section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Rifampin is a rifamycin B-derivative antibiotic172,259 active against mycobacteria and some gram-positive and -negative bacteria.

Uses ⬆ ⬇

[Section Outline]

Tuberculosis !!navigator!!

Active Tuberculosis

Rifampin is used in conjunction with other antituberculosis agents for the treatment of clinical tuberculosis.258 For information on the general principles used in the treatment of tuberculosis, see the Antituberculosis Agents General Statement 8:16.04.

The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) currently recommend several possible multiple-drug regimens for the treatment of culture-positive pulmonary tuberculosis.258 These regimens have a minimum duration of 6 months (26 weeks), and consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months).258 Rifampin is considered a first-line antituberculosis agent for the treatment of all forms of tuberculosis caused by Mycobacterium tuberculosis known or presumed to be susceptible to the drug, and is an essential component of all short-course regimens.258 For information on general principles used in the treatment of tuberculosis, see the Antituberculosis Agents General Statement 8:16.04.

Rifampin is commercially available in the US alone161 or in fixed combination with isoniazid259 or in fixed combination with isoniazid and pyrazinamide (Rifater®).172 The fixed-combination preparation containing rifampin, isoniazid, and pyrazinamide (Rifater®) is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.178

Oral rifampin is preferred for the treatment of tuberculosis, but the drug may be given IV for initial or retreatment of the disease when the drug cannot be given orally.161 IV rifampin is designated an orphan drug by the FDA for use in this condition.178

HIV-infected Individuals

When use of rifampin in conjunction with other antituberculosis agents is being considered for the treatment of tuberculosis or other mycobacterial infections (e.g., Mycobacterium avium complex [MAC] infections) in patients with human immunodeficiency virus (HIV) infection, the possibility that concomitant use of certain drugs might be contraindicated or that dosages may have to be altered because of clinically important pharmacokinetic interactions between rifampin and certain antiretroviral agents (e.g., HIV protease inhibitors [PIs], nonnucleoside reverse transcriptase inhibitors [NNRTIs]) should be considered.101,124,180,181,182,183 The CDC and other experts state that concomitant use of rifampin and most PIs or NNRTIs usually is not recommended and that use of alternatives (e.g., rifabutin) may be preferred for the treatment of active tuberculosis in HIV-infected patients receiving PIs or NNRTIs.194 (See Drug Interactions: Antiretroviral Agents.)

There is evidence that use of antituberculosis regimens that include once- or twice-weekly administration of rifamycins (e.g., rifampin, rifabutin, rifapentine) in HIV-infected patients with CD4+ T-cell counts less than 100/mm3 is associated with an increased risk for acquired rifamycin resistance.100 Therefore, until additional data are available regarding this issue, the CDC recommends that HIV-infected individuals with CD4+ T-cell counts less than 100/mm3 not receive rifamycin regimens for the treatment of active tuberculosis that involve once- or twice-weekly administration.100 These individuals should receive daily therapy during the initial phase, and daily or 3-times weekly regimens during the second phase; directly observed therapy also is recommended for both the daily and 3-times weekly regimens.100

Latent Tuberculosis Infection

Rifampin is used alone or in conjunction with other antituberculosis agents for the treatment of latent tuberculosis infection to prevent the development of clinical tuberculosis, especially in individuals exposed to isoniazid-resistant M. tuberculosis .194,215,269 Previously, “preventive therapy” or “chemoprophylaxis” was used to describe a simple drug regimen (e.g., isoniazid monotherapy) used to prevent the development of active tuberculosis disease in individuals known or likely to be infected with M. tuberculosis .215 However, since use of such a regimen rarely results in true primary prevention (i.e., prevention of infection in individuals exposed to infectious tuberculosis), the ATS and CDC currently state that “treatment of latent tuberculosis infection” rather than “preventive therapy” more accurately describes the intended intervention and potentially will result in greater understanding and more widespread implementation of this tuberculosis control strategy.215

Although a 9-month regimen of isoniazid monotherapy (once-daily or, alternatively, twice weekly) generally is considered the regimen of choice for the treatment of latent tuberculosis infection in most adult and pediatric patients and a 6-month regimen of isoniazid monotherapy (once-daily or, alternatively, 2 or 3 times weekly) is considered an acceptable alternative in some cases,117,118,119,164,176,215,225,269 a 4-month regimen (4-6 months in pediatric patients) of daily rifampin monotherapy also has been studied and can be considered as an alternative for the treatment of latent tuberculosis infection in selected individuals.176,194,195,196,215,269 Although a 2-month daily regimen of rifampin and pyrazinamide and a 2- to 3-month regimen of twice-weekly rifampin and pyrazinamide were previously recommended,176,194,215 these regimens have been associated with an increased risk of hepatotoxicity and generally should not be offered for the treatment of latent tuberculosis infection257,269 unless the potential benefits outweigh the risk of liver injury and death.257 (See Rifampin and Pyrazinamide Regimens under Tuberculosis: Treatment of Latent Tuberculosis, in Uses.)

Rifampin Monotherapy

A 4-month regimen of daily rifampin monotherapy is considered by the ATS and CDC to be an alternative regimen that can be used for the treatment of latent tuberculosis infection in both HIV-infected and HIV-seronegative adults.215 This rifampin regimen may be useful for those in whom isoniazid cannot be used because of drug resistance or intolerance.215

In infants, children, and adolescents, a 6-month regimen of daily rifampin monotherapy is recommended by the CDC and AAP as an alternative to isoniazid monotherapy for the treatment of latent tuberculosis infection if the source case has isoniazid-resistant and rifampin-susceptible M. tuberculosis or if isoniazid is not tolerated despite careful education and efforts to alleviate mild isoniazid adverse effects.176,269 The AAP states that optimal regimens for treatment of latent tuberculosis infection in pediatric patients with strains resistant to both isoniazid and rifampin are unknown; however, a multiple-drug regimen and consultation with a tuberculosis specialist is indicated.176

Rifampin and Pyrazinamide Regimens

Limited data suggest that a 2-month regimen consisting of rifampin and pyrazinamide given daily is effective in treating latent tuberculosis infection in HIV-infected patients,194,215 and the ATS and CDC state that the efficacy of this regimen is not expected to differ in HIV-negative patients.215 In a randomized, comparative study in HIV-infected adults, the efficacy and safety of a rifampin-pyrazinamide regimen given daily for 2 months was comparable to that of a 12-month regimen of isoniazid monotherapy for treatment of latent tuberculosis infection.194,215 An intermittent rifampin and pyrazinamide regimen that involves twice-weekly administration of the drugs for 2-3 months also may be effective for the treatment of latent tuberculosis infection when other regimens cannot be used.215

Based on results in HIV-infected adults, the ATS and CDC previously recommended use of the 2-month daily rifampin and pyrazinamide regimen for HIV-infected or HIV-seronegative adults who were known contacts of patients with isoniazid-resistant, rifampin-susceptible tuberculosis.194,215 However, hepatotoxicity (including some fatalities) has been reported in patients receiving rifampin and pyrazinamide regimens for the treatment of latent tuberculosis and, although multiple-drug regimens containing rifampin and pyrazinamide are still recommended for the treatment of active tuberculosis, the ATS, CDC, and IDSA now state that regimens containing both rifampin and pyrazinamide generally should not be offered for the treatment of latent tuberculosis in either HIV-infected or HIV-negative individuals.257 The American Academy of Pediatrics (AAP) also states that the 2-month rifampin and pyrazinamide regimen is not recommended for children.176

Based on a recent analysis of potential cofactors in patients with latent tuberculosis who developed hepatotoxicity while receiving a regimen of rifampin and pyrazinamide, this regimen should never be offered to patients who are currently taking other drugs associated with liver injury, patients who drink excessive amounts of alcohol (even if alcohol is discontinued during treatment), or patients with underlying liver disease or a history of isoniazid-associated liver injury.257 However, the ATS, CDC, and IDSA state that a rifampin and pyrazinamide regimen might be considered for the treatment of latent tuberculosis in carefully selected patients if the potential benefits of the regimen outweigh the risk for severe liver injury and death, but only when the preferred or alternative regimens (i.e., 9-month isoniazid regimens, 6-month isoniazid regimens, 4-month daily rifampin regimen) are judged unlikely to be completed and oversight can be provided by a clinician with expertise in the treatment of latent tuberculosis.257 An expert in the treatment of latent tuberculosis should be consulted before a regimen of rifampin and pyrazinamide is offered.257 If a rifampin and pyrazinamide regimen is used, patients should be informed of the potential for hepatotoxicity and certain precautions should be taken to ensure that the patient is closely monitored for adherence, tolerance, and adverse effects throughout the entire course of therapy.257 (See Precautions Related to Hepatotoxicity under Cautions: Precautions and Contraindications.)

HIV-infected Individuals

When use of rifampin is being considered for the treatment of latent tuberculosis infection in HIV-infected patients, the possibility that certain combinations of drugs might be contraindicated or drug dosages may have to be altered because of clinically important pharmacokinetic interactions between rifampin and certain antiretroviral agents (e.g., PIs, NNRTIs) should be considered.124 (See Drug Interactions: Antiretroviral Agents.) The ATS and CDC state that while therapy for latent tuberculosis infection with rifabutin in tuberculin-positive patients with HIV infection has not been evaluated in clinical trials, the use of rifabutin instead of rifampin in such regimens for treatment of latent M. tuberculosis infection is valid for the same scientific principles that support the use of rifabutin for the treatment of active tuberculosis.194,215 (See Uses: Tuberculosis, in Rifabutin 8:16.04.) However, the ATS and CDC state that substitution of rifapentine, a long-acting rifamycin, for rifampin in treatment regimens for latent tuberculosis infection currently is not recommended because the safety and efficacy of rifapentine in HIV-infected patients have not been established and drug interactions between rifapentine and PIs have not been adequately evaluated.194

For HIV-infected adults who are receiving concomitant antiretroviral therapy that includes PIs or NNRTIs, recommended regimens for treatment of latent M. tuberculosis infection are a 9-month regimen of isoniazid given daily or twice weekly; a 4-month regimen of rifabutin given daily; or a 2-month regimen of rifabutin and pyrazinamide given daily. 124,177,194,215 (See Rifabutin 8:16.04.)

For HIV-infected adults who are not receiving concomitant PIs or NNRTIs, recommended regimens for treatment of latent M. tuberculosis infection are the same as those for adults without HIV infection (i.e., usually a 9-month regimen of isoniazid given daily or twice weekly or a 4-month regimen of rifampin given daily).177,194,215

Pregnant Women

The ATS and CDC state that treatment of latent tuberculosis infection in pregnant women who are at high risk for progression to active disease, particularly those who were infected recently or have HIV infection, should not be delayed on the basis of pregnancy alone, even during the first trimester.194,215 For women whose risk of active disease is lower, some experts recommend delaying treatment until after delivery215

The preferred regimen for treatment of latent tuberculosis infection in pregnant women is a 6- or 9-month regimen of isoniazid monotherapy; those with HIV infection or radiographic evidence of prior tuberculosis should receive 9 rather than 6 months of isoniazid therapy.194,215 The ATS and CDC state that rifampin has been used to treat active tuberculosis in pregnant women† but there are no efficacy data to date to support use of the drug for treatment of latent tuberculosis infection in pregnant women.215 In addition, the ATS and CDC state that use of pyrazinamide can be considered in HIV-infected pregnant women after the first trimester of pregnancy but should be avoided in other pregnant women.215

Drug-Resistant Latent Tuberculosis Infection

In individuals likely to be infected with M. tuberculosis that are resistant to both isoniazid and rifampin and who are at high risk for developing tuberculosis, the ATS and CDC recommend regimens consisting of pyrazinamide and ethambutol or pyrazinamide and a quinolone anti-infective (e.g., levofloxacin or ofloxacin) for 6-12 months if the organisms from the index case are known to be susceptible to these drugs.215 Immunocompetent contacts may be managed by observation alone or be treated with such regimens for 6 months; immunosuppressed individuals, including those with HIV infection, should be treated for 12 months.215 Clinicians should review the drug-susceptibility pattern of M. tuberculosis isolated from the infecting source-patient before selecting a regimen for treating potentially multiple-drug resistant tuberculosis infections.194,215 In individuals likely to have been infected with M. tuberculosis that are resistant to both isoniazid and rifampin, the choice of drugs used for treatment of latent infection requires expert consultation.177,215 Prior to initiation of therapy for latent tuberculosis infection in patients with suspected multidrug-resistant tuberculosis, careful assessment to rule out active disease is necessary.215

The AAP states that, until susceptibility test results are available, both rifampin and isoniazid should be given to contacts who are likely to have been infected by an index case with isoniazid-resistant tuberculosis.176 If the index case is proven to be excreting organisms that are completely resistant to isoniazid, isoniazid should be discontinued and rifampin given for a total of at least 6 months.176 The AAP recommends consultation with an expert in making decisions about therapy for latent tuberculosis infection in children with isoniazid and/or rifampin-resistant M. tuberculosis .176

Hematopoietic Stem Cell Transplant Recipients

Individuals who undergo hematopoietic stem cell transplant (HSCT) are at increased risk for progression from latent tuberculosis infection to active disease because of immunosuppression.224 The CDC, IDSA, and the American Society of Blood and Marrow Transplantation (ASBMT) have established guidelines for preventing opportunistic infections in HSCT recipients.224 These guidelines include recommendations regarding treatment of latent tuberculosis in HSCT candidates and recipients.224 All HSCT candidates should be screened for active and latent tuberculosis infection; although a tuberculin skin test can be administered, this test may not be reliable in patients who are immunocompromised.224 Therefore, clinicians should not rely solely on the test to determine whether latent tuberculosis infection is present and whether preventive therapy should be administered.224

The CDC, IDSA, and ASBMT state that a regimen for the treatment of latent tuberculosis infection should be administered to all immunocompromised HSCT recipients or candidates (adults, adolescents, and children) who have been substantially exposed to someone with active, infectious (i.e., sputum-smear positive) pulmonary or laryngeal tuberculosis, regardless of tuberculin skin test results, and also should be administered to all HSCT recipients or candidates who have a positive skin test result and have not previously been treated and have no evidence of active tuberculosis.224

A 9-month regimen of daily isoniazid monotherapy is the regimen of choice when treatment of latent tuberculosis infection is indicated in HSCT candidates or recipients.224 The 2-month regimen of daily rifampin and pyrazinamide is not recommended for HSCT candidates or recipients because of limited safety and efficacy data in these individuals, risk of hepatotoxicity, and substantial drug interactions that have been reported between rifampin and several drugs used in HSCT patients (e.g., cyclosporine, tacrolimus, corticosteroids, fluconazole).224 (See Precautions Related to Hepatotoxicity and see Drug Interactions.) The guidelines for preventing opportunistic infections in HSCT recipients should be consulted for additional information on preventing opportunistic infections in these patients and for information on hospital infection control, strategies for safe living after transplantation, and hematopoietic stem cell safety.224

Completion of Treatment and Supervised Administration

The ATS and CDC state that completion of therapy for latent tuberculosis infection is based on the total number of administered doses of the antituberculosis agents, not the duration of therapy alone.194,215 If rifampin monotherapy regimen is used, at least 120 doses should be administered within 6 months.215 If a regimen in which a rifamycin (rifampin or rifabutin) and pyrazinamide is given daily, at least 60 doses should be administered within 3 months.194,215 Ideally, patients should receive the treatment regimens on a regular dosing schedule until completion of the indicated course; in practice, some doses may be missed requiring the course to be lengthened.215 Reinstitution of therapy in patients whose treatment has been interrupted might require a continuation of the regimen originally prescribed (as long as needed to complete the recommended duration of the particular regimen) or a complete renewal of the regimen if interruptions were frequent or prolonged enough to preclude completion of treatment as recommended.194,215 In either situation, when therapy is resumed after an interruption of 2 months or longer, a medical examination is indicated to rule out tuberculosis disease.194,215

All patients receiving an intermittent (e.g., twice-weekly) dosing regimen for the treatment of latent tuberculosis infection should receive directly observed therapy (DOT).215 In addition, the ATS and CDC state that, when feasible, DOT also should be used in patients receiving 2-month regimens and in some special settings (e.g., some institutional settings, community outreach programs, household contacts of patients with tuberculosis who are receiving home-based DOT).215

Mycobacterium avium Complex (MAC) Infections !!navigator!!

Rifampin is used as an alternative to rifabutin in multiple-drug regimens for the treatment of Mycobacterium avium complex (MAC) pulmonary infections†.176,191 The ATS currently recommends that therapy for MAC pulmonary infections in HIV-negative adults consist of at least 3 drugs, including clarithromycin (500 mg twice daily) or azithromycin (250 mg daily or 500 mg 3 times weekly), rifabutin (300 mg daily) or rifampin (600 mg daily), and ethambutol (25 mg/kg daily for 2 months, then 15 mg/kg daily).191 The ATS states that the addition of streptomycin given intermittently (2 or 3 times weekly for at least 2 months) may be considered for patients with extensive disease.191 (See Treatment of Pulmonary and Localized Extrapulmonary Infections, under Management of Other Mycobacterial Diseases: Mycobacterium avium Complex [MAC] Infections, in the Antituberculosis Agents General Statement 8:16.04.)

When use of rifampin is being considered for the treatment of MAC infection in HIV-infected patients, the possibility that drug regimens or dosages may have to be altered because of clinically important pharmacokinetic interactions between rifampin and certain antiretroviral agents (e.g., PIs, NNRTIs) should be considered.177,181,182 (See Drug Interactions: Antiretroviral Agents.)

Neisseria meningitidis Infections !!navigator!!

Rifampin is used to eliminate meningococci from the nasopharynx of asymptomatic Neisseria meningitidis carriers.161,163,176,179,266 The drug also is used for chemoprophylaxis in close contacts of individuals with invasive meningococcal disease† when the risk of infection is high.176,179,187,266,268 Rifampin is not indicated for the treatment of N. meningitidis infections since rapid emergence of resistant strains of the organism may occur during long-term therapy with the drug.161,163,176 IV penicillin G generally is considered the drug of choice for the treatment of invasive disease caused by N. meningitidis and ceftriaxone or cefotaxime are alternative agents.176,179

Patients with invasive meningococcal disease who have been treated with penicillin G or any anti-infective agent other than ceftriaxone or another third-generation cephalosporin may still be carriers of N. meningitidis and should receive an anti-infective regimen to eradicate nasopharyngeal carriage of the organism prior to hospital discharge.176,179,187 Rifampin, ceftriaxone, or ciprofloxacin can be used to eradicate nasopharyngeal carriage of N. meningitidis 176,179,187

Rifampin should not be used indiscriminately to eliminate meningococci from the nasopharynx of asymptomatic N. meningitidis carriers and should be used only when the risk of meningococcal meningitis is high.161,163 To avoid indiscriminate use of the drug, diagnostic laboratory procedures, including serotyping and susceptibility testing, should be performed to determine whether the carrier state exists and the appropriate drug therapy.161,163 Rifampin generally has been considered the drug of choice and is 72-90% effective in eradicating nasopharyngeal carriage of N. meningitidis .179,266 Alternatively, a single IM dose of ceftriaxone reportedly is 97-100% and a single oral dose of ciprofloxacin is 90-95% effective in eradicating nasopharyngeal carriage of the organism.179

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

When sporadic or cluster cases of meningococcal disease occur in the US, chemoprophylaxis is the principal means of preventing secondary cases in household and other close contacts of individuals with invasive disease.176,179,187 Recommended regimens for chemoprophylaxis against meningococcal disease include 2 days of oral rifampin therapy (not recommended in pregnant women), a single IM dose of ceftriaxone, or a single oral dose of ciprofloxacin (not recommended in individuals younger than 18 years of age unless no other regimen can be used and not recommended for pregnant or lactating women).176,179,187,266,268 Although the AAP and other clinicians suggest that rifampin is the drug of choice for chemoprophylaxis in pediatric patients in most instances,176,268 the CDC states that rifampin, ciprofloxacin, and ceftriaxone are all 90-95% effective and are all acceptable regimens for chemoprophylaxis.187 Sulfisoxazole is no longer included in CDC or AAP guidelines for chemoprophylaxis of meningococcal disease.187

The attack rate for household contacts who do not receive chemoprophylaxis has been estimated to be 4 cases per 1000 individuals exposed, which is 500-800 times greater than that for the general population.187 A decision to administer chemoprophylaxis to close contacts of an individual with invasive meningococcal disease is based on the degree of risk.176,179,187 Throat and nasopharyngeal cultures are not useful in determining the need for chemoprophylaxis and may unnecessarily delay administration of the regimen.176,187 The CDC and AAP currently recommend that chemoprophylaxis be administered to contacts of individuals with invasive meningococcal disease only when the contacts are considered at high risk of infection.176,179,187 These high-risk individuals include household contacts (especially young children) and any individual who has slept or eaten frequently in the same dwelling with the index case; child care and nursery school contacts who were exposed during the 7 days before the onset of disease in the index case; individuals exposed directly to oropharyngeal secretions of the index case (e.g., through kissing or sharing toothbrushes, eating utensils, or drinking containers) during the 7 days before the onset of disease in the index case; and medical personnel who had intimate exposure (e.g., through mouth-to-mouth resuscitation, unprotected contact during endotracheal intubation or suctioning) to the index case during the 7 days before the onset of disease.176,179,187 Chemoprophylaxis is not routinely recommended for contacts considered at low risk of infection.179 Individuals considered in most circumstances as being at low risk include casual contacts with no history of direct exposure to the index case's oral secretions (e.g., school or work contacts); individuals who had only indirect contact with the index case (only contact was with a high-risk contact of the index case); and medical personnel who had no direct exposure to the index case's oral secretions.176,179

When chemoprophylaxis is indicated in high risk contacts, it must be administered promptly (ideally within 24 hours after identification of the index case) since the attack rate of secondary disease is greatest in the few days following disease onset in the index case.176,179,187 All high-risk contacts should be informed that even if chemoprophylaxis is taken or started, the development of any suspicious clinical manifestation warrants early, rapid medical attention.179 Chemoprophylaxis probably is of limited or no value if administered more than 2 weeks after contact with the index case.179,187 If high-risk exposure to a new index case occurs more than 2 weeks after initial chemoprophylaxis, additional treatment is indicated.179

Outbreak Control

When an outbreak of meningococcal disease occurs in the US and the outbreak is caused by a vaccine-preventable meningococcal strain (i.e., serogroups A, C, Y, or W-135), large-scale vaccination programs with meningococcal polysaccharide vaccine in the appropriate target group is the principal control measure.188 Mass chemoprophylaxis programs (e.g., with rifampin, ceftriaxone, ciprofloxacin) in large population groups is not effective in most settings in which organization- or community-based outbreaks have occurred and disadvantages of such programs (e.g., costs, difficulty in ensuring simultaneous administration of the drugs to large populations, adverse effects of the drugs, emergence of resistant organisms) probably outweigh any possible benefit in disease prevention.188 However, when outbreaks involve small populations (e.g., a small organization such as a single school), administration of chemoprophylaxis to all individuals in the population may be considered.188 The CDC states that other measures, such as restricting travel to areas with a suspected meningococcal outbreak, closing schools or universities, or canceling sporting or social events, are not recommended to control meningococcal outbreaks in the US.188 In one reported outbreak of serogroup B meningococcal disease (a strain that cannot be prevented with currently available meningococcal polysaccharide vaccine) in a middle school, mass chemoprophylaxis with rifampin was 85% effective in eradicating carriage of meningococci and appeared to decrease transmission of the disease; however, rifampin-resistant isolates of N. meningitidis were recovered from some individuals who were carrying rifampin-susceptible strains prior to chemoprophylaxis.189 In an outbreak setting, some clinicians suggest that surveillance for rifampin resistance may be indicated and use of ciprofloxacin or ceftriaxone should be considered.266

While the vast majority of cases of meningococcal disease in the US are sporadic, the frequency of outbreaks of group C meningococcal disease has increased in the US and Canada since 1991 and there also have been small outbreaks as well as statewide epidemics caused by serogroup B.188,189 As a result, the CDC has published guidelines for the evaluation and management of suspected meningococcal outbreaks that can be used by US public health professionals (e.g., epidemiologists in state and local health departments), and these guidelines can be consulted for further information.188 In addition, the Childhood and Respiratory Diseases Branch, Division of Bacteria and Mycotic Diseases, National Center for Infectious Diseases, CDC can be consulted on these and other issues regarding meningococcal disease (404-639-2215 or 404-639-3311).188

Prevention of Haemophilus influenzae Type b Infection !!navigator!!

Rifampin is used for chemoprophylaxis in contacts of patients with Haemophilus influenzae type b (Hib) infection†.102,103,104,105,106,134,135,138,140,141,176 Rifampin is effective for eradicating oropharyngeal carriage of H. influenzae type b and is considered the most effective antimicrobial agent for eradicating carriage of the organism.102,103,104,105,106,134,138,141

Unvaccinated household contacts of an individual with Hib infection are at increased risk of infection if they are younger than 4 years of age.176 In addition, asymptomatic colonization with Hib occurs more frequently in household contacts of all ages than in the general population.176 Rifampin is approximately 95% effective in eradicating Hib from the pharynx of carriers, and limited data indicate that rifampin prophylaxis also decreases the risk of secondary invasive illness in exposed household contacts.176 Although child-care and nursery school contacts of an individual with Hib infection also may be at increased risk of secondary disease, experts disagree about the magnitude of the risk.176 The risk of secondary disease in children attending child-care centers seems to be lower than that observed for age-susceptible household contacts, and secondary disease in child-care contacts is rare when all contacts are older than 2 years of age.176 Efficacy of rifampin in preventing disease in child-care groups is not established.176

The AAP and US Public Health Service Advisory Committee on Immunization Practices (ACIP) state that rifampin is the drug of choice for chemoprophylaxis in contacts of patients with Hib infection.134,135,141,176 The AAP suggests the following guidelines for prophylaxis in household and child-care or nursery school contacts of patients with Hib infection:176

Dosage and Administration ⬆ ⬇

[Section Outline]

Reconstitution and Administration !!navigator!!

Rifampin usually is administered orally.161 When oral therapy is not feasible, the drug may be given by IV infusion.161 Rifampin should not be administered IM or subcutaneously since local irritation and inflammation can occur.161

Oral Administration

Rifampin should be given orally either 1 hour before or 2 hours after a meal with a full glass of water to ensure maximum absorption.161 The fixed-combination preparation containing rifampin and isoniazid and the fixed-combination preparation containing isoniazid, rifampin, and pyrazinamide also should be given either 1 hour before or 2 hours after a meal with a full glass of water.172,259

For patients who are unable to swallow the commercially available rifampin capsules, the contents of the capsules may be mixed with applesauce or jelly. Alternatively, a 1% rifampin suspension can be prepared by emptying the contents of four 300-mg or eight 150-mg capsules and mixing the contents vigorously with 20 mL of Syrup NF (simple syrup), and then further diluting with 100 mL of Syrup NF.161 Syrpalta® syrup (Emerson Laboratories), or Raspberry syrup (HumCo Laboratories) may also be used to prepare the suspension.161 The resulting suspensions contain 10 mg of rifampin per mL and are stable for 4 weeks when stored in a light-resistant (amber) glass or clear plastic bottle at room temperature (22-28°C) or refrigerated at 2-8°C.161 The extemporaneously prepared suspension must be shaken well prior to administration.161 The suspension is also suitable for use in children when lower doses are needed.161

An oral liquid formulation of rifampin containing 25 mg/mL also has been extemporaneously compounded using the capsules and a commercially available vehicle.98

Standardize 4 Safety

Standardized concentrations for an extemporaneously prepared oral liquid formulation of rifampin have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 99Multidisciplinary expert panels were convened to determine recommended standard concentrations. Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 99 For additional information on S4S (including updates that may be available), see [Web].99

Table 1: Standardize 4 Safety Compounded Oral Liquid Standards for Rifampin99

Concentration Standards

25 mg/mL

IV Infusion

For IV infusion, rifampin powder for injection should be reconstituted by adding 10 mL of sterile water for injection to the vial labeled as containing 600 mg of rifampin to provide a solution containing 60 mg/mL.161 The vial should be swirled gently to facilitate dissolution of the drug.161 Immediately prior to administration, the appropriate dose of reconstituted solution may be added to 500 mL of 5% dextrose injection and infused at a rate that allows complete infusion within 3 hours.161 Alternatively, the appropriate dose of reconstituted solution may be added to 100 mL of 5% dextrose injection and infused at a rate that allows complete infusion within 30 minutes.161 The manufacturer states that the 500- and 100-mL IV infusion solutions containing rifampin should be prepared and administered within a total of 4 hours; precipitation of rifampin from the infusion solution may occur beyond this time period.161

Extravasation during IV infusion of rifampin should be avoided.161 If local irritation or inflammation occurs at the site of infusion, the infusion should be discontinued and restarted at another site.161

Dosage !!navigator!!

Dosage of rifampin is identical for oral and IV administration.161

Active Tuberculosis

In the treatment of clinical tuberculosis, rifampin should not be given alone.258 The drug is considered a first-line agent for the treatment of all forms of tuberculosis and is an essential component of all short-course regimens.258 Therapy for tuberculosis should be continued long enough to prevent relapse. The minimum duration of treatment currently recommended for patients with culture-positive pulmonary tuberculosis is 6 months (26 weeks), and recommended regimens consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months).258 However, the American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and the Infectious Diseases Society of America (IDSA) state that completion of treatment is determined more accurately by the total number of doses and should not be based solely on the duration of therapy.258 For information on general principles of antituberculosis therapy and recommendations regarding specific multiple-drug regimens and duration of therapy, see the Antituberculosis Agents General Statement 8:16.04.

Because of concerns that there may be an increased risk of acquired rifamycin resistance in HIV-infected individuals with CD4+ T-cell counts less than 100/mm3 who receive intermittent rifamycin regimens, the CDC recommends that rifampin be administered once daily or 3-times weekly and that rifampin regimens that involve once- or twice-weekly administration be avoided in these HIV-infected individuals pending further accumulation of data.100 The CDC also recommends directly observed therapy for both the daily and 3-times weekly regimens.100

Adult Dosage

The manufacturer states that the usual dosage of rifampin for the treatment of active tuberculosis in adults is 10 mg/kg (up to 600 mg) once daily.161

The ATS, CDC, and IDSA recommend that when rifampin is used in conjunction with other antituberculosis agents in a daily regimen, adults and children 15 years of age or older should receive a rifampin dosage of 10 mg/kg (up to 600 mg) once daily.258

When an intermittent multiple-drug regimen is used, adults and children 15 years of age or older should receive a rifampin dosage of 10 mg/kg (up to 600 mg) 2 or 3 times weekly.258

Pediatric Dosage

The manufacturer states that the usual dosage of rifampin for the treatment of active tuberculosis in children is 10-20 mg/kg (up to 600 mg) daily.161

The ATS, CDC, IDSA, and American Academy of Pediatrics (AAP) recommend that when rifampin is used in daily multiple-drug regimens in pediatric patients, a dosage of 10-20 mg/kg (up to 600 mg) daily should be used.176,258

If an intermittent multiple-drug regimen is used in pediatric patients, the ATS, CDC, IDSA, and AAP recommend a rifampin dosage of 10-20 mg/kg (up to 600 mg) twice weekly.176,258

Fixed-Combination Preparations

When rifampin is administered as the fixed combination containing rifampin and isoniazid as part of a multiple-drug regimen for the treatment of pulmonary tuberculosis, the usual adult dosage is 2 capsules (600 mg of rifampin and 300 mg of isoniazid) once daily.258,259 Although the fixed-combination preparation was formulated for daily regimens, the ATS, CDC, and IDSA state that the fixed-combination preparation can be used in twice-weekly regimens† provided additional isoniazid is administered concomitantly.258 When used in an intermittent multiple-drug regimen, these experts state that 2 capsules of (600 mg of rifampin and 300 mg of isoniazid) and an additional 600 mg of isoniazid (i.e., 900 mg of isoniazid total) may be given twice weekly using directly observed therapy (DOT).258 The manufacturer states that the fixed combination containing rifampin and isoniazid should not be used for the initial treatment of tuberculosis and should only be used after efficacy of the rifampin and isoniazid dosages contained in the fixed-combination preparation has been established by titrating the individual components in the patient.259

When rifampin is administered as the fixed combination containing isoniazid, rifampin, and pyrazinamide (Rifater®) in the initial phase (e.g., initial 2 months) of multiple-drug therapy for pulmonary tuberculosis, the manufacturer states that the adult dosage of Rifater® given as a single daily dose is 4 tablets (480 mg of rifampin, 200 mg of isoniazid, 1.2 g of pyrazinamide) in patients weighing 44 kg or less, 5 tablets (600 mg of rifampin, 250 mg of isoniazid, 1.5 g of pyrazinamide) in those weighing 45-54 kg, and 6 tablets (720 mg of rifampin, 300 mg of isoniazid, and 1.8 g of pyrazinamide) in those weighing 55 kg or more.172 This fixed-combination preparation provides a higher rifampin dosage than is usually used in the US because rifampin is less bioavailable in this formulation.258 In individuals weighing more than 90 kg, additional pyrazinamide should be given in conjunction with the fixed-combination preparation to obtain an adequate dosage of this drug.258 The ratio of rifampin, isoniazid, and pyrazinamide in Rifater® may not be appropriate in children or adolescents younger than 15 years of age because of the higher mg/kg doses of isoniazid usually given in children compared with those given in adults.172

Treatment of Latent Tuberculosis Infection

Rifampin Monotherapy

When daily rifampin monotherapy is used as an alternative regimen for the treatment of latent tuberculosis infection, the ATS and CDC recommend that adults receive a rifampin dosage of 10 mg/kg (up to 600 mg) daily for 4 months.194,215 The ATS, CDC, and AAP recommend that infants, children, and adolescents receive 10-20 mg/kg (up to 600 mg) daily for 4-6 months.176,194,215,257

The ATS and CDC state that completion of treatment is determined more accurately by the total number of doses and should not be based solely on the duration of therapy.166 In adults, the rifampin monotherapy regimen should consist of at least 120 doses administered within 6 months (allowing for minor interruptions in the 4-month regimen).166

Rifampin and Pyrazinamide Regimens

Because of the risk of hepatotoxicity, rifampin and pyrazinamide regimens should be used with caution and only in selected individuals with close clinical and laboratory monitoring throughout the course of treatment.215,225,257 To facilitate clinical assessment and laboratory monitoring of serum concentrations of AST (SGOT) and bilirubin at baseline and at 2, 4, 6, and 8 weeks, no more than a 2-week supply of rifampin and pyrazinamide should be dispensed at a time.257 (See Precautions Related to Hepatotoxicity under Cautions: Precautions and Contraindications.)

When a 2-month daily regimen of rifampin and pyrazinamide is used for the treatment of latent tuberculosis infection† when the potential benefits of the regimen outweigh the risk of severe liver injury and death (see Rifampin and Pyrazinamide Regimens under Tuberculosis: Latent Tuberculosis Infection, in Uses), the ATS and CDC recommend that adults receive a rifampin dosage of 10 mg/kg (up to 600 mg) daily in conjunction with pyrazinamide.194,215 This daily regimen should consist of at least 60 doses administered within 3 months (allowing for minor interruptions in the 2-month regimen).194,166

If an intermittent (twice-weekly) regimen of rifampin and pyrazinamide is used for the treatment of latent tuberculosis infection when the potential benefits outweigh the risk of severe liver injury and death, the ATS and CDC recommend that adults receive a rifampin dosage of 10 mg/kg (up to 600 mg) given twice weekly for 2-3 months in conjunction with pyrazinamide given twice weekly.215 If this intermittent regimen is used, it should be given using DOT.215

Neisseria meningitidis Infection

Elimination of Pharyngeal Carrier State

When rifampin is used to eliminate meningococci from the nasopharynx of asymptomatic Neisseria meningitidis carriers, the recommended dosage in adults is 600 mg twice daily for 2 days.161 Children 1 month of age or older may receive rifampin in a dosage of 10 mg/kg twice daily for 2 days and children younger than 1 month of age may receive 5 mg/kg twice daily for 2 days.161

Prophylaxis in Household or Other Close Contacts

When rifampin is used for chemoprophylaxis in close contacts of individuals with invasive meningococcal disease† when the risk of infection is high, adults should receive 600 mg every 12 hours for 2 days.187 The usual dosage of rifampin for chemoprophylaxis of meningococcal disease in children older than 1 month of age is 10 mg/kg (maximum dose 600 mg) every 12 hours for 2 days.176,179,268 Neonates 1 month of age or younger should receive 5 mg/kg every 12 hours for 2 days for chemoprophylaxis of meningococcal disease.176,179,187,268 When chemoprophylaxis is indicated in high-risk contacts, it must be administered promptly (ideally within 24 hours after identification of the index case) since the attack rate of secondary disease is greatest in the few days following disease onset in the index case.176,179 Chemoprophylaxis probably is of limited or no value if administered more than 2 weeks after contact with the index case.179,187

Prevention of Haemophilus influenzae Type b Infection

When indicated for prophylaxis of Haemophilus influenzae type b infection† in adults and children, the recommended dosage of rifampin is 20 mg/kg (maximum dose 600 mg) once daily for 4 consecutive days.134,138,176 Dosage for very young infants has not been established, but some clinicians recommend a dosage of 10 mg/kg once daily for 4 consecutive days in neonates younger than 1 month of age.134,176

Leprosy

Multibacillary Leprosy

For the treatment of multibacillary leprosy†, the World Health Organization (WHO) recommends that adults receive rifampin in a dosage of 600 mg once monthly in conjunction with clofazimine (50 mg once daily and 300 mg once monthly), and dapsone (100 mg daily) given for 12 months.198,200,204,206,207 Children 10-14 years of age with multibacillary leprosy should receive rifampin in a dosage of 450 mg once monthly in conjunction with clofazimine (50 mg every second day and 150 mg once monthly), and dapsone (50 mg daily) given for 12 months,204 and children younger than 10 years of age should receive an appropriately adjusted dosage (e.g., rifampin [300 mg monthly], clofazimine [50 mg twice weekly and 100 mg once monthly], and dapsone [25 mg daily]) given for 12 months.204 The WHO recommends supervised administration of some drug doses included in the regimen (e.g., once-monthly doses).198,206 While the 12-month regimen is adequate for most patients with multibacillary leprosy, the WHO recommends that multibacillary leprosy patients with a high bacteriologic index who demonstrate no improvement (with evidence of worsening) of leprosy following completion of the initial 12 months of treatment should receive an additional 12 months of therapy.206

If a patient with multibacillary leprosy experiences severe adverse effects related to dapsone, dapsone may be discontinued from the regimen and therapy continued with rifampin and clofazimine given in the usually recommended dosages.206

If a patient with multibacillary leprosy will not accept or cannot tolerate clofazimine, the WHO recommends supervised administration of a once-monthly rifampin-based multiple-drug regimen (ROM) that includes rifampin (600 mg once monthly), ofloxacin (400 mg once monthly), and minocycline (100 mg once monthly) given for 24 months.198,206

For the treatment of multibacillary leprosy in adults who cannot receive rifampin because of a contraindication (e.g., hypersensitivity) or intolerance, intercurrent disease, or infection with rifampin-resistant Mycobacterium leprae , the WHO recommends supervised administration of a regimen of clofazimine (50 mg daily), ofloxacin (400 mg daily), and minocycline (100 mg daily) given for 6 months, followed by a regimen of clofazimine (50 mg daily) and ofloxacin (400 mg daily) or minocycline (100 mg daily) given for at least an additional 18 months.198,205,207

Paucibacillary Leprosy

For the treatment of paucibacillary leprosy†, the WHO recommends that adults receive rifampin in a dosage of 600 mg once monthly in conjunction with dapsone (100 mg daily) given for 6 months.198,205

Children 10-14 years of age with paucibacillary leprosy should receive rifampin in a dosage of 450 mg once monthly in conjunction with dapsone (50 mg daily) given for 6 months,204 and children younger than 10 years of age should receive an appropriately adjusted dosage (e.g., rifampin [300 mg once monthly] in conjunction with dapsone [25 mg daily]) given for 6 months.204

The WHO recommends supervised administration of some drug doses included in the regimen (e.g., once monthly doses).198,206

If a patient with paucibacillary leprosy experiences severe adverse effects related to dapsone, dapsone may be discontinued from the regimen and clofazimine substituted (given in the dosage recommended for the treatment of multibacillary leprosy) for a period of 6 months.206

Single-lesion Paucibacillary Leprosy

For the treatment of single-lesion paucibacillary leprosy† in certain patient groups (see Single-lesion Paucibacillary Leprosy under Uses: Leprosy), the WHO states that adults may receive a single-dose rifampin-based multiple-drug regimen (ROM) that includes a single 600-mg dose of rifampin, a single 400-mg dose of ofloxacin, and a single 100-mg dose of minocycline.198,207

For the treatment of single-lesion paucibacillary leprosy, children 5-14 years of age may receive a single 300-mg dose of rifampin, a single 200-mg dose of ofloxacin, and a single 50-mg dose of minocycline, and children younger than 5 years of age should receive an appropriately adjusted dose of each drug.204

Anthrax

Although the optimum regimen for the treatment of inhalational anthrax remains to be established, limited experience indicates that early treatment with a multiple-drug parenteral regimen that includes a fluoroquinolone and at least one other active anti-infective may improve survival.127,252,253 Several patients with inhalational anthrax† have been treated successfully with a multiple-drug regimen that included IV rifampin 300 mg every 12 hours, IV ciprofloxacin 400 mg every 8 hours, and IV clindamycin 900 mg every 8 hours.127 Some clinicians suggest that rifampin be given in a dosage of 20 mg/kg IV daily if the drug is included in a multiple-drug regimen for the treatment of anthrax meningitis.139

Brucellosis

If rifampin is used in conjunction with a tetracycline (doxycycline), co-trimoxazole, or a fluoroquinolone (ciprofloxacin or ofloxacin) for the treatment of brucellosis†, a rifampin dosage of 15-20 mg/kg (up to 600-900 mg) daily usually is recommended in adults or pediatric patients.139,176,227,229,230 Some clinicians recommend a rifampin dosage of 0.6-1.2 g daily in conjunction with other anti-infectives.270 An oral regimen usually is effective for the treatment of brucellosis.139,176,270 The anti-infective regimen should be continued for 4-6 weeks to prevent relapse; however, more prolonged therapy may be necessary in serious infections or when there are complications (e.g., meningoencephalitis or endocarditis).139,176 Some clinicians state that 6-8 weeks of treatment may be necessary in patients with skeletal disease and at least 3 months (and possibly more than 6 months) of treatment may be necessary in those with meningoencephalitis or endocarditis.139

If use of an anti-infective regimen is considered necessary for prophylaxis following a high-risk exposure to Brucella †, some experts recommend that the same regimen recommended for the treatment of brucellosis be given for 3-6 weeks.139

Cautions ⬆ ⬇

[Section Outline]

GI Effects !!navigator!!

The most frequent adverse effects of rifampin are GI disturbances, which include heartburn, epigastric distress, nausea, vomiting, anorexia, abdominal cramps, flatulence, and diarrhea. Rarely, adverse GI effects may be severe enough to require discontinuance of the drug.115 Although rifampin usually should be administered 1 hour before or 2 hours after food to ensure maximum absorption, adverse GI effects may be minimized by administering the drug during or immediately after a meal.115

Although rifampin has some in vitro activity against Clostridium difficile , C. difficile -associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis) has been reported rarely in association with rifampin therapy and should be considered in the differential diagnosis of patients who develop diarrhea during or following therapy with the drug.161

Nervous System Effects !!navigator!!

Headache, drowsiness, fatigue, ataxia, dizziness, inability to concentrate, mental confusion, behavioral changes, psychosis, visual disturbances, muscular weakness, myopathy, fever, generalized numbness, and pains in muscles, joints, and extremities have occurred,161 especially during the first few weeks of rifampin therapy.

Hepatic Effects !!navigator!!

Rifampin has caused transient increases in serum concentrations of AST (SGOT), ALT (SGPT), bilirubin, and alkaline phosphatase. Asymptomatic jaundice which subsided without discontinuance of the drug has occurred occasionally. However, hepatitis and fatalities associated with jaundice have been reported in patients with preexisting liver disease or in those who received other hepatotoxic agents concomitantly with rifampin. Rarely, hepatitis or a shocklike syndrome with hepatic involvement and abnormal liver function test results (thought to be allergic in nature) have been reported.

Hepatotoxicity with Combined Rifampin and Pyrazinamide

Severe hepatic injuries, including some fatalities, have been reported in patients receiving regimens that contain both rifampin and pyrazinamide for the treatment of latent tuberculosis infection.222,225,257 Between October 2000 and June 2003, the US Centers for Disease Control and Prevention (CDC) received a total of 48 reports of severe hepatic injury (i.e., hospitalization or death) in patients with latent tuberculosis infection receiving a rifampin and pyrazinamide regimen; there were 11 fatalities.257 In many fatal cases, onset of hepatic injury occurred during the second month of the 2-month regimen.225 Some patients who died were receiving the rifampin and pyrazinamide regimen because they previously experienced isoniazid-associated hepatitis and some had risk factors for chronic liver disease (e.g., serologic evidence of previous hepatitis A or B infection, idiopathic nonalcoholic steatotic hepatitis, alcohol or parenteral drug abuse, concomitant use of other drugs associated with idiosyncratic hepatic injury).225 Although data are limited, there is no evidence to date that HIV-infected individuals receiving this regimen are at any increased risk for severe hepatitis.225 There is evidence that the rate of severe liver injury and death related to the use of rifampin and pyrazinamide are higher than the rates reported for isoniazid-associated liver injury in the treatment of latent tuberculosis infection.257 Based on these reports, rifampin and pyrazinamide regimens should be used for the treatment of latent tuberculosis only when the potential benefits outweigh the risk of liver injury and death.257 (See Cautions: Precautions and Contraindications.)

Local, Sensitivity, and Dermatologic Reactions !!navigator!!

Extravasation during IV infusion of rifampin has caused local irritation and inflammation.161 Extravasation should be avoided; if it occurs, the infusion should be discontinued and restarted at another site.161

Hypersensitivity reactions characterized by a flu-like syndrome with episodes of fever, chills, and sometimes with headache, dizziness, and bone pain have occurred with rifampin.115 Edema of the face and extremities, decrease in blood pressure, and shock also have been reported.161 Dyspnea, sometimes accompanied by wheezing, may also occur.115,161 Occasionally, pruritus, urticaria, acneiform eruptions,154,155 rash, pemphigoid reactions, erythema multiforme including Stevens-Johnson syndrome,154,156,161 toxic epidermal necrolysis,161 vasculitis,161 eosinophilia, sore mouth, sore tongue, anaphylaxis,154 exfoliative dermatitis,153 and exudative conjunctivitis have also occurred. Anaphylaxis has been reported rarely.161 Some cutaneous reactions, including flushing and pruritus (with or without rash), are mild and self-limiting and do not appear to be hypersensitivity reactions to rifampin.161 More serious cutaneous reactions occur less frequently and do appear to be hypersensitivity reactions to the drug.161

Hypersensitivity reactions, especially the flu-like syndrome, are usually associated with high-dose intermittent rifampin therapy (900-1200 mg twice weekly) or treatment that has been resumed after a lapse of days or weeks.115,116 These hypersensitivity reactions reportedly occur in about 1% of patients who receive 600 mg of rifampin twice weekly.116

Hematologic Effects !!navigator!!

Thrombocytopenia, leukopenia, purpura, hemolytic anemia, hemolysis, hemoglobinuria, and decreased hemoglobin concentrations have occurred with rifampin. Acute hemolytic anemia has generally occurred only with intermittent rifampin therapy.115 Thrombocytopenia has been reported principally with high-dose intermittent rifampin therapy, but also has been reported rarely after rifampin therapy was discontinued and then resumed; thrombocytopenia occurs only rarely during daily rifampin therapy.161 Thrombocytopenia generally is reversible if rifampin is discontinued as soon as purpura occurs; cerebral hemorrhage and fatalities have been reported when rifampin therapy was continued or resumed after the appearance of purpura.161 In addition, disseminated intravascular coagulation has been reported rarely in patients receiving rifampin.161

Renal, Endocrine, and Metabolic Effects !!navigator!!

Increased BUN and serum uric acid concentrations, light chain proteinuria, hematuria, renal insufficiency, interstitial nephritis, acute tubular necrosis,161 and acute renal failure have occurred infrequently with rifampin. Rifampin has also been associated with precipitation of adrenocortical insufficiency in a few patients with compromised adrenal function,108,161 possibly resulting from increased cortisol metabolism secondary to hepatic microsomal enzyme induction.108 Menstrual disturbances have also been reported.161

Rifampin has been shown to decrease plasma concentrations of 25-hydroxy vitamin D (the major circulating metabolite of vitamin D) and/or 1α,25-dihydroxy vitamin D;223 isoniazid has similar effects and concomitant use of rifampin and isoniazid has been reported to alter vitamin D metabolism.161,223 In some cases, decreased plasma concentrations of vitamin D metabolites have been accompanied by decreased plasma calcium and phosphate concentrations and increased parathyroid hormone concentrations.161

Lupus-like Syndrome !!navigator!!

A drug-induced lupus-like syndrome consisting principally of malaise, myalgias, arthritis, and peripheral edema and accompanied by positive antinuclear antibody (ANA) test results has been reported in a few patients receiving rifampin (450-600 mg daily) or rifabutin (300 mg daily).193 Manifestations of the syndrome disappeared within 1-10 weeks following discontinuance of rifamycin therapy despite continuation of other antimycobacterial therapy; one patient who was rechallenged with rifabutin had a relapse of symptoms.193 All patients were receiving concomitant therapy with clarithromycin and/or ciprofloxacin, known inhibitors of the cytochrome P-450 enzyme system, and it has been suggested that this syndrome may have been associated with elevated serum concentrations of the rifamycin (elevated serum rifampin concentration was documented in one patient) caused by inhibition of rifamycin metabolism.193 (See Drug Interactions: Drugs Undergoing Hepatic Metabolism.)

Precautions and Contraindications !!navigator!!

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 (see Cautions: Hepatic Effects and see Cautions: Hematologic Effects), liver function (hepatic enzymes, bilirubin) and hematologic status (complete blood cell and platelet counts) should be assessed prior to initiation of rifampin therapy.161 Serum creatinine concentrations also should be assessed at baseline.161 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.161 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 therapy161 Routine laboratory monitoring for drug-induced toxicity in patients with normal baseline tests generally is not necessary.161

Although one manufacturer states that rifampin is not recommended for intermittent therapy,163 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. (See General Principles in the Antituberculosis Agents General Statement 8:16.04.) and a once-monthly rifampin regimen is used in multiple-drug regimens for the treatment of leprosy†.128,129,198,199,200,201,202,204,205,206

Precautions Related to Hepatotoxicity

Rifampin should be used in patients with impaired liver function only when clearly necessary and only under strict medical supervision.161 If the drug is used in patients with impaired hepatic function, liver function tests should be performed every 2-4 weeks.161 The drug should be discontinued if signs of hepatocellular damage occur.161 In some cases, hyperbilirubinemia (resulting from competition between rifampin and bilirubin for excretory pathways in the liver) can occur shortly after initiation of rifampin therapy.161 An isolated report of a moderate increase in bilirubin and/or transaminase concentrations, therefore, is not in itself an indication to discontinue rifampin therapy; the decision to discontinue therapy should be made after repeating the tests, noting trends in the concentrations, and considering the test results in conjunction with the patient's clinical condition.161

Because of reports of liver injury (including fatalities) when regimens containing rifampin and pyrazinamide were used in patients with latent tuberculosis infection, these regimens generally should not be offered to HIV-infected or HIV-negative patients.257 Regimens containing rifampin and pyrazinamide should be considered for the treatment of latent tuberculosis infection only when the potential benefits outweigh the risk of liver injury and death; when the preferred or alternative regimens (i.e., 9-month isoniazid regimens, 6-month isoniazid regimens, 4-month daily rifampin regimen) are judged unlikely to be completed; and when oversight can be provided by a clinician with expertise in the treatment of latent tuberculosis.257 A rifampin-pyrazinamide regimen should never be offered to patients who are currently taking other drugs associated with liver injury, patients who drink excessive amounts of alcohol (even if alcohol is discontinued during treatment), or patients with underlying liver disease or a history of isoniazid-associated liver injury.257 An expert in the treatment of latent tuberculosis should be consulted before a regimen of rifampin and pyrazinamide is offered.257 Individuals being considered for a 2-month rifampin-pyrazinamide regimen should be informed of potential hepatotoxicity, questioned regarding prior liver disease or history of adverse effects during treatment with isoniazid or other drugs, and cautioned against the concurrent use of potentially hepatotoxic drugs (including OTC drugs such as acetaminophen).257

If a decision is made to use a rifampin-pyrazinamide regimen, serum AST and bilirubin concentrations should be measured at baseline and at 2, 4, 6, and 8 weeks and patients should be reassessed in person by a health-care provider at 2, 4, 6 and 8 weeks for adherence, tolerance, and adverse effects.257 To facilitate these periodic assessments, no more than a 2-week supply of the drugs should be dispensed at a time.257 Patients should be instructed to discontinue the rifampin-pyrazinamide regimen immediately and seek clinical consultation if abdominal pain, emesis, jaundice, or other manifestations of hepatitis develop.257 The drugs should be discontinued and not reinitiated in asymptomatic patients who have an AST concentration exceeding 5 times the upper limit of normal, in patients with symptoms of hepatitis who have an AST concentration exceeding the upper limit of normal, and in patients who have serum bilirubin concentrations exceeding the upper limit of normal (regardless of the presence or absence of symptoms).257

Precautions in Leprosy Patients

Effective therapy of leprosy with antileprosy agents (e.g., dapsone, clofazimine, rifampin) generally results in abrupt changes in the clinical state of the patient. These changes have been termed leprosy reactional states and can be classified into 2 types: reversal reactions (type 1) and erythema nodosum leprosum (ENL) or lepromatous lepra reactions (type 2). (See Cautions: Leprosy Reactional States, in Dapsone 8:16.08, and see Leprosy Reactional States under Uses: Leprosy, in Clofazimine 8:16.08). In the US, the Gillis W. Long Hansen's Disease Center at 800-642-2477 should be contacted for further information on the management of leprosy reactional states.197

Although one manufacturer states that rifampin is not recommended for intermittent therapy,163 the World Health Organization (WHO) and many clinicians recommend that rifampin be given once monthly when used in recommended multiple-drug regimens for the treatment of leprosy†.128,129,198,199,200,201,202,204,205,206 Rifampin appears to be well tolerated in leprosy patients when administered once monthly as part of multiple-drug regimens.198,204,206,207,212 Most adverse effects reported in leprosy patients receiving the recommended rifampin regimens with one or more other drugs are mild.204,206,207,212 However, more severe adverse effects have been reported occasionally when rifampin was administered in leprosy patients, including renal failure, thrombocytopenia, flu-like syndrome, and hepatitis.204,212 Patients receiving intermittent therapy should be closely monitored for compliance and cautioned against intentional or accidental interruption of the dosage regimen.161

Other Precautions and Contraindications

Commercially available rifampin sterile powder for injection contains sodium formaldehyde sulfoxylate, a sulfite that may cause serious allergic-type reactions in certain susceptible individuals. The overall incidence of sulfite sensitivity in the general population is probably low, but in susceptible individuals, exposure to sulfites can result in acute bronchospasm or, less frequently, life-threatening anaphylaxis. Rifampin sterile powder for injection containing sodium formaldehyde sulfoxylate should be used with caution 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.

To reduce development of drug-resistant bacteria and maintain effectiveness of rifampin and other antibacterials, the drug should be used only for the treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.161 When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.161 In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.161 Patients should be advised that antibacterials (including rifampin) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).161 Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with rifampin or other antibacterials in the future.161

Pediatric Precautions !!navigator!!

Rifampin is used in pediatric patients for the treatment of active tuberculosis and treatment of latent tuberculosis infection,167,169,171,176 to eliminate nasopharyngeal carriage of Neisseria meningitidis ,161,163,176,179,187 for chemoprophylaxis against meningococcal disease†176,179,187 or Haemophilus influenzae type b (Hib) infection†,102,103,104,134,135,136,137,138,144,145,176 and for the treatment of leprosy.198,204,206

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 a 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.172

Mutagenicity and Carcinogenicity !!navigator!!

There was no evidence of mutagenicity when rifampin was tested in vitro and in vivo using bacteria, Drosophila melanogaster , or mice.161 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).161

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 2-10 times the maximum human dosage.161,163 There was no evidence of carcinogenicity in the male mice of this strain, in male or female mice of another strain, or in rats under similar experimental conditions.161,163 Although a causal relationship has not been definitely established, a few cases of accelerated growth of lung carcinoma has been reported in patients receiving rifampin.161

Pregnancy, Fertility, and Lactation !!navigator!!

Pregnancy

An increased incidence of congenital malformations (principally spina bifida and cleft palate) has been reported in the offspring of mice and rats given rifampin in a dosage of 150-250 mg/kg daily during pregnancy.161,163 The incidence of these anomalies was dose dependent.161 In addition, imperfect osteogenesis and embryotoxicity occurred when rifampin doses up to 20 times the usual daily human dose were used in pregnant rabbits.161 The manufacturer states that isolated cases of fetal malformations have been reported.161 Although safe use of the drugs during pregnancy has not been definitely established,161,163 rifampin (combined with isoniazid and/or ethambutol) has been used to treat clinical tuberculosis in pregnant women.147,149,150,151 There are no adequate and controlled studies to date using rifampin in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.161,163 The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) state that rifampin is considered safe for use in pregnant women.258 The manufacturer states that neonates of rifampin-treated mothers should be carefully observed for evidence of adverse reactions.161,163

Fertility

Studies have not been performed to date to determine whether rifampin has an effect on fertility.161

Lactation

Since rifampin is distributed into milk and because animal studies indicate that the drug has a potential for tumorigenic effects, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.161

Drug Interactions ⬆ ⬇

[Section Outline]

Antiretroviral Agents !!navigator!!

Rifamycin derivatives (e.g., rifampin, rifabutin) can accelerate the metabolism of certain antiretroviral agents (i.e., HIV protease inhibitors [PIs], nonnucleoside reverse transcriptase inhibitors [NNRTIs]) by induction of cytochrome P-450 (CYP) oxidases, which may result in subtherapeutic plasma concentrations of some of these PIs and NNRTIs.183 194 Rifampin also can affect the pharmacokinetics of some nucleoside reverse transcriptase inhibitors (e.g., zidovudine).161,251 In addition, PIs and some NNRTIs (e.g., delavirdine) reduce the metabolism of rifamycins, leading to increased plasma concentrations of rifamycins and an increased risk of toxicity.183,194 The potential for alterations in the plasma concentrations of antimycobacterial agent(s) and/or antiretroviral agent(s) must be considered when antimycobacterial agents are indicated for the management of latent or active tuberculosis or the prophylaxis or treatment of Mycobacterium avium complex (MAC) infections in HIV-infected patients who are receiving or are being considered for antiretroviral therapy.101,124,177,181,194,215 Because the management of these patients is complex and must be individualized, experts in the management of mycobacterial infections in HIV-infected patients should be consulted.124,180,194

HIV Fusion Inhibitors

Concomitant use of enfuvirtide and rifampin does not appear to have a clinically important effect on the pharmacokinetics of the HIV fusion inhibitor.272

HIV Protease Inhibitors

Because rifampin is a potent inducer of the CYP3A4 isoenzyme and can markedly reduce plasma concentrations of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, nelfinavir, or saquinavir, concomitant use of rifampin and these PIs is contraindicated.101,124,126,152,175,177,192,256,260

Concomitant use of rifampin and ritonavir-boosted indinavir is contraindicated.101 Concomitant use of rifampin (600 mg once daily) and ritonavir-boosted saquinavir (1 g of saquinavir and 100 mg of ritonavir twice daily) has resulted in drug-induced hepatotoxicity and marked increases in serum transaminase concentrations; therefore, concomitant use of rifampin with ritonavir-boosted saquinavir is contraindicated.101,260

Because concomitant use of rifampin and ritonavir results in decreased ritonavir concentrations, the manufacturer of ritonavir and some clinicians state that other antimycobacterial agents (e.g., rifabutin) should be used instead of rifampin in patients receiving ritonavir.101,216

For specific information on the pharmacokinetic interactions between PIs and rifampin, see Antimycobacterial Agents under Drug Interactions: Anti-infective Agents, in the individual monographs in 8:18.08.08.

Nonnucleoside Reverse Transcriptase Inhibitors

Concomitant use of rifampin and delavirdine results in a substantial decrease in concentrations of the nonnucleoside reverse transcriptase inhibitor.101,217 Because of this pharmacokinetic interaction, concomitant use of rifampin and delavirdine is contraindicated.101,124,217

Concomitant use of efavirenz and rifampin can result in decreased plasma concentrations and area under the plasma concentration-time curve (AUC) of the nonnucleoside reverse transcriptase inhibitor.101,218 The manufacturer of efavirenz states that the clinical importance of this pharmacokinetic interaction is unknown.218 Some experts recommend that consideration be given to increasing efavirenz dosage to 800 mg once daily when the drug is used in patients receiving rifampin.101

Concomitant use of nevirapine and rifampin results in a substantial decrease in peak plasma concentrations and AUC of nevirapine, and the manufacturer of the nonnucleoside reverse transcriptase inhibitor states that the drugs should not be used concomitantly.101,219 Some experts state that because the virologic consequences are uncertain and because the potential for additive hepatotoxicity exists, concomitant use of rifampin and nevirapine is not recommended; however, if the drugs are used concomitantly, the patient should be closely monitored.101

For specific information on the pharmacokinetic interactions between nonnucleoside reverse transcriptase inhibitors and rifampin, see Antimycobacterial Agents under Drug Interactions: Anti-infective Agents, in the individual monographs in 8:18.08.16.

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

Concomitant use of rifampin and tenofovir disoproxil fumarate does not have a clinically important effect on the pharmacokinetics of either drug.271 Dosage adjustments are not necessary when the drugs are used concomitantly.271

In a multiple-dose study in HIV-infected patients, concomitant use of zidovudine (200 mg every 8 hours) and rifampin (600 mg once daily) given for 14 days resulted in a 43% decrease in peak plasma concentrations of zidovudine, a 47% decrease in the AUC, and a 13% decrease in the plasma half-life of the antiretroviral agent.251

Drugs Undergoing Hepatic Metabolism !!navigator!!

Rifampin induces certain cytochrome P-450 liver enzymes responsible for the metabolism of a number of drugs.161 Concurrent administration of rifampin and any of the following drugs may result in decreased plasma concentrations of the drugs; dosage adjustments may be required and, in some cases, concomitant use is contraindicated.

Other Information ⬆ ⬇

[Section Outline]

Laboratory Test Interferences

Rifampin may cause cross-reactivity and false-positive results in urine screening tests for opiates that use Kinetic Interaction of Microparticles in Solution (KIMS) methods (e.g., Abuscreen OnLine opiates assay; Roche Diagnostic Systems).161 If opiate abuse is suspected, the finding should be confirmed by other diagnostic tests (e.g., gas chromatography/mass spectrometry).161

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 prior to 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.112

Acute Toxicity

The LD50 of rifampin in mice, rats, and rabbits is 0.885, 1.72, and 2.12 g/kg, respectively.161 In humans, acute overdosage with rifampin doses up to 9-12 g in adults and one or two 100-mg/kg doses in children 1-4 years of age have not been fatal; however, fatalities in adults have been reported following ingestion of 14- to 60-g doses of the drug.161 Alcohol or a history of alcohol abuse was involved in some of these cases of fatal and nonfatal overdosage.161

Manifestations !!navigator!!

Overdosage of rifampin produces symptoms that are principally extensions of common adverse reactions. These include nausea, vomiting, abdominal pain, pruritus, headache, lethargy, and brownish-red or orange discoloration of skin, urine, sweat, saliva, tears, and feces in proportion to the amount of drug ingested. Transient elevations in hepatic enzymes and/or bilirubin may occur. Following massive overdosage of rifampin, hepatic involvement can develop within a few hours and is manifested by liver enlargement (possibly with tenderness), jaundice, rapid increases in total and direct serum bilirubin and liver enzymes, and loss of consciousness. Hepatotoxicity may be more marked in patients with prior hepatic impairment.161 In addition, hypotension, sinus tachycardia, ventricular arrhythmias, seizures, and cardiac arrest have been reported in some cases of fatalities resulting from rifampin overdosages161 However, an effect upon the hematopoietic system, electrolyte concentrations, or acid-base balance is unlikely.

In one patient who ingested 12 g of rifampin, vomiting occurred 4 times within 1 hour of ingestion, and gastric lavage with 20 L of water was initiated 5 hours after ingestion.161 Plasma concentrations of rifampin in this patient were 400, 64, and 0.1 mcg/mL at 12, 24, and 72 hours, respectively, after the dose; urinary concentrations of the drug were 313, 625, and 78 mcg/mL at 30, 36, and 40 hours, respectively, after the dose.161 Results of liver function tests were only transiently increased for about 5 days after the overdosage and the patient's recovery was uneventful.161 Inadvertent administration of 1 or 2 rifampin doses of 100 mg/kg for chemoprophylaxis of Haemophilus influenzae type b infection (5 times the usual daily dose) in a group of children 1-4 years of age resulted in a glowing red discoloration of the skin, periorbital or facial edema, pruritus of the head, vomiting, headache, and diarrhea.123 Signs and symptoms of overdosage occurred within 0.5-4 hours after administration of the first or second excessive dose and lasted an average of 28 hours (range: 1-72 hours).123

Treatment !!navigator!!

Treatment of rifampin overdosage consists of intensive supportive and symptomatic therapy.161 In acute rifampin overdosage, the stomach should be emptied by gastric lavage.161 Activated charcoal slurry then may be instilled into the stomach to adsorb any drug remaining in the GI tract.161 An antiemetic may be required to control severe nausea and vomiting.161 Active diuresis, with measured intake and output, may promote excretion of the drug.161 If serious hepatic impairment occurs which lasts more than 24-48 hours, bile drainage or hemodialysis may be indicated.161 Reversal of liver enlargement and improvement of impaired hepatic function usually occur within 72 hours in patients with previously adequate hepatic function.

Mechanism of Action

Rifampin may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. Rifampin usually is rapidly bactericidal against Mycobacterium leprae in vivo.128,133

Rifampin suppresses initiation of chain formation for RNA synthesis in susceptible bacteria by inhibiting DNA-dependent RNA polymerase. The β subunit of the enzyme appears to be the site of action. Rifampin is most active against susceptible bacteria when they are 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 complex (MAC) , and M. intracellulare . Rifampin also is active against both dapsone-susceptible and dapsone-resistant M. leprae in experimental leprosy in mice.

Rifampin also is active in vitro against some gram-positive bacteria, including Staphylococcus aureus and Bacillus anthracis 252 , and some gram-negative bacteria, including Neisseria meningitidis , Haemophilus influenzae , Brucella melitensis ,230 and Legionella pneumophila . At very high concentrations, rifampin is active in vitro 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.241

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 US (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.252 Based on interpretive criteria established for staphylococci, these strains are considered susceptible to rifampin.252

In Vitro Susceptibility Testing !!navigator!!

The National Committee for Clinical Laboratory Standards (NCCLS) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to rifampin, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated.185 If results indicate that a clinical isolate has intermediate susceptibility to rifampin, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue concentrations and response rates may be lower than for strains identified as susceptible.185 Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated or when a high dosage of the drug can be used.185 This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.185 If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to rifampin, the strain is not inhibited by systemic concentrations of the drug achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliable in clinical studies.185

In vitro susceptibility testing of certain fastidious bacteria (e.g., Haemophilus , Streptococcus ) requires use of specialized culture media, testing procedures, and interpretive criteria not required for most other bacteria.185

Although results of susceptibility testing may indicate that strains of Staphylococcus , Enterococcus , or S. pneumoniae may be susceptible to rifampin, the drug should not be used alone in the treatment of infections caused by these organisms.185 (See Uses: Streptococcal and Staphylococcal Infections.)

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to rifampin, a disk containing 5 mcg of rifampin is used.185

When the disk-diffusion procedure is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus or Enterococcus with growth inhibition zones of 20 mm or greater are susceptible to rifampin, those with zones of 17-19 mm have intermediate susceptibility, and those with zones of 16 mm or less are resistant to the drug.185

When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using Haemophilus test medium (HTM), Haemophilus with growth inhibition zones of 20 mm or greater are susceptible to rifampin, those with zones of 17-19 mm have intermediate susceptibility, and those with zones of 16 mm or less are resistant to the drug.185

When the NCCLS standardized disk-diffusion procedure using Mueller-Hinton agar (supplemented with 5% sheep blood) is used to determine susceptibility of S. pneumoniae , S. pneumoniae with growth inhibition zones of 19 mm or greater are susceptible to rifampin, those with zones of 17-18 mm are have intermediate susceptibility, and those with zones of 16 mm or less are resistant to the drug.185

NCCLS states that disk-diffusion susceptibility tests are unreliable for determining susceptibility of Neisseria meningitidis to rifampin; dilution susceptibility tests should be used to determine susceptibility of this organism.185

Dilution Susceptibility Tests

When dilution susceptibility testing is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus or Enterococcus with MICs of 1 mcg/mL or less are susceptible to rifampin, those with MICs of 2 mcg/mL have intermediate susceptibility, and those with MICs of 4 mcg/mL or greater are resistant to the drug.185 These same interpretive criteria apply when the appropriate NCCLS standardized procedures are used to test susceptibility of Haemophilus or S. pneumoniae to rifampin.185

When dilution susceptibility testing is used, N. meningitidis with MICs of 1 mcg/mL or less are susceptible to rifampin, those with MICs of 2 mcg/mL have intermediate susceptibility, and those with MICs of 4 mcg/mL or greater are resistant to the drug.161 Rifampin is not likely to eradicate N. meningitidis from the nasopharynx of asymptomatic carriers when the organism is reported to be resistant using in vitro susceptibility procedures.

The in vitro susceptibility of mycobacteria to rifampin depends on the culture media used. Rifampin susceptibility powders are available for both direct and indirect methods of determining susceptibility of strains of mycobacteria. When determined in Middlebrook and Cohn 7H10 agar (7H10 agar) or other non-egg-containing media (e.g., Dubos), the minimum inhibitory concentration (MIC) of rifampin for most susceptible mycobacteria is 0.1-2 mcg/mL. When egg-containing media (e.g., Lowenstein-Jensen) are used, the MIC for most susceptible mycobacteria is 4-32 mcg/mL.

Resistance

Natural and acquired resistance to rifampin have been observed in vitro and in vivo in strains of M. tuberculosis , M. kansasii ,165 Neisseria meningitidis ,189,190 and most bacteria which are usually susceptible to the drug. In vitro, resistance to rifampin develops in a one-step process, probably as the result of modification of the β subunit of RNA polymerase. Resistant strains of initially susceptible organisms develop rapidly if rifampin is used alone in the treatment of clinical tuberculosis. When rifampin is combined with other antituberculosis agents in the treatment of the disease, emergence of resistant strains may be delayed or prevented. In patients with tuberculosis or the meningococcal carrier state, the small number of resistant strains of M. tuberculosis or N. meningitidis present within large populations of susceptible strains can rapidly become predominant.161

Strains of Staphylococcus aureus and Streptococcus pyogenes (group A β-hemolytic streptococci) with rifampin resistance have been isolated from at least one patient who received rifampin monotherapy.186

Strains of M. leprae resistant to rifampin have been reported rarely.128,133 Resistant strains of initially susceptible M. leprae have developed within 3-5 years in patients receiving rifampin alone for the treatment of leprosy.128,133

Cross-resistance has been demonstrated only between rifampin and other rifamycin derivatives.

Pharmacokinetics

Absorption !!navigator!!

Rifampin is well absorbed from the GI tract. If rifampin is administered with food, peak plasma concentrations of the drug may be slightly reduced (by about 30%) and delayed.122,161 Following a single 600-mg oral dose of rifampin in healthy fasting adults in one study, peak plasma concentrations of the drug averaged 7 mcg/mL and were attained within 2-4 hours. However, there is considerable interpatient variation, and peak plasma concentrations of the drug may range from 4-32 mcg/mL.

In a single-dose study in healthy fasting males, the extent of absorption (as measured by area under the plasma concentration-time curve) of isoniazid, rifampin, or pyrazinamide in dosages of 250 mg, 600 mg, or 1500 mg, respectively, was similar whether the drugs were administered individually as capsules (rifampin) and tablets (isoniazid and pyrazinamide) or as a fixed combination (Rifater®) containing isoniazid 50 mg, rifampin 120 mg, and pyrazinamide 300 mg per tablet. The effect of food on the pharmacokinetics of Rifater® has not been determined to date.

Following IV infusion over 30 minutes of a single 300- or 600-mg dose of rifampin in healthy adult men, peak plasma concentrations of the drug average 9 or 17.5 mcg/mL, respectively, and plasma concentrations remain detectable for 8 or 12 hours, respectively.161 Plasma concentrations of the drug attained with the 600-mg dose are disproportionately higher (up to 50% higher) than expected based on those attained with the 300-mg dose.161 When 600-mg doses of rifampin are given once daily by IV infusion over 3 hours for 7 days, plasma concentrations of the drug average 5.8 mcg/mL 8 hours after completion of the infusion on the first day of therapy and 2.6 mcg/mL 8 hours after completion of the infusion on the 7th day of therapy.161

In several studies in children receiving rifampin orally in a dosage of 10 mg/kg, peak serum rifampin concentrations ranged from 3.5-15 mcg/mL.161 In one study in fasting children 6-58 months of age who received 10 mg/kg of rifampin given orally (as an extemporaneously prepared oral suspension in simple syrup or as a dry powder mixed in applesauce), peak serum concentrations were attained 1 hour after the dose and averaged 10.7 or 11.5 mcg/mL, respectively.161 When a rifampin dose of approximately 300 mg/m2 was given by IV infusion over 30 minutes to children 3 months to 12.8 years of age, peak serum rifampin concentrations at the end of the infusion averaged 26 mcg/mL.161 Following multiple doses in these children, peak concentrations of the drug ranged from 11.7-41.5 mcg/mL 1-4 days after initiation of therapy and 13.6-37.4 mcg/mL 5-14 days after initiation of therapy.161

Plasma concentrations of rifampin are higher and more prolonged in patients with impaired hepatic function, especially in the presence of obstructive jaundice. There is no cumulative effect in patients with impaired renal function.

Distribution !!navigator!!

Rifampin is widely distributed into most body tissues and fluids including the liver, lungs, bile,161 pleural fluid, prostate, seminal fluid, ascitic fluid, CSF, saliva, tears, and bone. CSF concentrations of rifampin in patients with inflamed meninges are reported to be 10-20% of concurrent plasma concentrations of the drug. At a concentration of 10 mcg/mL, rifampin is 84-91% bound to plasma proteins. Rifampin crosses the placenta. Rifampin is distributed into milk.

Elimination !!navigator!!

The plasma half-life of rifampin following a single 600- or 900-mg oral dose in healthy adults is approximately 3.4-3.6 hours.161 During the first several weeks of continued daily administration of 600-mg oral doses of rifampin, there is a progressive decrease in plasma concentrations and half-life of the drug due to increased biliary excretion. In one study in adults with tuberculosis, the plasma half-life of rifampin was 1.7 hours after 3 months of daily 600-mg oral doses of the drug. The plasma half-life of the drug is increased in patients with renal impairment.161 In one study in individuals who received a single 900-mg oral dose of rifampin, the mean plasma half-life of the drug was 3.6 hours in healthy individuals, 5 hours in those with glomerular filtration rates of 30-50 mL/minute, 7.3 hours in those with rates less than 30 mL/minute, and 11 hours in anuric patients.161

The plasma half-life of rifampin in children 6-58 months of age averages 2.9 hours following oral administration of a single 10-mg/kg dose of the drug.161 Plasma half-life of the drug in children 3 months to 12.8 years of age following IV doses of the drug was 1.04-3.81 hours during the first few days of therapy and decreased to 1.17-3.19 hours after 5-14 days of therapy.161

Rifampin is metabolized in the liver to a deacetylated derivative which also possesses antibacterial activity. The drug and its deacetylated metabolite are excreted mainly via bile. Rifampin undergoes enterohepatic circulation161 and is largely reabsorbed, but the metabolite is not. Within 24 hours, 3-30% of a single 600-mg oral dose of rifampin is excreted in urine as unchanged drug and active metabolite. Approximately 60% of the oral dose is excreted in feces via biliary elimination. Plasma concentrations of rifampin are not appreciably affected by hemodialysis or peritoneal dialysis.

Chemistry and Stability

Chemistry !!navigator!!

Rifampin is a semisynthetic derivative of rifamycin B, an antibiotic derived from Streptomyces mediterranei. Rifampin occurs as a red-brown, crystalline powder and is very slightly soluble in water and slightly soluble in alcohol. The drug has a pKa of 7.9.

Commercially available rifampin sterile powder for injection contains sodium formaldehyde sulfoxylate; sodium hydroxide may have been added to adjust pH.161

Oral rifampin is commercially available alone, in fixed combination with isoniazid, and in fixed combination with isoniazid and pyrazinamide.172,259

Stability !!navigator!!

Rifampin capsules should be stored in tight, light-resistant containers at a temperature of 30°C or less,163 preferably between 15-30°C. The capsules should not be exposed to excessive heat.161 Tablets containing the fixed combination of rifampin, isoniazid, and pyrazinamide (Rifater®) should be protected from excessive humidity and stored at 15-30°C.172

Commercially available rifampin powder for injection should be protected from light and excessive heat (i.e., temperatures greater than 40°C).161 Following reconstitution with sterile water for injection, rifampin solutions containing 60 mg/mL are stable for 24 hours at room temperature.161 The manufacturer states that reconstituted solutions of rifampin that have been further diluted in 100 or 500 mL of 5% dextrose injection should be used within 4 hours of preparation.161 (See Reconstitution and Administration: IV Infusion, in Dosage and Administration.) A precipitate indicating incompatibility has been observed during simulated Y-site administration of rifampin (6 mg/mL in 0.9% sodium chloride) and diltiazem that is undiluted (5 mg/mL) or diluted (1 mg/mL in 0.9% sodium chloride).161

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

rifAMPin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

150 mg*

Rifadin®

Sanofi-Aventis

rifAMPin Capsules

300 mg*

Rifadin®

Sanofi-Aventis

rifAMPin Capsules

Rimactane®

Amide Pharm

Parenteral

For injection

600 mg*

Rifadin® IV

Sanofi-Aventis

rifAMPin for Injection

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

rifAMPin Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

300 mg with Isoniazid 150 mg*

Rifamate®

Sanofi-Aventis

rifAMPin and Isoniazid Capsules

Tablets

120 mg with Isoniazid 50 mg and Pyrazinamide 300 mg

Rifater®

Sanofi-Aventis

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

Only references cited for selected revisions after 1984 are available electronically.

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129. Report of a WHO Study Group. Chemotherapy of leprosy for control programmes. Technical Report Series No. 675. Geneva: World Health Organization; 1982:3-33.

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137. Murphy TV, Clements JF, Breedlove JA et al. Risk of subsequent disease among day-care contacts of patients with systemic Haemophilus influenzae type b disease. N Engl J Med . 1987; 316:5-10. [PubMed 3491319]

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