chemotherapy of tuberculosis

87
Chemotherapy Of Tuberculosis PREPARED BY ISHITA SHARMA M.ph Sem – 1 (Pharmacology 2015-17)

Upload: ishita-sharma

Post on 14-Jan-2017

125 views

Category:

Health & Medicine


0 download

TRANSCRIPT

Page 1: Chemotherapy of Tuberculosis

ChemotherapyOf

Tuberculosis

PREPARED BYISHITA SHARMA

M.ph Sem – 1(Pharmacology 2015-17)

Page 2: Chemotherapy of Tuberculosis

Points that we are going to focus on

are…

Page 3: Chemotherapy of Tuberculosis

* What is TB?* Brief review of

Mycobacterium tuberculosis* Drugs used in chemotheraoy

of TB* Treatment of TB

Page 4: Chemotherapy of Tuberculosis

What is

TUBERCULOSIS?

Page 5: Chemotherapy of Tuberculosis

Tuberculosis is a chronic granulomatous inflammatory reaction of the tissues to the presence of causative agent, Mycobacteria.

being characterized by a local aggregation of large number of macrophages.

Page 6: Chemotherapy of Tuberculosis

Generally caused by Mycobacterium tuberculosis

M. tuberculosis complex (MTBC) includes four other TB-causing mycobacteria :

i. M. bovis : once was a commom cause but introduction of pasteurized milk eliminated this as a health problem

ii. M. africanum : not widespread but is a significant cause in parts of Africa

iii. M. canetti : is rare and seems to be limited to Africaiv. M. microti : is also rare and mostly seen in

immunodeficient people

Page 7: Chemotherapy of Tuberculosis
Page 8: Chemotherapy of Tuberculosis

KOCH’S DISEASE : TUBERCULOSIS

• Robert Koch (1882) –

M. tuberculosis 1st ifentified and described on 24 March, 1882 by Robert Koch.

Page 9: Chemotherapy of Tuberculosis

What do you know about Mycobacterium Tuberculi…??

Page 10: Chemotherapy of Tuberculosis

Long, slender, straight or curved

Aerobic

Non-motile

Non-capsulated

Non-sporing

Acid-fast

Page 11: Chemotherapy of Tuberculosis

M. tuberculosis has a tough cell wall that prevents passage of nutrients into and excreted from the cell, therefore giving it the characteristic of slow growth rate.

The cell envelope contains a polypeptide layer, a peptidoglycan layer, and free lipids.

In addition, there is also a complex structure of fatty acids such as mycolic acids that appear glossy.

Page 12: Chemotherapy of Tuberculosis
Page 13: Chemotherapy of Tuberculosis

The cell wall also contains lipid complexes including acyl glycolipids and other complex such as free lipids and sulfolipids.

There are porins in the membrane to facilitate transport.

Beneath the cell wall, there are layers of arabinogalactan and peptidoglycan that lie just above the plasma membrane.

Page 14: Chemotherapy of Tuberculosis

ACID FASTNESS of Mycobacterium tuberculosis is due to presence of a high molecular weight, hydroxy acid containing carboxyl groups called Mycolic acid in the bacterial cell wall or in the semipermiable membrane around the cell.

[Acid-fast stain of Mycobacterium]

Page 15: Chemotherapy of Tuberculosis

DRUGS USED FOR CHEMOTHERAPY OF TB:

Page 16: Chemotherapy of Tuberculosis

FIRST LINE DRUGS: High antitubercular efficacy as well as low toxicityUsed routinelyE.g. Isoniazid (H)Rifampin (R)Pyrazinamide (Z)Ethamutol (E)Streptomycin (S)

Page 17: Chemotherapy of Tuberculosis

SECOND LINE DRUGS:Either low antitubercular efficacy or high toxicity or

bothUsed in special cicumstances onlyE.g.Ethionamide (Etm)Cycloserine (Cys)ParaAminoSalicylic Acid (PAS)Thiacetazone (Tzn)Kanamycin (Kmc)Amakacin (Am)Capreomycin (Cpr)

Page 18: Chemotherapy of Tuberculosis

NEWER DRUGS:

CiprofloxacinOfloxacinClarithromycinAzithromycinRifabutin

Page 19: Chemotherapy of Tuberculosis

ISONIAZIDIsoniazid is the most active drug for the treatment

of tuberculosis.

In vitro, isoniazid inhibits most tubercle bacilli and is bactericidal for actively growing tubercle bacilli.

Isoniazid is able to penetrate into phagocytic cells and thus is active against both extracellular and intracellular organisms.

Page 20: Chemotherapy of Tuberculosis

Mechanism of Action:Isoniazid inhibits synthesis of mycolic acids, which

are essential components of mycobacterial cellwalls.Isoniazid is a prodrug that is activated by KatG, the

mycobacterial catalase-peroxidase enzyme.The activated form of isoniazid exerts its lethal effect

by forming a covalent complex with an acylcarrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolicacid synthesis.

A gene called inhA which encodes for a fatty acid synthase enzyme is the target for the drug.

Page 21: Chemotherapy of Tuberculosis

Basis of Resistance:The most common mechanism of resistance is by

mutation of the catalase-peroxidase gene so that the bacilli do not generate the active metabolite of the drug.

Resistance may also involve mutation in the target inh A gene.

Other resistant bacilli lose the active INH concentrating process.

Combined with other drugs, INH has good resistance preventing action.

Page 22: Chemotherapy of Tuberculosis

Pharmaco Kinetics :Isoniazid is readily absorbed from the

gastrointestinal tract.The administration of a 300-mg oral dose (5

mg/kg in children) results in peak plasma concentrations of 3–5 g/mL within 1–2 hours.

Isoniazid diffuses readily into all body fluids and tissues.

Acetylated by N-acetyltransferase to N-acetylisoniazid; it is then biotransformed to isonicotinic acid and monoacetylhydrazine.

Page 23: Chemotherapy of Tuberculosis

Monoacetylhydrazine is associated with hepatotoxicity via formation of a reactive intermediate metabolite when N-hydroxylated by the cytochrome P450 mixed oxidase system.

Fast acetylators 1 hour t½

Slow acetylators 3 hour t½

Isoniazid metabolites and a small amount of unchanged drug are excreted mainly in the urine.

Page 24: Chemotherapy of Tuberculosis

Interactions:

Aluminium Hydroxide inhibits INH absorption. (by decreasing gastric emptying)

INH inhibits phenytoin, carbamazepine, diazepam and warfarin metabolism.

(may raise their blood levels)

PAS inhibits INH metabolism and prolongs its half life.

Page 25: Chemotherapy of Tuberculosis

Adverse effects:• Allergic Reactions :Fever and skin rashesDrug-induced systemic lupus erythematosus• Direct Toxicity :Isoniazid-induced hepatitis:The most frequent major toxic effect.Clinical hepatitis with loss of appetite, nausea,

vomiting, jaundice occurs in 1% of isoniazid recipients and can be fatal, particularly if the drug is not discontinued promptly.

Page 26: Chemotherapy of Tuberculosis

Peripheral neuropathy: is observed in 10–20% of patients given higher dosages but is infrequently seen with the standard 300 mg adult dose.

Neuropathy is due to a relative pyridoxine deficiency.

Isoniazid promotes excretion of pyridoxine, and this toxicity is readily reversed by administration of pyridoxine in a dosage as low as 10 mg/d.

Central nervous system toxicity: Less common includes memory loss, psychosis, and seizures.These may also respond to pyridoxine

Page 27: Chemotherapy of Tuberculosis

Miscellaneous: Other reactions include

hematologic abnormalitiesprovocation of pyridoxin deficiency anemiaTinnitusgastrointestinal discomfort

Page 28: Chemotherapy of Tuberculosis

RIFAMPINRifampin is a large (MW 823), complex

semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei.

Susceptible organisms are inhibited by less than 1 g/mL.

Page 29: Chemotherapy of Tuberculosis

It readily penetrates most tissues and into phagocytic cells.

It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities.

Page 30: Chemotherapy of Tuberculosis

Mechanism of Action:Rifampin binds strongly to the subunit of bacterial

DNA-dependent RNA polymerase and thereby inhibits RNA synthesis.

Basis of Resistance:Resistance results from one of several possible

point mutations in rpoB, the gene for the beta subunit of RNA polymerase.

These mutations prevent binding of rifampin to RNA polymerase.

Page 31: Chemotherapy of Tuberculosis

Human RNA polymerase does not bind rifampin and is not inhibited by it

Administration of rifampin as a single drug produces highly resistant organisms.

There is no cross-resistance to other classes of antimicrobial drugs but there is cross

resistance to other rifamycin derivatives. e.g.rifabutin.

Page 32: Chemotherapy of Tuberculosis

Pharmaco Kinetics:

Rifampin is well absorbed after oral administration and excreted mainly through the liver into bile.

It then undergoes enterohepatic recirculation, with the bulk excreted as a deacylated metabolite in feces and a small amount in the urine.

Rifampin is distributed widely in body fluids and tissues.

Rifampin is relatively highly protein-bound but adequate cerebrospinal fluid concentrations are achieved only in the presence of meningeal inflammation.

Page 33: Chemotherapy of Tuberculosis

Interactions:

It is a microsomal enzyme inducer-increases several CYP450 isoenzymes, including CYP3A4, CYP2D6, CYP1A2 and CYP2C subfamily.

It thus enhances its own metabolism as well as that of many drugs including warfarin, oral contraceptives, corticosteroids, sulfonylureas, digitoxins, steroids, HIV protease inhibitors, NNRTIs, theophylline, metoprolol, fluconazole, ketoconazole etc.

Page 34: Chemotherapy of Tuberculosis

Adverse Effects:Rifampin imparts a harmless orange color to urine,

sweat, tears, and contact lenses (soft lenses may be permanently stained).

Occasional adverse effects include rashes, thrombocytopenia, and nephritis.

It may cause jaundice and occasionally hepatitis. Rifampin commonly causes light chain proteinuria.

If administered less often than twice weekly, rifampin causes a flu-like syndrome characterized by fever, chills, myalgias, anemia, thrombocytopenia and sometimes is associated with acute tubular necrosis.

Page 35: Chemotherapy of Tuberculosis

ETHAMBUTOLEthambutol is a synthetic, water-soluble, heat-

stable compound.Susceptible strains of M tuberculosis and other

mycobacteria are inhibited in vitro by ethambutol 1–5 mcg/mL.

It is selectively tuberculostatic.Fast multiplying bacteria are more susceptible.Addition to the triple drug regimen of RHZ it has

been found to hasten the rate of sputum conversion & to prevent development of resistance.

Page 36: Chemotherapy of Tuberculosis

Mechanism of Action:

Ethambutol is an inhibitor of mycobacterial arabinosyl transferases, which are encoded by the embCAB operon.

Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall.

Page 37: Chemotherapy of Tuberculosis

Basis of Resistance:

Resistance to ethambutol is due to mutations resulting in overexpression of emb gene products or within the embB structural gene.

No cross resistance with any other antitubercular drug has been noted.

Page 38: Chemotherapy of Tuberculosis

Pharmaco Kinetics:

• Ethambutol is well absorbed from the gut. Following ingestion of 25 mg/kg, a blood level peak of 2–5 mcg/ml is reached in 2–4 hours.

• About 20% of the drug is excreted in feces and 50% in urine in unchanged form.

• Ethambutol accumulates in renal failure, and the dose should be reduced by half if creatinine clearance is less than 10 ml/min.

• Ethambutol crosses the blood-brain barrier only if the meninges are inflamed.

Page 39: Chemotherapy of Tuberculosis

Adverse Effects:

Hypersensitivity to ethambutol is rare.

The most common serious adverse event is retrobulbar neuritis causing loss of visual acuity and red-green color blindness (dose-related side effect).

Ethambutol is relatively contraindicated in children too young to permit assessment of visual acuity and red-green color discrimination.

Page 40: Chemotherapy of Tuberculosis

PYRAZINAMIDEPyrazinamide (PZA) is relative to nicotinamide,

stable, slightly soluble in water, and quite inexpensive.

At neutral pH, it is inactive in vitro, but at pH 5.5 it inhibits tubercle bacilli and some other mycobacteria.

Drug is taken up by macrophages and exerts its activity against intracellular organisms residing within this acidic environment.

Page 41: Chemotherapy of Tuberculosis

Mechanism of Action:

Pyrazinamide is converted to pyrazinoic acid, the active form of the drug, by mycobacterial pyrazinamidase, which is encoded by pncA.

It inhibits mycolic acid synthesis (same as INH but by interacting with a different fatty acid synthase encoding gene).

Page 42: Chemotherapy of Tuberculosis

Base of Resistance:

Resistance is due to mutations in pncA that impair conversion of pyrazinamide to its active form.

Impaired uptake of pyrazinamide may also contribute to resistance.

Page 43: Chemotherapy of Tuberculosis

Pharmaco Kinetics:

Pyrazinoic acid is hydroxylated by xanthine oxidase to 5-hydroxypyrazinoic acid

Serum concentrations of 30–50 mcg/ml at 1–2 hours after oral administration are achieved with dosages of 25 mg/kg/d.

Pyrazinamide is well absorbed from the gastrointestinal tract and widely distributed in body tissues, including inflamed meninges.

The half-life is 8–11 hours.

Page 44: Chemotherapy of Tuberculosis

Adverse Effects: Major are:hepatotoxicity (in 1–5% of patients)nauseaVomitingdrug feverHyperuricemiaThe latter occurs uniformly and is not a reason to

halt therapy.Hyperuricemia may provoke acute gouty arthritis.

Page 45: Chemotherapy of Tuberculosis

SUMMARY of MOA of 1st line drugs:

Page 46: Chemotherapy of Tuberculosis

STREPTOMYCIN

It is a bactericidal Aminoglycoside antibiotic drug.IT was 1st clinically useful antiTB drug.It is less effective than INH or Rifampin as it acts

only on extracellular bacilli (poor penitration into cell).

It penetrates tubercular cavities but does not cross the CSF & has poor action in acidic medium.

Page 47: Chemotherapy of Tuberculosis

Mechanism of Action:It transport through the bacterial cell wall and

cytoplasmic membrane (through porin channels) and bind to ribosomes resulting in inhibition of protein synthesis.

Base of Resistance:Resistance is due to a point mutation in either the

rpsL gene encoding the S12 ribosomal protein gene or rrs, encoding 16S ribosomal rRNA, that alters the ribosomal binding site.

Page 48: Chemotherapy of Tuberculosis

Adverse Effects:

Streptomycin is ototoxic and nephrotoxic.Vertigo and hearing loss are the most common side

effects and may be permanent.Toxicity is dose-related and the risk is increased in

the elderly.As with all aminoglycosides, the dose must be

adjusted according to renal function.Toxicity can be reduced by limiting therapy to no

more than 6months whenever possible.

Page 49: Chemotherapy of Tuberculosis

ETHIONAMIDE:Ethionamide is chemically related to isoniazid and also

blocks the synthesis of mycolic acids.It is poorly water soluble and available only in oral form.It is metabolized by the liver.Most tubercle bacilli are inhibited in vitro by

ethionamide.although effective in the treatment of tuberculosis, is

poorly tolerated because of the intense gastric irritation and neurologic symptoms that commonly occur.

Ethionamide is also hepatotoxic.

Page 50: Chemotherapy of Tuberculosis

CYCLOSERINE:It is an antibiotic obtained from S. orchidaceus, and

is a chemical analogue of D-alanine.Inhibits bacterial cell wall synthesis by inactivating

the enzymes which recemize L-alanine and link two D-alanine residues.

It is tuberculostatic.Cycloserine is absorbed orally, diffuses all over.CSF concentration is equal to that in plasma.About 1/3rd of a dose is metabolized, the rest is

excreted unchanged by kidney.

Page 51: Chemotherapy of Tuberculosis

The CNS toxicity of the drug is high:

SleepinessHeadachetremor and psychosis (convulsions may be)prevented by pyridoxine 100 mg/day.

o It is rarely used (only in resistant cases)

Page 52: Chemotherapy of Tuberculosis

PARAAMINO SALICYLIC ACID (PAS)

It is related to sulfonamides: chemically as well as in mechanism of action.It is not active against other bacteria: selectivity may

be due to difference in the affinity of folate synthase of TB and other bacteria for PAS.

PAS is tuberculostatic and one of the least active drugs.

It does not add to the efficacy of more active drugs that are given with it; only delays development of resistance.

Page 53: Chemotherapy of Tuberculosis

Resistance to PAS is slow to develop.PAS is absorbed completely by the oral route and

distributed all over except in CSF.About 50% PAS is acetylated; competes with

acetylation of INH (prolongs its t½).PAS formulations interfere with absorption of

rifampin.It is excreted rapidly by glomerular filtration and

tubular secretiont½ is short (1 hour)

Page 54: Chemotherapy of Tuberculosis

Patient acceptability of PAS is poor because of:Frequent anorexiaNauseaepigastric pain

Other adverse effects are:RashesFevermalaisegoiterliver dysfunction

Page 55: Chemotherapy of Tuberculosis

THIACETAZONEThiacetazone is a tuberculostatic, low efficacy drug.does not add to the therapeutic effect of H, S or E

but delays resistance to these drugs.Orally activePrimarily excreted unchanged in urine with a t½ of

12 hr.It is a reserve anti-TB drug, sometimes added to INH

in alternative regimens.

Page 56: Chemotherapy of Tuberculosis

The major adverse effects are: hepatitisExfoliative dermatitisStevens-Johnson syndromebone marrow depression (rarely) The common side effects are:anorexiaabdominal discomfortloose motionsminor rashes.A mild anaemia persists till Tzn is given.

Page 57: Chemotherapy of Tuberculosis

KANAMYCIN, AMIKACIN, CAPREOMYCIN :

All three are more toxic antibiotics used as reserve drugs in rare cases not responding to the usual therapy.

Any one of these is used at a time in combination with the commonly employed drugs to which resistance has not developed.

Because all exhibit similar oto- and nephrotoxicity, they are not combined among themselves or with streptomycin.

Page 58: Chemotherapy of Tuberculosis

Capreomycin, inaddition, can induce electrolyte abnormalities.

All act by inhibiting protein synthesis.

None is effective orally; none penetrates meninges.

All are excreted unchanged by the kidney.

Page 59: Chemotherapy of Tuberculosis

FLUOROQUINOLONES:

These are an important addition to the drugs available for tuberculosis,especially for strains that are resistant to first-line agents.

Resistance, which may result from any one of several single point mutations in the gyrase A subunit, develops rapidly if a fluoroquinolone is used as a single agent; thus, the drug must be used in combination with two or more other active agents.

Page 60: Chemotherapy of Tuberculosis

They penetrate cells and kill mycobacteria lodged in macrophages as well.

Because of their good tolerability, ciprofloxacin and ofloxacin are being increasingly included in combination regimens against MDR tuberculosis and MAC infection in HIV patients.

They are also being used to supplement ethambutol + streptomycin in cases when H, R, Z have been stopped due to hepatotoxicity.

Page 61: Chemotherapy of Tuberculosis

MACROLIDE ANTIBIOTICS:

Clarithromycin & Azithromycin, these macrolide antibiotics are most active against nontubercular mycobacteria including MAC, M. fortuitum, M. Kansasii and M. marinum.

Clarithromycin has been used to a greater extent because its MIC values are lower, but azithromycin may be equally efficacious due to its higher tissue and intracellular levels.

In AIDS patients, life-long therapy is required—may cause ototoxicity.

Page 62: Chemotherapy of Tuberculosis

TREATMENTOF

TUBERCULOSIS

Page 63: Chemotherapy of Tuberculosis

CONVENTIONAL REGIMEN:

H + Tzn or E with or without S(for initial 2 months)

Requires 12 to 18 months therapyPoor complianceHigh failure rate

Page 64: Chemotherapy of Tuberculosis

WHAT ISMDR-TB

&XDR-TB…?

Page 65: Chemotherapy of Tuberculosis

MDR-TB:Resistance to both H and R and may

be any number of other anti-TB drugs.

For H resistance: RZE given for 12 months is recommended.For H + R resistance: ZE + S/Kmc/Am/Cpr + Cipro/ofl ± Etm could be

used.

Page 66: Chemotherapy of Tuberculosis

Causes of MDR

66Patient mismanagement

Page 67: Chemotherapy of Tuberculosis

XDR-TB:

Resistant to at least 4 most effective cidal drugs, i.e. H, R, a FQ, one of Kmc/Am/Cpr with or without any number of other drugs.

Page 68: Chemotherapy of Tuberculosis

RECENT APPROACHES:

DOTS (Directly Observed Treatment Short course)

RNTCP (Revised National Tuberculosis Control Program)

National strategic plan TB India (2012-17)

Modification of drug regimen

Page 69: Chemotherapy of Tuberculosis

DOTSGenerally Consists of:

Diagnosing casesTreating patients for 6-8 months with

drugs Promoting adherence to the relatively

difficult treatment regimen

Page 70: Chemotherapy of Tuberculosis

The DOTS strategy ensures that infectious TB patients are diagnosed and treated effectively till cure, by ensuring availability of the full course of drugs and a system for monitoring patient compliance to the treatment.

The DOTS strategy is cost-effective and is today the international standard for TB control programmes.

Page 71: Chemotherapy of Tuberculosis

DOTS is a systematic strategy which has five components:

Political and administrative commitmentGood quality diagnosisGood quality drugsSupervised treatment to ensure the right treatmentSystemic monitoring and accountability

Page 72: Chemotherapy of Tuberculosis

SHORT COURSE CHEMOTHERAPY (SCC)

These are regimens of 6–9 month duration which have been found highly efficacious.

The dose of first line anti-TB drugs has been standardized on body weight basis and is applicable to both adults and children.

Page 73: Chemotherapy of Tuberculosis

Recommended doses of antitubercular drugs

Daily dose 3 × per week dose

DRUG Mg/kg For>50 kg

mg/kg For>50 kg

ISONIAZID 5 (4 – 6) 300 10 (8 – 12) 600

RIFAMPIN 10 (8 – 12) 600 10 (8 – 12) 600

PYRAZINAMIDE 25 (20-30) 1500 35 (30 – 40) 2000

ETHAMBUTOL 15 (15–20) 1000 30 (25 – 35) 1600

STREPTOMYCIN 15 (12-18) 1000 15 (12 – 18) 1000

Page 74: Chemotherapy of Tuberculosis

All regimens have:

Initial intensive phase:lasting for 2–3 months aimed to rapidly kill

the TB bacilli, bring about sputum conversion and afford symptomatic relief.

This is followed by

Continuation phase:Lasting for 4–6 months during which the remaining

bacilli are eliminated so that relapse does not occur.

Page 75: Chemotherapy of Tuberculosis

Category wise treatment regimen according to WHO

Page 76: Chemotherapy of Tuberculosis

Treatment regimen followed in India under the RNTCP (1997) :

TB Category Initiation Phase

Continuation Phase

I 2H₃R₃Z₃E₃ 4H₃R₃

II 2H3R3Z3E3S3 + 1H₃R₃Z₃E₃

5H3R3E3

III 2H3R3Z3 4H3R3

Page 77: Chemotherapy of Tuberculosis

RNTCP (1997) : To control TB, National Tuberculosis Control

Programme (NTCP) has been in operation in the country since 1962.

This could not achieve the desired results. Therefore, it was reviewed by an expert committee

in 1992 and based on its recommendations, Revised National TB Control Programme (RNTCP), which is an application of WHO-recommended strategy of DOTS, was launched in the country on 26 March 1997.

Page 78: Chemotherapy of Tuberculosis

The objectives of RNTCP are:

1. To achieve and maintain a cure rate of at least 85% among newly detected infectious TB cases

2. Achieve and maintain detection of at least 70% of such cases in the population

Page 79: Chemotherapy of Tuberculosis

NATIONAL STRATEGIC PLAN12th Five Year Plan of Government of India.

Proposed strategies:1. Case finding and diagnostics2. Patient friendly treatment services3. Scale-up of Programmatic Management of Drug

Resistance –TB4. Scale -up of Joint TB-HIV Collaborative Activities5. Control TB

Page 80: Chemotherapy of Tuberculosis

Modifiaction of Drug Regimen:

There are currently at least ten compounds in various stages of clinical development for TB.

Four of these are existing drugs that are either being redeveloped or repurposed for the treatment of TB and there are six new chemical compounds that are being specifically developed as TB drugs.

Page 81: Chemotherapy of Tuberculosis

Phase 1 Phase 2 Phase 3

Existing drugs redevelopedOrrepurposed for TB

1)Rifapentine 2)Linezolid

1)Gati floxacin 2)MoxiFloxacin

New drugs developed specifically for TB

1) SQ-109 2)PNU-100480

1) PA-824 2)AZD5847

1)Delamanid(OPC-67683)

Page 82: Chemotherapy of Tuberculosis

SIRTURO ( Bedaquiline) In December 2012 the FDA gave approval for the drug to

be used as part of combination therapy to treat adults with multi drug resistant (MDR) TB, when no other alternatives are available.

Diaryl quinolone drug.

Bedaquiline inhibits enzyme needed by M. tuberculosis to replicate & spread throughout body. This mechanism is unlike that of all other quinolone antibiotics, whose target is DNA gyrase.

Page 83: Chemotherapy of Tuberculosis

Drug Interactions:

Bedaquiline should not be co-administered with other drugs that are strong inducers or inhibitors of CYP3A4, the hepatic enzyme responsible for oxidative metabolism of the drug.

Co-administration with rifampin, a strong CYP3A4 inducer, results in a 52% decrease in the AUC of the drug. This reduces the exposure of the body to the drug and decreases the antibacterial effect.

Co-administration with ketoconazole, a strong CYP3A4 inhibitor, results in a 22% increase in the AUC, and potentially an increase in the rate of adverse effects experienced

Page 84: Chemotherapy of Tuberculosis

Adverse Effects:The most common are:

nauseajoint and chest painHeadache arrhythmias as it may induce long QT syndrome

Page 85: Chemotherapy of Tuberculosis

ANYQUERIES…??

Page 86: Chemotherapy of Tuberculosis

REFERENCES:Bertram G. Katzung-Basic & Clinical

Pharmacology(9th Edition)KD Tripathi - Essentials of Medical Pharmacology,

6th Editionwww.tbfacts.org/tb-drugswww.fda.gov

Page 87: Chemotherapy of Tuberculosis

THANK YOU…