- 1.
You are an antibiotic or steroid eyedrop just placed in the conjunctival fornix. Discuss the barriers to your journey into the eye.
Many eyedrop dispensers deliver a 50-μL eyedrop. However, only 20% of this volume is retained by the conjunctival cul-de-sac, and the excess immediately flows over the eyelids. Of the portion that remains, approximately 80% drains through the lacrimal system. In addition, because of the 15%/min tear turnover rate, almost all of the topically applied medication disappears from the conjunctival cul-de-sac in about 5 minutes. Irritating drugs produce reflex tearing and may be cleared even more quickly.
During this critical 5 minutes, the topically applied drug faces numerous tissue obstacles. Absorption by the conjunctiva quickly disperses the medication systemically via the conjunctival vasculature. The small portion that penetrates the episclera faces the relative impermeability of the sclera and the tight junctions of the retinal pigment epithelium. The cornea poses three different barriers to entry. The corneal epithelium and the endothelium possess tight junctions that force the drugs to pass through the cellular membranes and limit passage of hydrophilic drugs. The corneal stroma is water-rich and limits movement of lipophilic drugs. Even after entry into the anterior chamber, the lens effectively limits most drug penetration, and very little enters the posterior segment of the eye through topical administration.
Such formidable barriers seem insurmountable, but inflammation and infection render these barriers less effective, and modifications of the drug and/or its vehicle can facilitate entry into the eye. In addition, the desired site of action may be the ocular surface and not inside the eye.
- 2.
Given the above barriers, how would you increase delivery of topical antibiotics or steroids to the desired site of action?
The patient can perform punctal occlusion to decrease the amount of drainage through the lacrimal system by 65% and leave more drug for intraocular absorption. Of course, frequent instillation also increases drug absorption, but the practical limit is probably every 5 minutes because the subsequent eyedrop can wash out the previous eyedrop before intraocular absorption.
Changing the characteristics of the drug and/or its vehicle can also improve delivery. Increasing the concentration of the drug may be limited by the solubility of the drug in the vehicle, and the high tonicity of higher concentrations triggers reflex tearing that quickly clears the drug from the ocular surface. Also, increasing lipid solubility of the drug appears to promote corneal passage despite the dual barrier characteristic of the cornea. In addition, adding surfactants that disturb the corneal epithelium dramatically increases drug entry.
- 3.
Name the four different formulations of topical medications and the advantages and the disadvantages of each.
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Solutions are easily instilled, but contact time is minimal, requiring frequent administration. In addition, the “pulse” nature of absorption invites transient overdose and toxicity.
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Suspensions allow longer contact time, but the particulate nature of the preparation may be irritating and trigger reflex tearing. Suspensions settle to the bottom of the bottle and need to be shaken before the eyedrops are instilled. Patients also may complain of accumulation of the precipitates or forget to shake the bottle before administering the eyedrops.
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Gels are more viscous than solutions and suspensions and they are retained on the eye longer, allowing for better penetration of the active ingredients. In contrast to the suspensions, in which the active ingredient may precipitate, the gels allow for a more uniform distribution.
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Ointments increase the contact time further, requiring the least frequent instillation, but leave a film over the eye that blurs vision. In addition, water-soluble drugs do not dissolve in the ointment vehicle and are present as crystals. Crystals are trapped in the ointment vehicle until the crystals on the surface of the ointment contact the ocular surface after the ointment vehicle melts with exposure to body temperature. This type of absorption allows entry of constant but low amounts of the drug.
Other methods of delivery include soft contact lenses, soluble ocular inserts, or implantable devices. Medications inserted into punctal plugs are also being studied.
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- 1.
Punctal occlusion.
- 2.
Increase the frequency.
- 3.
Increase the concentration of drug in the drop.
- 4.
Increase the lipid solubility of the drug.
- 5.
Use surfactants to disturb the corneal epithelium.
- 4.
What are some of the indications for using topical antibiotics?
Topical antibiotics are used to treat conjunctivitis, conjunctival ulceration, corneal ulceration, and canaliculitis. They are also used as prophylaxes against infection before and after ocular surgeries such as cataract, glaucoma, retina, corneal transplant, refractive surgery, and ocular surface surgeries. Topical antibiotics are also used as prophylaxes in patients with corneal epithelial defects and in some cases patients who wear therapeutic contact lenses. Prophylaxis with antibiotics is becoming more controversial as it may select for more resistant bacteria should an infection occur.
- 5.
A 60-year-old man complains of crusting of the eyelids in the morning and chronic foreign-body sensation. Examination reveals moderate blepharitis with numerous collarettes around the eyelashes. What would you recommend?
Blepharitis often responds well to just warm compresses and eyelid scrubs, but supplemental antibiotic gels or ointments applied to the eyelash base or conjunctiva may be helpful, especially when numerous collarettes are seen around the eyelashes. Frequently used antibiotic ointments include erythromycin, bacitracin, and Polysporin. Azithromycin comes as an ophthalmic gel drop. Erythromycin and azithromycin are macrolide antibiotics that inhibit bacterial protein synthesis by binding to the 50S ribosomal unit. They have a broad spectrum of coverage but suffer from relatively poor intraocular absorption. They are most appropriate for blepharitis and conjunctivitis. Bacitracin is composed of numerous polypeptides that inhibit bacterial cell wall synthesis. Polysporin combines bacitracin and polymyxin B, which are peptides that act like detergents to lyse bacterial cell membranes, and offers better coverage of gram-negative bacteria.
- 6.
A 30-year-old woman with “cold” symptoms presents with redness and mucus discharge in both eyes. The ocular symptoms began in the right eye 1 week ago but now involve both eyes despite treatment of the right eye with sulfacetamide four times/day, as prescribed by her family physician. Examination reveals bilateral follicular conjunctivitis with preauricular adenopathy. What would you recommend?
History and examination are consistent with viral conjunctivitis. Artificial tears and cool compresses may provide comfort. Follow-up in 1 to 2 weeks is advisable to look for potential membranous conjunctivitis which may require topical steroids. Sulfacetamide is a bacteriostatic structural analog of p -aminobenzoic acid and inhibits synthesis of folic acid. It has a broad spectrum of coverage and good corneal penetration and becomes more effective when combined with trimethoprim, which blocks a successive step in bacterial folate metabolism. It appears to be used often by nonophthalmologists for initial treatment of red eyes; it is fine for mild bacterial conjunctivitis but is not helpful for viral conjunctivitis.
- 7.
A 55-year-old woman complains of discharge and redness of her right eye for 4 weeks. Her family physician told her that she had “pink eye” and prescribed erythromycin ointment, then sulfacetamide, and then ciprofloxacin, but the symptoms have not improved. Examination reveals diffuse papillary conjunctivitis with purulent discharge. There is no preauricular adenopathy or previous history of “cold” symptoms. What should you do?
The patient has chronic conjunctivitis, possibly bacterial. Topical therapy usually brings prompt relief, and you should make sure that she uses the medications properly. Assuming that she is getting the medications into the eye in a proper dosing regimen, conjunctival cultures can be performed to look for resistant or unusual bacteria. Testing for ocular Chlamydia may also be helpful. Chronic dacryocystitis should be investigated by applying firm pressure below the medial canthal tendon in an attempt to produce a diagnostic purulent discharge through the lacrimal punctum. An abscess in the nasolacrimal sac may provide a source of bacteria resistant to topical antibiotics.
- 8.
A 25-year-old man holding a towel over his right eye complains of copious discharge that began in the morning. Examination reveals diffuse conjunctival hyperemia and chemosis with thick, purulent discharge. A prominent preauricular adenopathy is also present. What should you do?
Hyperacute bacterial conjunctivitis in sexually active patients should prompt urgent conjunctival smears and cultures to look for gonococcal conjunctivitis. Although rare, gonococcal conjunctivitis requires immediate systemic antibiotics, with topical antibiotics as an adjunctive treatment only.
- 9.
A 26-year-old physician in a general surgery residency with a doctorate in pharmacology presents with foreign-body sensation and photophobia in both eyes after sleeping with soft contact lenses during his call night. A midperipheral 2-mm corneal ulcer with surrounding corneal stromal edema is present with scant anterior chamber reaction. What should you do?
The chances of developing a corneal ulcer increase by a factor of 10 when the patient sleeps with contact lenses. Corneal cultures are recommended, although some ophthalmologists may manage small corneal ulcers without cultures.
Initial therapy should cover a broad spectrum of bacteria. Traditionally, fortified cephalosporin and aminoglycoside have been used, but many believe that fluoroquinolones offer similar efficacy (especially for small ulcers) with less toxicity. In addition, fortified topical antibiotics are not universally available and need to be refrigerated.
Fluoroquinolones inhibit bacterial DNA synthesis by binding to DNA gyrase and inhibiting the supercoiling of bacterial DNA. They offer a superb spectrum of coverage in in vitro studies, although there is increasing resistance from methicillin-resistant Staphylococcus aureus and methicillin-resistant coagulation-negative Staphylococcus . Even so, they appear to be highly effective for most corneal ulcers, especially contact lens-induced corneal ulcers, but large clinical series with attention to resistance and treatment failure have not been completed.
Aminoglycosides bind to bacterial ribosomal subunits and interfere with protein synthesis. They offer a broad spectrum of coverage but require transport into the bacteria, which may be reduced in anaerobic environments of an abscess. Coadministration of antibiotics that alter bacterial cell-wall structure improves aminoglycoside penetration into bacteria and produces a synergistic effect.
Cephalosporins are β-lactam antibiotics synthesized or derived from compounds isolated from the fungus Cephalosporium acremonium . They inhibit bacterial transpeptidase, which is critical for bacterial cell-wall synthesis. In general, later generations provide broader coverage with better gram-negative but poorer gram-positive activity. Cefazolin is a first-generation cephalosporin that is traditionally combined with an aminoglycoside for the initial treatment of more severe or centrally located corneal ulcers. It covers gram-positive and some gram-negative organisms but misses Pseudomonas sp. and, therefore, requires the addition of an aminoglycoside or fluoroquinolone for initial broad-spectrum coverage.
- 10.
After corneal cultures are done, the patient is instructed to take ciprofloxacin drops every hour around the clock. Next day, he is in worse pain, and the corneal ulcer has enlarged to 3 mm with tenacious purulent discharge. What is your next step?
Make sure the eyedrops are getting into the eye. Ask the patient to demonstrate eyedrop administration. Several eyedrops fall on the floor, then on his cheeks, and finally he announces success when the eyedrops fall on his closed eyelids. Often, antibiotic failure is due to improper administration. Patients should be observed taking their eyedrops. A friend or family member may need to administer the eyedrops to be sure that the medications are getting to the source of infection, especially when frequent instillation is required. Indeed, some patients require hospitalization to receive intensive eyedrop administration.
In addition, the patient should have taken the drug more often. The manufacturer’s recommended dose of ciprofloxacin for corneal ulcers is two drops every 15 minutes for the first 6 hours, followed by two drops every half-hour for the remainder of the first day. Then, two drops every hour for the second day, decreasing to two drops every 4 hours for days 3 to 14, are suggested. However, this regimen may be altered in response to clinical exam and culture results. Frequent dosing of ciprofloxacin may produce a white precipitate over the ulcer, but this precipitate does not appear to impede the bactericidal activity and usually resolves when the dose is tapered.
Ofloxacin is also used but has different manufacturer’s recommendations:
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Days 1 and 2: One to two drops every 30 minutes while awake
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Awaken at 4 and 6 hours after retiring: Give one to two drops
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Days 3 to 7 or 9: One to two drops hourly while awake
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Days 7–9 to completion: One to two drops four times/day
Fourth-generation fluoroquinolones, gatifloxacin, moxifloxacin, and besifloxacin, are also available with better gram-positive coverage and comparable gram-negative coverage. These medications have not been FDA approved for the treatment of corneal ulcers but they are frequently used off-label for this condition.
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- 11.
The patient now prefers a “proven” treatment regimen with a long history and requests topical fortified antibiotics. However, he recalls that minimal bactericidal concentration for most pathogenic bacteria is far below that provided by the fortified antibiotics and accuses you of wasting money and drugs. Is he right?
No. In vitro and in vivo results in other sites of the body may not be applicable to the eye. Indeed, in the vitreous, the dose–response relationship has been demonstrated up to 100 times the in vitro minimal bactericidal concentration.
- 12.
The patient reminds you that he is penicillin-allergic and does not enjoy anaphylaxis. What antibiotics should you choose? How do you begin therapy?
Penicillin is not often used in ophthalmology because of poor penetration into the eye and active transport out of the eye by the organic acid transport system of the ciliary body. However, inflammation improves ocular penetration. Penicillin inhibits bacterial transpeptidase and prevents bacterial cell-wall synthesis. Varieties of modification of the original compound have produced varying spectra of activity. Penicillin G and V are still highly effective for many gram-positive and gram-negative bacteria, but many strains of S. aureus and S. epidermidis are now resistant. Penicillinase-resistant penicillins such as methicillin are useful for penicillinase-producing staphylococci. Broad-spectrum penicillins, ampicillin and amoxicillin, have better gram-negative coverage, and semisynthetic penicillins such as carbenicillin, piperacillin, and ticarcillin extend coverage to Pseudomonas, Enterobacter , and Proteus spp.
Immediate allergic response to penicillin, such as hives or anaphylaxis, is a strong contraindication for its use, and there is 10% cross-reactivity with cephalosporins. Therefore, for patients with penicillin allergy, cefazolin should be replaced with vancomycin. Vancomycin is a complex glycopeptide that inhibits bacterial cell-wall synthesis with principally gram-positive coverage, including methicillin-resistant S. aureus and Streptococcus faecalis , which is a frequent bacterial pathogen in infections of filtering blebs.
As mentioned above, an aminoglycoside is synergistic with cell-wall–inhibiting antibiotics, and the patient should be started on fortified vancomycin and tobramycin. Give the patient four doses—an alternating dose every 5 minutes—followed by alternation every half-hour to 1 hour. Actual dosing may vary in different institutions.
- 13.
The next morning the ulcer looks worse with 4-mm corneal infiltrate and purulent material overlying the ulcer. The corneal culture confirms Pseudomonas aeruginosa. Why did the patient not improve?
Pseudomonas corneal ulcers sometimes require double coverage. Fortified piperacillin or ticarcillin could be added in a non-penicillin-allergic patient. Frequent ciprofloxacin (or another fluoroquinolone) could also be resumed, especially in this case.
- 14.
The next day, the ulcer looks stable, but the patient complains of persistent and perhaps worsening pain. Examination reveals diffuse punctate corneal epithelial defects, inferior conjunctival erythema, and swollen lower eyelids. What should you do?
Toxicity is often less severe with topical administration; indeed, some common topical antibiotics such as neomycin and polymyxin cannot be given intravenously because of systemic toxicity. However, intensive regimens of potent antibiotics often produce surface toxicity with prominent involvement of lower more than upper conjunctiva. The toxicity is related to several factors, including the pH of the antibiotic drop and the presence of preservative in the solution. Fortified antibiotic drops, which are prepared by diluting intravenous antibiotics with preservative-free artificial tears and topical moxifloxacin, are preservative free. Occasionally, only analgesics and cool compresses can be offered if the infection is not under control. Fortified vancomycin should be decreased or discontinued because tobramycin and ciprofloxacin are more important for Pseudomonas ulcer, and the ulcer appears to be stabilizing.
- 15.
One week later the patient presents to you complaining of a dense white infiltrate in his cornea. Examination reveals superficial dense white material with gritty appearance in the area of the healing ulcer ( Fig. 10-1 ). What is going on?
Prolonged use of ciprofloxacin drops/ointments causes characteristic macroscopic deposits in up to 20% of patients through a compromised corneal epithelium. These eventually disappear after discontinuation of the ciprofloxacin eye medication.
