Paediatric Respiratory Reviews

Paediatric Respiratory Reviews 12 (2011) 31 38 Contents lists available at ScienceDirect Paediatric Respiratory Reviews Mini-symposium: Childhood TB in 2010 Management of multidrug-resistant tuberculosis in children: a survival guide for paediatricians H. Simon Schaaf *, Ben J Marais Department of Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, and Tygerberg Children s Hospital, Cape Town, South Africa EDUCATIONAL AIMS To discuss the epidemiology of and mechanisms responsible for the emergence of drug resistant TB in children To provide clear guidance on how best to diagnose and treat drug-resistant TB in children To discuss ancillary treatment options and the management of HIV-infected children with drug-resistant TB ARTICLE INFO SUMMARY Keywords: multidrug-resistant tuberculosis children XDR-TB MDR-TB treatment WHO estimated that of 9.4 million cases of tuberculosis (TB) worldwide in 2008, 440,000 (3.6%) had multidrug-resistant (MDR)-TB. Childhood TB is estimated at 10-15% of the total burden, but little is known about the burden of MDR-TB in children. Children in close contact with MDR-TB cases are likely to become infected with the same resistant strains and are vulnerable to develop disease. Although MDR- TB is a microbiological diagnosis, children should be treated empirically according to the drug susceptibility result of the likely source case, as often cultures cannot be obtained from the child. MDR- TB treatment in children is guided by the same principles, using the same second-line drugs as in adults, with careful monitoring for adverse effects. Co-infection with HIV poses particular challenges and requires early initiation of antiretroviral therapy. Preventive therapy for high-risk MDR-TB contacts is necessary, but no consensus guidance exists on how best to manage these cases. Pragmatic and effective Infection control measures are essential to limit the spread of MDR-TB. ß 2010 Elsevier Ltd. All rights reserved. HOW COMMON IS TUBERCULOSIS AND MDR-TB IN CHILDREN? The World Health Organization (WHO) estimated that in 2008, 440,000 (3.6%) of the 9.4 million tuberculosis (TB) cases worldwide had multidrug-resistant (MDR)-TB (i.e. resistance to isoniazid and rifampicin). 1 Childhood TB comprise approximately 10-15% of the global disease burden, with higher rates in developing countries. 2 Little data is available on the occurrence of MDR-TB in children. 3 A prospective drug resistance surveillance study conducted from 1994-2007 in the Western Cape province, South Africa, demonstrated a clear upward trend with an increase in any resistance (isoniazid and/or rifampicin) from 6.9% to 15.1% and in MDR-TB from 2.3% to 6.7%. 4 Since the majority of children (>90%) who develop TB do so within 12 months of infection, paediatric surveillance studies provide unique epidemiologic insight into current Mycobacterium * Corresponding author. Department of Paediatrics and Child Health, PO Box 19063, Tygerberg, 7505, South Africa. Tel.: +27 21 9389112; Fax: +27 21 9389138. E-mail address: hss@sun.ac.za (H.S. Schaaf). tuberculosis transmission patterns within communities, indicating which genotypes are successfully transmitted. 5,6 The absence of data on drug-resistant TB among children reflects the fact that cultures for M. tuberculosis and drug susceptibility testing (DST) are rarely done, since obtaining adequate specimens in child TB suspects are difficult and mycobacterial culture yields are low. In addition, careful identification of the likely adult source case is poorly performed and if child contacts are identified, the treatment response and/or DST of the adult source case is rarely considered when treatment or chemoprophylaxis is initiated in children. 4,7 This overview describes what is known about the epidemiology, diagnosis and management of children with MDR-TB. HOW DOES DRUG RESISTANCE DEVELOP AND SPREAD? There are two underlying concepts; 1) the acquisition of drug resistance by individual patients, originally infected with drugsusceptible bacilli (acquired drug resistance), and 2) transmission of drug-resistant bacilli (transmitted drug resistance). M. tuberculosis acquires drug resistance through spontaneous gene mutations; there is no horizontal gene transfer between 1526-0542/$ see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2010.09.010

32 H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 31 38 bacilli. Therefore, the risk of acquiring drug resistance is directly proportional to the number of bacilli present; a bacterial load of >10 6 bacilli is likely to contain some drug-resistant mutants. 8 Spontaneous resistance mutations occur with variable frequency; mutations against second-line drugs occur with greater frequency compared to first-line drugs. The estimated number of bacilli present in caseous foci (e.g. intrathoracic lymph node disease in children), is low (10 4-10 5 ), while large numbers of bacilli (10 7-10 9 ) are present within pulmonary cavities of adult-type lung disease. 8 Drug-resistant TB is a man-made disease reflecting sub-optimal case management. Treatment with a single drug rapidly selects for drug-resistant disease. Using a combination of 3-4 drugs kills different mycobacterial subpopulations and protects against the development of drug resistance. If single drugs are used in succession, or a weak combination of drugs with insufficient protection of companion drugs, then additional drug resistance accumulates. Acquisition and amplification of drug resistance result from poor drug regimens (e.g. adding a single drug to a failing regimen, prescribing a weak combination of drugs, interruption of drug supply or using drugs with poor bioavailability) and/or non-adherence to treatment. The risk is highest in adults with lung cavities and relatively low in children with paucibacillary disease. Delayed diagnosis and/or poor management of infectious drugresistant TB cases allows drug-resistant M. tuberculosis strains to be transmitted and cause disease, especially in vulnerable groups [()TD$FIG] such as young children and immunocompromised patients. Early diagnosis of drug-resistant TB is essential to limit ongoing transmission, and this is not achieved by sputum smear microscopy which is the only test available in most TB endemic areas. HOW TRANSMISSIBLE (INFECTIOUS) AND VIRULENT (ABLE TO CAUSE DISEASE) IS DRUG-RESISTANT TB? Snider et al 9 showed that isoniazid-resistant strains caused as much infection as drug-susceptible strains in child contacts. Successful transmission of MDR-TB strains from adult source cases to child contacts with progression to disease was also confirmed by DNA fingerprint studies. 10 Infection control studies from Peru showed that MDR-TB strains can be highly infectious and rapidly transmitted within poorly ventilated hospital wards. 11 The importance of close contact is reflected by the concordance observed between DST results in drug-resistant source cases and their close contacts who developed disease; varying from 46% in adults to 80% in children. 7,12,13 Discordant results may result from poor standardization of second-line DSTs, while contacts could also have been infected by other, often unidentified, source cases with drug-susceptible TB. In practice this means that special effort has to be made to obtain specimens for culture and DST in any child TB suspect who report recent close contact (within 12 months) with someone diagnosed with drug-resistant TB. While awaiting New child TB case Confirmed DR-TB DST known Confirmed DS-TB No Contact with infec ous TB case? Yes Yes or No Drug-resistant source case Source case DST not done & No source case known or - child failing 1 st -line treatment or DST not done, no risk factor - source retreatment or chronic TB case Drug-suscep ble source case Confirmed or Probable DR-TB Suspected DR-TB Probable or Confirmed DS-TB Treat as DR-TB according to Do culture/dst on child & source s Do culture/dst on child s DST result of child or source s isolate specimens. Treat as DS-TB specimens if DS not confirmed Do culture & DST Close follow-up essen al mainly if poor response to treatment if DR not confirmed Check DST results Check response to treatment If DST shows DR or if failing adherent therapy, treat as DR-TB Check DST results If DST shows DR treat as DR-TB DST = drug suscep bility test; DR = drug-resistant; DS = drug-suscep ble Reference to culture and DST implies that facili es are available [Adapted from ref 16] Figure 1. Algorithm for the diagnosis of suspected or confirmed drug-resistant TB in children.

H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 31 38 33 DST results, children should be treated according to the DST result of the likely source case s isolate. WHEN TO SUSPECT DRUG-RESISTANT TB IN A CHILD? Potential drug resistance should be considered in any child diagnosed with TB. The diagnosis of TB in children often relies on a constellation of; a history of contact with an infectious TB source case; symptoms and signs suggestive of TB (e.g. chronic cough, weight loss/failure to thrive or signs of pulmonary or extrapulmonary TB); and special investigations (e.g. tuberculin skin test (TST) and/or chest radiography). In most cases smear microscopy for acid-fast bacilli (AFB), culture and DST are not done, as adequate specimens are difficult to obtain and often negative. Although drug-resistant TB is primarily a microbiological diagnosis, a history of previous TB treatment or contact with adult drug-resistant TB cases is extremely important. The following practice points should guide the diagnosis of drug-resistant TB in children (see also Figure 1): 14 16 PRACTICE POINTS: MAKING THE DIAGNOSIS OF DRUG- RESISTANT TB IN CHILDREN Isolating M. tuberculosis and demonstrating drug resistance on DST remains the only way to confirm drugresistant TB Probable drug-resistant TB can be diagnosed when a child with TB reports recent close contact with an adult with drug-resistant TB Drug resistance should be suspected in any child who fails to improve while adherent to first-line anti-tb therapy or if the adult source case is a treatment failure, a retreatment case or recently died from TB Although children usually develop transmitted drugresistant TB, some children develop lung cavities with high bacillary loads and may acquire drug resistance if the treatment regimen is inadequate, supply of drugs is irregular or treatment adherence is poor. WHAT SPECIMENS TO COLLECT? When MDR-TB is suspected, every effort should be made to confirm the diagnosis by obtaining specimens for culture and DST. Respiratory specimens may be obtained by gastric aspirates, induced sputum and/or nasopharyngeal aspirates. Bronchoalveolar lavage offers no advantage over less invasive methods. Older children (>6-8 years) can often expectorate sputum. 17 More invasive methods for obtaining specimens may be justified in children with extrapulmonary TB, for example fine needle aspiration biopsy or formal biopsy from peripheral lymphadenitis, or pus swab if a draining sinus has formed. Other specimens that should be obtained are cerebrospinal fluid in TB meningitis, pleural or pericardial fluid if effusions are present, ascitic fluid, ear swabs in chronic otorrhoea, bone marrow aspiration if disseminated TB is suspected and biopsies/swabs from other areas such as abscesses or osteoarticular TB. from 6 weeks to 4 months. Automated liquid broth media, such as the Mycobacterial Growth Indicator Tube (MGIT) 960 system (Becton-Dickinson, Sparks, MD) improved culture yields and reduced time to culture and DST results (10-14 days in specimens with high organism loads). However, in children with paucibacillary TB, culture and DST results can still be delayed for 6-8 weeks. These systems are expensive and need well equipped laboratories and technical expertise. The risk posed by ongoing transmission of drug-resistant strains and the risk of amplification of resistance if patients are treated with incorrect regimens call for rapid and reliable diagnosis. More rapid culture and DST methods, such as the microscopic observed drug-susceptibility (MODS) assay, in which culture and DST is performed at the same time and results are known within 7-14 days shows benefit, but have not been implemented widely. 18 Since many of the genes encoding resistance have been determined, nucleic acid amplification tests (NAATs) offer great promise for rapid and accurate diagnosis. NAATs that have shown promise include the GenoType MTBDRplus (Hain Lifescience, Nehren, Germany) and INNO-LiPA.Rif.TB (Innogenetics, Zwijndrecht, Belgium). 3 The GenoType MTBDRplus identifies the majority of rifampicin and isoniazid resistance while the INNO-LiPA Rif.TB only identifies rifampicin resistance. Correlation with conventional culture and DST methods is high (95% for rifampicin resistance). 19 The INNO-LiPA.Rif.TB does not identify isoniazid resistance, while the GenoType MTBDRplus assay only identifies isoniazid resistance associated with the inha promoter region or katg gene mutations, which may cause over-diagnosis of rifampicin mono-resistance since a proportion of isoniazid-resistant strains will not be detected. Rifampicinmonoresistant TB cases diagnosed by these assays only should be managed as MDR-TB cases. Between 5-10% of all MDR-TB patients have extensively drugresistant (XDR)-TB (i.e. MDR-TB plus resistance to the fluoroquinolones and one of the second-line injectable agents). DST for firstline drugs other than isoniazid and rifampicin and second-line drugs are still done by conventional culture and DST methods, which remain time consuming and poorly standardized. New genetic tests, such as the GenoType MTBDRsl (Hain Lifescience for second-line drugs, Nehren, Germany) are being developed to improve time-to-detection and reliability of DSTs for these drugs, especially the fluoroquinolones and injectable agents. 20 WHAT ARE THE PRINCIPLES OF CASE MANAGEMENT? Children with MDR-TB are managed in much the same way as adults, but there are some differences. Confirmation of MDR-TB may not be possible and child TB cases in recent close contact with an adult MDR-TB case or failing to respond to adherent first-line treatment should be empirically treated as MDR-TB cases. Because of the paucibacillary nature of early primary disease (contained primary lung lesion or uncomplicated hilar/mediastinal lymph node enlargement), these children may need fewer drugs and shorter duration of treatment, 7,21 although there are no randomized control studies to confirm this. Important principles in the management of MDR-TB are summarized as follows: 14,15 WHAT DIAGNOSTIC METHODS ARE AVAILABLE? Many developing countries either have no culture and DST facilities (although there is a strong drive to improve laboratory capacity) or use solid culture media (Löwenstein-Jensen or agar plates) and the indirect proportion method for DST. Culture yields are poor with solid media, and culture and DST results could take PRACTICE POINTS: PRINCIPLES OF MDR/XDR-TB CASE MANAGEMENT Never add a single drug to a failing regimen; this may lead to amplification of resistance All treatment should be given daily and under direct observation

34 H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 31 38 Treat the child according to the DST results from the likely source case, unless M. tuberculosis culture and DST is available from the child Do second-line DST in all MDR-TB cases to exclude resistance to the fluoroquinolones and/or second-line injectables, as this may call for additional drugs early in therapy Give at least 3 (only in early primary disease) or preferably 4 drugs to which the patient or adult source case is naïve or their isolates susceptible A regimen should be build from different drug groups (see table 1) taking into account drug resistance, possible cross-resistance, adverse effects and previous use of drugs Caregivers need counseling and support regarding adverse effects, treatment duration and importance of adherence at every follow-up visit. Clinical, radiological and culture response to treatment should be monitored. Monthly smear microscopy and/or cultures should be done until confirmed negative on 3 consecutive occasions, thereafter 2-3 monthly follow-up cultures can be done Clinical monitoring for adverse effects should be done at every visit. Special investigations should be guided by the adverse effect profile of the drugs used WHICH DRUGS TO USE IN THE TREATMENT OF CHILDREN WITH MDR-TB AND XDR-TB? WHO identifies standardized, empirical and individualized treatment regimens. 15 The choice of treatment regimen will differ according to the availability of DST and drug resistance surveillance data in a particular setting. With standardized treatment all patients in certain categories (e.g. treatment failure) are started on the same fixed regimen. This may be the most pragmatic option, but is accompanied by a risk of amplifying drug resistance if not tailored according to ongoing drug resistance surveillance data. 22 Children are best managed with empirical or individualized treatment regimens, which utilize the same rationale. Empirical treatment is designed on the basis of previous treatment history and DST results of the child (or likely source case), while individualized treatment is based on the patient s own current DST result and previous treatment history. With extensive pulmonary or disseminated extrapulmonary disease, a minimum of 4 active drugs should be included in the regimen. 3 When building a regimen, start with first-line (Group 1 Table 1) drugs to which DST results show susceptibility. Previous treatment (i.e. treatment for >1 month) with any specific drug in a failing regimen should indicate possible resistance to that drug. DST results for pyrazinamide are difficult to obtain and for ethambutol notoriously unreliable. 23,24,25 Therefore, if either the child or the source case had previously been treated with pyrazinamide and/or ethambutol, then these drugs could still be used empirically or if DST shows susceptibility, but only as additional drugs. 25,26 Add one drug from group 2 (injectable agents). There is much debate about which injectable agent should be used in MDR-TB, because of cross-resistance between these drugs. We currently use amikacin in children because of fewer adverse effects and convenience of smaller ampoules appropriate for dosaging in children. The majority of MDR-TB patients are resistant to streptomycin, therefore this drug is not considered in MDR-TB therapy. However, in XDR-TB DST for streptomycin is worthwhile doing, since cross-resistance with second-line injectable agents may not be complete and if susceptible streptomycin could be added to an XDR-TB regimen. Thereafter add a fluoroquinolone (Group 3 Table 1). Levofloxacin and moxifloxacin are superior to ofloxacin and if resistance to ofloxacin is found, resistance to the newer generation fluoroquinolones such as moxifloxacin, may not be complete (important for management of XDR-TB). 27,28 Use of ciprofloxacin in anti-tb treatment is no longer recommended. 26 More than one drug from group 4 (Table 1), taking into account similar drugs and adverse effects, should be included in the Table 1 Drug groups for MDR and XDR-TB treatment regimens [Adapted from reference 26] Drug Group Drug name Daily dosage in mg/kg Maximum dose (mg) a Group 1: Oral first-line drugs Ethambutol 20-25 2000 Pyrazinamide 30-40 2000 b Group 2: Injectable agents. Streptomycin (1 st -line) 15-20 1000 Aminoglycosides Amikacin 15-20 1000 Kanamycin 15-20 1000 Cyclic polypeptide Capreomycin 15-20 1000 b Group 3: Fluoroquinolones Ofloxacin 15-20 800 Levofloxacin 7.5-10 750 Moxifloxacin 7.5-10 400 c Group 4: Second-line oral drugs Ethionamide (or prothionamide) 15-20 1000 Cycloserine (or terizidone) 10-20 1000 e Para-aminosalisylic acid (PAS; 4gr sachets) 150 12g d Group 5: Drugs of uncertain value High-dose INH 15-20 400 f Linezolid 10-12 twice daily 300 once/twice daily Amoxicillin/clavulanate 15 amoxicillin 3 x daily Clarithromycin 7.5-15 twice daily 500 twice daily g Thioacetazone 3-4 150 Imipenem/cilastatin (only IV) Clofazimine 3-5 300 a. DST could be unreliable use as additional drug if DST result susceptible or not done 25 b. Choose one drug in each of these groups; amikacin preferred to kanamycin in children c. Choose one or more of these drugs to make up total of 4 new drugs d. Consider use of these drugs if insufficient drugs to build an acceptable regimen with previous groups. Each drug only considered as half a drug, therefore 2 drugs in this group counts as one additional drug. e. PAS is administered in acidic base (e.g. yoghurt or orange juice) for improved absorption f. Linezolid dosage for TB is uncertain, but lower doses (300 mg twice daily or even 300 mg daily in adults) cause less adverse effects and still seem effective. 33 g. Thioacetazone should NOT be used in HIV-infected patients

H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 31 38 35 regimen according to DST or non-exposure to these drugs to a total of 4 active drugs. If these groups are not sufficient to build an acceptable regimen of 4 active drugs (excluding drugs with doubtful activity), drugs from group 5 could be added. WHO recommends that two drugs in group 5 should be added to make up one active drug. 26 Isoniazid at high-dose (15-20 mg/kg daily) may be beneficial especially when given with ethionamide where minimal inhibitory concentrations (MIC) for isoniazid and ethionamide DST are not available. Depending on which mutation causes resistance, either ethionamide or high-dose isoniazid is likely to retain some activity. 29 A randomized control trial in India showed that the addition of high-dose isoniazid to a standard MDR-TB treatment regimen, compared with normal dose (5 mg/kg) or no isoniazid, resulted in earlier sputum conversion and improvement in chest radiographs. 30 Linezolid, another group 5 drug, has been used with good clinical effect in MDR/XDR-TB cases, but cost and severe adverse effects are restricting its use. 31,32 Some reports have shown lower dosages (300 mg/day in adults) to be effective and to have fewer adverse effects. 33 Treatment of tuberculous meningitis requires drugs that effectively penetrate the blood-brain barrier such as isoniazid, pyrazinamide, the thioamides, cycloserine/terizidone and the fluoroquinolones. The second-line injectable drugs only penetrate the blood-brain barrier during acute inflammation. WHAT IS THE OPTIMAL TREATMENT DURATION? The optimal duration of MDR-TB treatment in children and adults remains unknown; current recommendations are based on personal experience and expected efficacy of the various secondline drugs. WHO guidelines 15,26 recommend treatment until 18 months after the first negative culture (24 months in XDR-TB). Because children often have paucibacillary disease shorter duration of treatment (12 months) may be sufficient for early, non-extensive disease. 7,21 In case of children with extensive lung involvement, severe forms of extrapulmonary disease or disseminated (meningitis or miliary TB) disease, the same duration as in adults apply. HOW TO ENSURE TREATMENT ADHERENCE? It is essential to ensure adequate adherence to treatment, since treatment options are limited. Treatment of MDR/XDR-TB should only be given as directly observed therapy by health care workers or treatment supporters. Hospitalization for the first 4-6 months of treatment is often required to administer second-line injectable agents, monitor for adverse effects and ensure adequate treatment response. Comprehensive and continuous counseling of the child and/or parent/caregiver is essential to ensure that they understand the seriousness of the situation and the justification of prolonged and complicated treatment regimens. Socioeconomic evaluation and support of the family is important. Teenagers need special attention and in our own experience, adherence should be checked with the person responsible for direct observation of treatment. Adverse effects of second-line drugs are more frequent than in first-line drug treatment; fortunately, these adverse effects can usually be managed without stopping drugs (see Table 2). 34 Nonavailability of child-friendly drugs and dosages complicates administration of drugs to children. Hospital/clinic-based and community-based treatment models provide comparable outcomes. 7,35 Some children require initial admission because of their clinical condition or social circumstances. In our experience hospitalization in a specialized unit during the intensive phase allows for daily injections by experienced nursing staff and better monitoring of adverse effects and repeat cultures. The remainder of the treatment is usually given at primary health care level. Community home-based directly observed treatment of HIV-uninfected MDR-TB patients in Peru was shown to be very effective. 35 In both models expert health care teams should be involved in the continued care of the children. Table 2 Adverse effects of first and second-line drugs used in the treatment of children with multidrug-and extensively drug-resistant tuberculosis Drug Adverse effects How to monitor Isoniazid Hepatotoxicity Jaundice, liver enzymes Rash Clinical observation for Peripheral neuropathy (rare) other adverse effects Psychosis Pyrazinamide Hepatotoxicity Jaundice, liver enzymes Arthralgia Clinical observation for Rash other adverse effects Ethambutol Optic neuritis (rare) Vision screening if possible Second-line injectable drugs Ototoxicity (starts with high frequency hearing Hearing test (audiology) loss and may continue after stopping culprit drug) Amikacin Nephrotoxicity (Renal failure and severe hypokalaemia) Kanamycin Capreomycin Serum creatinine and potassium levels Fluoroquinolones Gastro-intestinal disturbance Clinical observation and caregivers report Ofloxacin Insomnia Levofloxacin Arthralgia Serum uric acid if used with pyrazinamide Moxifloxacin Thioamides Gastro-intestinal disturbance (nausea, vomiting, Clinical observation abdominal pain and anorexia) Ethionamide Hepatotoxicity Jaundice serum alanine transferase and billirubin Prothionamide Hypothyroidism Thyroid stimulating hormone and free T4 levels Cycloserine Psychosis, convulsions, parasthesia, depression Clinical observation Terizidone Para-aminosalisylic acid (PAS) Gastro-intestinal disturbance (mainly diarrhoea) Clinical observation Hypothyroidism Thyroid stimulating hormone levels and free T4 Linezolid Myelosuppression Full blood counts Lactic acidosis Serum lactate level Peripheral neuropathy Clinical observation Pancreatitis Clinical observation

36 H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 31 38 HOW SHOULD ADVERSE EFFECTS BE MANAGED? Children should continue on effective MDR-TB treatment regimens, therefore, adverse effects should be managed rather than drugs stopped. Isoniazid, pyrazinamide and the thioamides should be stopped immediately if jaundice develops. Once liver enzymes return to normal these drugs could be reintroduced one by one, with careful monitoring for an increase in alanine transferase. The gastrointestinal disturbances caused by the thioamides and para-aminosalisylic acid (PAS) can be mostly overcome by splitting the dose or starting with a lower dose increasing to full dose in 1-2 weeks. Hypothyroidism (thioamides and PAS) may need addition of low-dose thyroxine supplementation until completion of MDR-TB treatment. Ethambutol may cause optic neuritis, which is difficult to monitor in children less than 5 years of age. Although the risk seems low at recommended dosages (15-25 mg/kg/day), 36 older children should be screened by testing visual acuity and colour vision. Vision disturbance is reversible if stopped early. All children on injectable agents should be evaluated at 1-2 monthly intervals for hearing loss. If hearing loss develops in a child responding well to treatment it may be considered to stop the injectable agent earlier (at four rather than six months). However, if the child has extensive disease and few effective drugs are available the risk versus benefit of continuing the injectable agent should be considered. Nephrotoxicity, renal failure and hypokalaemia in children is rare, although it has been described in adults. 27,37 Joint or musculoskeletal adverse effects from the fluoroquinolones in children seems mild and are rare. 7,35 Psychosis is rarely seen in children, but could be caused by isoniazid or cycloserine/ terizidone. Discontinuing isoniazid and/or lowering the dose of cycloserine/terizidone may be sufficient. ADJUNCTIVE THERAPIES Surgery Some conditions, such as severe airway obstruction by mediastinal lymph nodes, pericardial or pleural effusion, or noncommunicating hydrocephalus may require surgery. In adults, resectional lung surgery has been reported as an adjunct in the treatment of MDR/XDR-TB, especially those patients resistant to most drugs. 38,39 Patients for lung surgery need careful selection and experienced surgeons as these procedures are not without complications. 38,39 Nutritional support Malnutrition increases the risk of developing disease after M. tuberculosis infection, and optimal nutrition is an important part of treatment. Because the diagnosis and treatment of MDR-TB is often delayed, 7 nutritional status in these children may have deteriorated. Additionally TB is known to be a disease associated with poor socioeconomical circumstances, and second-line drugs such as ethionamide and PAS may have gastrointestinal adverse effects including nausea and anorexia. For these reasons children with MDR-TB usually require nutritional support. Several anti-tb and antiretroviral drugs may cause adverse neurological effects which could be associated with low levels of pyridoxine (vitamin B6). Low levels of pyridoxine was found in a large proportion of children hospitalized for TB and levels remained low in many HIV-infected children despite receiving daily recommended doses of pyridoxine. 40 Therefore pyridoxine is recommended in TB/HIV-co-infected children but also for MDR-TB patients receiving high-dose isoniazid and/or cycloserine/terizidone. 15,40 Recommended dosage is 1-2 mg/kg daily. 41 Corticosteroids Corticosteroids are often used in TB meningitis, large airway obstruction by mediastinal lymph nodes or pericardial TB. Most commonly oral prednisone at 2 mg/kg daily (maximum 60 mg) for 4 weeks (reduced over 1-2 weeks) is used. 42 The use of corticosteroids in children with undiagnosed MDR-TB may cause further progression of disease. 16 MANAGEMENT OF HIV-INFECTED CHILDREN WITH MDR-TB All child TB suspects should be screened for HIV infection if either living in a high prevalence HIV area (prevalence >1%) or considered to be at risk for HIV infection. 17 HIV-infected children with TB, especially MDR-TB, are at increased risk of severe disease and death, which emphasizes the need for early diagnosis and optimal treatment. Concomitant antiretroviral therapy (ART) markedly improves TB outcome in children and adults. 43,44 A prospective trial showed clear benefit for starting ART early in TB treatment despite the stage of HIV disease with no increase in adverse effects. 44 XDR-TB patients co-infected with HIV also had improved outcome if started early on ART. 3 WHO recommends starting ART within 2-8 weeks after starting anti-tb treatment in HIV-infected children with MDR-TB. 41 Drug interactions are usually not a problem with regimens not containing rifampicin. Reasons for postponing ART initiation include possible confusion of overlapping drug adverse effects and the risk for immune reconstitution inflammatory syndrome (IRIS), a paradoxical worsening of symptoms and signs with improvement in the body s immune response. 41 IRIS, if severe, could be managed by corticosteroids. In addition to early ART initiation, all co-infected child TB cases should receive cotrimoxazole prophylaxis and pyridoxine supplementation. 41 MANAGING CHILD CONTACTS OF INFECTIOUS MDR-TB CASES Preventive therapy for MDR-TB remains controversial. Current WHO guidelines do not recommend preventive therapy for contacts of MDR-TB patients. 15 Failure of isoniazid or isoniazid/ rifampicin preventive therapy in MDR-TB contacts has been documented. 12,45 No randomized controlled trials have been done on preventive therapy in MDR-exposed or infected individuals. There is general agreement that preventive therapy is warranted, especially for high-risk contacts such as immune compromised individuals or very young children, but there is no consensus on what regimen(s) should be used. 46 TB guidelines from the United States recommend a two-drug regimen for people with latent TB infection exposed to MDR- TB. 47,48 In a prospective observational study where child contacts of adult MDR-TB cases were offered individually tailored preventive therapy, with two drugs to which the source cases isolates were susceptible or naïve for a period of six months, was found to be effective. 21 Immune immature children (<3 years) and immunocompromised children, irrespective of their age are highly vulnerable. In TB endemic areas, exposure to multiple source cases, both drug-susceptible and drug-resistant TB, is not uncommon. We currently use a 3-drug combination of high-dose (15-20 mg/kg) isoniazid and two drugs to which the source case s isolate is susceptible or naïve, usually a fluoroquinolone (ofloxacin) and ethambutol (or ethionamide). Single-drug preventive therapy with the new generation fluoroquinolones (levofloxacin) is currently explored. Further studies are urgently needed to evaluate regimens and duration of preventive therapy in high-risk children in close contact with infectious MDR-TB cases.

H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 31 38 37 Preventive therapy for XDR-TB contacts is not recommended, but in the light of possible low-level isoniazid resistance, which could be confirmed by isoniazid MIC or presence of inha promoter region mutation on line probe assay, high-dose isoniazid (15-20 mg/kg) may provide some protection to high-risk child contacts. Most important is that child contacts of infectious MDR/XDR-TB source cases, especially those less than 5 years of age or those HIVinfected irrespective of age, should be closely followed up for a minimum of two years and appropriate treatment started as soon as TB is diagnosed. 15 INFECTION CONTROL Although childhood TB is generally not infectious, children with progressive lung disease or cavitary TB (often smear-positive) are infectious and should be isolated. 49,50 Isolation in hospital should last until they are sputum smear-negative on at least two occasions 2-4 weeks apart and preferably culture-negative as well. Also, accompanying or visiting adults may have infectious pulmonary TB and pose a transmission risk. 51 CONCLUSION Despite the lack of epidemiologic data on drug-resistant TB in children, it is evident that they are as much affected by the growing MDR/XDR-TB epidemic as adults, especially in settings where ongoing transmission is poorly controlled. Most children with MDR-TB have been infected by an infectious adult MDR/XDR-TB source case. Failing to identify such contact may delay diagnosis of MDR/XDR-TB, with unnecessary progression of disease and/or death. Since microbiological confirmation of drug-resistant TB in children is difficult, empiric treatment is reasonable and should be guided by the DST pattern of the likely source case. Children tolerate second-line anti-tb drugs well and, if diagnosed timeously their outcome is generally good. References 1. World Health Organization. Multidrug and extensively drug-resistant TB (M/ XDR-TB): 2010 global report on surveillance and response. Geneva, Switzerland. WHO/HTM/TB/2010.3. 2. Nelson LJ, Wells CD. Global epidemiology of childhood tuberculosis. Int J Tuberc Lung Dis 2004;8:636 47. 3. Schaaf HS, Moll AP, Dheda K. Multidrug- and extensively drug-resistant tuberculosis in Africa and South America: epidemiology, diagnosis and management in adults and children. Clin Chest Med 2009;30:667 83. 4. Schaaf HS, Marais BJ, Hesseling AC, Brittle W, Donald PR. Surveillance of antituberculosis drug resistance amongst children from the Western Cape Province of South Africa an upward trend. Am J Public Health 2009; 99:1486 90. 5. Rieder HL. Drug-resistant tuberculosis: issues in epidemiology and challenges for public health. Tuberc Lung Dis 1993;75:321 3. 6. Marais BJ, Victor TC, Hesseling AC, et al. Beijing and Haarlem genotypes are over-represented among children with drug resistant tuberculosis in the Western Cape Province of South Africa. J Clin Microbiol 2006;44:3539 43. 7. Schaaf HS, Shean K, Donald PR. Culture-confirmed multidrug-resistant tuberculosis inchildren: diagnostic delay, clinical features, response to treatment and outcome. Arch Dis Child 2003;88:1106 11. 8. Canetti G. Present aspects of bacterial resistance in tuberculosis. Am Rev Respir Dis 1965;92:687 703. 9. Snider Jr DE, Kelly GD, Cauthen GM, Thompson NJ, Kilburn JO. Infection and disease among contacts of tuberculosis cases with drug-resistant and drugsusceptible bacilli. Am Rev Respir Dis 1985;132:125 32. 10. Schaaf HS, Van Rie A, Gie RP, et al. Transmission of multidrug resistant tuberculosis. Pediatr Infect Dis J 2000;19:695 9. 11. Escombe A, Oeser C, Gilman R, et al. Natural ventilation for the prevention of airborne contagion. PLoS Med 2007;4:e68. 12. Kritski AL, Marques MJ, Rabahi MF, et al. Transmission of tuberculosis to close contacts of patients with multidrug-resistant tuberculosis. Am J Respir Crit Care Med 1996;153:331 5. 13. Steiner P, Rao M, Mitchell M, Steiner M. Primary drug-resistant tuberculosis in children: Correlation of drug-susceptibility patterns of matched patient and source case strains of Mycobacterium tuberculosis. Am J Dis Child 1985;139: 780 2. 14. Schaaf HS. Drug-resistant tuberculosis in children. S Afr Med J 2007;97: 995 7. 15. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva, Switzerland. WHO/HTM/TB/2006.361. 16. Mukherjee J, Schaaf HS. Multidrug-resistant tuberculosis in children. In: Tuberculosis: A Comprehensive Clinical Reference. Eds. H Simon Schaaf and Alimuddin Zumla. Saunders, Elsevier Publishers, London, UK 2009: 532 538. 17. World Health Organization. Guidance for national tuberculosis programmes on the management of tuberculosis in children. WHO, Geneva, Switzerland. WHO/ HTM/TB/2006.371. 18. Oberhelman RA, Soto-Castellares G, Caviedes L, et al. Improved recovery of Mycobacterium tuberculosis from children using the microscopic observation drug susceptibility method. Pediatrics 2006;118:100 6. 19. Barnard M, Albert H, Coetzee G, O Brien R, Bosman ME. Rapid molecular screening for multidrug-resistant tuberculosis in a high-volume public health laboratory in South Africa. Am J Respir Crit Care Med 2008;177: 787 92. 20. Hillemann D, Rusch-Gerdes S, Richter E. Feasibility of the genotype MTBDRsl assay for fluoroquinolone, amikacin-capreomycin, and ethambutol resistance testing of Mycobacterium tuberculosis strains and clinical specimens. J Clin Microbiol 2009;47:1767 72. 21. Schaaf HS, Gie RP, Kennedy M, Beyers N, Hesseling PB, Donald PR. Evaluation of young children in contact with adult multidrug-resistant pulmonary tuberculosis: a 30-month follow-up. Pediatrics 2002;109:765 71. 22. Marais BJ, Raviglione MC, Donald PR, et al. Scale-up of services and research priorities for diagnosis, management, and control of tuberculosis: a call to action. Lancet 2010;375:2179 91. 23. Mphahlele M, Syre H, Valvatne H, et al. Pyrazinamide resistance among South African multidrug-resistant Mycobacterium tuberculosis isolates. J Clin Microbiol 2008;46:3459 64. 24. Johnson R, Jordaan AM, Pretorius L, et al. Ethambutol resistance testing by mutation detection. Int J Tuberc Lung Dis 2006;10:68 73. 25. Hoek KGP, Schaaf HS, Gey van Pittius NC, van Helden PD, Warren RM. Resistance to pyrazinamide and ethambutol compromises MDR/XDR-TB treatment. S Afr Med J 2009;99:785 7. 26. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. Emergency update 2008. WHO, Geneva, Switzerland, 2008. WHO/HTM/TB/2008.402. 27. Dheda K, Shean K, Zumla A, et al. Early treatment outcomes of extensively drugresistant tuberculosis in South Africa are poor regardless of HIV status. Lancet 2010;375:1798 807. 28. Kam KM, Yip CW, Cheung TL, Tang HS, Leung OC, Chan MY. Stepwise decrease in moxifloxacin susceptibility amongst clinical isolates of multidrug-resistant mycobacterium tuberculosis: correlation with ofloxacin susceptibility. Microb Drug Resist 2006;12:7 11. 29. Schaaf HS, Victor TC, Venter A, et al. Ethionamide cross- and co-resistance in children with isoniazid-resistant tuberculosis. Int J Tuberc Lung Dis 2009; 13:1355 9. 30. Katiyar SK, Bihari S, Prakash S, Mamtani M, Kulkarni H. A randomized controlled trial of high-dose isoniazid adjuvant therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2008;12:139 45. 31. Condos R, Hadgiangelis N, Leibert E, Jacquette G, Harkin T, Rom WN. Case series report of a linezolid-containing regimen for extensively drug-resistant tuberculosis. Chest 2008;134:187 92. 32. Schaaf HS, Willemse M, Donald PR. Long-term linezolid treatment in a young child with extensively drug-resistant tuberculosis. Pediatr Infect Dis J 2009;28:748 50. 33. Koh WJ, Kwon OJ, Gwak H, et al. Daily 300 mg dose of linezolid for the treatment of intractable multidrug-resistant and extensively drug-resistant tuberculosis. J Antimicrob Chemother 2009;64:388 91. 34. Furin JJ, Mitnick CD, Shin SS, et al. Occurrence of serious adverse effects in patients receiving community-based therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2001;5:648 55. 35. Drobac PC, Mukherjee JS, Joseph JK, et al. Community-based therapy for children with multidrug-resistant tuberculosis. Pediatrics 2006;117:2022 9. 36. Donald PR, Maher D, Maritz JS, Qazi S. Ethambutol dosage for the treatment of children: literature review and recommendatiions. Int J Tuberc Lung Dis 2006;10:1318 30. 37. Peloquin CA, Berning SE, Nitta AT, et al. Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial disease. Clin Infect Dis 2004;38:1538 44. 38. Mohsen T, Zeid AA, Haj-Yahia S. Lobectomy or pneumonectomy for multidrugresistant tuberculosis can be performed with acceptable morbidity and mortality: A seven-year review of a single institution s experience. J Thorac Cardiovasc Surg 2007;134:194 8. 39. Dravniece G, Cain KP, Holtz TH, Riekstina V, Leimane V, Zaleskis R. Adjunctive resectional lung surgery for extensively drug-resistant tuberculosis. Eur Respir J 2009;34:180 3. 40. Cilliers K, Labadarios D, Schaaf HS, et al. Pyridoxal-5-phosphate plasma concentrations in children receiving tuberculosis chemotherapy including isoniazid. Acta Paediatr 2010 Feb 8 [Epub ahead of print]. 41. World Health Organization/International Union Against Tuberculosis and Lung Health. Guidance for national HIV and tuberculosis programmes on the

38 H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 31 38 management of tuberculosis in HIV-infected children: recommendations for a public health approach. IUATLD, Paris, France. 2010. 42. Schaaf HS, Nelson LJ. Tuberculosis drug therapy in children. In: Tuberculosis: A Comprehensive Clinical Reference. Eds. H Simon Schaaf and Alimuddin Zumla. Saunders, Elsevier Publishers, London, UK 2009: 627 637. 43. Walters LE, Cotton MF, Rabie H, Schaaf HS, Walters LO, Marais BJ. Clinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children on anti-retroviral therapy. BMC Pediatrics 2008;8:1. 44. Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. New Engl J Med 2010;362:697 706. 45. Sneag DB, Schaaf HS, Cotton MF, Zar HJ. Failure of chemoprophylaxis with standard anti-tuberculosis agents in child contacts of multidrug-resistant tuberculosis cases. Pediatr Infect Dis J 2007;26:1142 6. 46. Passanante MR, Gallagher CT, Reichman LB. Preventive therapy for contacts of multidrug-resistant tuberculosis. A Delphi survey Chest 1994;106:431 4. 47. American Thoracic Society. Centers for Disease Control and Prevention and Infectious Disease Society of America. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221 47. 48. American Academy of Pediatrics. Tuberculosis. In: Pickering LK, Baker CJ, Long SS, McMilan JA, eds. Red Book: 2006 Report of the Committee on Infectious Diseases. 27 th Ed, Elk Grove Village, IL. American Academy of Pediatrics 2006:678 704. 49. Marais BJ, Gie RP, Hesseling AC, Beyers N. Adult-type pulmonary tuberculosis in children 10-14 years of age. Pediatr Infect Dis J 2005;24:743 4. 50. Curtis AB, Ridzon R, Vogel R, et al. Extensive transmission of Mycobacterium tuberculosis from a child. N Engl J Med 1999;341:1491 5. 51. Munoz FM, Ong LT, Seavy D, Medina D, Correa A, Starke JR. Tuberculosis among adult visitors of children with suspected tuberculosis and employees at a children s hospital. Infect Control Hosp Epidemiol 2002;23:568 72.