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Antibiotic - Corticosteroid Combinations

This unique class of drugs will be discussed first in a highly clinically relevant context, and then a detailed look at the medicines themselves will follow.

This class of ophthalmic drugs is highly useful and rivals the pure topical corticosteroids in the treatment of the acute red eye. As with most drugs, there are clear indications and clear contraindications, with a gray zone in between.
In order to prescribe a combination drug with clinical precision, one has to have a masterful understanding of both antibiotics and corticosteroids. As many as half of all red eyes that we see are treated with a combination drug, rather than either a steroid or antibiotic alone. This observation clearly acknowledges two clinical realities:

• The need for topical antibiotics alone is relatively low, and
• Almost all acute red eyes have a significant inflammatory component.

So, how does the astute clinician choose between a pure steroid and a combination drug? The answer is relatively straightforward, but, as always, there are exceptions to generalizations. The pivotal issue is the integrity of the corneal epithelium. If the corneal epithelium is intact, there is little or no reason to prophylax against opportunistic bacterial pathogens. This is because an intact epithelium is itself firewall of defense. If there is significant epithelial compromise, then a combination drug may perfectly match the clinical need.

Remember that the conjunctiva will be inflamed in any patient presenting with an acute red eye. Simply put, the eye is red because it is inflamed. Also, the conjunctiva will be inflamed in almost all cases in which keratitis is present. With either keratitis (with an intact epithelium) or conjunctivitis, we almost always use a topical steroid.

An exception is the patient who presents with what appears to be a low grade bacterial conjunctiva (i.e., minimal discharge), yet with moderate to marked conjunctival injection. The patient usually complains that the affected eye was “stuck together when I woke up.” Of course, by the time the patient arrives at your office, any excess debris may have been cleaned from the lids and lashes. Further, blinking has moved considerable mucopurulent debris down the nasolacrimal system so that the objective slit lamp findings reveal only minimal microparticulant debris in the lacrimal lake; a clear, non-staining cornea; and/or a red eye. Here is where a combination product is used mainly to address the conjunctival inflammation, while concurrently eliminating the infectious component, even when the cornea is uninvolved. When there is significant corneal epithelial compromise, we almost always use a combination drug. For most cases, the choice of drug class is that simple.

Now that we have 90% of this topic covered, we need to spend the bulk of this article discussing other various exceptions and modifications to this rather simple decision tree. The best way to teach the concepts for drug class choice is perhaps by looking at a few specific clinical entities:

Thygeson’s Superficial Punctate Keratopathy (SPK). This not-so-uncommon keratitis is seen in young to middle-aged patients. The classic symptoms are foreign body sensation, photophobia and lacrimation. This idiopathic condition has cycles of exacerbation and remission over the course of 10 to 20 years, until it finally abates. It is during these exacerbations when symptoms prompt the patient to seek medical attention. This keratitis shows several tiny, usually central, subtle (but readily seen) staining defects with fluorescein dye.

If the patient is significantly symptomatic, a topical corticosteroid readily suppresses the keratitis and its attendant symptoms. If the presenting symptoms are tolerable, then artificial tears and patient education are likely all that is needed.

However, the point here is that even though there is some punctate staining in acute Thygeson’s SPK, all that is needed is a topical steroid. To our knowledge, this is the uniform recommendation in authoritative textbooks. While 1% concentrations of topical steroids are indicated in most all inflammatory eye conditions, Thygeson’s is exquisitely steroid sensitive. Therefore, our drug of choice in these cases is 0.2% loteprednol (Alrex). We generally treat symptomatic patients q.i.d. for one week, then b.i.d. for one to four weeks, until the phase of exacerbation subsides. Artificial tears complement virtually all acute ocular surface conditions, but there is no need for an antibiotic.

Epidemic Keratoconjunctivitis (EKC). If the EKC is severe, and especially if tarsal conjunctival membranes have formed, there can be epithelial compromise. The key here is to physically peel away these membranes, as they exert toxic and mechanical trauma to the epithelium. Be sure to wear gloves when performing this procedure, as minor bleeding often results.

These membranes are a marker of intense inflammation, and as such, corticosteroid therapy is of paramount importance. We generally use loteprednol 0.5% (Lotemax) q.i.d. for a week. By the end of this period, natural healing will likely have occurred and the steroid can be stopped, or tapered to b.i.d. for a few more days. While a combination drug, such as Zylet, TobraDex, or Maxitrol, could be used here, we almost always use a pure topical steroid. A concern regarding aminoglycoside toxicity on an already toxic ocular surface is probably not a practical concern, but could be in instances where the patient has concurrent dry eye.

In many advanced cases of EKC, subepithelial infiltrates (which do not stain) can develop. When these cause symptomatic, visual compromise, a steroid will readily clear this unique, immune keratitis. This generally requires two to four months of tapering therapy. Our routine has been to use Lotemax q.i.d. x 1 month, t.i.d. x 1 month, b.i.d. x 1 month, and then q.d. x 1 month. It usually takes two to four months for sufficient viral antigen to be physiologically leeched from stromal residence. So, when the steroid taper is completed, any small infiltrates that might reform should be symptomatically minimal, or silent.

Of note, antibiotic and combination drugs have little or no role in caring for patients with adenoviral infections, and concurrent bacterial infection is exceedingly rare.

Infectious Ulcers vs Sterile Infiltrates
	Is it an ulcer or an infiltrate? At left is an infectious ulcer. At right is a sterile infiltrate.

For several years now, we have successfully treated symptomatic patients with acute, grade II or higher EKC with a 60-second treatment of 5% Betadine Sterile Ophthalmic Prep Solution followed by ocular surface lavage. This accomplishes two objectives. First, eradication of the bulk of the adenoviral load hastens acute symptomatic recovery. Second, since the virus particles residence time has been considerably truncated, the potential for viral antigenic (stromal immune) keratitis is largely preempted.

Following the in-office treatment as described above, prescribe Lotemax, usually q.i.d. for four to six days to dampen or eliminate any residual inflammatory keratoconjunctivitis.

Herpes Simplex Keratitis. Here is another condition that commonly demonstrates considerable epithelial compromise.

Since corticosteroids cause local immunosuppression, their use is contraindicated—an exceedingly well-known principle. No authoritative textbook recommends the use of a prophylactic antibacterial agent in such cases. As clinicians, we do not know why the herpetic corneal defect does not invite opportunistic bacterial pathogens; we just know that antibacterial therapeutic intervention is not needed.

Trifluridine drops, perhaps in conjunction with preservative-free artificial tears, is the only therapeutic intervention warranted for herpes simplex epithelial keratitis. Oral antivirals, such as acyclovir (400mg 5 times daily x 7 days) can be used if there is trifluridine resistance, or if the patient has developed an allergic response to trifluridine.

Corneal Abrasions. Most such defects heal within a day or two, regardless of any therapeutic maneuvers. To our knowledge, no studies have prospectively followed “no treatment” of abrasions, but it would be interesting to know the absolute need for prophylactic antibiotic use, which is common practice in these situations. We imagine the rate of infectious keratitis would be very small. However, since antibiotics are safe, there is no mandate to take chances.

Conservative therapy with antibiotics has evolved into the standard of care for corneal abrasions. There are, however, circumstances—most notably delay in seeking care—where the abraded eye is considerably inflamed. While fungal infection is always a rare possibility if the traumatic agent was vegetative, 99.9% of the time fungus is not a player. That being said, we have occasionally used a short-acting cycloplegic agent and a combination drug in “hot” eyes with corneal abrasions. The steroid component calms the tissues and thus potentiates corneal re-epithelialization. A further note for the fungal worriers out there: If the delay in seeking care is two to four days, fungal involvement at this point is unlikely, since fungi are usually slow growing and would take many more days to proliferate to symptomatic proportions.

Now, if the patient gives a history of vegetative trauma, and reports that the abrasion initially healed up after a day or two, but is now (perhaps a week later) presenting with a hot eye and stromal infiltrates, fungal etiology should be considered. However, such symptoms are still most likely associated with a cell-mediated immune response to the initial trauma, rather than a fungal infection. The salient features of a fungal keratitis are:

• History of corneal injury (vegetative matter)
  
• Slowly progressive
  
• Hypopyon in advanced cases
  
• Not very painful (relatively)
  
• Feathery border (hyphate-like)
  
• Slightly raised, dirty white infiltration
  
• Satellite lesions
  
• Partial or complete ring
  
• Secondary anterior uveitis

For perspective, in our combined 50 years of intense clinical experience, we have seen a grand total of two cases of fungal infection following corneal abrasion, both of which were treated successfully. If, however, the traumatic vector of the corneal abrasion was inorganic, then in the setting of marked inflammation, a combination product could be considered. More conservatively, a pure antibiotic could be used for a day or two. If the traumatic keratoconjunctivitis fails to subside or if symptoms worsen, then a steroid can be added.

Phlyctenular Keratoconjunctivitis (PKC). Most usually seen in young girls, this staphylococcal hypersensitivity response commonly targets the limbal tissues as one or two raised, whitish lesions, which stain lightly with fluorescein. Nothing else looks like a phlyctenule. While one would think staphylococcal blepharitis would always be evident, such is not empirically the case. Certainly, if blepharitis is present, initiate proper care, but let’s first treat the inflammatory keratoconjunctivitis. When there is a staining defect at the corneolimbus, a prophylactic antibiotic is counterproductively conservative.
The key clinical feature is the inflammatory component—the eye is red. Here, a combination product is probably wise. We generally use a combination drug q2 hours for a day or two, then q.i.d. for four to six days, and then stop.

Peripheral staph, exotoxin corneal erosion (left).  Two days after antibiotic/ corticosteroid combination therapy (right).

Staph Marginal “Ulcers” (much more appropriately called “peripheral inflammatory epithelial defects”). These are uncommon events that have a similar pathophysiology to PKC. In these cases, the staphylococcal exotoxins begin to erode a section of the peripheral corneal epithelial tissues. The eye is red with accentuation of a sector of bulbar conjunctival inflammation adjacent to the affected cornea. The foci of compromised epithelium stains brightly with fluorescein dye. There may be a few cells in the anterior chamber. The epithelium stains as a result of the anterior stromal inflammatory process.

Once this subepitheleal inflammation is subdued by the corticosteroid, re-epithealization is potentiated. An antibiotic alone in this case is almost worthless. While an antibiotic can serve to protect against bacterial opportunistic potential, it will do nothing to curb the inflammatory process.

As with PKC, a combination product is perfectly suited to address the inflammatory process while simultaneously guarding the cornea against the possibility of bacterial infection. Therapeutic management is as described for PKC.

Keratoconjunctivitis Sicca (KCS). We have all seen dry eye patients with slit lamp-observable, coarse SPK. Also known as punctate epithelial erosions, SPK represents a break in epithelial integrity that theoretically provides a foothold for bacterial adherence and subsequent penetration. Yet, antibiotic intervention is rarely, if ever, indicated. Acknowledging the participation of inflammation in the pathogenesis of many cases of dry eye-related SPK, topical steroid and/or cyclosporin therapy is often employed (along with artificial tears, etc.) in the successful management of KCS. We have never read of an antibiotic role in the management of KCS.

Contact Lens-Associated Keratitis
Confusion abounds in eye care regarding the diagnosis and treatment of contact lens-related keratitis, although in most all cases, these clinical presentations are rather straightforward. Of course, our greatest concern is vision loss from a central bacterial corneal ulcer. The good news is that such ulcers are exceedingly rare. The problem, however, is threefold:

1) corneal infiltrates are quite common occurrences;

2) there is a lot of uncertainty among eye doctors as to the differentiation of corneal lesions; and

3) the ever-looming concern: “Is this the beginning of a potentially vision-threatening ulcerative process?” (This last point is particularly concerning when a positive epithelial defect is present.)

Corneal hypoxia is the most common cause of corneal infiltrative events, but with the advent of the super-oxygen permeable silicone hydrogel lenses, we should expect to see a dramatic decrease in the hypoxic-related keratitis.

Hypoxia can begin a cascade of events leading to leukocytic chemotaxis into the anterior stromal tissues. Once ample leukocytic recruitment occurs, exocytotoxic chemicals can lead to subsequent epithelial and stromal tissue compromise, which can cause a positive fluorescein staining defect.

It is these circumstances that lead many doctors to erroneously assume the worst and start the patient on a course of topical antibiotics. While this does no harm, it does no more good than simply discontinuing the use of the contact lenses, which, of course, is the first step of treatment for all contact lens-related eye problems.

There are numerous parameters to evaluating the differential diagnosis of leukocytic infiltration (largely from hypoxia) versus stromal opacification lesions (largely from bacterial infection). These are enumerated in “Ulcer vs. Infiltrate”.

Let’s look at some risk factors for ulcerative keratitis so that we can better quantify the likelihood of such occurrences:

• Poor tear film function
  
• Uncontrolled staphylococcal blepharitis
  
• Smoking
  
• Swimming while wearing contacts (especially in fresh water)
  
• Being under age 22±

While this is not an exhaustive list, it gives us some red flags by which we can exercise our clinical judgment, and enhance our patient education.

If you truly feel your patient has an infectious lesion, then start them on a fluoroquinolone every 15 minutes for three to six hours, then hourly until bedtime. We recommend our patients use Polysporin (or Neosporin) ointment at bedtime. Follow your patient daily and modify therapy based upon the clinical response.

There is a less intensive approach that can be used if you think your patient has a leukocytic infiltrate, and you choose a conservative approach. Here, we recommend the use of any fluoroquinolone or aminoglycoside hourly until the patient is seen back the next day.

In either diagnostic circumstance (bacterial infection or leukocytic infiltration), improvement will most always be evident, mainly because lens wear has been discontinued. Naïve practitioners who witness such improvement may wrongly deduce the lesion must have been an infective process, and be glad they used an antibiotic. Once again, infiltrates are very common, and bacterial keratitis is very rare.

The most accurate response to an immune/inflammatory condition (e.g., a leukocytic/sterile infiltrate) is a steroid. Since a small epithelial defect may or may not be present, or clinical judgment may be wrong (if the lesion actually is an early infectious disease process), always prescribe an antibiotic/steroid combination to treat these conditions. Prescribe the combination drug to be used q2h for two days, then q.i.d. for four days (mainly to quiet the inflammation and allow the eye to calm down).

Each doctor must evaluate each patient’s condition carefully and precisely. As stated at the outset, treatment of contact lens-associated keratitis is rather straightforward in most cases. In ambiguous cases, treat conservatively until the diagnosis becomes clear. Take note that between the two of us, we have seen less than a handful of cases of microbial keratitis.


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