Continuing Education Activity

Rifaximin is an antibiotic used to treat irritable bowel syndrome with diarrhea, reduce the risk of overt hepatic encephalopathy recurrence in adults, and treat travelers’ diarrhea caused by noninvasive strains of Escherichia coli. Rifaximin has a broad spectrum of activity against both gram-negative and gram-positive anaerobic and aerobic bacteria. This antibiotic is used primarily in diseases since it is specific to the gastrointestinal tract due to its nonabsorbable profile. This activity will review the indications, mechanism of action, administration, safety profile, and contraindications for rifaximin. In addition, this activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions) pertinent to the interprofessional team members.

Objectives:

• Identify the mechanism of action of rifaximin.
• Describe the adverse drug reactions of rifaximin therapy.
• Review the indications for using rifaximin therapy on a patient.
• Summarize interprofessional team strategies for improving care coordination and communication to advance rifaximin and improve outcomes.

Indications

Rifaximin is a nonabsorbable oral antibiotic. Rifaximin has a broad spectrum of activity against both gram-negative and gram-positive anaerobic and aerobic bacteria. This antibiotic is used primarily for gastrointestinal and liver diseases since it is specific to the gastroenterology tract due to its nonabsorbable profile. Rifaximin was first approved in the United States in 2004 but has been in use since 1987, when it first received approval in Italy.

In the United States, rifaximin is FDA-approved for the following indications.

• Treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults.[1]
• Reduction in risk of overt hepatic encephalopathy (HE) recurrence in adults.[2]
• Treatment of travelers’ diarrhea (TD) caused by noninvasive strains of Escherichia coli in adults and pediatric patients 12 years of age and older.[3]

Rifaximin is used for following non-FDA-approved(off-label) indications.

• Small intestinal bacterial overgrowth (SIBO)[4]
• Diverticulitis[5]
• Inflammatory bowel disease, Pouchitis[6]
• Spontaneous bacterial peritonitis[7]
• Clostridium difficile infection (CDI)[8]

Mechanism of Action

Rifaximin is a synthetic antimicrobial derived from the parent compound, rifamycin. It has broad-spectrum bactericidal activity against both gram-positive and gram-negative aerobic and anaerobic bacteria.[4] Rifaximin has also demonstrated an effect on enteric protozoa activity in HIV patients with Cryptosporidium parvum and Blastocystitis hominis intestinal infections. The medication acts on and inhibits the bacteria's ability to synthesize proteins. The drug accomplishes this by irreversibly binding to the bacterial DNA-dependent RNA polymerase called rpoB.[9]

Because rifaximin is non-absorbable, it reaches high concentrations within the gastrointestinal lumen, allowing it to work effectively on various gastrointestinal diseases without systemic effects.[10] There is a very low incidence of bacterial mutation and drug resistance to rifaximin in extra-intestinal bacteria. However, long-term use of rifaximin can result in resistant bacterial mutants in the enteric system.[11]

Pharmacokinetics

• Absorption: According to the manufacturer's information, the average time to reach peak rifaximin plasma concentrations in healthy subjects was about an hour. The mean Cmax ranged from 2.4 to 4 ng/mL after a single and multiple doses of rifaximin. Mean rifaximin exposure (AUC) in patients with hepatic encephalopathy was approximately 12-fold higher. A high-fat meal consumed 30 minutes preceding rifaximin dosing in healthy subjects delayed the time to peak plasma concentration (Tmax) from 0.75 to 1.5 hours, increased the systemic exposure (AUC) by 2-fold but did not significantly impact Cmax.

• Distribution: The mean protein binding is 67.5% in healthy subjects and 62% in patients with hepatic impairment.

• Metabolism: Rifaximin is metabolized mainly by CYP3A4. In addition, Rifaximin accounted for 18% of the radioactivity in plasma, suggesting that the absorbed rifaximin undergoes extensive metabolism.

• Excretion: The half-life of rifaximin in healthy subjects at steady-state plasma concentration was 5.6 hours and was 6 hours in IBS-D patients. In a mass balance study, when 14C-rifaximin was administered orally to healthy volunteers, of the 96.94% total recovery, 96.62% of the administered radioactivity was recovered in feces largely as the unchanged drug, 0.32% was recovered in the urine primarily as metabolites with 0.03% as the unchanged drug. Biliary excretion of rifaximin was indicated by a further study in which rifaximin was present in the bile in patients with intact gastrointestinal mucosa after cholecystectomy.

Administration

Rifaximin is administered orally and is typically available in 200 mg and 550 mg tablets. Since it is poorly absorbed in the gastrointestinal system, there are very low systemic blood levels. Most of the medication passes through the gastrointestinal tract and is excreted in the feces. The dose regimens vary depending on the disease process the patient is receiving treatment.

• For Irritable Bowel Syndrome with Diarrhea(IBS-D), the suggested dose of rifaximin is 400 mg three times or 550 mg twice daily for two weeks. IBS-D may require intermittent rifaximin treatment. Typically, 200 mg three times daily is given for three days in traveler's diarrhea. The recommended dosage for preventing traveler's diarrhea is rifaximin 200 mg twice daily or 600 mg daily.

• Hepatic encephalopathy requires a dose of 550 mg twice or three times daily and is usually continued for an extended period to prevent its recurrence. Rifaximin is generally used in combination with lactulose to treat hepatic encephalopathy. For small intestinal bacterial overgrowth, the typical dose of rifaximin is 400 mg three times daily for two weeks. For patients with hepatic encephalopathy, recurrent treatment is warranted. 

• Studies show that rifaximin at a dose of 400 mg twice daily for seven days every month improves diverticular disease symptoms and prevents their recurrence. Pouchitis patients may need doses of 400 to even 800 mg twice daily for 12 weeks; they may need periodic retreatment. Recurrent Clostridium difficile treatment in retrospective studies and case series was 400 mg twice daily for two weeks. Spontaneous bacterial peritonitis prophylaxis should use rifaximin three times daily indefinitely.[11]

Use in Specific Patient Population

• Hepatic Impairment: According to manufacturer labeling, following administration of rifaximin in the patients with hepatic encephalopathy, the systemic exposure (i.e., AUC) of rifaximin is proportionately increased in patients with mild, moderate, and severe hepatic impairment. No dose modification is generally necessary for patients with mild or moderate hepatic impairment. However, caution should be exercised when rifaximin is administered to patients with severe hepatic impairment (Child-Pugh Class C).

• Renal Impairment: According to manufacturer labeling, the pharmacokinetics of rifaximin in patients with impaired renal function have not been investigated. However, no dosage adjustment is typically necessary as the absorption of rifaximin is minimal.

• Pregnancy Considerations: There is no data on the use of rifaximin in pregnant women to inform a drug-associated risk. However, teratogenic effects were observed in preclinical animal studies after the administration of rifaximin to pregnant rats and rabbits. In rabbits, maxillofacial, cardiac, ocular, and spine malformations were observed. In addition, ocular malformations were reported in both rats and rabbits. Consequently, pregnant patients should be advised of the potential harm to the fetus.

• Breastfeeding Considerations: According to the manufacturer, the clinician should evaluate the developmental and health benefits of breastfeeding and the mother's clinical need for rifaximin, and any adverse effects on the breastfed infant from rifaximin. Rifaximin has poor oral absorption; therefore, it is not likely to reach the breastmilk or bloodstream of the infant and cause any adverse drug reactions in breastfed infants. Nevertheless, no published experience exists with rifaximin during breastfeeding; therefore, an alternate drug may be preferred, particularly while nursing a newborn or preterm infant.[12]

Adverse Effects

Rifaximin has an excellent safety profile due to its lack of systemic absorption. Clinical trials have shown that adverse effects of rifaximin are similar to or even lower frequency than placebo, trimethoprim-sulfamethoxazole, and ciprofloxacin. Clinical trials did not show any serious adverse events while using rifaximin. There were no deaths while using rifaximin in clinical trials. Rifaximin does not require dose adjustments for hepatic dysfunction.[9]

There are published case reports of rifaximin interacting with warfarin, which resulted in reductions in INR levels. In vivo studies have previously shown that CYP3A4 can be induced by rifaximin, affecting the bioavailability of CYP3A4 substrates. Although these studies have demonstrated that rifaximin can affect CYP3A4 enzyme activity, this would likely never happen in a patient because of the minimal systemic absorption.[13]

Patients treated with rifaximin may develop adverse drug reactions, including nausea, gastrointestinal upset, fatigue, peripheral edema, dizziness, and muscle spasms. In addition, long-term use has been associated with fungal or bacterial super-infections. There is little evidence that rifaximin causes clinically apparent liver disease or serum enzyme elevations despite widespread use. Likelihood score: E (unlikely cause of clinically apparent liver injury).[13]

Contraindications

Due to the excellent safety profile of rifaximin, there are very few contraindications.

• Patients with hypersensitivity to the rifaximin, rifamycins, or excipients should avoid this medication as hypersensitivity reactions like exfoliative dermatitis, angioneurotic edema, and anaphylaxis have been reported.

• Concomitant administration of P-glycoprotein (P-gp) inhibitors such as cyclosporine with rifaximin can substantially augment the systemic exposure to rifaximin and can lead to toxicity.

• Severe Hepatic Impairment: There is increased systemic exposure to rifaximin in patients with severe hepatic impairment. The clinical trials were conducted only on patients with MELD scores <25. Therefore, caution should be exercised when administering rifaximin in patients with severe hepatic impairment (Child-Pugh Class C).[14]

Monitoring

Rifaximin demonstrates poor absorption into the systemic blood system, and only trace amounts appear in the blood and urine following administration. Prior studies have shown less than 0.4% of the medication detectable in the blood or urine and undetectable levels in bile and breast milk. For this reason, the monitoring of rifaximin is unnecessary.[9]

However, the clinician should monitor disease progression (e.g., response to rifaximin treatment can be monitored by lactulose breath test in patients with IBS-D).[15]

Toxicity

Since rifaximin is poorly absorbed into the systemic blood system and passes through the digestive tract, there is no evidence to suggest there can be an accumulation of toxic levels in the body. There is no antidote to rifaximin. No specific information is available regarding the treatment of overdosage with rifaximin.

However, as per the manufacturer's label, in clinical studies at doses higher than the recommended dose, adverse reactions were similar in subjects who received doses higher than the recommended dosage. However, like in any case of overdose, the clinician should discontinue rifaximin, institute supportive measures, and treat symptomatically.

Enhancing Healthcare Team Outcomes

Although rifaximin has only been FDA-approved in the United States since 2004, new clinical trials and new off-label uses are continually under investigation. Therefore, it is essential to know FDA-approved and off-label uses. This medication is often a therapeutic choice for gastroenterologists, hospitalists, family medicine practitioners, and pharmacists. In addition, the fact that it has practically no contraindications, no need for monitoring, and no known toxicity makes it an ideal drug for patients with numerous gastrointestinal disorders.

Resistance to rifaximin is caused predominantly by mutations in the rpoB gene. The mutation in the rpoB gene changes the binding site on DNA-dependent RNA polymerase and reduces rifaximin binding affinity. Antimicrobial resistance (AMR) is a danger to global public health. It increases morbidity and mortality and leads to the development of multidrug-resistant pathogens. An antimicrobial stewardship program is a system-wide healthcare strategy designed to encourage, improve, monitor, and evaluate the rational use of antimicrobials to maintain their future efficacy against microorganisms. Hence it is the responsibility of the entire healthcare team, including clinicians, infectious disease specialists, nurses, and pharmacists, to promote the rational use of antibiotics such as rifaximin.[16]

It is important to consider that for prescribing rifaximin; insurance approval has to be obtained. Practitioners and nurses that are well versed and capable should be able to manage prior authorization of the medication.[17] It is always essential to evaluate whether rifaximin is the right management strategy and consider evidence-based strategies to optimize patient care.