Metronidazole: Antibiotic Mechanism, Indications, and Contraindications

Antibiotics that Interfere with DNA Synthesis

• Metronidazole increases formation of reactive oxygen species (free radicals) to produce breaks in bacteria's DNA.
• It enters bacteria via cell diffusion.
• Contraindicated in patients with renal or liver impairment.
• Effective against anaerobes, protozoans (Entamoeba histolytica, Giardia lamblia, and Trichomonas vaginalis), and most gram-negative and gram-positive anaerobic bacteria.
• Often used due to bacterial resistance to amoxicillin and tetracycline or due to intolerance (H. pylori).

Rifampicin and Fluoroquinolones

• Rifampicin is used for treatment of TB.
• Fluoroquinolones have concentration-dependent killing and nick and relax DNA supercoiled for DNA replication.
• Topoisomerases II are inhibited in gram-negative bacteria, while Topoisomerases IV are inhibited in gram-positive bacteria.
• First-generation fluoroquinolones include Ciprofloxacin and Ofloxacin (broad-spectrum drugs).
• Second-generation fluoroquinolones include Levofloxacin and Moxifloxacin (newer generation and better for gram-positive bacteria).
• Parent drug is Nalidixic acid (a quinolone).

Inhibitors of Cell Wall Synthesis

• Beta-lactams are time-dependent killing and inhibit peptidoglycan synthesis.
• Vancomycin is a glycopeptide that inhibits the second stage of cell wall peptidoglycan synthesis by binding to the D-alanyl-D-alanine precursor peptide side chain.
• Effective against MRSA infections, but contraindicated in patients with renal impairment.
• Penicillin allergic and has resistance to gram-positive bacteria.

Beta-Lactam Antibiotics

• Natural penicillins include Penicillin G potassium and Penicillin V phenoxy methyl.
• Penicillinase-resistant drugs include Cloxacillin and Methicillin.
• Amino-penicillins are extended drugs, effective against gram-positive and gram-negative organisms, and used for H. pylori.
• Amino-penicillins include Ampicillin and Amoxicillin.
• Ureidopenicillin includes Piperacillin.
• Cephalosporins include:
  • First-generation: Cefazolin
  • Second-generation: Cefuroxime and Cefoxitin
  • Third-generation: Cefotaxime, Ceftriaxone, and Ceftazidime
  • Fourth-generation: Cefepime and Cefpirome
• Carbapenems are a subclass of beta-lactams, used for treatment of severe infections of resistant bacteria, and include:
  • Doripenem (Doribax)
  • Imipenem (Primaxin)
  • Meropenem (Merem)
  • Ertapenem (Invanz)

Aminoglycosides

• Aminoglycosides are concentration-dependent, mainly administered intravenously, and have main activity against gram-negative bacilli and staphylococcal species.
• Systemic administration may lead to ototoxicity, nephrotoxicity, and respiratory depression.
• Reserved for severe systemic gram-negative infections.
• Excreted in topical ophthalmic use, but only for short therapy (5-7 days).
• Resistance occurs due to alteration of 30s subunit binding site, change in cell membrane permeability, and enzymatic inactivation.
• Adverse effects include vestibular and auditory dysfunction, nephrotoxicity (tubular necrosis), and respiratory depression (neuromuscular paralysis).

Beta-Lactamase Inhibitors

• Beta-lactamase inhibitors protect from the hydrolytic activity of beta-lactamases by "suicide" inactivation (inhibitor is hydrolyzed).
• Examples include:
  • Amoxicillin-clavulanate
  • Piperacillin-tazobactam
  • Ampicillin-sulbactam