in 40% of patients with chronic blepharitis,^57,58 although in an animal model immunity to Staphylococcus aureus is an absolute necessity for the production of ulcerative blepharitis, phlyctenules, and marginal infiltrates.^55,59,60 This animal model suggests that the eyelid and corneal lesions represent a hypersensitivity response rather than a direct bacterial infection. The cell wall of Staphylococcus aureus consists of three major components: peptidoglycan, protein A, and ribitol teichoic acid. Studies by Mondino⁵⁵ suggest that hypersensitivity to ribitol teichoic acid, the major antigenic determinant of Staphylococcus aureus, is important in the immunopathogenesis of blepharitis and corneal lesions in the rabbit model. Correspondingly, the antibody response to ribitol teichoic acid may be the only serologic test of clinical importance in the diagnosis of systemic staphylococcal diseases^7,8,61 and possibly chronic blepharitis. Giese and colleagues further evaluated the effect of Staphylococcus aureus phage lysate vaccination in the rabbit animal model but was unable to find a beneficial effect,⁶¹ despite finding enhanced antibody response to ribitol teichoic acid. This form of vaccination has produced minor improvement in some patients with furunculosis, pustular acne, pyoderma, eczema, bronchial asthma, upper respiratory infections, and staphylococcal enterocolitis.⁶¹

Infectious eczematoid dermatitis is an immune skin reaction occurring in middle-aged women that is related to staphylococcal or streptococcal blepharitis. It is often bilateral, with the entire upper lid involved with vesiculation, pustulation, crusting, and lichenification. Staphylococcal or streptococcal antigens act as haptens.

Angular blepharitis is associated with fissuring, scaling, maceration, lichenification, or erythema of the lateral or medial canthal area. There may be conjunctival hyperemia and follicular conjunctivitis.⁶² Phlyctenular keratitis, marginal catarrhal infiltrates, and corneal ulcers characteristic of staphylococcal blepharitis can occur. The disease is most common in adolescents in warm climates and can be recurrent. Moraxella lacunata is the main pathogen in warm environments, but Staphylococcus aureus may be more common in colder climates.⁶³ Dysgonic fermenter-2 bacterium has also been isolated.⁶⁴

Eyelid edema can be quite marked in association with acute catarrhal conjunctivitis from streptococcal infection but rarely progresses to gangrene.

CONJUNCTIVAL DISEASE

Ophthalmia neonatorum is an acute catarrhal (inflammatory) conjunctivitis of newborns with moderate mucopurulent discharge or a subacute conjunctivitis with a mild mucoid discharge. It is usually acquired in the newborn nursery but may be a harbinger or focus of systemic infection. Staphylococcal or streptococcal conjunctivitis can have a very acute purulent onset in neonates and can appear similar to gonococcal conjunctivitis.

Most cases of bacterial conjunctivitis in children are caused by gram-positive cocci (aerobic or anaerobic),⁶⁵ with Staphylococcus aureus being the most frequent cause of either acute or chronic bacterial conjunctivitis. Staphylococcal conjunctivitis in children presents acutely with scanty discharge and lower palpebral conjunctival involvement. Catarrhal conjunctivitis in adolescents and adults may occur as an acute conjunctival infection associated with redness, discharge, and foreign-body sensation caused by staphylococcal infection with or without associated blepharitis. The discharge is usually mild and mucoid with a mild papillary hypertrophy. Acute conjunctivitis can cause an acute purulent conjunctivitis from the elaboration of exotoxins and biologically active substances such as hemolysin, fibrinolysin, and coagulase, which produces a mucopurulent discharge and stickiness of the lids upon awakening. Staphylococcus epidermidis is an infrequent cause of conjunctivitis. A seasonal variation may be seen. Staphylococcal conjunctivitis in adults is occasionally chronic secondary to blepharitis with prominent involvement of the tarsal portion of the conjunctiva.

Epidemics of acute purulent pneumococcal conjunctivitis have been described, usually in the colder months in northern climates. It has a predilection for children and causes a moderately severe mucopurulent exudation and chemosis. Subconjunctival hemorrhages are often seen and usually involve the upper tarsal conjunctiva or fornix. Purulent conjunctivitis with other streptococci and staphylococci is not uncommon. Streptococcal conjunctivitis occasionally has a pseudomembrane or true membrane formation. The latter is characterized by a coagulative fibrinous exudate penetrating the epithelial and subepithelial tissues, especially involving the bulbar conjunctiva. Streptococcus pyogenes may present with an acute purulent conjunctivitis with chemosis and occasionally membranes or pseudomembranes. Scarlet fever may provoke an associated toxic conjunctivitis, and streptococcal impetigo can spread from the skin of the lids.

Chronic conjunctivitis is most commonly caused by Staphylococcus aureus with an associated blepharitis. The conjunctival inflammation may be the result of direct infection or the release of toxins, similar to the mechanism of marginal keratitis. Conjunctival findings in chronic staphylococcal blepharitis (chronic catarrhal conjunctivitis) include mild hyperemia and a chronic papillary conjunctival reaction with minimal cellular infiltration. Chronic streptococcal or staphylococcal conjunctivitis can also be seen in association with chronic dacryocystitis.

Angular conjunctivitis is seen in association with medial or lateral angular blepharitis and has findings similar to those of acute or chronic catarrhal conjunctivitis.

CORNEAL DISEASE

Corneal complications of Staphylococcus infections include an epithelial keratitis, catarrhal infiltrates, phlyctenules, and suppurative keratitis. Concomitant seborrheic blepharitis or keratoconjunctivitis sicca with staphylococcal blepharitis results in additional findings within the eyelid, cornea, and conjunctiva.⁶⁶ Long-term corneal changes from staphylococcal blepharitis include peripheral corneal vascularization, peripheral subepithelial opacities, and Salzmann's nodular degeneration.

Staphylococcal blepharitis produces a toxic punctate epithelial keratitis, especially of the inferior cornea. These lesions are fine, medium-sized, or blotchy and stain with fluorescein. Catarrhal corneal infiltrates of Staphylococcus are commonly seen at the 2, 4, 8, and 10 o'clock meridians of the peripheral cornea where there is eyelid margin contact with the cornea causing this immunologic response to staphylococcal antigens. These infiltrates are arc-shaped and are located 1 or 2 mm inside the limbus.

Phlyctenulosis, which is a cell-mediated hypersensitivity response to staphylococcal antigen, can occur at the limbus, cornea, or conjunctiva. It begins as a white or yellow superficial infiltrate that ulcerates and heals in approximately 2 weeks. The limbal phlyctenule often straddles the limbus but may occur in the cornea or conjunctiva alone. Scarring can occur and the inflammation can attract a leash of superficial blood vessels.

In one study, the frequency of staphylococcal marginal keratitis was the same in patients with or without enhanced cell-mediated immunity to Staphylococcus aureus protein A.⁵² Patients with marginal keratitis requiring treatment with steroids, however, were more likely to have enhancement.⁵² The cell walls of coagulase-negative staphylococci do not contain protein A. The present understanding of the pathogenesis of marginal keratitis is that it is caused by the expression of a cell-mediated immune response at the limbus to Staphylococcus aureus on the eyelids in patients with a prior systemic enhancement of cell-mediated immunity. This may indicate a possible role for selective desensitization. There are many unanswered questions about staphylococcal blepharitis; features of the disease are partially but not completely explained by toxins, cell wall antigenicity, cellular and humoral immunity, and host susceptibility.

Risk factors for suppurative bacterial corneal infections include contact lens wear, trauma, and corneal compromise. Staphylococcus aureus is one of the most common causative organisms in bacterial keratitis in the northern and northeastern United States and Canada, both in normal hosts and in immunocompromised corneas. It has a tendency for central corneal location with a hypopyon and occasionally a perforation. The keratitis is yellow-white with a well-demarcated stromal infiltrate located directly below the epithelial defect. Multiple, small, superficial satellite stromal infiltrates can develop. Posterior corneal abscesses can occur, leading to perforation. Occasionally, a staphylococcal ulcer is indolent, with only mild anterior chamber reaction and no hypopyon.

Corneal complications from streptococcal infection include a suppurative keratitis and a marginal keratitis. The suppurative keratitis of Streptococcus pneumoniae is a common cause of central corneal ulcers, and a presumptive diagnosis can be made from the serpiginous appearance of the ulcer. At the onset, the corneal epithelium becomes lusterless and hazy as the stroma becomes infiltrated. The corneal epithelium breaks down to form an ulcer, which spreads centrally with the leading edge undermined as the peripheral edge becomes sloping from healing. The cornea can rapidly become necrotic. Other streptococcal ulcers are characterized by infiltration, necrosis, and epithelial ulceration, with hypopyon uncommon but with no other distinguishing features. Occasionally a marginal ulcer develops in association with a streptococcal conjunctivitis or with erysipelas of the face.

Infectious crystalline keratopathy is commonly caused by α-hemolytic streptococci or nutritionally variant streptococci, among other organisms. These organisms may secrete an intrastromal glycocalyx or slime layer, which renders them relatively impervious to antimicrobials. The infection is indolent with minimal signs of inflammation and is difficult to eradicate. The infiltrates have the appearance of fine spicules or snowflakes in the anterior stroma. The overlying corneal epithelium is usually intact. The crystalline appearance may be related to the production of dextran by the organism or to the formation of a bacterial biofilm. The organisms involved in this infection are characteristically slow growing or have an inability to grow on culture media.

SCLERAL DISEASE

Bacterial scleritis is usually the result of scleral extension of primary corneal infections. Staphylococcal blepharitis can be associated with a painful, tender nodule in the sclera that may persist for several weeks. Primary bacterial scleritis with or without keratitis may occur and may follow accidental or surgical injury or a severe endophthalmitis. Less frequently, a scleral abscess is related to a metastatic staphylococcal or pneumococcal infection or is associated with an implanted retinal buckle. Posterior scleral staphylococcal or pneumococcal infection is rare but can produce exophthalmos, pain on ocular rotation, vitreitis, or iridocyclitis. Panophthalmitis, ocular perforation, or phthisis bulbi may ensue.

LACRIMAL DISEASE

Lacrimal gland infections (dacryoadenitis) caused by gram-positive organisms can occur from metastatic spread, from penetrating injuries, from surrounding infections of the skin, teeth, or sinuses, or from middle ear infections.

Dacryocystitis is a common complication of nasolacrimal duct obstruction in the elderly. Organisms include Staphylococcus and Streptococcus.

PRESEPTAL AND ORBITAL DISEASE

Orbital cellulitis is a spread of bacteria beyond the septum into the orbit and is characterized by significant symptoms. There may be headache, fever, lid edema, rhinorrhea, tenderness to palpation, proptosis, resistance to retropulsion of the globe, limitation of ocular motility, conjunctival hyperemia, and chemosis. Compression of the optic nerve can lead to vascular compromise, and posterior extension can lead to cavernous sinus thrombosis, subdural empyema, and intracranial abscess or cellulitis with loss of vision, sepsis, or death. Orbital cellulitis can occur after penetrating trauma, surgery, neonatal conjunctivitis, panophthalmitis, dacryocystitis, or bacteremia, or from direct extension of bacterial sinusitis. Although the most common organisms in adults are Staphylococcus aureus and Streptococcus pyogenes, the most common pathogen in children is H. influenzae; the latter may lead to bacteremia, metastatic infection, and meningitis.⁶⁷ In childhood orbital cellulitis, conjunctival culture, blood culture, and needle aspiration may be necessary to confirm the organism. Adults are more likely to have a portal of entry to culture but may require needle aspiration to confirm.

ENDOPHTHALMITIS

Staphylococcal endophthalmitis after trauma or intraocular surgery is caused by Staphylococcus aureus and Staphylococcus epidermidis. Both organisms can also cause panophthalmitis. Approximately 60% to 70% of postsurgical endophthalmitis cases are caused by Staphylococcus epidermidis (or other related coagulase-negative staphylococci). These strains do not typically express toxins, and components of their cell walls are only mildly inflammatory. Staphylococcus epidermidis endophthalmitis usually begins insidiously and progresses more slowly than does Staphylococcus aureus endophthalmitis.

The frequency of endophthalmitis may relate to the propensity of Staphylococcus epidermidis to adhere to medical devices, including intraocular implants. The organisms involved in endophthalmitis usually originate from the skin or conjunctival flora, as demonstrated by phage and DNA typing. Streptococcus pneumoniae or other streptococci cause an endophthalmitis in association with intraocular surgery or penetrating injury, especially in the presence of chronic pneumococcal dacryocystitis. Approximately 25% of endophthalmitis cases are caused by Staphylococcus aureus, Streptococcus pneumoniae, viridans streptococci, or Enterococcus. The remaining are caused by P. aeruginosa or Bacillus cereus. Experimental staphylococcal endophthalmitis is commonly studied. Most studies use 30 to 2000 Staphylococcus aureus organisms injected into the rabbit vitreous, with clinical infection noted within 24 to 48 hours. Streptococci are associated with the endophthalmitis that is seen in association with filtering conjunctival blebs. Streptococci are especially destructive within the eye, causing rapid retinal damage from enzyme activity and a poor visual result.

Endogenous endophthalmitis can arise from cutaneous infections, endocarditis, tonsillitis, otitis media, sinusitis, or osteomyelitis; in some instances it comes from unknown sources.

Post-traumatic endophthalmitis is characterized by a mix of organisms related to the contamination introduced. Bacillus species are the most devastating. Gram-positive cocci are occasionally present.

A sterile endophthalmitis (uveitis) can be seen in association with some gram-positive infections (especially Streptococcus), possibly as a result of toxins diffusing locally or from a distant infection site. Acute posterior multifocal placoid pigment epitheliopathy may be an immunologically mediated vascular disease associated with several causes, including group A streptococcal infection.⁶⁸

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