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69. Nitroimidazoles. RNA polymerase inhibitors

RNA polymerase inhibitors include the macrocyclines and rifamycins.

Nitroimidazoles

Compounds

  • Metronidazole
  • Tinidazole

The most important nitroimidazole is metronidazole, but tinidazole is very similar.

Mechanism of action

Nitroimidazoles are prodrugs which are metabolized into reactive metabolites by enzymes inside the pathogen cell. The reactive metabolites then bind to and damage DNA and proteins. This effect is bactericidal.

Mechanism of resistance

Decreased expression of the enzymes which activate them. Decreased penetration into the pathogen.

Pharmacokinetics

They are orally absorbed and penetrates tissues well (including the CNS). They are metabolised in the liver and excreted by the kidneys. They inhibit CYP2C9 and CYP3A4.

Adverse effects

  • Headache
  • Metallic taste

Nitroimidazoles inhibit aldehyde dehydrogenase and therefore give a disulfiram-like effect if alcohol is consumed.

Clinical use

Metronidazole is effective against anaerobic bacteria, and is often used in infections caused by anaerobes.

  • Entamoeba histolytica
  • Trichomoniasis
  • Giardia
  • C. difficile
  • H. pylori
  • Bacterial vaginosis

Metronidazole is the second choice in treating C. difficile colitis. It is also used in combination therapy to treat H. pylori.

Macrocyclines

The only important macrocycline is fidaxomicin.

Indications

Clostridium difficile infection.

Mechanism of action

Fidaxomycin inhibits RNA polymerase, causing a bactericidal effect. There’s a long postantibiotic effect.

Its antimicrobial spectrum is extremely narrow, targeting almost exclusively C. diff while sparing the normal intestinal flora.

Pharmacokinetics

It’s not absorbed from the gut, only acting locally.

Rifamycins

The most important rifamycins are rifampicin (known as rifampin in the US) and rifabutin.

Indications

Rifampicin is part of the first-line therapy for TB. Rifabutin is used in rifampin-resistant mycobacteria and to treat people with HIV and TB.

These drugs can also be used to treat H. influenzae type b and leprosy.

Mechanism of action

These drugs inhibit RNA polymerase, making them bactericidal.

Pharmacokinetics

Rifamycins are orally absorbed and well distributed.

They’re partially metabolized in the liver by CYP3A4 and mainly excreted by bile. Rifampicin is a strong CYP inducer, also for CYP3A4, thereby inducing its own elimination.

Interactions

Rifampicin is a strong CYP inducer for many of the isozymes, including the isozyme which is most involved in metabolism of drugs (CYP3A4). This causes it to interact with a large number of drugs. The maybe most clinically relevant is that it interacts with anti-HIV drugs.

Rifabutin is not a CYP inducer. For this reason, it’s preferred over rifampin in people who take anti-HIV drugs.

Side effects

  • Hepatotoxicity
  • Harmless orange discoloration of body fluids (urine, tears)
    • Due to the strong red-orange colour of these drugs