Tuberculosis: Robert L. Copeland, Jr., Ph.d

Tuberculosis Robert L. Copeland, Jr., Ph.D. October 1, 2009

Tuberculosis (TB) remains the leading cause of death worldwide from a single infectious disease agent. Indeed up to 1/2 of the world's population is infected with TB.  The registered number of new cases of TB worldwide roughly correlates with economic conditions: the highest incidences are seen in those countries of Africa, Asia, and Latin America with the lowest gross national products. WHO estimates that eight million people get TB every year, of whom 95% live in developing countries. An estimated 2 million people die from TB every year. 

It is estimated that between 2000 and 2020, nearly one billion people will be newly infected, 200 million people will get sick, and 35 million will die from TB - if control is not further strengthened. The mechanisms, pathogenesis, and prophylaxis knowledge is minimal. After a century of decline TB is increasing and there are strains emerging which are resistant to antibiotics. This excess of cases is attributable to the changes in the social structure in cities, the human immunodeficiency virus epidemic, and failure of most cities to improve public health programs, and the economic cost of treating.

TB is an ancient infectious disease caused by Mycobacterium tuberculosis. It has been known since 1000 B.C., so it not a new disease. Since TB is a disease of respiratory transmission, optimal conditions for transmission include:  overcrowding  poor personal hygiene  poor public hygiene

With the increased incidence of AIDS, TB has become more a problem in the U.S., and the world. It is currently estimated that 1/2 of the world's population (3.1 billion) is infected with Mycobacterium tuberculosis. Mycobacterium avium complex is associated with AIDS related TB.

Transmission Pulmonary tuberculosis is a disease of respiratory transmission, Patients with the active disease (bacilli) expel them into the air by:    

coughing, sneezing, shouting, or any other way that will expel bacilli into the air

Once inhaled by a tuberculin free person, the bacilli multiply 4 -6 weeks and spreads throughout the body. The bacilli implant in areas of high partial pressure of oxygen: lung renal cortex reticuloendothelial system

This is known as the primary infection. The patient will heal and a scar will appear in the infected loci. There will also be a few viable bacilli/spores may remain in these areas (particularly in the lung). The bacteria at this time goes into a dormant state, as long as the person's immune system remains active and functions normally this person isn't bothered by the dormant bacillus. When a person's immune system is depressed., a secondary reactivation occurs. 85-90% of the cases seen which are of secondary reactivation type occurs in the lungs.

Classification of Drugs

3 Groups depending upon the degree of effectiveness and potential side effects  First Line: (Primary agents)  are the most effective and have lowest toxicity.

Isoniazid Rifampin



Second Line:  Less effective and more toxic effects  include (in no particular order): p-amino salicylic acid,

Streptomycin, Ethambutol



Third Line  are least effective and most toxic. Amikacin, Kanamycin,

Capreomycin, Viomycin, Kanamycin, Cycloserine

Isoniazid Considered the drug of choice for the chemotherapy of TB. discovered in 1945 a hydrazide of isonicotonic acid  

is bacteriostatic for resting bacilli, bactericidal for growing bacilli.

Mechanism of action Unknown, but the hypothesis include effects on lipids, nucleic acid and biosynthesis. Primary action seems to inhibit the biosynthesis of mycolic acids which are part of cell wall structure.

Resistance Organism eventually develops resistance. The mechanism of resistance is related to the failure of the drug to penetrate or be taken up by the micro-organism (by active transport system), Remember treatment is up to 2 years.

Pharmacokineti cs Absorption: INH rapidly absorbed either oral or parenteral route. Peak [plasma] of 3-5 micrograms/milliliter after oral administration. Distribution: 





Diffuses readily into all bodily fluids does not bind to plasma proteins In the CSF the [conc] is about 20% of [plasma], t1/2 =1-3 hrs.

Excretion 75-95% of a dose excreted in the urine in 24 hr. - Mostly as a metabolite. - The main excretory product- acetylisoniazid. This is a result of enzymatic acetylation, Very important in terms of metabolism, Isoniazid is under genetic control, There are 2 groups of people. Fast and slow acetylators

Excretion cont. Those that have slow acetyl transferase activity are slow acetylators, may produce more of the toxic intermediate. This is an inherited trait ==> Autosomal Dominant The average [plasma] will be (1/3) to (1/2) of the slow acetylators Average t1/2, is less than 90 minutes, in the slow acetylators, t1/2 will be about 3 hours. Ethnicity- Eskimos,Native American Indians, and Asians are fast aceytlators,

Adverse Effects Induced Hepatitis (2% of Population) due to the buildup of toxic metabolic products of acetylisoniazid --> acetylhydrazine. This is more frequent in slow acetylators. Hepatic reactions to Isoniazid are also age dependent 

There is a 250X increase in the incidence of hepatitis over age. More frequent in the fast acetylators when measured intragroup, (Compare elderly fast acetylators patients with elderly slow patients,) Ranges from mild hepatitis to serious tissue necrosis.

Age dependency % incidence

age

 0.13

25

.59

35

1.09

45

1.75

55

2.5

>60

Patients with renal failure, the normal dose can be given, because it is secreted in the inactive form. Patients with hepatic insufficiency - give a reduced dose of the drug. ETOH causes induction of drug metabolizing enzymes, Isoniazid is broken down faster. Leads to lsoniazid hepatotoxicity. Glucose 6- Phosphate deficiency. People with a deficiency of Glucose-6-phosphate cannot adequately process the drug.

Drug Interaction Competition between Isoniazid and Phenytoin (anticonvulsant). They both compete for drug metabolism enzymes. Phenytoin interferes with metabolism of isoniazid by reduction in excretion or enhancement of effect of isoniazid

Rifampin Mechanism of Action Rifampin inhibits DNA dependent RNA polymerase of the bacilli.

Resistance: Due to alteration of the target (DNA dependent RNA polymerase) of the drug, prevents further initiation but not elongation. The microorganism can change the structure of the enzyme so that the drug no longer has an effect.

Pharmacokinetics Absorption peak levels reached 2-4 hrs. after oral dose rapidly eliminated in the bile and reabsorbed (enterohepatic circulation) It can be delayed with use of aminosalicylic acid. during this time there is a progressive deacylation of the drug; the metabolites maintain full effect Half life is 6 hours.

Distribution: Throughout the total body water Present in effective concentrations in many organs and body fluids including CSF, With Rifampin you must warn patients: The drug has an orange red color in body excretions, This color will be imparted to all body fluids.

Adverse Effects: Does not cause many side effects in any great frequency. G.I. reactions: Anorexia, Nausea ,Vomiting Mild abdominal pain, Hepatic Reactions in children, pregnant women and alcoholics, can result in minor elevations in serum transaminase as some jaundice

Allergic Reactions Fever Skin Eruptions Rash Pruritis Rifampin does induce microsomal drug metabolizing enzymes. This will decrease the half-life of some other drugs. (ie. phenytoin, digitoxin)

WARNING! Rifampin and Isoniazid are the most effective drugs for the treatment of TB, The drug enjoys high patient compliance and acceptability. But these 2 drugs should never be given alone! They are always used in combination because resistance occurs to one drug alone very rapidly. They are used in combination with each other initially as well as other drugs. Bacilli must become resistant to two drugs in order to remain viable. Statistically, the chances are verv small of the bacilli becoming resistant to both. .

2nd Line Drugs: Not as effective and have more toxicity Streptomycin The first drug used clinically for treatment of TB 1947-1952; was the only drug available at that time. is an aminoglycoside antibiotic acts by protein synthesis inhibitor and decreases the fidelity mRNA and garbles the message, leads to nonsense proteins. Streptomycin only binds to the 30s subunit.

Adverse Effects: affects C. Nerve 8: auditory and vestibular functions. - this drug is now 2nd 'line because of its toxicity. 

para- Aminosalicylic Acid a structural analog of PABA (p-aminobenzoic acid) is bacteriostatic inhibits de novo folate synthesis half life = 1 hour after 4 g. dose you can give this drug up to 12 grams per day. 80% of the drug is excreted in the urine and 50% of that is as an acetylated metabolite which is insoluble. You must make sure the patient's urine is normal or alkaline.

Adverse effects GI irritation due to the amount of drug given (high doses) nausea, vomiting, bleeding, occurs in 30-40% of the patients. be careful with those who have peptic ulcers Hypersensitivity reactions Rash, Fever some hepatotoxicity All will disappear when the drug is stopped This drug has poor patient acceptability and compliance: 

Third Line Drugs - least effective and most toxic Third line drugs are used when resistance is developed to 1st and 2nd line drugs; these drugs are also used in combination. Aminoglycosides Capreomycin - Viomycin Kanamycin

Adverse effects These drugs are: Nephrotoxic - will cause Proteinuria, Hematuria, Nitrogen metabolism, and Electrolyte disturbances However effect is reversible when drug is stopped.

Ototoxic will result in deafness and some loss of vestibular function, leads to cranial nerve 8 damage. The nerve damage is permanent. Capreomycin has replaced viomycin because of less toxic effects, but all three drugs have the same effects.

Cycloserine can cause CNS disturbances Therapeutic States Cycloserine should be used when re-treatment is necessary or when the micro-organism is resistant to the other drugs. It must be given in combination with other antituberculosis drugs. Mechanism of Action: An analog of D-alanine synthetase, will block bacterial cell wall synthesis.

Pharmacokinetics: Rapidly absorbed Peak [plasma] occurs in 3-4 hours Distributed throughout all body fluids, including CSF About 50% is excreted in unchanged form in the urine during the first 12 hours. Only about 35% of the drug metabolized This drug can accumulate to toxic conc in patients with renal insufficiency

Toxicity: Most common in the CNS: Headache, Tremor, Vertigo, Confusion, Nervousness, Psychotic states with suicidal tendencies , Paranoid reactions, Catatonic and depressed reactions

Chemoprophylaxis of TB Used only in high risk groups Household members and other close contacts of a patient with active TB. A positive skin test in persons less than 35 years. A positive skin test reactive in the immunosuppressed, persons with leukemia, and Hodgkin's Disease, HIV + patients with a positive TB test,

The drug of choice for chemoprophylaxis is isoniazid. Prophylaxis uses only one drug. In patients who are HIV+ and TB+ and have the disease; they are treated for a minimum of 9 months, The first 2 months using isoniazid and rifampin and for the next 7 months or longer, use only 2 or 3 of the 2nd/3rd line drugs and Isoniazid/Rifampin.

Chemotherapy of TB Most patients are treated in an ambulatory setting - admitted to the hospital diagnosis is established - initiate and stabilize therapy - send patient home , usually after 2 or 3 weeks First and second line agents are usually given orally. Third line drugs are given parenterally.

Treatment Isoniazid, Ethambutol, & Rifampin are given for 2 months. Isoniazid & Rifampin are given for 4 months. If you suspect resistance to isoniazid use Isoniazid, Ethambutol, Rifampin & Parazinamide. Incidence of drug resistance is 2-5% in the U.S. Prolonged bed rest is not necessary or helpful in obtaining a speedy recovery. The patient must be seen at regular and frequent intervals to follow the course of the disease and treatment. Look for toxic effects

Other Resources Tuberculosis Resources (Columbia Medical School)  http://www.cpmc.columbia.edu/tbcpp Tuberculosis, NIAID Fact Sheet http://www.niaid.nih.gov/factsheets/tb.htm Positive Skin Tests for Tuberculosis (American Family Physician) http://www.aafp.org/afp/961101ap/pat_1991.html National Tuberculosis Center http://www.umdnj.edu/~ntbcweb/ntbchome.htm CDC; Division of Tuberculosis Elimination http://www.cdc.gov/nchstp/tb/structure.htm Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children American Thoracic Society Medical Section of the American Lung Association American Journal of Respiratory and Critical Care Medicine Vol 149 1994  http://aepo-xdv-www.epo.cdc.gov/wonder/PrevGuid/p0000413/p0000413.htm Brief History of Tuberculosis http://www.umdnj.edu/~ntbcweb/history.htm