Anti Tuberculosis Drugs

Treatment Regimens for Active TB

Must contain 2+ drugs (isoniazid and rifampin are almost almost included)

Multidrug Resistant TB (MDR-TB)

Resistance to isoniazid + rifampin

Extensively Drug Resistant TB (XDR-TB)

Resistant to isoniazid + rifampin AND all fluroquinolones AND at least 1 injectable second line agent

What is the most common cause of TB treatment failure and drug resistant TB?

Nonadherence

Directly Observed Therapy (DOT)

Dosing in the presence of an observer, usually someone from the health department

Intermittent Dosing Schedules

Daily versus 2-3x/week (DOT combined with intermittent dosing promotes adherence and decreases risk of resistance)

Induction Phase of Drug-Sensitive TB

2-month duration, eliminates actively dividing extracellular tubercle bacilli (using isoniazid, rifampin, pyrazinamide, ethambutol)

Continuation Phase of Drug-Sensitive TB

4-month duration, eliminates intercellular bacteria persisters (using isoniazid + rifampin)

Single Agent Resistant Infections

Resistance to either isoniazid or rifampin (treatment is with the other 3 drugs), duration of treatment is 18-24 months 

MDR and XDR TB

Initial therapy may require 5-7 agents, treatment is prolonged (24+ months), uses second and third-line agents (more toxic, less effective)

What population has a higher incidence of TB?

HIV Population

What are the cornerstones of HIV treatment?

Protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs)

What does Rifampin decrease the effectiveness of?

Protease inhibitors and NNRTIs

What is critical to prevent undertreatment and emergence of resistant bacilli?

Ruling out active TB before starting treatment for latent TB

First-Line Agents of TB

Isoniazid + Rifampin + Rifampentine + Rifabutin (usually a combination of 3-4 are used to decrease risk of resistance)

Isoniazid

Primary agent for treating active + latent TB, inactivated in liver by acetylation, excreted in urine

Isoniazid Adverse Effects

Hepatoxicity, peripheral neuropathy caused by isoniazid induced B6 deficiency 

When on Isoniazid, ingesting with rifampin or rifapentine or rifabutin or pyrazinamide increases the risk of?

Hepatoxicity

If phenytoin levels increase, Isoniazid dose should?

Remain unchanged and phenytoin dose should be decreased

Most Common Adverse Effect of Rifampin

Hepatitis, discolors body fluids orange

Rifampin

Bactericidal to M. Tuberculosis, induces hepatic drug-metabolizing enzymes, including those responsible for its own inactivation causing half-life to decrease over time (best taken on an empty stomach)

What does Rifampin induce?

Cytochrome P450 isoenzymes which can hasten the metabolism of many other drugs

Rifapentine

Long-acting analogue of rifampin, same MOA/adverse effects/drug interactions, best absorbed when given with food

Rifabutin

Close chemical relative of rifampin, preferred to rifampin in patients with HIV infection, risk of uveitis

Pyrazinamide

Part of initial combination therapy for active TB caused by drug sensitive bacilli (adverse effects l/t hepatoxicity, non-gouty poly-arthralgias)

Ethambutol

Bacteriostatic, adverse effects l/t dose related optic neuritis which clears upon discontinuation of treatment and drug should be withdrawn if occurs

Second-Line Agents

Fluoroquinolones + Injectable Agents

Principle Indication of Second-Line Agents

Resistance to a first-line agent, always used in combination with first-line agents (to treat severe pulmonary TB and disseminated TB)

Bedaquiline

First unique anti-TB drug to be developed in 40+ years, works faster and better than all other anti-TB drugs

Black Box Warning of Bedaquiline

QT prolongation, risk of hepatotoxicity

Bedaquiline Administration

Under DOT + taken with food