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bacillus, but no particular drug is uniformly active against all strains of E. coli, so sensitivity testing should guide the choice of antibiotics. Antimicrobial resistance occurs through plasmidmediated determinants, several of which can be found in the same plasmid. These multiresistent plasmids can be transferred by conjugation.

For less severe E. coli infections, the initial treatment of choice may be ampicillin 2 to 4 g/day IM or IV. One may also consider other penicillins with β-lactamase inhibitor, cephalosporins, nitrofurantoin and trimethoprim-sulfamethoxazole. For more severe infections, the dose of ampicillin/sulbactam could be 3 g every 6 hours IV. One may also consider imipenem cilastatin, ciprofloxacin IV or cefotaxime.

Aminoglycoside antibiotics are most commonly used against coliform bacillary infections, including E. coli; they include kanamycin, gentamicin, amikacin and tobramycin.

Kanamycin is generally indicated for the initial treatment of serious E. coli infections. Severe urinary tract infections that seem to be resistant to other antimicrobial agents have responded to daily doses of kanamycin 15 mg/kg IM in divided doses every 6 to 8 hours.

Alternative treatment may be a total daily dose of parenteral gentamycin 3 to 5 mg/kg administered in divided doses every 8 hours. In severe infections that appear to be resistant to kanamycin and gentamicin, amikacin is indicated. Amikacin is given in daily doses of 15 mg/kg in two or three equally divided doses.

In severe cases of sepsis, a combination of antibiotics is given, which includes ampicillin and an aminoglycoside, the choice of which is based on knowledge of local susceptibility patterns. Ampicillin-sulbactam or cefatazime (a potent third-generation cephalosporin) is a suitable alternative, especially if an amino- glycoside-resistant nosocomial organism is suspected.

Neomycin appears to be most effective against E. coli gastroenteritis. An oral daily dose of 25 mg/kg is usually indicated for 1 or 2 days.

Ocular

In E. coli conjunctivitis, topical ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin, or 0.3% tobramycin ophthalmic solutions are applied topically approximately six to eight times daily until the infection appears to be resolved. For a severe case, a more aggressive dose should be given during the first 24 to 48 hours in about 12 to 24 doses daily. For example, loads of three every 2 hours (drop at 8:00 a.m., 8:05 a.m. and 8:10 a.m.; then 10:00 a.m., 10:05 a.m. and 10:10 a.m.; and so on) for a total of 24 installations daily. Use of the concept of loading with well-tolerated topical antibiotics enhances compliance and optimizes effective microbial killing.

Early systemic and local antibiotic therapy is essential for E. coli endophthalmitis. Blanket local antibiotic therapy should consist of 20 mg of subconjunctival gentamicin or tobramycin. Also, for topical treatment 0.3% tobramycin ophthalmic solution or 3rd and 4th generation quinolones, such as gatifloxacin, levofloxacin and moxifloxacin, 12 to 24 doses daily, may be added. In most cases of E. coli endophthalmitis, intravitreal injection of gentamicin or tobramycin 100 to 300 μg can be used. Amikacin can also be used at 400 μg. Intravitreal injection consists of a total of 0.1 mL.

Systemic or local corticosteroids administered in combination with antibiotics may reduce the massive inflammatory response of the eye, which often is as destructive as the infection. Their use should be considered when highly effective

antibiotics are being used at optimal dosing and there is a need to control the retinitis occurring.

Secondary involvement of the uveal tract may necessitate the use of a cycloplegic/mydriatic. Scopolamine 0.25% drops may be applied topically twice daily to aid in the relief of uveitis.

Supportive

Hospitalization is necessary for E. coli endophthalmitis infection.

PRECAUTIONS

The serum levels of aminoglycosides should be monitored to gauge therapeutic levels and to avoid toxicity because the ratio of therapeutic dose to toxic dose is very narrow. Ototoxicity and nephrotoxicity may occur even when serum levels have been appropriately monitored, so the risks should be weighed. The concurrent and/or sequential systemic use of potentially neurotoxic or nephrotoxic drugs should be avoided.

Isolation and antimicrobial therapy of contacts are essential to abort epidemic infantile diarrhea. Many E. coli infections are hospital acquired, so strict hygienic measures are essential.

COMMENTS

E. coli is rarely found in the normal flora of the conjunctiva. It is most commonly seen as a source of infection in ophthalmia neonatorum. E. coli endophthalmitis is a rare complication of E. coli septicemia. It has a poor prognosis and early diagnosis and treatment are essential if useful vision is to be retained.

REFERENCES

Aronson SB, Elliott JH: Ocular inflammations. St Louis, CV Mosby, 1972: 103–105, 112–114, 228–230.

Balestrazzi A, Blasi MA, Primitivo S, Balestrazzi: Escherichia coli endophthalmitis after trans-scleral resection of uveal melanoma. Eur J Ophthalmol 12(5):437–439, 2002.

Barnett BJ, Stephens DS: Urinary tract infection: an overview. Am J Med Sci 314(4):245–249, 1997.

Bonadio WA, Smith DS, Madagame E, et al: Escherichia coli bacteremia in children: A review of 91 cases in 10 years. Am J Dis Child 145:671–674, 1991.

D’Amico DJ, Caspers-Velu L, Libert J, et al: Comparative toxicity of intravitreal aminoglycoside antibiotics. Am J Ophthalmol 100:264, 1985.

Eisenstein BI: Escherichia coli infections. In: Isselbacher KJ, Braunwald E, Wilson JD, et al, eds: Harrison’s principles of internal medicine. 13th edn. New York, McGraw-Hill, 1994:661–663.

Endophthalmitis Vitrectomy Study Group: Results of the endophthalmitis vitrectomy study: a randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Arch Ophthalmol 113:1479, 1995.

Glasser DB, Baum J: Antibacterial agents. In: Tabbara K, Hyndiuk RA, eds: Infections of the eye. Little, Brown, Boston, 1996:207–230.

Hyndiuk RA, Cokington CD: Bacterial keratitis. In: Tabbara K, Hyndiuk R, eds: Infections of the eye: diagnosis and management. Little, Brown, Boston, 1996:323–347.

Shammas HF: Endogenous E. coli endophthalmitis. Surv Ophthalmol 21:429–435, 1977.

Turck M, Schaberg D: Infections due to enterobacteriaceae. In: Isselbacher KJ, Adams RD, Braunwald E, eds: Harrison’s principles of internal medicine. 9th edn. New York, McGraw-Hill, 1980:629–634.

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COURSE/PROGNOSIS

In the largest reported series of AGC, 21 cases of cultureconfirmed N. gonorrhoeae conjunctivitis were retrospectively analyzed. Most patients were between 20 and 26 years old, a distribution similar to that of other gonococcal infections. The median time between the onset of conjunctivitis and presentation to the physician was 4 days. The majority of patients denied exposure to N. gonorrhoeae from their partners or active genital infection themselves. However, 57% of patients were found to have concurrent urethritis on testing. Bilateral eye involvement was noted in 38%, with visual acuity of 20/40 in more than 50% at initial presentation. In nearly all patients, the degree of conjunctivitis on presentation was severe, with copious purulent drainage; only one patient presented with a mild conjunctivitis. Three patients also had superficial ulceration and two had perforating ulcerative keratitis on presentation. After antibiotic therapy, more than 90% of the involved eyes had a visual acuity of 20/50 or better. No patients progressed to ulcerative keratitis after therapy was initiated. The two individuals who presented with perforating ulcerative keratitis did poorly and remained with only light perception acuity after antibiotics and keratoplasty.

DIAGNOSIS

Clinical signs and symptoms

Adult gonococcal conjunctivitis

AGC is characterized by profuse purulent discharge, severe conjunctival injection and marked edema and hyperemia of the eyelids. Early in the course, AGC is limited to the mucosal surfaces. Rare cases of asymptomatic AGC have been described, but the prevalence of asymptomatic or minimally symptomatic gonococcal conjunctival infection is unknown. Some cases may be complicated by extension to the corneal epithelium, leading to varying degrees of chemosis and stromal or epithelial keratitis. The degree of corneal involvement varies considerably, but when it does occur findings commonly include subepithelial or stromal infiltrates and marginal corneal melt. N. gonorrhoeae is one of the few organisms that can penetrate intact corneal epithelium. If treatment is delayed, there may be rapid progression to ulcerative keratitis and perforation. This observation of a potentially fulminant course led the Centers for Disease Control and Prevention (CDC) in 1986 to recommend immediate hospitalization and intravenous antibiotics for 5 days. This approach has since been liberalized, but the potential for fulminant disease remains well recognized and is an important aspect of management.

Gonoccocal ophthalmia neonatorum

The clinical presentation of GON is similar to that of the AGC, as described, with copious purulent conjunctival discharge, hyperemia and edema. GON is considered a medical emergency because untreated cases commonly progress rapidly to corneal penetration and perforation of the globe, at times within 24 hours. Other localized manifestations of N. gonorrhoeae infection also may occur, including anorectal disease and rhinitis. Disseminated gonococcal infection can occur with neonatal infectious arthritis and meningitis. Neonates may acquire N. gonorrhoeae in utero if an infected mother develops premature rupture of membranes. This may result in a syndrome characterized by chorioamnionitis, meningitis, septicemia and pneumonia; N. gonorrhoeae can be recovered from orogastric aspirates of the neonate. Infants delivered by cesarean section

also have been reported to have GON from in utero infection.

Differential diagnosis

The differential diagnosis of ophthalmia neonatorum is wide and includes chemical conjunctivitis, bacterial infection (Moraxella catarrhalis, Staphylococcus aureus, Haemophilus spp., Streptococcus pneumoniae, Pseudomonas aeruginosa, enterococci and N. gonorrhoeae), Chlamydia trachomatis and herpes simplex virus. In the late 1800s, N. gonorrhoeae was the major cause of ophthalmia neonatorum, occurring in 10% of children in Europe with GON.

Laboratory findings

The diagnosis of gonococcal ocular disease should be suspected in all newborns who present several days after delivery with conjunctivitis, particularly if any of the following risk factors are present:

●The mother lacked routine prenatal care.

●The mother has a history of sexually transmitted disease or substance abuse.

●The infant did not receive ophthalmia prophylaxis.

Definitive diagnosis of GON cannot be made on clinical grounds alone and requires laboratory confirmation. Evaluation for other causes of ophthalmia neonatorum is imperative, particularly detection of C. trachomatis. Chlamydia ophthalmia can be diagnosed by both specific tissue culture tests and nonculture tests such as immunoassays, nucleic acid amplification tests and direct fluorescent antibody tests. Gonococcal ocular disease in the adult is much more difficult to recognize because of its rare occurrence. The findings of copious purulent conjunctivitis with or without corneal involvement should suggest the diagnosis; a positive history of current urethral or urinary symptoms in the patient (or partner) is very helpful, but its absence does not exclude N. gonorrhoeae infection.

A Gram’s stain smear is essential for the rapid diagnosis of N. gonorrhoeae. A ‘positive’ Gram’s stain is defined by the finding of typical gram-negative diplococci within polymorphonuclear leukocytes in conjunctival exudates. Many clinicians consider a positive Gram’s stain in the appropriate clinical setting to be compelling evidence for the presence of N. gonorrhoeae, even if a subsequent culture is negative. A Gram’s stain is considered ‘negative’ if no organisms are seen on oil immersion field, even in the presence of many neutrophils. An ‘equivocal’ Gram’s stain is characterized by (1) typical gram-negative diplococci that are found on the smear but are not cell associated or (2) atypical organisms that are neutrophil associated. The sensitivity of the Gram’s stain for detecting N. gonorrhoeae varies depending on the anatomic site, with a sensitivity of 95% to 100% from the male urethra (symptomatic) to 40% to 50% from the rectum. Limited data are available concerning the sensitivity of the Gram’s stain in gonococcal ocular disease, but it probably is high (more than 90% in one study). The specificity also is likely to be high, but occasionally Neisseria spp. other than N. gonorrhoeae can be detected. A positive or equivocal Gram’s stain of conjunctival exudate from a newborn is sufficient laboratory evidence to begin appropriate therapy. Treatment may be initiated in the newborn with conjunctivitis and a negative Gram’s stain if there is a high index of suspicion for gonococcal ocular disease based on the risk factors cited.

The definitive diagnosis of N. gonorrhoeae infection rests on laboratory confirmation of the organism. Isolation of the gonococcus in culture remains the gold standard and specimens

Disease Ocular Gonococcal • 16 CHAPTER

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should routinely be submitted for culture and antimicrobial susceptibility testing. Newer methods for the diagnosis of N. gonorrhoeae are increasingly popular and include nucleic acid probe technology and nucleic acid amplification techniques such as polymerase chain reaction (PCR). N. gonorrhoeae is a fastidious organism and requires specific culture techniques. Optimal isolation in culture requires a selective medium such as a chocolate agar, which contains antibiotics and incubation in 5% CO2. Several such media are effective, including Thayer–Martin medium (chocolate agar with vancomycin, colistin and nystatin), modified Thayer–Martin medium (trimethoprim, vancomycin, colistin and nystatin) and Martin– Lewis medium. Ideally, specimens should be inoculated onto appropriate chocolate agar as soon as possible because the organisms do not survive drying. Plates can be held at room temperature in candle extinction jars for several hours before incubation in CO2 at 35º to 37ºC. With proper collection and handling, growth of the organism can be seen within 24 to 48 hours. Alternatively, several commercially available transport systems can be used in settings in which immediate inoculation of media is not feasible. These systems preserve the viability of most of the organisms for a short period of time before plating onto selective media; if such a system is used, the specimen should be transported promptly to the laboratory.

In some laboratories, nonculture techniques such as PCR, probes and enzyme immunoassays are being used routinely for the detection of N. gonorrhoeae from genital sites. The relative merits of these newer assays compared with traditional culture techniques are matters of some debate, particularly for nongenital specimens. These assays have not been formally studied (or approved) for the detection of N. gonorrhoeae from conjunctival exudates or scrapings and are not legally acceptable in suspected cases of child abuse. The optimal management of gonococcal eye infections requires isolation of the organism in traditional culture.

TREATMENT

The treatment of AGC has evolved due to the emergence of strains that are resistant to penicillin by plasmid-mediated β- lactamase production, along with strains resistant to tetracyclines and some cephalosporins. Penicillinase-producing and non-penicillinase-producing strains of N. gonorrhoeae can cause AGC. Ceftriaxone is a parenteral third-generation cephaloporin recommended for the first-line treatment of more common manifestations of gonococcal infection, such as genital infection, pharyngitis and anorectal infection. This agent has the longest half-life of all of the available cephalosporins and is chemically stable in the presence of the β-lactamases produced by N. gonorrhoeae. The prolonged half-life results in sustained bactericidal levels of drug in the conjunctival sac.

ADULT GONOCOCCAL CONJUNCTIVITIS

Only a limited number of studies have examined the efficacy of ceftriaxone in AGC. In the largest series reported, 12 adults with culture-proved gonococcal conjunctivitis were treated in an unblinded fashion with 1 g of ceftriaxone IM along with a single ocular saline lavage. The mean patient age was 26 years old. Symptoms consistent with urethritis were present in 69%. Corneal epithelial erosions were present on initial examination in 31%, but none had infiltration of the corneal stroma. All

patients responded clinically with a significant decrease in the ocular discharge within 12 hours. There also was evidence of rapid microbiologic resolution, with all conjunctival scrapings taken at 6 hours negative in culture for N. gonorrhoeae.

Based on this and other studies, the CDC in 2002 recommended that uncomplicated AGC should be treated with 1 g ceftriaxone IM in a single dose, with a single lavage of the infected eye with a saline solution. There are no consensus recommendations for individuals with more serious corneal ulcerations; such patients should be hospitalized immediately and treated with extended courses of ceftriaxone on an individual basis.

Limited data are available regarding the use of fluoroquinolones in the treatment of AGC. In one study, oral norfloxacin was administered to 15 patients with culture-proved gonococcal conjunctivitis. Seven patients received 1200 mg norfloxacin PO for 3 days and eight patients received a single dose of 1200 mg. There was no progression of the corneal lesions during treatment and no significant toxicity was reported. Although quinolones are first-line agents for uncomplicated gonococcal infections of the urethra, cervix, rectum and pharynx, the CDC has not recommended the use of fluoroquinolones in AGC (as of 2005). In addition, there has been an increase of fluoroquinolones-resistant N. gonorrhoeae in Southeast Asia, areas in the Pacific, Hawaii, California; this has led the CDC in 2002 to advise against empiric quinolone use for the empiric treatment of genital N. gonorrhoeae in these areas. In 2004 a similar recommendation was made by the CDC to avoid the empiric treatment of genital gonorrhea infection with quinolones in men who have sex with men because of an increase in quinolone-resistant N. gonorrhoeae in this group in the US.

In 2003, the World Health Organization (WHO) recommended the following as first-line regimens for AGC:

●Ceftriaxone, 125 mg IM, as a single dose; or

●Spectinomycin, 2 g IM, as a single dose; or

●Ciprofloxacin, 500 mg PO, as a single dose.

In areas of the world where these antimicrobials are not available, an alternative regimen is kanamycin 2 g IM, as a single dose. The WHO also noted that these regimens were likely to be effective, although there was no specific published data to support their use in AGC.

Adults with gonococcal conjunctivitis require examination and testing for other sexually transmitted diseases, particularly Chlamydia trachomatis. Available studies suggest a significant coinfection rate with syphilis and a nontreponemal serologic test for syphilis should be considered, such as the rapid plasma reagin (RPR). Patients with AGC should also be told to refer their sex partner or partners for evaluation and treatment. There are no published series of gonococcal conjunctivitis in persons infected with human immunodeficiency virus (HIV). The CDC has recommended that HIV-infected persons with gonococcal infections of the cervix, urethra, rectum and pharynx be treated with the same regimens used for those who are negative for HIV. Individuals with AGC of unknown HIV status should be offered HIV testing.

PEDIATRIC AND ADOLESCENT GONOCOCCAL OCULAR DISEASE

There are no published studies regarding the optimal treatment regimen in this age group. Gonococcal infections in children

involving more common sites such as the urethra, pharynx and rectum are treated with the same regimen recommended for adults (1 g ceftriaxone IM as a single dose) if the child weighs more than 45 kg or 125 mg ceftriaxone IM as a single dose if the child weighs less than 45 kg. This regimen should be adequate for uncomplicated ocular disease as well. Quinolones (ciprofloxacin, ofloxacin, levofloxacin and others) have previously been avoided in children based on toxicity data to articular damage in animal studies. In 2002, the CDC noted that there was no data showing this articular damage occurred in children; treatment of gonococcal infections in children <18 years of age could also include the flurorquinolones. Because of the implications of gonococcal infection in children, referral should be made to experts who have experience and training in the evaluation of sexual assault or abuse.

GONOCOCCAL OPHTHALMIA

NEONATORUM

Optimal therapy for GON has similarly changed due to the increasing incidence of β-lactamase-producing gonococci. Previous recommendations by the CDC supported the use of aqueous crystalline penicillin G parenterally for non-β-lac- tamase-producing strains. However, penicillin has since been abandoned as first-line therapy for GON, given the prevalence of penicillinase-producing N. gonorrhoeae of more than 60% in some areas and the widespread development of chromosomally mediated resistance to penicillin in many strains of N. gonorrhoeae that do not produce β-lactamase. In a randomized clinical trial, 105 newborns in Kenya with GON were randomized to one of three regimens:

●A single dose of 125 mg ceftriaxone IM;

●A single dose of 75 mg kanamycin IM and 1% gentamicin ointment instilled in the eye q.i.d. for 7 days;

●A single dose of 75 mg kanamycin IM plus 1% tetracycline ointment in the eyes q.i.d. for 7 days.

All newborns who received ceftriaxone were clinically and microbiologically cured. One of 26 neonates receiving the kanamycin plus tetracycline ointment had persistent conjunctivitis and 2 of 24 neonates receiving kanamycin and gentamicin ointment were treatment failures. Ceftriaxone also was effective in eradicating extraocular N. gonorrhoeae.

In 2002, the CDC recommended GON treatment of 25 to 50 mg/kg ceftriaxone IV or IM in a single dose, not to exceed 125 mg. Topical therapy alone is not recommended and is considered unnecessary if systemic therapy is used. The World Health Organization also recommends ceftriaxone as the agent of choice; in areas of the world where ceftriaxone is not available alternatives include kanamycin 25 mg/kg IM as a single dose, to a maximum of 75 mg, or spectinomycin 25 mg/kgy IM as a single dose to a maximum of 75 mg. Ceftriaxone should be used with caution in infants with hyperbilirubinemia, especially those born prematurely, due to the liver metabolism of ceftriaxone. The CDC recommends hospitalization for infants with GON and careful observation for signs of disseminated infection such as meningitis and pneumonia. A single dose of ceftriaxone is likely curative for GON, although some clinicians prefer to continue daily dosing until cultures are negative at 2 to 3 days.

Treatment failures with ceftriaxone may be due to simultaneous infection with C. trachomatis, which is intrinsically resistant to cephalosporins. It is important to test initially for

C. trachomatis at the same time as for N. gonorrhoeae because the former is more common and the clinical presentations may be indistinguishable. Both culture and nonculture tests are available for the diagnosis of C. trachomatis; nonculture tests include direct fluorescent antibodies, enzyme immunoassays and nucleic acid amplification tests. For testing of C. trachomatis, the specimen should contain conjunctival cells and not only exudates. Ophthalmia neonatorum caused by C. trachomatis should be treated with 50 mg/kg/day erythromycin base or ethylsuccinate orally divided into four doses daily for 14 days.

The mothers of infants with GON should be tested for other sexually transmitted diseases and treated with standard regimens for gonococcal infections in the adult; current recommendations for uncomplicated infections of the cervix, urethra and rectum include one of the following:

● Cefixime 400 mg PO in a single dose (limited availability);

●Ceftriaxone 125 mg IM in a single dose;

●Ciprofloxacin 500 mg PO in a single dose;

●Ofloxacin 400 mg PO in a single dose.

Each of the regimens should include simultaneous treatment for C. trachomatis such as 1 g azithromycin PO in a single dose or 100 mg doxycycline PO b.i.d. for 7 days. The sex partners of mothers of infants with GON should be referred for evaluation.

OPHTHALMIA NEONATORUM PROPHYLAXIS

The prevention of ophthalmia neonatorum is best accomplished by good prenatal care in pregnant women, with active screening for gonococcal and chlamydial infections. However, prenatal care may be insufficient or unavailable to some. The instillation of a prophylactic ointment or solution into the eyes of all newborns to prevent gonococcal ophthalmia is a law in most states in the United States. Historically, Credá, as reported in 1881, demonstrated that a 2% silver nitrate solution applied topically rapidly reduced the incidence of GON infection. Silver nitrate administration, however, is associated with chemical conjunctivitis and gives incomplete protection against Chlamydia. This has led to recommended prophylaxis to also include 0.5% erythromycin or 1% tetracycline ophthalmic ointment administered in a single application. In a prospective study, all threetopical silver nitrate solution and erythromycin and tetracycline ointments were found to be equivalent in preventing GON. Nevertheless, with increasing resistance to both tetracycline and erythromycin, alternative prophylaxis has been explored. Povidone-iodine is a potent antiseptic and in a 5% solution, a single drop applied is well tolerated by the external eye. Povi- done-iodine in vitro has shown efficacy against N. gonorrhoeae as well as herpes simplex and C. trachomatis. In a controlled trial of prophylaxis against ophthalmia neonatorum, a 2.5% povidone-iodine solution was equally effective against gonococcal conjunctivitis as silver nitrate and erythromycin and more effective against Chlamydia than either of the two. However, the CDC does not recommend the routine use of povidoneiodine for ophthalmia prophylaxis until further information is available.

The regimens recommended in 2002 by the CDC are as follows:

●Silver nitrate 1% aqueous solution in a single application;

●Erythromycin 0.5% ophthalmic ointment in a single application;

Disease Ocular Gonococcal • 16 CHAPTER

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Simplex Herpes • 18 CHAPTER

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Clinical signs and symptoms

Ocular

Primary herpes infection of the eye is typically a unilateral blepharoconjunctivitis, characterized by:

●Vesicles on the skin of the eyelids;

●Follicular conjunctivitis, hyperemia;

●Preauricular adenopathy;

●Punctate keratitis (occasionally).

After primary infection, recurrent disease is usually in the form of a dendritic ulceration of the cornea.

However, epithelial ulceration can occasionally assume an amoebic or a geographic form. This more severe form of epithelial herpetic keratitis frequently appears in patients who are immunocompromised by the long-term use of topical corticosteroid preparations or by conditions such as infection with human immunodeficiency virus.

Between 10% and 20% of patients with herpetic corneal ulceration subsequently develop stromal inflammation, stromal scarring, or both.

The stromal involvement may be necrotizing, often associated with deep vascularization.

The stromal involvement may be non-necrotizing (most commonly disciform in configuration) due to severe endothelial disease and associated stromal edema.

The stromal patterns of involvement are associated with uveitis, iris atrophy and corneal hypesthesia.

Other manifestations and complications of ocular herpes simplex infection can include cataract, hypopyon, descemetocele, scleritis and occlusion of the nasolacrimal canaliculi.

Indolent (metaherpetic) ulceration occurs when healing of the epithelium is compromised by the underlying stromal inflammation, or it can be secondary to medication toxicity.

Laboratory findings

Laboratory diagnosis is made with viral cultures, immunohistochemistry, or polymerase chain reaction.

TREATMENT

Since most cases of HSV epithelial keratitis resolve spontaneously within 3 weeks, the rationale for treatment is to minimize stromal damage and scarring.

Local

Although primary ocular herpes is self-limited, treatment is recommended to limit corneal involvement. Treatment options include one of the following:

●Trifluridine 1.0% drops nine times daily for 10 days;

●Vidarabine 3.0% ointment five times daily for 10 days;

●Aciclovir 2 g/day PO for 10 days.

Oral aciclovir is the preferred treatment in patients who have good renal function and are unable to tolerate the topical medications. A cycloplegic agent may be added for relief from ciliary spasm.

Recurrent herpetic dendritic or geographic epithelial keratitis usually resolves spontaneously in 3 to 4 weeks if left untreated. However, treatment is recommended to reduce corneal damage from both the infection and the immune response to the infection.

Recommended treatment includes a combination of debridement and antiviral therapy with trifluridine, vidarabine, idoxuridine, or aciclovir.

Debridement is performed after the instillation of a topical anesthetic agent (4.0% cocaine or 0.5% proparacaine) into the conjunctival sac. The loose epithelium at the edges of the dendritic figure is wiped away with sterile cotton-tipped applicators or with the edge of a knife blade or platinum spatula.

Antiviral medications to be used after corneal debridement can be trifluorothymidine (trifluridine), idoxuridine, or vidarabine. Trifluridine, a pyrimidine analog, is the drug of choice in the United States for topical ophthalmic antiviral therapy. Although similar in structure to idoxuridine, it is twice as potent, and because of its biphasic solubility, it is 10-fold more soluble and so can achieve therapeutic intraocular concentrations. It is also considered more efficacious than vidarabine in the treatment of geographic ulcers. Of the three antiviral agents, trifluridine is the least vulnerable to resistant viral strains; there is no cross-allergenicity among trifluridine, idoxuridine, and vidarabine.

For recurrent herpetic episodes, the following are recommended doses:

●Trifluridine 1.0% drops nine times daily for 10 days and then tapered;

●Idoxuridine 1.0% drops once every waking hour and every 2 hours at night;

●Vidarabine 3.0% ointment five times daily.

Oral aciclovir is considered the treatment of choice for patients with recurrent disease in whom chronic suppression is desired or who are allergic to the available topical therapies. The recommended aciclovir dosage for active disease is 200 mg PO five times daily; for chronic suppression, as little as one 200-mg tablet every other day may be sufficient.

A study performed by the Herpetic Eye Disease Study Group showed no benefit by the addition of oral aciclovir to a regimen of topical trifluridine for the treatment of epithelial disease or for preventing the development of stromal disease or iridocyclitis.

Aciclovir is the most recent ophthalmic agent available for the treatment of herpes simplex; it is a prodrug that is activated through phosphorylation by a virus-specific thymidine kinase but only minimally activated by host cells. This gives aciclovir 3000 times greater effect against herpes simplex virus than against the host; its toxicity in the ointment form (not yet available in the United States) compares favorably with that of trifluridine, vidarabine, and idoxuridine. Aciclovir and trifluridine are equally effective in the treatment of epithelial disease.

Cidofovir (Vistide), a drug largely used against cytomegalovirus infections, may be effective in aciclovir-resistant cases.

Cimetidine has been studied recently in connection with augmentation or modification of the immunologic status of the patient with herpes as an adjunct to standard antiviral therapy. The efficacy of this combination modality has not been fully established.

In vitro studies using both fusion proteins (which block the interaction of T cells with antigen-presenting cells) and basic fibroblast growth factors have shown a beneficial effect of these as adjunctive treatments in decreasing the incidence of stromal keratitis and iridocyclitis.

Stomal herpetic keratitis occurs in 10% to 15% of patients with recurrent disease and carries the greatest visual morbidity risk. Stromal disease is believed to be a cell-mediated response to viral antigen; if the stromal involvement is accompanied by a concomitant epithelial defect, it is treated similarly to epithelial keratitis, with topical antiviral medication and a cycloplegic agent until the epithelium has healed. Both necrotizing and

non-necrotizing stromal disease without associated epithelial defect are treated with topical corticosteroids and topical or oral antiviral agents.

These agents are recommended to prevent or limit epithelial disease during the course of treatment with corticosteroids.

The strategy for topical corticosteroid therapy is frequent initial administration (every 1 to 4 hours), followed by tapering the dose to the lowest effective amount; prophylactic trifluridine is initiated and tapered at the same rate as the steroid until corticosteroid therapy is tapered down to once daily, at which time the topical antiviral is discontinued.

Elevated intraocular pressure associated with steroid use should be treated with timolol and systemic acetazolamide as necessary.

Indolent stromal ulceration is managed with antiviral and corticosteroid therapy, along with a soft contact lens to prevent corneal drying. When there is herpetic melting of the cornea, care must be taken not to abruptly stop corticosteroid therapy because doing so may result in ‘rebound’ inflammation and increase the melting process, which may proceed to perforation.

The anticollagenolytic activity of tetracycline may help to retard corneal melting when applied as a topical ointment. There also is a risk of medication-induced corneal toxicity or an anesthetic cornea when faced with chronic nonhealing epithelial defect or defects.

Supportive

Epithelial herpetic disease usually runs a short course of several days, and an initial dose of a short-acting cycloplegic, such as homatropine 5.0% is usually sufficient for ciliary spasm and pain; for stromal herpetic keratitis, uveitis, or both, the longeracting effect of atropine is preferred.

The presence of bacterial infection complicating herpetic keratitis is sufficiently uncommon to make the routine administration of antibiotics unnecessary. However, any abrupt change in the nature of the corneal lesion should arouse suspicion of a bacterial complication, and appropriate tests and treatment measures should be instituted promptly.

Surgical

If a descemetocele has formed and corneal perforation is imminent, penetrating keratoplasty must be considered; if the cornea perforates, the best management is keratoplasty, performed as expediently as possible. In such an emergency, it is possible to seal a perforated descemetocele using tissue adhesive and a bandage soft contact lens to allow reformation of the anterior chamber in preparation for definitive corneal transplantation.

Keratoplasty for corneal scarring secondary to stromal herpes simplex virus should be contemplated with caution; most corneal surgeons prefer to have the patient remain without recurrent disease for 6 to 12 months before considering the procedure.

PRECAUTIONS

A major problem related to therapy for recurrent herpetic keratitis is the difficulty in achieving a thorough and precise debridement that does not damage Bowman’s layer. Some forms of debridement are particularly injurious; the use of sharp instruments, cryotherapy, or strong chemicals such as phenol or iodine should be avoided because they are unnecessarily damaging. Adequate debridement usually can be achieved by

brushing the epithelial lesion or lesions with a cotton-tipped applicator, a technique that is both convenient and effective in that epithelial healing is rapid (usually within 24 hours) with an early resolution of the patient’s pain and discomfort. Any tendency for recurrent lesions to form in the early period after healing can be overcome by using a topical antiviral agent for 7 to 10 days after debridement.

Topical corticosteroids are effective in suppressing the inflammatory response of herpetic keratitis; however, their inappropriate use may result in severe epithelial disease or stromal necrosis, an increased tendency toward recurrence, elevation of intraocular pressure, and the possibility of cataract formation. Patients requiring topical corticosteroids for suppression of the inflammatory response usually must use the drug for a period of months, and withdrawal often is complicated by recurrence of inflammation. The immunosuppressive complications of steroid administration can largely be avoided by the concurrent use of antiviral therapy. Patient cooperation is a prerequisite for the safe administration of corticosteroids in herpetic keratitis.

There also exists a fine balance between the beneficial antiinflammatory action of steroids in the battle of host versus virus and the toxicity of the antiviral compounds. All topical antiviral medications available for clinical use in the United States are toxic to a degree; the signs of toxicity are similar for all such drugs. Punctate epithelial keratopathy, limbal follicles, a follicular conjunctival response, ptosis, punctal stenosis, and contact dermatitis may occur at any time after 10 to 14 days of antiviral therapy. In mild cases of antiviral toxicity, epithelial changes may be the only manifestation. Idoxuridine is the most toxic topical antiviral agent in clinical use, whereas vidarabine and trifluridine seem to be less toxic; topical aciclovir is not yet available in the United States. Oral aciclovir should be used with caution in patients who have renal disease.

COMMENTS

The major difficulties in treating herpetic keratitis are related to the tendency for recurrence and the management of stromal disease. Several mechanisms seem to be responsible for the recurrences. In its latent form, herpes simplex virus can be asymptomatically present in the cells of the cornea and in the central connections of the trigeminal nerve, particularly in the trigeminal ganglion. Disturbance of the nerve results in reactivation of the virus and its subsequent passage centrifugally along the nerve, with shedding from the nerve endings. Lesions tend to occur when the balance between latency and host defenses is disturbed, such as during febrile illness, during menses, or on exposure to sunlight.

The toxic potential of antiviral agents should always be considered in patients who heal poorly because these agents are inhibitors of cell division. Although continuous ocular drug delivery systems are currently under investigation, the limitations of such systems in preventing recurrences are related to the unacceptable toxicity from the chronic use of presently available topical medications.

REFERENCES

Chong EM, Wilhelmus KR, Matoba AY: Herpes simplex virus keratitis in children. Am J Ophthalmol 138(3):474–475, 2004.

Cohn J, Malet F, Chastel C: Acyclovir in herpetic anterior uveitis. Ann Ophthalmol 23:28–30, 1991.

Simplex Herpes • 18 CHAPTER

1DiseasesSECTIONInfectious •

Ekatomatis P: Herpes simplex dendritic keratitis after treatment with latanoprost for primary open angle glaucoma. Br J Ophthalmol 85(8):1008–1009, 2001.

Herbort CP, Buechi ER, Matter M: Blunt spatula debridement and trifluorothymidine in epithelial herpetic keratitis. Curr Eye Res 6:225–228, 1987.

Herpetic Eye Disease Study Group: A controlled trial of oral acyclovir for the prevention of stromal keratitis or iritis in patients with herpes simplex virus epithelial keratitis. Arch Ophthalmol 115:703–712, 1997.

Malouf DJ, Oates RK: Herpes simplex virus infections in the neonate. J Paediatr Child Health 31:332–335, 1995.

Ohashi Y, Nishida K, Yamamoto S, et al: Demonstration of herpes simplex virus DNA in idiopathic corneal endotheliopathy. Am J Ophthalmol 112:419–423, 1991.

Rong BL, Pavan-Langston D, Weng QP, et al: Detection of herpes simplex virus thymidine kinase and latency-associated transcript gene sequences in human herpetic corneas by polymerase chain reaction amplification. Invest Ophthalmol Vis Sci 32:1808–1815, 1991.

Wilhelmus KR, Dawson CR, Barron BA: Risk factors for herpes simplex virus epithelial keratitis recurring during treatment of stromal keratitis or iridocyclitis. Herpetic Eye Disease Study Group. Br J Ophthalmol 80:969–972, 1996.

19 INCLUSION CONJUNCTIVITIS 077.0

(Paratrachoma, Chlamydial

Conjunctivitis)

F. Hampton Roy, MD, FACS

Little Rock, Arkansas

ETIOLOGY/INCIDENCE

The Chlamydiae are obligate intracellular organisms derived from bacteria and comprise four species: Chlamydia trachomatis, C. psittaci, C. pneumoniae, and C. pecorum. C. trachomatis is exclusively a human pathogen and includes the agents of classic trachoma (always associated with serotypes A, B, Ba, and C) and of inclusion conjunctivitis or paratrachoma (serotypes D, E, F, G, H, I, J, and K). These organisms infect transitional epithelium of mucous surfaces. C. trachomatis also includes the agents of lymphogranuloma venereum (serotypes L1, L2, and L3), which infect epithelial cells and macrophages and are more pathogenic in human and animal models.

Serotypes D through K are sexually transmitted, and secondary eye involvement in adults occurs in about 1 of 300 genital cases. Infection of the eyes occurs by the transfer of infected genital discharges from the patients or their sexual partners on the hands or by oral-genital sexual activities. Genitally transmitted chlamydial infections are the major cause of nongonococcal urethritis in males and of cervicitis and salpingitis in females.

Infants exposed to chlamydial infection from the mothers’ cervix during birth develop chlamydial ophthalmia neonatorum at 5 to 12 days of age; of infants exposed during delivery, approximately 35% to 50% contract the disease. From 10% to 20% also develop chlamydial respiratory disease with pneumonia as late as 6 months postpartum; the infection also involves the gastrointestinal tract.

DIAGNOSIS

Clinical signs and symptoms

Patients with neonatal ophthalmia present with tearing, moderate discharge and swelling of the lids.

The eye is usually hyperemic, with infiltration and swelling of the conjunctiva and lids. If untreated, chlamydial conjunctivitis in newborns may resolve spontaneously in 5 to 9 months, but it has been known to persist for years with development of chronic follicular conjunctivitis, corneal neovascularization (vascular pannus) and conjunctival scarring.

Infants with chlamydial pneumonitis may present from 6 weeks to 6 months of age with rhinitis, cough, a pertussis-like inspiratory whoop, and eosinophilia.

In adults, ocular chlamydial infection produces chronic follicular conjunctivitis with keratitis. Because this adult disease is difficult to distinguish from the clinical findings in early trachoma, the term ‘paratrachoma’ has been used to describe the entire spectrum of eye disease with genitally transmitted chlamydial infection. Ocular chlamydial disease occurs most frequently in those 15 to 30 years old. The eye disease usually has an acute onset in one eye, with:

●Watering;

●Mucopurulent discharge and sticking of lids on waking;

●Foreign body sensation;

●Swelling of the lids;

●An ipsilateral swollen preauricular node;

●Follicular conjunctivitis with hyperemia;

●Diffuse infiltration;

●Superficial keratitis, including macropunctate epithelial erosions;

●Subepithelial infiltrates (like those of epidemic keratoconjunctivitis);

●Limbal infiltration; and

●Superficial neovascularization.

Rarely, C. psittaci strains produce follicular conjunctivitis in humans exposed to the appropriate animal hosts, specifically parrots and other psittacine birds (psittacosis agent) or young cats (feline pneumonitis agent). C. pneumoniae is an important cause of pneumonia in humans and can infect the eye. Both species cause a follicular conjunctivitis similar to that of

C. trachomatis.

Laboratory findings

Laboratory procedures to identify C. trachomatis infections are necessary to confirm the diagnosis and include:

●Giemsa staining of smears;

●Isolation in cell culture (definitive method, although time intensive);

●Direct fluorescent monoclonal antibodies (DFAs) to stain smears;

●Enzyme immunoassays (EIAs);

●DNA probes;

●DNA amplification tests (including the polymerase chain reaction and ligase chain reaction); and

●Serum antibody tests (including the complement fixation and microimmunofluorescent tests but less useful than the demonstration of agent due to preexisting antibody titers).

Microscopic examination of Giemsa-stained conjunctival smears is most useful in detecting neonatal chlamydial infections because the inclusions are so numerous, but it is much