Other Anti-Infective Drugs

Chapter 28 Other Anti-Infective Drugs

I. Antimycobacterial Drugs (Box 28-1)

• The management of tuberculosis is summarized in Table 28-1.

TABLE 28-1 Management of Tuberculosis

Therapeutic Goal and Drug-Related Patient Features	Initial Drug Treatment	Subsequent Drug Treatment
Prevention of Tuberculosis
Not resistant to isoniazid	Isoniazid (6mo)	None
HIV-negative; resistant to isoniazid; >50 years of age	Rifampin (6mo)	None
HIV-positive	Rifampin⁎ or rifabutin (12 months)	None
Treatment of Tuberculosis
Not resistant to isoniazid	Combination of isoniazid, rifampin, ethambutol, and pyrazinamide for 2 months	Combination of isoniazid and rifampin (4 more months if HIV-negative or 7 more months if HIV-positive)
Possibly resistant to isoniazid	Combination of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin (6 months)	Individualized therapy based on microbial susceptibility testing
Resistant to multiple drugs^†	Combination of at least four drugs believed to be active in patient population (6 months)	Individualized therapy based on microbial susceptibility testing

HIV, human immunodeficiency virus.

⁎ In HIV-infected patients, substitution of rifabutin for rifampin minimizes drug interactions with protease inhibitors and nucleoside reverse transcriptase inhibitors.

† Patients suspected of having multidrug resistance include those from certain demographic populations, those who have failed to respond to previous treatment, and those who have experienced a relapse of tuberculosis.

To prevent resistance anti-TB drugs are often administered under direct observed therapy (DOT).

A. Isoniazid (INH)

1. Pharmacokinetics

a. Metabolism occurs by acetylation (N-acetyltransferase; NAT)

• This enzyme is under genetic control

Isoniazid is metabolized by acetylation; fast or slow acetylators.

b. Individuals are either fast or slow acetylators.

2. Mechanism of action

a. Inhibits synthesis of mycolic acids

Isoniazid inhibits mycolic acid cell wall synthesis.

b. Thus, inhibits mycobacterial cell wall synthesis

c. Bactericidal

(1) Mutations in catalase-peroxidase (katg) preventing conversion of the prodrug isoniazid to its active metabolite

(2) Mutation in the mycobacterial inhA and KasA genes involved in mycolic acid biosynthesis

(3) Mutations in nicotinamide-adenine dinucleotide (NADH) dehydrogenase (ndh)

• Tuberculosis (Mycobacterium tuberculosis)

a. Prophylaxis in tuberculin converters (positive skin test)

Use rifampin for prophylactic treatment in those older than 50 years of age.

b. Treatment along with rifampin, ethambutol, pyrazinamide, or streptomycin (see Table 28-1)

4. Adverse effects

a. Hepatic damage (especially in individual’s >50 years of age); boxed warning

(1) Severe and sometimes fatal hepatitis may occur

(2) Usually occurs within the first 3 months of treatment, although may develop even after many months of treatment

Isoniazid is hepatotoxic.

b. Peripheral neuritis

(1) Reversed by pyridoxine

(2) More prominent in “slow” acetylators

c. Sideroblastic anemia due to pyridoxine deficiency

Pyridoxine protects against isoniazid peripheral neurotoxicity.

B. Rifampin

1. Pharmacokinetics

a. Well absorbed orally

b. Hepatic metabolism

c. Undergoes enterohepatic recirculation

d. Marked inducer of cytochrome P-450s

e. Penetrates well into tissues and phagocytic cells

2. Mechanism of action

a. Binds to the β-subunit of bacterial DNA-dependent RNA polymerase

b. Inhibits binding of the enzyme to DNA

• Blocks RNA transcription

• Mutations reduce binding of the drug to the polymerase

Rifampin inhibits DNA-dependent RNA synthesis.

a. Tuberculosis (M. tuberculosis)

(1) Prophylaxis in cases of isoniazid resistance or in individuals who are older than 50 years of age

(2) Treatment in combination with other drugs (see Table 28-1)

b. Prophylaxis in contacts of:

(1) Neisseria meningitidis

(2) Haemophilus influenzae type B

c. Legionnaires’ disease (in combination with azithromycin)

d. Leprosy (Mycobacterium leprae) (combination therapy)

4. Adverse effects

a. Red-orange discoloration of urine, tears, saliva

Treatment with rifampin often results in permanent discoloration of soft contact lenses.

b. Hepatotoxicity

c. Drug interactions

Rifampin: potent inducer of cytochrome P450 hepatic enzymes

(1) Rifampin, a potent inducer of the cytochrome P450 hepatic enzyme systems, can reduce the plasma concentrations of many drugs, including:

(a) Anticonvulsants

(b) Contraceptive steroids

Rifampin decrease the effectiveness if contraceptive steroids.

(c) Cyclosporine

(d) Ketoconazole

(f) Terbinafine

(2) Rifabutin is a less potent inducer of the cytochrome P450 hepatic enzyme system.

(a) Thus, it causes less robust drug-drug interactions

(b) It is preferred for patients on human immunodeficiency virus (HIV) medications

Drug-drug interactions are less with rifabutin than rifampin.

C. Ethambutol

1. Pharmacokinetics

a. Well absorbed orally

(1) Urine (50% unchanged drug)

(2) Feces (20% unchanged drug)

(3) Hepatic metabolism (20%)

2. Mechanism of action

a. Inhibits glycan synthesis (component of the mycobacterial cell wall)

b. Inhibits RNA synthesis

c. Bacteriostatic

• Tuberculosis (combination therapy; see Table 28-1)

4. Adverse effects

a. Optic neuritis

b. Reduction in red-green visual acuity

• Annual eye examination required

Ethambutol use requires regular eye examinations.

c. Hepatic toxicity

• Likely due to combination therapy

D. Pyrazinamide

1. Pharmacokinetics

a. Well absorbed orally

b. Hepatic metabolism

2. Mechanism of action

a. Requires metabolic conversion to pyrazinoic acid

Pyrazinamide is converted to pyrazinoic acid (active agent).

b. Bacteriostatic or bactericidal depending on drug’s concentration at infection site

c. Exact mechanism unknown

• May relate to lowered pH

• Tuberculosis (combination therapy; see Table 28-1)

4. Adverse effects

a. Hyperuricemia

b. Hepatotoxicity

Pyrazinamide produces hepatotoxicity.

c. Photosensitivity

d. Use with caution in following patients:

(1) Diabetes mellitus

(3) History of alcoholism

E. Rifabutin

1. General information

a. Like rifampin

b. But a less potent inducer of cytochrome P450 hepatic enzymes

Rifabutin preferred to use with HIV highly active antiretroviral therapy (HAART) cocktails since it is a less potent inducer of drug metabolisms than rifampin.

a. Substitute for rifampin in the treatment of tuberculosis in HIV-infected patients

b. Prevention and treatment of Mycobacterium avium complex

F. Streptomycin (see aminoglycosides in Chapter 27)

1. This aminoglycoside is used more frequently today because of increased incidence of drug-resistant M. tuberculosis strains

Streptomycin only used in initial therapy because it has to be injected and other agents are orally administered.

2. Other uses include:

a. Tularemia (Francisella tularensis)

b. Plague (Yersinia pestis)

c. In combination with a penicillin for the treatment of endocarditis.

G. Alternative drugs used in treatment of tuberculosis (Box 28-1)

1. Use increasing because of drug resistance

Because of resistance to first line drugs, second line drugs have to be used frequently.

2. Referred to as second line drugs and include:

c. Levofloxacin

f. Para-aminosalicylic acid (PAS)

1. Mechanism of action

a. Inhibitor of folic acid synthesis

• Like sulfonamides

b. Bacteriostatic

• Treatment of leprosy (M. leprae)

Dapsone used to treat leprosy.

3. Adverse effects

a. Optic neuritis

c. Contraindicated with glucose-6-phosphate dehydrogenase (G6PD) deficiency

• Leads to hemolytic anemia

II. Therapeutic Summary of Selected Drugs used in Treatment of Tuberculosis: Table 28-2

III. Antiviral Drugs (Box 28-2)

• The mechanism of viral replication and the effects of antiviral drugs are shown in Fig. 28-1.

A. Drugs used in the prevention and treatment of influenza

1. Amantadine and rimantadine

a. Mechanism of action

(1) Blocks viral uncoating by blocking M2 proton channel

Table 28-2 Therapeutic Summary of Selected Drugs used in Treatment of Tuberculosis

BOX 28-2 Antiviral Drugs

Drugs Used in the Treatment and Prophylaxis of Influenza

Antiherpes Drugs

Acyclovir congeners: famciclovir, penciclovir, valacyclovir

Interferons

Interferon alfa-2a

Interferon alfa-2b

Interferon alfacon-1

Interferon alfa-n3

Interferon beta-1a

Interferon beta-1b

Interferon gamma-1b

Peginterferon alfa-2a

Peginterferon alfa-2b

Other Antiviral Drugs

28-1 Mechanism of viral replication and the site of action of antiviral drugs. NRTI, nucleoside reverse transcriptase inhibitors; NNRTI, nonnucleoside reverse transcriptase inhibitors.

(From Wecker L, et al.: Brody’s Human Pharmacology, 5th ed. Philadelphia, Mosby, 2010, Figure 51-2.)

Amantadine blocks viral uncoating.

(2) Prevents release of viral nucleic acid into the host cell

(1) Influenza A (prophylaxis)

(2) Parkinson’s disease (see Chapter 11)

c. Adverse effects

(3) Impaired coordination

(4) Livedo reticularis

d. Amantadine or rimantadine: Advisory Committee on Immunization Practices (ACIP) 2008-2009 Influenza Guidelines (July 2008)

(1) Do not recommend the use for the treatment or chemoprophylaxis of influenza A infection for residents of the United States.

Influenza A highly resistant to amantadine.

(2) Based on current patterns of resistance to these medications.

2. Oseltamivir and zanamivir

a. Administration

(1) Oseltamivir: a prodrug given orally

Oseltamivir taken orally.

(2) Zanamivir given by inhalation

Zanamivir taken by inhalation.

b. Mechanism of action

(1) Inhibit viral neuraminidase

-amivir drugs inhibit viral neuraminidase.

(2) Prevents extrusion from host cell

(3) Prevents infection of new cells

(1) Treatment of influenza virus A and B in patients who have been symptomatic for no more than 2 days

(2) Prophylaxis against influenza virus A and B

d. Adverse effects

(2) Throat/tonsil discomfort/pain

(3) Nasal signs and symptoms

(5) Bronchospasm in asthmatics (zanamivir)

B. Interferons

1. Mechanism of action

a. Inhibit viral penetration

b. Inhibit viral uncoating

c. Inhibit peptide elongation

a. Interferon alfa (see Box 28-2)

(1) Hairy-cell leukemia

(2) Acquired immunodeficiency syndrome (AIDS)-related Kaposi’s sarcoma

(3) Condyloma acuminatum (venereal wart)

(4) Chronic hepatitis B

(5) Chronic hepatitis C

Interferon alfa for tumors and viral infections

b. Interferon beta (see Box 28-2)

• Multiple sclerosis (MS)

Interferon beta for MS

c. Interferon gamma-1b (see Box 28-2)

Interferon gamma-1b for chronic granulomatous disease

(1) Reduce frequency and severity of serious infections associated with chronic granulomatous disease

(2) Delay time to disease progression in patients with severe, malignant osteopetrosis

3. Adverse effects

c. Influenza symptoms

C. Antiherpes drugs

1. Acyclovir and congeners

(1) Famciclovir (prodrug to penciclovir)

(2) Penciclovir (topically)

(3) Valacyclovir (prodrug to acyclovir)

Prodrugs actively transported from gastrointestinal (GI) tract with marked improvement of bioavailability requiring less frequent dosing.

b. Bioavailability

(1) Acyclovir poor; has to be given 5 times a day

(2) Prodrugs excellent; given 2 to 3 times a day

c. Mechanism of action

(1) Converted to monophosphates by virus-specific thymidine kinase

Bioactivation by viral kinases provide selective toxicity to virus but mutations in kinases contribute to resistance.

(2) Then converted to triphosphate by cellular enzymes

(3) Triphosphates inhibit DNA synthesis and viral replication

(4) Compete with deoxyguanosine triphosphate for viral DNA polymerase

Drugs must be converted to the triphosphate to inhibit viral polymerases.

• Involves loss of thymidine kinase activity

(1) Herpes simplex (cold sores)

(2) Herpes genitalis

(3) Herpes zoster (shingles)

(4) Varicella zoster (chickenpox)

(5) Acyclovir given IV in immunocompromised patients

Cytomegalovirus (CMV) has no thymidine kinase, acyclovir is not effective.

f. Adverse effects

(3) Gastrointestinal (GI) distress

(4) Nephrotoxicity (IV administration)

2. Ganciclovir and valganciclovir

(1) Given IV for severe CMV retinitis

Ganciclovir for CMV.

(2) Available as ocular implant

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Apr 8, 2017 | Posted by admin in PHARMACY | Comments Off

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