PHLYCTENULOSIS (PHLYCTENULAR KERATOCONJUNCTIVITIS)

Signs and Symptoms

Inferior temporal phylectenule.

Phlyctenular keratoconjunctivitis is a nodular inflammation of the perilimbal tissues that occurs secondary to an allergic hypersensitivity response of the cornea.1­6 The disease has a worldwide distribution and is most often seen in the first and second decades in women (60%) living in crowded or impoverished quarters. The disease has been associated with systemic disorders such as Behçet's disease, tuberculosis, HIV and rosacea among others.4­6 Patients typically present with symptoms of tearing, ocular irritation, mild to severe photophobia and a history of similar episodes.1­3,6 If the underlying cause is staphylococcus, a rope-like, mucopurulent discharge may be present.2

There are two distinct types of phlyctenular lesions: corneal and conjunctival. Biomicroscopic evaluation of a conjunctival (vascularized) phlyctenule reveals a 1mm to 3mm, hard, slightly elevated, yellowish-white nodule, surrounded by a hyperemic response, in the vicinity of the inferior limbus. The lesions tend to be bilateral. Corneal phlyctenules produce more severe symptoms. They usually begin adjacent to the limbus as a white mound, with a radial pattern of vascularized conjunctival vessels on the conjunctival side.2 The lesion may then migrate toward the center of the cornea, progressing as a gray-white, superficial ulcer surrounded by infiltrate in the areas where the lesion has been.1­6

Pathophysiology

The exact mechanism by which phlyctenules are produced is unclear. Histologically, they are composed of lymphocytes, histocytes and plasma cells. Polymorphonuclear leukocytes are found in necrotic lesions.2 Their formation seems to be the result of a delayed hypersensitivity reaction to tuberculin protein, Staphyloccocus aureus, Coccidioides immitis, Chlamydia, ocular rosacea, some varieties of interstitial parasites, or Candida albicans.1­3 Rarely are cases idiopathic; such a diagnosis should be made by exclusion.

Management

Ocular management of phlyctenular keratoconjuntivitis begins with patient education to improve eyelid hygiene. Lid scrubs two to three times a day, along with artificial tears and ointments, may soothe and reverse mild cases. Moderate to severe cases require topical steroidal or steroidal/antibiotic combination medicines. Cycloplegia is only necessary if significant inflammation is present. In mild cases, lid scrubs and copious lubrication may suffice. In most cases, prednisolone acetate (Pred Forte, Allergan), one drop, q2h-qid is sufficient. A combination agent such as Tobradex is an excellent option. If the suspected etiology is staph or rosacea, 250mg of oral tetracycline qid or 250mg erythromycin qid, along with topical antibiotic ointments such as bacitracin or erythromycin hs, should be added.6 Additionally, topical metronidazole (Metrogel, Galderma) applied to the skin tid is also effective. Because tetracycline can damage and discolor the teeth of children, it is contraindicated in persons under the age of 10. Here, doxycycline, 100mg tid, or erythromycin 250mg qid po, may be substituted.1­3,6 Treatment should continue for two to four weeks. In suspicious cases, a chest X-ray, PPD, HIV titre and HLA typing (Behcet­HLA­B51) should be obtained.1­6

Clinical Pearls

  • Maintenance doses of oral and topical steroids and antibiotics may continue to relieve patients' signs and symptoms. This practice is acceptable, provided that the patient tolerates the regimen. Weekly follow-up is recommended. Once significant improvement is noted, the steroid should be tapered. The antibiotic coverage should continue, prophylactically, until the steroid is removed. Eyelid hygiene should be maintained indefinitely.1­3,5,6
  • Other potential differential diagnoses include infiltrates secondary to chronic blepharitis, inflamed pingueculum, herpes simplex and infectious or marginal corneal ulcer.1­3, 6

FOURTH-GENERATION FLUOROQUINOLONES: COMBATING OR PROMOTING BACTERIAL RESISTANCE?

FEW WOULD ARGUE that the fluoroquinolones represent the most potent and beneficial antibiotic agents currently available. Whether for peri-operative prophylaxis or management of bacterial ocular infection, fluoroquinolone antibiotics are clearly the market leader at this time. These drugs work by inhibiting the function of crucial bacterial enzymes involved in cellular replication. This leads to disruption of the DNA, which prevents bacteria from replicating, resulting in rapid death of the invading organisms.

The fourth-generation fluoroquinolones include Vigamox (0.5% moxifloxacin, Alcon) and Zymar (0.3% gatifloxacin, Allergan). They differ chemically and pharmacologically from previous generations with respect to side chains located at the C-7 and C-8 positions. These side chains impart enhanced bactericidal activity and prevent bacterial defenses from rendering the drugs inert. Subsequently, these new drugs display excellent intrinsic activity against both common and atypical bacterial pathogens. And, while many common bacterial strains are known to have developed resistance to older fluoroquinolones such as ciprofloxacin and ofloxacin,1 these organisms appear to be fully susceptible to the new fourth-generation fluoroquinolones.

Research has demonstrated that these new drugs are significantly more potent against a wide range of bacterial pathogens.2,3 In addition, at least one of the new fourth-generation fluoroquinolones, Vigamox, boasts improved dosing (tid vs. qid), higher concentration (0.5% vs. 0.3%), more neutral pH (6.8 vs. 4.5 to 6.0), and absence of added preservatives such as benzalkonium chloride. Clearly, with all these advantages, what could possibly deter the eye care community from immediately adopting this medication as the new drug of choice?

Unfortunately, many have expressed hesitation to begin utilizing the new fourth-generation fluoroquinolones like Vigamox and Zymar for fear of creating new, resistant strains of bacteria.
After all, it has been less than 15 years since Ciloxan and Ocuflox were introduced, and we are already seeing significant resistance to these drugs. Hence, some argue that if we use our new "big guns" on routine ocular infections, rather than reserve them for severe infections, we will promote and accelerate the process of resistance.

While virtually all antibiotics are subject to resistance over time, the new fourth-generation fluoroquinolones stand the best chance of overcoming this trend. By their very design, they have been engineered to defy bacterial resistance. Older fluoroquinolones are known to target the enzyme DNA gyrase (topoisomerase II) in Gram-negative bacteria, and topoisomerase IV in Gram-positive bacteria. By contrast, the new fourth-generation drugs have the capacity to block both of these enzymes simultaneously in both Gram-positive and Gram-negative bacteria; this means that, for resistance to occur, mutations would have to occur simultaneously at two sites rather than just one. Another characteristic of the new drugs helps to combat bacterial efflux, a process by which the pathogens actively pump the drugs out of the cytoplasm. The surest way to prevent resistance is to not use doses below that recommended in the product insert. Antibiotics should not be tapered. They should be used to their desired effect and then abruptly discontinued. Using sublethal dosing will lead to resistance. For example, Vigamox is dosed tid. Dosing should not be below tid.

No one can predict the future, but one observation can be made with relative confidence--the continued use of older, second- and third-generation fluoroquinolones will certainly not help to overcome the current trends in bacterial resistance. The fourth-generation fluoroquinolones, on the other hand, offer our current patients the best possibility for a positive outcome. Whether for surgical prophylaxis or the treatment of bacterial ocular infection, drugs such as Vigamox and Zymar deserve serious consideration.

  1. Goldstein MH, Kowalski RP, Gordon YJ. Emerging fluoroquinolone resistance in bacterial keratitis: A 5-year review. Ophthalmology 1999; 106(7):1313-8.
  2. Mather R, Karenchak LM, Romanovski EG, et al. Fourth-generation fluoroquinolones: New weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol 2002; 133(4):163-6.
  3. Kowalski RP, Dhaliwal DK, Karenchak LM, et al. Gatifloxacin and moxifloxacin: An in vitro susceptibility comparison to levofloxacin, ciprofloxacin, and ofloxacin using bacterial keratitis isolates. Am J Ophthalmol 2003; 136(3):500-5.

 

  1. Cullom RD, Chang B. Cornea : Phylectenulosis. In : Cullom RD, Chang B. The Wills Eye Manual: Office and Emergency Room Diagnosis and Treatment of Eye Disease. Philadelphia, PA: J.B. Lippincott Co. 1994;64-65.
  2. Wagoner MD, Bajart AM, Allansmith MR. Phlyctenulosis. In: Fraunfelder FT, Roy FH Current Ocular Thearapy 3. Philadelphia, PA ; W.B. Saunders Co. 1990 :454-456.
  3. Schimmel DJ. Infiltrative Keratitis. In: Onofrey, B.E. Clinical Optometric Pharmacology and Therapeutics. Philadelphia, PA: J.B. Lippincott Co. 1994; 1-13.
  4. Hochedez P, Zeller V, Truffo, C, et al. Lymph-node tuberculosis in patients infected or not with HIV: general characteristics, clinical presentation, microbiological diagnosis and treatment. Pathol Biol 2003; 51(8­9):496-502.
  5. Hashida N, Ohguro N, Yamamoto S, et al. Unusual neutrophil infiltration under the soft contact lens in a patient with Behcet's disease. Jpn J Ophthalmol 2003; 47(5):469-72.
  6. Blaustein BH, Gurwood AS. Recurrent phlyctenular keratoconjunctivitis: a forme fruste manifestation of rosacea. Optometry 2001; 72(3):179-84.

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