ANT

MYCOBACTERIAL
AGENTS
PILLA MD.
Learning Objective
• Introduction
• Antimycobacterial Drugs
• Mechanism of Action& Basis of Resistance
• Pharmacokinetics
• Clinical Use
• Adverse Effects/Drug Interactions
• Summary
Introduction
• Tuberculosis has plagued humankind worldwide for
thousands of years
• TB is caused by bacteria (Mycobacterium
tuberculosis) and it most often affects the lungs
• TB is spread through the air when people with lung
TB cough, sneeze or spit
• A person needs to inhale only a few germs to become
infected
Cont..
• About one-quarter of the world's population has a TB
infection, which means people have been infected by TB
bacteria but are not (yet) ill with the disease and cannot
transmit it
• People infected with TB bacteria have a 5–15% lifetime
risk of falling ill with TB
• Those with compromised immune systems, such as
people living with HIV, malnutrition or diabetes, or
people who use tobacco, have a higher risk of falling ill
Cont..
• When a person develops active TB disease, the
symptoms (such as cough, fever, night sweats, or
weight loss) may be mild for many months
• This can lead to delays in seeking care, and results in
transmission of the bacteria to others
• People with active TB can infect 5–15 other people
through close contact over the course of a year
• Without proper treatment, 45% of HIV-negative people
with TB on average and nearly all HIV-positive people
with TB will di
Cont...
• Despite the first anti-tuberculosis drugs being
discovered more than 60 years ago, tuberculosis today still
kills an estimated 1.5 million people each year
• Progress in the scaling up of tuberculosis diagnostic,
treatment, and control efforts worldwide over the past decade
has been associated with improvements in tuberculosis
control in many parts of the world
• However, progress has been substantially undermined by
the HIV-1 epidemic, the growing challenge of drug
resistance, and other increasingly important epidemiological
factors that continue to fuel the tuberculosis epidemic
Microbiology of Mycobacterium
tuberculosis
• M tuberculosis was first identified by the German
scientist Robert Koch in 1882
• The M tuberculosis complex of organisms, which can
cause human disease, consists of M tuberculosis,
Mycobacterium africanum, Mycobacterium bovis,
Mycobacterium microti, and Mycobacterium
canetti
• M bovis was responsible for about 6% of all human
tuberculosis deaths in Europe before the introduction of
milk pasteurisation
• Subsequent attenuation of a laboratory strain of M bovis
led to the development of the BCG vaccine in 1921
Cont..
• M tuberculosis is an obligate intracellular pathogen that can infect
several animal species, although human beings are the principal hosts
• It is an aerobic, acid-fast, non-motile, non-encapsulated, non-
spore forming bacillus
• It grows most successfully in tissues with high oxygen content, such
as the lungs
• Compared with the cell walls of other bacteria, the lipid-rich cell wall is
relatively impermeable to basic dyes unless combined with phenol
• Thus, M tuberculosis is neither gram positive nor gram negative but is
instead described as acid-fast, since once stained it resists
decolourisation with acidified organic solvents
Cont...
• M tuberculosis divides every
15–20 h, which is extremely
slow compared with other
bacteria
• This slow replication rate
and ability to persist in a
latent state result in the
need for long durations of
both drug therapy of
tuberculosis and for
preventive therapy in people
with M tuberculosis infection
Cont....
• The lipid rich mycobacterial cell wall is
impermeable to many agents(e.g. drugs).

• Mycobacterial species are intracellular pathogens,

and organisms residing within macrophages are
inaccessible to drugs that penetrate these cells poorly.

• Finally,mycobacteria are notorius for their ability to

develop resistance.
Cont...
• Combinations of two or more drugs are required to
overcome these obstacle and to prevent emergence of
resistance during the course of therapy.

• The response of mycobacterial infections to

chemotherapy is slow, and treatment must be
administered for months to years, depending on
which drugs are used.
Antimycobacterial Drugs
• Aims of Anti-TB Treatment
• Cure TB patients
• Prevent death
• Avoid TB recurrence (relapse)
• Prevent development of drug-resistant organisms
• Prevent transmission of TB to the community
Basic Classification of Anti-
Tuberculosis Drugs
First Line Drugs • If there is resistance to first
• Isoniazid (INH or H) line anti-TB drugs, the
following second line drugs
• Rifampicin (RIF or R) can be initiated;
• Pyrazinamide (PZA or Z) • Ethionamide
• Streptomycin (SM or S) • Cycloserine
• Ethambutol (EMB or E) • Capreomycin
• Kanamycin
• Streptomycin
• Fluoroquinolones (e.g.
Ofloxacin, Moxifloxacin)
TB Treatment Regimens
• Tuberculosis is treated in two phases which differ in
number of drugs used
• Initial phase (intensive) that includes the use of at
least four drugs
• A continuation phase which includes the use of at
least two drugs
• Treatment requires specialized knowledge, particularly
where the disease involves resistant organisms or non-
respiratory organs
Initial (Intensive) Phase
• There is rapid killing of the TB bacilli and hence reduce the bacterial
population as rapidly as possible and to prevent the emergence of drug-
resistant bacteria
• Patients mostly become non-infectious in about 2 weeks
• The treatment of choice for the initial phase is the daily use of: RHZE
• Isoniazid
• Rifampicin
• Pyrazinamide
• Ethambutol
• Streptomycin is rarely used in the initial phase of treatment unless
resistance to isoniazid has been established before therapy is
commenced. It can also be used in retreatment (relapse) cases.
• The initial phase drugs should be continued for at least two months
Continuation Phase
• After the initial phase, treatment is continued for at
least 4 months with:
• Isoniazid and Rifampicin (preferably given as a
combination preparation).
• During continuation phase, drugs kill the persistent
mycobacteria and prevent relapse after
completion of treatment.
Isoniazid
• Isoniazid is the most active drug for the treatment of
tuberculosis caused by susceptible strains.
• It has the structural similarity to pyridoxine =(Vit.B6)
• It is bactericidal for actively growing tubercle
bacilli, but bacteriostatic for slow growing
mycobacteria
• Isoniazid penetrates into macrophages and is active
against both extra- and intracellular organisms.
Cont..
Mechanism of action
• It inhibits synthesis of mycolic acids, which are essential
components of mycobacterial cell walls.
• Isoniazid is a prodrug that is activated by KatG, the
mycobacterial catalase-peroxidase.
Mode of resistance
• Resistance-deletions in katG gene (encodes catalase
needed for INH bioactivation)
Mechanism of Action and
Basis of
Resistance
INH, a
prodru
g

Mycolic acid,
essential
KatG enzyme, a component of cell
mycobacterial wall
catalase
peroxidase
enzyme, activates
INH

DN
PKs:
• Isoniazid is readily absorbed from the gastrointestinal
tract.
• Dosage: 300mg daily per oral or 5mg/kg/d for children.
Peak plasma concentration 3-5mcg/ml achieved
within 1-2 hours.
• Isoniazid metabolites and a small amount of unchanged
drug are excreted mainly in the urine.
Clinical uses
• Infections caused by mycobacterium tuberculosis along
with other antitubercular drugs.Dosage: 300mg/day per oral
adults, or 900mg twice/week. 5mg/kg/day in children.
• Isoniazid can be used to prevent development of TB
disease in a program referred to as Isoniazid Preventive
Therapy (IPT) ,Patient Living with HIV (PLHIV) who have been
exposed to TB with no ‘active’ TB (no signs and symptoms)
are given INH to prevent them from developing active TB.
• INH is the primary drug used to treat latent tuberculosis,
300mg/day alone or 900mg twice/week for 9 months.
Side effects
• Unwanted effects depend on the dosage and occur in
about 5% of individuals
• Peripheral neuropathy ( treat with pyridoxine )
• Liver problems (Hepatitis) -jaundice and right upper
quadrant pain,
• It also causes a skin rash, fever, nausea and vomiting
may cause haemolytic anaemia in individuals with
glucose 6-phosphate dehydrogenase deficiency.
Drug interaction
• It decreases the metabolism of the antiepileptic agents Phenytoin,
ethosuximide and carbamazepine, resulting in an increase in the
plasma concentration and toxicity of these drugs.
Rifampicin
• It is a semisynthetic derivative of rifamycin, an
antibiotic produced by Streptomyces mediterranei.
• It is active in vitro against gram-positive and gram-
negative cocci, some enteric bacteria, mycobacteria,
and chlamydia
Cont..
Mechanism of action
• Binds to the b-subunit of bacterial DNA-dependent RNA
polymerase and thereby inhibits RNA synthesis (inhibit
transcription)

Mode of restistance
• Resistance results from point mutations in the gene for
the b subunit of RNA polymerase.
• These mutations result in reduced binding of rifampin to
RNA polymerase.
Cont..
• Human RNA polymerase does not bind rifampin and is
not inhibited by it.
• Rifampin is bactericidal for mycobacteria.
• It readily penetrates most tissues and into phagocytic
cells. It can kill organisms that are poorly accessible to
many other drugs, such as intracellular organisms and
those sequestered in abscesses and lung cavities.
PKs
• Rifampin is well absorbed after oral admin
• Distributed widely in body fluids and tissue
• It is excreted mainly through the liver into bile.It then
undergoes an enterohepatic circulation, with the bulk
excreted as a de-acylated metabolite in feces and a
small amount in the urine.
• Rifampin is relatively highly protein bound and
adequate CSF concentrations are achieved only in the
presence of meningeal inflammation
Clinical uses
• Mycobacterial infections: Rifampin usually
600mg/day, 10mg/kg/day, orally must be admin. with
isoniazid or other antiTB drugs to patients with active
tuberculosis to prevent emergence of DR mycobacteria.
• Atypical mycobacterial infections
• Leprosy.
• In these above two conditions rifampin 600mg daily or
twice weekly for 6 months is effective in combination
with other agents.
Cont..
• As alternative of isoniazid in prophylaxis of latent
tuberculosis 600mg/day as a single agent for 4 months, in
patients with isoniazid- resistance or rifampin-susceptible
bacilli.
• In exposure to a case of active tuberculosis caused by an
isoniazid resistant, rifampin susceptible strain.
• To eliminate meningococcal carriage,600mg BD for 2/7
• To eradicate staphylococcal carriage with combination to
other agent
• Osteomyelitis and prosthetic valve endocarditis caused by
staphylococci in combination therapy with other agent.
 Adverse effects:
1.Rifampin imparts a harmless orange color to urine,
sweat, tears and contact lenses.
2.Occasional adverse effects:
Drug interactions:
• Rifampin strongly induces most cytochrome p450
isoforms (3A4,2C9,2D6,2C19,1A2).

• Anticoagulants,cyclosporine,anticonvulsants,
contraceptives, methadone, protease inhibitors, non-
nucleoside reverse transcriptase inhibitors…….

• Administration of rifampin results in significantly lower

serum levels of these drugs.……?
Ethambutol
• Ethambutol is a synthetic water soluble, heat stable compound,
the dextro-isomer of the structure dispensed as the
dihydrochloride salt.
• Mechanism of action
Ethambutol inhibits mycobacterial arabinosyl transferases.
Arabinosyl transferases are involved in the polymerization
reaction of arabinoglycan,an essential component of the
mycobacterial cell wall.

• Resistance to ethambutol is due to mutation resulting in

overexpression of emb gene products or within the emb B
structural gene
PKs :
• Ethambutol is well absorbed from the gut.
• After ingestion of 25mg/kg,a blood level peak 2-mcg/mL is
reached in 2-4 hours.
• About 20% drug excreted in feces and 50% in urine in unchanged
form.
• Ethambutol crosses the blood brain barrier only if the meninges
are inflammed.
• Ethambutol accumulates in renal failure and the dose
should be reduced by half if creatinine clearance is less
than 10mL/min.
• Resistance to ethambutol emerges rapidly when used alone,
therefore it is always given with other antitubercular agents
Clinical Uses
• Tuberculosis: Ethambutol hydrochloride 15-25mg/kg/d is usually
given as a single daily dose in combination with isoniazid or
rifampin.
Adverse effects:
• Retrobulbar (optic) neuritis resulting in loss of visual acuity and
red green color blindness. Usually occur at doses of 25mg/kg/day
continued for several months.
Precaution&Contraindication
• Periodic visual acuity testing is desirable if the 25mg/kg/day
dosage is used.
• Itis relatively contraindicated in children too young to permit
assessment of visual acuity and red green color discrimination
Pyrazinamide
• Pyrazinamide (PZA) is a relative of nicotinamide, stable and slightly
soluble in water.
• It is inactive at neutral PH, But at PH 5.5 it inhibits tubercle bacilli,
and some other mycobacteria at concentrations of approximately
20mcg/ml.
• Thedrug is taken up by macrophages & exerts its activity against
mycobacteria residing within the acidic environment of lysosomes.
• Pyrazinamide is converted to pyrazinoic acid,its active form by
microbial pyrazinamidase, which is encoded by pncA
Cont...
• The drug target and mechanism of action are unclear
• Resistance may be due to impaired uptake of
pyrazinamide or mutations in pncA that impair
conversion of pyrazinamide to its active form.
Cont...
• Pyrazinamide is well absorbed from GIT.
• It is widely distributed in body tissues, including inflammed
meninges.
• The half life is 8-11 hours.
• The parent compound is metabolized by the liver, but metabolites
are renally cleared.
• Dosage: 25-35 mg/kg/day or 40-50mg/kg thrice/week.
• CLINICAL USE
• Pyrazinamide is an important front line drug used in conjuction with
isoniazid & rifampin in short course (i.e 6 months) regimens as a
sterilizing agent active against residual intracellular organisms that
may cause relapse.
Advese effects of Pyrazinamide
• Hepatotoxicity (in 1-5% of patients- major adverse effect).
• Hyperuricaemia (it may provoke acute gouty arthritis).
• Nausea, vomiting, & drug fever.
Summary
• The mode of action of first-line TB medicines is as
follows:
• Isoniazid (H): Kills rapidly growing organisms and
dormant organisms
• Pyrazinamide (Z): Kills TB bacilli inside the macrophage
and in cavities
• Rifampicin (R) and pyrazinamide (Z): Kill slow-growing
organisms and have sterilizing activity
• Isoniazid (H), rifampicin (R), and ethambutol (E): Protect
each other from development of resistanc
Fixed Dose Combinations (FDCs)
used in Tanzania
• The MOHSW introduced FDC and Rifampicin-based regimen during the
continuation phase in February 2006.
• This has reduced TB treatment duration from 8 to 6 months. These include:
• 4FDC RHZE: Rifampicin 150 mg, Isoniazid 75mg Pyrazinamide 400 mg, and
ethambutol 275 mg.
• 3FDC RHZ: Rifampicin 150 mg, Isoniazid 75 mg, Pyrazinamide 400 mg.
• 3FDC RHZ for children only: Rifampicin 60 mg, Isoniazid 30 mg,
Pyrazinamide 150 mg
• 2FDC RH for daily use: Rifampicin 150 mg, Isoniazid 75 mg
• 2FDC RH for three weekly use: Rifampicin 150 mg, Isoniazid 150 mg
• 2FDC RH for children: Rifampicin 60 mg, Isoniazid 30 mg
• 2FDC EH: Ethambutol 400 mg, Isoniazid 150 mg
Advantage of Fixed Dose Combinations

• Increased patient acceptance and compliance with fewer pills

• Short duration of treatment because of RH in the continuation phase
• Improved drug management, ordering, procurement, distribution and
dispensing/handling at different levels of the NTLP
• Lowered risk of misuse of single drugs and of emergence of drug-
resistant TB due to reduced use of mono-therapy
Drug Resistance
• Drug resistant-TB is defined as TB for which anti-TB
drugs have little or no effect against the TB causing
agent
• Drug resistant TB may be classified into:
• 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
Drug Resistant TB
Cont..
Risk Factors for Drug Resistance
• Too low drug dose
• Drug interactions resulting in too low drug dose
• Inadequate combination of drugs too short duration of
treatment
• Monotherapy
• Patient does not take all TB drugs as prescribed
• Irregular and selective intake of drugs
• Use of sub-standard anti-TB drugs
• Adding a single drug to treatment regimen when treatment
is failing
Cont...
• Treatment of Drug-Resistant Tuberculosis in Tanzania
• Patients found to have RR-TB or MDR-TB at any point in
time should be started on an adequate second-line
drug regimen.
• The treatment of DR-TB involves standardised and
individualised approaches consisting of intensive and
continuation phases.
• The suggested duration of treatment by WHO offers two
options:
• a total treatment duration of 18-20 months or
• a total duration of 15-17 months after culture conversion
THANK
YOU