Rifamycin derivatives

Rifamycin derivatives are a family of bactericidal antibiotics primarily used in the treatment of mycobacterial infections such as tuberculosis (TB), leprosy, and Mycobacterium avium complex (MAC). They are also employed in prophylaxis and treatment of meningococcal infections, traveler’s diarrhea, and Clostridioides difficile infections depending on the agent and formulation. Rifamycins are derived from the actinomycete Streptomyces rifamycinica and exert their effects through potent and selective inhibition of bacterial DNA-dependent RNA polymerase, leading to suppression of RNA synthesis and bacterial cell death.

This class of antibiotics includes several clinically important agents, the most prominent of which are rifampin (rifampicin), rifabutin, rifapentine, rifaximin, and rifalazil. These agents vary in their pharmacokinetic profiles, tissue penetration, and antimicrobial spectrum, allowing tailored use for specific infections and host contexts.

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1. Overview of Rifamycin Class

Core Structure: Rifamycins share a macrocyclic naphthohydroquinone nucleus linked to an aliphatic ansa chain. This structure allows them to penetrate bacterial membranes and bind selectively to bacterial RNA polymerase β-subunit.

Derivatives:

• Rifampin (Rifampicin)

• Rifabutin

• Rifapentine

• Rifaximin

• Rifalazil (investigational)

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2. Mechanism of Action

Rifamycin derivatives bind to the β-subunit of prokaryotic DNA-dependent RNA polymerase and inhibit the initiation of RNA transcription. This:

• Prevents elongation of RNA chains

• Halts protein synthesis

• Results in bactericidal activity against both replicating and some dormant bacteria

Notably:

• They are selective for bacterial RNA polymerase; do not inhibit eukaryotic transcription enzymes

• Activity is concentration-dependent

• Resistance can occur through mutations in the rpoB gene

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3. Antimicrobial Spectrum

Target Organisms	Sensitivity to Rifamycins
Mycobacterium tuberculosis	High (rifampin, rifabutin, rifapentine)
Mycobacterium leprae	High (rifampin)
Mycobacterium avium complex (MAC)	Rifabutin > rifampin
Neisseria meningitidis	Rifampin (prophylaxis)
Staphylococcus aureus (including MRSA)	Rifampin (in combination only)
Clostridioides difficile	Rifaximin, rifampin (limited utility)
Enterotoxigenic E. coli (ETEC)	Rifaximin
Anaerobes	Rifaximin (intestinal)
Chlamydia, Legionella, Brucella	Rifampin (with others)

4. Individual Rifamycin Derivatives

A. Rifampin (Rifampicin)

• Brand Names: Rifadin, Rimactane

• Route: Oral, IV

• Bioavailability: ~68% (oral); food reduces absorption

• Half-life: ~3–5 hours

• Indications:

  • First-line for tuberculosis (with isoniazid, pyrazinamide, ethambutol)

  • Leprosy

  • Meningococcal prophylaxis

  • MRSA or prosthetic joint infections (with other agents)

• Notable Features:

  • Potent inducer of CYP450 enzymes

  • Penetrates well into CSF, bile, lungs

  • Causes red-orange discoloration of body fluids

B. Rifabutin

• Brand Name: Mycobutin

• Route: Oral

• Bioavailability: ~20%

• Half-life: ~45 hours (long)

• Indications:

  • Prophylaxis and treatment of MAC in HIV/AIDS

  • Alternative to rifampin in patients on antiretrovirals (less CYP3A4 induction)

• Advantages:

  • Less hepatic enzyme induction

  • Good intracellular penetration

• Adverse Effects:

  • Uveitis, arthralgia, neutropenia

C. Rifapentine

• Brand Name: Priftin

• Route: Oral

• Bioavailability: ~70%

• Half-life: ~13 hours

• Indications:

  • Latent TB infection (LTBI) – weekly dosing with isoniazid for 12 weeks (3HP regimen)

  • Pulmonary TB (intermittent dosing)

• Notes:

  • Long half-life allows intermittent therapy

  • Not for HIV patients with CD4 < 200 unless careful monitoring

D. Rifaximin

• Brand Name: Xifaxan

• Route: Oral (non-absorbed)

• Bioavailability: <1%

• Indications:

  • Traveler’s diarrhea (non-invasive E. coli)

  • Hepatic encephalopathy (↓ ammonia-producing gut flora)

  • IBS with diarrhea (IBS-D)

  • C. difficile (non-FDA approved; off-label use)

• Advantages:

  • Minimal systemic absorption → very safe

  • No effect on CYP enzymes

E. Rifalazil (Investigational)

• Long half-life rifamycin under study for:

  • TB

  • Chlamydia

  • C. difficile

• Not yet FDA approved

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5. Pharmacokinetics Comparison

Drug	Route	Bioavailability	Half-Life	CYP Induction	CSF Penetration	Notes
Rifampin	Oral/IV	~68%	3–5 h	Strong	Yes	High resistance risk when used alone
Rifabutin	Oral	~20%	45 h	Mild	Moderate	Better for HIV co-treatment
Rifapentine	Oral	~70%	13 h	Moderate	Low	Weekly TB treatment
Rifaximin	Oral	<1%	6 h	None	No	Stays in GI tract

6. Adverse Effects

System	Adverse Effects
General	Fever, rash, fatigue
Gastrointestinal	Nausea, vomiting, diarrhea
Hepatic	Transaminase elevations, hepatotoxicity
Hematologic	Thrombocytopenia, leukopenia (esp. rifabutin)
Dermatologic	Pruritus, flushing
Ocular	Uveitis (rifabutin), optic neuritis (rare with rifampin)
Urine/Secretions	Orange-red discoloration (rifampin, rifabutin)
Hypersensitivity	Anaphylaxis, DRESS syndrome (rare)

7. Contraindications and Precautions

• Hypersensitivity to rifamycins

• Severe hepatic dysfunction: Risk of worsening liver failure

• Concurrent protease inhibitor use: Rifampin contraindicated (rifabutin preferred)

• Pregnancy: Rifampin is pregnancy category C; used cautiously, often with vitamin K

• Monotherapy in TB: Always avoid → rapid resistance

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8. Drug Interactions

CYP450 Enzyme Induction (especially rifampin and rifapentine)

Interacting Drug/Class	Effect	Action
Oral contraceptives	↓ Effectiveness	Use backup contraception
Warfarin	↓ INR	Increase dose or monitor INR closely
Antiretrovirals (PIs, NNRTIs)	↓ plasma levels	Use rifabutin instead
Anticonvulsants	Altered levels	Dose adjustments needed
Azoles (e.g., fluconazole)	↓ azole levels	Monitor for treatment failure

Rifaximin has negligible interactions due to lack of systemic absorption.

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9. Resistance Considerations

• Monotherapy leads to resistance rapidly, particularly in TB and leprosy

• Resistance arises from point mutations in the rpoB gene coding RNA polymerase β-subunit

• Combination therapy (e.g., RIPE regimen in TB) prevents emergence of resistance

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10. Clinical Uses Summary by Agent

Drug	Primary Uses
Rifampin	TB (active), leprosy, prosthetic infections, meningitis prophylaxis
Rifabutin	TB in HIV, MAC, alternate for rifampin in HAART patients
Rifapentine	LTBI (with isoniazid weekly x12 weeks), active TB (intermittent regimens)
Rifaximin	Traveler’s diarrhea, hepatic encephalopathy, IBS-D
Rifalazil	Under development; TB, C. difficile, STIs

11. Monitoring and Clinical Guidelines

Monitoring Parameters:

• LFTs: Baseline and periodic (hepatotoxicity risk)

• CBC: Especially with rifabutin (neutropenia risk)

• Drug levels: Not routinely done but useful in treatment failure

• Visual examination: With rifabutin if prolonged use

Guidelines:

• CDC and WHO TB Guidelines:

  • Rifampin: cornerstone of initial intensive phase (RIPE regimen)

  • Rifapentine: for 3HP regimen in LTBI

• ATS/IDSA MAC Guidelines:

  • Use rifabutin + macrolide + ethambutol

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12. Generic and Brand Name Summary

Generic Name	Brand Names	Use/Notes
Rifampin	Rifadin, Rimactane	First-line for TB, meningitis prophylaxis
Rifabutin	Mycobutin	TB in HIV, MAC
Rifapentine	Priftin	LTBI, long-acting
Rifaximin	Xifaxan	GI infections, nonabsorbed
Rifalazil	—	Investigational