Treatment of Pulmonary and

Extra-Pulmonary
Tuberculosis in Adults
Tuozo, Charles Ezra Anthony L.
• It is crucial to understand that
once treatment is initiated for TB,
whether bacteriologically
confirmed or clinically diagnosed,
clinicians assume a public health
responsibility both to the
individual patient and to the
community at large.
• Evaluation of TB patients before
and during treatment should not
only be clinical, it should also
involve assessment of risk factors
leading to disruption of treatment.
• A TB patient, who is cured or has completed treatment with
appropriate standardized treatment regimen, no longer
becomes infectious thus preventing further disease
transmission and emergence of drug-resistance.
• For clinicians who likely cannot monitor the adherence of their
individual patients to TB treatment, they need to consider
referring to healthcare providers (public or private facilities)
offering support for supervised treatment services.
Definition of Terms
• New Case – patient who has never been treated for TB or has
taken antiTB drugs for less than 1 month.
• Retreatment Case – patient who has received 1 month or more
of anti-TB drugs in the past (excluding prophylaxis or treatment
for latent TB infection), further classifed by the outcome of most
recent course of treatment, as follows:
Definition of Terms
1. Relapse – patient has previously been treated for TB, declared
cured or treatment completed at the end of most recent course of
treatment, and is now diagnosed with a recurrent episode of TB
(either a true relapse or a new episode of TB caused by
reinfection)
2. Treatment after failure – patient has previously been treated
for TB and declared treatment failed at the end of most recent
course of treatment
Definition of Terms
3. Treatment after lost to follow-up (TALF) – patient has
previously been treated for TB, declared lost to follow-up at the
end of most recent course of treatment (previously known as
Return After Default)
4. Previous Treatment Outcome Unknown (PTOU) – patient
has previously been treated for TB but outcome after their most
recent course of treatment is unknown or undocumented
5. Other - patients who do not ft into any of the categories listed
above.
Outline of Issues on Treatment of TB
A. PRE-TREATMENT EVALUATION
B. TREATMENT OF PULMONARY AND EXTRAPULMONARY
TB
C. ORGANIZATION AND SUPERVISION OF TREATMENT
D. MONITORING OF OUTCOMES AND TREATMENT
RESPONSE
E. MONITORING FOR AND MANAGEMENT OF ADVERSE
REACTIONS
F. ADJUNCTIVE THERAPY FOR TB
A. PRE-TREATMENT EVALUATION
1. What pre-treatment clinical evaluation
should be done to patients with TB disease?
• Thorough history and physical examination should be done on
all patients with TB disease.
History should include:
 past medical history (previous TB treatment, risk factors for
hepatic, renal and ocular toxicity),
sexual history, personal and social history,
and occupation. (Strong recommendation, moderate quality
evidence)
• The liver risk factors that should be identifed include chronic
alcohol consumption, viral hepatitis, pre-existing liver diseases,
exposure to hepatotoxic agents, previous abnormal results of
ALT/AST/bilirubin and HIV infection. (Strong recommendation,
moderate quality evidence)
• Baseline testing of visual acuity using Snellen and color
perception charts are advised when ethambutol is to be used.
(Strong recommendation, low quality evidence)
2. What baseline laboratory examinations should
routinely be requested before starting anti-TB treatment?

• Baseline testing for serum alanine aminotransferase (ALT) and

serum creatinine are recommended before starting anti-TB
treatment.
• In resource-limited settings, baseline ALT and serum creatinine,
at the least, should be requested for patients older than 60
years old, and those with risk factors for liver or kidney disease
before starting TB treatment. (Strong recommendation,
moderate quality evidence)
• All patients should be taught how to recognize symptoms of
common adverse effects and to consult if they develop such
symptoms.
• All patients with TB with history of high-risk behavior for HIV
and coming from areas with high prevalence of HIV (see Table
13) should be offered provider initiated counseling and testing
(PICT) for HIV. (Strong recommendation, moderate quality
evidence)
• Screening for diabetes mellitus using Fasting Blood Sugar
(FBS), Random Blood Sugar (RBS), or 75g Oral Glucose
Tolerance Test (OGTT) is recommended for all patients with TB.
At present, HbA1c is not routinely recommended in the
Philippines to screen for DM due to problems with
standardization; if available, however, should be confirmed by
FBS, RBS or 75-grams OGTT. Proper management of glucose
levels is essential to treatment of TB. (Strong recommendation,
high quality evidence)
• Serum uric acid testing is NOT recommended before starting
anti TB treatment. The finding of asymptomatic
hyperuricemia is not an indication to avoid pyrazinamide.
(Strong recommendation, moderate quality evidence)
B. TREATMENT OF PULMONARY AND
EXTRAPULMONARY TB
3. What is the effective treatment
regimen for new PTB cases?
• The effective treatment regimen for new PTB cases (without
risk factors for drug resistance) is 2 months of isoniazid,
rifampicin, pyrazinamide, and ethambutol (2HRZE) as intensive
phase followed by 4 months of isoniazid and rifampicin (4HR)
as continuation phase or Category I (2HRZE/4HR) regardless of
bacteriologic status. (Strong recommendation, high quality
evidence)
4. How should retreatment cases be
managed?
• All retreatment cases should immediately be referred to the
nearest Xpert® MTB/Rif facility for rifampicin susceptibility
testing. (Strong recommendation, high quality evidence)
• Category II regimen (2HRZES/1HRZE/5HRE) should only be
given among confrmed Rifampicin-sensitive retreatment cases
or in circumstances where Xpert® MTB/Rif services cannot be
performed (i.e. no access or no sputum specimen). (Strong
recommendation, moderate quality evidence)
• Rifampicin-resistant cases should immediately be referred to a
PMDT facility for further management
5. How should PTB patients who have
interrupted treatment be managed?
• Patients who fail to follow-up as scheduled should be
immediately traced through: telephone call, text message or
home/workplace visit.
• Assess the cause of interruption and agree on solutions and
treatment plans based on length of interruption and duration of
treatment prior to interruption as outlined in Table 19.
7. What are the effective treatment regimens and
duration of treatment for EPTB?

• The effective treatment regimen for majority of new EPTB cases

is Category I (2HRZE/4HR). CNS, bones/joints are to be treated
with Category Ia (2HRZE/10HR). Table 20 and Table 21 list the
treatment regimens for different EPTB. (Strong
recommendation, low-high quality evidence)
• Referral to relevant specialties is warranted in managing EPTB
for optimal treatment.
8. How effective are corticosteroids for
the treatment of EPTB?
• The use of corticosteroids as adjunctive therapy is
recommended ONLY for patients with TB meningitis and/or TB
pericarditis.
• In TB meningitis, the recommended regimen is
dexamethasone 0.4 mg/kg/24H with a reducing course over
6-8 weeks (Strong recommendation, high quality evidence)
• In TB pericarditis, the recommended regimen is prednisolone
60 mg for the first 4 weeks, 30 mg for weeks 5-8, 15 mg for
weeks 9-10 and 5 mg for week 11 (Strong recommendation,
moderate quality evidence)
 9. What is the role of surgery in the
management of EPTB?
CNS
• Hydrocephalus, tuberculous cerebral
abscess, and vertebral TB with
paraparesis are indications for
neurosurgical referral.
• Early VP shunting should be
considered among those with non-
communicating hydrocephalus and
among those with communicating
hydrocephalus failing medical
management. (Strong recommendation,
moderate quality evidence)
Spine
Surgery for spinal tuberculosis in addition
to the standard chemotherapy is indicated
in patients started on
(a) ambulant chemotherapy who develop
progressive kyphosis;
(b) patients with compression of the spinal
cord in whom the neurological status
deteriorates in spite of chemotherapy.
(Strong recommendation, moderate
quality evidence)
Lymph Node
Therapeutic lymph node excision is
not recommended for TB
lymphadenitis unless unusual
circumstances arise (e.g. large
fluctuant lymph nodes that are
about to spontaneously drain).
(Strong recommendation, moderate
quality evidence)
Pericardium
Open surgical drainage under general
anesthesia is an option for patients with TB
pericardial effusion. (Weak recommendation,
low quality evidence)
Pleura
Surgical procedures like pigtail
drainage and decortication
may be needed in
symptomatic patients due to
pleural loculation and
thickening. (Weak
recommendation, low quality
evidence)
Gastrointestinal and Peritoneum
Surgery is reserved for complications such as gut obstruction,
fistula formation, and intractable ulceration. (Strong
recommendation, moderate quality evidence)
Liver
Hepatectomy may be an option for nodular hepatic TB when
malignancy is possible. Percutaneous aspiration and drainage
may be needed in patients with multiple large hepatic TB
abscess. Biliary decompression is done in patients with
obstructive jaundice when necessary. (Weak recommendation,
low quality evidence)
Genitourinary
Reconstructive surgery is an option for patients who have
symptoms caused by sequelae of genitourinary tuberculosis.
(Weak recommendation, low quality evidence)
C. ORGANIZATION AND SUPERVISION
OF TREATMENT
10. How should anti-TB medications be
administered?
Patient-centered, directly observed therapy (DOT) should be
offered to all patients who will undergo treatment for TB in health
facilities with accredited DOTS programs

In patient-centered DOT, a patient is given the opportunity to

choose where they want to be treated, and who will supervise
them, either a healthcare worker, community health worker or
family member, depending on clinical, social, cultural
circumstances.
Outcomes are better with patient-centered DOT in terms of
completion of treatment, smear conversion and default rates
compared to daily health facility based treatment and is less
expensive in a programmatic setting. (Strong recommendation,
high quality evidence)
11. What are the effective ways of tracking
patients and monitoring adherence to treatment?

The healthcare provider should educate the patient and

treatment partner along with the following strategies to track and
monitor adherence to treatment:
• Remind patients of their appointments, by pre-appointment
phone calls and SMS
• Default reminder letter or home visits for those who miss
appointments
• Use of SMS as reminders
• Give incentives and enablers such as nutritious, culturally
appropriate daily meals and food packages
• Coordinate with DOTS centers and support groups
(Strong recommendation, moderate quality evidence)
12. How effective are fixed-dose combination
drugs compared to single-drug formulations?

Fixed-dose combination (FDC) drugs are convenient in terms of

acceptability, side effects and adherence and are preferred
especially in a programmatic setting. They are similar to single-
drug formulations (SDF) in preventing treatment failure or
disease relapse when given under DOT. (Strong
recommendation, moderate quality evidence)
Single-drug formulations are useful for the following situations:
• Those who experience adverse reactions or at risk for adverse
reactions (elderly, liver disease)
• With co-morbid conditions requiring dose adjustments (liver or
kidney disease) or expected to have significant drug interactions
(HIV, DM)
13. How effective is daily vs. intermittent
regimen for the treatment of TB?
• Daily regimen is recommended for the treatment of TB
particularly if FDC is used.
• Intermittent regimens less than 3x/week are not preferred
because of the greater impact of missed doses on success rates.
• Thrice weekly intermittent regimens may be offered in special
situations where daily regimen is not feasible (Strong
recommendation, moderate quality evidence)
Monitoring of
Outcomes and
Treatment Response
 How should we monitor treatment response?
• Clinically diagnosed and bacteriologically-confirmed cases treated with first-line drugs:
1 sputum smear microscopy at the end of the intensive phase of treatment
o New cases – end of 2 months; if (+), repeat at the end of 3rd month; if still (+), do
Xpert®MTB/Rif, sputum culture and DST
o Retreatment cases – end of 3 months; if (+), do Xpert®MTB/Rif, sputum culture and
DST
o Negative at end of intensive phase - no further sputum monitoring
• Sputum specimen at end of 5 and 6 months should be obtained for all new smear positive
TB patients. If (+), do culture and DST
• Drug-resistant strain - referred to a PMDT center
• All PTB and EPTB patients - monitored clinically. Body weight is a useful progress indicator
that should be monitored and medication doses adjusted according to weight
• Xpert MTB/RIF - poor specificity as an early sputum biomarker for monitoring TB
treatment, less rapid fall in mycobacterial load compared to sputum smear, does not
differentiate between viable, dormant, and nonviable intact MTB
 • Cured - A patient with bacteriologically-
confirmed TB at the beginning of treatment and
who is smear- or culture-negative in the last
month of treatment and on at least one
previous occasion in the continuation phase.

How should • Treatment completed – A patient who

completes treatment without evidence of
failure but with no record to show that sputum
we classify smear or culture results in the last month of
treatment and on at least one previous

treatment
occasion are negative, either because tests are
not done or because results are unavailable.
This group includes:
outcomes? - A bacteriologically-confirmed patient who has
completed treatment but without DSSM follow-up
in the last month of treatment and on at least 1
previous occasion.
- A clinically diagnosed patient who has
completed treatment.
 • Treatment Failed - A patient whose sputum
smear or culture is positive at five (5) months
or later during treatment OR a clinically-
diagnosed patient for whom sputum
How should examination cannot be done and who does
not show clinical improvement anytime

we classify
during treatment.
• Died – A patient who dies for any reason
during the course of treatment.
treatment • Lost to follow-up - A patient whose
treatment is interrupted for two (2)
outcomes? consecutive months or more.
• Not evaluated - A patient for whom no
treatment outcome is assigned. This includes
cases transferred to another DOTS facility
and whose treatment outcome is unknown.
When is a patient on TB treatment
considered non-infectious?

• Patients who are bacteriologically-confirmed and do not have risk factors for drug-resistance
are considered non-infectious when they have received at least 14 daily doses of treatment
with sputum conversion and clinical improvement.
• Patients who are clinically diagnosed and do not have risk factors for drug-resistance are
considered non-infectious when they have received at least 5 daily doses of treatment with
clinical improvement.
What is paradoxical treatment
response and how should it be
managed?

Paradoxical Response (PR)

• unusual expansion or new formation of a tuberculous lesion (pulmonary or extra-pulmonary)
during TB treatment in the absence of evidence of disease relapse or presence of another
diagnosis
• most common in patients with extra-pulmonary and disseminated TB (miliary TB and TB
meningitis)
• Non-severe form – No specific treatment, anti-TB treatment should be continued
• Severe form - symptomatic treatment, Corticosteroid treatment appears to be safe
Monitoring for and
Management of
Adverse Reactions
What are the common adverse reactions to
anti-TB drugs?

Minor adverse reactions

• Gastrointestinal intolerance
• Mild or localized skin reactions
• Orange/red-colored urine
• Pain at the injection site
• Burning sensation in the feet due to peripheral neuropathy
• Arthralgia due to hyperuricemia
• Flu-like symptoms (fever, muscle pains, inflammation of the respiratory tract)
What are the common adverse
reactions to anti-TB drugs?

Major adverse reactions

• Severe skin rash due to hypersensitivity
• Jaundice due to hepatitis
• Impairment of visual acuity and color vision due to optic neuritis
• Hearing impairment, ringing of the ears, dizziness due to damage of the eighth cranial nerve
• Oliguria or albuminuria due to renal disorder
• Psychosis and convulsion
• Thrombocytopenia, anemia, shock
How should the most common adverse reactions due
to anti-TB drugs be monitored and managed?

• Minor adverse reactions - symptomatic therapy. First-line

drugs should not be stopped without adequate
justification.
• Major adverse reactions - all drugs must be discontinued;
Switching to single drug formulations may be needed.
Referral to a specialist is warranted
Adjunctive Therapy for TB
Should immunomodulators be given as an adjunct in the
management of TB?
• Immunomodulators are NOT recommended as adjunctive therapy for
TB. The value of these immunomodulatory agents remain unclear and
well-conducted RCTs are needed to establish benefit for routine use.

Should vitamin and micronutrient supplementation be

routinely given?
• Vitamin and micronutrient supplementation should NOT be routinely given as
adjunctive therapy for TB (except for vitamin B6 or if the patient has pre-existing
nutritional deficiency). No significant difference in mortality, treatment
completion, bacterial eradication, or mean body mass index was shown in RCTs.
Treatment of Drug-
resistant TB in Adult
Filipinos
How should DR-TB be
managed?

• All DR-TB patients should be managed under programmatic setting.

Management of DR-TB involves the use of second line drugs that are
more expensive, less effective and more toxic for at least 18 months.
Management outside the proper framework will only lead to further
drug resistance.
• Immediate referral to the nearest PMDT Treatment Center or Satellite
Treatment Center is mandatory.
Second-line Drugs for TB
A. Fluoroquinolones – later generation agents such as levofloxacin (high-
dose) and moxifloxacin are recommended
B. Second-line injectable aminoglycosides kanamycin, amikacin, and
streptomycin and the injectable polypeptide capreomycin
C. Other oral agents (ethionamide and prothionamide, cycloserine and
terizidone, linezolid, and clofazimine)
D. Add-on agents (three subgroups):
D1 (the first-line drugs pyrazinamide, ethambutol, and high-dose isoniazid)
D2 (the two new drugs- diarylquinolone bedaquiline and delamanid)
D3 (PAS, imipenem-cilastatin, meropenem, amoxicillin-clavulanate, and amithiozone
[thiacetazone])
The Programmatic Management of
Drug-resistant Tuberculosis (PMDT)

PMDT is a set of strategies and activities under the National TB Control

Program using DOTS framework to effectively address the problem on
DR-TB. It is managed by the Department of Health in coordination with
local and international partners.
Basic elements of a PMDT program:

1. Sustained political commitment to treat DR-TB

2. Availability of quality-assured laboratory services for DSSM, TB culture, DST
and Xpert® MTB/Rif
3. Standardized and individualized treatment strategies that utilize second line
drugs under DOTS
4. Uninterrupted supply of high-quality second-line anti-TB drugs
5. Institution of parameters to promote patient adherence to treatment
6. An information system for proper data management, monitoring of
performance and evaluation of the intervention
The PMDT uses two (2)
strategies for treatment:

• Standardized Regimen Drug Resistant (SRDR) – for patients with

confirmed RR-TB using Xpert® MTB/Rif test
• Individualized treatment approach – for patients with available
comprehensive drug susceptibility testing results that warrant
modification of the standardized regimen
What is the role of surgery in
the management of DR-TB?

• Surgery is an option in the treatment of TB patients with DR-TB in localized cavitary

forms with continuous M. tuberculosis excretion, confirmed by bacterial examination
and DST, after four to six months of supervised anti-TB chemotherapy.
• Surgery should be considered as integral component of MDR-TB treatment programs,
even in resource-limited countries, as long as adequate surgical expertise and
facilities are present.
• Multidisciplinary approach involving surgeons, anesthesiologists and specialists
should be taken when a patient is being considered for surgery.
References
• Clinical Practice Guidelines for the Diagnosis, Treatment, Prevention
and Control of Tuberculosis in Adult Filipinos 2016 Update