Infectious Keratitis after Surgery

Abstract

Although infectious keratitis after refractive surgery is rare, it is of great importance due to its great devastating power. The most important etiology of infectious keratitis after refractive surgery is: Staphylococcus epidermidis. The risk factors associated with the development of infectious keratitis are divided into: pre-surgical, intra-surgical and post-surgical. The time of onset of symptoms after refractive surgery is one of the most important antecedents associated with the causative microorganism. Less than 7 days is considered “early onset”. After 7 days of “late onset.” The initiation of empirical treatment is recommended in the case of early onset of symptoms with 4th generation fluoroquinolone alternated with fortified cefazolin. In the case of late onset (more than 7 days after surgery), start with 4th generation fluoroquinolone alternating with Amikacin as well as oral doxycycline. At the end of the surgery, it is recommended to apply a drop of moxifloxacin. Regarding post-surgical measures, the time of contact lens use should be limited, avoid contaminated environments and administer antibiotics for a period of 7–10 days, or until the epithelial defect has been completely resolved.

1. Introduction

Among the complications after refractive surgery is keratitis, of which there are infectious and non-infectious types. Non-infectious keratitis is the most frequent and generally has the best prognosis. As for infectious infiltrative keratitis, it is a relatively uncommon clinical entity, although a very feared one.

The corneal defense mechanisms against infections are varied and generally effective; within these mechanisms are the following [1, 2]:

• The constant flow of tears that is produced in the conjunctiva and distributed by the eyelid all over the surface of the cornea minimizes the accumulation of detritus.

• The corneal epithelium is a semipermeable physical barrier in which the rapid turnover of cells, their desquamation, and the tear film make bacterial adhesion difficult.

• The corneal temperature is lower than that of the rest of the body, thus hampering bacterial replication.

• The tear contains lysozymes, i.e., lactoferrins which are enzymes that limit bacterial growth.

All these mechanisms, however, can become impaired in cases of trauma, burns, alterations of the ocular surface, and also in some cases of refractive surgery.

Photoablative refractive surgery, either laser in situ keratomileusis (LASIK) or surface surgery (PRK), makes the cornea more liable to infections. Although infectious keratitis is a rare complication, it can also be devastating if adequate and timely measures are not taken [2]. As for the novel technique of small incision lenticule extraction (SMILE), only a few cases of infectious keratitis have been described so far [3, 4, 5].

2. Etiology

Even during refractive surgery there may be contamination by bacteria in the corneal stroma in up to 24% of cases. These bacteria are mostly of Gram-positive type, in most cases, Staphylococcus epidermidis, which does not necessarily manifest as infectious keratitis due to stromal defense mechanisms [6]. The causative agents fall within the same spectrum across the different surgical techniques. Atypical mycobacterial keratitis related to inadequate sterilization has also been described, including superficial punctate keratitis, contact lens use, and other history of previous refractive surgery or touch-ups, particularly radial keratotomy [7, 8].

Currently, the most frequently related agents are Gram-positive cocci [8, 9]. Although less frequently, other possible causative agents have been reported, namely, additional Gram-positive bacteria such as Nocardia spp and Corynebacterium spp, Gram-negative bacteria such as Pseudomonas aeruginosa and Serratia, fungi, Acanthamoeba, and even polymicrobial infections. Also, among the most common causative agents of viral infections are adenovirus [10, 11, 12, 13].

3. Risk factors

The following have been identified as the main predisposing factors for infection: disruption of the barrier function of the corneal epithelium, use of bandage contact lenses and topical corticosteroids, history of blepharitis, previous corneal surgery, contamination during surgery, dry eye, lack of perioperative antibiotics, and herpes simplex virus (HSV) infection [14, 15]. The use of contaminated surgical instruments, the surgeon’s hands, the presence of infectious agents on the ocular surface, and environmental conditions could also be associated with contamination and hence with the development of corneal infections [16].

Several factors inherent in the procedure explain the increased risk of infection after a photorefractive keratectomy (PRK) compared with other techniques. Among them, the defect in the epithelium caused during surgery, and the time of about 4 days for its regeneration, entails a loss of the protective function of the corneal epithelium and may create an area prone to adhesion and reproduction of microorganisms. Other factors are the use of therapeutic contact lenses, which are routinely used after surgery, and the use of topical corticosteroids [15, 17].

In addition, a recent retrospective study has linked the use of face masks in the previous COVID-19 pandemic with a slight increase in the incidence of infectious keratitis in patients undergoing refractive surgery [18]. Another risk factor to be considered is the possible link with methyl-resistant infectious agents [18, 19] (Table 1 and Figure 1).

Preoperative	Dry eye
	Blepharitis, Meibomian gland dysfunction
Intraoperative	Inadequate sterilization
	PRK > LASIK
	Use of contact lenses
	Face masks
Postoperative	Use of contact lenses
	Epithelial defect
	Iadequate postoperative follow-up
	Poor postoperative hygiene
	Healthcare workers
	Face masks

Table 1.

Risk factors associated with infectious keratitis.

Figure 1.

Slit-lamp microscopy image of the patient’s right eye showing a central infectious infiltrate.

4. Epidemiology

The incidence of infectious keratitis following refractive surgery varies according to different studies. A major review reported a frequency of 1 in 1000 for PRK, and 1 in 5000 for LASIK [13, 20]. The higher incidence of infectious keratitis for PKR than for LASIK is evident in multiple studies [15, 19]. On the other hand, there is little evidence and few studies yet on the frequency and treatment of infectious keratitis after SMILE [3, 4, 21].

5. Diagnosis

The clinical presentation of an infection after refractive surgery comprises decreased visual acuity, secretion, pain, epithelial defect, flap edema, reaction in anterior chamber, ciliary injection, and lacrimation. The signs and symptoms are much more varied in the case of infections by bacteria than by fungi and mycobacteria, where the symptoms can be at first frankly discreet [22].

The time of symptom onset after refractive surgery is one of the most important antecedents associated with the causative microorganism. If the symptoms begin within 7 days after the procedure (early onset), it is more likely that the infection is caused by Gram-positive bacteria or mycobacteria. If the symptoms appear after 7 days of the procedure (late onset) there is a greater likelihood that the causative agent is a mycobacterium, a fungus, Gram-positive bacteria or an Acanthamoeba [22, 23, 24, 25]. As for Acanthamoeba keratitis, it is considered of late-onset and is often not directly related to surgical intervention, but to either the incorrect use of contact lenses or contaminated liquids. It could also occur due to a previous infection. For instance, if surgical interventions such as LASIK are performed on the cornea, intrastromal cysts could be reactivated [26, 27].

For several reasons, bacterial keratitis after refractive surgery presents some variants with respect to infectious infiltrative keratitis not associated with photoablation procedures. In the case of LASIK, it is during the procedure that we take the microorganism to the depth of the corneal stroma and then cover it with the flap. Consequently, an ulcer as such is not observed but rather an abscess below the flap or on the ablated stroma in the case of PRK may appear [28].

6. Differential diagnosis

The clinical presentation of infectious keratitis is not usually easy to identify, the main differential diagnoses are the following:

• Inflammatory infiltrates: These are dense clusters of inflammatory cells that manifest as an opacity generally less than 1 mm in diameter and poorly defined limits. The treatment is based on steroidal anti-inflammatories, which are contraindicated in presence of infection. They can appear 24–48 h after refractive surgery and do not usually show the inflammatory features of bacterial keratitis [6, 10].

• Diffuse lamellar keratitis: It is an inflammatory condition that begins 24–48 h after refractive surgery. It looks as a diffuse opacity at the interface of the lamella with a morphology similar to desert sands (it is commonly known as Sahara sands), i.e., there are no dense clusters as in the case of inflammatory infiltrates, especially in the initial stages. Its treatment is based on steroidal anti-inflammatories, which are also contraindicated if there is infection. The rest of the eyeball is not usually involved, as it does not show ciliary injection, cellularity, and flare in the anterior chamber, which are usually present in infectious processes [29, 30].

• Interface fluid syndrome (IFS) or PISK (Pressure-Induced Stromal Keratopathy). It is a localized inflammation, showing fluid in the interface area or a diffuse haze between the interface area and the inner layer of the corneal tissue. It occurs due to increased intraocular pressure (IOP) as a response to corticosteroid treatment during the early postoperative phase (between 10 and 20 days). Cases have been reported even up to 10 years after surgery [31, 32, 33]. Measuring IOP increase can be difficult using Goldmann tonometry in the center of the cornea, so it is best doing it in the peripheral part of the cornea. This condition is managed using topical medications to reduce eye pressure. Contrary to most other complications, use of corticosteroids is not recommended; therefore, it is important to have an accurate differential diagnosis [34].

• Epithelial growth at the interface. It is caused by the proliferation of epithelial cells at the interface. It is whitish in appearance, painless, without inflammatory reaction, confined to the edge of the flap, and of later presentation. However, it can generate irregular astigmatism and decreased vision if the visual axis is compromised (Figures 1 and 2).

Figure 2.

Slit-lamp microscopy of the same patient’s right eye showing corneal surface with fluorescein staining, showing the central epithelial defect.

7. Treatment

Once the suspicion of infectious keratitis has been established, what follows is to lift the flap in the case of LASIK for taking cultures and washing with antibiotics. Some studies have shown that patients in whom this procedure is performed before 3 days after onset of symptoms have a better final visual capacity than those in whom this maneuver takes longer to be done [9, 22, 28].

During scraping, smears for Gram, Lowenstein-Jensen, and Middlebrook stains should be taken [30]. The culture should include media such as blood agar, chocolate, Sabouraud, and thioglycolate, with special emphasis on culture in special media such as Lowenstein-Jensen and Middlebrook in the event that the infection has appeared 7 days or more after surgery, considering atypical bacteria [30]. Culture results reveal that Gram-positive bacteria are the most common organisms present [8].

After taking the culture, it is recommended to wash the interface with fortified vancomycin 50 mg/ml in cases of early onset, and fortified amikacin 35 mg/ml in cases of late onset [30].

In most cases, the cause of the infection is difficult to determine. Among predisposing factor are the history of corneal surgery, excessive intraoperative manipulation, intraoperative contamination, and persistent postoperative epithelial defects of the cornea [7, 35, 36].

The start of empirical treatment is recommended in the case of early symptom onset with fourth-generation fluoroquinolone (after impregnation each 5 min for 30 min) alternated with fortified cefazolin 50 mg/ml every 30 min. In the case of patients who work in hospitals or who have been exposed to hospital environments, cefazolin should be replaced with fortified vancomycin 50 mg/ml due to the risk of methicillin-resistant Staphylococcus aureus (MRSA) [30].

In the case of late symptom onset (more than 7 days after surgery), treatment is started with fourth-generation fluoroquinolone (after impregnation) every 30 min, alternating with amikacin 35 mg/ml as well as doxycycline orally 100 mg 2 times a day [30].

Once the empirical treatment is commenced, the result of the stains and culture is expected. The stains are a useful guide, although their specificity and sensitivity may vary depending on the reported microorganism. The positive report of a stain for Gram-positive bacteria has a high sensitivity and a very low specificity, since these bacteria can be present on the ocular surface as normal flora. On the other hand, Gram-negative bacilli have a much higher sensitivity and specificity, and without waiting for culture results we can modify the empirical treatment initiated by replacing cefazolin or vancomycin with fortified ceftazidime [30].

Currently, new treatment modalities have emerged, such as corneal crosslinking, which is an alternative in cases where conventional medical treatment is not sufficient [3, 37]. Corneal crosslinking is highly recommended in patients who have undergone surgery with the SMILE technique [19]. As for antibiotic use, fourth-generation fluoroquinolones are not only a valuable tool in treatment, but are also useful for the prophylaxis of both lamellar and surface refractive procedures, showing superiority in comparison with other antibiotics, such as tobramycin (Figure 3) [17].

Figure 3.

Treatment nomogram.

8. Prognosis

The prognosis of infectious keratitis is usually good. The best corrected visual acuity, 20/20 or better, is seen in 37% of cases, 20/40 or better in 76.5% of cases, and worse than 20/40 in 23.5% of cases [7]. Some important factors influencing visual prognosis are early diagnosis, removal of the contact lens, and early initiation of treatment with reinforced broad-spectrum antibiotics. However, it is not a complication that should be taken lightly; the literature reports flap amputations, perforations, keratoplasties, acanthamoeba infections, endophthalmitis, and even enucleation.

9. Prophylaxis

Among the prophylactic measures prior to surgery are the detection of alterations in the eyelids, blepharitis, and anomalies on the ocular surface. During the procedure, appropriate intraoperative measures must be taken, such as correct performance of asepsis, antisepsis, and proper sterilization of the instruments. Any debris present at the flap interface should be removed, as well as any textile material or tab. At the end of surgery, it is recommended to apply one drop of moxifloxacin 5 mg/ml. Regarding post-surgical measures, the time spent wearing contact lenses should be limited, contaminated environments should be avoided, and antibiotics should be administered for a period of 7–10 days, or until the epithelial defect has completely resolved [38].

10. Conclusion

An infection following refractive surgery is considered a potentially devastating complication, which could occur even months after surgery. Antibiotic prophylaxis is thus recommended to provide broad-spectrum coverage with focus on Gram-positive bacteria.