RECENT WHO GUIDELINES

ON DRTB TREATMENT
 Key considerations in drug-resistant TB
treatment
Access to DST –Reliable,Quality Assured DST
Xpert MTB/RIF® for rifampicin
LPA to detect mutations associated with resistance to R,
H, FQ, SLI
Phenotypic DST
*Reliable and reproducible methods BDQ, LZD, DLM, CFZ
&Z
**** Indirect evidence for Eto/Pto resistance inferred from
the presence of InhA on FLA.
 Options in drug-resistant TB treatment
regimens
Regimen for isoniazid-resistant TB
Shorter regimen for MDR/RR-TB
Shorter regimen for MDR/RR-TB with quinolone
resistance
Longer regimen for MDR/RR-TB
 H Resistance regimen
Isoniazid is one of the most important components of
first-line TB treatment regimens. Patients with Hr-TB
who are treated with 2HREZ/4HR4 stand a much
higher risk of treatment failure, relapse or acquisition
of additional resistance than those who have drug-
susceptible TB. The acquisition of MDR-TB is a serious
consequence of inadequate treatment of Hr-TB, given
that it would necessitate a much longer treatment with
more second-line agents.
Regimen for rifampicin-susceptible
and isoniazid-resistant TB
Hr-TB regimen: 6(H)REZ-Lfx
If levofloxacin cannot be used FQ resistance/
intolerance/contraindications to the use of
fluoroquinolone, then 6(H)REZ may be prescribed
daily for 6 months.
 The shorter all-oral Bedaquiline-
containing regimen for MDR/RR-TB
For MDR/RR-TB patients without previous exposure
to second-line medicines for more than 1 month,
where there is no fluoroquinolone resistance and the
patients do not have extensive TB disease or severe
extrapulmonary TB.
* not pregnant; children 6 years old and above
 Extensive TB disease:
Extensive TB disease presence of bilateral cavitary
disease, / extensive parenchymal damage on chest
radiography.
In children aged under 15 years, the presence of
cavities or bilateral disease on chest radiography.
Severe extrapulmonary TB presence of miliary TB or
TB meningitis.
In children aged under 15 years, EP forms of disease
other than lymphadenopathy (peripheral nodes or
isolated mediastinal mass without compression).
Composition and duration of the regimen

The regimen can be summarized as: 4–6 Bdq(6 m)

-Lfx-Cfz-Z-E-Hh-Eto / 5 Lfx-Cfz-Z-E
Initial phase: 4–6 Bdq(6 m)-Lfx-Cfz-Z-E-Hh-Eto
Continuation phase: 5 Lfx-Cfz-Z-E
 ADVANTAGES OF SHORTER BDQ
BASED REGIMEN
Better and safer standards of care in pts with DR TB.
Excessive adverse effects of injectables sp. Hearing loss
eliminated.
In comparison to all oral longer regime they seemed
no mark differences in the outcomes. However modest
beneficial effects noted in success versus all
unfavourable outcomes and loss to follow-up.
Analysis from data from South African an outcome of
failure and reoccurrence combined was 3.4%
comparable to STREAM TRIAL relapse 3.3%
 What if the patient fails the
regimen
BDQ and FQ are the backbone of the regimen, it is
vital to monitor resistance to these medicines during
treatment if there is no culture conversion by month
6. NTPs need to rapidly establish DST for bedaquiline,
to monitor bedaquiline resistance;
 LONGER ALL ORAL REGIMEN

18 Bdq (6 m or longer)-(Lfx or Mfx)-Lzd-(Cfz or Cs)

Salient feature added in the document
Prolonged use of bedaquiline
New evidence on the safety profile of the prolonged use of
bedaquiline became available that supports its safe use beyond
6 months in patients who receive appropriate schedules of
baseline and follow-up monitoring. The added benefit of the
use of bedaquiline beyond 6 months remains unclear .
The regimen needs to have atleast three effective agents. BDQ
stopped at 6 months, however if another drug stopped before
the end of treatment because of toxicity and reliable DST is
not available for one or more agents on the regimen but
background resistance is known to be high and the agents
included are unlikely to cure the patient. Extension of BDQ
can be considered.
 Concurrent use of BDQ and DLM
GDG concluded after assessing the safety data in 2019
no additional safety concerns with regard to
concurrent use of BDQ & DLM.
Concurrent use recommended in patients with limited
treatment options probably due to extensive drug
resistance profile or intolerance to other SLD.
Appropriate schedules of safety monitoring
recommended for such patients.
 Use of Newer Drugs in Pregnancy
An observational study in South Africa included
information on 58 mothers who received bedaquiline
during pregnancy. fetal exposure to bedaquiline in utero
was associated with low birth weight (<2500 g), with no
other significant differences in infant outcomes,
pregnancy outcomes or maternal treatment outcomes,
including weight gain in the infants until 1 year of age.
Outcomes of treatment and pregnancy and post partum
surveillance for congenital anomalies, should be
documented for future recommendations of MDR
treatment.
 USE OF LONGER REGIMEN IN SEVERE
FORMS OF EP-TB,TBM
WHO recommendations on longer MDR-TB regimens
apply also to patients with extrapulmonary disease,
depending on the specific location of the disease and
tne DST of the infecting strain.
 The bedaquiline, pretomanid and linezolid
(BPaL) regimen for MDR-TB with additional
fluoroquinolone resistance
The Nix-TB study was conducted in South Africa in
2015–2017 to assess safety, efficacy, tolerability and
pharmacokinetic properties of a 6–9-month
treatment regimen composed of bedaquiline,
pretomanid and linezolid (BPaL) for treatment of
XDR-TB, intolerant and non-responsive MDR-TB
BPaL regimen: 6–9 Bdq- Pa-Lzd
The bedaquiline, pretomanid and linezolid (BPaL) regimen for
MDR-TB with additional fluoroquinolone resistance
 BPaL regimen be used under operational research
conditions conforming to WHO standards, which
include
 Ethical approval
 Patient-centred care and support
 Pre-defined eligibility criteria
 Patient informed consent
 Implementation according to the principles of good
clinical practice
 ADSM
 Treatment monitoring and outcome evaluation
 Comprehensive, standardized data collection.
 Dosing
Dosing of component drugs for adults and
adolescents (aged 14 and over)
Drug Dose
Bedaquiline (100 400 mg once daily for 2 weeks, then
mg tablet) 200 mg 3 times per week afterwards
Pretomanid (200 200 mg once daily
mg tablet)
Linezolid (600 mg 1200 mg once daily (adjustable)
tablet)
Eligibility
Diagnosed with bacteriologically confirmed pulmonary TB
and has laboratory-confirmed resistance to rifampicin and
fluoroquinolones with or without resistance to injectable
agents; and
aged at least 14 years, weighs 35 kg or more; and
willing for informed consent and to adhere to the follow-up
schedule
Non pregnant or breastfeeding and is willing to use effective
contraception; and
no known allergy to any of the BPaL component drugs; and
no evidence in DST results of resistance to any of the
component drugs, or has not been previously exposed to any
of the component drugs for 2 weeks or longer; and
No extrapulmonary TB (including meningitis, other CNS
TB, or TB osteomyelitis).
 Relative contraindications
Relative contraindication
Concurrent use of medications that have known interactions or overlapping
toxicities with BPaL component drugs
Notes
Inducers of CYP450 enzymes: Efavirenz , Rifamycins, Antiepileptics
Inhibitors of CYP450 enzymes: Ritonavir-boosted Pis, Fluconazole or
itraconazole, Clarithromycin or erythromycin
Drugs that prolong the QT interval, Drugs that increase serotonin level
High risk of cardiac arrhythmia
Severe anaemia,
thrombocytopenia or leukopenia
Severe hepatic failure
Severe renal failure
Severe neuropathy
 Discontinuation of any component of the
BPaL regimen due to severe toxicity
If either BDQ or pretomanid needs to be discontinued, the
entire BPaL regimen should also be discontinued.
If Lzd is permanently discontinued during the initial 4
consecutive weeks of treatment, the entire regimen
discontinued.
Temporary cessation of linezolid or of the full regimen is
allowed for suspected drug-related toxicity upto 35
consecutive days.
If Lzd needs to be permanently discontinued at a later
stage of the regimen, with the linezolid 1200 mg, assess the
patient status and either discontinue the regimen or
continue with BDQ and pretomanid.
 Considerations for implementation
Despite the promising treatment success rates observed
in the Nix-TB study, the regimen may not currently be
considered for programmatic use worldwide until
additional evidence on efficacy and safety has been
generated.
 However in Patients with extensive drug-resistance
profiles that make it difficult/impossible to construct a
regimen based on existing recommendations. On
compassionate groundss the BPaL regimen may be
considered as a last resort under prevailing ethical
standards.
Adjuncts to MDR-TB treatment
Surgery in treatment of M/XDR-TB

Elective partial lung resection (lobectomy or wedge

resection) as an adjunct to the chemotherapy of
MDR/RR-TB and XDR/TB patients. The
recommendation does not apply to radical
pneumonectomy, which had no statistically significant
effect.
 Use of corticosteroids

In patients with tuberculous meningitis, an

initial adjuvant corticosteroid therapy with
dexamethasone or prednisolone tapered over 6–8
weeks should be used.
In patients with tuberculous pericarditis, an
initial adjuvant corticosteroid therapy may be
used.
Treatment of HIV co-infected MDR/RR-TB
patients
ART is recommended for all patients with HIV
and drug-resistant TB requiring second-line anti-
tuberculosis drugs irrespective of CD4 cell count,
as early as possible (within the first 8 weeks)
following initiation of anti-tuberculosis
treatment.