RIFABUTINA EN VADEMCUM

	RIFABUTINA

	DESCRIPCION La rifabutina es un agente antimicobacteriano activo por vía oral. Es un derivado de la rifamicina, que ha demostrado recientemente ser eficaz como un agente profiláctico contra el complejo de Mycobacterium avium (MAC) en pacientes con SIDA. La rifabutina se recomienda como una alternativa a claritromicina o azitromicina para la profilaxis primaria en pacientes infectados conj VIH. La rifabutina también se considera una alternativa a la rifampicina para la tuberculosis y la profilaxis de la tuberculosis en pacientes infectados por el VIH cuando el gérmen es probable que sea resistente a la isoniazida. Mecanismo de acción: la rifabutina parece inhibir la polimerasa de ARN dependiente de ADN en cepas susceptibles de E. coli y B. subtilis, suprimiendo así la síntesis de ARN. No se sabe si este mecanismo es responsable de la actividad frente a M. avium o M. intracellularis. También hay algunas pruebas de que interfiere con la síntesis del DNA de M. tuberculosis. La rifabutina presenta una acción bactericida o bacteriostática dependiendo de las concentraciones del fármaco en el sitio infectado y la susceptibilidad del organismo . En general , los siguientes organismos son susceptibles a la rifabutina : algunas cepas de M. tuberculosis y M. leprae y M. avium-intracellularis. La rifabutina tiene acciones similares in vitro a las de rifampicina contra organismos grampositivos y gramnegativos. Farmacocinética : tras la administración oral, la rifabutina es rápidamente absorbida desde el tracto gastrointestinal. Aproximadamente el 53% de una dosis se absorbe, pero la biodisponibilidad es solamente del 12-20% en pacientes VIH-positivos. Los alimentos ricos en grasas reducen la velocidad de absorción. Las concentraciones plasmáticas pico se alcanzan en 1-4 horas. Debido a su lipofilia, la rifabutina se distribuye ampliamente, con una sustancial acumulación intracelular. Las concentraciones del antibiótico en el pulmón son aproximadamente 5-10 veces mayor que las concentraciones séricas . La semi-vida promedio es de 45 horas. Los metabolitos primarios son hidroxi-31 y 25-OH-desacetil- rifabutina . Este último compuesto exhibe una actividad comparable a la del fármaco principal, aportando cerca del 10% de la acción antimicrobiana total de la rifabutina. Aproximadamente el 53% de una dosis se excreta en la orina principalmente como metabolitos y el 5% por separación biliar. Aproximadamente el 30% se excreta en las heces.
	INDICACIONES Y POSOLOGIA Los siguientes organismos son generalmente considerados susceptibles de rifabutina en vitro: Mycobacterium avium ; Mycobacterium intracellulare; Mycobacterium leprae Y Mycobacterium tuberculosis Tratamiento de la infección por complejo Mycobacterium avium (MAC) en pacientes-infectados con VIH Administracion oral Adultos: se recomienda una dosis de 450-600 mg PO una vez al día. Se han comparado dos combinaciones de diferentes fármacos en en pacientes con bacteriemia con SIDA y MAC. Los pacientes fueron evaluados durante un período de 16 semanas . El régimen de 3 antibióticos claritromicina, etambutol y rifabutina fue superior para el régimen de 4 antibióticos ciprofloxacina, clofazamina, etambutol y rifampicina. La bacteremia se resolvió antes y con mayor frecuencia con el grupo de 3 fármacos que en el grupo de 4. La dosis de rifabutina en este estudio fue inicialmente 600 mg PO una vez al día , pero posteriormente fue reducida a 300 mg PO una vez al día debido a una incidencia inaceptablemente alta de uveitis. Niños : el uso seguro y eficaz de la rifabutina no ha sido establecido . Para la profilaxis de la infección por MACen pacientes infectados de VIH: ï¿½ profilaxis primaria frente al complejo Mycobacterium avium en adultos y adolescentes < 50 CD4 + células/mm3 infectados por el VIH_ Administración oral : Adultos y adolescentes: como alternativa a la claritromicina o azitromicina, el CDC recomienda la rifabutina en dosis de 300 mg PO una vez al día. Alternativamente, puede administrarse rifabutina 300 mg PO una vez al día en combinación con azitromicina . También se ha utilizado alternativamente, un régimen de 150 mg PO dos veces al día. Un estudio de pacientes VIH-positivos con < 100 CD4 + células reveló que la rifabutina 300 mg PO una vez diariamente en combinación con azitromicina fue superior para la profilaxis primaria que cualquiera de los fármacos solos Se debe tener en cuenta que todos los pacientes en este estudio también recibieron profilácticamente fluconazol. El fluconazol ha demostrado aumentar significativamente el AUC de la rifabutina AUC. La profilaxis del MAC primario puede suspenderse en pacientes adultos con recuentos de CD4 + > 100 células/ï¿½l a los 3 ï¿½ 6 meses La profilaxis primaria del MAC debe reiniciarse si la cuenta de CD4 + cae < 50 células/ï¿½l. ï¿½ profilaxis primaria frente al complejo Mycobacterium avium en niños infectados por el VIH > 6 años de edad con una cuenta de CD4 + < 50 células/mm3 o en niños de 2 ï¿½ 6 años de edad con una cuenta de CD4 +< 75 células/mm3: Administracion oral Niños de 6 años de edad : como alternativa a la claritromicina o azitromicina, el CDC recomiendan la rifabutina 300 mg PO una vez al día la seguridad de la interrupción de la profilaxis primaria de MAC en niños cuyos recuentos de CD4 + han aumentado en respuesta a la terapia antiretroviral altamente activa no ha sido estudiada. para Mycobacterium avium complejo (MAC) profilaxis secundaria en pacientes infectados por el VIH con enfermedad diseminada , después del tratamiento de la enfermedad aguda : dosis Oral : adultos y adolescentes : el CDC recomienda claritromicina más etambutol con o sin rifabutina 300 mg PO una vez al día . Alternativamente , se puede administrar azitromicina plus ethambutal con rifabutina 300 mg PO una vez al día . [1446] niños y neonatos : el CDC recomienda claritromicina más etambutol con o sin rifabutina (máximo 300 mg) de 5 mg/kg PO una vez al día . Alternativamente , se puede administrar azitromicina plus ethambutal con rifabutina 5 mg/kg (máximo 300 mg) PO una vez al día . [1446] como alternativa a la rifampicina para el tratamiento de tuberculosisï¿½ en pacientes infectados por VIH en combinación con otros agentes antituberculosos :
	ï¿½for secondary Mycobacterium avium complex (MAC) prophylaxis in HIV-infected patients with disseminated disease, after treatment of the acute illness: Oral dosage: Adults and adolescents: The CDC recommends clarithromycin plus ethambutol with or without rifabutin 300 mg PO once daily. Alternatively, azithromycin plus ethambutal may be given with rifabutin 300 mg PO once daily.[1446] Children and infants: The CDC recommends clarithromycin plus ethambutol with or without rifabutin 5 mg/kg (maximum 300 mg) PO once daily. Alternatively, azithromycin plus ethambutal may be given with rifabutin 5 mg/kg (maximum 300 mg) PO once daily.[1446] As an alternative to rifampin for the treatment of tuberculosisï¿½ in HIV-infected patients in combination with other antitubercular agents: NOTE: The American Thoracic Society (ATS) and the CDC currently recommend short-course regimens (e.g., at least 6 months) for the treatment of uncomplicated pulmonary tuberculosis and most cases of extrapulmonary tuberculosis in adults. According to the ATS, CDC, and American Academy of Pediatrics (AAP), short-course regimens are also suitable in children. Directly observed therapy (DOT) should be used for all regimens administered 2 or 3 times per week. HIV-infected patients should always receive induction therapy with four drugs by DOT. When drug susceptibility results are available, the regimen should be altered as appropriate. Although regimens that are adequate for pulmonary TB should also be effective in treating extrapulmonary disease, some experts extend the duration of therapy o 9 months for patients with disseminated disease, miliary disease, disease involving the bones or joints, or tuberculosis lymphadenitis. In addition, treatment may be extended to 9 months or longer in HIV-infected patients, dependent upon clinical signs and symptoms or conversion of sputum cultures from positive to negative. NOTE: Rifabutin is used as an alternative to rifampin in the following regimens when patients are contraindicated to receive rifampin due to concomitant therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors. Rifabutin is contraindicated for use with delavirdine. The patient should be carefully monitored for potential rifabutin drug toxicity and decreased antiretroviral medication activity while receiving rifabutin with other antiretroviral agents (see Drug Interactions). NOTE: Rifabutin has only been evaluated in twice weekly DOT regimens. Dosage recommendations for three times weekly administration have not been established. Oral dosage: Adults with HIV infection: Rifabutin 5 mg/kg PO (up to 300 mg) is given once daily for 2 months (in combination with isoniazid, pyrazinamide, and either ethambutol or IM streptomycin), followed by isoniazid combined with rifabutin 5 mg/kg PO daily or two times per week for an additional 4 months. An alternative short-course regimen recommended by the CDC consists of rifabutin 5 mg/kg (up to 300 mg) PO once daily for 2 weeks (in combination with isoniazid, pyrazinamide, and either ethambutol or IM streptomycin), followed by twice weekly administration of the same drug combination for 6 weeks (DOT), then 4 months of twice weekly therapy with isoniazid plus rifabutin (DOT).[1942] Children with HIV infection: Rifabutin 10ï¿½20 mg/kg PO (up to 300 mg) is given once daily for 2 months (in combination with isoniazid, pyrazinamide, and either ethambutol or IM streptomycin), followed by isoniazid in combination with rifabutin 10ï¿½20 mg/kg PO daily or two times per week for an additional 4 months. An alternative short-course regimen recommended by the CDC consists of rifabutin 10ï¿½20 mg/kg (up to 300 mg) PO once daily for 2 weeks (in combination with isoniazid, pyrazinamide, and either ethambutol or IM streptomycin), followed by twice weekly administration of the same drug combination for 6 weeks (DOT), then 4 months of twice weekly therapy with isoniazid plus rifabutin (DOT).[1942] As an alternative to isoniazid regimens for tuberculosis prophylaxisï¿½ when a newly-positive skin test (>= 5 mm) is confirmed or when the patient has been in contact with someone with active tuberculosis and there is a high probability of exposure to isoniazid-resistant tuberculosis: NOTE: Rifabutin is used as an alternative to rifampin in the following regimen when patients are contraindicated to receive rifampin due to concomitant therapy with protease inhibitors or non-nucleoside reverse transcriptase inhibitors. Rifabutin is contraindicated for use with delavirdine. The patient should be carefully monitored for potential rifabutin drug toxicity and decreased antiretroviral medication activity while receiving rifabutin with other antiretroviral agents (see Drug Interactions). Oral dosage: Adults: As an alternative to rifampin, the CDC recommends a dose of 300 mg PO once daily given in combination with daily pyrazinamide for a total of 2 months or, rifabutin 300 mg PO once daily for a total of 4 months. No specific data have been reported for the use of rifabutin-containing regimens for tuberculosis prophylaxis, but this recommendation is supported by analogy treatment for active TB where rifabutin can be substituted for rifampin with no loss of efficacy and by animal studies.[46] [1446] Children: As an alternative for rifampin, the CDC states that rifabutin 10ï¿½20 mg/kg PO (up to 300 mg) once daily may be given in combination with daily pyrazinamide for a total of 2 months. No reports have been published concerning the efficacy of rifabutin and pyrazinamide therapy in children, although a randomized trial involving a limited number of children indicated that rifampin and pyrazinamide was well tolerated. It may be inferred that rifabutin, when substituted for rifampin, would be expected to be well-tolerated.[46] Patients with renal impairment: No dosage adjustment needed. ï¿½non-FDA-approved indication Oral Administration ï¿½Administer with food to reduce gastrointestinal irritation. Contraindications Rifabutin should not be administered to patients with known rifamycin hypersensitivity, including rifampin, because cross-sensitivity between agents is possible. Like rifampin, rifabutin can discolor bodily fluids such as urine, saliva, tears, and sputum. Patients should be warned of this occurrence. Wearers of soft contact lenses should be warned that the lenses may be permanently stained. Rifabutin is classified as FDA category B drug for use during pregnancy. Rifabutin should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. It is not known if rifabutin is excreted into breast milk. A decision as to whether or not to continue breast-feeding should be based upon the risks to the infant taking into consideration the benefit to the mother. While the manufacturer recommends against the use of rifabutin in active tuberculosis infection, the CDC states that rifabutin may be used in place of rifampin in regimens for both tuberculosis treatment and prophylaxis. Interactions Limited data indicate that concurrent administration of rifabutin and zidovudine, ZDV results in decreased plasma concentrations of zidovudine. The effectiveness of zidovudine against HIV does not appear to be altered. Although further study is needed, this interaction should be suspected if alterations in zidovudine concentrations become evident. The CDC currently considers the nucleoside reverse transcriptase inhibitors, including zidovudine, compatible for concomitant use with rifabutin and no dosing adjustments are necessary. Antretroviral protease inhibitors and non-nucleoside reverse transcriptiase inhbitors (NNRTIs) may be given in combination with rifabutin in specific situations.[1299] However, rifabutin should not be administered concurrently with delavirdine. When giving rifabutin in combination with ritonavir (with or with out another protease inhibitor), the dose of rifabutin should be substantially reduced (i.e., in adults, rifabutin 150 mg PO 2ï¿½3 times per week). The combination of saquinavir soft-gel capsules (SGC) or saquinavir hard-gel capsules (HGC) and ritonavir co-administered with rifabutin (adult dosage, 150 mg PO 2ï¿½3 times per week) is a possibility; however, pharmacokinetic and clinical experience are limited. When a patient is receiving saquinavir SGC and two nucleoside reductase inhibitors (NRTIs), the dose of rifabutin should not be decreased. There is limited but favorable clinical experience with the concurrent use of rifabutin (in reduced doses and/or regular doses) and amprenavir, indinavir, nelfinavir at increased doses (1000 mg daily), or nevirapine. Concurrent use of rifabutin and efavirenz requires increasing the rifabutin dose to either 450 mg or 600 mg daily or 600 mg 2ï¿½3 times per week. When both an inhibitor and inducer of cytochrome P450 (e.g., a protease inhibitor in combination with a NNRTI) are used with rifabutin, a different complex interaction occurs and the appropriate drug-dose adjustments to ensure optimum levels of both the antiretrovirals and rifabutin are unknown. In patients undergoing therapy with complex combinations of protease inhibitors or NNRTIs, the use of antituberculosis regimens containing no rifamycins can be considered. However, for HIV-infected patients with active tuberculosis, use of a tuberculosis treatment regimen that does not contain a rifamycin, although possible, may be sub-optimal and is usually not recommended. The effectiveness of oral contraceptives, including progestin-only formulations, can be decreased following administration of rifabutin, possibly as a result of hepatic enzyme induction. Additional or alternative methods of birth control should be considered. The effectiveness of other estrogens and progestins may also be reduced. Uveitis has been associated with high dose (e.g., 1500 mg/day) rifabutin. Uveitis has also been reported after low-dose (e.g., 300 mg/day) rifabutin if fluconazole was used concomitantly.[856] Fluconazole has been shown to significantly increase rifabutin AUC[1240] thus, it is likely that the development of uveitis is directly associated with rifabutin plasma concentrations. Because HIV-infected patients are likely to be receiving rifabutin and fluconazole concomitantly,[1239] these patients should be monitored for this adverse reaction. Since fluconazole is a relatively mild inhibitor of hepatic metabolism, clinicians should be altert for a similar adverse reaction if other, more potent, hepatic enzyme inhibitors are administered concomitantly with rifabutin. The adverse manifestations of these drug-drug interactions need to be weighed against the potential benefits. Limited data suggest that the risk of MAC bacteremia is lowered when fluconazole is added to rifabutin.[1265] Rifabutin, like rifampin, can accelerate the hepatic clearance of corticosteroids, although rifabutin appears to be a less potent hepatic enzyme inducer than rifampin. Patients may require higher doses of corticosteroids if rifabutin is added to therapy. Rifabutin appears to be a less potent hepatic enzyme inducer than rifampin; however, the clinical significance of this finding has not been determined. Unlike with rifampin, acetylation of isoniazid by rifabutin is not affected. Although, rifabutin appears to be a less potent hepatic enzyme inducer than rifampin, the clinical significance of this finding has not been determined. Rifabutin may increase the metabolism and decrease the effectiveness of alfentanil, alprazolam, cevimeline, estazolam, fentanyl, levobupivacaine, midazolam, and zonisamide. Rifabutin may interfere with the development of an immune response following Bacillus Calmette-Guerin vaccine, BCG. Bexarotene is extensively metabolized by the CYP3A4 hepatic isoenzyme. When significant CYP3A4 inducers like rifabutin are administered concomitantly with bexarotene, the health care professional may need to observe the patient for reduced effects from bexarotene. Alosetron is partially metabolized by CYP3A4. Rifabutin can induce the activity of this hepatic isoenzyme and increase the metabolism of alosetron. Concomitant administration of rifabutin and alosetron has not been evaluated. Concurrent administration of a rifamycin with either tamoxifen or toremifene may lead to decreased antiestrogen effects due to hepatic enzyme induction by the rifamycin. Following chronic dosing with rifampin, the AUCs of tamoxifen and toremifene are reduced substantially and the Cmax of each agent is reduced by roughly 55%. The half-lifes of tamoxifen and toremifene may be decreased by over 40%. Similar induction of tamoxifen and toremifene metabolism would be expected with concurrent rifabutin therapy. Although specific drug interactions with mifepristone, RU-486 have not been studied, rifabutin may induce mifepristone metabolism via CYP3A4. Given the partial metabolism of galantamine through the hepatic CYP3A4 isoenzyme, the effectiveness of the drug could theoretically be reduced by the concomitant administration of CYP3A4 inducers such as rifabutin. Adverse Reactions The primary reasons for discontinuation of therapy with rifabutin are rash (urticaria) (4%), GI upset (3%), and neutropenia (2%). In clinical trials, the incidence of neutropenia has been significant compared to placebo. Reported gastrointestinal effects include nausea/vomiting (6%), dyspepsia (3%), abdominal pain (4%), and flatulence (2%). Urine discoloration occurs in 30% of study patients receiving rifabutin compared with 6% in controls. Discoloration of tears, perspiration, feces, saliva, and sputum also can occur. The drug can also contact lens discoloration. Thrombocytopenia has been observed during rifabutin therapy. Although the incidence has not been significant when compared with placebo, a causal relationship has been established. Less frequently reported adverse reactions to rifabutin include seizures, taste perversion, nonspecific T wave changes on ECG, and myalgia. Fewer than 1% of patients have experienced arthralgia, hemolysis or hemolytic anemia, and hepatitis. Elevated hepatic enzymes, including serum alkaline phosphatase and aspartate aminotransferase (AST), have occurred in patients with disseminated disease. Uveitis with ocular pain and visual impairment has been reported with rifabutin therapy.[745] [856] It was generally associated with doses greater than 1500 mg/day, however, uveitis was reported in 2 patients receiving drug regimens including rifabutin administered at doses of 600 mg/day PO[745] and in four patients receiving only 300 mg/day PO, although these 4 patients were also receiving fluconazole, a known inhibitor of hepatic metabolism.[856] In 4 patients, uveitis developed only after 7 months of therapy.[856] In a study of HIV-positive patients receiving combination therapy for MAC bacteremia, 24 of 63 patients receiving 600 mg/day and 3 of 53 patients receiving 300 mg/day developed uveitis. The onset was at a median of day 42.[1235] Although these patients were receiving other drugs concomitantly, clinicians should be aware of this adverse reaction to rifabutin at potentially lower doses.
	PRESENTACION Rifabutin Mycobutinï¿½
	REFERENCIAS Centers for Disease Control and Prevention. 1999 USPHS/IDSA Guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. Morbid Mortal Weekly Rep 1999;48:1ï¿½66. Masur H and the Public Health Service Task Force on prophylaxis and therapy for Mycobacterium avium complex. Recommendations on prophylaxis and therapy for disseminated Mycobacterium avium complex disease in patients infected with the human immunodeficiency virus. N Engl J Med 1993;329:898ï¿½904. Shafran SD, Singer J, Zarowny DP et al. A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. N Engl J Med 1996;335:377ï¿½83. Havlir DV, Dube MP, Sattler FR et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. N Engl J Med 1996;335:392ï¿½8. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. Morbid Mortal Weekly Rep 1998;47(no. RR-20):1ï¿½58. Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR 2000;49:1ï¿½54. Centers for Disease Prevention and Control. Notice to readers: Updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected individuals taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR 2000;49:185ï¿½9. Havlir D, Torriani F, Dube M. Uveitis associated with rifabutin prophylaxis. Ann Intern Med 1994;121:510ï¿½2. Trapnell CB, Narang PK, Li R et al. Increased plasma rifabutin levels with concomitant fluconazole therapy in HIV-infected patients. Ann Intern Med 1996;124:573ï¿½6. Havlir DV, Dube MP, Sattler FR et al. Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. N Engl J Med 1996;335:392ï¿½8. Narang PK, Trapnell CB, Schoenfelder JR et al. Fluconazole and enhanced effect of rifabutin prophylaxis. N Engl J Med 1994;330:1316ï¿½7. Frank MO, Graham MB, Wispelway B. Rifabutin and uveitis. N Engl J Med 1994;330:868. Shafran SD, Singer J, Zarowny DP et al. A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. N Engl J Med 1996;335:377ï¿½83.