Presentation about tuberculosis, it's epidemiology, pathology, antituberculosis drugs, and their mechanism of actions, ADR's and case study of a tuberculosis patient.
2. TUBERCULOSIS
PATHOGENESIS:
• Air borne disease
• Caused by rod shaped aerobic bacilli called mycobacterium tuberculosis
• Apart from lungs, can effect bones, meninges, kidneys, intestines
• Bacterial cell wall mainly contain mycolic acid, so it is given mycobacterium tuberculosis
name
• Enzymes reductase and synthase, acyl reductase(proteinous) beta-keto acyl synthase are
responsible for production of mycolic acid.
EPIDEMIOLOGY:
• 2 billion people are infected of this disease.
• One of the leading cause of deaths.
• 30 million people are diagnosed with active TB in 2017.
• BCG vaccines are used for prophylaxis in children.
3. TYPES AS PER EXPOSURE
1) LATENT TB
INFECTION (LTBI):
Microbe is present, but
growth is not rapid.
Stationery in nature no
sign and symptoms.
Quite difficult to
diagnose.
2-10% LTBI converts to
ATBI.
Isoniazid is used as
prophylaxis for 9 months,
300mg Qday.
900mg every week with
Rifapentine 600mg for 12
weeks (9 tablets week).
Direct observation
therapy (dot), patient is
directly observed,
diagnosis and monitoring
of patient.
2) ACTIVE TB
INFECTION:
•First line treatment:
INH 5mg/kg/day, max:
300mg/day
RIF 10mg/kg/day, max:
600mg/day.
ENB 15mg/kg/day, if
weight of patient is 40-
55kg then 800mg, if 56-
75kg then 1200mg, if 76-
90kg then 1600mg.
PZA 25mg/kg/day, if
weight of patient is 40-
55kg then 1000mg, if 56-
75kg then 1500mg, if 76-
90kg then 2000mg.
4. Second line treatment:
Streptomycin
Amikacin
Kanamycin
Capreomycin
Cycloserine 10-15mg/kg/day (500-1000mg/day 2 doses).
Ethionamide 15-20 mg/kg/day (1000mg in 1 or 2 doses).
Para amino salicylic acid 4-12 g/day in 2-3 doses.
Fluoroquinolones (levofloxacin 500mg q12h, moxifloxacin 400mg q24h).
Linezolid 600mg q12h.
Bedaquiline 400mg q24h for two weeks then 200mg 3 times in a week for 22 weeks.
Therapy duration is 6 months for atbi.
First line treatment in initial 2 months, then rifampicin and isoniazid are given for 4 months.
15mg/kg/day, (1g IV or
I/M everyday).
5.
6. ISONIAZID
Derivative of isonicotinic acid, analogue of pyridoxine.
Bacteriostatic in LTBI, bactericidal in ATBI.
Acts on cell wall of microbes so it is called cell wall synthesis inhibitors i.e., Inhibits the production of mycolic acid.
Available in prodrug form.
Peroxidase enzyme is responsible to convert prodrug into active form.
KINETICS:
Readily absorbed orally, on empty stomach because food may inhibit its absorption
Given breakfast.
Available equally in blood and CSF.
Excreted through kidneys.
ADRS’ :
Peripheral neuropathy, nausea, vomiting, drug associated fever, hepatitis, abdominal cramp.
7. RIFAMYCINS:
TYPES:
1. Rifampicin or rifampin
2. Rifabutin.
3. Rifapentin.
ANTIBACTERIAL SPECTRUM:
Broader spectrum against mycobacterium tubercle.
Spectrum is broader than isoniazid, but potency of isoniazid is more than rifampicin.
MECHANISM OF ACTION:
Protein synthesis inhibitor.
Inhibits DNA dependent RNA polymerase enzyme
Blocks RNA polymerase, so transcription process is blocked.
RNA polymerase acts as substrate.
RESISTANCE:
Bacteria changes the gene in RNA polymerase by genetic mutation.
8. -Well absorbed orally and IV.
-10%-20% available in body fluids and CSF (widely
distributed).
-Also effective in cerebral TB.
-Metabolized by cytochrome P450, also induces CYP450.
-Cimetidine, quinidine, digoxin are also substrate of this -
CYP450 enzyme, so their concentration decreases when
administered with rifampicin.
-Mainly excreted through liver in feces, some proportion
is excreted from kidneys.
-Main ADR is red urine discoloration, reddish feces,
nausea, drug-induced fever, vomiting, hepatitis.
KINETICS:
9. RIFABUTINE:
Derivative of RIFAMPIN, but is less inducer of CYP450 enzyme.
Preferred in patients of TB and HIV, because HIV drugs are metabolized from liver.
RIFAPENTINE:
Longer duration of action and half life than rifampicin.
Quickly doses are given.
In initial phase, once weekly (4 months/8 weeks).
In rest of phase, twice a weekly. (4 months/8 weeks).
PYRAZINAMIDE:
Bactericidal drug.
Unknown mode of action.
It is a prodrug, converted into pyrazinoic acid by enzyme pyrazinamidase.
Orally active.
Widely distributed in CSF.
Excreted in URINE, METABOLIZED BY LIVER.
PROMINENT ADR is urate retention, also causes gout attack.
Urate retention Monosodium urate crystals formed from uric acid.
10. ETHAMBUTOL:
Bacteriostatic in nature.
It replaces para amino salicylic acid.
Arabinosyl inhibitor.
Well absorbed from oral route, concentration is present in csf as well.
Metabolized by cyp450 enzyme.
ADRS:- hyperpigmentation, blurred vision, red-green color blindness.
11. CASE STUDY OF ANTI TUBERCULOSIS DRUGS:
A 20 YEAR OLD PREGNANT FEMALE PRESENTS FOR HIV CARE
A 20-YEAR-OLD WOMAN, IN HER FIRST TRIMESTER OF PREGNANCY, PRESENTS TO THE ANTE-NATAL CLINIC (ANC) FOR
ROUTINE CARE. AFTER COUNSELING SHE VOLUNTEERED FOR HIV TESTING AND WAS FOUND TO BE HIV POSITIVE. SHE IS
NOW ENROLLED IN THE PREGNANCY HIV CLINIC FOR ANTENATAL CARE SPECIFIC TO HER NEEDS.
ON HISTORY
THIS IS HER FIRST PREGNANCY; IT WAS UNPLANNED AND OCCURRED DUE TO UNPROTECTED SEXUAL INTERCOURSE. SHE
HAS NEVER USED ORAL CONTRACEPTIVES NOR HAS SHE PRACTICED SAFE SEX. THIS IS HER THIRD PARTNER THIS YEAR.
SHE COMPLAINS THAT SHE HAS LOST 4KG IN THE PAST TWO MONTHS. DURING THIS TIME SHE HAS ALSO HAD A
PERSISTENT COUGH.
ON EXAMINATION
THIN, BUT NO SIGNS OF WASTING.
NO LYMPHADENOPATHY
CRACKLES IN THE UPPER LOBE OF THE LEFT LUNG.
NO OTHER SIGNIFICANT FINDINGS
FBC:
5.40 WCC (4.00-10.00 X 109/L)
64% NEUTROPHILS; 33% LYMPHOCYTES.
HEMOGLOBIN: 9.5 G/DL (12.1-16.3 G/DL)
CD4 COUNT: 320 CELLS/MM3 (1000-1800 CELLS/MM3)
SPUTUM SAMPLE: AFB POSITIVE
12. Discussion
The essential or first line TB drugs are:
ISONIAZID, RIFAMPICIN, ETHAMBUTOL, PYRAZINAMIDE AND STREPTOMYCIN.
There are three main properties of TB drugs:
BACTERICIDAL ACTIVITY
STERILISING ACTIVITY
ABILITY TO PREVENT RESISTANCE
The essential (first line) TB drugs have these properties in different proportions.
Isoniazid and rifampicin are the most powerful bactericidal drugs, active against all populations of TB bacilli.
Rifampicin is the most potent sterilizing drug available.
Pyrazinamide and streptomycin are also bactericidal against certain populations of TB bacilli. Pyrazinamide
is only active in an acid environment. Streptomycin is bactericidal against rapidly multiplying TB bacilli.
Ethambutol is used in association with more powerful drugs to prevent the emergence of resistant bacilli.
13. TB treatment
Essential or first line treatment for a newly diagnosed patient is isoniazid, rifampicin, pyrazinamide, and ethambutol
for two months (initial phase), then isoniazid and rifampicin alone for a further four months (continuation phase).
The first two months of treatment is given with DOTS (directly observed treatment, short-course) which helps to
improve adherence. Usually during the first two weeks tubercle bacilli are rapidly killed and infectious patients
become non-infectious. During the continuation phase fewer drugs are needed but for a longer period. The sterilizing
effect of the drugs eliminates the remaining bacilli and prevents relapse.
At the end of the second month of treatment, most patients will have a negative sputum smear, however if a patient
has a positive sputum smear at this time, this may indicate one of the following:
most frequently, that the initial phase of therapy was poorly supervised and that patient adherence was poor;
occasionally that there is a slow rate of progress with sputum smear conversion, e.g. if a patient had extensive
cavitation and a heavy initial bacillary load;
rarely, that the patient may have drug-resistant TB that does not respond to first-line treatment.
TB in pregnant women
Untreated tuberculosis (TB) represents a greater hazard to a pregnant woman and her fetus than the treatment does.
The outcome of a pregnancy is not altered by TB drugs. Even though the drugs do cross the placenta they do not have
harmful effects on the fetus. However, infants born to mothers with untreated TB are usually low birth weight babies
and may be born with TB themselves. Therefore TB treatment of pregnant women should be initiated whenever the
disease is present.
14. TB treatment in HIV positive pregnant women
In patients who have both TB and HIV, TB treatment takes priority over ARV therapy, and should never be
compromised. If a patient is diagnosed with TB, they must be started immediately on treatment. Rather delay
or replace the ARV therapy if there are drug interactions than delay the TB treatment. TB treatment with DOTS
should be initiated immediately in a pregnant woman diagnosed with active TB, irrespective of whether she is
on ARVs or not.
When TB infection is present before starting ARVs, consider the following:
If CD4 count > 200 and patient is less then WHO stage IV disease – start TB treatment and asses the need for
ARVs at completion of TB therapy using CD4 count and clinical criteria.
If CD4 count < 200 and/or WHO stage IV disease present – delay ARVs until after 2 month of TB therapy
If CD4 count < 50 – introduce ARVs as soon as patient is stabilized on TB therapy ( typically 2 wks.).
If TB develops and patients are already on ARVs then continue ARVs throughout the TB treatment. The
following changes should be made:
1st line ARV therapy change nevirapine to efavirenz
2nd line therapy lopinavir/ritonavir, increase the dosage of ritonavir to 400mg
15. Contraindicated treatments
Nevirapine and rifampicin should not be used together, because rifampicin is a potent inducer of liver enzymes
and lowers the blood levels of nevirapine (Dose adjustments for co administration have not yet been
established).
Nevirapine and rifampicin-based TB treatment should not be used together because of the potential
hepatotoxicity. Efavirenz is contraindicated in pregnancy, especially during the first trimester, because of its
potential for birth defects of the CNS. However, if there is no alternative drug available, efavirenz should only be
used after the first trimester, and if it has to be used in the first trimester the mother must be counseled.
Streptomycin is contraindicated in pregnancy because it is ototoxic to the fetus and can cause permanent
deafness.
Plan for this patient:
Adherence counseling.
Begin ARVs after the first two months of TB treatment. Full dose HAART to include stavudine, lamivudine,
nevirapine. If the therapy is used for at least 12 weeks before delivery and throughout the breast feeding it will
reduce HIV transmission rates to the baby down to 1-2%.
When ARVs are started TB symptoms may transiently worsen as part of Immune Reconstitution Inflammatory
Syndrome (IRIS).
Acknowledgement
This case study was taken from Immunopaedia