35 Drugs for treating Tuberculosis and Principles of Chemotherapy  Session 01
31
August

By Adem Lewis / in , , /


Welcome to this session on Drugs for treating
Tuberculosis and Principles of Chemotherapy. I am doctor Rajeswari former scientist from
NIRT Chennai. Before we start this session, let us look
into the definition of tuberculosis; Tuberculosis is a chronic infection, characterized by granuloma
formation, affecting elderly children, all age groups affecting all the organs not only
lungs; especially in the host of human beings who are immune compromised especially cell
mediated immunity. So, today’s session the first half we look
into the drugs that are available for treating TB and in the second half we look into the
principles of chemotherapy that govern the management. As we all aware tuberculosis is an ancient
disease dating back to 1000’s of years and the usual management prior to 1940 would be
to give them rest adequate rest especially sanatorium line of management and give proper
diet to improve the immunity of the host. Drugs started coming in the treatment of TB
from 1940 onwards and the first drug that was tried the treatment of tuberculosis were
streptomycin. The famous streptomycin trials are the first
chemo therapeutic trials and that showed mono therapy will be a failure and if you treat
patients with a single drug they will all go into failure with resistant organisms. Then followed the era of PAS, INH patients
are treated with 2 drugs 9 INH or PAS INH or 3 drugs streptomycin, PAS and INH. This continued till the 1960’s and we had
a wonder drug called rifampicin and this ah bactericidal drug that gave a opportunity
for us to treat the patient within 6 months period and ah that changed the picture completely. Let us look into the number of drugs that
came after 60 also. For 50 years there were not many drugs, then
in the last decade there are a number of drugs that are being tried and they are in phase
2 and phase 3 trials especially bedaquiline, delamanid these 2 are the drugs approved by
the US and European regulatory authorities. Now this diagram clearly tells you the number
of drugs and their availability in various periods. Way back started with streptomycin, PAS INH
and came the pyrazinamide then rifampicin. Ooph after 60’s the management totally was
different because of the rifampicin and pyrazinamide they look at the regimens now. After 60’s and 80’s we started getting quinolones
in the picture, number of quinolone there are about 16 or 17 quinolones and about 3
or 5 are useful in the treatment of tuberculosis now currently we have bedaquiline and other
drugs. If you look at the lower half of this slide
you will see the number of regiments; the earlier years in 50’s and 60’s it was a standard
chemotherapeutic regimen consisting of 2 drugs namely INH PAS or streptomycin or and INH
these regiments were given for a period of 12 to 18 months. They also had a relapse rate of more than
20 percent the cure rate was only around 50 to 60 percent. So, there was a need to improve the treatment
regimens luckily we had a rifampicin in 1960’s and the picture change totally currently the
line of management is used for drugs namely the rifampicin, INH, pyrazinamide ethambutol
and we are able reduce the duration of treatment to 6 months and they are known as short course
chemotherapy; we will look into the details in subsequent slides. Now the recently available drugs are given
here they are being tried as I told you earlier they are in phase 2 and phase 3 trials. WHO classified the anti-TB drugs in 2011 as
5 groups the group; group 1 was fully oral drugs INH, rifampicin, ethambutol, pyrazinamide
as I told you these are the 4 key drugs in short course chemotherapy. Group 2 consists of injectable streptomycin,
kanamycin; group 3 fluoroquinolones mainly levo, maxi, gati and ofloxacin. Group 4 fully bacteriostatic second line drugs
like ethionamide, cycloserine and group 5 other anti-TB drugs with limited data on efficacy,
like linezolid, clofazimine etcetera . Now the anti-TB drugs for resistance that
classification is slightly different, currently we have multi drug resistant tuberculosis. Now what is multi drug resistant TB? It is bacteria that are resistant to 2 key
drugs in the chemotherapy namely rifampicin and INH to bactericidal drugs; when patient
developed organisms resistant to both the rifampicin and INH they are called them MDR-TB
patients. And the classification here is slightly different
as you can see group A drug is fluoroquinolones, group B is second line drug injectable drugs
like amikacin, group C is other second line agents like ethionamide, prothionamide, group
D once again its divided into D 1, D 2, D 3 consisting of pyrazinamide, ethambutol,
bedaquiline, delamanid and other drugs. Now, in MDR-TB the regiments are being designed
including all these 4 groups of drugs that will be a separate session for you. Currently there are a number of drugs that
are in the pipeline, some are in the discovery phase, some are in the preclinical development
stage, some are in the clinical development stage; phase 1, phase 2 and phase 3. If you look at the newer drugs bedaquiline
and delamanid and pretemanid they are in phase 3 trials and they may be available shortly
for our regular use . Now, this figure clearly explains the mechanism
of action of the anti-TB drugs look at the isoniazid and ethambutol; they prevent the
formation of the cell wall. Look at the pyrazinamide; it disrupts the
plasma membrane formation. If you take ah quinolones they act the DNA
gyrase level inhabiting the necessary synthesis. If you take the rifampicin it acts through
RNA polymerase inhibits transcription. The other drug um bedaquiline a newer drug
acts at the ATP synthase level. Now we come to aims of TB treatment; the main
aim is to cure the patient and restore the quality of life and productivity, also to
bring down mortality and also to bring down the morbidity basically of tuberculosis; from
the patients point of view it is also important to prevent relapse of tuberculosis. So, from the patients point of view cure and
then restore quality of life, prevent death and prevent relapses these 4 are the most
important aims. Now, from the community point of view aims
are a bit slightly different, we have to aim in reducing the transmission of TB to others
by giving bactericidal drugs and killing the rapid kill achieving rapid kill of bacteria,
making the patients smear and culture negative. Also we have to look at the transmission of
drug resistance, development of drug resistance from the community point of view; this is
also achieved by rapid kill of the organisms by giving short course chemotherapy drugs
of rifampicin INH pyrazinamide . Now let us go into the principles of chemotherapy
in tuberculosis; first aim is safety and efficacy, any drug that is prescribed or any regimen
that is prescribed to a patient should be safe for the patient and it also should be
effective. Now prior to start of treatment please look
at the liver function and renal functions ensure they have a proper functioning liver
and kidney. This is important then you start the chemotherapy
I say totally earlier drugs consisting of reforms in INH ethambutol pyrazinamide short
course chemotherapy. The other principle is to use multiple drugs,
combination of drugs; now why are we using multiple drugs we will come to that in the
next slide. Never give a single drug, single drug will
always lead to failure and resistance always your aim is to give combination of drugs. Now, it is not only enough to give drugs,
it it is also important to ensure treatment regularity and adherence and help the patient
to complete this treatment and WHO recommends directly observed treatment or dots in this
regard. A community provider or a somebody from the
patients house or a health worker helps a patient in completing the treatment. It is also equally important to look for associated
co morbidity like HIV and diabetes and treat them accordingly. So, to summarize safety efficacy is very important,
use multiple drug combination that is also very important and see that the patient completes
this treatment and help him by giving dots. Now, why did we give a multiple drug or combination
of drugs in in tuberculosis? There are a number of reasons ranging from
bacteriological reasons, environmental reasons and pharmacological reasons. The most important is bacteriological where
you find naturally occurring drug resistant mutants that has to be attacked and also the
subgroup of populations, bacillary populations with different metabolic activity we will
see these 2 in later slides. These are very important in designing regiment. Environmental and pharmacological is also
equally important; environmental is it depend the drugs penetration depends upon so many
factors it may be the membrane or it may be the blood brain barrier and accordingly her
to prescribe drugs. The third reason it is also equally important
is the pharmacological reason; where the patient is given all the drugs together as a single
dose to ensure peak serum activity which is usually above the MIC of the bacteria which
ensures killing of the bacteria. Now what are naturally occurring drug resistant
mutants in TB? If you see ah cavitatory tuberculosis, the
cavity will be teeming with bacteria and it will be millions; when you have millions of
bacteria viable bacteria there are a few that may develop resistant through any one of the
anti-TB drugs; which are called naturally occurring drug resistant mutants in tuberculosis. So, this is seen whenever the bacillary load
is very high especially in smear positive pulmonary TB lesions. They are mutants as I told you earlier are
present naturally to different drugs and in difference frequency in an untreated smear
positive pulmonary tuberculosis patient; more the number of bacteria more than they are
mutants. Now this figure clearly tells you the rates
of spontaneous mutations conferring resistance to anti TB drugs; if you look at isoniazid,
if you look at rsifampicin ethambutol the drug mutation rates are different for different
drugs, but as you as was mentioned earlier spontaneous mutation developed whenever the
bacterial count is very high more than 10 to the power of 8. Now, this figure clearly explains the mechanism
of amplification of resistance. The previous slide we saw the spontaneous
mutations conferring resistance to anti TB drugs, now in this slide we will be looking
at the amplification of resistance to the drugs. If you look at this picture; whenever only
INH is used if the patient harbors INH resistant organisms the this mono therapy amplified
the resistance and you find more of INH resistance organisms whereas, when you treat them with
3 drugs namely INH, rifampacin and pyrazinamide all the 3 are affected and ultimately with
multi drug therapy no bacterial resistance is seen to all the 3 drugs after the end of
treatment. If you look at here already you are starting
with INH resistant patient you are treating only with INH, INH resistant bacteria multiply
in larger numbers when you treat this patient with true drugs namely INH and rifampicin
this place a way of our development of rifampicin resistance as well. So, the net result would be you have a patient
with multi drug resistant TB when you use only a single drug or two drugs. So, the principle would be to prevent the
amplification of resistance use more than 2 bactericidal drugs use at least minimum
4 drugs in the earlier phase. Now, let us look at the role of the multi
drug therapy in TB treatment the start of the treatment mutants resistant to single
drug capable of multiplication are present, if you give mono therapy it will lead to failure
and more of resistance will be seen. So, if you give 2 drugs concurrently chances
of survival and selection of drug resistant organisms are very very small. The rule is mutants resistant 1 drug are susceptible
to other drugs and vice versa; you use this principle in the treatment of tuberculosis
there you give multi drugs more than 4 drugs to bactericidal drugs at least in that combination
to attack to achieve a kill of all the bacteria in the start of treatment. Thank you.


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