The various anti-bacterial agents can be given by topically, subconjunctivally or by systemic route in a case of bacterial keratitis (Table 4.1).1 Topical route using concentrated or fortified antibiotics is generally preferred as higher concentration of the antibiotics are achieved by this route.
Fortified antibiotics are prepared by adding the required amount of parenteral agent to an artificial tear solution or to a commercially prepared topical solution.
Subconjunctival injections of antibiotic can achieve therapeutic levels due to leakage from the injection site into the tear film and direct penetration into the adjacent tissue. However, since there is no added benefit over topical administration we do not use subconjunctival antibiotics routinely.
Systemic therapy is usually less effective in achieving therapeutic drug levels and carries the risk of systemic toxicity. These are usually used to treat corneal infections
in cases of scleral involvement, perforated corneas or impending perforations disease.
ANTIBACTERIAL AGENTS
Beta Lactam Antibiotics
Penicillin is the prototype drug of this group. They act by interfering in the synthesis of the bacterial cell wall proteoglycans.Topical beta lactam antibiotics are never available commercially they are somewhat unstable in solution and tend to breakdown in days or weeks.
Cephalosporins
Like penicillins, cephalosporins contain a beta lactam ring which is required for its bactericidal action. The nucleus of the cephalosporins is 7 aminocephalosporanic acid, which is resistant to the action of penicillinases produced by staphylococci.
Cefazolin is primarily effective against gram-positive organisms.
Ceftazidime is a third generation cephalosporin, which acts against Pseudomonas species. It also has some activity against gram-positive organisms. It is particularly useful in cases of Pseudomonas keratitis
TABLE 4.1
Emperical therapy for bacterial keratitis
Gram’s stain Topical Subconjunctival Systemic
Gram-positive cocci Cefazolin, 50 mg/mL Cefazolin, 100 mg Cefazolin, 200 mg/kg/day Gram-negative cocci Penicillin, 100,000 U/mL Penicillin, 1 million U Penicillin, 2- 6 million U q 4 hr Gram-positive rods Gentamicin, 14 mg/mL Gentamicin, 20- 40 mg Gentamicin, 3 mg/kg/day Gram-positive filaments Penicillin, 100,000 U/mL Penicillin, 1 million U Penicillin, 2- 6 million U q 4 hr Gram-negative rods Cefazolin, 50 mg/mL, and Cefazolin, 100 mg, and Cefazolin, 200 mg/kg/day, and
gentamicin, 14 mg/mL gentamicin, 20- 40 mg gentamicin, 3 mg/kg/day Acid-fast bacilli Amikacin, 10 mg/mL Amikacin, 25 mg Amikacin, 5 mg/kg/day
which are resistant to aminoglycosides or fluoroquino-lones.2
Tetracyclines
Tetracyclines are broad-spectrum bacteriostatic antibiotics. Various forms of tetracycline are available, including chlortetracycline (topical), oxytetracycline, doxycycline, minocycline, and tetracycline. They act by inhibiting bacterial protein synthesis by binding to the 30-S ribosomes.
They are active against gram-positive organisms, gram-negative bacteria, mycoplasma, chlamydia and amoeba. They are not effective against P. aeruginosa, Bacteroides species, or group B streptococci. The various microorganisms acquire a plasmid-mediated resistance to tetracycline.
Glycopeptides
Vancomycin is a glycopeptide, which is effective penicillin-resistant Staphylococci. It inhibits the synthesis of peptidoglycan polymers during bacterial cell wall formation. It is active against gram-positive bacteria and remains one of the most potent agent against methicillin resistant Staphylococcus aureus and coagulase negative Staphylococci. Vancomycin should be reserved for cephalosporin-resistant Staphylococci. Vancomycin is effective against Streptococci and also against gram-positive bacilli such as Clostridia, Corynebacteria, Bacillus, L. monocytogenes, Actinomyces, and lactobacilli.
Aminoglycosides
Aminoglycosides act particularly against, gram-negative bacilli. They have a selective affinity to bacterial 30-S and 50-S ribosomal subunits to produce a nonfunctional 70-S initiation complex that results in inhibition of bacterial cell protein synthesis. Unlike other antibiotics that impair protein synthesis, they are bactericidal.
Aminoglycosides have a bactericidal activity against aerobic, gram-negative bacilli such as Pseudomonas aeruginosa. However, there is resistance developing against Pseudomonas to gentamicin, tobramycin and to some extent amikacin. For Pseudomonas keratitis an aminoglycoside may be combined with a third generation cephalosporin. For Nocardia keratitis amikacin is the drug of choice.3
Macrolides
Macrolides are bacteriostatic agents (e.g. erythromycin, tetracycline) that can suppress the growth of susceptible gram-positive cocci. These drugs cause inhibition of bacterial protein synthesis by reversibly binding to the 50-S ribosomal unit thereby preventing elongation of peptide chain in bacteria. Erythromycin acts both as a bactericidal and a bacteriostatic agent depending on the concentration of the drug and is effective against gram -positive and some gram-negative organisms. S.
pneumoniae and S. pyogenes are highly susceptible . It is one of the least toxic and best tolerated antibiotic agents.
However, its penetration into cornea is sub-optimal due to lack of solubility and bioavailability.
Newer macrolides such as azithromycin and clari-thromycin have higher tissue concentrations and are more effective against C. trachomatis, and non-tuber-culous mycobacteria where they are used topically.4
Fluoroquinolones
The fluoroquinolone agents are the latest class of antibacterials. Four generations of fluoroquinolones have evolved :
1. First generation: Nalidixic acid-rarely used 2. Second generation: Ciprofloxacin and ofloxacin 3. Third generation: Levofloxacin
4. Fourth generation: Moxfloxacin and gatifloxacin.
Mechanism of Action
Fluoroquinolone agents act by inhibiting the super coiling of DNA by the enzyme DNA gyrase. This action is bactericidal and occurs during cell replication.
Fluoroquinolones have the advantage of low toxicity due to the lack of DNA gyrase in mammalian cells. The available topical agents include norfloxacin (0.3%), cipro-floxacin (0.3%), lomecipro-floxacin, fleroxacin, percipro-floxacin, and ofloxacin (0.3%), moxifloxacin (0.5%) and gatifloxacin (0.3%).
Moxfloxacin and gatifloxacin are C8-methoxy fluoroquinolones, and demonstate increased activity against gram-positive bacteria and atypical mycobac-teria when compared to ciprofloxacin, ofloxacin and levofloxacin in vitro and in vivo.
The available formulations of gatifloxacin (Zymar, Allergan, Inc.) and moxifloxacin (Vigamox, Alcon Inc.) are 0.3 percent and 0.5 percent respectively. The
27 chemical structures of the C8-methoxy fluoroquinolones
add protection from bacterial resistance in addition to enhancement of bactericidal properties. The substitution of the methoxy group at the eighth carbon on the basic ring in both gatifloxacin and moxifloxacin reduces the likelihood of ocular pathogens developing resistance to these fluoroquinolones. The methoxy group allows binding of the antibiotics to two bacterial enzymes -DNA gyrase and topoisomerase IV. As a result, C8 methoxy fluoroquinolones require two simultaneous mutations for development of resistance, the chance of which are one in ten trillion . Previous generations of fluoroquinolones required only a single mutation.
Moreover, a bulky side chain at the C7 position of these antibiotics makes it the difficult for the antibiotics to reach out of the bacterial cells.
Spectrum of Activity
The fluoroquinolones have broad-spectrum of activity and are more active against gram-negative bacteria than gram-positive bacteria. They are active against enteric gram-negative rods, such as Haemophilus influenzae and Neisseria gonorrhoeae. The third generation fluoroquino-lones are active against Staphylococcus aureus, Non-coagulase Staphylococci, and Pseudomonas aeruginosa.
Ofloxacin and ciprofloxacin have a comparable spectrum of activity against gram-positive and gram-negative organisms.5
The pathogens with respond less to fluroquinolones include Streprotoccus Pneumoniae, S. Viridans MRSA, anaerobes and non-aerugines Pseudomonas.6,7
Side Effects
The side effects of the fluoroquinolones may occur locally or they may be systemic. The topical adminis-tration of ciprofloxacin has been associated with crystal deposits in the cornea. This occurs in approximately 20 percent of patients treated with ciprofloxacin in cases of bacterial keratitis8 (Fig. 4.1). This crystallization has not been seen with norfloxacin or ofloxacin, presumably due to their high solubility. The advantage of crystalline deposits is that it acts as a depot from which the drug is released. However the disadvantage is that its presence retards epithelialisation.
The systemic side effects of fluoroquinolone include toxicity, fever, rash, and nausea which occurs in 4 percent of patients. Occasionally patients have elevation of levels of liver enzymes. The drugs can
crystallize in the urine, especially in patients who are dehydrated. Interstitial nephritis has been reported after high doses of ciprofloxacin. Insomnia and restlessness have occurred in elderly patients taking fluoroquino-lones. Children should not be given quinolones because animal studies have shown crystal deposits in cartilage and hence the topical fluoroquinolones are not recommended for children younger than 2 years.
PREPARATION OF FORTIFIED TOPICAL ANTIBIOTICS
(Adapted from Basic Clinical and Science Course 2000-2001. American Academy of Opthalmology)
1. Cefazolin 50 mg/ml or ceftazidime 50 mg/mL a. Add 9.2 mL of artificial tears to a vial of cefazolin,
1 g (powder for injection).
b. Dissolve. Take 5 mL of this solution and add it to 5 ml of artificial tears.
c. Refrigerate and shake well before instillation.
2. Tobramycin 14 mg/mL or gentamicin 14 mg/mL a. Withdraw 2 mL of tobramycin or gentamicin
injectable vial (40 mg/mL).
b. Add 2 mL to a tobramycin or gentamicin ophthal-mic solution (5 mL) to give a 14 mg/mL solution.
3. Vancomycin 15 mg/mL, vancomycin 25 mg/mL or vancomycin 50 mg/mL
a. Add 33 mL of 0.9 percent sodium chloride for injection (no preservatives) or artificial tears to a 500 mg vial of vancomycin to produce a solution of 15 mg/mL. Add 20 mL of 0.9 percent sodium chloride for injection (no preservatives) or
Figure 4.1: Ciprofloxacin deposit in a case of corneal transplantation
artificial tears to produce a solution of 25 mg/
mL. Add 10 mL of 0.9 percent sodium chloride for injection (no preservatives) or artificial tears to produce a solution of 50 mg/mL.
b. Refrigerate and shake well before instillation.
4. Amikacin
Intravenous formulation can be used (80 mg/2 cc ampules).
5. Trimethoprim/sulfamethoxazole
16 mg/mL and 80 mg/mL commercial preparation can be used.