Last edited: 7/15/2022

8. ANTIMYCOBACTERIALS
Antimycobacterials Medical Editor: Donya Moslemzadeh

OUTLINE
MECHANISM OF ACTION CLINICAL USE ADVERSE EFFECTS II) SUMMARY
RIFAMYCIN MYCOBACTERIUM TUBERCULOSIS RIFAMPIN III) REVIEW QUESTIONS
DAPSONE MYCOBACTERIUM L EPRAE PYRAZINAMIDE (PZA) IV) REFERENCES
STREPTOMYCIN MYCOBACTERIUM AVIUM ETHAMBUTOL
ISONIAZID (INH) INTRACELLULAR COMPLEX - MAC DAPSONE
PYRAZINAMIDE (PZA) ISONIAZID (INH)
ETHAMBUTOL STREPTOMYCIN

MECHANISM OF ACTION
RIFAMYCIN
MOA: Drugs in this group:
o RNA Polymerase Inhibitors o Rifampin
→ Inhibits mRNA production o Rifabutin
→ Inhibits protein production  Used in MAC infection, especially in HIV+ patients
o Proteins are integral to the structure and function of  unlike Rifampin, Rifabutin has no interactions with
the Mycobacterium the CYP450 system
→ no effects on the metabolism of HIV
treatment medications

DAPSONE
MOA:

Inhibit PABA pathway (metabolic pathway)

→ Inhibit the inversion of Para-Aminobenzoic Acid (PABA) to
Dihydrofolic acid
→ prevents normal bacterial utilization of PABA for the synthesis of folic acid

→ Inhibits nucleotides production (ex: Thymine) → inhibits Nucleic

acid synthesis

STREPTOMYCIN
● Aminoglycosides
● 2nd line treatment for TB infection
MOA:
o Bind to the 30s ribosomal subunit
→ inhibit it from interacting with RNA
→ ↓ protein synthesis

Antimycobacterials ANTIBIOTIC PHARMACOLOGY: NOTE #8. 1 of 7

 ISONIAZID (INH)
MOA: Mycobacterium Cell wall structure ( inside -out)
o In Mycobacterium cell, o Inner cell membrane → Phospholipid bilayer
→ activated by KatG ( the mycobacterial catalase- o Peptidoglycan Layer
peroxidase ) o Arabinogalactan Layer (Polysaccharide)
→ binds to NAD o Mycolic acid ( Fatty acid)
→ INH + NAD → Inhibits Enoyl Reductase o Glycolipid Layer
• (This enzyme stimulates the production of
Mycolic acid) The 2 Most integral components of the Mycobacterium
→ ↓ Mycolic acid Cell wall are :
→ Interfere with cell wall synthesis o Mycolic Acid
→ Bactericidal effect o Arabinogalactan

PYRAZINAMIDE (PZA)
MOA is Unknown
→ May inhibit the Fatty acid Synthase Enzyme
→ Inhibit Mycolic acid Synthesis

ETHAMBUTOL
MOA:
o Inhibit Arabinosyl Transferase
→ ↓ Cell wall integrity
→ Cell death
o Arabinose + Galactose
→ with Arabinosyl Transferase action turns into
→ Arabinogalactan
• Integral part of the Bacteria cell wall

2 of 7 ANTIBIOTIC PHARMACOLOGY: NOTE #8. Antimycobacterials

 CLINICAL USE
MYCOBACTERIUM TUBERCULOSIS
(1) Clinical Manifestations
● Pulmonary TB
o Lungs are the major sites of involvement
o Lesions are typically formed in the upper lobes of the
lungs
o It can spread to other organs, especially in
Immunocompromised patients
● Disseminated TB
o Brain → Meningitis, Cephalitis
o Bone → Osteomyelitis
o Adrenal Glands → Adrenal failure
o Liver → Liver failure
o Lymph nodes → Lymphadenopathy, Scrofula
 Scrofula = Tuberculous lymphadenitis in the
cervical region

(i) Latent TB
→ No active Pneumonia infection
→ Asymptomatic and non-infectious
→ Positive Tuberculin Skin Test

(ii) Active TB
→ Pulmonary Symptoms
→ Ghon Complex Figure 1. Clinical Manifestations of Mycobacterium TB.
→ Ranke Complex
→ Disseminated to other organs
● Inhalation of aerosol droplets containing M.
tuberculosis
(2) Treatment with subsequent deposition in the lungs leads to one of
four possible outcomes:
(i) Latent TB
● Monotherapy 1) Immediate clearance of the organism
o INH for 6-9 months 2) Primary disease: immediate onset of active disease
 Duration depends on how frequently it is taken 3) Latent infection
o Rifampin for 4 months 4) Reactivation disease: onset of active disease many
years following a period of latent infection

(ii) Active TB
Primary disease :
● 1 Step – 2 months
st

o RIPE regimen The tubercle bacilli establish infection in the lungs after
 Rifampin they are carried in droplets small enough to reach the
 INH alveolar space (5 to 10 microns). If the innate defense
 Pyrazinamide system of the host fails to eliminate the infection, the
 Ethambutol bacilli proliferate inside alveolar macrophages, which
may migrate away from the lungs to enter other tissue.
● 2nd Step – 4 months
o Rifampin + INH While in the lungs, macrophages produce cytokines and
● B6 Supplement chemokines that attract other phagocytic cells, including
o The common adverse effect of INH → B6 Deficiency monocytes, other alveolar macrophages, and
→ neuropathy, anemia, and increased risk of neutrophils, which eventually form a nodular
granulomatous structure called a tubercle. If the
seizures
bacterial replication is not controlled, the tubercle
● +/- Streptomycin enlarges and the bacilli enter local draining lymph nodes.
o If disseminated to other organs This leads to lymphadenopathy, a characteristic
o Better seek Infectious Disease Specialist consultation manifestation of primary TB. The lesion (called Ghon
focus) produced by the expansion of the tubercle into the
lung parenchyma and lymph node enlargement or
calcification together comprise the Ranke complex.
Bacteremia also may accompany the initial infection.

Antimycobacterials ANTIBIOTIC PHARMACOLOGY: NOTE #8. 3 of 7

 MYCOBACTERIUM LEPRAE MYCOBACTERIUM AVIUM INTRACELLULAR
COMPLEX - MAC
(3) Clinical Manifestations
= Leprosy
(5) Clinical Manifestations
● Skin lesions
o Hypopigmented skin lesions ● Pulmonary MAC
o Fibro cavity disease
● Neuropathy
o Nerve palsy ● Disseminated MAC (mostly in immunocompromised
 Thickening of the nerves → increase compression patients)
on the nerves o Liver
o Common involvement sites o Bone marrow
 Ulnar Nerve (claw hand) o Spleen
 Peroneal Nerve (foot drop)

Figure 2. Clinical Manifestations of Mycobacterium Leprae.

(4) Treatment
● Dapsone + Rifampin
● +/- Clofazimine

Figure 3. Clinical Manifestations of MAC.

(6) Treatment

● Ethambutol + Rifampin + Macrolides ( Clarithromycin,

Azithromycin)
● +/- Aminoglycosides or Fluoroquinolones
→ In severe or refractory cases

4 of 7 ANTIBIOTIC PHARMACOLOGY: NOTE #8. Antimycobacterials

 ADVERSE EFFECTS

RIFAMPIN ISONIAZID (INH)

Red-Orange discoloration of Body fluids Hepatotoxicity
o (Normal- harmless side effect)
Anion-Gap Metabolic Acidosis
False Positive Urine opiates test
o Lactic acidosis (Increase Lactate)
o Keto acidosis (increase B-
CYP450 inducer
Hydroxybutyric acid)
o Decrease the concentration and
efficacy of the drugs that are Drug-Induced Lupus SLE
metabolized via this system
o Interactions with HIV treatment SHIPP
→ Nucleoside (and nucleotide)  Sulfa drugs
reverse transcriptase inhibitors (NRTIs)  Hydralazine
→ Non-nucleoside reverse transcriptase inhibitors  INH
(NNRTIs)  Procainamide
→ Protease inhibitors (PIs)  Phenytoin
o In HIV+ → switch to Rifabutin
B6 Deficiency
Minor Minor Hepatotoxicity

PYRAZINAMIDE (PZA) Peripheral Neuropathy

 Alter the myelination of Neurons
Hepatotoxicity
Anemia
Hyperuricemia  Alter the activity of enzymes
→ competes with uric acid for elimination via the kidney inside the RBCs
→ ↓ Uric acid in the Urine and increase it in the blood  Alter the production of RBCs
→ Hyperuricemia
Reduce Seizure threshold
Gout exacerbation o Refractory to BZD
o increase the uric acid
STREPTOMYCIN
crystal formation
Nephrotoxicity
→ Monitor
ETHAMBUTOL → Cr
Optic Neuritis → BUN
→ Urine Output
→ Change in visual acuity

→ 8th Cranial Nerve

→ Vestibular dysfunction
Teratogenic

DAPSONE
Contraindicated in Myasthenia Gravis
Methemoglobinemia
o Oxidized hemoglobin
→ convert to the ferric state
→ unable to bind with O2
→ Hypoxia (cytotoxic, histotoxic)
Acute hemolysis in G6PDH deficient patients

Neutropenia

Antimycobacterials ANTIBIOTIC PHARMACOLOGY: NOTE #8. 5 of 7

 II) SUMMARY

Table 1 Summary of Antifungals Please Fill your Part TIA

Mechanisms of Action Clinical Usese Adverse Effects

● In HIV+ switch to Rifabutin

● Latent TB
o Monotherapy for 4 months
RNA Polymerase Inhibitor ● Active TB ● Red-Orange urine (normal- harmless)
→ inhibit RNA production ● False Positive opiates urine test
Rifampin → inhibit Protein production
o RIPE 2 months, Rifampin + INH 4 months
● CYP450 inducer
● Leprosy ● Minor hepatotoxicity
o Dapson + Rifampin
● MAC
o Rifampin + Ethambutol + Macrolide

● Anion-Gap Metabolic Acidosis

o Lactic acidosis
● Latent TB o Keto acidosis
Inhibits Enoyl Reductase o Monotherapy for 6-9 months ● Drug-Induced Lupus SLE
Isoniazid → inhibit Mycolic acid synthesis ● Active TB ● B6 Deficiency
o RIPE 2 months, Rifampin + INH 4 months o Peripheral Neuropathy
o Anemia
● Reduce Seizure threshold

MOA Not fully understood Active TB ● Hepatotoxicity

Pyrazinamide → May inhibit Mycolic acid synthesis o RIPE 2 months ● Hyperuricemia
● Gout exacerbation

● Active TB
Inhibit Arabinosyl Transferase o RIPE 2 months
Ethambutol → ↓Arabinogalactan Synthesis
● MAC
● Optic Neuritis
→ ↓Cell wall integrity
o Rifampin + Ethambutol + Macrolid
● Nephrotoxicity
Bind to the 30s ribosom subunit ● Ototoxicity
Streptomycin → ↓ protein synthesis ● 2nd line TB treatment, sever or refractory cases ● Teratogenic
● Contraindicated in Myasthenia Gravis

Inhibit PABA pathway Leprosy ● Methemoglobinemia

Dapsone → Inhibit Nucleic acid synthesis o Dapson + Rifampin ● Acute hemolysis in G6PDH deficient patients
● Neutropenia

6 of 7 ANTIBIOTIC PHARMACOLOGY: NOTE #8. Antimycobacterials

 III) REVIEW QUESTIONS

1) Which combination is suitable to treat MAC infection

in an HIV+ patient?
a) Ethambutol + Azithromycin + Rifampin
b) Clarithromycin + Dapsone
c) Clarithromycin + Ethambutol + Rifabutin
d) Azithromycin + INH
2) Which one is not an adverse effect of Rifampin?
a) Methemoglobinemia
b) Orange Urine
c) False Positive Opiates urine test
d) Decrease the efficacy of NNRTIs used to treat HIV
3) Which statement is true about the INH mechanism of
action?
a) Inhibits the production of Arabinogalactan, an
essential component of the mycobacterial cell wall
b) Inhibits the RNA production
c) Inhibits the protein Synthesis by binding to
Ribosome
d) Inhibits the synthesis of mycolic acid, an essential
component of the mycobacterial cell wall
4) Which multidrug regimen is used to treat Leprosy?
a) Rifampin + INH
b) Dapsone + Rifampin + Clofazimine
c) Rifampin + Ethambutol + Clarithromycin
d) Rifampin + Dapsone + INH
5) In a patient with Active TB and Gout which drug is
not recommended as part of TB treatment?
a) Rifampin
b) INH
c) Pyrazinamide
d) Ethambutol

IV) REFERENCES
● UpToDate 2022

Antimycobacterials ANTIBIOTIC PHARMACOLOGY: NOTE #8. 7 of 7