Pharmacotherapy of Tuberculosis

May 2, 2023

M.I.M.E.R.Medical College 1

PHARMACOTHERAPY OF TUBERCULOSIS

Dr Siddiqui Waseem Akram (PGY- 3)

May 2, 2023M.I.M.E.R.Medical College

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INTRODUCTION Chronic granulomatous

disease caused by Mycobacterium tuberculosis

Attacks lungs mainly, but can affect other parts of body

Spread through cough, sneeze, or respiratory fluids


3GLOBAL BURDEN OF TB

2 billion infected (1 in 3 of global population)

9.4 million new cases in 2008

4 million new sm+ve PTB cases in 2008

Global incidence of TB peaked in 2004 & is declining

1.77mn deaths in 2007, 98% in low-income countries

MDR-TB -prevalence in new cases around 3.6% Ref: WHO Global Report, 2006

May 2, 2023M.I.M.E.R.Medical College4


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TB IN INDIA India has highest burden of TB

40% population infected

Annual risk of infection 1.5%

Lifetime risk 10%

Incidence- 2.1 million of global incidence of 9 mn

TB prevalence- 2.6 million

Sputum +ve cases/yr- 0.8 million

Death due to TB- 0.37 million “Global Tuberculosis Control, WHO, Geneva, 2014

May 2, 2023

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M.I.M.E.R.Medical College

PHARMACOTHERAPY OF TB


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CLASSIFICATION

Isoniazid (H) Rifampicin (R) Pyrazinamide (Z) Ethambutol (E) Streptomycin (S)

Ethionamide (Eto) Cycloserine (Cs) Terizidone (Trd) Para Aminosalicylic

acid (PAS) Rifabutin Rifapentine

FIRST LINE SECOND LINEFluoroquinolones Moxifloxacin (Mfx) Levofloxacin (Lvx) Ofloxacin (Ofx) Ciprofloxacin (Cfx) Amikacin (Am)

Injectable Capreomycin (Cm) Amikacin (Am) Kanamycin (Km)

Newer drugsBedaquilinePretomanid

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GROUPING OF ANTI-TB DRUGSGroup 1:First-line oral agents

•Isoniazid (H)• Pyrazinamide (Z)• Ethambutol (E)• Rifampin (R)

Group 2:Injectable agents• Streptomycin (S)• Kanamycin (Km)• Amikacin (Am)• Capreomycin (cm)

Group 3:Fluoroquinolones• Levofloxacin (lfx) • Moxifloxacin (mfx) • Ofloxacin (ofx)

Group 4:Oral bacteriostatic second-line agents• Para-aminosalicylic acid (pAS)• Cycloserine (cs)• Terizidone (Trd)• Ethionamide (eto) • Protionamide (pto)


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Group 5: Agents with unclear role in treatment of drug resistant-TB• Clofazimine (cfz)• Linezolid (lzd)• Amoxicillin/clavulanate (Amx/clv)• Thioacetazone (Thz)• Imipenem/ Cilastatin (ipm/cln)• Clarithromycin (clr)

GROUPING OF ANTI-TB DRUGS

May 2, 2023

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FIRST LINE DRUGS


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ISONIAZID Active only against M.tuberculi

Cheapest drug

Inhibits resting microbes (bacteriostatic), kills multiplying (bactericidal)

Effective against extracellular & intracellular organisms


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MOA

Prodrug ↓ Mycobacterial catalase-peroxidase(KatG) (activated) ↓ Covalent complex with acyl carrier protein (AcpM) & KasA ↓ Blocks mycolic acid synthesis & kills bacteria


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Mechanism of Resistance

Inherent resistance-Primary

Mutation of catalase peroxidase gene

Mutation of inh A gene


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Pharmacokinetics Rapidly & completely absorbed

Widely distributed

Penetrates & accumulates into caseous lesion

Minimum tuberculostatic concentration is 25 – 30 ng/ml

Metabolized through N-acetylationSlow acetylator t1/2 3 hour (Drug causes toxicity,

peripheral neuropathy )

Rapid acetylator t1/2 1 hour (Metabolite causes toxicity, hepatotoxicity)


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ADR

Peripheral neuropathy

Structurally analogue to pyridoxine & form hydrazone (highly water soluble) with pyridoxal & rapidly excreted in urine

Rx- Pyridoxine 10 mg/day prophylaxis &100mg/day-for toxicity

Hepatitis (elderly & liver disease) Because of CYP2E1 induced hepatotoxic metabolite

generation


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Drug interactions

Isoniazid reduces metabolism of phenytoin, Carbamazepine, Diazepam, Theophylline & Warfarin by inhibiting CYP2C19 & CYP3A4

Al- hydroxide inhibits INH absorption


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RIFAMPICIN Semi synthetic derivatives of Rifamycin B (Streptomyces

mediterranei)

Most active agent

Active against gram +ve & -ve cocci, some enteric bacteria, mycobacteria & chlamydia

Extra & intracellular organisms

Slow dividing (main)

Sterilizing agent & prevents resistance


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MOA: Binds to subunit of bacterial DNA-dependent RNA

polymerase & inhibits RNA synthesis.

Resistance Mutation to β subunit of bacterial RNA polymerase

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Pharmacokinetics:

Oral & IV formulations available

Well absorbed

Food ↓ absorbtion

Widely distributed (80 – 90% protein bound)

t½ 3 hours

Metabolized & excreted by liver (enterohepatic circulation)



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ADR Red discoloration of Body fluids

(urine, tear & sputum )

Fatal hepatitis (Existing liver disease)

Flu like syndrome

Nausea, Vomiting

Dizziness & Confusion


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Drugs interaction Powerful enzyme inducer - own metabolism as well

as other drugs like

Phenytoin, OCP, Glucocorticoids, Clarithromycin, Ketoconazole, Theophyllline


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TB & atypical mycobacterial

infectionsLeprosy Prophylaxis in

H. influenza

Resistant staph infections

Brucellosis

Pneumococcal meningitis

To eradicate carrier state

Uses


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PYRAZINAMIDE Synthetic, orally effective, bactericidal

Used with INH & Rifampicin

Prodrug, converted to pyrazinoic acid (pyrazinamindase of m. tuberculosis)

Inactive at neutral pH

Bactericidal to dividing organisms (Intracellular)

Sterilizing agent


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Inhibition of synthesis of mycolic acids

pncA gene-enzyme-activates pyrazinamide-pyrazinoic acid

Lipid content of mycobacteria is reduced

Interacts with a different fatty acid synthase encoding gene

Mechanism of acation


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Resistance

Mutation of pncA gene

Impaired uptake


26 Widely distributed

CSF (TB meningitis)

Safe in pregnancy

Metabolised in liver

Excreted in urine

T ½=6-10h

Dosage: 25- 35 mg/kg/day

Pharmacokinetics


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ADR

Hepatotoxicity (C/I in liver ds)

Hyperuricaemia, may precipitate gout

Fever, Malaise, Urticaria, Skin rash

Arthralgia

GI upset – Anorexia, Nausea, Vomiting


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ETHAMBUTOL

Tuberculostatic

Fast multiplying organisms are affected

Atypical mycobacteria

Taken up by the erythrocytes & slowly released

Hasten sputum conversion and prevent development of resistance

Resistance emerges rapidly if drug is used alone

Used as alternative to streptomycin


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MOA: Inhibits mycobacterial arabinosyl transferase,

involved in polymerization reaction of arabinoglycan, essential component of mycobacterial cell wall

Mechanism of resistance: Mutation of emb gene


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Pharmacokinetics

75-80% absorbed from GIT

Wide distribution

Crosses the blood brain barrier only if the meninges are inflamed

Excreted by GF & TS

t ½ =4h

Dosage: 15-30 mg/kg/day


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ADR Optic neuritis: dose related, initially Red/ Green

color blindness followed by a in visual acuity (disappear following withdrawal of drug)

Hypersensitivity: skin rash, fever, itching

Other adverse effects: Arthralgia, GI disturbance, Headache & mental disturbance


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STREPTOMYCIN

First clinically useful antitubercular drug

Streptomyces griseus

Active mainly against extracellular bacilli

Supplimental 1st line drug

Dosage : 1g/day or 15mg/kg/day i.m or i.v


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MOA

Interference with initiation complex of peptide formation

Misreading of mRNA→ Incorporation of incorrect AA into peptide→Nnonfunctional or toxic protein

Breakup of polysomes into nonfunctional monosomes


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Mechanism of resistance

1. Production of transferase enzyme, inactivates aminoglycosides by acetylation, adenylylation or phosphorylation (Major action)

2. Impaired entry of drug

3. Receptor protein on 30s ribosomal subunit deleted or altered (Mutation)


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ADR

Dose related, & risk is in elderly

Ototoxicity

Nephrotoxicity

Rash

Fever


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Summary

DRUGS MOA

Isoniazid (INH) Inhibits synthesis of mycolic acid, an essential component of bacterial cell wall

Rifampin (RMO) & Rifabutin

Binds to & inhibits DNA dependant RNA polymerase (no new RNA synthesis)

Ethambutol (ETB) Inhibits arabinosyl transferase enzyme & prevents polymerisation of arabinoglycans (essential component of mycobacterial cell wall)

Pyrazinamide (PZA) Inhibits mycobacterial fatty acid synthase-1 enzyme & disrupts mycolic acid synthesis



Drug Clinical setting Daily doseRifampicin Children 10-20 mg/kg

Adults weighing >50 kg 600 mgIsoniazid Children 10 mg/kg

Adults 200 – 300 mgEthambutol Children & adults: Initial 8

weeks25 mg/kg

Children & adults: Subsequently

15 mg/kg

Pyrazinamide Children & adults 20-35 mg/kgStreptomycin Children 30 mg/kg

Adult 1 gm

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SECOND LINE DRUGS


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CONSIDER SECOND-LINE DRUG, If

Resistance to first-line agents

Failure of clinical response to conventional therapy

Serious treatment-limiting ADR

Expert guidance available for toxic effects


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ETHIONAMIDE

Chemically related to isoniazid

Poorly water soluble (Only oral preparation)

Both extra and intracellular

Mechanism of action: Ethionamide blocks synthesis of mycolic acids in

susceptible organisms.


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Pharmacokinetics

Metabolized by the liver

Dosage : 500 - 750mg/day

Start with 250mg daily, ↑ up to 1g/day or 15mg/kg/day.


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ADR

Intense gastric irritation

Optic neuritis (alleviated by pyridoxine)

Hepatotoxicity


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CAPREOMYCIN Obtained from Streptomyces capreolus

Mechanism of action :

Peptide protein synthesis inhibitor

Important agent for drug resistant tuberculosis

Strains resistant to Amikacin, susceptible to Capreomycin

Dosage : 15mg/kg/day im


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ADR

Nephrotoxicity

Ototoxicity – Tinnitus, Deafness, Vestibular disturbance

Local pain & sterile abscesses at injection site


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CYCLOSERINE :

Streptomyces orchidaceus

Structural analog of D- alanine

Mechanism of action :

Inhibits incorporation of D- alanine into peptidoglycan pentapeptide & inhibits mycobacterial cell wall synthesis


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ADR CNS dysfunction, including depression & psychosis

Peripheral neuropathy

Seizures

Tremors

Pyridoxine 150mg/day should be given with cycloserine because this ameliorates neurologic toxicity.

Dosage: 0.5 - 1g/day in two or three divided doses


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AMINOSALICYLIC ACID (PAS)

Folate synthesis antagonist, active exclusively against mycobacterium tuberculosis

Structurally similar to p-aminobenzoic acid(PABA) and the sulfonamides

Dosage: 4 -12g/day PO (adult) 300mg/kg/day for children PO


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Pharmacokinetics & Adverse effects Readily absorbed from GIT

Widely distributed

Excreted in urine

Adverse effects :

Hypersensitivity reactions (fever, joint pain, hepatosplenomegaly, hepatitis,granulocytopenia, adenopathy)

Peptic ulcer & gastric hemorrhage


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FLUOROQUINOLONES

Active against typical & atypical mycobacteria

Moxifloxacin is the most active against M tuberculosis

Ciprofloxacin, Levofloxacin, Moxifloxacin


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Important drugs, especially for strains resistant to first line agents

Dosage : Ciprofloxacin 750mg BD,PO Levofloxacin 500mg OD.PO Moxifloxacin 400mg OD. PO


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MOA

Inhibit bacterial DNA synthesis by inhibiting bacterial Topoisomerase II (DNA Gyrase) & topoisomerase IV


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ADR

Nausea, Vomiting, Diarrhea (MC)

Headache, Dizziness

Skin rash, Photosensitivity.

Damage growing cartilage

Tendinitis & Tendon rupture

Insomnia


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KANAMYCIN & AMIKACIN

Kanamycin, streptomycin – resistant strains, but the availability of less toxic alternatives (eg capreomycin and amikacin) has renderd it obsolete

Prevalence of Amikacin resistant is low & most MDR remain Amikacin susceptible

Amikacin is active against atypical mycobacteria.

Dosage : 15mg/kg IV infusion


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LINEZOLID

Used in combination with Second & Third line drugs for MDR strains

Dosage : 600mg/day


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ADR

Bone marrow depression

Irreversible peripheral neuropathy

Optic neuropathy


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RIFABUTIN/ RIFAPENTINE

Derived from rifamycin & related to rifampin

Significant activity against M.tuberculosis , M avium & M.fortuitum

Dosage 300mg/day

Mechanism of action: Bacterial RNA polymerase inhibitor


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Effective in prevention & treatment of atypical mycobacterial infection in AIDS

Weak enzyme inducer of cyt P450 enzymes.

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NEWER DRUGS


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BEDAQUILINE (SIRTURO, TMC207, R207910)

First new 40 years

Approved on 28 December 2012 to treat resistant TB

Binds to oligomeric & proteolipic subunit-c of mycobacterial ATP synthase leads to inhibition of ATP synthesis & death

↑ QT interval, abnormal & fatal heart rhythm (Increased risk of death)

Nausea, Joint pain, Headache & ↑ liver enzyme


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PRETOMANID (PA-824) Bicyclic nitroimidazole-like molecule

Active against both replicating & non-replicating organisms

Cell wall inhibition (like isoniazid) & respiratory poisoning (like cyanide)

Inhibits mycolic acid biosynthesis through unknown molecular mechanism

Respiratory poisoning through NO release

Safe, Well tolerated, & efficacious at doses of 100–200 mg daily

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DOTS


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DOTS

DOTS, to ensure cure by providing medicine & confirming it’s taken

INTENSIVE PHASE- pt swallows drug in presence of health worker

CONTINUATION PHASE- 1 wk medicine in multiblister combipack (1st dose in presence of health worker)

Next week medicine only after return of empty blister


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Advantages

High cure rate

↓ Drug resistance

ADR can be monitored


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PHASES OF CHEMOTHERAPY

INITIATION PHASE

• 2-3 months• 4-5 drugs• Rapidly kills bacilli• INH• Rifampicin• Ethambutol• Pyrazinamide

CONTINUATION PHASE

• 4-6 months• 2-3 drugs• Eliminates remaining

bacilli• Prevents relapse• INH+Pyridoxine• Rifampicin


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CLASSIFICATION OF PATIENTS

Category Type of Patient Regimen Duration in months

Category I New Sputum Positive Seriously ill sputum negative, Seriously ill extra pulmonary,Sputum Negative, extra pulmonary not Seriously ill

2 (HRZE)3,4 (HR)3

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Category II Sputum Positive relapse,Sputum Positive failure,Sputum Positive treatment after default

2 (HRZES)3,1 (HRZE)3

5 (HRE)3

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67DRUG-RESISTANT TB: Definitions

Mono-resistant: Resistance to a single drug

Poly-resistant: Resistance to more than one drug, but not the combination of isoniazid and rifampicin

Multidrug-resistant (MDR): Resistance to at least isoniazid and rifampicin

Extensively drug-resistant (XDR): MDR plus resistance to fluoroquinolones and at least 1 of the 3 injectable drugs (amikacin, kanamycin, capreomycin)


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RNTCP’S regimen for MDR-TB

Intensive phase (6-9 months) Continuation phase (18 months)

1. Kanamycin2. Ofloxacin/ Levofloxacin3. Ethionamide4. Cycloserine5. Pyrazinamide6. Ethambutol

1. Ofloxacin/ Levofloxacin2. Ethionamide3. Cycloserine4. Ethambutol

+Pyridoxine 100 mg/ day

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SPECIAL CASES


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TB IN PREGNANT WOMEN

H, R, Z, E are safe

Z is not recommended in US

9 months (2HRE+ 7HR)

Pyridoxine


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TB IN AIDS PATIENTS 5% of TB pts are HIV +ve

HIV +ve pts have higher incidence of extra pulmonary, sever & more lethal TB

Duration of therapy 6-9 months (2HRZE + 4-7 HR)

Rifabutin → Rifampin (9-12 months), if pts is on ART

MDR-TB with HIV should be Rx like in non- HIV pts

Pyridoxine


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TB Meningitis

Long duration

5 drugs in continuation phase

Continuation phase- extended by 3 months

Higher dose

Glucocorticoid


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Chemoprophylaxis

Prevent progression of latent infection to active TB

INH- 300mg (10mg/kg) daily for 6 months

In case of INH resistance, INH (5mg/kg) + R (10mg/kg) daily for 3 months

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M.I.M.E.R.Medical CollegeTHAN

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Health & Medicine

Pharmacotherapy of Tuberculosis