Tuberculosis: Definition, Classification, and Diagnosis

General Information

• Tuberculosis case definition: Any person suffering from disease caused by Mycobacterium tuberculosis complex and who has positive smear microscopy, culture, or rapid molecular MTB/RIF test, or other diagnostic methods authorized by MINSAL, or who clinically meets the case definition.
• Respiratory symptomatic: Any person ten years of age or older who presents with productive cough for fifteen days or more.

Classification and Diagnostic Tests

• Tuberculosis is classified as pulmonary, extrapulmonary, and meningeal.
• Diagnostic studies include:
• Smear Microscopy.
• BAAR Cultures.
• Rapid Molecular Test (MTB/RIF).
• Biopsies for histological and microbiological testing.
• Tuberculin Test (PPD).
• Adenosine Deaminase (ADA).
• Chest X-ray.
• Axial Computed Tomography and/or Nuclear Magnetic Resonance.

Culture Indications

• High suspicion of TB and two negative smear microscopy results.
• Suspicion of infant tuberculosis.
• Suspicion of extrapulmonary tuberculosis.
• People with HIV and suspicion of TB.
• Failure.
• Loss in follow-up.
• Relapse.
• Contact with TB-MDR or TB-RR case.
• History of or current stay in penitentiary or bartolinas.
• TB/HIV co-infection.
• Smear microscopy with one to nine bacilli in one hundred fields that do not become negative in the second, fourth, or fifth month of treatment.
• National or foreign migrant.
• Patient with anti-tuberculosis treatment who does not improve clinically, even though control smear microscopy tests are negative.
• Mycobacteriosis.
• People with diabetes.
• TB-RR or TB-MDR case.
• Health personnel.
• Native populations.
• Homeless population.

Rapid Molecular MTB/RIF Test Indications

• Respiratory symptomatic with two negative smear microscopy tests and presumptive TB.
• Person with HIV with signs and symptoms suggestive of TB.
• Persons deprived of liberty, or with a history, with signs and suggestive symptoms of TB.
• Respiratory symptomatic with diabetes.
• Respiratory symptomatic with immunodeficiencies.
• TB case that does not test negative in the second, fourth, or fifth month of treatment; or in the ninth month, in case of re-treatment.
• Previously treated (relapses, failures, loss in follow-up).
• Suspicion of extrapulmonary TB.
• Contacts of case with TB-MDR or TB-RR.
• Children with presumptive TB.
• Health personnel.
• Others (specify).
• Indication by previous result (in case the result is an error or invalid, a new sample is processed).

Treatment

• Treatment for sensitive cases (new and in re-treatment).
• Treatment for drug-resistant cases.
• Treatment of severe forms of TB.

Treatment Objectives

• Cure the patient of TB.
• Reduce morbidity and mortality from TB.
• Prevent relapses.
• Decrease the transmission of TB to other people.
• Prevent drug resistance.
• Monitor adherence to treatment and adverse reactions that patients may present.

Tuberculin Test Support

• Contacts of a person with bacteriologically confirmed pulmonary TB (under 5 years and over 5 years.
• People with HIV.
• Persons with immunodeficiencies (CKD, DM, people who have had organs or tissues transplanted, people in treatment with immunosuppressants, among others).
• Newly hired health personnel located in areas at risk of becoming infected with M. tuberculosis.
• Other groups: people deprived of liberty, migrants, homeless people and those who use illicit drugs.

Therapeutic Regimen of Anti-Mycobacterials

• The therapeutic regimen for anti-mycobacterials includes acids, cycloserine, rifampicin, isoniazid, ethionamide, pyrazinamide, ethambutol, clofazimine, and dapsone.
• Anti-tuberculosis drugs are classified as first-line drugs, second-line drugs, and third-line drugs.

Therapeutic Regimen

• New sensitive cases or extrapulmonary TB, including cases with TB/HIV coinfection and people deprived of liberty:
• First phase: 2HRZE6
• Continuation Phase: 4H6R6
• Sensitive re-treatment cases.
• First phase: 4HRZE6
• Continuation Phase: 5H6R6
• The source is World Health Organization, Treatment for Tuberculosis, Guidelines for Programs, 2017.

Nomenclature

• 2HRZE6:
• Months --> Days
• Isoniazid
• Rifampicin
• Pyrazinamide
• Ethambutol

Therapeutic Regimen for Children

• Patients under ten years of age with clinically diagnosed pulmonary TB, intrathoracic ganglion TB, peripheral tuberculous lymphadenitis.
• First phase: 2HRZ6
• Continuation phase: 4HRZ6.
• Patients under ten years of age with pulmonary or extrapulmonary TB and with HIV.
• Extended pulmonary disease (miliary), pulmonary TB with positive bacteriology, severe forms of extrapulmonary TB (except tuberculous meningitis and osteoarticular TB).
• First phase: 2HRZE6
• Continuation phase: 4H3R3.
• Positive bacteriology: TB meningitis and osteoarticular TB.
• First phase: 2HRZE6
• Continuation phase: 10 H3R3.
• Patient with negative bacteriology pulmonary TB with extensive lesions of the parenchyma, all forms of extrapulmonary TB.
• The source is World Health Organization, Treatment for Tuberculosis, Guidelines for Programs, 2017.

Therapeutic Regimen for Resistant

• Cases of TB-RR or TB-MDR confirmed or highly presumptive with or without HIV, including resistant TB in children and other vulnerable groups.
• First phase: Standardized scheme or individualized regimens for this category
• Continuation phase: Standardized scheme or individualized regimens for this category

Isoniazid

• Mechanism of action: Methanolized by the KatG catalase (catalase-peroxidase) generates an isonicotinoyl radical that interacts with NAD and NAPD (nicotinoyl-NAD isomer), inhibits the activity of reductase.
• The proteins transporters of enoyl acid (Inha) and KasA = inhibit mycolic acid (cell wall).
• Nicotinoyl NADP interferes with the synthesis of nucleic acids. Reactive oxygen species (H2O2).
• Bactericidal and bacteriostatic.
• Bioavailability: 100%.
• Metabolism: Hepatic arilamine NAT2.
• Drug interactions: CYP2C19 and CYP3A (potent) inhibitor, CYP2D6 (weak). CYP2E1 inducer.

Management of Extrapulmonary TB

• Steroid use in evidence-based for therapeutic purposes include:
• Lymph node: Not recommended.
• Osteoarticular: Not recommended.
• Pleural: Not recommended.
• Pericardial: Strong recommendation.
• CNS: meningitis: Strong recommendation.
• Disseminated Disease: Not recommended.
• Genitourinary: Not recommended.
• Peritoneal: Not recommended.
• Dexamethasone 0.25 mg/kg every 8 hours, until stabilization and continue with prednisone 1-2 mg/kg/day (maximum dose 60 mg) for four weeks, with progressive decrease of 30% of the dose each week, until its suspension (approximately two weeks).

Rifampicin

• Mechanism of action: Binds to the beta subunit of RNA polymerase dependent on DNA (stable drug-enzyme complex).
• Bacteriostatic.
• Metabolism: B-esterases and microsomal cholinesterases.
• Elimination: Bile (feces) and (1/3) in urine.
• Bioavailability 68%, protein binding 85%, half-life 2-5 hours, CYP3A inducer.

Pyrazinamide

• Analogue of synthetic pyrazine nicotinamide)(1936 Merck-Germany- Tb-1952 laboratory).
• Mechanism of action: Blocks the function of the enzyme by collapsing the proton motive force of the transmembrane.
• Bactericidal and bacteriostatic.
• Metabolism: Microsomal deamidase.
• Elimination: Kidneys (inhibits the excretion of urates).
• Bioavailability 90%.

Ethambutol

• Inhibits the arabinosil transferase III (Bacterial Wall).
• Crosses the blood-brain barrier during inflammation of the meninges.
• Bacteriostatic.
• Bioavailability: 80%, 10-40% binds to proteins.
• Higher elimination in children than in adults (renal), 80% is not metabolized.

Antibiotic Mechanism

• Fluoroquinolone: Inhibits DNA synthesis and supercoiling.
• Rifampicin: Inhibits RNA synthesis.
• Streptomycin: Inhibits protein synthesis.
• Macrolides: Inhibit protein synthesis Nitromidazoles bicyclic: (1) inhibit the mycolic acid and protein biosynthesis (2) generate reactive nitrogen species.
• Bedaquiline: inhibits synthesis of ATP.
• Oxazolidinones: It inhibits the start of protein synthesis by binding to the ribosomal.
• Membrane processes inhibiting synthesis of the the cell wall;
• Isoniazid and ethionamide - Inhibits Mycolic acid synthesis.
• Ethambutol - inhibits cell wall synthesis
• Pyrazinamide - inhibits cell membrane synthesis and Trans-Translation

Tuberculosis Medication in Children

• The upper end of the isoniazid dose range applies to children under 5 years of age. As the children grow, the lower end of the dose range becomes more appropriate.
• When children approach a body weight of 25 kg, the dosage recommended for adults can be used in fixed combination formulations.

Dosage Guidelines with First-Line Anti-Tuberculosis

• Dosages of Medications:
• Isoniazid: 10 (7-15) mg/Kg . Maximum dose of 300mg.
• Rifampicin: 15 (10-20) mg/Kg. Maximum dose of 600mg
• Pyrazinamide: 35 (30-40) mg/Kg. Maximum dose of 2,000mg
• Ethambutol: 20 (15-25) mg/Kg. Maximum dose of 1,600mg.
• The source is adapted from Guidance for National Tuberculosis, programmes on the management of Tuberculosis in Children.
• Recommended weight range for the dosage:
• 30-39kg, 2 tablets
• 40-54kg, 3 tablets
• 55-70kg, 4 tablets

• 71kg, 5 tablets

Adverse Reactions

• To follow up for mild adverse reactions:
• Isoniazid: insomnia, euphoria, gastritis, burning sensation in the feet: Adjust dose, take single morning antagonists H2, pyridoxine 100 mg per day.
• Rifampicin: Transient erythroderma, gastralgia, nausea: Symptomatic treatment. Make shots during meals.
• Pyrazinamide: Transient erythroderma, nausea, anorexia, joint pain: Symptomatic treatment. Acetyl salicylic acid.
• Ethambutol: Nausea: Symptomatic treatment. Adjust dose.

Special Clinical Cases and Recommendations

• If the patient is a nursing mother. Medication for TB may be secreted by breast milk in small amounts and breastfeeding may continue during the treatment.
• It is recommended to take the biosecurity measures in positive bacteriological patients and mother must wear surgical mask.
• Treatment started? What follow-up should be done in the patient with a new case of pulmonary TB? - perform BK in the second month
• Potential options
• BK negative - Pass the next phase
• BK positive --> Perform tests
• When do the patients get cured? - Cured the person with pulmonary tuberculosis confirmed bacteriologically at the beginning of the treatment that's present with negative testing at the end of the treatment
• Tuberculosis are classified into:
• Pulmonary
• BK testing (do it twice)
• PMR MTB/RIF
• Isolation
• Extrapulmonary
• Adenosine Deaminase (ADA) testing, (pleural, meningeal, pericardial, peritoneal or mesenteric, fluid)