**9.3 Acanthamoeba keratitis**

There is no consensus on the standard treatment for *Acanthamoeba* keratitis. Trophozoites are sensitive to a variety of antibiotics, antifungals, antiseptics, and antineoplastic agents. In contrast, cysts are highly resistant to a number of these drugs [113]. Effective topical treatment for *Acanthamoeba cysts* may include diamidines and biguanides such as propamidine-isethionate 0.1%, hexamidine-diisethionate 0.1%, dibromopropamidine 0.1%, polyhexamethylene-biguanide 0.02%, or chlorhexidine 0.02% [130]. A combination therapy of a biguanide and a diamidine is often used initially on an hourly schedule for the first 48 hours; treatment is then tapered according to the clinical response and potential epithelial toxicity and may be continued for several months. The objective is to eradicate *Acanthamoeba* trophozoites and cysts, with the resolution of the corneal inflammatory response [113].

## **9.4 Topical corticosteroids in infectious keratitis**

The use of topical corticosteroids in infectious keratitis remains controversial [131]. Some authors advocate their use suggesting corticosteroids minimize corneal

#### *Contact Lens-Associated Infectious Keratitis: Update on Diagnosis and Therapy DOI: http://dx.doi.org/10.5772/intechopen.100261*

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 [132]. 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 [134]. 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 [121]. 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-*Nocardia* ulcers and more extensive scars in *Nocardia* ulcers at one year [121]. In a recent report by the American Academy of Ophthalmology, authors suggest using topical corticosteroids after 48 hours of antibiotic therapy in culture-positive non-*Nocardia* bacterial keratitis [122].

Similar results were described by Wouters et al. in eyes with *Acanthamoeba* keratitis [135]. Topical corticosteroid use was associated with a delay in diagnosis (23 *vs.* 62 days, p < 0.001), increased disease severity, worst visual outcomes (<20/80, p = 0.03), and the need for an urgent corneal transplant [135].

In a recent murine model of *Candida albicans*, topical 0.1% dexamethasone exacerbated fungal keratitis by increasing the aggressivity of the pathogen, reducing the neutrophil infiltration, and inhibiting the formation of neutrophil extracellular traps [136].

#### **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 [137].

Price et al. performed the first prospective study assessing the efficacy of CXL in infectious keratitis [139]. PACK-CXL was deemed more effective for bacterial keratitis involving the superficial layers of the corneal stroma [139]. Another prospective clinical trial randomized 40 eyes to receive either PACK-CXL in addition to antimicrobial therapy or antimicrobial therapy alone [140]. 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% *vs.* 21%) [140]. A recent meta-analysis performed by Ting et al., including four randomized-control trials, demonstrates that adjuvant PACK-CXL results in shorter mean healing times and quicker resolution of infiltrates when comparing with antimicrobial treatment alone. Despite the latter, high-quality randomized controlled trials are required to establish PACK-CXL's efficacy in infectious keratitis fully [141].

#### **9.6 Rose bengal photodynamic antimicrobial therapy (RB-PDAT)**

RB-PDAT is an emerging therapeutic modality for the management of infectious keratitis [142]. It was first introduced by Amescua et al. in 2017 for the management of a patient with multidrug-resistant *Fusarium keratoplasticum* keratitis [143]. In this therapeutic modality, rose bengal, a routinely used dye in ophthalmology, is excited with a green light at a wavelength of 500–550 nm to generate reactive oxygen species [144]. Rose bengal is a type II photosensitizer that, when activated, induces cellular apoptosis by converting triplet oxygen to singlet oxygen [142]. A pilot study performed by Naranjo et al. including *Acanthamoeba* keratitis (10 cases), *Fusarium spp.* (4 cases), *Pseudomonas aeruginosa* (2 cases), and *Curvularia spp.* (1 case), evaluated the clinical outcomes of RB-PDAT. One patient had no microbiological diagnosis [144]. Most individuals (14/18, 79%) were contact-lens wearers. Successful therapy, defined as avoiding therapeutic keratoplasty, was achieved in 72% of the cases. Although adequately powered randomized controlled trials are required to ascertain the efficacy of RB-PDAT, preliminary results are promising.

#### **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 [145]. 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 [145]. 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 [145]. Guo et al. developed self-assembled micelles of poly(ethylene glycol)-blockpoly(glycidyl methacrylate) (PEG-b-PGMA) to deliver natamycin [146]. 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 [147].

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 [148]. Zhao et al. demonstrated that nitrogen-doped carbon quantum dots sized 2–5 nm can destroy the cell structure of *Staphylococcus aureus* and methicillin-resistant *Staphylococcus aureus* (MRSA) [149].

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 [150]. In their series, most eyes (15/17, 88%) achieved complete conjunctival re-epithelization. Seven of them achieved a mean bestcorrected visual acuity of ~20/100, remaining disease-free at least one month after

#### *Contact Lens-Associated Infectious Keratitis: Update on Diagnosis and Therapy DOI: http://dx.doi.org/10.5772/intechopen.100261*

sclerokeratoplasty [150]. 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 [151]. In *Acanthamoeba* keratitis, TKP is recommended in cases of corneal perforation unresponsive to repeat gluing, severe corneal abscess, or significant cataract [113]. Because of the risk of rejection with large grafts in *Acanthamoeba* keratitis, corneal grafts must be kept to the minimum size required [113]. In cases of fungal keratitis, Selver et al. demonstrated that smaller grafts (< 8 mm) were associated with lower rejection rates, but higher recurrence rates possibly related to incomplete removal of infected tissue [151, 152].
