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.

Tuberculosis%20-%20pulmonary Treatment

Principles of Therapy

  • Essential principles of care for persons with active or suspected tuberculosis (TB) include:
    • Prompt and accurate diagnosis
    • Use of standardized and effective treatment regimen plus proper treatment support and supervision
    • Monitor treatment response
  • Patients should be provided with adequate knowledge regarding the disease and the importance of treatment compliance 
  • Optimal duration of sputum-positive pulmonary tuberculosis (PTB) is at least 6 months
Treatment Goals
  • Treat the patient and bring back quality of life and productivity
  • Prevent death and relapse of TB
  • Lower TB transmission
  • Stop the development and 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 and to employ daily intensive-phase dosing especially in TB patients starting treatment with Isoniazid resistance
  • Achieve goals with the lowest possible dose and minimal toxic drug effects
Treatment Phases
  • Initial or intensive phase is when combination drugs are used to rapidly kill replicating populations of M tuberculosis and occurrence of drug resistance is prevented
    • Bactericidal effect leads to fast conversion of bacteriological sputum and improvement in clinical symptoms
  • Continuation phase is when drugs slowly and intermittently kill replicating populations
    • Remaining bacteria are eliminated and consequent relapse is prevented
Dosing Frequency
  • In individuals with drug-susceptible PTB, daily intake of the required medications is recommended and the thrice-weekly regimen is no longer advisable, both in the intensive and 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 and acquired drug resistance were all higher in the latter
    • When daily regimen was compared to thrice-weekly regimen in the continuation phase, TB recurrence and 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, and that medications are taken without fail
    • Higher risk of failure and acquired drug resistance were also noted in patients with 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) and/or digital medication monitor (phone calls, messaging), material support (food, transportation fees, monetary allowance, etc), education of staff members and psychological support
    • Health education and counseling on the disease and treatment adherence is recommended for all patients on TB treatment
  • 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 and 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 and 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 and 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 and 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 and DST should be done upon return of the patient who missed 2 consecutive months of treatment
Hospitalization
  • Recommended in severely ill patients and for those with 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 and 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 and the 4-month fluoroquinolone-containing therapy should be avoided
  • For smear-negative, with intrathoracic lymph node and 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 Rifampicin-susceptible and Isoniazid-resistant TB Patients
  • Recommended treatment by the WHO is 6 months (H)REZ and Levofloxacin [6(H)REZ-Lfx]
  • 6(H)REZ may be used in Isoniazid-resistant TB patients with unknown Rifampicin susceptibility and with fluoroquinolone resistance or intolerance to Levofloxacin
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 and for at least 4 months after the patient had smear and 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 and 2nd-line injectable agents or are regarded as having such resistance improbable and did not have prior 2nd-line drug treatment may have a shorter duration of MDR-TB therapy of 9-12 months
    • Shorter all-oral Bedaquiline-containing regimen for 9-12 months is recommended by the WHO as the preferred regimen for patients diagnosed with MDR-TB or RR-TB without previous treatment with 2nd-line drugs for >1 month and without resistance to fluoroquinolones, and in patients without extensive TB disease (eg presence of bilateral cavitary disease or extensive parenchymal damage on chest X-ray) or severe EPTB (eg miliary TB or TB meningitis) 
    • Shorter MDR-TB therapy is not advisable in patients who received treatment with 2nd-line drugs for >1 month and those with extrapulmonary disease
    • The following may follow the short-term regimen: Adult and 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 and non-pregnant women
    • Children and patients with HIV can be regarded with the same consideration as adults and people without HIV, respectively, in terms of using the shorter regimen
  •  Longer treatment regimen is recommended for patients with MDR-TB or RR-TB who are not eligible for shorter all-oral regimens, including patients with resistance to fluoroquinolones
    • Include all 3 group A agents and at least 1 group B agent or as alternative 1-2 group A agents and all group B agents
    • Group C agents are added to the regimen when group A and B agents cannot be used alone
    • Clavulanic acid is not recommended for inclusion in the longer regimens for MDR-TB and RR-TB
    • Fully oral regimen for longer MDR-TB treatment is preferred
    • A total treatment duration of 18-20 months is suggested for most patients with MDR-TB or RR-TB on longer regimens or 15-17 months after culture conversion
      • Duration of therapy may be modified according to patient’s response to treatment
      • In longer regimens for MDR-TB or RR-TB containing Amikacin or Streptomycin, an intensive phase of 6-7 months is suggested which may be modified based on patient’s response to treatment
  • Treatment regimen composed of Bedaquiline, Pretomanid and Linezolid for 6-9 months may be used under operational research conditions in patients with pulmonary MDR-TB with resistance to fluoroquinolones and had no previous exposure to or treated not >2 weeks with Bedaquiline and Linezolid
Complications
TB Patients with 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 and under ART therapy, a 6-month duration is preferred rather than 8-months or more with regards to TB treatment completion
  • May be eligible for treatment with shorter all-oral Bedaquiline-containing regimen for MDR-TB but combination with Ritonavir should be avoided or administered with caution
Patients with Tuberculous Meningitis
  • Corticosteroid (Dexamethasone or Prednisolone) should be added in the treatment, tapered for 6-8 weeks
Patients with Tuberculous Pericarditis
  • Corticosteroid may also be added in the treatment
Patients with LTBI
  • Preferred regimens are Rifamycin-based regimens because of their high treatment completion rates, safety and effectiveness:
    • Isoniazid-Rifapentine combination administered once weekly for 3 months: Strongly recommended for adults and children >2 years old and in HIV-positive individuals
    • Rifampicin daily for 4 months: Recommended for HIV-negative adults and children of all ages
    • Isoniazid-Rifampicin combination daily for 3 months: Recommended for adults and children of all ages and in HIV-positive individuals
  • Alternative recommended regimens (considered less effective due to higher toxicity risk and lower treatment completion rates):
    • Isoniazid daily for 6 months: Strongly recommended for HIV-negative adults and children of all ages andconditionally recommended for HIV-positive adults and children regardless of age
    • Isoniazid daily for 9 months: Conditionally recommended for both HIV-negative and HIV-positive adults and children regardless of age
  • 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 and 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 and liver function tests (LFTs) is recommended during treatment of patients with pre-existing liver disease
Rifampicin (R)
  • Semisynthetic derivative of Rifamycin
  • Has bactericidal action and potent sterilizing effect against tubercle bacilli in both cellular and extracellular locations
  • Indicated for all forms of TB caused by organisms that are known or presumed to be susceptible and is also considered to be an essential component of all short-course regimens
  • Should always be administered together with other effective anti-TB drugs because of high risk for development of resistance
  • 6 months regimen is recommended since 2 months regimen is associated with more relapses and deaths
  • Clinical monitoring and LFTs is recommended during treatment of patients with 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 and in areas of acute inflammation
  • Highly effective against acute inflammatory changes during the first 2 months of treatment
  • Has shortened the treatment regimen and reduced the risk of relapse
Ethambutol (E)
  • Generally used in combination with 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 with known or suspected high levels of Isoniazid resistance and Isoniazid susceptibility testing is not done
2nd-Line Anti-Tuberculosis (TB) Agents
  • Should be used in patients with MDR-TB
Aminoglycosides
  • In the revised grouping, it currently belongs to group C for use in susceptible MDR-TB and RR-TB patients in longer treatment regimen
  • Eg Amikacin, Streptomycin
    • Amikacin is preferred over Streptomycin
    • Have been used extensively for the treatment of MDR-TB
    • Capreomycin and Kanamycin are no longer included in any regimen for MDR-TB due to increased risk of treatment failure, relapse or death
Streptomycin (S)
  • An aminoglycoside antibiotic derived from Streptomyces griseus that is used for TB and gram-negative sensitive infections
  • Streptomycin and 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 and attains bactericidal concentrations, particularly in tuberculous cavities
Bedaquiline
  • Recently approved treatment for adult patients with pulmonary MDR-TB and RR-TB
    • Given as part of the combination therapy for extensively drug-resistant TB (XDR-TB) and MDR-TB allergic to >2 drugs
    • In the revised grouping, it is currently under group A for the longer regimen of MDR-TB and RR-TB treatment
Delamanid
  • A nitro-dihydro-imidazooxazole that inhibits mycolic acid synthesis and has been recently approved for the treatment of MDR-TB and RR-TB patients aged ≥3 years on longer regimens
    • Given as part of the combination therapy for MDR-TB in adult patients who are intolerant or resistant to standard effective treatment regimen
    • In the revised grouping, it is currently under group C, as part of the add-on medications to complete the longer regimen of MDR-TB and RR-TB treatment when group A and B agents cannot be used
  • May be useful in patients with increased risk for poor outcomes (eg drug intolerance or contraindication, extensive or advanced disease, resistance to fluoroquinolones and/or injectable drugs, and XDR-TB)
  • May now be used in patients 6-17 years of age in the longer regimen of MDR-TB and RR-TB therapy
Fluoroquinolones
  • Belong to group A drugs used to treat MDR-TB and RR-TB under the longer treatment regimen
  • Eg Levofloxacin, Moxifloxacin
  • Ofloxacin and Ciprofloxacin are removed from the list of medications approved for MDR-TB and RR-TB because of lack of information regarding their effectivity
Oral Bacteriostatic 2nd-Line Agents
  • Agents belonging to group B or C that may be used in MDR-TB and RR-TB longer term regimen
  • Eg Ethionamide/ Prothionamide, Cycloserine/Terizidone, Linezolid, Clofazimine, in order of preferred use as recommended by the WHO
  • Terizidone may be used to replace Cycloserine, while Prothionamide may be used instead of Ethionamide
  • Ethionamide is often added to the treatment regimen due to its low cost
  • Ethionamide or Prothionamide and Para-aminosalicylic acid may be included in the longer regimens for MDR-TB and RR-TB only if Bedaquiline, Linezolid, Clofazimine or Delamanid are not used or when there are no other possible options
Pretomanid
  • A recently approved oral nitroimidazooxazine antimycobacterial given as part of the combination therapy with Bedaquiline and Linezolid for treatment of XDR-TB or treatment-intolerant or non-responsive MDR-TB
  • Approved for limited and specific patient population only since further studies are needed to prove its safety and effectiveness in other patient groups
Medicines for Longer MDR-TB and RR-TB Treatment Based on Groups
  • Group A: Levofloxacin or Moxifloxacin, Bedaquiline, Linezolid
    • Highly recommended to be included in all longer MDR-TB regimens and used for all patients with MDR-TB or RR-TB eligible for longer regimens
    • Have shown to be highly effective in improving treatment outcomes and decreasing mortality
  • Group B: Clofazimine, Cycloserine or Terizidone
  • Group C (in order of preference): Ethambutol, Delamanid, Pyrazinamide, Imipenem/cilastatin or Meropenem, Amikacin or Streptomycin, Ethionamide or Prothionamide, Para-aminosalicylic acid
    • Less effective drugs
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, and may promote patient’s compliance due to smaller number of tablets to consume
  • Some trials have shown that FDC and 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 with contraindication to individual drug component
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