Tuberculosis medical therapy: Difference between revisions

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|Lapse is ≥14 d in duration
|Lapse is ≥14 d in duration
| colspan="2" style="width: 400px;" |*Restart treatment from the beginning
| colspan="2" style="width: 400px;" |Restart treatment from the beginning
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! rowspan="4" |During continuation phase
! rowspan="4" |During continuation phase
|Received ≥80% of doses and sputum was AFB smear negative on initial testing
|Received ≥80% of doses and sputum was AFB smear negative on initial testing
| colspan="2" style="width: 400px;" |Further therapy may not be necessary
| colspan="2" style="width: 400px;" |Additional therapy may not be necessary


|-
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|*Received ≥80% of doses and sputum was AFB smear positive on initial testing
|*Received ≥80% of doses and sputum was AFB smear positive on initial testing
| colspan="2" style="width: 400px;" |Continue therapy until all doses are completed
| colspan="2" style="width: 400px;" |Continue the treatment until all doses are completed


|-
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|Received <80% of doses and accumulative lapse is <3 mo in duration
|Received <80% of doses and accumulative lapse is <3 mo in duration
| colspan="2" style="width: 400px;" |Continue therapy until all doses are completed (full course), unless consecutive lapse is >2 mo
| colspan="2" style="width: 400px;" |Continue therapy until all doses are completed (full course), unless consecutive lapse is >2 mo
If treatment cannot be completed within the recommended time frame for regimen, restart therapy from the beginning (ie, restart intensive phase, to be followed by a continuation phase
If treatment regimen cannot be completed within the recommended time frame, restart therapy (ie, restart intensive phase then the continuation phase)


|-
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|*Received <80% of doses and lapse is ≥3 mo in duration
|*Received <80% of doses and lapse is ≥3 mo in duration
| colspan="2" style="width: 400px;" |Restart therapy from the beginning, new intensive and continuation phases (ie, restart intensive phase, to be followed by continuation phase)
| colspan="2" style="width: 400px;" |Restart therapy with new intensive and continuation phases (ie, restart intensive phase then the continuation phase)


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Revision as of 03:15, 28 March 2021

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2]; Ahmed Zaghw, M.D. [3]; Ammu Susheela, M.D. [4]; Sara Mehrsefat, M.D. [5]

Overview

The treatment of tuberculosis with anti-TB drugs is divided mainly into two phases; the initiation phase and maintenance phase. If there is a high likelihood of infection, start anti-TB treatment the patient even if the AFB stain is negative, while waiting for the culture results. The patient should come back in few weeks. Patients usually feel better a few weeks post-treatment. Patients have to be monitored for side effects and treatment failure. In addition, all TB cases are tested for drug resistance in the U.S.

Deciding To Initiate Treatment

  • The decision to initiate combination anti-tuberculous therapy is made according to the following:
Factors to be considered in deciding to initiate treatment empirically for active tuberculosis (TB) ( prior to microbiologic confirmation)[1]

Drugs Used in the Treatment of Tuberculosis

Groups Drugs
Group 1:
First-line oral drugs
Group 2:
Injectable drugs
Group 3: Fluoroquinolones
Group 4:
Oral bacteriostatic second-line drugs
Group 5:
Agents with unclear role in treatment of drug resistant-TB
Adapted from WHO 2013 Treatment of Tuberculosis: Guidelines – 4th ed.[2]

Standard Treatment Regimens

Empirical Anti-Tuberculosis Therapy
  • In developing endemic countries and in cases with high clinical suspicion of tuberculous pericarditis, it is recommended to start with empiric antituberculous treatment before establishing a definitive diagnosis. In the clinical settings where the diagnosis cannot be confirmed according to bacteriology, histology, or pericardial fluid analysis, clinical response to antituberculous treatment can be suggestive of a diagnosis of tuberculous pericarditis.[3]
  • In developed countries where TB is not endemic, antituberculous treatment should not be started empirically without a definitive diagnosis.[4]

Standard Regimens for New Patients

Adults

  ▸  Preferred regimen

  ▸  Alternate regimen 1

  ▸  Alternate regimen 2

Children

  ▸  Preferred regimen

Preferred Regimen - Adults
Intensive phase
(Administer each drug daily for 8 weeks)
Isoniazid 300 mg PO (5 mg/kg/day)
PLUS
Rifampicin 600 mg PO (10 mg/kg/day)
PLUS
Pyrazinamide 2 g PO (25 mg/kg/day)
PLUS
Ethambutol 1.6 g PO (15 mg/kg/day)
Continuation phase
(Administer each drug for 18 weeks)
Isoniazid 300 mg daily PO (5 mg/kg/day)
PLUS
Rifampicin 600 mg daily PO (10 mg/kg/day)
OR
Isoniazid 300 mg PO twice weekly (5 mg/kg/day)
PLUS
Rifampicin 600 mg/day PO twice weekly (10 mg/kg/day)
Alternate Regimen 1 - Adults
Intensive phase
Isoniazid 300 mg/day PO for 2 weeks (5 mg/kg/day)
PLUS
Rifampicin 600 mg/day PO for 2 weeks (10 mg/kg/day)
PLUS
Pyrazinamide 2 g/day PO for 2 weeks (25 mg/kg/day)
PLUS
Ethambutol 1.6 g PO for 2 weeks (15 mg/kg/day)
FOLLOWED BY
Isoniazid 300 mg/day PO twice weekly for 6 weeks (5 mg/kg/day)
PLUS
Rifampicin 600 mg/day PO twice weekly for 6 weeks (10 mg/kg/day)
PLUS
Pyrazinamide 2 g/day PO twice weekly for 6 weeks
PLUS
Ethambutol 1.6 g PO for 2 weeks (15 mg/kg/day)
Continuation phase
Isoniazid 300 mg/day PO biweekly for 18 weeks (5 mg/kg/day)
PLUS
Rifampicin 600 mg/day PO biweekly for 18 weeks (10 mg/kg/day)
Alternate Regimen 2 - Adults
'Intensive phase
Isoniazid 300 mg/day PO thrice weekly for 8 weeks (5 mg/kg/day)
PLUS
Rifampicin 600 mg/day P.O thrice weekly for 8 weeks (10 mg/kg/day)
PLUS
Pyrazinamide 2g/day PO thrice weekly for 8 week (25 mg/kg/day)
PLUS
Ethambutol 1.6 g PO thrice weekly for 8 weeks (15 mg/kg/day)
Continuation phase
Isoniazid 300 mg/day PO thrice weekly for 18 weeks (5 mg/kg/day)
PLUS
Rifampicin 600 mg/day PO thrice weekly for 18 weeks (10 mg/kg/day)
Preferred Regimen-Children
Intensive phase
(Administer each drug daily for 8 weeks)
Isoniazid 10 mg/kg PO (Max: 300 mg/day)
PLUS
Rifampicin 15 mg/kg PO (Max: 600 mg/day)
PLUS
Pyrazinamide 35 mg/kg PO (Max: 2 g/day)
PLUS
Ethambutol 20 mg/kg PO (Max: 1.6 g/day)
Continuation phase
(Administer each drug daily for 18 weeks)
Isoniazid 10 mg/kg PO (Max: 300 mg/day)
PLUS
Rifampicin 15 mg/kg PO (Max: 600 mg/day )
Table adapted from WHO 2013 Treatment of Tuberculosis: Guidelines – 4th ed.[2]

Standard Regimens for Previously Treated Patients

The previously treated patients should receive the 8-months regimen with first-line drugs.

Standard regimens for previously treated patients
Rapid molecular-based method
▸ Drug Susceptibility Testing (DST) results available in 1–2 days confirm or exclude MDR to guide the choice of regimen
Conventional method
High likelihood of MDR: Empirical MDR regimen
Low likelihood of MDR: 2HRZES / HRZE / 5HRE

(H = isoniazid, R= rifampicin, Z = pyrazinamide, E = ethambutol, S = streptomycin)
Regimen should be modified once DST results are available up to 2–3 months after the start of treatment.

Extrapulmonary Tuberculosis Treatment

The principles underlying the treatment of pulmonary tuberculosis can also be applied to extrapulmonary disease. Increasing evidence, including randomized controlled trials, reports that 6–9 month isoniazid and rifampicin containing regimens are effective for most of extrapulmonary sites of disease.[5]

Type of Extrapulmonary Tuberculosis Treatment
Lymph Node Tuberculosis
  • 6-month regimen is adequate for initial treatment
  • Therapeutic lymph node excision is not indicated
  • Incision and drainage in case of cervical lymphadenitis (associated with prolonged wound discharge and scarring)
  • Aspiration was reported to be useful (for large fluctuant lymph nodes that appear to be about to drain spontaneously)
Bone, Joint, and Spinal Tuberculosis
Pericardial Tuberculosis
  • A 6-month regimen is adequate
  • Adjunctive corticosteroids therapy is no longer recommended. However, selective use of [corticosteroids]] in patients who are at the highest risk for inflammatory complications may be possible in the following conditions:
Pleural Tuberculosis
  • A standard 6-month regimen
  • No evidence to suggest the routine use of adjunctive corticosteroids
  • Tuberculous empyema (occurs when a cavity ruptures into the pleural space), management includes:
    • Drainage (often requiring a surgical procedure)
    • Antituberculous chemotherapy
    • The optimal duration of therapy is not defined
Tuberculous Meningitis
  • Adult
    • INH, PZA, RIF, and EMB in an initial 2-month phase. INH and RIF continued for another 7–10 months
  • Children
  • Optimal duration of chemotherapy is not defined
  • Lumbar punctures may be performed to monitor changes in the cerebrospinal fluid cell during the treatment course
  • Adjunctive corticosteroids is tapered over 6–8 weeks
Disseminated Tuberculosis (miliary tuberculosis)
  • Standard daily 6-month regimen is adequate
  • The role of adjunct corticosteroid treatment in patients with miliary tuberculosis has not been established
Genitourinary Tuberculosis
  • Standard daily 6-month regimen is adequate
  • In cases of Ureteral obstruction
    • Procedures to relieve the obstruction are indicated.
  • In cases of hydronephrosis and renal failure due to obstruction
  • In cases of poorly functioning or nonfunctioning kidney (especially if hypertension or continuous flank pain is present)
    • Nephrectomy is considered
  • In cases of large tubo-ovarian abscesses
    • Surgery may be indicated
Abdominal Tuberculosis
  • Standard daily 6-month regimen is adequate
  • Adjunctive corticosteroids therapy is not recommended

Monitoring during treatment

Directly observed treatment, short-course (DOTS) strategy

5 components of DOTS strategy
Government committed to sustained TB control and activities
Case detection by sputum smear microscopy among symptomatic patients self reporting to health services
Standardized treatment, with supervision and patient support
An effective drug supply and management system
Monitoring and evaluation system, and impact measurement

Monitoring the Patients and Baseline Evaluations

Assessment of Treatment Response in New and Previously Treated Pulmonary TB

Definition of Treatment Response

Outcome Definition
Cure A patient with positive sputum smear/positive culture at the beginning of the therapy that are converted into smear-negative/culture-negative in the last month of therapy and on at least one previous occasion.
Treatment completed A patient who completed treatment but who does not have a negative sputum smear or culture result in the last month of therapy and on at least one previous occasionb ( Two consecutive negative specimens )
Treatment failure A patient with positive sputum smear or culture at 5 months or later during treatment course or has a multidrug-resistant (MDR) strain at any point of time during the course of treatment, whether they are smear-positive or smear-negative.
Died A patient who dies for any cause during the treatment course.
Default A patient whose course of treatment was interrupted for ≥ 2 months.
Transfer out A patient who was transferred to another recording and reporting unit and whose outcome of treatment is unknown.
Treatment success A sum of cured and completed treatmentc
A: These definitions can be applied to both pulmonary smear-positive and smear-negative patients, and also to patients with extrapulmonary disease.
b: The sputum examination may not have been performed or the results may not be available.
c: For smear- or culture-positive patients only.

Identification and Management of Patients at Increased Risk of Treatment Failure and Relapse

  • Approximately 80% of patients with pulmonary tuberculosis caused by drug-susceptible organisms who are started on standard four-drug therapy will have negative sputum cultures at this time. Patients with positive cultures after 2 months of treatment should undergo a careful evaluation to determine the cause.
  • The risk factors for adverse outcomes (treatment failure or relapse) include:

Prevention of Adverse Effects of Drugs

Isoniazid-induced peripheral neuropathy manifests as:

  • Adding Pyridoxine is recommended as a preventive treatment (10 mg/day with anti-TB drugs). Other guidelines recommend 25 mg/day.[6]

Symptom-Based Approach for Side-Effects of Anti-tuberculous Drugs

The Role of Drug-Susceptibility Testing (DST)

  • Initial Phase:
  • Ideally, DST is performed for all TB patients at the initiation of treatment to determine most appropriate therapy for each patient. However, the target of universal access to DST has not yet been recognized for most of the worldwide TB patients. Although countries are increasing laboratory capacity and implementing new rapid tests, WHO recommends that sputum specimens for testing susceptibility to isoniazid and rifampicin be performed for the following patient groups at the start of treatment:
  • All previously treated patients. The highest levels of MDR are detected in patients whose previous course of treatment has failed.
  • All individuals living with HIV plus they are diagnosed with active TB, particularly if they live in areas of high MDR prevalence. It is necessary to detect MDR as soon as possible in patients living with HIV because of their high risk of mortality.
  • Continuation Phase:
  • If rapid molecular-based DST is available, the results of MDR can be confirmed or excluded within 1-2 days, hence it can guide the choice of treatment regimen.
  • If DST is not available, the first-line drugs include 2HRZES/1HRZE/5HRE if country-specific data reports low or medium levels of MDR in its patients or if such data are not available
  • When DST results become available, treatment regimens should be adjusted accordingly.

Recommendations For New Patients

  • In new patients, if the specimen performed at the end of the intensive phase second month is smear-positive, sputum smear microscopy should be done at the end of the third month (strong/High grade of evidence).
  • In new patients, if the specimen performed at the end of third month is smear-positive, sputum culture and drug susceptibility testing (DST) should be done (strong/High grade of evidence)
  • For smear-positive pulmonary TB patients treated with first-line drugs, sputum smear microscopy may be performed at the completion of the intensive phase of treatment (conditional/High or moderate grade of evidence).
  • Sputum should be collected after the 1st dose of the intensive phase treatment. The end of the intensive phase is defined as the end of the 2nd month in new patients and the end of the 3rd month in previously treated patients receiving the 8-month regimen of first-line agents. This recommendation also applies to smear-negative patients.
  • Sputum specimens must be collected for smear examination at every follow-up sputum check. They must be collected without interrupting the treatment course and transported to the laboratory urgently.
  • The status of sputum smear at the end of the intensive phase is a poor predictor of relapse. However, identification of a positive sputum smear is still an essential way of the patient assessment.
  • The number of sputum smear-positive patients converted to negative at the end of the intensive phase is considered a good indicator of TB program performance.

Management of Treatment Interruption[1]

Time Point of Interruption Details of Interruption Approach
During intensive phase *Lapse is <14 d in duration Lapse is <14 d in duration Continue treatment to complete planned total number of doses (as long as all doses are completed within 3 mo)
Lapse is ≥14 d in duration Restart treatment from the beginning
During continuation phase Received ≥80% of doses and sputum was AFB smear negative on initial testing Additional therapy may not be necessary
*Received ≥80% of doses and sputum was AFB smear positive on initial testing Continue the treatment until all doses are completed
Received <80% of doses and accumulative lapse is <3 mo in duration Continue therapy until all doses are completed (full course), unless consecutive lapse is >2 mo

If treatment regimen cannot be completed within the recommended time frame, restart therapy (ie, restart intensive phase then the continuation phase)

*Received <80% of doses and lapse is ≥3 mo in duration Restart therapy with new intensive and continuation phases (ie, restart intensive phase then the continuation phase)

Managing Side-Effects of Anti-TB Drugs[7]

Side-Effects Causative Drugs Management
Severe Side-Effects
Skin Rash With Or Without Itching Streptomycin, Isoniazid, Rifampicin, Pyrazinamide Stop anti-TB drugs
Deafness (no wax on otoscopy) Streptomycin Stop anti-TB drugs
Dizziness (vertigo and nystagmus) Streptomycin Stop anti-TB drugs
Jaundice (other causes excluded), hepatitis Isoniazid, Rifampicin, Pyrazinamide Stop anti-TB drugs
Confusion/jaundice (drug-induced acute liver failure) Most anti-TB drugs Stop anti-TB drugs
Visual impairment (other causes excluded) Ethambutol Stop anti-TB drugs
Shock, purpura, acute renal failure Rifampicin Stop anti-TB drugs
Decreased Urine Output Streptomycin Stop anti-TB drugs
Minor Side-Effects
Anorexia, nausea, abdominal pain Isoniazid, Rifampicin, Pyrazinamide Give drugs with small meals or before bedtime, swallow pills slowly with small sips of water.
If symptoms persist or worsen, or there is protracted vomiting or any sign of bleeding,
consider the side-effect to be major and refer to clinician urgently.
Joint pains Pyrazinamide Aspirin or non-steroidal anti-inflammatory drug, or paracetamol
Burning, numbness or tingling sensation in the hands or feet Isoniazid Pyridoxine 50–75 mg daily
Drowsiness Isoniazid Reassurance. Give drugs before bedtime
Orange/red urine Rifampicin Reassurance, Patients should be told when starting treatment that this may happen and is normal
Flu-like syndrome Intermittent dosing of Rifampicin Change from intermittent to daily Rifampicin
† Fever, chills, malaise, headache, bone pain

Treatment Failure

  • Failure to respond to anti-TB drugs means;
  • Smear or culture-positivity at the fifth month or later.
  • Detection of MDR-TB at any point of therapy.
  • Treatment failure necessitate to step-wise approach to identify the causes of failure which could be due to any of the following features[8]
  • Poor supervision of the initial phase
  • Poor patient adherence
  • Poor quality of anti-TB drugs
  • Inappropriate doses of anti-TB drugs (below than recommended range)
  • Slow resolution due to extensive cavitation and a heavy initial bacillary load
  • Co-morbid conditions that interfere either with adherence or with response
  • MDR M. tuberculosis with no response to the first-line treatment
  • Non-viable bacteria remain visible by microscopy

Treatment Regimen

  • 1. Standard regimens for new patients [9]
  • 1.1. Adult
  • 1.1.1. Initial phase
  • Preferred regimen: Isoniazid 300 mg PO (5 mg/kg/day) qd for 8 weeks AND Rifampicin 600 mg PO (10 mg/kg/day) qd for 8 weeks AND Pyrazinamide 2 g PO (25 mg/kg/day) qd for 8 weeks AND Ethambutol 1.6 g PO (15 mg/kg/day) qd for 8 weeks
  • Alternative regimen (1): Isoniazid 300 mg/day PO for 2 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO for 2 weeks (10 mg/kg/day) AND Pyrazinamide 2 g/day PO for 2 weeks (25 mg/kg/day) AND Ethambutol 1.6 g PO for 2 weeks (15 mg/kg/day), followed by Isoniazid 300 mg/day PO twice weekly for 6 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO twice weekly for 6 weeks (10 mg/kg/day) AND Pyrazinamide 2 g/day PO twice weekly for 6 weeks AND Ethambutol 1.6 g PO for 2 weeks (15 mg/kg/day)
  • Alternative regimen (2): Isoniazid 300 mg/day PO thrice weekly for 8 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO thrice weekly for 8 weeks (10 mg/kg/day) AND Pyrazinamide 2g/day PO thrice weekly for 8 week (25 mg/kg/day) AND Ethambutol 1.6 g PO thrice weekly for 8 weeks (15 mg/kg/day)
  • 1.1.2 Continuation phase
  • Preferred regimen (1): Isoniazid 300 mg PO (5 mg/kg/day) qd AND Rifampicin 600 mg PO (10 mg/kg/day) qd for 18 weeks
  • Preferred regimen (2): Isoniazid 300 mg PO twice weekly (5 mg/kg/day) AND Rifampicin 600 mg/day PO twice weekly (10 mg/kg/day) for 18 weeks
  • Alternative regimen (1): Isoniazid 300 mg/day PO biweekly for 18 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO biweekly for 18 weeks (10 mg/kg/day)
  • Alternative regimen (2): Isoniazid 300 mg/day PO thrice weekly for 18 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO thrice weekly for 18 weeks (10 mg/kg/day)
  • 1.2 Pediatric
  • 1.2.1 Initial phase
  • Preferred regimen: Isoniazid 10 mg/kg PO (Maximum, 300 mg/day) AND Rifampicin 15 mg/kg PO (Maximum, 600 mg/day) AND Pyrazinamide 35 mg/kg PO (Maximum, 2 g/day) AND Ethambutol 20 mg/kg PO (Maximum, 1.6 g/day), each for 8 weeks
  • 1.2.2 Continuation phase
  • Preferred regimen: Isoniazid 10 mg/kg PO (Maximum, 300 mg/day) AND Rifampicin 15 mg/kg PO (Maximum, 600 mg/day), each drug daily for 18 weeks
  • 2. RR-TB or MDR-TB Tuberculosis[10]
  • 2.1 Adult
  • Preferred regimen: At least 5 agents combination
  • 2.2 Pediatric
  • Preferred regimen: At least 5 agents combination
  • 3. XDR Tuberculosis [11]
  • 3.1 Adult
  • Preferred regimen: 3 agents combination
  • 3.2 Pediatric
  • Preferred regimen: 3 agents combination

Ocular tuberculosis

  • 1. Pathogen-directed antimicrobial therapy[12][13]
  • 1. Adult patients
  • 1.1 Intensive phase
  • Preferred regimen: Isoniazid 5 mg/kg (max: 300 mg) PO qd for 2 months AND Rifampin 10 mg/kg (max: 600 mg) PO qd for 2 months AND Pyrazinamide 15–30 mg/kg (max: 2 g) PO qd for 2 months AND Ethambutol 15-20 mg/kg (max: 1 g) PO qd for 2 months
  • 1.2 Continuation phase
  • Preferred regimen: Isoniazid 5 mg/kg (max: 300 mg) PO qd for 4 months AND Rifampin 10 mg/kg (max: 600 mg) PO qd for 4 months
  • 2. Pediatric patients
  • 2.1 Intensive phase
  • Preferred regimen: Isoniazid 10-15 mg/kg (max: 300 mg) PO qd for 2 months AND Rifampin 10-20 mg/kg (max: 600 mg) PO qd for 2 months AND Pyrazinamide 15-30 mg/kg (max: 2 g) PO qd for 2 months AND Ethambutol
  • 2.2 Continuation phase
  • Preferred regimen: Isoniazid 10–15 mg/kg (max: 300 mg) PO qd for 4 months AND Rifampin 10–20 mg/kg (max: 600 mg) PO qd for 4 months
  • Note (1): Ethambutol may be administered at a dose of 15-20 mg/kg (max: 1 g) PO qd for 2 months but is generally avoided because of potential ocular toxicity.[14]
  • Note (2): A short course of systemic corticosteroids may be necessary initially if there is sight-threatening inflammation.


Contraindicated medications

Active tuberculosis is considered an absolute contraindication to the use of the following medications:

References

  1. 1.0 1.1 Clinical Infectious Diseases. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. (2016) http://cid.oxfordjournals.org/content/63/7/e147.full.pdf+html Accessed on October 14, 2016
  2. 2.0 2.1 "2013 WHO Treatment of Tuberculosis: Guidelines for National Programmes (4th Edition)".
  3. Mayosi, BM.; Burgess, LJ.; Doubell, AF. (2005). "Tuberculous pericarditis". Circulation. 112 (23): 3608–16. doi:10.1161/CIRCULATIONAHA.105.543066. PMID 16330703. Unknown parameter |month= ignored (help)
  4. Soler-Soler, J.; Sagristà-Sauleda, J.; Permanyer-Miralda, G. (2001). "Management of pericardial effusion". Heart. 86 (2): 235–40. PMID 11454853. Unknown parameter |month= ignored (help)
  5. Clinical Infectious Diseases. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. (2016) http://cid.oxfordjournals.org/content/63/7/e147.full.pdf+html Accessed on October 14, 2016
  6. "Treatment of tuberculosis". MMWR Recomm Rep. 52 (RR-11): 1–77. 2003. PMID 12836625. Unknown parameter |month= ignored (help)
  7. "http://whqlibdoc.who.int/publications/2004/9241546034.pdf" (PDF). External link in |title= (help)
  8. "http://whqlibdoc.who.int/publications/2004/9241546034.pdf" (PDF). External link in |title= (help)
  9. Treatment of tuberculosis guidelines. Geneva: World Health Organization. 2010. ISBN 9789241547833.
  10. WHO treatment guidelines for drug- resistant tuberculosis 2016 update. http://apps.who.int/iris/bitstream/10665/250125/1/9789241549639-eng.pdf?ua=1Accessed on October 14, 2016
  11. "WHO".
  12. Blumberg, Henry M.; Burman, William J.; Chaisson, Richard E.; Daley, Charles L.; Etkind, Sue C.; Friedman, Lloyd N.; Fujiwara, Paula; Grzemska, Malgosia; Hopewell, Philip C.; Iseman, Michael D.; Jasmer, Robert M.; Koppaka, Venkatarama; Menzies, Richard I.; O'Brien, Richard J.; Reves, Randall R.; Reichman, Lee B.; Simone, Patricia M.; Starke, Jeffrey R.; Vernon, Andrew A.; American Thoracic Society, Centers for Disease Control and Prevention and the Infectious Diseases Society (2003-02-15). "American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis". American Journal of Respiratory and Critical Care Medicine. 167 (4): 603–662. doi:10.1164/rccm.167.4.603. ISSN 1073-449X. PMID 12588714.
  13. American Thoracic Society; CDC; Infectious Diseases Society of America (2003-06-20). "Treatment of tuberculosis". MMWR. Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. 52 (RR-11): 1–77. ISSN 1057-5987. PMID 12836625.
  14. Bennett, John (2015). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Elsevier/Saunders. ISBN 978-1455748013.

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