1. DR SAUMU WAYUWA KPA ANNUAL SCIENTIFIC CONFERENCE 2019
DRUG RESISTANT TB IN CHILDREN
DR SAUMU WAYUWA
KPA ANNUAL SCIENTIFIC CONFERENCE 2019

2. OUTLINE Resistance patterns Epidemiology MDR TB in children Diagnosis
Management

3. TB RESISTANCE PATTERNS
Mono-resistant TB
Resistant to any one drug.
Poly-resistant TB
Resistant to more than one drug but not both isoniazid and rifampicin.
Multi-drug resistant (MDR) TB
Resistant to at least both isoniazid and rifampicin.
Extensive drug resistant (XDR) TB
Resistant to rifampicin, isoniazid, an injectable and a quinolone.

4. BACILLARY POPULATIONS
1. Rapidly multiplying bacilli
- Optimum medium: Extracellular. PH 6.5-7, maximum oxygenation (cavity wall)
- Large number of bacilli → High probability of spontaneous mutations and natural resistance
2. Slowly multiplying bacilli
- Intramacrophagic location. Acid pH. Population<105 Relapse capacity
3. Intermittently growing bacilli
- Unfavourable conditions. Solid caseum. Extracellular
- Population <105. Relapse capacity
4. Bacilli in latent state: Not susceptible to drugs
- Reactivations and relapses

5. M. TUBERCULOSIS RESISTANCE
Natural resistance – characteristic of the bacilli
Acquired resistance – therapy problem (resistance in previously treated patients)
Primary resistance – transmission problem (resistance in previously untreated patients)

6. DR TB TRENDS IN KENYA

7. GLOBAL EPIDEMIC MDR-TB SITUATION
WHO Reports 2014, 2015, 2016 and 2017
Since 2013, more than 50% of new cases of MDR-TB were among people who have never been treated for TB before, highlighting the importance of transmission and the lack of appropriate infection control measures, particularly at community level

8. MDR-TB IN CHILDREN Is mainly primary (transmitted) drug resistance
Disease in children usually (>90%) develops within 12 months of infection
Is more difficult to acquire because of the paucibacillary nature of primary disease
Possible if cavitary pulmonary disease
Children with DR TB are not major contributors to the spread of DR TB in the community
Good source for surveillance on drug resistant TB
May reflect the transmission of these organisms in the community

9. MDR-TB IN CHILDREN Children at high risk
Contacts of patients with MDR-TB
Living in MDR-TB high prevalence areas

10. RATES OF MDR-TB AMONG CONTACTS OF MDR-TB PATIENTS
Study
Country
Number of contacts
Percentage of patients with MDR-TB
(# of TB case/total # with active TB)
Kritski et al. (1996)
Brazil
218
62% (8/13)
Schaaf et al. (2000)
South Africa
149
83% (5/6)
Texeira et al. (2001)
133
Schaaf et al. (2002)
119
75% (3/4)
Bayona et al (2003)
Peru
945
84% (35/42)

11. MDR-TB IN CHILDREN Further suspect drug-resistant TB:
If a child gets worse on treatment or fails despite adherence to treatment
If an adult index case with unknown susceptibility pattern is:
a treatment failure (sputum smear positive after 5 months treatment)
a retreatment case
a chronic TB case (TB despite 2 previous treatment courses)

12. Drug-susceptible vs. drug-resistant TB in children
DIAGNOSIS OF MDR-TB IN CHILDREN
Drug-susceptible vs. drug-resistant TB in children
No clinical or radiological difference between these two groups
Clinical features and chest radiography does not distinguish DS from DR/MDR TB
Confirmed MDR TB is a laboratory diagnosis

13. DIAGNOSIS OF MDR-TB IN CHILDREN
Confirmed DR TB is a laboratory diagnosis : nucleic acid amplification test (e.g. Xpert MTB/RIF) or culture with DST Bacteriological diagnosis should always be attempted for drug sensitivity testing Probable DR TB is diagnosed in a child with active TB disease and a recent close contact with DR TB Suspected DR TB is when a child fails to improve while adherent to first-line anti-TB treatment OR if the adult source case is a treatment failure, a retreatment case or recently died from TB

14. DIAGNOSIS OF MDR-TB IN CHILDREN
Bacteriologic confirmation of TB is more difficult
Lower bacillary load
Less forceful cough
Difficult to obtain specimens
More extra pulmonary cases (< 5 years)
Important role for X-ray film
Gene Xpert is a useful tool

15. DIAGNOSIS OF MDR TB History of contact/previous treatment Sputum smear
Drug Susceptibility Test (DST)
- Molecular DST
Gene xpert
LPA
- Conventional DST
Liquid culture (MGIT)
Solid culture

16. BASELINE LABORATORY INVESTIGATIONS
Sputum smear, FLD and SLD LPA, culture and DST
Hemogram
UECr
LFTs
TSH
HIV
CXR
Audiometry
ECG

17. DR TB CLINICAL REVIEW
County physician, Pediatrician, CTLC/SCTLC, CASCO, Pharmacist, Lab technologist, Nutritionist, Social worker, PHO, psychologist
Review team meets at central facility at county/sub county level
Patients brought by their facility DOTs nurse/clinician
Team reviews the following;
Patient’s progress
Patient`s suspected or documented ADR`s
Sputum smears and cultures
Biochemistry lab results
Deliberations and notes recorded in patient log book

18. PRINCIPLES OF MANAGEMENT OF MDR-TB IN CHILDREN
The same principles apply as for adults.
Do not add a single drug to a failing regimen
At least 4 susceptible drugs.
Lower bacillary load  Probably enough with only 3 drugs??
Use the adult index case’s isolate DST pattern if no isolate from child is available
Favorable treatment outcomes: adverse reactions are very infrequent, even with SLD
Caution with Bdq <6 years and Dlm <3 years
Longer oral or shorter MDR/RR-TB regimens - weight based dosing

19. DESIRABLE CHARACTERISTICS OF DRUGS
Adapted from: Caminero JA, et al. Treatment of TB. Eur Respir Monogr 2012; 58: 154–166
Caminero et al. Treatment of drug-susceptible and drug-resistant TB. Eur Respir Monograph 2018:
Bactericidal – to rapidly eliminate the bulk of active bacilli
INH, RIF, Lfx/Mfx, SLD Inject, Lzd, Bdq, Dlm
2. “Sterilization” – killing dormant or intermittent growing bacilli
RIF, PZA, hMfx, Lfx, Lzd, Cfz, Bdq, Dlm
3. Prevention of Resistance with drug combination
4. Minimal Toxicity

20. WHO RECOMMENDATIONS FOR DR-TB TREATMENT
WHO 2011 update
WHO 2016 update

21. Group Medicine Abbreviation
WHO DR-TB Guidelines Grouping Medicines for use in Longer MDR-TB Regimens
Group
Medicine
Abbreviation
Group A
Include all three medicines
(unless they cannot be used)
Levofloxacin o
Moxifloxacin
Lfx
Mfx
Bedaquiline
Bdq
Linezolid
Lzd
Group B
Add both medicines
Clofazimine
Cfz
Cycloserine or
Terizidone Cs
Trd
Group C
Add to complete the regimen and when medicines
from Group A and B cannot be used
Ethambutol E
Delamanid
Dlm
Pyrazinamide Z
Imipenem/cilastatin or Meropenem
Ipm/Cln
Mpn
Amikacin or
(Streptomycin) Am
(S)
Ethionamide or
Prothionamide
Eto
Pto
p-aminosalicylic acid
PAS

22. MDR TB TREATMENT REGIMENS
Short term regimen
Intensive phase 4-6 Km-Mfx-Pto-Cfz-E-Z-Hhigh-dose
Continuation phase 5 Mfx-Cfz-Z-E
Individualized regimen

23. CLINICAL AND LABORATORY FOLLOW UP
Month
Clinical consult
Smear
Culture
DST
LFTs*
UECs
TSH
Chest X-Ray
Start √ 1
Every 2 Weeks 2 3 4
Monthly
Quarterly but monthly for HIV infected patients
Where Indicated 5 6 7 8 9
Every 3 months 10 11 12
Till Completion
Every 6 months

24. OUTCOMES OF MDR-TB TREATMENT IN CHILDREN
Systematic review and meta-analysis reviewed treatment outcomes for children with MDR-TB.
Eight studies, which reported outcomes on 315 patients, contributed to the database.
Average duration of treatment ranged from 6 months to 34 months.
The pooled estimate for treatment success (defined as a composite of cure and completion) was 81.7% with death in 5.9%, and default in 6.2% of patients.
Adverse reactions occurred in 39.1% of the children, the most common of which were nausea and vomiting followed by hearing loss, psychiatric effects and hypothyroidism.
Ettehad D, Schaaf HS, Seddon JA, Cooke GS, Ford N. Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2012;12:
Good treatment outcomes due to paucibacillary disease and DOTS (as compared to adults with high bacilli load/presence of cavities making treatment difficult-resistance selection)

25. SUMMARY OF MANAGEMENT OF MDR-TB IN CHILDREN
Confirm MDR TB… if possible
Management and review by DR TB clinical review team
Use the adult index case’s isolate DST pattern if no isolate from child is available
Give at least 4 or more drugs to which the patient’s isolate is susceptible to and/or naïve
Counsel parents at every visit about possible adverse events, and the importance of adherence to treatment
DOT with daily treatment is essential
Close Follow-up is essential: clinical, radiologic and cultures

26. THANK YOU