Rifabutin

Abstract

Synopsis

Rifabutin is a derivative of rifamycin S with activity against mycobacteria including atypical organisms such as Mycobacterium avium and M. intracellulare, also referred to as Mycobacterium avium-intracellulare complex (MAC). To date, rifabutin is the only drug to have been studied in large prospective placebo-controlled trials that has been shown to significantly reduce the incidence of disseminated MAC infection when administered prophylactically as a single agent to patients with acquired immune deficiency syndrome (AIDS). Initial studies also indicate that rifabutin may be a useful component of multiple drug regimens for the treatment of MAC infection, although further studies combining rifabutin with other recently available antimycobacterial drugs are required to determine the most effective regimens. When rifabutin is combined with at least two other antimycobacterial drugs, the combination appears to be of similar efficacy to rifampicin (rifampin)-containing regimens in patients with newly diagnosed pulmonary tuberculosis.

Since available therapy for MAC infection inpatients with AIDS is still suboptimal, rifabutin, at present the only first-line agent for prophylaxis against disseminated MAC infection inpatients with advanced human immunodeficiency virus (HIV) infection, has the potential to make a valuable contribution to the continuing attempts to preserve the quality of life of patients with AIDS.

Overview of Disease

Until recently, infection due to the intracellular bacteria Mycobacterium avium and Mycobacterium intracellulare was rarely observed and was generally restricted to pulmonary sites in patients with underlying pulmonary pathology. Disseminated disease is becoming more common in patients with acquired immune deficiency syndrome (AIDS), and is associated with significant morbidity. Since the treatment is less than optimal, it seems appropriate to attempt prevention of the disease in at-risk patients.

Antimicrobial Activity

Rifabutin has generally proved more active than rifampicin (rifampin) against clinical isolates of M. avium, M. intracellulare or Mycobacterium avium-intracellulare complex (MAC) from patients with or without AIDS. Many clinical isolates of MAC are susceptible in vitro to rifabutin 0.5 mg/L, a suggested susceptibility breakpoint since this concentration is not usually exceeded in plasma following administration of rifabutin 300mg. Rifabutin is generally more active in vitro than rifampicin against rifampicin-susceptible isolates of M. tuberculosis. It is also active against some rifampicin-resistant isolates, although there is substantial cross-resistance in vitro between the two drugs. Rifabutin and rifampicin exhibit similar activity against Staphylococcus aureus, Haemophilus ducreyi and Chlamydia trachomatis.

At concentrations attainable in human plasma following oral administration of a single 300mg dose (about 0.37 mg/L), rifabutin has bacteriostatic activity in vitro against MAC. Under simulated in vivo conditions, bactericidal action against a selected strain of M. intracellulare was evident after 8 days’ exposure to rifabutin 5 mg/L. MAC isolates are generally more susceptible to rifabutin when tested in broth medium than in agar.

Depending on the criteria used, synergistic activity against MAC isolates was reported for combinations of rifabutin with ethambutol, clarithromycin, amikacin and ethambu-tol/sparfloxacin.

Rifabutin readily penetrates into human polymorphonuclear leucocytes, achieving an intracellular: extracellular ratio of about 9 to 15 compared with about 5 for rifampicin. The bactericidal effect of rifabutin against MAC isolates within murine macrophages was increased when rifabutin was administered in combination with ethambutol.

Emergence of resistance to rifabutin among tested isolates of MAC and M. tuberculosis appeared to be less likely than that to rifampicin following repeated subculture with subinhibitory drug concentrations.

In vivo, rifabutin alone was, at best, moderately effective in decreasing the lung and spleen bacterial count in animal models with established M. avium, M. intracellulare or MAC infection, and of comparable efficacy to clarithromycin and azithromycin in preventing MAC disease. However, efficacy against established infection was improved when rifabutin was combined with ethambutol, azithromycin, clarithromycin, amikacin or kanamycin. When used prophylactically in Beige mice infected with MAC, rifabutin was of similar efficacy to clarithromycin in limiting bacterial invasion of the lungs, although it was less effective in controlling spleen infection.

Pharmacokinetic Properties

Oral administration of single doses of rifabutin 300 to 900mg to male patients with human immunodeficiency virus (HIV) infection resulted in mean maximum plasma concentrations of 0.37 to 0.9 mg/L. Mean absolute bioavailability is about 20% after a single dose. The area under the rifabutin plasma concentration-time curve is significantly higher on day 1 than at steady-state 28 days later, probably because of autoinduction of metabolism, although the magnitude of the difference in individual patients is generally small. When rifabutin is administered with food its absorption is delayed but not decreased.

The apparent volume of distribution is about 8 to 9 L/kg, and the extent of binding to plasma proteins varies between 71 and 94%. Rifabutin concentrations in tissue samples obtained at surgery from patients administered a single 150 or 300mg dose 5 to 12 hours earlier were up to 8.5 times greater than those in plasma. Rifabutin is eliminated largely by metabolism, unchanged drug accounting for about 8 to 9% of the administered dose. Systemic clearance was reported as 0.81 L/h/kg and renal clearance as 0.18 L/h/kg in healthy volunteers. The reported mean plasma elimination half-life varies between individuals and studies, ranging from 32 to 67 hours. Total recovery of radioactivity (unchanged rifabutin and metabolites) in urine was 44% in 72 hours and 53% over a period of 96 hours, with 29 to 49% recovered in faeces over the same periods after a single oral dose of [¹⁴C]rifabutin. Although the pharmacokinetic properties of rifabutin are influenced by hepatic and renal impairment, dosage alteration is probably required only in patients with severe renal or hepatic dysfunction.

Therapeutic Efficacy

The prophylactic efficacy of rifabutin alone has been compared with that of placebo against MAC bacteraemia in patients with AIDS. A 300mg once daily dose of rifabutin significantly reduced the incidence of MAC bacteraemia, and alleviated the associated signs and symptoms and some laboratory abnormalities. However, increased survival has yet to be demonstrated in successfully treated patients. In mostly noncomparative prospective and retrospective studies in patients with disseminated MAC infection and AIDS, rifabutin combined with 3 or 4 other anti-mycobacterial drugs was associated with conversion to negative blood culture in 8 to 90% of patients. In prospective trials, a bacteriological response was achieved in 55 to 88% of patients treated with rifabutin 300 to 600mg daily. Although there was no clear correlation between dosage and clearance of mycobacteria, relapse was more frequent in patients treated with regimens containing rifabutin 300mg than in those including rifabutin 450 or 600mg daily. The efficacy of rifabutin-containing regimens appeared to be uninfluenced by prior prophylactic administration of the drug.

In the treatment of patients with newly diagnosed pulmonary tuberculosis, rifabutin-containing regimens appeared to be of similar efficacy to regimens containing rifampicin; both regimens achieving a bacteriological response in about 90% of patients. Rifabutin combined with other antimycobacterial drugs was associated with an overall response rate (negative sputum culture) of about 33% in 2 studies in patients with multidrug-resistant pulmonary tuberculosis. When efficacy was assessed by more rigid criteria in another study, there was no evidence of sustained benefit, although culture results remained negative for periods of 6 to 24 weeks in about one-quarter of the patients.

Tolerability

In patients with AIDS treated prophylactically with rifabutin 300mg daily or placebo, the overall incidence rate for the occurrence of at least one adverse event was comparable in patients receiving rifabutin (51%) and placebo (50%). Myalgia, eructation and taste perversion were, however, significantly more common with rifabutin than placebo. When rifabutin was combined with other drugs in the treatment of MAC infection, gastrointestinal events occurred in 13% of patients and adverse events necessitated treatment withdrawal in 11% of patients. Uveitis has recently been reported in patients treated with a combination of rifabutin (≥450mg daily), clarithromycin and ethambutol or fluconazole. Like other rifamycin derivatives, rifabutin causes discoloration of the urine, and may cause an orange/tan discoloration of the skin in patients with AIDS receiving prolonged treatment. Other reported adverse events include rash (3%), nausea/vomiting (0.4%), neutropenia (0.4%), anaemia (0.4%) and, rarely, clinically important impairment of liver function. There is some evidence that the incidence of adverse events is related to dosage.

Drug Interactions

Since rifabutin induces drug metabolising enzymes in the liver, it has the potential to interact with other drugs metabolised in the liver. Preliminary reports suggest that rifabutin 300mg daily does not influence the pharmacokinetic properties of concomitantly administered isoniazid or acetyl-isoniazid, or of concomitantly administered fluconazole or didanosine. However, concomitant administration of rifabutin and fluconazole resulted in increased plasma concentrations of rifabutin, the clinical significance of which has still to be clarified. There was a tendency for rifabutin to increase the clearance and volume of distribution of zidovudine. The effect of rifabutin in increasing the clearance of cyclosporin appeared to be less marked than that of rifampicin. Dosage adjustment of methadone may be necessary in some patients during concomitant rifabutin administration.

Dosage and Administration

The recommended prophylactic regimen for patients with HIV infection and a CD4+ T lymphocyte count of < 100 cells/μl is rifabutin 300mg once daily orally. This regimen should be continued for the patient’s lifetime unless multiple drug therapy for MAC infection becomes necessary.

Rifabutin 300 to 600mg once daily has also been used in combination with at least 2 other antimycobacterial drugs for the treatment of disseminated or localised MAC infection.

In the treatment of newly diagnosed pulmonary tuberculosis and that caused by mycobacteria resistant to rifampicin, rifabutin 300 to 600mg once daily has been administered with at least 2 other antimycobacterial drugs chosen according to the susceptibility pattern of the cultured bacilli.