Tuberculosis

Tuberculosis

Definition

·        Tuberculosis remains a leading cause of infectious morbidity and mortality worldwide.

·        World Health Organization (WHO) called tuberculosis a "global emergency, 1993"

·        About 8 million new cases of tuberculosis each year.

·        Miliary tuberculosis is a systemic version of TB affecting many organ systems due to hematogenous spread.

Etiology

·         Mycobacterium tuberculosis—the major etiologic agent worldwide; humans are the sole reservoir

·         M. bovis—transmitted from milk of infected cows; rare since institution of pasteurization

·         M. africanum—rare; only in Africa

Risk Factors

• Occupational: healthcare workers—airborne transmission, infection from extrapulmonary disease such as draining an abscess, autopsies; embalmers—from body fluids generating infectious aerosols
• Contact with infected person
• Location of birth: Asia, Africa, Latin America
• HIV infection
• Residence in a long-term care facility
• Immunosuppressive therapy
• Tuberculosis infection: increases likelihood of developing active disease within two years
• Low income, medically underserved individuals
• In areas with a high incidence of TB, exogenous re-infection is a major cause of recurrence after effective treatment.

Signs and Symptoms

• Asymptomatic—especially from initial infection
• Mild fever, headache, chills, night sweats
• Malaise, fatigue
• Anorexia, weight loss
• Cough—nonproductive or mucopurulent
• Hemoptysis
• Pleuritic chest pain
• Dyspnea
• Adenopathy
• Children—asymptomatic and extrapulmonary manifestations are more frequent than in adults; look for signs of meningitis, adenopathy

Differential Diagnosis

• Bacterial pneumonia
• Other nontubercular mycobacterial infections
• Lymphomas
• Sarcoidosis
• Lung abscess

Drug Therapies

Standard antibiotics for tuberculosis include:

• Isoniazid—adults 5 mg/kg/day, children 10 to 20 mg/kg/day, 300 mg maximum for both; side effects: hepatitis (risk increased with alcohol consumption), peripheral neuropathy, rash, fever; additional drug interactions and toxicity for patients with HIV
• Rifampin—adults 10 mg/kg/day, maximum 600 mg/day, children 10 to 20 mg/kg/day; side effects: gastrointestinal upset, hepatitis, orange discoloration of body fluids (and contact lenses); additional drug interactions and toxicity for patients with HIV
• Pyrazinamide—15 to 30 mg/kg/day, 2 g maximum; side effects: hepatitis, hyperuricemia possibly with polyarthralgias (both reduced by concurrent rifampin administration)
• Ethambutol—least potent against M. ; 15 to 25 mg/kg/day for 2 months, then reduce to 15 mg/kg/day; side effects: retrobulbar optic neuritis and color perception problems, avoid with children
• Streptomycin—used least often because of toxicity; intramuscular or intravenous administration of 10 to 15 mg/kg/day, maximum 1 g/day, up to 5 times per week for adults, 20 to 40 mg/kg/day with 1 g/day maximum for children; side effects: ototoxicity (both hearing loss and vestibular dysfunction), nephrotoxicity, teratogenic
• Pyridoxine (vitamin B₆) added to regimen particularly in populations at risk for vitamin deficiency (e.g., malnourished, alcoholics, elderly, pregnant and nursing mothers) or at risk for neuropathy (diabetics, HIV, chronic renal failure)

Experimental drugs:

• Rifapentine—longer acting, allowing dosing twice a week
• Fluoroquinolones (e.g., ciprofloxacin)—antibacterial; concentrations higher in respiratory secretions than in serum; well tolerated, but insufficient data to use as standard treatment; less effective with HIV
• Rifabutin—as effective as rifampin with concurrent HIV, but reduces time to sputum conversion; 150 mg/day associated with fewest adverse effects; possible role with multidrug resistance

TUBERCULOSIS THERAPY

Based on antitubercular activity

1.      Tuberculocidal agents – Isoniazid, Rifampicin, Streptomycin, pyrazinamide, capreomycin, Kanamycin, Ciprofloxacin.

2.      Tuberculostatic agents – Ethambutol, ethionamide, thiacetazone, cycloserine, PAS.

First line drugs

Isoniazid (INH) – Tuberculocidal for rapidly multiplying bacilli but static for resting bacilli.

INH destroys:

a)      intracellular bacilli as it penetrates into the cells, and

b)      Bacilli multiplying in the walls of the cavities.

Thus it is effective against both intra and extracellular organisms.If used alone, mycobacteria develop resistance.

Mechanism of action: INH inhibits the synthesis of mycolic acids which is an important component of the mycobacterial cell wall.

Pharmacokinetics: INH is completely absorbed orally, penetrates all tissues, tubercular cavities, necrotic tissues and CSF. It is metabolised by acetylation. Metabolites are excreted in urine.

ADRs: Peripheral neuritis (due to interference with utilization and increased excretion of pyridoxine) can be avoided by giving prophylactic pyridoxine (10 – 50 mg) with INH.

Hepatitis, CNS toxicity, anorexia etc.

Rifampicin – Antibiotic obtained from Streptomyces mediterranei.

The other rifamycins are rifabutin and rifapentine.

Rifampicin is bactericidal to M.tuberculosis, M.leprae and atypical mycobacteria. Also inhibits, most Gram +ve and –ve bacteria like Staph.aureus, N.meningitidis, E.coli, Proteus, Pseudomonas and legionella.

Antitubercular action: Only drug acts on persisters; acts on both intra and extracellular organisms & is effective against TB bacilli resistant to other drugs.

MOA: Rifampicin binds to DNA dependent RNA polymerase and inhibits RNA synthesis in the bacteria.

Pharmacokinetics: has good tissue penetrability – reaches caseous material, cavities and CSF; It also appears in saliva, tears, sweat.

It is a microsomal enzyme inducer.

ADRs: Skin rashes, diarrhoea, nephritis & hepatotoxicity.

It stains the secretions including tears, saliva and sweat orange red.

Use:

1.      TB and atypical mycobacterial infections.

2.      Leprosy

3.      Prophylaxis of H.influenza and meningococcal meningitis

4.      Resistant staphylococcal infections.

5.      Brucellosis – Rifampicin 600 – 900 mg+ Doxy 200 mg daily for 6 weeks.

6.      To eradicate carrier state – rifampin eradicates the nasal carrier state of N.meningitidis, H.influenza and S.aureus – 600 mg BD for 2 days.

Rifubutin: similar to Rifampicin, may be used in TB pts with AIDS who are receiving antiviral drugs.

Rifapentine – analog of Rifampicin.

Pyrazinamide: Tuberculocidal,

MOA not known.

It is effective against intracellular bacilli.

ADRs: Hepatotoxicity

Hyperuricaemia – due to ↓excretion of uric acid may result in gouty arthritis.

Arthralgia, vomiting etc.

Streptomycin: Tuberculocidal, acts against extracellular organisms due to poor penetrating power.

Second line drugs

Ethambutol: Tuberculostatic, acts on fast multiplying bacilli in the cavities. Also effective against atypical mycobacteria.

It inhibits the incorporation of mycolic acids into the mycobacterial cell wall.

Optic neuritis resulting in ↓ visual acuity and inability to differentiate red from green is an important ADR which needs withdrawal of the drug. Colour vision should be monitored during treatment.

Anorexia, headache, fever, allergic reactions.

Thiacetazone: Tuberculostatic with low efficacy.

It delays the development of resistance to other drugs.

ADRs: Hepatotoxicity, dermatitis, GI side effects.

Ethionamide: Tuberculostatic, effective against both intra and extracellular organisms.

It is also effective in atypical mycobacteria.

ADRs: Anorexia, metallic taste in the mouth, hepatitis, peripheral neuritis.

Ethionamide is a secondary agent used only when primary drugs are ineffective.

Para-aminosalicylic acid (PAS): related to sulfonamides is tuberculostatic.

GI effects like nausea, anorexia & epigastric pain and diarrhoea make it poorly tolerated drug.

Rarely used.

Other second line drugs

Amikacin, kanamycin and capreomycin – They are oto and nephrotoxic and are used only in resistant cases.

Amikacin is effective against atypical mycobacteria.

Cycloserine – antibiotic that inhibits cell wall synthesis, is tuberculostatic, also effective against some gram-positive organisms.

It causes CNS toxicity including headache, tremors, psychosis and sometimes seizures. It is used only in resistant TB.

Fluoroquinolones – Ciprofloxacin, ofloxacin and sparfloxacin inhibit TB bacilli and atypical mycobacteria.

They are useful in multidrug resistant TB in combination with other drugs.

Treatment of TB

A combination of trt is given to

- delay the development of resistance

- reduce toxicity

- shorten the course of trt.

Chemotherapy is given in 2 phases –

-       First phase – initial, intensive phase of 1 – 3 months duration aimed at killing as many as possible.

-       Second phase – continuation phase to destroy the dormant or persisters – duration 6 – 9 months.

Short-term regimens

Directly Observed Treatment (DOT) is a strategy that is found to be effective & is recommended throughout the world.

INH + R + Z + E/S daily for 2 months

Followed by

INH + R daily for 4 months.

Role of glucocorticoids:

As steroids depress host defense mechanisms, they should be used only in conditions like TB meningitis, miliary TB, pleural effusion, renal TB.

Steroids suppress inflammatory reaction which can lead to extensive fibrosis and damage.

Rifampicin – 600 mg

INH      - 300 mg

Pyrazinamide – 2000 mg

Ethambutol - 1500 mg

Streptomycin – 1 gm