Principles of Treatment

for Tuberculosis

Soedarsono
(15 %)
(29.1%)

(37.7%)
 Infection Disease
Exposed Infection
to with
DR-TB drug –resistant
strain
Drug-resistant
Risk factors Risk factors tuberculosis
Risk
factors
Drug-susceptible
Tuberculosis
Infection with
Exposed
to drug-susceptible
DS-TB strain
Principles of Therapy

 Drug administered concomitantly to

prevent the development of resistance
 Prolonged chemotherapy to prevent
disease relapse
 DOT – core management
(Caminero JA presented)
 Anti-tuberculosis Therapy

First Line Drugs Second Line Drugs

 Isoniazid  Para-aminosalicylic
acid
 Rifampin  Capreomycin/Amika
 Pyrazinamide -cin/Kanamycin
 Ethionamide
 Ethambutol  Cycloserine
 Streptomycin  Quinolones
Ginsberg, 2008
 BACTERIAL ACTIVITIES
POPULATION ANTI-TB DRUGS

The BASIS of
ANTI-TB DRUGS
REGIMENS

RESISTANCE FALL & RISE

PATTERN PHENOMENA
(Caminero JA presented)
 SPECIAL BACTERIAL POPULATIONS
HYPOTHESIS AND ACTION OF THE SPESIFIC DRUGS
HIGH
A INH( Rif, Strep, Emb)
Continuous
growth
Potency to Failure, PZA Rif
Speed of
Resistance
bacterial
growth C B

D Acid Spurts of
inhibition metabolism
Dormant
(no cure) Potency to Relapse
LOW
A = rapidly growing bacteria killed mainly INH ; B = bacilli only metabolizing in spurts
killed mainly by Rif ; C = bacilli inhibited by an acid environment killed mainly by PZA ; D
= dormant bacilli
 The “Fall and Rise Phenomen”
10 8
Number of bacilliper mil of sputum (logarithmic scale)

Isoniazid-susceptible Isoniazid-resistant
10 7 Smear + organisms organisms
Culture +

10 6

10 5

10 4

Smear –
3
10 Culture +

10 2

10 1 Smear –
Culture –

10 0
0 3 6 9 12 15 18
Start of treatment Weeks of treatment
(isoniazid alone)
 Estimated bacterial population in the different tuberculosis lesions

Number of bacilli required for the appearance of

a mutant resistant to different drugs

Guidelines for Clinical and Operational Management of Drug-Resistant Tuberculosis, IUATLD, 2013
For New Case Never Treated

>108 Organisms in
TB Cavity or AFB +
1 resistant RIF
100 resistant INH
100 resistant Strep
100 resistant EMB
0 resistant INH+Rif
0 resistant INH+Rif+EMB
ACTIVITIES of ANTI-TB DRUGS

(Caminero JA presented)
Do all of the foregoing
with
minimum toxicity !
 Chemotherapy in Tuberculosis:
Activity of the different anti-TB drugs

Guidelines for Clinical and Operational Management of Drug-Resistant Tuberculosis, IUATLD, 2013
 Bacteriologic
Fundaments of
TB Treatment
 Core vs Companion drugs in the
Intensive & Continuation Phases
• All treatment must have :
– Core drugs : minimun of 2 very active drugs for killing &
sterilizing M. tuberculosis.
– Accompanying drugs that kill little but are responsible for
protecting the core drugs not become resistant.
• The treatment design consist of :
– An intensive phase that includes at least 4 drugs
(2 core & 2 accompanying)  bacillary load had been
reduced to a minimun
– A continuation phase during which the accompanying
drugs can be discontinued & which is prolonged until cure
is ensured with minimum risk of relapse.
Guidelines for Clinical and Operational Management of Drug-Resistant Tuberculosis, IUATLD, 2013
 Rationale for an ideal initial treatmet regimen

• The ideal basis for TB treatment regimen for the first

2 months : H+R+Z, followed by H+R for another 4
months  potent bactericidal and sterilizing action
with few relapses ( < 1%-2%)
• Why Z should only be administered for 2 months ?
– After this period the great majority of lesion and cells
presenting in acid pH condition have disappeared.
– The sterilising action of Z is scarce or nil after the second
month of treatment if R has been included in the regimen.
• If R not included, Z could possibly continue to have
sterilising action for much longer than the intial 2
months
Guidelines for Clinical and Operational Management of Drug-Resistant Tuberculosis, IUATLD, 2013
 Justifications for adding a fourth drug
in the initial phase of treatment
• In the event of initial resistance to H and considering
the high proportion of natural resistent to Z :
– R stands very much alone for treating those with very large
microbial populations.
– A fourth drug must thus be added to the initial treatment
to protect R if the patient has been contaminated by a
strain of H-resistant M. tuberculosis
• Add a fourth drug in the first phase of TB treatment is
accepted, the choise may centre on S or E.
• E is preferable for 2 reasons : bacteriological and
other operative.
Guidelines for Clinical and Operational Management of Drug-Resistant Tuberculosis, IUATLD, 2013
Standard Regimen and Dosing Frequency
for New TB Patients (WHO, 2009)
 Standard regimens for PREVIOUSLY TREATED
PATIENTS (depending on the availability of routine DST to guide the
therapy of individual treatment patients)

Treatment of Tuberculosis Guidelines . WHO, 2009

 In all treatmet regimens, attempts should be
made to use as many first-line drugs as possible.

• If a drugs that has been rendered ineffective is

correctly identified, than the following
regimens can be recommended :
– If pyrazinamide (Z) cannot be used: 2HRE/7HR
– If isoniazid (H) cannont be used: 2REZ/10RE
– If rifampicin (R) cannot be used: 2HEZ(S)/10HE
– If ethambutol (E) cannot be used: 2HRZS/4HR

Caminero JA, A Tuberculosis Guide for

Specialist Physicians, 2003
 Extrapulmonary TB (EPTB)
• In countries with comprehensive diagnostic and
reporting systems, EPTB accounts for 20-25% of
reported cases.
• EPTB (without pulmonary involvement)
comprised 14% of notified cases.
• The most common of EPTB : lymphatic, pleural,
bone and joint disease.
• More likely to result in a fatal outcome :
pericardial, meningeal and miliary TB.
NCCCC, 2006. ATS, CDC, IDSA, 2003, 52: 1-77
 Treatment of EPTB
• PTB and EPTB disease should be treated with
the same regimens.
• Some experts recommend
– 9-12 months of treatment for TB meningitis.
– 9 months of treatment for TB of bones or joints
• In TB meningitis, Ethambutol should be
replaced by streptomycin
NCCCC, 2006.
ATS, CDC, IDSA, 2003, 52: 1-77
WHO, 2008.
NEJM, 2004,351:1741-1751
 Summary
• The treatment of TB must be based on two important
bacteriological considerations:
– the combination of drugs needed to avoid the selection of resistances
– prolonged treatment to ensure that all bacteria in their various phases
of metabolic growth are effectively killed
• A minimum of 4 drugs not previously utilised on the
patient or with possible susceptibility should be used.
• Length of treatment will depend on the drugs used. If
rifampicin (R) can be included, treatment may be
reduced to 9 or even 6 months if pyrazinamide (Z) is
also utilised.
• All treatment regimens must have as a core at
least two very active drugs responsible for killing
and sterilising M. tuberculosis, and two or more
other accompanying drugs that kill little but
protect the core drugs so that the bacillus does
not acquire resistance.

• Length of treatment and chances for success are

dependent on these core drugs. The best anti-TB
drugs currently are R and H, and these should
always be the core of initial treatment plans.