Management of Tuberculosis: Therapeutic Approach

Pulmonary tuberculosis (Tuberculosis of lungs) or Extra-pulmonary tuberculosis (Tuberculosis of organs other than lungs) in humans is caused by Mycobacterium tuberculosis, a human tubercle bacillus. Mycobacterium tuberculosis is an obligate anaerobic bacterium, whose natural reservoir is human beings. Mycobacterium tuberculosis (MTB) is non-motile and does not produce spores. The generation time of MTB is 15 to 20 hours, so it is also called slow growing bacterium.

Tuberculosis (TB) of any type remains a challenging clinical problem and important public health issue the world over. In the recent past the World Health Organization (WHO) has documented an annual incidence of 9.27 million new cases of TB with a prevalence of 13.7 million cases. Majority of TB cases exist in Africa and South East Asia. The annual incidence rate in Africa and South East Asia has been reported as 356 and 182 cases per 100,000 population respectively that is much higher than the global incidence rate.

The ‘gold standard’ in the diagnosis of TB has been the detection of Mycobacterium tuberculosis in the sputum smear or in the pathological lesions (by histopathological methods). The rapid diagnosis of TB is fundamental to clinical outcome. On general physical examination careful attention should be given to the presence of lymphadenopathy (swollen/enlarged lymphnodes), draining sinuses, non-healing ulcers, spinal or joint lesions etc.

Extensive research has been going on in the field of management of TB through anti-tubercular treatment (ATT) ever since the discovery of rifampicin in 1960s. The major objectives of research in anti-tubercular treatment (ATT) include the shortening of duration of therapy, preventing the emergency of drug resistance, avoiding toxicity and shortening the period of infectivity. Direct Observation Therapy-Short Course (DOTS) is the most effective strategy propagated for the management of tuberculosis. Several new drugs and non-pharmacological therapeutic modalities are under extensive study for the effective management of tuberculosis.

A)  Pharmacological Approach to Management of TB:

Pharmacological drugs can be classified as

Ø  Drugs susceptible for MTB.

Ø  Drugs susceptible for conventional ‘drug-resistant bacilli’, which include the followings:

·         Re-purposed drugs (e.g. Fluoroquinolones)

·         New dosages of already available drugs (e.g. Rifampicin rifamycin or high dose isoniazid)

·         New drugs (e.g. Bedaquiline for ‘multi drug resistant-TB).

B)  Preventive Approach to Management of TB:

Ø  Vaccination: The use of BCG vaccination is recommended. Recombinant BCGs are also under clinical trials.

Ø  Chemoprophylaxis for Latent-TB: Chemoprophylaxis is recommended for new born babies born to ‘sputum smear positive’ mothers. Chemoprophylaxis should also be recommended for the cases having ‘Latent-TB’. Interferon gamma release assay test (IGRAs) and Mantoux Test (a Skin Test) are useful tests for establishing a diagnosis of Latent-TB. However, these tests do not necessarily indicate the presence of active tuberculosis and requirement of ATT.

C)  Non-pharmacological Approach to Management of TB:

Ø  Non-pharmacological advances are based on immunomodulation and immunotherapy. Use of protective cytokines, anti-cytokine agents (such as thalidomide pentoxiphylline) and immune-enhancement with ‘heat killed Mycobacterium vaccine’ and other recombinant BCGs have been under clinical trials. These modalities have not been recommended for standard clinical practice.

Ø  Strategies for Airborne Infection Control:  ‘International Guidelines on Airborne Infection Control in Healthcare Settings’ should be adopted. These guidelines are very important in the isolation wards, multi-drug resistant-TB (MDR-TB) wards and the Medical Laboratories conducting TB tests, for prevention of spread of infection among health workers in hospitals.

 

 

Rational Drug Combinations

The combination of two or more drugs with near about identical plasma half-life, in the same pharmaceutical formulation is termed as 'fixed dose combination' (FDC). The formulation may be in the form of tablet, capsule, syrup, powder or injection. The ratio of dose depends on peak plasma concentration and body mass of the patient. Some of the fixed dose combinations (FDCs) discussed below are 'rational drug combinations' as these have been found advantageous in terms of better therapeutic efficiency, reduced adverse effects, convenience of dose and better patient compliance.

Some rational drug combinations as per WHO's essential drug list and other lists:

1. Amoxycillin + Clavulanic Acid

The combination is indicated in bacterial infections producing b-Lactamase. Amoxycillin is inactivated by b-Lactamase if given alone. Clavulanic acid is b-Lactamase inhibitor and thus restores the sensitivity of Amoxycillin against the b-Lactamase producing bacteria. Escherechia coli, Klebsiella, H. influenzae, N. gonorrhoe, Staphylococci, Proteus, M. catarrhalis and Bacteroid species are known b-Lactamase producing bacteria.

2. Cotrimoxazole (Sulfamethaxazole +Trimethoprim)

Cotrimoxazole is prescribed to treat bacterial infections. We know that a variety of bacteria survive and proliferate in our body by synthesis of folate. Sulfamethaxazole inhibits folate's synthesis while Trimethoprim inhibits dihydrofolate reductase which converts folate
to tetrahydrofolate. Thus the combination is synergistic and potent bactericidal and provides wider spectrum of antibacterial activity. The combinations is a rational drug combination in terms of drug action.

3. Imipenem + Cilastatin

This combination drug is an antibiotic and used to treat bacterial infection. The drugs we take orally or through injection, are exposed to the metabolic enzymes present in our stomach as well as other organs. Imipenem is a broad-spectrum antibiotic but the enzyme dehydropeptidase present in kidney destroys it. The Cilastatin present in the combination inhibits the dehydropeptidase present in kidneys and thus prevents the inactivation of Imipenem.

4. Neomycin + Bacitracin

This combination is used in powder, solution and ointment form to treat bacterial infections of skin, ulcers of mucous membranes, infected wounds and conjunctivitis. Infected dermatosis and infected corneal ulcers are also treated by this rational drug combination.

5. Benzoic Acid + Salicylic Acid

The Benzoic acid is an antifungal agent, very effective in acidic pH. The Salicylic acid is a keratolytic agent, and thus improves the penetration of Benzoic acid and provides additional acidic environment.

6. Sulfadoxine + Pyrimethamine

This FDC is indicated for the treatment of chloroquine resistant falciparum malaria (Plasmodium falciparum) along with quinine therapy or artemisinin therapy. The combination is justified as sulfadoxine inhibits folate synthesis by the malarial parasite while pyrimethamine inhibits the action of dihydrofolate reductase which converts folate to
tetrahydrofolate thus blocks the growth and survival of malarial parasite.

7. Artemether + Lumefantrine

This FDC is indicated for the treatment of chloroquine resistant falciparum malaria (Plasmodium falciparum). One tablet of this combination contains Artemether (20 mg) and Lumefantrine (120 mg). The combination drug is very effective against blood schizonts and prevents relapse of malaria. It has been reported that Lumefantrine is less cardio-toxic drug in
comparison to side effects of halofantrine.

8. Drug Combinations for Anti-Tuberculosis Therapy (ATT)

• INH + Rifampicin


• INH + Ethambutol


• INH + Rifampicin + Pyrazinamide


• INH + Rifampicin + Pyrazinamide + Ethambutol

The treatment of tuberculosis is very critical. Antitubercular drugs are used in combination for better efficacy, to shorten duration of therapy, to prevent emergence of resistant organisms and for better patient compliance.

Important Tips:

i.) During intensive care phase, 3-5 drugs are used for 2-3 months. These drugs reduce bacterial load, ameliorate the acute symptoms and make patient non-contagious.

ii.) During continuation phase, 2 or 3 drugs are used for 4-7 months. These drugs kill all the persisters and thus sterilize all the organ and tissues.

iii.) Complete cure of tuberculosis should be ensured to prevent relapse.

9. Drug Combinations for Anti-retroviral Therapy (ART)

• Zidovudine + Lamivudine


• Zidovudine + Lamivudine + Navirapine


• Stavudine + Lamivudine + Navirapine


• Emtricitabine + Tenofovir


• Efavirenz + Emtricitabine + Tenofovir


• Lopinavir + Ritonavir

These are highly active antiretroviral drugs used in the treatment of AIDS (HIV infection). Antiretroviral drugs are combined to prevent resistance, limit toxicity and for synergistic effect. There are four groups of antiretroviral drugs depending on their anti-viral actions as:

• Zidovudine, Lamivudine, Stavudine and Emtricitabine are nucleoside reverse transcriptase inhibitors (NRTIs).


• Navirapine and Efavirenz are non nucleoside reverse transcriptase inhibitors (NNRTIs).


• Tenofovir is very effective nucleotide reverse transcriptase inhibitor.


• Lopinavir and Ritonavir are protease inhibitors (PIs).

10. Ethinyl estradiol + Norethisterone

Used for female contraception as FDC pill from 5^th day of menstrual cycle for 21 days.

Justified role of ingredients in combination:

Estrogen (Ethinyl estradiol) and progesterone (Norethisterone) by exerting negative feedback over the pituitary gland, reduce the secretion of Follicle Stimulating Hormone (FSH)
and Luetinizing Hormone (LH). In the absence of LH, the ovulation does not occur and the ovulatory cycle becomes an anovulatory cycle. Estrogen with progesterone make endometrium unfit for implantation of ovum. Progesterone ensures withdrawal bleeding after stoppage of medication. Progesterone also prevents risk of endometrial carcinoma due to estrogen (if used alone as contraceptive).

11. Lignocaine + Adrenaline

This is used as local anesthetic in the ratio of 1:50,000 - 1:200,000. The combination drug is administered for infiltration anesthesia, nerve block, spinal anesthesia and epidural anesthesia.

Justification for the combination:

i.) Adrenalin is a vasoconstrictor, so it reduces the absorption of Lignocaine and prevents its early clearance.

ii.) Adrenalin prolongs duration of action of local anesthetic, reduces its toxicity and provides almost blood less zone for the surgery.

Limitations:

This combination is not indicated for anesthetizing organs and tissues supplied by end arteries. So, ear lobes, finger tips, toes, nose tip and penis should not be anesthetized with this combination anesthesia.

12. Glucose (5%) with Saline (0.9%)

This glucose saline fluid is used as intra-venous maintenance fluid for dehydration. Dextrose provides energy and saline covers the deficiency of sodiumand chloride in extracellular compartments.

13. Acriflavin + Glycerin

Acriflavin in glycerin is used as anti-infective agents for dressing the wounds, cuts, ulcers, burns and umbilical cord.

14. Aluminium Hydroxide + Magnesium Hydroxide

This rational drug combination is used in hyperaciditym peptic ulcer, upper GI bleeding and gastro-esophageal reflux disease (GERD) to neutralize gastric acid.

Advantage: Aluminium hydroxide causes constipation but Magnesium hydroxide causes diarrhoea if used alone. So, the combination would not cause any intestinal upset.

15. Metronidazole + Diloxanide Furoate

Metronidazole is a pan-amoebicidal drug to which Diloxanide Furoate is added to make it effective to kill the cysts also. The combination drug is used in the management of amoebiasis.

16. b₂-Agonist + Inhaled Corticosteroid

• Salbutamol + Beclomethasone


• Formeterol + Budesonide

Salbutamol and Formeterol are b₂ -agonists and cause bronchodilation. Inhaled corticosteroid (Beclomethasone or Budesonide) helps to control the bronchial asthma by its anti-inflammatory and immunosuppressive action.