Chapter 122 Infectious Endophthalmitis
Infectious endophthalmitis is a condition in which the internal structures of the eye are invaded by replicating microorganisms, resulting in an inflammatory response that ultimately may involve all tissues of the eye. Exogenous endophthalmitis occurs when the outer wall of the eye sustains a break as a result of surgical intervention or trauma; only rarely do microorganisms invade through the cornea or sclera without an overt disruption of these tissues. Endogenous endophthalmitis is less common and occurs when the microorganisms spread to the eye from a source elsewhere in the body, usually through the blood stream. The most common causative agents are bacteria, but fungi and parasites can also cause endophthalmitis. The time course of the disease may be acute, subacute, or chronic.
The majority of endophthalmitis cases occur after surgery, and over 90% of all cases are caused by bacteria. Each clinical setting of infection has its own characteristics, and as knowledge is refined, various constellations of findings have emerged. In certain clinical settings, there is an increased likelihood of infection by certain groups of bacteria. In turn, the clinical condition that is present at the onset of infection and the pathogenicity of the bacteria involved are the primary determinants of the outcome. For example, endophthalmitis following cataract surgery is most often caused by Staphylococcus epidermidis, and these eyes have a reasonably good prognosis. Injured eyes, on the other hand, have an increased likelihood of infection with Gram-positive Bacillus spp., which has a markedly worse prognosis.
Infective agents that commonly cause endophthalmitis
Bacteria are the most common group of organisms causing endophthalmitis. Gram-positive organisms are responsible for 60–80% of acute infections in all large series. These organisms vary widely in their virulence and, therefore, in their effect on the eye.
Staphylococci are Gram-positive organisms that grow singly, in pairs, in chains, or in clusters. They are members of the family Micrococcaceae, and the individual organisms have a diameter of 0.2–1.2 µm. The main groups of staphylococci producing endophthalmitis are Staphylococcus aureus and coagulase-negative staphylococci.
S. aureus is a nonspore-forming facultative anaerobic organism that colonizes human skin and mucous membranes intermittently. It is often cultured from conjunctiva in asymptomatic persons. S. aureus is identified by positive reactions to catalase, coagulase, deoxyribonuclease test, and mannitol fermentation. S. aureus produces many enzymes, including catalase, which correlates with pathogenicity. β-Lactamases (which play a role in antimicrobial resistance), coagulase, and hyaluronidase are also bacterial products. Toxins produced by S. aureus include: exfoliatins, which produce dramatic epidermal changes in skin infections; toxins associated with toxic shock syndrome, and enterotoxins, which are a major cause of food poisoning.
Coagulase-negative staphylococci have at least 11 different subspecies, including S. epidermidis, S. capitis, S. haemolyticus, and S. hominis. Only S. epidermidis is consistently pathogenic for humans. S. epidermidis is a prevalent and persistent species colonizing human skin and mucous membranes.
S. epidermidis has been increasingly identified as a cause of human infection often associated with foreign bodies, such as implanted catheters, and has become the most common cause of postoperative endophthalmitis.1–7 Hospitals may not subspeciate coagulase-negative staphylococci, reporting them all as S. epidermidis.
Production of an exopolysaccharide (or “slime”) may be one factor allowing adherence of S. epidermidis to plastic surfaces, permitting resistance to phagocytosis and failure of antimicrobial therapy. Virtually all S. epidermidis infections are hospital-acquired, whereas S. saprophyticus infections almost always involve the urinary tract and are acquired outside hospital. S. epidermidis is often resistant to multiple antibiotics, particularly meticillin, and should be considered cross-resistant to all β-lactam antibiotics. Almost all are susceptible, however, to vancomycin and rifampin.
Streptococci are facultative anaerobic organisms or obligate anaerobes that are spherical or ovoid and found in pairs or chains. They are Gram-positive, nonspore-forming, catalase-negative, and nonmotile organisms. The genus Streptococcus has over 20 species, and its classification is complex. The viridans group of Streptococcus includes S. mitis, S. mutans, and S. pneumoniae (previously called Diplococcus pneumoniae). If the Gram-stain is positive, the quellung reaction may be used to identify pneumococcus. The viridans-group streptococci are predominantly respiratory tract pathogens found in short chains. They have been subtyped by surface antigens into 84 known serotypes. In the laboratory they exhibit fastidious growth, replicating best on complex media and often requiring carbon dioxide. They are thought to produce toxins that increase their pathogenicity. The drug of choice for these organisms is penicillin, but they are also sensitive to vancomycin.
Group D streptococci are separated into enterococcal species, including S. faecalis, S. faecium, and S. durans, and nonenterococcal species (S. bovis and S. equinus). S. faecalis and S. faecium are found in the gastrointestinal tract in humans and in human feces. Group A streptococci (S. pyogenes) make up some of the most important human pathogens, accounting for both acute rheumatic fever and post-streptococcal acute glomerulonephritis. In the laboratory, they produce β-hemolysis on blood agar plates, with discoloration around the colonies. These organisms grow in pairs or chains and are Gram-positive, nonmotile, nonspore-forming, and catalase-negative. They are facultatively anaerobic, nutritionally fastidious, and usually grow on complex media when supplemented with blood or serum. They may produce extracellular products, including hemolysins, pyrogenic exotoxin, streptokinase, and hyaluronidase.
Group B streptococci (S. agalactiae) are facultative Gram-positive diplococci that are usually easily grown. They have a narrow zone of β-hemolysis on blood agar plates. They are usually isolated from the lower gastrointestinal tract or genital tract of pregnant women and can produce infection in both neonates and adults. These organisms are universally susceptible to penicillin and also ampicillin, vancomycin, and first-, third- and fourth-generation cephalosporins and ciprofloxacin.
A study of 48 cases of streptococcal endophthalmitis showed that all were sensitive to vancomycin, while nine (19%) were resistant to cefazolin or cephaloridine, and 16 (33%) were resistant to gentamicin.8
The genus Bacillus has more than 13 members, the most widely known of which is B. anthrax. The most common intraocular pathogen is B. cereus, with B. subtilis also identified as a cause of endophthalmitis.9 Bacillus is an aerobic spore-forming rod that is Gram-positive or Gram-variable in stain. The size varies from 3 × 0.4 µm to 9 × 2 µm. These organisms grow singly, in chains, or in diplobacillary form. In nature they are usually found in decaying organic matter, dust, soil, vegetables, water, and human flora. B. cereus is an important cause of food poisoning and may cause bacteremia as a result of wound or burn infections. It produces multiple extracellular products, including antimicrobial substances, enzymes, and toxins. The enterotoxins are diarrheal and emetic in action, and there are two additional toxins that may be correlated with virulence. Some toxins have produced severe inflammation when injected into the eye.10 Identification by the laboratory is usually as a cultural contaminant.
Risk factors for Bacillus infection include intravenous (IV) drug use, sickle-cell disease, foreign bodies including IV catheters, immunosuppression from malignancy, neutropenia, corticosteroid use, and acquired immunodeficiency syndrome (AIDS). Bacillus is now the most commonly identified organism in traumatic endophthalmitis.11–14 The infection is particularly virulent and may destroy the eye in 12–24 hours. It is unique in inducing fever and leukocytosis in endophthalmitis.
Vancomycin is the drug of choice against Bacillus spp. because β-lactam antibiotics are rarely effective in vitro against B. cereus. Strains other than B. cereus are susceptible to penicillin, cephalosporins, ciprofloxacin, and gentamicin.
Corynebacterium diphtheriae is a Gram-positive bacillus that is nonsporulating, noncapsulated, nonmotile, and pleomorphic. Humans are the only known reservoir for C. diphtheriae and spread is by airborne respiratory droplets or by direct contact. Occasionally C. diphtheriae resides on skin. The main cause of virulence is a potent exotoxin producing diphtheria and skin infection. The choice for primary treatment of this organism is penicillin or erythromycin.
There are seven species of Listeria that have been identified, but only L. monocytogenes is pathogenic for humans. Listeria organisms are Gram-positive, nonspore-forming aerobic rods that are motile at room temperature and hemolytic on colony growth. They appear coccoid-shaped in smears. In nature these organisms are found in soil, dust, animal feed, water, sewage, and colonizing animals and humans. L. monocytogenes causes a wide variety of infections including dermatitis and conjunctivitis, but it is a fairly rare infection and the prevalence of symptomatic disease is therefore difficult to estimate. Because of its rarity, there are no good control studies defining the most efficacious drugs, but ampicillin or penicillin are most likely the drugs of choice.
The genus Clostridium includes all anaerobic Gram-positive spore-forming bacilli. There are 60 recognized species, 30 of which cause clinical disease. These organisms are ubiquitous, found in soil, decaying vegetation, marine sediment, and the gastrointestinal tract of humans, vertebrates, and insects. They are often isolated as part of polymicrobial isolates from infected sites. C. perfringens is well known for its ability to cause gas gangrene, a rare infection. It may also produce exotoxin and food poisoning. Penicillin G is the drug of choice, although vancomycin is an appropriate choice for C. difficile.
Propionibacterium organisms are Gram-positive or Gram-variable rods that are often pleomorphic, anaerobic, and nonsporulating. Propionibacteria are a predominant component of skin flora and are also found on mucosal surfaces of the mouth, intestines, urethra, and vagina. They are the most common clinical isolate of Gram-positive, nonsporulating bacteria. They are found in acne, prosthetic joints, cerebrospinal fluid shunts, endocarditis, and osteomyelitis. They have been identified as a cause of postoperative endophthalmitis of a chronic granulomatous nature, almost exclusively found in patients with intraocular lenses (IOLs).15–20 P. acnes is almost always the clinical isolate.
Neisseria organisms are Gram-negative diplococci. N. meningitidis has fastidious growth requirements, growing best in a moist environment at 35–37°C under carbon dioxide. It has been serotyped on the basis of capsulopolysaccharides into at least 13 serogroups. The carrier state for N. meningitidis is the human nasopharynx. Paradoxically, however, despite the fact that it is frequently found in asymptomatic patients, the primary disease manifestations are meningococcal meningitis and sepsis, which tend to occur in epidemics. Both N. meningitidis and N. gonorrhoeae have been demonstrated to cause endophthalmitis on rare occasions. The disease is almost always endogenous in origin.
Moraxella organisms are Gram-negative cocci in the family Neisseriaceae. They were previously known as diplococcus of Morax-Axenfeld. Moraxellae are normal inhabitants of the upper respiratory tract and are also found on the skin and in the urogenital tract. They are strictly anaerobic, nonsaccharolytic, nonmotile, and grow on routine media. They are best known clinically as a cause of external eye disease and rarely cause systemic disease. The classic infection of M. lacunata is chronic angular blepharoconjunctivitis, which occurs in rare epidemics. M. liquefaciens is a variant of M. lacunata and is occasionally a cause of serious systemic disease. Moraxellae are almost universally sensitive to penicillin but β-lactamase-producing strains are now found.
Haemophilus influenzae is a small, nonspore-forming bacterium that is a strict parasite of humans. It is found principally in the upper respiratory tract but is also found in the conjunctiva and in the genital tract. It requires growth factors for isolation and takes up dye inconsistently on staining. Noncapsulated strains are normal inhabitants of the nasopharynx, but invasive diseases such as meningitis, septic arthritis, epiglottitis, and bacteremia tend to be caused by encapsulated strains. Contiguous spread to areas adjacent to the nasopharynx, including otitis media and conjunctivitis, is more often caused by noncapsulated strains. Other Haemophilus spp., such as H. ducreyi and H. hemolyticus, have similar distribution and growth characteristics but a significantly lower pathogenicity. In treatment of meningitis, the drug of choice is a combination of chloramphenicol and ampicillin.
The genus Pseudomonas comprises a group of nonmotile, Gram-negative, strictly aerobic organisms found in soil, water, and marine environments. They are straight or slightly curved bacilli that are motile, catalase-positive, and grow well over a wide range of temperatures. The nonfastidious growth requirements of Pseudomonas allow a wide distribution in nature. They may be part of normal human flora but are predominantly isolated as a result of nosocomial opportunistic infection. There are five major groups based on ribosomal RNA and DNA homology. The pathogenesis of disease created by Pseudomonas is complex and includes the production of extracellular proteases and other toxic proteins, as well as hemolysin, endotoxin, and exotoxin A.
Pseudomonas produces a wide variety of clinical syndromes, including endocarditis on prosthetic valves and in IV drug users, lower respiratory infections in persons with compromised defense mechanisms, bacteremia in immunocompromised patients, meningitis and brain abscesses, corneal ulcers, keratitis, ophthalmia neonatorum, scleral abscess, and conjunctivitis. Pseudomonas is the most common cause of Gram-negative endophthalmitis. Most cases of endophthalmitis are produced by P. aeruginosa, but other species have also been isolated in clinical cases.11,21 Sensitivities include aminoglycosides and ceftazidime.21,22
The family Enterobacteriaceae comprises a large heterogeneous group of Gram-negative, nonspore-forming facultative anaerobes; they are among the most important human pathogens. They are widely distributed in soil and plants and are colonizers of the gastrointestinal tract of humans and animals. Although they are uncommonly found outside the gastrointestinal tract, they are a leading cause of nosocomial disease. Escherichia coli is the best-studied free-living organism. It is a cause of urinary tract infection and traveler’s diarrhea and is the most common cause of nosocomial bacteremia.
The tribe Klebsiellae consists of four genera: Klebsiella, Enterobacter, Serratia, and Hafnia. They are all colonizers of the human gastrointestinal tract and are rarely associated with disease in normal hosts; however, they are major causes of nosocomial and opportunistic infections, inducing a wide variety of clinical syndromes.
The genus Klebsiella contains a group of three species of bacteria, including K. pneumoniae. They are a relatively common isolate in Gram-negative endophthalmitis23 and are characteristically resistant to multiple antibiotics. Enterobacter organisms are opportunistic pathogens that rarely produce human disease. When they function as opportunistic pathogens, however, they may be resistant to first-generation cephalosporins. Serratia spp. are opportunistic pathogens that have only been recognized as capable of producing human disease since the 1960s. They are more likely to colonize the respiratory and urinary tracts of hospitalized patients than other Enterobacteriaceae. Most hospital infections are caused by catheterization and instrumentation of the urinary and respiratory tracts. These organisms have multiple drug resistances but are most often sensitive to amikacin.
The order Actinomycetales has three major families of pathogens: the Mycobacteriaceae, Actinomycetaceae, and Nocardiaceae. Actinomycetales comprises a heterogeneous group only partially defined as a collection of microorganisms. They are facultatively anaerobic and are prokaryotic filamentous bacteria. These organisms are slow-growing and Gram-positive. They exhibit true branching and form mycelia-type colonies with branching filaments that grow from an ill-defined center. Reproduction, however, is by bacterial fission, and their growth is inhibited by antibiotics.
The genus Actinomyces includes A. israelii, the primary cause of human actinomycosis. A. israelii grows best anaerobically and may be isolated in 30–50% of all cultures taken from the mouth. It is not highly virulent, but is an endogenous oral pathogen. Actinomycosis presents as a slow-growing cutaneous or soft-tissue swelling of the head, face, or neck. A. israelii is susceptible to penicillin, cefazolin, ampicillin, and erythromycin, in addition to other antibiotics.
Nocardia spp. are aerobic actinomycetes that reproduce by fragmenting into bacillary and coccoid elements, distinguished by filamentous growth with true branching. N. asteroides is a predominant human pathogen. These organisms grow in a wide range of temperatures on simple media but may grow slowly in mixed cultures. They are weakly Gram-positive or stain irregularly. They are also acid-fast. Nocardia spp. have a wide distribution in nature. They may be a respiratory saprophyte in humans, as well as being isolated from the skin. Most human infections begin in the respiratory tract. They are found most often in humans in debilitated states or in immunosuppressed patients, and the infections evade the bactericidal mechanisms of the host. In humans they produce a suppurative necrosis and abscess formation typical of pyogenic infection. They usually enter the eye as a result of a traumatic injury or from hematogenous spread. They respond to sulfanilamides, trimethoprim-sulfamethoxazole, and minocycline.
Fungi are typically divided into yeasts and molds, although some, such as Candida, may grow in both forms. Yeasts are typically round or oval and reproduce by budding. Characteristic yeasts include Candida, Cryptococcus neoformans, Blastomyces dermatitidis, and Coccidioides immitis. Molds are composed of tubular structures called hyphae. They grow by branching in a longitudinal extension. Classic molds include Aspergillus and the agents of mucormycosis. Organisms that grow in the host as yeast-like forms, but at room temperature in vitro as molds, are called dimorphic fungi and include Histoplasma capsulatum, Blastomyces, and C. immitis. Most fungi reproduce asexually by forming spores through mitosis, although sexual reproduction can occur. Fungi that are pathogenic for humans are typically nonmotile and have rigid cell walls that can be stained with Gomori methenamine-silver and, when the organisms are viable, by periodic acid–Schiff. Only Candida can be seen well on Gram-stain. Inside the fungal cell wall are sterol-containing cytoplasmic membranes, which are the site of action of polyene macrolide antibiotics, including amphotericin B and nystatin.
Candida is predominantly a unicellular organism that is small, thin-walled, ovoid, and reproduces by budding. Yeast forms, hyphae, and pseudohyphae may all be identified in clinical specimens; their identification is facilitated by staining with KCl 10%. On culture, it grows as a smooth, creamy-white colony that usually must be identified by physiologic rather than morphologic means. Candida is widespread in soil, hospital environments, inanimate objects, food, and as a commensal of humans, being isolated from diseased skin, the gastrointestinal tract, female genitalia, and the urine of patients with Foley catheters. The incidence of Candida infections has increased with the use of immunosuppression, indwelling catheters, and with increased IV drug use.24,25 Candida typically causes endophthalmitis as a complication of candidemia26 or as a result of epidemics of contaminated irrigating solutions used in intraocular surgery.27 It typically responds to amphotericin, triazoles,28 and 5-fluorocytosine.
Aspergillus spp. have been increasingly identified in endophthalmitis. Aspergillus is a ubiquitous mold with many species, the most common of which are A. fumigatus and A. flavus. Aspergillus grows well in soil, decaying vegetation, hay, dung, compost piles, hospital air-conditioner filters, and potted plants, and may be isolated from the air. IV drug users are not uncommonly found to have Aspergillus fungemia, thought to be caused by contamination of the injected material during its preparation. Exposure to Aspergillus is nearly universal, but disease from Aspergillus is uncommon, suggesting that host factors are important.
Aspergillus creates corneal ulcers after trauma, and endophthalmitis is seen after hematogenous spread, especially in immunosuppressed patients or those abusing IV drugs. Amphotericin is the drug of choice, at times combined with 5-fluorocytosine. Invasive Aspergillus in the soft tissues may require surgical treatment for successful eradication.
Histoplasma capsulatum is a dimorphic fungus found in soil, particularly in areas where avian and bat excrement collect, including blackbird and pigeon roosts and chicken houses. Old buildings where bats and pigeons have roosted are frequent sources of H. capsulatum. The mycelial form consists of septate-branching, hyphae-bearing spores, while the yeast form is oval. Reproduction occurs through budding. Within the viable tissues, H. capsulatum is found almost entirely within macrophages. It is best stained with methenamine-silver but may also be identified with hematoxylin and eosin. Infection begins in H. capsulatum with inhalation of spores. Immunity is based on cellular immune mechanisms, and H. capsulatum is killed by activated macrophages after living as an intracellular parasite.
Histoplasmosis is the most common human fungus infection in the USA. Virtually all persons in the Ohio river valley and along the lower Mississippi river have been infected. Two eye syndromes are produced by H. capsulatum. The presumed ocular histoplasmosis syndrome consists of a morphologic triad of fundus scarring consisting of peripheral punched-out spots, macular disciform scars, and peripapillary scarring. This is thought to be a late effect of H. capsulatum after hematogenous spread has created earlier choroidal infections. Organisms have not been identified in this form of the disease. Endophthalmitis associated with disseminated histoplasmosis has been described in an immunocompromised host.29 Amphotericin is the drug of choice in active disease but is not indicated in presumed ocular histoplasmosis syndrome.
Blastomyces dermatitidis is a dimorphic fungus that grows in a mycelial form at room temperature, and as a yeast at 37°C. These organisms have not been well studied but probably exist in nature in warm, moist soil of wooded areas rich in organic debris. B. dermatitidis is commonly found in outdoorsmen and hunters. It is thought to enter the lung, subsequently producing a widespread pyogranulomatous infection through hematogenous spread involving the lungs, skin, bone, and genitourinary tract. It is a relatively uncommon cause of endophthalmitis. Amphotericin is the treatment of choice.
Protozoa (as represented by Toxoplasma gondii), helminths (including Onchocerca volvulus, Taenia solium, and Toxocara canis), and ectoparasites all produce infestations that may cause a chronic intraocular infection.
Helminths are worms of sufficient size to be visible to the naked eye. Helminths may be the most prevalent infective causative agents in human disease. They are divided into three groups: (1) nematodes, or roundworms; (2) trematodes, or flukes; and (3) cestodes, or tapeworms. Onchocerciasis is produced by Onchocerca volvulus and is the leading cause of blindness in the world, with over 30 million humans affected. Onchocerca is transmitted to humans by bites of blackflies. The larvae then make their way through the skin and lodge in connective tissue, where adult worms tend to collect in nodules of tissue. Within the eye they produce chronic infestation. The microfilariae, swimming in the anterior chamber, may be identified by slit-lamp examination. A single dose of ivermectin is capable of killing the microfilariae but not the adult worms.
Taenia solium, a trematode, is the pork tapeworm for which humans are the only definitive host. Ingestion of the organism allows the development of the intermediate-stage Cysticercus cellulosae. This organism may invade almost any area of the body, including the vitreous cavity. Other helminths of ocular importance are Toxocara canis and T. cati. The predominant hosts for these organisms are dogs and cats, respectively. There are a large number of viable eggs, particularly from T. canis, in the environment. Eggs are spread by direct ingestion or, in the case of dogs, by eating infected meat. T. canis in children produces a chronic inflammatory granulomatous disease involving the vitreous and retina.30
Toxoplasmosis is the most common protozoon causing eye disease.31 Toxoplasma gondii is an obligate intracellular protozoon that is ubiquitous in nature, infecting all herbivorous, carnivorous, and omnivorous animals. The definitive host is the cat. The ingestion of raw or uncooked meat allows tissue cysts to enter the gastrointestinal tract where they are broken down. They then invade the walls of the gastrointestinal tract and spread throughout the body to many tissues. The organisms remain viable for the life of the host. Although most humans are asymptomatic for the infection, a recurrent panuveitis may be an ocular manifestation of infestation.
Ectoparasites are organisms that live on the skin of a host, from which they derive their sustenance. The phylum Arthropoda includes the two-winged, or dipterous, flies. The larvae or maggots of these flies may invade living or necrotic tissue of animals and humans, producing myiasis. Multiple dipterous flies are thought to be capable of producing ocular myiasis. It is thought that the larvae are imbedded in the eye, that they burrow directly through the sclera and then under the retina. Typically, they leave asymptomatic tracks throughout the fundus, but a number of cases of destructive endophthalmitis have been reported, particularly from Scandinavia.
Meyers-Elliott and Dethlefs32 injected Klebsiella oxytoca organisms into the vitreous cavity of the phakic rabbit. Pathologic evaluation demonstrated widespread polymorphonuclear leukocyte invasion throughout ocular tissues within 24 hours and significant photoreceptor degeneration within 48 hours. Peak numbers of organisms could be cultured from the eye at 24 hours, but they declined spontaneously, with no organisms being recovered after 72 hours. Pathologic signs continued to increase once the cavity was sterile, however, implicating endotoxins as important to ongoing tissue damage. Davey and colleagues33 injected K. pneumoniae and Pseudomonas aeruginosa into the vitreous of the phakic rabbit and noted that bacterial growth peaked at 48 hours, with the number of organisms falling spontaneously after this. Measurable changes in biochemical parameters of the vitreous did not seem to account for this phenomenon; the authors postulated that it might be a characteristic of Gram-negative infections. Meredith and coworkers34 created an experimental model of Staphylococcus epidermidis endophthalmitis by injecting various numbers of organisms into the vitreous cavity of the aphakic rabbit. Low numbers of organisms produced mild disease with slow progression; some infections appeared to be self-limited. Larger numbers of organisms produced infections of greater intensity, which were almost uniformly steadily progressive. Organisms could not be recovered from the vitreous cavity after 96 hours, however, regardless of the size of the initial inoculum. This fact suggests that progressive inflammatory signs were related to factors other than continuing active infection. Other models of S. epidermidis have yielded organisms from the phakic eye as long as 7 days after their injection into the vitreous. Peyman35 produced endophthalmitis with S. aureus in phakic rabbits to compare various treatment regimens, reporting uniformly poor results with loss of the eye in untreated animals.
Beyer et al.36 studied the role of the posterior capsule in the development of S. aureus endophthalmitis in the primate. Nine monkeys had bilateral lens extraction; in one eye a large capsulotomy was performed, while in the other the capsule was intact. Inoculation of 105 S. epidermidis organisms was made into the anterior chamber, and the vitreous was cultured after 72 hours. Only one culture was positive with the capsule intact, but all nine cultures were positive when the capsule was opened. The experiment was repeated with a posterior-chamber lens implanted. None of ten eyes with an intact capsule and IOL was culture-positive, whereas 40% of the eyes with the capsule open and a lens in place were culture-positive and an additional 20% showed histopathologic signs of vitreous inflammation. An intact posterior capsule thus appeared to inhibit the spread of infection from the anterior chamber into the vitreous cavity, an effect that was not compromised by the addition of a posterior-chamber IOL.
Anaerobic organisms have also been used to produce clinical disease in the rabbit. The injection of 1000 organisms of Fusobacterium necrophorum into the vitreous cavity of the phakic rabbit produced clinical infection in 100% of eyes. Propionibacterium acnes was studied in the aphakic rabbit with and without a posterior-chamber IOL.37 Injection of 108 organisms into the anterior chamber produced a severe infection, while inoculation of 2.5 × 106 produced clinical inflammation that peaked at 3 days but persisted for up to 24 days. The presence of an IOL appeared to favor the development of chronic, low-grade inflammation.
Postoperative infection is the cause of roughly two-thirds of all cases of endophthalmitis in most clinical series. Although infectious endophthalmitis may follow any operative procedure performed on the eye, most cases follow cataract extraction, and almost all are bacterial in origin. Studies from a single institution suggest that the incidence of endophthalmitis over the past several decades has been declining. At the Bascom Palmer Eye Institute, the incidence from 1984 to 1994 was 0.09%, dropping to 0.05% from 1995 to 2001.38 Recent studies indicate that causative organisms in infection after cataract surgery are usually genetically identical to the patient’s own flora.39,40 In 75–95% of the reported cases, the causative organisms are Gram-positive. A significant percentage of cases of apparent infectious endophthalmitis proved to be culture-negative.2,3,41
Allen42 reviewed 30 000 intracapsular cataract procedures performed at the Massachusetts Eye and Ear Infirmary from 1964 to 1977, and found an incidence of endophthalmitis of 0.057%. A review of 23 625 cases of extracapsular cataract extraction from Bascom Palmer Eye Institute revealed an incidence of 0.072%.5 More recent figures from two studies in the phacoemulsification era suggest an incidence of 0.03%43 to 0.04%38,44 National registries in Sweden45 and Norway46 identified rates of 0.1% and 0.11–0.16%, respectively.
Symptomatically, typically the patient notes a sudden increase in pain 1–7 days after surgery. Examination demonstrates conjunctival chemosis and increased injection, often with a significant amount of yellowish exudate in the conjunctival cul-de-sac. The upper lid becomes edematous and may be difficult to open to complete a thorough examination. The cornea demonstrates variable degrees of edema, and pigmented cells may accumulate on its posterior surface. The surgical wound may show signs of dehiscence, and in advanced cases exudate can stream from the wound. The anterior chamber shows heavy flare and cells, and hypopyon is often present in the inferior angle, sometimes mixed with a tinge of red blood. In more extreme cases the anterior chamber is filled with exudate, and the cornea is white. When an IOL is in place, a fibrin membrane is usually present over both surfaces.
Heavy cellular debris is present in the vitreous, and there may be focal accumulations of whitish material or sheets of opacification within the vitreous. The intraocular pressure may be low, normal, or high. The pupil often dilates poorly, making examination with an indirect ophthalmoscope difficult. Retinal periphlebitis47 has been reported as an early sign, but in most cases the retinal vessels are seen poorly, if at all. With more severe disease, large areas of opacity are seen within the vitreous; there may be a red reflex, or only a dark appearance to the posterior cavity.
Infection caused by Staphylococcus epidermidis and other species of coagulase-negative staphylococci may have the clinical onset delayed by 5 days or more after surgery. Even then, the clinical signs and symptoms may be mild and may be difficult to distinguish from a noninfectious inflammatory process.1,4,48,49 There was no hypopyon or pain in 25% of confirmed cases in the Endophthalmitis Vitrectomy Study (EVS).50 In this study a number of clinical features at initial presentation were associated with microbiologic factors. More severe initial findings suggest infection with Gram-negative bacteria, Streptococcus or Staphylococcus aureus. Factors noted at initial diagnosis correlating with Gram-negative and Gram-positive organisms other than Gram-positive coagulase micrococci included corneal infiltrate, cataract wound abnormalities, afferent pupillary defect, loss of red reflex, initial light perception-only vision, and symptom onset within 2 days of surgery. Gram-negative organisms were not identified in those eyes in which retinal vessels were visualized preoperatively; 61.9% of those eyes had equivocal or no growth. Diabetes mellitus was associated with a higher yield of Gram-positive, coagulase-negative micrococci, while there was a shift toward other Gram-positive organisms in eyes undergoing secondary IOL implantation compared with those that had initial cataract surgery.51,52
Late-onset disease may occur with predisposing anatomic problems such as a persistent conjunctival filtering bleb or the presence of a vitreous wick.53 Chronic, low-grade inflammation that ultimately proves to be of an infectious origin may occur in rare instances and has been termed chronic postoperative endophthalmitis or delayed-onset endophthalmitis.16,54 This may occur secondary to coagulase-negative Gram-positive organisms (such as S. epidermidis)16,54 and also results from infections with the anaerobic species Propionibacterium acnes.15–20 In reviews of cases of endophthalmitis after cataract extraction, a significant incidence of intraoperative complications has been found.16–18,55–57 Postoperative filtering blebs, wound leaks,55 and vitreous wick are also found more frequently in infected eyes.2 Infection can also result after the cutting of sutures holding the cataract wound or after an invasive procedure to incise the posterior capsule.2,58
The type of cataract incision has recently attracted attention as a possible contributor to the incidence of postoperative infection. A case–control study demonstrated a threefold greater risk of endophthalmitis with clear corneal incisions than with scleral tunnel incision.59 However, this has not been confirmed by newer studies.60,61 Temporal incisions were noted to have a higher incidence of infection than superior incisions in another study.62 A case–control study of secondary IOL implantation showed endophthalmitis to be associated with diabetes mellitus, transscleral suture fixation of posterior-chamber IOLs, polypropylene haptics, preoperative eyelid abnormalities, re-entry of the eye through a previous wound, and postoperative wound defects.63
Gram-positive organisms are found in 75–90% of culture-positive cases.3,51 Most common is S. epidermidis, followed by S. aureus and Streptococcus spp. Gram-negative organisms accounted for only 6% of the culture-positive cases in the Endophthalmitis Vitrectomy Study.3,51 Fungi are rare, with the exception of epidemics such as those of Candida parapsilosis64 and Paecilomyces lilacinus,65 which were traced to infected irrigating solutions. Bacterial epidemics have also been traced to an infected phacoemulsifier (Pseudomonas),66 and to infected viscoelastic material (Bacillus spp.).67 Culture-negative cases account for 25–35% of cases of pseudophakic endophthalmitis.2,3,51,68
Since endophthalmitis after corneal transplantation is rarely seen, its characteristics are less well defined. In two large series of corneal transplants, an incidence of 0.11% and 0.08% of postoperative endophthalmitis was reported.38,69 In a review of over 90 000 cases between 1972 and 2002, the incidence after PKP was 0.38%.70 Guss et al.69 studied 445 corneal transplant cases and demonstrated that, in addition to three acute cases, there were eight other cases, six of which occurred after an ulcerative process in the graft. Endophthalmitis of delayed or late onset can also result from suture abscess formation or from bacterial access to the anterior chamber associated with a loose suture.71 In an ulcerative process, entry may occur because of disruption of continuity of the graft, or the bacteria may invade through an intact but thinned cornea. Endophthalmitis following corneal transplantation has also been associated with a vitreous wick. Unlike endophthalmitis following cataract surgery, the onset of the disease may be relatively painfree and is heralded by an increased anterior-chamber reaction, hypopyon, and loss of red reflex. The bacteria usually involved in these cases are Gram-positive, with Staphylococcus spp. and Streptococcus spp. being equally represented; fungal and Gram-negative cases are least common. In the series of Leveille et al.,72 three of four acute cases were associated with a contaminated donor rim; this was not noted in any of the cases reported by Guss et al.69 The prognosis in post-corneal transplantation cases is poor; nine of the 11 cases reported by Guss et al.69 had final vision of light perception or no light perception.
The risk of developing endophthalmitis after filtering surgery is similar to the risk following cataract extraction,5,38,73–76 but most of these cases occur months to years after the original procedure. A prodrome of browache, headache, or eye pain is not uncommon.77 There may be an antecedent conjunctivitis, but often the abrupt onset of pain and redness constitutes the presenting signs and symptoms. An inferior location to the bleb and use of antifibrotic agents increase the likelihood of subsequent infection.78–80 The blebs may appear intact in these cases, although some may be Seidel-positive.53,80 Thin, avascular, and leaking blebs appear to be at increased risk of infection.77 The material within the bleb is white or yellow, giving a “white-on-red” appearance against the conjunctival erythema. Eyes with glaucoma drainage devices are also at risk for infection.75 The spectrum of bacteria isolated from culture-positive bleb infection is quite different from that of endophthalmitis following cataract surgery, with 31–57% demonstrating Streptococcus spp. as the causative organism53,77,79,81–83 More recent series have found more cases caused by Staphylococcus spp. and Enterococcus spp. than older reports. Gram-negative species are also more common than after acute post-cataract infections.83 Visual outcomes remain generally poor in these cases, even with modern therapy. In two large series, 50% of eyes had final visual acuity of 20/400 or better,82,83 in part because of the influence of Streptococcus spp. infections on the outcome.
The incidence of endophthalmitis after pars plana vitrectomy appears to be about the same as that after other intraocular procedures.38,84 The diagnosis is most difficult to make because the normal postoperative pain and intraocular inflammation after vitrectomy may mask the symptoms. The diagnosis rests on findings that are more severe than usual; appearance of hypopyon is often rapid and should cause particular concern.84,85 In one case with intraocular silicone, findings were limited to a whitish material collecting between the silicone and the retina.86 The spectrum of bacteria in these cases is similar to other acute postoperative infections. In spite of this, the prognosis is uniformly poor, and retention of vision is rare.
The first large, multicenter studies in the era of small gauge vitrectomy suggested a significant higher rate of endophthalmitis with 25-gauge sutureless vitrectomy (0.23 and 0.84)87,88 Since then, several large series have not confirmed these findings.89–92 Optimized wound construction, modifications in case selection and a lower threshold for suturing appear to reduce the incidence of endophthalmitis in small gauge cases to the level of standard 20-gauge cases.
Introduction of organisms into the eye may occur during a pars plana injection of intraocular gas for pneumatic retinopexy.93 In recent years intraocular injection of medications to treat age-related macular degeneration, macular edema, retinal vein occlusions, cytomegalovirus retinitis and uveitis have increased in frequency dramatically, resulting in increased numbers of cases of endophthalmitis. The reported incidence of endophthalmitis following intravitreal injections varies significantly. A recent review paper described a rate of endophthalmitis from 0.014% up to 0.87% per injection. The overall incidence was 0.051% (50/98 962).94 Injection technique used varied from study to study. To this day there is no clear consensus on a “standard” injection protocol as for the use of a sterile drape, gloves, surgical mask or topical antibiotics. So far, only the use of povidone iodine and a lid speculum is routinely recommended.95 Cultures most frequently showed coagulase-negative staphylococci as causative organism, with atypical organisms being more common after the use of triamcinolone.94 With triamcinolone, the typical clinical signs of endophthalmitis may be masked by antiinflammatory effects and the presentation may be difficult to differentiate from a pseudohypopyon without infection which can occur after triamcinolone injection caused by deposition of the injected material in the anterior chamber.96
Most infections after retinal detachment by scleral buckling are confined to the extrascleral implant. In past years these have resulted in endophthalmitis, but this is now an exceedingly rare occurrence because scleral flaps, diathermy, and polyethylene implants only rarely used. Organisms may be introduced into the eye during an inadvertent perforation of the sclera by a suture or during the drainage procedure. Since these maneuvers introduce organisms present in the tear film or adjacent skin and lashes, staphylococcal species are most commonly reported. It has been suggested that the diagnosis, like that after pars plana vitrectomy, rests on findings of pain and inflammation in the early postoperative course that are more severe than expected.
Endophthalmitis is a rare but devastating complication of strabismus surgery. True endophthalmitis probably always occurs after an inadvertent suture perforation, although a scleral abscess at the site of a suture could possibly lead to an intraocular infection. Lethargy, asymmetric eye redness, eyelid swelling, and fever have been reported as presenting signs, but diagnosis may be delayed.97 Prognosis is poor in these eyes, possibly because delays in diagnosis are common.97,98