**7. Treatment**

The most important goal of medical treatment is to preserve vision and maintain corneal transparency. The medical treatment of a BK should be started promptly before the etiological agent is known. The initial treatment is usually empiric as culture results can take over 48hours, and the infection can progress rapidly without treatment. All patients should start on broad-spectrum antibiotic therapy, covering both gram-positive and negative bacteria after obtaining the smear results. Due to the high probability of bacterial etiology, in doubtful cases of fungal and viral infections, an antibiotic is also used in addition to drugs against these pathogens. In the case of severe infections characterized by heterogeneous bacterial flora or in the case of larger and deep stromal ulcers, it usually prompts the use of two broad-spectrum antibiotics to prevent irreversible vision-threatening sequelae. The antibiogram, which we obtain a few days after the implementation of empirical treatment, allows to verify the initial diagnosis and decide whether to continue or modify the initial treatment. Treatment should be changed based on the results of culture and susceptibility testing. Different indications in the antibiogram should not lead to a change in the treatment profile if there is observed a clinical improvement after the implementation of empirical treatment [12].

#### **7.1 Antibiotics**

The main goal of treatment is broad-spectrum topical antibiotics, which should be used until culture results are available. The basis of the therapy is obtaining high concentrations of antibiotics within the infected tissue. For severe BK, an initial frequent dosage every 5–15min is recommended. Thus, the eye drops are applied even hourly in the first day of therapy. At the beginning of therapy, in order to increase the effectiveness of the therapy, eye drops with a higher concentration of the drug (fortified eye drops) are often used than in commercial usage.

The main group of antibiotics used in bacterial keratitis is fluoroquinolones. Fluoroquinolones are the group of antibiotics that provide excellent tissue penetration, quickly reaching high concentrations within tissues and have a broad spectrum of bactericidal activity. There are four generations of fluoroquinolones, of which the broadest spectrum of activity has the fourth generation of fluoroquinolones, including moxifloxacin and gatifloxacin. Within the third generation, the commercially available drug is levofloxacin. Treatment can also be carried out using secondgeneration drugs, that is, which is the drug of choice in gonorrhea infections. The AAO BK Preferred Practice Pattern, the Royal College of Ophthalmologists Focus, UK initially recommends monotherapy with fluoroquinolones (ciprofloxacin 3 mg/ml, ofloxacin 3 mg/ml, moxifloxacin 5 mg/ml, levofloxacin 15 mg/ml, gatifloxacin 3 mg/ ml, or besifloxacin 6 mg/ml). An alternative includes a combination of cephalosporin or vancomycin plus and an aminoglycoside. Vancomycin should be used in the case of

#### *Bacterial Keratitis DOI: http://dx.doi.org/10.5772/intechopen.113365*

multidrug resistant gram-positive isolates [9, 31]. Lately is noted increasing resistance for ofloxacin and ciprofloxacin; hereof, moxifloxacin and gatifloxacin are being used with more efficacy in managing bacterial keratitis [56].

Aminoglycosides are the second group of antibiotics that should be considered when treating BK. Aminoglycosides are represented by amikacin 0,3% topical eye drops (fortified amikacin eyedrops: 40 mg/ml), neomycin 0,5% eye ointment, gentamicin 0,3% topical eye drops (fortified gentamicin eye drops: 14 mg/ml (1.4%)), and tobramycin - 0,3% topical eye drops (fortified tobramycin eye drops: 14 mg/ml (1.4%)). Due to the broad spectrum of activity against gram-positive bacteria (excluding streptococci and pneumococci) and gram-negative bacteria, they are combined in the first line with fluoroquinolones. The mechanism of action of the fluoroquinolones is blocking of topoisomerase IV and DNA gyrase. The mechanism of action of aminoglycosides is to block protein synthesis at the ribosomal level. The combination of antibiotics from both groups is effective in the treatment of an unspecified etiological factor.

Other antibiotics that demonstrate a high therapeutic effectiveness in BK is vancomycin, which is used in severe infections. Fortified vancomycin 5% is very active against methicillin-resistant *Staphylococcus aureus* (MRSA). Whereas topical cefazolin 5% (fortified) is best appropriate for non-penicillinase-producing gram-positive bacteria [56].

The systemic antibiotics have indications in non-resolving progressive bacterial ulcers, especially with associated scleritis or endophthalmitis [57]. Fluoroquinolones, which demonstrate excellent penetration into ocular tissues when combined with intensive topical antibiotic treatment, are especially recommended.

#### **7.2 Topical corticosteroid therapy**

The use of additional adjuvant topical corticosteroid therapy remains still controversial [12, 58]. When the disease process is advanced and tissue necrosis occurs, or when inflammation is accompanied by intense cellular inflammatory infiltration into the cornea, weak steroids could be used. Topical corticosteroid therapy should be used with caution under constant clinical observation of the patient's involving eye because it may worsen the infection, local immunosuppression, corneal melting, and increased intraocular pressure [9, 58]. Topical corticosteroid therapy is used as an aim of suppression of inflammation to reduce corneal scarring, neovascularization, and vision loss. Hence, common or indiscriminate use of corticosteroids is inappropriate; however, it do not appear to increase the overall risk of failure or management of BK.

#### **7.3 Other topical drugs therapy**

Cycloplegics medications are commonly used as adjuvant drugs to relieve the pain, reduce ciliary spasm, and reduce cells and flare, as well as to prevent posterior synechiae formation that is often associated with iritis accompanying BK. They are indicated in cases with significant anterior chamber inflammation [12, 55, 56]. Antiglaucoma drugs are useful to control and reducing intraocular pressure by help drain the hypopyon by opening the trabecular meshwork and drainage channels, as well as to help in controlling trabeculitis secondary to the inflammatory process. A total of 0.5% timolol is commonly used. Two groups of topical drugs should be avoided, namely prostaglandin analogs and miotics because they exacerbate inflammation of the eye [12, 55, 56].

There should also be taken care of basic hygiene measures, which include careful removal of residual purulent secretion, which contains enzymes from decayed and

endotoxins of dead bacteria, which makes it difficult for drugs to penetrate into the tissues. The moisturizing of the eye surface with the use of artificial tear preparations, that purpose is to restore disturbed homeostasis of the eye surface, as well as to help epithelial healing, reduce irritation, wash away debris and necrotic enzymes, and smoothen the ocular surface and cornea are also important.

#### **7.4 Surgical treatment**

Corneal cross-linking (CXL) is a relatively new option for anti-infective treatment, especially in cases of superficial bacterial keratitis, and is increasingly used as an additional adjuvant treatment, which has been confirmed in clinical trials [59–61]. The interaction of UV light and riboflavin damages the DNA and RNA of bacterial and viral pathogens and prevents their protein synthesis and replication, leading to the death of the microorganism [62]. Moreover, the cornea after CXL is more resistant to proteolytic enzymes produced by bacteria [63]. CXL, besides as adjuvant treatment for BK, can be also used as primary treatment in the early stages of infectious ulcerative keratitis. PACK-CXL (photoactivated chromophore for keratitis) is the procedure that uses of CXL besides the Dresden protocol for the treatment of infectious keratitis [60]. PACK-CXL, as an additional to the standard of care in cases of cultureproven bacterial keratitis, has a positive effect on the final visual acuity and time to resolution, compared with the standard-of-care treatment [64]. Recently studies reported that CXL therapy for IK patients with corneal thinning and/or including anterior part of the stroma is promising procedure [65].

There are several cases in which surgical interventions are indicated. The application of cyanoacrylate tissue adhesive is the first-line intervention for corneal perforation, providing a successful tectonic support for a short time, although requiring reapplication with a month after first application [66]. Depending on the cause of the perforation, indications for applications, and definition of success the success of this adhesive ranges between 29% and 86% [66].

Amniotic membrane has a great effect in acceleration corneal healing. Amniotic membrane transplantation (AMT) is an alternative therapeutic treatment option to cyanoacrylate glue application along with bandage contact lens (BCL) in the case of impending corneal perforation or corneal perforation [66, 67]. Although in the case of larger perforation (>2 mm), therapeutic keratoplasty should be performed.

Conjunctival flap (Gunderson flap) is another alternative treatment in the case of impending corneal perforation or corneal perforation if a donor cornea is unavailable. Conjunctival flap is considered as one of the oldest methods to treat corneal perforation when access to corneal graft is impossible [68]. In order to implement the accurate role of the conjunctival flap in treatment before keratoplasty in cases of BK there are needed extra studies. The technique relies on dissection of the upper conjunctiva, and a thin flap of the conjunctiva is covered over the cornea and sutured [69].

Therapeutic penetrating keratoplasty is used in the treatment of BK and is indicated when the disease progresses despite treatment, nonhealing corneal ulcers (above 2 weeks), descemetocele or perforation occurs, or keratitis does not respond to antimicrobial treatment [70]. Therapeutic penetrating keratoplasty helps eliminate the focus of infection and as a tectonic keratoplasty restores anatomical integrity in perforated corneal ulcers. During the procedure, it is advisable to remove all areas of infection and perform peripheral iridectomy because the pupil may be secclusio due to inflammatory membranes in its lumen. When exudates are present in the lens or there is a cataract, then the lens is removed. If the posterior capsule is tact, a thorough anterior vitrectomy

#### *Bacterial Keratitis DOI: http://dx.doi.org/10.5772/intechopen.113365*

is made. Clearing corneal margin of 0.5 mm from the diseased cornea is removed and put the graft is kept 0.5 mm larger than the host cornea. It is recommended to use single seams (9–0 or 10–0 nylon). After the procedure, topical antibiotics, cycloplegics, and topical steroids are used. Although the probability of graft survival is reduced in about a half, at 4years post-intervention, in eyes with inflammation or with corticosteroid use at the time of graft, therapeutic penetrating keratoplasty remains the major intervention for the management of rapidly progressing severe infections and in large corneal perforations [67, 70]. When the visual acuity is poor, the cornea has scarred and healed and the infective foci have been eliminated after BK treatment penetrating keratoplasty (PKP) can be performed in order to restore the patient's vision. PKP is possible to conduct after 6 to 8 months of quieted after BK treatment [70].

#### **7.5 Alternatives methods of treatment**

In the literature based on animal studies showed that cryotherapy may have a possible advantageous result on BK involving the sclera. Although more studies about cryotherapy on the human cornea are still essential to answer for its efficacy and safety on human corneas [71, 72].

Mitomycin C (MMC) is an antimetabolite isolated from Streptomyces caespitosus. MMS has been successfully used in refractive surgery to reduce postoperative corneal haze and scaring due to its anti-fibroblast activity [73]. In one research, authors found that MMS has a broad-spectrum antimicrobial activity against a broad range of bacteria, including *E. coli*, *S. aureus*, and *P. aeruginosa* [74]. However, further studies are required to evaluate the effect of MMC on human corneas in BK because above mentioned results from laboratory studies are limited. While the inflammation process (i.e., an acute infection) and inflammatory cells (such as keratocytes, fibroblasts) produce enzymes: collagenases and matrix metalloproteinases (MMPs) that are involved in protein degradation and keratolysis. Anti-collagenases are promising adjuvant option in treatment BK though there are no high-quality randomized controlled trials in humans to help clinicians in the use of doxycycline for the corneal ulceration treatment, although its widespread use among corneal specialists [75–77].

Antimicrobial photodynamic therapy is another new approach for IK treatment based on three agents: oxygen, light radiation, and photosensitizer. Photodynamic therapy has proved as an effective therapy against infectious agents it does not present selective pressure on resistance development by both gram-positive and gram-negative bacteria. Thus, this new treatment option has an unusual potential for treatment of BK cases that have not achieved a good response after traditional antibiotic therapy [78].

In the newest reports, the bacteriophage therapy is growing as an effective alternative to treat ocular infections. A variety of nanotechnology-based formulations, such as nanoemulsions, liposomes, polymeric nanoparticles, dendrimers, and nanofibres, have been recently reported to be effective results in bacteria resistance to antibiotics. There are bacteriophage-based nanoformulation techniques for the successful treatment of ocular infections caused by multidrug-resistant S. aureus and other bacteria [79].

## **8. Conclusions**

Corneal opacity represents the fifth leading cause of blindness globally, with infectious keratitis being the main culprit. Bacterial keratitis is a severe condition of the eyes that could have a burden impact on human health in both developed and developing countries. Understanding of the major risk factors for BK particularly CL wear, trauma, ocular surface diseases, and postocular surgery will simplify a more effective public health intervention to modify and reduce the risk of BK. Early and prompt medical treatment is needed to avoid complications. The vision-threatening bacterial ulcers, if treated on time, can have an excellent visual effect. In the past few decades, it has been observed the increased rate of antimicrobial resistance (AMR) in ocular infection in several countries highlights the need for reasonable use of antibiotics. It should be a tighter control of OTC antibiotics and development of new therapeutic strategies. Improvement in the diagnostic efficiency of microbiological investigations of BK with emerging new technologies will allow for fast and proper diagnosis and could also provide a better guidance on the appropriate use of antimicrobial therapy in the future, eventually reducing the risk of AMR. The prognosis of BK is governed by a multiplicity of factors. The good prognosis for BK is in the case of bacterial ulcer located in the superficial corneal layers (anterior one-third of the stroma), as well as a result of a good compliance between doctor and patient and regular follow-up, and regular use of medications. Involvement of sclera or endophthalmitis, ulcer involving more than two-thirds of stroma, located in the visual axis, stromal melt, and corneal thinning exacerbate much more the prognosis. New approaches for the treatment of bacterial keratitis are necessary to outcome the increasing antibiotic resistance.
