Side effects attributed to rifabutin include rash, gastrointestinal intolerance, neutropenia, myalgias, and dysguesia. They often have endorphin rushes that lead them to feel upbeat until they crash with fatigue. I would worry more about her toddler being tired all the time than her weight. There are four questions you will want to ask as part of telephone screening:. Patients often disregard other relevant information that would bring a balanced view to the situation. This study will see if a medicine already approved to treat inflammation in other medical conditions can decrease inflammation due to obesity.
Symptoms of Heat Stroke
Cognitive behavioural therapy really helped me to change the distorted thoughts flying around my head and move on from my eating disorder. You can access talking treatments through the NHS. Your GP should be able to make a referral. There can be long waiting lists on the NHS, so you may also want to consider seeing a therapist privately — but be aware that private therapists usually charge for appointments.
There are no drugs specifically for eating disorders, but you may be offered medication to treat some underlying factors such as depression or anxiety. If you have anorexia, you may be offered antidepressants or antipsychotics. Being underweight can mean that drugs are absorbed more quickly into your bloodstream, which could make medication harmful or not as effective as it should be. Your doctor will decide whether to offer you medication, and you can decide whether you want to take it.
If you are an outpatient or day patient, you will go home most evenings and weekends. If you are an inpatient, you will stay in the hospital or clinic for most of your treatment. How long you are admitted for will depend on how much help you need to recover. You will normally receive a range of support as an inpatient.
The staff at the hospital or clinic could include:. Your weight and general health will be monitored. There may be guidance on buying, preparing and serving food, how to cope with stress and anxiety, how to be more assertive, and how to manage anger and communicate well. Refeeding means being given food with the aim of bringing your weight up to a healthy level — it involves helping you to gain weight so that your energy levels and your physical health improve.
You may be given specific foods because they have certain nutritional values or are particularly good at helping people gain weight. How this works varies from one clinic to another. Some doctors may do this over a longer period of time, allowing you to gradually increase your weight, whereas others will want to help you back to a healthy weight as soon as possible. This can be a distressing process, especially if you do not want to gain weight, and may be something you want to talk about with your doctor in more detail.
There are only a few NHS eating disorder clinics, so you may not always be able to access treatment close to where you live. This may mean going to a clinic further away, or it could mean going to a general mental health hospital. There are also private treatment centres. Some may offer similar treatment to NHS clinics, while others will have a wider range of complementary and art therapies.
Read Nicole's blog about treatment in a clinic and saying goodbye to anorexia. Researchers are investigating techniques that stimulate the brain using magnetic fields or a weak electrical current.
Your stories Workplace bullying and eating disorders Mel blogs about the impact being bullied at work had on her. Do I have a right to recovery? Lucy talks about how not ever having a diagnosis has impacted on her recovery. My anorexia diagnosis and finding help Jess blogs about being diagnosed with anorexia and the challenges she faced in getting the right treatment.
What treatment is available? Talking to your doctor Online self-help programmes Talking treatments Medication Admission to a clinic Non-invasive brain stimulation techniques Note: Talking to your doctor Talking about your eating problems can be scary, but if you'd like treatment and support, the first step is usually to visit your doctor GP. No known interactions exist between isoniazid and the antiretroviral medications used for the treatment of HIV infection.
Rifampin is a rifamycin derivative that is bactericidal for M. Most strains of M. Penetration through noninflamed meninges is poor, but therapeutic concentrations are achieved in cerebrospinal fluid when the meninges are inflamed.
The most common adverse reaction to rifampin is gastrointestinal upset. Other reactions include skin eruptions, hepatitis, and, rarely, thrombocytopenia Table 8. The frequency of these reactions is low. Because rifampin induces hepatic microsomal enzymes, it may accelerate clearance of drugs metabolized by the liver e.
By accelerating the metabolism of estrogen, rifampin may interfere with the effectiveness of oral contraceptives. In persons with HIV infection who are taking HIV protease inhibitors, rifampin is usually contraindicated because drug interactions between rifampin and these agents can lead to increased rifampin levels and decreased protease-inhibitor levels, resulting in increased risk for rifampin toxicity and decreased protease-inhibitor efficacy.
Rifampin is also contraindicated or should be used with caution in HIV-infected patients who are taking non-nucleoside reverse transcriptase inhibitors NNRTIs. Rifampin is excreted in urine, tears, sweat, and other body fluids and colors them orange.
Patients should be advised of discoloration of body fluids and of possible permanent discoloration of soft contact lenses. Pyrazinamide is bactericidal for M. The drug is active against organisms in macrophages, presumably because of the acid environment within the cell. The most common side effect of pyrazinamide is gastrointestinal upset Table 8.
The most severe adverse reaction is liver injury. Hyperuricemia also occurs, but acute gout is uncommon No known interactions exist between pyrazinamide and antiretroviral medications. Rifabutin is another rifamycin that is highly active against M. Its mechanism of action is the same as that of rifampin, so that most rifampin-resistant strains are also resistant to rifabutin.
The major advantage of rifabutin is the longer serum half-life and reduced hepatic induction of microsomal metabolism compared with that of rifampin.
Doses of up to mg daily are usually well tolerated. Side effects attributed to rifabutin include rash, gastrointestinal intolerance, neutropenia, myalgias, and dysguesia. Hepatotoxicity is rare, but rifabutin can cause drug-induced hepatitis. Rates of side effects increase when rifabutin is administered with a CYP-3A4 inhibitor e. Doses of these medications may have to be increased when administered with rifabutin. When administered with rifabutin, protease inhibitors, used for the treatment of HIV infection, may lead to increased levels of rifabutin and decreased levels of the protease inhibitor; however, these effects are generally less than those that occur with rifampin and can be accommodated by dose adjustments Table 8.
The choice of the specific treatment regimen is based on many considerations as detailed in the following sections. Public Health Service Rating System. To help clinicians make informed treatment decisions based on the most current research results, evidence-based ratings are assigned to the drug treatment recommendations general recommendations have no rating Table 9.
The ratings system is similar to that used in previous PHS documents 3 and includes a letter and a Roman numeral: Thus, clinicians can use the ratings to differentiate between recommendations based on data from clinical trials and those based on the opinions of experts familiar with the relevant clinical practice and scientific rationale for such practice when clinical trial data are not available. The antituberculosis medications used in these regimens have varying doses, toxicities, and monitoring requirements Table 8.
All patients being given twice-weekly treatment should receive DOT, because nonadherence to intermittent dosing results in a larger proportion of the total doses missed than does daily dosing. DOT should be used whenever feasible, especially with 2-mo regimens and in certain settings e.
Isoniazid for 9 mo. The isoniazid daily regimen for 9 mo receives an A recommendation. Prospective, randomized trials of up to 12 mo of therapy in HIV-uninfected persons suggest that the maximal beneficial effect of isoniazid is achieved by 9 mo; minimal additional benefit is gained by extending treatment to 12 mo. Thus, this updated recommendation represents a shortening of the previous recommendation of isoniazid daily for 12 mo for HIV-infected persons and a lengthening of the previously recommended 6 mo for HIV-uninfected persons 1.
Both mo and 6-mo regimens of isoniazid have substantially reduced rates of TB in HIV-infected persons compared with placebo 88 , but the 6-mo regimen has not been directly compared with the mo regimen in HIV-infected persons. Thus, the recommendation for 9 mo of isoniazid in HIV-infected persons is based on extrapolation of available data.
Intermittent dosing of 9 mo of isoniazid for treatment of LTBI has not been studied comparatively. However, analogous with the continuation phase of treatment for active TB where twice-weekly dosing is equivalent to daily dosing , twice-weekly dosing of isoniazid is also acceptable for treatment of LTBI, but is recommended at the B level as an acceptable alternative regimen. Isoniazid for 6 mo. Although a 9-mo regimen of isoniazid is the preferred treatment of LTBI for an individual patient, a 6-mo regimen also provides substantial protection and has been demonstrated to be superior to placebo in both HIV-infected and HIV-uninfected persons 32, From a societal perspective, treatment for 6 mo rather than 9 mo may provide a more cost-effective outcome Thus, based on individual situations, health departments or other providers may prefer to concentrate efforts in ensuring the implementation of a 6-mo rather than a 9-mo course of isoniazid.
Isoniazid for 6 mo, taken either daily or twice weekly, is recommended at the B level for HIV-negative persons and at the C level for HIV-positive persons. The shorter regimen is not recommended for children or persons with radiographic evidence of prior tuberculosis. Rifampin and pyrazinamide for 2 mo. The 2-mo daily regimen of rifampin and pyrazinamide is recommended on the basis of a prospective randomized trial of treatment of LTBI in HIV-infected persons that demonstrated the 2-mo regimen to be similar in safety and efficacy to a mo regimen of isoniazid Although this regimen has not been evaluated in HIV-uninfected persons with LTBI, the efficacy is not expected to differ significantly.
However, the toxicities may be increased ; therefore, the recommendation is made at the A level for HIV-infected persons and at the B level for HIV-uninfected persons until further data are available. Two randomized, prospective trials of intermittent dosing of rifampin and pyrazinamide for 2 and 3 mo, respectively, have been reported in HIV-infected persons 86, ; in neither case was the sample size adequate to conclude with certainty that efficacy was equivalent to daily dosing.
Moreover, both studies compared the twice-weekly rifampin and pyrazinamide regimen to the 6-mo isoniazid regimen. Therefore, rifampin and pyrazinamide given twice weekly for mo may be considered when alternative regimens cannot be given. This recommendation is made at the C level. Rifampin for 4 mo. Rifampin given daily for 3 mo has resulted in better protection than placebo in treatment of LTBI in HIV-uninfected persons with silicosis in a randomized prospective trial This option may be useful for patients who cannot tolerate isoniazid or pyrazinamide.
Because more than one regimen can be used to treat LTBI, health care providers should discuss options with the patient, and, when possible, help patients make the decision, unless medical indications dictate a specific regimen.
Discussion should include the length and complexity of the regimens, possible adverse effects, and potential drug interactions. Completion of therapy is based on total number of doses administerednot on duration of therapy alone.
The 9-mo regimen of daily isoniazid should consist of doses, at minimum, administered within 12 mo, allowing for minor interruptions in therapy. The 6-mo regimen of isoniazid should consist of at least doses administered within 9 mo. Twice-weekly isoniazid regimens should consist of at least 76 doses administered within 12 mo for the 9-mo regimen and 52 doses within 9 mo for the 6-mo regimen. The daily regimen of rifampin or rifabutin and pyrazinamide should consist of at least 60 doses to be administered within 3 mo.
The regimen of daily rifampin alone should consist of at least doses administered within 6 mo. Ideally, patients should receive medication on a regular dosing schedule until completion of the indicated course. However, in practice some doses may be missed, requiring the course to be lengthened. When reinstituting therapy for patients who have interrupted treatment, clinicians might need to continue the regimen originally prescribed as long as needed to complete the recommended duration of the particular regimen or renew the entire regimen if interruptions were frequent or prolonged enough to preclude completion of treatment as recommended.
In either situation, when therapy is restored after an interruption of more than 2 mo, a medical examination to rule out active TB disease is indicated. Treatment of HIV-infected persons. Recommendations for HIV-infected adults largely parallel those for HIV-uninfected adults, although the quality of evidence and strengths of the recommendations vary Table In addition, rifampin is generally contraindicated or should be used with caution in persons who are taking protease inhibitors PIs or NNRTIs Experts have recommended that for HIV-infected persons who are candidates for treatment of LTBI and need PI or NNRTI therapy, rifabutin can be substituted for rifampin in some circumstances; rifabutin can safely be used with indinavir, nelfinavir, amprenavir, ritonavir, and efavirenz, but not with hard-gel saquinavir, or delavirdine.
Caution is advised if rifabutin is administered with soft-gel saquinavir, because data regarding use of rifabutin with soft-gel saquinavir or nevirapine are limited. No specific data have been generated for treatment of LTBI with rifabutin-containing regimens, but such a recommendation is supported by analogy with treatment for active TB where rifabutin can be substituted for rifampin with no loss of efficacy and by experimental studies in mice , Rifabutin can be administered at one half the usual daily dose i.
The daily rifabutin dose is mg or mg when used with efavirenz; pharmacokinetic studies suggest that rifabutin might be given at usual doses with nevirapine. For patients receiving multiple PIs or a PI in combination with an NNRTI, drug interactions with rifabutin are likely more complex; in such situations, the use of rifabutin is not recommended until additional data are available. The substitution of rifapentine for rifampin is not recommended because rifapentine's safety and effectiveness have not been established for patients infected with HIV Furthermore, the drug interactions between rifapentine and HIV protease inhibitors have not been studied in detail, although one study has indicated that rifapentine causes substantial reduction in the serum level of indinavir when the drugs are given together Furthermore, some experts recommend treatment of possible LTBI for HIV-infected residents of institutions that pose an ongoing high risk for exposure to M.
These regimens include 9 mo of isoniazid, 2 mo of rifampin plus pyrazinamide, or 4 mo of rifampin with or without isoniazid , providing that infection with drug-resistant organisms is judged to be unlikely. Patients who begin multidrug therapy for suspected pulmonary TB but are subsequently determined not to have active disease i.
Persons with evidence suggestive of healed, primary TB i. Their risk for TB and need for treatment of LTBI should be determined by consideration of other risk factors and the size of the tuberculin reaction Table 7. Although one study demonstrated a decrease in lymphocyte reactivity to tuberculin during pregnancy , other studies have not demonstrated an effect of pregnancy on cutaneous delayed hypersensitivity to tuberculin , The current classification scheme for interpreting the Mantoux tuberculin skin test is likely valid in pregnancy, although it has not been verified in this group of women.
There is no evidence that the tuberculin skin test has adverse effects on the pregnant mother or fetus Although the need for treatment of active TB during pregnancy is unquestioned, the treatment of LTBI in pregnant women is more controversial.
Some experts prefer to delay treatment until after delivery because pregnancy itself does not increase the risk of progression to disease, and two studies suggest that women in pregnancy and the early postpartum period may be vulnerable to isoniazid hepatotoxicity 91, However, because conditions that promote hematogenous spread of organisms to the placenta e.
The possible risk for isoniazid hepatotoxicity must be weighed against the risk for developing active TB and the consequences to both the mother and her child should active disease develop. Extensive use of isoniazid during pregnancy has indicated that although it readily crosses the placental barrier, the drug is not teratogenic even when given during the first 4 mo of gestation Hemorrhagic disease of the newborn has been described following the use of rifampin in the mother However, extensive experience with the use of rifampin to treat TB in pregnant women suggests it is safe in most circumstances.
Although pyrazinamide has been used to treat TB in pregnant women, no published data exist concerning the effects of the drug on the fetus. Thus, although pyrazinamide may be considered after the first trimester in women with HIV infection , it should otherwise be avoided.
The preferred regimen for treatment of LTBI in pregnant women is isoniazid, administered either daily or twice weekly. Although rifampin is probably safe, no efficacy data support its use.
For women at high risk for progression of LTBI to disease, especially those who are infected with HIV or who have been infected recently, initiation of therapy should not be delayed on the basis of pregnancy alone, even during the first trimester.
Pregnant women taking isoniazid should receive pyridoxine supplementation. Toxic effects of antituberculosis drugs delivered in breast milk have not been reported.
Breastfeeding is not contraindicated when the mother is being treated for LTBI. However, infants whose breastfeeding mothers are taking isoniazid should receive supplemental pyridoxine. The amount of isoniazid provided by breast milk is inadequate for treatment of the infant. Several fundamental aspects of the natural history and treatment of LTBI in children must be considered when making recommendations about therapy.
Infants and young children i. The risk for progression decreases gradually through childhood. Infants and young children are more likely than older children and adults to develop life-threatening forms of TB, especially meningeal and disseminated disease. The risk for isoniazid-related hepatitis is minimal in infants, children, and adolescents, who generally tolerate the drug better than adults , Isoniazid therapy is widely accepted for use in children.
Because of differences in pathogenesis of TB infection and disease in children compared with adults, information from clinical trials involving adults cannot be applied directly to children without confirmatory pediatric trials. The only published efficacy trials of treatment of LTBI in children have studied isoniazid alone. Routine monitoring of serum liver enzyme concentrations is not necessary but should be considered in children at risk for hepatic disease.
When children taking antituberculosis therapy develop hepatitis, a search for causes other than isoniazid or other drugs should be undertaken and the therapy discontinued.
Routine administration of pyridoxine is not recommended for children taking isoniazid, but should be given to 1 breastfeeding infants, 2 children and adolescents with diets likely to be deficient in pyridoxine, and 3 children who experience paresthesias while taking isoniazid.
Isoniazid given twice weekly has been used extensively to treat LTBI in children, especially schoolchildren and close contacts of case patients On the basis of clinical experience, this method of administration is safe, but its effectiveness has not been established definitively.
DOT should be considered when it is unlikely that the child and family will be adherent to daily self-administration. In the United States, rifampin alone has been used for the treatment of LTBI in infants, children, and adolescents when isoniazid could not be tolerated or the child has had contact with a case patient infected with an isoniazid-resistant but rifamycin-susceptible organism However, no controlled clinical trials have been conducted.
A 3-mo regimen of rifampin and isoniazid has been used in England, with programmatic data suggesting that the regimen is effective No reports have been published concerning the efficacy of rifampin and pyrazinamide therapy in children with LTBI, although a randomized study involving a limited number of children indicated that this regimen was well tolerated The American Academy of Pediatrics currently recommends a 9-mo course of isoniazid Most experts recommend that routine monitoring of serum liver enzyme concentrations be performed and pyridoxine given when HIV-infected children are treated with isoniazid.
The optimal length of rifampin therapy in children with LTBI is not known; however, the American Academy of Pediatrics recommends 6 mo of treatment Similarly, of high school students who took rifampin after being exposed to a patient with isoniazid-resistant, active TB, none developed TB during the second year of the study However, one episode of rifampin prophylaxis failure was reported among contacts of a case patient with isoniazid-resistant TB in a community outbreak For contacts of patients with isoniazid-resistant, rifampin-susceptible TB, a 2-mo regimen of rifampin and pyrazinamide is recommended.
For patients with intolerance to pyrazinamide, a 4-mo regimen of rifampin alone is recommended. In situations in which rifampin cannot be used, rifabutin can be substituted. Persons infected with isoniazid- and rifampin-resistant organisms are unlikely to benefit from treatment with regimens containing these agents.
Therefore, use of a regimen containing other agents active against M. When possible, selection of drugs for such a regimen should be guided by in vitro susceptibility test results from the isolate to which the patient was exposed and is presumed infected.
For persons who are likely to be infected with MDR TB and at high risk of developing TB, pyrazinamide and ethambutol or pyrazinamide and a fluoroquinolone i. Immunocompetent contacts may be observed without treatment or treated for at least 6 mo; immunocompromised contacts e.
Side effects of pyrazinamide and fluoroquinolones include gastrointestinal symptoms and hepatic transaminase elevations All persons with suspected MDR TB infection should be followed for at least 2 yr, irrespective of treatment. The combination of pyrazinamide and ethambutol for mo is recommended if the isolate is susceptible to both drugs.
Long-term use of fluoroquinolones in children should be avoided. Deleterious effects on growing cartilage have been observed in animals treated with fluoroquinolones , although no defects in bone growth occurred among a limited number of children with cystic fibrosis treated with ciprofloxacin or ofloxacin When pyrazinamide and ethambutol cannot be used, many experts recommend using a combination of two other drugs to which the infecting organism is likely susceptible , Low-risk tuberculin test reactors.
When treatment of LTBI is being considered for persons who are at low risk for developing TB, the decision should be based on factors such as likelihood of drug toxicity if treatment is given and likelihood of TB transmission to vulnerable contacts e. Included in this decision are the patient's preferences and values. When the assessed risk of drug toxicity exceeds the anticipated benefits of therapy, treatment for LTBI is not usually appropriate.
The criteria previously described should be applied without modification Directly observed therapy and measures to increase adherence.
Any regimen that is given intermittently i. Some experts recommend that the 2-mo regimen of daily rifampin and pyrazinamide also be given by DOT, which, for ease of administration, may consist of five observed and two self-administered doses each week. Patients with the highest priority for DOT are those at the highest risk of progression from latent to active TB, including persons with HIV infection and young children who are contacts of infectious patients with pulmonary TB.
DOT may be conveniently and effectively used for the treatment of household contacts of patients receiving DOT for active TB and for treatment observed by staff members in certain facilities e. If it is not possible to provide DOT to enhance adherence with treatment of LTBI, the prescribed regimen should be incorporated into patients' daily routines.
Medical providers can encourage adherence to treatment by establishing rapport with patients. Providers should explain in simple, clear language what LTBI is, the health threat it presents, and how it is eradicated. Patients should be encouraged to ask questions. Patient education should ideally be conducted in the patient's primary language, or through a medical interpreter, if necessary.
Each visit between patient and medical provider during therapy is an opportunity to reinforce the patient's understanding of LTBI and its treatment.
In addition to education about potential drug toxicity, patients should be told about common side effects and counseled on drug management. For example, medications should be taken with food when gastrointestinal symptoms have occurred after medication was taken on an empty stomach, and salicylic acid can be used for symptomatic treatment of arthralgia caused by pyrazinamide.
Most interventions to improve adherence require substantial financial resources. Providing flexible clinic hours, reducing waiting times for patients, spending time with patients to counsel and educate, and directly observing patients ingesting medications increase operating expenses.
Even the least intensive approaches to improve adherence increase program costs. The costs of these approaches to improving patient adherence underscore the need to target tuberculin testing and treatment of LTBI to those groups with an increased risk for recent infection or those persons at high risk for progression to active TB, if infected.
In addition, programs should invest in approaches to increase adherence, especially for those persons who are at greatest risk for progressing to disease. Better success in motivating patients to accept and to complete treatment is necessary to achieve the full potential of this intervention to protect persons from TB and to reduce the incidence of the disease in the community.
The pretreatment evaluation of persons who are targeted for treatment of LTBI provides an opportunity for health care providers to a establish rapport with patients, b discuss the details of the patients' risk for TB, c emphasize the benefits of treatment and the importance of adherence to the drug regimen, d review possible adverse effects of the regimen, including interactions with other drugs, and e establish an optimal follow-up plan.
The evaluation should include an interview conducted in the patients' primary language with assistance of qualified medical interpreters, if necessary. The patient history should document risk factors for TB, prior treatment for TB or LTBI, and preexisting medical conditions that constitute a contraindication to treatment or are associated with an increased risk for adverse effects of treatment. A detailed history of current and previous drug therapy should be obtained, with particular attention to previous adverse reactions to drugs contemplated for treatment of LTBI, and to current use of drugs which may interact with the drugs used for treatment.
Women receiving rifampin and oral contraceptives are at increased risk for becoming pregnant and should be advised to consider an additional form of contraception. Practitioners should consider using a standardized history form to ensure that all elements of the pretest evaluation are thoroughly covered for each patient. Baseline laboratory testing is not routinely indicated for all patients at the start of treatment for LTBI Table 8. Baseline testing is also indicated for patients infected with HIV, pregnant women and those in the immediate postpartum period i.
Baseline testing is no longer routinely indicated in persons older than 35 yr of age. Clinical monitoring is indicated for all patients; this involves education of patients about the symptoms and signs that can result as adverse effects of the drug s being prescribed and the need for prompt cessation of treatment and clinical evaluation should symptoms occur.
These include any of the following: Clinical monitoring begins at the first visit and should be repeated at each monthly visit. At monthly visits, patients should be instructed to interrupt therapy and contact their providers immediately upon the onset of such symptoms or any unexplained illness occurring during treatment.
Patients being treated for LTBI should receive a clinical evaluation, including a brief physical assessment checking for signs of hepatitis, at least monthly if receiving isoniazid alone or rifampin alone and at 2, 4, and 8 wk if receiving both rifampin and pyrazinamide Table 8.
These evaluations represent opportunities to review the indications for treatment, adherence with therapy since the last visit, symptoms of adverse drug effects and drug interactions, and plans to continue treatment.
As with the baseline evaluation, a standardized questionnaire may facilitate those interviews. Routine laboratory monitoring during treatment of LTBI is indicated for patients whose baseline liver function tests are abnormal and for other persons at risk for hepatic disease Table 8. In addition, laboratory testing e. Some experts recommend that isoniazid be withheld if a patient's transaminase level exceeds 3 times the upper limit of normal if associated with symptoms and five times the upper limit of normal if the patient is asymptomatic.
Reporting of serious adverse events. Practitioners and other health professionals should report serious adverse events associated with the treatment of LTBI to the U. Food and Drug Administration's MedWatch program.
Serious adverse events include those associated with hospitalization, permanent disability, or death. However, the specificity of the test is decreased by cross reactions from BCG vaccination and sensitization by nontuberculous mycobacteria. When used in populations in which the risk for TB is low, the test's positive predictive value is poor.
In addition, the requirement that the person tested return for the test to be read h after test administration creates operational problems. Thus, more specific and sensitive tests are needed to diagnose LTBI and to identify persons at greatest risk for progressing to active disease. Especially useful would be tests that distinguish skin-test reactions caused by TB infection from those caused by BCG vaccination or infection with nontuberculous mycobacteria, tests that correlate with the presence of living organisms, and tests that accurately identify LTBI in immunodeficient persons.
More data are needed regarding the acceptability, tolerability, and effectiveness of the 2-mo regimen of daily rifampin and pyrazinamide in HIV-negative persons. Data are especially needed from older adults and children.
No studies of rifampin alone taken twice weekly for the treatment of LTBI have been conducted. Data from two studies in HIV-infected persons that included intermittent i. Before additional trials of intermittent rifampin regimens are undertaken, animal model data are needed to compare these regimens with regimens using other longer-acting rifamycin derivatives see Efficacy Studies of New Drugs. It is unlikely that a formal efficacy study of intermittent isoniazid for the treatment of LTBI will be undertaken, unless it is included as a control arm for studies of newer regimens.
However, several TB-control programs have had considerable experience using this regimen. Data from these programs should be examined, especially as they relate to acceptability and completion of treatment. The analysis of aggregate data available in TB programs may also be useful in estimating the effectiveness of this regimen. Studies are needed to provide information regarding the use of newer regimens for the treatment of LTBI in children and pregnant women.
The safety of pyrazinamide for pregnant women and their fetuses should be determined. More information is needed regarding hepatotoxicity of isoniazid in pregnant and postpartum women. Studies are needed to establish the safety and effectiveness of rifampin alone and rifampin plus pyrazinamide for treatment of LTBI in infants, children, and adolescents. The best target populations for these studies would be HIV-infected children in places in which TB is prevalent and household contacts of TB case patients.
In addition, the effectiveness of twice-weekly regimens for treatment of LTBI in children should be confirmed. Finally, epidemiologic research to determine the best tools to identify children at high risk for LTBI should be undertaken. These recommendations call for the establishment of LTBI treatment programs in new community settings e. Consequently, operational research will be needed to evaluate the implementation of these programs in settings other than health departments. These studies should assess the knowledge base of treating clinicians and identify the obstacles to be overcome for the successful implementation of community-based LTBI treatment programs.
If field and programmatic data establish the effectiveness and acceptability of the rifampin and pyrazinamide regimen for the treatment of LTBI, the availability of a combination product would facilitate its administration. However, the argument concerning the usefulness of combination products in preventing the emergence of drug resistance in patients with active TB is not as compelling for persons being treated for LTBI. Nonetheless, methods to facilitate provision of this treatment and increase adherence e.
However, several rifamycin derivatives with half-lives substantially greater than rifampin are of interest because of the possibility of widely spaced, intermittent administration. In experimental studies involving mice, the combination of rifapentine and isoniazid given once weekly for 3 mo was as active as rifampin and pyrazinamide given daily for 2 mo Rifalazil, which has an even longer half-life, is more active than rifapentine and perhaps could be dosed less frequently without compromising efficacy The class of nitroimidazole compounds is also of interest because of their potential activity against dormant tubercle bacilli Unfortunately, no animal models of LTBI exist that optimize the preclinical evaluation of new drugs.
Studies of Immunomodulators and Vaccines Recent studies have indicated that immunotherapy with specific cytokines and immunomodulators may be beneficial to response to TB treatment. However, their application in the treatment of LTBI is uncertain. Some epidemiologic studies have suggested that high levels of certain cytokines e.
If further studies support this finding, interventions that stimulate production of protective cytokines may have a role in the treatment of LTBI. The development of a postinfection vaccine to be administered to persons with LTBI has been given high priority Future decision and cost-effectiveness analyses should be expanded to include targeted testing.
Instead of beginning at the "treat-don't-treat" point, new models might be most useful if they begin with the decision of whether to test. These studies should focus on groups at high risk and specific subgroups characterized by varied risks and benefits of treatment.
Using this conceptual framework will help place decision modeling more clearly into a "real world" context, incorporating the linked contingencies that exist. Future decision and cost-effectiveness analyses should compare the shorter course regimens to the longer, 9-mo regimen of daily isoniazid.
These analyses will benefit from investigations of the toxicities and efficacies of shorter regimens. In addition, although adherence presumably will be better with shorter treatment regimens, the rifampin and pyrazinamide regimen may be less well-tolerated in some groups of patients, thus resulting in low adherence.
Decision and cost-effectiveness analyses should explore a range of toxicities in the models until investigations better establish these risks. By investigating the effect of a range of toxicities and adherence on the decision outcome, studies can help identify priority areas for research. Updated analyses on the use of alternate regimens for the treatment of drug-resistant LTBI are also needed. When two different perspectives are relevant for a decision, both perspectives should be modeled and analyzed.
For example, when the benefits to an individual person with LTBI are different from the benefits to the public, both perspectives must be made explicit in decision models. When decision analysis is inadequate to deal with public health issues e. Policies designed to target and treat populations at high risk for TB are motivated by the need to benefit the individual patient as well as the health of the public by averting active disease in persons most likely to develop it.
As policies are instituted that identify high-risk groups for testing and treatment, the social and ethical ramifications of these policies must be considered. The individual persons who comprise many of the high-risk groups targeted for testing and treatment often represent disenfranchised segments of urban populations e.
Ideally, the outcomes and utilities that are used in these decision models will incorporate the values and preferences of these patients and the outcomes important to the general public.
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A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. Efficacy of various durations of isoniazid preventive therapy for tuberculosis: Isoniazid INH prophylaxis with isoniazid in inactive tuberculosis: The risk of tuberculosis in patients with fibrous lesions radiographically diagnosed. Tuberculosis morbidity of young men in relation to tuberculin sensitivity and body build.
A double-blind placebocontrolled clinical trial of three antituberculosis chemoprophylaxis regimens in patients with silicosis in Hong Kong. Silicosis in northern Rhodesia copper miners. Silicosis and risk of lung cancer or lung tuberculosis: Tuberculosis in patients undergoing maintenance hemodialysis. Risk of tuberculosis in dialysis patients: Tuberculosis in patients with end-stage renal disease.
The role of diabetes mellitus in the higher prevalence of tuberculosis among Hispanics. Incidence of pulmonary tuberculosis among diabetics: Peptic ulcer, partial gastrectomy, and pulmonary tuberculosis. Pulmonary tuberculosis after gastric resection.
Tuberculosis after jejunoileal bypass for obesity. Mycobacterial infections in renal transplant recipients: Tuberculosis in heart transplant recipients. Mycobacteriosis in patients with malignant disease.
Tuberculosis complicating neoplastic disease: The prevalence of tuberculosis and positive tuberculin skin tests in a steroid-treated asthmatic population. Reversion and reconversion rate of tuberculin skin test reactions in correlation with use of prednisone. Is tuberculosis chemoprophylaxis necessary for patients receiving corticosteroids for respiratory disease? Mycobacterium tuberculosis infection in a corticosteroid-treated rheumatic disease patient population.
Tuberculosis risk factors in adults in King County, Washington, through Centers for Disease Control. A strategic plan for the elimination of tuberculosis in the United States. Managed care and public health departments: Screening in special populations: Directly observed isoniazid preventive therapy for released jail inmates. Results of a directlyobserved intermittent isoniazid preventive therapy program in a shelter for homeless men. A tuberculin screening and isoniazid preventive therapy program in an inner-city population.
Cost-effectiveness of directly observed chemoprophylaxis of tuberculosis among drug users at high risk for tuberculosis.
Des Jarlais, and D. Tuberculosis screening at a syringe exchange program. Screening for infection and disease as a tuberculosis control measure among indigents in New York City, Diagnostic standards and classification of tuberculosis in adults and children.
The tuberculin skin test. Tuberculin reactions read at 2 and 7 days. Interpretation of the tuberculin skin test. The influence of Calmette-Guérin Bacillus immunization on the booster effect of tuberculin testing in healthy young adults. Determinants of tuberculin reactivity among health care workers: Prevalence of tuberculin positivity and skin test anergy in HIV-I seropositive and seronegative intravenous drug users.
Anergy skin testing and tuberculosis preventive therapy for HV-1 infected persons: Prevention of experimental tuberculosis with isoniazid.
How much isoniazid is needed for prophylaxis? How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults? Preventive therapy with isoniazid: Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection. A trial of three regimens to prevent tuberculosis in Ugandan adults infected with the human immunodeficiency virus. Isoniazid preventive therapy for tuberculosis in HIV-I-infected adults: Twice weekly tuberculosis preventive therapy in HIV infection in Zambia.
A controlled trial of isoniazid in persons with anergy and human immunodeficiency virus infection who are at high risk for tuberculosis. Isoniazid prophylaxis for tuberculosis in HIV infection: Prevention of tuberculosis among tuberculin reactors: Isoniazid hepatitis among pregnant and postpartum Hispanic patients.
Severe acetaminophen toxicity in a patient receiving isoniazid. Isoniazid potentiation of acetaminophen hepatotoxicity in the rat and 4-methylpyrazole inhibition of it. Twenty isoniazid-associated deaths in one state. Severe isoniazidassociated hepatitisNew York, Tuberculosis control policies in major metropolitan health departments in the United States.
Hepatotoxicity associated with isoniazid preventive therapy: Isoniazid for the tuberculin reactor: The age threshold for isoniazid chemoprophylaxis: Monitored isoniazid prophylaxis for low-risk tuberculin reactors older than 35 yr of age: Decision analysis, public health policy, and isoniazid chemoprophylaxis for young adult tuberculin skin reactors.
Experimental short-course preventive therapy of tuberculosis with rifampin and pyrazinamide. Antagonism between isoniazid and the combination pyrazinamide-rifampin against tuberculosis infection in mice.
Preventive chemotherapy of tuberculosis in Cornell model mice with combinations of rifampin, isoniazid, and pyrazinamide. Effectiveness of rifabutin alone or in combination with isoniazid in preventive therapy of mouse tuberculosis. Rifampicin and isoniazid prophylactic chemotherapy for tuberculosis.
Chemotherapy and management of tuberculosis in the United Kingdom. Rifampin and pyrazinamide vs. An international, randomized trial of rifampin and pyrazinamide versus isoniazid for prevention of tuberculosis in HIV-infected persons. Short-course preventive therapy for tuberculosis abstract.
Results of a randomized, controlled trial to assess the toxicity and patient adherence with two short-course regimens for the prevention of tuberculosis, a two-momth regimen of rifampin and pyrazinamide or a four-month regimen of rifampin only, in comparison with a control regimen of six months-isoniazid [thesis].
USPHS tuberculosis short-course chemotherapy trial Assessment of rifampin containing regimens for tuberculosis preventive therapy: Compliance and tolerance of new antituberculotic short- term chemoprevention regimes in childhood: Improving patient compliance in tuberculosis treatment programs. When tuberculosis treatment fails: Tuberculosis beliefs among recent Vietnamese refugees in New York State. A patient education program to improve adherence rates with antituberculosis drug regimens.
Harborview Medical Center, University of Washington. A clinical trial of a financial incentive to go to the tuberculosis clinic for isoniazid after release from jail. Acceptance and safety of directly observed versus self-administered isoniazid preventive therapy in aboriginal peoples in British Columbia. The outcome of chemoprophylaxis on tuberculosis prevention in the Canadian Plains Indian. Directly observed preventive therapy: A dose, 6-month therapy for pulmonary and extrapulmonary tuberculosis: Determinants of rifabutin-associated uveitis in patients treated with rifabutin, clarithromycin, and ethambutol for Mycobacterium avium complex bacteremia: Concurrent ritonavir and rifabutin increases risk of rifabutin-associated adverse events [Abstract no.
Efficacy and safety of rifabutin in the treatment of patients with newly diagnosed pulmonary tuberculosis. Acquired riifamycin monoresistance in patients with HIV-related tuberculosis treated with once-weekly rifapentine and isoniazid. Tuberculosis in association with pregnancy. Lymphocyte reactivity to antigen in pregnancy. The tuberculin test in pregnancy. Tuberculin sensitivity in pregnancy. Treatment of tuberculosis during pregnancy. Antituberculous therapy in pregnancy: Van De Casseye, M.
Hemorrhagic disease of the newborn in the offspring of rifampin and isoniazid treated mothers. Should women taking antituberculosis drugs breast-feed? Little Brown, Boston, MA. Isoniazid prophylaxis in Alaskan boarding schools: Preventive effects of isoniazid in the treatment of primary tuberculosis in children. Hepatotoxicity from isoniazid and rifampin among children treated for tuberculosis. Clinical hepatotoxicity of isoniazid in children. Rifampin preventive therapy for tuberculosis infection: American Academy of Pediatrics.
Report of the Committee on Infectious Diseases, 25th ed. In press Koplan, J.