Corneal transplant surgery, or keratoplasty, is performed in ˜50,000 patients in the United States each year. The major indications for transplantation include keratoconus, pseudophakic bullous keratopathy, Fuchs dystrophy, herpetic corneal infection, and trauma. 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. In this procedure, the ophthalmologist trephines a central disk from a cadaver 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. Lamellar keratoplasty, in which only a layer of donor cornea is used, has become increasingly common in recent years and is associated with faster recovery periods. Lamellar keratoplasty may involve the anterior layer of the cornea (deep anterior lamellar keratoplasty, DALK) but more often involves the posterior (inner) layer of the cornea, which includes the endothelium. The two types of endothelial keratoplasties are Descemet stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK). In 2018, almost twice as many donor corneas were used for endothelial keratoplasties as for PKs in the United States.¹

Most posttransplantation HAIs have been reported after traditional full-thickness PKs, since partial-thickness lamellar keratoplasties are newer procedures. HAIs include donor-host transmission of systemic infections, keratitis (infection of the cornea), and endophthalmitis (infection of the vitreous and/or aqueous).

Systemic infections transmitted from donors to recipients via corneal transplantation include rare cases of Creutzfeldt-Jakob disease (three cases), rabies (eight cases), and hepatitis B virus (two cases).² Herpes simplex virus (HSV) in the donor cornea has been transmitted to the recipient and may rarely cause postoperative HSV keratitis or contribute to graft failure.^3,4 No cases of corneal transplant-related transmission of human immunodeficiency virus (HIV) have been reported, although this is a theoretical risk. The EBAA requires a review of the donor’s medical history and serologic screening for various pathogens including hepatitis B, hepatitis C, human T-cell lymphotropic virus (HTLV), and HIV. Patients who have died from progressive encephalopathy are also excluded as cornea donors.

Keratitis refers to infectious or noninfectious inflammation of the cornea. Infectious keratitis may occur after corneal transplant surgery, but the onset may be delayed. Two large retrospective reviews found a 1.5%-2.5% incidence of infectious keratitis during the initial 2- to 3-month postoperative period but a higher risk during several years of follow-up.^5,6 Risk factors for PK-related infectious keratitis include persistent corneal epithelial defects and suture abscesses. In lamellar keratoplasty, infection may occur within the cornea at the interface between graft and native cornea. Candida species have been the most common causes of these infections, and intraocular spread of infection leading to endophthalmitis has been described.⁷

Endophthalmitis is an uncommon but potentially devastating complication of corneal transplantation, with an estimated incidence of 0.1%-1%.⁸ The incidence based on voluntary reporting to the EBAA is only 0.03%, but this may be an underestimate given the nature of voluntary reporting.⁹
The onset of endophthalmitis symptoms is typically within 2 weeks postoperatively, although may be delayed as much as 2 months. Both bacterial and fungal endophthalmitis cases have been described. Although the source of infection is usually a contaminated donor cornea, as discussed below, case clusters of infection related to contaminated eye bank storage media have occurred. A study from Saudi Arabia, for example, reported a cluster of four cases of endophthalmitis that developed 1 week after PK (three Enterococcus faecalis, one Candida glabrata), with storage media as a likely source of contamination.¹⁰ 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.¹¹

Prevention Preventing postkeratoplasty infection has been a priority for eye banks and surgeons. Eye bank corneal storage media contain either gentamicin (McCarey-Kaufman media) or gentamicin plus streptomycin (Optisol GS). The latter is the most common storage media in the United States. No antifungal agent is present, and there have been multiple reports of Candida endophthalmitis occurring in patients who have received Candida-colonized donor corneal tissue.^2,12 The risk of fungal infection appears to be higher for lamellar than PK, possibly due to longer processing times for lamellar grafts in the eye bank, with associated tissue warming.¹³ Adding an antifungal agent to the storage media has been evaluated in several experimental studies, with mixed results due to lack of efficacy or antifungal toxicity to the corneal endothelium.^14,15

Many cornea surgeons routinely culture the unused rim of the donor cornea at the time of surgery, hoping to identify patients at risk for developing postoperative endophthalmitis. The value of this practice is controversial because the incidence of culture-positive donor rims is high but posttransplantation endophthalmitis is low. However, several large studies have shown a positive predictive value of corneal donor rim cultures for fungal endophthalmitis if the donor rims grew fungi, primarily Candida. A meta-analysis of studies involving over 17,000 corneal grafts found that 14% had positive donor rim cultures and only 0.2% of transplant recipients developed endophthalmitis.¹⁶ However, 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. In another study, the EBAA reviewed 121 culture-positive post-PK endophthalmitis cases reported to eye banks from 1994 to 2003 and found that half had concordant donor and recipient microbial isolates, with concordance rates higher for fungal than bacterial cases.¹⁷ Some surgeons prescribe prophylactic antifungal eye drops if corneal donor rim cultures grow fungi. One study reported that this reduced the incidence of fungal keratitis from 16% to 2%, although the impact on endophthalmitis is unknown as there were no cases of fungal endophthalmitis.¹⁸

A keratoprosthesis (KPro) is an artificial cornea implanted in eyes that have corneal-related vision loss but which either have failed traditional cadaveric corneal transplant surgery or have an unacceptably high risk for failing primary traditional keratoplasty. The most common type of KPro used worldwide is the Boston KPro, invented at the Massachusetts Eye and Ear Infirmary by Dr. Claes Dohlman. Endophthalmitis is the most serious infectious complication in KPro eyes, but nearly all endophthalmitis cases occur months to years after surgical implantation and are not HAIs. Chronic daily use of antibiotic eyedrops targeted against the usual KPro-related bacterial endophthalmitis pathogens has successfully decreased the endophthalmitis rate.¹⁹

Commonly used laser-assisted corneal procedures to correct refractive errors (ie, the need for glasses) include photorefractive keratectomy (PRK), laser-assisted in situ keratomileusis (LASIK), and small incision lenticule extraction (SMILE). While PRK was approved by the Food and Drug Administration (FDA) in 1995, LASIK was approved in 1999 and quickly became more popular. SMILE was FDA-approved in 2016. In PRK, the laser is applied directly to the corneal surface. In LASIK, a hinged corneal flap is created first using a microkeratome or more often a femtosecond laser, then a laser ablates some of the central corneal stroma underneath the flap before the flap is replaced. In SMILE, a laser is used to cut a lenticule-shaped disk of tissue within the cornea, and this tissue is then removed through a very small side cut in the cornea. In some cases, corneal collagen cross-linking (usually done with riboflavin and ultraviolet light) is also used at the time of the LASIK or SMILE procedure (LASIK Xtra and SMILE Xtra, respectively) in order to make the cornea stronger and prevent corneal ectasia (bulging of a portion of the thinned cornea).

LASIK has been one of the most commonly performed corneal procedures, with millions of procedures performed since its introduction over 20 years ago. Infectious keratitis is an uncommon complication of LASIK with a reported incidence between 0% and 1.5%.²⁰ However, noninfectious (sterile inflammatory) keratitis has a higher incidence. In a study from Utah of ˜10,500 LASIK procedures, the incidence of post-LASIK keratitis was 2.7%, but 88% of these cases were noninfectious.²¹ Most noninfectious cases are due to diffuse lamellar keratitis (DLK), also called the “sands of the Sahara” because of the granular appearance of the corneal flap/stroma interface. The etiology is unknown, and cultures are negative. Most cases occur within the first week, but rare cases of delayed-onset (months to years) DLK have been described.²² Outbreaks of DLK have occurred, with some attributed to endotoxins in the sterilizers used at the LASIK center.²³ The majority of DLK cases are sporadic, however. The incidence of DLK appears to be higher in the eyes with LASIK flaps created by the femtosecond laser rather than the microkeratome, but the reason is not clear.²⁴

Infectious keratitis post-LASIK is rare but often caused by viruses (adenovirus, HSV),²¹ Gram-positive bacteria (staphylococci, streptococci),²⁵ or nontuberculous mycobacteria (NTM).^26,27 Fungal infections have also been reported, primarily from tropical regions. Of the NTM involved, most have been members of the Mycobacterium
chelonae group. There have been several outbreaks of NTM keratitis post-LASIK, most due to M chelonae and reported from various countries including the United States,²⁶ Japan,²⁸ and Brazil.²⁷ The source of post-LASIK NTM keratitis outbreaks has not been identified in most reports. In one cluster of Mycobacterium szulgai keratitis cases at a center in Texas, the source was found to be ice used by one ophthalmologist to chill syringes of saline solution before intraprocedure lavage.²⁹ In a cluster of M chelonae cases from a center in Brazil, the source was distilled water used in instrument reprocessing.²⁷

In SMILE, as in LASIK, the noninfectious condition DLK can occur. The reported rate of DLK has varied from 0.5% to 2%.^30,31 In one study, two-thirds of DLK cases had a “classic” appearance, while in one-third, the appearance was unusual (multifocal interface keratitis). SMILE is a much newer procedure than LASIK, but there may be a lower risk of HAIs; one study of over 6000 SMILE procedures reported no infectious complications.³¹ A case of bilateral keratitis due to Mycobacterium abscessus was recently described after SMILE.³²

Glaucoma that is refractory to medical or laser therapy may be controlled by several types of surgeries. One of the most commonly performed glaucoma operations is trabeculectomy surgery, in which a microscopic drainage system is surgically created in the sclera and then covered with sclera and conjunctiva, which then creates a “filtering bleb” 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; and early-onset postoperative cases are very rare—usually <0.1%.³³ Many cases of bleb-related endophthalmitis are not considered HAIs, because they are often late-onset, due to progressive thinning of the bleb and its surrounding ocular tissues over many years.

Another way to control severe glaucoma is through the use of glaucoma drainage implants, such as the Ahmed valve or Baerveldt glaucoma implant. 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”), which is usually sutured to the superior surface of the globe. Aqueous humor then leaks slowly out of this reservoir into the subconjunctival space and thereby the systemic circulation. Endophthalmitis is a rare complication of glaucoma drainage implants, and as in filtering blebs, most cases occur beyond the immediate postoperative period and so are not HAIs. In a retrospective study of Ahmed shunts placed in 542 eyes between 1994 and 2003 in Saudi Arabia, endophthalmitis developed in 9 eyes (1.7%), but only 1 of these infections occurred <6 weeks postoperatively.³⁴

In recent years, a number of other newer glaucoma procedures have been developed and are termed “minimally invasive glaucoma surgery” or MIGS procedures. Although these procedures are thought to be less effective than traditional trabeculectomy surgery, they may be associated with fewer postoperative infections since a bleb is not created. These procedures include internal minishunts or stents, trabeculotomies (eg, gonioscopy-assisted transluminal trabeculotomy or GATT), endoscopic cyclophotocoagulations, and canaloplasties.

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 causes of cataracts include trauma, diabetes, chronic use of corticosteroids, and chronic inflammation in the eye (eg, uveitis). Cataract surgery is one of the most common surgical procedures performed, with over 3.5 million surgeries performed annually in the United States and an estimated 20 million procedures worldwide. Surgery has been performed on an ambulatory basis in the United States 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, leaving the posterior lens capsule intact, and replacing the lens with a synthetic intraocular lens (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 self-sealing sutureless corneal incision.

Endophthalmitis is the major infectious complication of cataract surgery, occurring in ˜0.1% of cases. This incidence has been relatively stable for decades. The onset of symptoms is usually within 1 week of surgery (75% of cases). Symptoms include eye pain, redness, and decreased vision, but the patient is afebrile, has a normal or slightly elevated white blood count, and typically feels otherwise well. 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. This “contamination” of the aqueous humor is common, yet endophthalmitis is rare presumably because of constant aqueous turnover (every 100 minutes) and the immune system’s ability to clear small inocula of bacteria from the aqueous. Unlike the aqueous, the vitreous is a gel-like structure that a person is born with; it does not regenerate. Therefore, if the posterior lens capsule is pierced during cataract removal and therefore microbes contaminating the aqueous reach the vitreous, the risk of endophthalmitis is increased severalfold. In addition to posterior capsule breaks, other risk factors for developing postcataract endophthalmitis include inadvertent bleb creation and wound leak.

The microbiology of acute postcataract endophthalmitis reflects the ocular surface origin of pathogens in most cases. In a large prospective study, 70% of cases of postcataract bacterial endophthalmitis were culture-positive, and of those, 94% were due to Gram-positive cocci including coagulase-negative staphylococci (70% of culture-positive cases), Staphylococcus aureus (10%), and streptococci (9%).³⁵ In tropical climates such as in India, fungi may cause up to 20% of postoperative endophthalmitis cases.³⁶ Visual outcome in endophthalmitis is associated with the pathogen. Streptococci of any type usually produce the worst outcomes, followed by S aureus and Gram-negative bacilli. Endophthalmitis due to molds also has a poor prognosis. Infections due to coagulase-negative 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 Cutibacterium (formerly Propionibacterium) acnes or fungi and are HAIs because the infection was most likely introduced at the time of surgery. Cases due to C. acnes usually present with low-grade, chronic inflammation in the aqueous that mimics anterior uveitis. Topical corticosteroids may temporarily decrease the inflammation. The diagnosis may not be suspected until several months postoperatively.

Prevention The optimal method to prevent postcataract endophthalmitis is unknown. Generally accepted prophylaxis includes the application immediately preoperatively of povidone-iodine, a 5% solution to the conjunctiva and a 10% solution to lid skin. Some ophthalmologists also inject cefuroxime into the anterior chamber (ie, intracamerally) at the end of surgery as prophylaxis. This is based on a randomized controlled trial from Europe that found that intracameral cefuroxime prophylaxis was associated with a lower rate of postoperative endophthalmitis than the control group (0.07% vs 0.34%).³⁷ The control group’s rate of endophthalmitis, however, was three times higher than the rate usually reported for postcataract endophthalmitis, so acceptance of this prophylaxis has not been universal. Topical antibiotics, such as topical fluoroquinolones, are often given postoperatively although randomized controlled trials to evaluate efficacy have not been performed.

Outbreaks Postcataract endophthalmitis may occur from contaminated instruments or ophthalmic solutions. Several outbreaks have been linked to contaminated phacoemulsifiers, including outbreaks due to Pseudomonas and Ochrobactrum anthropi.^38,39 Contaminated fluids or IOLs have led to outbreaks of postcataract endophthalmitis due to Bacillus species,⁴⁰ Pseudomonas aeruginosa,⁴¹ Burkholderia cepacia,⁴² Stenotrophomonas maltophilia,⁴³ and Fusarium.⁴⁴ Contamination of trypan blue solution used to mark the anterior lens capsule during cataract surgery led to a cluster of six cases of Pseudomonas endophthalmitis at a center in Spain,⁴⁵ as well as six cases of Pseudomonas and Burkholderia endophthalmitis in the United States.⁴² An outbreak of 20 cases of endophthalmitis due to multidrug-resistant Pseudomonas occurred, following cataract surgery in India.⁴⁶ Outbreak investigation found Pseudomonas in the phacoemulsifier’s tubing, the povidone-iodine solution, and the operating room’s air conditioning system. Contamination of humidifier water in a ventilation system with Acremonium kiliense led to four cases of endophthalmitis in an ambulatory surgical center.⁴⁷ Aspergillus endophthalmitis occurred in five patients during a period of hospital construction.⁴⁸ The timing of symptom onset may be delayed in some postoperative outbreaks, particularly those due to fungi. In an outbreak of Fusarium postcataract endophthalmitis involving 20 patients in the Czech Republic, the onset of symptoms occurred an average of 31 days postoperatively (range 16-79).⁴⁹ The etiology was thought to be contaminated viscoelastic filling material.