Anti-TB drugs

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Questions and Answers

What is a significant characteristic of Mycobacterium tuberculosis that aids in its identification?

It is predominantly anaerobic.

It does not form spores.

It is a gram-negative bacteria.

It contains a high percentage of mycolic acids in its cell wall. (correct)

Which of the following statements regarding Isoniazid is accurate?

It inhibits the synthesis of mycolic acids in mycobacterial cell walls. (correct)

It is effective against only intra-cellular organisms.

It has a structure dependent on amino acid composition.

It is best administered as a single agent to avoid resistance.

What historical action did the US government take in 1925 to combat tuberculosis in children?

Launch a nationwide tuberculosis awareness campaign.

Ban the sale of raw milk.

Institute a national requirement for pasteurization of milk. (correct)

Mandate tuberculosis vaccinations for all children.

Which diagnostic test is indicative of tuberculosis?

Positive PPD skin test at 48 hours Signup and view all the answers

What happens when Isoniazid is used as a single agent?

It leads to resistance in the pathogen. Signup and view all the answers

Which of the following is NOT listed as a second-line drug for treating TB?

Dapsone Signup and view all the answers

Which mechanism of action does Bedaquiline employ that is notably different from other TB treatments?

Inhibits ATP synthesis Signup and view all the answers

Which of the following antibiotics is derived from Streptomycetes species of bacteria?

Capreomycin Signup and view all the answers

What is the primary role of Dapsone in leprosy treatment?

Inhibiting folic acid synthesis Signup and view all the answers

Which condition leads to the use of second-line drugs for TB treatment?

Resistance to first-line drugs Signup and view all the answers

What type of clinical trial was conducted for streptomycin treatment in tuberculosis?

Double blind randomized trial Signup and view all the answers

For which reason is pyridoxine administered alongside isoniazid?

To prevent peripheral neuropathy Signup and view all the answers

What is the most common adverse drug reaction (ADR) associated with isoniazid?

drug induced hepatitis Signup and view all the answers

Why should ethambutol be avoided in children

It causes red-green color blindness Signup and view all the answers

What is the role of rifampin in tuberculosis treatment?

It inhibits bacterial RNA synthesis. Signup and view all the answers

Which organism produces rifampin, and what is its classification?

Streptomyces mediterranei; semisynthetic produced Signup and view all the answers

How does pyrazinamide function within the body?

It is converted to its active form by the bacteria. Signup and view all the answers

Which of the following is NOT a common side effect of rifampin?

Nausea and vomiting Signup and view all the answers

What is isoniazid structurally similar to?

Pyridoxine (vitamin B6) Signup and view all the answers

Isoniazid is a prodrug.

True Signup and view all the answers

What is pyrazinamide similar in structure to?

nicotinamide Signup and view all the answers

Match each second line TB drug to its MOA

capreomycin = peptide antibiotic which inhibits protein synthesis (Katzung pg 880) aminosalicylic acid = works like the sulfa drugs by blocking folic acid synthesis (Katzung pg 881) linezolid = Inhibit protein synthesis by binding to the 23S of the 50 S subunit bedaquiline = inhibits ATPase in mycobacteria Signup and view all the answers

Match each leprosy drug to its MOA

<h1>dapsone = inhibits folate synthesis like the sulfa drugs rifampin = binds to bacterial RNA polymerase and stops RNA synthesis bactericidal for mycobacteria clofazimine = a phenazine dye with an unknown MOA</h1> Signup and view all the answers

Study Notes

Tuberculosis

Leading cause of death in children under 10 in the early 20th century.
Raw milk was a major source of Mycobacterium tuberculosis.
US government, in 1925, required all milk to be pasteurized to try to eradicate TB in children.

Mycobacterium tuberculosis

Robert Koch discovered a stain for tuberculosis in 1882.
TB was the leading cause of death in the 1940s; more than 20 million deaths per year worldwide.
Penicillin was ineffective against TB.

Mycobacterium tuberculosis diagnosis

Positive purified protein derivative (PPD) skin test at 48 h after application.
Positive sputum stain for acid-fast bacillus.
Organism cell wall contains 60% long chain fatty acids called mycolic acids.
Auramine O fluorescence and Kinyoun dyes stain with selectivity.
Clinical signs, symptoms, and chest X-rays can be used for diagnosis.

M. tuberculosis Presentation

Cough for several weeks.
Recent weight loss.
Night sweats, subjective feeling of fatigue.
Emigrants from countries with endemic TB.
Chest radiographs with atypical infiltrates.

Isoniazid

Structure is similar to pyridoxine.
Active against intra and extracellular organisms.
Inhibits mycolic acid synthesis in mycobacterial cell walls.
A prodrug that is converted into a drug by a bacterial enzyme.
Single-agent use can lead to resistance.
Lesions often contain one mutant resistant organism per 10^6 total organisms.
A combination of two different drugs is always required to prevent resistance.
Dosing is based on rapid versus slow acetylators (pharmacogenomics).
Administered with pyridoxine (vitamin B6).
Most common adverse drug reaction (ADR) is drug-induced hepatitis.
Many patients develop elevated AST, which does not lead to hepatitis.
10 – 20% of patients develop peripheral neuropathy (PN) (dose-dependent).
PN is caused by pyridoxine deficiency, because isoniazid promotes excretion of pyridoxine.
Reason why pyridoxine is given with isoniazid.

Rifampin

Semisynthetic produced by Streptomyces mediterranei.
Resistant mutants found at 1 x 10^6.
Never used alone.
Inhibits RNA synthesis through inhibition of a bacterial DNA-dependent RNA polymerase.
ADR includes yellow urine, sweat, tears, and contact lenses being permanently stained.

Ethambutol

Synthetic that inhibits mycobacterial arabinosyl transferase, which is required for cell wall synthesis.
Most common ADR is red-green color blindness.
Not indicated for children who are too young to allow for assessment of color blindness.

Pyrazinamide

Mycobacterium convert the prodrug pyrazinamide into pyrazinoic acid, the active drug.
Inhibits cell wall synthesis and/or function in an unknown way.
May induce acute gouty arthritis.

Second-Line Drugs to Treat Tuberculosis

Used only when:
- Resistance to first-line drugs develops
- First-line drugs fail
- First-line ADRs limit patient compliance

Second-Line Drugs

Ethionamide: Similar to isoniazide, inhibits mycolic acid synthesis.
Capreomycin: Intramuscular, protein synthesis inhibitor.
Cycloserine: Cell wall synthesis inhibitor (see Chapter 43).
Aminosalicylic acid (PAS): Folate synthesis inhibitor.
Kanamycin & Amikacin: Aminoglycosides (see Chapter 45).
Fluoroquinolones: (see Chapter 46).
Linezolid: (see Chapter 44).
Rifabutin: Similar to rifampin.
Rifapentine: Analog of rifampin.
Bedaquiline: inhibits ATP synthesis (first new mechanism since 1971).

Leprosy

Also known as Hansen’s disease.
Mycobacterium leprae is the causative agent.
M. leprae has not been grown in vitro, only in mouse footpads.
Dapsone and other sulfones: Related to sulfa drugs; inhibits folate synthesis.

Dapsone

The world’s first drug used to treat Leprosy.
Discovered in the early 1940s.
Inhibits folic acid synthesis, stops DNA replication.
Often used in combination with rifampin to prevent resistance.
Retained in the skin, making it effective for treating skin lesions.
Half-life (t1/2) 1 – 2 days, perfect for once-daily dosing.

Streptomyces

Gram-positive anaerobic soil bacteria.
Resemble fungi but are true prokaryotes.
Give soil its smell.
Mycobacterium, carried by cows, is added to soil, and causes the death of the TB organism.

Albert Schatz

Discharged from the army in 1943.
Started graduate work at Rutgers University in New Jersey under Selman Waksman.
Isolated Streptomycin from Actinomyces on October 19, 1943.

Streptomycin

Jones, D., Metzger, H.J., Schatz, A., Waksman, S. (1944). Control of gram-negative bacteria in experimental animals by streptomycin. Science 100(2588), 103-105. (Published August 4)
Schatz isolated “antibiotic” that inhibits TB on October 19, 1943.
Schatz named the compound “streptomycin”.
Waksman coined the word “antibiotic”.
Schatz-Waksman US Patent 2,449,866 assigned to Rutgers University.
Schatz, A., Waksman, S.A. (1944). Effect of streptomycin upon Mycobacterium tuberculosis and related organisms. Proc.Soc.Exp.Biol.Med. 67, 244-248.

Streptomycin Mechanism of Action

Mechanism of action against M. tuberculosis

Streptomycin in Humans

Corwin and Feldman at the Mayo Clinic injected streptomycin into a human being for the first time on November 20, 1944.
Injected into a 21-year-old with advanced TB.
After 5 months of injections, the patient was free of TB.
For the first time in history, a patient was cured of TB.
In the US, the death rate from TB fell from 50/100,000 in 1939 to 7/100,000 in 1947.

Randomized Clinical Trial (RCT)

Medical Research Council Streptomycin in Tuberculosis Trials Committee. (1948). Streptomycin treatment for pulmonary tuberculosis. British Medical Journal 2, 769-783.
One of the first double-blind clinical trials of a drug using randomization for placebo versus drug selection.

Streptomycin Controversy

Waksman becomes an international hero and never talks about Schatz except as “a graduate student who helped."
Schatz earns his PhD, leaves Rutgers in 1946 for a teaching position at Brooklyn College at $4,950/year.
The royalty on the Schatz-Waksman Patent, assigned to Rutgers University, was 200,000permonth(1940sdollars).(Anewcarcost200,000 per month (1940s dollars). (A new car cost 200,000permonth(1940sdollars).(Anewcarcost900, apartment rent was 40permonth,andtuitionatHarvardwas40 per month, and tuition at Harvard was 40permonth,andtuitionatHarvardwas420 per year).
Schatz files suit against Waksman on March 10, 1950, because Waksman made a separate private deal with Merck, which earned him up to $350,000 to date.
Schatz sues for recognition to be named co-discover and wins.

Selman Waksman

Won the Nobel Prize in 1952.

Antibiotics From Streptomyces

1999 world market for antibiotics was about $23 Billion.
About 200 different antibiotics are available.
About 8,100 different antibiotics were discovered and described as of 1999.
Over 50% were found in Streptomyces species of bacteria.

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Description

Explore the critical historical aspects and diagnostic methods of tuberculosis. This quiz will cover the impact of tuberculosis in the early 20th century, its link to raw milk, and advancements in diagnosis methods. Test your knowledge on the symptoms and treatment of Mycobacterium tuberculosis.