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Antibiotics

As predicted last year, we have indeed been blitzed with a promotional overdose of “fourth generation” antibiotics. We wonder if the discovery of penicillin was as highly touted! These new antibiotics do, however, perform beautifully, just like their predecessors.

Fluoroquinolones

• Ciloxan (ciprofloxacin 0.3%, Alcon)
• Iquix (levofloxacin 1.5%, Vistakon Pharmaceuticals)
• Ocuflox (ofloxacin 0.3%, Allergan)
• Quixin (levofloxacin 0.5%, Vistakon Pharmaceuticals)
• Vigamox (moxifloxacin 0.5%, Alcon)
• Zymar (gatifloxacin 0.3%, Allergan)

The only “new” antibiotic approved since last year is asuperchargedconcentration of levofloxacin 1.5% ophthalmicsolution, Iquix
(Vistakon Pharmaceuticals). We areall familiar with Quixin, Vistakon Pharmaceuticals’ 0.5% levofloxacin; Iquix will be the new big kid on the block once it becomes available. (Vistakon is still unsure of a launch date.) Levofloxacin, by virtue of its high solubility, can be relatively highly concentrated, thus allowing a 1.5% solution. Unique to all the newer fluoroquinolones, it enjoys an FDA indication for bacterial keratitis.

As with any of the fluoroquinolones, the key to a clinical cure of bacterial infection is to reach and maintain a high inhibitory concentration at the infection site. This is accomplished by frequent dosing, and we truly doubt it makes any difference which of the fluoroquinolones you choose to use. To wit, it would be interesting to see the change (or lack thereof) in the incidence of postoperative infection with the widespread use of these newer antibiotics.

A very nice article looked at the antibiotic susceptibility patterns of coagulase-negative staphylococcus bacteria.1 It found that the greatest sensitivities were “to vancomycin, the aminoglycosides (except neomycin), and levofloxacin.” Unfortunately, moxifloxacin, gatifloxacin, and 1.5% levofloxacin were not available at the time this study was initiated; undoubtedly, these three would have performed at least as well. When this study looked at a multi-resistant bacteria, the aminoglycosides outperformed even the fluoroquinolones, and were 95% as effective as vancomycin, the gold standard in treating gram-positive pathogens.


Another article discussing in vitro antibacterial activity—which compared gatifloxacin and moxifloxacin with levofloxacin, ciprofloxacin and ofloxacin against isolates of bacteria known to cause corneal infection—reported that “for most keratitis isolates, there were no susceptibility differences among the five fluoroquinolones.”2 The authors also say, “Minor differences in minimal inhibitory concentrations among fluoroquinolones may be less important clinically, however, as long as effective antibiotic tissue concentrations remain high.” This is best accomplished via frequent dosing schedules with higher concentrations of fluoroquinolone. The authors go on the state, “the actual clinical efficacy of the newer fluoroquinolones remains to be defined by the results of clinical trials for the treatment of bacterial keratitis and conjunctivitis.” The salient points from these two recent articles nicely summarize the key elements of the topical fluoroquinolones.

Bear in mind that all the ophthalmic fluoroquinolones have systemic counterparts. These orally administered drugs have been more rigorously studied and have been in clinical use longer than their ophthalmic offspring. Whatever these drugs do systemically, they do even better when they are topically applied. Since the efficacy of the fluoroquinolones is largely concentration-dependent, and we can place enormously greater drug per unit volume on the ocular surface than a can a pill distributed throughout the entire body, it is usually a simple task to kill ocular bacterial pathogens.

Although our sources were unable to get us the exact numbers for 2004, they conveyed that (as of June 2004) the percent national market share of oral fluoroquinolones in first quarter 2004 was very similar to the same period a year previously, no more than 2 percentage points higher or lower. Their popularity rank was in the same order: levofloxacin, ciprofloxacin, moxifloxacin, gatifloxacin, ofloxacin. Two conclusions that can be drawn from this are that the “real” doctors just don’t get it, or the eye doctors are being very heavily marketed. The nice thing is, all of the fluoroquinolones work well when used properly. Pick one and go for it!

The two most hyped ophthalmic fluoroquinolones are moxifloxacin (Vigamox, Alcon) and gatifloxacin (Zymar, Allergan). Of these two fine drugs, we generally prefer moxifloxacin for three reasons: its 0.5% concentration, its pH of 6.8, and it is self-preserved. Gatifloxacin is 0.3%, has a pH of 6.0, and contains BAK as a preservative.

Aminoglycosides

• Gentamicin
  
• Tobramycin
  
• Neomycin
  

Aminoglycosides are less expensive than fluoroquinolones and are effective for most “garden variety” cases of bacterial conjunctivitis, making them our drug of choice for treating most acute bacterial infections.

There are two notable aminoglycosides: gentamicin and tobramycin. Because tobramycin ophthalmic solution is available in generic form and is slightly more effective while slightly less toxic than gentamicin, we invariably prescribe tobramycin when we need an aminoglycoside. The third aminoglycoside, neomycin, is not available as a stand-alone drug, but is found in certain combination drugs such as Neosporin, Maxitrol, etc.

Aminoglycosides work by inhibiting protein synthesis. They’re most effective against gram-negative bacteria, especially Pseudomonas species, but are also effective against most gram-positive bacteria.
Though aminoglycoside toxicity is legendary—clinical signs include epithelial breakdown (SPK), injection in the inferior cul-de-sac, and a weepy erythema and edema of the eyelid tissues—these responses are usually not serious and mostly occur after the drug is used in excess of a week or two. In our years of clinical practice, we have never seen such an occurrence. For short-term use, these drugs are excellent cost-effective choices for killing bacterial ocular pathogens. Rarely are they used long enough to produce any significant side effects, unless the patient is pre-sensitized.
Tobramycin and gentamicin are available in solution (0.3%) and ointment (0.3%) form, but generally should not be used beyond one week because of their toxic potential.
Being aminoglycosides, they can cause allergic reactions similar to those seen with neomycin, but are less likely to do so. When bactericidal therapy is needed in ointment form, Polysporin is our choice.

Erythromycin
Erythromycin, which is only available in ophthalmic ointment form, is our drug of choice for pressure patching corneal abrasions and for nocturnal antibiosis/lubrication. It is gentle on the cornea and provides good antibacterial prophylaxis. It is a wonderful drug that is available generically and is used extensively in primary eye care of the external eye tissues.

Erythromycin, which is bacteriostatic, works by inhibiting protein synthesis. The topical form of this drug is effective against many gram-positive and some gram-negative organisms. If used over several days, staphylococcal resistance may develop. The drug is only available as a 0.5% ointment. For these reasons erythromycin is not a drug of choice for active therapy, but is an excellent prophylactic and supportive antibiotic.
Erythromycin is commonly used in labor and delivery suites as a second-line therapy to tetracycline ophthalmic ointment for neonatal prophylaxis against Neisseria, Treponemia and Chlamydia ocular inoculation during birth process. Topical erythromycin is commonly known by the brand name Ilotycin by Dista, and from Bausch & Lomb as an 0.125 oz. conventional ophthalmic tube and a 1gm unit-dose tube. Erythromycin ophthalmic ointment is widely available from numerous other generic manufacturers.

Bacitracin
Bacitracin ophthalmic ointment is our drug of choice for treating bacterial blepharitis. The drug, which breaks down cell walls, works well against staphylococcal bacteria, the main bacterial cause of blepharitis and the most common ocular pathogen. If there is clinically significant lid margin inflammation concurrent with the staph. blepharitis, then a one-week course of TobraDex is better initial medical therapy.

Its effectiveness and minimal toxicity would make bacitracin a drug of choice for treating gram-positive infections, except that it is only available as an ophthalmic ointment. Even so, bacitracin can sometimes be very difficult to find, so we tend to prescribe Polysporin (the polymyxin B is just inertly “along for the ride”).

Also keep in mind that the mainstay of therapy for blepharitis is meticulous long-term eyelid hygiene. But a short course of bacitracin in chronic staphylococcal blepharitis would augment the hygienic maneuvers and hasten the recovery process. Its singular practical use, in our opinion, is in these select cases of moderate to severe staphylococcal blepharitis. It is available from Bausch & Lomb and other generic manufacturers.

Polymyxin B Combinations
Many drugs are relatively “broad-spectrum” yet do not adequately cover Pseudomonas and other gram-negative species. As bacitracin is effective against gram positive organisms, polymyxin B is a potent killer of gram negative bacteria, including Pseudomonas. Resistance, toxicity and allergic reactions are rare. It works by destroying the cell membrane’s structural and functional integrity, resulting in cell death. For this reason, polymyxin B is commonly found in the following combination products.

• Polytrim ophthalmic solution (Allergan). Trimethoprim, a diaminopyrimidine, achieves bacteriostasis by interfering with folic acid synthesis. Specifically, it interrupts the synthesis of tetrahydrofolic acid, the metabolically usable form of folic acid. Trimethoprim is active against most common gram-positive and gram-negative ocular pathogens, except Pseudomonas species.

Trimethoprim sulfate (0.1%) with polymyxin B is marketed as Polytrim ophthalmic solution by Allergan, and available generically. This combination product is an excellent antibiotic for treating bacterial conjunctivitis in children and adults. Untoward side effects are very rare. It is clinically effective against most common ocular pathogens, and is minimally toxic to the eye. It has a high clinical efficacy against Haemophilus influenzae and Streptococcus pneumoniae, the most common causes of bacterial eye infections in children, making it our drug of choice in these cases. To wit, pediatricians are the largest prescribers of Polytrim.

It isn’t available in ointment form, and may not be suitable for smaller children in whom drop instillation is physically impossible or crying washes out the drops. In those cases, you could substitute Polysporin or Ciloxan ophthalmic ointment; both have good coverage against Haemophilus and Streptococcus species.

Interestingly, it has been reported that “H. influenzae type-B is now nearly non-existent as a pathogen in childhood epiglottis, meningitis, buccal cellulitis, and otitis.”4 This may well be valid for conjunctivitis as well. It does appear that most infections tend to be strep and staph. Therefore, good coverage against gram-positive organisms is essential.

The recommended frequency of administration is one drop every three hours (q3h) while awake. This is a bit more frequent than the more common four times-a-day schedule. As with most other anti-bacterial agents, treatment should continue for a full week.

• Polysporin (Monarch Pharmaceuticals). This is an excellent broad-spectrum antibiotic combination that enjoys widespread use in eye care. The combination of bacitracin and polymyxin B is excellent for two reasons:

1. It is highly efficacious against most of the common ocular pathogens, both gram positive and gram negative.

2. It is relatively non-toxic to global epithelial tissues. It can play a role in any bacterial infectious process, but it is only available in ointment form, which limits its practical use.

We discourage use of ointments in adults for daytime therapy because it is not very patient-friendly. But if there is an indication for using an effective antibiotic at nighttime to get around-the-clock antibacterial coverage, certainly Polysporin (or Ciloxan) would be an excellent choice. In the event of a “dirty” corneal abrasion, such as a scratch by a dirty piece of metal, then it might be preferable to use Polysporin (or Ciloxan) instead of erythromycin. However, these are relatively rare occurrences.

Doctors can prescribe this drug safely in most bacterial infections. In blepharitis therapy, since polymyxin B is non-toxic, Polysporin can be substituted for bacitracin should the pharmacy not have bacitracin. Ciloxan ointment could also be used for infectious blepharitis.

• Neosporin (Monarch Pharmaceuticals). Bacitracin (or gramicidin) with polymyxin B and neomycin is available as Neosporin as a solution and an ointment. In the solution, gramicidin replaces bacitracin, since bacitracin is unstable in water. In terms of activity, gramicidin is virtually identical to bacitracin but more water-soluble.

The addition of neomycin, an aminoglycoside, kills a broad spectrum of bacteria by inhibiting protein synthesis. It’s effective against most gram-positive and gram-negative bacteria, with the notable exception of Pseudomonas.

We rarely use it, however, because of the possibility of neomycin reactions, although they are uncommon. About 5% of all patients will experience a delayed, type IV hypersensitivity reaction to neomycin. If the patient has not been exposed to the drug before, the reaction can occur after several days of therapy. If the patient has been previously sensitized, the reaction can happen more quickly, usually within 12 to 72 hours.

If such a classic neomycin hypersensitivity were to occur, you will usually see erythema and mild edema of the eyelids, conjunctival injection, and possibly superficial punctate keratitis. The reaction usually is most pronounced in the inferonasal region of the eye because gravity and blink mechanics carry the drug there. The primary therapy is to discontinue the drug.

The reaction typically resolves on its own within a few days. Consider recommending cold compresses and/or a topical steroid ointment such as FML, or a combination ophthalmic ointment containing 10% sodium sulfacetamide and either 0.2 or 0.25% prednisolone (Blephamide, Isopto-cetapred) or 0.5% prednisolone (Metimyd or Vasocidin), applied to the inflamed tissues once or twice during the day and then at bedtime. The antibacterial agent plays no role here; the only way to obtain low concentrations of prednisolone in ointment form is in such combination products.

Triamcinolone 0.1% dermatological cream has become our favorite for treating all expressions of delayed (Type IV) hypersensitivity contact dermatitis.

Because newer antibiotics are now available that are less toxic and equally or superiorly efficacious, there is little reason to use products containing neomycin. Clinicians have other options that work just as well without the unnecessary risk of annoying neomycin side effects.

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