MDR-­‐TB

 IN  CHILDREN  

Rina  Triasih  
 
Department  of  Paediatric,  Faculty  of  Medicine,    
Universitas  Gadjah  Mada/  Dr.  Sarjito  Hospital  
Yogyakarta,  Indonesia  
 Outline    
•  Problems  and  challenges  
•  Epidemiology  
•  Approach  to  diagnose  
•  Management  
•  IdenJficaJon  and  management  of  adverse  
reacJon  
•  Management  of  child  contact  of  DR  TB  case  
 The  problems  and  challenges  

“The trouble is that we have

the perfect recipe for making
children with TB invisible,
especially children with drug-
resistant TB.”

(Becerra, 2014)
 The  problems  and  challenges  
•  Non  specific  symptoms  of  TB  in  children  à  more  likely  
to  be  missed.  
•  Children  haven’t  been  a  priority  for  TB  test  
•  Sputum  smear  microscopy  and  culture:  
–  Specimen  collecJon:  difficult  
–  Low  yield:    <  20%  
•  Once  infected  with  TB,  children  progress  more  quickly  
to  acJve  disease  and  death  than  adults  
Problems  and  Challenges:  DR  TB  in  children  

Bacteriological  confirma:on  of  drug-­‐resistant  

TB  in  children  is  complicated  by  :  
•  challenges  in  obtaining  respiratory  specimens  
•  the  paucibacillary  nature  of  childhood  TB  
•  the  lack  of  resources  for  culture  and/or  DST  in  
high-­‐burden  seZngs.  
MDR  TB  disease  in  children:    
epidemiology  
•  Very  limited  data  available  

•  The  burden  of  MDR  TB  in  children  is  likely  to  reflect  
that  which  occurs  in  adults,  so…..  

•  MDR  TB  is  common  in  children  in  seZngs  where  

MDR  TB  in  adult    is  common  
 
•  MDR  TB  is  increasing  in  children  in  seZngs  where  
overall  MDR  TB  is  increasing    
Propor:on  of  MDR  among  new  TB  cases    
Latest  available  data,  1994-­‐2012  

The  boundaries  and  names  shown  and  the  designaJons  used  on  this  map  do  not  imply  the  
expression  of  any  opinion  whatsoever  on  the  part  of  the  World  Health  OrganizaJon  concerning  the  
legal  status  of  any  country,  territory,  city  or  area  or  of  its  authoriJes,  or  concerning  the  delimitaJon  
of  its  fronJers  or  boundaries.    Doaed  lines  on  maps  represent  approximate  border  lines  for  which  
there  may  not  yet  be  full  agreement.    
©  WHO  2013.  All  rights  reserved  
MDR  TB  disease  in  children:    
epidemiology  
•  Mainly  be  from  transmission  of  drug-­‐resistant  TB  to  
the  child,  rather  than  acquired  from  prior  exposure  
to  TB  treatment  

•  Children  with  MDR  TB  are  not  major  contributors  to  

the  spread  of  MDR  TB  in  the  community  

•  MDR  TB  in  children  is  associated  with  increased  

morbidity  and  mortality  compared  to  drug-­‐sensiJve  
disease  
 Indonesia  
•  Ranks  8  of  27  countries  with  high  burden  of  MDR  
TB  
•  Number  of  cases:  6,  900  kasus    
–  5.900  new  cases  
–  1000  re-­‐treated  cases  
•  MDR  TB  in  children:  
–  Yogyakarta:  1  
–  DKI:  2  
–  East  Java:  2  
(data  from  personal  communica2on)  
Development  of  drug  resistance  TB  

Wild M. TB strain
Spontaneous mutation

Strains with genetic

drug resistance
Selection: inadequate treatment

Acquired drug resistance

Transmission

Primary drug resistance

Criteria  for  suspected  MDR  TB  

•  Previous  TB  treatment  in  the  past  6-­‐12  months    

•  Close  contact  with  a  person  known  to  have  MDR-­‐TB  
•  Close  contact  with  a  person  who  has  died  from  TB,  
failed  TB  treatment,  or  is  non-­‐  adherent  to  TB  
treatment    
•  Failure  to  improve  clinically  aier  2-­‐3  months  of  first-­‐
line  TB  treatment,  including  persistence  of  posiJve  
smears  or  cultures,  persistence  of  symptoms,  and  
failure  to  gain  weight    
       (Note:radiological  improvement  is  frequently  delayed)    
 
Approach  to  diagnose  TB  in  children    
WHO  Guidance  2006  

1.  Careful  history  

 includes  history  of  TB  contact  
 symptoms  suggesJve  of  TB  
2.  Clinical  examinaJon  
 includes  growth  assessment  
3.  Tuberculin  skin  test  
4.  Bacteriological  confirmaJon  whenever  possible  
5.  InvesJgaJons  relevant  for  suspected  PTB  or  
suspected  EPTB  
6.  HIV  tesJng    
 Approach  to  diagnose  MDR  TB  in  children    
•  Careful  history  
 History  of  contact  with  MDR  TB  case  is  criJcal  informaJon  
 Consider  in  child  failing  first-­‐line  TB  treatment  despite  
adherence    
•  Clinical  examinaJon  
•  InvesJgaJons  relevant  for  suspected  PTB  or  EPTB  
     Important  to  try  to  get  samples  for  culture  and  DST    
•  HIV  tesJng    
 Failure  to  respond  to  TB  treatment  should  consider  HIV-­‐related  
lung  disease  that  is  not  TB  as  well  as  the  possibility  of  MDR  TB  
•  Bacteriological  confirmaJon  and  drug  suscepJbility  
tesJng  whenever  possible  
 Sputum  (or  other  relevant  specimen)  should  be  collected  for  
culture  with  drug  sensiJvity  tesJng  (or  LPA  or  Xpert  MTB/RIF)  
 Suspect of MDR TB

YES NO

•  Clinical assessment Evaluation for

•  Sputum/other susceptible
specimentà DST TB

Results of dx work up
available

NO
YES

Clinically Clinically
MDR TB DS TB No diagnosis stable unstable
confirmed confirmed confirmed
Await Consider
Tx based 1 st line diagnosis & empiric Tx of
on DST TB drugs close monitor MDR TB
Prac:ce  points:  diagnosis  of  MDR  TB  in  a  child  

 
Confirmed  DR  TB  is  a  laboratory  diagnosis  :  culture  with  DST  or  
nucleic  acid  amplificaJon  test  (e.g.  Xpert  MTB/RIF)  
 
Probable  DR  TB  is  diagnosed  in  a  child  with  TB  and  a  recent  close  
contact  with  DR  TB  
 
Suspected  DR  TB  is  when    a  child  fails  to  improve  while  adherent  to  
first-­‐line  anJ-­‐TB  treatment  OR  if  the  adult  source  case  is  a  
treatment  failure,  a  retreatment  case  or  recently  died  from  TB  
 
 Types  of  specimen  
Types of Specimens

minimum
Prac:ce  points:  management  of  MDR  TB  
 
•  All  children  with  suspected  MDR  TB  should  be  
referred  to  a  facility  that  can  do  culture  and  drug  
suscepJbility  tesJng  -­‐  usually  a  terJary  facility  

•  Hospitalisa:on  is  usually  required  for  treatment  

because  it  includes  injectables  
 
•  Treat  according  to  DST  results  from  child  or  from  
likely  source  case  (if  results  from  child  not  available)  
 
 
Prac:ce  points:  management  of  MDR  TB  
 
•  Give  at  least  4  drugs,  to  which  paJent  or  adult  
source  case  is  suscepJble  

•  All  treatment  daily  and  under  direct  observa:on  

•  Caregivers  need  counselling  and  support  regarding  

adverse  effects,  treatment  duraJon  and  adherence  

•  Careful  monitoring  for  clinical  response  and  adverse  

events  à  should  ideally  be  managed  by  experienced  
paediatrician  at  terJary  level  
 The  regimen  
•  The  basic  principles    and  medicaJons  used  of  
treatment  regimen  are  the  same  as  those  for  
adults  with  MDR-­‐TB.    
•  Major  difference:  children’s    treatment  regimen  
is  oWen  empiric  and  based  on  the  drug  
suscepJbility  paaern  of  source  cases.    
•  Most  second-­‐line  drug  formulaJons  are  not  
child-­‐friendly  
•  Current  dosing  recommendaJons  are  based  on  
adult  mg/kg  doses.    
Approach  to  treatment  of  MDR  TB  in  children  

1.  Choice  of  treatment  will  be  influenced  by  availability  of  
DST  in  child  or  contact,  and  drug  resistance  surveillance  
in  a  parJcular  seZng  
2.  Minimum  of  4  acJve  drugs  if  extensive  pulmonary  or  
disseminated  disease  
3.  Start  with  first-­‐line  drugs  to  which  DST  results  show  
suscepJbility  (e.g.  ethambutol,  PZA)  
4.  Add  an  injectable  (e.g.  amikacin)  
5.  Add  fluoroquinolone  (e.g.  levofloxacin  or  moxifloxacin)  
6.  DuraJon  18  months  –  limited  evidence  
7.  HospitalisaJon  for  4-­‐6  months  for  injectable  
8.  DOT  by  health  worker    
 AnJ  TB  treatment  for  MDR  
Group   Classifica:on     Drugs    

1   first  line  ATT   isoniazid,  rifampicin,  ethambutol,  

  pirazinamide  
2   Injectable  ATT   streptomicine,  kanamycine,  amikasin,  
Capreomycine  
3   Fluoroquinolones   -­‐  ciprofloxacin,  ofloxacin,  levofloxacin,  
moxifloxacsin  
4    Oral  bacteriostaJc   ethionamid,  cycloserin,  para-­‐
agents     aminosalicylic  acid  (prothionamid,  
thioacetazon,  terisadon)  
5     Drugs  of  uncertain   clofasamin,  amoxicillin/clavulanat,  
values:     clarithromycine,  linezolid  
Weight-Based Dosing in Children
Weight-Based Dosing in Children
Group  4:  oral  bacteriostaJc  agent  
Group  5:  anJ  TB  drugs  with  unclear  efficacy  or  
unclear  role  in  MDR  TB  

hours
 Monitoring  
A proposed monitoring schedule

1 3 4 5 6 9 15 18

Mangement of Drug-Resistant Tuberculosis in Children 2

Iden:fica:on  and  management  of  adverse  events  
Management  of  child  contact  of  DR  TB  case  

IdenJficaJon  and  symptoma:c  screening  of  all  contacts  

of  DR  TB  cases  is  important  
 
InvesJgaJon  of  symptomaJc  contacts  should  include  
sputum  for  culture  and  drug  sensiJvity  (or  LPA  or  Xpert  
MTB/RIF)    
 
AsymptomaJc  contacts  need  to  be  followed  and  
informed  that  prompt  evaluaJon  is  required  should  
symptoms  develop  
Management  of  child  contact  of  DR  TB  case  

There  is  very  liXle  evidence  and  no  agreed  consensus  on  the  use  of  
or  opJmal  regimen  for  prevenJve  therapy  for  asymptomaJc  contacts  
of  DR  TB  cases  :  
 
(a)  not  to  provide  any  prevenJve  therapy  +  careful,  regular    
           follow-­‐up    
 
(b)  Provide  prevenJve  therapy:  at  least  2  drugs  to  which  the  DR  
           TB  index  case  is  suscep:ble  or  naïve  and  treat  for  at  least  6    
             months  
           à    Especially  for  high-­‐risk  contacts  such  as  HIV-­‐infected  or  young  
                         children  
Management Algorithm for Child Contacts of MDR-TB Cases
 Management  
Management of  cfor
Algorithm hild  
Childcontact  
Contacts with   MDR  TCases
of MDR-TB B  
****  The  composiJon  of  the  prevenJve  regimen  depends  
on  the  naJonal  program,  but  could  be:  
(1)  a  fluoroquinolone  and  high  dose  INH  
(2)  A  fluroquinolone,  high  dose  INH  and  EMB  
(3)  A  fluoroquinolone  and  EMB    
(4)  High  dose  INH  alone  
(5)  A  fluoroquinolone  alone  
 
AddiJonal  studies  are  underway  to  provide  a  strong  
evidence  base  for  prevenJve  therapy  recommendaJon  
THANK  YOU