Living Textbook MC610

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RNA Transcription Inhibitors

Fidaxomicin is a narrow spectrum antibiotic that blocks the initiation of RNA transcription, by preventing the opening of the DNA template.

Fidaxomicin is very effective in inhibiting RNA polymerase of Clostridium spp. It has little effect on other bacteria, so it preserves the normal flora.

It is used as a third line treatment for pseudomembranous colitis.

Rifamycins are isolated from streptomyces sp. and are effective against a wide variety of bacteria, including mycobacterium, but cannot penetrate Gram negative cells.  They inhibit bacterial RNA polymerase by binding to the β-subunit of the enzyme, and block RNA synthesis. They are highly effective against rapidly dividing mycobacterium, and are specific to bacterial RNA polymerase.
Rifampin and Rifapentine are semisynthetic agents that are used in combination with INH. 

They bind reversibly to RNA polymerase via at least three binding points:

  1. Hydrophobic interaction between the naphthalene ring and proteins in the enzyme via a π-π interaction.
  2. Hydrogen bonding between hydroxyl groups on C21 and C23 with RNA polymerase.
  3. Hydrogen bonding between the
  4. hydroxyl groups at C1 and C8 and amino acids in the active site.

Both agents are orally active, but should be given on an empty stomach.  They have a red-orange color that will cause coloration of different fluids such as urine and tears and may stain the skin and contact lenses.
They induce some CYP450 isozymes, which may decrease the effectiveness of other drugs such as oral contraceptives, warfarin, other antimicrobials and many antiviral agents used in treatment of HIV.
Resistance arises via mutations to bacterial RNA polymerase, which diminishes the binding capacity of Rifamycins.
Rifapentine (Priftin®) is considered more active than Rifampin, and has a longer half-life resulting in a less frequent dose regimen. It
differs in the 3-substitution, which is thought to be responsible for cell entry, and thus this agent shows better oral bioavailability and has a superior dosing regimen.

Rifabutin is similar to Rifampin, but is a weaker inducer of CYP450 and can be useful in patients on other medications such as AIDS patients.

Rifaximin is poorly absorbed from the GIT, so used for its local effects.

Clinical Applications:

General: Bactericidal with a narrow spectrum, mostly Gram positive.

Fidaxomicin:

Coverage is largely limited to Clostridium difficile

Indications and Uses:  In Clostridium difficile-associated diarrhea (CDAD)

Rifampin:

Coverage of many Gram positive bacteria including MRSA and other Staphylococcus spp.  Limited activity against Gram negative bacteria except for Neisseria meningitides.  Effective against M. tuberculosis.

Indications and Uses: Treatment of active and latent TB and leprosy, in combinations.  Useful in treatment of asymptomatic carriers of Neisseria meningitides and in prophylaxis for those in contact with carriers of this organism.

Rifapentine:

Indications and Uses: Useful in both active and latent TB.

Rifabutin:

Indications and Uses: Indicated for Mycobacterium avium complex (MAC) and in TB.

Rifaximin:

Indications and Uses: Indicated in traveler’s diarrhea, irritable bowel syndrome and hepatic encephalopathy and is sometimes used in recurrent C. difficile infections.