Anti Tuberculosis Agents

7/28/2019 Anti Tuberculosis Agents

1/41

Anti-TuberculosisAgents

Supervised By :

Dr. Zaki AbdulGhany

Done By : Arwa .O. Al-Khatib


2/41

Tuberculosis

Tuberculosis is a kind of communicable chronic

disease caused by M.tuberculosis,which can invade

various tissues and organs of the whole body. The mycobacteria are slow-growing

intracellular bacilli that cause tuberculosis.

treatment must be administered for monthsto years depending on which drugs are used.

Usually, a drug-combination regimen is

required for treatment of tuberculosis;

otherwise microbial resistance, notorious to

any single drug, develops rapidly

The main cause of TB, Mycobacterium tuberculosis (MTB), is a

smallaerobicnon-motile bacillus. High lipidcontent of this

pathogen accounts for many of its unique clinical characteristics.Itdivides every 16 to 20 hours, an extremely slow rate compared

with other bacteria, which usually divide in less than an hour.

Since MTB has a cell wall but lacks aphospholipidouter

membrane, it is classifiedas a Gram-positive bacterium.
http://en.wikipedia.org/wiki/Mycobacterium_tuberculosishttp://en.wikipedia.org/wiki/Aerobic_organismhttp://en.wikipedia.org/wiki/Bacillushttp://en.wikipedia.org/wiki/Lipidhttp://en.wikipedia.org/wiki/Cell_divisionhttp://en.wikipedia.org/wiki/Phospholipidhttp://en.wikipedia.org/wiki/Bacterial_cell_structurehttp://en.wikipedia.org/wiki/Bacterial_cell_structurehttp://en.wikipedia.org/wiki/Tuberculosis_classificationhttp://en.wikipedia.org/wiki/Gram-positivehttp://en.wikipedia.org/wiki/Gram-positivehttp://en.wikipedia.org/wiki/Gram-positivehttp://en.wikipedia.org/wiki/Gram-positivehttp://en.wikipedia.org/wiki/Tuberculosis_classificationhttp://en.wikipedia.org/wiki/Bacterial_cell_structurehttp://en.wikipedia.org/wiki/Bacterial_cell_structurehttp://en.wikipedia.org/wiki/Phospholipidhttp://en.wikipedia.org/wiki/Cell_divisionhttp://en.wikipedia.org/wiki/Lipidhttp://en.wikipedia.org/wiki/Bacillushttp://en.wikipedia.org/wiki/Aerobic_organismhttp://en.wikipedia.org/wiki/Mycobacterium_tuberculosis


3/41

Pathogenesis TB infection begins when the mycobacteria reach the pulmonary

alveoli, where they invade and replicate within the endosomes ofalveolar macrophages.The primary site of infection in the lungs is

called the Ghon focus, and is generally located in either the upper partof the lower lobe. Bacteria are picked up by dendritic cells, which donot allow replication, although these cells can transport the bacilli tolocal (mediastinal) lymph nodes. Further spread is through thebloodstream to other tissues and organs where secondary TB lesionscan develop in other parts of the lung ,peripheral lymph nodes,kidneys, brain, and bone.[All parts of the body can be affected by thedisease, though it rarely affects the heart, skeletal muscles, pancreasand thyroid

Tuberculosis is classified as one of the granulomatous inflammatoryconditions. Macrophages, T lymphocytes, B lymphocytes, andfibroblasts are among the cells that aggregate to form granulomas,with lymphocytes surrounding the infected macrophages. Thegranuloma prevents dissemination of the mycobacteria and provides alocal environment for interaction of cells of the immune system.Bacteria inside the granuloma can become dormant, resulting in alatent infection. Another feature of the granulomas of humantuberculosis is the development of abnormal cell death (necrosis) inthe center oftubercles. To the naked eye this has the texture of softwhite cheese and is termed caseousnecrosis
http://en.wikipedia.org/wiki/Pulmonary_alveolushttp://en.wikipedia.org/wiki/Endosomeshttp://en.wikipedia.org/wiki/Endosomeshttp://en.wikipedia.org/wiki/Pulmonary_alveolushttp://en.wikipedia.org/wiki/Pulmonary_alveolushttp://en.wikipedia.org/wiki/Macrophageshttp://en.wikipedia.org/wiki/Endosomeshttp://en.wikipedia.org/wiki/Macrophageshttp://en.wikipedia.org/wiki/Ghon_focushttp://en.wikipedia.org/wiki/Ghon_focushttp://en.wikipedia.org/wiki/Dendritic_cellhttp://en.wikipedia.org/wiki/Dendritic_cellhttp://en.wikipedia.org/wiki/Mediastinalhttp://en.wikipedia.org/wiki/Lymph_nodehttp://en.wikipedia.org/wiki/Hearthttp://en.wikipedia.org/wiki/Skeletal_musclehttp://en.wikipedia.org/wiki/Pancreashttp://en.wikipedia.org/wiki/Thyroidhttp://en.wikipedia.org/wiki/Hearthttp://en.wikipedia.org/wiki/Skeletal_musclehttp://en.wikipedia.org/wiki/Pancreashttp://en.wikipedia.org/wiki/Thyroidhttp://en.wikipedia.org/wiki/Macrophagehttp://en.wikipedia.org/wiki/T_cellhttp://en.wikipedia.org/wiki/T_cellhttp://en.wikipedia.org/wiki/Granulomahttp://en.wikipedia.org/wiki/B_cellhttp://en.wikipedia.org/wiki/B_cellhttp://en.wikipedia.org/wiki/Fibroblasthttp://en.wikipedia.org/wiki/Macrophagehttp://en.wikipedia.org/wiki/T_cellhttp://en.wikipedia.org/wiki/B_cellhttp://en.wikipedia.org/wiki/Granulomahttp://en.wikipedia.org/wiki/Granulomahttp://en.wikipedia.org/wiki/Fibroblasthttp://en.wikipedia.org/wiki/Lymphocyteshttp://en.wikipedia.org/wiki/Lymphocyteshttp://en.wikipedia.org/wiki/Granulomahttp://en.wikipedia.org/wiki/Lymphocyteshttp://en.wikipedia.org/wiki/Necrosishttp://en.wikipedia.org/wiki/Tubercle_(anatomy)http://en.wikipedia.org/wiki/Necrosishttp://en.wikipedia.org/wiki/Tubercle_(anatomy)http://en.wikipedia.org/wiki/Caseoushttp://en.wikipedia.org/wiki/Necrosishttp://en.wikipedia.org/wiki/Caseoushttp://en.wikipedia.org/wiki/Necrosishttp://en.wikipedia.org/wiki/Necrosishttp://en.wikipedia.org/wiki/Caseoushttp://en.wikipedia.org/wiki/Tubercle_(anatomy)http://en.wikipedia.org/wiki/Necrosishttp://en.wikipedia.org/wiki/Lymphocyteshttp://en.wikipedia.org/wiki/Granulomahttp://en.wikipedia.org/wiki/Fibroblasthttp://en.wikipedia.org/wiki/B_cellhttp://en.wikipedia.org/wiki/T_cellhttp://en.wikipedia.org/wiki/Macrophagehttp://en.wikipedia.org/wiki/Granulomahttp://en.wikipedia.org/wiki/Thyroidhttp://en.wikipedia.org/wiki/Pancreashttp://en.wikipedia.org/wiki/Skeletal_musclehttp://en.wikipedia.org/wiki/Hearthttp://en.wikipedia.org/wiki/Lymph_nodehttp://en.wikipedia.org/wiki/Mediastinalhttp://en.wikipedia.org/wiki/Dendritic_cellhttp://en.wikipedia.org/wiki/Dendritic_cellhttp://en.wikipedia.org/wiki/Dendritic_cellhttp://en.wikipedia.org/wiki/Ghon_focushttp://en.wikipedia.org/wiki/Ghon_focushttp://en.wikipedia.org/wiki/Ghon_focushttp://en.wikipedia.org/wiki/Macrophageshttp://en.wikipedia.org/wiki/Endosomeshttp://en.wikipedia.org/wiki/Pulmonary_alveolushttp://en.wikipedia.org/wiki/Pulmonary_alveolus


4/41

What is the difference between TB infection and TBdisease?

In most people who become infected, the body's

immune system is able to fight the TB bacteria andstop them from multiplying. The bacteria are notkilled, but they become inactive and are storedharmlessly in the body. This is TB infection. People

with TB infection have no symptoms and cannotspread the infection to others. However, the bacteriaremain alive in the body and can become activeagain later.

If an infected person's immune system cannot stopthe bacteria from multiplying, the bacteriaeventually cause symptoms of active TB, or TBdisease. To spread TB to others, a person must haveTB disease.


5/41

Latent TB

Most people who breathe in TB germs do

not get sick. When a persons immune

system is strong, it builds a wall around

the germs so they cant spread and

hurt the body. These walls are called

tubercles thats how tuberculosis gets

its name. Once the germs are trapped

inside the tubercles, they slow down

and stop activity, as if they went to sleep.

This is calledlatent (sleeping) TB.

Active TB

When a person cant fight TB germs, they

become sick. The TB germs multiply

and do a lot of damage to the body. Thisis calledactive TB


6/41

Anti-Tuberculosis Therapy Drug therapy is the cornerstone of TB

management Goals :

Kill TB rapidly

Prevent emergence of resistance

Eliminate persistent bacilli from the host to

prevent relapse Drug therapy :

First line agents

Greatest efficacy with acceptable toxicity

Second-line agents Less efficacy, greater toxicity, or both

If properly used, can achieve cure rate ~98%

Increasing prevalence of multidrug resistant TB(MDRTB)


7/41

Anti-Tuberculosis Agents

First-line Drugs Rifampin

Isoniazid

Pyrazinamide

Ethambutol

Streptomycin

Second-line Drugs

Rifabutin

Quinolones

Capreomycin Amikacin, kanamycin

Para-aminosalicylic acid (PAS)

Cycloserine

Ethionamide


8/41


9/41

Treatment Principles Disease burden

Asymptomatic patients have an organism load of ~103 organisms

Cavitary pulmonary TB has a load of 1011 organisms

As the number of organisms increases, likelihood of

drug-resistant mutants increases

Mutants found at rates of 1 in 106 to 1 in 108 organisms

Drug therapy regimens

Latent TB

Monotherapy, usually with isoniazid (INH)

Risk of selecting out resistant organisms is low

Active TB

Combination therapy of at least 2 drugs, generally three or more

Rates for multiple drug mutations occur as an additive function

1 in 1013 (INH rate of 106 + RIF rate of 107)


10/41

Treatment Principles (cont.) 3 subpopulations of mycobacteria proposed to exist

Extracellular, rapidly dividing mycobacteria, oftenwithin cavities

(107 to 109)

Killed most readily by INH > RIF > streptomycin > other

drugs Organisms residing within caseating granulomas (semi-

dormant

metabolic state; 105 to 107)

Activity of PZA > INH and RIF

Intracellular mycobacteria present within macrophages(104 to

106)

RIF, INH, PZA and quinolones believed to be most active


11/41

Treatment Principles (cont.)

Toxicities

Hepatoxicity

Risk factors = multiplehepatotoxic agents,

alcohol abuse Regimen and Dosing

Duration varies

Condition of patient,

extent of disease,presence of drugresistance, and

tolerance of medications


12/41

Iseman M. NEJM, 329:784, 1993


13/41

First-Line Agents


14/41

Rifampin

Inhibits DNA-dependent RNApolymerase :

Bactericidal (very effective)

Allows short course therapy (6-9 mosvs. 18 mos)

IV/PO

Toxicities :

hepatic enzymes (AST, ALT,bilirubin, alkaline phosphatase)

GI distress

Red-orange discoloration of body

fluids Rash

DRUG INTERACTIONS :

Potent inducer of CYP450 metabolism( concentrations ofother drugs.


15/41

Rifampin It can kill organisms that are poorly

accessible to many other drugs, such asintracellular organisms and those

sequestered in abscesses

and lung cavities.

Drug-resistance to RFP, due to targetmutations in RNA polymerase, occurs readily.

No cross-resistance to other classes of

antimicrobial drugs.

It often uses in combination with otheragents

(Tuberculosis, rifampin) in order to prevent

emergence of drug-resistant mycobacteria


16/41

Isoniazid(INH) the most activeInhibits mycolic acid synthesis

Long-chain fatty acids of the

mycobacterial cell wall Bactericidal against growing MTB

Bacteriostatic against nonreplicating

MTB

PO only

Well absorbed

Toxicities

serum transaminases (AST, ALT)

Slow acetylators may be at increased risk

NeurotoxicityUsually manifests as peripheral

neuropathy administer pyridoxine

(vitamin B6) daily

risk alcoholics, children, diabetics,

malnourished, dialysis patients, HIV+

Isoniazid is able to penetrate into

phagocytic cells and thus is active against

both extracellular and intracellular

organisms.


17/41

Antimetabolites and Other

Antibacterial Agents

interfering with the synthesis of mycolic acid , the component of mycobacterium cell wall.


18/41

First Line Agents (cont.)Pyrazinamide

Pyrazinamide is only used incombination with other drugssuch as isoniazid and

rifampicin in the treatment ofMycobacterium tuberculosis. Itis never used on its own.

Bactericidal

PO only

Metabolized in the liver, butmetabolites are renally excreted.

Mechanism :

M. tuberculosis has the enzyme

pyrazinamidase which is only active

in acidic conditions.Pyrazinamidase

converts pyrazinamide to the active

form, pyrazinoic acid which

accumulates in the bacilli. Pyrazinoic

acid was thought to inhibit the

enzyme fatty acid synthase (FAS) I,

which is required by the bacterium

to synthesise its fat nutrient.

Toxicities

liver enzymes

Hyperuricemia

Nausea/vomiting
http://en.wikipedia.org/wiki/Isoniazidhttp://en.wikipedia.org/wiki/Rifampicinhttp://en.wikipedia.org/wiki/Rifampicinhttp://en.wikipedia.org/wiki/Isoniazidhttp://en.wikipedia.org/wiki/Tuberculosis_treatmenthttp://en.wikipedia.org/wiki/Mycobacterium_tuberculosishttp://en.wikipedia.org/wiki/Mycobacterium_tuberculosishttp://en.wikipedia.org/wiki/Mycobacterium_tuberculosishttp://en.wikipedia.org/wiki/Mycobacterium_tuberculosishttp://en.wikipedia.org/wiki/Mycobacterium_tuberculosishttp://en.wikipedia.org/wiki/Pyrazinamidasehttp://en.wikipedia.org/wiki/Acidhttp://en.wikipedia.org/wiki/Pyrazinoic_acidhttp://en.wikipedia.org/wiki/Fatty_acid_synthasehttp://en.wikipedia.org/wiki/Fatty_acid_synthasehttp://en.wikipedia.org/wiki/Fatty_acid_synthasehttp://en.wikipedia.org/wiki/Pyrazinoic_acidhttp://en.wikipedia.org/wiki/Pyrazinoic_acidhttp://en.wikipedia.org/wiki/Pyrazinoic_acidhttp://en.wikipedia.org/wiki/Acidhttp://en.wikipedia.org/wiki/Pyrazinamidasehttp://en.wikipedia.org/wiki/Mycobacterium_tuberculosishttp://en.wikipedia.org/wiki/Tuberculosis_treatmenthttp://en.wikipedia.org/wiki/Rifampicinhttp://en.wikipedia.org/wiki/Isoniazid


19/41

Mechanism of action of

Pyrazinamide


20/41

Ethambutol

Mechanism : Inhibits cell wall

components, throughinhibiting

arabinosyltransferases. Generally bacteriostatic

PO only

Renal excretion

Toxicities Optic neuritis (dose-

related)

Hyperuricemia


21/41


22/41

Streptomycin Streptomycin is the first

antimicrobial drug used totreat tuberculosis. It iseffective against mosttubercle bacilli, but its activity

is weaker than that of INHand RFP.

Streptomycin penetrates intocells poorly, an drug

resistance is produced easily. It is always given together

with other drugs to preventemergence of resistance.


23/41

Streptomycin

Inhibits protein synthesis

(aminoglycoside)

Bactericidal

Poor activity in acidicenvironment.

IM/IV

Renal excretion

Toxicities

Vestibular toxicity

Dizziness, problems withbalance, tinnitus

Nephrotoxicity Can be permanent


24/41

Second-Line Agents


25/41

Second Line Agents

Rifabutin Often used as an alternative to

rifampin

Less potent inducer CYP450

Drug interactions still important

Cross resistance amongrifamycins

PO only

Toxicities

Uveitis (ocular pain, blurredvision.

Quinolones :interfering withDNA replication

Levofloxacin, moxifloxacin,

gatifloxacin

Bactericidal against

extracellular organisms and

achieve good intracellularconcentrations

IV/PO

Uses

MDR-TB

IV alternative

Well tolerated option

Toxicities

Nausea, abdominal pain

Headache, insomnia,

restlessness
http://en.wikipedia.org/wiki/DNA_replicationhttp://en.wikipedia.org/wiki/DNA_replicationhttp://en.wikipedia.org/wiki/DNA_replicationhttp://en.wikipedia.org/wiki/DNA_replication


26/41

Second Line Agents Capreomycin inhib.of protein synth.)

Uses MDR-TB

IM/IV

Cross-resistance with

aminoglycosides

Toxicities

Injection pain Hearing loss, tinnitus

Renal dysfunction

Amikacin, kanamycin

Aminoglycosides

Cross-resistance with

streptomycin Uses

MDR-TB

IV/IM alternative

Toxicities

Renal toxicity

Hearing loss, tinnitus

Para-amino salicylic acid (PAS)

Inhib .folic acid synth.

Synthetic structural analog of

aminobenzoic acid

Bacteriostatic for extracellular organisms only

Uses

MDR-TB (bacteriostatic)

PO only

Toxicities (can be severe)

Hepatotoxicity

Mortality reported ~21%

Hypothyroidism


27/41

Second Line Agents Cycloserine

Mode of action :

Inhibition of cell wall synthesis Uses

MDR-TB

Bacteriostatic for bothintracellular and extracellular

organisms. PO only

Toxicities

Central nervous system

effects (confusion, irritability,

somnolence, headache,

vertigo, seizures)

Peripheral neuropathy

Ethionamide

inhibit peptide synthesis Uses

MDR-TB (bacteriostatic)

Bacteriostatic for extracellular

organisms only

PO only

Toxicities

Nausea/vomiting

Peripheral neuropathy

Psychiatric disturbances

liver enzymes

glucose

Goiter with or without

hypothyroidism

Gynecomastia, impotence,

menstrual irregularities


28/41


29/41

Drug-Resistant TB Acquired resistance

Suboptimal therapy that encourages selective growth of mutants

resistant to one or more drugs

Factors leading to suboptimal therapy

Intermittent drug supplies

Use of expired drugs

Unavailability of combination preparations

Use of poorly formulated combination preparations

Inappropriate drug regimens

Addition of single drugs to failing regimens in the absence of

bacteriologic control

Poor supervision of therapy

Unacceptably high cost to patient (drugs, travel to clinic.


30/41


31/41

DrugResistant M. tuberculosis

Epidemiology

Primary drugresistance

initial drugresistance

Secondary drugresistance

acquire drugresistance


32/41

Clinical factors promoting resistance

Delayed diagnosis and isolation Inappropriate drug regimen.

Inadequate initial therapy

Incomplete course of treatment

Inappropriate treatment modifications Adding single drug to a failing regimen

Inappropriate use of chemoprophylaxis

Failure to isolate MDR TB patients Failure to employ DOT

Over the counter anti TB


33/41

Mechanism of resistance

INH

Chromosomally mediated Loss of catalase/peroxidase

Mutation in mycolic acidsynthesis

Regulators of peroxide response Rifampin

Reduced binding to RNApolymerase Clusters of mutations at Rifampin

Resistance Determining Region(RRDR)

Reduced Cell wall permeability


34/41

Treatment of MDR TBFactors determining Success:Culture of MDR TB

.Reliable susceptibility Reliable history of previous drugregimens

.Program to assure delivery of prescribed drugs (DOT)Directly Observed Treatment .

.Correct choice of modified treatment regimen

.Drug Susceptibility Testing (DST) of second-line drugs (SLD)

. MODS( The microscopic-observation drug-susceptibilityassay is based on three principles: 1) mycobacteriumtuberculosis (MTB) grows faster in liquid media than onsolid media 2) microscopic MTB growth can be detectedearlier in liquid media than waiting for the macroscopicappearance of colonies on solid media, and that growth ischaracteristic of MTB, allowing it to be distinguished fromatypical mycobacteria or fungal or bacterial contamination3) the drugs isoniazid and rifampicin can be incorporatedinto the MODS assay to allow for simultaneous directdetection of MDRTB, obviating the need for subculture toperform an indirect drug susceptibility test.

.Reliable follow up


35/41

New Chemotherapeutic Agents

Derivatives of Rifamycin Rifabutin: Sensitive subset of

Rifampin resistant strains

Rifapentine: Extended half-lifebut more mono-resistance to

rifamycins

New flouroquinolones

Gatifloxacin, Moxifloxacin,levofloxacin, sparfloxacin

Nitroimidazoles

related to metronidazole. Maywork better against latentbacilli


36/41

Likelihood of infection with MDR TB

Intermediate to highLow

High possibility

for disease

YesNo

Consider Multidrug

prophylaxis

Confirmed R

to INH+RIF

Standard

recommendation

For non-MDR TB contacts


37/41

Strains with genetic

drug resistance

Wild M. TB strain

Acquired drug

resistance

Primary drugresistance

Spontaneous mutation

Selection: inadequate treatment

Transmission

Development of anti-tuberculosis drug resistance

Pablos-Mendez et al. WHO, 1997

BCG the current vaccine for


38/41

BCG - the current vaccine for

tuberculosis Bacille Calmette Guerin (BCG) is the current

vaccine for tuberculosis. It was first used in1921. BCG is the only vaccine available todayfor protection against tuberculosis. It is mosteffective in protecting children from thedisease

It is prepared from a strain of the attenuated(weakened) live tuberculosis bacillus,Mycobacterium bovis, that has lost itsvirulence in humans by being speciallysubcultured in an artificial medium for 13

years, and also prepared from Mycobacteriumtuberculosis. The bacilli have retained enoughstrong antigenicity to become a somewhateffective vaccine for the prevention of humantuberculosis.

C l i
http://en.wikipedia.org/wiki/Mycobacterium_bovishttp://en.wikipedia.org/wiki/Mycobacterium_bovishttp://en.wikipedia.org/wiki/Mycobacterium_tuberculosishttp://en.wikipedia.org/wiki/Mycobacterium_tuberculosishttp://en.wikipedia.org/wiki/Mycobacterium_tuberculosishttp://en.wikipedia.org/wiki/Mycobacterium_tuberculosishttp://en.wikipedia.org/wiki/Vaccinehttp://en.wikipedia.org/wiki/Vaccinehttp://en.wikipedia.org/wiki/Vaccinehttp://en.wikipedia.org/wiki/Mycobacterium_tuberculosishttp://en.wikipedia.org/wiki/Mycobacterium_tuberculosishttp://en.wikipedia.org/wiki/Mycobacterium_bovishttp://en.wikipedia.org/wiki/Mycobacterium_bovis


39/41

Conclusions.In moderate cases, 3 sensitive drugs other than PZA

are probably enough, even in initial phases of MDR-TB

chemotherapy, for culture conversion and preventingfurther drug resistance.

In advanced cases, 4 or more sensitive drugs otherthan PZA may be necessary. But this is not yetconcluded and controversial, and probably dependentpartly on the indication of adjunctive surgery.

If sensitive, PZA should be used in initial 2 to 3

months, after that, when other sensitive drugs can beused, PZA should be replaced by other sensitive drugs.

Injectable drugs and fluoroquinolones should be use ifpossible.


40/41

References

Hugo & Russells Pharmaceutical Microbiology

Prescott ,Harley, AND Kleins Microbiology

http://www.cdc.gov/nchstp/tb/default.htm

Division of Tuberculosis EliminationNational Center for HIV, STD and TB Prevention, Centers for DiseaseControl http://www.nationaltbcenter.edu/National Tuberculosis CenterOne of three Tuberculosis centers sponsored by Centers for DiseaseControl

http://www.who.int/gtb/Tuberculosis Prevention and ControlWorld Health Organization

http://www.lungusa.org/diseases/lungtb.htmlTuberculosis (TB)American Lung Association
http://www.cdc.gov/nchstp/tb/default.htmhttp://www.cdc.gov/nchstp/tb/default.htmhttp://www.nationaltbcenter.edu/http://www.nationaltbcenter.edu/http://www.who.int/gtb/http://www.who.int/gtb/http://www.lungusa.org/diseases/lungtb.htmlhttp://www.lungusa.org/diseases/lungtb.htmlhttp://www.who.int/gtb/http://www.nationaltbcenter.edu/http://www.cdc.gov/nchstp/tb/default.htm


41/41

THANK YOU

Anti Tuberculosis Agents

Documents

Transcript of Anti Tuberculosis Agents