MDR TB AND ADVANCEMENTRS

1. Multi Drug Resistance
in Tuberculosis
Causesand Management
a
Dr Shivansh verma
PG 1 Pharmacology
SRMS IMS BLY

2. Learning Objectives
• History of Tuberculosis .
• Introduction to Tuberculosis.
• Sites of Infection.
• Route and Mode of Invasion of Tuberculosis.
• Pathophysiology and Symptoms of Tuberculosis .
• Pharmacological management of Tuberculosis.
• MDR in Tuberculosis and its Causes and mechanism of resistance development.
• Goals of MDR Tuberculosis Treatment.

3. History Of Tuberculosis
• Tuberculosis in humans can be traced back to 9000 years ago in Atlit Yam city in
Israel.
• Tuberculosis is found in remains of mother & child buried together .
• The earliest written mentions of Tuberculosis in India were 3300 years ago.
• In 1600 -1800 AD Tuberculosis caused 25% of deaths alone in Europe.
• On 24 march 1882 Hermann Heinrich Robert Koch was the first scientist to isolate
the Tubercle Bacillus.

4. Introduction
• Tuberculosis also known as TB.
• Tuberculosis is chronic granulomatous infection caused by Mycobacterium
Tuberculosis .
• Tuberculosis is one the leading cause of death from infectious diseases around the
world .
• Most often affects the lungs.
• Tuberculosis spreads through the air when infected people cough, sneeze or spit.

5. • Untreated Tuberculosis cases can transmit diseases to at least 10 to 15 people
in a year.
• Contacts of an active case are at 10 to 60 times higher risk of developing
the disease.

6. Sites , Route and Mode of Invasion
• Bacilli enters via inhalation route.
• Gets lodged in lungs primely and spread through out the body over time.
• Predominantly affect the lungs ,causing pulmonary Tuberculosis.
• Common extrapulmonary Tuberculosis sites are
1. Lymph nodes
2. Bones
3. Intestine
4. Genitourinary tract
5. Meninges

7. Pathophysiology and Symptoms of
Tuberculosis
• After the entry of bacilli they are engulfed by macrophages and reaches Hilar lymph
nodes this is called as primary stage.
• In second stage in order to restrict spread of infection T cells attempt to contain the
infection by forming granulomas .
• In third stage bacilli escapes from the primary focus and infect other organs in
individuals with weaker immune system .
• The most severe form is miliary Tuberculosis ,which can affect the whole body
,organs including Liver and Spleen.

8. Schematic view of pathogenesis of
Tuberculosis

9. Symptoms and Diagnosis
 It is characterized by prolonged purulent cough
with sputum blood may or may not be present .
• Evening rise of fever .
• Loss of weight .
• Muscle weakness .
• Loss of appetite for more than 2 weeks .
Tb is diagnosed by chest x- ray and sputum microscopy .
For testing 2 days sputum testing is most widely used method .
Liquid probe assay and liquid culture media are also some other methods available .

10. Multi Drug Resistance in Tuberculosis
• Multidrug-resistant TB (MDR-TB). A TB patient, whose biological specimen is
resistant to both :
• H and R with or without resistance to other first-line anti-TB drugs.
• MDR-TB patients may have additional resistance to any/all FQ or any other anti-TB
drug

11. Causes of Multi Drug Resistance in
Tuberculosis
• The resistance is caused by a genetic mutation that makes a drug ineffective against the mutant bacilli.
• Some mechanisms of drug resistance include:
1. Cell wall: The cell wall of M. tuberculosis (TB) contains complex lipid molecules which act as a barrier to
stop drugs from entering the cell.
2. Drug modifying & inactivating enzymes: The TB genome codes for enzymes (proteins) that inactivate
drug molecules. These enzymes are usually phosphorylate, acetylate, or adenylate drug compounds.
3. Drug efflux systems: The TB cell contains molecular systems that actively pump drug molecules out of
the cell.
4. Mutations: Spontaneous mutations in the TB genome can alter proteins which are the target of drugs,
making the bacteria drug-resistant.

12. Goals of MDR TB treatment
• Render the patient non-infectious, break the chain of transmission and
decrease pool of infection.
• Decrease TB deaths and related comorbidity by ensuring relapse-free cure.
• Minimize & prevent development and amplification of drug resistance.

13. Gene's Involved in Resistance development in
MDR - Tuberculosis

14. Mechanism of Resistance development in
MDR - Tuberculosis
• Mechanisms of drug resistance include:
1. Cell wall: The cell wall of M. tuberculosis (TB) contains complex lipid molecules which act as a barrier to
stop drugs from entering the cell.
2. Drug modifying & inactivating enzymes: The Tuberculosis genome codes for enzymes (proteins) that
inactivate drug molecules. These enzymes are usually phosphorylate, acetylate, or adenylate drug
compounds.
3. Drug efflux systems: The Tuberculosis cell contains molecular systems that actively pump drug molecules
out of the cell.
4. Mutations: Spontaneous mutations in the Tuberculosis genome can alter proteins which are the target of
drugs, making the bacteria drug-resistant.
CNTD……..

15. One example is a mutation in the rpoB gene, which encodes the beta subunit of
the bacterium's RNA polymerase enzyme. In non-resistant Tuberculosis, rifampin
binds the beta subunit of RNA polymerase and disrupts transcription elongation.
Mutation in the rpoB gene changes the sequence of amino acids and eventual
conformation, or arrangement, of the beta subunit. In this case, rifampin can no
longer bind or prevent transcription, and the bacterium is resistant.

16. • Other mutations make the bacterium resistant to other drugs. For example, there are
many mutations that confer resistance to isoniazid (INH), including in the
genes katG, inhA, ahpC and others. Amino acid replacements in the NADH binding
site of InhA apparently result in INH resistance by preventing the inhibition of
mycolic acid biosynthesis, which the bacterium uses in its cell wall.
• Mutations in the katG gene make the enzyme catalase peroxidase unable to convert
INH to its biologically active form. Hence, INH is ineffective and the bacterium is
resistant. The discovery of new molecular targets is essential to overcome drug-
resistance problems

17. Prevention Of MDR in Tuberculosis
• Drug resistance cannot be addressed by mere diagnosis and treatment of
DR- Tuberculosis.
• Basic Tuberculosis diagnostic and treatment services should receive priority.
• Systems for early detection and treatment of DR- Tuberculosis should be
integrated into existing Tuberculosis services and the general health system.
• Health-care facilities and congregate settings should be provided with proper
infection control measures.
• Transmission should be prevented by addressing non-specific determinants like
access to care, comorbidities and awareness.

18. Drugs used in management of MDR Tuberculosis
First line drugs Group 1 (oral) Isoniazid (INH/H),
Rifampicin (R),Pyrazinamide (Z),
Ethambutol (E)
Second line drugs Group 2 (injectables) Streptomycin (S) , Capreomycin
Amikacin , Kanamycin
Group 3 (Fluoroquinolones) Ciprofloxacin, Ofloxacin
Levofloxacin, Moxifloxacin
Group 4 (oral) Cycloserine , Rifabutin
Rifapentine , Ethionamide
PAS ,Terizidone , Prothionamide
Group 5 (reserve drugs) Bedaquiline , Clarithromycin
Clofazimine, Linezolid
Amoxycillin+clavulanic acid
Imipenem/ Cilastatin

19. Isoniazid (INH/H)
• INH inhibits the synthesis of mycolic acid ,as it is needed for cell wall synthesis.
• INH is a prodrug and mycobacterial enzyme catalase peroxidase converts it to its
active form to block , mycolic acid synthesis.
• INH is bactericidal to actively growing tubercle bacilli.
• INH is a long acting drug in ATT .
• INH is ATT drug having activity only against M tuberculosis and also against atypical
mycobacteria ,M Kansai.

20. Isoniazid (INH/H)
Mechanism of action
• Isoniazid is a prodrug and must be activated by bacterial catalase.
• activation is associated with reduction of the mycobacterial ferric Kat G
catalase-peroxidase by hydrazine and reaction with oxygen to form an
oxy ferrous enzyme complex. Once activated, isoniazid inhibits the
synthesis of mycolic acids, an essential component of the bacterial cell
wall.
• Specifically isoniazid inhibits Inh A, the enoyl reductase
from Mycobacterium tuberculosis, by forming a covalent adduct with the
NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding
competitive inhibitor of Inh A.

21. Isoniazde MOA and MOR

22. Pharmacokinetics Dosage Clinical
Uses
Adverse Effects Drug
Interaction
Isoniazid
(INH/H)
• Orally absorbed.
• CSF conc can reach
100%.
• Metabolized in Liver
by N –
acetyltransferase to
acetyl isoniazid.
300 mg
OD Can be
increased up to
600 mg once
daily.
1- ATT 1-Peripheral Neuritis .
2-Hepatotoxicity.
3-Xerostomia .
4- Drug induced SLE
has also been
reported .
1-
Aluminum
hydroxide
inhibits the
INH
absorption

23. Rifampicin: R
• Rifampicin is a semisynthetic derivative of a macrocyclic antibiotic rifamycin.
• MOA – It binds to RNA polymerase and inhibits bacterial DNA dependent RNA
polymerase so that it can not synthesis new RNA

24. Mechanism of Resistance development in
Rifampicin
• Resistance in Rifampicin is a result of point mutation .
• Mutation occurs in rpoB gene .
• rpoB gene is present Beta subunits of RNA polymerase.
• This mutation in rpoB gene prevents the binding of drug to RNA
polymerase.
• Hence if used alone resistance develops rapidly.

25. Pharmacokinetics Dosage Clinical Uses Adverse
Effects
Drug
Interaction
Rifampicin
(R)
• Well absorbed orally.
• Food decreases
absorption.
• Metabolized in liver.
• Metabolites are excreted
by bile and urine .
• Potent ,microsomal
cytochrome P450 inducer.
• Other CYP Isoenzymes
CYP3A4, CYP2C &
CYP1A2 are also induced
by rifampin.
600 mg per day 1- ATT.
2- Leprosy.
3-Tubercular meningitis.
4- Prophylaxis of
Meningococcal & H
influenzae meningitis &
career state.
5- Second/ third choice of
MRSA
6- Combination of
rifampicin & doxycycline
is first line therapy of
BRUCELLOSIS.
1-Hepatits..
2-Prurities.
3-Harmless
orange
colored
urine .
1- Warfarin.
2- OCP.
3-Corticoster-
iods .

26. Pyrazinamide(Z)
• It is a tuberculocidal drug .
• More active in acidic medium.
• Highly effective in initial first 2 months of therapy.
• By killing residual intracellular bacilli it has good sterilizing activity.
• Inclusion of pyrazinamide has shortened the duration of treatment
• Also its inclusion has led to reduction in risk of relapse.

27. Mechanism of Action and Resistance
development in Pyrazinamide
• Drug enters in bacilli by passive diffusion an is converted into pyazinoic acid by
pyrazinamidase enzyme .
• Pyazinoic acid is its active metabolite which inhibits Mycobacterial fatty acid
synthase-I enzyme .
• synthase-I enzyme deficiency causes disruption in cell wall synthesis of
mycobacterium.
• Mutation in the gene (pcnA) that encodes for pyrazinamidase enzyme causes
resistance .

28. Pharmacokinetics Dosage Clinical Uses Adverse
Effects
Drug
Interaction
Pyrazinamide
(Z)
• Well absorbed orally.
• Metabolized in liver.
• Well distributed in CSF.
• Excreted in urine .
1500 mg/day 1- first line ATT
2- Tubercular
Meningitis
1- Hyperuricemia
2- Abdominal distress .
3- Arthralgia.
4- Flushing ,rashes
5- Loss of diabetes
control.
6- Dose related
Hepatotoxicity.

29. Ethambutol (E)
• Ethambutol ,a synthetic compound
• It is static drug also active against MAC and other mycobacteria .
• MOA – It inhibits arabinosyl transferase enzyme to prevent polymerization of
arbinoglycans inhibiting cell wall synthesis.
• It should be avoided in children below 5 years of age.
• Also used in MAC infection .

30. Mechanism of Resistance development in
Ethambutol (E)
• Resistance develop slowly in Ethambutol.
• Resistance is associated with mutation in embAB gene .

31. Pharmacokinetics Dosage Clinical Uses Adverse Effects
Ethambutol (E) • Absorbed only 70%..
• Metabolized in liver.
• Well distributed in CSF.
• Gets Excreted rapidly in
urine .
800 mg/day 1- first line ATT.
2- M-avium
complex .
1- Retro bulbar Neuritis
Impairing visual acuity and red
green.
discrimination.(reverseable)
2- Abdominal distress .
3- Arthralgia.
4- Flushing ,rashes.
5- Loss of diabetes control.
6- Dose related Hepatotoxicity.

32. Streptomycin
• It is an Aminoglycoside antibiotic.
• Bactericidal in nature ,but has poor penetration due to which acts only on extracellular
tubercular bacilli.
• Also active against some atypical mycobacteria such as M kansaii and M bacilli.
• Given intramuscular
• MOA - Inhibits 30 S ribosomal protein synthesis.
• MOR – point mutation of gene rpsl or rrrs that codes for ribosomal protein and
ribosomal t-RNA respectively.

33. Pharmacokinetics Dosage Clinical Uses Adverse Effects
Streptomycin(S) • Given Intramuscular.
• Metabolized in liver.
• Well distributed in CSF.
• Gets Excreted rapidly in
urine .
1000 mg/day 1- First line ATT.
2- SABE.
3-Plague.(along with
tetracycline)
4- DOC in Tularemia
(bacterium Francisella
tularensis)
1-Nephrotoxicity .
2- Ototoxicity.
3- Pain at site of injection

34. Treatment Regimen for new & previously
treated patients
Treatment Group Type of Patient Regimen Total Duration
IP CP
New • Microbiologically
confirmed TB cases.
• Clinically diagnosed TB
cases.
2 HRZE 4 HRE 6 Months
Previously treated • Recurrent TB.
• Treatment after failure.
• Treatment after lost to
follow –up.
• Other Previously treated
patients.
2 HRZES + 1HRZE 5 HRE 8 Months

35. Second line drugs
Drugs Pharmacokinetics Dosage Clinical Use Adverse effect
Fluoroquinolones
(ciprofloxacin, levofloxacin)
Orally , parentally
Metabolized in liver
750 mg tds (cipro)
400 mg bd (levofloxacin)
MAC ,UTI ,STDs,
Typhoid
Photosensitivity
QT prolongation
Ethionamide Orally , Metabolized in liver 250 mg bd MDR TB Hepatotoxic, Nausea , vomiting
Prothionamide Orally , Metabolized in liver 500 mg bd MDR TB, MAC Hepatotoxic, Nausea , Vomiting
Para Amino salicyclic Acid Orally , Metabolized in liver 8-10 gm/ day in 3-4
divided doses
MDR TB Hepatotoxic, Skin rash
Hypothyroidism, Arthralgia,
Lupus like reaction
Cycloserine Orally , Excreted by kidney 500 mg bd daily Renal TB Neurotoxicity
Terizidone Orally , Excreted by kidney 250-750 mg od Pulmonary TB
Extra pulmonary TB
Ototoxicity
Thiacetazone Low efficacy No longer in use No longer in use Life threatening
Hypersensitivity
Rifabutin/Rifapentine Orally
Food decreases absorption.
Metabolized in liver.
Excreted in bile and urine
300 mg/day Treatment of TB in HIV Skin rash ,GI intolerance
,Neutropenia
Kanamycin ,Amikacin IM/IV
Metabolized in liver
750-1000 mg/ day DR TB
Nephrotoxic ,ototoxic

36. New Drugs Bedaquiline
• Newer drug approved by FDA.
• MOA- targets proton pump of ATP synthesis.
• Causing inadequate ATP generation thus inhibiting bacterial metabolism.
• It kills both rapidly dividing and slowly dividing bacilli.
• MOR – mutation of ATP synthase enzyme or efflux pump.

37. Pharmacokinetics Dosage Clinical Uses Adverse Effects
Bedaquline (Bdq) • Given orally.
• Metabolized in liver.
by CYP3A4.
400 mg OD
for 2 weeks &
then
200 mg TDS
for 22 weeks
1-MDR TB
2-XDR TB
• nausea,
 joint and chest pain,
 headache
 QT Prolongation

38. Treatment Regimen for different drug resistant TB
Type of TB case treatments Treatment regimen in IP Treatment regimen in CP
Rifampicin resistant+
isoniazid sensitive or unknown
(6-9)kanamycin ,levofloxacin,
Ethionamide ,cycloserine ,
Ethambutol ,INH ,Z
(18 )Levofloxacin,
Ethionamide ,cycloserine
Ethambutol ,INH
MDR TB (6-9) kanamycin ,levofloxacin,
Ethionamide ,cycloserine ,
Ethambutol ,Z
(modified treatment based on the
Inh resistance)
(18 )Levofloxacin,
Ethionamide ,cycloserine
Ethambutol
XDR TB (6-12) Capreomycin ,para amino
salicylic acid , Moxifloxacin,
High dose Ciprofloxacin,
linezolid's , amoxicillin /
clavulanic acid
(18) para amino salicylic acid ,
Moxifloxacin,
High dose H, Ciprofloxacin,
Linezolid's , Amoxicillin /
Clavulanic acid

39. THANK YOU