TB drugs Miller

MDR TB

Resistant to two first line antibiotics

XDR TB

Resistant to some first and some second line antibiotics

Steps of MTB pathogenesis

TB droplets are inhaled and travel deep into the lungs

The bacterial cells are engulfed by macrophages through phagocytosis

The bacteria prevents lysosomes from fusing with the phagosome (prevent immune response)

Infected cells migrate and spread through the lymphatic system

The adaptive immune response matures after 2-3 weeks and tries to wall of the infection forming granulomas

In most immunocompetent patients these granulomas contain dormant bacteria, but reactivation can occur

Result of TB reactivation

Liquefication of granulomas, uncontrolled multiplication, allow disease spread

Why are TB infections difficult to treat

1. Slow growing, doubling time in 24 hours

2. Dormant and semi-dormant cells complicate treatment, dormant bacteria are resistant to nearly all antibiotics

3. Antibiotics work best on rapidly dividing cells, so effects on mycobacteria are also slower

4. Duration of therapy is months

5. Susceptibility tests can take weeks

6. Drug Resistance

7. Drug interactions

Methods of Drug resistance

Unique Cell wall structure (High lipid content, drug cannot penetrate)

Efflux pumps (drug is exported from cell)

Dormancy (drugs that influence metabolic processes do not work)

Mutation (Prevents drug recognition)

Bacterial cell wall characteristics

Provides semi-permeable barrier

Protects from changes in osmotic pressures

Prevents digestion from host enzymes

Keeps shape of bacterium

Mycobacterium Cell wall structure

Consists of peptidoglycan, arabinogalactan, and mycolic acids. Peptidoglycan provides structural support, arabinogalactan links peptidoglycan to mycolic acids, and mycolic acids form a thick, waxy, lipid-rich outer layer. This waxy layer makes mycobacteria resistant to drying and contributes to their characteristic acid-fast staining properties.

What drugs are used as first line treatments for TB disease

Rifampin

Isoniazid

Pyrazinamide

Ethambutol

Isoniazid (INH) Characteristics

Bactericidal against replicating M. TB

Bacteriostatic against dormant M. TB

Monotherapy is used for latent infections

Prodrug

Adverse Effects of Isoniazid

Hepatotoxicity - monitor LFTs, stop if hepatitis symptoms, limit alcohol

Peripheral neuropathy - administer B6 (pyridoxine) as prevention

MOA of Isoniazid

Halts Mycolic acid synthesis - Isoniazid is activated by KatG in mycoplasma and forms a nicotinoyl radical. The radical reacts with NAD+ to produce adducts. The adducts inhibit essential enzymes important for mycolic acid synthesis.

Halts nucleic acid synthesis - Isoniazid is activated by KatG in mycoplasma and forms a nicotinoyl radical. The radical reacts with NADP+ to produce an inhibitor of nucleic acid synthesis

Isoniazid metabolite

The prodrug is metabolized in humans by NAT2 isoforms to its principle metabolite N-acetyl isoniazid which is excreted by the kidneys. Further metabolism can produce toxic metabolites that act as acylating agents contributing to hepatotoxicity.

NAT2 Polymorphism

Polymorphism can lead to fast and slow acetylators.

Reach Cmax both in one hour

Slow acetylators

Reach a higher Cplasm and have a longer t1/2

More risk for adverse effects of INH

Fast Acetylators

Diminished response to standard dose of INH

Greater risk of bioactivation of arylamine/hydrazine carcinogens by NAT2

Rifamycin characteristics

Orally active

Broad spectrum

Highly efficient at treating TB

Excreted in bodily fluids (can change to color to red)

May induce CYP3A4 and CYP2C

Potentially hepatotoxic

Hypersensitivity reported in ~20% of patients

MOA of rifamycin’s

Rifampin binds to the DNA-dependent RNA polymerase to form a stable drug-enzyme complex. Inhibits RNA polymerase, thereby stopping transcription of DNA to mRNA. RNA Synthesis stops, halting protein synthesis.

Pharmacokinetic properties of Rifabutin

Cmax: 0.2-0.6

T1/2: 32-67 hours

CYP3A4 induction: weak

Pharmacokinetic properties of Rifampin

Cmax: 8-20

T1/2: 2-5 hours

CYP3A4 induction: Pronounced

Pharmacokinetic properties of Rifapentine

Cmax: 5-6

T1/2: 14-18 hours

CYP3A4 induction: Moderate

Characteristics of Pyrazinamide

Biostere of nicotinamide

Bactericidal against M. Tuberculosis

Resistance develops rapidly, use in combination therapy

In vivo active at pH 5.5 not 7

Potential for hepatotoxicity

Prodrug

MOA of pyrazinamide

MTB produces enzyme nicotinamidase which deaminates pyrazinamide to pyrazinoic acid (HPOA). The HPOA is then transported out of the cell by an efflux pump. The mechanism of killing is unclear. Potentially has to do with inhibition of fatty acid synthase type 1 that interferes with mycolic acid synthesis. Potentially reduces intracellular pH. Disruption of membranes transport by HPOA.

Characteristics of Ethambutol

Water soluble, heat stable, only active against mycobacteria.

Used in combination with RIP to prevent resistance

MOA of ethambutol

Inhibits arabinosyl transferases that are involved in the synthesis of the arabinogalactan layer of the mycobacterium wall

Side Effects of Ethambutol

Optic Neuritis - decreased visual acuity and red/green color discrimination

Generally resolves after drug discontinuation

What drugs are used to treat MDR

BPaL

Bedquiline characteristics

Cationic amphiphilic drug (water + fat loving)

High accumulation in tissues

MOA of Bedquiline

Targets ATP synthase, impacting energy metabolism `

Metabolism of Bedquiline

By CYP3A4 to M2

Resistance to Bedquiline

Mutations to the target site

Efflux pumps

Side effects of Bedquiline

QTC prolongation - monitor ECG

Use with caution in patients with reduced kidney function

Chest pain, musculoskeletal pain, increased liver enzymes

Pretomanid characteristics

Used in MDR and XDR TB

A bicyclic nitroimidazole

Prodrug

MOA of pretomanid

Activated in the mycobacteria by a nitro reductase enzyme to create reactive metabolites that inhibit mycolic acid and protein synthesis. Cell respiration is also impaired in non-replicating mycobacteria.

Pretomanid Metabolism

By 3A4

Side effects of Pretomanid

Peripheral Neuropathy

Acne

Skin rashes

LFT increase

Low sugar

Nausea

Linezolid characteristics

Used for MDR with BP

Oxazolidinone ring

MOA of linezolid

Inhibits protein synthesis

Adverse effects of Linezolid

Bone marrow suppression, peripheral neuropathy during prolonged exposure, serotonin syndrome

Serotonin syndrome and linezolid

Linezolid inhibits MAO so concurrent use with SSRIs should be avoided

Tedizolid

Lacks MAO inhibition or serotonin toxicity of linezolid

What drugs are first line for TB

RIPE

BPaL (for MDR)

What drugs are second line for TB

Aminoglycosides, FQs, Macrolides

Streptomycin

Suppresses mycobacterial infections, but does not eradicate infection. Does not penetrate human cells.

AEs of streptomycin

Neurotoxicity in patients with renal dysfunction

Mainly auditory and vestibular effects

Aminoglycoside Drug Examples

Streptomycin, Kanamycin, amikacin

Aminoglycoside Characteristics

Broad spectrum activity

Bactericidal

Water soluble

Not significantly absorbed in GI tract

Excreted in active form at high concentrations

Wide distribution in body

Low protein binding

Aminoglycoside toxicities

Ototoxicity to function of the eight cranial nerve (hearing loss, vertigo)

Kidney tubular necrosis leading to reduced GFR

Effects of aminoglycosides on protein synthesis

They bind to the 30S subunit and interfere with initiation of protein synthesis by fixing the ribosomal complex to the start codon.

They also cause misreading of mRNA leading to premature termination of translation and incompletely synthesized proteins

Cause incorporation of incorrect amino acids resulting in abnormal or nonfunctional proteins

MOA of fluoroquinolones

Inhibit the cutting and closing activity of DNA gyrase. At higher concentration they block decatenating activity of topoisomerase IV. DNA cannot then be properly stored, replicated, repaired, and transcribed

Characteristics of FQs

Rapidly and nearly completely absorbed through oral administration

Broad spectrum

Black box warning for tendon rupture

Chelation with polyvalent metals - do not administer with antacids or dairy

Macrolides MOA

Inhibit bacterial protein synthesis by binding to the 50S subunit

Macrolides interaction

Common. Competes for P-450 liver enzyme. Can result in longer drug half-lives and enhanced toxicity by increasing the effective doses of other drugs