references : nelson text book of pediatrics national institutes of health website pediatric rotation

1. Treatment of drug resistant
tuberculosis
Balqees Majali

2. • resistance to at least isoniazid and
rifampin
MDR-TB
• MDR
• resistance to any fluoroquinolone
and at least 1 of 3 injectable drugs
(kanamycin, capreomycin,
amikacin
XDR-TB

3. Drug
resistance
primary
Infected with
M.tuberculosis that is
already resistant
Secondary
*Poor adherence
* inadequate
treatment regimens

4. Risk factors :
• history of previous antituberculosis treatment.
• co-infection with HIV.
• exposure to another adult with infectious
drug-resistant tuberculosis

5. … exposure to an infectious source case
with DR-TB
Assessment for evidence of TB
disease :
• comprehensive symptom screen
• clinical examination
• chest radiography
Any concerns that the
child has TB disease further investigation
If the child is :
*symptom free
* Growing well
* with no concerning clinical signs
Evaluation for risk of infection :
*TST and/or IGRA
* Assessment on the basis of exposure
Investigations

6. Treatment of drug resistant TB infection
• Children exposed to either rifampicin mono-resistant
TB or isoniazid mono-resistant TB can usually be given
either isoniazid or rifampicin alone, respectively
• The British National Institute for Health and Care
Excellence advises follow up with no medical treatment
as does the WHO
• The US Centers for Disease Control and Prevention
(CDC), the American Thoracic Society and the
Infectious Diseases Society of America advise giving
two drugs to which the source case’s strain is
susceptible
• The European Centre for Disease Prevention and
Control suggest that either treatment or close follow
up are legitimate options

7. Follow up of healthy contacts
… The WHO and several other guidelines
recommend 2 years of follow up.
Clinical follow-up is likely sufficient but where
resources permit, chest radiology at 3–6-month
intervals can detect early disease when
symptoms may not be obvious.

8. Treatment of drug-resistant TB disease
• Treatment of drug-resistant tuberculosis is
successful only when at least 2 bactericidal
drugs are given to which the infecting strain of
M. tuberculosis is susceptible
• The specific treatment plan must be
individualized for each patient according to
the results of susceptibility testing on the
isolates from the child or the adult source case

9. • 9 mo with rifampin,
pyrazinamide, and ethambutolisoniazid-
resistant
• the total duration of therapy
often must be extended to 12-
24 mo, and intermittent
regimens should not be used
resistance to
isoniazid and
rifampin
In 2016, WHO endorsed 9-12 mo shorter treatment regimen
for adults and children with MDR-TB who were not
previously treated with second-line drugs, or in whom
resistance to second-line fluoroquinolones or injectable
agents is unlikely.

10. New drug groupings published by the World Health Organization in 2016
Drug group Drug name Important advese effects
A ) Fluoroquinolones Levofloxacin Sleep disturbance, GI
disturbance, arthritis,
peripheral neuropathy,
Moxifloxacin As levofloxacin with QTc
prolongation
Gatifloxacin As levofloxacin with QTc
prolongation
B) Second-line injectable
agents
Amikacin Ototoxicity, nephrotoxicity
Kanamycin As amikacin
Capreomycin As amikacin

11. C) Other
core second-
line agents
Ethionamide/Prothionamid
e
Gastrointestinal disturbance, metallic taste,
hypothyroidism
Cycloserine/Terizidone Neurological and psychological effects
Linezolid Diarrhoea, headache, nausea,
myelosuppression, neurotoxicity, optic neuritis,
lactic acidosis and pancreatitis
Clofazimine Skin discoloration, abdominal pain, QTc
prolongation

12. D) Add-on agents
D1 Pyrazinamide Arthritis/arthralgia, hepatitis
Ethambutol Optic neuritis
High-dose isoniazid Hepatitis, peripheral neuropathy
D2 Bedaquiline Headache, nausea, liver dysfunction,
QTc prolongation
Delamanid Nausea, vomiting, dizziness,
paresthesia, anxiety, QTc prolongation
D3 p-aminosalicylic acid GI intolerance, hypothyroidism,
hepatitis
Imipenem-cilastatin GI intolerance, hypersensitivity
reactions, seizures, liver and renal
dysfunction
Meropenem As Imipenem
Amoxicillin-clavulanate As Imipenem

13. Follow up
Children should be monitored for three
reasons :
• to determine response to therapy
• to identify adverse events early
• to promote adherence

14. Follow up assessment
Assessement of response to treatment Assessment of adverse events
• activity levels,
• respiratory function and neurological
development.
• Height and weight should be measured
monthly and
• for children with pulmonary disease,
respiratory samples for smear microscopy
and culture
• Children with pulmonary disease should
have a chest radiograph at 3 and 6
months and at any time if clinically
indicated
• It is also useful to have a chest radiograph
at the end of therapy to provide a
baseline for follow-up.
thyroid function
every 2 months
ethionamide and
para-aminosalicylic
acid (PAS)
• Renal function
every 2 months
• hearing
evaluation every
month
injectable drugs
Color vision
assessment every
month
ethambutol

15. All children Base line Month Ongoing
1 2 3 4 5 6 9 12 15 18
HIV status *
Toxicity (symptoms,
signs)
* * * * * * * * * * * *
Height and weight * * * * * * * * * * * *
Audiology * * * * * * *
Colour vision testing * * * * * * * * * * * *
Chest radiograph * * *
TB culture and DST * * * * * * *
Creatinine and
potassium
* * * * * * *
TSH, free T4 * * * * * * * *
Haematology (FBC) * * * * * * * * * *
ECG * * * * * * * * * *
HIV-positive
LFTs, Cholesterol * * * *
CD4 count and viral
load
* * * *

16. How to manage adverse events ?
Stevens-Johnson syndrome, necessitate immediate cessation of all drugs until the
symptoms have resolved
If either colour vision or hearing are found to be deteriorating, consideration should
be given to stopping the ethambutol (vision) or injectable medication (hearing)
Gastrointestinal upset is most pronounced with ethionamide and PAS and
frequently this can be managed without stopping the drug by dose escalation, by
dividing the dose or by anti-emetics in older children/adolescents
If the thyroid stimulating hormone (TSH) is elevated and the free T4 is low then
consideration should be given to starting thyroxine substitution
Peripheral neuropathy can be treated by either increasing the dose of pyridoxine or
reducing the dose of isoniazid or linezolid

17. Hepatotoxicity usually starts with new-
onset vomiting. Clinical hepatitis (tender
liver, visible jaundice) necessitates
immediate cessation of all hepatotoxic
drugs
Treatment should continue with the
remaining drugs and consideration given to
starting any other available medications
that are not hepatotoxic
The hepatotoxic drugs can be re-introduced
if felt to be necessary, one-by-one every 2
days, while checking the liver enzymes to
identify the possible causative drug(s).

18. Prevention of TB

19. In general :
* Tuberculosis control programs work on case finding and treatment, which interrupts
secondary transmission of infection from close contacts
* Infected close contacts are identified by positive TST or IGRA testing and can be started on
appropriate treatment to prevent transmission
In health care settings :
* appropriate physical ventilation of the air around the source case.
* Offices, clinics, and hospital rooms used by adults with possible tuberculosis should have
adequate ventilation, with air exhausted to the outside (negative-pressure ventilation).
* Health care providers should have annual screening with a
TST or IGRA.
Vaccination :
The original vaccine organism was a strain of attenuated Mycobacterium bovis. The preferred
route of administration is intradermal injection with a syringe and needle because this is the
only method that permits accurate measurement of an individual dose. The official
recommendation of the World Health Organization is a single dose administered during
infancy

20. THANK YOU!