Tuberculosis Drugs and Resistance Mechanisms

• Multiple drugs that treat tuberculosis (TB) act mechanistically in different ways.
• Active TB must be treated with multiple drugs concurrently due to the rapid development of resistance.
• These drugs function as inhibitors of nucleic acid and protein synthesis.
• They also disrupt cell wall and cell membrane synthesis and inhibit membrane transport.

Mechanisms of Resistance to Mycobacterium

• Drugs are exported from the cell (streptomycin, isoniazid, ethambutol) before reaching their target.
• Anaerobic conditions lead to a dormant, nonreplicating state.
• Drugs blocking metabolic processes are ineffective during dormancy (except rifamycin and fluoroquinolone).
• Alteration of an enzyme prevents conversion of a prodrug to its active form (pyrazinamide, isoniazid).
• Alteration of the target protein structure prevents drug recognition (rifamycin, ethambutol, streptomycin, fluoroquinolone, macrolide).

Rifamycins

• Specific antibiotics include rifampin, rifabutin, and rifapentine.
• These inhibit RNA polymerase by binding to the beta subunit of the DNA-dependent RNA polymerase (bactericidal).
• Concurrent use with other drugs improves effectiveness; resistance develops rapidly when used alone.
• Used for meningococcal prophylaxis and given to household contacts of children with Haemophilus influenzae type B (HiB).
• Demonstrates variable gram-positive activity.
• Causes red discoloration of bodily fluids as a side effect.
• Rifampin has many drug interactions and decreases blood levels of many medications, while rifabutin has a lower impact.
• Rifampin strongly induces cytochrome P450 enzymes (CYP450), speeding up drug metabolism.
• May require dose adjustments or alternative drugs when used with anticoagulants, immunosuppressants, antifungals, opioids, and sedatives.

Isoniazid

• Inhibits mycolic acid synthesis, disrupting the bacterial cell wall.
• It is a prodrug converted into its active form by bacterial catalase-peroxidase (KatG).
• Diffuses into mycoplasma, where KatG activates it to the nicotinoyl radical.
• The nicotinoyl radical reacts with NAD+ to produce adducts that inhibit essential cell wall synthesis enzymes.
• The nicotinyl radical interacts with NADP+ to produce an inhibitor of nucleic acid synthesis.
• N-acetyl isoniazid metabolizes isoniazid, converting it to an inactive metabolite excreted in urine.
• Drug of choice for a positive PPD and in combination treatments for TB.
• Administer pyridoxine to prevent peripheral neuropathy.
• Contraindicated in hepatic impairment.
• Side effects include hepatotoxicity, drug-induced SLE, anion gap metabolic acidosis, and vitamin B6 deficiency.
• Monitor liver function, sputum, and culture.

Pyrazinamide

• Inhibits cell membrane synthesis and trans-translation, potentially killing mycobacteria in macrophages.
• The exact mechanism is unknown and works best in acidic pH.
• Contraindicated in hepatic impairment.
• Side effects include hyperuricemia and hepatotoxicity.
• Monitor liver function tests, sputum, and culture.

Ethambutol

• Decreases carbohydrate polymerization of the mycobacterial cell wall by blocking arabinosyltransferase.
• Contraindicated in hepatic impairment.
• A side effect is color blindness (difficulty distinguishing between red and green).
• Requires baseline and periodic (monthly) visual testing.

Aminoglycosides

• Specific antibiotics include gentamycin, amikacin, tobramycin, neomycin, and streptomycin.
• Streptomycin serves as a second-line option for Mycobacterium tuberculosis.
• They block translocation of the peptide chain and cause misreading of mRNA, leading to cell death.
• Aminoglycosides bind to the 30S ribosomal subunit at the start codon (AUG) of mRNA.
• Premature termination of translation and formation of nonfunctional ribosomal streptomycin monosomes can occur.
• Abnormal proteins disrupt cellular processes and have toxic effects (bactericidal, concentration-dependent).
• Used with penicillins to enhance penetration, beneficial since aminoglycosides act intracellularly.
• Tobramycin inhalation is used for cystic fibrosis patients with Pseudomonas infections.
• Tobramycin and gentamicin peak levels should be 4 - 10 mcg/mL and troughs 0.5 - 2 mcg/mL for serious infections.
• Primarily targets gram-negative bacteria and can synergize with vancomycin and penicillin against certain gram-positive bacteria.
• Resistance occurs through methylation of the ribosome binding site and decreased permeation due to active efflux.
• Side effects include nephrotoxicity, ototoxicity, neuromuscular blockade, and teratogenicity.

Tuberculosis

• Caused by Mycobacterium tuberculosis, which contains mycolic acids in its cell wall.
• Transmitted by airborne droplets.
• It infects macrophages in the lungs and can establish latent or active TB disease.
• Standard treatment involves a 4-drug regimen of RIPE (rifampin, isoniazid, pyrazinamide, ethambutol).
• Initial two months: all four drugs.
• Months 2-6: rifampin + isoniazid (RI).
• Total duration: 6 months.
• Multiple drugs prevent resistance by attacking TB bacteria in multiple ways.

Why use multiple drugs?

• Prevents resistance by attacking TB bacteria in multiple ways.
• Mycobacteria mutate rapidly, so multiple drugs reduce the risk of resistance.
• Each drug targets different bacterial pathways, making it harder for TB to survive.