Infectious Endophthalmitis



Infectious Endophthalmitis


Travis A. Meredith



Infectious bacterial endophthalmitis occurs when bacteria gain entrance to the interior of the eye, replicate, and produce an inflammatory response that may eventually involve tissues throughout the eye. Most infections occur after a breech of the external coats of the eye by surgery or trauma. Direct invasion of the interior of the eye through the cornea or sclera following local abscess can occur but is relatively uncommon. Endogenous endophthalmitis occurs when an infected source elsewhere in the body leads to metastatic intraocular infection. There are many classifications of endophthalmitis, but the most commonly recognized categories are: (a) Postsurgical: acute, and delayed or chronic; (b) posttraumatic; (c) bleb-related; and (d) endogenous: fungal, bacterial, and other.

Eyes with apparent infection may not grow out bacteria when appropriately subjected to culture. These cases are commonly called sterile endophthalmitis and accounted for 31% of the post-cataract surgery infected eyes entered into the Endophthalmitis Vitrectomy Study (EVS).1,2 Polymerase chain reaction (PCR) evidence indicates that many of these cases may be the result of bacteria present in the eye that do not grow on culture.3,4 Another syndrome, commonly referred to as a Toxic Anterior Segment Syndrome, is a reaction to intraocular foreign material, such as intraocular lenses or toxic irrigating solutions.5 The term pseudo-endophthalmitis also has been used, probably incorrectly, to designate accumulation of injected corticosteroid in the anterior chamber producing a white layering called a pseudohypopyon.


INCIDENCE

In most mixed clinical series, approximately two-thirds of cases of endophthalmitis are caused by postoperative infection.6,7,8,9 The majority of cases of endophthalmitis occur after cataract extraction because of the frequency of the procedure. The causative organisms are presumed in most cases to be introduced during surgery, and genetic studies have demonstrated that after cataract surgery the organisms isolated are genetically identical to the patient’s own flora.10,11 There is some difference in incidence based on the epidemiologic approach. National registries in Sweden12 and Norway13 found rates of 0.1% and 0.11% to 0.16%, respectively. In hospital-based surveys, Allen reported from the Massachusetts Eye and Ear Infirmary for the 13-year period ending in 1977 that the incidence of endophthalmitis was 0.057%.14 A review from the Bascom Palmer Eye Institute, of 23,625 cases of cataract extraction, revealed an incidence of 0.072%,15 but a more recent study, from 1995 to 2001, noted that there was a drop in incidence to 0.05%.16 A review found that a freestanding (ASC) experience documented a 0.3% incidence.6 The incidence after pars vitrectomy is similar.16,17

In cases of endophthalmitis after cataract extraction, a significant relationship to operative and postoperative complications has been identified. Capsular rupture, vitreous loss, wound leaks, postoperative filtering blebs, and vitreous wick have been identified as associated with the postoperative infection.18 The type of incision may contribute to the incidence of postoperative infection. In a recent case-control study from an ASC, a threefold greater risk of and optimize with clear corneal incisions was identified compared to scleral tunnel incisions.19 A higher incidence of infection has been noted in temporal incisions that was superior incisions in another study.20 In secondary intraocular lens (IOL) implantation, a case-control study showed an association of infection with diabetes mellitus, propylene haptics, scleral suture fixation of posterior chamber IOLs, preoperative eyelid abnormalities, postoperative wound defects, and re-entry of the eye through a previous wound.21

Intraocular injections of corticosteroid and antibiotics have become increasingly common and will undoubtedly increase in the future, because intraocular injections are being introduced for treatment of macular degeneration. A review of 4,382 eyes that received 14,866 injections documented 38 cases of endophthalmitis for risk of 0.2% per injection.22

After filtration bleb surgery the immediate incidence of infection is similar to cataract surgery or higher, but the eye remains at risk as long as the bleb is present. Studies suggest that the rate of infection on a yearly basis may be as much as 1% to 7.9%.23,24,25 Glaucoma drainage devices also may become infected.26

Posttraumatic cases account for roughly 25% of all cases of endophthalmitis.6,7,8,9 The likelihood of infection is at least 100 to 300 times higher than after elective cataract surgery. Rates of infection after penetrating injury are approximately 2% to 3%,27 rising to 11% to 20% with retained intraocular foreign body.28,29,30 The National Eye Trauma Registry System surveyed 429 cases of intraocular foreign bodies and documented an incidence of endophthalmitis of 6.9%. There was no significant difference in risk depending on whether the foreign body was metallic, nonmetallic, or organic material.29 Thirty percent of injuries in rural environments in one study became infected.31

The relevant group for incidence studies for endogenous endophthalmitis is not clear. Patients with known fungal septicemia frequently develop white dots in the choroid and retina that respond as a systemic disease is treated. Frank endogenous infection is relatively uncommon.


CLINICAL PRESENTATION AND CHARACTERISTICS


ACUTE POSTOPERATIVE ENDOPHTHALMITIS

Acute postoperative endophthalmitis may follow any intraocular surgery. Because cataract surgery is by far the most common ophthalmologic procedure, infections following lens extraction and IOL implantation are most often encountered. Infection may follow minor manipulations such as cutting sutures in corneal grafts or cataract incisions.32 Infection usually begins within the first 6 weeks, often within the first 1 to 2 weeks. More virulent organisms generally produce symptoms earlier. There is also a subgroup, termed delayed or chronic endophthalmitis, in which the onset of infectious symptoms may be delayed for 2 to 4 months.33,34

The EVS was a National Eye Institute supported multicenter randomized clinical trial that evaluated four treatment regimens in post-cataract endophthalmitis. The study is important in understanding the current demographics and clinical parameters of post-cataract infection in United States. The study also served to validate proper diagnostic techniques and establish certain treatment regimens as most likely to be successful.2

Patients typically notice increased pain, sometimes beginning with a scratchy or irritated sensation. This usually is accompanied by blurred vision. Patients may notice increased exudates as well. In the EVS approximately 75% of patients had pain as a presenting symptom.35 The time of onset of symptoms is correlated with the organism’s virulence. In a large study of Staphylococcus epidermis endophthalmitis by Omerod36,37 58% of the cases had the onset within the first week after surgery, whereas 42% were delayed into the second week or later. In the EVS there was a tendency for infections produced by more virulent organisms such as Staphylococcus aureus, Streptococcus, and gram-negative infections to present in the first two days after surgery.38 The eye has varying degrees of redness, exudate, and lid edema. Slit-lamp examination may reveal wound complications or wound infiltrate, although in the phacoemulsification era these are relatively less common than identified previously. Increased anterior chamber flare and cell is almost always present; as the condition becomes more severe, variable degrees of fibrin are noted. Hypopyon is considered the hallmark of infection but it was only seen at presentation in 75% of the EVS patients.35 In early cases when the fundus may still be seen, vasculitis has been described as one of the earliest findings.39 Vitreous inflammation, however, is an invariable part of the presenting picture and usually is severe enough to obscure a clear fundus detail. Eyes with more virulent organisms are more likely to present with swollen eyelids, have light perception-only vision, demonstrate an afferent papillary defect, a corneal infiltrate, and loss of the red reflex.38

In the EVS, 69% of the eyes were culture positive, but 31% were culture-negative. Of culture-positive eyes, 70% grew coagulase-negative staphylococci. Only 6% of eyes grew gram-negative organisms. Polymicrobial infections were identified in 9% of the cases.2,40

After most intraocular surgery the major differential is between infection and an exaggerated inflammatory reaction to the surgery. When there is significant retained lens material, inflammation usually is greater than expected.41 Retained cortical material may produce an increased inflammation, which usually is evident from seeing pieces of cortex in the peripheral portion of the capsular bag or displaced into the vitreous or anterior chamber. Retained nuclear material usually creates less inflammation.


DELAYED-ONSET POSTOPERATIVE ENDOPHTHALMITIS

Endophthalmitis may present some weeks after the initial surgical procedure. Less virulent bacteria and fungi usually are suspected. Propionibacterium acnes produce a particular syndrome that may be suspected from the clinical presentation.42,43,44 In the initial description of this disorder the average interval between cataract surgery and microbiological confirmation of the infection was 12 months. Most cases present 2 months or later after the initial surgery. The majority of patients present with granulomatous anterior uveitis, although nongranulomatous reactions also are observed, and some patients can even have hypopyon. A finding that is almost pathognomonic is a white plaque found on the capsule. These may be observed to increase in size under serial observation.45,46 Some relatively nonvirulent bacteria can produce a chronic inflammatory response as do fungi. There is no other constellation of findings that can distinguish between fungal infection and less virulent bacteria. Culture and stains are necessary to make the diagnosis in these cases. The laboratory must be notified that the specimen must be specifically analyzed for fungi; for those in which P. acnes is suspected that the culture must be held for 2 weeks because the organism is slow growing.


BLEB-RELATED ENDOPHTHALMITIS

Most cases of bleb-related endophthalmitis occur months to years after the original procedure. Both intentional filtration blebs and traumatic blebs are susceptible to infection. Patients may have a prodrome of browache and/or headache. There often is an antecedent conjunctivitis manifested as redness of the eye with some degree of exudation.23,24,25,47,48 Patients who have inferior bleb and those in whom antifibrotic agents have been used are more susceptible to infection.23,24,25 Although some blebs are Seidel-positive, intact blebs also may become infected. Thin blebs may be at higher risk. A recent report documented that bleb manipulations and bleb revisions are significant risk factors for the creation of bleb-related endophthalmitis.49

The clinical presentation is classically described as “white-on-red” because the bleb is filled with white or yellow material in contrast with the surrounding conjunctival erythema. Examination findings of the cornea, anterior chamber, iris, and vitreous are similar to that in postoperative endophthalmitis.

An important differential diagnosis is that of blebitis versus bleb-related endophthalmitis. Absence of vitreous involvement indicates the diagnosis of blebitis.48,50 Bleb-related infections have a very different bacterial spectrum than those from endophthalmitis following cataract surgery Streptococcus sp. are identified in 31% to 57% of eyes.49 More recently, Staphylococcus and Enterococcus have been reported increasingly as the causative organisms, and gram-negative species also are found.49,51


TRAUMATIC ENDOPHTHALMITIS

In traumatic endophthalmitis bacteria are introduced into the eye by traumatic penetration of the sclera or cornea. Studies have shown that not all patients who are culture-positive at vitrectomy for trauma develop endophthalmitis, possibly as the result of removal of the organism by the vitrectomy.30,52 The differential diagnosis is between posttraumatic uveitis and true infection; severe inflammatory signs from the initial injury may make the diagnosis of endophthalmitis more difficult.

Typically patients have increased pain and redness postoperatively. Gram-positive organisms are responsible for approximately two-thirds of postoperative infections. Gram-negative organisms may cause 10% to 15% of the infections. However, several series have indicated that Bacillus infections are a responsible for 20% to 25% of posttraumatic infections, and most of these are associated with intraocular foreign bodies.28,31,53,54,55

The rapidity of onset of symptoms may offer some clue to bacteriologic diagnosis, because Bacillus spp. produce a rapidly progressive infection. Findings in Bacillus infection include marked chemosis and exudates, a ring infiltrate of the cornea, diffuse opacification of the cornea, and severe intraocular inflammation. In other cases of endophthalmitis, a hypopyon appears and the vitreous may become more clouded after otherwise successful surgery.

Fungal infections may have a late onset and are seen in as many as 15% of cases of traumatic endophthalmitis. In the clinical presentation of these infections there may be the appearance of yellow or white fluffy material in the anterior chamber and/or vitreous cavity. Other cases are indolent and have progressively increased inflammatory changes in the anterior chamber and vitreous cavity.


ENDOGENOUS ENDOPHTHALMITIS

Endogenous endophthalmitis occurs primarily in patients with systemic illness. Many of these individuals are immune compromised; others may have systemic illness including endocarditis, urinary tract infections, recent gastrointestinal surgery, or hepatobiliary infections.56,57,58,59 In a large series of endogenous fungal endophthalmitis, important predisposing factors were intravenous hyperalimentation, a history of cancer, and a fever of unknown origin.60 The presenting symptoms and signs depend on the series being reviewed. Illness may be detected in an outpatient setting where ocular symptoms are the first presenting signs of the generalized illness. Others present as a complication in patients with known systemic sepsis or immunosuppression. In two series most initial contact was made with an ophthalmologist, whereas in another series most of the patients were hospitalized at diagnosis. Initial symptoms may be mild with decreased vision and redness, pain, and photophobia. Because patients may be quite ill, sometimes these symptoms are not adequately stressed to the caregivers on an acute medical service.59 The initial misdiagnosis rate approaches 50% in some series.56,58 Initial incorrect diagnoses included iritis and uveitis, conjunctivitis, glaucoma, and cellulitis. Therefore, diagnosis is frequently delayed until the disease has become more advanced. Bilateral presentation is fairly common and is reported in 15% to 26% of cases.56,57,58,59

When endogenous endophthalmitis is considered, an internist or infectious disease specialist usually is consulted to search for the systemic source of infection. Blood cultures are frequently critical in establishing the diagnosis. A wide range of organisms are causative for this infection and 50% to 62% of the cases have been reported owing to fungal agents. Candida spp. are the most common isolate in some series, whereas Aspergillus has been noted by other authors. Gram-positive organisms are more prevalent than gram-negative organisms.56,57,58,59


PRINCIPLES OF DIAGNOSIS

The clinician must be alerted to the possibility of the diagnosis of endophthalmitis by the clinical findings. In eyes with greater than expected intraocular inflammation based on the clinical setting, a high degree of suspicion is important. Failure to appreciate the potential severity of the problem may delay diagnosis. If endophthalmitis is suspected frequent observation versus active intervention must be chosen. In some instances it may be appropriate to initiate anti-inflammatory therapy and monitor the patient two to three times daily until the clinical course in becomes clear.

For unequivocal diagnosis samples of the aqueous and vitreous must be obtained for culture, sensitivity, and stain using the techniques described in the following. Samples from the vitreous are more often positive that are samples from aqueous.61,62 Vitreous samples are positive as frequently from a tap/biopsy as they are after vitrectomy to obtain the specimen.22 Undiluted vitreous and aqueous may be placed on the following media for culture: enriched thioglycolate liquid medium, chocolate agar, Sabouraud’s agar. Anaerobic cultures typically use either thioglycolate enriched broth or blood agar enriched with hemin and vitamin K. In some institutions material from the vitreous cassette after vitrectomy is filtered through a 0.45μ membrane filter. The filter is subsequently divided into three pieces under sterile conditions and used for culture.2

Stains are prepared from anterior chamber and vitreous specimens. In the EVS, the findings of a positive gram stain were associated with significantly worse final media clarity and visual acuity. The gram stain result did not reveal any subgroups in which vitrectomy had a beneficial value and therefore was of little consequence in making initial therapeutic decisions.63 In the EVS there was no difference between the positive rate for culture between samples obtained by tap and those which were obtained by vitrectomy. There was no significant difference in operative complication between the two methods.


PRINCIPLES OF THERAPY

In modern endophthalmitis therapy, intravitreal antimicrobial injections are the mainstay of treatment.64 Pars plana vitrectomy has an important role in management of several clinical presentations and stages of the disease. Subconjunctival antibiotic injection and topical antibiotic injection were previously considered major routes for antibiotic administration, but now has a less important role.65 Corticosteroid therapy is important in improving the final outcome, but there is debate over the proper routes of administration.


ANTIMICROBIAL THERAPY


Choice of Antimicrobial Agent

Because endophthalmitis therapy must be initiated emergently, the identity of the organism is unlikely to be known at the time antimicrobial agents must be chosen. The vast majority of endophthalmitis infections are gram-positive in origin.2,66,67 As noted, the clinical setting often determines which organisms are more likely to be present. Because it is almost impossible initially to rule out gram-negative organisms as the cause of most infections on clinical examination, broad-spectrum antibiotic coverage usually is chosen.38 In practice, this usually means empiric treatment with two separate antimicrobial agents as the initial choice.

Desirable characteristics for antimicrobial agents for treatment of bacterial endophthalmitis include the following:68



  • Broad spectrum of coverage. Gram-positive organisms including methicillin-resistant staphylococci and Bacillus as well as gram-negative organisms must be covered.


  • Bactericidal properties. A bactericidal drug is preferable because the eye is an immune-privileged site.


  • Excellent therapeutic ratio (activity/toxicity) after intravitreal injection. The therapeutic window is the dose range between the lowest potentially efficacious dose and the upper limits established by tissue toxicity in the host. In evaluation of drugs for intraocular injection, the usual parameters studied for indications of toxicity are electroretinographic testing, histologic sectioning, and electron microscopic studies. Toxicity may be increased by repeated injections of certain antibiotics, a phenomenon that has not been extensively studied at this time.69,70,71


  • Excellent therapeutic ratio after systemic administration. Medications administered orally or parenterally typically have poor penetration from the bloodstream into the eye.68,72,73 There are several blood–eye barriers that reduce the ability of the antimicrobial to achieve access to intraocular structures. The concentration of antimicrobial in the aqueous humor is typically higher than that in the vitreous cavity. Intravitreal antimicrobial levels do not reach or exceed the minimum inhibitory concentration (MIC) in the vitreous cavity for many of the target organisms after systemic administration. Lipid-soluble compounds penetrate into the eye better than the hydrophilic antibiotics such as aminoglycosides. Inflammation may break down blood–eye barriers allowing increased penetration.68,74,75,76 Aminoglycosides and amphotericin have significant systemic toxicity, limiting their effectiveness.77 Combinations of antibiotics such as vancomycin and aminoglycosides may improve coverage, but have additive toxicities.


  • Pharmacodynamics. The most favorable pharmacokinetic parameters are for a drug to access the eye readily from the bloodstream but to be retained within the eye for long periods of time after intraocular injection. This combination of characteristics is rarely, if ever, seen.

The highest possible initial dose is chosen whenever possible so that the drug remains above the MIC for the longest period of time. Drugs with longer half-lives are also preferred because the effective dose of drug is thought to be eliminated from the drug by the expiration of five half-lives. The upper limit of drug concentration is defined by the toxicity, usually in the form of retinal deterioration. If other characteristics are equivalent, then choice of the drug exceeding the MIC by the greatest degree is preferable. Some authors have suggested that concentrations of 10 to 30 times the MIC are necessary to effectively treat infections elsewhere in the body.


Intraocular Injections

The standard of care for most cases of endophthalmitis is intraocular injection of antimicrobial agents. Antibiotics injected into the vitreous cavity are eliminated from the eye by either an anterior or posterior route. β-Lactam antimicrobials were removed posteriorly, whereas the aminoglycosides exit through the anterior (trabecular meshwork) route.78,79 The removal of the vitreous shortens the half-life of antimicrobials, whereas lens removal also can shorten the half-life of those using an anterior route of elimination. Inflammation breaks down blood–retinal barriers and also decreases the half-life of anteriorly eliminated drugs.80,81,82,83

Although some controversy exists, there is a short half-life of most injected antimicrobials, so that effective duration of action of many antibiotics may be somewhere between 36 and 72 hours. Toxicity has been demonstrated in the form of retinal vascular shutdown by intravitreal aminoglycosides84,85,86,87 and retinal necrosis in the case of other antibiotics.70,71 Combinations of antimicrobials such as vancomycin and amikacin may increase their toxicities.70,71 The antimicrobials usually chosen for intraocular injections at this time are the following agents:

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Jul 11, 2016 | Posted by in OPHTHALMOLOGY | Comments Off on Infectious Endophthalmitis

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