Antimicrobial Agents: Tetracyclines and Antifungals

Antimicrobial Agents: Tetracyclines, Chloramphenicol, and Antifungals

• Antibiotics are compounds produced by microorganisms that inhibit other microorganisms.
• Tetracyclines are a class of antibiotics with a nucleus of 4 cyclic rings. They are obtained from soil actinomycetes and are broad-spectrum antibiotics.
• Tetracyclines inhibit protein synthesis by binding to 30S ribosomes in susceptible organisms, preventing the binding of aminoacyl tRNA to mRNA, thus hindering peptide chain growth.
• Tetracyclines have a wide antimicrobial spectrum initially, but indiscriminate use has led to the development of antibiotic resistance in numerous species.
• Common tetracycline types are demeclocycline, minocycline, and doxycycline.
• Doxycycline has better oral bioavailability and isn't affected by food chelates as much as other tetracyclines.
• Tetracyclines are administered orally and widely distributed in the body. They are mainly excreted by the kidneys.
• Adverse effects of tetracyclines may include: epigastric pain, nausea, vomiting, diarrhea, hepatotoxicity (fatty liver infiltration, jaundice), nephrotoxicity. (renal problems excluding Doxycycline), phototoxicity, tooth discoloration, hyper sensitivity. These problems can be more severe with degraded tetracycline use.
• Tetracyclines should not be used during pregnancy, lactation, or in children, and caution is advised in renal or hepatic insufficiency patients.
• Chloramphenicol is an older antibiotic, initially derived from bacteria, now chemically synthesized.
• Chloramphenicol's mechanism of action is bacteriostatic, binding to 50S ribosome and inhibiting protein synthesis. It's similar to other tetracyclines in spectrum, but highly effective against Salmonella typhi.
• Chloramphenicol is rapidly absorbed orally, and conjugated by the liver with glucuronic acid. Use with caution in patients with cirrhosis and/or immature livers (neonates).
• Adverse effects of Chloramphenicol include bone marrow suppression (aplastic anemia, agranulocytosis), myelosuppression, and idiosyncratic reactions, including fatal aplastic anemia.
• Uses for Chloramphenicol are extremely limited due to resistant strains and safer alternatives. It’s currently used in pyogenic meningitis and enteric fever.
• Antifungal drugs treat both superficial and deep (systemic) mycosis.
• Fungal infections emerged in the 1950s due to the use of broad-spectrum antibiotics, corticosteroids, chemotherapy, and immunosuppressants, and the emergence of AIDS.
• Antifungal drugs include polyenes, azoles, allylamines, and echinocandins.
• Amphotericin B is a polyene antibiotic with numerous double bonds that inhibits fungi, specifically targeting ergosterol in fungal membranes.
• The administration of Amphotericin B is done intravenously.
• Adverse effects of Amphotericin B are usually dose-dependent acute/short-term (chills, fever, pain, nausea, vomiting, dyspnea) and long-term nephritis, and potentially fatal bone marrow suppression.
• Liposomal Amphotericin B formulations have decreased toxicity compared to standard Amphotericin B.
• Nystatin is another polyene antibiotic, derived from Streptomyces noursei, with similar properties to Amphotericin B but with higher systemic toxicity.

Antifungal Drug Classifications

• Polyenes:
  • Amphotericin B
  • Nystatin
• Azoles:
  • Clotrimazole
  • Miconazole
  • Oxiconazole
  • Ketoconazole
  • Fluconazole
  • Itraconazole
  • Voriconazole
• Allylamines:
  • Terbinafine
• Echinocandins:
  • Caspofungin
• Griseofulvin

Specific Antifungal Drug Details

• Griseofulvin:
  • Fungistatic and effective against dermatophytes.
  • Poor oral absorption; better absorption with fatty meals.
  • Keratophilic, deposits in keratin-producing cells of skin, nails, and hair and persists for weeks.
• Fluconazole:
  • Water-soluble triazole with good oral bioavailability.
  • Less anti-androgenic activity compared to other drugs, less likely to cause undesirable hormonal effects.
• Itraconazole:
  • Variable oral absorption; affected by food and gastric acid.
• Voriconazole:
  • Second-generation broad-spectrum azole; used for invasive fungal infections like aspergillosis, candidiasis, histoplasmosis, and blastomycosis.
• Terbinafine:
  • Orally and topically active against dermatophytes and candida spp.
  • Inhibits squalene epoxidase.
• Tolnaftate:
  • Poor skin penetration; primarily topical.
• Ciclopirox olamine:
  • Newer for tinea infections, good keratin penetration but poor systemic absorption.

Candidiasis

• Candidiasis is a fungal infection caused by Candida albicans.
• Different types of candidiasis exist based on location
• Vaginal, Oral, Cutaneous, Invasive infections, and Candida granuloma.

Antifungal Drug Administration, Toxicity, and Uses

• Amphotericin B is usually administered intravenously (IV).
• Administration of other antifungal drugs such as fluconazole is usually oral.
• Many antifungal drugs show some degree of toxicity, including acute, short-term effects (chills, pain, vomiting) and more severe, longer-term adverse effects like kidney damage.
• Careful attention to patient needs and treatment response are essential to managing fungal infections.