The Treatment

of Tuberculosis
 Treating TB

• Old concepts
 Nutritional support
 Fresh Air, elevation, caves
• Sanatoriums
– Weimar

 Exercise
 Surgical
 Death rate in 1900 was 194/100K
British Sanatorium 1880s
Denver sanatorium
in the 1920s
 Treatment

• Before 1940s: open air

(sanatorium)
• 1946: streptomycin
• 1952: isoniazid
• 1970: rifampin
 The aims of TB treatment
• to cure the patient
• to prevent death from active TB or its late
effects
• to prevent relapse of TB
• to decrease transmission of TB to others
• to prevent the development of acquired drug
resistance
It is vital to achieve these aims while preventing the
selection of resistant bacilli in infectious patients.
 The basic principles
• Regimens should be based on the history of drugs
taken by the patient
• Regimens should consist of at least four drugs
with either certain, or almost certain,
effectiveness
• Drugs are administered at least six days a week
• Treatment duration
• Each dose is given as DOT throughout the
treatment
First Line Anti-Tuberculosis Drugs

• Isoniazid (INH, H)
• Rifampicin (RIF, R)
• Pyrazinamide (PZA, Z)
• Ethambutol (EMB, E)
 Modern TB Chemotherapy

• INH – kills rapidly growing organisms and

dormant organisms
• PZA – kills TB bacilli inside the
macrophage and cavities
• RIF and PZA kill slowly growing organisms
 sterilizing activity
• INH, RIF and EMB protect each other from
development of resistance
Activities of Antituberculosis Drugs

Early Preventing
Sterilizing
Drug bactericidal drug
activity
activity resistance
Isoniazid ++++ +++ ++
Rifampicin ++ +++ ++++
Pyrazinamide + + +++
Streptomycin ++ ++ ++
Ethambutol ++ - +++ ++ +
Highest ++++ High +++ Intermediate ++ Low +
 Classification of antituberculosis
drugs
Group 1. First-line oral antituberculosis drugs

• Isoniazid - H
• Rifampicin - R
• Ethambutol - E
• Pyrazinamide - Z

• Group 1 anti-TB drugs, the most potent and best tolerated,

should be used if there is good laboratory evidence and
clinical history that suggests the drugs from this group is
effective.
 Group 2. Injectable anti-TB drugs
(injectable agents or parental agents)
• Kanamycin - Km
• Amikacin - Am
• Capreomycin – Cm

• All patients should receive a second-line Group 2 injectable

agent in the intensive phase of MDR-TB treatment unless
resistance is documented or highly suspected. Either
kanamycin, amikacin or capreomycin can be used as a first
choice if all meet the criteria of “likely to be effective”
• There are high rates of streptomycin resistance in strains of
MDR-TB; therefore, streptomycin is not considered a
second-line anti-TB injectable agent
 Group 3. Fluoroquinolones

• Levofloxacin - Lfx
• Moxifloxacin - Mfx

• Fluoroquinolones are often the most effective anti-

TB drugs in MDR-TB regimen
• All MDR-TB patients should be treated using “later-
generation” fluoroquinolones – levofloxacin or
moxifloxacin
 Group 4. Oral bacteriostatic second-line
antituberculosis drugs

• Ethionamide - Eto
• Prothionamide - Pto
• Cycloserine - Cs
• Para-aminosalicylic acid - PAS
• Para-aminosalicylate sodium - PAS-Na

• Group 4 drugs are added on the basis of estimated

susceptibility, drug history, efficacy, adverse effects
profile and cost
Group 5. Group 5 drugs are not recommended by
WHO for routine use in MDR-TB treatment

• Bedaquiline - Bdq
• Delamanid - Dlm
• Linezolid - Lzd
• Clofazimine - Cfz
• Amoxicillin/clavulanate - Amx/Clv
• Imipenem/cilastatin - Ipm/Cln
• Meropenem - Mpm
• High-dose isoniazid - High dose H
• Thioacetazone - T
• Clarithromycin - Clr
 Group 5

• Group 5 drugs are not recommended by WHO for routine

use in MDR-TB treatment
• Although all of them have demonstrated some activity at
least in vitro or in animal models, the quality of the evidence
of their efficacy and safety in humans for the treatment of
drug-resistant TB varies
• Most of these drugs are, with the exception of bedaquiline
and delamanid, not registered for treatment of MDR-TB
making their use “off-label”
• However, they remain as options in cases where adequate
regimens are impossible to design with medications from
Groups 1–4
• If a situation requires the use of Group 5 drugs, often experts
will recommend using two to three drugs from the group
given the limited knowledge of efficacy
New Drugs in TB Treatment

• Bedaquiline, formerly TMC207, is a new

diarylquinoline antibiotic with specific activity
against Mycobacterium tuberculosis and several
nontuberculous mycobacteria
• It acts by inhibiting ATP synthase, interfering with
the energy generation needed by the bacterial cell
• Based on clinical evaluations for safety, tolerability
and efficacy, bedaquiline has recently received
accelerated approval for the treatment of pulmonary
multidrug-resistant TB in adults
 New Drugs in TB Treatment
• Delamanid (OPC-67683), a nitro-dihydro-
imidazooxazole derivative, is a new antituberculosis
medication that inhibits mycolic acid synthesis and
has shown potent in vitro and in vivo activity against
drug-resistant strains of Mycobacterium
tuberculosis
• Delamanid was associated with an increase in
sputum-culture conversion at 2 months among
patients with multidrug-resistant tuberculosis
 Second-line Drugs
• Increased treatment
difficulties
 Expensive,unavailable
 More side effects
 Difficult Ab penetration
 Longer treatment
• Controversy
 Standard treatments
 Everything it takes
 Patient registration group
(Classification based on history of previous
TB treatment):
These classifications focus on history of previous
treatment only and are independent of bacteriological
confirmation or site of disease

• New case
• Previously treated patients have received 1 month or more
of anti-TB drugs in the past. They are further classified by the outcome of
their most recent course of treatment as follows:
 Relapse patients
 Treatment after failure patients
 Treatment after loss to follow-up patients
 Other previously treated patients
 New case
New patients have never had treatment for TB, or have
taken anti-TB drugs for less than 1 month
Previously treated patients:
 “Relapse patients” — patients who have been treated and
declared cured, but whose smear examinations are once again
positive
 “Treatment after failure patients” — patients whose
smear examinations have remained positive or have once again
become positive 5 or more months after starting treatment
 “Treatment after loss to follow-up patients” —
patients who return to the health centre smear-positive after
interrupting treatment for more than two consecutive months
 “Other previously treated patients”- are previously
treated for TB but with an unknown or undocumented outcome
for their most recent treatment episode
 DR-TB cases

• Resistant form of TB
 Phases of TB treatment

• initial intensive phase, which rapidly reduces the

bacterial population
• the initial intensive phase consists of at least four
drugs
• continuation phase, which destroys those bacteria
that remain
• the continuation phase is given for 4 months if the
two most bactericidal drugs, isoniazid and
rifampicin, are used, and for 6 months if isoniazid
and a bacteriostatic drug are used
 Treatment schedules
recommended for patient registration group

Recommended treatment
schedule
Patient registration group Initial phase Continuation
phase

New case

• Pulmonary TB 2 HRZE 4 HR

• Extra-pulmonary TB 2 HRZE 10 HR
(TB meningitis)
 Treatment of Active TB

• Four drug regimen during first 2

months:
• INH 300 mg
• Rifampin 600 mg
• PZA 15-30 mg/kg
• Ethambutol 15-25 mg/kg or streptomycin 15
mg/kg
• Two drug regimen for next 4 months:
• INH and rifampin
 Treatment schedules
recommended for patient registration group

Recommended treatment
schedule
Patient registration group
Initial phase Continuation
phase

Previously treated
patients:
• Relapse patients
• Treatment after failure
3HRZE 5 HRE
patients
• Treatment after loss to
follow-up patients
• Other previously treated
patients
 Ongoing Diagnostic Monitoring

• Monthly sputum collection (until two

negative smears)
• Look for smear positive cases after
initial two months of therapy
• Liver function tests if abnormalities
on screening or risk factors for
hepatitis
 Monitoring the efficacy of treatment
by bacteriological examinations
• At the end of the initial phase sputum conversion
is observed in most cases. If the patient is still
smear-positive the initial phase should be prolonged
by 1 month
• At the end of the 4th month for 6-month regimens,
and at the end of the 5th month for 8-month
regimens
• During the last month (at the 6th or 8th month,
depending on the regimen). These smear
examinations confirme the success or failure of the
treatment
• In the case of extra-pulmonary tuberculosis, follow-
up is essentially clinical
 Treatment outcome
Outcome Definition
Cured A pulmonary TB patient with bacteriologically
confirmed tuberculosis
at the beginning of treatment and who was smear-
or culture-negative in the last month of treatment
and on at least one previous occasion.
Treatment A TB patient who completed treatment without
completed evidence of failure
BUT there is no record to show that sputum smear
or cul
ture results in the last month of treatment and on at
least one previous occasion are negative, either
because they were not done or because results
were not available.
Treatment A TB patient whose sputum smear or culture is
failed positive at month 5 or later during treatment.
 Treatment outcome
Outcome Definition

Died A TB patient who dies for any reason before

starting or during the course of treatment.

Lost to A TB patient who did not start treatment or whose

follow-up treatment was interrupted for 2 consecutive
months or more.

Not A TB patient for whom no treatment outcome is

evaluated assigned.(This includes cases “transferred out” to
another treatment unit and where the treatment
outcome is unknown to the reporting unit)
Treatment The sum of cured and treatment completed
success
 Problems of TB therapy

• Toxicity e.g. liver

• Multiple therapy
• Prolonged treatment
• Drug interactions e.g. anti HIV drugs
 Directly observed treatment

means that an observer watches the

patient swallowing their tablets, in a way
that is sensitive and supportive to the
patient's needs. This ensures that a TB
patient takes the right antituberculosis
drugs, in the right doses, at the right
intervals
 Directly Observed Therapy (DOT)

• DOT can lead to reductions in

relapse and acquired drug
resistance

• Use DOT with other measures to

promote adherence

• DOT is the key to CURE

Directly Observed Therapy (DOT)
 What is DOTS?
• D.O.T.S stands for Directly-Observed
Treatment Short Course
• It is a comprehensive strategy endorsed
by the World Health Organization (WHO)
and International Union Against
Tuberculosis and Lung Diseases
(IUATLD) to detect and cure TB patients
Programmatic management of DR-
TB(PMDT)
• A case management strategy under
development, designed to manage MDR-
TB using second line drugs within the
DOTS strategy in low – and middle –
income countries.

To prevent further development

and spread of MDR-TB.
Drug Resistance
 Definition of Drug Resistant TB

 Mono-resistance- resistance to any one

anti tuberculosis drug
Poly-resistance- resistance to more than
two anti tuberculosis drugs, exception to
Isoniazid and Rifampin
 Definition of Drug Resistant TB

• Multi-Drug Resistance (MDR):

resistance to at least both isoniazid and
rifampicin

• eXtensive-Drug Resistance (XDR):

resistance to any fluoroquinolone, and at
least one of three second-line injectable
drugs (capreomycin, kanamycin and
amikacin), in addition to multidrug resistance

• Treatment based on susceptibilities

• Higher risk of mortality
 Drug Resistance Definitions

• Primary drug resistance

 Applies to previously untreated patients who
are found to have drug- resistant organisms,
presumably because they have been infected
from an outside source of resistant
Mycobacterium tuberculosis.

• Acquired drug resistance

 Applies to patients who initially have drug-
susceptible bacteria that become drug-
resistant due to inadequate, inappropriate, or
irregular treatment or, more importantly,
because of non-adherence in drug taking.
 Causes of Resistance

• Irregular Self Administration with Failure

to closely supervise
• Care of patients by non specialists
• Increased immigration
 Persons at Increased Risk
for Drug Resistance

• History of treatment with TB drugs

• Contacts of persons with drug resistant
TB
• Smears or cultures remain positive
despite 2 months of TB treatment
• Received inadequate treatment regimens
for >2 weeks
 Standardized treatment

• Regimens are designed on the basis of

representative DRS data of specific
treatment categories
• However, suspected MDR-TB should always
be confirmed by DST results whenever
possible. All patients in a defined group or
category receive the same treatment
regimen
 Empirical treatment

• Each regimen is individually designed on the

basis of the previous history of
antituberculosis treatment and with the help
of representative DRS survey data
• Commonly, an empirical treatment is adjusted
in each patient when his or her DST results
become available
 Individualized treatment

• Each regimen is designed based on the

patient’s past history of TB treatment
and individual DST results
 The basic principles
• Regimens should be based on the history of drugs
taken by the patient
• Regimens should consist of at least four drugs
with either certain, or almost certain,
effectiveness
• Drugs are administered at least six days a week
• An injectable agent (an aminoglycoside or
capreomycin) is used for a minimum of 6 months
• Treatment is for a minimum duration of 18 months
beyond conversion
• Each dose is given as DOT throughout the
treatment
 Formation of MDR TB treatment schedules
(Design of MDR TB treatment)
Levofloxacina OR Moxifloxacina
Group A Bedaquiline
Linezolid
Clofazimina
Group B Cicloserina
Etambutol
Delamanid
Pirazinamidă
Group C Imipenem-cilastatin OR Meropenem
Amikacină OR Streptomicină
Etionomidă OR Protionamidă
48
Acid p-aminosalicilic
 Monitoring the efficacy of MDR TB
treatment

• Clinical
• DOT
• Microbiological (every month: microscopy,
culture LY and BACTEC)
• Radiologic
 Consequences of MDR

• Delay in diagnosis
• Treatment duration extended
 18 to 24 mo.
• Second line drugs
 Effectiveness decreases
 Toxicity increases
• Expensive to treat
• Community transmission
 Interventions to prevent drug-resistant TB

1. Early detection and high quality treatment of

drug-susceptible TB
2. Early detection and high quality treatment of
drug-resistant TB
3. Effective implementation of infection control
measures
4. Strengthening and regulation of health
systems
5. Addressing underlying risk factors and social
determinants
Treatment options for XDR?
www.cdc.gov/tb/xdrtb/
Tuberculosis
anywhere
is
Tuberculosis
everywhere
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Drug treatment of sensitive TB
Drug treatment of MDR TB
Drug treatment of XDRTB