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IN THE MANAGEMENT OF

By

Dr. Soji Ige FWACP


Senior Lecturer
College of Medicine, University of Ibadan
Pulmonologist
University College Hospital, Ibadan,

INTRODUCTION
Prior to 1950s the mainstay of management was
bedrest, fresh air, sunshine (where available)
and in suitable cases, surgical intervention
resection of tuberculosis lesions
more commonly the active management depended
on collapse therapy, collapsed therapy rested
diseased lung and might take the form of artificial
pneumothorax, pneumoperitoneum. Collapse of
the lung by pleural plombage in which the pleural
& hence the underlying lung, were compressed by
implanted material (e.g lucile balls or mineral oil).

Drugs
Schatz and Waksman in 1944 discovered
streptomycin, which heralded a new era of
tuberculosis chemotherapeutics
PAS by Lehmann, followed by INH in 1952
Controlled Clinical Trials on Early Drugs
British Medical research Council - World 1st
control clinical trial
Treated Group

Control Group

51% showed radiographic improvement 8% showed radiographic improvement


7% died
21% diead
All patients deteriorated after 3 months All patients deteriorated after 3 months
Conclusion: Mycobacterial resistance to strep emerged after 3 months of treatment

Drugs (Continued)
Development of PAS and Isoniazid
Study

Strep. And PAS or


Strep. and INH or
PAS and INH, prevented the emergence of drug-resistant
organisms

Report from Edinburgh in 1958 showed that


combination theraphy with Strep, PAS and INH,
prevent the emergence of drug-resistant
organisms and to effect a 100% cure

These early regimens are for 18 months or 2 years

Short Course Chemotherapy


Comes with the passage of time and the introduction of new drugs

Principles of Modern Chemotherapy


Four different populations of bacterial exist within tuberculous lesions
and each is particularly accesible to the action of a different
antitubeculosis drug
a)rapidly growing bacilli e.g in cavity walls (Active cavity with
neutral pH)
- INH/RIF/SM
- bactericidal
b & c) Slowly growing population as in cells (macrophages) and solid
caseous tissue (persisters) RIF/PZA/INH
RIF and PZA are potent sterilizing agents.
PZA is particularly effective against bacilli in an acid (presumably
intracellular) environment pH< 5.6
d) a fourth population of totally dormant bacilli not killed by any drug

Principles of Modern Chemotherapy of


Tuberculosis
INH
RIF
RIF
SM

INH
PZA

Actively multiplying
extracellular bacilli

Inadequate Rx:

Treatment
Failure

Slowly multiplying
intracellular and in
closed caseous
lession

Adequate Rx:
bactericidal
action

Adequate Rx:
sterilizing action

Elimination
of
extracellula
r

Elimination of
persisters

Lasting cure of
tuberculosis

Inadequate Rx:
Late growth of
persisters
Relapse

Classification of Antituberculous Drugs


First-line drugs - RIF, INH, Ethambutol,
PZA, SM
Second-line drugs
Cycloserine
Ethionamide
Prothionamide

Aminoglycoside
capreomycin
kanamycin
viomycin

Fluoroquinolone
Ciprofloxacin
Ofloxacin

Newer Drugs
Rifambutin
Rifapentin

Chemotherapy Regimen for Pulmonary


Tuberculosis
Standard 6-month short-course chemotherapy
2SHRZ/4RH
2EHRZ/4RH
Standard 9-month short-course chemotherapy
2SHR/7RH
2EHR/7RH
The relevance of compliance and the strategies that
can be employed to guard against the emergence of
drug resistance organisms is important
This is called by the provision of DOTS (directly
observed therapy short-course)

Relapse rates with different 6-month chemotherapy


regimens in patients with drug-sensitive bacilli
Reference

Initial
Phase

Continuation
Phase

No. of
Subjects

Follow-up Relapse
(Months) %

Singapore Tuberculosis Service/


British Medical Council [86]

2SHRZ
2SHRZ

4HRZ
4HR

84
80

6
6

0
1

Singapore Tuberculosis Service/


British Medical Council [96]

2SHRZ
1SHRZ
2HRZ

4H3R3Z3
5H3R3
4H3R3

97
94
109

24
24
24

1
1
1

Algerian Working Group/British


2EHRZ
Medical Council Co-operative Study

4HR

229

24

Third East African/British Medical


Research Council Study [98)

2SHRZ

4TH

89

Tanzania/British Medical Research 2SHRZ


Council Study [99]

4TH

105

24

Snider et al. [100]

4H2R2
4H2R2

56
116

24
24

2
3

2SHRZ
2HRZ

E, ethambutol; H, isoniazid; R, rifampicin; S, streptomycin; T, thiacetazone; Z, pyrazinamide.


Subscript indicate degree of intemittency e.g H2 represents isoniazid twice weekly; numbers preceding letters
indicate duration in months, e.g 4HR represents 4 months of therapy with daily isoniazid and rifampicin

Chemotherapy Regimen for Pulmonary


Tuberculosis (continued)

Other non-standard 6-month regimens


2SHRZ/4H3R3
1SHRZ/5H3R3
2HRZ/4H3R3
Studies from Singapore, Algeria, East
Africa and Poland based on an intial 1 or 2
months four-drug phase of therapy followed
by a variety of 4-month intermittent or daily
regimens had satisfactory success rates

Treatment of Smear-negative Pulmonary Disease


Standard short-course chemotherapy in developed
countries
National tuberculosis programmes in the developing
world recommend the most appropriate regimens for
smear-positive and smear negative cases in their own
countries where the luxury of routine mycobacterial
culture and sensitivity pattern determination is usually
not available.
In Nigeria we use:
2SHRZ/6TH; 2EHRZ/6TH before
and now 2SHRZ/6EH; 2EHRZ/6EH

Empirical Treatment of Smear-negative


Disease
Where TB is suspected on clinical and radiological
grounds but bacteriological proof is lacking
Start standard short-course chemotherapy while
awaiting the results of bacteriological
Such cases cultures
should be kept
under review
6 months
Complete treatment if the cultures
prove for
positive
or
if treatment is to be stopped
negative
Treatment should stop in an unusual event of a clinical
and radiological response to treatment is inappropriate
(i.e usually too fast or too complete). In such cases a
simple bacterial pneumonia may have responded to
rifampicin

Assessing Treatment Response


In patients with positive bacteriology, sputum status should
be assessed monthly; by 2 months more than 85% of
positive sputum culture should have converted to negative.
Ideally drug sensitivity pattern should be checked.
Failure to convert ring alarm bells about patients
compliance and/or the emergence of drug resistant disease.
Drug sensitivity pattern should be rechecked
Clinically, after 1-4 weeks the patient should be feeling
better, have gained weight and be free from fever, cough
and sputum.
Chest radiographic changes should have improved after 2
months and continue to improve over several months,
eventually leaving residual fibrotic and/or cavitary change.
CXR is also taken at the end of treatment

Assessing Treatment Response


(Continued)

Failure of clinical or radiographic appearances to


change after 2-3 months should lead to concerns
about compliance and/or drug-resistant disease
monitoring of adverse reactions during standard
short-course chemotherapy.
Baseline measurement of visual acuity
FBC and platelets
Liver function test (bilirubin and liver enzymes)
Uric acid

EXTRAPULMONARY TUBERCULOSIS
Standard 9-month
chemotherapy or 6month chemotherapy

Lymph node tuberculosis


Genitourinary tuberculosis

Standard 6 or 9-month
chemotherapy plus
prednisolone 40mg OD for
6 months

Steroid to prevent
ureteric stricture
Standard 6-month chemotheray

central nervous system

The continuation phase is


prolonged duration of
treatment is 9-12 months

Add prednisolone 1mg/1kg/day

Miliary Tuberculosis
Standard 6-month chemotherapy

Treatment in Special Situations


Pregnancy
Childhood
HIV Infection

Streptomycin is ototoxic
to the fetus and is
contraindicated
Because of difficulties
in monitorin for ocular
toxicity, Ethambutol is
best avoided

With the standard short-course chemotherapy,


relapse rates are no more common in HIV-positive
than in HIV-negative patients if the continuation
phase of treatment is prolonged to give a total
duration of chemotherapy of 9 months.
The rate of sputum culture conversion is similar in
both groups

Drug Resistance and the Management of Diseases


due to Drug-resistant Organisms
The three stages in the development and spread of drug-resistant tuberculosis
Colony of mycobacterium tuberculosis
(1)

Natural mutations

Resistant mutants
(2)

Selection of resistant strains by inadequate


treatment

Secondary (multiple) drug- resistance


tuberculosis
(3a)

Transmission
in droplets

Primary (multiple) drug- resistance tuberculosis


(3b)

Further transmission

More primary (multiple) drug- resistance


tuberculosis

HIV infection
Inadequate infection control

Diagnostic delay

Drug Resistance and the Management of


Diseases due to Drug-resistant Organisms
(continued)

There are 3 stages


The fourth contribution to the problem comes from
migration of patients with primary and secondary
resistance into the control area.
Tuberculosis patients with secondary drug-resistant
tuberculosis may infect others who are then said to have
tuberculosis that demonstrates primary resistance
Such transmission is facilitated by HIV infection, where
disease development and progression seem more rapid.
Primary resistance. Like secondary drug resistance may
be transmitted to others thus spreading drug-resistance
disease within the community.

Treatment of Drug-resistant Disease


The essence of success is to treat with at
least two and preferably three drugs to
which the organisms is known or believed
to be sensitive until sputum cultures have
been negative for at least 6 and possibly 12
months.
Where disease is intractable, surgical
resection may be of value

Summary
The worst possible scenerio, one in which
tubercle bacilli become increasingly resistant
to multiple drugs resulting effectively in a
return to the prechemotherapy era of
tuberculosis with 50-80% mortality rates, will
only be avoided if the long-established
principles of treating tuberculosis are rigidly
observed. At present, this means considering
the need for DOT for every patient