The Pathogenesis of Infectious Endophthalmitis
Jonathan J. Hunt
Michelle C. Callegan
Endophthalmitis is an infection and inflammation of the posterior segment of the eye that can result in vision loss. This intraocular infection can occasionally result in loss of the eye despite aggressive antibiotic, anti-inflammatory, and surgical intervention. This chapter will review predisposing factors, infectious agents responsible for endophthalmitis, and therapeutic challenges. This chapter will also include an update on experimental findings from the analyses of the pathogenic mechanisms of infection and inflammation during endophthalmitis.
PREDISPOSING FACTORS AND SOURCE OF THE ORGANISM
Endophthalmitis results from the introduction of microorganisms into the interior of the eye. Bacteria, fungi, or other pathogens can seed the anterior or posterior segment during intraocular surgery (postoperative) or penetrating globe injury (posttraumatic), or following metastatic spread from the bloodstream into the eye from a distant infection site (endogenous). Microorganisms that cause endophthalmitis vary widely in their ability to cause infection and inflammation, and range from relatively avirulent organisms found in the ocular environment (normal flora) to highly pathogenic organisms found in the environment.1,2
Most reported endophthalmitis cases follow intraocular surgery. Of all types of ocular surgery, cataract surgery most commonly causes postoperative endophthalmitis.3 West et al3 reported an increase in the number of postoperative endophthalmitis cases, from 0.1% in the 1990s, to 0.2% for the period 2000 to 2003. Phacoemulsification accounted for approximately 48% of the postcataract endophthalmitis cases, whereas 38.5% and 6.6% of cases followed extracapsular or intracapsular extraction, respectively.4
Most reported endophthalmitis cases are caused by organisms found as normal flora of the eyelid margin and the tear film. Coagulase-negative staphylococci (CNS), commonly found as normal flora of the ocular environment, can contaminate the anterior chamber5 and have been reported to cause 40% to 70% of acute post-cataract surgery endophthalmitis.6,7,8,9 Other organisms involved include Staphylococcus aureus, Streptococcus, other Gram-positive bacteria, and an increasing number of Gram-negative bacteria.6,7,8,9 Fungi are also a common cause of postoperative endophthalmitis10 and involve several species, including Candida, Aspergillus, and Fusarium. Preoperative topical antibiotics and antiseptics are commonly used to decrease organism load in the tear film and surrounding tissues, but these solutions do not sterilize the area.5,11,12 The low rate of endophthalmitis despite the presence of contaminating microorganisms in or near the eye following surgery may be owing to a combination of factors, including low numbers of microorganisms following prophylaxis, lack of virulence of normal flora, and/or a functional ocular immune defense system.
Delayed-onset postoperative endophthalmitis may occur weeks to several months following surgery. These chronic, indolent infections may be a result of infection with organisms that gain access into the eye through wound defects, sutures, vitreous wicks, or thin-walled filtering blebs. In the case of filtering blebs, a higher prevalence of streptococci, enterococci, and Gram-negative bacteria have been recovered.13,14,15 Relatively slow-growing or avirulent organisms (such as Propionibacterium acnes or CNS) introduced at the time of surgery may also be sequestered in a niche or biofilm inside the eye. Such organisms may be protected from antibiotic and antiseptic activity, only to cause transient and chronic inflammation weeks to months following surgery.16,17
Posttraumatic endophthalmitis occurs with greater frequency than postoperative endophthalmitis (3%-17% vs. 0.2%). These infections have a higher potential for vision loss because of the variety of environmental organisms that may enter the eye following trauma. In most series, staphylococci other than CNS are the most common, followed by Bacillus cereus.18,19,20,21,22 During traumatic injury, intraocular foreign bodies (IOFBs) may become embedded inside the eye. The association of IOFBs with traumatic injuries predisposes a risk of developing endophthalmitis, particularly if antimicrobial therapy was delayed.21,23,24,25,26,27 Of all reported penetrating eye injuries, 2% to 16% developed severe endophthalmitis. The incidence and severity of these cases were dependent on whether IOFB removal was immediate or delayed.18,26,28,29
Endogenous endophthalmitis results from metastatic spread of organisms via the bloodstream into the posterior vasculature of the eye. Endogenous endophthalmitis is relatively rare but can be especially damaging because of the potential for bilateral infection in 15% to 25% of cases.30,31 The visual outcome of endogenous endophthalmitis has not improved over the past 55 years, despite the use of improved antibiotics and aggressive surgical intervention.32 Patients with systemic infections may not have ocular symptoms, so initial ocular changes of endogenous endophthalmitis may go unrecognized until ocular pain or vision loss is noted. Populations at greatest risk for endogenous endophthalmitis include the immunocompromised and intravenous drug users.30,33,34,35 A recent review reported that 56% of patients with endogenous bacterial endophthalmitis were also immunocompromised, with diabetes as the most common underlying disease.30 For endogenous endophthalmitis, type II diabetes is the most common underlying condition, particularly in patients with secondary Klebsiella liver abscess.30 Prolonged intravenous drug abuse is the second most common underlying condition associated with endogenous endophthalmitis. Concurrent immunosuppressive treatment was also associated with one third of endogenous endophthalmitis cases.30 Etiologic agents of endogenous endophthalmitis include opportunistic and environmental bacterial and fungal pathogens.30,33,34,35,36 More than 50% of endogenous endophthalmitis cases are caused by fungal organisms such as Candida albicans, which was reported to cause 75% to 80% of fungal cases.36 Bacterial causes of endogenous endophthalmitis include Klebsiella spp., the most common Gram-negative pathogen, and Bacillus spp. and CNS, the most common Gram-positive pathogens.30
THERAPEUTIC CHALLENGES OF ENDOPHTHALMITIS
The goal of therapeutic management of endophthalmitis is to sterilize the eye, arrest inflammation, minimize tissue damage, and rescue functional vision. However, treatment of intraocular infection and inflammation is a unique problem. The interior of the eye is lined with extremely sensitive retinal cells that can be irreversibly damaged from infection, inflammation, and/or high concentrations of antimicrobials used during treatment.37,38,39 In addition, the interior of the eye is sequestered from the systemic circulation by the blood-ocular barrier. This barrier effectively isolates the vitreous and anterior chamber from assault by immune mediators and inflammatory cells, but also prevents the diffusion of systemically administered medications into the eye.40,41,42
Recommended management of postoperative or posttraumatic endophthalmitis in most cases includes intravitreal, periocular, and/or topical antimicrobials and, in severe cases, the addition of vitrectomy. Endogenous endophthalmitis may include these therapies in addition to systemic antimicrobials. To date, there is no universal therapeutic regimen for endophthalmitis. However, an adequate treatment strategy should consider the nature of the pathogen itself (i.e., Gram-positive vs. Gram-negative, potential virulence, and antibiotic susceptibility), as well as the unique challenges posed by ocular barriers and retinal cell sensitivity. During the initial presentation of endophthalmitis, the infecting organism is usually not known, and clinical signs of infection may not provide sufficient clues to pathogen identity.43 Factors such as rate of evolving severity, wound appearance, source of IOFB (if present), and corneal inflammatory ring infiltrates may provide useful prognostic information. Because the identity of the pathogen is often unknown at presentation, the choice of empiric antibiotic therapy is critical to successful treatment. Most ocular isolates continue to be susceptible to ceftazidime and amikacin, which are commonly used in combination with vancomycin for therapy. However, the emergence of antibiotic-resistant organisms, particularly fluoroquinolone- and vancomycin-resistant Gram-positive pathogens, may alter future therapeutic approaches.44,45,46,47
Intraocular inflammation is critical for removal of microorganisms during endophthalmitis, but bystander retinal tissue damage often results. The polymorphonuclear neutrophil (PMN) is the primary infiltrating cell type in infectious endophthalmitis.48,49,50,51,52,53 PMNs often liberate toxic oxygen metabolites and proteolytic enzymes that can damage sensitive retinal tissues. The reported benefits of intravitreal anti-inflammatory agents for arresting inflammation during endophthalmitis vary widely. The use of intravitreal corticosteroid/antibiotic combinations for treating endophthalmitis have been reported to be detrimental,54 be beneficial55,56,57,58 or have no effect.59,60,61,62,63 Despite relative lack of clinical studies reporting beneficial outcomes, dexamethasone is commonly used as an adjunct to antibiotic therapy for endophthalmitis.
Vitrectomy is often used to eliminate bacteria, inflammatory cells, and other toxic substances from an infected posterior segment. Removal of these potentially harmful factors facilitates removal of vitreous membranes that may lead to retinal detachments, maintenance of transparency and vitreal diffusion, and faster vision recovery. The Endophthalmitis Vitrectomy Study (EVS) reported that immediate vitrectomy was beneficial in cases of acute endophthalmitis following cataract surgery where patients had light perception vision.37 Immediate vitrectomy and intravitreal antibiotics have been recommended for posttraumatic endophthalmitis cases with retained IOFBs.64,65 Vitrectomy may also benefit the management of postoperative endophthalmitis following surgery other than cataract surgery or postcataract surgery endophthalmitis in eyes that are refractive to initial nonvitrectomy treatment.37,64,66 For endogenous endophthalmitis, vitrectomy contributed to significant improvements in vision, but any delay in vitrectomy resulted in loss of visual acuity.67 Most reports concur that vitrectomy with intravitreal antimicrobials should be performed immediately in severe cases of endophthalmitis, especially those involving IOFBs.68
PATHOGENIC MECHANISMS OF ENDOPHTHALMITIS
Clinical signs at the time of endophthalmitis presentation may predict a poor visual outcome.37 The severity of the injury (surgical, penetrating with or without IOFB, etc.), the time from injury to presentation, the presence of infection on presentation, or the identity of the infecting pathogen may predict the course of disease. However, the clinical spectrum of endophthalmitis can differ greatly because of the wide range of inciting events, extent of ocular injury, or variety of organisms that can cause disease. Endophthalmitis can manifest as a painless intraocular inflammation caused by relatively avirulent organisms such as CNS, or recurrent low-grade inflammation caused by P. acnes, or rapidly blinding and intractable panophthalmitis caused by B. cereus.9,69,70 Although the offending pathogen is not always predictive of the intensity of inflammation during infection, certain organisms are more likely to cause significant inflammation than others. B. cereus, for example, is typically associated with an explosive infection course with significant inflammation compared to infection with CNS. However, severe or chronic endophthalmitis caused by relatively avirulent organisms, such as CNS or Bacillus species other than B. cereus, has been reported.71,72,73,74
The potential for endophthalmitis severity has been ascribed to an organism’s complement of virulence factors. In experimental models of endophthalmitis, injection of similar inocula of different bacterial species can cause infection courses of varying severity. Studies analyzing genetically altered bacterial mutant strains deficient in specific virulence factors (i.e., toxins or other secreted factors) are defining those factors important to endophthalmitis. The bacterial cell surface is also considered to be important in virulence because of the direct interaction of cell surface components (i.e., peptidoglycan, teichoic acid, polysaccharide capsules, lipopolysaccharide, and adhesins) with host cells and the innate immune system. An organism’s’ behavior in the eye during infection may also contribute to its virulence. These aspects of endophthalmitis pathogenesis will be discussed in detail in the paragraphs that follow.
Coagulase-negative staphylococci are relatively avirulent Gram-positive bacteria that reside as normal ocular flora.75 S. epidermidis is the leading etiologic agent of postoperative endophthalmitis, accounting for 81.9% of isolates in the Endophthalmitis Vitrectomy Study (EVS).4,75,76,77 Eyes infected with S. epidermidis generally have a good outcome with up to 80% of patients retaining 20/100 vision.78 CNS has been reported to cause significant loss of vision only rarely.71,79,80 The major virulence factor for CNS in the eye is the ability to form biofilms and/or adhere to intraocular lenses (IOLs). Biofilms are masses of cells attached to both a surface and each other by specific proteins and extracellular polysaccharide. The altered physiology of bacteria in a biofilm is believed to account for their resistance to antibiotics and host innate immunity81 Organisms that readily form biofilms have multiple adhesins on their surfaces. Specifically, S. epidermidis possesses adhesins such as AtlE, fibrinogen-binding protein Fbe/Sdrg, fibronectin-binding protein Embp, the icaADBC locus that encodes polysaccharide intercellular protein (PIA), accumulation-associated protein (Aap), and the biofilm-associated protein (Bap/Bhp).82,83,84,85,86 Although CNS are a major cause of endophthalmitis, rigorous studies of the contribution of these various adhesins to endophthalmitis have not been reported.
Patients with indwelling medical devices often become infected with S. epidermidis, many times because of contamination from the patient’s own flora.87 &In the case of IOL surgery, the lens could be contaminated by ocular flora during the procedure and gain access to the interior of the eye. In the EVS, the most common source of ocular contamination was found to be the ocular flora.75 Cultures taken from the eyelid and intraocular isolates were matched by pulse-field gel electrophoresis (PFGE) banding in 67.7% of cases.75 Furthermore, PFGE typing showed that patients from the same facility had nonidentical CNS strains, eliminating the surgical environment and personnel as the major source of contamination.75 Several in vitro studies have shown that CNS readily attach to IOL lens material and form biofilms, and that adherence varies with lens material, degree of surface irregularity, and coating type.88,89,90,91,92 The use of polypropylene haptics has been associated with an increased risk of endophthalmitis, as CNS appear to adhere best to polypropylene haptics, followed by polymethyl methacrylate (PMMA).92 CNS adhered less well to heparin-coated PMMA or AcrySof lenses.88,91 Huang et al93 reported that IOL hydrophilicity also seems to be a factor in bacterial adherence. Silicone lenses hydrophilically coated with 2-methacryloyloxyethyl phosphoryl-choline (MPC) allowed 2.6-fold less binding than uncoated silicone IOLs using a non-biofilm-forming strain of S. epidermidis in vitro.93 Not surprisingly, adherence was enhanced in vitro when lenses were coated with fibronectin, a vitreous component likely to be in contact with IOLs during implantation.94 In terms of specific S. epidermidis adhesins, the genes for PS/A and ica conferred greater adhesion to AcrySof IOLs in vitro.90 However, Duggiralla et al95 reported that the presence of the ica locus alone did not indicate propensity to form biofilms, as only 15% of S. epidermidis commensal isolates were able to form biofilms in vitro and 71% of this group contained the ica locus. In this study, ocular isolates clustered well, and separately from commensal isolates by fluorescence-amplified fragment length polymorphism (FAFLP) of seven different genetic loci. Therefore, the role of individual adhesins in the pathogenesis of S. epidermidis endophthalmitis remains an open question.