Alternative Treatment Approaches in Bacterial Keratitis

Abstract

Microbial keratitis can cause unilateral blindness, which can occur after ocular trauma and subsequent infection, causing unilateral blindness in 1.5 to 2 million corneal ulceration cases globally per year, particularly in developing and tropical countries. The conventional treatment options are largely topical in a loading dose regimen. This chapter enumerates the recent advances in its management. Parenteral, and intracorneal, intrastromal antimicrobial injections are attempted as adjuvants in refractory cases. Novel drug reservoir contact lenses have higher bioavailability by creating an antimicrobial lake with increased tear film exchange through the fenestration. Sustained release intrastromal antimicrobial implants for the treatment of deep corneal infections and abscesses have increased efficacy. An intensive loading dose with topical agents could be reduced with alternative approaches, thus reducing the treatment burden and improving patient compliance.

1. Introduction

Bacterial keratitis (BK) is an acute condition perverting the vision to cause blindness if untreated acutely. Currently, microbial keratitis may be epidemic and may exceed 2 million cases per year worldwide [1]. In the US among one million infectious keratitis around 58,000 cases of BK were reported [2]. Bacterial infection was predominant in developed countries whereas developing countries face challenges in corneal infections due to fungal, bacterial, and other origins. One of the reports from the south Indian cities claimed 113 MK in 100,000 individuals [3].

Generally, the bacterial keratitis in its acute condition, the treatment was initiated with a time lag due to delayed presentations in developing countries. In addition, Gram staining and culture sensitivity with antibiogram are time-consuming procedures with challenging availability at all primary or secondary eye care setups.

Hence, while initiating the therapy the size of the ulcer or the intensity of the severity would have progressed to another grade. An intensive approach would impact early recovery and prevent the incidence of smaller ulcers becoming larger corneal ulcers.

Surgical modalities of therapeutic Deep Anterior Lamellar Keratoplasty (DALK), and therapeutic penetrating keratoplasty in cases of fulminating bacterial keratitis, impending perforation, or actual perforation are not discussed in this chapter. Other alternate modalities of treatment of BK are given importance and are discussed here.

2. Bacterial keratitis management

2.1 Standard medical treatment

Bacterial keratitis is generally treated instantaneously upon its diagnosis by clinicians. After confirming bacterial etiology, the patient should be started on broad-spectrum antibiotic therapy, covering both gram-positive and negative bacteria. Once the culture results are available after 48 to 72 hours, the treatment may be switched to targeted antibacterial therapy if an empirical therapy is not responsive. To treat peripheral ulcers without visual axis involvement (<3 mm), monotherapy with fourth generations of quinolones is initiated. In the case of larger and deep stromal ulcers, it is better to start two antibacterials to prevent irreversible vision-threatening sequelae [4].

2.1.1 Topical antibiotics

The topical fluoroquinolones are available as 0.3% ciprofloxacin, 0.3% ofloxacin, 0.5% moxifloxacin, and 0.3% gatifloxacin. They are primarily instilled as monotherapy. Recently, growing resistance has been noted for ciprofloxacin and ofloxacin; hence, moxifloxacin and gatifloxacin are being used with more efficacy in managing bacterial keratitis [5].

The most common cephalosporins implicated is bacterial keratitis with topical cefazolin 5% (fortified). It is best suitable for non-penicillinase-producing gram-positive bacteria.

Aminoglycosides including fortified topical tobramycin 0.3% or gentamicin 0.3%, or amikacin 1 g/ml injection are very effective against gram-negative bacteria, streptococci, and staphylococci but have a very limited response against pneumococci. Fortified cefazolin and tobramycin as combination therapy are most commonly employed as an alternative to monotherapy with fourth-generation quinolones in bacterial keratitis. Fortified vancomycin 5% is very active against methicillin-resistant staphylococcus aureus (MRSA).

Poor drug availability due to pre-corneal factors and deeper penetration into corneal layers remains a challenge with topical therapy and hence alternative treatment options are needed to be explored.

The role of systemic antibiotics in the management of bacterial keratitis is limited. It was used only in endophthalmitis, scleritis, or non-resolving progressive bacterial ulcers. The drugs implicated are ciprofloxacin 750 mg BD or an aminoglycoside with cephalosporin [6].

2.1.2 Steroids

The main treatment is the topical antibiotic for the management of bacterial keratitis and the clinical benefits are appreciable when corticosteroids were used along with topical antibiotics. The topical steroids in the case of microbial keratitis are controversial. Steroids minimize tissue damage by reducing neovascularization, stromal melting, and scarring [7, 8]. Overall pain control and comfort are obvious in steroids that also improve patient compliance [8]. Conversely, steroid therapy may delay epithelial healing and potentiate bacterial keratitis, leading to stromal thinning and melting.

Four clinical trials, including one randomized, placebo-controlled, double-masked trial known as the Steroid for Corneal Ulcer Trial (SCUT), have compared clinical outcomes in bacterial keratitis treated with antibiotics and steroids vs. antibiotics alone [8, 9].

Earlier trials with topical steroids yielded an ambiguous result; however, it gave insight into the subgroup analysis within SCUT patients with low vision patients conveying an appreciable visual improvement at 3 months when compared with placebo, as did patients with invasive Pseudomonas strains. No significant difference in adverse effects was noted between steroid and placebo arms [9].

3. Alternative treatment approaches in bacterial keratitis novel drug delivery methods

Antibiotic eye drops were the most common first-line treatment option and this requires high drug compliance for the therapeutic outcome. The frequent eye drops administration makes them wearisome and thus poor healing.

Exploiting contact lenses for constant drug delivery (zero-order kinetics) was highly challenging. The soft contact lenses exhibiting the feature of drug uptake and release were explored to extend their use in attaining therapeutic index. The pharmacokinetic profile in contact lens drug release is nonlinear kinetics, as there is an immediate drug release and later it tends to decrease to a sub-therapeutic level in the subsequent hours.

Research has also focused on the controlled release of medications from delivery systems incorporated into a contact lens hydrogel material, including copolymerizing the hydrogel and poly (hydroxyethyl methacrylate) (pHEMA) with other monomers.

Hydrogel prototype lenses are used to release the drug in the form of microemulsions. Only first-order kinetics was achieved by manipulating the surface of the contact lenses with the drug-containing liposomes. The physiochemical environment of the human eye with alkaline pH and physiological temperature were the odd factors that prohibit the sustained release of the drug.

Formerly many non-contact lens techniques were attempted in futile to achieve long-term drug release. Ocusert by Alza Corp., Palo Alto, CA, was specifically designed to be placed in the cul-de-sac and had demonstrated zero-order kinetics and it was not widely used except to treat glaucoma, whereas the collagen shields require surgical removal of corneal epithelium to promote corneal re-epithelialization and thereby antibiotic prophylaxis. This method was also not being used due to its hostile natures such as difficulty in self-insert, requiring topical anesthesia, and replacement of a new collagen shield, every 3 days.

As a result, novel drug delivery methods are needed to increase compliance and therefore the efficacy of treatment.

The challenges in achieving the desired sustained release system in an ophthalmic drug were the bioavailability of the drug, the biocompatibility of the contact lenses, absorption and release of the drug in a zero-order kinetics to achieve an extended-release of the drug, etc. In the early 1960s, hydrogel contact lens were introduced and used as a drug-eluting contact lens and as a bandage contact lens. The hydrogel contact lenses as bandage contact lenses were helpful in cornea protection and corneal re-epithelization with antibiotic drops. Unlikely the extended release of antibiotic eye drops could not be established in the hydrogel contact lenses.

A prototype contact lens for sustained drug delivery by incorporating a thin drug-PLGA [Poly (lactic-co-glycolic acid)] film into a pHEMA hydrogel [Poly (2-hydroxyethyl methacrylate)], and this polymer was used in the making of regular contact lenses also. This warrants a regular adjustment of polymer molecular mass and medication concentration in the drug-PLGA film, to reach the zero-order kinetics. This ocular drug delivery system was prominent to maintain therapeutic concentration for about a month. This prototype contact lens design was used as a platform for ocular drug delivery and therapeutic applications. The contact lenses are used as the antibacterial prototype lenses through antibiotic coating with ciprofloxacin-PLGA 65:35 films (pHEMA).

In this prototype contact lens phenomenon, there was an initial drug release in the first 24 hours, followed by this burst the prototype contact lens maintains zero-order kinetics for more than 4 weeks. For instance, 134 μg of ciprofloxacin per day was released constantly to maintain the zero-order kinetics. The ciprofloxacin (23%) was released from the lenses in a month.

A drug-eluting contact lens with a combination of drugs say, moxifloxacin (MF) and dexamethasone (DM), were experimented with. In this study, a polymeric contact lens using chitosan, glycerol, and polyethylene glycol (PEG) was developed along with MF and DM. Drug-loaded contact lenses were tested with a combination of drugs as well as individually, and all three lenses were compared to treatment with individual drug solutions. Both required therapeutic concentration and corneal drug distribution of MF were significant in drug-loaded contact lenses when compared to topically given drug solutions in rabbits and humans. It also features in vitro and in vivo antimicrobial activity through mucoadhesion by contact lenses [10].

The moxifloxacin in nanoparticles increased the corneal penetration compared to MF in solution. The improved therapeutic effect was obtained when in situ gel formation was combined with nanoparticles that is, nanoparticles can also be used to load antibiotics; moxifloxacin nanoparticles show increased corneal penetration. When the liquid gets into contact with the corneal surface, it forms an in situ gel that maintains bioavailability [11, 12].

Another breakthrough in nanoparticle research is molecular imprinting. Antibodies were formed through the conversion of nanoparticles into synthetic antibodies equivalent. These antibodies target the lipopolysaccharides in P. aeruginosa, in a keratitis model. Methicillin-resistant Staphylococcus aureus (MRSA) was also targeted in a similar approach.

Apart from lenses offering the sustained release of drugs, antimicrobial compounds have been incorporated into the lens itself; AGMNA, a metal–organic framework featuring silver (a natural antimicrobial agent), has been developed both for inclusion into the contact lens structure and as a lens disinfecting agent, with high effectiveness and minimal toxicity [13].

In the above study, the Metal–Organic Framework (MOF) of formula {[Ag6(μ3-HMNA)4(μ3-MNA)2]2 − ·[(Et3NH)+]2·(DMSO)2·(H2O)} (AGMNA), a known efficient antimicrobial compound which contains the anti-metabolite, 2-thio-nicotinic acid (H2MNA), was incorporated in polymer hydrogels using hydroxyethyl-methacrylate (HEMA).

pHEMA@AGMNA-1 has antimicrobial activity against the microbial keratitis etiologies gram-negative P. aeruginosa and gram-positive Staphylococcus epidermidis and S. aureus. The following organism is incubated with pHEMA@AGMNA-1 discs with % bacterial viability say P. aeruginosa, S. aureus, and S. epidermidis [13]. Furthermore, pHEMA@AGMNA-1 exhibits low toxicity.

3.1 Microemulsions

Microemulsions are another novel method of ocular drug delivery and have shown a promising result in a combined in vivo and in vitro study [14]. A tiny droplet with a diameter of 10 to 100 nm is formed by the drug with the surfactant. The lipid-water-lipid sandwich of the cornea makes an effective microemulsions delivery [15]. The outer layer of the cornea is a barrier to hydrophilic substances but is lipid-soluble; thus, microemulsions can effectively deliver a drug to the stroma.

Antibiotics can also be similarly delivered to the eye by liposomes, a capsule made of a phospholipid bilayer. Furthermore, Mishra et al. found that contact lenses equipped with liposomes are capable of providing a stable release of antibiotics over 6 days, which was effective against S. aureus in vitro.

3.2 Plasma and phage therapy

Plasma and phage therapy was a novel therapeutic option in BK treatment. Plasma is an ionized gas capable of exhibiting antimicrobial properties via its ability to produce reactive oxygen species; it also exhibits wound healing and anti-inflammatory properties [16].

Reitberger et al. studied the argon-based plasma therapy and opined that it shall be successfully exploited in combination with antibiotics [16]. Phage therapy involves using a viral bacteriophage to infect and kill bacteria. There was only one study to support the efficiency of phage therapy against P. aeruginosa keratitis in mice [17]. Also, a case study reports the efficacy of phage therapy against MRSA keratitis. The effectiveness of phage therapy against a wide number of different non-ocular bacterial colonies has been confirmed by other studies, but there is a need for further investigation focusing specifically on S. aureus keratitis isolates.

3.3 Photoactivated chromophore for keratitis-corneal cross-linking (PACK-CXL)

It works on the mechanism of collagen fiber photopolymerization on the corneal tissue to get stiffened by applying a combination of ultraviolet A radiation and a chromophore (riboflavin). This is a non-invasive procedure performed with topical anesthesia.

The photoactivated chromophore and ultraviolet A light have antibacterial properties and are effective in treating infectious keratitis. The antibacterial mechanism involved here is inhibition of microbial replication, intercalation of the chromophore with microbial nucleic acids, RNA damage, DNA damage, cell wall damage, and oxidation of nucleic acid residues by reactive oxygen species, as well as increased resistance of the stiffened cornea to enzymatic damage from the microorganisms. Other potential advantages of UVA and riboflavin application over antibiotics include eliminating ocular surface toxicity and avoiding adherence issues associated with the need for frequent eye drop administration, among others [18].

PACK-CXL with ultraviolet A and riboflavin was applied on the day of diagnosis. According to the Dresden modified protocol, riboflavin 0.1% solution was administered to the cornea every minute for 15 minutes, followed by exposure to 370-nm UVA light (with a fluence of 3 mW/cm²) from a distance of 1 cm for 30 minutes. Following this, the eye was given a saline rinse and a contact lens was placed. A post-operative regimen of 0.1% fluorometholone acetate eye drops was instilled for 2 days (4 times a day) and for 1 week (3 times a day). The contact lens was removed one day after placement.

The epithelial healing was monitored as a mark of recovery where the patient will receive antibiogram results based on topical antibiotic eye drops along with artificial tear eye drops. During this period, the patient will also wear UV protection glasses. The patient was observed for the presence or absence of corneal ulcer and a comparison was made for treatment response against different time points.

The significance of ulcer healing was moderate in the early weeks of the treatment i.e., from between Day 1 and Week 1. The healing tends to increase over time Month 3 > Month 1 > Week 1. Complete recovery in all treated eyes was accomplished except for four cases due to emergency surgery.

3.4 Thymosin beta 4: a potential novel adjunct treatment for bacterial keratitis

Topical Thymosin beta 4 (Tβ4) was an amino acid protein and it exerts a pharmacological action of promoting wound healing and reducing corneal inflammation when it is used as an adjunct to ciprofloxacin. The mechanism of action was reducing inflammatory mediators and inflammatory cell infiltration that gives an antibacterial activity and wound healing in the experimental model of P. aeruginosa-induced keratitis. Tβ4 as a novel therapeutic method has the potential to treat corneal pathogenesis and other infections including immune-based inflammatory diseases [19].

3.5 Novel drug repository contact lens

Ponniah et al. [20] studied a newer drug-delivery mechanism, called the drug-depository contact lens (DDCL; Hyper-CL (Acofilcon A)), and evaluated the effectiveness of DDCLs for bacterial keratitis.

It was an open-label randomized controlled trial that compares the topical antimicrobial eye drops with and without the application of DDCL in treating bacterial keratitis.

The basic principle was fenestration; that is, the topically administered antibiotic drop would migrate through the fenestration holes and reaches the space between the backside of the therapeutic contact lens and the corneal surface. This increased the contact time of antibiotic eye drop and wound, thus enabling relatively speedy recovery when compared to conventional antibiotic eye drop alone.

They evaluated the effects of DDCL using clinical parameter guidelines recommended by the American Academy of Ophthalmology, viz., corneal infiltration size, ulcer size, anterior chamber reactions, corneal haze, visual acuity, and pain. Topical antibiotic Moxifloxacin (0.5%), a Fourth-generation fluoroquinolone having a wide spectrum of antibacterial activity, was used in the study.

In this study, it was observed that corneal infiltration resolution was on day 5 in the antibiotic-only group and day 3 in the DDCL group. Both the groups had lesions healed completely after 2 weeks; however, improvement in terms of healing and pain score was significant in the DDCL group (Figures 1 and 2) [20].

Figure 1.

Corneal ulcer heal in BK infection—DDCL + antibiotics along with corneal OCT.

Figure 2.

Changes in pain over time.

DDCL, a therapeutic soft contact lens that was also a repository contact lens, has facilitated the promotion of healing and pain relief in patients suffering from BK. The extended contact of antibiotics over the corneal surface has impacted faster healing of ulcers without an experience of ocular surface toxicity.

3.6 Novel implantable sustained release antibacterial disc

Intra corneal sustained-release dosage forms are novel targeted drug delivery systems to release a drug slowly to maintain a constant drug concentration at the site of action for a specific time with minimum side effects such as ocular surface toxicities.

A novel implantable sustained-release antibacterial disc that provides a likely effect in the treatment of posterior corneal infections and abscesses regarding effective drug penetration and reduced surface toxicities was investigated by the team in South India (Figure 3).

Figure 3.

Implantable sustained release antibacterial disc [21].

3.7 Intrastromal injections with antibiotic agents in the management of bacterial keratitis

Khan et al. were the first to study the intrastromal injections of antibiotic agents in the management of recalcitrant bacterial keratitis. It was studied on patients with infectious crystalline keratopathy secondary to Streptococcus paranguis, where cefuroxime 250 μL/mL was administered in intrastromal injection. Yet, the patients initially needed to undergo debridement of mucous plaque and epithelium to expose corneal stroma and biofilm. Intrastromal injection of cefuroxime (1 ml) in the lesion and stroma region was injected by hydration technique [22].

In this case, cefuroxime was chosen above other antibiotics, such as vancomycin, not only for its sensitivity and low inhibitory concentration but also because it is less harmful to the ocular surface.

Liang et al. reported another case of resistant bacterial keratitis. About 0.02 mL of tobramycin (0.3%) in a single intrastromal injection was administered with a 30 G needle. After 6 months, the keratitis became dormant, and 5 years later, there was no sign of a recurrence [23].

Pak et al. was the first to explain triple-bacterial keratitis which was caused by penicillin-resistant S. aureus, pan-sensitive Staphylococcus epidermidis, and Achromobactin species and its treatment with intrastromal antibiotic injection. When topical treatment failed to treat the keratitis, a new strategy was used and 0.2 mL of 0.5% moxifloxacin was administered intrastromally, precisely at the edge of the infiltrate. The study explained that the complete remission of the keratitis was accomplished with the first dose at the initial and the second dose after 2 weeks [24].

4. Conclusions

Novel approaches are inculcated in the existing bacterial keratitis management to thwart the challenges in disease prognosis rate. Earlier topical antibiotics were the only options for treating bacterial keratitis and surgical management for fulminant keratitis.

The topical antibiotics too have some limitations in terms of bioavailability despite having frequent administration. Novel drug delivery systems were explored to overcome the limitation of topical applications.

These alternative interventions including drug delivery contact lenses, drug repository contact lenses, microemulsions, bacteriophage, pack-CXL, intrastromal injections, etc., provide hope and feasible options for treating bacterial keratitis.

A corneal physician can decide on the various armamentarium tools in addition to intensive topical therapy in treating bacterial keratitis.

Acknowledgments

Thanks go to Dr. Velupillai Ranilakshmi, Prof. Heber Anandan, and Dr. Antonysamy Arulanandham.

Conflict of interest

The authors declare no conflict of interest.