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Drug-resistant tuberculosis
in children
HS Schaaf
Desmond Tutu TB Centre,
Department of Paediatrics and Child Health,
Stellenbosch University, and
Tygerberg Children’s Hospital
Introduction
§ WHO estimated that 511 000 new cases of MDR-TB
occurred in 2007, 4.9% of all TB cases
§ South Africa estimated to contribute 16 000 new MDRTB cases per year – 4th amongst the 27 high-burden
MDR-TB countries world-wide (7000 notified cases)
§ XDR-TB in every province – both in HIV-infected and
uninfected patients.
§ Lately, RMP mono-resistance seems on the increase in
especially HIV-infected adults
MDR-TB mainly a man-made disease
§ Poor management of drug-susceptible or monoresistant TB cases, e.g. incorrect regimens
(adding a single drug or weak combinations),
interrupting treatment (drug supplies, poor bioavailibility), poor adherence by patients
§ Poor management of MDR-TB cases leads to
transmission of MDR-TB strains, e.g. late
diagnosis, not doing DST in relapse/retreatment
cases, poor infection control measures
especially in high prevalence HIV settings
Lessons from case?
§ Adult TB cases: TAKE A HISTORY! – know when to
screen for MDR-TB
§ Child contacts – screen for TB disease – if no disease,
appropriate prophylaxis – regimen, timing & follow-up
§ Screen with CXR and interpret correctly
§ TB disease: Treat children according to DST of adult
source case until result of own culture and DST available
§ Good weight gain not always a sign of good clinical
response
§ What about management of MDR-TB in pregnancy?
§ MDR-TB is a curable disease (and pre-XDR TB)
MDR-TB in children
§ Is mainly new (transmitted) drug resistance – this has
been confirmed with DST and DNA-fingerprinting
§ Is more difficult to acquire because of the
paucibacillary nature of primary disease, but is
possible with cavitary pulmonary disease
§ In our experience DR-TB is not less infectious and
does not cause less disease than DS-TB
§ Disease in children usually (>90%) develops within 12
months of infection
§ Contact tracing and follow-up of children exposed to
MDR/XDR-TB should receive high priority
Drug resistance surveys amongst
childhood TB cases reported after 2000
Country
Year
Central African Rep
INH-R
MDR
1998-2000 25/165
15 (9.1%)
1 (0.6%)
Egypt
?
4 (5.4%)
2 (2.7%)
Greece
1994-2004 16/77
12 (15.6%)
3 (3.9%)
NA (10%)
NA(3.5%)
1 (1%)
0
India – TB Res Centre 1996
Madagascar
Any DR
18/73
?/201
1997-2000 1/97
Epidemiology: 4 surveys TCH in WCP
Characteristics
1994-98
2003-05
2005-07
2007-09
All cult+ cases
338 (%)
323 (%)
291 (%)
294 (%)
Med age (yrs)
2.6
2.5
2.75
2.1
193 (57.1)
173 (53.6)
154 (52.9)
156 (53.1)
32 (9.5)
59 (18.3)
65 (22.3)
50 (17.0)
HIV test done
166 (49.1)
243 (75.2)
174 (59.8)
217 (73.8)
HIV-infected*
13 (7.8)
64 (26.3)
49 (28.2)
63 (29.0)
Boys
Prev TB Rx
*As percentage of tests done
Significant increases in previously treated children
and HIV-infected children from 1st to 2nd survey
Epidemiology: 4 surveys in WCP of SA
DST results
1994-98
2003-05
2005-07
2007-09
All cult+ cases
338 (%)
323 (%)
291 (%)
294 (%)
306 (90.5)
320 (99.1)
285 (97.9)
292 (99.3)
Any DR
21 (6.9)
41 (12.8)
43 (15.1)
INH mono-R
14 (4.6)
22 (6.9)
22 (7.7)
RMP mono-R
0
0
2 (0.7)
7 (2.3)
19 (5.9)
19 (6.7)
DSTs done*
MDR
*Further percentages based on number of DST results
No significant differences in last 3 surveillance periods
Ethambutol resistance
DST results
EMB-R in any
DR tested
EMB-R in
MDR cases
2003-05
2005-07
2007-09
1/36 (2.8)
4/27 (14.8) 13/36 (36.1)
1/16 (6.3)
4/17 (23.5) 12/24 (50.0)
§ P = 0.001 and 0.01 for EMB resistance in any DR
and MDR cases, respectively
§ None had confirmed XDR, although 1 child was a
contact of an XDR-TB case
§ 2 had resistance to ofloxacin and 1 to amikacin
New DR vs. Previously Rx DR (2003-2007)
Results
New cases Previous Rx
OR (95%CI)
Number with DST
481 (%)
123 (%)
Any DR
47 (9.8)
36 (29.3)
0.26 (0.16-0.45)
MDR
15 (3.1)
21 (17.1)
0.16 (0.08-0.34)
29 of 36 (81%) previously treated cases transmitted DR:
§ 5 MDR contacts failed H or HR prophylaxis
§ 6 more index cases (parents) MDR TB
§ 3 confirmed DR reinfection with RFLP
§ 2 original cultures MDR missed (wrong Rx)
§ 10 no response to adherent Rx (5 index cases died, no DST)
§ 3 INH-R cases completed adherent Rx >1yr before
– 2 new contacts (1 died) and 1 with CD4<1%
History of contact and DST comparisons
§ Concordance between DST in source cases
to DST in child contacts was approximately
78% in these studies
§ Therefore - Need to try and confirm drug
resistance in the child
§ While awaiting culture/DST results in the
child, treat according to adult source case’s
DST result
Messages from surveilllance
§ These surveys show a high prevalence of DR and MDRTB in the WCP
§ Despite previous treatment, >90% of all DR-TB in
children was most likely transmitted DR
§ Although hospital-based surveys are potentially biased,
we did not find a significant difference in a communitybased vs. hospital-based survey (data not shown)
§ DR not significantly different between HIV-infected and
HIV-uninfected cases
§ The few DSTs known in adult source cases hampers
effective management of child TB contacts
Diagnosis : M/XDR-TB in children
§ DR TB is a microbiological diagnosis
§ In children often difficult (paucibacillary TB):
▫ Confirmed if DR M. tuberculosis strain is isolated
from a child
▫ Probable DR-TB if known contact with an adult DR
PTB case
▫ Suspect DR-TB if:
• a child gets worse on Rx, failing adherent Rx
• an adult source case with unknown DST result is a
treatment failure, a retreatment case or died of TB
during adherent Rx
Management of MDR-TB in children
§ Confirm MDR-TB if at all possible
§ If MDR TB is confirmed, also do DST for 2nd-line drugs
§ Management – at a specialized MDR-TB clinic
§ Use 1st-line drugs to which isolate is susceptible plus
2nd-line drugs (50% MDR children EMB-resistant!)
§ Be aware of different drug groups and cross-resistance
§ 2nd-line drugs are generally more toxic than 1st-line
drugs
§ Adverse events more difficult to assess in children
Principles of childhood MDR-TB Rx
§ NEVER add one drug to a failing regimen
§ DOT with daily treatment only is essential
§ Give 3-4 or more drugs to which the patient’s isolate
is susceptible and/or naïve (extent of disease)
§ Use the adult index case’s isolate DST pattern if no
isolate from child is available
§ Counsel patients/parents at every visit for support,
about adverse events, and importance of adherence
§ Follow-up is essential; clinical, radiological and
cultures
11-month-old
Morning tablets
MDR-TB Rx
Difficult to
accurately
break tablets
to correct dosage.
Also receives
an injectable
Drugs for treatment of MDR-TB
Group 1 -Remaining First-Line Drugs
Drug
Daily dosage
mg/kg
Maximum
Ethambutol↔
PZA
20-25
25-40
2.5g
2.0g
INH (Group 5)
15-20
400mg
1200
High-dose INH combined with ETH could give one
effective drug
Cannot rely on any of these drugs
2nd-line or reserve anti-TB drugs
Group 2: Second line injectables
Drug
Aminoglycosides:
- Kanamycin
- Amikacin
Capreomycin
120 0
Unit size
Daily dosage
mg/kg Maximum in mg (SA)
15-30
15-30
15-30
1.0 g
1.0 g
1.0 g
1000
100/250/500
1000
Drugs for treatment of MDR-TB
Group 3: Fluoroquinolones
Drug
Fluoroquinolones: ↔
- Ofloxacin
- Levofloxacin
- Moxifloxacin
15-20
7.5-10
7.5-10
800mg
750mg
400mg
200/400
250/500
400
- Ciprofloxacin
30-40
2.0g
250/5ml
250/500
(Ciprofloxacin NOT
recommended)
1200
Daily dosage
Unit size
mg/kg Maximum in mg (SA)
2nd-line or reserve anti-TB drugs
Group 4: Second-line oral bacteriostatic drugs
Drug
Unit size
Daily dosage
mg/kg Maximum in mg (SA)
Ethionamide/
Prothionamide
15-20
1.0g
250
Cycloserine/
Terizidone
10-20
750 mg
250
8-12.0g
4g
sachets
PAS
150 (2-3
(para-aminosalisylic divided
acid)
doses)
120 0
2nd-line or reserve anti-TB drugs
Group 5: Drugs of unclear role in DR-TB treatment
Drug
Daily dosage
mg/kg
Maximum
Linezolid (New)
10 mg/kg/dose 12 hrly
600/day?
Clarithromycin
7.5 mg/kg/dose 12 hrly
1000/day
Amoxicillin/
Clavulanic acid
10-15 (amox)
mg/kg/dose 8 hrly
Clofazimine
Thioacetazone
Imipenem/
cilastatin
1200
Do not use in HIV-infected patient
Side effects 2nd-line drugs
Drug
Side effects
Tests
Amikacin/
ototoxicity,
hearing test,
Kanamycin/
nephrotoxicity
creatinine, K+ levels
Capreomycin
Ethionamide
Fl-quinolones
GIT disturbance (split dose, escalate)
hepatotoxicity,
ALT?
hypothyroidism
TSH (T4)
GIT disturbance± clinical observation
insomnia, arthralgia
Side effects 2nd-line drugs
Drug
Side effects
Tests
Cycloserine/
Terizidone
psychosis,
depression,
parasthesias
GIT disturbance
hypothyroidism
myelosuppression
periph neuropathy
lactic acidosis
pancreatitis
more common in adults
PAS
Linezolid
add pyridoxine
TSH (T4)
FBC -Hb, platelets, WCC
clinical
lactate
clinical, amilase?
Duration of treatment
§ Optimal duration of treatment in children is not
known
§ Cavitary or extensive pulmonary TB: as for
adults 18 months after first negative culture
§ Primary, non-cavitary MDR-TB - Often culturenegative (paucibacillary): 12-15 months
treatment probably sufficient.
§ Intensive phase including 2nd-line injectable
drug, continuation phase mainly stop
injectable drug
Outcome
§ Few studies on outcome of DR-TB in children
§ Peru – cure/Rx completed obtained in 36 of 38 (95%)
MDR-TB cases
[Drobac et al Pediatrics 2006]
§ South Africa – study of 39 culture-confirmed
childhood MDR-TB cases had 4 (10%) deaths and a
majority of children clinically cured
[Schaaf et al ADC 2003]
§ Need more morbidity and long-term mortality data –
HIV-infected/uninfected
Prophylaxis for DR-TB contacts
§ No RCT available. WHO 2006 MDR guidelines: INH only
(possible DS contact) or clinical follow-up
§ Failure of INH or INH/RMP to prevent MDR TB reported.
§ INH mono-resistance: RMP x 4 mo
§ RMP-monoresistance: INH x 6 mo (Line-Probe test?)
§ MDR-TB: INH (15-20mg/kg) + EMB or ETH + OFL x6 mo
§ Pre-XDR or XDR-TB – only high-dose INH (1520mg/kg)?
§ In both MDR and XDR-TB regular follow-up for a
minimum of 12 months (WHO recommends 2 yrs)
§ Acknowledgements
- Peter Donald
- Robert Gie
- Nulda Beyers
- Ben Marais
- Anneke Hesseling
- Rob Warren
- Wendy Brittle
- Tommy Victor
- Paul van Helden
- Nursing Staff and Research Assistants
- The Children and their Parents
§ Financial Support
- SA MRC
- Harry & Doris Crossley Foundation
- National Research Foundation SA