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PubMed1994

Rifabutin for the treatment of newly-diagnosed pulmonary tuberculosis: a multinational, randomized, comparative study versus Rifampicin. Rifabutin Study Group.

SETTING: Patients with newly-diagnosed drug-sensitive, radiographically active and bacteriologically confirmed pulmonary tuberculosis recruited at 6 centres in Argentina, Brazil and Thailand. OBJECTIVE: To assess the efficacy, tolerability and toxicity of two regimens containing different daily dosages of rifabutin in comparison with rifampicin. DESIGN: Multicentred, randomised, comparative study. In each group, study medications were administered daily for 6 months combined with isoniazid (6 months), and with pyrazinamide and ethambutol (both stopped after 2 months). Treatment success patients were followed-up for up to 2 years. RESULTS: A total of 520 patients were enrolled and randomly assigned to receive either rifampicin (n = 175), or rifabutin 150 mg (n = 174) or rifabutin 300 mg (n = 171). Considering all patients with positive baseline culture, the success rates at the last valid observation for each patient were 89%, 94% and 92% in the rifampicin, rifabutin 150 mg, and rifabutin 300 mg groups, respectively. The median time to culture conversion was comparable in the 3 groups and was 34 days for rifampicin and 37 days for each of the rifabutin groups. During the drug-free follow-up period, one relapse occurred in the rifampicin group, and two in each of the rifabutin groups. The 3 treatment schedules appeared well tolerated. No patients had to discontinue therapy because of an adverse event in the rifabutin 150 mg group, compared to one in the rifampicin and 5 in the rifabutin 300 mg group. CONCLUSION: All 3 regimens proved effective and well tolerated. Rifabutin at 150 mg/d showed the best risk-to-benefit ratio, in that this group had the highest proportion of patients completing treatment, the highest bacteriological conversion rates and the lowest incidence of adverse events.

Adolescent↗
PubMed1994

Efficacy of rifabutin in the treatment of disseminated infection due to Mycobacterium avium complex. The Rifabutin Treatment Group.

The incidence of infection with Mycobacterium avium complex (MAC) is increasing among patients with AIDS. Although numerous antimicrobial regimens have been proposed as treatment for this infection, it is unclear which therapy is most effective. For this reason, we prospectively evaluated rifabutin (600 mg/d) vs. a placebo, each in combination with clofazimine and ethambutol, for the treatment of MAC bacteremia. Patients in the rifabutin group had a significantly higher rate of microbiological response (defined as either sterilization of the blood or at least a 2-log10 reduction in mycobacterial titers). By week 4 of therapy, 7 of 11 patients receiving rifabutin, vs. 0 of 13 in the placebo group, had responded (P < .001). Similar results were seen at later time points (7 of 10 vs. 1 of 8 responded to rifabutin by week 8, and 6 of 9 vs. 1 of 7 responded to a placebo by week 12). These results indicate that, in combination with other antimicrobial agents, rifabutin may be effective in the treatment of disseminated MAC infection.

AIDS-Related Opportunistic Infections↗
PubMed1998

Does in vitro susceptibility to rifabutin and ethambutol predict the response to treatment of Mycobacterium avium complex bacteremia with rifabutin, ethambutol, and clarithromycin? Canadian HIV Trials Network Protocol 010 Study Group.

The in vitro susceptibilities of baseline Mycobacterium avium complex (MAC) blood isolates from 86 patients with AIDS who were treated with clarithromycin, ethambutol, and rifabutin were determined to examine whether these results predict bacteriologic response to treatment. No patient received prior prophylaxis with clarithromycin or azithromycin. Minimum inhibitory concentrations (MICs) of clarithromycin for all isolates were < or = 2 micrograms/mL. The median MIC of rifabutin was between 0.25 and 0.5 microgram/mL, and all isolates were susceptible to < or = 2 micrograms of rifabutin/mL. The median MIC of ethambutol was 4 micrograms/mL, and the MIC90 was 8 micrograms/mL. There was no correlation between ethambutol susceptibility and subsequent bacteriologic clearance. At all time points through week 12, bacteriologic clearance occurred more frequently in patients with isolates for which MICs of rifabutin were lower, but this difference was statistically significant only at week 2. Susceptibility testing for baseline MAC isolates from AIDS patients not previously treated with clarithromycin or azithromycin does not appear to be useful in guiding therapy.

AIDS-Related Opportunistic Infections↗
PubMed1998

Determinants of rifabutin-associated uveitis in patients treated with rifabutin, clarithromycin, and ethambutol for Mycobacterium avium complex bacteremia: a multivariate analysis. Canadian HIV Trials Network Protocol 010 Study Group.

Uveitis occurred in a substantial proportion of AIDS patients receiving rifabutin, 600 mg daily, together with clarithromycin and ethambutol for treatment of Mycobacterium avium complex bacteremia. A case-control study was undertaken to examine potential risk factors for developing uveitis. Of eight parameters examined, only baseline body weight predicted the development of uveitis by both univariate and multivariate analyses (P = .001). The incidence of uveitis was 14% in patients weighing >65 kg, 45% in patients between 55 and 65 kg, and 64% in patients <55 kg. Concomitant therapy with fluconazole, a drug known to raise serum rifabutin concentrations, was not associated with an increased incidence of uveitis. The risk of uveitis was markedly reduced when rifabutin was given at 300 mg daily in combination with clarithromycin and ethambutol.

AIDS-Related Opportunistic Infections↗
PubMed2003

Steady-state pharmacokinetic interaction of modified-dose indinavir and rifabutin.

BACKGROUND: Combined administration of the human immunodeficiency virus protease inhibitor indinavir (800 mg every 8 hours) with the antimycobacterial rifabutin (300 mg daily) results in a significant decrease in indinavir concentrations with subsequent risk of treatment failure, as well as a significant increase in rifabutin concentrations with increased toxicity. Therefore this study was designed to evaluate alternative dosing regimens. METHODS: Eighteen healthy volunteers received 300 mg rifabutin daily alone for 14 days and then 1000 mg indinavir every 8 hours plus rifabutin at a reduced dose of 150 mg daily, given at 8 am or noon in a randomized crossover sequence for 14 days. Ten human immunodeficiency virus-infected subjects received 800 mg indinavir every 8 hours for 14 days and then 1000 mg indinavir every 8 hours plus 150 mg rifabutin daily at 8 am for 14 days. Twenty-four-hour pharmacokinetic sampling was performed at the end of each 14-day study period. RESULTS: Indinavir, 1000 mg every 8 hours, coadministered with 150 mg rifabutin daily produced an area under the concentration-time curve similar to that of 800 mg indinavir every 8 hours. The mean area under the concentration-time curve values of rifabutin and 25-desacetyl rifabutin, when 150 mg rifabutin every morning was coadministered simultaneously with 1000 mg indinavir every 8 hours, were 70% and 120% higher than with 300 mg rifabutin daily alone. Drug concentrations were not different when rifabutin and indinavir were administered simultaneously at 8 am or staggered by 4 hours. CONCLUSIONS: Increasing indinavir's dose to 1000 mg every 8 hours when coadministered with rifabutin at a reduced dose of 150 mg daily compensates for rifabutin induction of indinavir metabolism. Rifabutin concentrations were still higher than with rifabutin alone despite a 50% reduction of rifabutin dose, which is the current recommendation when these 2 drugs are combined. The clinical significance of the increase in rifabutin and 25-desacetyl rifabutin concentrations is not known.

Adolescent↗
PubMed2004

Indinavir and rifabutin drug interactions in healthy volunteers.

Two studies examined the pharmacokinetics of indinavir and rifabutin when coadministered in healthy subjects. Rifabutin, which induces the expression of cytochrome P450 (CYP) 3A, and indinavir, which inhibits that enzyme system, are frequently coadministered in patients infected with HIV. The second study was undertaken to determine if altering the dose of rifabutin coadministered with indinavir would minimize the drug interaction observed in the first study. Two studies, each with a three-period crossover design, were performed. In study 1, standard doses of rifabutin and indinavir (300 mg of rifabutin qd and 800 mg indinavir q8h) were administered as monotherapy (with placebo to the other drug) or in combination to 10 volunteers for 10 days. In study 2, 150 mg qd of rifabutin together with 800 mg q8h of indinavir, 300 mg qd of rifabutin alone, or 800 mg q8h of indinavir alone was administered to 14 volunteers for 10 days. In study 1, the geometric mean ratio (GMR) (90% confidence interval [CI]) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 300 mg qd compared to indinavir alone (with rifabutin placebo), was 0.66 (0.56, 0.77), while that of the AUC((0-24h)) of rifabutin, coadministered with indinavir compared to rifabutin alone (with indinavir placebo), was 2.73 (1.99, 3.77). In study 2, the GMR (90% CI) of the AUC((0-8h)) of indinavir, coadministered with rifabutin 150 mg qd compared to indinavir alone, was 0.68 (0.60, 0.76), while that of the AUC((0-24h)) of rifabutin, when rifabutin 150 mg qd was coadministered with indinavir compared to rifabutin 300 mg qd alone, was 1.54 (1.33, 1.79). For both studies 1 and 2, indinavir and rifabutin administered alone or in combination were generally well tolerated. No clinical or laboratory adverse experience was serious. These data demonstrate the important pharmacokinetic interactions between indinavir and rifabutin when they are coadministered. Indeed, these observations formed the basis for the subsequent ACTG 365 study that explored dose adjustments for these agents in combination regimens to preserve the sustained antiviral activity of indinavir in the absence of adverse events as a result of elevated circulating levels of rifabutin.

Adult↗
PubMed1998

The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin.

OBJECTIVE: To investigate the effects of ritonavir on the pharmacokinetics of rifabutin. METHODS: In a multiple-dose, randomized, parallel-group, double-blind study, subjects received 150 mg rifabutin daily for 24 days coadministered on days 15 to 24 with twice-daily doses of either placebo or ritonavir (300 mg on day 15, 400 mg on day 16, and 500 mg on days 17 to 24). Plasma concentrations of rifabutin and 25-O-desacetylrifabutin were measured by HPLC, and the pharmacokinetics were determined after the rifabutin doses on days 14 and 24. RESULTS: For subjects receiving rifabutin and placebo who completed the study (n = 11), there were small but statistically significant differences (< or = 32%) in several rifabutin and 25-O-desacetylrifabutin pharmacokinetic parameters between the regimens of rifabutin alone and rifabutin with placebo. In contrast, the effect of ritonavir on rifabutin pharmacokinetics of subjects completing the study (n = 5) was substantial. Rifabutin mean minimum observed concentration (Cmin), maximum observed concentration (Cmax), and area under the concentration-time curve [AUC(0-24)] increased by approximately sixfold, 2.5-fold, and fourfold, respectively, and 25-O-desacetylrifabutin mean Cmin, Cmax, and AUC(0-24) increased by approximately 200-, 16-, and 35-fold, respectively, when coadministered with ritonavir compared with rifabutin administered alone. The sum of the mean AUC(0-24) of rifabutin and 25-O-desacetylrifabutin increased nearly sevenfold when coadministered with ritonavir. CONCLUSIONS: Ritonavir inhibited the metabolism of rifabutin and 25-O-desacetylrifabutin, suggesting that both are metabolized at least in part by CYP3A. Ritonavir may have enhanced rifabutin bioavailability by reducing either intestinal of hepatic metabolism of both. Clarithromycin is an alternative to rifabutin for antimycobacterial therapy that may be administered concurrently with ritonavir. Administration of ritonavir with a reduced rifabutin dosage regimen (150 mg every Monday, Wednesday, and Friday) is being investigated.

Adult↗
PubMed1995

Rifabutin-associated uveitis.

OBJECTIVE: To review rifabutin-associated uveitis and discuss the mechanism and potential role of drug interactions with clarithromycin and fluconazole in contributing to this adverse event. DATA SOURCES: A MEDLINE search (1991 through September 1994) of English-language literature using the main MeSH headings "rifabutin" and "uveitis" and the subheadings "adverse effects" and "chemically induced." Relevant articles also were selected from references of identified articles. Abstracts from recent medical conferences of infectious diseases, pharmacology, and HIV were screened for additional data. STUDY SELECTION AND DATA EXTRACTION: All articles and abstracts reporting uveitis potentially related to rifabutin were considered for inclusion. Fifty-four cases were identified. Pertinent information from the case reports, as judged by the authors, was selected and synthesized for discussion. DATA SYNTHESIS: Rifabutin is being prescribed increasingly for the treatment and prophylaxis of Mycobacterium avium complex (MAC) infection in the HIV-infected population. Uveitis was initially thought to be a rare, dose-limited complication of rifabutin therapy. In an early dose-ranging tolerance study, uveitis was associated with daily doses of 1200 mg or more. Because this toxicity appeared to be dose-related, lower dosages (300-600 mg/d) of rifabutin were selected for study in subsequent clinical trials. More recent reports noting the association of uveitis with these lower dosages of rifabutin have raised concerns about the prevalence of this adverse event. In the 54 identified cases, patients presented with symptoms of unilateral or bilateral uveitis from 2 weeks to more than 7 months following initiation of rifabutin therapy. In all reported cases, patients were receiving concurrent therapy with clarithromycin and/or fluconazole, both of which have inhibitory effects on rifabutin metabolism. In most cases, uveitis resolved within 1-2 months following discontinuation of rifabutin with or without administration of topical corticosteroids. CONCLUSIONS: Rifabutin is prescribed frequently for the prophylaxis and treatment of MAC infection, especially in patients with HIV. Uveitis is a rare, dose-related toxicity of this therapy. The risk of rifabutin-associated uveitis may be increased in patients receiving concurrent therapy with clarithromycin or fluconazole because of drug interactions. Patients receiving therapy with combinations of any of these agents should be warned about signs and symptoms of uveitis and be monitored closely for the development of rifabutin toxicity. If uveitis develops, rifabutin therapy should be discontinued promptly.

Anti-Bacterial Agents↗
PubMed1997

A comparative study of the redox-cycling of a quinone (rifamycin S) and a quinonimine (rifabutin) antibiotic by rat liver microsomes.

Rifamycin S and rifabutin are clinical drugs used to treat tuberculosis and leprosy. The formation of reactive oxygen species during the redox-cycling of rifamycin S (quinone) and rifabutin (quinonimine) was evaluated. The semiquinone (or semiquinonimine) and hydroquinone (or hydroquinonimine) formed during the reduction of the parent molecules by microsomal electron transfer in the presence of nicotinamide-adenine dinucleotide phosphate, reduced (NADPH) or nicotinamide-adenine dinucleotide, reduced (NADH) reoxidizes in air to generate superoxide radical and hydrogen peroxide. In the presence of added iron, hydroxyl radicals, formed by the Fenton reaction, were detected using 5,5'-dimethyl-1-pyroline-N-oxide as the spin-trap. Rifamycin S, a quinone, redox cycles more efficiently than rifabutin, a quinonimine, as approximately five times the concentration of hydroxyl radical adduct of 5,5'-dimethyl-1-pyroline-N-oxide (DMPO) was detected, when compared with rifabutin. The NADPH-dependent microsomal production of hydroxyl radical in the presence of rifamycin S was somewhat higher than the NADH-rifamycin S system with most iron chelators. However, with rifabutin, NADH-dependent microsomal production of hydroxyl radical was higher than that found with the NADPH-rifabutin system. An exception was the iron chelator, diethylene-triamine-pentacetic acid (DTPA), in which NADPH-dependent rates exceeded the rates with NADH with both antibiotics. Rat liver sub-mitochondrial particles also generated hydroxyl radical in the presence of NADH and either rifamycin S or rifabutin. The electron transport chain inhibitors such as rotenone and antimycin A enhanced the signal intensity of DMPO-OH, suggesting NADH dehydrogenase (complex I) as the major component involved in the reduction of rifamycin S. Rifamycin S was shown to be readily reduced to rifamycin SV, the corresponding hydroquinone by Fe(II); under similar conditions Fe(II) did not reduce rifabutin. Using optical spectroscopy, we determined that rifamycin S forms a complex with Fe(II). The stoichiometry of the complex was Fe(rifamycin S)3 in phosphate buffer at pH 7.4. Rifabutin did not form a detectable complex with Fe(II). The redox cycling of rifamycin S and rifabutin did not cause microsomal lipid peroxidation. In fact, the Fe:ATP induced lipid peroxidation was completely inhibited by these two molecules. These results indicate that rifamycin S and rifabutin can interact with rat liver microsomes to undergo redox-cycling, with the subsequent production of hydroxyl radicals when iron complexes are present. Compared to NADPH, NADH is almost as effective (rifamycin S) or even more effective (rifabutin) in promoting these interactions. These interactions may play a role in the hepatotoxicity associated with the use of these antibiotics.

Animals↗
PubMed2001

A pharmacokinetic study of intermittent rifabutin dosing with a combination of ritonavir and saquinavir in patients infected with human immunodeficiency virus.

AIM: Our primary aim was to evaluate the plasma exposures and safety of rifabutin and its active 25-O-desacetyl metabolite during concomitant therapy of intermittent rifabutin dosing regimens with a combination of ritonavir and saquinavir. METHODS: Twenty-four patients without mycobacterial infection who were human immunodeficiency virus seropositive and who were receiving 400 mg each of ritonavir and saquinavir twice daily participated in a 3-period, 2-group longitudinal pharmacokinetic study. Patients were equally randomized to receive 300 mg of rifabutin every 7 days (group 1) or 150 mg of rifabutin every 3 days (group 2) for 8 weeks. Blood samples were collected over the dosing intervals of the protease inhibitors at baseline (period 1) and of the 3 drugs after 4 weeks (period 2) and 8 weeks (period 3) for HPLC measurement of plasma concentrations of the 3 drugs and 25-O-desacetylrifabutin. RESULTS: Nineteen patients (group 1, n = 10; group 2, n = 9) completed the study. Five individuals withdrew from the study; 3 of them experienced side effects, and 2 were lost to follow-up. For combined groups, mean saquinavir and ritonavir overall (area under the concentration-time curve [AUC]) and peak (C(max)) plasma exposures averaged over periods 2 and 3 did not change significantly (8% to 19%; P > .05) compared with those in period 1 (90% confidence intervals, -7% to 26% for ritonavir and -2% to 38% for saquinavir). Rifabutin and metabolite AUC and C(max) exposures were stable over the 8 weeks, with intraindividual coefficients of variation of 12% to 19%. Oral clearance of rifabutin was similar in both groups (321 mL/min in group 2 versus 372 mL/min in group 1; P = .34). Rifabutin C(max) values were significantly lower in group 2 (310 ng/mL versus 496 ng/mL in group 1; P = .004). Rifabutin and metabolite predose levels were significantly higher in group 2 (rifabutin: 54 ng/mL versus 17 ng/mL; desacetyl rifabutin: 55 ng/mL versus 28 ng/mL; P < .002). CONCLUSIONS: Rifabutin exposures were similar at 4 and 8 weeks and had minimal effect on ritonavir and saquinavir exposures. Intermittent rifabutin dosing over 8 weeks provided a safe and manageable regimen for concurrent therapy with a combination of ritonavir and saquinavir.

AIDS-Related Opportunistic Infections↗
PubMed2000

In vitro activity of rifabutin and rifampin against clinical isolates of Mycobacterium tuberculosis in Taiwan.

BACKGROUND AND PURPOSE: To determine the in vitro activity of rifabutin against Mycobacterium tuberculosis (MTB) and the cross-resistance rate between rifampin and rifabutin. METHODS: A total of 56 clinical isolates of MTB, including 23 multidrug-resistant (MDR) isolates and 33 susceptible isolates, were tested for susceptibility to rifampin and rifabutin using the absolute concentration method. The concentrations of drugs tested were 2.5 and 5 mg/mL for rifampin and 0.1, 0.5, 1, 2.5, 5, and 10 mg/mL for rifabutin. RESULTS: All 33 MTB isolates that were susceptible to rifampin were also susceptible to rifabutin. None of the 23 MDR-MTB isolates were inhibited by rifabutin at a concentration of 0.1 mg/mL. Among these 23 MDR isolates, three were susceptible to rifabutin at concentrations > or = 0.5 mg/mL, six were susceptible to rifabutin at concentrations > or = 5 mg/mL, 18 were susceptible to rifabutin at concentrations > or = 10 mg/mL and five were not inhibited at any of the concentrations tested. The cross-resistance rate between rifampin and rifabutin was 87%. CONCLUSIONS: Our results indicate that the in vitro activity of rifabutin against drug-susceptible MTB isolates is greater than that of rifampin. For MDR-MTB isolates, the cross-resistance is high between rifampin and rifabutin.

Antibiotics, Antitubercular↗
PubMed1996

The clinical pharmacokinetics of rifabutin.

Rifabutin is structurally similar to rifampin, but there are important pharmacokinetic differences between the two drugs. Rifabutin is more lipid soluble than is rifampin, resulting in more-extensive tissue uptake, a larger volume of distribution, lower maximum plasma concentrations, lower trough concentrations, a longer terminal half-life, and higher tissue-to-plasma drug concentration ratios. The oral bioavailability of rifabutin is low. Like rifampin, rifabutin induces its own metabolism during multiple dosing. Rifabutin is extensively metabolized. The two major metabolites of rifabutin contribute to its antimicrobial activity. Rifabutin induces hepatic metabolism but is not as potent an inducer as is rifampin. Rifabutin does not affect the pharmacokinetics of antiretroviral drugs that are excreted in the urine. Although rifabutin decreases plasma concentrations of zidovudine, this finding does not appear to be clinically relevant. When administered during rifabutin prophylaxis, fluconazole decreases the incidence of Mycobacterium avium complex bacteremia. The coadministration of clarithromycin and rifabutin results in increased plasma concentrations of rifabutin and decreased plasma concentrations of clarithromycin; however, the plasma concentration of clarithromycin's active metabolite is increased.

Animals↗
PubMedDate not supplied

The use of rifabutin in Europe for the treatment of mycobacterial infection in AIDS patients.

The MICs of rifabutin on Mycobacterium avium are compatible with its efficacy in clinical infections. Two North American trials established the prophylactic effect of rifabutin in disseminated M. avium disease in AIDS patients. Several prospective non-randomized trials show the clinical and bacteriological efficacy of rifabutin. A large European study conducted from 1990 to 1993 randomized 382 patients, selected on a clinical basis, to receive a combination of ethambutol + clofazimine + isoniazid + placebo or rifabutin for 12 weeks. Of these, 200 were eligible, i.e. had a positive blood culture at day 0. The percentage of patients with fever decreased from 78% to 23% in the rifabutin arm and from 76% to 11% in the placebo group (difference statistically not significant). The percentage of positive blood cultures decreased from 100% to 70% and 29% in the placebo group and from 100% to 45% and 18% in the rifabutin group at weeks 0, 6 and 12 respectively. The rate of adverse events was 35% in the placebo and 30% in the rifabutin group (difference statistically not significant). Two other French randomized trials are being analysed: the first one compares a 14-day regimen of rifabutin to placebo. It shows a 70% success rate in the rifabutin arm and a 8% success rate in the control group. The second trial demonstrates that when given in addition to clarithromycin, unlike clofazimine a combination of rifabutin + ethambutol is effective in decreasing the relapse rate with acquired resistance to clarithromycin. After clarithromycin, rifabutin is the second drug which was proven to be active against disseminated M. avium disease in a controlled placebo trial.

AIDS-Related Opportunistic Infections↗
PubMed2005

Rifabutin based triple therapy for eradication of H. pylori primary and secondary resistant to tinidazole and clarithromycin.

BACKGROUND: Rifabutin has been empirically used in Helicobacter pylori infections resistant to triple therapy. There are no data on primary and secondary resistance to rifabutin and its use in specific cases. AIM: To analyse the susceptibility and resistance to rifabutin in H. pylori-positive patients with or without previous H. pylori therapy and to test the efficacy of rifabutin in H. pylori resistant to clarithromycin and tinidazole. METHODS: Four hundred and twenty H. pylori-positive patients without previous exposure to triple therapy and 104 patients who had already received one course of triple therapy underwent upper endoscopy for dyspeptic symptoms and H. pylori susceptibility test. Amoxicillin, clarithromycin, tinidazole and rifabutin were evaluated for resistance and susceptibility. Forty patients with primary resistance to both clarithromycin and tinidazole and with susceptibility to amoxicillin and rifabutin, and 65 patients with secondary resistance and susceptibility to the same antibiotics were identified. All these patients received a 10-day triple therapy with pantoprazole amoxicillin and rifabutin. Treatment success was evaluated by the 13C-Urea Breath test. RESULTS: In naive patients 23% of strains were resistant to clarythromycin, 35% to tinidazole, 9% to both antibiotics, and none was resistant to rifabutin In patients already treated the percentages of resistant strains were 76, 64.4, 62.5 and 1%, respectively. With rifabutin based triple therapy eradication rates were (Per Protocol and Intention-to-Treat analysis) 100 and 87.5% in primary resistance to clarithromycin and tinidazole and 82.2 and 78.5% in secondary resistance. CONCLUSION: H. pylori primary and secondary resistances to clarithromycin and tinidazole are high in our geographic area, while resistance to rifabutin is rare. Rifabutin-based triple therapy, can be successfully used in primary and secondary resistance to clarithromycin and tinidazole according to the in vitro susceptibility test.

Adult↗
PubMed2005

Evaluation of the drug interaction between rifabutin and efavirenz in patients with HIV infection and tuberculosis.

BACKGROUND: Because of drug-drug interactions mediated by hepatic cytochrome P450, tuberculosis treatment guidelines recommend an increase in rifabutin from 300 mg to 450 or 600 mg when combined with efavirenz-based antiretroviral therapy. To assess this recommendation, rifabutin and efavirenz pharmacokinetic parameters were investigated. METHODS: Plasma concentrations of rifabutin were determined as a baseline control in 15 patients with tuberculosis and human immunodeficiency virus (HIV) infection who were treated with rifabutin 300 mg and isoniazid 15 mg/kg (up to 900 mg) twice weekly. Rifabutin, isoniazid, and efavirenz concentrations were determined after a median of 21 days (interquartile range, 20-34 days) of daily efavirenz-based antiretroviral therapy with twice-weekly rifabutin 600 mg and isoniazid 15 mg/kg. RESULTS: The mean rifabutin area under the concentration-time curve (AUC(0-24)) increased 20% from the baseline value (geometric mean, 5.0 vs. 4.2 microg.h/mL; ratio of geometric means, 1.2 [90% confidence interval, 1.0-1.4]). Also, the mean efavirenz AUC(0-24) in the 15 patients taking concomitant rifabutin 600 mg twice-weekly was 10% higher than that in 35 historical subjects with HIV infection who were not taking rifabutin. Efavirenz-based antiretroviral therapy was effective; HIV load decreased 2.6 log copies/mL, and the median CD4+ T cell count increased from 141 to 240 cells/mm3 after a median of 21 days of efavirenz-based antiretroviral therapy. No statistically significant differences in isoniazid pharmacokinetic parameters were found. CONCLUSIONS: The rifabutin dose increase from 300 mg to 600 mg was adequate to compensate for the efavirenz drug interaction in most patients, and no drug interaction with isoniazid was detected. Efavirenz therapy administered at a standard 600-mg dose achieved adequate plasma concentrations in patients receiving intermittent rifabutin and isoniazid therapy, was generally well tolerated, and demonstrated potent antiretroviral activity.

Adult↗
PubMed1997

Metabolism of rifabutin and its 25-desacetyl metabolite, LM565, by human liver microsomes and recombinant human cytochrome P-450 3A4: relevance to clinical interaction with fluconazole.

Rifabutin and fluconazole are often given concomitantly as therapy to prevent opportunistic infections in individuals infected with the human immunodeficiency virus. Recent reports have shown increased levels of rifabutin and its 25-desacetyl metabolite, LM565, in plasma when rifabutin is administered with fluconazole. Since fluconazole is known to inhibit microsomal enzymes, this study was undertaken to determine if this rifabutin-fluconazole interaction was due to an inhibition of human hepatic enzymes. The metabolism of both rifabutin and LM565 was evaluated in human liver microsomes and recombinant human cytochrome P-450 (CYP) 3A4 in the presence of fluconazole and other probe drugs known to inhibit CYP groups 1A2, 2C9, 2D6, 2E1, and 3A. The concentrations of rifabutin (1 microg/ml), LM565 (1 microg/ml), and fluconazole (10 and 100 microg/ml) used were equal to those observed in plasma after the administration of rifabutin and fluconazole at clinically relevant doses. High-performance liquid chromatography was used to assess the metabolism of rifabutin and LM565. Rifabutin was readily metabolized to LM565 by human microsomes, but the reaction was independent of NADPH and was not affected by the P-450 inhibitors. No rifabutin metabolism by recombinant CYP 3A4 was found to occur. LM565 was also metabolized by human microsomes to two products, but metabolism was dependent on NADPH and was affected by certain P-450 inhibitors. In addition, LM565 was readily metabolized by the recombinant CYP 3A4 to the same two products found with its metabolism by human microsomes. Therefore, rifabutin is metabolized by human microsomes but not via cytochrome P-450 enzymes, whereas LM565 is metabolized by CYP 3A4.

Anti-Bacterial Agents↗
PubMed2001

Effects of repeated rifabutin administration on the pharmacokinetics of intravenous and oral ciprofloxacin in mice.

The combination of rifabutin and ciprofloxacin is potentially useful for the treatment of disseminated Mycobacterium avium-intracellulare (MAC) diseases in HIV-infected patients. Rifabutin is a metabolic enzyme inducer structurally similar to its predecessor, rifampin. Using a mouse model, the effects of repeated exposure of rifabutin on the pharmacokinetics of ciprofloxacin after intravenous (i.v.) and oral (p.o.) dosing were investigated in the present study. Results showed that repeated exposure of rifabutin, relative to control, caused a 16% increase in the plasma clearance (CL) of ciprofloxacin after i.v. dosing (4.19 vs. 4.87 L/h/kg). Estimates of elimination half-life (T1/2) were not affected by rifabutin (control: 0.81 vs. rifabutin pretreated: 1.18 h). The data obtained after oral dosing showed that repeated rifabutin dosing caused a significant reduction in the maximal plasma concentration (Cmax: 1.34 vs. 0.91 microg/mL) and a longer time to Cmax (Tmax: 0.17 vs. 0.33 h). These changes might be in part attributable to the increase in oral clearance (CL/F) by 18%. With or without rifabutin pretreatment, the T1/2 estimates of ciprofloxacin for p.o. dosing were similar (2.37-2.58 h) and were approximately twice as long as those obtained after i.v. dosing. Since the changes in systemic exposure as a result of rifabutin pretreatment were similar after i.v. and p.o. dosing, the oral bioavailability (F) of ciprofloxacin remained unaffected by rifabutin at approximately 38%. The effects of rifabutin on the pharmacokinetics of ciprofloxacin appear to be moderate in the mouse model which might be attributable to the absorption and distribution behavior of the quinolone antibiotic. The therapeutic implications of this interaction, if any, remain to be defined.

Absorption↗
PubMed2001

Pharmacokinetic Interaction between amprenavir and rifabutin or rifampin in healthy males.

The objective of this study was to determine if there is a pharmacokinetic interaction when amprenavir is given with rifabutin or rifampin and to determine the effects of these drugs on the erythromycin breath test (ERMBT). Twenty-four healthy male subjects were randomized to one of two cohorts. All subjects received amprenavir (1,200 mg twice a day) for 4 days, followed by a 7-day washout period, followed by either rifabutin (300 mg once a day [QD]) (cohort 1) or rifampin (600 mg QD) (cohort 2) for 14 days. Cohort 1 then received amprenavir plus rifabutin for 10 days, and cohort 2 received amprenavir plus rifampin for 4 days. Serial plasma and urine samples for measurement of amprenavir, rifabutin, and rifampin and their 25-O-desacetyl metabolites, were measured by high-performance liquid chromatography. Rifabutin did not significantly affect amprenavir's pharmacokinetics. Amprenavir significantly increased the area under the curve at steady state (AUC(ss)) of rifabutin by 2.93-fold and the AUC(ss) of 25-O-desacetylrifabutin by 13.3-fold. Rifampin significantly decreased the AUC(ss) of amprenavir by 82%, but amprenavir had no effect on rifampin pharmacokinetics. Amprenavir decreased the results of the ERMBT by 83%. The results of the ERMBT after 2 weeks of rifabutin and rifampin therapy were increased 187 and 156%, respectively. Amprenavir plus rifampin was well tolerated. Amprenavir plus rifabutin was poorly tolerated, and 5 of 11 subjects discontinued therapy. Rifampin markedly increases the metabolic clearance of amprenavir, and coadministration is contraindicated. Amprenavir significantly decreases clearance of rifabutin and 25-O-desacetylrifabutin, and the combination is poorly tolerated. Amprenavir inhibits the ERMBT, and rifampin and rifabutin are equipotent inducers of the ERMBT.

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