Corneal transplant, or keratoplasty, is performed in over 40,000 patients in the United States each year. The major indications for transplantation include keratoconus, pseudophakic bullous keratopathy, Fuch’s dystrophy, herpetic corneal infection, and trauma (4). In the United States, cadaver donor corneas are stored by local eye banks in an antibiotic-containing solution by protocols established by the Eye Bank Association of America (EBAA).

The traditional corneal transplant is a penetrating keratoplasty (PK), or full-thickness transplant. During this transplant procedure, the surgeon trephines a central disk from a donor cornea and uses this to replace the central disk of the patient’s native cornea. The donor cornea is sutured to the residual rim of the patient’s native cornea. The patient typically uses topical corticosteroid eye drops for months to years postoperatively to prevent rejection; many patients are continued on these indefinitely. Sutures are left in place for months to years. Healthcare-associated infections include donor-host transmission of systemic infections, keratitis (infection of the cornea), and endophthalmitis (infection of the vitreous).

Systemic donor infections have rarely been transmitted through PK. Premorbid bacterial sepsis in the donor appears to have no effect on the incidence of posttransplantation endophthalmitis in the recipient (5,6). Diseases transmitted from donors to recipients via corneal transplantation that have been reported in the literature include three cases of Creutzfeldt-Jakob disease (7,8), eight cases of rabies (9, 10, 11, 12, 13, 14), and two cases of hepatitis B virus from the same donor (15).

The possibility of transmission of herpes simplex virus (HSV) from donor cornea to recipient has been demonstrated in some cases and suspected in others (16,17). HSV in the donor cornea may cause primary graft failure and keratitis after transplantation (18). Cases of healthcareassociated herpetic graft infection are rare, however. Other viruses that potentially could be transmitted through PK include human immunodeficiency virus (HIV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, and rubella (19). The EBAA requires review of the donor’s medical history and recommends serologic screening for hepatitis B, hepatitis C, and HIV-1 and HIV-2 (20). Patients who have died from progressive encephalopathy are also excluded as cornea donors. The recommended screening is highly effective. Eye banks affiliated with EBAA provided over 400,000 corneas during a 12-year period, and there were no cases of donor to recipient transmission of a systemic infectious disease during this time (20).

A more common infectious complication after PK is infectious keratitis. Many cases occur beyond the postoperative time period and would not be considered healthcare-associated. A retrospective review of 885 transplants performed over a 16-year period revealed a 4% overall incidence of infectious keratitis, but a 1.5% incidence over the initial 2 months postoperatively (21). A similar study of 285 patients who received transplants over a 5-year period found a 2.5% incidence of keratitis in the first 3 months, but an overall incidence of 7% (22). Bacteriology in these studies was not specified by time of onset of infection, but S. pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, and Serratia marcescens were the most common pathogens. Risk factors for keratitis included persistent corneal epithelial defects and suture abscesses. Suture abscesses may develop months after surgery. One study of 18 suture abscesses found they developed 1 to 53 months postoperatively (mean: 21 months), so few would be considered healthcare-associated (23). A recent study from India of 37 patients with suture-related corneal graft infection found that 31 developed the infection within 1 year postoperatively (23a). The median time to onset of corneal infiltrates in the latter group was 87 days.

Endophthalmitis, or infection within the eye involving the vitreous and/or aqueous humor, is a rare but potentially devastating complication of PK that occurs in 0.2% to 0.4% of recipient eyes (24,25). Onset of symptoms is within 2 months of surgery, but most cases occur within 2 weeks. Both bacterial and fungal endophthalmitis have resulted from PK. In a US study of 1,010 corneal transplants, streptococci caused three cases and Candida one case of posttransplant endophthalmitis (25). A study from Saudi Arabia reported a cluster of endophthalmitis that developed in four patients 1 week after PK (three Enterococcus faecalis, one Candida glabrata) (26). Contamination of the donor corneas during storage was the likely source of infection. Endophthalmitis due to aminoglycoside-resistant Alcaligenes has been described, and this is significant because aminoglycosides are the only antibiotics present
in standard tissue storage media (27). Eye bank corneal storage media contain either gentamicin (McCarey-Kaufman media) or gentamicin plus streptomycin (Optisol GS). No antifungal agent is present, and candidal endophthalmitis has occurred in patients who received Candida-contaminated corneal tissue (28,29).

The source of infection in nearly all cases of post-PK endophthalmitis is thought to be microbial colonization of the donor cornea. Most corneal surgeons routinely culture the unused rim of the donor cornea at the time of surgery in an attempt to predict patients at risk for endophthalmitis. The value of this practice is controversial, as the incidence of culture-positive donor rims is high but post-PK endophthalmitis is low. This was illustrated by a study of 774 donor corneal rim cultures in which 5% were positive, yet no patient who received these corneas developed endophthalmitis (30). The only two patients in this study who did develop endophthalmitis received culturenegative corneas. However, Wilhelmus and Hassan found that positive donor rim cultures did have predictive value (24). They performed a meta-analysis of studies involving 17,614 corneal grafts and found that 14% had positive donor rim cultures and only 0.2% developed endophthalmitis. However, using Bayesian analysis, they showed that positive donor rim cultures predicted a 1% endophthalmitis risk overall, and donor rims that were culture positive for fungi predicted a 3% probability of developing fungal endophthalmitis. The significance of a positive donor rim fungal culture was also seen in a study from New York Eye and Ear Infirmary (29A). In that study, 13% of nearly 2,500 donor rim cultures were positive during a 5-year period, and 28 of these (8.6%) grew fungi. All were Candida species, and 4 of the 28 recipient eyes (14%) developed fungal infections. The Medical Review Subcommittee of the EBAA reviewed 121 culture-positive post-PK endophthalmitis cases reported to eye banks from 1994 to 2003, and found that 49% had concordant donor and recipient microbial isolates (29b). The prevalence of concordance was greater in fungal than bacterial post-PK endophothalmitis cases. Longer storage times increase the risk of developing post-PK endophthalmitis, and this may be especially true of Candida endophthalmitis. Another study from the EBAA found that the chance of developing fungal endophthalmitis was 3.4 times that of bacterial endophthalmitis when donor corneas had been preserved 4 days or longer (29C). It is unknown whether prophylactic antifungal eye drops should be prescribed to eyes that receive donor corneas with rim cultures positive for fungi, but these studies suggest that may be a consideration.

New Corneal Transplantation Techniques In the past several years, new techniques have been developed that allow transplantation of only a portion of donor cornea to replace the specific level of diseased cornea in the patient’s eye. Some patients have an abnormality of their corneal endothelium, the single-cell-thick layer of the cornea that abuts the aqueous humor. Conditions that require endothelial replacement include Fuch’s endothelial dystrophy, pseudophakic bullous keratopathy, and failed previous graft. These patients may be helped by a posterior lamellar keratoplasty procedure, such as Descemet’s Stripping Automated Endothelial Keratoplasty (DSAEK) or Descemet’s Membrane Endothelial Keratoplasty (DMEK). The first procedure, DSAEK, has become the preferred treatment for endothelial dysfunction over PK, because it allows faster visual recovery and retains the strength of the eye better than PK. In 2007, 85% of corneas provided by the EBAA for patients with endothelial dysfunction were used in endothelial keratoplasty procedures (31). The second procedure, DMEK, was first used in humans in 2006 (32). A recent prospective multicenter study found that DMEK provided a higher rate of 20/20 vision compared with DSAEK, although donor preparation and attachment were more challenging than that with DSAEK (31). A case each of Candida keratitis and endophthalmitis has been reported after DSAEK (33,34).

Other patients have a surface abnormality but a normal corneal endothelium; these patients may need only the anterior layers of their cornea replaced, by Deep Anterior Lamellar Keratoplasty (DALK). In DALK, the patient’s corneal endothelium is functional and only the more superficial layers require transplanting. With DALK, banked donor corneas that would be unsuitable for PK due to endothelial deficiencies can be utilized, or even the same cornea that supplied the endothelium for DMEK could supply the anterior layers for DALK. In a study from France, nearly 50% of donor corneas at one eye bank would have been unusable for PK, but over 70% of these were used for DALK (35).

Eye bank technicians now routinely dissect corneas for DSAEK. This may increase the risk of contamination of tissues to airborne bacteria during microkeratome processing (36).

A keratoprosthesis (KPro) is an artificial cornea implanted in eyes that are blind from corneal disorders but in whom corneal transplants have failed. A major complication of KPro is endophthalmitis, which occasionally occurs during the first year postoperatively so would be considered healthcare associated, but usually occurs abruptly years later. It is similar in that regard to bleb-related endophthalmitis (see below). A widely used type of KPro is the Boston KPro, a plastic implant shaped like a collar button that replaces the central part of a corneal transplant. The rate of endophthalmitis in patients with a Boston KPro is now very low since these patients use long-term daily prophylactic antibiotic eye drops (e.g., vancomycin plus a quinolone) (37).

Laser in situ keratomileusis (LASIK) is one of the most commonly performed eye surgeries. Unlike other eye surgeries, LASIK is performed in patients who have normal eyes except for refractive error, i.e., the need for glasses. Over 1 million LASIK procedures were performed in the United States in 2000, up from 400,000 procedures in 1998 and 200,000 in 1997 (38,39). The LASIK uses a microkeratome to cut a thin, hinged flap across the corneal surface, exposing the corneal stroma beneath. A laser then ablates some of this central stroma and the flap is replaced, leaving a flattened cornea. The procedure is often performed using only semisterile technique (e.g., the microkeratome blade is sterile but the microkeratome handle is not).
The procedure is an outpatient procedure and is often performed in free-standing LASIK centers. Many centers are owned by the ophthalmologist who performs the procedures, so underreporting of complications is likely.

The most common complication of LASIK is keratitis, both infectious and noninfectious. In a study from Salt Lake City, Utah, of approximately 10,500 LASIK procedures, the incidence of post-LASIK keratitis was 2.66%, and 88% of these cases were noninfectious (40). Most noninfectious keratitis cases in this study and others were due to diffuse lamellar keratitis (DLK). This syndrome, also called “sands of the Sahara” because of the granular appearance of the corneal flap/stroma interface, occurs in 1% to 5% of eyes (39). The etiology is unknown, and cultures are negative. One outbreak in 52 patients in which cultures were negative was thought to be related to endotoxins (41). Sterilizers used at the center were found to have reservoirs contaminated with gram-negative bacterial biofilms, and it was postulated that these biofilms produced endotoxins that contaminated the instruments during sterilization.

Infectious keratitis occurred in 0.3% of eyes in the Utah study, and viruses caused 70% of these 33 cases (40). All 18 cases (55%) due to adenoviral keratitis recovered 20/20 vision, while all 5 (15%) of the eyes with herpes simplex keratitis lost one to two lines of visual acuity. Ten cases (30%) had a bacterial, fungal, or parasitic etiology. A study of 204,586 LASIK procedures from a private ophthalmologic institution with 19 centers in Spain found that infectious keratitis developed in 72 eyes (63 patients) during the first 6 months postoperatively, for an incidence of 0.035% (42). A majority (60%) of patients developed symptoms within 7 days of the procedure; the mean time to presentation was 16 days. Cultures were obtained in 54 eyes and were positive in 21, and all were due to grampositive bacteria: S. epidermidis (nine cases), S. pneumoniae (eight cases), viridans streptococci (two cases), S. pyogenes (one case), and S. aureus (one case). There were no case clusters in this study. Khan et al. (39) reviewed the world literature through 2001 and found that in the 31 eyes with positive cultures, rapidly growing nontuberculous mycobacteria, primarily Mycobacterium chelonae, accounted for 29%. S. aureus (31%) and molds such as Aspergillus and Curvularia (16%) were other important etiologies, although the high incidence of molds likely reflected the contributions of reports from tropical areas. Nontuberculous mycobacteria and S. aureus were also the major pathogens in a study of 13 patients (15 eyes) with post-LASIK keratitis referred to an eye institute in Miami from centers in Florida and South America (43). Nontuberculous mycobacteria (e.g., M. chelonae, Mycobacterium abscessus) caused six of 15 cases, whereas S. aureus caused four. Two cases involved gram-negative bacilli (Pseudomonas, Stenotrophomonas). Excluding two patients with late (>6 months) onset of keratitis due to molds and related to trauma, patients developed keratitis symptoms an average of 16 days postoperatively (range 2-65 days).

Nontuberculous mycobacteria have been the cause of several outbreaks. Freitas described an outbreak of 10 cases of M. chelonae that occurred in a center in Brazil during a 2-week period in 2000 (44). Corneal infiltrates appeared during the third postoperative week. The CDC investigated a California cluster of M. chelonae post-LASIK keratitis and then emailed members of the American Academy of Ophthalmology to solicit reports of other cases of nontuberculous mycobacterial keratitis (45). Forty-three additional cases were reported, including 31 that were part of 2 unrelated LASIK-associated outbreaks.

Post-LASIK S. aureus keratitis likely represents contamination from normal colonizing eye flora, and the incidence may be increased in patients with chronic meibomian gland dysfunction (e.g., marginal blepharitis). These patients should be free of any signs of eyelid disease at the time of the procedure to minimize infectious complications. The nontuberculous mycobacterial infections likely represent environmental contamination at the time of the procedure. For this reason, some authors recommend that LASIK be performed with sterile technique, including sterile instruments, sterile plastic bags covering portions of the laser that can’t be sterilized, sterile gloves and drapes, eyelid antisepsis with povidone iodine, and prophylactic topical antibiotics (43).

A rare complication after LASIK is endophthalmitis. A recent case was reported following a retrobulbar injection of saline to assist with globe suction by the microkeratome (46). Ten days postoperatively, the patient presented with visual acuity of count fingers and presumed bacterial endophthalmitis. At surgery, a perforation site was found in the inferonasal retina. Following intravitreal antibiotic therapy, vision returned to 20/20.

Glaucoma that is refractory to medical therapy may be controlled by placement of a filtering bleb. This is a surgically created defect in the sclera that allows excess aqueous to filter out of the eye and into the systemic circulation. The bleb may become infected (blebitis) and bacteria may rapidly enter the eye and cause endophthalmitis. Bleb-related endophthalmitis usually occurs abruptly, months to years postoperatively. Early-onset cases are rare. One study of 988 procedures in China found only one case of early-onset infection (47). A retrospective review of 49 cases found that endophthalmitis developed an average of 2 years after bleb placement (range 1 month to 8 years) (48). Most cases of bleb-related endophthalmitis are therefore not considered HAIs.

Another way to control severe glaucoma is through use of glaucoma drainage implants, such as the Ahmed shunt. These plastic devices have a tube, inserted into the anterior chamber, that directs aqueous humor out of the eye and into a perforated reservoir (“plate”) sutured to the superior surface of the globe. Aqueous humor then leaks slowly out of this reservoir into the overlying conjunctiva and thereby the systemic circulation. Endophthalmitis is a rare complication of glaucoma drainage implants, and as in filtering blebs, most cases occur beyond the postoperative period so are not HAIs. In a retrospective study of Ahmed shunts placed in 542 eyes between 1994 and 2003 at one eye hospital in Saudi Arabia, endophthalmitis had developed in 9 eyes (1.7%) (49). Eight of the nine cases occurred more than 6 weeks postoperatively (range 30-330 days). S. pneumoniae, other streptococci, and H. influenzae were the primary pathogens, accounting for six of the infections, similar to the situation in bleb-related endophthalmitis.

Cataracts are the leading cause of blindness worldwide and affect nearly half of all people over age 65. A cataract is a clouding of the lens, and this occurs naturally over time with exposure to ultraviolet light. Other factors may also lead to cataracts, including trauma, diabetes, chronic use of corticosteroids, and chronic inflammation in the eye (e.g., uveitis).

Cataract Surgery Cataract surgery is one of the most common surgical procedures performed in the United States, with over 2 million cases annually. Surgery has been performed on an ambulatory basis since 1985, when Medicare instituted a policy that covered only outpatient cataract surgery. Surgery involves making a small incision through either the sclera or cornea, removing the native lens pulp (leaving the posterior lens capsule intact), and replacing it with a synthetic IOL. The most common technique for native lens removal is phacoemulsification, in which the lens is ultrasonically broken up and aspirated. This allows for a very small incision that may be left unsutured, as it self-seals. “Clear cornea” surgery, where the incision is made through the cornea rather than tunneled through the sclera, was first described in 1992 but is now commonly performed. The incision is small (4 mm or less in width) and self-sealing. The stroma of the cornea remains swollen for up to 24 hours postoperatively so aids in this sealing process (50).

Incidence, Pathophysiology, Risk Factors for Endophthalmitis Endophthalmitis is the major infectious complication of cataract surgery, occurring in approximately 0.1% of cases (range 0.08-0.3%) (51, 52, 53, 54). This incidence has been stable for decades. Onset of symptoms is usually within days of surgery: 75% present within 1 week of surgery. Symptoms include eye pain, redness, and decreased vision, but the patient otherwise feels well. Patients are afebrile, the white blood count is normal or only slightly elevated, and blood cultures are negative.

Nearly all cases are due to microorganisms introduced into the aqueous humor at the time of surgery from the patient’s own ocular surface flora. Contamination of the aqueous humor during surgery with surface flora is common, with between 8% and 43% of aqueous cultures positive at the end of surgery in uncomplicated cases (55, 56, 57, 58). Endophthalmitis is rare, however, presumably because of aqueous turnover rate (every 100 minutes) and the immune system’s ability to clear small inocula of bacteria from the aqueous (59). The vitreous is gel-like and permanent, so it is much less resistant to infection than the aqueous.

Risk factors for developing postcataract endophthalmitis include surgical complications, such as inadvertent bleb creation, wound leak, or posterior capsule break. The last allows communication with the vitreous (“vitreous wick”), increasing the risk of endophthalmitis 14-fold (60). Clear corneal incisions may carry a higher risk of postoperative endophthalmitis than does traditional scleral tunnel surgery (61), although clinical features, microbiology, and outcomes of endophthalmitis resulting from either type of incision are similar (62). In one large European study, the use of clear corneal incisions was associated with a 5.88-fold increase in risk over scleral tunnel incisions (63). That study also found that the use of a silicone IOL rather than acrylic IOL had a threefold increased risk of developing endophthalmitis.

Microbiology The bacteriology is well defined. In a study of 420 patients with acute postcataract bacterial endophthalmitis, cultures of vitreous or aqueous were negative in 30% (3,64). In the 70% with positive cultures, gram-positive cocci caused 94% of cases, with coagulasenegative staphylococci the most common etiology (70% of culture-positive cases). S. aureus (10%), streptococci (9%), and gram-negative bacilli (6%) were other causes. Visual outcome depends on the etiology, with streptococci of any type producing the worst outcomes, followed by S. aureus and gram-negative bacilli. Infections due to coagulasenegative staphylococci, or culture-negative cases, fare best.

Chronic Postcataract Endophthalmitis While most cases of postcataract endophthalmitis present acutely, there are rare cases that present subacutely or chronically. These are usually due to Propionibacterium acnes or fungi. Cases due to P. acnes usually present with low-grade, chronic inflammation in the aqueous that mimics anterior uveitis. The diagnosis may not be suspected until months postoperatively. Fungal endophthalmitis following cataract surgery is rare, but more common in tropical countries than those with temperate climates.

Outbreaks Clusters of endophthalmitis cases due to contaminated instruments or ophthalmic solutions have been described, but are rare. Three outbreaks due to P. aeruginosa, two in Europe and one in the United States, have been linked to use of a contaminated phacoemulsifier (65, 66, 67). In all three outbreaks, the outbreak pathogen was found contaminating the internal pathways of the phacoemulsifier. Intrinsically contaminated fluids or lenses used in ocular surgery have led to outbreaks with P. aeruginosa or Bacillus species (68), P. aeruginosa (69), or Paecilomyces lilacinus (70, 71). Contamination of trypan blue solution used to mark the anterior lens capsule during cataract surgery in Spain led to an outbreak of 6 cases of Pseudomonas postcataract endophthalmitis at one center within 4 months (72). A cluster of 20 cases of a multidrug-resistant Pseudomonas endophthalmitis occurred during a 2-month period in 2008 at an eye center in southern India (73). Pseudomonas was recovered from the phacoemulsifier’s tubing, the povidineiodine solution, and the operating room’s air conditioning system; most strains tested similar to the air conditioner’s strains. Contamination of humidifier water in a ventilation system with Acremonium kiliense led to four cases of endophthalmitis in an ambulatory surgical center (74). Aspergillus endophthalmitis occurred in five patients during a period of hospital construction, which again demonstrates the need to follow standard guidelines during renovation or new construction (75) (see Chapter 83). An outbreak in Thailand from 1997 to 1998 in which 9.4% of patients developed postoperative endophthalmitis was determined to be due to inadequate sterilization procedures and use of multidose intraocular irrigating solution (76).

Prevention The optimal method to prevent postcataract endophthalmitis is unknown. A number of nonrandomized or retrospective studies have tried to determine efficacy of various interventions. Speaker and Menikoff (77), in an open-label nonrandomized trial, compared 5% povidoneiodine topical solution as prophylaxis in one operating room suite with silver protein solution prophylaxis in another suite. Surgeons continued to use “their customary prophylactic antibiotics.” The study found a significantly lower incidence of culture-positive endophthalmitis in the suite using the povidone-iodine (0.06% vs. 0.24%). Since this study was published, it has been generally accepted that 5% povidone-iodine solution should be used on the conjunctiva during preoperative preparation. Whether the iodine should be then flushed with sterile saline is unknown.

Other nonrandomized studies have advocated intraoperative irrigation of the anterior chamber with antibiotics, antibiotic injection into the aqueous at the end of the case, postoperative subconjunctival antibiotic injections, and perioperative topical antibiotics. Preoperative and postoperative topical antibiotics are routinely used, with topical moxifloxacin and gatifloxacin most commonly used for this purpose in the United States A retrospective study of 20,000 cataract surgeries performed at the John A. Moran Eye Center at the University of Utah found an overall incidence of postcataract endophthalmitis of 0.07%, with no significant difference between groups that used moxifloxacin versus gatifloxacin eye drops (78). In another retrospective study, the Utah group found that prophylaxis with fourth-generation quinolone eye drops was more effective than third-generation quinolone eye drops (ofloxacin, ciprofloxacin) in preventing postcataract endophthalmitis, 0.06% versus 0.2%, p = .001 (79).

There are few prospective randomized trials evaluating optimal prophylaxis for cataract surgery, since a large number of patients would need to be enrolled given the low incidence of postcataract endophthalmitis (0.1%). Recently, a prospective trial involving 24 eye clinics in 9 European countries (Austria, Belgium, Germany, Italy, Poland, Portugal, Spain, Turkey, and the United Kingdom) has been published (80). This study by the European Society of Cataract & Refractive Surgeons (ESCRS) used a 2 × 2 design and placebo control to evaluate the efficacy of (a) intracameral injection of cefuroxime (1 mg in 0.1 ml normal saline) at the end of the cataract surgery, and/or (b) perioperative levofloxacin eyedrops. The study was started in September 2003 and stopped early, January 2006, due to interim analysis showing clear benefit from intracameral cefuroxime injection. The incidence of endophthalmitis in the control group (23 cases per 6,862 surgeries, 0.34%) was nearly five times higher than in the group that received intracameral cefuroxime (5 cases in 6,836 surgeries, 0.07%), and this difference was significant (p = .002). This includes both culture-positive and culture-negative cases; the difference was even greater if only culture-positive cases were considered. Of note, the incidence of endophthalmitis in the control group was higher than most previously published studies. The use of perioperative levofloxacin eye drops was associated with a small reduction in risk, but this was not statistically significant.

Environmental controls should include standard operating room environmental air controls (i.e., at least 15 air exchanges per hour with at least 3 air changes per hour being fresh air, air filtered through filters of at least 90% efficiency). All operative equipment and irrigating fluids should be sterile prior to use, and the use of multiple dose dispensers should be avoided or limited.