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SchaafHS,MaraisBJ..Managementofmultidrug-resistanttuberculosisinchildren:asurvivalguideforpaediatriciansARTICLEinPAEDIATRICRESPIRATORYREVIEWSMARCH2011ImpactFactor:2.2DOI:10.1016/j.prrv.2010.09.010Source:PubMed

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H.SimonSchaafStellenboschUniversity218PUBLICATIONS5,467CITATIONS

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BenMaraisChildren'sHospitalatWestmead217PUBLICATIONS4,636CITATIONS

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Paediatric Respiratory Reviews 12 (2011) 3138

fordruof H

Contents lists available at ScienceDirect

Paediatric RespirHOW 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 worldwidehad multidrug-resistant (MDR)-TB (i.e. resistance to isoniazid andrifampicin).1 Childhood TB comprise approximately 10-15% of theglobal disease burden, with higher rates in developing countries.2

Little data is available on the occurrence of MDR-TB in children.3 Aprospective drug resistance surveillance study conducted from1994-2007 in the Western Cape province, South Africa, demon-strated a clear upward trend with an increase in any resistance(isoniazidand/or rifampicin) from6.9%to15.1%and inMDR-TB from2.3% to 6.7%.4 Since themajority of children (>90%) who develop TBdo so within 12 months of infection, paediatric surveillance studiesprovide unique epidemiologic insight into current Mycobacterium

tuberculosis transmission patterns within communities, indicatingwhich genotypes are successfully transmitted.5,6

The absence of data on drug-resistant TB among children reectsthe fact that cultures for M. tuberculosis and drug susceptibilitytesting (DST) are rarely done, since obtaining adequate specimens inchild TB suspects are difcult and mycobacterial culture yields arelow. In addition, careful identication of the likely adult source caseis poorly performed and if child contacts are identied, thetreatment response and/or DST of the adult source case is rarelyconsidered when treatment or chemoprophylaxis is initiated inchildren.4,7 This overview describes what is known about theepidemiology, diagnosis andmanagement of childrenwithMDR-TB.

HOW DOES DRUG RESISTANCE DEVELOP AND SPREAD?

There are two underlying concepts; 1) the acquisition of drugresistance by individual patients, originally infected with drug-susceptible bacilli (acquired drug resistance), and 2) transmissionof drug-resistant bacilli (transmitted drug resistance).

M. tuberculosis acquires drug resistance through spontaneousgene mutations; there is no horizontal gene transfer between

A R T I C L E I N F O

Keywords:

multidrug-resistant

tuberculosis

children

XDR-TB

MDR-TB

treatment

S U M M A R Y

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 ofMDR-TB in children. Children in close contactwithMDR-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.

2010 Elsevier Ltd. All rights reserved.

* 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).

1526-0542/$ see front matter 2010 Elsevier Ltd. All rights reserved.doi:10.1016/j.prrv.2010.09.010Mini-symposium: Childhood TB in 2010

Management of multidrug-resistant tubpaediatricians

H. Simon Schaaf *, Ben J Marais

Department of Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch U

EDUCATIONAL AIMS

To discuss the epidemiology of and mechanisms responsible To provide clear guidance on how best to diagnose and treat To discuss ancillary treatment options and the managementculosis in children: a survival guide for

rsity, and Tygerberg Childrens Hospital, Cape Town, South Africa

the emergence of drug resistant TB in childreng-resistant TB in childrenIV-infected children with drug-resistant TB

atory Reviews

bacilli. Therefore, the risk of acquiring drug resistance is directlyproportional to the number of bacilli present; a bacterial load of>106 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 frequencycompared to rst-line drugs. The estimated number of bacillipresent in caseous foci (e.g. intrathoracic lymph node disease inchildren), is low (104-105), while large numbers of bacilli (107-109)are present within pulmonary cavities of adult-type lung disease.8

Drug-resistant TB is aman-made disease reecting sub-optimalcase management. Treatment with a single drug rapidly selects fordrug-resistant disease. Using a combination of 3-4 drugs killsdifferent mycobacterial subpopulations and protects against thedevelopment of drug resistance. If single drugs are used insuccession, or a weak combination of drugs with insufcientprotection of companion drugs, then additional drug resistanceaccumulates. Acquisition and amplication of drug resistanceresult from poor drug regimens (e.g. adding a single drug to afailing regimen, prescribing a weak combination of drugs,interruption of drug supply or using drugs with poor bioavail-ability) and/or non-adherence to treatment. The risk is highest inadults with lung cavities and relatively low in children withpaucibacillary disease.

Delayed diagnosis and/or poor management of infectious drug-resistant TB cases allows drug-resistantM. tuberculosis strains to betransmitted and cause disease, especially in vulnerable groups

such as young children and immunocompromised patients. Earlydiagnosis of drug-resistant TB is essential to limit ongoingtransmission, and this is not achieved by sputum smear micro-scopy which is the only test available in most TB endemic areas.

HOW TRANSMISSIBLE (INFECTIOUS) AND VIRULENT (ABLE TOCAUSE DISEASE) IS DRUG-RESISTANT TB?

Snider et al9 showed that isoniazid-resistant strains caused asmuch infection as drug-susceptible strains in child contacts.Successful transmission of MDR-TB strains from adult source casesto child contactswith progression to diseasewas also conrmed byDNA ngerprint studies.10 Infection control studies from Perushowed that MDR-TB strains can be highly infectious and rapidlytransmitted within poorly ventilated hospital wards.11

The importance of close contact is reected by the concordanceobserved between DST results in drug-resistant source cases andtheir close contacts who developed disease; varying from 46% inadults to 80% in children.7,12,13 Discordant results may result frompoor standardization of second-line DSTs, while contacts couldalso have been infected by other, often unidentied, source caseswith drug-susceptible TB. In practice this means that special efforthas to bemade to obtain specimens for culture andDST in any childTB suspect who report recent close contact (within 12 months)with someone diagnosed with drug-resistant TB. While awaiting

[()TD$FIG]

New child TB case

Conrmed DR-TB DST known Conrmed DS-TB

No

Contact with infecous TB case?Yes Yes or No

noe tr

DR

cte

reoo

tre

-sb

te

H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 313832Drug-resistant source case Source case DST - child failing 1st-lin

- source retreatment o

Conrmed or Probable DR-TB Suspected

Treat as DR-TB according to Do culture/DST onDST result of child or sources isolate specimens. Trea

Do culture & DST Close follow-upif DR not conrmed

Check DSTCheck response tIf DST shows DR

adherent therapy,

DST = drug suscepbility test; DR = drug-resistant; DS = drugReference to culture and DST implies that facilies are availa[Adapted from ref 16]

Figure 1. Algorithm for the diagnosis of suspect done & No source case known orreatment or DST not done, no risk factorchronic TB case Drug-suscepble source case

-TB Probable or Conrmed DS-TB

hild & sources Do culture/DST on childsas DS-TB specimens if DS not conrmedssenal mainly if poor response to treatment

sults Check DST resultstreatment If DST shows DR treat as DR-TBr if failingat as DR-TB

uscepblele

d or conrmed drug-resistant TB in children.

WHAT SPECIMENS TO COLLECT?

When MDR-TB is suspected, every effort should be made toconrm the diagnosis by obtaining specimens for culture and DST.Respiratory specimens may be obtained by gastric aspirates,

from 6 weeks to 4 months. Automated liquid broth media, such asthe Mycobacterial Growth Indicator Tube (MGIT) 960 system(Becton-Dickinson, Sparks, MD) improved culture yields andreduced time to culture and DST results (10-14 days in specimenswith high organism loads). However, in children with paucibacil-lary TB, culture and DST results can still be delayed for 6-8 weeks.These systems are expensive and need well equipped laboratoriesand technical expertise.

resistant TB Probable drug-resistant TB can be diagnosed when a childwith TB reports recent close contact with an adult withdrug-resistant TB

Drug resistance should be suspected in any child who failsto improve while adherent to rst-line anti-TB therapy orif the adult source case is a treatment failure, a retreatmentcase or recently died from TB

Although children usually develop transmitted drug-resistant TB, some children develop lung cavities withhigh bacillary loads and may acquire drug resistance if thetreatment regimen is inadequate, supply of drugs isirregular or treatment adherence is poor.

H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 3138 33induced sputum and/or nasopharyngeal aspirates. Bronchoalveo-lar lavage offers no advantage over less invasive methods. Olderchildren (>6-8 years) can often expectorate sputum.17 Moreinvasive methods for obtaining specimens may be justied inchildren with extrapulmonary TB, for example ne needleaspiration biopsy or formal biopsy from peripheral lymphadenitis,or pus swab if a draining sinus has formed. Other specimens thatshould be obtained are cerebrospinal uid in TBmeningitis, pleuralor pericardial uid if effusions are present, ascitic uid, ear swabsin chronic otorrhoea, bone marrow aspiration if disseminated TB issuspected and biopsies/swabs from other areas such as abscessesor osteoarticular TB.

WHAT DIAGNOSTIC METHODS ARE AVAILABLE?

Many developing countries either have no culture and DSTfacilities (although there is a strong drive to improve laboratorycapacity) or use solid culture media (Lowenstein-Jensen or agarplates) and the indirect proportion method for DST. Culture yieldsare poor with solid media, and culture and DST results could takeDST results, children should be treated according to the DST resultof the likely source cases isolate.

WHEN TO SUSPECT DRUG-RESISTANT TB IN A CHILD?

Potential drug resistance should be considered in any childdiagnosed with TB. The diagnosis of TB in children often relies on aconstellation of; a history of contact with an infectious TB sourcecase; symptoms and signs suggestive of TB (e.g. chronic cough,weight loss/failure to thrive or signs of pulmonary or extra-pulmonary TB); and special investigations (e.g. tuberculin skin test(TST) and/or chest radiography). In most cases smear microscopyfor acid-fast bacilli (AFB), culture and DST are not done, asadequate specimens are difcult to obtain and often negative.Although drug-resistant TB is primarily a microbiological diag-nosis, a history of previous TB treatment or contact with adultdrug-resistant TB cases is extremely important.

The following practice points should guide the diagnosis ofdrug-resistant TB in children (see also Figure 1):1416

PRACTICE POINTS: MAKING THE DIAGNOSIS OF DRUG-RESISTANT TB IN CHILDREN

Isolating M. tuberculosis and demonstrating drug resis-tance on DST remains the only way to conrm drug-The risk posed by ongoing transmission of drug-resistantstrains and the risk of amplication of resistance if patients aretreated with incorrect regimens call for rapid and reliablediagnosis. More rapid culture and DST methods, such as themicroscopic observed drug-susceptibility (MODS) assay, in whichculture and DST is performed at the same time and results areknown within 7-14 days shows benet, but have not beenimplemented widely.18 Since many of the genes encodingresistance have been determined, nucleic acid amplication tests(NAATs) offer great promise for rapid and accurate diagnosis.NAATs that have shown promise include the GenoTypeMTBDRplus(Hain Lifescience, Nehren, Germany) and INNO-LiPA.Rif.TB (Inno-genetics, Zwijndrecht, Belgium).3 The GenoType MTBDRplusidenties the majority of rifampicin and isoniazid resistance whilethe INNO-LiPA Rif.TB only identies rifampicin resistance.Correlation with conventional culture and DST methods is high(95% for rifampicin resistance).19 The INNO-LiPA.Rif.TB does notidentify isoniazid resistance, while the GenoTypeMTBDRplus assayonly identies isoniazid resistance associated with the inhApromoter region or katG gene mutations, which may causeover-diagnosis of rifampicin mono-resistance since a proportionof isoniazid-resistant strains will not be detected. Rifampicin-monoresistant TB cases diagnosed by these assays only should bemanaged as MDR-TB cases.

Between 5-10% of all MDR-TB patients have extensively drug-resistant (XDR)-TB (i.e. MDR-TB plus resistance to the uoroqui-nolones and one of the second-line injectable agents). DST for rst-line drugs other than isoniazid and rifampicin and second-linedrugs are still done by conventional culture and DST methods,which remain time consuming and poorly standardized. Newgenetic tests, such as the GenoType MTBDRsl (Hain Lifescience forsecond-line drugs, Nehren, Germany) are being developed toimprove time-to-detection and reliability of DSTs for these drugs,especially the uoroquinolones and injectable agents.20

WHAT ARE THE PRINCIPLES OF CASE MANAGEMENT?

Children with MDR-TB are managed in much the same way asadults, but there are some differences. Conrmation of MDR-TBmay not be possible and child TB cases in recent close contact withan adult MDR-TB case or failing to respond to adherent rst-linetreatment should be empirically treated as MDR-TB cases. Becauseof the paucibacillary nature of early primary disease (containedprimary lung lesion or uncomplicated hilar/mediastinal lymphnode enlargement), these children may need fewer drugs andshorter duration of treatment,7,21 although there are no rando-mized control studies to conrm this. Important principles in themanagement of MDR-TB are summarized as follows:14,15

PRACTICE POINTS: PRINCIPLES OF MDR/XDR-TB CASEMANAGEMENT

Never add a single drug to a failing regimen; this may leadto amplication of resistance

All treatment should be given daily and under directobservation

WHICH DRUGS TO USE IN THE TREATMENT OF CHILDREN WITH

tailored according to ongoing drug resistance surveillance data.22

Children are best managed with empirical or individualizedtreatment regimens, which utilize the same rationale. Empiricaltreatment is designed on the basis of previous treatment historyand DST results of the child (or likely source case), whileindividualized treatment is based on the patients own currentDST result and previous treatment history.

With extensive pulmonary or disseminated extrapulmonarydisease, a minimum of 4 active drugs should be included in theregimen.3 When building a regimen, start with rst-line (Group 1 Table 1) drugs to which DST results show susceptibility. Previoustreatment (i.e. treatment for >1 month) with any specic drug in afailing regimen should indicate possible resistance to that drug. DSTresults for pyrazinamide are difcult to obtain and for ethambutolnotoriously unreliable.23,24,25 Therefore, if either the child or thesource case had previously been treated with pyrazinamide and/orethambutol, then thesedrugscould still beusedempiricallyor ifDSTshows susceptibility, but only as additional drugs.25,26

Add one drug from group 2 (injectable agents). There is muchdebate about which injectable agent should be used in MDR-TB,because of cross-resistance between these drugs. We currently useamikacin in children because of fewer adverse effects andconvenience of smaller ampoules appropriate for dosaging inchildren. The majority of MDR-TB patients are resistant tostreptomycin, therefore this drug is not considered in MDR-TBtherapy. However, in XDR-TB DST for streptomycin is worthwhiledoing, since cross-resistance with second-line injectable agentsmay not be complete and if susceptible streptomycin could be

Treat the child according to the DST results from the likelysource case, unless M. tuberculosis culture and DST isavailable from the child

Do second-line DST in all MDR-TB cases to excluderesistance to the uoroquinolones and/or second-lineinjectables, as this may call for additional drugs early intherapy

Give at least 3 (only in early primary disease) or preferably4 drugs towhich the patient or adult source case is nave ortheir isolates susceptible

A regimen should be build from different drug groups (seetable 1) taking into account drug resistance, possiblecross-resistance, adverse effects and previous use of drugs

Caregivers need counseling and support regarding adverseeffects, treatment duration and importance of adherenceat every follow-up visit.

Clinical, radiological and culture response to treatmentshould be monitored. Monthly smear microscopy and/orcultures should be done until conrmed negative on 3consecutive occasions, thereafter 2-3 monthly follow-upcultures can be done

Clinical monitoring for adverse effects should be done atevery visit. Special investigations should be guided by theadverse effect prole of the drugs used

H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 313834MDR-TB AND XDR-TB?

WHO identies standardized, empirical and individualizedtreatment regimens.15 The choice of treatment regimen will differaccording to the availability of DST and drug resistance surveil-lance data in a particular setting. With standardized treatment allpatients in certain categories (e.g. treatment failure) are started onthe same xed regimen. This may be the most pragmatic option,but is accompanied by a risk of amplifying drug resistance if notTable 1Drug groups for MDR and XDR-TB treatment regimens [Adapted from reference 26]

Drug Group Drug name

a Group 1: Oral rst-line drugs Ethambutol

PyrazinamidebGroup 2: Injectable agents.

Aminoglycosides

Streptomycin (1st-line)

Amikacin

Kanamycin

Cyclic polypeptide CapreomycinbGroup 3: Fluoroquinolones Ooxacin

Levooxacin

MoxioxacincGroup 4: Second-line oral drugs Ethionamide (or prothionamide)

Cycloserine (or terizidone)ePara-aminosalisylic acid (PAS; 4gr

dGroup 5: Drugs of uncertain value High-dose INHfLinezolid

Amoxicillin/clavulanate

ClarithromycingThioacetazone

Imipenem/cilastatin

Clofazimine

a. DST could be unreliable use as additional drug if DST result susceptible or not don

b. Choose one drug in each of these groups; amikacin preferred to kanamycin in child

c. Choose one or more of these drugs to make up total of 4 new drugs

d. Consider use of these drugs if insufcient drugs to build an acceptable regimen with

group counts as one additional drug.

e. PAS is administered in acidic base (e.g. yoghurt or orange juice) for improved absor

f. Linezolid dosage for TB is uncertain, but lower doses (300mg twice daily or even 30

g. Thioacetazone should NOT be used in HIV-infected patientsadded to an XDR-TB regimen.Thereafter add a uoroquinolone (Group 3 Table 1).

Levooxacin and moxioxacin are superior to ooxacin and ifresistance to ooxacin is found, resistance to the newer generationuoroquinolones such as moxioxacin, may not be complete(important for management of XDR-TB).27,28 Use of ciprooxacinin anti-TB treatment is no longer recommended.26

More than one drug from group 4 (Table 1), taking into accountsimilar drugs and adverse effects, should be included in the

Daily dosage in mg/kg Maximum dose (mg)

20-25 2000

30-40 2000

15-20 1000

15-20 1000

15-20 1000

15-20 1000

15-20 800

7.5-10 750

7.5-10 400

15-20 1000

10-20 1000

sachets) 150 12g

15-20 400

10-12 twice daily 300 once/twice daily

15 amoxicillin 3 x daily

7.5-15 twice daily 500 twice daily

3-4 150

(only IV)

3-5 300

e25

ren

previous groups. Each drug only considered as half a drug, therefore 2 drugs in this

ption

0mg daily in adults) cause less adverse effects and still seem effective.33

regimen according to DST or non-exposure to these drugs to a totalof 4 active drugs.

If these groups are not sufcient to build an acceptable regimenof 4 active drugs (excluding drugs with doubtful activity), drugsfrom group 5 could be added. WHO recommends that two drugs ingroup 5 should be added tomake up one active drug.26 Isoniazid athigh-dose (15-20 mg/kg daily) may be benecial especially whengiven with ethionamide where minimal inhibitory concentrations(MIC) for isoniazid and ethionamide DST are not available.Depending on which mutation causes resistance, either ethiona-mide or high-dose isoniazid is likely to retain some activity.29 Arandomized control trial in India showed that the addition ofhigh-dose isoniazid to a standard MDR-TB treatment regimen,compared with normal dose (5 mg/kg) or no isoniazid, resulted inearlier sputum conversion and improvement in chest radio-graphs.30 Linezolid, another group 5 drug, has been usedwith goodclinical effect in MDR/XDR-TB cases, but cost and severe adverseeffects are restricting its use.31,32 Some reports have shown lowerdosages (300 mg/day in adults) to be effective and to have feweradverse effects.33

Treatment of tuberculous meningitis requires drugs thateffectively penetrate the blood-brain barrier such as isoniazid,pyrazinamide, the thioamides, cycloserine/terizidone and theuoroquinolones. The second-line injectable drugs only penetratethe blood-brain barrier during acute inammation.

WHAT IS THE OPTIMAL TREATMENT DURATION?

involvement, severe forms of extrapulmonary disease or dissemi-nated (meningitis or miliary TB) disease, the same duration as inadults apply.

HOW TO ENSURE TREATMENT ADHERENCE?

It is essential to ensure adequate adherence to treatment, sincetreatment options are limited. Treatment of MDR/XDR-TB shouldonly be given as directly observed therapy by health care workersor treatment supporters. Hospitalization for the rst 4-6months oftreatment is often required to administer second-line injectableagents, monitor for adverse effects and ensure adequate treatmentresponse.

Comprehensive and continuous counseling of the child and/orparent/caregiver is essential to ensure that they understand theseriousness of the situation and the justication of prolonged andcomplicated treatment regimens. Socioeconomic evaluation andsupport of the family is important. Teenagers need specialattention and in our own experience, adherence should be checkedwith the person responsible for direct observation of treatment.Adverse effects of second-line drugs are more frequent than inrst-line drug treatment; fortunately, these adverse effects canusually be managed without stopping drugs (see Table 2).34 Non-availability of child-friendly drugs and dosages complicatesadministration of drugs to children.

Hospital/clinic-based and community-based treatment modelsprovide comparable outcomes.7,35 Some children require initialadmission because of their clinical condition or social circum-

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H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 3138 35The optimal duration of MDR-TB treatment in children andadults remains unknown; current recommendations are based onpersonal experience and expected efcacy of the various second-line drugs. WHO guidelines15,26 recommend treatment until 18months after the rst negative culture (24 months in XDR-TB).Because children often have paucibacillary disease shorterduration of treatment (12 months) may be sufcient for early,non-extensive disease.7,21 In case of children with extensive lung

Table 2Adverse effects of rst and second-line drugs used in the treatment of children wi

Drug Adverse effects

Isoniazid Hepatotoxicity

Rash

Peripheral neuropathy (rare)

Psychosis

Pyrazinamide Hepatotoxicity

Arthralgia

Rash

Ethambutol Optic neuritis (rare)

Second-line injectable drugs Ototoxicity (starts with high frequen

loss and may continue after stopping

Amikacin Nephrotoxicity (Renal failure and sev

Kanamycin

Capreomycin

Fluoroquinolones Gastro-intestinal disturbance

Ooxacin Insomnia

Levooxacin Arthralgia

Moxioxacin

Thioamides Gastro-intestinal disturbance (nausea

abdominal pain and anorexia)

Ethionamide Hepatotoxicity

Prothionamide Hypothyroidism

Cycloserine Psychosis, convulsions, parasthesia, d

Terizidone

Para-aminosalisylic acid (PAS) Gastro-intestinal disturbance (mainly

Hypothyroidism

Linezolid Myelosuppression

Lactic acidosis

Peripheral neuropathy

Pancreatitisstances. In our experience hospitalization in a specialized unitduring the intensivephaseallows fordaily injectionsbyexperiencednursing staff and better monitoring of adverse effects and repeatcultures. The remainder of the treatment is usually given at primaryhealth care level. Community home-based directly observedtreatment of HIV-uninfected MDR-TB patients in Peru was shownto be very effective.35 In both models expert health care teamsshould be involved in the continued care of the children.

ultidrug-and extensively drug-resistant tuberculosis

How to monitor

Jaundice, liver enzymes

Clinical observation for

other adverse effects

Jaundice, liver enzymes

Clinical observation for

other adverse effects

Vision screening if possible

earing

prit drug)

Hearing test (audiology)

hypokalaemia)

Serum creatinine and potassium levels

Clinical observation and caregivers report

Serum uric acid if used with pyrazinamide

miting, Clinical observation

Jaundice serum alanine transferase and billirubin

Thyroid stimulating hormone and free T4 levels

ssion Clinical observation

rrhoea) Clinical observation

Thyroid stimulating hormone levels and free T4

Full blood counts

Serum lactate level

Clinical observation

Clinical observation

H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 313836HOW SHOULD ADVERSE EFFECTS BE MANAGED?

Children should continue on effective MDR-TB treatmentregimens, therefore, adverse effects should be managed ratherthan drugs stopped. Isoniazid, pyrazinamide and the thioamidesshould be stopped immediately if jaundice develops. Once liverenzymes return to normal these drugs could be reintroduced oneby one, with careful monitoring for an increase in alaninetransferase. The gastrointestinal disturbances caused by thethioamides and para-aminosalisylic acid (PAS) can be mostlyovercome by splitting the dose or starting with a lower doseincreasing to full dose in 1-2 weeks. Hypothyroidism (thioamidesand PAS) may need addition of low-dose thyroxine supplementa-tion until completion of MDR-TB treatment.

Ethambutol may cause optic neuritis, which is difcult tomonitor in children less than 5 years of age. Although the riskseems low at recommended dosages (15-25 mg/kg/day),36 olderchildren should be screened by testing visual acuity and colourvision. Vision disturbance is reversible if stopped early.

All children on injectable agents should be evaluated at 1-2monthly intervals for hearing loss. If hearing loss develops in a childresponding well to treatment it may be considered to stop theinjectable agent earlier (at four rather than sixmonths). However, ifthe child has extensive disease and few effective drugs are availablethe risk versus benet of continuing the injectable agent should beconsidered. Nephrotoxicity, renal failure and hypokalaemia inchildren is rare, although it has been described in adults.27,37

Joint or musculoskeletal adverse effects from the uoroquino-lones in children seems mild and are rare.7,35 Psychosis is rarelyseen in children, but could be caused by isoniazid or cycloserine/terizidone. Discontinuing isoniazid and/or lowering the dose ofcycloserine/terizidone may be sufcient.

ADJUNCTIVE THERAPIES

Surgery

Some conditions, such as severe airway obstruction bymediastinal lymph nodes, pericardial or pleural effusion, or non-communicating hydrocephalus may require surgery. In adults,resectional lung surgery has been reported as an adjunct in thetreatment of MDR/XDR-TB, especially those patients resistant tomost drugs.38,39 Patients for lung surgery need careful selectionand experienced surgeons as these procedures are not withoutcomplications.38,39

Nutritional support

Malnutrition increases the risk of developing disease after M.tuberculosis infection, and optimal nutrition is an important part oftreatment. Because the diagnosis and treatment ofMDR-TB is oftendelayed,7 nutritional status in these children may have deterio-rated. Additionally TB is known to be a disease associated withpoor socioeconomical circumstances, and second-line drugs suchas ethionamide and PAS may have gastrointestinal adverse effectsincluding nausea and anorexia. For these reasons children withMDR-TB usually require nutritional support.

Several anti-TB and antiretroviral drugs may cause adverseneurological effects which could be associated with low levels ofpyridoxine (vitamin B6). Low levels of pyridoxine was found in alarge proportion of children hospitalized for TB and levelsremained low in many HIV-infected children despite receivingdaily recommended doses of pyridoxine.40 Therefore pyridoxine isrecommended in TB/HIV-co-infected children but also for MDR-TBpatients receiving high-dose isoniazid and/or cycloserine/terizi-done.15,40 Recommended dosage is 1-2 mg/kg daily.41Corticosteroids

Corticosteroids are often used in TB meningitis, large airwayobstruction by mediastinal lymph nodes or pericardial TB. Mostcommonly oral prednisone at 2 mg/kg daily (maximum 60 mg) for4 weeks (reduced over 1-2 weeks) is used.42 The use ofcorticosteroids in children with undiagnosed MDR-TB may causefurther progression of disease.16

MANAGEMENT OF HIV-INFECTED CHILDREN WITH MDR-TB

All child TB suspects should be screened for HIV infection ifeither living in a high prevalence HIV area (prevalence >1%) orconsidered to be at risk for HIV infection.17 HIV-infected childrenwith TB, especially MDR-TB, are at increased risk of severe diseaseand death, which emphasizes the need for early diagnosis andoptimal treatment. Concomitant antiretroviral therapy (ART)markedly improves TB outcome in children and adults.43,44 Aprospective trial showed clear benet for starting ART early in TBtreatment despite the stage of HIV disease with no increase inadverse effects.44 XDR-TB patients co-infected with HIV also hadimproved outcome if started early on ART.3 WHO recommendsstarting ART within 2-8 weeks after starting anti-TB treatment inHIV-infected children with MDR-TB.41

Drug interactions are usually not a problem with regimens notcontaining rifampicin. Reasons for postponing ART initiationinclude possible confusion of overlapping drug adverse effectsand the risk for immune reconstitution inammatory syndrome(IRIS), a paradoxical worsening of symptoms and signs withimprovement in the bodys immune response.41 IRIS, if severe,could be managed by corticosteroids. In addition to early ARTinitiation, all co-infected child TB cases should receive cotrimox-azole prophylaxis and pyridoxine supplementation.41

MANAGING CHILD CONTACTS OF INFECTIOUS MDR-TB CASES

Preventive therapy for MDR-TB remains controversial. CurrentWHO guidelines do not recommend preventive therapy forcontacts of MDR-TB patients.15 Failure of isoniazid or isoniazid/rifampicin preventive therapy in MDR-TB contacts has beendocumented.12,45 No randomized controlled trials have been doneon 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 compromisedindividuals or very young children, but there is no consensus onwhat regimen(s) should be used.46

TB guidelines from the United States recommend a two-drugregimen for people with latent TB infection exposed to MDR-TB.47,48 In a prospective observational study where child contactsof adult MDR-TB cases were offered individually tailoredpreventive therapy, with two drugs to which the source casesisolates were susceptible or nave for a period of six months, wasfound to be effective.21 Immune immature children (

H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 3138 37Preventive therapy for XDR-TB contacts is not recommended,but in the light of possible low-level isoniazid resistance, whichcould be conrmed by isoniazid MIC or presence of inhA promoterregion mutation on line probe assay, high-dose isoniazid (15-20 mg/kg) may provide some protection to high-risk childcontacts.

Most important is that child contacts of infectiousMDR/XDR-TBsource cases, especially those less than 5 years of age or those HIV-infected irrespective of age, should be closely followed up for aminimum of two years and appropriate treatment started as soonas TB is diagnosed.15

INFECTION CONTROL

Although childhood TB is generally not infectious, childrenwithprogressive lung disease or cavitary TB (often smear-positive) areinfectious and should be isolated.49,50 Isolation in hospital shouldlast until they are sputum smear-negative on at least two occasions2-4 weeks apart and preferably culture-negative as well. Also,accompanying or visiting adults may have infectious pulmonaryTB and pose a transmission risk.51

CONCLUSION

Despite the lack of epidemiologic data on drug-resistant TB inchildren, it is evident that they are asmuch affected by the growingMDR/XDR-TB epidemic as adults, especially in settings whereongoing transmission is poorly controlled. Most children withMDR-TB have been infected by an infectious adult MDR/XDR-TBsource case. Failing to identify such contact may delay diagnosis ofMDR/XDR-TB, with unnecessary progression of disease and/ordeath. Since microbiological conrmation of drug-resistant TB inchildren is difcult, empiric treatment is reasonable and should beguided by the DST pattern of the likely source case. Childrentolerate second-line anti-TB drugswell and, if diagnosed timeouslytheir 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, Switzer-land. WHO/HTM/TB/2010.3.

2. Nelson LJ, Wells CD. Global epidemiology of childhood tuberculosis. Int J TubercLung Dis 2004;8:63647.

3. Schaaf HS, Moll AP, Dheda K. Multidrug- and extensively drug-resistant tuber-culosis in Africa and South America: epidemiology, diagnosis and managementin adults and children. Clin Chest Med 2009;30:66783.

4. Schaaf HS, Marais BJ, Hesseling AC, Brittle W, Donald PR. Surveillance ofantituberculosis drug resistance amongst children from the Western CapeProvince of South Africa an upward trend. Am J Public Health 2009;99:148690.

5. Rieder HL. Drug-resistant tuberculosis: issues in epidemiology and challengesfor public health. Tuberc Lung Dis 1993;75:3213.

6. Marais BJ, Victor TC, Hesseling AC, et al. Beijing and Haarlem genotypes areover-represented among children with drug resistant tuberculosis in the Wes-tern Cape Province of South Africa. J Clin Microbiol 2006;44:353943.

7. Schaaf HS, Shean K, Donald PR. Culture-conrmed multidrug-resistant tuber-culosis inchildren: diagnostic delay, clinical features, response to treatment andoutcome. Arch Dis Child 2003;88:110611.

8. Canetti G. Present aspects of bacterial resistance in tuberculosis. Am Rev RespirDis 1965;92:687703.

9. Snider Jr DE, Kelly GD, Cauthen GM, Thompson NJ, Kilburn JO. Infection anddisease among contacts of tuberculosis cases with drug-resistant and drug-susceptible bacilli. Am Rev Respir Dis 1985;132:12532.

10. Schaaf HS, Van Rie A, Gie RP, et al. Transmission of multidrug resistanttuberculosis. Pediatr Infect Dis J 2000;19:6959.

11. Escombe A, Oeser C, Gilman R, et al. Natural ventilation for the prevention ofairborne contagion. PLoS Med 2007;4:e68.

12. Kritski AL, Marques MJ, Rabahi MF, et al. Transmission of tuberculosis to closecontacts of patients with multidrug-resistant tuberculosis. Am J Respir Crit CareMed 1996;153:3315.

13. Steiner P, Rao M, Mitchell M, Steiner M. Primary drug-resistant tuberculosis inchildren: Correlation of drug-susceptibility patterns of matched patient andsource case strains of Mycobacterium tuberculosis. Am J Dis Child 1985;139:7802.

14. Schaaf HS. Drug-resistant tuberculosis in children. S Afr Med J 2007;97:9957.

15. World Health Organization. Guidelines for the programmatic managementof 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 andAlimuddin Zumla. Saunders, Elsevier Publishers, London, UK 2009: 532538.

17. World Health Organization. Guidance for national tuberculosis programmes onthemanagement of tuberculosis in children. WHO, Geneva, Switzerland. WHO/HTM/TB/2006.371.

18. Oberhelman RA, Soto-Castellares G, Caviedes L, et al. Improved recovery ofMycobacterium tuberculosis from children using the microscopic observationdrug susceptibility method. Pediatrics 2006;118:1006.

19. Barnard M, Albert H, Coetzee G, OBrien R, Bosman ME. Rapid molecularscreening for multidrug-resistant tuberculosis in a high-volume publichealth laboratory in South Africa. Am J Respir Crit Care Med 2008;177:78792.

20. Hillemann D, Rusch-Gerdes S, Richter E. Feasibility of the genotype MTBDRslassay for uoroquinolone, amikacin-capreomycin, and ethambutol resistancetesting of Mycobacterium tuberculosis strains and clinical specimens. J ClinMicrobiol 2009;47:176772.

21. Schaaf HS, Gie RP, Kennedy M, Beyers N, Hesseling PB, Donald PR. Evaluation ofyoung children in contact with adult multidrug-resistant pulmonary tubercu-losis: a 30-month follow-up. Pediatrics 2002;109:76571.

22. Marais BJ, Raviglione MC, Donald PR, et al. Scale-up of services and researchpriorities for diagnosis, management, and control of tuberculosis: a call toaction. Lancet 2010;375:217991.

23. Mphahlele M, Syre H, Valvatne H, et al. Pyrazinamide resistance among SouthAfrican multidrug-resistant Mycobacterium tuberculosis isolates. J Clin Micro-biol 2008;46:345964.

24. Johnson R, Jordaan AM, Pretorius L, et al. Ethambutol resistance testing bymutation detection. Int J Tuberc Lung Dis 2006;10:6873.

25. Hoek KGP, Schaaf HS, Gey van PittiusNC, vanHelden PD,Warren RM. Resistanceto pyrazinamide and ethambutol compromises MDR/XDR-TB treatment. S AfrMed J 2009;99:7857.

26. World Health Organization. Guidelines for the programmatic management ofdrug-resistant tuberculosis. Emergency update 2008. WHO, Geneva, Switzer-land, 2008. WHO/HTM/TB/2008.402.

27. Dheda K, Shean K, Zumla A, et al. Early treatment outcomes of extensively drug-resistant tuberculosis in South Africa are poor regardless of HIV status. Lancet2010;375:1798807.

28. KamKM, Yip CW, Cheung TL, TangHS, LeungOC, ChanMY. Stepwise decrease inmoxioxacin susceptibility amongst clinical isolates of multidrug-resistantmycobacterium tuberculosis: correlation with ooxacin susceptibility. MicrobDrug Resist 2006;12:711.

29. Schaaf HS, Victor TC, Venter A, et al. Ethionamide cross- and co-resistance inchildren with isoniazid-resistant tuberculosis. Int J Tuberc Lung Dis 2009;13:13559.

30. Katiyar SK, Bihari S, Prakash S,MamtaniM, Kulkarni H. A randomized controlledtrial of high-dose isoniazid adjuvant therapy for multidrug-resistant tubercu-losis. Int J Tuberc Lung Dis 2008;12:13945.

31. Condos R, Hadgiangelis N, Leibert E, Jacquette G, Harkin T, RomWN. Case seriesreport of a linezolid-containing regimen for extensively drug-resistant tuber-culosis. Chest 2008;134:18792.

32. Schaaf HS, Willemse M, Donald PR. Long-term linezolid treatment in a youngchild with extensively drug-resistant tuberculosis. Pediatr Infect Dis J2009;28:74850.

33. KohWJ, KwonOJ, GwakH, et al. Daily 300 mg dose of linezolid for the treatmentof intractablemultidrug-resistant and extensively drug-resistant tuberculosis. JAntimicrob Chemother 2009;64:38891.

34. Furin JJ, Mitnick CD, Shin SS, et al. Occurrence of serious adverse effects inpatients receiving community-based therapy for multidrug-resistant tubercu-losis. Int J Tuberc Lung Dis 2001;5:64855.

35. Drobac PC, Mukherjee JS, Joseph JK, et al. Community-based therapy forchildren with multidrug-resistant tuberculosis. Pediatrics 2006;117:20229.

36. Donald PR, Maher D, Maritz JS, Qazi S. Ethambutol dosage for the treatment ofchildren: literature review and recommendatiions. Int J Tuberc Lung Dis2006;10:131830.

37. Peloquin CA, Berning SE, Nitta AT, et al. Aminoglycoside toxicity: daily versusthrice-weekly dosing for treatment of mycobacterial disease. Clin Infect Dis2004;38:153844.

38. Mohsen T, Zeid AA, Haj-Yahia S. Lobectomy or pneumonectomy for multidrug-resistant tuberculosis can be performed with acceptable morbidity and mor-tality: A seven-year review of a single institutions experience. J Thorac Cardi-ovasc Surg 2007;134:1948.

39. Dravniece G, Cain KP, Holtz TH, Riekstina V, Leimane V, Zaleskis R. Adjunctiveresectional lung surgery for extensively drug-resistant tuberculosis. Eur Respir J2009;34:1803.

40. Cilliers K, Labadarios D, Schaaf HS, et al. Pyridoxal-5-phosphate plasma con-centrations in children receiving tuberculosis chemotherapy including isonia-zid. Acta Paediatr 2010 Feb 8 [Epub ahead of print].

41. World Health Organization/International Union Against Tuberculosis and LungHealth. Guidance for national HIV and tuberculosis programmes on the

management of tuberculosis in HIV-infected children: recommendations for apublic health approach. IUATLD, Paris, France. 2010.

42. Schaaf HS, Nelson LJ. Tuberculosis drug therapy in children. In: Tuberculosis: AComprehensive Clinical Reference. Eds. H Simon Schaaf and Alimuddin Zumla.Saunders, Elsevier Publishers, London, UK 2009: 627637.

43. Walters LE, Cotton MF, Rabie H, Schaaf HS, Walters LO, Marais BJ. Clinicalpresentation and outcome of tuberculosis in human immunodeciency virusinfected children on anti-retroviral therapy. BMC Pediatrics 2008;8:1.

44. Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviraldrugs during tuberculosis therapy. New Engl J Med 2010;362:697706.

45. Sneag DB, Schaaf HS, Cotton MF, Zar HJ. Failure of chemoprophylaxis withstandard anti-tuberculosis agents in child contacts of multidrug-resistanttuberculosis cases. Pediatr Infect Dis J 2007;26:11426.

46. Passanante MR, Gallagher CT, Reichman LB. Preventive therapy for contacts ofmultidrug-resistant tuberculosis. A Delphi survey Chest 1994;106:4314.

47. American Thoracic Society. Centers for Disease Control and Prevention andInfectious Disease Society of America. Targeted tuberculin testing and treat-ment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S22147.

48. American Academy of Pediatrics. Tuberculosis. In: Pickering LK, Baker CJ, LongSS, McMilan JA, eds. Red Book: 2006 Report of the Committee on InfectiousDiseases. 27th Ed, Elk Grove Village, IL. American Academy of Pediatrics2006:678704.

49. Marais BJ, Gie RP, Hesseling AC, Beyers N. Adult-type pulmonary tuberculosis inchildren 10-14 years of age. Pediatr Infect Dis J 2005;24:7434.

50. Curtis AB, Ridzon R, Vogel R, et al. Extensive transmission of Mycobacteriumtuberculosis from a child. N Engl J Med 1999;341:14915.

51. Munoz FM, Ong LT, Seavy D, Medina D, Correa A, Starke JR. Tuberculosis amongadult visitors of children with suspected tuberculosis and employees at achildrens hospital. Infect Control Hosp Epidemiol 2002;23:56872.

H.S. Schaaf, B.J. Marais / Paediatric Respiratory Reviews 12 (2011) 313838