US Pharm. 2011;36(4):HS-7-HS-18.
Endophthalmitis, or inflammation of the eyeball interior, is a rare but severe intraocular disorder that often results from infectious inoculation of the vitreous body (jellylike area behind the lens). When not treated appropriately, the condition can result in loss of vision or loss of the affected eye. The source of infection is either endogenous or exogenous. Endogenous, or metastatic, endophthalmitis occurs when a systemic infection invades the vitreal space. This form is more likely to occur in patients with underlying risk factors, particularly immunosuppression. Exogenous endophthalmitis most commonly develops after intraocular surgery—particularly cataract surgery—but also may present following an acute eye injury.1,2
Overall, an estimated 25% of endophthalmitis cases result from ocular trauma, and the incidence of endophthalmitis after open-globe injury is approximately 7%.1 Injuries involving intraocular foreign bodies may have an incidence of endophthalmitis as high as 30%.3 Risk factors for developing endophthalmitis after acute eye injury include lens capsule rupture, dirty wound, older age, presence of intraocular foreign bodies, and initial presentation more than 24 hours after injury.1 In fact, one study reported that the risk may actually increase with each hour of delay in seeking treatment.4
Clinical Presentation and Diagnosis
Following ocular trauma, endophthalmitis may develop within hours or occur up to several weeks afterward, depending upon the virulence of the infecting organism. Symptoms include pain, redness, reduced and/or blurred vision, and lid swelling. Pain and swelling are common after a traumatic injury, and the occurrence of symptoms that are more severe than those expected from the injury itself must be investigated.1
Upon presentation, the examination may include a best-corrected visual acuity examination, a slit-lamp examination, indirect ophthalmoscopy, and Goldmann applanation tonometry (measurement of intraocular pressure by pressing and flattening an area on the corneal surface).5 Hypopyons (layers of pus in the anterior chamber) are found on examination in nearly 75% of patients with endophthalmitis and are suggestive of the diagnosis. Examination may also reveal progressive vitritis, anterior chamber inflammation, and corneal edema. Retinal vasculitis and hemorrhage are less common, but they can occur in more severe disease.1,3
In addition to direct examination, CT or ultrasound imaging may prove helpful in identifying the location of intraocular foreign bodies. MRI should not be used because of the risk of injury if the foreign body is magnetic.3 Left untreated, the disease can progress to panophthalmitis (inflammation of the entire eye), corneal infiltration, perforation, orbital cellulitis, or phthisis bulbi (in which the eye is shrunken, atrophied, and nonfunctional).1,3
The cause of endophthalmitis will determine the likely infecting organisms and guide the choice of empiric therapy. In one review, Bacillus and Staphylococcus species were present in 95% of culture-positive cases of endophthalmitis involving foreign bodies, with Bacillus being more common when the foreign bodies were of organic composition.6 Infection also may be caused by Propionibacterium acnes, Pseudomonas species, Streptococcus species, other gram-negative organisms, fungi, or a mixture of pathogens.1,3
There is no clear correlation between culture results obtained following an acute eye injury and the development of posttraumatic endophthalmitis. One study found that 33% of patients with positive cultures did not develop endophthalmitis, whereas other studies have shown development of the disease in 17% to 42% of patients with negative cultures. Therefore, the routine procurement of cultures following an acute eye injury is not recommended at this time.1
Because endophthalmitis is a sight-threatening medical emergency, antimicrobial therapy covering the most likely causative organisms must be administered quickly. According to current treatment guidelines, the antimicrobials must be administered intravitreally in all cases to ensure adequate penetration into the infected space. Unless culture results are available, empiric therapy to cover both gram-positive and gram-negative organisms should be used.1
Current treatment guidelines recommend the administration of one dose of intravitreal vancomycin 1 mg/0.1 mL with one dose of intravitreal ceftazidime 2.25 mg/0.1 mL (TABLE 1).1,7,8 Amikacin 0.4 mg/0.1 mL may be administered instead of ceftazidime in patients with beta-lactam allergy, but it should be used cautiously owing to the increased risk of retinal toxicities, such as macular infarction.9,10
According to the most recent U.S. report, 99% of gram-positive organisms cultured in endophthalmitis are sensitive to vancomycin and 90% of gram-negative organisms are sensitive to ceftazidime or amikacin.1 However, the incidence of drug resistance is increasing in other disease states, and this possibility should not be overlooked here. In particular, case reports of vancomycin-resistant Enterococcus have been reported in patients with endophthalmitis.11
Intravitreal fluoroquinolones—notably, moxifloxacin—have been considered as alternatives to vancomycin and ceftazidime because of their broad spectrum of activity, allowing for coverage of gram-positive and gram-negative bacteria with a single agent.1 Data also suggest that these agents could be used topically or systemically rather than intravitreally.2 Because of the wide use of these drugs in prophylaxis and treatment of superficial ocular infections, however, resistance is of great concern. Therefore, if fluoroquinolones are used, they must be prescribed in conjunction with another medication that has more reliable gram-positive coverage.1
Most patients are responsive to empiric therapy; however, after 24 hours, the affected eye may actually appear to worsen.3 Antibiotics injected intravitreally tend to have extended elimination half-lives; because of this, readministration of antibiotics must be determined based upon clinical progression.12 The general recommendation is to consider a second course of antibiotics if the patient does not appear to be improving 36 to 48 hours following the initial administration.3
Although fungal infections—most commonly by Candida species—are more likely to occur with endogenous disease, intravitreal amphotericin B (5-10 mcg/0.1 mL) may be administered in cases of exogenous disease if a fungal infection is highly suspected.1 Intravitreal fluconazole and voriconazole also have been explored as therapeutic alternatives to amphotericin B.3
The use of intravitreal anti-infective agents to treat endophthalmitis has generally been shown to be safe in the doses recommended above.3,12 However, the incidence of adverse events may increase with additional exposure, especially with amikacin.3,10 In addition to retinal toxicity, adverse events following intravitreal injections include pain at the injection site, subconjunctival hemorrhage, and elevated intraocular pressure. Floaters, vitreous or subretinal hemorrhage, retinal detachment, central artery occlusion, corneal abrasion, or uveitis may also develop.12
Because these medications must be reconstituted and diluted prior to administration, strict aseptic technique must be employed to prevent complications from contaminated solutions. Given the severity of endophthalmitis and its poor prognosis, the benefit of administering antibiotics intravitreally outweighs the risks mentioned above, and this mode of administration remains the standard of therapy.
Older treatment approaches to exogenous endophthalmitis advocated the use of intravenous antibiotics alone or in combination with topical, subconjunctival, or intravitreal antibiotics.3,12 However, the Endophthalmitis Vitrectomy Study demonstrated that intravenous antibiotics did not provide a therapeutic benefit in exogenous endophthalmitis when used in addition to intravitreal antibiotics; therefore, their use is not recommended.13 The lack of benefit is likely due to insufficient drug penetration across the blood–ocular barrier, leading to subtherapeutic concentrations.2
Subconjunctival and topical antibiotics provide no additional benefit in the treatment of endophthalmitis and are not used routinely. Furthermore, although prophylactic intravitreal or systemic antibiotics may be clinically appropriate in cases of severe eye injury, their use in preventing endophthalmitis remains controversial, and guidelines have not been established.3
Based upon this information, it is imperative for pharmacists to clarify orders written for the treatment of endophthalmitis that do not include intravitreal injections. If the provider appears to be treating endophthalmitis without intravitreal antimicrobials, either the diagnosis or the route of administration may have been transcribed incorrectly.
The role of corticosteroids—whether systemic, intravitreal, or subconjunctival—remains poorly defined. Used adjunctively, these medications are believed to reduce the inflammatory response, thereby lessening retinal damage, but studies are inconclusive.2 Most studies have shown no benefit, and one retrospective review indicated poorer visual outcomes in patients who received intravitreal dexamethasone.1,5
Pars plana vitrectomy (PPV) has been studied in both exogenous and endogenous endophthalmitis.13 The procedure involves removing the vitreous fluid and any remaining debris from the affected eye, potentially achieving improved visual outcomes in patients with moderate-to-severe disease.3 Some studies have suggested using vitrectomy empirically when infection with virulent organisms is suspected, or only after patients show poor response 24 to 48 hours following treatment.3 Immediate vitrectomy combined with intraocular antibiotics has been advocated in cases of retained intraocular foreign bodies; however, this was shown to improve outcomes in 53% of cases but worsen outcomes in 40%.2
A possible benefit from PPV is the reduction of toxins, pathogens, opacities, and inflammatory cells; additionally, PPV may enable improved distribution of intravitreal antibiotics and allow for a vitreal sample to be collected for culturing. One disadvantage of the procedure, however, is that a vitreoretinal surgeon may be required, meaning that the procedure may not be available to every patient presenting with endophthalmitis symptoms.1 Because ambiguity exists as to the true benefit of PPV and because not all facilities are able to offer this procedure, the use of PPV in all cases cannot be recommended.
Irrespective of the initial cause, the prognosis for endophthalmitis is generally poor, and patients are often left with limited visual acuity. The visual outcome of endophthalmitis occurring after an acute eye injury frequently is worse than in a similar injury in which endophthalmitis did not develop, or in the case of endophthalmitis not caused by an acute injury.3
Poor outcome could be due to difficulty in quickly and accurately diagnosing the condition, a delay in receiving treatment, or the inherent virulence of the typical causative organisms.2 Other predictors of poor outcome include initial visual acuity of light perception only; older age; corneal ring ulcers; compromised posterior capsule; abnormal intraocular pressure; afferent papillary defect; rubeosis iridis; and absence of the red fundus reflex.1
Time to development of endophthalmitis after injury is another indicator of prognosis; a shorter time to development correlates with greater virulence of the infecting organism and often predicts a poorer outcome. Gram-negative and toxin-producing species such as Bacillus often cause more severe damage. In cases involving Bacillus species, 75% of eyes have total vision loss.3,5 Less severe infections are observed with gram-positive coagulase-negative cocci. In patients with exogenous endophthalmitis, the chance of attaining 20/100 vision or better is 80% when cultures show no growth or coagulase-negative Staphylococcus.1
Endophthalmitis following an acute eye injury is a medical emergency that could result in total vision loss if it is not treated promptly. Pharmacists must be aware of the current treatment recommendations and have protocols in place to quickly and accurately formulate the required intravitreal antimicrobial injections. Patients who do not respond to initial treatment should be reevaluated and considered for additional antimicrobial injections or surgical intervention.
1. Kernt M, Kampik A. Endophthalmitis: pathogenesis, clinical presentation, management, and perspectives. Clin Ophthalmol. 2010;4:121-135.
2. Novosad BD, Callegan MC. Severe bacterial endophthalmitis: towards improving clinical outcomes. Expert Rev Ophthalmol. 2010;5:689-698.
3. Lemley CA, Han DP. Endophthalmitis: a review of current evaluation and management. Retina. 2007;27:662-680.
4. Essex RW, Yi Q, Charles PG, Allen PJ. Post-traumatic endophthalmitis. Ophthalmology. 2004;111:2015-2022.
5. Pijl BJ, Theelen T, Tilanus MA, et al. Acute endophthalmitis after cataract surgery: 250 consecutive cases treated at a tertiary referral center in the Netherlands. Am J Ophthalmol. 2010;149:482-487.
6. Thompson JT, Parver LM, Enger CL, et al. Infectious endophthalmitis after penetrating injuries with retained intraocular foreign bodies. Ophthalmology. 1993;100:1468-1474.
7. Vancomycin (sterile vancomycin hydrochloride) package insert. Lake Forest, IL: Hospira, Inc; 2008.
8. Fortaz (ceftazidime) package insert. Research Triangle Park, NC: GlaxoSmithKline; February 2007.
9. Amikacin (amikacin sulfate) package insert. Bedford, OH: Bedford Laboratories; 2007.
10. Campochiaro PA, Lim JI. Aminoglycoside toxicity in the treatment of endophthalmitis. Arch Ophthalmol. 1994;112:48-53.
11. Sharma S, Desai RU, Pass AB, Saffra NA. Vancomycin-resistant enterococcal endophthalmitis. Arch Ophthalmol. 2010;128:794-795.
12. Peyman GA, Lad EM, Moshfeghi DM. Intravitreal injections of therapeutic agents. Retina. 2009;29:875-912.
13. Endophthalmitis Vitrectomy Study Group. Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Arch Ophthalmol. 1995;113:1479-1496.
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