Rifampin, Isoniazid, and Pyrazinamide (Systemic)
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VA CLASSIFICATION
Primary: AM500
Commonly used brand name(s): Rifater.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
†Not commercially available in Canada.
Category:
Antibacterial (antimycobacterial)—
Indications
General considerations
Tuberculosis is a highly infectious life-threatening bacterial disease with 8 million new cases and 3 million deaths reported worldwide each year to the World Health Organization (WHO) {164}. The vast majority of these cases are in developing countries; however, tuberculosis also has emerged as an important public health problem in the U.S. in recent years after the decline in number of cases observed between 1950 and 1980 {164}.
The resurgence of tuberculosis in the U.S. has been complicated by an increase in the proportion of patients with strains resistant to antituberculosis medications. Outbreaks of multidrug-resistant tuberculosis have been documented in hospitals and prisons {145} {151} {153} {160}. Drug-resistant tuberculosis, particularly that caused by strains resistant to isoniazid and rifampin, is much harder to treat and often is fatal {145} {153}. Among acquired immunodeficiency syndrome (AIDS) patients infected with tuberculosis bacilli resistant to both rifampin and isoniazid, a case-fatality rate of 91% has been reported {155}. Recent investigations of outbreaks of multidrug-resistant tuberculosis have found an extraordinarily high case-fatality rate, with the median time to mortality being reached between 4 and 16 weeks {167}. In almost all instances, these outbreaks have involved patients with severe immunosuppression by infection with the human immunodeficiency virus (HIV) {167}.
Acquired drug resistance develops during treatment for drug-sensitive tuberculosis with regimens that are poorly conceived or poorly complied with, allowing the emergence of naturally occurring drug-resistant mutations {165}. Resistant organisms from affected patients may subsequently infect other people who have not been infected with Mycobacterium tuberculosis previously, resulting in primary drug resistance {165}.
Resistance to antituberculosis agents can develop not only in the strain that caused the initial disease, but also as a result of reinfection with a new strain of M. tuberculosis that is drug-resistant {169}. Reinfection with a new multidrug-resistant M. tuberculosis strain can occur during therapy for the original infection or after completion of therapy {169}. Most recent data suggest that outcomes can be improved if patients promptly begin therapy with two or more drugs that have in vitro activity against the multidrug-resistant isolate {167}.
HIV infection is the strongest risk factor yet identified for the development of active tuberculosis disease in persons infected with tuberculosis {142} {143} {150} {154} {155} {160} {165} {169} {171} {173}. In addition, persons with HIV infection are at an increased risk of tuberculosis resulting either from newly acquired disease or from reactivation of latent infections {165}. Tuberculosis is a major clinical manifestation of immunodeficiency induced by HIV {174}. In hospital-based retrospective studies, high rates of tuberculosis have been found among patients with AIDS {174}. In communities where tuberculosis and HIV infection are common, the prevalence of HIV seropositivity among patients with tuberculosis is greatly increasing {174}.
WHO has estimated that 5.6 million people worldwide and 80,000 people in the U.S. are infected with both HIV and tuberculosis {164}. Persons dually infected with M. tuberculosis and HIV have a high risk of developing clinically active tuberculosis {174}. One study of HIV-positive drug users with positive tuberculin skin test results found a rate of the development of active tuberculosis to be 8 cases per 100 person-years (8% yearly) as compared with the 10% lifetime risk (1 to 3% risk within the first year after skin test conversion) in the general population {165}.
Persons who are known to be HIV-infected and who are contacts of patients with infectious tuberculosis should be carefully evaluated for evidence of tuberculosis {143} {149}. If there are no findings suggestive of current tuberculosis, preventive therapy with isoniazid should be given {149}. Because HIV-infected contacts are not managed in the same way as those who are not HIV-infected, HIV testing is recommended if there are known or suspected risk factors for their acquiring HIV infection {143} {149}.
According to investigators at the National Institute of Allergy and Infectious Diseases (NIAID), levels of HIV in the bloodstream increase 5- to 160-fold in HIV-infected persons who develop active tuberculosis {156}. Clinical and epidemiologic observations have demonstrated that HIV-infected individuals have an estimated 113-times higher risk and AIDS patients have a 170-times higher risk compared with uninfected persons {164}. Furthermore, the problem of drug resistance may worsen as the HIV epidemic spreads {145} {155}. Immunosuppressed patients with HIV infection who subsequently become infected with M. tuberculosis have an extraordinarily high risk of developing active tuberculosis within a short period of time {155}.
In addition to the convincing evidence that HIV infection increases the risk and worsens the course of tuberculosis, there is increasing clinical evidence that coinfection with M. tuberculosis accelerates progression of disease caused by HIV infection {177}. Understanding the interaction of these two pathogens is clinically important, given the high prevalence of patients coinfected with HIV and M. tuberculosis in both the U.S. and Africa; it is estimated that by the year 2000 about 500,000 deaths per year will occur in coinfected patients worldwide {177}.
Persons with a positive tuberculin skin test and HIV infection, and persons with a positive tuberculin skin test and at risk of acquiring HIV infection with unknown HIV status should be considered for tuberculosis preventive therapy regardless of age {149}. One study showed that isoniazid prophylaxis in HIV-infected, tuberculin-positive individuals not only decreased the incidence of tuberculosis disease, but also delayed the progression to AIDS and death {164}.
Twelve months of preventive therapy is recommended for adults and children with HIV infection and other conditions associated with immunosuppression {149}. Persons with HIV infection should receive at least 6 months of preventive therapy. The American Academy of Pediatrics recommends that children receive 9 months of therapy {149}.
Tuberculosis control programs should ensure that drug susceptibility tests are performed on all initial isolates of M. tuberculosis and that the results are reported promptly to the primary care provider and the local health department {141}. Tuberculosis control programs should monitor local drug resistance rates to assess the effectiveness of local tuberculosis control efforts and to determine the appropriateness of the currently recommended initial tuberculosis treatment regimen for the area {141}.
Relapse of rifampin-resistant tuberculosis has been reported in HIV-infected patients {157} {158}. Reinfection with new strains of M. tuberculosis has also been reported in these patients {157}. Rifampin-resistant tuberculosis is a serious threat because responses to therapy are more difficult to achieve and require long courses of treatment {157} {158}. Therefore, careful follow-up of HIV-infected patients with treated tuberculosis is essential {157} {158}.
Multidrug-resistant tuberculosis also has been transmitted to persons without HIV infection in health care facilities {169}. Together with the lack of effective agents for second-line treatment and methods of prophylaxis, the transmission of multidrug-resistant strains of M. tuberculosis may create a substantial reservoir of latently infected people and the potential for clinical multidrug-resistant tuberculosis for many years to come {169}.
Several studies have documented a high prevalence of extrapulmonary disease in HIV-infected patients with clinical tuberculosis disease, particularly in conjunction with pulmonary manifestations {175}. Cutaneous miliary tuberculosis, also known as tuberculosis cutis miliaris disseminata , was in the past a rare condition in adults, with only 24 cases reported in nearly a century {175}. However, since the first reported case of cutaneous miliary tuberculosis in 1990 in a patient with AIDS, five additional cases have been reported in HIV-infected patients {175}. Its appearance can be quite nondescript; therefore, a high level of suspicion must be maintained, particularly for patients with CD4+ cell counts of < 200 per cubic millimeter, in order to diagnose the condition and initiate therapy appropriately {175}.
Accepted
Tuberculosis (treatment)—Rifampin, isoniazid, and pyrazinamide combination is indicated in the initial phase of the short-course treatment of all forms of {137} tuberculosis {01} {06} {11} {12} {19}. During this phase, usually lasting 2 months, rifampin, isoniazid, and pyrazinamide combination should be administered on a daily, continuous basis {01} {138}. Additional medications are indicated if multidrug-resistant tuberculosis is suspected {136} {138}.
Pharmacology/Pharmacokinetics
Note: Preliminary data suggest that patients coinfected with human immunodeficiency virus (HIV) and mycobacteria (Mycobacterium tuberculosis or Mycobacterium avium ) have altered pharmacokinetic profiles for antimycobacterial agents {148}. In particular, malabsorption of these agents appears to occur frequently and could seriously affect the efficacy of treatment {148} {166}.
Physicochemical characteristics:
Molecular weight—
Rifampin: 822.96 {140}
Isoniazid: 137.14 {01}
Pyrazinamide: 123.11 {01}
Mechanism of action/Effect:
Rifampin, a semisynthetic broad-spectrum bactericidal antibiotic {19}, inhibits bacterial RNA synthesis by binding strongly to the beta subunit of DNA-dependent RNA polymerase, preventing attachment of the enzyme to DNA and thus blocking initiation of RNA transcription {01}.
Isoniazid (INH) is a synthetic, bactericidal antitubercular agent {19}, which is active against many mycobacteria, primarily those that are actively dividing. Its exact mechanism of action is not known, but it may relate to inhibition of mycolic acid synthesis and disruption of the cell wall in susceptible organisms {01} {41}.
Pyrazinamide may be bacteriostatic or bactericidal, depending on its concentration and the susceptibility of the organism. Its exact mechanism of action is not known. It is active in vitro at an acidic pH {01} {19} of 5.5 or less, similar to that found in early, active tubercular inflammatory lesions {01} {43} {44} {45}.
Absorption:
Rifampin is well absorbed from the gastrointestinal tract {01} {60}.
Isoniazid is readily absorbed following oral administration {01} {101}; however, it may undergo significant first-pass metabolism {107} {108}. Absorption and bioavailability of isoniazid are reduced when administered with food {108}.
Pyrazinamide is rapidly and almost completely absorbed from the gastrointestinal tract {01} {43} {47}.
Note: Pharmacokinetic studies in humans have demonstrated no interactions among rifampin, isoniazid, and pyrazinamide as a fixed combination; absorption, metabolism, and excretion do not appear to be altered {02}. However, a study showed decreased bioavailability of antituberculosis medications in a patient with acquired immunodeficiency syndrome (AIDS) {133}.
Distribution:
Rifampin diffuses well to most body tissues and fluids, including the cerebrospinal fluid (CSF), where concentrations are increased if the meninges are inflamed; concentrations in the liver, gallbladder, bile, and urine are higher than those found in the blood. Therapeutic concentrations are achieved in the saliva, reaching 20% of serum concentrations. Rifampin crosses the placenta, with fetal serum concentrations at birth found to be approximately 33% of the maternal serum concentration {61}; it penetrates into aqueous humor and is distributed into breast milk. Because it is lipid-soluble, rifampin may reach and kill susceptible intracellular, as well as extracellular, bacteria and Mycobacteria species {01}.
Vol D—1.6 L per kg.
Isoniazid is widely distributed to all fluids and tissues, including CSF, pleural and ascitic fluids, skin, sputum, saliva, lungs, and muscle. It crosses the placenta and is distributed into breast milk {41} {101} {108}.
Vol D—0.57 to 0.76 L per kg {129} {130}.
Pyrazinamide is widely distributed to most fluids and tissues, including liver, lungs, kidneys, and bile. Pyrazinamide has excellent penetration into CSF, ranging from 87 to 105% of the corresponding serum concentration {38} {39}.
Vol D—0.57 to 0.74 L per kg {47} {48} {49}.
Protein binding:
Rifampin—High to very high (89%) {61}.
Isoniazid—Very low (0 to 10%) {107} {108} {109}.
Pyrazinamide—Low (10 to 20%) {48} {49}.
Pyrazinoic acid—Low (approximately 31%) {49}.
Biotransformation:
Rifampin—Hepatic; rapidly deacetylated by auto-induced microsomal oxidative enzymes to the active metabolite (25- O-desacetylrifampin). Other identified metabolites include rifampin quinone, desacetyl rifampin quinone, and 3-formylrifampin {01} {61}.
Isoniazid—Hepatic; isoniazid is acetylated by N-acetyltransferase to N-acetylisoniazid; it is then biotransformed to isonicotinic acid and monoacetylhydrazine. Monoacetylhydrazine is associated with hepatotoxicity via formation of a reactive intermediate metabolite when N-hydroxylated by the cytochrome P450 mixed oxidase system {108}. The rate of acetylation is genetically determined. Approximately 50% of blacks and Caucasians are slow acetylators and the rest are rapid acetylators; the majority of Eskimos and Asians are rapid acetylators. The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of isoniazid and, thus, to an increase in toxic reactions {01}. Slow acetylators are characterized by a relative lack of hepatic N-acetyltransferase {101}.
Pyrazinamide—Hepatic; hydrolyzed by a microsomal deamidase to pyrazinoic acid, an active metabolite, and then hydroxylated by xanthine oxidase to 5-hydroxypyrazinoic acid {35} {43} {47} {48}.
Note: Pharmacokinetic studies in humans have demonstrated no interactions among rifampin, isoniazid, and pyrazinamide as a fixed combination; absorption, metabolism, and excretion of each medication does not appear to be altered {02}.
Half-life:
Rifampin:
Absorption half-life—
Approximately 0.6 hour {61}.
Elimination half-life—
Initially, 3 to 5 hours; with repeated administration, half-life decreases to 2 to 3 hours {61}.
Isoniazid:
Adults (including elderly patients) {107}—
Fast acetylators—0.5 to 1.6 hours.
Slow acetylators—2 to 5 hours.
Acute or chronic liver disease—May be prolonged (6.7 hours vs 3.2 hours in controls).
Children (1.5 to 15 years of age)—
2.3 to 4.9 hours {108}.
Neonates—
7.8 and 19.8 hours in two newborns who received isoniazid transplacentally. The long half-life may be due to the limited acetylation capacity of neonates {111}.
Pyrazinamide:
Distribution—
Approximately 1.6 hours {47}.
Elimination—
Normal renal function—Approximately 9.5 hours (12 hours for pyrazinoic acid) {47} {48}.
Chronic renal failure—Approximately 26 hours (22 hours for pyrazinoic acid) {48}.
Time to peak serum concentration
Rifampin—1.5 to 4 hours after oral administration; peak concentration may be decreased and delayed following administration with food {55}.
Isoniazid—1 to 2 hours {01}.
Pyrazinamide—1 to 2 hours {43} {47} {48}.
Pyrazinoic acid—4 to 5 hours {47} {48}.
Peak serum concentration
Rifampin {61}:
Adults: 7 to 9 micrograms per mL (mcg/mL) after a single 600-mg oral dose.
Children (6 to 58 months of age): Approximately 11 mcg/mL after a dose of 10 mg per kg of body weight (mg/kg).
Isoniazid:
3 to 7 mcg/mL (21.9 to 51 micromoles per L) after a single 300-mg oral dose {108}.
Pyrazinamide {47} {48}:
Approximately 19 mcg/mL after a single dose of 14 mg/kg.
Approximately 39 mcg/mL after a single dose of 27 mg/kg.
Pyrazinoic acid {47} {48}:
Approximately 3 mcg/mL after a single dose of 14 mg/kg.
Approximately 4.5 mcg/mL after a single dose of 27 mg/kg.
Elimination:
Rifampin—
Biliary/fecal; enterohepatic recirculation of rifampin, but not of its deacetylated active metabolite {60}; 60 to 65% of dose appears in feces {55}.
Renal; 6 to 15% excreted as unchanged drug and 15% excreted as active metabolite in urine; 7% excreted as inactive 3-formyl derivative {55}.
Rifampin does not accumulate in patients with impaired renal function {60}; its rate of excretion is increased during the first 6 to 10 days of therapy, probably because of auto-induction of hepatic microsomal oxidative enzymes; after high doses, excretion may be slower because of saturation of its biliary excretory mechanism {55}.
In dialysis—
Rifampin is not removed from the blood by either hemodialysis or peritoneal dialysis {55}.
Isoniazid—
Renal; approximately 75 to 95% excreted by kidneys within 24 hours, primarily as the inactive metabolites, N-acetylisoniazid and isonicotinic acid; of this amount, 93% of the isoniazid excreted in the urine may occur as the acetylated form in fast acetylators and 63% in slow acetylators, with the remainder, in both cases, occurring as the free or conjugated form {101}.
Biliary/fecal; small amounts are excreted in feces {101}.
In dialysis—
Significant amounts of isoniazid are removed from the blood by hemodialysis. A single 5-hour hemodialysis period removes up to 73% of the isoniazid in the blood {108}.
Peritoneal dialysis is of limited benefit {110}.
Pyrazinamide—
Renal; approximately 3% of unchanged pyrazinamide, 33% of pyrazinoic acid, and 36% of remaining identifiable metabolites excreted in urine within 72 hours {47}.
In dialysis—
A single 3- to 4-hour hemodialysis session reduces serum pyrazinamide concentrations by approximately 55% and pyrazinoic acid concentrations by 50 to 60% {48} {49}.
Note: Pharmacokinetic studies in humans have demonstrated no interactions among rifampin, isoniazid, and pyrazinamide as a fixed combination; absorption, metabolism, and excretion of each drug do not appear to be altered {02}.
Precautions to Consider
Cross-sensitivity and/or related problems
Patients hypersensitive to ethionamide, niacin (nicotinic acid), rifamycins (e.g., rifabutin), or other medications chemically related to rifampin, isoniazid, or pyrazinamide may be hypersensitive to this medication also.
Carcinogenicity/Tumorigenicity
Rifampin, isoniazid, and pyrazinamide—Increased frequency of chromosomal aberrations was observed in vitro in lymphocytes obtained from patients treated with combinations of rifampin, isoniazid, and pyrazinamide and with combinations of streptomycin, rifampin, isoniazid, and pyrazinamide {01}.
Rifampin—Studies in a strain of female mice known to be particularly susceptible to the spontaneous development of hepatomas have shown that rifampin, given in doses of 2 to 10 times the maximum human dose for 1 year, causes a significant increase in the development of hepatomas. However, studies in male mice of the same strain, in other strains of male and female mice, and in rats have not shown that rifampin is tumorigenic {01} {55}.
Isoniazid—Isoniazid has been shown to cause pulmonary tumors in a number of strains of mice {01}. However, isoniazid has not been shown to be carcinogenic or tumorigenic in humans {97} {101}.
Pyrazinamide—Pyrazinamide was administered in the diet of rats and mice. The estimated daily dose was 2 grams per kg (grams/kg), or 40 times the maximum human dose, for the mice, and 0.5 gram/kg, or 10 times the maximum human dose, for the rats. Pyrazinamide was not carcinogenic in rats or male mice. No conclusion was possible for female mice due to insufficient numbers of surviving control mice {01} {35}.
Mutagenicity
Pyrazinamide—Pyrazinamide was not mutagenic in the Ames bacterial test, but it did induce chromosomal aberrations in human lymphocyte cell cultures {01} {35}.
Pregnancy/Reproduction
Note: Pregnant women with tuberculosis should be managed in concert with an expert in the management of tuberculosis {176}. Women who have only pulmonary tuberculosis are not likely to infect the fetus until after delivery, and congenital tuberculosis is extremely rare {176}. In utero infections with tubercle bacilli, however, can occur after maternal bacillemia occurs at different stages in the course of tuberculosis {176}. Miliary tuberculosis can seed the placenta and thereby gain access to the fetal circulation {176}. In women with tuberculous endometritis, transmission of infection to the fetus can result from fetal aspiration of bacilli at the time of delivery {176}. A third mode of transmission is through ingestion of infected amniotic fluid in utero {176}.
If active disease is diagnosed during pregnancy, a 9-month regimen of isoniazid and rifampin, supplemented by an initial course of ethambutol if drug resistance is suspected, is recommended {176}. Pyrazinamide usually is not given because of inadequate data regarding teratogenesis {176}. Hence, a 9-month course of therapy is necessary for drug-susceptible disease {176}. When isoniazid resistance is a possibility, isoniazid, ethambutol, and rifampin are recommended initially {176}. One of these medications can be discontinued after 1 or 2 months, depending on results of susceptibility tests {176}. If rifampin or isoniazid is discontinued, treatment is continued for a total of 18 months; if ethambutol is discontinued, treatment is continued for a total of 9 months {176}. Prompt initiation of chemotherapy is mandatory to protect both the mother and fetus {176}. If isoniazid or rifampin resistance is documented, an expert in the management of tuberculosis should be consulted {176}.
Asymptomatic pregnant women with positive tuberculin skin tests and normal chest radiographs should receive preventive therapy with isoniazid for 9 months if they are HIV seropositive or have recently been in contact with an infectious person {176}. For these individuals, preventive therapy should begin after the first trimester {176}. In other circumstances in which none of these risk factors is present, although no harmful effects of isoniazid to the fetus have been observed, preventive therapy can be delayed until after delivery {176}.
For all pregnant women receiving isoniazid, pyridoxine should be prescribed {176}. Isoniazid, ethambutol, and rifampin appear to be relatively safe for the fetus {176}. The benefit of ethambutol and rifampin for therapy of active disease in the mother outweighs the risk to the infant {176}. Streptomycin and pyrazinamide should not be used unless they are essential to the control of the disease {176}.
Pregnancy—
Rifampin
Rifampin crosses the placenta {19}. It has rarely caused postnatal hemorrhages in the mother and infant when administered during the last few weeks of pregnancy; vitamin K may be indicated. Neonates should be carefully observed for evidence of adverse effects {19}.
Imperfect osteogenesis and embryotoxicity were reported in rabbits given up to 20 times the usual daily human dose. Studies in rodents have shown that rifampin given in doses of 150 to 250 mg per kg of body weight (mg/kg) a day causes congenital malformations, primarily cleft palate and spina bifida {01}.
FDA Pregnancy Category C {01}.
Isoniazid
Isoniazid crosses the placenta {19}, resulting in fetal serum concentrations that may exceed maternal serum concentrations. Problems in humans have not been documented {51}.
Studies in rats and rabbits have shown that isoniazid may be embryocidal. However, isoniazid has not been shown to be teratogenic in mice, rats, or rabbits {01} {101}.
FDA Pregnancy Category C {01}.
Pyrazinamide
Adequate and well-controlled studies in humans have not been done; the risk of teratogenicity has not been determined {36}.
Animal reproduction studies have not been conducted with pyrazinamide {01} {35}.
FDA Pregnancy Category C {01}.
Breast-feeding
Rifampin:
Rifampin is distributed into breast milk. {19} Problems in humans have not been documented {01} {62}.
Isoniazid:
Isoniazid is distributed into breast milk {01} {19}. An estimated 0.75 to 2.3% of the daily adult dose could be ingested by the infant {108}. Problems in nursing newborns have not been documented and breast-feeding should not be discouraged. However, because isoniazid concentrations are so low in breast milk, breast-feeding cannot be relied upon for adequate tuberculosis prophylaxis or therapy for nursing infants {51}.
Pyrazinamide:
Pyrazinamide is distributed into breast milk in small amounts {01} {19} {37}.
Pediatrics
Note: If an infant is suspected of having congenital tuberculosis, a Mantoux tuberculin skin test, chest radiograph, lumbar puncture, and appropriate cultures should be performed promptly {176}. Regardless of the skin test results, treatment of the infant should be initiated promptly with isoniazid, rifampin, pyrazinamide, and streptomycin or kanamycin {176}. In addition, the mother should be evaluated for the presence of pulmonary or extrapulmonary (including uterine) tuberculosis {176}. If the physical examination or chest radiograph support the diagnosis of tuberculosis, the patient should be treated with the same regimen as that used for tuberculous meningitis {176}. The drug susceptibilities of the organism recovered from the mother and/or infant should be determined {176}.
Possible isoniazid resistance should always be considered, particularly in children from population groups in which drug resistance is high, especially in foreign-born children from countries with a high prevalence of drug-resistant tuberculosis {176}. For contacts who are likely to have been infected by an index case with isoniazid-resistant but rifampin-susceptible organisms, and in whom the consequences of the infection are likely to be severe (e.g., children up to 4 years of age), rifampin (10 mg per kg of body weight, maximum 600 mg, given daily in a single dose) should be given in addition to isoniazid (10 mg per kg, maximum 300 mg, given daily in a single dose) until susceptibility test results for the isolate from the index case are available {176}. If the index case is known or proven to be excreting organisms resistant to isoniazid, then isoniazid should be discontinued and rifampin given for a total of 9 months {176}. Isoniazid alone should be given if no proof of exposure to isoniazid-resistant organisms is found {176}. Optimal therapy for children with tuberculosis infection caused by organisms resistant to isoniazid and rifampin is unknown {176}. In deciding on therapy in this situation, consultation with an expert is advised {176}.
Adjuvant treatment with corticosteroids in treating tuberculosis is controversial {176}. Corticosteroids have been used for therapy in children with tuberculous meningitis to reduce vasculitis, inflammation, and, as a result, intracranial pressure {176}. Data indicate that dexamethasone may lower mortality rates and lessen long-term neurologic impairment {176}. The administration of corticosteroids should be considered in all children with tuberculous meningitis, and also may be considered in children with pleural and pericardial effusions (to hasten reabsorption of fluid), severe miliary disease (to mitigate alveolocapillary block), and endobronchial disease (to relieve obstruction and atelectasis) {176}. Corticosteroids should be given only when accompanied by appropriate antituberculosis therapy {176}. Consultation with an expert in the treatment of tuberculosis should be obtained when corticosteroid therapy is considered {176}.
Rifampin, isoniazid, and pyrazinamide—The ratio of the individual medications in rifampin, isoniazid, and pyrazinamide combination may not be appropriate in children or adolescents up to the age of 15 (e.g., higher mg-per-kg doses of isoniazid usually are given in children than in adults). Safety and effectiveness of this combination preparation in children or adolescents up to 15 years of age have not been established {01}.
Rifampin—Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of rifampin in children {60}.
Isoniazid—Studies performed in children have not demonstrated pediatrics-specific problems that would limit the usefulness of isoniazid in children. However, newborn infants may have a limited acetylation capacity, prolonging the elimination half-life of isoniazid {126}.
Children do not require routine hepatic function determinations unless they have pre-existing hepatic disease {125} {127}.
Pyridoxine supplementation is not usually required in children if dietary intake is adequate {125}.
Pyrazinamide—Appropriate studies on the relationship of age to the effects of pyrazinamide have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date {40} {41}.
Geriatrics
Rifampin—Appropriate studies on the relationship of age to the effects of rifampin have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date.
Isoniazid—Patients over 50 years of age are more likely to develop hepatitis while receiving isoniazid than are patients in younger age groups {01} {100}.
Pyrazinamide—Appropriate studies on the relationship of age to the effects of pyrazinamide have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date {35}.
Pharmacogenetics
Isoniazid—Patients can be divided into two groups: slow and rapid acetylators of isoniazid. Approximately 50% of blacks and Caucasians are slow acetylators; the majority of Eskimos and Asians are rapid acetylators. The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of isoniazid and, thus, an increase in toxic reactions {01}. Slow acetylators are characterized by a relative lack of hepatic N-acetyltransferase {101}. Patients who are slow acetylators may be more prone to develop adverse effects, especially peripheral neuritis, and may require lower-than-usual doses. Rapid acetylators do not generally require higher doses, nor is isoniazid less effective in these patients {01}.
Dental
Rifampin—The leukopenic and thrombocytopenic effects of rifampin may result in an increased incidence of certain microbial infections, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in the use of regular toothbrushes, dental floss, and toothpicks. Rifampin may cause a hypersensitivity reaction of sore mouth or tongue {60}.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Acetaminophen{98}{119}{120} (concurrent use of acetaminophen with isoniazid may increase the potential for hepatotoxicity and, possibly, nephrotoxicity; isoniazid is thought to induce {119} cytochrome P450, resulting in a greater proportion of acetaminophen being converted to toxic metabolite)
» Alcohol (concurrent daily use of alcohol may result in increased incidence of isoniazid- and rifampin-induced hepatotoxicity and increased metabolism of isoniazid and rifampin; dosage adjustments of isoniazid and rifampin may be necessary; patients should be monitored closely for signs of hepatotoxicity and should be advised to restrict intake of alcoholic beverages {01} {101})
» Alfentanil (chronic preoperative or perioperative use of isoniazid, a hepatic enzyme inhibitor, may decrease the plasma clearance and prolong the duration of action of alfentanil {101})
Allopurinol or
Colchicine or
Probenecid or
Sulfinpyrazone (pyrazinamide may increase serum uric acid concentrations and decrease the efficacy of gout therapy; dosage adjustments of these medications may be necessary to control hyperuricemia and gout when antigout medications are used concurrently with pyrazinamide; probenecid may compete with rifampin for hepatic uptake when used concurrently, resulting in increased and more prolonged rifampin serum concentrations and/or toxicity; however, the effect on rifampin serum concentrations is inconsistent, and concurrent use of probenecid to increase rifampin serum concentrations is not recommended {61})
» Aminophylline or
» Oxtriphylline or
» Theophylline (rifampin may increase metabolism of theophylline, oxtriphylline, and aminophylline by induction of hepatic microsomal enzymes, resulting in increased theophylline clearance {01} {65} {79} {80}; concurrent use with isoniazid may reduce the metabolism of theophylline, increasing theophylline plasma concentrations {117})
Anesthetics, hydrocarbon inhalation, except isoflurane (long-term use of hepatic enzyme–inducing agents, such as rifampin, prior to anesthesia, except isoflurane, may increase anesthetic metabolism, leading to increased risk of hepatotoxicity {72})
Antacids, especially aluminum-containing (antacids may delay and decrease absorption and serum concentrations of orally administered isoniazid; concurrent use should be avoided, or patients should be advised to take oral isoniazid at least 1 hour before aluminum-containing antacids {103})
» Anticoagulants, coumarin- or indandione-derivative{01}{72}{73} (concurrent use with rifampin may enhance the metabolism of these anticoagulants by induction of hepatic microsomal enzymes, resulting in considerable decrease in the activity and effectiveness of the anticoagulants; prothrombin time determinations may be required as frequently as daily; dosage adjustments of anticoagulants may be required before and after rifampin therapy; concurrent use with isoniazid may result in increased anticoagulant effect because of the inhibition of enzyme metabolism of anticoagulants)
» Antidiabetic agents, oral{01}{72}{81} (concurrent use with rifampin may enhance the metabolism of tolbutamide, chlorpropamide, and glyburide by induction of hepatic microsomal enzymes, resulting in lower serum sulfonylurea concentrations; although not documented, other oral antidiabetic agents may also interact with rifampin; dosage adjustment may be required)
» Azole antifungals{01}{67}{89}{90}{91}{93} (concurrent use may increase the metabolism of the azole antifungals, lowering their plasma concentrations; depending on the clinical situation, the dose of an azole antifungal may need to be increased during concurrent use with rifampin)
Barbiturates{72} (concurrent use with rifampin may enhance the metabolism of hexobarbital by induction of hepatic microsomal enzymes, resulting in lower serum concentrations; there are conflicting data on rifampin's effect on phenobarbital; dosage adjustment may be required)
Benzodiazepines (isoniazid may decrease the hepatic metabolism of benzodiazepines, such as diazepam, chlordiazepoxide, flurazepam, and prazepam, that are metabolized by phase I reactions [ N-demethylation and hydroxylation]; it may also impair the oxidation of triazolam, by increasing plasma benzodiazepine concentrations; isoniazid may decrease first-pass metabolism and elimination of midazolam in the liver, probably by competitive inhibition at the cytochrome P450 binding sites, increasing steady-state plasma concentrations of midazolam {103} {114}; concurrent use with rifampin may enhance the elimination of diazepam, resulting in decreased plasma concentrations; whether this effect applies to other benzodiazepines has not been determined; dosage adjustment may be necessary {01} {85})
Beta-adrenergic blocking agents, systemic{01}{65} (concurrent use of metoprolol or propranolol with rifampin has resulted in reduced plasma concentrations of these two beta-adrenergic blocking agents due to enhanced metabolism of hepatic microsomal enzymes by rifampin; although not documented, other beta-adrenergic blocking agents may also interact with rifampin)
Bone marrow depressants (see Appendix II ) (concurrent use of bone marrow depressants with rifampin may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, close observation for myelotoxic effects should be considered)
» Carbamazepine (concurrent use with isoniazid increases serum carbamazepine levels and toxicity, probably through inhibition of carbamazepine metabolism {104} {105}; also, carbamazepine may induce microsomal metabolism of isoniazid, increasing formation of an INH-reactive intermediate metabolite, which may lead to hepatotoxicity {114})
Cheese, such as Swiss or Cheshire, or
Fish, such as tuna, skipjack, or Sardinella (concurrent ingestion with isoniazid may result in redness or itching of the skin, hot feeling, rapid or pounding heartbeat, sweating, chills or clammy feeling, headache, or lightheadedness; this is thought to be due to the inhibition of plasma monoamine oxidase and diamine oxidase by isoniazid, interfering with the metabolism of histamine and tyramine found in fish and cheese {01} {112} {113})
» Chloramphenicol{68}{69} (concurrent use with rifampin may enhance the metabolism of chloramphenicol by induction of hepatic microsomal enzymes, resulting in significantly lower serum chloramphenicol concentrations; dosage adjustment may be necessary)
Clofazimine{61} (concurrent use with rifampin has resulted in reduced absorption of rifampin, delaying its time to peak concentration and increasing its half-life)
Clofibrate{01}{86} (concurrent use with rifampin may enhance the metabolism of clofibrate by induction of hepatic microsomal enzymes, resulting in significantly lower serum clofibrate concentrations)
» Contraceptives, estrogen-containing, oral{01}{55} (concurrent use with rifampin may decrease the effectiveness of estrogen-containing oral contraceptives because of stimulation of estrogen metabolism or reduction in enterohepatic circulation of estrogens, resulting in menstrual irregularities, intermenstrual bleeding, and unplanned pregnancies; patients should be advised to use an additional method of contraception throughout the whole cycle while taking rifampin and estrogen-containing oral contraceptives concurrently)
» Corticosteroids, glucocorticoid and mineralocorticoid (concurrent use with rifampin may enhance the metabolism of corticosteroids by induction of hepatic microsomal enzymes, resulting in a considerable decrease in corticosteroid plasma concentrations; dosage adjustment may be required; rifampin has also counteracted endogenous cortisol and produced acute adrenal insufficiency in patients with Addison's disease {61} {72} {75}; concurrent use of prednisolone, and other related corticosteroids, with isoniazid may increase hepatic metabolism and/or excretion of isoniazid, leading to decreased plasma concentrations and effectiveness of isoniazid, especially in patients who are rapid acetylators; isoniazid dosage adjustments may be required {103})
Cycloserine (concurrent use may result in increased incidence of central nervous system [CNS] effects such as dizziness or drowsiness; dosage adjustments may be necessary and patients should be monitored closely for signs of CNS toxicity {103})
Cyclosporine{52}{59}{65}{92} (concurrent use with pyrazinamide may decrease the serum concentration of cyclosporine, possibly leading to inadequate immunosuppression; cyclosporine serum concentrations should be monitored; rifampin may enhance metabolism of cyclosporine by induction of hepatic microsomal enzymes and intestinal cytochrome P450 enzymes; dosage adjustment may be required)
Dapsone{61} (concurrent use with rifampin may decrease the effect of dapsone because of increased metabolism resulting from stimulation of hepatic microsomal enzyme activity; dapsone concentrations may be decreased by half; dapsone dosage adjustments are not required during concurrent therapy with rifampin for leprosy)
» Digitalis glycosides{01}{65}{70}{71} (concurrent use with rifampin may enhance the metabolism of digoxin or digitoxin by induction of hepatic microsomal enzymes, resulting in significantly lower serum digoxin or digitoxin concentrations; dosage adjustment may be necessary)
» Disopyramide or{01}{84}
» Mexiletine or{01}{82}
Propafenone or{88}
» Quinidine or{01}{72}{77}{78}
» Tocainide{01}{83} (concurrent use with rifampin may enhance the metabolism of these antiarrhythmics by induction of hepatic microsomal enzymes, resulting in significantly lower serum antiarrhythmic concentrations; serum antiarrhythmic concentrations should be monitored and dosage adjustment may be necessary)
» Disulfiram (concurrent use in alcoholics may result in increased incidence of CNS effects such as dizziness, incoordination, irritability, or insomnia; reduced dosage or discontinuation of disulfiram may be necessary {103})
Enflurane (isoniazid may increase formation of the potentially nephrotoxic inorganic fluoride metabolite when used concurrently with enflurane {103})
» Estramustine or
» Estrogens{74} (concurrent use of estramustine or estrogens with rifampin may result in significantly reduced estrogenic effect because of stimulation of estrogen metabolism or reduction in enterohepatic circulation of estrogens)
» Hepatotoxic medications, other (see Appendix II ) (concurrent use of rifampin and isoniazid and other hepatotoxic medications may increase the potential for hepatotoxicity and should be avoided)
» Human immunodeficiency virus (HIV) protease inhibitors (rifampin accelerates the metabolism of protease inhibitors, such as indinavir, nelfinavir, ritonavir, and saquinavir through induction of hepatic P450 cytochrome oxidases, resulting in subtherapeutic levels of the protease inhibitors; in addition, protease inhibitors retard the metabolism of rifampin, resulting in increased serum levels of rifampin and the likelihood of increased toxicity; concurrent use of HIV protease inhibitors with rifampin is not recommended {144} {152} {161} {162} {163})
» Ketoconazole (concurrent use of ketoconazole with isoniazid has been reported to decrease serum concentrations of ketoconazole; isoniazid should be used with caution when given concurrently with ketoconazole {01} {67})
» Methadone (concurrent use with rifampin may decrease the effects of methadone because of stimulation of hepatic microsomal enzyme activity and/or impaired absorption, resulting in symptoms of methadone withdrawal if the patient is dependent on methadone; dosage adjustments may be necessary during and after rifampin therapy {72})
Neurotoxic medications, other (see Appendix II ) (concurrent use of other neurotoxic medications with isoniazid may produce additive neurotoxicity)
» Phenytoin (concurrent use with isoniazid inhibits the metabolism of phenytoin, resulting in increased phenytoin serum concentrations and toxicity; phenytoin dosage adjustments may be necessary during and after isoniazid therapy, especially in slow acetylators of isoniazid {101} {124}; concurrent use with rifampin may stimulate the hepatic metabolism of phenytoin, increasing its elimination and thus counteracting its anticonvulsant effects; careful monitoring of serum hydantoin concentrations and dosage adjustments may be necessary before and after rifampin therapy {01} {66} {76})
Pyridoxine (isoniazid may cause peripheral neuritis by acting as a pyridoxine antagonist or increasing renal excretion of pyridoxine; requirements for pyridoxine may be increased in patients receiving isoniazid concurrently {01} {101})
Trimethoprim{87} (concurrent use with rifampin may significantly increase the elimination and shorten the elimination half-life of trimethoprim)
» Verapamil, oral{01}{65} (rifampin has been found to accelerate the metabolism of oral verapamil, resulting in a significant decrease in serum verapamil concentration and reversing its cardiovascular effects; concurrent use of intravenous verapamil with rifampin was found to have only minor effects on verapamil's clearance and no significant effect on cardiovascular function)
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With diagnostic test results
Coomb's (antiglobulin) tests, direct{131} (rarely, may become positive during rifampin therapy)
Dexamethasone suppression test{58} (rifampin may prevent the inhibitory action of a standard dexamethasone dose administered for the overnight suppression test, rendering the test abnormal; it is recommended that rifampin therapy be discontinued 15 days before the dexamethasone suppression test is administered)
Folate determinations, serum and
Vitamin B 12 determinations, serum{54} (therapeutic concentrations of rifampin may interfere with standard microbiological assays for serum folate and vitamin B 12; alternative methods must be considered when determining serum folate and vitamin B 12 concentrations in patients taking rifampin)
Glucose, urine{96} (isoniazid may cause hyperglycemia with a secondary glycosuria, giving a positive response to copper sulfate tests; glucose enzymatic tests are not affected)
Ketone determinations, urine{48}{53} (may react with sodium nitroprusside tests, such as Acetest or Chemstrip K; both pyrazinamide and pyrazinoic acid produce an interfering pink-brown color reaction with nitroprusside)
Sulfobromophthalein (BSP) uptake and excretion{01} (hepatic uptake and excretion of BSP in liver function tests may be delayed by rifampin, resulting in BSP retention; the BSP test should be performed prior to the daily dose of rifampin to avoid false-positive test results)
Urinalyses based on spectrometry or color reaction{131} (rifampin may interfere with urinalyses that are based on spectrometry or color reaction, due to rifampin's reddish-orange to reddish-brown discoloration of urine)
With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT]) (values may be increased {35} {60})
Bilirubin, serum and{100}{106}
Blood urea nitrogen (BUN) and
Uric acid, serum (concentration may be increased {35} {60})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problems exist
» Alcoholism, active or in remission{55}{100} (increased risk of hepatitis with daily consumption of alcohol)
Gout, history of{128} (pyrazinamide can increase serum uric acid concentrations and precipitate an acute attack of gout)
» Hepatic function impairment, severe{35}{94}{99}{101} (rifampin, isoniazid, and pyrazinamide are metabolized in the liver and may also be hepatotoxic)
» Hypersensitivity to isoniazid, ethionamide, pyrazinamide, niacin (nicotinic acid), or other chemically related medications
Hypersensitivity to rifampin and rifabutin
Renal failure, severe{01} (there may be an increased risk of isoniazid toxicity in patients who have severe renal failure [creatinine clearance < 10 mL/min or 0.17 mL/sec])
Seizure disorders{100} (isoniazid may be neurotoxic and cause seizures)
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
» Hepatic function determinations{09}{35}{41}{60}{99} (ALT [SGPT], AST [SGOT], alkaline phosphatase, and serum bilirubin determinations may be indicated prior to and monthly or more frequently during treatment; however, elevated serum enzyme values may not be predictive of clinical hepatitis and may return to normal despite continued treatment; patients with impaired hepatic function should not receive rifampin, isoniazid, and pyrazinamide combination unless it is crucial to therapy)
» Ophthalmologic examinations{01} (symptoms of optic neuritis may occur in either adults or children during treatment due to adverse effects of isoniazid; ophthalmologic examinations may be required immediately and periodically thereafter; ophthalmologic examinations are not recommended in asymptomatic patients)
Uric acid concentrations, serum{35} (may be required during treatment, since elevated serum uric acid concentrations frequently occur due to pyrazinamide, possibly resulting in precipitation of acute gout)
Side/Adverse Effects
Note: Isoniazid has been reported to cause severe, and sometimes fatal, hepatitis {04} {20}, which is more prevalent in patients over 50 years of age. If signs and symptoms of hepatotoxicity occur, rifampin, isoniazid, and pyrazinamide combination should be discontinued promptly {99}. The incidence of clinical hepatitis in young healthy adults is 0.3%, but can increase to 2.6% for patients who drink alcohol daily, have chronic liver disease, or are elderly {106}.
Pyridoxine deficiency is sometimes observed in adults receiving high doses of isoniazid and probably results from isoniazid's competition with pyridoxal phosphate for the enzyme apotryptophanase {01}.
Peripheral neuritis due to isoniazid usually can be prevented by administration of pyridoxine (10 to 25 mg per day). Pyridoxine is recommended for patients at risk of neuritis, including patients over 65 years of age, pregnant women, patients with diabetes mellitus, chronic renal failure, alcoholism, or malnutrition, and patients taking anticonvulsant medications {106}.
Intermittent use of rifampin may increase the chance of a patient developing the “flu-like” syndrome, as well as acute hemolysis or renal failure. These reactions are thought to be immunologically mediated and intermittent use should be limited to those conditions, such as leprosy, in which its safety and efficacy have been established {56} {57}.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Arthralgia (pain in the large and small joints)—related to hyperuricemia, usually mild and self-limiting{07}{43}{44}{45}{50}
hepatitis {01}(dark urine; yellow eyes or skin)
hepatitis prodromal symptoms {01}(loss of appetite; nausea and vomiting; unusual tiredness or weakness)
peripheral neuritis {18}{100}(clumsiness or unsteadiness; numbness, tingling, burning, or pain in hands and feet)
Incidence less frequent
“Flu-like” syndrome (chills; difficulty in breathing; dizziness; fever; headache; muscle and bone pain; shivering{60})
hypersensitivity {05}{46}(itching; redness; skin rash)
Incidence rare
Blood dyscrasias (sore throat; unusual bleeding or bruising{41}{107})
interstitial nephritis (bloody or cloudy urine; greatly decreased frequency of urination or amount of urine{01})
neurotoxicity (seizures; mental depression; mood or other mental changes{01})
optic neuritis (blurred vision or loss of vision, with or without eye pain{100})
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Gastrointestinal disturbances (diarrhea; nausea and vomiting; stomach pain{41}{60}{100})
Incidence less frequent
Fungal overgrowth (sore mouth or tongue{01})
Those not indicating need for medical attention
Incidence more frequent
Reddish-orange to reddish-brown discoloration of urine, feces, saliva, sputum, sweat, and tears{01}{60}
Note: Tears discolored by rifampin may also discolor soft contact lenses {01}.
Overdose
For specific information on the agents used in the management of rifampin, isoniazid, and pyrazinamide overdose, see
• Pyridoxine (Systemic) monograph;
• Diazepam in Benzodiazepines (Systemic) monograph; and/or
• Thiopental in Barbiturates (Systemic) monograph.
However, there is no experience with rifampin, isoniazid, and pyrazinamide combination overdose in humans {01}.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
The information below applies to rifampin and/or isoniazid overdose only {01} {63} {64} {121} {122} {123}. Experience with pyrazinamide overdose is limited {01}.
Clinical effects of rifampin and/or isoniazid overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic effects
Gastrointestinal disturbances (nausea and vomiting)
mental obtundation (mental changes)
metabolic acidosis
neurotoxicity (coma; disorientation; dizziness; hyperreflexia; lethargy; seizures; slurred speech)
periorbital or facial edema (swelling around the eyes or the whole face)
pruritus, generalized (itching over the whole body)
Redman syndrome (red-orange discoloration of skin, mucous membranes, and sclera)
{01}{63}{64}{121}{122}{123}
Note: Patients may be asymptomatic for 30 minutes to 2 hours after an acute overdose. Early symptoms include nausea and vomiting, dizziness, slurred speech, lethargy, disorientation, and hyperreflexia. Seizures usually occur within 1 to 3 hours after ingestion, and are often repetitive and refractory to treatment with usual anticonvulsants. Lactic acid accumulation produces an anion-gap metabolic acidosis within a few hours, which is often severe and refractory to treatment with sodium bicarbonate. Hyperglycemia, glycosuria, and ketonuria have also been reported {121} {122} {123}.
Treatment of overdose
To decrease absorption:
Because seizures may occur soon after ingestion, induction of emesis with ipecac is not recommended. Gastric lavage may be performed within 2 to 3 hours of ingestion, and activated charcoal and a cathartic may be administered if the patient's seizures are controlled and the airway protected {121} {122} {123}.
Specific treatment:
Administering intravenous pyridoxine in a gram-for-gram dose, equivalent to the amount of isoniazid ingested; dose should be administered as a 5 or 10% solution in water for injection over 30 to 60 minutes. If the amount of isoniazid ingested is unknown, administering 5-gram doses of pyridoxine every 5 to 30 minutes until seizures stop or consciousness is regained {121} {122} {123}.
Controlling seizures with diazepam, which acts synergistically with pyridoxine. Phenytoin should be used with caution, if at all, since isoniazid inhibits phenytoin metabolism. Thiopental has been effective in treating refractory seizures {121} {122} {123}.
Carefully administering sodium bicarbonate if pyridoxine and diazepam do not control seizure activity. Use caution against overcorrection and watch for hypokalemia or hyperkalemia {121} {122} {123}.
Supportive care:
Supportive measures such as establishing intravenous lines, hydration, correction of electrolyte imbalance, oxygenation, and support of ventilatory function are essential for maintaining the vital functions of the patient. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation {121} {122} {123}.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Rifampin, Isoniazid, and Pyrazinamide (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Hypersensitivity to rifampin, isoniazid, pyrazinamide, ethionamide, niacin (nicotinic acid), rifabutin, or other chemically related medications
Pregnancy—Isoniazid and rifampin cross the placenta
Breast-feeding—Isoniazid, pyrazinamide, and rifampin are distributed into breast milk
Use in children—Use of the fixed-dose combination is not recommended in pediatric patients up to 15 years of age
Use in the elderly—Patients 50 years of age and older have the highest incidence of hepatitis with use of isoniazid
Other medications, especially daily alcohol consumption, alfentanil, aminophylline, coumarin- or indandione-derivative anticoagulants, oral antidiabetic agents, azole antifungals, carbamazepine, chloramphenicol, oral estrogen-containing contraceptives, corticosteroids, digitalis glycosides, disopyramide, disulfiram, estramustine, estrogens, other hepatotoxic medications, HIV protease inhibitors, ketoconazole, methadone, mexiletine, oxtriphylline, phenytoin, quinidine, theophylline, tocainide, or oral verapamil
Other medical problems, especially alcoholism, active or in remission, or hepatic function impairment
Proper use of this medication
Taking this medication with food or antacids, but not within 1 hour of aluminum-containing antacids, if gastrointestinal irritation occurs
» Compliance with full course of therapy, which may take months or years
» Taking pyridoxine concurrently to prevent or minimize symptoms of peripheral neuritis
» Proper dosing
Taking as soon as possible; not taking if almost time for next dose; not doubling doses; intermittent dosing may result in more frequent and/or severe side effects
» Proper storage
Precautions while using this medication
» Regular visits to physician to check progress, as well as ophthalmologic examinations if signs of optic neuritis occur
Checking with physician if no improvement within 2 to 3 weeks
» Using an alternate method of contraception if taking estrogen-containing oral contraceptives concurrently
» Avoiding alcoholic beverages while taking this medication
» Checking with physician if vascular reactions occur following concurrent ingestion of cheese or fish with isoniazid-containing medication
» Medication causes urine, feces, saliva, sputum, sweat, and tears to turn reddish-orange to reddish-brown and may also permanently discolor soft contact lenses; avoiding the wearing of soft contact lenses
» Need to report to physician promptly prodromal signs of hepatitis or peripheral neuritis
Using caution in use of regular toothbrushes, dental floss, and toothpicks; deferring dental work until blood counts have returned to normal; checking with physician or dentist concerning proper oral hygiene
Possible interference with diagnostic tests
» Diabetics: May interfere with urine ketone determinations
Side/adverse effects
Hepatitis caused by isoniazid is more likely to occur in patients 50 years of age and older
Reddish-orange to reddish-brown discoloration of urine, stools, saliva, sputum, sweat, and tears may be alarming to patient, although medically insignificant; however, tears discolored by rifampin may also discolor soft contact lenses
Signs of potential side effects, especially arthralgia, hepatitis, hepatitis prodromal symptoms, peripheral neuritis, “flu-like” syndrome, hypersensitivity, blood dyscrasias, interstitial nephritis, neurotoxicity, and optic neuritis
General Dosing Information
Rifampin, isoniazid, and pyrazinamide combination is indicated in the initial phase of the short-course treatment of tuberculosis. During this phase, which should last 2 months, rifampin, isoniazid, and pyrazinamide combination should be administered on a daily, continuous basis {01} {06} {08} {10} {11}.
Following the initial phase of treatment with rifampin, isoniazid, and pyrazinamide combination, treatment should be continued with rifampin and isoniazid for at least 4 months. Treatment should be continued for a longer period of time if the patient is still sputum- or culture-positive, if resistant organisms are present, or if the patient is human immunodeficiency virus (HIV)–positive {01} {06} {10} {11}.
In the treatment of tuberculosis, the small number of resistant cells present within large populations of susceptible cells can rapidly become the predominant type. Since resistance can emerge rapidly, susceptibility tests should be performed in the event of persistent positive cultures during the course of treatment. Bacteriologic smears and cultures should be obtained before the start of therapy {138}, and they should be repeated throughout therapy to monitor response to the treatment. If test results show resistance to rifampin, isoniazid, or pyrazinamide and the patient is not responding to therapy, the drug regimen should be modified {01}.
The duration of treatment with an antituberculosis regimen is at least 6 months, and treatment may be continued for 2 years {118} {149}. Uncomplicated pulmonary tuberculosis is often successfully treated within 6 to 12 months. Several different treatment regimens are currently recommended {51}.
The duration of antituberculosis therapy is based on the patient's clinical and radiographic responses, smear and culture results, and susceptibility studies of Mycobacterium tuberculosis isolates from the patient or the suspect source case {176}. With directly observed therapy (DOT), clinical evaluation is an integral component of each visit for administration of medication {176}. Careful monitoring of the clinical and bacteriologic responses to therapy on a monthly basis in sputum-positive patients is important {176}.
If therapy is interrupted, the treatment schedule should be extended to a later completion date {176}. Although guidelines cannot be provided for every situation, the following factors need to be considered in establishing a new date for completion {176}: • The length of interruption {176};
• The time during therapy (early or late) in which interruption occurred {176}; and
• The patient's clinical, radiographic, and bacteriologic status before, during, and after interruption {176}. Consultation with an expert is advised {176}.
Therapy should be administered based on the following guidelines, published by the American Thoracic Society (ATS) and by the Centers for Disease Control and Prevention (CDC) and endorsed by the American Academy of Pediatrics (AAP) {149}. • A 6-month regimen consisting of isoniazid, rifampin, and pyrazinamide given for 2 months followed by isoniazid and rifampin for 4 months is the preferred treatment for patients who are infected with fully susceptible organisms and who adhere to the treatment course {147} {149}.
• Ethambutol (or streptomycin in children too young to be monitored for visual acuity) should be included in the initial regimen until the results of drug susceptibility studies are available, unless there is little possibility of drug resistance (i.e., there is less than 4% primary resistance to isoniazid in the community, and the patient has had no previous treatment with antituberculosis medications, is not from a country with a high prevalence of drug resistance, and has no known exposure to a drug-resistant case) {149}.
• Alternatively, a 9-month regimen of isoniazid and rifampin is acceptable for persons who cannot or should not take pyrazinamide {149}. Ethambutol (or streptomycin in children too young to be monitored for visual acuity) should also be included until the results of drug susceptibility studies are available, unless there is little possibility of drug resistance {149}. If isoniazid resistance is demonstrated, rifampin and ethambutol should be continued for a minimum of 12 months {149}.
• Consideration should be given to treating all patients with DOT {149}. DOT programs have been demonstrated to increase adherence in patients receiving antituberculosis chemotherapy in both rural and urban settings {165}.
• Multidrug-resistant tuberculosis (i.e., resistance to at least isoniazid and rifampin) presents difficult treatment problems {149}. Treatment must be individualized and based on susceptibility studies. In such cases, consultation with an expert in tuberculosis is recommended {149}.
• Children should be managed in essentially the same ways as adults, but doses of the medications must be adjusted appropriately and specific important differences between the management of adults and children addressed {149}. However, optimal therapy of tuberculosis in children with HIV infection has not been established {176}. The Committee on Infectious Diseases of the AAP recommends that therapy always include at least three drugs initially and be continued for a minimum period of 9 months {176}. Isoniazid, rifampin, and pyrazinamide with or without ethambutol or an aminoglycoside should be given for at least the first 2 months {176}. A fourth drug may be needed for disseminated disease and whenever drug-resistant disease is suspected {176}.
• Extrapulmonary tuberculosis should be managed according to the principles and with the drug regimens outlined for pulmonary tuberculosis, except in children who have miliary tuberculosis, bone/joint tuberculosis, or tuberculous meningitis. These children should receive a minimum of 12 months of therapy {149}.
• A 4-month regimen of isoniazid and rifampin is acceptable therapy for adults who have active tuberculosis and who are sputum smear– and culture–negative, if there is little possibility of drug resistance {149}.
ATS, CDC, and AAP recommend preventive treatment of tuberculosis infection in the following patients: • Preventive therapy with isoniazid given for 6 to 12 months is effective in decreasing the risk of future tuberculosis disease in adults and children with tuberculosis infection demonstrated by a positive tuberculin skin test reaction {149}.
• Persons with a positive skin test and any of the following risk factors should be considered for preventive therapy regardless of age {149}: —Persons with HIV infection {149}.
—Persons at risk for HIV infection with unknown HIV status {149}.
—Close contacts of sputum-positive persons with newly diagnosed infectious tuberculosis {149}.
—Newly infected persons (recent skin test convertors) {149}.
—Persons with medical conditions reported to increase the risk of tuberculosis (i.e., diabetes mellitus, corticosteroid therapy and other immunosuppressive therapy, intravenous drug users, hematologic and reticuloendothelial malignancies, end-stage renal disease, and clinical conditions associated with rapid weight loss or chronic malnutrition) {149}.
In some circumstances, persons with negative skin tests should be considered for preventive therapy {149}. These include children who are close contacts of infectious tuberculosis cases and anergic HIV-infected adults at increased risk of tuberculosis, tuberculin-positive adults with abnormal chest radiographs showing fibrotic lesions probably representing old healed tuberculosis, adults with silicosis, and persons who are known to be HIV-infected and who are contacts of patients with infectious tuberculosis {149}.
• In the absence of any of the above risk factors, persons up to 35 years of age with a positive skin test who are in the following high-incidence groups also should be considered for preventive therapy {149}: —Foreign-born persons from high-prevalence countries {149}.
—Medically underserved low-income persons from high-prevalence populations (especially blacks, Hispanics, and Native Americans) {149}.
—Residents of facilities for long-term care (e.g., correctional institutions, nursing homes, and mental institutions) {149}.
• Twelve months of preventive therapy is recommended for adults and children with HIV infection and other conditions associated with immunosuppression {149}. Persons without HIV infection should receive preventive therapy for at least 6 months {149}.
• In persons younger than 35 years of age, routine monitoring for adverse effects of isoniazid should consist of a monthly symptom review {149}. For persons 35 years of age and older, hepatic enzymes should be measured prior to starting isoniazid and monitored monthly throughout treatment, in addition to monthly symptom reviews {149}.
• Persons who are presumed to be infected with isoniazid-resistant organisms should be treated with rifampin rather than with isoniazid {149}.
• As with the treatment of active tuberculosis, the key to success of preventive treatment is patient adherence to the prescribed regimen {149}. Although not evaluated in clinical studies, directly observed, twice-weekly preventive therapy may be appropriate for adults and children at risk who cannot or will not reliably self-administer therapy {149}.
Protease inhibitors interact with rifamycin derivatives, such as rifampin and rifabutin, which are used to treat and prevent the mycobacterial infections commonly observed in HIV-infected patients {144}. Rifamycins accelerate the metabolism of protease inhibitors through induction of hepatic cytochrome P450 oxidases, resulting in subtherapeutic levels of the protease inhibitors {144}. In addition, protease inhibitors retard the metabolism of rifamycins, resulting in increased serum levels of rifamycins and the likelihood of increased drug toxicity {144}.
Rifampin is an essential component of the currently recommended regimen for treating tuberculosis {144}. This regimen is effective in treating HIV-infected patients with tuberculosis and consists of isoniazid and rifampin for a minimum period of 6 months, plus pyrazinamide and either ethambutol or streptomycin for the first 2 months {144}. Therefore, information concerning the pharmacokinetic interactions between protease inhibitors and rifampin is important for health care workers involved in tuberculosis control and the care of patients coinfected with tuberculosis and HIV, because clinicians may decrease or restrict the use of rifampin in the treatment of patients who are candidates for therapy with both protease inhibitors and rifampin {144}.
Because of the common association of tuberculosis with HIV infection, an increasing number of patients probably will be considered candidates for combined therapy with rifampin and protease inhibitors {144}. Prompt initiation of appropriate pharmacologic therapy for patients with HIV infection who acquire tuberculosis is critical because tuberculosis may become rapidly fatal {144}. The management of these patients is complex, requires an individualized approach, and should be undertaken only by or in consultation with an expert {144}. In addition, all HIV-infected patients at risk for tuberculosis infection should be carefully evaluated and administered isoniazid preventive treatment if indicated, regardless of whether they are receiving protease inhibitor therapy {144}.
For HIV-infected patients diagnosed with drug-susceptible tuberculosis and for whom protease inhibitor therapy is being considered but has not been initiated, the suggested management strategy is to complete tuberculosis treatment with a regimen containing rifampin before starting therapy with a protease inhibitor {144}. The duration of antituberculosis regimen is at least 6 months, and therapy should be administered according to the guidelines developed by ATS and CDC, including the recommendation to carefully assess clinical and bacteriologic responses in patients coinfected with HIV and to prolong treatment if response is slow or suboptimal {144}.
There are three options for managing HIV-infected patients with tuberculosis who are undergoing protease inhibitor therapy when tuberculosis is diagnosed {144} {152}. Option I is discontinuation of therapy with the protease inhibitor while a tuberculosis treatment regimen that includes rifampin is followed {144} {152}. However, because that interruption in the administration of the prescribed protease inhibitor can induce HIV resistance to the protease inhibitor and possibly to other medications within the protease inhibitor class, and because discontinuation of the protease inhibitor therapy may be detrimental to the patient's clinical status, some clinicians may be reluctant to discontinue protease inhibitor therapy for the duration of tuberculosis treatment. In such cases, option II and option III may be considered {144} {152}. Because the risks and benefits of all of these options are unknown, clinicians should make management decisions on a case-by-case basis to provide optimal patient care {144} {152}. • Option I. This option involves discontinuing therapy with the protease inhibitor and completing a short (minimum 6 months) course of tuberculosis treatment with a regimen containing rifampin {144} {152}. The antituberculosis regimen should be administered according to the guidelines developed by ATS and CDC, and the duration of therapy should be prolonged in patients with slow or suboptimal responses {144} {152}. Protease inhibitor therapy may be resumed when treatment with rifampin is discontinued {144} {152}. Antiretroviral agents other than protease inhibitors may be used concurrently with rifampin {144} {152}. Although the risks associated with complete discontinuation of protease inhibitor therapy during tuberculosis treatment are unclear, they may be serious; however, the risks and complications associated with tuberculosis treatment regimens that do not include rifampin are known {144} {152}. Potential consequences include prolonged duration of therapy to at least 18 to 24 months, increased likelihood of treatment failure and mortality, slower conversion of sputum culture to negative with patients remaining infectious for longer periods of time, and the adverse effect of tuberculous disease on the progression of HIV infection {144} {152}. Therefore, antituberculosis treatment regimens without rifampin are not recommended for the treatment of rifampin-susceptible tuberculosis {144} {152}.
• Option II. To minimize the interruption of protease inhibitor therapy, one option is to use a four-drug tuberculosis treatment regimen that includes rifampin (i.e., daily isoniazid, pyrazinamide, rifampin, and ethambutol or streptomycin) for a minimum of 2 months, and until bacteriologic response is achieved (i.e., sputum conversion to culture-negative status) and the results from the susceptibility testing are available {144} {152}. After bacteriologic response and drug susceptibility have been documented (usually 3 months), treatment may be modified to a 16-month continuation-phase regimen consisting of isoniazid (15 mg per kg of body weight) and ethambutol (50 mg per kg of body weight) two times per week. This regimen allows the reintroduction of protease inhibitor therapy {144} {152}. Some experts recommend adding a third agent, such as streptomycin, during this continuation phase if the infecting organism is not resistant to the agent {144} {152}. Option II cannot be recommended for patients with proven isoniazid-resistant tuberculosis {144} {152}.
• Option III. Another management option is to continue protease inhibitor therapy with indinavir (800 mg every 8 hours) and administer a four-drug, 9-month tuberculosis treatment regimen containing daily rifabutin (150 mg a day) instead of rifampin {144} {152}. When this option is used for tuberculosis management, clinicians should conduct careful monitoring, possibly including measurement of serum concentrations of rifabutin {144} {152}. This alternative tuberculosis therapy is recommended based on the pharmacokinetic characteristics of rifabutin and limited data from clinical trials {144} {152}. Rifabutin is a rifamycin derivative with comparable antituberculosis activity in vitro , but with less hepatic cytochrome P450 enzyme–inducing effect than rifampin {144} {152}. An international multicenter study indicated that a 6-month regimen containing rifabutin at a daily dose of either 150 or 300 mg is as effective in treating tuberculosis as a similar regimen containing rifampin {144} {152}. In a small clinical trial, a rifabutin-containing regimen was effective in treating tuberculosis in patients coinfected with HIV {144} {152}. In addition, limited data from pharmacokinetic studies suggest that the combination of rifabutin 150 mg a day and indinavir resulted in acceptable levels of both agents {144} {152}. Option III cannot be recommended for patients undergoing therapy with ritonavir or saquinavir {144} {152}. For these patients, the decision to change the prescribed protease inhibitor to indinavir and to prescribe rifabutin for tuberculosis therapy should be made in consultation with an expert in the use of protease inhibitors to manage HIV infection {144} {152}.
Neither option II nor option III has been studied in large clinical trials of HIV-infected patients or patients undergoing protease inhibitor therapy during tuberculosis treatment. For these reasons, if either of these options is selected for managing patients with tuberculosis, CDC recommends the following interim guidelines until additional data are available and formal guidelines are issued {144} {152}: • On initiation of therapy, frequent bacteriologic evaluations should be performed to document sputum conversion to culture-negative status, and after culture conversion, to detect any possible treatment failures {144} {152}.
• The duration of therapy should be extended to at least 18 months for option II or 9 months for option III {144} {152}.
• Only indinavir should be used with option III {144} {152}.
• Monitoring for drug toxicity should be performed carefully {144} {152}.
• DOT should be used throughout treatment {144} {152}.
• During the first 2 years after completion of therapy, periodic evaluation should be performed (including an assessment of bacteriologic status at 6 months), and patients should be instructed to report symptoms indicating relapse of tuberculous disease promptly {144} {152}.
HIV-infected patients diagnosed with drug-resistant tuberculosis or diagnosed clinically with tuberculosis but without culture and susceptibility test results should be evaluated on a case-by-case basis and managed in consultation with a tuberculosis expert {144} {152}.
Most infants £ 12 months of age with tuberculosis are asymptomatic at the time of diagnosis, and the gastric aspirate cultures in these patients have a high yield for M. tuberculosis {166}. When an infant is suspected of having tuberculosis, a thorough household investigation should be undertaken {166}. A 6-month regimen of isoniazid and rifampin supplemented during the first 2 months by pyrazinamide has been found to be well tolerated and effective in infants with pulmonary tuberculosis {166}. Furthermore, twice-weekly DOT appears to be as effective as daily therapy and is an essential alternative in patients for whom social issues prevent reliable daily therapy {166}.
Physicians caring for children should be familiar with the clinical forms of the disease in infants to enable them to make an early diagnosis {166}. Any child, especially one in a high-risk group or area, who has unexplained pneumonia, cervical adenitis, bone or joint infections, or aseptic meningitis should have a Mantoux tuberculin skin test performed, and a detailed epidemiologic history for tuberculosis should be obtained {166}.
Management of a newborn infant whose mother, or other household contact, is suspected of having tuberculosis is based on individual considerations {176}. If possible, separation of the mother, or contact, and infant should be minimized {176}. The Committee on Infectious Diseases of the AAP offers the following recommendations in the management of the newborn infant whose mother, or any other household contact, has tuberculosis {166}: • Mother, or any other household contact, with a positive tuberculin skin test reaction but no evidence of current disease: Investigation of other members of the household or extended family to whom the infant may later be exposed is indicated {176}. If no evidence of current disease is found in the mother or in members of the extended family, the infant should be tested with a Mantoux tuberculin skin test at 3 to 4 months of age {176}. When the family members cannot be promptly tested, consideration should be given to administering isoniazid (10 mg per kg of body weight a day) to the infant until skin testing and other evaluation of the family members have excluded contact with a case of active tuberculosis {176}. The infant does not need to be hospitalized during this time if adequate follow-up can be arranged, but adherence to medication administration should be closely monitored {176}. The mother also should be considered for isoniazid therapy {176}.
• Mother with untreated (newly diagnosed) disease or disease that has been treated for 2 or more weeks and who is judged to be noncontagious at delivery: Careful investigation of household members and extended family is mandatory {176}. A chest radiograph and Mantoux tuberculin skin test should be performed on the infant at 3 to 4 months and at 6 months of age {176}. Separation of the mother and infant is not necessary if adherence to treatment for the mother and infant is assured {176}. The mother can breast-feed {176}. The infant should receive isoniazid even if the tuberculin skin test and chest radiograph do not suggest clinical tuberculosis, since cell-mediated immunity of a degree sufficient to mount a significant reaction to tuberculin skin testing may develop as late as 6 months of age in an infant infected at birth {176}. Isoniazid can be discontinued if the Mantoux skin test is negative at 3 to 4 months of age, the mother is adherent to treatment and has a satisfactory clinical response, and no other family members have infectious tuberculosis {176}. The infant should be examined carefully at monthly intervals {176}. If nonadherence is documented, the mother has an acid-fast bacillus (AFB)–positive sputum or smear, and supervision is impossible, the infant should be separated from the ill family member and Bacillus Calmette-Guérin (BCG) vaccine may be considered for the infant {176}. However, the response to the vaccine in infants may be delayed and inadequate for prevention of tuberculosis {176}.
• Mother has current disease and is suspected of having been contagious at the time of delivery: The mother and infant should be separated until the infant is receiving therapy or the mother is confirmed to be noncontagious {176}. Otherwise, management is the same as when the disease is judged to be noncontagious to the infant at delivery {176}.
• Mother has hematogenously spread tuberculosis (e.g., meningitis, miliary disease, or bone involvement): The infant should be evaluated for congenital tuberculosis {176}. If clinical and radiographic findings do not support the diagnosis of congenital tuberculosis, the infant should be separated from the mother until she is judged to be noncontagious {176}. The infant should be given isoniazid until 3 or 4 months of age, at which time the Mantoux skin test should be repeated {176}. If the skin test is positive, isoniazid should be continued for a total of 12 months {176}. If the skin test is negative and the chest radiograph is normal, isoniazid may be discontinued, depending on the status of the mother and whether there are other cases of infectious tuberculosis in the family {176}. The infant should continue to be examined carefully at monthly intervals {176}.
Health care or correctional institutions experiencing outbreaks of tuberculosis that are resistant to isoniazid and rifampin, or that are resuming therapy for a patient with a prior history of antitubercular therapy, may need to begin five- or six-drug regimens as initial therapy. These regimens should include the four-drug regimen and at least three medications to which the suspected multidrug-resistant strain may be susceptible {51}.
Oral Dosage Forms
RIFAMPIN, ISONIAZID AND PYRAZINAMIDE TABLETS
Note: Rifater contains rifampin 120 mg, isoniazid 50 mg, and pyrazinamide 300 mg {01}. However, the World Health Organization (WHO) recommends the fixed-dose combination of rifampin 150 mg, isoniazid 75 mg, and pyrazinamide 400 mg for the daily administration in the initial phase of tuberculosis treatment {179}. The WHO also recommends the fixed-dose combination of rifampin 150 mg, isoniazid 150 mg, and pyrazinamide 500 mg for intermittent (3 times weekly) administration during the continuation phase of tuberculosis treatment {179}. Neither of these WHO-recommended fixed-dose combinations are commercially available in the U.S.
Usual adult dose
Tuberculosis
Patients weighing 44 kg or less: Oral, 4 tablets once a day.
Patients weighing between 45 and 54 kg: Oral, 5 tablets once a day.
Patients weighing 55 kg or more: Oral, 6 tablets once a day {01}.
Usual pediatric dose
Tuberculosis
Children and adolescents up to 15 years of age: Use of the fixed-dose combination is not recommended {01}.
Adolescents 15 years of age and older: See Usual adult dose .
Note: See individual components for dosage recommendations.
Strength(s) usually available
U.S.—
120 mg rifampin, 50 mg isoniazid, and 300 mg pyrazinamide (Rx) [Rifater{01}]
Canada—
Not commercially available.
Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by the manufacturer. Protect from excessive humidity. {01}
Auxiliary labeling:
• Continue taking the medicine for full time of treatment.
• Avoid alcoholic beverages {01}.
• May discolor body fluids {01}.
Revised: 09/17/1998
References
- Rifater package insert (Marion Merrell Dow—US), Rev 6/94, Rec 6/95.
- Acoxella G, Luisetti M, Gialdroni GG, et al. Bioavailability of isoniazid, rifampicin and pyrazinamide (in free combination or fixed-triple formulation) in intermittent antituberculous chemotherapy. Monaldi Arch Chest Dis 1993; 48(3): 205-9.
- Moulding T, Dutt AK, Reichman LB. Fixed-dose combinations of antituberculous medications to prevent drug resistance. Ann Intern Med 1995; 122: 951-4.
- Türktas H, Unsal M, Örüç O. Hepatotoxicity of antitubercular therapy (rifampicin, isoniazid and pyrazinamide) or viral hepatitis. Tuber Lung Dis 1994; 75(1): 58-60.
- Macnab MF, Bohmer PD, Seager JR. Evaluation of the 3-drug combination, Rifater, versus 4-drug therapy in the ambulatory treatment of tuberculosis in Cape Town. S Afr Med J 1994; 84: 325-8.
- Nightingale SL. From the Food and Drug Administration. JAMA 1994; 272(5): 344.
- San José ME, Sarandeses A, Alvarez D, et al. Determination of iron by the Ferrochem II: interference by tuberculostatics. Scand J Clin Lab Invest 1993; 53: 653-8.
- Wolde K, Lema E, Roscigno G, et al. Fixed dose combination short course chemotherapy in the treatment of pulmonary tuberculosis. Ethiop Med J 1992; 30(2): 63-8.
- Tsakalidis D, Pratsidou P, Hitogloumakedou A, et al. Intensive short course chemotherapy for treatment of Greek children with tuberculosis. Pediatr Infect Dis J 1992; 11: 1036-42.
- Kamolratanakul P, Chunhaswasdikul B, Jittinandana A, et al. Cost-effectiveness analysis of three short-course anti-tuberculosis programmes compared with a standard regimen in Thailand. J Clin Epidemiol 1993; 46(7): 631-6.
- Pust RE. Tuberculosis in the 1990s: resurgence, regimens, and resources. South Med J 1992; 85(6): 584-93.
- Ekmekçi A, Sayli A. Cytogenic study of tuberculosis patients before and after tuberculostatic drug treatment. Mutat Res 1995; 334(2): 175-83.
- Concato J. Endemic tuberculosis among homeless men in New York City. Arch Intern Med 1994; 154: 2069-73.
- Shafer RW, Small PM, Larkin C, et al. Temporal trends and transmission patterns during the emergence of multidrug-resistant tuberculosis in New York City: a molecular epidemiologic assessment. J Infect Dis 1995; 171: 170-6.
- Stoker N. Tuberculosis in a changing world; don't stint on surveillance and control. BMJ 1994; 309: 1178-9.
- Weltman AC, Rose DN. Tuberculosis susceptibility patterns, predictors of multidrug resistance, and implications for initial therapeutic regimens at a New York City hospital. Arch Intern Med 1994; 154: 2161-7.
- Heym B, Honoré N, Truffot-Pernot C, et al. Implications of multidrug resistance for the future of short-course chemotherapy of tuberculosis: a molecular study. Lancet 1994; 344: 293-8.
- Rabassa AA, Trey G, Shukla U, et al. Isoniazid-induced acute pancreatitis. Ann Intern Med 1994; 121: 433-4.
- Houston S, Fanning A. Current and potential treatment of tuberculosis. Drugs 1994; 48(5): 689-708.
- Driver CR, Valway SE, Morgan WM, et al. Transmission of Mycobacterium tuberculosis associated with air travel. JAMA 1994; 272(13): 1031-5.
- Kent RJ, Uttley AHC, Stoker NG, et al. Transmission of tuberculosis in British center for patients infected with HIV. BMJ 1994; 309: 639-40.
- Wenger PN, Otten J, Breeden A, et al. Control of nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis among healthcare workers and HIV-infected patients. Lancet 1995; 345: 235-40.
- Sepkowitz KA. AIDS, tuberculosis, and the health care worker. Clin Infect Dis 1995; 20: 232-42.
- Morris S, Bai GH, Suffys P, et al. Molecular mechanisms of multiple drug resistance in clinical isolates of Mycobacterium tuberculosis. J Infect Dis 1995; 171: 954-60.
- Zolopa AR, Hahn JA, Gorter R, et al. HIV and tuberculosis infection in San Francisco's homeless adults; prevalence and risk factors in a representative sample. JAMA 1994; 272: 455-61.
- Rosenblum LS, Castro KG, Dooley S, et al. Effect of HIV infection and tuberculosis on hospitalizations and cost of care for young adults in the United States, 1985 to 1990. Ann Intern Med 1994; 121: 786-92.
- Iseman MD, Starke J. Immigrants and tuberculosis control. N Engl J Med 1995; 332(16): 1094-5.
- Jaber B, Gleckman R. Tuberculous pancreatic abscess as an initial AIDS-defining disorder in a patient infected with the human immunodeficiency virus: case report and review. Clin Infect Dis 1995; 20: 890-4.
- Blumberg HM, Watkins DL, Berschling JD, et al. Preventing the nosocomial transmission of tuberculosis. Ann Intern Med 1995; 122: 658-63.
- Maloney SA, Pearson ML, Gordon MT, et al. Efficacy of control measures in preventing nosocomial transmission of multidrug-resistant tuberculosis to patients and health care workers. Ann Intern Med 1995; 122: 90-5.
- Jarvis WR, Bolyard EA, Bozzi CJ, et al. Respirators, recommendations, and regulations: the controversy surrounding protection of health care workers from tuberculosis. Ann Intern Med 1995; 122: 142-6.
- De Cock KM, Grant A, Porter JDH. Preventive therapy for tuberculosis in HIV-infected persons: international recommendations, research, and practice. Lancet 1995; 345: 833-6.
- Centers for Disease Control and Prevention (CDC). Co-incidence of HIV/AIDS and tuberculosis—Chicago, 1982-1993. MMWR Morb Mortal Wkly Rep 1995; (44)11: 227-31.
- Centers for Disease Control and Prevention (CDC). Proportionate mortality from pulmonary tuberculosis associated with occupations—28 states, 1979-1990. MMWR Morb Mortal Wkly Rep 1995; 44(1): 14-9.
- Pyrazinamide package insert (Lederle—US), Rev 3/92, Rec 6/92.
- Centers for Disease Control and Prevention (CDC). Tuberculosis among pregnant women—New York City, 1985-1992. JAMA 1993; 270(11): 1293, 1296.
- Holdiness MR. Antituberculosis drugs and breast-feeding. Arch Intern Med 1984; 144: 1888.
- Ellard GA. Penetration of pyrazinamide into the cerebrospinal fluid in tuberculosis meningitis. BMJ 1987; 294: 284-5.
- Phuapradit P, Supmonchai K, Kaojarern S, et al. The blood/cerebrospinal fluid partitioning of pyrazinamide: a study during the course of treatment of tuberculosis meningitis. J Neurol Neurosurg Psychiatry 1990; 53(1): 81-2.
- Le Bourgeois M, de Blic J, Paupe J, et al. Good tolerance of pyrazinamide in children with pulmonary tuberculosis. Arch Dis Child 1989; 64(1): 177-8.
- Reed MD, Blumer JL. Clinical pharmacology of antitubercular drugs. Pediatr Clin North Am 1983; 30(1): 177-93.
- Benitz WE, Tatro DS. The pediatric drug handbook. 2nd ed. Chicago: Year Book Medical Publishers, Inc.; 1988. p. 615-6.
- Steele MA, Des Prez RM. The role of pyrazinamide in tuberculosis chemotherapy. Chest 1988; 94(4): 845-50.
- Mandell GL, Douglas RG, Bennet JE, editors. Principles and practice of infectious diseases. 3rd ed. New York: Churchill Livingstone; 1990. p. 354.
- Girling DJ. The role of pyrazinamide in primary chemotherapy for pulmonary tuberculosis. Tubercle 1984; 65: 1-4.
- Cohn DL. A 62-dose, 6-month therapy for pulmonary and extrapulmonary tuberculosis. Ann Intern Med 1990; 112(6): 393-4.
- Lacroix C, Hoang TP, Nouveau J, et al. Pharmacokinetics of pyrazinamide and its metabolites in healthy subjects. Eur J Clin Pharmacol 1989; 36: 395-400.
- Stamatakis G, Montes C, Trouvin JH, et al. Pyrazinamide and pyrazinoic acid pharmacokinetics in patients with chronic renal failure. Clin Nephrol 1988; 30(4): 230-4.
- Lacroix C, Hermelin A, Guiberteau R, et al. Haemodialysis of pyrazinamide in uraemic patients. Eur J Clin Pharmacol 1989; 37: 309-11.
- Zierski M, Bek E. Side-effects of drug regimens used in short-course chemotherapy for pulmonary tuberculosis. A controlled clinical study. Tubercle 1980; 61: 41-9.
- Centers for Disease Control and Prevention (CDC). Initial therapy for tuberculosis in the era of multidrug resistance: recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Morb Mortal Wkly Rep 1993; 42(RR-7): 1-8.
- Jiménez del Cerro LA, Hernández FR. Effect of pyrazinamide on ciclosporin levels. Nephron 1992; 62: 113.
- Pyrazinamide (Lederle). In: PDR Physicians' desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data; 1995. p. 1282-3.
- Tan TQ, Mason EO, Ou C-N, et al. Use of intravenous rifampin in neonates with persistent staphylococcal bacteremia. Antimicrob Agents Chemother 1993; 37(11): 2401-6.
- Rifadin (Marion Merrell Dow). In: PDR Physicians' desk reference. 49th ed. 1995. Oradell, NJ: Medical Economics Data; 1995. p. 1421-3.
- Harland RW, Lindblom SS, Munnell MO. Anaphylaxis from rifampin. Am J Med 1992; 92: 581-2.
- Levine M, Collin K, Kassen BO. Acute hemolysis and renal failure following discontinuous use of rifampin. Ann Pharmacother 1991; 25: 743-4.
- Kyriazopoulou V, Vagenakis AG. Abnormal overnight dexamethasone suppression test in subjects receiving rifampicin therapy. J Clin Endocrinol Metab 1992; 75(1): 315-7.
- Hebert MF, Roberts JP, Prueksaritanont T, et al. Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin Pharmacol Ther 1992; 52(5): 453-7.
- Rimactane (Ciba). In: PDR Physicians' desk reference. 49th ed. 1995. Montvale, NJ: Medical Economics Data; 1995. p. 896.
- Venkatesan D. Clinical pharmacokinetic considerations in the treatment of patients with leprosy. Clin Pharmacokinet 1989; 16: 365-86.
- American Academy of Pediatrics (AAP). Transfer of drugs and other chemicals into human milk. Pediatrics 1989; 84(5): 924-36.
- Holdiness MR. A review of the redman syndrome and rifampicin overdosage. Med Toxicol Adverse Drug Exp 1989; 4(6): 444-51.
- Wong P. Acute rifampin overdose: a pharmacokinetic study and review of the literature. J Pediatr 1984; 104(5): 781-3.
- Baciewicz AM, Self TH, Bekemeyer WB. Update on rifampin drug interactions. Arch Intern Med 1987; 147: 585-8.
- Kay L. Influence of rifampicin and isoniazid on the kinetics of phenytoin. Br J Clin Pharmacol 1985; 20: 323-6.
- Engelhard D, Stutman HR, Marks MI. Interaction of ketoconazole with rifampin and isoniazid. N Engl J Med 1984; 311(26): 1681-3.
- Kelly HW. Interaction of chloramphenicol and rifampin. J Pediatr 1988; 112(5): 817-20.
- Prober CG. Effect of rifampin on chloramphenicol levels. N Engl J Med 1985; 312(12): 788-9.
- Poor DM, Self TH, Davis HL. Interaction of rifampin and digitoxin. Arch Intern Med 1983; 143: 599.
- Gault H. Digoxin-rifampin interaction. Clin Pharmacol Ther 1984; 35(6): 750-4.
- Baciewicz AM, Self TH. Rifampin drug interactions. Arch Intern Med 1984; 144: 1667-71.
- Heimark LD. The mechanism of the warfarin-rifampin drug interaction in humans. Clin Pharmacol Ther 1987; 42: 388-94.
- True RJ. Interactions between antibiotics and oral contraceptives. JAMA 1982; 247(10): 1408.
- McAlister WAC. Rifampicin reduces effectiveness and bioavailability of prednisolone. Br Med J 1983; 286: 923-5.
- Abajo FJ. Phenytoin interaction with rifampin. Br Med J 1988; 297: 1048.
- Bussey HI. The influence of rifampin on quinidine and digoxin. Arch Intern Med 1984; 144: 1021-3.
- Twum-Barima Y, Carruthers SG. Quinidine-rifampin interaction. N Engl J Med 1981; 304: 1486-9.
- Robson RA. Theophylline-rifampicin interaction: nonselective induction of theophylline metabolic pathways. Br J Clin Pharmacol 1984; 18: 445-8.
- Brocks DR. Theophylline-rifampin interaction in a pediatric patient. Clin Pharm 1986; 5: 602-4.
- Self TH, Tsiu SJ, Fowler JW. Interaction of rifampin and glyburide. Chest 1989; 96(6): 1443-4.
- Pentikainen PJ. Effect of rifampin treatment on the kinetics of mexiletine. Eur J Clin Pharmacol 1982; 23: 261.
- Rice TL. Influence of rifampin on tocainide pharmacokinetics in humans. Clin Pharm 1989; 8: 200-5.
- Staum JM. Enzyme induction: rifampin-disopyramide interaction. Ann Pharmacother 1990; 24: 701-3.
- Ohnhaus EE. The effect of antipyrine and rifampin on the metabolism of diazepam. Clin Pharmacol Ther 1987; 42: 148-56.
- Houin G, Tillement JP. Clofibrate and enzymatic induction in man. Int J Clin Pharmacol 1978; 16: 150-4.
- Buniva G, Palminteri R, Berti M. Kinetics of a rifampicin-trimethoprim combination. Int J Clin Pharmacol Biopharm 1979; 17(6): 256-9.
- Castel JM. Rifampicin lowers plasma concentrations of propafenone and its antiarrhythmic effect. Br J Clin Pharmacol 1990; 30: 155-6.
- Coker RJ. Interactions between fluconazole and rifampicin. Br Med J 1990; 30: 155-6.
- Pasko MT, Piscitelli SC, Van Slooten AD. Fluconazole: a new triazole antifungal agent. Ann Pharmacother 1990; 24: 860-7.
- Lazar JD, Wilner KD. Drug interactions with fluconazole. Rev Infect Dis 1990; 12(3): S327-S333.
- Vandevelde C. Rifampin and ansamycin interactions with cyclosporine after renal transplantation. Pharmacotherapy 1991; 11(1): 88-9.
- Sarma GR, Kailasam S, Nair NGK, et al. Effect of prednisolone and rifampin on isoniazid metabolism in slow and rapid inactivators of isoniazid. Antimicrob Agents Chemother 1980; 18(5): 661-6.
- Heifets LB. Expedited detection of drug resistance in tuberculosis patients. Ann Emerg Med 1994; 24(3): 457-61.
- Wolinsky E. Statement of the Tuberculosis Committee of the Infectious Diseases Society of America. Clin Infect Dis; 16: 627-8.
- Wallach J. Interpretation of diagnostic tests. 4th ed. Boston: Little Brown and Company; 1986. p. 661.
- Laniazid package insert (Lannett—US), Rev 1/86, Rec 5/86.
- Epstein MM. Inhibition of the metabolism of paracetamol by isoniazid. Br J Clin Pharmacol 1991; 31: 130-42.
- I.N.H.(Ciba). In: PDR Physicians' desk reference. 42nd ed. 1988. Oradell, NJ: Medical Economics Company; 1988. p. 869-70.
- Nydrazid package insert (Squibb—US), Rev 11/87, Rec 3/89.
- I.N.H. package insert (Ciba—US), Rev 8/87, Rec 1/89.
- Committee on Infectious Diseases, American Academy of Pediatrics (AAP). Chemotherapy for tuberculosis in infants and children. Pediatrics 1992; 89(1): 161-5.
- Hansten PD. Isoniazid drug interactions. Drug Interactions Newsletter 1983; 3(2): 7-11.
- Wright JM, Stokes EF, Sweeney VP. Isoniazid-induced carbamazepine toxicity and vice versa. N Engl J Med 1982; 307(21): 1325-7.
- Valsalan VC, Cooper GL. Carbamazepine intoxication caused by interaction with isoniazid. Br Med J 1982; 285: 261-2.
- Salpeter S. Tuberculosis chemoprophylaxis. West J Med 1992; 157: 421-4.
- Gilman AG, Goodman LS, Rall TW, Murad F, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan; 1985. p. 1199.
- Holdiness MR. Clinical pharmacokinetics of the antituberculosis drugs. Clin Pharmacokinet 1984; 9: 511-44.
- Wyngaarden JB, Smith LH, editors. Cecil textbook of medicine. Philadelphia: WB Saunders Company; 1990. p. 117.
- I.N.H. package insert (Lilly—US), Rev 9/88, Rec 1/89.
- Miceli JN, Olson WA, Cohen SN. Elimination kinetics of isoniazid in the newborn infant. Dev Pharmacol Ther 1981; 2: 235-9.
- Hauser MJ, Baier H. Interactions of isoniazid with foods. Drug Intell Clin Pharm 1982; 16: 617-8.
- Smith CK, Durack DT. Isoniazid and reaction to cheese. Ann Intern Med 1978; 88(4): 520-1.
- Shinn AF, Shrewsbury RP. EDI, evaluation of drug interactions. 3rd ed. St Louis: Mosby; 1985. p. 222, 446.
- Theuer CP. Tuberculosis in patients with human immunodeficiency virus infection. West J Med 1989; 150: 700-4.
- Centers for Disease Control and Prevention (CDC). Tuberculosis and human immunodeficiency virus infection: recommendations of the Advisory Committee for the Elimination of Tuberculosis (ACET). MMWR Morb Mortal Wkly Rep 1989; 38(14): 236-50.
- Torrent J. Theophylline-isoniazid interaction. Drug Intell Clin Pharm 1989; 23: 143-4.
- Combs DL, O'Brien RJ Geiter LJ. USPHS tuberculosis short-course chemotherapy trial 21: effectiveness, toxicity, and acceptability. Ann Intern Med 1990; 112(6): 397-406.
- Murphy R, Swartz R, Watkins PB. Severe acetaminophen toxicity in a patient receiving isoniazid. Ann Intern Med 1990; 113(10): 799-800.
- Moulding TS, Redeker AG, Kanel GC. Acetaminophen, isoniazid, and hepatic toxicity. Ann Intern Med 1991; 114(5): 431.
- Haddad LM, Winchester JF, editors. Clinical management of poisoning and drug overdose. Philadelphia: WB Saunders Company; 1983. p. 615-8.
- Ellenhorn MJ, Barceloux DG. Medical toxicology. Diagnosis and treatment of human poisoning. New York: Elsevier; 1988. p. 364-72.
- Bredemann JA, Krechel SW, Eggers GWN. Treatment of refractory seizures in massive isoniazid overdose. Anesth Analg 1990; 71: 55
- Witmer DR, Ritschel WA. Phenytoin-isoniazid interaction: a kinetic approach to management. Drug Intell Clin Pharm 1984; 18: 483-6.
- Behrman RE, Vaughan VC III, editors. Nelson textbook of pediatrics. 13th ed. Philadelphia: WB Saunders Company; 1987. p. 635-6.
- Yaffe SJ, Aranda JV. Pediatric pharmacology. Therapeutic principles in practice. 2nd ed. Philadelphia: WB Saunders Company; 1992. p. 17.
- Yaffe SJ, Aranda JV. Pediatric pharmacology. Therapeutic principles in practice. 2nd ed. Philadelphia: WB Saunders Company; 1992. p. 218.
- Amodio MI, Bengualid V, Lowy FD. Development of acute gout secondary to pyrazinamide in a patient without a prior history of gout. Ann Pharmacother 1990; 24: 1115-6.
- Kergueris MF. Acetylation character of isoniazid in the rabbit and in man. Eur J Drug Metab Pharmacokinet 1983; 8(2): 133-6.
- Horai Y. Isoniazid disposition, comparison of isoniazid phenotyping methods in and acetylator distribution of Japanese patients with idiopathic systemic lupus erythematosus and control subjects. Br J Clin Pharmacol 1982; 13: 361-74.
- Wallach J. Interpretation of diagnostic tests. A synopsis of laboratory medicine. 4th ed. Boston: Little, Brown and Company; 1986. p. 660, 666.
- Centers for Disease Control and Prevention (CDC). Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 1994. MMWR Morb Mortal Wkly Rep 1994; 43(RR-13): 1-132.
- Berning SE, Hitt GA, Iseman MD, et al. Malabsorption of antituberculosis medications by a patient with AIDS [letter]. N Engl J Med 1992; 327(25): 1817-8.
- Reviewer comment, 09/95.
- Panel comment, 09/95.
- Panel comment, 08/95.
- Panel comment, 08/95.
- Panel comment, 09/95.
- Panel comment, 09/95.
- Fleeger CA, editor. USAN 1996. USP dictionary of USAN and international drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 1995. p. 608.
- Centers for Disease Control and Prevention (CDC). Recommendations of the Advisory Council for the Elimination of Tuberculosis. Essential components of a tuberculosis prevention and control program. MMWR Morb Mortal Wkly Rep 1995; 44(RR-11): 1-16.
- Centers for Disease Control and Prevention (CDC). Recommendations of the Advisory Council for the Elimination of Tuberculosis. Screening for tuberculosis and tuberculosis infection in high-risk populations. MMWR Morb Mortal Wkly Rep 1995; 44(RR-11): 19-34.
- Centers for Disease Control and Prevention (CDC). Recommendations of the Advisory Council for the Elimination of Tuberculosis (ACET). Prevention and control of tuberculosis in correctional facilities. MMWR Morb Mortal Wkly Rep 1996; 45(RR-8): 1-27.
- Centers for Disease Control and Prevention (CDC). Clinical update: impact of HIV protease inhibitors on the treatment of HIV-infected tuberculosis patients with rifampin. MMWR Morb Mortal Wkly Rep 1996; 45(42): 921-5.
- Centers for Disease Control and Prevention (CDC). Multidrug-resistant tuberculosis outbreak on an HIV ward—Madrid, Spain, 1991-1995. MMWR Morb Mortal Wkly Rep 1996; 45(16): 330-3.
- Centers for Disease Control and Prevention (CDC). Characteristics of foreign-born hispanic patients with tuberculosis—eight U.S. counties bordering Mexico. MMWR Morb Mortal Wkly Rep 1996; 45(47): 1032-6.
- Centers for Disease Control and Prevention (CDC). Tuberculosis morbidity—United States, 1995. MMWR Morb Mortal Wkly Rep 1996; 45(18): 365-70.
- Peloquin CA, Nitta AT, Burman WJ, et al. Low antituberculosis drug concentrations in patients with AIDS. Ann Pharmacother 1996; 30: 919-25.
- The American Thoracic Society (ATS). Ad Hoc Committee on the Scientific Assembly on Microbology, Tuberculosis, and Pulmonary Infections. Treatment of tuberculosis and tuberculosis infection in adults and children. Clin Infect Dis 1995; 21: 9-27.
- Khan EJ, Starke JR. Diagnosis of tuberculosis in children: increased need for better methods. Emerg Infect Dis 1995; 1(4): 115-23.
- Rullán JV, Herrera D, Cano R, et al. Nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis in Spain. Emerg Infect Dis 1996; 2(2): 125-9.
- Centers for Disease Control and Prevention (CDC). The Division of Tuberculosis Elimination (DTBE). The use of HIV protease inhibitors with rifampin. TB Notes 1996; 3: 15-9.
- Frieden TR, Sherman LF, Maw KL, et al. A multi-institutional outbreak of highly drug-resistant tuberculosis—epidemiology and clinical outcomes. JAMA 1996; 276(15): 1229-35.
- Mendez AP, Sterling TR, Frieden TR. The relationship between delayed or incomplete treatment and all-cause mortality in patients with tuberculosis. JAMA 1996; 276(15): 1223-8.
- Raviglione MC, Snider DE, Kochi A. Global epidemiology of tuberculosis—morbidity mortality of a worldwide epidemic. JAMA 1995; 273(3): 220-6.
- National Institute of Allergy and Infectious Diseases (NIAID). Tuberculosis increases HIV replication in HIV-infected people. NIAID news for release, Thursday, Aug 1, 1996.
- Horn DL, Hewlett D, Haas WH, et al. Superinfection with rifampin-isoniazid-streptomycin-ethambutol (RISE)-resistant tuberculosis in three patients with AIDS: confirmation by polymerase chain reaction fingerprinting. Ann Intern Med 1994; 121(2): 115-6.
- Bishai WR, Graham NMH, Harrington S, et al. Brief report: rifampin-resistant tuberculosis in a patient receiving rifabutin prophylaxis. N Engl J Med 1996; 334(24): 1573-6.
- Allos BM, Gensheimer KF, Bloch AB, et al. Management of an outbreak of tuberculosis in a small community. Ann Intern Med 1996; 125(2): 114-7.
- Nardell EA, Brickner BW. Tuberculosis in New York City—focal transmission of an often fatal disease. JAMA 1996; 276(15): 1259-60.
- Norvir package insert (Abbott—US), Rev 02/96.
- Invirase package insert (Roche—US), Rev 12/95.
- Crixivan package insert (Merck—US), Rev 03/96.
- Goletti D, Weissman D, Jackson RW, et al. Effect of Mycobacterium tuberculosis on HIV replication: role of immune activation. J Immunol 1996; 157: 1271-8.
- Hoffmann ND, Kelly C, Futterman D. Tuberculosis infection in human immunodeficiency virus-positive adolescents and young adults: a New York City cohort. Pediatrics 1996; 97(2): 198-203.
- Vallejo JG, Ong LT, Strake JR. Clinical features, diagnosis, and treatment of tuberculosis in infants. Pediatrics 1994; 94(1): 1-7.
- Telzak EE, Sepkowitz K, Alpert P, et al. Multidrug-resistant tuberculosis in patients without HIV infection. N Engl J Med 1995; 333(14): 907-11.
- Goble M, Iseman MD, Madsen LA, et al. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993; 328 (8): 527-32.
- Small PM, Shafer RW, Hopewell PC, et al. Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection. N Engl J Med 1993; 328 (16): 1137-44.
- Bradford WZ, Martin JN, Reingold AL, et al. The changing epidemiology of acquired drug-resistant tuberculosis in San Francisco, USA. Lancet 1996; 348: 928-31.
- Snider GL. Tuberculosis then and now: a personal perspective on the last 50 years. Ann Intern Med 1997; 126(3): 237-43.
- Piscitelli SC, Flexner C, Minor JR, et al. Drug interactions in patients infected with human immunodeficiency virus. Clin Infect Dis 1996; 23: 685-93.
- Friedman LN, Williams MT, Singh TP, et al. Tuberculosis, AIDS, and death among substance abusers on welfare in New York City. N Engl J Med 1996; 334(13): 828-33.
- Antonucci G, Girardi E, Raviglione MC, et al. Risk factors for tuberculosis in HIV-infected persons: a prospective cohort study. JAMA 1995; 274(2): 143-8.
- Libraty DH, Byrd TF. Cutaneous miliary tuberculosis in the AIDS era: case report and review. Clin Infect Dis 1996; 23: 706-10.
- American Academy of Pediatrics (AAP). Tuberculosis. In: Peter G, ed. 1994 Red book: report of the Committee on Infectious Disaeases. 23rd ed. Elk Grove Village, IL: American Academy of Pediatrics; 1994 480-500.
- Nakata K, Rom WN, Honda Y, et al. Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication in the lung. Am J Crit Care Med 1997; 155: 996-1003.
- Fujiwara PI, Cook SV, Rutherford CM, et al. A continuing survey of drug-resistant tuberculosis, New York City, 1994. Arch Intern Med 1997; 157: 531-6.
- World Health Organization (WHO). Treatement of tuberculosis: guidelines for national programs, 2nd ed. 1997. World Health Organization/TB/97.220.
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