Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

Table 11-14

Antifungal Drugs: Clinical Application, Side Effects, and Comments

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Continued

211

Table 11-14

Antifungal Drugs: Clinical Application, Side Effects, and Comments—cont’d

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subgroup of azole antifungals that were developed to provide an effective group of drugs with lower toxicity issues than amphotericin B. Ketoconazole, fungistatic in activity, has been largely replaced by itraconazole and other triazoles that have good broad-spectrum activity for many ocular fungi and less liver toxicity. Ketoconazole has very good activity against Candida albicans but spotty species dependent Aspergillus coverage. The response to therapy is generally slow, making this drug inappropriate for severe or progressing fungal disease. It has been used as a topical suspension in concentrations from 1% to 5% depending on the formulation. However, it is not commercially available.

Miconazole

Miconazole comes in topical (1% ophthalmic suspension), subconjunctival depot (10 mg/0.5 ml), and oral

(200–400 mg/day) formulations but is not commercially available now in any of these formulations. Miconazole is relatively broad spectrum and active against most yeast but has variable coverage of Aspergillus and Fusarium. Miconazole is generally well tolerated with topical and subconjunctival administration, but cases of corneal toxicity have been reported.

Itraconazole

Pharmacology

Please refer to the general pharmacology section for antifungal drugs.

Clinical Uses

Itraconazole is a broad-spectrum synthetic triazole that has good oral bioavailability and is less toxic than amphotericin B and ketoconazole.The solution has better bioavailability than the capsule and provides higher plasma concentration levels. Compared with fluconazole and ketoconazole, itraconazole penetrates all ocular tissues poorly when orally administered. Itraconazole can be used as a 1% ophthalmic suspension but is not very effective in treating severe fungal keratitis.

Side Effects

Itraconazole is generally well tolerated with oral administration with gastrointestinal symptoms as the most common reaction.

Contraindications

Itraconazole is contraindicated in patients who have shown hypersensitivity to the drug or its components.

214 CHAPTER 11 Anti-Infective Drugs

There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing itraconazole to patients with hypersensitivity to other azoles. Refer to Table 11-14 for drug interactions.

Fluconazole

Pharmacology

Please refer to the general pharmacology section for antifungal drugs.

Clinical Uses

Fluconazole has been used topically and in subconjunctival injection. Fluconazole, fungistatic in action, is mainly effective against yeast, including Candida and Cryptococcus, but has no clinically significant activity against molds, such as Aspergillus. Resistance has been developing, especially in immunocompromised patients.

Fluconazole has a bioavailability of about 90% with oral or intravenous administration and appears to penetrate well into the ocular fluids. Fluconazole has a relatively long half-life of approximately 30 hours. Fluconazole lacks the broad-spectrum coverage necessary to be effective against many of the most commonly encountered fungal organisms that cause endophthalmitis.

Side Effects

Fluconazole is one of the best tolerated antifungal drugs, with the most common complaint being gastrointestinal. Hepatotoxicity occurs only in a small number of patients.

Contraindications

Fluconazole is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its components. There is no information regarding crosshypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing fluconazole to patients with hypersensitivity to other azoles. Refer to Table 11-14 for drug interactions.

Voriconazole

Pharmacology

Voriconazole exhibits dose-dependent pharmacokinetics. Voriconazole has 96% oral bioavailability and reaches peak plasma concentrations in 2 to 3 hours after oral administration. Please refer to the general pharmacology section for antifungal drugs.

Clinical Uses

Voriconazole is the first of the second-generation broad-spectrum triazoles approved by the FDA and the first antifungal agent since amphotericin B to be approved for first-line treatment of invasive aspergillosis.Voriconazole has now replaced amphotericin B as the treatment of choice for systemic Aspergillus infections. Voriconazole also has activity against Fusarium. It is a derivative of

fluconazole that shows activity to some fungi resistant to fluconazole.

Side Effects

Voriconazole is well tolerated after oral or intravenous administration.

Contraindications

Voriconazole is contraindicated in patients with known hypersensitivity to voriconazole or its components. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Caution should be used when prescribing voriconazole to patients with hypersensitivity to other azoles. Refer to Table 11-14 for drug interactions.

Echinocandin Antifungal Drugs

Caspofungin

Pharmacology

Caspofungin has linear pharmacokinetics and a half-life of 9 to 11 hours, permitting once a day usage. Please refer to the general pharmacology section for antifungal drugs.

Clinical Uses

Caspofungin, the first FDA-approved echinocandin antifungal, is fungicidal in activity. Caspofungin has activity against a wide range of fungi, including all Candida species. Caspofungin shows activity against some azole-resistant organisms. An investigation showed that caspofungin and amphotericin B were synergistic or synergistic to additive for a least half of the Aspergillus and Fusarium isolates evaluated in vitro. Topical formulations are not available.

Side Effects

Very few drug interactions occur with the echinocandins, compared with the azoles. This is because echinocandins are not acted on by the major liver enzymes.

Contraindications

Caspofungin is contraindicated in patients with hypersensitivity to any component of this product.

Micafungin

Pharmacology

Please refer to the general pharmacology section for antifungal drugs.

Clinical Uses

Micafungin has activity against Candida, including azoleresistant C. albicans. It has some activity against molds such as Aspergillus but no activity against Fusarium.

Side Effects

Refer to Table 11-14 for side effects.

Contraindications

Micafungin is contraindicated in patients with hypersensitivity to any component of this product.

Anidulafungin

Anidulafungin is available as an intravenous infusion. It is fungicidal and effective against azoleand amphotericin B–resistant strains of Candida. Anidulafungin has a halflife of 24 hours and is the least protein bound of the echinocandins, at 84%. Anidulafungin does not need to be dose adjusted for hepatic or renal insufficiency and appears to not have any significant drug interactions.

ANTIPROTOZOAL DRUGS

Drugs Used to Treat Acanthamoeba Keratitis

Acanthamoeba keratitis is known to be difficult to diagnosis and to treat. Most patients are initially treated for viral, fungal, of bacterial keratitis before the diagnosis of

Acanthamoeba. Most Acanthamoeba infections are associated with contact lens wear (85% to 92%), but a smaller number are secondary to trauma. The incidence of Acanthamoeba keratitis may be greater than 1 per 30,000 contact lens wearers per year as indicated by cohort studies and questionnaires. The frequency of Acanthamoeba keratitis in contact lens wearer may be 1 per 10,000/year or higher.

Acanthamoeba are amoeba that can exist in two forms, as trophozoites or as cysts. Acanthamoeba are found in fresh water and soil, and the cystic form can be airborne. Not all strains of Acanthamoeba are pathogenic. Fifty percent of the apparently healthy adults tested had Acanthamoeba cultured from their nasal passages. Both trophozoites and cysts can adhere to the surface of unworn soft contact lenses. A break in the corneal epithelium can then allow an organism present on a contact lens to invade the eye tissues.

A retrospective review indicated that an early diagnosis (less than 18 days) results in a better final visual acuity and lessens the likelihood of needing penetrating keratoplasty. In the early stages of an infection, the trophozoite form predominates and is confined to the epithelium. As the infection progresses, the organism enters the stroma and encysts. The cystic form protects the organism from adverse conditions and is more resistant to treatment. Thus treatment failures are more frequent in advanced infections because the organism is deeper in the cornea and encysted. A biocidal agent must destroy both the trophozoite and cystic stages to be clinically effective. Although most agents are effective against trophozoites, not all agents are consistently effective against cysts.

A clinical suspicion of an Acanthamoeba infection is the critical first therapeutic step. Acanthamoeba can be diagnosed by eye smears, culture, tissue biopsy, polymerase chain reaction, and confocal microscopy.

Unfortunately, no reliable readily available methods test the sensitivity of Acanthamoeba organisms to various antimicrobials.A significant study determined a poor correlation between the clinical outcomes of individual cases and the in vitro sensitivity results. This study concluded that there was no value in a technique that gives only minimum cidal values for 90% of the organisms, when it is essential to achieve a 100% pharmaceutical kill for successful treatment. There is also no method for definitively testing whether the organism has been eradicated from the cornea, except for stopping treatment and waiting for a recurrence.

There are no drugs specifically approved by the FDA to treat Acanthamoeba, necessitating the compounding of all medications.Antimicrobial agents are generally used in combination to increase the likelihood of a successful response. Treatment is often prolonged as the mean time to healing is about 100 days. A small number of patients develop Acanthamoeba sclerokeratitis. It is not known whether this severe scleral inflammation is infective or immune mediated.

Randomized controlled studies have not been performed for Acanthamoeba treatments because of the difficulty in recruiting a sufficient number of cases within a given time frame. Evidence-based information is scant, because many of the reports have been in the form of single case reports, studies of small numbers of patients, or retrospective reviews of patient records.

Two classes of antimicrobial agents are currently used to treat most Acanthamoeba infections, biguanides and diamidines. The biguanides include polyhexamethylene biguanide (PHMB) and chlorhexidine (bis-biguanide), and the diamidines include propamidine (Brolene),hexamidine (Desomedine), and pentamidine. Published reports of the amoebicidal activities of the different agents vary, which may be due to different degrees of pathogenicity and virulence among different Acanthamoeba species or strains.

PHMB† is generally the preferred agent, either in combination or as a monotherapy. Chlorhexidine has also been used as a monotherapy, but it does not appear to be as effective as when used in combination. Propamidine is used combination with a biguanide, PHMB, or chlorhexidine, because biguanides have the lowest minimum cysticidal concentrations in vitro and are generally more effective against Acanthamoeba cysts. PHMB is also used in combination with hexamidine, because some clinicians believe hexamidine is more efficacious and less toxic than propamidine. The use of neomycin should be avoided because cysts are almost always resistant (Table 11-16).

The greatest frequency of ocular toxicity has been reported with propamidine. Superficial punctate

†PHMB has been used as a disinfectant in swimming pools and contact lens solutions.

Table 11-16

Agents used to treat Acanthamoeba

aMCC is the lowest concentration of a test solution that results in no cyst formation or growth of Acanthamoeba trophozoites after 7 days of incubation.

Drugs Infective-Anti 11 CHAPTER 216

keratopathy is common. Propamidine keratopathy was reported in two patients who presented with corneal microcysts in a pattern that followed the lacrimal lake contour.

Rarely, non-Acanthamoeba amebic keratitis may present. There is limited clinical evidence that nonacanthamoeba infections may respond to Acanthamoeba treatment. Two cases were reported of presumed non-Acanthamoeba keratitis in contact lens wearers in which the clinical presentation resembled Acanthamoeba keratitis. Nonacanthamoeba cysts (Vahlkampfia jugosa and Naegleria) were cultured from the contact lenses. One patient responded to treatment with PHMB 0.2% and propamidine 0.1% and the other patient was lost to follow-up.

Drugs Used to Treat Ocular

Toxoplasmosis

Toxoplasmosis is a recurrent, potentially blinding, disease caused by the obligate intracellular parasite Toxoplasma gondii. Toxoplasmosis affects millions of people worldwide. Cats are the definitive host for the parasite but not the primary source of human infection. Environmental contamination of the soil, water, fruits and vegetables, and infection in other animals cause most human infections. Human infection may be either congenital or acquired, and acquired disease appears to be the most prevalent.

Once ingested, Toxoplasma invades the retina where it transforms into the cyst form. Primary and recurrent toxoplasmic retinitis is believed to occur when cysts rupture, releasing trophozoites that multiply in surrounding cells to cause retinal and choroidal inflammation. Ocular toxoplasmosis is self-limiting and usually resolves in 6 to 8 weeks without treatment. However, vision may be threatened if the macula or optic nerve is involved. Antimicrobial drugs are thought to limit proliferation of trophozoites during the active phase, thereby limiting the inflammatory response and resultant retinal damage. None of the currently available drugs destroys cysts in the eye tissues, so recurrent disease is not prevented. Please refer to Chapter 31 for the treatment of toxoplasmosis.

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220 CHAPTER 11 Anti-Infective Drugs

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