Anti-Tuberculosis Agents Supervised By : Dr.

Zaki Abdul Ghany

Done By : Arwa .O. Al-Khatib

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.
The main cause of TB, Mycobacterium tuberculosis (MTB), is a small aerobic non-motile bacillus. High lipid content of this pathogen accounts for many of its unique clinical characteristics. It divides 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 a phospholipid outer membrane, it is classified as a Gram-positive bacterium.

treatment must be administered for months to 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

Pathogenesis
TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within the endosomes of alveolar macrophages.The primary site of infection in the lungs is called the Ghon focus, and is generally located in either the upper part of the lower lobe. Bacteria are picked up by dendritic cells, which do not allow replication, although these cells can transport the bacilli to local (mediastinal) lymph nodes. Further spread is through the bloodstream to other tissues and organs where secondary TB lesions can develop in other parts of the lung ,peripheral lymph nodes, kidneys, brain, and bone.[All parts of the body can be affected by the disease, though it rarely affects the heart, skeletal muscles, pancreas and thyroid Tuberculosis is classified as one of the granulomatous inflammatory conditions. Macrophages, T lymphocytes, B lymphocytes, and fibroblasts are among the cells that aggregate to form granulomas, with lymphocytes surrounding the infected macrophages. The granuloma prevents dissemination of the mycobacteria and provides a local environment for interaction of cells of the immune system. Bacteria inside the granuloma can become dormant, resulting in a latent infection. Another feature of the granulomas of human tuberculosis is the development of abnormal cell death (necrosis) in the center of tubercles. To the naked eye this has the texture of soft white cheese and is termed caseous necrosis

 What is the difference between TB infection and TB disease? In most people who become infected, the body's immune system is able to fight the TB bacteria and stop them from multiplying. The bacteria are not killed, but they become inactive and are stored harmlessly in the body. This is TB infection. People with TB infection have no symptoms and cannot spread the infection to others. However, the bacteria remain alive in the body and can become active again later. If an infected person's immune system cannot stop the bacteria from multiplying, the bacteria eventually cause symptoms of active TB, or TB disease. To spread TB to others, a person must have TB disease.

 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 called latent (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. This is called active TB

 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 :

Anti-Tuberculosis 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)

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

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)

Treatment Principles (cont.)

3 subpopulations of mycobacteria proposed to exist Extracellular, rapidly dividing mycobacteria, often within cavities (107 to 109) Killed most readily by INH > RIF > streptomycin > other drugs Organisms residing within caseating granulomas (semidormant 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

Treatment Principles (cont.)

Toxicities Hepatoxicity Risk factors = multiple hepatotoxic agents, alcohol abuse Regimen and Dosing Duration varies Condition of patient, extent of disease, presence of drug resistance, and tolerance of medications

Iseman M. NEJM, 329:784, 1993

First-Line Agents

Rifampin
Inhibits DNA-dependent RNA polymerase : Bactericidal (very effective) Allows short course therapy (6-9 mos vs. 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 of other drugs.

Rifampin
It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities. Drug-resistance to RFP, due to target mutations in RNA polymerase, occurs readily. No cross-resistance to other classes of antimicrobial drugs. It often uses in combination with other agents (Tuberculosis, rifampin) in order to prevent emergence of drug-resistant mycobacteria

Inhibits 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 Neurotoxicity Usually manifests as peripheral neuropathy administer pyridoxine (vitamin B6) daily risk alcoholics, children, diabetics, malnourished, dialysis patients, HIV+

Isoniazid (INH) the most active

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

Antimetabolites and Other Antibacterial Agents

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

First Line Agents (cont.)

Pyrazinamide

Pyrazinamide is only used in combination with other drugs such as isoniazid and rifampicin in the treatment of Mycobacterium tuberculosis. It is never used on its own. Bactericidal PO only Metabolized in the liver, but metabolites 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

Mechanism of action of Pyrazinamide

Ethambutol
Mechanism : Inhibits cell wall components, through inhibiting arabinosyltransferases. Generally bacteriostatic PO only Renal excretion Toxicities Optic neuritis (doserelated) Hyperuricemia

Streptomycin
Streptomycin is the first antimicrobial drug used to treat tuberculosis. It is effective against most tubercle bacilli, but its activity is weaker than that of INH and RFP. Streptomycin penetrates into cells poorly, an drug resistance is produced easily. It is always given together with other drugs to prevent emergence of resistance.

Streptomycin
Inhibits protein synthesis (aminoglycoside) Bactericidal Poor activity in acidic environment. IM/IV Renal excretion Toxicities Vestibular toxicity Dizziness, problems with balance, tinnitus Nephrotoxicity Can be permanent

Second-Line Agents

Second Line Agents

Rifabutin Often used as an alternative to rifampin Less potent inducer CYP450 Drug interactions still important Cross resistance among rifamycins PO only Toxicities Uveitis (ocular pain, blurred vision. Quinolones :interfering with DNA replication Levofloxacin, moxifloxacin, gatifloxacin Bactericidal against extracellular organisms and achieve good intracellular concentrations IV/PO Uses MDR-TB IV alternative Well tolerated option Toxicities Nausea, abdominal pain Headache, insomnia, restlessness

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

 Cycloserine Mode of action : Inhibition of cell wall synthesis

Second Line Agents

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

Uses MDR-TB Bacteriostatic for both intracellular and extracellular organisms. PO only Toxicities Central nervous system effects (confusion, irritability, somnolence, headache, vertigo, seizures) Peripheral neuropathy

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.

DrugResistant M. tuberculosis
Epidemiology Primary drug resistance initial drug resistance Secondary drug resistance acquire drug resistance

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

Mechanism of resistance
INH
Chromosomally mediated Loss of catalase/peroxidase Mutation in mycolic acid synthesis Regulators of peroxide response

Rifampin
Reduced binding to RNA polymerase
Clusters of mutations at Rifampin Resistance Determining Region (RRDR)

Reduced Cell wall permeability

Treatment of MDR TB
Factors determining Success: Culture of MDR TB .Reliable susceptibility Reliable history of previous drug regimens .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-susceptibility assay is based on three principles: 1) mycobacterium tuberculosis (MTB) grows faster in liquid media than on solid media 2) microscopic MTB growth can be detected earlier in liquid media than waiting for the macroscopic appearance of colonies on solid media, and that growth is characteristic of MTB, allowing it to be distinguished from atypical mycobacteria or fungal or bacterial contamination 3) the drugs isoniazid and rifampicin can be incorporated into the MODS assay to allow for simultaneous direct detection of MDRTB, obviating the need for subculture to perform an indirect drug susceptibility test. .Reliable follow up

New Chemotherapeutic Agents

Derivatives of Rifamycin Rifabutin: Sensitive subset of Rifampin resistant strains Rifapentine: Extended half-life but more mono-resistance to rifamycins New flouroquinolones Gatifloxacin, Moxifloxacin, levofloxacin, sparfloxacin Nitroimidazoles related to metronidazole. May work better against latent bacilli

Likelihood of infection with MDR TB

Low

Intermediate to high

High possibility for disease

No
Confirmed R to INH+RIF Standard recommendation For non-MDR TB contacts

Yes

Consider Multidrug prophylaxis

Development of anti-tuberculosis drug resistance

Wild M. TB strain
Spontaneous mutation

Strains with genetic drug resistance

Selection: inadequate treatment

Acquired drug resistance

Transmission

Primary drug resistance

Pablos-Mendez et al. WHO, 1997

 Bacille Calmette Guerin (BCG) is the current vaccine for tuberculosis. It was first used in 1921. BCG is the only vaccine available today for protection against tuberculosis. It is most effective in protecting children from the disease It is prepared from a strain of the attenuated (weakened) live tuberculosis bacillus, Mycobacterium bovis, that has lost its virulence in humans by being specially subcultured in an artificial medium for 13 years, and also prepared from Mycobacterium tuberculosis. The bacilli have retained enough strong antigenicity to become a somewhat effective vaccine for the prevention of human tuberculosis.

BCG - the current vaccine for tuberculosis

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 preventing further drug resistance. In advanced cases, 4 or more sensitive drugs other than PZA may be necessary. But this is not yet concluded and controversial, and probably dependent partly 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 be used, PZA should be replaced by other sensitive drugs. Injectable drugs and fluoroquinolones should be use if possible.

References
Hugo & Russells Pharmaceutical Microbiology
Prescott ,Harley, AND Kleins Microbiology

http://www.cdc.gov/nchstp/tb/default.htm Division of Tuberculosis Elimination National Center for HIV, STD and TB Prevention, Centers for Disease Control http://www.nationaltbcenter.edu/ National Tuberculosis Center One of three Tuberculosis centers sponsored by Centers for Disease Control http://www.who.int/gtb/ Tuberculosis Prevention and Control World Health Organization http://www.lungusa.org/diseases/lungtb.html Tuberculosis (TB) American Lung Association

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