Pharmacotherapy of drug resistant Tuberculosis

Pharmacotherapy
of Drug
resistant TB
Presenter-
Dr Nikita Ingale,
JR2
Pharmacology GMCH Nagpur
Guide-
Dr Vijay Motghare
Professor and Head
Pharmacology, GMCH Nagpur

Tuberculosis…
- Tuberculosis is a chronic granulomatous disease and a major health problem in developing countries.
- As per WHO statistics for 2017, there were 9.6 million new TB cases globally, to which India was the highe
st contributor with 2.2 million cases.
- India has the dubious distinction of being the highest TB burden country for the past many years; where ab
out 600
people die from TB every day.
- In 2012 the Government of India has declared TB to be a notifiable disease, so that any doctor who treats
a TB
patient, has to notify it to the Govt.
- Control and treatment or TB in India is covered under a National programme which provides free treatment t
o all TB cases. PT of Drug resistant TB

Classification…
PT of Drug resistant TB

Alternative grouping…
PT OF MDR TB
-Most potent
-Best tolerated
-Routine use
-Potent
-Bactericidal
-Injectable
-Bactericidal
-Oral
-Given for
MDR TB
-Less effective
-Bacteriostatic
-Toxic drugs
oral
-Uncertain efficacy
-Not for MDR TB
-Reserve drugs
-For XDR TB

- Intracellularly and at
inflamed sites where pH is
low.
- They are particularly
vulnerable to pyrazinamide,
while isoniazid Rifampicin
and Ethambutol are less
active and Streptomycin is
inactive.
M tuberculosis
Rapid growing Slow growing Spurters Dormant
-high bacillary load as
in the wall of a cavity,
pH is neutral.
- highly susceptible to
isoniazid and lesser
extent to Rifampicin,
Ethambutol and
Streptomycin.
- Mostly in caseous
material, pH is neutral
- Rifampicin is most
active on this
subpopulation.
-totally inactive for
prolonged period.
- No antitb drug
(except bedaquiline
) is active

H R Z E S
WHY ARE THESE FIRST LINE DRUGS?

H R Z E S
Isoniazid
Action tuberculocidal
Kills  rapid and slow growers
Site  extra + intracellular
Medium  alkaline + acidic
Works even in resistance
Watch for slow and fast acetylators
Streptomycin
Kills  rapid growers
Site  extracellular only
Medium  alkaline
S Dependance
Watch for Oto & nephrotoxicity
Rifampicin
Kills  rapid, slow growers,
spurters
Medium  alkaline + acidic
Strong enzyme inducer
Watch hepatotoxicity & orange urine
Ethambutol
Action tuberculostatic
Kills  rapid growers
Early sputum conversion
Delays resistance
Watch for retrobulbar neuritis
No use in paediatric
Pyrazinamide
Kills  slow growers
Site  intracellular
Medium  acidic
Watch for hepatotoxic, hyperuricemia
2nd line drugs
Kanamycin amikacin capreomycin
Fluoroquinolones
PAS = 12 g/day [0.5 g/tablet]
Ethionamide
Cycloserine

Confusion ????
ISONIAZID
RESISTANCE
STREPTOMYCIN
DEPENDANCE
KAT GENE inhA GENE
High dose isoniazid

Category wise treatment regimen…
H = ISONIAZID
R = RIFAMPICIN
Z = PYRAZINAMIDE
E = ETHAMBUTOL
S = STREPTOMYCIN
IP = INTENSIVE PHASE
CP = CONTINUATION PHASE

Monodrug resistant TB…
- The bacilli are resistant to one 1st line ATD, but not Rifampicin -resistant.
- When the liquid culture drug sensitivity test (LC-DST) or line probe assay ( LPA) reports resistance to one first line
drug, other than Rifampicin resistance, the treatment regimen according to RNTCP-2016 consists of:
Monodrug resistant TB
R + two of the 1st line drugs +
one injectable 2nd line drug +
one FQ daily 3- 6 months
the injectable drug is stopped
while the remaining 4 oral drugs
are continued for 9- 12

Polydrug resistant TB…
- The patient's bacilli are resistant to more than one 1st line Anti Tubercular Drugs, except both
Rifampicin and Isoniazid resistance
- According to both WHO and RNTCP, a case of Polydrug resistant-TB is treated as
Poly Drug resistant TB
R + one injectable 2nd line drug
+ one FQ + any Ist line drug for
3-6 months
the injectable drug is stopped
while the remaining 3 oral drugs
are continued for 9- 12

Rifampicin resistant TB…
PT OF MDR TB
- The patient's bacilli are resistant to Rifampicin but not to Isoniazid, with or without resistance to other Anti
Tubercular Drugs.
- According to both WHO and RNTCP, a case of RR-TB is treated as MDR-TB-

Multidrug resistant TB…
- A Multidrug resistant-TB (MDR-TB) case is -
-whose sputum is culture positive for Mycobacterium tuberculosis
-is resistant in vitro to Isoniazid and Rifampicin with or without resistance to other
anti-tb drugs
-based on results from a quality assured certified Culture & Drug Sensitivity Test (DST)
laboratory.

General principles in treating MDR TB…
- The regimen should have at least 4 drugs certain to be effective.
- Often 6 drugs are included, since efficacy of some may be uncertain.
- Reliance about efficacy may be placed on DST results, and the anti-TB drugs used previously in that individu
al.
- Avoid combining cross resistance drugs, e.g. two FQs, Km with Am or Eto with Pto, or Cs with terizidone.
- Include drugs from group I to group IV in a hierarchial order. Group I drugs (Z, E) can be included, add one in
ectable
Drug, one FQ and then from group IV

standardised RNTCP guidelines for MDR TB…
Km = Kanamycin
Lfx = levofloxacin
Eto = Ethionamide
Cs = Cycloserine
E = Ethambutol
+ Pyridoxine 100mg/day
IP CP

Extensively drug resistant TB…
-An extensively drug resistant tuberculosis (XDR TB) case-
is an MDR-TB case
M. tuberculosis isolate is resistant to at Isoniazid, Rifampicin
Resistant to Fluoroquinolone (ofloxacin, levofloxacin, or moxifloxacin)
Resistant to any Second-line injectable anti-TB drug (kanamycin, amikacin, or capreomycin)
at a quality assured certified C & DST laboratory.
MDR-TB cases that are resistant to at least 4 mo
st effective cidal drugs,
viz. H,R,FQ and one of Km/Am/Cm.

- The WHO estimated that 9.7% of MDR-TB patients had XDR-TB in 2015. with expanding laboratory facilities, more
XDR-TB cases are likely confirmed.
- The XDR-TB is very difficult to treat, has a rapid course and high mortality.
- To prevent further amplification of resistance, the standard MDR regimen must be immediately stopped when XDR-T
B is detected or suspected.
- The RNTCP (2016) has recommended a treatment regimen for XDR-TB consisting of 7 drugs in the intensive phase (6-
12 months) and 6 drugs in the continuation phase (18 months).

Cm = capreomycin 1000 mg
Mfx = moxifloxacin 400 mg
High dose H = high dose isoniazid 900 mg
PAS = PAS 12 g
Cfz = clofazimine 200 mg
Lzd = linezolid 600 mg
Amx/ Clv = [875 + 125 mg] amoxicillin + clavulanate tabs morning &
one tab evening

REPURPOSED
DRUGS FOR
DRUG
RESISTANT TB

Confusion ????
REPROFILED DRUGS..??
REPOSITIONED DRUGS??
REPURPOSED DRUGS??
New uses of old drugs
U have a drug approved for some disease, now we search
for some new indications for the same drug
U have a drug which has failed to gain its approval for
some disease, now we reinvestigate that drug for some
other indication
REPROFILED DRUGS / REPURPOSED DRUGS/ REPOSITIONED DRUGS

Repurposed drugs for TB…
PT OF MDR TB

Clofazimine…
- It is a riminophenazine originally used to treat leprosy, not traditionally been used against tuberculosis, because it has
little bactericidal activity.
- However, recent studies have shown that it has sterilizing and treatment-shortening potentials, although the mechanism
of action has yet to be fully elucidated.
- cross-resistance between clofazimine and bedaquiline can occur.
- Clofazimine is presently being considered for the treatment of XDR-TB.

Carbapenems…
- they become active in the presence of clavulanic acid, causing cell wall disruption via peptidoglycan
modulation and thus becoming strongly bactericidal.
- Combination of a carbapenem with clavulanate has proven to be active against M/ XDR-TB, with excellent tolerability.
- The main drawbacks of carbapenems are their high cost, their possible contribution to greater antimicrobial resistance
and the need to administer them parenterally.

Linezolid….
- Linezolid, an oxazolidinone, inhibits the 50S ribosomal subunit in protein synthesis, has demonstrated antimycobacterial
efficacy, and is included in many drug trial regimens
- However, its toxicity profile limits its use beyond drug-resistant tuberculosis.
- In the past, the WHO classified linezolid as a Group 5 drug, whereas it is now considered a core second-line agent, in the
new WHO Group C (Chart 1).
- Sutezolid and delpazolid are two newer generation oxazolidinones used in early clinical trials; the hope is that they will b
e just as effective as linezolid and less toxic.
Bone marrow suppression, anaemia

NOVEL DRUGS
FOR DRUG
RESISTANT TB

Novel drugs for TB…
PT OF MDR TB

Bedaquiline…
- It hasbeen developedby JohnsonjohnsonPharmaceutical Ltd. for the treatment of MDR-TB.
- Indication  adults above 18 yrs of age as a combination therapy for pulmonary tuberculosis due to multidrug
resistant mycobacterium tuberculosis
- Bedaquiline (BDQ) inhibits mycobacterial ATP synthase, limiting energy production within mycobacterial cell.
- It has exhibited strong bactericidal and sterilizing activity against M. tuberculosis in in vitro tests and in animal models
by killing both rapidly multiplying as well as dormant bacilli.
- M. tuberculosis develops resistance to BDQ primarily by mutation of ATP synthase enzyme,no cross resistance between
BDQ and any anti-TB drug

Bedaquiline…
- well absorbed orally, fatty meal improves absorption.
- It is highly plasma protein bound and extensively distributed in tissues.
- Metabolism occurs in liver, mainly by CYP3A4. Clinically significant drug interactions occur with CYP3A4 inducers
and inhibitors.
- The terminal t1⁄2 of BDQ is very long (- 160 days). probably due to redistribution from tissues. It is excreted mainly in
faeces
- The US-FDA approved BDQ in 2012, and it has been marketed internationally as SIRTURO 100 mg tab. The W
HO in 2013 have issued guidelines for use of BDQ in drug resistant TB, following which the RNTCP (2016)
has introduced BDQ in India for MDR-TB at selected centers through its conditional access programme
KEM Hospital Mumbai
BJMC Ahmedabad
GMC Guwahati
NIRT Chennai
NITRD, New Delhi
RBIPMT, New Delhi

Patients eligible for BDQ administration-
MDR TB resistant to all fluroquinolones
XDR TB resistant to all newer fluroquinolones
Treatment failures of MDR
Treatment failures of XDR TB
Mixed pattern DR TB

Present recommendations for the use of BDQ…
•It should be used only for pulmonary MDR-TB in adults (>18 yr)
•Women patients should be nonpregnant and willing to remain so during BDQ use.
•It should be used only in combination with at least 3 other anti-TB drugs to which the bacilli of the patient are shown to b
e susceptible in vitro
•It should be used only when an effective regimen cannot otherwise be provided.
•BDQ should be given for a maximum of 24 weeks in a dose of 400 mg/day for 2 weeks followed by 200 mg 3 times a
week for the next 22 weaks.
•Each BDQ tablet should be swallowed whole with meals.
Price = 1000 US Dollars for 24 weeks

•The background anti-TB drugs should be continued after stopping BDQ for the total 24 weeks treatment of MDR-TB. This
is to ensure that any surviving bacilli are not exposed to BDQ alone, which persists in the body for > 5 months after stopping.
•BDQ is not to be used for drug-sensitive TB, or extrapulmonary TB or for nontubercular mycobacteria.
•Adverse effects of BDQ arc nausea. headache, arthralgia and prolongation of QTc interval.
•BDQ has the potential to cause hepatotoxicity.
Present recommendations for the use of BDQ…

Bedaquiline dosing…

Delamanid…
- Chemical class: nitroimidazole
- It hasbeen developed by OtsukaPharmaceutical Ltd. for the treatment of MDR-TB.
- Delamanid was first approved by the European Medicines Agency (EMA) in November 2014 and subsequently by regulatory
authorities in Japan,Republicof Korea,HongKong,Turkeyand Philippines
- Delamanid is indicated for use as part of an appropriate combination regimen for pulmonary MDR-TB in adult and adolescent
(6-17 years)patients

Delamanid…
- Eachfilm-coated tablet contains 50mgDelamanid.
- Mechanism of Action: Bactericidal (Half-life: 36hours)
Byblocking the synthesisof mycolic acids(i.e., stopping the bacteria from creatingbuilding blocksimportant for their cel
l walls).
Bypoisoning them with nitric oxide, which the drugsrelease when metabolized
- Basedon the examination of the data on globalclinical trials conducted and approval by EuropeanUnion (EU)andJapanfor this
drug, and risk benefit analysis,thecommittee recommendedforwaiver of localclinicaltrialas Delamanid is requiredas an unmet.
need inemergency forthetreatment of MDR/XDR-TB inadult.
- TheCommittee recommendedforapprovalof thedrugintheconditionalaccessprogramme through RNTCP.

Delamanid Avaliability…
Location Nodal DR-TB Centre Laboratories
Punjab Chandigarh
 GMCH32,Chandigarh
 TBH,Patiala
 GMC,Amritsar
 GGSMC,Faridkot
 PGIMER,Chandigarh
 IRL,Punjab
Rajasthan
 SMS,Jaipur(1 &2)
 JLNMC,Ajmer
 SNMC,Jodhpur
 RNTMC,Udaipur
 GMC, Kota
 SPMC,Bikaner
 SMS,Jaipur
 IRL,Ajmer
 C-DSTlab,Jodhpur
Karnataka
 RGICD,Bangalore
 KIMS, Hubli
 PKTB& CDH,Mysore
 DGH,Gulbarga
 VIMS, Bellary
 District Wenlock Hospital,Mangalore
 NTI, Bangalore
 IRL,Bangalore
 KIMS, Hubli
Odisha
 SCB,Cuttack
 MKCG,Behrampur
 VSS,Burla
 RMRC,Bhubaneswar
 IRL,Cuttack
Kerala
Lakshadweep
 ICD& GMC,Trivandrum
 ICD & GMC,Kozhikode
 IRL,Trivandrum

Delamanid dosing…
- All patients will receive Tab. Delamanid 100 mg (two tablets of 50 mg) orally twice a day for 24 weeks (6 months) in
combination with anoptimized background regimen
- Week 0–24 Delamanid 100mg(two tablets of 50 mg) orally twice aday plus background regimen
- Week 25 (start of month 7) to end of treatment: Continue other second-line anti-TB drugs only as per RNTCP
recommendations.
Price = 1700 US Dollars for 6 months

Delamanid dosing…
Resistance
Pattern
DSTGuided
Regimenclass
IntensivePhase Continuation
Phase
Regimenwith New drugsforMDR-TB
MDRTB
MDRTB (6-9)KmEtoCs
Z.Lzd3. Cfz +(6) Dlm
(18) EtoCsLzd3 Cfz
Regimenwith New drugsfor XDR-TB:
XDR-TB XDR-TB
(6-12) Cm1 Eto
Cs Z. Lzd3. Cfz E +
(6)Dlm
(18) EtoCsLzd3CfzE

Bedaquiline or Delamanid???

Pregnancy and Tuberculosis…
- WHO recommend the standard 6 month (2HRZE + 4HRE) regimen
- Streptomycin is contraindicated because it is ototoxic to the foetus.
- In india, the current (20I6) RNTCP guidelines also consider the 4 oral 1st t line drugs to be safe,
and recommend full course of TB treatment as in nonpregnant.
- Treatment of TB should not be withheld or delayed because of pregnancy.
- All pregnant women being treated with INH should receive pyridoxine 10- 25 mg/day

Pregnancy and multidrug tuberculosis…
START MDR TB
TREATMENT
Start treatment Start treatment

TUBERCULOSIS
AND
BREASTFEEDING

Breastfeeding and Tuberculosis…
- All 1st line ATDs are compatible with breastfeeding
- full course should be given to the mother, and breastfeeding
should be continued.
- The infant should receive 6 month isoniazid preventive treatment after
ruling out active TB followed by BCG vaccination.
- Breast-fed infants whose mothers are taking INH, and those on INH
preventive therapy should be supplemented with pyridoxine 5 mg/day

AIDS and Tuberculosis…
- Risk of developing TB in HIV positive subjects increases by about 8 times.
- adverse reactions to anti-TB drugs are more common in HIV patients.
- Thrice weekly regimen should not be used, because it is associated with 2-3 times higher rate of relapse and failure.
- Pyridoxine 25- 50 mg/day is routinely given along with isoniazid to counteract its neurological side effects
- All receive cotrimoxazole preventive therapy to reduce mortality by preventing Pneumocystis jirovecii

AIDS and Tuberculosis…
Drug interactions between anti-TB and antiretroviral (ARV) drugs-
- Rifampin and protease inhibitors (indinavir, ritonavir)  rifampin is replaced by rifabutin given for 9- 12 months
- Rifampin and NNRTls (nevirapine,) rifampin is replaced by rifabutin given for 9- 12 months
- Rifampin and NRTl ( zidovudine)  is not induced by rifampin  no dose adjustment is needed.

TUBERCULOSIS
AND
HEPATOTOXIC
PATIENTS

Hepatotoxicity and Tuberculosis…
- In case hepatitis develops, all drugs should be stopped and the reaction allowed to subside.
- If TB is severe, nonhepatotoxic drugs Streptomycin + Ethambutol + one FQ should be started while the reaction clears
.
- the discontinued drugs are restarted one at a time.
- Rifampicin is resumed first followed 7 days later by isoniazid .
- If hepatitis recurs, the last added drug is stopped permanently and the regimen is reconstructed.

Summary…
Drug sensitive TB-
Multidrug resistant TB-
Extensively drug resistant TB-

Summary…
- The 'standard' RNTCP regimen is used in all confirmed or suspect MDR-TB cases after the DST results
- The XDR-TB is very difficult to treat, has a rapid course and high mortality. However, to prevent
further amplification of resistance, the standard MDR regimen must be immediately stopped when
XDR-TB is detected or suspected
- For pregnancy in tuberculosis, same treatment regimen has to be followed except streptomycin, as it is
teratogenic
- All Ist line ATDs are compatible with breastfeeding; full course should be given to the mother, and
breastfeeding should be continued.
- Two novel drugs, bedaquiline and delamanid have been recently approved

References…
- Goodman, L., Gilman, A. and Brunton, LEllis R. Levin, Wendy S. Vitek, and Stephen R. Ham
mes Goodman & Gilman's manual of pharmacology and therapeutics.13th edition. Antituberc
ular drugs. New York: McGraw-Hill Medical. P809-830
- K park. Communicable diseases. Park’s Textbook of Preventive and Social Medicine. 23rd e
dition. Jabalpur, Brij Mohan Bhanot; 2017.p486.
- Denise Rossato, Margareth Dalcolmo, Simon Tiberi,Marcos Abdo, New and repurposed
drugs to treat multidrug- and extensively drug-resistant tuberculosis, J Bras Pneumol. 2018;4
4(2):153-160 http://dx.doi.org/10.1590/S1806-37562017000000436

References…
- RNTCP technical and operational guidelines for tuberculosis control in India 2016,
central TB division, directorate general of health services, New Delhi
- www.tbcindia.gov.in
- Guidelines on programme management of drug resistant TB in India, 2017
- RNTCP guidelines for use of Delamanid in drug resistant TB, 2018
- RNTCP guidelines for use of Bedaquiline in drug resistant TB, 2018

Next PG Activity-
08/02/19
Drug review
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Dr Shubhangi

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