Antifungal and Antiviral Drugs PDF

VetBooks.ir Antimicrobial Drugs 365 is more complete and metabolism is slower in monogastric animals, especially horses, which may explain the greater toxicity in thi...

VetBooks.ir Antimicrobial Drugs 365 is more complete and metabolism is slower in monogastric animals, especially horses, which may explain the greater toxicity in this species. 5. Adverse effects. Toxicity of ionophores when used in species for which they are approved is uncommon, unless mixing errors occur. Ionophore toxicity is due to cellular electrolyte imbalances, increased extracellular K+ , and intracellular Na+ and Ca2+ concentrations, resulting in cellular damage and death. The in- creased intracellular Ca2+ concentration is due to the exchange of Na+ for Ca2+ by Na+ –Ca2+ exchanger; this exchange is particularly prominent in cardiac and skeletal muscles and these are usually the most severely affected. Horses are the most susceptible species to toxic effects when accidentally exposed to ionophore- containing feeds. XIV. ANTIFUNGAL AGENTS A. Griseofulvin 1. Chemistry. Griseofulvin is a cyclohexane benzofuran antibiotic derived from Peni- cillium griseofulvin. It is insoluble in water. 2. Mechanism of action. Griseofulvin is actively taken up by growing dermatophytes (ringworm). It binds to microtubules to inhibit spindle formation and mitosis. It is fungistatic for dermatophytes such as Microsporum spp. and Trichophyton spp. Its action is slow as infected cells are shed and replaced with uninfected cells. 3. Therapeutic uses. Griseofulvin is used in dogs, cats, and horses for multifocal der- matophyte infections. 4. Pharmacokinetics. The GI absorption rate varies from 25–70%. The absorption is increased by high-fat foods and by preparations consisting of micronized particles. It distributes to keratin precursor cells of skin, hair shafts, and nails. It is metabo- lized by the liver by demethylation and glucuronide conjugation and excreted in urine. Griseofulvin’s plasma t 1/2 in dogs is less than 6 hours, but is stored in the growing keratin cell producing skin, hair, and horn. 5. Administration. Griseofulvin is administered orally twice a day to dogs and cats and once daily to horses for 4–6 weeks. 6. Adverse effects. Untoward effects are rare. Leucopenia and anemia may occur as an idiosyncratic reaction in kittens. B. Nystatin and Natamycin 1. Chemistry. Nystatin and natamycin are polyene antibiotics derived from Strepto- myces spp. 2. Mechanism of action. Nystatin and natamycin are fungicidal to yeast infections caused by Candida spp. and Malassezia spp. They act by binding to erogsterol of the protoplast membrane of fungi to alter permeability and allow leakage of cell contents. 3. Therapeutic uses. Nystatin and natamycin are too toxic for parenteral use. They are administered topically for yeast infections of the eye, ear, and skin, and ad- ministered orally for treating mucosal yeast infections of the mouth and GI tract. Nystatin is used as a feed additive in poultry to prevent crop mycosis and my- cotic diarrhea. Nystatin is a component of topical proprietary preparations such as Panalog R , which also include thiostrepton, a polypeptide antibiotic, and triamci- nolone, a glucocorticoid. 4. Pharmacokinetics. Nystatin is not absorbed orally and is excreted in the feces. 5. Administration. Nystatin is administered orally every 6–8 hours for Candidal in- fections in dogs and cats. Natamycin is used topically primarily for ocular mycotic infections and is the drug of choice for treating fungal keratitis in horses. 6. Adverse effects. Adverse effects are rare since the drugs are not supposed to enter the systemic circulation. Occasional GI upset may be observed with high dose. VetBooks.ir 366 Chapter 15 XIV C C. Azoles 1. Chemistry. Ketoconazole, itraconazole, and fluconazole are imidazole antifun- gals for systemic use. Other imidazoles used only topically for dermatophyte, As- pergillus or yeast infections include miconazole and clotrimazole. 2. Mechanism of action. The azoles inhibit the synthesis of ergosterol in fungal cyto- plasmic membranes by blocking cytochrome P450 enzymes and increasing cellu- lar permeability. At high doses, mammalian steroid synthesis (corticosteroids and sex steroids) is inhibited. Azoles are fungistatic for most pathogenic fungi causing systemic infections such as Blastomyces, Coccidioides, Cryptococcus, and Histo- plasma spp. They are also effective against candidiasis and griseofulvin-resistant dermatophytes. 3. Therapeutic uses. Ketoconazole is used in dogs, cats, horses, and birds for sys- temic mycoses and for severe yeast infections. It is also used in dogs and cats at high dosage for the treatment of hyperadrenocorticism (see Chapter 12, III E 4 b). Fluconazole and itraconazole have replaced ketoconazole in most treatment reg- imens for the systemic mycoses because of their longer t 1/2 , greater activity, and lower toxicity. Clotrimazole and miconazole are used topically in the treatment of Candida, Aspergillus, and dermatophyte infections. 4. Pharmacokinetics a. Following oral administration, azoles are well absorbed in the presence of food that stimulates bile flow. b. They are widely distributed, particularly in tissues high in lipid content; how- ever, minimal amounts are found in cerebrospinal fluid (∼10% of other tissue levels). c. They are metabolized by microsomal enzymes of the liver and excreted in bile. d. The t 1/2 of ketoconazole in dogs is 1–6 hours. In humans, fluconazole’s plasma t 1/2 is ∼30 hours and itraconazole’s t 1/2 is 20–60 hours. Because of their long t 1/2 , these two azoles do not reach steady state plasma levels for 6–14 days after beginning therapy, unless loading doses are given. Patients with impaired renal function may have t 1/2 extended significantly and dosage adjustment may be required. 5. Administration. Ketoconazole is administered orally twice a day for 3–6 months for systemic mycotic infections. Fluconazole and itraconazole are administered orally or IV once a day to dogs and cats for systemic mycoses for periods of 1–3 months, depending on the type of pathogenic fungi being treated. Clotrimazole and miconazole are applied topically for the treatment of yeast or dermatophyte infections or via nasal infusion for treating nasal aspergillosis. 6. Adverse effects. Anorexia, vomiting, and diarrhea may occur, especially in cats, treated with ketoconazole. Suppression of adrenal or gonadal steroids may also occur but the effects are transient at doses employed in antifungal therapy. Ad- verse effects are rare with fluconazole or itraconazole therapy, unless in patients with impaired renal function. D. Amphotericin B 1. Chemistry. Amphotericin B is a polyene macrolide that is stabilized with sodium desoxycholate as a colloidal suspension. 2. Mechanism of action. Amphotericin B binds to ergosterol of fungal cell mem- branes to form pores or channels, which result in leakage of cell contents. It is fungicidal against most organisms causing systemic mycoses, including Aspergillus, Blastomyces, Coccidioides, Cryptococcus, and Histoplasma spp. 3. Therapeutic uses. Amphotericin B is used to treat systemic fungal infections in dogs, cats, horses, and birds. Combined therapy with ketoconazole, fluconazole, itraconazole (to reduce toxicity), or flucytosine (for CNS, bone, or ocular infec- tions) is common. 4. Pharmacokinetics. Amphotericin B is not absorbed from the GI tract. After IV administration, it slowly distributes to most tissues except the CNS, eye, and bone. Elimination is biphasic with plasma t 1/2 of 24–48 hours and 1–2 weeks. VetBooks.ir Antimicrobial Drugs 367 Approximately 65% of amphotericin B is excreted unchanged into urine (20%) and feces (45%). 5. Administration. Amphotericin B is diluted in 5% dextrose and administered IV. Treatment frequency and duration vary with the type of infection. 6. Adverse effects. Renal toxicity is a serious side effect. Amphotericin B produces renal vasoconstriction, decreased GFR, and damage to tubular epithelium. BUN must be monitored weekly during therapy. E. Flucytosine 1. Chemistry. Flucytosine (5-FC) is a fluorinated pyrimidinethat is deaminated by fungi (not mammalian cells) to 5-fluorouracil, a potent antimetabolite. 2. Mechanism of action. Flucytosine inhibits thymidylate synthase and DNA and RNA synthesis in susceptible fungi. It is fungicidal against Cryptococcus, Candida, and Aspergillus spp. 3. Therapeutic uses. Flucytosine is combined with amphotericin B for synergistic action in the treatment of cryptococcosis (especially meningeal cryptococcosis) in dogs and cats. It is used alone in treating aspergillosis and candidiasis in psittacine birds. 4. Pharmacokinetics. Flucytosine is well absorbed orally and widely distributed, in- cluding the CNS. It is excreted unchanged in urine. The plasma t 1/2 in humans is 3–6 hours. No information is available for animals. The t 1/2 may be prolonged in patients with compromised renal function. 5. Administration. Flucytosine is administered orally 3–4 times a day for a minimum of 4 weeks. 6. Adverse effects. Toxicity is low. Mild GI disturbances and, more rarely, bone mar- row suppression have been reported. F. Terbinafine 1. Chemistry. Terbinafine is an allylamine derivative. 2. Mechanism of action. Terbinafine inhibits the synthesis of ergosterol—a compo- nent of fungal cell membranes. By blocking the enzyme squalene monooxygenase (squalene 2,3-epoxidase), terbinafine inhibits the conversion of squalene to sterols (especially ergosterol) and causes accumulation of squalene. Both these effects are thought to contribute to its antifungal action. Unlike azoles, terbinafine does not block cytochrome P450 enzymes. It is fungicidal against dermatophytes and fungistatic against yeast. 3. Therapeutic uses. When administered orally (30 mg/kg/day) or topically, terbinafine is useful for treating dermatophytic infections in dogs and cats. It is also useful for treating birds for systemic mycotic infections such as aspergillosis. 4. Pharmacokinetics. No information is available for animals. In humans, it is read- ily absorbed (>70%) when given orally. Since terbinafine is lipophilic, food may enhance GI absorption of the drug by increasing bile secretion. Terbinafine is dis- tributed to skin and into the sebum. Over 99% of drug in the plasma is bound to albumin. Drug in the circulation is metabolized in the liver into demethylated, deaminated, and dealkylated conjugates, which are excreted into urine. The elim- ination t 1/2 is ∼36 hours. The drug may persist in adipose tissue and skin for more than 30 days. 5. Adverse effects. Terbinafine appears to be well tolerated by animals. XV. ANTIVIRAL AGENTS A. Amantadine 1. Chemistry. Amantadine is 1-aminoadamantane. 2. Mechanism of action. When influenza viruses replicate within the host cell, a vi- ral membrane protein known as M2 forms an ion-channel for H+ influx from the VetBooks.ir 368 Chapter 15 XV A endosome into the virion prior to fusion of the viral membrane with the endosomal membrane. Amantadine binds to M2 protein and blocks its ion channel activity and thus inhibits viral uncoating and replication. In addition to its antiviral activity, amantadine antagonizes the N-methyl-D- aspartate (NMDA) receptor in the CNS. NMDA receptors are important in pain sen- sation, especially chronic pain. Amantadine combined with other analgesics such as opiates or NSAIDs alleviates chronic pain. 3. Therapeutic uses. The primary use of amantadine in veterinary medicine is as an adjunct to NSAIDs for the treatment of chronic pain in dogs and cats. It is effective for treating some, but not all, influenza viruses. Because oral absorption in horses is variable, it has been used IV to treat equine-2 influenza but its potential for induc- ing seizures when administered by this route limits its use. 4. Pharmacokinetics. Given orally, ∼50% of the dose of amantadine is absorbed in horses and high levels are attained in secretions. It is excreted unchanged by the kidneys. The elimination t 1/2 in horses is ∼3.5 hours. The information for dogs and cats is not available. 5. Administration. As an adjunct to chronic pain therapy, amantadine is administered orally once a day to dogs and cats. 6. Resistance. Develops quite rapidly. 7. Adverse effects. Infrequently, the following signs are seen: agitation, loose stools, flatulence, or diarrhea, particularly early in therapy. B. Acyclovir 1. Chemistry. Acyclovir is a guanosine derivative with selectivity for particular herpes viruses. 2. Mechanism of action. Acyclovir is metabolized to the monophosphate by thymi- dine kinase, which is more active in the virus than in the host cell. The host cell then converts the monophosphate to the triphosphate that inhibits the viral DNA polymerase, ending the nucleotide chain prematurely. 3. Therapeutic uses. Acyclovir is used to treat ocular and respiratory infections of her- pes virus 1 of cats. Although acyclovir is active against equine herpes virus type-l in vitro, oral absorption is poor in horses and therapeutic levels are not attained 4. Pharmacokinetics. Acyclovir is poorly absorbed (∼20%) after oral administration. It is widely distributed throughout body tissues and fluids, including the brain, semen, and CSF. It has low protein binding and crosses the placenta. Acyclovir is primarily metabolized by the liver and has a t 1/2 of ∼3 hours in humans. No information is available for animals. 5. Administration. Acyclovir is administered orally twice a day to cats. 6. Adverse effects. Leucopenia and anemia may occur. These are reversible if therapy is discontinued. C. Zidovudine (AZT) 1. Chemistry. Zidovudine is an analog of thymidine. 2. Mechanism of action. Zidovudine is phosphorylated by host cell enzymes to AZT 5 -triphosphate, which competes with host 5 -thymidine, which is essential for proviral DNA formation by reverse transcriptase of the virus. The incorporation of the 5 -triphosphate zidovudine into the viral DNA chain produces the termination of viral DNA synthesis. Mammalian α-DNA polymerase does not incorporate the zidovudine. 3. Therapeutic uses. Zidovudine may be used in cats to treat FIV infection where it produces temporary alleviation of the clinical signs and increase in quality of life and survival time in most cats, particularly when clinical signs of immunodeficiency are evident. It does not inhibit the viremia. Clinical improvement occurs 14 days after the start of treatment. Zidovudine is not effective against feline leukemia virus at nontoxic doses 4. Pharmacokinetics. Zidovudine is well absorbed orally and has a t 1/2 of ∼2 hours in cats. It is metabolized in the liver by glucuronide conjugation and excreted in urine. t 1/2 may be extended in cats that have low levels of glucuronyl transferase. VetBooks.ir Antimicrobial Drugs 369 TABLE 15-1. Websites for Antimicrobial Information VIN http://www.vin.com/ FDA—human http://www.accessdata.fda.gov/scripts/cder/drugsatfda Compendium veterinary product http://www.bayerdvm.com/ Resources/cvp main.cfm?CFID=307632&CFTOKEN=61494892 Merck veterinary manual http://www.merckvetmanual.com/ mvm/index.jsp?cfile=htm/bc/toc 191200.htm 5. Administration. Zidovudine is administered orally 2–3 times a day for a minimum of 4 weeks. 6. Resistance. Mutation of virus target sites may result rapidly and resistance to zi- dovudine is expected with long-term use. 7. Adverse effects. Anemia and reduction in hemoglobin are the most common side effects observed in cats. Diarrhea and weakness may also occur. Reduced dosage should be employed in cats with renal or hepatic insufficiency. D. Cat omega interferon 1. Chemistry. Interferons are cytokines, proteins produced by host cells when they are attacked by viruses. Cat omega interferon is produced by genetic engineering and is a type 1 interferon closely related to alpha interferon. It has a t 1/2 of 1–2 hours in dogs and cats. 2. Mechanism of action. Interferon’s mechanism of action is not a direct attack on the virus but by altering host cell metabolism to induce proteins that protect against viral invasion by several methods including destruction of mRNA and blockade of translational proteins resulting in the inhibition of viral replication. 3. Therapeutic uses. Feline omega interferon can be used to treat cat viral infections, including calci virus, FeLF, FIV, and other feline viral infections as well as canine parvovirus. 4. Administration. Interferons may be given SC or by other parenteral routes (depend- ing on the virus to be treated) once a day. 5. Adverse effects. Transient anorexia and weight loss may occur in cats. Fever, myelotoxicity, and myalgia may develop with parenteral administration at higher dosages (Tables 15-1 and 15-2).