Quinolones & Folic Acid Antagonists Flashcards

Quinolones

Mechanism of Action

• Inhibit nucleic acid synthesis by inhibiting bacterial replication.
• Enter the bacterium through porins.
• Inhibit DNA gyrase (topoisomerase II) leading to inhibition of DNA replication and cell death.
• Inhibit topoisomerase IV, decreasing bacterial division.
• Effective against both Gram-negative and Gram-positive bacteria.

Classification of Quinolones

1st Generation: Non-fluorinated

• Nalidixic Acid
  • Used only in urinary tract infections with Gram-negative bacilli.
  • Rapid resistance limits its use.

2nd to 4th Generation: Fluoroquinolones

• Newer fluorinated derivatives achieving systemic levels, used in systemic infections.
• More potent.
• Broader spectrum.
• Better safety profile.

Generations and Spectrum

• 1st generation: Mainly Gram-negative.
• 2nd generation: Weak against Gram-positive bacteria and anaerobes.
• 3rd & 4th generation: Increased activity against Gram-positive bacteria and anaerobes.

Members & Spectrum

• 1st Generation:
  • Nalidixic acid: Narrow spectrum, Gram-negative bacilli.
• 2nd Generation:
  • Ciprofloxacin:
    • Gram-negative (including Pseudomonas species).
    • Some Gram-positive.
    • Effective against Chlamydia & Mycoplasma pneumoniae.
• 3rd Generation:
  • Levofloxacin:
    • Effective against Gram-negative bacteria.
    • Effective against Gram-positive (including Streptococcus pneumoniae).
    • Effective against Chlamydia & Mycoplasma pneumoniae.
• 4th Generation:
  • Moxifloxacin:
    • Same as 3rd generation (but not effective on Pseudomonas).
    • Effective against Anaerobes.

Therapeutic Applications of Fluoroquinolones

• Typhoid fever: Ciprofloxacin is the 1st choice in third-world countries.
• Urinary tract infections: All except Moxifloxacin.
• Anaerobic infections: Moxifloxacin.
• Respiratory infections: Levofloxacin & Moxifloxacin (respiratory quinolones), but not Ciprofloxacin.
• Ciprofloxacin is the most potent fluoroquinolone for pseudomonal infections and is used as an alternative to more toxic drugs, such as aminoglycosides.
• Levofloxacin is often effective in treating resistant respiratory infections unresponsive to β-lactam antibiotics such as amoxicillin-clavulanic acid.

Pharmacokinetics

• Absorption
  • Decreased absorption if administered with sucralfate, antacids (Al or Mg), or dietary supplements with Fe, Zn, or Ca.
• Distribution & Elimination
  • High levels in bone, urine, and kidney.
  • Excreted renally (Except Moxifloxacin, which is excreted in bile).

Adverse Reactions

• Gastrointestinal: Nausea, vomiting, diarrhea.
• Central nervous system: Headache & dizziness (use cautiously in epilepsy).
• Phototoxicity: Avoid excessive sunlight & apply sunscreens.
• Connective tissue:
  • Arthropathy
  • Tendinitis & tendon rupture, especially in the Achilles tendon (FDA Black Box Warning, 2008). Occurs during treatment or up to several months after completion of therapy, especially in the elderly.
• Cardiovascular
• Drug interactions:
  • Decreased absorption with antacids.
  • Enzyme inhibitor, increases serum level of theophylline.
  • Increases warfarin & cyclosporine levels.

Contraindications

• Pregnancy & lactating females.
• Children < 18 years.
• Elderly > 60 years.

Folate Antagonists

Mechanism of Action

• Inhibit folic acid synthesis, which is essential for bacterial DNA & RNA synthesis.
• In bacteria, folate is synthesized. Human cells utilize already-formed folic acid; this explains the selectivity of sulfonamides to bacteria.

Folic acid \rightarrow Folinic acid

• Sulfonamides: Structural analogs of p-aminobenzoic acid (PABA). Compete with PABA for the enzyme dihydropteroate synthetase, inhibiting bacterial dihydrofolic acid synthesis.
• Trimethoprim: Inhibits dihydrofolate reductase in bacteria and humans.

Pharmacokinetics

• Absorption: Well absorbed orally, except Sulfasalazine.
• Distribution: Cross the placenta & BBB.
• Metabolism: Acetylated in the liver, producing a toxic metabolite that precipitates at neutral or acidic pH, leading to crystalluria and stone formation in the kidneys.
• Elimination: Renal.

Therapeutic uses

• Chronic inflammatory bowel disease: Sulfasalazine.
• Malaria: Sulfadiazine + pyrimethamine (inhibits DHF reductase).
• Burns: Topical sulfadiazine to prevent bacterial colonization.

Adverse Reactions

• Crystalluria: Prevent by adequate hydration & alkalinization of urine.
• Hypersensitivity: Rashes & angioedema.
• Hemopoietic disturbance: Hemolytic anemia in patients with G6PD-deficiency.
• Kernicterus: In newborns, sulfa drugs displace bilirubin from binding sites on serum albumin, allowing free bilirubin to pass into the CNS (baby’s BBB is not fully developed), leading to jaundice & CNS affection.
• Drug interaction: Increases the effect of warfarin due to displacement from albumin.

Contraindication

• Newborns, infants, pregnant women.

Trimethoprim

Mechanism of Action

• Similar to sulfonamides.

Adverse effects

• Produces manifestations of folic acid deficiency, such as megaloblastic anemia, especially in pregnant women.

Cotrimoxazole

Mechanism of Action

• Combination of sulfamethoxazole + trimethoprim.

Advantages

• Synergistic combination.
• Less and delayed bacterial resistance.
• More potent (Bactericidal) & wider-spectrum.

Therapeutic uses

• Urinary tract infections

Adverse effects

• Skin rash, GIT upset & haematological disturbance.

Metronidazole

Mechanism of Action

• Inhibits proteins and DNA, resulting in cell death.

Therapeutic Uses

• Used in the treatment of infections caused by anaerobic bacteria

Adverse effects

• Nausea, vomiting, epigastric distress, and abdominal cramps.
• Metallic Taste (Unpleasant)
• If taken with alcohol, causes a disulfiram-like effect.

Clinical scenarios/examples

• 27 year old intravenous drug abuser with S. aureus resistant to methicillin should be treated with Vancomycin
• 19 year old military recruit with bacterial meningitis should be treated with ceftriaxone

Important side notes and contraindications

• Tetracyclines, Chloramphenicol, Sulfonamides, and Quinolones are all antibiotics that are contraindicated in infants and children
  • Tetracyclins: teeth discoloration and bone deformity
  • Chloramphenicol: grey baby sydrome
  • Sulfonamides: kernicterus in newly-born
  • Quinolones: arthropathy
• Clindamycin and tetracycline may cause Clostridium difficile diarrhea and pseudomembranous colitis
  • This can be treated with Vancomycin orally
• Rapid IV infusion of Vancomycin may cause red man syndrome

Useful combinations

• Penicillin + probencid
• Imipenem + cilastatin

Antibiotics to use cautiously

• penicillins, cephalosporines and erythromycin are generally safe to use during pregnancy

Drugs acting against pseudomonas infection

• Anti-pseudomonas penicillins
• Third and forth generation cephalosporines
• Imipenem, aztreonam
• Aminoglycosides
• ciprofloxacin