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

Clinical Uses

Topical for HSV. Acyclovir is available in Europe and Canada as a 3% ophthalmic ointment but is not commercially manufactured as a topical formulation in the United States. The most common side effects of acyclovir 3% ointment are punctate superficial keratitis, occurring in about 10% of patients, and burning or stinging on application (4%) (Table 11-11; see also Table 11-10).

Oral for HSV. The use of oral acyclovir has been extensively studied in several National Eye Institute multicenter randomized trials called the Herpetic Eye Disease Study (see Table 11-10). Prolonged oral antiviral prophylaxis is most important in patients with a history of HSV stromal disease to lessen the likelihood of recurrent episodes and progressive corneal opacification. Recurrent HSV keratitis has been reported after penetrating keratoplasty, laser in situ keratomileusis, photorefractive keratectomy, and YAG laser peripheral iridotomy. Clinical researchers suggested that prophylactic oral antiviral therapy should be considered after refractive surgery, after YAG peripheral iridotomy, and after penetrating keratoplasty in high-risk patients.

The treatment of HSV epithelial keratitis with oral acyclovir has not been studied by the Herpetic Eye Disease Study, but there is some evidence to suggest that oral acyclovir may be as effective as topical acyclovir. The clinical management of HSV in immunocompromised patients differs from that of immunocompetent patients because the immunocompromised experience more frequent and more severe infections.

Oral for Herpes Zoster Ophthalmicus (HZO). The MIC for VZV is higher than that of HSV types 1 and 2. Because higher plasma concentrations are needed to be effective against zoster, higher dosages of acyclovir are needed to effectively treat active zoster infections.Therapy for ocular zoster is similar to therapy for zoster elsewhere in the body.

Several randomized double-blind trials provided evidence that oral acyclovir 800 mg, five times daily, is the most effective dosage for treating HZO. Studies also stressed the importance of initiating treatment within the first 72 hours to prevent severe complications of HZO (i.e., keratitis, uveitis, secondary glaucoma, scleritis, optic neuritis, and acute retinal necrosis [ARN]).When there is ophthalmic involvement, it is recommended to treat even if the rash has been present for more than 72 hours. In addition, there is evidence that 7 days of treatment may be adequate. Studies have been shown that oral acyclovir may lessen the incidence and duration of postherpetic neuralgia associated with HZO, as shown in Table 11-10.

Herpes zoster is a common opportunistic infection in people with depressed immune systems. For example, zoster affects 8% to 11% of people with HIV. A retrospective cohort study of 239 HIV patients suggested that zoster infection rates have not changed in the current highly active antiretroviral therapy (HAART) era. A number

of complications can develop in the immunocompromised patient, such as persistent skin lesions, disseminated VZV, encephalitis, and ARN.ARN, which may also occur in healthy adults, is most often caused by VZV but can be caused by HSV (see Chapter 32 for the treatment of ARN). Two studies suggest that acyclovir ointment does not have a role in the treatment of herpes zoster ocular inflammation. Refer to Table 11-11 for dosage information and to Table 11-10 for study conclusions and details. Zostavax, a recently approved live attenuated vaccine, has been reported to significantly reduce the morbidity, incidence of postherpetic neuralgia, and incidence of herpes zoster in adults over 60 years of age.

Side Effects

Oral acyclovir is a remarkably safe drug. Common side effects include nausea, vomiting, diarrhea, and abdominal pains. Additional side effects include skin rash, photosensitivity, headaches, dizziness, hallucinations, lethargy, confusion, seizures, and coma. Side effects are most frequent in patients with renal impairment. Rarer complications include anemia, leukopenia, thrombocytopenia, increases in blood urea and creatinine, acute renal failure, reversible increases in bilirubin and liver enzymes, hepatitis, and jaundice. Cautious dosing and monitoring are recommended in elderly and immunocompromised patients and in patients with renal or liver disease.

Contraindications

Acyclovir is contraindicated in patients with a history of hypersensitivity or intolerance to acyclovir, valacyclovir, or any component of the formulation.

Valacyclovir

Pharmacology

Valacyclovir, a prodrug of acyclovir, is available only in oral formulation.Valacyclovir is hydrolyzed by esterases in the gastrointestinal tract and liver, converting more than 95% to acyclovir, to provide significantly greater bioavailability than oral acyclovir.

Clinical Uses

Oral valacyclovir may be an effective treatment for HSV keratitis, as shown in a small randomized trial. No large clinical trials have been done to date to study the efficacy and safety of valacyclovir in HSV keratitis. Two large prospective clinical trials of immunocompetent participants provided evidence that valacyclovir is similar to acyclovir in efficacy and safety for the treatment of genital HSV infections. There is also evidence that valacyclovir is safe and effective in suppressing recurrent genital HSV infection in HIV-infected patients. Multicenter trials evaluating oral acyclovir and oral valacyclovir for the treatment of HZO found both treatments to be similar in efficacy and safety. Valacyclovir may be effective in resolving or lessening postherpetic neuralgia and has a convenient dosing schedule.

Table 11-11

Most Commonly Used Herpes Simplex and Zoster Antiviral Drugsa

Drug Structure Clinical Indications Dosage Comments

O

H3C

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Side Effects

The side effects of valacyclovir are similar to acyclovir. Cautious dosing and monitoring are recommended in elderly and immunocompromised patients and in patients with renal or liver disease.

Contraindications

Valacyclovir is contraindicated in patients with a history of hypersensitivity or intolerance to acyclovir,valacyclovir, or any component of the formulation.

Famciclovir

Pharmacology

Famciclovir, an oral prodrug of penciclovir, is well absorbed orally and is rapidly converted to active penciclovir with a bioavailability of 65% to 77%. Penciclovir is active against HSV-1, HSV-2, and VZV with potency and spectrum of activity similar to acyclovir, in that penciclovir selectively affects viral DNA synthesis and inhibits replication. The plasma half-life of the active drug, penciclovir phosphate, is very long, which permits infrequent dosing.

Clinical Uses

No randomized controlled trials have evaluated the efficacy of famciclovir for the treatment of recurrent HSV keratitis. Randomized controlled trials have studied the efficacy and safety of famciclovir in the suppression of recurrent genital HSV infection, indicating that famciclovir is an effective and well-tolerated treatment for the suppression of genital HSV infection.

There is evidence that famciclovir is similar to acyclovir in efficacy, safety, and side effects for the treatment of HZO. In addition, famciclovir and valacyclovir are comparable in efficacy and safety when treating herpes zoster in immunocompetent patients. A large prospective study provided evidence that famciclovir therapy significantly decreases (twofold) the duration of postherpetic neuralgia when compared with a placebo.When famciclovir was compared with acyclovir in treating immunocompromised patients, the treatments showed a similar efficacy and safety profile.

Side Effects

The most common side effects are headache, nausea, and gastrointestinal disturbances. A small number of patients experienced fatigue, pruritus, paresthesia, migraine, and dysmenorrhea.

Contraindications

Famciclovir is contraindicated in patients with known hypersensitivity to the product, or its components, or penciclovir cream (Denavir®).

Topical Ganciclovir

Topical ganciclovir has also been shown to be active against HSV keratitis. Ganciclovir gel is commercially available outside of the United States as a 0.15% ophthalmic gel. Two small trials indicated that topical ganciclovir and

topical acyclovir are similar in efficacy and safety. Ganciclovir gel was reported to be more comfortable than the acyclovir ointment, with less stinging, burning, and blurred vision. Similar findings were reported by a multicenter randomized trial comparing 0.15% ganciclovir gel and 3% acyclovir ointment.

Drugs for the Treatment of CMV Infections

CMV retinitis is the most common opportunistic eye infection in patients with AIDS and immunocompromised transplant patients. Antiviral medications used in the treatment of CMV are generally administered in two stages: induction therapy, to achieve disease regression, followed by maintenance therapy. The incidence of CMV retinitis has decreased significantly with the advent of HAART for AIDS, and antiviral therapy for CMV may often be discontinued in patients who respond favorably to

HAART and achieve an elevation in CD4 cell levels above 100/μl. Refer to Chapter 32 for the drug treatment of ocular CMV infections.

Drugs for the Treatment of AIDS

HIV is an RNA retrovirus that infects CD4 lymphocytes, macrophages, and dendritic cells. Untreated HIV infection causes the progressive loss of CD4 T cells, the immune system white blood cells that protect against infection and malignancy. AIDS is diagnosed based on a low CD4 count, a high viral load, and the increased susceptibility to various infections or malignancies.

Currently, four categories of antiretroviral drugs are used in HIV therapy: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors,and fusion inhibitors. HAART is a treatment strategy combining several antiretroviral drugs (two or more nucleoside reverse transcriptase inhibitors with either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor) to more effectively suppress HIV replication. HAART lowers the likelihood of viral resistance developing, which is an increasingly common problem. In patients who respond to HAART achieving immune recovery status, CD4 counts may increase up to normal levels and viral loads may fall below detectable levels (below 200,000 Eq/ml). Over 85% of patients treated with HAART achieve CD4 counts equal to 350 cells/mcl, which will likely protect them against developing opportunistic infections. HAART has significantly decreased the incidence of opportunistic eye diseases, such as CMV retinitis, HZO, ARN, and toxoplasmosis retinochoroiditis, infections which are most likely to occur with CD4 counts less than 50 cells/mcl.

The current limiting factors for long-term success of HAART are adverse effects and patient compliance, suggesting that improving the safety profile may be an effective strategy to improve outcome. These medications have potential serious side effects such as

hepatomegaly, hepatotoxicity, nephrotoxicity, renal failure, lactic acidosis, pancreatitis, and more. The most frequent side effects for these drugs include nausea, vomiting, diarrhea, rash, anorexia, fever, arthralgias, myalgias, abdominal pains, headache, peripheral neuropathy, and elevated liver enzymes. Table 11-12 lists the current antiretroviral drugs, modes of action, dosing, and non-anti- retroviral drug interactions.

ANTIFUNGAL DRUGS

There are more than 70,000 species in the diverse group of fungal organisms, but only two basic types of fungi, yeasts and molds. Yeasts are single cells, usually round or oval in shape, with diameters varying from 3 to 15 mcm. Yeasts usually reproduce by budding. Molds have branching cylindrical tubules called hyphae, varying in diameter from 2 to 10 mcm. The hyphae may be divided into compartments by cross-walls, called septae. Molds grow by branching and apical extension. The growth of hyphae produces a multicellular filamentous mass on culture media called a mycelium. Dimorphic fungi exist in two distinct morphologic forms: a yeast phase in host tissues and a mycelial phase on culture media. It is sometimes possible to identify a specific fungus in tissue sections or in smears based on characteristic structural features.

Fungi are more complex than bacteria and viruses and are classified as eukaryotic cells, with an internal membrane system dividing the cell into different regions, membrane-enclosed organelles, and DNA contained in a membrane bound nucleus. In addition, fungi have a rigid cell wall containing polysaccharides and chitin that determines the organism’s shape. The complexity of fungal organisms, and a closer similarity to mammalian cells than to bacteria or viruses, makes it more challenging to develop antimicrobials with selective toxicity.

As with bacteria, fungal virulence factors can be divided into two main categories: virulence factors that facilitate infection and virulence factors that affect the host. Virulence factors that promote adherence to host cells and facilitate fungal invasion include capsule production to inhibit phagocytosis and cytokines to depress the host immune system. Multiple virulence factors target the host, such as cell wall polysaccharides that activate the complement cascade and provoke an inflammatory reaction or the secretion of cytokines and mycotoxins that directly damage host tissues.

Surprisingly, only a small number of fungi cause eye infections. The most common ocular fungal pathogens are the yeast Candida and the molds Aspergillus, Fusarium, and Curvularia. Fungi can infect virtually every eye structure, including the cornea, conjunctiva, lens, ciliary body, vitreous, and the entire uveal tract. Predisposing factors include contact lenses, topical steroids, trauma, and a compromised immune system. There is an increasing number of fungal infections and an

increasing diversity of infecting fungal species in immunosuppressed and immunocompromised patients. Fungal infections may be localized or disseminated, and the eye can become infected by direct inoculation or endogenous spread.

Clinical treatment should not be started without laboratory evidence of a fungal infection, because prolonged toxic therapy is often required. As with bacterial infections, patient history and clinical appearance are not diagnostic. Laboratory identification of fungi includes microscopic examination of smears or scrapings and cultures. Fungi can be identified using Gram, Giemsa, Gomori’s methenamine silver, periodic acid–Schiff, and calcofluor stains (in order of increasing sensitivity). More advanced testing is now available, including DNA sequencing for yeast and molds and polymerase chain reaction to identify molds, such as Aspergillus. Recently, the National Committee for Clinical Laboratory Standards began adapting, standardizing, and validating susceptibility testing for antifungal agents against yeasts and molds. This testing is similar to antibacterial susceptibility testing, and fungi are classified as susceptible, susceptible dose dependent, intermediate, or resistant to specific antifungals. Therefore reliable MICs are now available for some fungi and antifungal drugs. However, MICs can vary depending on the testing methods used. Clinical trials are now needed to better demonstrate the relationship between in vitro susceptibility data and the clinical response to topical antifungal medications. Case reports documented positive clinical responses despite resistance in vitro, illustrating the difficulty in choosing antifungal agents based on susceptibility results.

Antifungal treatment options usually have one or more limitations, such as significant side effects, a narrow antifungal spectrum of activity, poor tissue penetration, or fungal resistance.During the past few years,the echinocandin antifungals became available (anidulafungin, micafungin, and caspofungin). There are now four main classes of antifungals: polyenes, pyrimidines, azoles, and echinocandins. The antifungals listed for each group are only those mentioned in the chapter and are not all-inclusive.

General Pharmacology of

Antifungal Drugs

1.Polyenes (amphotericin B and lipid formulations of amphotericin B, natamycin): Polyenes work by binding to ergosterol present in the cell membranes of sensitive fungi to increase permeability. Polyenes bind human cell membranes to a lesser extent. Polyenes are concentration dependent in action, tending to be fungistatic at low concentration and fungicidal at higher concentration. Resistance is relatively rare.

2.Pyrimidines, or antimetabolites (Flucytosine): Pyrimidines block thymidine synthesis in susceptible fungi, impairing DNA synthesis.Pyrimidines are fungistatic,and resistance can develop during treatment.

Table 11-12

Antiretrovirals for HIV

Nucleoside reverse transcriptase inhibitors: NRTIs are substrates for reverse transcriptase, which converts viral RNA into proviral DNA for incorporation into the host cell DNA. NRSIs are phosphorylated by host cell enzymes to resemble normal nucleotides.When reverse transcriptase uses NRTI triphosphate instead of a nucleoside to form proviral DNA, the necessary chemical bonds cannot form and the DNA chain formed is left incomplete.

Nonnucleoside reverse transcriptase inhibitors: NNRTIs are a distinct class of synthetic compounds that interfere with reverse transcriptase activity by binding next to the enzyme’s active site, altering the configuration. NNRTIs are not phosphorylated and are only active against HIV-1, not HIV-2.

Protease inhibitors: HIV protease is essential for virus infectivity because protease is needed for viral replication. Protease inhibitors bind reversibly to the active site of HIV protease preventing protease from cleaving the viral precursor polypeptide and blocking viral maturation. Immature viral particles are noninfectious.

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3.Azoles (voriconazole, posaconazole, ketoconazole, itraconazole, fluconazole, miconazole): At concentrations obtainable with oral use, the azoles impair the biosynthesis of ergosterol in the fungal cell membrane, increasing membrane permeability and inhibiting fungal growth. Azole antifungals are not selective and can also inhibit many mammalian cytochrome P450-dependent enzymes. Therefore, drug interactions can occur between azole antifungals and medications metabolized through the P450 pathway.

Azoles are fungistatic,and resistance has been increasing among immunocompromised patients.

4.Echinocandins (caspofungin, micafungin, anidulafungin): Echinocandins target the fungal cell wall by inhibiting glucan synthesis, thus depleting glucan polymers in the fungal cell wall and causing an abnormally weak cell wall. Echinocandins are selective in action,

because there is no counterpart to a cell wall in the mammalian cell. Oral bioavailability is poor for these new fungicidal drugs.

Few randomized controlled studies have been performed for antifungal drugs because of the difficulty in recruiting a sufficient number of cases within a given time frame. Evidence-based information is scant, as 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 (Table 11-13).

Polyene Antifungal Drugs

Amphotericin B

Pharmacology

Amphotericin B is produced by a strain of bacteria, Streptomyces nodosus. Please refer to the general pharmacology section for antifungal drugs.

Clinical Uses

Amphotericin B, a broad-spectrum antifungal, has been used as a topical formulation (ointment and solution) to treat fungal keratitis and as an injectable to treat intraocular infections. In a recent case report intrastromal injections were combined with intravitreal amphotericin B in one patient to successfully treat recurrent Candida keratitis and endophthalmitis. Topical amphotericin B is not commercially available but can be obtained through a compounding pharmacy. It is the first line of treatment for Candida infections in many countries. Amphotericin B is not effective in oral formulation due to poor bioavailability. Three lipid formulations are now commercially available (Table 11-14), providing the advantage of the same in vitro spectrum of activity with less nephrotoxicity and better therapeutic indices than amphotericin B deoxycholate. Until recently, amphotericin B was the treatment of choice for invasive fungal infections of the orbit and endophthalmitis due to dimorphic fungi. Evidence has been based primarily on single case reports

because there have been no randomized controlled trials to evaluate the efficacy and safety of intravenous amphotericin B by itself (Table 11-15; see also Table 11-14).

Side Effects

Adverse reactions, particularly renal toxicity, are limiting factors in achieving an effective dose with conventional amphotericin B (see Table 11-14).

Contraindications

Amphotericin B is contraindicated if there is a known sensitivity to any formulation component.

Natamycin (Pimaricin)

Pharmacology

Please refer to the general pharmacology section for antifungal drugs.

Clinical Uses

It is currently the only U.S. Food and Drug administration– (FDA) approved topical ophthalmic for fungal infections. Natamycin is the broad spectrum well-tolerated drug of choice for filamentous fungi.Natamycin is generally effective against Fusarium, Aspergillus, Curvularia,and Acremonium, but the response is variable for some fungi.

Side Effects

Please refer to Table 11-14.

Contraindications

Natamycin is contraindicated in individuals with a history of hypersensitivity to any of its components.

Pyrimidine Antifungal Drugs

Flucytosine

Flucytosine, a fungistatic antifungal, is rarely used because resistance is a major problem among many types of fungi. Monotherapy is not effective, and flucytosine must be used in combination with another antifungal. Flucytosine shows selective activity against yeast fungi and only moderate activity against Aspergillus. It has been used successfully in oral combination with amphotericin B. Flucytosine is generally well tolerated systemically, but bone marrow and liver toxicity can occur with plasma levels above 100 mcg/ml. Dosing must be adjusted in patients with liver toxicity. It is not available as a commercially prepared topical. Topical penetration of a 1% solution is generally good. It has been used in combination with miconazole and natamycin.

Azole Antifungal Drugs

Ketoconazole

Ketoconazole was the first successful, oral, broadspectrum azole antifungal. Ketoconazole is in the imidazole

Table 11-13

Antifungal Drug Evidence-Based Guidelines

Polyene antifungals

Amphotericin B: Abelcet (ABLC) [injectable: 5 mg/ml, lipid complex],Ambisome (L-AMB) [injectable: 50 mg/vial, liposomal],Amphocin (injectable: 50 mg/vial, nonlipid),Amphotec (ABCD) [injectable: 50 mg/vial, 100 mg/vial, colloidal dispersion], Fungizone [injectable: 50 mg/vial, nonlipid], generic also available.

Azole antifungals

Itraconazole: Sporanox capsule, oral: 100 mg; solution, oral: 10 mg/ml; injectable: 10 mg/ml (generic also available)

Fluconazole: Difucan Suspension, oral: 200 mg/5 ml, 50 mg/5 ml; tablet, oral:100 mg; 150 mg; 200 mg; 50 mg

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Table 11-13

Antifungal Drug Evidence-Based Guidelines—cont’d

Echinocandin antifungals

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