Limiting the Risk of Infectious Keratitis Following LASIK

How to manage this complication if it does occur.

BY GITANE PATEL, M.D., M.P.H. AND JAY S. PEPOSE, M.D., PH.D.

Infectious keratitis, of either early or late onset, is an uncommon, potentially devastating sight-threatening complication following LASIK. While the true incidence is uncertain, it has been estimated that the rate of infectious keratitis averages approximately one in 1,000 after photorefractive keratectomy (PRK), where the epithelium and Bowman's is compromised and a bandage contact lens may be present, in comparison to one in 5,000 following LASIK.¹

However, the reported incidence varies widely² and for LASIK ranged between zero to as high as 1.5% (i.e., one in 67). The largest single reported series of 25,337 PRK procedures comes from the United States Army and Navy.³ This large retrospective study showed an incidence of culture-proven or suspected infectious keratitis in one in 5,067 procedures, all of which were early-onset infections with gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA), consistent with other studies.⁴

In LASIK, the infectious inoculum is implanted in the anterior stroma, creating initially what is in effect an abscess or loculated, focal lamellar keratitis. Similar to cataract surgery, where infectious agents can be cultured from aqueous or ocular surface in cases that do not develop endophthalmitis, cultures of the LASIK flap interface or microkeratome blade similarly show the presence of microorganisms, even in cases that do not evolve into infectious keratitis.^5,6 The observation that most culture-positive cases do not result in infectious keratitis is probably a reflection of both acquired and innate immune defense mechanisms of the cornea, the dose of the inoculum, the virulence of the pathogen, and the prophylactic, perioperative and postoperative use of antibiotics.

The ensuing inflammation can sometimes mimic diffuse lamellar keratitis (DLK) but can be differentiated in that the infiltrates are generally more focal in cases of infection, may be accompanied by pain and irritation, conjunctival and ciliary injection, and inflammation that does not always respect the boundary of the flap interface and can rapidly extend anteriorly or posteriorly. Epithelial defects, flap edema or melt, purulent discharge and hypopyon can also ensue.¹ Initiating treatment of misdiagnosed DLK with an intense, prolonged course of topical corticosteroids can further increase the risk of late-onset opportunistic infections.

Limiting the Threat of Infectious Keratitis

A special report from the Academy of Cataract and Refractive Surgery (ASCRS) suggested first treating any ocular surface conditions, including dry eye and blepharitis, before surgery.⁷ Patients with dry eye should be aggressively pre-treated with cyclosporine (Restasis, Allergan), punctal plugs and topical lubricants to try to keep an intact ocular surface postoperatively. In addition to warm compresses and lid scrubs, pre-existing blepharitis can be treated with bacitracin or Neosporin ointment, and rosacea with oral doxycycline or related compounds. Some have utilized sterile gloves and gowns, but there are no evidence-based efficacy studies to support or refute this practice. Preparing the eyelids with povidone-iodine (Betadine) antiseptic and the use of lid drapes is recommended. Using only sterile fluids to wash instruments as well as the eye, and not introducing nonsterile solutions (such as in preparing ice-pledgets for LASEK or PRK) may reduce the risk of mycobacterial and other infections. A few surgeons use a separate set of instruments for each eye if binocular surgery is to be performed.

Patients should wear eye shields immediately following surgery, at night and when napping, and avoid eye rubbing that can result in epithelial defects or movement of the flap. Avoiding swimming, gardening and sleeping with pets during the perioperative and early postoperative period represent useful instructions to help limit the risk of infections.⁸ Prophylactic antibiotics, most commonly a fourth-generation fluoroquinolone, should be continued during the early postoperative period. Protective eyewear, such as UV-blocking sunglasses, can help to avoid direct eye trauma outdoors.

Caution should be taken in performing simultaneous bilateral LASIK or PRK in patients with acquired or innate immune deficiencies, as bilateral bacterial keratitis has been reported in some cases.² For LASEK or PRK patients, the same risks of ulcerative keratitis inherent to use of an extended-wear contact lens apply, which showed close to a threefold increase associated with smoking.⁸ Patients should be instructed not to handle or reinsert their contact lenses and to report any associated conditions that present, such as hordeolum.^3,9 Therefore, it would be wise to counsel PRK and LASEK patients not to smoke, especially while the contact lens is in place and to counsel them on proper lens hygiene.

LASIK or PRK patients who work in a medical or hospital environment may also be at higher risk of bacterial colonization and infection with MRSA. Taking a nasal swab for culture may aid in determining those associated with a healthcare environment who may be colonized, and prophylactic antibiotic treatment can be considered. Some have suggested considering unilateral treatment in those colonized, along with warning the patient to call if there is any discomfort, decreased vision, photophobia, redness or discharge.⁹

The ultraviolet excimer laser energy has been demonstrated to reactivate latent herpes simplex virus in some individuals,^10,11 as well as in animal studies.¹² This warrants consideration of herpes simplex virus (HSV) in the differential diagnosis of persistent epithelial defects or delayed healing in PRK or LASIK patients, or epithelial defects following LASIK that could represent geographic HSV keratitis and would warrant discontinuing corticosteroids and initiating antiviral therapy. In addition to being aware of these signs, it seems prudent to prophylactically treat patients with a history of ocular herpes simplex keratitis or recurrent labial keratitis with oral valtrex or acyclovir.¹⁰ Whereas a history of ocular herpes simplex keratitis is not an absolute contraindication to laser vision correction, it is not without risk of viral reactivation, and has led to corneal perforation.¹¹ In addition to use of systemic antiviral prophylaxis, prudence would dictate selecting patients in whom the herpes has been inactive for a minimum of 1 year before surgery, those without stromal disease, and with regular topography and pachymetry maps and normal corneal sensitivity.

Early- vs. Late-Onset Pathogens

Early infections generally occur within 10 days of surgery. The most common pathogen would be Staphylococcus, including MRSA (now the most common single cause of post-LASIK infectious keratitis). Up to half of healthcare workers may be colonized by MRSA, and close contacts as well as those who have a history of hospitalization are at risk. Community-acquired MRSA is also on the rise. Streptococci represent a less common cause of early-onset infection, as do gram-negative species. These can evolve rapidly into a fulminant purulent keratitis.

As the use of fourth-generation flouroquinolones has become more widespread, and with a greater appreciation of the need to exclude non-sterile fluids during all phases of surgery and preparation, late-onset infection has become increasingly uncommon. In 2003, a survey by ASCRS revealed that atypical mycobacteria comprise 48% of post-LASIK infectious keratitis. The latest survey taken by the ASCRS Cornea Clinical Committee (Figure 1), released this year, shows atypical mycobacteria to be rare. Other late-onset organisms include fungi and nocardia. These entities can present anywhere from 10 days to months after surgery.

Figure 1. Results of the 2007 ASCRS Survey reveal that MRSA, along with other gram-positive bacteria, have become the most frequent pathogens in LASIK-associated keratitis, while reports of atypical mycobacterium are now rare. (Results presented by Terry Kim, M.D., and Eric Donnenfeld, M.D., on behalf of the ASCRS Cornea Clinical Committee at ASCRS 2008 Cornea Day, Chicago.)

Herpetic infection may occur early or late after laser refractive surgery. The 193 μm excimer laser has been shown to reactivate the virus in some cases, even in patients with a history of recurrent herpes labialis without any known ocular involvement. As a result, patients with a history of HSV keratitis, if considered for surgery, should be pretreated with oral acyclovir or valacyclovir before the procedure. Some surgeons consider those with a history of HSV keratitis to be sub optimal candidates, but patients with herpetic stromal disease may be at particularly high risk. Following reactivation, patients may present with any of the more common manifestations, including the typical dendritic keratitis, necrotizing stromal keratitis, endotheliitis, trabeculitis, or iridocyclitis. DLK may or may not be present.

When Signs of Infection are Present

For early infections, Staphylococci, including MRSA, should be at the top of the list of suspects. The surgeon should have a low threshold to lift the flap, scrape for smears, cultures and sensitivities, then irrigate the flap interface with antibiotics, reposition the flap and initiate ongoing antibiotic treatment. The interface scraping should be plated directly onto culture media and into broth, rather than relying on transport swabs. Smears on glass slides should be prepared for Gram and other stains.

Appropriate culture media include blood agar, chocolate agar, Sabouraud's agar and thioglycolate broth. The use of Lowenstein-Jensen media or Middlebrook 7H9 agar is indicated if there is high suspicion of atypical mycobacteria or nocardia, more common pathogens in late-onset infections. In addition to fourth-generation fluoroquinolones, alternating with fortified vancomycin or fortified cefazolin for early-onset infection, or with fortified amikacin for late-onset infections, can be considered. If MRSA is suspected, fortified vancomycin is the drug of choice. Most surgeons prefer alternating the two drugs, at least one of which is rapidly bacteriocidal, in order to achieve effective and broad-spectrum coverage. Oral doxycycline or one of its derivatives may be given in light of its metalloproteinase inhibition to help reduce the occurrence of corneal melt. Blepharitis can be treated with bacitracin or Neosporin ointment.

For late-onset infections, which can present 10 days to months from surgery, topical clarithromycin or azithromycin and fortified amikacin may be considered, in addition to the above, for their effectiveness against atypical mycobacteria, some of which may be resistant to the fourth-generation fluoroquinolones.^14,15 Topical azithromycin is now readily available commercially. In addition, all patients should have a Gram or acridine orange stain for bacteria, Gomorimethanamine silver stain for fungi, and Ziehl-Neelsen stain to detect atypical mycobacteria and nocardia. Treatment should be modified based upon the results of stains, cultures, sensitivities and in vivo response to treatment.

For persistent infection, it may be necessary to take a corneal biopsy and/or PCR analysis in order to identify the pathogen. Flap amputation may be necessary in some cases in order to increase antibiotic penetration and reduce bacterial load. In extreme cases, penetrating keratoplasty may be necessary.

For PRK or LASEK patients, differentiation of early infectious keratitis from sterile contact lens-related infiltrates or infiltrates resulting from the use of a non-steroidal antiinflammatory agent is critical. Central or paracentral infiltrates, particularly those larger than 2 mm and those associated with significant pain or anterior chamber reaction, should be cultured and smears obtained. The bandage contact lens should be removed from suspicious cases and also may be sent for culture.¹³ Fortified antibiotics should be used, along with a fourth-generation fluoroquinolone. In patients with a history of working in a medical environment or a history of recent hospitalization, MRSA should be suspected and fortified vancomycin should be part of the antibiotic regimen.

A patient 1 day following LASIK presented with pain, decreased vision and focal clustered infiltrates, some extending beyond the flap margin. These are warning signs of early LASIK-associated microbial keratitis, requiring flap lift, culture and scraping, antibiotic irrigation of the interface and intensive antibiotic treatment.

The current ASCRS recommended practice has been to stop steroid medications when infectious keratitis is suspected following LASIK, LASEK or PRK. However, an ongoing clinical trial (Steroid for Corneal Ulcer Trial, Acharya et al.), is evaluating the efficacy of topical steroids at the onset of infection. A pilot study has shown a possible benefit for the practice, and the trial at this time is ongoing. Thus, it is at this time unclear whether it is best to abruptly discontinue or to taper corticosteroids and the decision must be individualized for each case.

An Evolving Risk

Over the last 12 years, excimer laser vision correction surgery has become an increasingly popular option in vision correction, second in frequency only to cataract surgery. However, novel surgical techniques bring about novel challenges. A key challenge for the LASIK surgeon is to remain vigilant, recognize and properly diagnose post-LASIK infections early, obtain scrapings for stains, cultures and sensitivities, initiate aggressive and appropriate treatment, and to quickly reestablish good vision. We must stay diligent of emerging infections resistant to fourth-generation fluoroquinolones^9,14-16 and to other antibiotics,¹⁷ so that LASIK continues to be a safe and highly effective procedure for vision correction. OM

References

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Dr. Pepose is Medical Director of Pepose Vision Institute and professor of Clinical Ophthalmology at Washington University in St. Louis. He is a subspecialist in corneal and refractive surgery and has participated in many clinical trials, including the first excimer laser phase 3 study in the United States in 1988. Dr. Pepose trained in ophthalmology at The Wilmer Institute at the Johns Hopkins Hosptial and has a Ph.D. in microbiology and immunology from UCLA School of Medicine. He has published over 150 peer-reviewed articles and is an executive editor of The American Journal of Ophthalmology.

Dr. Patel is a fellow in corneal and refractive surgery at Pepose Vision Institute in St. Louis. In addition to pursuing training in refractive surgery, he also has an interest in international ophthalmology and has an M.P.H. from the University of Southern California. Neither Dr. Pepose nor Dr. Patel has any financial interest in any of the products mentioned in this article.