Prevalence of causal microorganisms of contact lens-associated infectious keratitis.
The focus of this chapter is to review the most recent advances in the diagnosis and treatment of contact-lens-related infectious keratitis, the most sight-threatening complication of contact lens wear. In the last decades, contact lenses technology has confronted several challenges, including the need for safer and more comfortable polymer materials. The development of high coefficient oxygen permeability (Dkt) and low-water content disposable contact lens translated into a significant improvement in ocular discomfort related to dry eye and allergic reactions, decreasing biofilm build-up on the external surface of the lens. Additionally, the emergence and boom-effect of corneal refractive surgery have also driven the development of better contact lens manufacturing. Despite these substantial technological advances, contact lens users continue to be at risk for developing corneal infections. We describe recent epidemiologic data, and advances in understanding the complex pathogenesis of the disease, including the clinical characteristics of the infectious process produced by bacteria, fungi, and protozoans. Finally, the recent development of diagnostic techniques and therapeutic regimens are discussed.
- contact lens
- infectious keratitis
Contact lenses are a useful tool for correcting refractive errors; over 125 million people wear them worldwide . The widespread use of contact lenses is associated with a variable range of complications up to 39–60.99% of contact lens wearers. Complications range from mild superficial punctate keratitis to vision-threatening conditions such as contact-lens-related infectious keratitis. Infectious keratitis is a potentially blinding condition, and it rarely occurs in healthy eyes; it comprises bacterial, fungal, and
A classical definition of contact lens-associated infectious keratitis (CLAIK) includes a corneal epithelial defect or ulcer, accompanied by a stromal infiltrate, requiring corneal scraping and culturing . However, corneal cultures are not readily available for all practitioners, suggesting a purely clinical definition . Stapleton et al. proposed the following definition: a corneal infiltrate with an overlying epithelial defect and one or more of the following: lesions within the 4 mm of the central cornea, anterior chamber reaction, and pain .
The annual incidence of CLAIK per 10 000 wearers ranges from 0.4–4.0 for rigid gas permeable (RGP) contact lenses, 2.2–4.5 for daily use of soft contact lenses, and 9.3–20.9 for overnight soft contact lenses wear . Hence, daily wear of RGP contact lenses continues to have the lowest infectious keratitis rates ; however, the incidence of associated microbial keratitis remains unchanged despite the development of new contact lens materials .
Orthokeratology (ortho-K) for myopia prevention and cosmetic and decorative lenses have recently gained popularity among young wearers. On the one hand, ortho-K patients are closely monitored during treatment by their practitioners; conversely, cosmetic contact lens wear (color or party) lacks care education and professional supervision. There are reports of microbial keratitis in both wear modalities [14, 15]. In the case of cosmetic lens wear not dispensed by eye care professionals, a report shows an increased risk of infectious keratitis by a factor of 12.3 (OR 95%-CI = 4.8–31.5 Furthermore, lack of lens care education in the same study increased the risk of infectious keratitis by 26.5 times (OR 95%-CI = 10.0–70.2) .
CLAIK is mainly attributed to bacterial pathogens with up to 90% of the cases (Table 1). Moreover, although fungal and protozoal infections are infrequent, they are more severe . The most common bacterial agent involved in CLAIK is
|6–55.55% [3, 17, 18, 19, 20, 21, 22]|
|Other coagulase-negative ||8–17.64% [20, 21, 22]|
|2–17.1% [3, 17, 18, 19, 20, 21, 22]|
|2–12.5% [3, 19, 20, 21, 22]|
|1.96–12.5% [3, 19, 21]|
|2–12.5% [19, 21, 22]|
|3.92–5.9% [20, 21]|
|1–1.96% [21, 22]|
On the other hand, keratitis caused by
It is noteworthy to mention the occurrence of CLAIK associated with multiple microorganisms. A retrospective analysis of CLAIK, performed by Karaca et al., demonstrated that 20% (12 cases) were mixed infections. All of them were mixed bacterium-bacterium infections.
5. Risk factors
Among the many different risk factors predisposing to CLAIK, overnight wear and poor hygiene are the two most frequent ones, accounting for 43% and 33% of the cases, respectively . Regarding corneal infection in overnight wear, the risk is higher with increased extended wear and inexperienced patients [36, 37]. Interestingly, in severe keratitis, mishandling of the contact lens case (poor hygiene and lack of replacement) accounts for 63% of the population-attributed risk for bacterial and fungal infection. Moreover, swimming with contact lenses on and traveling are also risk factors for infection. The former for
Other risk factors of infectious keratitis in contact lens wearers include being a male, probably related to poor compliance and reluctance to seek regular care attention . Genetic susceptibility related to small mutations of defensins, interleukins, and other inflammatory mediators seems to play a role in CLAIK (Table 2) .
|Risk factors||Highest risk||Lowest risk|
|Wear schedule||Overnight use||Daily wear only|
|Days of weekly use||6–7 days|
|Hand washing before cleaning||Not always||Always|
|Contact lens type||Daily disposable||Rigid lenses |
|Case hygiene/replace time||Poor||Excellent|
|Purchase of contact lens||Internet/mail order||Optometrist |
|Showering with lenses||Yes||No |
|Water exposure1||Yes2||No |
|Ocular surface and systemic diseases||Presence||absence |
|Socioeconomic status3||High ||Low |
|Caucasian race1||Yes||No |
|Previous ocular trauma||Presence||Absence |
The primary vector for bacterial transmission in CLAIK is the contact lens through various contaminants, including the eyelids, hands, storage case, cosmetics, and contaminated water or lens solutions [44, 45]. Contact lenses wear alone alters the normal physiology of the cornea. To a greater or lesser extent, the local hypoxia induced by contact lenses causes a decreased epithelial metabolic rate, resulting in epithelial thinning, loss of tight cell junctions, and hemidesmosomes, which lead to epithelial abrasions predisposing to opportunistic infections. Other corneal hypoxic effects include vascularization and hypoesthesia.
The understanding of CLAIK pathogenesis has changed over time as contact lens materials evolved. Contact lens wear increased in popularity when soft hydrogel contact lenses were introduced, given a higher comfort for the wearer . However, their intrinsic low-oxygen transmissibility was demonstrated to be problematic. It is well-known that lower oxygen transmissibility is related to a higher rate of bacterial binding to the corneal surface; hypoxic conditions in human corneas increase wild-type cystic fibrosis transmembrane conductance regulator (CFTR) expression, which is the cellular receptor for
Because solving the hypoxia mechanism did not result in a reduced incidence rate of microbial keratitis, other alternative pathogenic mechanisms are suggested for corneal infection, including inadequate tear exchange. Deficient tear exchange leads to the entrapment of debris and microbes on the posterior surface of contact lenses and hinders the natural antimicrobial functions of the tear film. In fact, there is a reduction in the antimicrobial activity of the tear film on the posterior surface of silicone hydrogel soft contact lenses after 8 hours of wearing them . This mechanism could explain why soft contact lenses are associated with a higher risk of infectious keratitis than rigid gas permeable lenses, given the inadequate tear exchange in the former [52, 53].
Microbes responsible for infectious keratitis may come from the lid margins, the wearers’ fingers upon contact lens insertion, or removal, directly from the contact lens or indirectly from the storage case or the lens care solution . Contact lens case contamination has been reported in up to 80% of contact lens wearers, despite adequate compliance with care regimens [55, 56]. The formation of bacterial biofilm on the contact lens surface and storage cases has been previously reported, and it may also play a role in the pathogenesis of microbial keratitis . Bacterial cells within a biofilm show increased resistance to antimicrobial agents . Moreover, multiple biguanide-based contact lens solutions have no effect against biofilms of
Animal models have also been used to improve understanding CLAIK. In mouse and guinea pig models, a corneal erosion must occur to produce infectious keratitis; animals with non-scratched corneas only show non-infectious inflammatory responses . This has led to the hypothesis that a corneal defect or erosion is a prerequisite for CLAIK to occur and not microbial contamination alone . Corneal erosions are known complications in contact lens wearers, especially on extended wear schedules [61, 62].
Several risk factors have been associated with microbial keratitis. The most consistent factor is overnight wear, which increases the risk for microbial keratitis by 10 to 15 times compared to daily wear, irrespective of lens type [9, 12, 50, 63, 64, 65]. The extended wear risk of infectious keratitis also increases by 9 times with aphakia correction in elderly patients; 12 times greater in patients misusing daily-wear lenses for overnight wear. Other risk factors include contact lens case hygiene, inadequate or lack of handwashing, infrequent case replacement, and smoking; wearing contact lenses while swimming or showering also increases the risk [27, 17, 66, 67, 68, 69, 70, 71]. Contact lens wearers who live or travel to tropical locations also have a higher risk for microbial keratitis . According to the lens type, the risk for microbial keratitis is as follows: daily disposable < rigid gas permeable < daily wear of soft contact lens < extended wear of soft contact lens [3, 35, 72].
Furthermore, contact lens wear results in a decrease in basal cell proliferation on the cornea and vertical migration of differentiated cells to the surface of the epithelium, and an abnormal accumulation of older epithelial cells [73, 74].
The pathogenesis of CLAIK is complex and involves intrinsic lens properties, including lens material and oxygen transmissibility and environmental variables such as bacterial contamination; user behavior, such as schedule wear and poor hygiene coupled with the alteration of normal corneal physiology, loss of epithelial adherence mechanisms and corneal erosions, lead to the development of microbial keratitis . In summary, microbial contamination of the lens is followed by microbial adhesion to the corneal epithelium; then microtrauma or erosion to the epithelium occurs, resulting in the microbial invasion of the corneal stroma (Figure 2) .
Proper diagnosis of CLAIK is based on a complete ocular history of contact lens wear, patient’s symptoms, a complete ophthalmological examination, corneal scrape, and culture, including the removed contact lens, the case, and solution .
7.1 Symptoms and signs
Symptoms common to microbial keratitis include a rapid onset of ocular pain, red eye, tearing, foreign body sensation, conjunctival mucopurulent discharge, and photophobia with a variable degree of vision loss. These symptoms are be accompanied by prominent signs including, eyelid swelling, ciliary injection, conjunctival chemosis, a corneal epithelial defect or ulceration, stromal inflammatory/microbial infiltrate, edema, endothelial keratic precipitates (KPs), and anterior chamber reaction (inflammatory cells, flare, fibrin, plasmoid bodies, hypopyon) [11, 76, 77, 78].
There are clinical features that may guide the clinician to a possible etiological agent. Bacterial keratitis is characterized by a round, or oval epithelial defect with an underlying stromal infiltrate and anterior chamber reaction or hypopyon (Figure 3A–C) .
The classical findings in
7.2 Smear staining and culture
Corneal scrapings are obtained in the office under the slit lamp. A topical anesthetic agent is instilled, ideally proparacaine hydrochloride 0.5% or a preservative-free anesthetic . The corneal material is obtained with a sterile platinum spatula, blade, forceps, or a calcium alginate swab moistened in thioglycolate broth. The smear stains helpful in identifying the causative organism are Gram stain, Giemsa stain, and Acridine orange are the most frequently used for detecting bacteria. The Gram stain permits identification of gram-positive and -negative coccus and rods, which is essential to choose the initial antibiotic type before the antibiogram and sensitivity profile of the microorganism in question is available. For example, cephalosporins are more appropriate for gram-positive and aminoglycosides for gram-negative bacteria .
In case of presumptive fungal infection, special stains like potassium hydroxide (KOH) and calcofluor white (CFW) are more reliable to initiate antifungal therapy than Gram staining is for bacterial infection (Figure 4A and B) [82, 83].
|Staining technique||Visualized microorganisms|
|Gram||Bacteria, fungi and |
|Giemsa||Bacteria, fungi and |
|Potassium hydroxide (KOH)||Fungi|
|Acridine orange||Bacteria, fungi and |
|Calcofluor white (CFW)||Fungi and |
|Acid fast (modified Ziehl-Neelsen)||Mycobacteria and |
According to the American Academy of Ophthalmology Bacterial Keratitis Preferred Practice Pattern, cultures and smears should be obtained in cases of suspected microbial keratitis in the following conditions:
the presence of a large, central infiltrate and/or accompanied with stromal melting
chronic or unresponsive infection despite broad-spectrum antibiotic therapy
atypical clinical findings suggestive of fungal, protozoal, or mycobacterial agents
multifocal infiltrates or a history of corneal surgery .
Corneal scrapings should be directly inoculated into the culture media at room temperature and immediately taken to the laboratory for further processing. If culture media are not readily available, scrapings should be inoculated into transport media, including brain-heart infusion media and amies medium with charcoal. Both transport media may be used for aerobic and facultative anaerobic bacteria and, the latter, also for fungi . Standard culture media include blood agar, chocolate agar, Sabouraud dextrose agar, thioglycolate broth, and mannitol salt agar. If
|Blood agar||Aerobic, anaerobic, and facultative anaerobic bacteria. |
|Chocolate agar||Aerobic, anaerobic, and facultative anaerobic bacteria. Ideal for isolation |
|Sabouraud dextrose agar||Fungi and |
|Thioglycolate broth||Aerobic and anaerobic bacteria|
|CDC anaerobe blood agar|
|Non-nutrient agar with |
|Brain-heart infusion broth||Filamentous fungi and yeasts. Aerobic and facultative anaerobic bacteria.|
|Amies medium without charcoal||Aerobic and facultative anaerobic bacteria. Fungi [66, 82, 84, 85]|
7.3 Tissue biopsy
A corneal biopsy may be performed if there is an inadequate response to treatment or if cultures are repeatedly negative, particularly for suspicious
To obtain the tissue specimen, topical antibiotics must be suspended at least 24–48 hours before the procedure . Also, appropriate planning and consultation with the microbiologist and pathologist is recommended (i.e., need for special stains for fastidious organisms, appropriate fixatives if electron microscopy is required) .
The biopsy must be performed under appropriate magnification at either the operating room or under the slit lamp, with free lamellar dissection using a diamond-sharp blade, set at 0.2 to 0.3 mm depth, or a 3 to 5 mm diameter trephine (skin biopsy punches), cutting to approximately 0.2 to 0.3 mm depth to avoid corneal perforation . After trephination, the base of the tissue block must be gently pulled upward and sideways with a Colibri 0.12 mm tooth forceps to cut it off with a sharp knife (i.e., Grieshaber knife, Beaver blade No.66) or a Vannas scissors, completing the lamellar keratectomy .
The tissue biopsy must include a leading edge of the infiltrate or ulcer, including an uninvolved tissue margin .
The tissue sample’s processing technique (i.e., electron and light microscopy histopathologic analysis, immunofluorescence, or histochemistry) depends on the clinical features and the amount of tissue available. For small specimens (<3 mm), it is suggested to use only the technique potentially yielding the best result, which must be selected based on a clinical suspicion .
If a large sample is obtained, the specimen is divided under sterile technique with a sharp #11 or a 15° knife. Each portion is placed in the appropriate fixative .
With a cotton-tipped applicator or a moistened cellulose (Weck-cel) sponge, swab the base of the keratectomy and streak the culture material on plates containing transport media .
7.4 Molecular biology techniques
The most common approach to diagnose CLAIK is to culture microorganisms from corneal scrapings. However, more than 99% of the biosphere’s microbes are not cultivable using standard laboratory culture techniques . Furthermore, identifying slow-growing bacteria (e.g., atypical mycobacteria) or fungi with atypical phenotypes is tedious and time-consuming . The advent of molecular culture-independent high-throughput sequencing approaches has allowed further identification and characterization of microorganisms that cause CLAIK .
7.4.1 Polymerase chain reaction (PCR)
PCR is a highly sensitive technique that allows rapid amplification of tiny samples of DNA. In the context of infection, it may be used to detect the presence of pathogenic DNA of specific microorganisms . The 16S and 18S rRNA are the most frequently used marker genes for assessing bacterial and fungal profiles, respectively. They are found in all respective microorganisms and have enough variation for phylogenetic analysis and sequence conservation for accurate alignment . The 16S rRNA gene sequence is 1,550 bp long, and it is composed of nine variable regions (V1-V9) interspaced in more conserved regions. By amplifying the 16S rRNA region with PCR, the background host contamination encountered in routing culturing techniques is reduced significantly .
Kim et al. compared the detection rate of PCR compared with traditional cultures in patients with infectious corneal ulcers . Of 108 samples taken from ulcers, 52% were culture-positive and 89% PCR-positive for fungal primers (18S rRNA), bacterial primers (16s rRNA), or both. Of note, other nonpathogenic organisms (i.e.,
7.4.2 Next-generation sequencing (NGS)
NGS encompasses an evolving group of high-throughput sequencing technologies which allow massive sequencing of nucleic acid. The Sanger (1970s), a precursor to NGS, is a first-generation sequencing platform with high accuracy when dealing with one bacterium. In fact, the Human Genome Project (2003) was completed with the automatization of this technique. Isolated bacterial sequencing required multiple reactions with the Sanger platform, and thus, it was complex and time consuming . Second-generation platforms (Illumina HiSeq 2500), although able to generate high sequence throughput data in a single reaction, they only sequenced part of the 16S gene [94, 103, 104]. Current third-generation platforms use nanopore sequencing technology directly from clinical samples to diagnose bacterial keratitis in real time and with higher accuracy .
Metagenomic NGS (mNGS) is an emerging approach that analyzes microbial, and host’s genetic material (DNA and RNA) in samples from patients . mNGS may detect all potential pathogens (bacteria, fungi, parasites, and viruses) in a clinical or environmental sample and simultaneously interrogate host responses by performing billions of reads in a single run [105, 106]. Unfortunately, the untargeted nature of this approach most likely results in host-derived reads .
Obtaining a rapid, real-time diagnosis of the causative microbe in bacterial keratitis will allow the ophthalmologist to initiate prompt and adequate antibiotic therapy; thus, improving the visual outcome and reducing antibiotic resistance . However, test validation, reproducibility, high costs, among others, are significant drawbacks for the routine use of NGS and mNGS in clinical settings. Nevertheless, they must be considered in refractory difficult-to-identify cases of infection.
7.5 In vivo confocal microscopy (IVCM)
IVCM is a non-invasive imaging technique that allows dissection of the corneal architecture at a cellular level, providing real-time images equivalent to those obtained from ex-vivo histopathological techniques (tissue biopsy) . It is currently used to evaluate corneal nerves in healthy eyes and those affected by ectatic corneal diseases, neurotrophic keratopathy, corneal dystrophies, ocular surface inflammation, contact lens wear, and infectious keratitis [108, 109, 110].
The role of IVCM in CLAIK relies on the identification of fungal hyphae and
Although IVCM may be used in culture-negative cases or when the clinical diagnosis is unclear, this technique requires an experienced examiner. The rearmost since cellular features exhibited in microbial keratitis may be easily confused with nerve fibers, activated stromal keratocytes, and Langerhans cells . Moreover, its small field of view precludes fair dismissal of
8. Differential diagnosis
8.1 Microorganism profile
According to the clinical features of the infectious/inflammatory process seen in CLAIK, specific differences, although not compelling, help identify the infectious agent involved in the process. For example, Gram-negative bacteria are usually associated with a significant anterior chamber reaction and larger ulcers compared to Gram-positive ones. Also,
8.2 Infectious versus inflammatory keratitis
One of the first dilemmas confronted by professionals taking care of patients wearing contact lenses is to know if the corneal lesion is infectious or inflammatory (Figure 6A and B). The difficulty arises because the ocular immune response to foreign stimuli, including microbes and their products, foreign bodies, trauma, allergic and toxic reactions, is non-specific inflammation, which may be indistinguishable from infection in that respect [78, 117, 118]. A study asking ophthalmologists to identify sterile from culture-proven CLAIK found good predictability (76%, 95% CI = 67–84) with 79 cases classified correctly .
Some key clinical features help to differentiate between sterile from infectious keratitis. In sterile inflammation, the absence of eyelid edema, no conjunctival discharge, peripheral location of the lesion, and minimal or no anterior chamber reaction contrast with significant eyelid edema, abundant mucopurulent discharge, central/paracentral lesions, and severe reaction and hypopyon formation in infectious keratitis .
First and foremost, efforts should be focused on the prevention of CLAIK. Wearers should be educated on the proper use of contact lenses. They should be counseled to avoid overnight wear and exposure to water and be educated on appropriate hygiene practices when handling contact lenses and timely contact lens replacement .
To make the right management decisions, recognizing the risk factors for CLAIK, its different clinical infectious patterns, and getting the causal microorganism identification/isolation are critical to obtaining an optimal therapeutic response, avoiding sight-threatening severe complications.
9.1 Bacterial keratitis
An early diagnosis and appropriate treatment of infectious keratitis are essential. Broad-spectrum topical antibiotics are the first-line therapy for bacterial keratitis and should be initiated immediately after cultures are obtained, while waiting for the results. Antibiotics should be indicated, taking into consideration the local epidemiological data, frequency of specific pathogens, and antibiotic sensitivities (Table 5) [82, 119]. Severe keratitis should be treated with an initial loading dose every 5 to 15 minutes for the first hour, followed by hourly instillation for 24 to 48 hours; a topical fortified antibiotic or fluoroquinolone may be used .
|Drug||Topical concentration||Subconjunctival dose||Activity|
|Cephalosporins: Inhibit bacterial cell wall formation by disrupting the synthesis of peptidoglycans.|
Less susceptibility to β-lactamases compared with penicillins.
|Cefazolin1||50 mg/mL||100 mg in 0.5 mL||Gram-positive cocci|
|Ceftriaxone||50 mg/mL||100 mg in 0.5 mL||Gram-negative cocci2|
|Ceftazidime||50 mg/mL||100 mg in 0.5 mL||Gram-negative cocci / rods|
|Fluoroquinolones1: Inhibit bacterial DNA gyrase and topoisomerase IV, enzymes required for bacterial DNA synthesis.|
|Ciprofloxacin||3–6 mg/mL||Not available||Gram-negative cocci / rods|
|Ofloxacin||3–6 mg/mL||Not available||Gram-negative cocci / rods|
|Levofloxacin||5–15 mg/mL||Not available||+ gram-positive cocci|
|Moxifloxacin||5–6 mg/mL||Not available||+ gram-positive cocci and NTM|
|Gatifloxacin||5–6 mg/mL||Not available|
|Besifloxacin||5–6 mg/mL||Not available|
|Aminoglycosides: Bind to ribosomal subunits, resulting in defective mRNA translation and inhibition of protein biosynthesis.|
|Gentamicin1||9–14 mg/mL||20 mg in 0.5 mL||Gram-negative rods|
|Tobramycin1||9–14 mg/mL||20 mg in 0.5 mL||Gram-negative rods|
|Amikacin||20–40 mg/mL||20 mg in 0.5 mL||NTM / |
|Penicillins: Inhibit bacterial cell wall formation by disrupting the peptidoglycan synthesis.|
|Penicillin G||100,000 U/mL||1,000,000 U/mL||Nonpenicillinase producing gram-positive organisms|
|Methicillin||50 mg/mL||200 mg/mL||Penicillinase-producing gram-positive organisms|
|Piperacillin||7 mg/mL||200 mg/mL||Gram-positives and some gram-negatives, including |
|Glycopeptides: Inhibit cell wall formation of gram-positive bacteria|
|Vancomycin3||15–50 mg/mL||25 mg in 0.5 mL||Gram-positive cocci|
|Macrolides: Inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit.|
|Erythromycin4||5 mg/gram||Not available||Gram-positive bacteria|
|Clarithromycin||10 mg/mL||20 mg in 0.5 mL||NTM|
|Bacterial folic acid inhibitors: Folic acid, used in DNA synthesis is required by bacteria for growth and replication.|
|Sulfacetamide5||100 mg/mL||20 mg in 0.5 mL|
|20 mg in 0.5 mL|
In a recent meta-analysis, no difference in effectiveness, defined as complete corneal re-epithelialization, was observed between the use of commercially available fourth-generation topical fluoroquinolones and aminoglycoside-cephalosporin fortified combinations; there was no difference in time to resolution either. However, symptoms of ocular discomfort and toxic conjunctivitis were more frequent when using fortified aminoglycoside-cephalosporin combinations (see Appendix 1) .
Treatment should be tapered according to response to a minimum of four times a day, avoiding toxicity from prolonged and unnecessary use of antibiotics . If no clinical stabilization or improvement is observed after the first 48 hours of treatment, the therapeutic regimen should be modified; culture results and antibiotic sensitivity should guide the clinician under these conditions. Good therapeutic response features include decreased pain, conjunctival discharge, eyelid edema, reduced corneal stromal edema, a decreased anterior chamber response, and signs of re-epithelialization. Patients with severe keratitis should be followed daily until clinical improvement is observed. Cycloplegic agents may be indicated in cases of severe keratitis with significant anterior chamber reaction to prevent the formation of irissynechiae and reduce the pain .
The use of topical corticosteroids is controversial but may have a role in treating certain bacterial keratitis to reduce corneal scarring. According to a subgroup analysis of the Steroids for Corneal Ulcers Trial (SCUT) in non-
9.2 Fungal keratitis
Fungal keratitis is often more aggressive than bacterial keratitis. However, there is no consensus on standard treatment, and randomized clinical trials on this subject are scarce . Most antifungal medications available for ocular infections have significant limitations, including low bioavailability and limited ocular penetration in deep-seated lesions (Table 6) [123, 124, 125]. Furthermore, antifungal susceptibility testing has limited availability and is rarely used in ordinary contact lens and cornea clinics . The Mycotic Ulcer Treatment Trial I (MUTT I) showed that topical natamycin is superior to topical voriconazole treating fungal keratitis in general, particularly in those caused by
|Polyenes: bind to ergosterol in the fungal cell wall; disruption of cell wall|
Dose: initial dose of one drop every 30 minutes with tapering to every 3 to 6 hours
|Amphotericin B||0.05%–0.50%||First-line therapy for |
|Azoles: inhibit the synthesis of ergosterol through the cytochrome P-450-dependent enzyme|
|Echinocandins: block beta-glucan synthesis|
|Allylamines: block ergosterol biosynthesis by inhibition of squalene epoxidase|
9.3 Acanthamoeba keratitis
There is no consensus on the standard treatment for
9.4 Topical corticosteroids in infectious keratitis
The use of topical corticosteroids in infectious keratitis remains controversial . Some authors advocate their use suggesting corticosteroids minimize corneal inflammation, opacification, and neovascularization. Others oppose their use, claiming that they might exacerbate microbial replication, delay epithelial healing, accelerate stromal melting, and increase the risk of perforation . Several authors have demonstrated in non-controlled studies that prior corticosteroid use in bacterial keratitis significantly increases the risk of antibiotic failure and corneal ulceration [132, 133]. A Cochrane review of three small randomized trials found no benefit in healing times or visual acuity outcomes with adjuvant corticosteroid treatment . The Steroids for Corneal Ulcers Trial (SCUT), the largest randomized controlled trial to date, showed no overall benefit of steroid use in visual acuity, scar size, or perforation rate at 3-months follow-up . Of note, steroids (prednisolone sodium phosphate 1%) or placebo were started after 48 hours of topical 0.5% moxifloxacin. The SCUT also demonstrated that adjuvant corticosteroids, compared to placebo, resulted in one-line improvement in visual acuity in non-
Similar results were described by Wouters et al. in eyes with
In a recent murine model of
9.5 Corneal collagen crosslinking (CXL)
Corneal CXL is a therapeutic modality consisting of photoactivation of a chromophore, riboflavin (vitamin-B2), by ultraviolet (UVA) light at a wavelength of 370 nm. This technique is mainly used for stabilizing the corneal curvature and vision in patients with keratoconus and ectatic disorders [137, 138]. Studies suggest that guanine oxidation of nucleic acids and reactive oxygen species generation by activated riboflavin results in nucleic acid destruction with subsequent microbial proliferation. In 2013, the term photoactivated chromophore for infectious keratitis-corneal collagen crosslinking (PACK-CXL) emerged .
Price et al. performed the first prospective study assessing the efficacy of CXL in infectious keratitis . PACK-CXL was deemed more effective for bacterial keratitis involving the superficial layers of the corneal stroma . Another prospective clinical trial randomized 40 eyes to receive either PACK-CXL in addition to antimicrobial therapy or antimicrobial therapy alone . Although PACK-CXL did not shorten the corneal healing time compared to the control group, it did result in an absent incidence of corneal perforation or recurrence of infection (0%
9.6 Rose bengal photodynamic antimicrobial therapy (RB-PDAT)
RB-PDAT is an emerging therapeutic modality for the management of infectious keratitis . It was first introduced by Amescua et al. in 2017 for the management of a patient with multidrug-resistant
9.7 Future drug-delivery systems
Despite the high efficacy and broad spectrum of the antimicrobials used in infectious keratitis, their insolubility in water, low precorneal residence time on the ocular surface, inadequate control of drug release and penetration, nasopharyngeal drainage, and toxicity hinders their performance . To overcome such limitations, recent developments on drug-delivery systems are emerging.
Chhonker et al. developed amphotericin-B-loaded lecithin/chitosan nanoparticles with enhanced mucoadhesive properties for the prolonged ocular application . The nanoparticles sized 161.9 to 230.5 nm improve drug bioavailability by approximately 2.04 fold and precorneal residence time by 3.36 fold in rabbit eyes . Guo et al. developed self-assembled micelles of poly(ethylene glycol)-block-poly(glycidyl methacrylate) (PEG-b-PGMA) to deliver natamycin . The sustained drug release from micelles allows reducing the frequency of natamycin application from 8 to only 3 times per day in rabbits with fungal keratitis. The use of contact lenses as drug carriers or sustained-release deposits has also been evaluated to improve antimicrobial efficacy. Huang et al. developed a hybrid hydrogel-based contact lens, loaded with voriconazole, comprised of quaternized chitosan, graphene oxide, and silver nanoparticles .
Another strategy employs carbon dots, which are small, highly fluorescent non-toxic element nanoparticles that measure less than 10 nm and are considered to replace metal-based quantum dots . Zhao et al. demonstrated that nitrogen-doped carbon quantum dots sized 2–5 nm can destroy the cell structure of
There is a paucity of studies evaluating the efficacy of drug-delivery mechanisms to manage infectious keratitis in humans. Such mechanisms may enhance drug penetration, better compliance, and reduced toxicity, thus improving patient outcomes.
9.8 Surgical procedures
Surgical management must be considered to maintain the globe integrity in patients with unresponsive keratitis associated with severe stromal melt with impending perforation risk. Zhong et al. demonstrated that full-thickness conjunctival flap covering surgery with amniotic membrane transplantation might represent a viable option to save the eyeball for eyes with severe fungal keratitis without corneal perforation . In their series, most eyes (15/17, 88%) achieved complete conjunctival re-epithelization. Seven of them achieved a mean best-corrected visual acuity of ~20/100, remaining disease-free at least one month after sclerokeratoplasty . However, melting of the conjunctival flap, with subsequent endophthalmitis requiring evisceration, occurred in two eyes.
Therapeutic keratoplasty (TKP) should be reserved for patients who are not candidates for other therapies, and if possible, after quiescent infection . In
Despite significant technological development in contact lens materials resulting in remarkable improvement in safety and comfort, microbial keratitis continues to be a severe sight-threatening complication in contact lens wearers. Overnight extended contact lens wear and deficient lenses and case hygiene continue to be the primary risk factors for CLAIK worldwide; hence improvement in contact lens hygiene, education, and handling is necessary to reduce this potential complication.
The clinician must be able to promptly recognize the condition and identify the causative microorganism through corneal scraping, smear, and culture in case of severe keratitis, and treat the disease according to the suspected etiological agent; Empirical treatment must be initiated in every case and modified according to the clinical response and microbiology laboratory results.
|Tobramycin 14 mg/mL or gentamicin 14 mg/mL|
|Cefazolin 50 mg/mL or ceftazidime 50 mg/mL|
|Amikacin 10–40 mg/mL|
|Vancomycin 15 mg/mL, 25 mg/mL, or 50 mg/mL|
|Linezolid 2 mg/mL (for methicillin-resistant Staphylococcus aureus)|
|Colistin 0.19% (for multiple drug-resistant |
|Trimethoprim (16 mg/mL) - sulfamethoxazole (80 mg/mL)|
|Imipenem – cilastin (1%)|