Rifampin

Ashithkumar Beloor Suresh; Alan Rosani; Preeti Patel; Roopma Wadhwa

Rifampin

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Continuing Education Activity

Rifampin, also known as rifampicin, belongs to the antimicrobial class of drugs. This medication is used to manage and treat diverse mycobacterial infections and gram-positive bacterial infections. Rifampin exhibits antibacterial activity against a wide range of gram-positive cocci, including Mycobacteria and Clostridium difficile, and specific gram-negative organisms, including Neisseria meningitidis, N gonorrhoeae, and Hemophilus influenza. Rifampin exerts bactericidal antimicrobial effects by inhibiting DNA-dependent RNA polymerase (RNAP). This inhibition occurs either by sterically obstructing the path of the elongating RNA at its 5′ end or by reducing the RNAP's affinity for short RNA transcripts. Rifampin uniquely targets microbial RNAP, effectively arresting ongoing RNA synthesis. This activity describes the indications, mechanism of action, and contraindications of rifampin as a valuable drug for treating tuberculosis, leprosy, and methicillin-resistant Staphylococcus aureus. This activity also highlights the adverse event profile, off-label applications, dosage, pharmacodynamics, pharmacokinetics, monitoring, and pertinent interactions of rifampin, which are essential for healthcare team members caring for patients with infectious diseases.

Objectives:

Identify the indications for rifampin, including its role in managing mycobacterial and gram-positive bacterial infections.
Screen patients for potential contraindications, drug interactions, and comorbidities before prescribing rifampin.
Implement appropriate dosing and administration strategies for rifampin to optimize treatment outcomes and minimize the development of bacterial resistance.
Apply knowledge of rifampin's pharmacokinetics and pharmacodynamics to adjust dosages in patients with specific conditions or drug interactions.

Indications

Rifampin, also known as rifampicin, exhibits antibacterial activity against a wide range of gram-positive cocci, including Mycobacteria and Clostridium difficile, and specific gram-negative organisms, including Neisseria meningitidis, N gonorrhoeae, and Hemophilus influenza.

Rifampin is approved by the U.S. Food and Drug Administration (FDA) for treating active and latent tuberculosis (TB).[1] Rifampin is primarily recognized as a cornerstone in the multidrug treatment for tackling drug-susceptible TB induced by Mycobacterium tuberculosis. Rifampin is concurrently administered to patients with isoniazid (INH), ethambutol, and pyrazinamide for the first 2 months, followed by 4 months of rifampin and INH therapy alone.[2] This treatment regimen has a total duration of 6 months and has 83% effectiveness in eradicating TB.[3]

Rifampin also holds FDA approval for eliminating asymptomatic carriers of N meningitidis from the nasopharynx. Rifampin is also used for prophylaxis among high-risk groups with close contact and a history of travel to regions endemic to the condition. Rifampin is recommended for infections where the causative microorganisms are identified and their susceptibility to drugs has been ascertained. To avert drug resistance, rifampin is typically paired with other antimicrobial agents.[4]

Rifampin is used off-label in cases of leprosy and, to a lesser extent, for addressing severe gram-positive bacterial infections such as osteomyelitis, endocarditis, anthrax, and brain abscess. As a prophylactic measure, rifampin is used for carriers of H influenzae who can transmit the infection to children younger than 4.[5]

Following the guidelines from the Infectious Disease Society of America for managing ventriculitis and meningitis, it is suggested that rifampin, in conjunction with other antimicrobial agents, can be considered for treating infections caused by susceptible strains of Staphylococcus aureus. A systematic review also demonstrated rifampin's efficacy when combined with sulfamethoxazole or trimethoprim for treating methicillin-resistant S aureus (MRSA) infection in patients with cystic fibrosis.[6] However, it is noteworthy that MRSA strains progressively develop resistance to rifampin.[7]

Rifampin, in combination with other antimicrobials, is also used in catheters impregnated with antimicrobial agents for cerebrospinal fluid (CSF) shunts and drains.[8] Central venous catheters infused with rifampin and minocycline have been shown to reduce the incidence of catheter-related bloodstream infections (CRBSI).[9][10]

The International Society for Peritoneal Dialysis guidelines suggest using rifampin for treating peritonitis caused by coagulase-negative staphylococci, such as S epidermidis, and for TB peritonitis.[11] Rifampin is used in combination with other antimicrobials for the management of hidradenitis suppurativa.[12] As outlined by the American Association for the Study of Liver Diseases, rifampin is also used as a secondary option for managing the pruritus associated with primary sclerosing cholangitis [13] and primary biliary cirrhosis.[14][15]

Mechanism of Action

Rifampin exerts bactericidal antimicrobial effects by inhibiting DNA-dependent RNA polymerase (RNAP). This inhibition occurs either by sterically obstructing the path of the elongating RNA at its 5′ end or by reducing the RNAP's affinity for short RNA transcripts. Rifampin uniquely targets microbial RNAP, effectively arresting ongoing RNA synthesis.[16][17] Rifampin does not affect the mammalian RNAP enzyme, minimizing the range of potential adverse effects in humans. Moreover, rifampin exhibits bactericidal properties against both intracellular and extracellular M tuberculosis.[18]

The pruritus observed in cholestatic diseases, such as primary biliary cirrhosis, is mainly attributed to elevated levels of bile acids. The antipruritic impact of rifampin, particularly effective in cholestatic disorders, is achieved through upregulating microsomal enzymes, namely cytochrome P3A (CYP3A). This enzymatic upregulation leads to the hydroxylation of bile acids. The hydroxylation of bile acids diminishes their reabsorption in the ileum, consequently providing additional relief from pruritic symptoms.[19]

Pharmacokinetics

Absorption: Rifampin is rapidly absorbed from the gastrointestinal tract. However, the absorption of the drug reduces by 30% when administered with food.

Distribution: Rifampin is widely distributed throughout the body, including the CSF, imparting an orange-red color hue to urine, sweat, saliva, tears, and sputum. The drug has a high volume of distribution values, which are 1.6 L/kg in adults and 1.1 L/kg in infants. The plasma protein binding of rifampin is about 80%. The unbound fraction of rifampin comprises nonionized molecules, allowing for widespread tissue distribution.[20] In inflamed meninges, a substantial quantity of the drug can permeate the CSF, making it clinically valuable for bacterial meningitis treatment.[21]

Metabolism: Rifampin undergoes enterohepatic circulation. Furthermore, the drug acts as an inducer of enzymes, including CYP3A4, CYP2C9, CYP2C19, CYP2C8, and CYP1A2. In addition, rifampin also induces P-glycoprotein and UGT1A1 (UDP-glucuronosyltransferase).[22] Furthermore, the deacetylation of rifampin yields a metabolite that retains antibacterial activity.[23]

Elimination: The half-life of rifampin at a steady-state plasma concentration ranges around 2 to 3 hours. Approximately 30% of the administered dose is eliminated through the urine. The principal route of elimination for rifampin is via the bile, with subsequent excretion occurring in the feces.[24]

Administration

Dosage Forms

Rifampin exhibits remarkable lipid solubility and is available in both oral and intravenous (IV) formulations. Rifampin can be administered intravenously to critically ill patients facing life-threatening infections resulting from gram-positive organisms, particularly when oral formulations demonstrate reduced effectiveness. As mentioned earlier, the absorption of rifampin is hindered by food intake. Hence, it is recommended to administer rifampin either 1 hour before or 2 hours after meals.

Adult Dosage

Rifampicin should be administered to patients orally or via IV injections at 10 mg/kg per dose once daily, without surpassing 600 mg per day. This regimen should be sustained for a minimum of 6 months. Rifampin is utilized for the treatment of all types of TB. The initial phase of short-course therapy for TB typically involves a 3-drug regimen of rifampin, INH, and pyrazinamide administered over approximately 2 months.

The American Thoracic Society, the Centers for Disease Control and Prevention (CDC), and The Advisory Council for the Elimination of Tuberculosis advise the addition of either ethambutol or streptomycin as a fourth drug to a treatment regimen that includes rifampin, INH, and pyrazinamide for TB treatment unless the probability of INH resistance is exceedingly low. The necessity for adding a fourth medication should be reassessed upon obtaining the results of susceptibility testing.

If the prevalence of INH resistance within the community is below 4%, it is feasible to contemplate an initial treatment regimen using fewer than 4 drugs. After the initial phase, the treatment should persist with rifampin and INH for at least 4 months. Maintenance therapy should be continued for an extended duration if the patient's sputum culture is positive or if resistant organisms are detected, especially if the patient is HIV-positive.

Latent TB

The CDC and National Tuberculosis Controllers Association recommend a daily dosage of 10 mg/kg of rifampin for 4 months. The highest daily dose should not exceed 600 mg. An alternate regimen involves a combination of rifampin with INH for 3 months.[1]

Meningococcal carriers

To eliminate N meningitidis from the nasopharynx, it is recommended to administer rifampin orally at a dosage of 600 mg twice daily for 2 days.

Specific Patient Populations

Renal impairment: Rifampin does not necessitate dosage adjustments in the presence of renal insufficiency.

Hepatic impairment: Rifampin is usually avoided in patients with preexisting liver diseases due to its potential for significant hepatotoxicity. However, dosage adjustments can be considered if the potential benefit is worth the risk.

Pregnancy considerations: Rifampin can be safely administered during pregnancy and is not associated with congenital malformations or neonatal complications.[25][26]

Breastfeeding considerations: Low rifampin concentrations in breast milk do not cause adverse effects in breastfed infants. The CDC suggests that breastfeeding should be continued, and mothers should receive counseling regarding the potential for breast milk discoloration.[27]

Older patients: Cases of rifampin-induced esophagitis have also been documented, especially in older patients. The advised course of action is to ingest rifampin with a full glass of water 1 or 2 hours before meals.[28]

Pediatric considerations: For the meningococcal carrier state, the recommended rifampin dosage for pediatric patients younger than 1 month is 10 mg/kg every 12 hours for 2 days. For pediatric TB patients, rifampin is administered at a dose of 10 to 20 mg/kg concurrently with other antitubercular agents.[29]

Adverse Effects

Although rifampin is generally well tolerated in patients, the drug can still cause adverse effects that may be dose-dependent or dose-independent.

Dose-dependent adverse effects of rifampin include orange discoloration of body fluids such as tears, which might stain contact lenses, sweat, saliva, urine, and feces due to its excretion in these fluids. Gastrointestinal symptoms such as nausea, anorexia, and diarrhea are also associated.[30]

Although diarrhea is an uncommon adverse effect caused by rifampin, it is advisable to conduct tests for C difficile infection to exclude the possibility of rifampin-induced pseudomembranous colitis in patients. In such instances, the addition of metronidazole and discontinuation of rifampin have been reported to alleviate symptoms substantially.[31]

Constipation is the predominant adverse effect experienced when rifampin is used for pruritus associated with primary biliary cirrhosis.[32] Asymptomatic hepatitis has also been reported in patients undergoing rifampin treatment for pruritus.[33]

Hepatotoxicity is a potential occurrence, particularly in individuals with existing liver conditions. Although the enzyme elevation pattern is hepatocellular, it can manifest as cholestatic or mixed.[34]

Dose-independent adverse effects of rifampin encompass hypersensitive reactions such as urticaria, flu-like symptoms, thrombocytopenia, hemolysis, and renal failure. These hypersensitivity reactions are frequent when rifampin is administered intermittently or over an extended period. Many of the aforementioned adverse effects tend to resolve upon discontinuation of rifampin.[35][30]

Rifampicin-induced pneumonitis cases have been reported, a condition that is similar to COVID-19 pneumonia.[36]

Drug-Drug Interactions

Rifampin is a potent cytochrome P450 enzyme inducer. A thorough review of the patient's medication regimen should be conducted to avoid any dampening effects of concurrently administered drugs in combination with rifampin.[37] The drug is also a potent inducer of numerous drug-metabolizing enzymes, particularly cytochrome P450 (CYP) 3A4, and drug transporter proteins such as hepatic P-glycoprotein. This characteristic of rifampin diminishes the effectiveness of concurrently administered drugs and consequently might restrict its use.

Commonly involved drugs include HIV protease inhibitors, antimycotics such as itraconazole and ketoconazole, cyclosporine, which can lead to graft rejections, calcium channel blockers such as verapamil, nifedipine, and diltiazem, sulfonylureas, oral contraceptives, and warfarin. Upon initiating rifampin, it usually takes approximately a week for the induction of drug-metabolizing enzymes to generate clinically significant interactions. Moreover, this effect persists for nearly 2 weeks after discontinuing rifampin.[38]

The drugs that can be significantly impacted if administered with rifampin include:

Rifampin induces CYP3A4, substantially reducing oxycodone, morphine, and methadone concentrations, potentially leading to opioid withdrawal. Hence, dosage adjustments become necessary.[39][40]

Concomitant usage of rifampin diminishes the plasma concentration of simvastatin due to the induction of CYP3A4.[41]

Rifampin induces CYP3A4 and significantly increases the clearance of quinine.[42]

Rifampin induces CYP2C19, causing an elevation in the concentration of the active metabolite of clopidogrel, thereby potentially raising the risk of bleeding. On the other hand, rifampin reduces the effectiveness of ticagrelor by activating the CYP3A4 enzyme, which lowers its concentrations. Hence, concurrent utilization of these drugs should be avoided.[43][44]

Rifampin's induction of CYP2C8 leads to a reduction in rosiglitazone concentration. Consequently, concurrent use of these medications demands careful consideration.[45]

Rifampin induces CYP2C9, reducing glyburide and glipizide concentration levels and potentially worsening glycemic control. Therefore, its use should be approached with caution.[46]

Concurrently administering rifampin with telithromycin significantly diminishes telithromycin's concentration and exposure (AUC). Consequently, it is advisable to avoid their simultaneous use.[47]

Rifampin is an inducer of P-glycoprotein and can reduce the serum concentration of direct oral anticoagulants (DOAC), including dabigatran, apixaban, and rivaroxaban. As a result, their combined usage warrants caution.[48][49][50] The European Heart Rhythm guidelines suggest that utilizing DOACs alongside rifampin necessitates vigilance and monitoring.[51]

Rifampin reduces the plasma concentration and efficacy of metoprolol and propranolol.[52][53]

Rifampin functions as a UGT1A1 inducer, which can lead to diminished concentrations of cabotegravir and raltegravir. Hence, concurrent administration of these drugs should be avoided.[54][55]

Concurrent administration of rifampin with hepatotoxic drugs, such as halothane, should be avoided due to the increased risk of hepatotoxicity.[56]

Concurrent administration of rifampin with certain antiviral drugs for hepatitis C treatment, such as daclatasvir, simeprevir, sofosbuvir, and telaprevir, is not recommended. This combination significantly lowers plasma concentrations and is contraindicated based on existing data.[57]

Contraindications

A history of allergy to rifampin or other rifamycins, such as rifabutin, rifaximin, and rifapentine, constitutes a notable contraindication to drug usage. In treating drug-resistant TB, particularly rifampin-resistant TB or polydrug-resistant TB, rifampin should be omitted from the regimen. Antibiotic susceptibility testing for TB should be conducted to ensure appropriate treatment.[58]

Rifampin is contraindicated in patients receiving fosamprenavir, atazanavir, darunavir, tipranavir, and saquinavir. This is because rifampin can lower the concentrations of these drugs, thereby reducing their antiviral effectiveness and increasing the risk of viral resistance development.[59]

Rifampin is contraindicated with ritonavir-boosted saquinavir regimens due to the risk of severe hepatotoxicity.[60]

Concomitant use of rifampin and praziquantel is not recommended, as it can lower praziquantel levels and lead to treatment failure. Therefore, in cases requiring praziquantel, it is advised to consider utilizing alternative agents or discontinuing rifampin at least 4 weeks before its administration.[61]

Box Warnings

Severe cutaneous adverse drug reactions such as Stevens-Johnson syndrome, drug reactions with eosinophilia and systemic symptoms, and toxic epidermal necrolysis have been documented. In such cases, immediate discontinuation of rifampin and suitable supportive measures are warranted.[62]

Paradoxical drug reactions have been associated with rifampin, which is characterized by the appearance and recurrence of new physical and radiological signs in patients receiving appropriate TB treatment. Notably, these reactions are typically transient and should not be misconstrued as indicators of treatment failure.[63]

Rifampin can trigger false-positive results in screening tests for opiates.[64] These false-positive outcomes are differentiated through mass spectrometry and gas chromatography techniques.

Monitoring

Due to the significant hepatotoxicity associated with rifampin, it is recommended to conduct baseline liver function tests (LFTs) before initiating treatment. In the presence of symptoms indicative of hepatotoxicities, such as nausea, vomiting, abdominal pain, worsening LFTs, and pruritus, it is advised to reduce the dosage or discontinue the medication altogether. Serial blood draws to monitor LFTs are recommended in such cases. For TB treatment, guidelines dictate that rifampin use should be discontinued if alanine aminotransferase levels increase to 3 times the upper limit of normal, accompanied by symptoms such as jaundice, abdominal pain, nausea, and anorexia. In addition, rifampin discontinuation is also recommended if ALT levels rise to 5 times the upper limit of normal, even in the absence of symptoms.[65]

Regularly monitoring drug concentration levels of concurrently administered medications is essential due to rifampin's capability to induce microsomal enzymes.[37] Special attention is required when monitoring rifampin in certain conditions and patient groups, such as individuals with diabetes, malabsorption syndromes, HIV, or older patients. This is due to the potential factors of reduced drug absorption and heightened drug interactions caused by altered metabolism or clearance.[66]

Rifampin can lead to a reduction in serum digoxin concentration, thereby prompting therapeutic drug monitoring.[67] Furthermore, when rifampin is concurrently administered with tacrolimus, it decreases tacrolimus concentrations. Therefore, therapeutic drug monitoring and dosage adjustment for tacrolimus are recommended.[68]

Toxicity

Rifampin is usually well tolerated in patients due to its rapid metabolism ability in the liver, even in high concentrations. However, rifampin can cause toxicity either related to dosage, primarily affecting the liver, or treatment duration, involving immunoallergic reactions.[30] Dose-related toxic effects become apparent after ingesting approximately 9 to 15 g of rifampin.[69]

Signs and Symptoms of Overdose

Various symptoms can manifest due to rifampin toxicity, including metabolic acidosis, characterized by nausea, vomiting, abdominal pain, hyperventilation, and fatigue, and thrombocytopenia, characterized by skin and mucosal bleeding. Additional drug toxicity includes oliguric renal failure, convulsions, cholestatic jaundice, and red man syndrome, characterized by periorbital edema, redness of the skin, and swelling of the face. Unfortunately, there is no specific antidote available for rifampin toxicity.

Management of Overdose

The treatment approach is primarily supportive and encompasses airway maintenance, administration of antiemetic medications, gastric lavage with activated charcoal, correction of electrolyte and acid-base imbalances, promoting active diuresis, and, in severe cases, resorting to dialysis.[30][70] Although hepatotoxicity induced by rifampin is reversible, it necessitates discontinuation of the drug.[34]

Pharmacobezoars release medication gradually in the gastrointestinal tract, which can lead to prolonged toxicity. In cases of overdose involving rifampin and INH, endoscopic decontamination has been utilized to remove the pharmacobezoar, which helps mitigate the risk of prolonged drug exposure.[71]

Enhancing Healthcare Team Outcomes

Rifampin is a frequently utilized antimicrobial agent, and bacterial resistance to it is progressively more prevalent. Consequently, rifampin should be administered in conjunction with other antimicrobial agents, particularly in specific infections such as TB, or when the susceptibility of the bacterial organism to rifampin has been ascertained. The interprofessional clinical team should acquire a comprehensive drug history to avert substantial drug interactions. Patients should be educated about the mild and severe adverse effects of rifampin and informed to seek medical attention immediately if they experience any of them.

As rifampin is indicated for conditions such as TB and leprosy, which demand extended treatment, the interprofessional healthcare team should ensure patient education regarding the significance of adhering to the appropriate dosage and frequency of administration. Clinicians responsible for treating infectious diseases should be consulted to ensure the proper use of rifampin to mitigate the risk of antimicrobial resistance.

Recent research indicates that the involvement of specialized pharmacists dealing with infectious diseases can enhance adherence to antimicrobial stewardship programs.[72] The nursing staff is critical to rifampin therapy by promptly notifying prescribing clinicians about the adverse reactions, interactions, or indications of therapeutic failure. Open communication among all interprofessional team members is essential for successful rifampin treatment.

Social workers can contribute to assessing patient compliance. In an inpatient setting, effective communication among physicians, advanced practice practitioners, specialists, pharmacists, and nursing staff is crucial to ensure adherence to drug dispensing protocols in line with recommended guidelines. The interprofessional healthcare team ensures patient-centered care and strives to achieve the best outcomes while minimizing complications.

Details

References

[1]

Sterling TR, Njie G, Zenner D, Cohn DL, Reves R, Ahmed A, Menzies D, Horsburgh CR Jr, Crane CM, Burgos M, LoBue P, Winston CA, Belknap R. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports. 2020 Feb 14:69(1):1-11. doi: 10.15585/mmwr.rr6901a1. Epub 2020 Feb 14 [PubMed PMID: 32053584]

[2]

Sotgiu G, Centis R, D'ambrosio L, Migliori GB. Tuberculosis treatment and drug regimens. Cold Spring Harbor perspectives in medicine. 2015 Jan 8:5(5):a017822. doi: 10.1101/cshperspect.a017822. Epub 2015 Jan 8 [PubMed PMID: 25573773]

Level 3 (low-level) evidence

[3]

Seid MA, Ayalew MB, Muche EA, Gebreyohannes EA, Abegaz TM. Drug-susceptible tuberculosis treatment success and associated factors in Ethiopia from 2005 to 2017: a systematic review and meta-analysis. BMJ open. 2018 Sep 25:8(9):e022111. doi: 10.1136/bmjopen-2018-022111. Epub 2018 Sep 25 [PubMed PMID: 30257846]

Level 1 (high-level) evidence

[4]

Rothstein DM. Rifamycins, Alone and in Combination. Cold Spring Harbor perspectives in medicine. 2016 Jul 1:6(7):. doi: 10.1101/cshperspect.a027011. Epub 2016 Jul 1 [PubMed PMID: 27270559]

Level 3 (low-level) evidence

[5]

Mieras LF, Taal AT, van Brakel WH, Cambau E, Saunderson PR, Smith WCS, Prakoeswa CRS, Astari L, Scollard DM, do Nascimento DC, Grosset J, Kar HK, Izumi S, Gillini L, Virmond MCL, Sturkenboom MGG. An enhanced regimen as post-exposure chemoprophylaxis for leprosy: PEP+. BMC infectious diseases. 2018 Oct 5:18(1):506. doi: 10.1186/s12879-018-3402-4. Epub 2018 Oct 5 [PubMed PMID: 30290790]

[6]

Lo DK, Muhlebach MS, Smyth AR. Interventions for the eradication of meticillin-resistant Staphylococcus aureus (MRSA) in people with cystic fibrosis. The Cochrane database of systematic reviews. 2022 Dec 13:12(12):CD009650. doi: 10.1002/14651858.CD009650.pub5. Epub 2022 Dec 13 [PubMed PMID: 36511181]

Level 1 (high-level) evidence

[7]

Wang C, Fang R, Zhou B, Tian X, Zhang X, Zheng X, Zhang S, Dong G, Cao J, Zhou T. Evolution of resistance mechanisms and biological characteristics of rifampicin-resistant Staphylococcus aureus strains selected in vitro. BMC microbiology. 2019 Sep 18:19(1):220. doi: 10.1186/s12866-019-1573-9. Epub 2019 Sep 18 [PubMed PMID: 31533633]

[8]

Tunkel AR, Hasbun R, Bhimraj A, Byers K, Kaplan SL, Scheld WM, van de Beek D, Bleck TP, Garton HJL, Zunt JR. 2017 Infectious Diseases Society of America's Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2017 Mar 15:64(6):e34-e65. doi: 10.1093/cid/ciw861. Epub [PubMed PMID: 28203777]

Level 1 (high-level) evidence

[9]

Hanna H, Benjamin R, Chatzinikolaou I, Alakech B, Richardson D, Mansfield P, Dvorak T, Munsell MF, Darouiche R, Kantarjian H, Raad I. Long-term silicone central venous catheters impregnated with minocycline and rifampin decrease rates of catheter-related bloodstream infection in cancer patients: a prospective randomized clinical trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2004 Aug 1:22(15):3163-71 [PubMed PMID: 15284269]

Level 1 (high-level) evidence

[10]

Lorente L. Antimicrobial-impregnated catheters for the prevention of catheter-related bloodstream infections. World journal of critical care medicine. 2016 May 4:5(2):137-42. doi: 10.5492/wjccm.v5.i2.137. Epub 2016 May 4 [PubMed PMID: 27152256]

[11]

Li PK, Chow KM, Cho Y, Fan S, Figueiredo AE, Harris T, Kanjanabuch T, Kim YL, Madero M, Malyszko J, Mehrotra R, Okpechi IG, Perl J, Piraino B, Runnegar N, Teitelbaum I, Wong JK, Yu X, Johnson DW. ISPD peritonitis guideline recommendations: 2022 update on prevention and treatment. Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis. 2022 Mar:42(2):110-153. doi: 10.1177/08968608221080586. Epub [PubMed PMID: 35264029]

[12]

Alikhan A, Sayed C, Alavi A, Alhusayen R, Brassard A, Burkhart C, Crowell K, Eisen DB, Gottlieb AB, Hamzavi I, Hazen PG, Jaleel T, Kimball AB, Kirby J, Lowes MA, Micheletti R, Miller A, Naik HB, Orgill D, Poulin Y. North American clinical management guidelines for hidradenitis suppurativa: A publication from the United States and Canadian Hidradenitis Suppurativa Foundations: Part II: Topical, intralesional, and systemic medical management. Journal of the American Academy of Dermatology. 2019 Jul:81(1):91-101. doi: 10.1016/j.jaad.2019.02.068. Epub 2019 Mar 11 [PubMed PMID: 30872149]

[13]

Howard P, Twycross R, Grove G, Charlesworth S, Mihalyo M, Wilcock A. Rifampin (INN Rifampicin). Journal of pain and symptom management. 2015 Dec:50(6):891-5. doi: 10.1016/j.jpainsymman.2015.09.004. Epub 2015 Sep 30 [PubMed PMID: 26432572]

[14]

Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, Lunsford KE, Martinez M, Sapisochin G, Shroff R, Tabibian JH, Assis DN. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology (Baltimore, Md.). 2023 Feb 1:77(2):659-702. doi: 10.1002/hep.32771. Epub 2022 Oct 20 [PubMed PMID: 36083140]

[15]

Hegade VS, Kendrick SF, Jones DE. Drug treatment of pruritus in liver diseases. Clinical medicine (London, England). 2015 Aug:15(4):351-7. doi: 10.7861/clinmedicine.15-4-351. Epub [PubMed PMID: 26407384]

[16]

Campbell EA, Korzheva N, Mustaev A, Murakami K, Nair S, Goldfarb A, Darst SA. Structural mechanism for rifampicin inhibition of bacterial rna polymerase. Cell. 2001 Mar 23:104(6):901-12 [PubMed PMID: 11290327]

[17]

McClure WR, Cech CL. On the mechanism of rifampicin inhibition of RNA synthesis. The Journal of biological chemistry. 1978 Dec 25:253(24):8949-56 [PubMed PMID: 363713]

[18]

Tanner L, Mashabela GT, Omollo CC, de Wet TJ, Parkinson CJ, Warner DF, Haynes RK, Wiesner L. Intracellular Accumulation of Novel and Clinically Used TB Drugs Potentiates Intracellular Synergy. Microbiology spectrum. 2021 Oct 31:9(2):e0043421. doi: 10.1128/Spectrum.00434-21. Epub 2021 Sep 29 [PubMed PMID: 34585951]

[19]

Wietholtz H, Marschall HU, Sjövall J, Matern S. Stimulation of bile acid 6 alpha-hydroxylation by rifampin. Journal of hepatology. 1996 Jun:24(6):713-8 [PubMed PMID: 8835747]

[20]

Smith PB, Cotten CM, Hudak ML, Sullivan JE, Poindexter BB, Cohen-Wolkowiez M, Boakye-Agyeman F, Lewandowski A, Anand R, Benjamin DK Jr, Laughon MM, Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee. Rifampin Pharmacokinetics and Safety in Preterm and Term Infants. Antimicrobial agents and chemotherapy. 2019 Jun:63(6):. doi: 10.1128/AAC.00284-19. Epub 2019 May 24 [PubMed PMID: 30910891]

[21]

American Thoracic Society, CDC, Infectious Diseases Society of America. Treatment of tuberculosis. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports. 2003 Jun 20:52(RR-11):1-77 [PubMed PMID: 12836625]

[22]

Chattopadhyay N, Kanacher T, Casjens M, Frechen S, Ligges S, Zimmermann T, Rottmann A, Ploeger B, Höchel J, Schultze-Mosgau MH. CYP3A4-mediated effects of rifampicin on the pharmacokinetics of vilaprisan and its UGT1A1-mediated effects on bilirubin glucuronidation in humans. British journal of clinical pharmacology. 2018 Dec:84(12):2857-2866. doi: 10.1111/bcp.13750. Epub 2018 Oct 11 [PubMed PMID: 30171692]

[23]

Soraci L, Cherubini A, Paoletti L, Filippelli G, Luciani F, Laganà P, Gambuzza ME, Filicetti E, Corsonello A, Lattanzio F. Safety and Tolerability of Antimicrobial Agents in the Older Patient. Drugs & aging. 2023 Jun:40(6):499-526. doi: 10.1007/s40266-023-01019-3. Epub 2023 Mar 28 [PubMed PMID: 36976501]

[24]

Butranova OI, Ushkalova EA, Zyryanov SK, Chenkurov MS. Developmental Pharmacokinetics of Antibiotics Used in Neonatal ICU: Focus on Preterm Infants. Biomedicines. 2023 Mar 17:11(3):. doi: 10.3390/biomedicines11030940. Epub 2023 Mar 17 [PubMed PMID: 36979919]

[25]

Bothamley G. Drug treatment for tuberculosis during pregnancy: safety considerations. Drug safety. 2001:24(7):553-65 [PubMed PMID: 11444726]

[26]

Tran JH, Montakantikul P. The safety of antituberculosis medications during breastfeeding. Journal of human lactation : official journal of International Lactation Consultant Association. 1998 Dec:14(4):337-40 [PubMed PMID: 10205455]

[27]

. Rifampin. Drugs and Lactation Database (LactMed®). 2006:(): [PubMed PMID: 30000407]

[28]

Smith SJ, Lee AJ, Maddix DS, Chow AW. Pill-induced esophagitis caused by oral rifampin. The Annals of pharmacotherapy. 1999 Jan:33(1):27-31 [PubMed PMID: 9972381]

[29]

Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, Chaisson LH, Chaisson RE, Daley CL, Grzemska M, Higashi JM, Ho CS, Hopewell PC, Keshavjee SA, Lienhardt C, Menzies R, Merrifield C, Narita M, O'Brien R, Peloquin CA, Raftery A, Saukkonen J, Schaaf HS, Sotgiu G, Starke JR, Migliori GB, Vernon A. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2016 Oct 1:63(7):e147-e195. doi: 10.1093/cid/ciw376. Epub 2016 Aug 10 [PubMed PMID: 27516382]

Level 1 (high-level) evidence

[30]

Grosset J, Leventis S. Adverse effects of rifampin. Reviews of infectious diseases. 1983 Jul-Aug:5 Suppl 3():S440-50 [PubMed PMID: 6356277]

[31]

Yim SY, Koo JS, Kim YJ, Park SJ, Kim JN, Jung SW, Yim HJ, Lee SW, Choi JH, Kim CD. Rifampin-induced Pseudomembranous Colitis with Rectosigmoid Sparing. Clinical endoscopy. 2011 Dec:44(2):137-9. doi: 10.5946/ce.2011.44.2.137. Epub 2011 Dec 31 [PubMed PMID: 22741126]

[32]

Hofmann AF. Rifampicin and treatment of cholestatic pruritus. Gut. 2002 Nov:51(5):756-7 [PubMed PMID: 12377823]

[33]

Prince MI, Burt AD, Jones DE. Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis. Gut. 2002 Mar:50(3):436-9 [PubMed PMID: 11839728]

[34]

. Rifampin. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. 2012:(): [PubMed PMID: 31643637]

[35]

Khurana S, Singh P. Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials. Liver international : official journal of the International Association for the Study of the Liver. 2006 Oct:26(8):943-8 [PubMed PMID: 16953834]

Level 1 (high-level) evidence

[36]

Ata F, Shaher Mousa Hussein M, Mismar AY, Sharma R, Bozom IAM, Alsiddig Ali Ibrahim Z, Ibrahim WH. Rifampicin-Induced Pneumonitis Mimicking Severe COVID-19 Pneumonia Infection. The American journal of case reports. 2020 Aug 25:21():e927586. doi: 10.12659/AJCR.927586. Epub 2020 Aug 25 [PubMed PMID: 32840240]

Level 3 (low-level) evidence

[37]

Chen J, Raymond K. Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor. Annals of clinical microbiology and antimicrobials. 2006 Feb 15:5():3 [PubMed PMID: 16480505]

[38]

Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT. Pharmacokinetic interactions with rifampicin : clinical relevance. Clinical pharmacokinetics. 2003:42(9):819-50 [PubMed PMID: 12882588]

[39]

Nieminen TH, Hagelberg NM, Saari TI, Pertovaara A, Neuvonen M, Laine K, Neuvonen PJ, Olkkola KT. Rifampin greatly reduces the plasma concentrations of intravenous and oral oxycodone. Anesthesiology. 2009 Jun:110(6):1371-8. doi: 10.1097/ALN.0b013e31819faa54. Epub [PubMed PMID: 19417618]

[40]

Badhan RKS, Gittins R, Al Zabit D. The optimization of methadone dosing whilst treating with rifampicin: A pharmacokinetic modeling study. Drug and alcohol dependence. 2019 Jul 1:200():168-180. doi: 10.1016/j.drugalcdep.2019.03.013. Epub 2019 May 20 [PubMed PMID: 31122724]

[41]

Kyrklund C, Backman JT, Kivistö KT, Neuvonen M, Laitila J, Neuvonen PJ. Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations. Clinical pharmacology and therapeutics. 2000 Dec:68(6):592-7 [PubMed PMID: 11180018]

[42]

Pukrittayakamee S, Prakongpan S, Wanwimolruk S, Clemens R, Looareesuwan S, White NJ. Adverse effect of rifampin on quinine efficacy in uncomplicated falciparum malaria. Antimicrobial agents and chemotherapy. 2003 May:47(5):1509-13 [PubMed PMID: 12709315]

[43]

Wang ZY, Chen M, Zhu LL, Yu LS, Zeng S, Xiang MX, Zhou Q. Pharmacokinetic drug interactions with clopidogrel: updated review and risk management in combination therapy. Therapeutics and clinical risk management. 2015:11():449-67. doi: 10.2147/TCRM.S80437. Epub 2015 Mar 19 [PubMed PMID: 25848291]

[44]

Teng R, Mitchell P, Butler K. Effect of rifampicin on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy subjects. European journal of clinical pharmacology. 2013 Apr:69(4):877-83. doi: 10.1007/s00228-012-1436-x. Epub 2012 Oct 24 [PubMed PMID: 23093043]

[45]

Park JY, Kim KA, Kang MH, Kim SL, Shin JG. Effect of rifampin on the pharmacokinetics of rosiglitazone in healthy subjects. Clinical pharmacology and therapeutics. 2004 Mar:75(3):157-62 [PubMed PMID: 15001966]

[46]

Morales Castro D, Dresser L, Granton J, Fan E. Pharmacokinetic Alterations Associated with Critical Illness. Clinical pharmacokinetics. 2023 Feb:62(2):209-220. doi: 10.1007/s40262-023-01213-x. Epub 2023 Feb 2 [PubMed PMID: 36732476]

[47]

Zhanel GG, Hisanaga T, Wierzbowski A, Hoban DJ. Telithromycin in the treatment of acute bacterial sinusitis, acute exacerbations of chronic bronchitis, and community-acquired pneumonia. Therapeutics and clinical risk management. 2006 Mar:2(1):59-75 [PubMed PMID: 18360582]

[48]

Otsuka Y, Choules MP, Bonate PL, Komatsu K. Physiologically-Based Pharmacokinetic Modeling for the Prediction of a Drug-Drug Interaction of Combined Effects on P-glycoprotein and Cytochrome P450 3A. CPT: pharmacometrics & systems pharmacology. 2020 Nov:9(11):659-669. doi: 10.1002/psp4.12562. Epub 2020 Nov 12 [PubMed PMID: 33030266]

[49]

Sennesael AL, Larock AS, Hainaut P, Lessire S, Hardy M, Douxfils J, Spinewine A, Mullier F. The Impact of Strong Inducers on Direct Oral Anticoagulant Levels. The American journal of medicine. 2021 Oct:134(10):1295-1299. doi: 10.1016/j.amjmed.2021.06.003. Epub 2021 Jun 25 [PubMed PMID: 34181907]

[50]

Laureano M, Crowther M, Eikelboom J, Boonyawat K. Measurement of Dabigatran Drug Levels to Manage Patients Taking Interacting Drugs: A Case Report. The American journal of medicine. 2016 Oct:129(10):e247-8. doi: 10.1016/j.amjmed.2016.06.017. Epub 2016 Jul 9 [PubMed PMID: 27401948]

Level 3 (low-level) evidence

[51]

Steffel J,Verhamme P,Potpara TS,Albaladejo P,Antz M,Desteghe L,Haeusler KG,Oldgren J,Reinecke H,Roldan-Schilling V,Rowell N,Sinnaeve P,Collins R,Camm AJ,Heidbüchel H, The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. European heart journal. 2018 Apr 21; [PubMed PMID: 29562325]

[52]

Liu W, Yan T, Chen K, Yang L, Benet LZ, Zhai S. Predicting Interactions between Rifampin and Antihypertensive Drugs Using the Biopharmaceutics Drug Disposition Classification System. Pharmacotherapy. 2020 Apr:40(4):274-290. doi: 10.1002/phar.2380. Epub 2020 Mar 26 [PubMed PMID: 32100890]

[53]

Agrawal A, Agarwal SK, Kaleekal T, Gupta YK. Rifampicin and anti-hypertensive drugs in chronic kidney disease: Pharmacokinetic interactions and their clinical impact. Indian journal of nephrology. 2016 Sep:26(5):322-328 [PubMed PMID: 27795624]

[54]

Ford SL, Sutton K, Lou Y, Zhang Z, Tenorio A, Trezza C, Patel P, Spreen W. Effect of Rifampin on the Single-Dose Pharmacokinetics of Oral Cabotegravir in Healthy Subjects. Antimicrobial agents and chemotherapy. 2017 Oct:61(10):. doi: 10.1128/AAC.00487-17. Epub 2017 Sep 22 [PubMed PMID: 28739783]

[55]

Wenning LA, Hanley WD, Brainard DM, Petry AS, Ghosh K, Jin B, Mangin E, Marbury TC, Berg JK, Chodakewitz JA, Stone JA, Gottesdiener KM, Wagner JA, Iwamoto M. Effect of rifampin, a potent inducer of drug-metabolizing enzymes, on the pharmacokinetics of raltegravir. Antimicrobial agents and chemotherapy. 2009 Jul:53(7):2852-6. doi: 10.1128/AAC.01468-08. Epub 2009 May 11 [PubMed PMID: 19433563]

[56]

Alempijevic T, Zec S, Milosavljevic T. Drug-induced liver injury: Do we know everything? World journal of hepatology. 2017 Apr 8:9(10):491-502. doi: 10.4254/wjh.v9.i10.491. Epub [PubMed PMID: 28443154]

[57]

Kempker RR, Alghamdi WA, Al-Shaer MH, Burch G, Peloquin CA. A Pharmacology Perspective of Simultaneous Tuberculosis and Hepatitis C Treatment. Antimicrobial agents and chemotherapy. 2019 Sep 9:63(12):. pii: AAC.01215-19. doi: 10.1128/AAC.01215-19. Epub 2019 Oct 7 [PubMed PMID: 31591118]

Level 3 (low-level) evidence

[58]

Mase SR, Chorba T. Treatment of Drug-Resistant Tuberculosis. Clinics in chest medicine. 2019 Dec:40(4):775-795. doi: 10.1016/j.ccm.2019.08.002. Epub [PubMed PMID: 31731984]

[59]

Abdelgawad N, Chirehwa M, Schutz C, Barr D, Ward A, Janssen S, Burton R, Wilkinson RJ, Shey M, Wiesner L, McIlleron H, Maartens G, Meintjes G, Denti P. Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis. Wellcome open research. 2022:7():72. doi: 10.12688/wellcomeopenres.17660.2. Epub 2022 Nov 28 [PubMed PMID: 37008250]

[60]

Schmitt C, Riek M, Winters K, Schutz M, Grange S. Unexpected Hepatotoxicity of Rifampin and Saquinavir/Ritonavir in Healthy Male Volunteers. Archives of drug information. 2009 Mar:2(1):8-16 [PubMed PMID: 19381336]

[61]

Ridtitid W, Wongnawa M, Mahatthanatrakul W, Punyo J, Sunbhanich M. Rifampin markedly decreases plasma concentrations of praziquantel in healthy volunteers. Clinical pharmacology and therapeutics. 2002 Nov:72(5):505-13 [PubMed PMID: 12426514]

[62]

Jin HJ, Kang DY, Nam YH, Ye YM, Koh YI, Hur GY, Kim SH, Yang MS, Kim S, Jeong YY, Kim MH, Choi JH, Kang HR, Jo EJ, Park HK, Korean Severe Cutaneous Adverse Reactions Consortium (KoSCAR). Severe Cutaneous Adverse Reactions to Anti-tuberculosis Drugs in Korean Patients. Allergy, asthma & immunology research. 2021 Mar:13(2):245-255. doi: 10.4168/aair.2021.13.2.245. Epub [PubMed PMID: 33474859]

[63]

Guo T, Guo W, Song M, Ni S, Luo M, Chen P, Peng H. Paradoxical Reaction In The Form Of New Pulmonary Mass During Anti-Tuberculosis Treatment: A Case Series And Literature Review. Infection and drug resistance. 2019:12():3677-3685. doi: 10.2147/IDR.S211556. Epub 2019 Nov 26 [PubMed PMID: 32063717]

Level 2 (mid-level) evidence

[64]

Keary CJ, Wang Y, Moran JR, Zayas LV, Stern TA. Toxicologic testing for opiates: understanding false-positive and false-negative test results. The primary care companion for CNS disorders. 2012:14(4):. doi: 10.4088/PCC.12f01371. Epub 2012 Jul 26 [PubMed PMID: 23251863]

Level 3 (low-level) evidence

[65]

Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, Peloquin CA, Gordin FM, Nunes D, Strader DB, Bernardo J, Venkataramanan R, Sterling TR, ATS (American Thoracic Society) Hepatotoxicity of Antituberculosis Therapy Subcommittee. An official ATS statement: hepatotoxicity of antituberculosis therapy. American journal of respiratory and critical care medicine. 2006 Oct 15:174(8):935-52 [PubMed PMID: 17021358]

[66]

Chawla PK, Udwadia ZF, Soman R, Mahashur AA, Amale RA, Dherai AJ, Lokhande RV, Naik PR, Ashavaid TF. Importance of Therapeutic Drug Monitoring of Rifampicin. The Journal of the Association of Physicians of India. 2016 Aug:64(8):68-72 [PubMed PMID: 27762112]

[67]

Reitman ML, Chu X, Cai X, Yabut J, Venkatasubramanian R, Zajic S, Stone JA, Ding Y, Witter R, Gibson C, Roupe K, Evers R, Wagner JA, Stoch A. Rifampin's acute inhibitory and chronic inductive drug interactions: experimental and model-based approaches to drug-drug interaction trial design. Clinical pharmacology and therapeutics. 2011 Feb:89(2):234-42. doi: 10.1038/clpt.2010.271. Epub 2010 Dec 29 [PubMed PMID: 21191377]

[68]

Chenhsu RY, Loong CC, Chou MH, Lin MF, Yang WC. Renal allograft dysfunction associated with rifampin-tacrolimus interaction. The Annals of pharmacotherapy. 2000 Jan:34(1):27-31 [PubMed PMID: 10669182]

[69]

Sridhar A, Sandeep Y, Krishnakishore C, Sriramnaveen P, Manjusha Y, Sivakumar V. Fatal poisoning by isoniazid and rifampicin. Indian journal of nephrology. 2012 Sep:22(5):385-7. doi: 10.4103/0971-4065.103930. Epub [PubMed PMID: 23326053]

[70]

Girling DJ, Hitze KL. Adverse reactions to rifampicin. Bulletin of the World Health Organization. 1979:57(1):45-9 [PubMed PMID: 311712]

[71]

Marano M, Lonati D, Torroni F. Pharmacobezoar after overdose of isoniazid and rifampin. Clinical toxicology (Philadelphia, Pa.). 2023 Jan:61(1):84-85. doi: 10.1080/15563650.2022.2142602. Epub 2022 Nov 22 [PubMed PMID: 36413204]

[72]

Jantarathaneewat K, Montakantikul P, Weber DJ, Nanthapisal S, Rutjanawech S, Apisarnthanarak A. Impact of an infectious diseases pharmacist-led intervention on antimicrobial stewardship program guideline adherence at a Thai medical center. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2022 Jul 22:79(15):1266-1272. doi: 10.1093/ajhp/zxac107. Epub [PubMed PMID: 35390112]