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
  • Patients should be provided w/ adequate knowledge regarding the disease & the impotance of treatment compliance 
  • 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 with 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
  • In individuals with drug-susceptible PTB, daily intake of the required medications is recommended & the thrice-weekly regimen is no longer advisable, both in the intensive & continuation phases
  • Twice-weekly dosing is no longer recommended because of increase in noncompliance rate
  • Thrice-weekly dosing is also no longer recommended since:
    • Studies showed that when daily regimen was compared to thrice-weekly regimen throughout the duration of treatment, TB recurrence, failure in therapy & acquired drug resistance were all higher in the latter
    • When daily regimen was compared to thrice-weekly regimen in the continuation phase, TB recurrence & failure in therapy were seen more in the latter, however, there was no difference when it comes to acquired drug resistance, hence, if thrice-weekly regimen is to be used in the continuation phase, it is important that the patient is under DOT, & that medications are taken without fail
    • Higher risk of failure & acquired drug resistance were also noted in patients w/ pre-treatment Isoniazid resistance using the 3x/week dosing during the intensive phase; hence, daily intensive-phase dosing is preferable
Treatment Adherence Interventions
  • Includes: Tracers (home visitation) &/or digital medication monitor (phone calls, messaging), material support (food, transportation fees, monetary allowance, etc), education of staff members & psychological support
  • Treatment administration strategies include: Directly observed therapy (DOT), non-everyday DOT, video-observed treatment (VOT), unsupervised therapy
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
  • DOT given at home or in the local municipal area is preferred rather than in a health care institution
  • DOT facilitated by health care practitioners or lay people who underwent training are preferred than those provided by relatives & those that are self-administered
Video-observed Therapy (VOT)
  • Advantages include: Compliance is observed even if the patient is far away, more convenient with regards to schedules, less expenses & can be used as an alternative or as an adjunct with other types of treatment administration
Decentralized Versus Centralized Model of Care
  • Decentralized care
    • Recommended for MDR-TB patients, including those who were hospitalized for <1 month for treatment initiation or management of complications
    • That which is centered in the local district area, wherein care is delivered in health care centers by general physicians, community-based health care workers & volunteers
    • May not be applicable for certain groups of patients, such as those with severe or highly infectious TB, with concomitant medical disorders, or non-compliant patients
    • Practices under this type of care should not hinder the need for hospitalization
  • Centralized care
    • Carried out by hospitals & specialized institutions or clinics particularly allocated for drug-resistant TB patients, facilitated by physicians or other health care providers with specialty in this field
    • Implemented during the intensive phase of treatment or until culture or smear conversion
Treatment Interruption
  • If patient misses a treatment, the NTP should contact the patient
    • Within a day after missing treatment during the initial phase
    • Within 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
    • In patients with drug-susceptible PTB, the 6-month Rifampicin-based therapy 2HRZE/4HR is the preferred treatment & the 4-month fluoroquinolone-containing therapy should be avoided
  • For smear-negative, with 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, with 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 with or without extensive parenchymal involvement, with severe extrapulmonary TB (high HIV/Isoniazid resistance risk factor)
    • Intensive phase - HRZE x 2 months; Continuation phase - HR x 4 months
Tuberculosis (TB) Retreatment
  • Is recommended for patients who had treatment interruption or disease recurrence
    • Treatment regimen will depend upon the patient’s DST result
    • More prone to develop drug resistance compared to new TB patients
  • If there is no resistance to the initial treatment of 2HRZE/4HR, this same therapy can be given
  • If resistance to Rifampicin is detected, WHO-based treatment regimen for MDR-TB is recommended
Treatment Regimen for Multidrug-resistant Tuberculosis (MDR-TB) Patients
  • Regimen depends on drug susceptibility tests
  • Intensive phase is defined by the duration of treatment with 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 with extensive pulmonary damage
  • Individuals diagnosed to have MDR-TB or RR-TB who are identified to have absence of resistance to fluoroquinolones & 2nd-line injectable agents or are regarded as having such resistance improbable & did not have prior 2nd-line drug treatment may have a shorter duration of MDR-TB therapy of 9-12 months
    • Shorter MDR-TB therapy is not advisable in patients who received treatment with 2nd-line drugs for >1 month & those with extrapulmonary disease
    • The following may follow the short-term regimen: Adult & children diagnosed with RR-TB without MDR-TB, even without documented resistance to Isoniazid; patients free from resistance to the medications used in the shorter regimen & non-pregnant women
    • Children & patients with HIV can be regarded with the same consideration as adults & people without HIV, respectively, in terms of using the shorter regimen
  • For the longer regimen, individuals diagnosed to have MDR-TB or RR-TB are required in the intensive phase to take at least 5 TB drugs, which are composed of the following: Pyrazinamide, 1 drug from group A, 1 drug from group B & 2 drugs from group C
    • If the recommended number is not met, drugs from group D2 or D3 can compensate for the lack of required number in order to complete the 5 drugs recommended
    • May consider addition of agents from group C or D if Pyrazinamide treatment cannot be tolerated
    • High-dose Isoniazid &/or Ethambutol may be considered in individuals with MDR-TB or RR-TB
Complications
TB Patients w/ HIV
  • Whether CD4 cell count is increased, decreased or normal, antiretroviral treatment (ART) should be initiated
  • ART is introduced in the therapy within the first 8 weeks after starting TB treatment
  • Introduced within the first 2 weeks after starting TB treatment only if the patient is significantly immunocompromised (eg CD4 cell count below 50 cells/mm3)
  • In those with concomittant TB meningitis, side effects that are more severe were observed when ART is introduced early than when it was initiated after 8 weeks (2 months) of TB therapy
  • For patients who have PTB, that is drug-susceptible & under ART therapy, a 6-month duration is preferred rather than 8-months or more with regards to TB treatment completion
Patients w/ Tuberculous Meningitis
  • Corticosteroid (Dexamethasone or Prednisolone) should be added in the treatment, tapered for 6-8 weeks
Patients w/ Tuberculous Pericarditis
  • Corticosteroid may also be added in the treatment
Patients w/ LTBI
  • Isoniazid-Rifapentine combination, administered weekly for 12 weeks (3 HP) is approved for adults, patients 2-17 years of age, those who are afflicted with HIV & acquired immunodeficiency syndrome (AIDS) & are under antiretroviral therapy which does not affect the actions of Rifapentine
  • May be given via DOT or self-administered in patients ≥2 years of age
1st-Line Anti- Tuberculosis (TB) Agents (Group 1)
  • Recommended for patients without previous anti-TB treatment & without 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 B injectable agents for use in susceptible MDR-TB & RR-TB patients in longer treatment regimen
  • 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
    • Although it is not usually part of the 2nd-line agents in the long-term duration of MDR-TB therapy, it may be used instead if the other 3 drugs in group B are 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
  • May also be used in RR-TB
    • Given as part of the combination therapy for extensively drug-resistant TB (XDR-TB) & MDR-TB allergic to >2 drugs
    • In the revised grouping, it is currently under group D2, as part of the add-on medications for the longer regimen of MDR-TB & RR-TB treatment
  • 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 also be used in RR-TB 
  • 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)
  • May now be used in patients 6-17 years of age in the longer regimen of MDR-TB & RR-TB therapy
Fluoroquinolones
  • Belong to group A drugs used to treat MDR-TB & RR-TB under the longer treatment regimen
  • Eg Levofloxacin, Moxifloxacin, Ofloxacin, Gatifloxacin
  • Ofloxacin & Ciprofloxacin are removed from the list of medications approved for MDR-TB & RR-TB because of lack of information regarding their effectivity
Oral Bacteriostatic 2nd-Line Agents
  • Agents belonging to group C that may be used in MDR-TB & RR-TB longer term regimen
  • Eg Ethionamide/ Prothionamide, Cycloserine/Terizidone, Linezolid, Clofazimine, in order of preferred use as recommended by the WHO
  • Prothionamide may be used instead of Ethionamide, while Terizidone may be used to replace Cycloserine
  • Ethionamide is often added to the treatment regimen due to its low cost
Pretomanid
  • A recently approved oral nitroimidazooxazine antimycobacterial given as part of the combination therapy with Bedaquiline & Linezolid for treatment of XDR-TB or treatment-intolerant or non-responsive MDR-TB
  • Approved for limited & specific patient population only since further studies are needed to prove its safety & effectiveness in other patient groups
Medicines for MDR-TB & RR-TB Treatment Based on Groups
  • Group A: Fluoroquinolones (in order of preference): Levofloxacin, Moxifloxacin, Gatifloxacin
  • Group B: 2nd-line injectable agents: Amikacin, Capreomycin, Kanamycin, Streptomycin (refer to the description above regarding Streptomycin use)
  • Group C: Other core 2nd-line agents (in order of preference): Ethionamide/ Prothionamide, Cycloserine/Terizidone, Linezolid, Clofazimine
  • Group D: Add-on agents (not included in the MDR-TB regimen core):
    • D1: Pyrazinamide, Ethambutol, high-dose Isoniazid
    • D2: Bedaquiline, Delamanid
    • D3: Para-aminosalicylic acid, Imipenem-cilastatin, Meropenem, Amoxicillin-clavulanate (Carbapenems & Clavulanate should be used concomitantly; Clavulanate is available only in combination with Amoxicillin), Thioacetazone (contraindicated in HIV patients)
    • Composed of agents that are not included in the core group of 2nd-line medications
    • Resistance of M tuberculosis to the macrolides (Clarithromycin, Azithromycin) enabled their removal in the list of agents for MDR-TB
Fixed-Dose Combinations (FDC)
  • Preferred preparation in managing drug-susceptible TB patients, instead of the individual drugs
  • Separate medications may be beneficial for certain individuals who have accompanying medical disorders (eg those with kidney or renal disease, drug intolerance) since each drug may need to undergo dose adjustment 
  • ≥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

Surgical Intervention

  • Elective partial lung resection (eg lobectomy, wedge resection), with an appropriate MDR-TB therapy may be utilized as a treatment approach in patients w/ MDR-TB or RR-TB
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