Clinical Scenario
A 30 year old male patient comes to a clinic with
the complaint of cough for 1 week, profuse
nocturnal sweating and loss of appetite. On
examination his body temperature was 38.5ºC and
there were unilateral crepitations in the left lung.
Chest X-ray reveals an infiltrate in the left upper
lobe with a possible cavitation. An acid-fast stain
reveals many thin rods of pinkish hue.
What is the patient most likely suffering from?
Which drugs should be given to the patient?
Anti-Tuberculous
Drugs
SGD
What is Tuberculosis?
What is the clinical presentation?
What is the causative organism of TB?
A chronic granulomatous disease caused by Mycobacterium
tuberculosis
Common communicable disease in the world
Major health problem in the developing countries
Estimated incidence of TB is around 250,000 per year in
Pakistan
It kills 64,000 people in Pakistan each year, accounting for 26%
of the nations avoidable deaths
Chest x-ray usually
shows:
diffuse infiltrates in
lung parenchyma
Cavitation
DOTS (Directly Observed Treatment,
Short-Course)
Tuberculosis control strategy recommended by the World Health
Organization in 1995, for non-compliant patient.
A DOT Lay Worker meets with the clients to help with TB
medication, provides education and watch clients swallow each
dose of anti-TB medication.
The five elements of DOTS:
1. Political will
2. Case detection through quality-assured bacteriology
3. Standardized treatment, with supervision and patient support
4. An effective drug supply and management system
5. Systematic monitoring and accountability for every patient
diagnosed.
How do we classify anti-tubercular
drugs…………. ?
Classification of Anti-Tuberculous
Drugs
Classification
1st line essential drugs– most 2nd line drugs—these are
effective & basic components of used if there is resistance to
anti-tubercular treatment
1st line drugs or if 1st line
1st line supplemental drugs– drugs are contraindicated for
effective & possesses an some reason.
acceptable limit of toxicity. These
These drugs are less effective
are kept as reserved drugs & used
in special settings (hospitalized & slightly more toxic than 1st
patients or those intolerant to the line drugs(except
adverse effects of 1st line drugs) Fluoroquinolones)
Learning Objectives:
Discuss the adverse effects of 1st line Anti-TB drugs
Discuss the second line drugs used in TB
Discuss drugs used for various anti-TB regimes
Discuss chemoprophylaxis of TB
ADVERSE EFFECTS OF
ISONIAZID
What is this?
MAJOR ADVERSE EFFECTS
Peripheral neuropathy: Hepatotoxicity: Jaundice, Hepatitis
Numbness Abnormal liver fuction tests
Paresthesia
Mental disturbances
Pyridoxine has a therapeutic
effect on isoniazid induced
neurotoxicity
OTHER ADVERSE EFFECTS
Restlessness
Muscle twitching
Insomnia
Hemolysis
Hypersensitivity with rash and fever
Adverse Effects of Rifampin
What are these?
Other Adverse Effects
GI upset (nausea, anorexia, abdominal pain)
Cutaneous reaction (rash)
Flu-like syndrome (sore throat, fever, headache,
pain in muscles and joints)
RARELY, it may cause:
Nephritis, Renal failure
Hemolytic Anemia
Thrombocytopenia
PYRAZINAMIDE
MAJO
R
Hyperuricemia
Other Adverse Effects
Gastrointestinal irritation (nausea, anorexia)
Hepatitis
Rash
Photosensitivity reactions
Myalgia
ETHAMBUTOL
ADVERSE EFFECTS
ADVERSE EFFECTS
MAJOR:
impairment of vision, reversible on discontinuance
red–green color blindness (dose dependent)
Optic neuritis
RARE adverse Effects:
Headache
Hyperuricemia
Peripheral neuropathy
Very rarely – hepatitis
STREPTOMYCIN
Aminoglycoside
MOA:
Inhibits the protein synthesis of mycobacteria
USE:
Least used 1st line A.T.D
More active against extracellular bacilli -Inactive against intracellular bacilli
Limitation:
i) dose related toxicity (nephrotoxicity, ototoxicity)
ii) development of resistant organisms
iii) given IM
Adverse effects: Ototoxicity, Nephrotoxicity
SECOND-LINE DRUGS FOR
TUBERCULOSIS
When to use the second-line Anti-TB drugs?
RATIONALE OF USE
Resistance to first-line agents
OR
Failure of clinical response to conventional therapy
OR
Serious treatment-limiting adverse drug reactions of the first line
agents
SECOND LINE ANTI-TUBERCULAR
DRUGS
Thioamides (ethionamide)
Fluoroquinolones (Ofloxacin and Levofloxacin)
Aminoglycosides (kanamycin, amikacin)
Polypeptides (capreomycin)
Cycloserine
PAS (Aminosalicylic Acid)
Ethionamide
chemically related to isoniazid
MOA:
blocks the synthesis of mycolic acids
metabolized by the liver
Adverse Effects:
gastric irritation( nausea, vomiting) and neurologic symptoms
hepatotoxic
Administration & Indication:
cross-resistance between isoniazid and ethionamide is uncommon, pyridoxine co-
administrated
Used in drug-resistant TB
Capreomycin
MOA:
Capreomycin is a bactericidal agent of the polypeptide class
protein synthesis inhibitor
Administration & Indication:
injectable agent (I/V)
Mainly used for MDR-TB
Adverse Effects:
nephrotoxic and ototoxic
Tinnitus, deafness and vestibular disturbances
local pain and sterile abscesses
Cycloserine
MOA:
Cyclic analogue of D-alanine
Inhibitor of cell wall synthesis
Renal clearance
Adverse Effects:
Peripheral neuropathy
Causes central nervous system dysfunction (headaches, confusion, depression,
seizures, and changes of behavior)
Pyridoxine co-administered
Cycloserine should be avoided in patients with a history of epilepsy and mental illness
Indication: Orally effective, limited use in MDR TB only because of toxicity
Aminosalicylic Acid
(PAS)
MOA:
Folate synthesis antagonist
Structurally similar to p-aminobenzoic acid (PABA) and sulfonamides
Adverse Effects:
Main adverse effects of PAS are abdominal pain, nausea and peptic ulceration
Hypersensitivity reactions (fever, joint pain, skin rashes, hepatitis)
Hypothyroidism
Indication:
important component of many regimens for MDR-TB.
Amikacin and Kanamycin
MOA:
Both are aminoglycosides
Bactericidal
Inhibit the protein synthesis of mycobacteria
Indications:
Valuable in patients with resistance to streptomycin
Adverse Effects:
Ototoxicity, Nephrotoxicity, Skin rash
Fluoroquinolones
MOA:
Inhibits DNA synthesis and supercoiling of Mycobacteria
Indications:
Ofloxacin and Levofloxacin are used for drug-resistant TB.
Later-generation fluoroquinolones (moxifloxacin) have some efficacy against
ofloxacin-resistant strains and is recommended for the treatment of XDR-TB
Adverse Effects:
Anorexia, nausea, vomiting
Headache, dizziness, anxiety
Rupture of Achilles tendon
ANTI-TUBERCULAR DRUG
REGIMEN
1. Standard regimen:
Anti-TB drugs are given as 2/3/4 drug combination regimens for different durations.
Combination regimen should include at least two drugs to which mycobacteria are sensitive.
The response to chemotherapy is slow, so given for months to years
Mycobacteria show these characteristics:
Grows more slowly than other bacteria
Grows inside macrophage – poorly penetrated by drugs
Excellent ability to develop resistance – Multiple Drug Resistant (MDR)
Lipid-rich mycobacterial cell wall is impermeable to many agents
Standard regimens
Initial Intensive Phase for 2 months:
Therapy is initiated with 4 drug regimen:
Isoniazid
Rifampin
Pyrazinamide
Ethambutol or Streptomycin
Continuation Phase for 4 months:
Only a few bacilli are left in this phase, so only 2 or 3 drugs are
enough.
Isoniazid and Rifampin (commonly used)
Isoniazid , Rifampin , Pyrazinamide / Ethambutol may be used
sometimes
Pyridoxine: 25 to 50mg/day, to minimize adverse reactions to
isoniazid.
Myrin-P
Contains ethambutol, rifampicin, isoniazid and pyrazinamide.
Given daily during the initial phase treatment with the dose adjusted
according to body weight as follows:
PATIENT BODY WEIGHT (KG) Initial Phase 02 Months (New
Cases)
03 Months (Re Treatment Cases)
MYRIN TABLETS
30-39 2 tablets
40-54 3 tablets
55 & above 4 tablets
Alternative regimens:
Alternative regimens for fully susceptible organisms include:
INH + Rifampin for 9 months
INH + Ethambutol for 18 months.
LATENT TB
A state of persistent immune response to stimulation by M.
tuberculosis antigens with no evidence of active TB.
Majority of infected people have no signs and symptoms of TB but are
at risk of developing active TB and may become infectious
ADULTS
isoniazid, 300 mg daily or twice weekly, for 6 months
or
rifampin, 10 mg/kg daily, for 4 months.
CHILDREN
isoniazid 10-15 mg/kg daily (maximum 300 mg), or 20-30 mg/kg two
times a week directly observed, for 9 months.
or
rifampin 10-20 mg/kg daily for 6 months is recommended
Drug-Resistant TB
Mono-resistant: Resistance to a single drug
Poly-resistant: Resistance to more than one drug, but not the
combination of isoniazid and rifampicin
Multidrug-resistant (MDR): Resistance to at least isoniazid and
rifampicin
Extensively drug-resistant (XDR): MDR plus resistance to
fluoroquinolones and at least 1 of the 3 injectable drugs (amikacin,
kanamycin, capreomycin)
Chemoprophylaxis of TB
This is indicated only in :
(a) Contacts of open cases who show recent Mantoux conversion.
(b) Children with positive Mantoux and a TB patient in the family.
(c) Neonate of tubercular mother.
(d) Patients of leukemia, diabetes, silicosis, or those who are HIV
positive or are on corticosteroid therapy who show a positive
Mantoux.
(e) Patients with old inactive disease who are assessed to have
received inadequate therapy.
Chemoprophylaxis of TB
The standard drug for chemoprophylaxis of TB is
Isoniazid 300 mg (10 mg/kg in children) daily for 6
months.
Because of spread of INH resistance, a combination of
Isoniazid (5 mg/kg) and Rifampicin (10 mg/kg,
maximum 600 mg) daily given for 3 months is preferred
in some areas.
Quiz
Q: Fill in the blanks with the appropriate answer:
1. __________ can be used to reverse the peripheral neuropathy
induced by Isoniazid.
2. ___________ is the most common adverse effect associated
with the use of Ethambutol.
3. Ehionamide, a second-line anti-TB drug is a chemically related
to ___________ .
4. PAS (amino salicylic acid) exerts its action by inhibiting the
synthesis of _____________ .
5. In the continuation phase of standard regimen,______ and
______ are commonly used for 4 months.
MCQs
1. A 63-year old man presented to the hospital complaining of
abdominal pain and stiffness in several joints. He was recently
diagnosed with tuberculosis and started on a regimen of 4 anti-
tubercular drugs, one month ago. Lab results shoed raised
serum uric acid levels. Which of the following drugs has most
likely caused the patient’s current symptoms?
A. Isoniazid
B. Rifampicin
C. Pyrazinamide
D. Ethambutol
MCQs
2.Which of the following is the second-line drug
for the treatment of MDR-TB?
A. Isoniazid
B. Cycloserine
C. Rifampicin
D. Ethambutol
E. Pyrazinamide
MCQs
3. A 24-year-old male has returned to the clinic for his 1-month
check-up after starting treatment for tuberculosis. He is
receiving isoniazid, rifampin, pyrazinamide, and ethambutol. He
states he feels fine, but now is having difficulty reading his
morning newspaper and feels he may need to get glasses.
Which of the following drugs may be causing his decline in
vision?
A. Isoniazid
B. Rifampin
C. Pyrazinamide
D. Ethambutol
MCQs
4. A 10-year-old boy has uncomplicated pulmonary tuberculosis. After
initial hospitalization, he is now being treated at home with isoniazid,
rifampin and ethambutol. Which statement about this case is
accurate?
(A) A baseline auditory function test is essential before drug
treatment is initiated
(B) His mother, who takes care of him, does not need INH prophylaxis
(C) His 3-year-old sibling should receive INH prophylaxis
(D) The patient may develop symptoms of polyarthralgia
(E) The potential nephrotoxicity of the prescribed drugs warrants
periodic assessment of renal function
MCQs
5. Which statement about anti-tubercular drugs is accurate?
(A) Anti-mycobacterial actions of streptomycin involve
inhibition of arabinosyl transferases
(B) Cross resistance between Isoniazid and Ethionamide is
common
(C) Ocular toxicity of ethambutol is prevented by thiamine
(D) Pyrazinamide treatment should be discontinued
immediately if gout occurs
(E) Use of RIFAMPIN can cause orange discoloration of the
contact lens
1. The primary reason for the use of drug combinations in the
treatment of tuberculosis is to
(A) Delay or prevent the emergence of resistance
(B) Ensure patient compliance with the drug regimen
(C) Increase antibacterial activity synergistically
(D) Provide prophylaxis against other bacterial infections (
E) Reduce the incidence of adverse effects
Questions 2–5. A 21-year-old woman from Southeast Asia has been staying
with family members in the United States for the last 3 mo and is looking
after her sister’s preschool children during the day. Because she has difficulty
with the English language, her sister escorts her to the emergency
department of a local hospital. She tells the staff that her sister has been
feeling very tired for the last month, has a poor appetite, and has lost weight.
The patient has been feeling somewhat better lately except for a cough that
pro duces a greenish sputum, sometimes specked with blood. With the
exception of rales in the left upper lobe, the physical examination is
unremarkable and she does not seem to be acutely ill. Laboratory values
show a white count of 12,000/μL and a hematocrit of 33%. Chest x-ray film
reveals an infiltrate in the left upper lobe with a possible cavity. A Gram-
stained smear of the sputum shows mixed flora with no dominance. An acid-
fast stain reveals many thin rods of pinkish hue. A preliminary diagnosis is
made of pulmonary tuberculosis. Sputum is sent to the laboratory for culture.
2. At this point, the most appropriate course of action is to
(A) Hospitalize the patient and start treatment with 4 anti tubercular
drugs (B) Hospitalize the patient and start treatment with rifampin
(C) Prescribe isoniazid for prophylaxis and send the patient home to
await culture results
(D) Provide no drugs and send the patient home to await culture
results
(E) Treat the patient with isoniazid plus rifampin
3. Which drug regimen should be initiated in this patient when
treatment is started?
(A) Amikacin, isoniazid, pyrazinamide, streptomycin
(B) Ciprofloxacin, cycloserine, isoniazid, PAS (
C) Ethambutol, isoniazid, pyrazinamide, rifampin
(D) Isoniazid, pyrazinamide, rifampin, streptomycin
(E) PAS, pyrazinamide, rifabutin, streptomycin
4. Which statement concerning the possible use of isoniazid (INH) in
this patient is false?
(A) Dyspnea, flushing, palpitations, and sweating may occur after
ingestion of tyramine-containing foods
(B) In patients from Southeast Asia, lower maintenance doses are
necessary (C) Peripheral neuritis may occur during treatment
(D) The patient should take pyridoxine daily
(E) The risk of the patient developing hepatitis from INH is less than
2%
5. On her release from the hospital, the patient is advised not to rely
solely on oral contraceptives to prevent pregnancy because they may
be less effective while she is being maintained on antimycobacterial
drugs. The agent most likely to interfere with the action of oral
contraceptives is
(A) Amikacin
(B) (B) Ethambutol
(C) (C) Isoniazid
(D) (D) Pyrazinamide (
(E) E) Rifampin
6. A patient with AIDS and a CD4 cell count of 100/μL has persistent
fever and weight loss associated with invasive pulmonary disease
due to M avium complex (MAC). Optimal management of this patient
is to
(A) Choose an antibiotic based on drug susceptibility of the cultured
organism (B) Initiate a two-drug regimen of INH and pyrazinamide
(C) Prescribe rifabutin because it prevents the development of MAC
bacteremia
(D) Start treatment with the combination of azithromycin,
ethambutol, and rifabutin
(E) Treat with trimethoprim-sulfamethoxazole
7. A 10-year-old boy has uncomplicated pulmonary tuberculosis. After
initial hospitalization, he is now being treated at home with isoniazid,
rifampin, and ethambutol. Which statement about this case is
accurate?
(A) A baseline test of auditory function test is essential before drug
treatment is initiated
(B) His mother, who takes care of him, does not need INH prophylaxis
(
C) His 3-year-old sibling should receive INH prophylaxis
D) Polyarthralgia is a potential adverse effect of the drugs the boy is
taking (E) The potential nephrotoxicity of the prescribed drugs warrants
periodic assessment of renal functio
8. Which statement about antitubercular drugs is accurate?
(A) Antimycobacterial actions of streptomycin involve inhibition of
arabinosyltransferases (
B) Cross-resistance of M tuberculosis to isoniazid and pyrazinamide is
common (C) Ocular toxicity of ethambutol is prevented by thiamine
(D) Pyrazinamide treatment should be discontinued immediately if
hyperuricemia occurs
(E) Resistance to ethambutol involves mutations in the emb gene
. Once-weekly administration of which of the following antibiotics has
prophylactic activity against bacteremia caused by M avium complex
in AIDS patients?
(A) Acedapsone
(B) Azithromycin
(C) Clarithromycin
(D) Kanamycin (
E) Rifabutin
10. Risk factors for multidrug-resistant tuberculosis include
(A) A history of treatment of tuberculosis without rifampin (
B) Recent immigration from Asia and living in an area of over 4%
isoniazid resistance
(C) Recent immigration from Latin America
(D) Residence in regions where isoniazid resistance is known to exceed
4%
(E) All of the above
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