Antimycobacterial Agents

Antimycobacterial agents represent a diverse group of compounds that have activity against mycobacterial infections, including tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis, leprosy Leprosy Leprosy, also known as Hansen's disease, is a chronic bacterial infection caused by Mycobacterium leprae complex bacteria. Symptoms primarily affect the skin and peripheral nerves, resulting in cutaneous manifestations (e.g., hypopigmented macules) and neurologic manifestations (e.g., loss of sensation). Leprosy and Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium avium complex (MAC) disease. The 1st-line agents for tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis are rifampin, isoniazid, pyrazinamide, and ethambutol. The drugs vary in their mechanisms of action: rifampin inhibits RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure synthesis, isoniazid inhibits mycolic acid synthesis, pyrazinamide acts on membrane transport and protein synthesis, and ethambutol prevents cell wall synthesis. Monotherapy is not recommended because of the increased risk of drug resistance. Multidrug treatment takes several months and requires sputum monitoring. As for leprosy Leprosy Leprosy, also known as Hansen's disease, is a chronic bacterial infection caused by Mycobacterium leprae complex bacteria. Symptoms primarily affect the skin and peripheral nerves, resulting in cutaneous manifestations (e.g., hypopigmented macules) and neurologic manifestations (e.g., loss of sensation). Leprosy, an infection due to Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium leprae, rifampin is also used, with dapsone. The lepromatous form requires a 3rd agent (clofazimine). Pulmonary infections with MAC are managed with macrolides Macrolides Macrolides and ketolides are antibiotics that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking transpeptidation. These antibiotics have a broad spectrum of antimicrobial activity but are best known for their coverage of atypical microorganisms. Macrolides and Ketolides (azithromycin), rifampin, and ethambutol.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Antimycobacterial agents represent a diverse group of compounds used against mycobacterial infections (e.g., TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis, leprosy Leprosy Leprosy, also known as Hansen's disease, is a chronic bacterial infection caused by Mycobacterium leprae complex bacteria. Symptoms primarily affect the skin and peripheral nerves, resulting in cutaneous manifestations (e.g., hypopigmented macules) and neurologic manifestations (e.g., loss of sensation). Leprosy, Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium avium complex).

Antimycobacterial agents

Table: Treatment regimens for mycobacterial infections
Bacteria Treatment regimen* Prophylaxis
Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
  • RIPE: Rifampin (RIF), Isoniazid (isoniazid (isonicotinic acid hydrazine (INH)), Pyrazinamide (PZA), Ethambutol (EMB)
  • 3- to 4-drug regimen (to reduce resistance)
Isoniazid
M. leprae
  • Dapsone + rifampin (for tuberculoid form)
  • Add clofazimine in lepromatous form
None
M. avium complex (MAC) predominant species within the complex include:
  • M. avium
  • M. intracellulare
  • M. chimaera
  • MAC pulmonary disease: macrolides Macrolides Macrolides and ketolides are antibiotics that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking transpeptidation. These antibiotics have a broad spectrum of antimicrobial activity but are best known for their coverage of atypical microorganisms. Macrolides and Ketolides (azithromycin or clarithromycin) + rifamycin (e.g., rifampin) + EMB
  • If not tolerated: 2-drug regimen
  • If cavitary disease: add parenteral aminoglycoside
Azithromycin or rifabutin
*1st-line agents

Rifampin

Description and pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is "what the body does to the drug," whereas pharmacodynamics is "what the drug does to the body." Pharmacokinetics and Pharmacodynamics

  • Most commonly used rifamycin (rifamycins also include rifabutin and rifapentine)
  • Macrocyclic antibiotic
  • Resistance if used alone
  • Ramps up cytochrome P450 (leads to ↓ bioavailability of coadministered drugs) 
  • Red-orange to orange body fluids (e.g., urine, sweat, tears, saliva)
  • Mechanism of action: inhibit DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure-dependent RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure polymerase enzyme, blocking the synthesis of mRNA
Chemical structure rifampin

Skeletal formula of rifampin

Image: “Skeletal formula of rifampin” by Vaccinationist. License: Public Domain

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: reduced by food (take on an empty stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach)
  • Distribution: lipophilic, widely distributed in all tissues and fluids (including CSF)
  • Metabolism: hepatic (caution needed in hepatic disease)
  • Elimination: mainly excreted in bile/feces, some urine (≤ 30%)

Drug–drug interactions

  • Increases cytochrome P450 (↓ levels of other drugs)
  • Interactions include: 
    • Warfarin
    • Oral or other hormonal contraceptives Hormonal contraceptives Hormonal contraceptives (HCs) contain synthetic analogs of the reproductive hormones estrogen and progesterone, which may be used either in combination or in progestin-only formulations for contraception. Hormonal Contraceptives
    • Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids
    • Cyclosporine
    • HMG-CoA reductase inhibitors ( statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins)
    • Macrolides, azole antifungals
    • Phenytoin
    • Levothyroxine
    • Sulfonylurea 
    • Antiretrovirals

Adverse effects and contraindications

  • Adverse effects:
    • Hepatic: ↑ liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests (hepatotoxicity) especially those at risk (e.g., alcoholic individuals, individuals taking other hepatotoxic drugs)
    • Rash
    • Orange/red discoloration of bodily secretions
    • Hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia, neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
    • Nephritis
    • Flu-like syndrome
  • Contraindications: 
    • Hypersensitivity or previous severe reaction to rifampin
    • Precaution in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease
    • Concurrent use with protease inhibitors (↑ hepatotoxicity)

Mechanism of resistance

  • Mutations in the rpoB gene (encodes the beta chain of mycobacterial RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure polymerase)
  • Effect of mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations: reduced drug binding

Isoniazid

Description and pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is "what the body does to the drug," whereas pharmacodynamics is "what the drug does to the body." Pharmacokinetics and Pharmacodynamics

  • Also known as isonicotinic acid hydrazide
  • Bactericidal
  • A prodrug activated by M. tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis catalase-peroxidase (encoded by KatG) → N-acetyl INH (major metabolite)
  • Prophylaxis against TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
  • Monotherapy for latent TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
  • Mechanism of action: inhibits mycolic acid synthesis (affects mycobacterial cell wall)
Chemical structure of isoniazid

Skeletal formula of isoniazid (isonicotinic acid hydrazine (INH))

Image: “Skeletal formula of isoniazid” by Fvasconcellos. License: Public Domain

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: well absorbed orally, but may be reduced or delayed by food
  • Distribution: widely distributed throughout the body
  • Metabolism: hepatic metabolism via acetylation (genetically determined)
    • 50% of Caucasians and Blacks → rapid acetylators (exhibit lower peak serum concentrations)
    • 80%–90% of Asians and those of the Alaska and Arctic regions → rapid acetylators
  • Elimination: renal (up to 96% excreted unchanged)

Drug–drug interactions

  • Inhibition of the cytochrome P (CYP) hepatic enzyme system by INH leads to drug interactions (↑ concentration of other drugs). 
  • Include (but not limited to):
    • Carbamazepine
    • Phenytoin
    • Theophylline

Adverse effects and contraindications

  • Adverse effects (“INH Injures Nerves and Hepatocytes”):
    • Hepatic: ↑ liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests (hepatotoxicity)
    • Neurologic: 
      • Peripheral neuropathy, ataxia, paresthesia (depletes vitamin B6, so supplementation is needed)
      • Headache
      • Depression and dysphoria
      • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures and psychosis
    • Hematologic: hemolytic anemia (triggered by INH in glucose-6-phosphate dehydrogenase deficiency Glucose-6-phosphate Dehydrogenase Deficiency Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a type of intravascular hemolytic anemia. The condition is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an oxidative stressor that causes damage to red blood cells, which lack sufficient NADPH to protect them from oxidative injury. Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency)
    • Immunologic: flu-like syndrome, drug-induced systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus
    • Rash
  • Contraindications: 
    • Hypersensitivity or previous severe reaction to INH
    • Precaution in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease

Mechanism of resistance

  • Mutation of inhA (protein involved in mycobacterial cell wall synthesis)
  • Mutation of KatG (down-regulated enzyme activity)

Pyrazinamide

Description and pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is "what the body does to the drug," whereas pharmacodynamics is "what the drug does to the body." Pharmacokinetics and Pharmacodynamics

  • Synthetic pyrazine analogue of nicotinamide
  • Metabolized to pyrazinoic acid (POA), the active form of pyrazinamide through the action of M. tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis pyrazinamidase 
  • ↑ Activity in acidic pH
  • Mechanism of action: 
    • Exact mechanism is uncertain.
    • Likely to involve POA (initially excreted from the cell), which is then protonated
    • Protonated POA diffuses back into the cell, acidifying the intracellular environment and inhibiting membrane transport and protein synthesis.
Chemical structure of pyrazinamide antimycobacterial agents

Structure of pyrazinamide

Image: “Structure of pyrazinamide” by Fvasconcellos. License: Public Domain

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: rapid absorption, with oral bioavailability of approximately 90%
  • Distribution: widely distributed in tissues and fluids, including CSF
  • Metabolism: hepatic metabolism to active and inactive metabolites
  • Elimination: renally excreted; metabolites accumulate in kidney dysfunction (requires dose adjustment)

Drug–drug interactions

  • Rifampin: ↑ risk of hepatotoxicity (can be fatal)
  • Cyclosporine: ↓ serum concentrations of cyclosporine

Adverse effects and contraindications

  • Adverse effects:
    • Hepatic: ↑ liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests (hepatotoxicity)
    • Hyperuricemia (metabolite of pyrazinamide inhibits uric acid elimination)
    • Nongouty polyarthralgia
    • GI upset
    • Thrombocytopenia, sideroblastic anemia Sideroblastic anemia Sideroblastic anemias are a heterogeneous group of bone marrow disorders characterized by abnormal iron accumulation in the mitochondria of erythroid precursors. The accumulated iron appears as granules in a ringlike distribution around the nucleus, giving rise to the characteristic morphological feature of a ring sideroblast. Sideroblastic Anemia
    • Rash, photosensitivity
  • Contraindications:
    • Hypersensitivity to pyrazinamide
    • Acute gout Gout Gout is a heterogeneous metabolic disease associated with elevated serum uric acid levels (> 6.8 mg/dL) and abnormal deposits of monosodium urate in tissues. The condition is often familial and is initially characterized by painful, recurring, and usually monoarticular acute arthritis, or "gout flare," followed later by chronic deforming arthritis. Gout
    • Severe hepatic damage
    • Not safe in pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-HCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care

Mechanism of resistance

  • Mutation of pncA (encodes pyrazinamidase) → M. tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis produces pyrazinamidase with reduced affinity to pyrazinamide.
  • Effect: ↓ conversion to POA → no effect on cell wall synthesis

Ethambutol

Description and pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is "what the body does to the drug," whereas pharmacodynamics is "what the drug does to the body." Pharmacokinetics and Pharmacodynamics

  • Bacteriostatic
  • Activity against different species of Mycobacteria Mycobacteria Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium, but no effect on other genuses
  • Mechanism of action:
    • Inhibits arabinosyltransferase, an enzyme encoded by embB genes
    • Arabinosyltransferase polymerizes arabinose (required in arabinogalactan synthesis in the cell wall)
    • Effect: disruption of mycobacterial cell wall synthesis
Chemical structure of ethambutanol

Structure of ethambutol

Image: “Structure of ethambutol” by Fvasconcellos. License: Public Domain

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: approximately 80% absorbed by oral administration 
  • Distribution: widely in most tissues and fluids, but not CSF
  • Metabolism: partial hepatic metabolism 
  • Elimination: most (up to 80%) excreted renally

Drug–drug interactions

Aluminum hydroxide ↓ drug absorption

Adverse effects and contraindications

  • Adverse effects:
    • Optic neuropathy (“Eye-thambutol”) often noted as:
      • A change in visual acuity
      • Red-green color blindness
    • Hepatotoxicity
    • GI (nausea, vomiting, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain)
    • Hematologic ( neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia)
    • Headache, dizziness, confusion
    • Peripheral neuritis
  • Contraindications: 
    • Hypersensitivity to ethambutol 
    • Optic neuritis

Mechanism of resistance

  • Mutations involving the embB genes 
  • Effect: ↑ production of arabinosyltransferase causes varying degrees of resistance.

Other Anti-TB Agents

Other agents are used depending on the underlying conditions and presence of multidrug-resistant Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium.

  • Aminoglycosides Aminoglycosides Aminoglycosides are a class of antibiotics including gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin. The class binds the 30S ribosomal subunit to inhibit bacterial protein synthesis. Unlike other medications with a similar mechanism of action, aminoglycosides are bactericidal. Aminoglycosides:
    • Streptomycin and amikacin
    • Bactericidal 
    • Mechanism: inhibits translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation by binding the 30S ribosomal subunit
    • Adverse effects:
      • Nephrotoxicity → accumulation of aminoglycosides in the renal cortex
      • Ototoxicity (can be irreversible; in pregnant women, can cause permanent deafness in the child)
      • Neuromuscular blockade (rare)
  • Bedaquiline:
    • Part of the BPaL (bedaquiline + pretomanid + linezolid) regimen (pulmonary extensively drug-resistant TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis [XDR- TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis] or multidrug-resistant TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis [MDR- TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis]): bedaquiline + pretomanid + linezolid
    • Classified as a diarylquinoline  
    • Bactericidal 
    • Mechanism: inhibits mycobacterial ATP synthase ATP synthase Multisubunit enzyme complexes that synthesize adenosine triphosphate from energy sources such as ions traveling through channels. Electron Transport Chain (ETC) 
    • Adverse effect: QT prolongation
  • Bicyclic nitroimidazoles Nitroimidazoles Nitroimidazoles are prodrugs composed of an imidazole ring with an attached nitro group. Nitroimidazoles are reduced within susceptible microorganisms, leading to free radical formation and disruption of DNA integrity. Nitroimidazoles:
    • Pretomanid: 
      • Part of the BPaL regimen (pulmonary XDR- TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis or MDR- TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis)
      • Mechanism: inhibition of cell wall synthesis (blocks the oxidation of hydroxymycolate to ketomycolate)
    • Delamanid: inhibits mycolic acid synthesis (for MDR- TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis approved in Europe, not yet in the Uninted States)
  • Clofazimine:
    • For drug-resistant TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
    • Requires approval from FDA for anti- TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis use 
    • Available in areas where clofazimine is used for leprosy Leprosy Leprosy, also known as Hansen's disease, is a chronic bacterial infection caused by Mycobacterium leprae complex bacteria. Symptoms primarily affect the skin and peripheral nerves, resulting in cutaneous manifestations (e.g., hypopigmented macules) and neurologic manifestations (e.g., loss of sensation). Leprosy
    • Adverse effects: GI problems
  • Cycloserine: 
    • For drug-resistant TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
    • Mechanism: blocks peptidoglycan production, thus disrupting mycobacterial cell wall synthesis
    • Adverse effects: neuropsychiatric symptoms
  • Ethionamide:
    • For drug-resistant TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
    • Structural analog of INH
    • A prodrug
    • Mechanism: inhibits mycolic acid synthesis (similar to INH)
    • Adverse effects: GI irritation, peptic ulcer Peptic ulcer Peptic ulcer disease (PUD) refers to the full-thickness ulcerations of duodenal or gastric mucosa. The ulcerations form when exposure to acid and digestive enzymes overcomes mucosal defense mechanisms. The most common etiologies include Helicobacter pylori (H. pylori) infection and prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs). Peptic Ulcer Disease
  • Fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones:
    • Levofloxacin and moxifloxacin (greater in vitro activity than ciprofloxacin)
    • Bactericidal 
    • Mechanism: inhibit bacterial DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure gyrase and disrupt DNA replication DNA replication The entire DNA of a cell is replicated during the S (synthesis) phase of the cell cycle. The principle of replication is based on complementary nucleotide base pairing: adenine forms hydrogen bonds with thymine (or uracil in RNA) and guanine forms hydrogen bonds with cytosine. DNA Replication
  • Oxazolidinones Oxazolidinones The oxazolidinones (linezolid and tedizolid) are bacterial protein synthesis inhibitors. Their unique binding site on the 23S ribosomal RNA of the 50S ribosome gives them zero cross-resistance with other antibiotics. Oxazolidinones
    • Part of the BPaL regimen (pulmonary XDR- TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis or MDR- TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis)
    • Mechanism:
      • Bind to the bacterial 23S rRNA of the 50S subunit 
      • Blocks the formation of the 70S initiation complex → prevents translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation
    • Adverse effects: bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow suppression, neuropathy, GI symptoms, and/or retinitis
  • Para-aminosalicylic acid (PAS):
    • Bacteriostatic
    • Efficacy against TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis limited
    • Mechanism: interrupts folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 synthesis
    • Adverse effects:
      • GI side effects
      • With ethionamide → hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism
  • Rifabutin:
    • A rifamycin, like rifampin
    • Less drug–drug interactions than rifampin, as it is a less potent inducer of the cytochrome P450 enzyme system
    • Preferred in HIV
  • Additional information: kanamycin (an aminoglycoside) and capreomycin (a cyclic peptide):
    • No longer recommended for anti- TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis treatment 
    • Both drugs were associated with worse outcomes.
Anti-tb agents and mechanisms

Anti- TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis agents and mechanisms
Left:
Thioamides (ethionamide) inhibit cell wall synthesis (affect mycolic acid); mechanism similar to isoniazid.
Bicyclic nitroimidazoles Nitroimidazoles Nitroimidazoles are prodrugs composed of an imidazole ring with an attached nitro group. Nitroimidazoles are reduced within susceptible microorganisms, leading to free radical formation and disruption of DNA integrity. Nitroimidazoles inhibit mycolic acid synthesis.
Ethambutol inhibits cell wall synthesis (affects arabinogalactan).
Cycloserine inhibits cell wall synthesis.
Pyrazinamide affects the plasma membrane transport.
Diarylquinoline (bedaquiline) inhibits ATP synthase ATP synthase Multisubunit enzyme complexes that synthesize adenosine triphosphate from energy sources such as ions traveling through channels. Electron Transport Chain (ETC).
Right:
Para-aminosalicylic acid (PAS) interrupts DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure precursors by disrupting folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 synthesis.
Fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones inhibit DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure gyrase.
Cyclic peptides (capreomycin) inhibit protein synthesis (no longer recommended).
Aminoglycosides Aminoglycosides Aminoglycosides are a class of antibiotics including gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin. The class binds the 30S ribosomal subunit to inhibit bacterial protein synthesis. Unlike other medications with a similar mechanism of action, aminoglycosides are bactericidal. Aminoglycosides inhibit protein synthesis by blocking translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation.

Image: “Mechanisms of action of current TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis drugs” by NIAID. License: CC BY 2.0

Agents against Mycobacterium leprae and Mycobacterium avium Complex

Agents against Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium leprae

  • 1st-line regimen:
    • Dapsone + rifampin for 12 months for tuberculoid leprosy Leprosy Leprosy, also known as Hansen's disease, is a chronic bacterial infection caused by Mycobacterium leprae complex bacteria. Symptoms primarily affect the skin and peripheral nerves, resulting in cutaneous manifestations (e.g., hypopigmented macules) and neurologic manifestations (e.g., loss of sensation). Leprosy
    • Dapsone + rifampin + clofazimine for 24 months for lepromatous leprosy Leprosy Leprosy, also known as Hansen's disease, is a chronic bacterial infection caused by Mycobacterium leprae complex bacteria. Symptoms primarily affect the skin and peripheral nerves, resulting in cutaneous manifestations (e.g., hypopigmented macules) and neurologic manifestations (e.g., loss of sensation). Leprosy
  • Medications:
    • Dapsone: 
      • Agent with antibacterial, antifungal and antiprotozoal activity
      • Mechanism of action: inhibits bacterial dihydropteroate synthase in the folate Folate Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Folate and Vitamin B12 pathway → ↓ synthesis of nucleic acid
      • Adverse effects: hemolysis (especially at doses > 200 mg/day), methemoglobinemia Methemoglobinemia Methemoglobinemia is a condition characterized by elevated levels of methemoglobin in the blood. Methemoglobin is the oxidized form of hemoglobin, where the heme iron has been converted from the usual ferrous (Fe2+) to the ferric (Fe3+) form. The Fe3+ form of iron cannot bind O2, and, thus, leads to tissue hypoxia. Methemoglobinemia
    • Rifampin (see anti- TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis drugs)
    • Clofazimine (see anti- TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis drugs)

Agents against Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium avium complex

  • For MAC pulmonary disease, use a 3-drug combination regimen:
    • Azithromycin: 
      • Macrolide (inhibits bacterial protein synthesis by binding reversibly to the 50S ribosomal subunit)
      • Adverse effects: hepatotoxicity, QT prolongation
    • Rifampin
    • Ethambutol
  • For cavitary disease, add parenteral streptomycin or amikacin (aminoglycosides) as a 4th agent (for the first 8–12 weeks).

References

  1. Drew, R., Sterling, T. (2021). Antituberculous drugs: an overview. UpToDate. Retrieved August 21, 2021, from https://www.uptodate.com/contents/antituberculous-drugs-an-overview
  2. Drew, R. (2021). Rifamycins (rifampin, rifabutin, rifapentine). UpToDate. Retrieved August 22, 2021, from https://www.uptodate.com/contents/rifamycins-rifampin-rifabutin-rifapentine
  3. Drew, R. (2021). Isoniazid: an overview. UpToDate. Retrieved August 22, 2021, from https://www.uptodate.com/contents/isoniazid-an-overview
  4. Drew, R. (2021). Ethambutol: an overview. UpToDate. Retrieved August 22, 2021, from https://www.uptodate.com/contents/ethambutol-an-overview
  5. Drew, R. (2021). Pyrazinamide: an overview. UpToDate. Retrieved August 22, 2021, from https://www.uptodate.com/contents/pyrazinamide-an-overview
  6. Gumbo, T. (2017). Chemotherapy of tuberculosis, mycobacterium avium complex disease, and leprosy. Chapter 60 of Brunton, L.L., Hilal-Dandan, R., Knollmann, B.C. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=172485532
  7. National Institute of Diabetes and Digestive and Kidney Diseases. (2018). Rifampin LiverTox: clinical and Research Information on drug-induced liver injury. https://www.ncbi.nlm.nih.gov/books/NBK548314/
  8. Schluger, N. (2021). Epidemiology and molecular mechanisms of drug-resistant tuberculosis. UpToDate. Retrieved August 22, 2021, from https://www.uptodate.com/contents/epidemiology-and-molecular-mechanisms-of-drug-resistant-tuberculosis
  9. Soeroto, A.,  Darmawan, G., Supriyadi, R., Bhaskara, P., Santoso, P., Alisjahbana, B., Parwati, I. (2019). Comparison of serum potassium, magnesium, and calcium levels between kanamycin and capreomycin-based regimen-treated multidrug-resistant tuberculosis patients in Bandung (CEASE MDR-TB): a retrospective cohort study. International Journal of Microbiology 2019, Article ID 5065847. https://doi.org/10.1155/2019/5065847

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