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

bone growth depression and tooth discoloration, women in the last half of pregnancy, nursing mothers, and children under 8 years of age should avoid tetracyclines.

Intracranial hypertension (pseudotumor cerebri) secondary to the use of many tetracycline analogues can occur in infants and adults.When the antibiotic is discontinued,cerebral fluid pressure and any accompanying visual and ophthalmoscopic changes usually return to normal over days or weeks. Rarely, tetracycline causes blood dyscrasias such as hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia.

Vestibular toxicity appears to be unique to minocycline. Lightheadedness, loss of balance, dizziness, nausea, and tinnitus beginning 2 to 3 days after starting therapy can occur in up to 70% of patients. Although these side effects are usually reversible after discontinuing the drug, they have severely limited the use of minocycline.

Tetracyclines can interact significantly with other drugs, and these interactions should be considered when patients are taking concomitant medications. Tetracyclines can potentiate the effects of Coumadin-type anticoagulants and seriously interfere with blood clotting. They may also interfere with the bactericidal action of the penicillins after concomitant parenteral administration, and such use should be avoided. By increasing hepatic drug metabolism, carbamazepine, diphenylhydantoin, and barbiturates decrease the half-life of doxycycline by approximately 50%. Doxycycline dosages must therefore be increased to compensate for this factor or a different antibiotic selected.

Tetracycline use may be related to breast cancer. However, more research is needed to determine whether the relationship is causal.

Contraindications

Tetracyclines are contraindicated in patients with known hypersensitivity or intolerance to any member of the tetracycline family. The use of tetracyclines during tooth development can cause permanent discoloration of teeth and is thus contraindicated in pregnant or breast-feeding women and in children 8 years of age or younger.

Macrolides

The macrolide antibiotics include erythromycin, clarithromycin, and azithromycin.

Pharmacology

Macrolides inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing elongation of the peptide chain. These drugs have low toxicity because they do not bind to mammalian ribosomes.

Erythromycin is active against gram-positive cocci with the exception of enterococci. Erythromycin is also active against Mycoplasma pneumoniae, Chlamydia trachomatis, Chlamydia pneumoniae, and Borrelia burgdorferi. Clarithromycin and azithromycin have antibacterial spectra similar to that of erythromycin except that they have enhanced activity against H. influenzae.

A common mechanism of resistance to the macrolides is due to a change in the bacterial ribosomal RNA that results in poor binding of the drug to the ribosome. Resistance is developing to the macrolides among the gram-positive cocci including Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus pyogenes and Streptococcus pneumoniae, and also H. influenzae.

Erythromycin. Erythromycin is available in topical, oral, and intravenous preparations. Only the free base has biologic activity in vivo. When given orally, however, gastric acid inactivates the erythromycin base, resulting in decreased absorption.Thus a large number of formulations and derivatives have been prepared to optimize stability and absorption.When oral erythromycin preparations are administered in the correct dose and with proper timing in relation to food intake, no one type of preparation appears to offer a significant therapeutic advantage in treating mild to moderate infections.

Erythromycin estolate is usually not recommended for adults because of the increased risk of cholestatic hepatitis. In children, however, this derivative rarely causes hepatitis, and some pediatric specialists prefer this formulation because of better availability.

Erythromycin has been a widely used macrolide antibiotic because of its relative lack of toxicity and good activity against susceptible organisms. However, because resistance to erythromycin by Streptococcus pneumoniae is developing, this drug is less often used as a first-line drug for the treatment of respiratory infections such as acute sinusitis, otitis media, bacterial bronchitis, and pneumonia. However, erythromycin or another macrolide remains the substitute of choice for Streptococcus pyogenes pharyngitis and tonsillitis, for prophylaxis of endocarditis, and for recurrences of rheumatic fever when the patient is allergic to penicillin.

Staphylococcal infections of the eyelid are commonly treated with erythromycin ointment applied to the lid margins (see Table 11-1).Warm moist compresses should be applied to the lid, and then the lid margins should be gently cleaned with diluted baby shampoo or a commercial lid cleanser before applying the drug. Erythromycin ointment can be applied only at bedtime or more often as required by infection severity. For the prophylaxis of ophthalmia neonatorum, a 0.5- to 1-cm ribbon of erythromycin ointment is instilled into each conjunctival sac and not flushed from the eyes after application.

Chlamydia trachomatis infections in infants and children are primary indications for the use of oral erythromycin. This antibiotic is as effective as the tetracyclines for chlamydial infections and is safer for pregnant women,nursing mothers, and children under 8 years of age.

Erythromycin is also an effective alternative to tetracycline for the treatment of adult chlamydial sexually transmitted disease. Adults should receive 2 g of erythromycin daily in four divided doses for at least 7 days. Trachoma and inclusion conjunctivitis in older children or adults

192 CHAPTER 11 Anti-Infective Drugs

can also be effectively treated with oral erythromycin by using a 3-week course of 2 g daily in four divided doses. Patients receiving full oral therapeutic doses of antibiotic do not need topical antimicrobial treatment with ophthalmic erythromycin ointment.

Clarithromycin. Clarithromycin, a more recently developed macrolide antibiotic, is a 6-O-methyl derivative of erythromycin. It is stable in gastric acid and is well absorbed. Because the half-life of clarithromycin is approximately twice that of erythromycin, patients take clarithromycin only twice daily compared with four times a day for erythromycin.

Clarithromycin is indicated for the treatment of mild to moderate upper and lower respiratory tract infections as well as skin infections caused by susceptible strains of Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, H. influenzae, Legionella pneumophila, and Mycoplasma pneumoniae. The usual dosage is 250 to 500 mg twice a day for 7 to 14 days.

Azithromycin. Azithromycin is another recently developed macrolide antibiotic. After oral administration on an empty stomach, azithromycin is rapidly absorbed and widely distributed throughout the body. Because azithromycin has an extended half-life, once-daily dosing is effective and encourages patient compliance.

Azithromycin is indicated for mild to moderate infections of the respiratory tract and skin caused by susceptible strains of Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, H. influenzae, and

Moraxella catarrhalis. Treatment of pneumonia, tonsillitis, and skin infections is two 250-mg tablets as a single dose on the first day followed by 250 mg once daily on days 2 through 5 (a “Z-Pak” is five 250-mg tablets packaged to encourage compliance with this treatment regimen). Treatment of bacterial exacerbation of chronic obstructive pulmonary disease and sinusitis is 500 mg once daily for 3 days. These infections can also be treated with a single 2-g dose of Zmax (azithromycin extended release).

A single 1-g dose of azithromycin is a recommended treatment for chlamydial urethritis and cervicitis. Similarly, a single 1-g dose is effective for the treatment of chlamydial conjunctivitis and trachoma in adolescents and adults, whereas a single oral dose of 20 mg/kg can be used for treatment in children.

Side Effects

Gastrointestinal irritation, including abdominal cramps, nausea, vomiting, and diarrhea, is the most common adverse event produced by erythromycin and is usually associated with oral administration. Irritation is dose related and more common with daily doses of 2 g or more. Some brands of enteric-coated tablets and the ester derivatives (e.g., ethylsuccinate) can be taken with food to minimize these adverse effects.

Like erythromycin, the most common side effects of azithromycin and clarithromycin are gastrointestinal, with diarrhea, nausea, and abdominal pain being the most frequently reported. Clarithromycin can also cause headache and dyspepsia.Other side effects of azithromycin include palpitations, vaginitis, headache, dizziness, fatigue, and hypersensitivity reactions.

The most serious toxicity of erythromycin involves cholestatic hepatitis, which occurs mainly in adults and only when the estolate preparation of erythromycin is used. Mild allergic reactions such as urticaria and other rashes, fever, and eosinophilia have occurred occasionally after erythromycin use. Sensorineural hearing loss,although extremely rare, has been reported after the use of large doses of erythromycin or the use of erythromycin in the presence of renal failure.The hearing loss usually improves gradually on discontinuation of the drug. Concurrent use of macrolides and theophylline has been associated with increases in the serum concentrations of theophylline.

Macrolide use may be related to breast cancer. However, more research is needed to determine whether the relationship is causal.

Contraindications

Macrolide antibiotics are contraindicated in patients with known hypersensitivity or intolerance to any macrolide. Because clarithromycin can have adverse effects on embryo–fetal development in animals, this drug should be avoided in pregnant women unless no other therapy is appropriate. Concurrent administration of the macrolides and astemizole or terfenadine can cause elevated antihistamine levels,resulting in life-threatening cardiac arrhythmias, and should be avoided.

Chloramphenicol

Pharmacology

Chloramphenicol inhibits protein synthesis by binding to the 50S subunit of the bacterial ribosome and blocking aminoacyl-tRNA binding.

Clinical Uses

Chloramphenicol is active against most gram-positive and gram-negative bacteria, Rickettsia, Chlamydia, spirochetes, and Mycoplasma; however P. aeruginosa is resistant to this drug. Despite its broad antibacterial spectrum, generally good tolerance by patients, and desirable pharmacokinetic characteristics, chloramphenicol’s ability to cause fatal aplastic anemia limits its usefulness. Indications for chloramphenicol include severe or lifethreatening infections caused by susceptible organisms that are not responsive to less toxic drugs.

Topical application of chloramphenicol solution or ointment is effective against most bacterial infections of the external eye. However, because aplastic anemia has also occurred after topical ocular use of chloramphenicol, its use must be limited to infections for which less toxic antibiotics prove ineffective.

Side Effects

Chloramphenicol causes two types of hematopoietic abnormality. The first is a dose-related toxic effect causing a bone marrow depression associated with inhibition of mitochondrial protein synthesis. Usually, discontinuing the antibiotic reverses this toxicity.

A second, more serious, type of bone marrow depression consists of aplastic anemia. Considered an idiosyncratic reaction rather than a toxic reaction, aplastic anemia occurs most commonly weeks to months after completion of therapy and is not dose related. In the most severe form of aplastic anemia, pancytopenia with an aplastic marrow is present. Prognosis is very poor because the anemia is usually irreversible.

Contraindications

Because serious and fatal blood dyscrasias can occur after the administration of chloramphenicol, it should be used only in serious infections for which less potentially dangerous drugs are ineffective or contraindicated. Chloramphenicol is contraindicated in patients with known hypersensitivity or intolerance to this drug, who have blood cell or bone marrow disorders, or who are undergoing dialysis and have other complications such as cirrhosis.

Drugs Affecting Folate Metabolism

Antibacterial drugs that affect the folate (folic acid) metabolism of bacteria include sulfonamides, pyrimethamine, and trimethoprim.

Sulfonamides, Pyrimethamine, and Trimethoprim

Pharmacology

Sulfonamides were the first group of chemotherapeutic agents used for the prevention or treatment of bacterial infections in humans. Sulfonamides (e.g., sulfisoxazole) act by inhibiting bacterial synthesis of folic acid,a chemical required for synthesis of nucleic acid and protein. These drugs competitively inhibit the first step in the synthesis of folic acid—the conversion of para-aminobenzoic acid into dihydrofolic acid. Because humans absorb preformed folic acid from food, sulfonamide inhibition has only a minimal effect on human cells.

Pyrimethamine and trimethoprim reversibly inhibit the second step in the synthesis of folic acid by inhibiting the enzyme dihydrofolate reductase, which catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid. The trimethoprim-binding affinity is much stronger for the bacterial enzyme than the corresponding mammalian enzyme, which produces selective toxicity. A powerful synergism exists between either pyrimethamine or trimethoprim and sulfonamides (e.g., sulfamethoxazole and trimethoprim) because of sequential blockage of the same biosynthetic pathway.

Acquired resistance to sulfonamides is widespread. Mechanisms of resistance include overproduction of

para-aminobenzoic acid by the bacteria, decreased enzyme affinity for the sulfonamide, decreased bacterial permeability to the drug, and increased inactivation of the drug by bacteria. Bacteria resistant to one sulfonamide are commonly resistant to all of them.

Clinical Uses

Sulfamethoxazole in combination with trimethoprim is an effective and inexpensive treatment for acute uncomplicated urinary tract infection. This combination is also useful for treatment of Pneumocystis carinii pneumonitis in immunologically impaired patients.

Pyrimethamine is used for prophylaxis and treatment of malaria. An ocular use of pyrimethamine is in the treatment the protozoan disease toxoplasmic retinochoroiditis. In this disease recurrent necrotizing lesions in the retina/choroid result from the active multiplication of previously encysted Toxoplasma gondii. The classic use of pyrimethamine along with sulfadiazine appears to be effective for the treatment of the active form of this disease. The synergism of the combined drugs greatly enhances the therapeutic effect. Topical ophthalmic preparations of sulfonamides include sulfacetamide and sulfisoxazole and sulfacetamide in combination with the steroids prednisolone acetate, prednisolone phosphate, and fluorometholone alcohol.

These antibacterial drugs have been used extensively in the past for the treatment of blepharitis and conjunctivitis. However, they are rarely used today because of widespread bacterial resistance and the availability of more effective antibacterial drugs.

A combination of trimethoprim and polymyxin B is available as a topical ophthalmic solution and ointment (see Table 11-6). Trimethoprim has significant in vitro activity against gram-positive and gram-negative organisms, including staphylococci, streptococci, Haemophilus, and gramnegative enterics. However, because it is not active against Pseudomonas, polymyxin B is included in the combination to cover gram-negative bacteria, including Pseudomonas.

Trimethoprim–polymyxin B is effective for the treatment of blepharitis, conjunctivitis, and blepharoconjunctivitis. Side effects are very rare. Because it is clinically effective against H. influenzae and Streptococcus pneumoniae, which are the most common causes of bacterial pediatric eye infections, it is a drug of choice for treating eye infections in children.

Side Effects

The sulfonamides can produce a wide variety of side effects, and an adverse reaction to one sulfonamide frequently precludes the use of other sulfonamide derivatives. The most common adverse effects are gastrointestinal disturbances, including anorexia, nausea, vomiting, and diarrhea.

Allergic skin reactions such as rash and urticaria and the more severe Stevens-Johnson syndrome can occur. Skin reactions have an increased incidence when the

194 CHAPTER 11 Anti-Infective Drugs

sulfamethoxazole–trimethoprim combination is used as compared with use of a sulfonamide alone.

Oral use of sulfonamides, pyrimethamine, and trimethoprim can cause blood dyscrasias such as hemolytic anemia, aplastic anemia, leukopenia, and agranulocytosis. Because these blood changes are due to a drug-induced folic acid deficiency, administering folinic (not folic) acid can counteract the toxicity. Use of folinic acid bypasses the need for dihydrofolate reductase by supplying the fully reduced folate.

Myopia, with or without induced astigmatism, has been reported in patients taking systemic sulfonamides. The refractive state usually returns to normal when the serum drug level decreases.

The most frequently reported reactions to topically applied sulfonamides are local irritation, stinging, and burning. Contact dermatitis is common with topical application of these drugs, and they can cause more serious dermatologic problems such as erythema nodosum, erythema multiforme (Stevens-Johnson syndrome), and exfoliative dermatitis. In addition to hypersensitivity reactions, topical administration of sulfonamides can lead to local photosensitization, which can result in sunburn on the lid margins or skin of the face.

Trimethoprim–polymyxin B is well tolerated with few reported serious adverse reactions after topical ophthalmic use. The most frequent adverse event (about 4%) is local irritation, including transient burning or stinging, itching, or redness. Less than 2% of patients experience a hypersensitivity reaction consisting of lid edema, itching, increased redness, tearing, or periocular rash. Because no cross-allergic reactions occur between the sulfonamides and trimethoprim,trimethoprim–polymyxin B can be used in patients allergic to the sulfonamides.

Contraindications

Sulfonamides are contraindicated in patients with known hypersensitivity or intolerance to any member of this drug family. Sulfonamides are also contraindicated in pregnancy at term, for nursing mothers, and for infants less than 2 months old because they can promote kernicterus in the newborn by displacing bilirubin from plasma proteins. The sulfonamides, pyrimethamine, and trimethoprim are contraindicated in patients with documented blood dyscrasias.

Caution should be used in prescribing sulfonamides for patients taking oral hypoglycemic drugs such as tolbutamide or chlorpropamide, because the sulfonamides can potentiate the hypoglycemic effect of these drugs. Sulfonamides can enhance the action of Coumadin-type anticoagulants and should be used with caution in patients taking these drugs.

Drugs Affecting Bacterial DNA Synthesis

Drugs that inhibit bacterial DNA synthesis include fluori-

related to nalidixic acid: lomefloxacin, norfloxacin, enoxacin, ciprofloxacin, ofloxacin, sparfloxacin, gemifloxacin, levofloxacin, gatifloxacin, and moxifloxacin.

Fluoroquinolones

Pharmacology

Fluoroquinolones act by rapidly inhibiting bacterial DNA synthesis, which leads to cell death. The primary targets are DNA gyrase (topoisomerase II) and topoisomerase IV, which are involved in maintaining the superhelical structure of DNA during synthesis. Human cells lack these enzymes so they are not affected by fluoroquinolones.

Bacteria have developed resistance to the fluoroquinolones by two main mechanisms. The first involves modifying the enzyme(s) targeted by the drug: either DNA gyrase or topoisomerase IV or both. The second involves reduction of fluoroquinolone access to its target enzyme either by efflux pumps that remove the fluoroquinolone from the cell or by the cell’s membrane acquiring reduced permeability to the fluoroquinolone.

Table 11-9

Fluoroquinolones for Oral Therapy

Clinical Uses

The classification of the fluoroquinolones into generations is somewhat informal and unstandardized. However, it does serve a clinical purpose by helping to classify them on the basis of their spectra of action and indications (Table 11-9).

Some second-generation fluoroquinolones (e.g., lomefloxacin, norfloxacin, and enoxacin) have, compared with nalidixic acid, improved activity against gram-negative bacteria, including Pseudomonas, and are used almost exclusively for urinary tract infections.

Ciprofloxacin and ofloxacin have broader spectra of activity that includes some gram-positive organisms so they have been used for a broad range of infections. Oral ciprofloxacin or ofloxacin is indicated for the treatment of complicated urinary tract infections and prostatitis. Ofloxacin is an effective therapy for chlamydial urethritis/ cervicitis and acute pelvic inflammatory disease. Oral ciprofloxacin or ofloxacin is effective in the treatment of acute diarrhea caused by enterotoxic E. coli (e.g., travelers’ diarrhea), Salmonella, Shigella, and Campylobacter.

Ciprofloxacin and ofloxacin have been used extensively to treat upper and lower respiratory tract infections. However, there are concerns about the increasing resistance of S. pneumoniae to these drugs.

Newer fourth-generation fluoroquinolones such as gatifloxacin, gemifloxacin, and moxifloxacin have improved activity against pneumococci, including macrolideand penicillin-resistant strains, and are often termed the “respiratory quinolones.” They are indicated for acute exacerbations of chronic bronchitis, community-acquired pneumonia, and sinusitis.

Ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, gatifloxacin, and moxifloxacin are available as topical ophthalmic solutions, and ciprofloxacin is available as an ophthalmic ointment (see Table 11-5). These drugs are broad spectrum and effective against both gram-positive and gram-negative bacteria. However, the clinical utility and effectiveness of the older fluoroquinolones (ciprofloxacin, norfloxacin, and ofloxacin) have been eroded due to growing rate of resistance, particularly among gram-positive bacteria. Moxifloxacin and gatifloxacin have enhanced activity against gram-positive bacteria while maintaining potency against gram-negative bacteria. These fourth-generation quinolones are active not only against fluoroquinolone-resistant staphylococci and streptococci, but also against penicillinand macrolide-resistant isolates as well.

All the available ophthalmic fluoroquinolones are indicated for bacterial conjunctivitis with a treatment regimen of usually one to two drops four times a day. However, because the newer gatifloxacin and moxifloxacin have wider spectra and less resistance, they should probably be reserved for treatment of the more serious infection, bacterial keratitis.

Ciprofloxacin and ofloxacin are also indicated for bacterial keratitis caused by a variety of pathogens. These

two antibiotics offer the convenience of “off-the-shelf” treatment for bacterial corneal ulcers. The suggested regimen for ciprofloxacin therapy is one to two drops applied to the affected eye every 15 minutes for the first 6 hours and then every 30 minutes for the rest of the day. The dosage on day 2 is one to two drops every hour. Monotherapy with ciprofloxacin or ofloxacin, although usually successful, is becoming more controversial as resistance develops to these antibiotics. Some suggest that fluoroquinolone monotherapy be used only for small off-visual axis corneal ulcers and that larger more visual-threatening ulcers should be treated with fortified antibiotics.

Although the fourth-generation drugs, moxifloxacin and gatifloxacin, are not approved for treatment of bacterial keratitis, they are now the preferred fluoroquinolones for this disease. They have wide spectra of activity and lesser resistance by the common corneal pathogens, especially the gram-positive cocci.

Side Effects

As a group the fluoroquinolones are generally well tolerated with a low incidence of adverse reactions. When adverse effects are reported after systemic administration, they are usually gastrointestinal, dermatologic, and central nervous system reactions, which rarely necessitate withdrawal of therapy. The typically reported gastrointestinal symptoms include nausea, anorexia, and dyspepsia; diarrhea, abdominal pain, and vomiting are less frequently reported. Liver enzyme abnormalities occur in 2% to 3% of patients and are usually mild and reversible. Although nonspecific skin rashes, pruritus, and urticaria have been reported, it is phototoxicity that manifests as a severe sunburn that has received the most attention. Sparfloxacin has caused a high rate of phototoxicity, but phototoxic reactions to ciprofloxacin, ofloxacin, and levofloxacin are rare. The central nervous system reactions produced by fluoroquinolones include headache, dizziness, mild tremor, or drowsiness. Because it can cause hypoglycemia or hyperglycemia in diabetics, oral gatifloxacin is no longer available.

Fluoroquinolones as a group produce destructive arthropathy in weight-bearing diarthrodial joints of juvenile animals after prolonged administration of high dosages. This effect has never been observed in children. However, these drugs are not recommended for systemic administration in children, adolescents below the age of 18 years, or pregnant women.

An association between fluoroquinolones and tendonitis, especially involving the Achilles tendon, has been reported.

Magnetic resonance imaging can be useful for early detection of damage, and discontinuation is recommended at the first sign of tendon pain or inflammation.

The frequency of adverse reactions to the topical ophthalmic fluoroquinolones is low. The most frequently reported adverse reactions to ciprofloxacin are local burning or discomfort after instillation, bitter taste after

196 CHAPTER 11 Anti-Infective Drugs

instillation, white precipitates, foreign body sensation, itching, and conjunctival hyperemia, chemosis, and photophobia. Frequent instillation of ciprofloxacin for treatment of corneal ulceration can result in white precipitates forming on the surface of the eye, but the precipitates typically do not require discontinuation of therapy. Opaque deposits can also form on “bandage’’ soft contact lenses when ciprofloxacin and prednisolone are used concurrently. Corneal epithelial cytotoxicity of the fluoroquinolones has been evaluated in animal models, and each drug was found to have only minimal toxicity at therapeutic concentrations.

Topical administration of the fluoroquinolones to immature animals does not cause arthropathy, and the ophthalmic dosage form does not appear to affect the weight-bearing joints in humans. All the topical ophthalmic fluoroquinolones, except levofloxacin, are approved for use in patients 1 year of age and older.

Contraindications

The quinolones are contraindicated in patients with a history of hypersensitivity to any drug in this family. Absorption of the fluoroquinolones is reduced by antacids, iron, and zinc salts, and thus they should not be taken concurrently. Oral ciprofloxacin and enoxacin inhibit the metabolism of theophylline, and toxicity can occur when these two drugs are administered concurrently. Oral administration of the fluoroquinolones can cause convulsions and should therefore be done with caution in patients with central nervous system disorders. These drugs are not recommended for systemic administration in children, adolescents younger than age 18 years, or pregnant women. Topical administration is contraindicated for use in patients younger than 1 year of age.

ANTIVIRAL DRUGS

Ranging in size from about 20 to 300 nm, viruses are the smallest of the infectious organisms. Electron micrograph studies show viruses to vary not only in size, but also in shape, symmetry, and surface characteristics. The basic structure of a virus particle (virion) consists of an outer protein coat, or capsid, that protects and delivers the inner viral genetic material, or genome, within a host cell (Figure 11-2). The genome material is either singleor double-stranded DNA or RNA. Most viruses contain or encode enzymes that orchestrate viral replication inside the host cell. Newly synthesized viral genetic material and capsids assemble to form multiple viral progeny that are released from the infected cell to infect other cells. The replication process generally results in host cell death, or apoptosis. However, viruses like herpesviruses can cause latent infections by incorporating the viral genome into host DNA, thereby escaping detection by the host’s immune system and allowing the host cell to survive. Recurrent disease results from activation of the

Figure 11-2 Steps in viral replication. Step 1:Attachment of virus to host cell using specialized receptors on the virus and host cell. Step 2: Penetration of virus into host cell and uncoating of virus. Step 3: Duplication of viral DNA or RNA using host DNA/RNA. Step 4: Assembly of viral genome and capsid within host cell and then release of progeny. (The host cell can then either die or survive, depending on the virus and host cell type.)

viral genetic material, by various triggers or stressors, to produce progeny.

Effective antiviral agents must interfere with viral replication to stop virus multiplication. Ideally, the antiviral demonstrates selective toxicity by preferentially inhibiting viral replication while sparing host cell–directed nucleic acid or protein synthesis. Most of the currently available antiviral drugs are antimetabolites that inhibit nucleic acid synthesis (refer to step 3 in Figure 11-2). Currently approved antiviral drugs target viral enzymes, such as thymidine kinase, to inhibit viral replication. Thymidine kinase helps cells incorporate the nucleoside thymidine into DNA. Because thymidine is an integral building block of DNA, inhibiting the action of thymidine kinase blocks DNA duplication. The more selective the antiviral agent is for viral enzymes, the less likely are host side effects.

Herpesviruses range in size from 120 to 300 nm and have DNA genomes and outer lipid membranes (envelopes). As enveloped viruses,herpesviruses are sensitive to drying and adverse conditions. Herpesviruses are spread by inoculation of susceptible mucous membranes or direct cell-to-cell contact. Over 100 herpesviruses have been identified, but only 5 cause human eye infections with any frequency: herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella zoster virus (VZV), cytomegalovirus (CMV), and Epstein-Barr virus.

Herpesviruses can cause blepharitis, conjunctivitis, epithelial and stromal keratitis, uveitis, retinitis, and ARN. HSV-1 is the most frequent cause of primary and recurrent eye disease. The host immune system influences the rates of reactivation. Immunocompromised patients tend to have more frequent reactivations and more severe disease manifestations. The strain of virus also affects the

disease severity, presumably because of the presence of virulence genes. In addition to neuronal or ganglionic latency, there is evidence of persistent HSV DNA in the cornea between episodes. Studies have also suggested that donor-to-host transmission of HSV-1 through corneal grafts may occur. Furthermore, genotypic analysis of HSV isolates has shown that subsequent infection by different HSV strains is possible.

Adenoviruses also have DNA as their genetic material and are smaller than herpesviruses, with diameters of 70 to 100 nm. Adenoviruses do not have lipid envelopes and can survive on inanimate objects. Adenoviral serotypes 3, 7, 8, 19, and 37 cause conjunctivitis and epidemic keratoconjunctivitis. Currently, no antivirals are approved for ocular adenoviral infections. Studies have shown that topical cidofovir may be effective in lowering the frequency of severe corneal opacities, but additional studies are needed to address corneal toxicity.

This section contains information primarily about the antiviral activity, pharmacology, and treatment of herpesvirus infections. There is limited information on the antiviral treatment of adenovirus infections. The antiretroviral agents used to treat RNA viruses responsible for AIDS are listed and their functions reviewed. However, there is no information on clinical trials pertaining to antiretroviral agents.

Drugs for the Treatment of Herpes Simplex and Herpes Zoster

Viral Infections

Idoxuridine

Due to corneal toxicity and the availability of more effective drugs, idoxuridine is infrequently used. Idoxuridine has poor ocular bioavailability and is not effective for deep stromal disease. Resistance to idoxuridine can develop during treatment. Idoxuridine is too toxic for systemic use.

Vidarabine

Vidarabine, once marketed under the trade name Vira-A™, has been discontinued by the manufacturer and is only available through compounding pharmacies.* Vidarabine may be effective in cases that fail to respond to idoxuridine or in rare cases of hypersensitivity to trifluridine.

*Compounding pharmacies provide a valuable patient service by supplying drugs that are not commercially available or are not available in a formulation a patient can use (i.e., due to preservative allergies, etc.). Not all compounding pharmacies formulate ophthalmic medications. Pharmacies that compound products for ophthalmic use must be able to formulate sterile accurately prepared products. It is best to use a pharmacy that specializes in compounding ophthalmic drugs. Also, keep in mind that when using compounded medications, there can be no assurance of quality and safety that the FDA demands of commercial manufacturers.

Trifluridine

Pharmacology

Trifluridine has a mechanism of action similar to idoxuridine and vidarabine. Trifluridine is an effective inhibitor of thymidine synthetase and inhibits DNA synthesis in both virus-infected and normal host cells.

Clinical Uses

Trifluridine is the current drug of choice in the United States for topical treatment of primary and recurrent HSV keratitis, types 1 and 2. The average healing time is 6 to 7 days. Treatment of dendritic and geographic corneal ulcers with trifluridine is generally superior to idoxuridine and vidarabine. A randomized double-blind trial demonstrated that trifluridine and topical acyclovir had similar efficacy for treating HSV keratitis in both time of healing and frequency of healing (Table 11-10). A report of four patients with Thygeson’s superficial punctate keratitis suggested trifluridine may be an effective treatment.

Side Effects

Compared with idoxuridine and vidarabine, trifluridine is less toxic. Side effects include transient burning and stinging, contact dermatitis, corneal punctate keratopathy and edema, conjunctival hyperemia and chemosis, impaired stromal wound healing, keratitis sicca, punctal narrowing, and increased intraocular pressure. The toxic side effects may mimic infection and may be assumed to be a worsening of the disease. A report indicated that long-term use of trifluridine, as well as idoxuridine and vidarabine, could cause conjunctival scarring and cicatrization.

Contraindications

Trifluridine is contraindicated in patients who are allergic to or intolerant of the drug or any of its components.

Acyclovir

Pharmacology

Acyclovir is a purine analogue to guanine that is specific for virus-infected cells of HSV-1, HSV-2, VZV, and some CMVs. The highly selective antiviral action of acyclovir inhibits viral DNA polymerases significantly more than host DNA polymerases, significantly reducing host toxicity, and enables oral and intravenous administration. Acyclovir causes termination of the DNA chain and leads to irreversible inactivation of viral DNA polymerase. The prevalence of resistance to acyclovir is small. A recent study showed a resistance prevalence of 0.3% in immunocompetent patients and 3.6% in immunocompromised patients.

Viral strains resistant to acyclovir are frequently resistant in vitro to other viral drugs,especially ganciclovir. This pattern supports the theory that thymidine kinase mutations are most often responsible for acyclovir resistance. Because absorption from the gastrointestinal tract is variable and incomplete, oral bioavailability is poor, with 10% to 30% absorbed. Acyclovir has a relatively short half-life in plasma.

Table 11-10

Antiviral Drug Evidence-Based Guidelines

Trifluridine: Viroptic (1% ophthalmic solution)

See topical acyclovir studies detailed below

Acyclovir: Topical available outside of the United States. Zovirax:Tablets, oral—400 mg, 800 mg; capsule, oral—200 mg; suspension, oral—200 mg/5 ml; injectable— 50 mg/ml; generic also available

Drugs Infective-Anti 11 CHAPTER 198

Drugs Infective-Anti 11 CHAPTER

Continued

199

Table 11-10

Antiviral Drug Evidence-Based Guidelines––cont’d

Drugs Infective-Anti 11 CHAPTER 200