LC12_ANTIMYOBACTERIAL AND ANTIFUNGAL

I. First Line Drugs Used in Tuberculosis

  • Isoniazid

  • Rifampin

  • Ethambutol

  • Pyrazinamide

Details:

I.1 Overview

  • Isoniazid and rifampin are noted as the most active drugs.

  • An initial intensive phase of treatment is recommended for the first 2 months due to the prevalence of resistant strains.

  • The addition of pyrazinamide during this intensive phase reduces the total duration of therapy to 6 months without loss of efficacy.

A. Isoniazid

  • Description:

    • Most active drug for treating tuberculosis caused by susceptible strains.

    • A small molecule (molecular weight 137) that is freely soluble in water.

    • Structurally similar to pyridoxine.

    • Penetrates into macrophages, active against both extracellular and intracellular organisms.

A.1 Mechanism of Action

  • Inhibits synthesis of mycolic acids, essential for mycobacterial cell walls.

  • Activated by KatG (mycobacterial catalase-peroxidase).

  • Activated form forms a covalent complex with acyl carrier protein (AcpM) and KasA (beta-ketoacyl carrier protein synthase), blocking mycolic acid synthesis.

A.2 Basis of Resistance

  • Resistance linked to mutations resulting in overexpression of inhA.

  • Mutation/deletion of katG gene.

  • Promoter mutations resulting in overexpression of ahpC (protection from oxidative stress).

  • Mutations in kasA.

  • Overproducers of inhA express low-level isoniazid resistance and cross-resistance to ethionamide.

  • KatG mutants express high-level isoniazid resistance, often not cross-resistant to ethionamide.

A.3 Pharmacokinetics

  • Readily absorbed from the gastrointestinal tract, best on an empty stomach.

  • Peak concentration can decrease by 50% if taken with a fatty meal.

  • Reaches peak plasma concentrations in 1-2 hours.

  • Diffuses into all body fluids and tissues.

  • Central nervous system concentrations range from 20% to 100% of simultaneous serum concentrations.

  • Metabolism, particularly acetylation by liver N-acetyltransferase, is genetically determined.

    • Average plasma concentration in rapid acetylators about one-third to one-half that of slow acetylators.

    • Half-lives: rapid acetylators <1 hour, slow acetylators 3 hours.

  • Excreted: metabolites and small amount unchanged in urine.

  • No dosage adjustment in renal failure; for severe hepatic insufficiency, dose must be guided by serum concentrations.

A.4 Clinical Uses

  • Typical dosage: 5 mg/kg/day; adult dose: 300 mg once daily.

  • Up to 10 mg/kg/day for serious infections or malabsorption issues.

  • A 15 mg/kg dose or 900 mg may be given twice to three times weekly with another anti-tuberculosis agent (e.g., rifampin 600 mg).

  • Can be administered orally or parenterally.

  • As a single agent, indicated for latent tuberculosis:

    • Dosage: 300 mg/day or 900 mg twice weekly for 9 months.

A.5 Adverse Reactions

  • Incidence and Severity:

    • Directly related to dosage and duration of administration.

  • Immunologic Reactions:

    • Fever and skin rashes observed; reports of drug-induced systemic lupus erythematosus.

  • Direct Toxicity:

    • Hepatitis is the most common major toxic effect (1% incidence).

    • Clinical hepatitis symptoms include loss of appetite, nausea, vomiting, jaundice, right upper quadrant pain; can be fatal if not discontinued promptly.

    • Risk of hepatitis increases with age, alcohol use disorder, pregnancy, and postpartum period.

  • Peripheral Neuropathy:

    • Occurs in 10-20% of patients taking >5 mg/kg/day.

    • More likely in slow acetylators, malnutrition, alcohol use disorder, diabetes, AIDS, end-stage renal disease; related to relative pyridoxine deficiency.

  • Central Nervous System Toxicity:

    • Includes memory loss, psychosis, ataxia, seizures; toxicity reversed by administering low doses of pyridoxine (10 mg/day).

B. Rifampin

  • Description:

    • A semisynthetic derivative of rifamycin, antibiotic by Amycolatopsis rifamycinica.

    • Active against most gram-positive organisms, some gram-negative organisms (e.g., Neisseria, Haemophilus), mycobacteria, and chlamydiae.

B.1 Mechanism of Action

  • Binds to the β subunit of bacterial DNA-dependent RNA polymerase, inhibiting RNA synthesis.

  • Bactericidal for mycobacteria.

  • Penetrates various tissues well, including phagocytic cells, killing intracellular organisms and those in abscesses/lung cavities.

B.2 Resistance

  • Results from point mutations in rpoB, the gene for RNA polymerase's β subunit, reducing binding affinity.

B.3 Pharmacokinetics

  • Well absorbed; primarily excreted via liver into bile.

  • Undergoes enterohepatic recirculation; mostly excreted as a deacylated metabolite in feces, small amount in urine.

  • No dosage adjustment for renal or hepatic insufficiency necessary.

B.4 Clinical Uses

  • Mycobacterial infections:

    • 600 mg/day (10 mg/kg/day) orally, combined with isoniazid to prevent drug resistance emergence.

    • Used twice weekly in some short-course therapies.

    • Effective for atypical mycobacterial infections and leprosy.

  • Other Indications:

    • 600 mg orally twice daily for 2 days to eliminate meningococcal carriage.

    • Prophylaxis with 20 mg/kg (max 600 mg/day for 4 days) for contacts of children with Haemophilus influenzae type B.

B.5 Adverse Reactions

  • Color of urine, sweat, tears turns orange.

  • Adverse effects include rashes, thrombocytopenia, nephritis.

  • May cause cholestatic jaundice and occasionally hepatitis; common cause of light-chain proteinuria.

  • If given less than twice weekly, can cause flu-like syndrome (fever, chills, myalgias, anemia, thrombocytopenia).

  • Associated with acute tubular necrosis.

C. Ethambutol

  • Description:

    • Synthetic, water-soluble compound (dihydrochloride salt).

C.1 Mechanism of Action

  • Inhibits arabinosyl transferase, encoded by embCAB operon, involved in arabinoglycan polymerization (essential for mycobacterial cell wall).

  • Bacteriostatic drug.

C.2 Resistance

  • Due to mutations causing overexpression of embB gene; resistant strains emerge rapidly if used alone, hence always combined with other antituberculous agents.

C.3 Pharmacokinetics

  • Well absorbed from the gut, peaks in 2-4 hours.

  • 20% excreted in feces, 50% unchanged in urine.

  • Accumulates in renal failure; dosage adjustment recommended if creatinine clearance < 30 mL/min.

C.4 Clinical Use

  • Always given with other antituberculous drugs to avoid rapid resistance emergence.

  • Standard dose: 15-25 mg/kg, usually given daily in combination with isoniazid, rifampin, pyrazinamide.

C.5 Adverse Reactions

  • Hypersensitivity is rare; serious adverse event is retrobulbar neuritis leading to vision loss and red-green color blindness.

  • Monthly visual acuity checks recommended for high doses or renal impairment; restricts use in children unable to assess vision.

D. Pyrazinamide

  • Description:

    • Nicotinamide relative, used for tuberculosis treatment.

    • Slightly soluble, active in acidic environments (e.g., within lysosomes).

D.1 Mechanism of Action

  • Converted to pyrazinoic acid (active form) by mycobacterial pyrazinamidase (encoded by pncA).

  • Disrupts mycobacterial cell membrane metabolism and transport functions.

D.2 Resistance

  • Due to impaired uptake or mutations in pncA affecting conversion to active form.

D.3 Pharmacokinetics

  • Serum concentrations peak at 1-2 hours post oral administration.

  • Well absorbed and widely distributed, including inflamed meninges; half-life of 8-11 hours.

D.4 Clinical Uses

  • Used with isoniazid and rifampin in short-course regimens as a "sterilizing" agent against residual intracellular organisms.

D.5 Adverse Reactions

  • Major adverse effects: hepatotoxicity (1-5% incidence), nausea, vomiting, drug fever, photosensitivity, hyperuricemia.

II. Systemic Antifungal Drugs for Systemic Infections

A. Amphotericin B

  • Description:

    • An antifungal antibiotic from Streptomyces nodosus, a polyene macrolide.

    • Insoluble in water, prepared colloidally for IV injection; poorly absorbed orally.

A.1 Pharmacokinetics

  • >90% serum protein-bound, minimal hepatic and renal impairment effects; half-life of approximately 15 days.

A.2 Mechanism of Action

  • Selective action due to differences in lipid composition between fungal (ergosterol) and mammalian (cholesterol) membranes.

    • Binds to ergosterol, altering membrane permeability, leads to cell death.

A.3 Resistance

  • Occurs if ergosterol binding is impaired; associated with decreased ergosterol concentration or alterations that reduce binding affinity.

A.4 Antifungal Activity

  • Effective against significant yeasts, such as Candida albicans and Cryptococcus neoformans, endemic mycoses (e.g., Histoplasma capsulatum), molds like Aspergillus fumigatus.

A.5 Clinical Uses

  • First-line for life-threatening mycotic infections, often induction therapy, especially in immunosuppressed patients.

  • Topical/administered for fungal arthritis, candiduria; poor tolerance for intrathecal administration.

A.6 Adverse Effects

  • Infusion-related toxicity common; renal damage most significant.

    • Can lead to prerenal renal failure or irreversible tubular injury; metabolic derangements possible.

B. Flucytosine

B.1 Pharmacokinetics

  • Well absorbed, peaks 1-2 hours post-dose, poorly protein-bound, penetrates body fluids, eliminated primarily via kidneys.

B.2 Mechanism of Action & Resistance

  • Taken up by fungal cells via cytosine permease; converted to active forms affecting DNA/RNA synthesis; resistance through altered metabolism.

B.3 Clinical Uses

  • Limited to combination therapy due to synergy with other agents; often with amphotericin B for cryptococcal meningitis.

B.4 Adverse Effects

  • Bone marrow toxicity (anemia, leukopenia), derangement of liver enzymes, potential toxic enterocolitis.

C. Azoles

C.1 Mechanisms of Action and Resistance

  • Selective toxicity through greater affinity for fungi compared to human cytochrome P450.

  • Inhibition of ergosterol synthesis through P450 enzyme inhibition.

C.2 Clinical Uses, Adverse Effects, and Drug Interactions

  • Broad activity against many species; common minor adverse reactions, liver enzyme abnormalities, interactions via P450 inhibition.

C.3 Specific Azoles

  • Ketoconazole:

    • First oral azole; more toxic to mammalian enzymes.

  • Itraconazole:

    • Preferred for dimorphic fungi treatment; undergoes hepatic metabolism but has less adverse interaction potential.

  • Fluconazole:

    • Preferred for cryptococcal meningitis; minimal hepatic impact.

  • Voriconazole:

    • Treatment of invasive aspergillosis, noted for visual disturbances.

  • Posaconazole:

    • Broad spectrum including mucormycosis; absorption enhanced with fatty meals.

  • Isavuconazole:

    • Newest triazole with similar action to posaconazole.

D. Echinocandins

D.1 Chemistry and Pharmacokinetics

  • Large cyclic peptides linked to fatty acids; intravenous formulations only.

D.2 Mechanism of Action

  • Inhibit β(1-3)-glucan synthesis, disrupting fungal cell walls.

D.3 Clinical Uses

  • Licensed for candidemia, esophageal candidiasis; highly tolerated with minor side effects.

D.4 Adverse Effects

  • Usually well tolerated; minor gastrointestinal issues, and elevation in liver enzymes with interactions.

III. Oral Systemic Antifungal Drugs for Mucocutaneous Infections

A. Griseofulvin

  • Description:

    • Insoluble fungistatic derived from penicillium; used in systemic dermatophytosis treatment.

    • Administered in microcrystalline form (up to 1g/day), absorbed better with fatty food.

A.1 Mechanism of Action

  • Uncertain, sits in newly forming skin bonding to keratin, protecting against new infections.

A.2 Adverse Effects

  • Allergic reactions resembling serum sickness, skin reactions, hepatotoxicity, interactions with warfarin, phenobarbital.

B. Terbinafine

  • Description:

    • Systemic allylamine, effective for dermatophytes; more tolerated than griseofulvin.

B.1 Mechanism of Action

  • Fungicidal, inhibits squalene epoxidase affecting ergosterol biosynthesis.

B.2 Adverse Effects

  • Rare, primarily gastrointestinal upset or headache; cases of serious hepatotoxicity reported.

Topical Antifungal Therapy

  • Nystatin:

    • Active against Candida, used for local infections like oral thrush.

  • Topical azoles:

    • Include clotrimazole, miconazole for vaginal candidiasis.

  • Topical Allylamines:

    • Terbinafine, naftifine for tinea cruris, corporis.