Chapter 22: Drug Therapy for Tuberculosis and Mycobacterium Avium Complex Disease

What does the WHO say about TB?

TB is one of the top 10 causes of death globally, occurring in many areas around the world. It is estimated that one-third of the world is infected with 2 million dying annually.

Describe the Etiology of Tuberculosis

Mycobacterium tuberculosis (Tubercle bacillus) is the causative agent of Tuberculosis. These bacilli that multiply slowly and can stay dormant in the body for years.

Describe the Etiology of Mycobacterium Avium Complex Disease

Mycobacterium avium and Mycobacterium intracellulare are the causative agents for Mycobacterium Avium Complex Disease. They closely resemble each other and are thus grouped as Mycobacterium avium complex (MAC). MAC is found in water, soil, and animals. Disease is rarely caused in those who are immunocompetentl.

What are the four phases in the initiation and progression of Tuberculosis?

1. Transmission

2. Primary Infection

3. Latent TB Infection

4. Active TB

What are the symptoms of TB?

• Low-grade temperature

• Weight loss

• Cough (Productive or non-productive)

• Fatigue

• Night sweats

• Hemoptysis

• Dyspnea & Orthopnea (In advanced stages)

What are the symptoms of MAC?

• Productive cough

• Weight loss

• Hemoptysis

• Fever

Describe Transmission

The first phase of the initiation and progression of TB, transmission occurs when an in unaffected individual inhales airborne droplets exhaled by an infected person. Factors affecting transmission includes the number of bacteria expelled by the infected person and the closeness and duration of contact between the two individuals.

Describe Primary Infection

The second phase of the initiation and progression of TB, some people develop mild, pneumonia-like illness in this phase 2-10 weeks following exposure. Eventually, however, macrophages encapsulate the bacilli in calcified tubercles that they are not able to eliminate. The tubercles hold a mass of dormant TB bacilli in the enter and are found in the upper lobes of the lung. They are visible on a chest radiograph.

Describe Latent TB Infection

The third phase of the initiation and progression of TB, by this point the immune system has stopped growth of the bacilli. The remaining bacteria become inactive and dormant if the latent infection is not treated. These dormant bacteria are able to reactivate and cause Active TB at any point during the remainder of the patient’s life, but activation usually occurs during the weakening of the immune system. Those with Latent TB Infection are asymptomatic and cannot spread TB.

Describe Active TB

The fourth phase of the initiation and progression of TB, some people may jump to this stage when they initially become infected. However, those with latent TB develop active TB during further exposure to TB or when their immune system has been compromised. This infection can spread to other part of the body as well, not just the lungs, in what is known as disseminated TB. Usually when active TB occurs, the microbe is increasingly resistant to medications.

New and reactivated TB infections are more likely in which population?

Those with a diminished immune system.

What are some key causes of the development of drug-resistant M. tuberculosis?

• ATB Noncompliance

• Prescription of wrong treatment

• Lack of appropriate resources to properly treat

• Poor quality drugs

• Development of new strains in those who are immunocompromised

Describe MDR-TB

A TB that is resistant to isoniazid (INH) and rifampin (RIF). It is also associated with rapid progression and a high death rate. This infection is very expensive to treat.

Describe Extensively Drug-Resistant Tuberculosis (XDR-TB)

A TB that is even more resistant than MDR-TB. There are essentially no effective drugs for treatment of this microbe.

Describe the purpose of drug therapy in the treatment of latent TB

Drug therapy for latent TB is centered on prevention of the infection from progressing to active TB.

Describe the purpose of drug therapy in the treatment of active TB

Drug therapy for active TB is centered on preventing the disease from worsening and preventing spread of the disease to those who are not infected.

The use of multiple drugs to treat TB (Latent and active) are usually necessary, why?

To prevent to development of resistance.

When is the use of second-line medications to treat TB necessary?

• Patient unable to tolerate first-line medications

• Microbe resistant to first-line medications

What medications are used to treat latent TB?

• Isoniazid (INH)

• Rifampin (RIF)

• Rifapentine

What are the first-line medications are used to treat active TB?

• Isoniazid (INH)

• Rifampin (RIF)

• Rifamycins

• Ethambutol

• Pyrazinamide

Why is the usage of multiple medications necessary to treat TB?

This prevents the emergency of drug-resistant TB.

What are the goals of therapy for TB (Active and latent)?

• Cure latent or active infection

• Avoid the development of resistant TB

• Minimize TB transmission

What are the goals of therapy for active TB?

• Decrease signs and symptoms

• Render patient non-infectious

• Ensure drug therapy compliance

What are the results of adequate drug therapy with regards to TB?

Improvement in 2-3 weeks such as:

• Decreased fever and cough

• Weight gain

• Improved well-being

Describe the timeline for the treatment of TB

Treatment usually lasts either 6 months or 3 months following a negative sputum culture for AFB. Should a sputum culture remain positive after the 6 month mark, the patient may have a drug-resistant microbe.

Describe treatment for MDR-TB

Treatment usually lasts 20-26 months and can include 4-6 medications.

What is the most commonly used anti-TB drug?

Isoniazid (INH)

Describe Isoniazid Pharmacokinetics

Able to cross the BBB.

Describe the Mechanism of Action of Isoniazid

Selective inhibition of mycobacterium bacterial cell wall formation. Able to target both active and latent TB.

Describe Isoniazid Uses

• May be used alone or with other drugs in treating latent TB (Treatment of choice for latent TB)

• Always used in combination with other drugs to treat active TB

A black box warning for Isoniazid exists, why?

This medication has the possibility of causing fatal hepatitis during or after therapy. Monitor liver function tests including AST and ALT. Ensure the patient consumes no alcohol while taking this medication and monitor liver enzymes prior to starting treatment.

Older adults are more at risk for what when administered Isoniazid?

Hepatotoxicity/Peripheral Neuropathy

Discuss special precautions when administering Isoniazid

Foods and antacids slows the absorption of this medication.

Patients taking Isoniazid may also take Vitamin B6 (Pyridoxine), why?

A common side effect of this medication is leg numbness and tingling. Vitamin B6 can prevent this.

What is the rifamycin prototype?

Rifampin (RIF)

Unless resistance exists, what is the most effective drug regimen?

Isoniazid and Rifampin which are synergistic together.

Describe Rifampin Pharmacokinetics

Rifampin reaches highest concentration in the liver, lungs, gallbladder, and kidneys. It is also able to cross the BBB. Metabolism occurs in the liver and excretion occurs mainly via bile but in small amounts in urine as well. Monitor liver enzymes.

Describe the Mechanism of Action of Rifampin

Bactericidal for TB microbes via inhibition of RNA synthesis leading to synthesis of defective and nonfunctional proteins.

Describe Rifampin Usage

• Can be used alone for latent TB

• Used in combination with other anti-TB drugs for active TB

• Treatment of MAC

• Treatment for leprosy

• Treatment for prosthetic valve endocarditis

What is a harmless effect of Rifampin that the patient may be initially anxious about?

A harmless red/orange coloring of the tears, urine, sweat, and other body fluids.

What can prolonged usage of Rifampin lead to?

Superinfections (Ex. C. diff)

Rifampin decreases the effect of what?

• Oral contraceptives

• Warfarin (Monitor PT and INR)

What considerations should you make regarding the administration of Rifampin?

Take the medication on an empty stomach and ensure the patient does not consume alcohol.

Describe Rifapentine (Prifitin)

A Rifamycin that is a first-line medication for the treatment of TB and can be used with Isoniazid. Monitor patients on this medication for hyperuricemia and reassure them that orange discoloration of body fluids is normal.

Describe Rifabutin (Mycobutin)

A Rifamycin that is a first-line medication for the treatment of TB and can also be used to treat MAC in HIV patients. Possible side effects of this medication is G.I. upset and uveitis. Red-orange discoloration of body fluids is normal.

Describe Uveitis

A possible side effect of Rifabutin in which inflammation and pain in the eye can occur along with impaired vision.

What are some Adjuvant 1st Line Anti-TB Medications?

• Pyrazinamide

• Ethambutol (Myambutol)

Describe Pyrazinamide

An adjuvant 1st line anti-TB medication used in a multi-drug anti-TB regimen. It is bactericidal, however, mechanism of action is unknown. Possible side effects include G.I. upset and gout. This medication is contraindicated in the event of preexisting liver impairment.

Describe Ethambutol (Myambutol)

An adjuvant 1st-line anti-TB medication that can be used in a 4-drug regimen against active TB. It is tuberculostatic via the inhibition of RNA synthesis, interfering with protein synthesis. Assess the patient for visual acuity and red/green discrimination as this medication can cause optic neuritis.

Describe Optic Neuritis

A possible side effect of Ethambutol in which the optic nerve becomes inflamed.

In what situations would second-line TB drugs be used?

• TB strains resistant to first-line medications

• TB patient cannot tolerate first-line medications

• MDR-TB and XDR-TB

Describe how second-line drugs for TB compare to first-line drugs

Second-line drugs are used in combination with first-line medications, but differ in several ways:

• Less effective

• More frequent and more severe adverse effects

• May be more expensive

Describe the medication regimen for the treatment of MAC

The macrolides azithromycin and clarithromycin are the main medications used in the treatment of MAC, with ethambutol (Preferable) or rifabutin also being used in addition. A third drug may be used in the severely immune compromised, being rifabutin or fluoroquinolone.

Strategies to increase adherence to antitubercular drug regimens

• Short-course regiments, intermittent drug administration, and directly observed therapy (DOT)

• Educating patients, family, and patient contacts

• Support services and resources

• Individualizing treatment regimens to increase patient convenience

• Promotion of communication and continuity of care