rifampin; rifampicin (Rifadin, Rimactane)

Introduction

Tradename: Rifadin, Rimactane.

Indications

• treatment of tuberculosis in combination with other agents, especially isoniazid, pyrazinamide & ethambutol
• prophylaxis for meningiococcal meningitis (post-exposure)
• adjunctive agent for treatment of Staphylococcal infection
  • including MRSA & coagulase-negative Staphylococci
  • patients with indwelling foreign bodies
• prophylaxis of Haemophilus influenzae type B
• adjunctive agent for treatment of
  • osteomyelitis
  • anthrax
    • cutaneous anthrax
    • inhalation anthrax
  • leprosy
  • brucellosis

Contraindications

(& cautions)

• MUST be in conjunction with a bactericidal agent in the treatment of Staphylococcal infection due to the rapid emergence of resistance
• NOT effective for Staphyloccal urinary tract infections
• diminishes effectiveness of oral contraceptives: use backup method of contraception to prevent pregnancy
• use with caution or not at all with antiretroviral protease inhibitors or non-nucleoside reverse transcriptase inhibitors
• coadministration of ritonavir or saquinavir

pregnancy category = c

safety in lactation = ?

Dosage

• tuberculosis: 10-20 mg/kg up to 600 mg PO/IV QD
• 600 mg PO QD as adjunctive agent for treatment of Staphylococcus infection
• 600 mg PO BID for 4 days for meningiococcal exposure & Haemophilus influenzae exposure

Tabs: 150 & 300 mg.

Powder for injection: 600 mg (contains sulfite).

Dosage adjustment in renal failure

Table

creatinine clearance	dosage
> 50-90 mL/min	600 mg every 24 hours
10-50 mL/min	300-600 mg every 24 hours
< 10 mL/min*	300-600 mg every 24 hours

* No additional dosing for hemodialysis

Pharmacokinetics

• well absorbed orally
• food delays absorption
• 1st pass hepatic metabolism is saturated with higher doses
• penetrates well into cells & most tissues
• penetration through non-inflammed meninges is poor, but good CSF concentrations are obtained through inflammed meninges
• peak serum concentrations 1.5-2 hours after oral ingestion
• serum levels of 6-7 ug/mL with usual dose
• MIC of 0.5 ug/mL for most strains of M. tuberculosis
• eliminated by deacetylation in the liver
  • metabolite desacetylrifampin is less active than parent compound
• 12-15% excreted in the urine, thus minimally effective for urinary tract infections (Staphylococcus)
• elimination 1/2life is 3 hours (3-11 hours ESRD)
  • shorter after the 1st few days of therapy
  • increases with increasing dosage & decreases with chronic administration

elimination via liver

elimination via kidney

1/2life = 2.6-5.1 hours

protein binding = 75-90 %

elimination by hemodialysis = -

elimination by peritoneal dialysis = -

Monitor

• liver function tests (serum AST, serum ALT, serum bilirubin) baseline & at 6 & 12 weeks all patients
• in patients with symptoms of liver dysfunction, check serum ALT & serum AST every 2-4 weeks

Antimicrobial activity

Gram positive

• Streptococcus
  • Streptococcus group A
  • Streptococcus group B
  • Streptococcus group C
  • Streptococcus group G
  • Streptococcus pneumonia
• Enterococcus faecalis (+/-)
• Staphylococcus aureus (MSSA, MRSA)
• Staphylococcus epidermidis

Gram negative

• Neisseria gonorrhoeae
• Moraxella catarrhalis
• Haemophilus influenzae
• Francisella tularensis
• Brucella species

Atypical bacteria

• Chlamydia species
• Mycobacterium tuberculosis

Adverse effects

• not common (1-10%)
  • diarrhea
  • epigastric cramps
  • discoloration of urine, feces, saliva, sputum, sweat & tears (reddish orange)*
  • fungal overgrowth
• uncommon (< 1%)
  • drowsiness, fatigue, ataxia, confusion, fever, headache, rash, pruritus, nausea/vomiting, stomatitis, eosinophilia, blood dyscrasias, leukopenia, thrombocytopenia, hepatitis, irritation at site of IV injection, renal failure, flu-like syndrome
• other
  • GI upset (most common): nausea/vomiting
  • skin eruptions
  • cholestatic jaundice (rare)
  • acute renal failure at doses > 10 mg/kg
    • interstitial nephritis
    • minimal change glomerulonephropathy

* Rifampin is excreted in the urine, tears, sweat & other body fluids coloring them orange. Permanent discoloration of soft contact lenses may occur.

Drug interactions

• rifampin induces cyt P450s CYP1A2, CYP2C9 & CYP3A4 decreasing levels of:
  • methadone, warfarin, glucocorticoids, estrogens*, digoxin, oral hypoglycemic agents, digitoxin, quinidine, verapamil, mexiletine, theophylline, anticonvulsants, ketoconazole, cyclosporine, barbiturates, chloramphenicol
• halothane
• benzodiazepines
• beta-blockers
• isoniazid in combination increases hepatotoxicity
• pyrazinamide in combination may increase hepatotoxicity
• rifampin decreases serum levels of:
  • atovaquone
  • saquinavir
• others
  • opiates, verapamil, clofibrate, progestins, disopyramide, probenecid, dapsone
• use with caution or not at all with antiretroviral protease inhibitors or non-nucleoside reverse transcriptase inhibitors
  • do not use in combination with rilpivirine or etravirine
  • do not use in combination with ritonavir or saquinavir

* diminishes effectiveness of oral contraceptives

• drug interaction(s) anticonvulsants with anti-bacterial agents
• drug interaction(s) of antibiotics with warfarin
• drug interaction(s) of beta-adrenergic receptor antagonists with rifampin

Laboratory

• specimen:
  • serum, plasma (heparin, EDTA)
  • stable for 3 months at -20 degrees C
• methods: MB, HPLC

Mechanism of action

• inhibits DNA-dependent RNA polymerase of mycobacteria & other microorganisms
• bactericidal for M. tuberculosis

More general terms

• rifamycin (rifamycin SV, Rifocin, Aemcolo)
• heterocyclic compound, 4 or more rings
• heterocyclic compound, bridged-ring
• ester
• ether
• ketone
• phenol
• alcohol
• alkene; olefin
• amide
• amine
• prokaryote-specific molecule

Additional terms

• cytochrome p450 1A2 (cytochrome P3-450, phenacetin deethylase, cytochrome p450-4, CYP1A2)
• cytochrome P450 2C9; cytochrome P450 BP-1; cytochrome P450 MP-4; S-mephenytoin-4-hydroxylase; limonene 6-monooxygenase; limonene 7-monooxygenase (CYP2C9, CYP2C10)
• cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4)

Component of

• isoniazid/rifampin (Rifamate)
• isoniazid/pyrazinamide/rifampin (Rifater)

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=25839
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5280982
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5068
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=161976