SUPAWAN CHANPRADAB Division of Infectious Diseases Department of Pediatrics Queen Sirikit National Institute of Child Health Children usually have low organism numbers. Cavitating disease is relatively rare (about 6% of cases or fewer in those under 13 years of age) In contrast, children develop extrapulmonary TB more often than adults do.Severe and disseminated TB occur especially in young children (less than 3 years old). Treatment outcomes in children are generally good, low risk of adverse events associated with use of the recommended treatment regimens. First - Line Treatment of Tuberculosis (TB) for Drug-Sensitive TB Because of the high risk of disseminated tuberculosis in infants and children younger than 4 years of age, treatment should be started as soon as the diagnosis of tuberculosis is suspected. In general, the regimens recommended for adults are also the regimens of choice for infants, children, and adolescents with tuberculosis, with the exception that ethambutol is not used routinely in children. When clinical or epidemiologic circumstances suggest an increased probability of INH resistance, EMB can be used safely at a dose of 15--20 mg/kg per day, even in children too young for routine eye testing. Streptomycin, kanamycin, or amikacin also can be used as the fourth drug, when necessary. Treatment of Tuberculosis, Morbidity and Mortality Weekly Report, June 20, 2003. Antituberculosis treatment in children The main objectives of anti-TB treatment are : 1. Cure the patient of TB (by rapidly eliminating most of the bacilli) 2. prevent death from active TB or its late effects 3. prevent relapse of TB (by eliminating the dormant bacilli) 4. prevent the development of drug resistance (by using a combination of drugs) 5. decrease TB transmission to others Guidance for national tuberculosis programmes on the management of tuberculosis in children : World Health Organization, 2006. Recommended treatment regimens Anti-TB treatment is divided into two phases: 1. Intensive phase The purpose : to rapidly eliminate the majority of organisms and to prevent the emergence of drug resistance. uses a greater number of drugs 2. Continuation phase The purpose : to eradicate the dormant organisms. fewer drugs because the risk of acquiring drug resistance is low, as most of the organisms have already been eliminated. In either phase, treatment can be given daily or three times weekly. Guidance for national tuberculosis programmes on the management of tuberculosis in children : World Health Organization, 2006. In general, extrapulmonary tuberculosis in children can be treated with the same regimens as pulmonary disease. Exceptions are disseminated tuberculosis and tuberculous meningitis : 9--12 months of treatment is recommended. The optimal treatment of pulmonary tuberculosis in children and adolescents with HIV infection is unknown. The American Academy of Pediatrics recommends that initial therapy should always include at least three drugs, and the total duration of therapy should be at least 9 months, although there are no data to support this recommendation. Treatment of Tuberculosis, Morbidity and Mortality Weekly Report, June 20, 2003. The recommended treatment regimens for children. Guidance for national tuberculosis programmes on the management of tuberculosis in children : World Health Organization, 2006. Guidance for national tuberculosis programmes on the management of tuberculosis in children : World Health Organization, 2006. N Engl J Med, Vol. 345, No. 3. July 19, 2001. Table - Drug side effects SIDE EFFECTS AND INTERACTIONS OF DRUGS,CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT. SIDE EFFECTS AND INTERACTIONS OF DRUGS,CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT SIDE EFFECTS AND INTERACTIONS OF DRUGS,CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT SIDE EFFECTS AND INTERACTIONS OF DRUGS,CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT Baseline and Follow-Up Evaluations At the time treatment is initiated appropriate specimens collected for microscopic exam and mycobacterial culture. three sputum specimens should be obtained 8--24 hours apart. Susceptibility testing for INH, RIF, and EMB should be performed on an initial positive culture Second-line drug susceptibility testing should be done only in reference laboratories and be limited to specimens from patients who have had prior therapy, have been in contact of a patient with known drug resistance, have demonstrated resistance to rifampin or two other first-line drugs, or who have positive cultures after more than 3 months of treatment. Measurements of AST, bilirubin, alkaline phosphatase, and serum creatinine and a platelet count Testing of visual acuity (Snellen chart) and color vision (Ishihara tests) should be performed when EMB is to be used. In addition, it is recommended that all patients with tuberculosis have counseling and testing for HIV infection Patients with epidemiologic factors suggesting a risk for hepatitis B or C, for example, injection drug use, birth in Asia or Africa, or HIV infection, should have serologic tests for these viruses During treatment a sputum specimen for AFB smear and culture should be obtained at monthly intervals until two consecutive specimens are negative on culture. For patients who had positive AFB smears at the time of diagnosis, follow-up smears may be obtained at more frequent intervals (e.g., every 2 weeks until two consecutive specimens are negative) to provide an early assessment of the response to treatment, especially for patients in situations in which the risk of transmission is high. a repeat chest radiograph at completion of 2 months of treatment may be useful but is not essential As a routine, it is not necessary to monitor liver or renal function or platelet count unless there were abnormalities at baseline or there are clinical reasons to obtain the measurements Patients who have stable abnormalities of hepatic or renal function at baseline should have repeat measurements early in the course of treatment Patients receiving EMB should be questioned regarding visual disturbances at monthly intervals; monthly repeat testing of visual acuity and color vision is recommended for patients receiving an EMB dose exceeding 15--20 mg/kg (the recommended range) and for patients receiving the drug for more than 2 months. Definition of Completion of Therapy Treatment for a defined duration without accounting for the number of doses taken can result in undertreatment. Therefore, the determination of whether or not treatment has been completed is based on the total number of doses taken---not solely on the duration of therapy In some cases, either because of drug toxicity or nonadherence to the regimen, the specified number of doses cannot be administered within the targeted time period Adverse drug reactions Adverse events caused by anti-TB drugs are much less common in children than in adults. Mild adverse effects can generally be managed with symptomatic therapy, whereas with more severe effects the offending drug or drugs must be discontinued. ข ข ข Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003. Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003. Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003. Adverse drug reactions Gastrointestinal upset : nausea, vomiting, poor appetite, abdominal pain Rash Drug fever Hepatitis Miscellaneous : Arthalgias (joint pain) Flushing reactions Influenza Syndrome Neurotoxicity Optic Neuritis (vision) Gastrointestinal upset : nausea, vomiting, poor appetite, abdominal pain Gastrointestinal reactions are common, particularly in the first few weeks of therapy. Many of the antituberculosis drugs can cause gastrointestinal upset In the presence of gastrointestinal symptoms serum AST and bilirubin should be measured. If the AST level is less than three times the upper limit of normal, the symptoms are assumed not to be due to hepatic toxicity. The initial approach to gastrointestinal intolerance, not associated with hepatic toxicity, is to change the hour of drug administration and/or to administer the drugs with food. If patients are taking daily DOT, the timing of the drug administration should be altered, preferably to be closer to mealtime. Alternatively, food can be taken at the time of DOT administration. Patients receiving self-administered therapy can take the medications at bedtime. If gastrointestinal intolerance persists it may be best for all medications to be taken with meals. Rash All drugs used in treating tuberculosis can cause a rash. The response to a patient with a rash depends on its severity. The rash may be minor, affecting a limited area or being predominantly manifested as itching, antihistamines should be given for symptomatic relief, but all antituberculosis medications can be continued. A petechial rash may suggest thrombocytopenia in patients taking RIF. The platelet count should be checked and, if low, RIF hypersensitivity should be presumed to be the cause. RIF should be stopped and the platelet count monitored until it returns to baseline; RIF should not be restarted. a generalized erythematous rash, especially if it is associated with fever and/or mucous membrane involvement, all drugs should be stopped immediately. If the patient has severe tuberculosis, three new drugs (e.g., an aminoglycoside and two oral agents) should be started. When the rash is substantially improved the medications can be restarted one by one, at intervals of 2-3 days. RIF should be restarted first (because it is the least likely to cause rash, and it is the most important agent), followed by INH, and then EMB or PZA. If the rash recurs the last drug added should be stopped. drug rash Figure 1 & 2: Pruritic erythematous maculopapular lesions over the abdomen Thrombocytopenia--a rare but potentially serious side effect of initial daily and interrupted use of rifampicin usually occurs during high-dose intermittent treatment. About 6 percent of patients receiving high-dose twice-weekly rifampicin develop thrombocytopenia. only a few cases of thrombocytopenia develop during daily treatment or after administration of rifampicrn following an interruption of therapy. diagnosed by the temporal relationship between the start of drug administration and the onset ofthrombocytopenia, and confirmed by recovery after the cessation of the drug. platelet count usually returns to normal range within 36 hours might be explained by the existence of IgG and IgM antibodies to RIF. These antibodies could fix a complement on the platelets in th presence of rifampicin, resulting in platelet destruction. Chest 1989;96;202-203. Drug fever Recurrence of fever in a patient who has been receiving therapy for several weeks should suggest drug fever, especially if the patient is showing microbiological and radiographic improvement. The clinical hallmark of drug fever is that the patient looks and feels well despite having a high fever (often greater than 39ºC) , no specific pattern to the fever. Eo may or may not be present. The first step in management To ensure that there is no superinfection or worsening of tuberculosis. If these potential causes are excluded all drugs should be stopped, fever usually will resolve within 24 hours. Patients with severe TB should be given at least 3 new drugs in the interim. Once the fever has resolved, the same protocol as described above for restarting drugs in the presence of a rash should be followed. Hepatitis Three of the first-line antituberculosis drugs, INH, RIF, and PZA, can cause drug-induced liver injury INH + rifampin > INH alone >> pyrazinamide alone > rifampin alone > ethionamide AST level three or more times the upper limit of normal in the presence of symptoms or five or more times the upper limit of normal in the absence of symptoms • If the AST level < 5 times : mild toxicity AST level 5-10 times : moderate toxicity AST level > 10 times : severe toxicity * Toxic hepatitis with isoniazid and rifampin: a meta-analysis. Chest 1991;99:465–471. an asymptomatic increase in AST concentration occurs in nearly 20% of patients treated with the standard four-drug regimen* In the absence of symptoms, therapy should not be altered but the frequency of clinical and laboratory monitoring should be increased. In most patients, asymptomatic aminotransferase elevations resolve spontaneously. However, if AST levels > 5 times the upper limit of normal (with or without symptoms) or > 3 times normal in the presence of symptoms, hepatotoxic drugs should be stopped immediately and the patient evaluated carefully. *Toxic hepatitis with isoniazid and rifampin: a meta-analysis. Chest 1991;99:465–471. In addition to AST elevation, occasionally there are disproportionate increases in bilirubin and alkaline phosphatase. This pattern is more consistent with rifampin hepatotoxicity Patients should be screened for other causes of hepatitis (Serologic testing for hepatitis A, B, and C), questioned carefully regarding symptoms suggestive of biliary tract disease, exposures to other potential hepatotoxins, particularly alcohol and hepatotoxic medications. If treatment for TB needs to be continued for severe forms of TB, nonhepatotoxic anti-TB drugs should be introduced (at least 3 drugs e.g. ethambutol, aminoglycoside and fluoroquinolone) The suspect antituberculosis medications should be restarted one at a time after the AST concentration returns to less than two times the upper limit of normal. (In patients with elevated baseline AST from preexisting liver disease, drugs should be restarted when the AST returns to near baseline levels.) Because RIF is much less likely to cause hepatotoxicity than is INH or PZA and is the most effective agent, it should be restarted first. RIF → INH → PZA ( every 1 week if AST does not increase) If symptoms recur or AST increases the last drug added should be stopped. If RIF and INH are tolerated, and hepatitis was severe, PZA should be assumed to be responsible and should be discontinued. In this last circumstance, depending on the number of doses of PZA taken, severity of disease, and bacteriological status, therapy might be extended to 9 months. Risk factors for hepatotoxicity from antituberculosis drugs: a case- control study A case-control study was undertaken to assess the role of age, sex, disease extent, nutritional status, past history of liver disease, infection with hepatitis viruses, acetylator status, and high alcohol intake as risk factors in the development of hepatotoxicity in patients with pulmonary tuberculosis receiving antituberculosis. METHODS: The cases comprised 86 consecutive patients who were diagnosed as having hepatitis induced by antituberculosis drugs and who were negative for any of the hepatitis markers. The control group comprised 406 consecutive patients who completed antituberculosis treatment without developing hepatitis. RESULTS: The cases were older and their serum albumin levels were lower than in the control group. High alcohol intake was more common among the cases, they had more extensive disease radiologically, and the proportion of slow acetylators was higher. No differences were observed between the two groups in the other risk factors analysed. CONCLUSIONS: only advanced age, hypoalbuminaemia, high alcohol intake, slow acetylator phenotype, and extensive disease were risk factors for the development of hepatotoxicity. The risk of hepatitis in the presence of one or more of these risk factors may be increased. JN Pande et al.Thorax, Vol 51, 132-136. KATHMANDU UNIVERSITY JOURNAL OF SCIENCE, ENGINEERING AND TECHNOLOGY VOL.II, No.1, FEBRUARY, 2006. Risk factors for hepatotoxicity 1. hypoalbuminaemia * , 2. advanced age * **** 3. high alcohol intake * , **** 4. slow acetylator phenotype * 5. extensive disease *, **, *** , 6. Female ** *** 7. Poor nutritional status **, *** , **** 8. chronic viral infection with HBV, HCV **** 9. HIV **** * Thorax, Vol 51, 132-136. ** KATHMANDU UNIVERSITY JOURNAL OF SCIENCE, ENGINEERING AND TECHNOLOGY VOL.II, No.1, 2006. *** Ann Pharmacother 2004; 38(6): 1074-9. **** Indian J Exp Biol 2003; 41(11):1226-32. A study from Nepal reported the incidence of hepatotoxicity as 8%.. The mild elevation of transaminases seen in as many as 20% of patients who are treated during the first 2 months of therapy The more severe hepatitis seen in up to 1% of adults who are treated may be a consequence of the production of more reactive species by the cytochrome P-450 enzyme system Incidence of hepatotoxicity due to antitubercular medicines and assessment of risk factors. Ann Pharmacother 2004; 38(6): 1074-9 The biochemical mechanism of isoniazid hepatotoxicity remains incompletely defined. The most widely accepted theory is that isoniazid metabolism produces reactive metabolites that bind to and damage cellular macromolecules in the liver. some studies suggest that people who are slow acetylators are at greater risk, suggesting that slow metabolism results in diversion of isoniazid metabolism to an alternate (eg, cytochrome P-450–mediated) pathway that may produce a toxic metabolite. Recent studies show that polymorphism of N-acetyl transferase 2 (NAT2) genes and glutathione-s-transferase (GST) are the major susceptibility risk factors for ATT induced hepatitis. Slow acetylators of NAT2 develop more severe hepatotoxicity than rapid acetylators making it a significant risk factor. Antituberculosis drug-induced hepatitis: risk factors, prevention and management. Indian J Exp Biol 2003; 41(11):1226-32. Antituberculosis Drugs and Hepatotoxicity VOL.12 NO.1 JANUARY 2007. Grading of adverse drug events (2) Grading of adverse drug events (1) Grading of adverse drug events (2) Guidelines on co-trimoxazole prophylaxis for HI V-related infections among children, adolescents and adults, World Health Organization 2006. Miscellaneous Adverse Effects : Arthalgias (joint pain) Arthalgias Type 1 pyrazinamide>>ethambutol>isoniazid pain and tenderness of joints: fingers, shoulders, knees, etc. (usually mild) Management TB medications do not require discontinuation low dose nonsteroidal antiinflammatory agents (NSAIDS) can be used for pain relief as needed if symptoms persist, consider referral for rheumatologic evaluation Arthalgias Type 2 (Gouty Arthritis) pyrazinamide>>ethambutol pain, tenderness and swelling of joints: fingers, shoulders, knees, etc. symptoms are usually severe signs: elevated serum uric acid concentrations Management TB medications usually do not require discontinuation If acute swelling is present, the affected joint should be aspirated and examined for urate crystals to confirm the diagnosis of acute gouty arthritis. Drug : nonsteroidal antiinflammatory agents, colchicine Consider referral for rheumatologic evaluation for acute gouty arthritis attacks Flushing reactions flushing and/or itching of the skin with or without a rash hot flashes, palpitations,headache and/or increased blood pressure usually involves the face and scalp; may cause redness/watering of the eyes usually occurs 2-3 hours after drug ingestion Reaction : rifampin, pyrazinamide : isoniazid + tyramine containing foods (cheese, red wine) or certain fish (tuna, skipjack) Management flushing is usually mild and resolves without therapy if flushing is bothersome to the patient, an antihistamine may be administered to treat Influenza Syndrome rifampin > rifabutin (intermittent regimens > daily regimens) fever, headache, bone pain usually occurs 1-2 hours after drug administration usually resolves within 12 hours of drug administration Management switch from intermittent therapy to daily dosing (7 days/week) symptomatic therapy may be required when switching from intermittent to daily therapy to prevent the reaction with initial doses Neurotoxicity : Peripheral Neuropathy INH>>>ethambutol prickling, tingling or burning sensation of the fingers and/or toes usually occurs in a stocking glove distribution rarely occurs in children unless severe malnutrition is present. uncommon if the patient is receiving pyridoxine (vitamin B6) Treatment : pyridoxine 100-200mg po q day while the patient is receiving INH. Nervous System Effects in Children INH *** Clinical Presentation : drowsiness or hyperactivity dizziness, tonic/clonic seizures (rare) Management 1. Drowsiness a. make sure the dose does not exceed 10 mg/kg/d b. add pyridoxine 50mg to the regimen c. administer medications around afternoon naps or at bedtime 2. Hyperactivity a. make sure the dose does not exceed 10mg/kg/d b. switch to twice weekly dosing as soon as possible 1) if the child becomes hyperactive only on the days of medication administration, then the medication is the cause 2) add pyridoxine 50mg daily for 6 weeks, then twice weekly for the remainder of therapy 3. Dizziness a. make sure the dose does not exceed 10mg/kg/d 4. Tonic/clonic seizures a. hospitalize the child and administer isoniazid to document the reaction b. if a seizure occurs, discontinue isoniazid and add an alternative agent to the regimen Optic Neuritis (vision) ethambutol >>INH Clinical Presentation : blurred vision (decrease in the “sharpness” of objects) “spots” present in patient’s field of vision red/green color blindness optic neuritis has not been documented in children Management discontinue drug Guidelines for the Management of Adverse Drug Effects of Antimycobacterial Agents, Lawrence Flick Memorial Tuberculosis Clinic Philadelphia Tuberculosis Control Program November 1998. Isoniazid (INH) A prospective cohort study of 11,141 patients receiving INH preventive therapy reported a rate of hepatitis lower than that previously reported. Of these, 11 patients (0.10% of those starting, and 0.15% of those completing therapy) developed clinical hepatitis. Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a Public Health Tuberculosis Clinic. JAMA 1999; 281(11):1014-8. Hepatotoxicity is rare in children receiving INH. In a 10-year retrospective analysis, the incidence of hepatotoxicity in 564 children receiving INH (10 milligrams per kilogram per day (mg/kg/day) to a maximum of 300 mg/day) for the prophylactic treatment of tuberculous was 0.18%. Incidence of hepatotoxicity in children receiving isoniazid chemoprophylaxis. Pediatr Infect Dis J 1989; 8:649-50. However, the incidence of hepatotoxicity in children receiving INH and rifampicin for TB was 3.3% in another retrospective study (14 of 430 children). Hepatotoxicity from isoniazid and rifampin among children treated for tuberculosis. Pediatrics 1983; 72:491-9. Pyrazinamide The most common adverse effect of this drug is hepatotoxicity. Hepatotoxicity is dose related and may occur any time during therapy. In the Centre for Diseases Control (CDC) update, 48 cases of hepatotoxicity were reported in association with a 2-month regimen of Rifampin-pyrazinamide for the treatment of latent tuberculosis between October 2000 and June 2003. Thirty-seven patients recovered and 11 died of liver failure. Of the 48 reported cases, 33 (69%) occurred in the second month of therapy. CDC: Update: Adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection-United States, 2003. MMWR 2003; 52 (31):735-9. Strategies to minimize the occurrence of hepatotoxicity Liver function tests are to be done before the start of treatment and monitored every 2 weeks during the initial two months in the risk groups like patients with pre-existing liver disorders, alcoholics, the elderly and the malnourished. Close clinical and biochemical monitoring is to be done in hepatitis B carriers also as there is higher incidence of liver dysfunction and symptomatic hepatitis. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology 2000; 3: 201-6. Ethambutol There are fewer reports of hepatotoxicity with Ethambutol in the treatment of TB. Abnormal liver function tests have been reported in some patients taking ethambutol; however, these patients were also taking other antiTB drugs known to cause liver dysfunction. The management of anti-tuberculosis drug-induced hepatotoxicity. Int J Tuberc Lung Dis 2001; 5 (1): 65-9. Rifampicin Transient abnormalities in liver function are common in the initial stages of therapy. But in some cases it may cause severe hepatotoxicity, more so in those with pre-existing liver disease, forcing the physician to change treatment and opt for liver friendly treatment. Rifampicin causes transient elevations in hepatic enzymes usually within the first 8 weeks of therapy in 10% to 15% of patients, with less than 1% of the patients demonstrating overt rifampicin-induced hepatotoxicity. The occurrence of mortality associated with hepatotoxicity has been reported to be 16 in 500,000 patients receiving rifampicin. A higher incidence of hepatotoxicity has been reported in patients receiving rifampicin with other anti TB agents, and is estimated to be fewer than 4%. McNeill L, Allen M, Estrada C, et al: Pyrazinamide and rifampin vs isoniazid for the treatment of latent tuberculosis: improved completion rates but more hepatotoxicity. Chest 2003; 123:102-6 Manifestations of rifampicin-induced hypersensitivity The side effects of rifampicine due to an immunoallergic mechanism are rare and usually observed during discontinued treatment or administration of high doses. OBSERVATIONS: An immediate hypersensitivity reaction with anaphylactic manifestations and increase in IgE occurred in a 39 year-old man suffering from resistant tuberculosis. The reaction occurred within the first hour following a low dose of rifampicin administered in a desensitisation attempt, the outcome of which was favourable after administration of corticosteroids and antihistamines. A type II hypersensitivity reaction occurred in a 76 year-old male patient in the form of thrombopenia on D76 of a twice weekly treatment, diagnosed because of hemoptysis with normalisation of platelet level on withdrawal of rifampicin. An immune complex hypersensitivity reaction was responsible for hepato-renal failure on D68 of twice weekly treatment and required permanent withdrawal of rifampicin and dialysis, which led to subsequent improvement. COMMENTS: These clinical cases illustrate the variability of the hypersensitivity mechanisms observed with rifampicin, the difficulty in imputability tests and methods for immunological confirmation, the interest of continuous treatment which avoids a certain number of these accidents, and that of desensitisation during immediate hypersensitive reactions which permits the continuation this major anti-tuberculosis drug. Presse Med. 2003 Jul 26;32(25):1167-9. Education of caregivers regarding sign and symptom of potential A/E is preferable SIDE EFFECTS AND INTERACTIONS OF DRUGS,CHEST, 76: 6, DECEMBER, 1979 SUPPLEMENT or more severe liver injury may occur from one week to many months after the initiation of isoniazid therapy; however, the majority_of cases of isoniazid-pssociated hepatitis occur within the first three months of treatment, In most patients,.improvement occurs shortly after isoniazid has been discontinu&cLıpd is almost always complete. Monitoring liver enzymes has not proved useful in detectinıgjsoniazid- associated hepatitis except in those patients who report gastrointestinal symptoms such as anorexia, nausea, vomiting or jaundice.