tuberculosis%20-%20pulmonary
TUBERCULOSIS - PULMONARY
Tuberculosis (TB) suspect is any one who has signs or symptoms suggestive of TB (eg >2 weeks productive cough).
Definite TB is considered in patients with culture or molecular line probe assay positive for Mycobacterium tuberculosis, or in patients with at least 1 sputum smear positive for acid-fast bacilli.
TB cases are also classified based on the disease anatomical site, bacteriological results (including drug resistance), previous treatment history and patient's HIV status.
Pulmonary TB is a case of TB that involves the lung parenchyma.
Miliary TB is considered as PTB since lung lesions are also seen.
TB in the pleural effusion, mediastinal and/or hilar lymph nodes with no evidence of abnormalities in the chest x-ray are considered extrapulmonary TB.
Patients presenting with both PTB and extrapulmonary TB are classified as a case of PTB.

Principles of Therapy

  • Essential principles of care for persons w/ active or suspected tuberculosis (TB) include:
    • Prompt & accurate diagnosis
    • Use of standardized & effective treatment regimen plus proper treatment support & supervision
    • Monitor treatment response
  • Optimal duration of sputum-positive pulmonary tuberculosis (PTB) is at least 6 months
Treatment Goals
  • Treat the patient & bring back quality of life & productivity
  • Prevent death & relapse of TB
  • Lower TB transmission
  • Stop the development & transmission of drug resistance
    • Acquired resistance occurs during therapy when resistance to >1 drug develops in organisms that were initially susceptible to the drugs
    • Best way to prevent is to use at least 2 bactericidal drugs to which the organisms are sensitive & to employ daily intensive-phase dosing especially in TB patients starting treatment w/ Isoniazid resistance
  • Achieve goals w/ the lowest possible dose & minimal toxic drug effects
Treatment Phases
  • Initial or intensive phase is when combination drugs are used to rapidly kill replicating populations of M tuberculosis & occurrence of drug resistance is prevented
    • Bactericidal effect leads to fast conversion of bacteriological sputum & improvement in clinical symptoms
  • Continuation phase is when drugs slowly & intermittently kill replicating populations
    • Remaining bacteria are eliminated & consequent relapse is prevented
Dosing Frequency:
  • Daily or thrice-weekly regimens are recommended
    • Thrice-weekly regimen is only applicable for patients under DOT program, w/o HIV, & not living in HIV-prevalent countries
  • Twice-weekly dosing is no longer recommended because of increase in noncompliance rate
  • Studies have shown that failure or relapse rates in patients on daily or 3x/week regimens are the same but higher rate of acquired drug resistance in patients on 3x/week dosing
  • Higher risk of failure & acquired drug resistance were also noted in patients w/ pretreatment Isoniazid resistance using the 3x/week dosing during the intensive phase; hence, daily intensive-phase dosing is preferable
Directly Observed Therapy (DOT)
  • Poor compliance to anti-TB regimen is the most common cause of treatment failure
  • Part of the patient-centered care adherence plan
    • Helpful way to monitor adherence of patient to therapy
  • Process where a health care worker watches the patient to swallow each dose of the drug to ensure that completion of treatment is achieved
  • Ideally prevents the emergence of drug resistance when a suitable regimen is given
Treatment Interruption
  • If patient misses a treatment, the NTP should contact the patient
    • W/in a day after missing treatment during the initial phase
  • W/in a week if during the continuation phase
  • Culture & DST should be done upon return of the patient who missed 2 consecutive months of treatment
Hospitalization
  • Recommended in severely ill patients & for those w/ complications of the disease or its treatment that need closer clinical monitoring
  • May also be considered in patients during the intensive phase for whom there are no other means of ensuring treatment adherence & support

Pharmacotherapy

Treatment Regimen for New Tuberculosis (TB) Patients
  • Therapy consists of 1st-line anti-TB agents
  • For smear-negative, w/ intrathoracic lymph node & tuberculous peripheral lymphadenitis [human immunodeficiency virus (HIV)-negative, low drug resistance]
    • Intensive phase - HRZ x 2 months; Continuation phase - HR x 4 months
  • For smear-positive, w/ extrapulmonary TB (HIV-negative, low drug resistance)
    • Intensive phase - HRZE x 2 months; Continuation phase - HR x 4 months
  • For smear-positive or smear-negative w/ or w/o extensive parenchymal involvement, w/ severe extrapulmonary TB (high HIV/Isoniazid resistance risk factor)
    • Intensive phase - HRZE x 2 months; Continuation phase - HR x 4 months
Treatment Regimen for Multidrug-resistant Tuberculosis (MDR-TB) Patients
  • Regimen depends on drug susceptibility tests
  • Intensive phase is defined by the duration of treatment w/ the injectable agents
    • Injectable agents should be continued for a minimum of 6 months & for at least 4 months after the patient had smear & culture conversion
  • Therapy should be continued for a minimum of 18 months until after culture conversion
  • Therapy may be extended for up to 24 months in patients w/ extensive pulmonary damage
1st-Line Anti- Tuberculosis (TB) Agents (Group 1)
  • Recommended for patients w/o previous anti-TB treatment & w/o risk factors for drug resistance
  • Initial/intensive phase: Combination of 4 drugs for 2 months used
  • Continuation phase: Isoniazid + Rifampicin combination for 4 months
Isoniazid (H)
  • Highly bactericidal against replicating tubercle bacilli
  • Indicated for all forms of TB caused by organisms that are known or presumed to be susceptible
  • Clinical monitoring & liver function tests (LFTs) is recommended during treatment of patients w/ pre-existing liver disease
Rifampicin (R)
  • Semisynthetic derivative of Rifamycin
  • Has bactericidal action & potent sterilizing effect against tubercle bacilli in both cellular & extracellular locations
  • Indicated for all forms of TB caused by organisms that are known or presumed to be susceptible & is also considered to be an essential component of all short-course regimens
  • Should always be administered together w/ other effective anti-TB drugs because of high risk for development of resistance
  • 6 months regimen is recommended since 2 months regimen is associated w/ more relapses & deaths
  • Clinical monitoring & LFTs is recommended during treatment of patients w/ pre-existing liver disease
  • Has narrow therapeutic index, thus dosage should not be lower than recommended dose
Pyrazinamide (Z)
  • Indicated for all forms of TB caused by organisms that are known or presumed to be susceptible
  • Only weakly bactericidal but has potent sterilizing activity, particularly in macrophages & in areas of acute inflammation
  • Highly effective against acute inflammatory changes during the first 2 months of treatment
  • Has shortened the treatment regimen & reduced the risk of relapse
Ethambutol (E)
  • Generally used in combination w/ other anti-TB agents to prevent/delay the emergence of resistant strains
    • Included in initial treatment regimen primarily to prevent emergence of Rifampicin resistance when primary resistance to Isoniazid may be present
    • Added to Isoniazid + Rifampicin continuation phase in patients from populations w/ known or suspected high levels of Isoniazid resistance & Isoniazid susceptibility testing is not done
2nd-Line Anti-Tuberculosis (TB) Agents
  • Should be used in patients w/ MDR-TB
Aminoglycosides
  • Belong to group 2 injectable agent for use in susceptible MDR-TB patients
  • Eg Kanamycin, Amikacin, Capreomycin, Streptomycin
    • Considered 1st choice among the injectable agents for MDR-TB which has lower resistance, lower cost & less ototoxic side effect as compared to Streptomycin
    • Have been used extensively for the treatment of MDR-TB
Streptomycin (S)
  • An aminoglycoside antibiotic derived from Streptomyces griseus that is used for TB & gram-negative sensitive infections
  • Streptomycin & Ethambutol are approximately equivalent when used in the initial treatment phase but Streptomycin use may be limited based on local M tuberculosis resistance patterns
    • Has high resistance in drug-resistant TB
    • Streptomycin may be substituted if Ethambutol is contraindicated
  • Not absorbed from the gastrointestinal (GI) tract but after intramuscular (IM) administration, it diffuses readily into the extracellular component of most body tissues & attains bactericidal concentrations, particularly in tuberculous cavities
Bedaquiline
  • Recently approved treatment for adult patients w/ pulmonary MDR-TB
    • Given as part of the combination therapy for extensively drug-resistant TB & MDR-TB allergic to >2 drugs belonging to group 4
  • May only be considered for immunocompromised patients (children, HIV-positive persons, pregnancy), patients w/ extrapulmonary TB, and those w/ comorbidities if other therapies are unavailable or ineffective
Delamanid
  • A nitro-dihydro-imidazooxazole that inhibits mycolic acid synthesis & has been recently approved for the treatment of MDR-TB
    • Given as part of the combination therapy for MDR-TB in adult patients who are intolerant or resistant to standard effective treatment regimen
  • May be useful in patients w/ increased risk for poor outcomes (eg drug intolerance or contraindication, extensive or advanced disease, resistance to fluoroquinolones &/or injectable drugs, & XDR-TB)
Fluoroquinolones
  • Belong to group 3 drugs used to treat MDR-TB
  • Eg Levofloxacin, Moxifloxacin, Ofloxacin, Gatifloxacin
  • Ciprofloxacin is no longer recommended to treat TB patients
Oral Bacteriostatic 2nd-Line Agents
  • Agents belonging to group 4 drugs that may be used in MDR-TB
  • Eg Para-aminosalicylic acid (PAS), Cycloserine, Terizidone, Ethionamide, Prothionamide
  • Ethionamide is often added to the treatment regimen due to its low cost
  • PAS is considered 1st, if cost is not a constraint, because it is well tolerated & has no cross-resistance to other agents
Agents w/ Unclear Role in MDR-TB Treatment
  • Agents belonging to group 5 drugs
  • Eg Clofazimine, Linezolid, Amoxicillin/clavulanate, Thioacetazone, Imipenem/Cilastatin, Clarithromycin
  • Not recommended for routine use in MDR-TB patients
  • May be used in extremely drug-resistant TB
  • Should be used in consultation w/ a specialist
Fixed-Dose Combinations (FDC)
  • ≥2 drugs incorporated in a single tablet that reduces the number of pills that needs to be consumed
  • May prevent having drug resistance secondary to monotherapy
  • Advantageous since prescription errors may be less frequent because of more straightforward dosage recommendations, easier adjustment of dosage based on patient’s weight, & may promote patient’s compliance due to smaller number of tablets to consume
  • Some trials have shown that FDC & monotherapy are equally effective but FDC are more acceptable to patients
  • Does not prevent the need for separate drugs in patients who will develop drug toxicity or intolerance, or in patients w/ contraindication to individual drug component
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