Antibacterial

Rifabutin is primarily prescribed as an antibiotic with bactericidal properties to treat tuberculosis. Its action on bacteria stems from its semi-synthetic derivative, rifamycin S., which blocks RNA polymerase in a DNA-dependent manner. It works well against a variety of bacteria, including Gram-positive and Gram-negative bacteria, Mycobacterium tuberculosis, M. leprae, and M. avium intracellulare. It is particularly effective against highly resistant mycobacteria. Antibiotic and antitumor drug rifabutin. Rifabutin inhibits the bacterial RNA polymerase, increases ubiquitination and protein degradation, and tampers with the HSP-90 molecular chaperone.

---

Rifabutin and its active metabolite, 25-O-desacetyl-rifabutin, have demonstrated in vitro activity against the Mycobacterium avium complex (MAC) organism isolated from HIV-positive and -negative individuals. Rifabutin has also demonstrated in vitro activity and clinical efficacy against Mycobacterium tuberculosis. [1]

Drug interactions between rifamycins and highly active antiretroviral therapy (HAART) have raised concerns in the treatment of human immunodeficiency virus (HIV)-infected patients with tuberculosis. We conducted a study of this interaction by measuring serum drug levels of all HIV-infected patients with tuberculosis who were admitted to A. G. Holley State Tuberculosis Hospital (Florida) from October 1997 through December 1998, who were concomitantly treated with rifabutin and HAART. All 25 patients studied became culture-negative within 2 months of initiation of therapy for tuberculosis and remained negative for a median of 13 months follow-up after completion of therapy. HIV viral loads (mean+/-SEM) decreased significantly from 4.95+/-0.21 log10 copies/mL before initiation of HAART to 2.77+/-0.07 log10 copies/mL before discharge (P<.001); 20 of 25 patients achieved viral loads of <500copies/mL. In summary, the concomitant use of rifabutin and HAART can lead to successful treatment of HIV-infected patients with tuberculosis without increased side effects[5].

Rifabutin shows good in vitro activity against H. pylori. Mean H. pylori rifabutin resistance rate (calculated from 11 studies including 2982 patients) was 1.3% (95% confidence interval = 0.9-1.7%). When only studies including patients naïve to H. pylori eradication treatment were considered, this figure was even lower (0.6%). On the other hand, higher values of rifabutin resistance were calculated (1.59%) when only post-treatment patients were considered. Overall, mean H. pylori eradication rate (intention-to-treat analysis) with rifabutin-containing regimens (1008 patients) was 73% (67-79%). Respective cure rates for second-line (223 patients), third-line (342 patients) and fourth/fifth-line (95 patients) rifabutin therapies were 79% (67-92%), 66% (55-77%) and 70% (60-79%) respectively. For treating H. pylori infection, almost all studies have administered rifabutin 300 mg/day; this dose seems to be more effective than 150 mg/day. The ideal length of treatment remains unclear, but 10- to 12-day regimens are generally recommended. The mean rate of adverse effects was 22% (19-25%). Myelotoxicity is the most significant, although this complication was rare. Until now, all patients have recovered of leucopenia uneventfully in a few days, and there have been no reports of infection or other adverse outcomes related to it[2].

One hundred subjects were included. The indications for rifabutin (RFB) use wereRifampin (RMP)-related AE (57%), con- current antiretroviral therapy (21%), potential/actual interaction with other medications (14%), and as part of an alternative regimen in liver disease (8%). Nineteen patients experienced an AE while taking RFB. Among patients with a prior RMP-related AE, 80% of whom were successfully treated with RFB, only a dermatologic AE was associated with subsequent RFB intolerance.

Rifabutin is primarily metabolized and eliminated via the cytochrome P450 3A (CYP3A) pathway. [1]
In healthy subjects, the geometric mean (%CV) of steady-state pharmacokinetic parameters after once-daily administration of 300 mg rifabutin alone were: AUC₂₄ = 5,030 (18%) ng·h/mL, Cmax = 522 (31%) ng/mL, C₂₄ = 78.9 (28%) ng/mL. The median Tmax was 4 hours (range 2–6 hours). [1]
The apparent terminal half-life of rifabutin is 45 hours (range 16–69 hours). [1]
Concomitant use of rifabutin with the non-nucleoside reverse transcriptase inhibitor lecithin did not significantly affect the pharmacokinetics of rifabutin. The adjusted geometric mean ratios (lecivirine + rifabutin / rifabutin alone) were: AUC₂₄ 1.02 (90% CI: 0.96, 1.08), Cmax 1.10 (90% CI: 0.98, 1.24), and C₂₄ 1.00 (90% CI: 0.94, 1.06). [1] However, co-administration with lecivirine reduced exposure to the active metabolite 25-O-deacetylated rifabutin. The adjusted geometric mean ratios for metabolite AUC₂₄ and Cmax were 0.73 (90% CI: 0.68, 0.79) and 0.73 (90% CI: 0.66, 0.81), respectively. [1]

Rifabutin is generally well tolerated in patients with rifampicin-related adverse reactions. However, patients with a history of rifampicin-related skin events have a 9-fold higher risk of developing rifabutin-related adverse reactions than patients with a history of liver injury.
According to study criteria, the adverse reactions observed with rifabutin included liver injury, skin events, gastrointestinal intolerance, musculoskeletal events, cytopenia, and angioedema.
Among patients with underlying liver disease, 3 out of 8 (38%) experienced rifabutin-related adverse reactions, suggesting caution when using rifabutin in patients with hepatoprotective regimens.
The manufacturer states that rifabutin is contraindicated in patients with clinically significant adverse reactions to any rifamycin class of drugs. [4]

[1]. Effect of rifampin and rifabutin on the pharmacokinetics of lersivirine and effect of lersivirine on the pharmacokinetics of rifabutin and 25-o-desacetyl-rifabutin in healthy subjects. Antimicrob Agents Chemother. 2012 Aug;56(8):4303-9.

[2]. Fourth-line rescue therapy with rifabutin in patients with three Helicobacter pylori eradication failures. Aliment Pharmacol Ther. 2012 Apr;35(8):941-7.

[3]. Review article: rifabutin in the treatment of refractory Helicobacter pylori infection. Aliment Pharmacol Ther. 2012 Jan;35(2):209-21.

[4]. Experience with rifabutin replacing rifampin in the treatment of tuberculosis. Int J Tuberc Lung Dis. 2011 Nov;15(11):1485-9, i.

[5]. Use of rifabutin with protease inhibitors for human immunodeficiency virus-infected patients with tuberculosis. Clin Infect Dis. 2000 May;30(5):779-83.

Rifampin is a prescription antibacterial drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of tuberculosis (TB). Rifampin is also FDA-approved for the treatment of asymptomatic carriers of Neisseria meningitidis. Tuberculosis can be an opportunistic infection (OI) of HIV infection. Rifabutin is a broad-spectrum antibiotic used to prevent disseminated Mycobacterium avium complex (MAC) infection in HIV-infected individuals. Rifabutin is a rifamycin-type antimycobacterial drug. Rifabutin is a rifamycin-type antibiotic with a structure and activity similar to rifampin and rifapentine, primarily used to prevent MAC infection in patients with advanced HIV infection. Rifabutin is associated with transient and asymptomatic elevations in serum transaminases, which may be one of the causes of clinically apparent acute liver disease. Rifabutin is a semi-synthetic anisometropic antibiotic with potent antimycobacterial activity. Rifabutin inhibits bacterial DNA-dependent RNA polymerase, thereby inhibiting the initiation of RNA synthesis, ultimately leading to the repression of RNA synthesis and transcription.

---

Indications
For the prevention of disseminated Mycobacterium avium complex (MAC) infection in patients with advanced HIV infection.

---

Rifabutin is indicated for the prevention of disseminated Mycobacterium avium complex (MAC) infection in patients with advanced human immunodeficiency virus (HIV) infection. (This information is included on the US product label.) Rifabutin also has in vitro activity against a variety of Mycobacterium tuberculosis strains. However, there is no evidence that rifabutin is effective in preventing tuberculosis. Isoniazid and rifabutin can be used simultaneously for the prevention of tuberculosis and Mycobacterium avium complex infection. Cross-resistance exists between rifampin and rifabutin in highly rifampicin-resistant Mycobacterium avium complex isolates. /Included in U.S. Product Label/

---

View More

Pharmacodynamics
Rifabutin is an antibiotic that inhibits the activity of DNA-dependent RNA polymerase in susceptible cells. Specifically, rifabutin interacts with bacterial RNA polymerase but does not inhibit mammalian RNA polymerase. It has bactericidal activity and broad-spectrum antibacterial activity against most Gram-positive and Gram-negative bacteria (including Pseudomonas aeruginosa) and Mycobacterium tuberculosis. Due to the rapid emergence of resistant bacteria, the use of rifabutin is limited to the treatment of mycobacterial infections and a few other indications. Oral rifabutin is well absorbed and widely distributed in tissues and fluids throughout the body, including cerebrospinal fluid. Rifabutin is metabolized in the liver and excreted primarily via bile, with a small amount excreted in the urine; however, no dose adjustment is required for patients with renal insufficiency.

---

Absorption> Rifabutin is readily absorbed from the gastrointestinal tract, with an average absolute bioavailability of 20%.
Excretion Route> A mass balance study of rifabutin in three healthy adult volunteers using 14C-labeled rifabutin showed that 53% of the oral dose was excreted in the urine, primarily as metabolites. Approximately 30% of the dose was excreted in the feces.

---

Metabolism/Metabolites> Hepatic metabolism. Of the five identified metabolites, 25-O-deacetyl and 31-hydroxy are the most abundant. Pre-metabolites have activity comparable to the parent drug and contribute up to 10% to the total antibacterial activity. Biological half-life: 45 ± 17 hours.

---

Mechanism of Action
Rifabutin works by inhibiting DNA-dependent RNA polymerase in Gram-positive and some Gram-negative bacteria, leading to RNA synthesis inhibition and cell death.
Rifabutin inhibits DNA-dependent RNA polymerase in susceptible Escherichia coli and Bacillus subtilis strains, but has no effect on mammalian cells. Rifabutin does not inhibit drug-resistant Escherichia coli strains. It is currently unclear whether rifabutin inhibits DNA-dependent RNA polymerase in Mycobacterium avium or intracellular Mycobacterium (which together constitute the Mycobacterium avium complex).

---

Rifabutin is an antibacterial drug used to treat tuberculosis and nontuberculous mycobacterial infections.
Because rifampin has a strong CYP-inducing effect, it often presents problems in patients co-infected with HIV. For patients co-infected with HIV and Mycobacterium tuberculosis, rifabutin can be used as an alternative to rifampin because it has a weaker CYP-inducing effect. [1]
The active metabolite 25-O-deacetylated rifabutin contributes 10% to the total antibacterial activity of rifabutin. [1]
This study concluded that although a decrease in metabolite exposure was observed, no dose adjustment of rifabutin was necessary when used in combination with lecithin, as this decrease was considered clinically insignificant. [1]

C46H62N4O11

847.0047

846.441

C, 65.23; H, 7.38; N, 6.61; O, 20.78

72559-06-9

Rifabutin-d7;2747918-39-2

136276712

Purple to purplish red solid powder

1.3±0.1 g/cm3

969.6±65.0 °C at 760 mmHg

169-171ºC

540.2±34.3 °C

0.0±0.3 mmHg at 25°C

1.623

3.45

5

14

5

61

1880

9

C12=C3C(=C(C)C4O[C@](C)(OC=C[C@H](OC)[C@@H](C)[C@@H](OC(=O)C)[C@H](C)[C@@H]([C@H](C)[C@@H](O)[C@@H](C)C=CC=C(C)C(=O)NC(C3=O)=C3NC5(CCN(CC(C)C)CC5)N=C13)O)C(=O)C2=4)O |t:10,31,33,&1:7,12,15,17,22,24,25,27,29|

ATEBXHFBFRCZMA-NYGPAKPVSA-N

InChI=1S/C46H62N4O11/c1-22(2)21-50-18-16-46(17-19-50)48-34-31-32-39(54)28(8)42-33(31)43(56)45(10,61-42)59-20-15-30(58-11)25(5)41(60-29(9)51)27(7)38(53)26(6)37(52)23(3)13-12-14-24(4)44(57)47-36(40(32)55)35(34)49-46/h12-15,20,22-23,25-27,30,37-38,41,49,52-54H,16-19,21H2,1-11H3,(H,47,57)/b13-12+,20-15+,24-14+/t23-,25+,26+,27+,30-,37-,38+,41+,45-/m0/s1

Rifamycin XIV, 1',4-didehydro-1-deoxy-1,4-dihydro-5'-(2-methylpropyl)-1-oxo-

Ansamycin; Rifabutin; LM-427; LM 427; LM427; Mycobutin; Rifabutina;

2934.99.03.00

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 50~100 mg/mL (59.03~118.06 mM)
Ethanol : ~100 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (2.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: 10% DMSO+40% PEG300+5% Tween-80+45% Saline

---

 (Please use freshly prepared in vivo formulations for optimal results.)