Rifampin

Mechanism of Action

Rifampin may be bacteriostatic or bactericidal in action, depending on the concentration of the drug at the site of infection and the susceptibility of the infecting organism. Rifampin usually is rapidly bactericidal against Mycobacterium leprae in vivo.

Rifampin suppresses the initiation of chain formation for RNA synthesis in susceptible bacteria by inhibiting DNA-dependent RNA polymerase. The beta subunit of the enzyme is the site of action.

Rifampin is most active against susceptible bacteria undergoing cell division; however, the drug also has some effect when bacteria are in the metabolic resting state. Although rifampin is reported to have an immunosuppressive effect in some animal experiments, this effect is probably not clinically important in humans. Spectrum Rifampin is active in vitro and in vivo against Mycobacterium tuberculosis, M. bovis, M. marinum, M. kansasii, and some strains of M. fortuitum, M. avium, and M. intracellulare. Rifampin is also active against dapsone-susceptible and dapsone-resistant M. leprae in experimental leprosy in mice.

Rifampin is also active in vitro against some gram-positive bacteria, including Staphylococcus aureus and Bacillus anthracis, and some gram-negative bacteria, including Neisseria meningitidis, Haemophilus influenzae, Brucella melitensis, and Legionella pneumophila. Rifampin is active in vitro at very high concentrations against Chlamydia trachomatis, poxviruses, and adenoviruses. In vitro, most strains of N. meningitidis are inhibited by rifampin concentrations of 0.1-1 mcg/mL.

Clinical isolates of Ehrlichia phagocytophila have been inhibited in vitro by rifampin concentrations of 0.125 mcg/mL or less. Results of in vitro susceptibility testing of 11 B. anthracis isolates that were associated with cases of inhalational or cutaneous anthrax that occurred in the U.S. (Florida, New York, District of Columbia) during September and October 2001 in the context of an intentional release of anthrax spores (biologic warfare, bioterrorism) indicate that these strains had rifampin MICs of 0.5 mcg/mL or less. Based on interpretive criteria established for staphylococci, these strains are considered susceptible to rifampin.

Pharmacokinetics

Rifampin is well absorbed from the GI tract, but food can reduce and delay peak plasma concentrations by about 30%. After a 600-mg oral dose, peak levels average 7 mcg/mL within 2-4 hours, with a 4-32 mcg/mL range. IV administration results in higher concentrations, averaging 9 mcg/mL for 300 mg and 17 mcg/mL for 600 mg doses. In children receiving 10 mg/kg orally, peak concentrations range from 3.5-15 mcg/mL. IV doses of approximately 300 mg/m² yield about 26 mcg/mL peak levels. Plasma concentrations are higher in patients with hepatic impairment but not cumulative in renal impairment.

Rifampin distributes widely into body tissues and fluids, with CSF concentrations at 10-20% of plasma levels in cases of meningitis. It is approximately 84-91% bound to plasma proteins and crosses the placenta and into breast milk.

The plasma half-life is about 3.4-3.5 hours after a single oral dose. Still, it decreases with continued daily use due to increased biliary excretion. In renal impairment, the half-life increases significantly. Rifampin is metabolized in the liver to an active derivative and excreted mainly via bile, with 3-30% excreted unchanged in urine within 24 hours. Hemodialysis or peritoneal dialysis does not significantly affect plasma concentrations of rifampin.

Uses

Active Tuberculosis

Rifampin is a first-line antibiotic used alongside other agents to treat tuberculosis (TB), specifically in culture-positive pulmonary cases. Recommended treatment regimens typically last at least six months, divided into an intensive phase of two months followed by a continuation phase. In the U.S., rifampin is available as a standalone medication or in combination with isoniazid (Rifamate®) and with isoniazid and pyrazinamide (Rifater®), the latter being designated an orphan drug by the FDA. While oral administration is preferred, intravenous rifampin is also available for cases where oral intake is impossible.

Treating Tuberculosis in HIV-infected Individuals

When considering rifampin for treating tuberculosis (TB) or mycobacterial infections in HIV-infected patients, it is crucial to evaluate potential drug-drug interactions with antiretroviral agents, particularly HIV protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Although prior guidelines recommended avoiding rifampin with these antiretrovirals, recent updates suggest that under specific circumstances, rifampin can be used with certain regimens, such as efavirenz combined with nucleoside reverse transcriptase inhibitors or ritonavir-boosted protease inhibitors, with appropriate dosage adjustments.

However, the CDC advises against using rifamycins in HIV patients with CD4+ T-cell counts below 100/mm³ due to an increased risk of developing drug resistance. Daily and directly observed therapy is recommended for these patients during the initial treatment phase to ensure adherence and effectiveness.

Latent Tuberculosis Infection

Rifampin is used alone or with other antituberculosis agents to treat latent tuberculosis infection (LTBI) and prevent the progression to active TB, especially in cases of isoniazid-resistant Mycobacterium tuberculosis. The CDC now prefers the term “treatment of latent tuberculosis infection” over “preventive therapy” to better reflect its purpose. While a 9-month regimen of isoniazid is standard, a 4-month regimen of daily rifampin is an effective alternative with higher completion rates and fewer side effects. However, regimens involving rifampin and pyrazinamide are discouraged due to increased hepatotoxicity risks.

When considering rifampin for treating latent tuberculosis infection (LTBI) in HIV-infected patients, it is essential to assess potential drug interactions with antiretroviral agents, particularly protease inhibitors and NNRTIs. The ATS and CDC recommend rifabutin as a suitable alternative to rifampin due to its similar efficacy and fewer interactions with antiretrovirals. However, the use of rifapentine is not recommended because its safety in HIV-infected patients has not been established. For HIV-infected adults on protease inhibitors or NNRTIs, recommended LTBI treatment regimens include a 9-month isoniazid regimen, a 4-month daily rifabutin regimen, or a 2-month daily rifabutin and pyrazinamide regimen. In contrast, those not on these antiretrovirals can follow standard regimens, such as a 9-month isoniazid course or a 4-month rifampin course.

Rifampin Monotherapy

The ATS and CDC recommend a 4-month regimen of daily rifampin as an alternative for treating latent tuberculosis infection (LTBI) in both HIV-infected and HIV-seronegative adults, mainly when isoniazid cannot be used due to resistance or intolerance. For pediatric patients exposed to tuberculosis, the AAP advises starting treatment with both isoniazid and rifampin; if isoniazid resistance is confirmed, rifampin should be continued for at least 6 months. Optimal treatment regimens for pediatric patients with strains resistant to both drugs remain unclear, necessitating consultation with a tuberculosis specialist.

Rifampin and Pyrazinamide Regimens

A 2-month daily regimen of rifampin and pyrazinamide is considered effective for treating latent tuberculosis infection (LTBI) in HIV-infected patients, with similar efficacy to a 12-month isoniazid regimen. However, due to reports of hepatotoxicity, the ATS, CDC, and IDSA now generally advise against using this combination for LTBI in both HIV-infected and HIV-negative individuals. The AAP also does not recommend this regimen for children. If considered, it should only be used in carefully selected patients with close monitoring for liver injury, especially in those with risk factors like liver disease or concurrent use of hepatotoxic drugs.

Pregnant Women

The ATS and CDC recommend that treatment for latent tuberculosis infection (LTBI) in pregnant women at high risk for progression to active disease, especially those recently infected or with HIV, should not be delayed due to pregnancy, even in the first trimester. The preferred treatment is a 6- or 9-month regimen of isoniazid monotherapy; women with HIV or prior tuberculosis should receive 9 months. While rifampin is used for active TB in pregnant women, its efficacy for LTBI treatment remains unproven, and pyrazinamide may be considered for HIV-infected pregnant women after the first trimester but should generally be avoided in others. For lower-risk women, treatment can be postponed until after delivery to minimize potential risks.

Drug-Resistant Latent Tuberculosis Infection

For individuals likely infected with multidrug-resistant Mycobacterium tuberculosis (M. tuberculosis) resistant to both isoniazid and rifampin, the ATS and CDC recommend treatment with pyrazinamide plus either ethambutol or a fluoroquinolone (e.g., levofloxacin) for 6-12 months, depending on drug susceptibility. Immunocompetent contacts may be observed or treated for 6 months, while immunosuppressed individuals, including those with HIV, should be treated for 12 months. Until susceptibility results are available, both rifampin and isoniazid should be given to contacts of isoniazid-resistant cases. If resistance is confirmed, isoniazid should be discontinued, and rifampin should continue for at least 6 months. Expert consultation is advised for managing LTBI in children with resistant strains, and active disease must be ruled out before starting therapy.

Hematopoietic Stem Cell Transplant Recipients

Individuals undergoing hematopoietic stem cell transplant (HSCT) are at higher risk for progressing from latent tuberculosis infection to active disease due to immunosuppression. The CDC, IDSA, and ASBMT recommend screening all HSCT candidates for tuberculosis and administering treatment for latent infection regardless of tuberculin skin test results if there has been significant exposure. A 9-month isoniazid monotherapy is the preferred treatment. At the same time, the 2-month rifampin and pyrazinamide regimen is not recommended due to safety concerns and drug interactions. Close monitoring is essential, and guidelines should be followed to prevent opportunistic infections in these patients.

Completion of Treatment and Supervised Administration

Completion of therapy for latent tuberculosis infection (LTBI) is based on the total number of doses administered, not just the duration. For rifampin monotherapy, at least 120 doses should be given within 6 months, while a regimen combining rifamycin and pyrazinamide requires at least 60 doses in 3 months. If treatment is interrupted for 2 months or longer, a medical evaluation is necessary before resuming therapy. Directly observed therapy (DOT) is recommended for patients on intermittent dosing regimens. It should also be used when feasible for other treatment settings to ensure adherence and completion.

Mycobacterium Avium Complex (MAC) Infections

Rifampin is an alternative to rifabutin in multiple-drug regimens for treating Mycobacterium avium complex (MAC) pulmonary infections. The ATS recommends that therapy for MAC in HIV-negative adults should include at least three drugs: clarithromycin or azithromycin, rifabutin or rifampin, and ethambutol. For HIV-infected patients, clinicians must consider potential pharmacokinetic interactions between rifampin and antiretroviral agents, which may necessitate adjustments in drug regimens or dosages. Studies indicate that while rifampin has similar treatment success rates to rifabutin, its role in MAC treatment remains debated due to concerns about efficacy and macrolide interactions.

Neisseria Meningitidis Infections

Rifampin is used to eliminate Neisseria meningitidis from the nasopharynx of asymptomatic carriers and for chemoprophylaxis in close contact with invasive meningococcal disease cases. It is not recommended for treating active infections due to the risk of resistance. The preferred treatment for invasive disease is intravenous penicillin G, with ceftriaxone or cefotaxime as alternatives. Patients with invasive disease may still carry N. meningitidis and should receive treatment to eradicate the carriage before discharge. Rifampin, ceftriaxone, or ciprofloxacin can be used for this purpose. Still, rifampin should only be used when there is a high risk of meningococcal meningitis, following appropriate diagnostic testing to confirm carrier status. Ceftriaxone and ciprofloxacin are effective alternatives for eradicating nasopharyngeal carriage.

Chemoprophylaxis in Household and Other Close Contacts of Individuals with Invasive Meningococcal Disease

When sporadic or cluster cases of meningococcal disease occur in the U.S., chemoprophylaxis is crucial for preventing secondary cases in close contact. Recommended regimens include:

• 2 days of oral rifampin (not for pregnant women);
• a single IM dose of ceftriaxone;
• a single oral dose of ciprofloxacin (not for individuals under 18 or pregnant/lactating women).

While the AAP suggests rifampin as the preferred choice, the CDC states that all three antibiotics are 90-95% effective.

Chemoprophylaxis is recommended for high-risk contacts, including household members and those directly exposed to the index case’s secretions. It should be administered promptly, ideally within 24 hours, as the risk of secondary disease is highest shortly after the index case’s onset. Additional treatment is necessary if more than 2 weeks have passed since exposure. Casual contacts without direct exposure do not require prophylaxis.

Outbreak Control

During outbreaks of meningococcal disease in the U.S. caused by vaccine-preventable strains (serogroups A, C, Y, or W-135), large-scale vaccination with meningococcal polysaccharide vaccine is the primary control measure. Mass chemoprophylaxis with antibiotics like rifampin, ceftriaxone, or ciprofloxacin is generally considered ineffective for large populations due to logistical challenges and potential adverse effects. However, it may be appropriate for smaller groups like a single school.

The CDC does not recommend travel restrictions or event cancellations to control outbreaks. Mass chemoprophylaxis has shown effectiveness in serogroup B outbreaks but carries the risk of developing rifampin-resistant strains. Although most meningococcal cases are sporadic, the CDC has published guidelines for public health professionals on managing suspected outbreaks. The Childhood and Respiratory Diseases Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, CDC can be consulted on these and other issues regarding meningococcal disease at 404-639-2215 or 404-639-3311.

Prevention of Haemophilus Influenzae Type B Infection

Rifampin is the drug of choice for chemoprophylaxis in contact with patients with Haemophilus influenzae type b (Hib) infection, effectively eradicating oropharyngeal carriage of the bacteria. It is approximately 95% effective and reduces the risk of secondary invasive illness among exposed household contacts, particularly those under 4 years old who are unvaccinated or incompletely vaccinated. Chemoprophylaxis is recommended for all household contacts of an infected individual, especially if children younger than 48 months are not fully vaccinated. It should also be administered to any child under 12 months, regardless of vaccination status. Prophylaxis should be initiated as soon as possible, ideally within the first week after hospitalization of the index case. For child-care and nursery school settings, rifampin prophylaxis is advised if two or more cases occur within 60 days and unimmunized children are present. However, the necessity of prevention after a single case is debated among experts. Pregnant women are not recommended to receive rifampin due to unknown effects on the fetus. The ACIP supports these guidelines, emphasizing prompt notification and education for parents regarding potential risks and symptoms associated with Hib disease.

Leprosy

Rifampin is used in combination with other anti-infective agents in multiple-drug regimens for treating all forms of leprosy, including multibacillary and paucibacillary types. The World Health Organization (WHO) recommends rifampin-based regimens due to their effectiveness, tolerability, and ability to reduce the emergence of resistant strains of Mycobacterium leprae. Rifampin is bactericidal against M. leprae and is administered monthly, often alongside dapsone and clofazimine. The WHO advises a 12-month regimen for multibacillary leprosy and a 6-month regimen for paucibacillary leprosy. Although rifampin-resistant strains have been reported, they are not a significant concern currently. Early detection and effective treatment are crucial for controlling the spread of leprosy, as no vaccine is available.

For multibacillary leprosy, the WHO recommends a 12-month regimen of rifampin, clofazimine, and dapsone. If patients with a high bacterial index show no improvement after 12 months, an additional 12 months of treatment is advised. If dapsone causes severe adverse effects, it can be discontinued, and treatment can continue with rifampin and clofazimine.

Alternative agents like ofloxacin and minocycline may be used if rifampin or clofazimine cannot be tolerated. For paucibacillary leprosy, a 6-month regimen of rifampin and dapsone is recommended. In cases of single-lesion paucibacillary leprosy, a single-dose regimen of rifampin, ofloxacin, and minocycline has shown effectiveness. It is considered a cost-effective alternative in areas with high incidence.

In the U.S., the Gillis W. Long Hansen’s Disease Center at 800-642-2477 should be contacted for further information on the treatment of leprosy.

Anthrax

Strains of Bacillus anthracis from the 2001 anthrax attacks in the U.S. were found to be susceptible to rifampin in vitro. Although clinical data on rifampin for anthrax treatment are limited, it was included in several regimens for inhalational anthrax, such as combinations with ciprofloxacin and clindamycin or vancomycin. The CDC recommends initiating treatment with a parenteral regimen that includes ciprofloxacin, doxycycline, and additional effective antibiotics. A regimen with ciprofloxacin and chloramphenicol or rifampin is suggested for suspected meningitis. Multiple-drug regimens are also advised for cutaneous anthrax with systemic involvement.

Bartonella Infections

Rifampin treats infections caused by Bartonella henselae, such as cat scratch disease and bacillary angiomatosis. While cat scratch disease is often self-limiting in healthy individuals, treatment may be necessary for those with severe symptoms or immunocompromised patients. Recommended anti-infectives include azithromycin, ciprofloxacin, erythromycin, co-trimoxazole, doxycycline, gentamicin, and rifampin. Erythromycin or doxycycline combined with rifampin has been effective for ocular infections caused by B. henselae.

Brucellosis

Rifampin is used as an adjunct in treating brucellosis, typically alongside tetracyclines, which are the primary choice. Combining rifampin with an aminoglycoside (like streptomycin or gentamicin) is recommended to reduce relapse risk, especially in severe cases such as meningitis or endocarditis. Some experts advocate for a three-drug regimen of tetracycline, an aminoglycoside, and rifampin for complicated infections. While doxycycline and streptomycin are commonly preferred, a doxycycline-rifampin combination may be less effective due to potential interactions affecting drug levels. Alternative regimens include co-trimoxazole, ciprofloxacin with rifampin, and chloramphenicol. Postexposure prophylaxis is not generally advised but may be considered after high-risk exposures to Brucella.

Ehrlichia Infections

Although doxycycline is considered the drug of choice for infections caused by Ehrlichia, rifampin is an alternative for treating infections caused by E. phagocytophilia.

Legionella Infections

In the treatment of infections caused by Legionella pneumophila (Legionnaires’ disease), rifampin is used as an adjunct to a macrolide (e.g., azithromycin, erythromycin), a fluoroquinolone (e.g., ciprofloxacin, ofloxacin, levofloxacin), or a tetracycline (e.g., doxycycline). Many clinicians consider azithromycin or fluoroquinolone the preferred drugs for treating Legionnaires’ disease; some clinicians also consider erythromycin a drug of choice for this infection. A parenteral regimen is usually necessary for the initial treatment of severe disease, and rifampin may be added to the initial regimen in severely ill and/or immunocompromised patients. If L. pneumophila is identified in patients with community-acquired pneumonia, the Infectious Diseases Society of America (IDSA) recommends the use of a macrolide (with or without rifampin) or a fluoroquinolone or a regimen of doxycycline (with or without rifampin).

Rhodococcus Infections

Rifampin is used with vancomycin to treat infections caused by Rhodococcus equi. R. equi has been identified as a cause of pulmonary infections (e.g., lung abscess) in immunocompromised individuals such as solid organ transplant recipients or patients with HIV infection. While optimum regimens for treating these infections have not been identified, combination regimens are usually recommended. Some clinicians suggest that R. equi infections be treated with a vancomycin regimen with fluoroquinolone, rifampin, a carbapenem (e.g., imipenem, meropenem), or amikacin.

Staphylococcal and Streptococcal Infections

Rifampin is used as an adjunct to other anti-infective agents (e.g., third-generation cephalosporins, vancomycin) for the treatment of serious infections such as bacteremia, pneumonia, and meningitis caused by penicillin-resistant Streptococcus pneumoniae or oxacillin-resistant Staphylococcus aureus or S. epidermidis (previously known as methicillin-resistant S. aureus or S. epidermidis). Rifampin should not be used alone in the treatment of these infections.

Precautions and Contraindications

Rifampin is contraindicated in patients with a history of hypersensitivity to the drug or any of the rifamycins. Because rifampin used alone or in conjunction with other drugs has been associated with adverse hepatic effects (e.g., severe liver injury) and adverse hematologic effects, liver function (hepatic enzymes, bilirubin) and hematologic status (complete blood cell and platelet counts) should be assessed before initiation of rifampin therapy.

Serum creatinine concentrations also should be assessed at baseline. Adult patients receiving rifampin generally should be seen at least monthly and questioned concerning adverse reactions; those reporting abnormalities should have follow-up, including laboratory monitoring, as necessary.

Patients should be advised to contact their clinician immediately if they develop fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, and/or pain or swelling of the joints during rifampin therapy. Routine laboratory monitoring for drug-induced toxicity in patients with normal baseline tests generally is not necessary.

Although one manufacturer states that rifampin is not recommended for intermittent therapy, the American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) currently recommend intermittent rifampin regimens that involve administration 2 or 3 times weekly for the treatment of uncomplicated pulmonary and most cases of extrapulmonary tuberculosis and a once-monthly rifampin regimen is used in multiple-drug regimens for the treatment of leprosy.

Precautions Related to Hepatotoxicity

Rifampin should be used in patients with impaired liver function only when necessary and under strict supervision, with liver tests every 2-4 weeks. Discontinue if hepatocellular damage occurs. Hyperbilirubinemia may arise shortly after starting therapy. However, isolated increases in bilirubin or transaminases do not automatically require discontinuation; decisions should consider test trends and clinical conditions.

Regimens containing rifampin and pyrazinamide pose risks of liver injury, including fatalities. They should generally be avoided in both HIV-infected and HIV-negative patients unless the benefits outweigh the risks. These regimens should not be given to patients on other hepatotoxic drugs, those with excessive alcohol use, or those with underlying liver disease.

Before starting a rifampin-pyrazinamide regimen, consultation with a tuberculosis expert is essential. Patients must be informed about potential hepatotoxicity and monitored closely, with serum AST and bilirubin levels checked at baseline and at intervals during treatment. If symptoms of hepatitis develop or if AST/bilirubin levels exceed normal limits, the regimen should be discontinued immediately.

Precautions in Leprosy Patients

Rifampin is used in multiple-drug regimens for treating all forms of leprosy, including multibacillary, paucibacillary, and single-lesion types. The World Health Organization (WHO) recommends rifampin-based regimens due to their effectiveness, tolerability, and ability to reduce the risk of drug resistance. The monthly administration of rifampin is effective against Mycobacterium leprae, and a low relapse rate was observed.

For multibacillary leprosy, the WHO advises a 12-month regimen of rifampin, clofazimine, and dapsone. If patients with a high bacterial index show no improvement after this period, an additional 12 months may be necessary. In cases of severe adverse effects from dapsone, it can be replaced with rifampin and clofazimine. Alternative agents like ofloxacin and minocycline are available for those intolerant to clofazimine.

For paucibacillary leprosy (2-5 lesions), a 6-month regimen of rifampin and dapsone is recommended. If adverse effects occur, dapsone may be substituted with clofazimine. Single-lesion paucibacillary leprosy can be treated effectively with a single-dose regimen of rifampin, ofloxacin, and minocycline.

Other Precautions and Contraindications

Commercially available rifampin sterile powder for injection contains sodium formaldehyde sulfoxylate. This sulfite may cause allergic-type severe reactions in specific susceptible individuals. The overall incidence of sulfite sensitivity in the general population is probably low. Still, in susceptible individuals, exposure to sulfites can result in acute bronchospasm or, less frequently, life-threatening anaphylaxis.

Rifampin sterile powder containing sodium formaldehyde sulfoxylate should be used cautiously for injection in atopic, nonasthmatic individuals.

Rifampin and its metabolites may impart a red-orange color to urine, feces, sputum, sweat, and tears; patients should be informed of this possibility. Soft contact lenses worn during rifampin therapy may become permanently stained.

Pediatric Precautions

Rifampin is used in pediatric patients for the treatment of active tuberculosis and treatment of latent tuberculosis infection, to eliminate nasopharyngeal carriage of Neisseria meningitidis, for chemoprophylaxis against meningococcal disease or Haemophilus influenzae type b (Hib) infection, and for the treatment of leprosy.

Safety and efficacy of the fixed-combination preparation containing rifampin, isoniazid, and pyrazinamide (Rifater®) have not been established in children younger than 15 years of age; the ratio of rifampin and isoniazid contained in this preparation may not be appropriate in this age group since higher doses of isoniazid usually are used in pediatric patients.

Mutagenicity and Carcinogenicity

There was no evidence of mutagenicity when rifampin was tested in vitro and in vivo using bacteria, Drosophila melanogaster, or mice.

However, in vitro studies indicate an increase in chromatid breaks in whole blood cell cultures exposed to rifampin and an increased frequency of chromosomal aberrations in lymphocytes obtained from patients treated with drug regimens that included rifampin, isoniazid, and pyrazinamide (with or without streptomycin). In one strain of mice known to be particularly susceptible to the spontaneous development of hepatomas, there was an increase in hepatomas in the female mice after a year of rifampin at a dosage of 2-10 times the maximum human dosage.

There was no evidence of carcinogenicity in the male mice of this strain, in male or female mice of another strain, or rats under similar experimental conditions.

Although a causal relationship has not been established, a few cases of accelerated growth of lung carcinoma have been reported in patients receiving rifampin.

Pregnancy, Fertility and Lactation

Rifampin has been associated with an increased incidence of congenital malformations, particularly spina bifida and cleft palate, in offspring of animals given high doses during pregnancy. Although isolated cases of fetal malformations have been reported, rifampin is used in pregnant women to treat tuberculosis when the benefits outweigh the risks. The American Thoracic Society, CDC, and IDSA consider rifampin safe for pregnant women. Still, no adequate studies are confirming its safety. Neonates born to rifampin-treated mothers should be monitored for adverse reactions. Since rifampin is excreted in breast milk and may have tumorigenic potential, a decision should be made regarding continuing nursing or the drug based on its importance to the mother.

Drug Interactions

Interactions with Rifampin

• Metabolism Acceleration:
  • Rifampin accelerates the metabolism of HIV protease inhibitors and NNRTIs, potentially leading to subtherapeutic levels.
  • It also affects nucleoside reverse transcriptase inhibitors (e.g., zidovudine).
• Increased Plasma Concentrations:
  • Some HIV protease inhibitors and NNRTIs (e.g., delavirdine) can increase rifamycins’ plasma concentrations, raising toxicity risks.
• Consultation:
  • Experts should be consulted for managing interactions in HIV-infected patients.

Specific Drug Interactions

• HIV Protease Inhibitors:
  • Contraindicated: Rifampin with amprenavir, atazanavir, indinavir, lopinavir, nelfinavir.
  • Ritonavir: Decreased concentrations; use rifabutin instead.
  • Saquinavir: Use with caution; rifampin may reduce its levels.
• NNRTIs:
  • Delavirdine: Concomitant use is contraindicated due to decreased concentrations.
  • Efavirenz: May require increased dosage (800 mg) when used with rifampin.
  • Nevirapine: Significant decrease in concentrations; careful monitoring is advised.
• Nucleoside Reverse Transcriptase Inhibitors:
  • Zidovudine: Concomitant use leads to significant decreases in plasma concentrations.

Other Drug Interactions

• Anticoagulants: Monitor prothrombin times closely when used with rifampin.
• Antifungals: Avoid concomitant use with itraconazole and ketoconazole due to decreased serum concentrations.
• Immunosuppressants: Monitor cyclosporine and tacrolimus levels closely when used with rifampin.
• Oral Contraceptives: Rifampin reduces effectiveness; consider alternative contraception.
• Verapamil: Significant reductions in bioavailability; alternatives should be considered.
• Aminosalicylic Acid: May impair GI absorption of rifampin.
• Antacids: Administer rifampin at least 1 hour before antacids to avoid absorption issues.

Laboratory Test Interferences

• False Positives: Rifampin may cause false-positive results in urine opiate tests.
• Serum Tests: Interferes with assays for serum folate and vitamin B12; alternative methods should be considered.
• Sulfobromophthalein Test: Complete this test before administering rifampin to avoid false-positive results.

Rifampin interferes with microbiologic assays for serum folate and vitamin B12. Alternative test methods should be considered for patients receiving rifampin.

Rifampin reduces hepatic uptake of sulfobromophthalein sodium. To avoid false-positive sulfobromophthalein test results, the test should be completed before administration of the daily dose of rifampin. In vitro studies indicate that serum rifampin concentrations greater than 100 mcg/mL, which might occur in acute overdosage, may cause false elevations in total serum bilirubin concentration determined by the modified Malloy method utilizing diazotized sulfanilic acid as a reagent.

Acute Toxicity

The LD50 of rifampin is 0.885 g/kg in mice, 1.72 g/kg in rats, and 2.12 g/kg in rabbits. In humans, acute overdoses up to 9-12 g in adults and 100 mg/kg in children have not been fatal, but doses of 14-60 g have resulted in fatalities, particularly in those with a history of alcohol abuse.

Symptoms of Overdose

• Common reactions include nausea, vomiting, abdominal pain, pruritus, headache, lethargy, and discoloration of bodily fluids.
• Severe cases may lead to liver enlargement, jaundice, increased bilirubin and liver enzymes, hypotension, arrhythmias, seizures, and cardiac arrest.

Treatment

• Supportive care includes gastric lavage and activated charcoal to absorb the drug.
• Monitor liver function; if hepatic impairment lasts 24-48 hours, consider bile drainage or hemodialysis.
• Recovery is typically within 72 hours for patients with adequate liver function.

In children receiving high doses of chemoprophylaxis, symptoms appeared within 0.5-4 hours and lasted an average of 28 hours.

Preparations

Formulation	Dosage	Product Name	Manufacturer
Oral Capsules	150 mg	Rifadin®	Aventis
Oral Capsules	150 mg	Rifampin Capsules	Eon
Oral Capsules	300 mg	Rifadin®	Aventis
Oral Capsules	300 mg	Rifampin Capsules	Eon
Oral Capsules	300 mg	Rimactane® (with parabens)	Sandoz
Parenteral For Injection	600 mg	Rifadin® IV (with sodium formaldehyde sulfoxylate)	Aventis
Parenteral For Injection	600 mg	Rifampin for Injection	Bedford
Oral Capsules	300 mg with Isoniazid 150 mg	Rifamate®	Aventis
Tablets	120 mg with Isoniazid 50 mg, Pyrazinamide 300 mg	Rifater® (with povidone and propylene glycol)	Aventis