BNF for Children 2011-2012

292 5.1.9 Antituberculosis drugs BNFC 2011–20125 InfectionsFor prevention of tuberculosis in susceptible close contactsor those who have become tuberculin-positive, seeTable 2, section 5.1. For advice on immunisation againsttuberculosis and tuberculin testing, see section 14.4.Monitoring Since isoniazid, rifampicin and pyrazinamideare associated with liver toxicity, hepatic functionshould be checked before treatment with these drugs.Those with pre-existing liver disease should have frequentchecks particularly in the first 2 months. If there isno evidence of liver disease (and pre-treatment liverfunction is normal), further checks are only necessary ifthe patient develops fever, malaise, vomiting, jaundiceor unexplained deterioration during treatment. In viewof the need to comply fully with antituberculous treatmenton the one hand and to guard against serious liverdamage on the other, children and their carers should beinformed carefully how to recognise signs of liver disordersand advised to discontinue treatment and seekimmediate medical attention should symptoms of liverdisease occur.Renal function should be checked before treatment withantituberculous drugs and appropriate dosage adjustmentsmade. Streptomycin or ethambutol should preferablybe avoided in patients with renal impairment,but if used, the dose should be reduced and the plasmadrugconcentration monitored.Visual acuity should be tested before ethambutol isused (see below).Major causes of treatment failure are incorrect prescribingby the physician and inadequate complianceby the child or their carer. Monthly tabletcounts and urine examination (rifampicin impartsan orange-red coloration) may be useful indicatorsof compliance with treatment. Avoid both excessiveand inadequate dosage. Treatment should be supervisedby a specialist paediatrician.Isoniazid is cheap and highly effective. Like rifampicinit should always be included in any antituberculousregimen unless there is a specific contra-indication. Itsonly common side-effect is peripheral neuropathy whichis more likely to occur where there are pre-existing riskfactors such as diabetes, chronic renal failure, malnutritionand HIV infection. In these circumstances, and inbreast-fed infants treated with isoniazid, pyridoxine(section 9.6.2) should be given prophylactically fromthe start of treatment. Other side-effects such as hepatitis(important: see Monitoring above) and psychosis arerare.Rifampicin, a rifamycin, is a key component of anyantituberculous regimen. Like isoniazid it should alwaysbe included unless there is a specific contra-indication.During the first two months (‘initial phase’) of rifampicinadministration transient disturbance of liver functionwith elevated serum transaminases is common butgenerally does not require interruption of treatment.Occasionally more serious liver toxicity requires achange of treatment particularly in those with pre-existingliver disease (important: see Monitoring above).On intermittent treatment six toxicity syndromes havebeen recognised—influenza-like, abdominal, and respiratorysymptoms, shock, renal failure, and thrombocytopenicpurpura—and can occur in 20 to 30% ofpatients.Rifampicin induces hepatic enzymes which acceleratethe metabolism of several drugs including oestrogens,corticosteroids, phenytoin, sulfonylureas, and anticoagulants;interactions: Appendix 1 (rifamycins). Important:the effectiveness of hormonal contraceptives isreduced and alternative family planning advice shouldbe offered (section 7.3.1).Rifabutin is indicated in adults for prophylaxis againstM. avium complex infections in patients with a low CD4count; it is also licensed in adults for the treatment ofnon-tuberculous mycobacterial disease and pulmonarytuberculosis. There is limited experience in children. Aswith rifampicin it induces hepatic enzymes and theeffectiveness of hormonal contraceptives is reducedrequiring alternative family planning methods.Pyrazinamide is a bactericidal drug only active againstintracellular dividing forms of Mycobacterium tuberculosis;it exerts its main effect only in the first two orthree months. It is particularly useful in tuberculousmeningitis because of good meningeal penetration. Itis not active against M. bovis. Serious liver toxicity mayoccasionally occur (important: see Monitoring above).Ethambutol is included in a treatment regimen if isoniazidresistance is suspected; it can be omitted if therisk of resistance is low.Side-effects of ethambutol are largely confined to visualdisturbances in the form of loss of acuity, colour blindness,and restriction of visual fields. These toxic effectsare more common where excessive dosage is used or ifthe child’s renal function is impaired. The earliest featuresof ocular toxicity are subjective and children andtheir carers should be advised to discontinue therapyimmediately if deterioration in vision develops andpromptly seek further advice. Early discontinuation ofthe drug is almost always followed by recovery of eyesight.Those who cannot understand warnings aboutvisual side-effects should, if possible, be given an alternativedrug. In particular, ethambutol should be usedwith caution in children until they are at least 5 years oldand capable of reporting symptomatic visual changesaccurately.Where possible visual acuity should be tested by Snellenchart before treatment with ethambutol.Streptomycin is now rarely used in the UK except forresistant organisms. Plasma-drug concentration shouldbe measured in patients with impaired renal function inwhom streptomycin must be used with great care. Sideeffectsincrease after a cumulative dose of 100 g, whichshould only be exceeded in exceptional circumstances.Drug-resistant tuberculosis should be treated by a specialistpaediatrician with experience in such cases, andwhere appropriate facilities for infection-control exist.Second-line drugs available for infections caused byresistant organisms, or when first-line drugs cause unacceptableside-effects, include amikacin, capreomycin,cycloserine, newer macrolides (e.g. azithromycin andclarithromycin), quinolones (e.g. moxifloxacin) and protionamide(prothionamide; no longer on UK market).Availability of suitable formulations may limit choice inchildren.CYCLOSERINECautions monitor haematological, renal, and hepaticfunction; interactions: Appendix 1 (cycloserine)