ANTIMYCOBACTERIAL DRUGS
1. Drugs for mycobacterium tuberculosis
2. Drugs for atypical mycobacteria
3. Drugs for leprosy
How mycobacteria differs
from other bacteria?
• Lipid rich cell wall impermeable to
many drugs(mycolic acids of cell wall
• Intrinsically resistant to most
antibiotics
• Rapidly develop resistance
• Susceptibility to antibiotics differ in
subpopulation of mycobacteria
Subpopulation of bacilli
• Rapidly growing --- wall of a cavity
• Slow growing – intracellular
• Spurts --- caseous material -- grows
intermittently with intermittent spurts
• Dormant -- totally inactive --completely resistant to many drugs,
No AT drug is effective
AT drugs
• First line
– Isoniazid (INH)
---
H
–Rifampin (rifampicin) --- R
– Pyrazinamide (PZA)
– Ethambutol
-----
Z
E
• Second line
Streptomycin - S
and others drugs
Subpopulation of bacilli &
susceptibility to antibiotics
• Rapidly growing ---Highly susceptible
to H, to a lesser extent to R, E, & S
• Slow growing – Z - R,E,S
• Spurts --- caseous material -- R
• Dormant -- No AT drug is effective
A combination of
drugs is always used
to
To delay the emergence of
resistance and
To enhance efficacy
Why to use two or > 2 drugs?
• Drug – resistant mutants are normally
present --- 1 bacillus in 106
• TB lesions often contain > 108 tubercle bacilli,
• Single drug --- resistant mutants readily
selected
• Two or > 2 drugs --- probability of resistance
---- 1 in 106, or 106 X 106 = 1012
• Two or more drugs should always be used to
treat active tuberculosis to prevent emergence
of resistance during therapy.
1st line drugs
2nd line drugs
• Antitubercular • Efficacy --- Low or
high toxicity or both
efficacy --• More expensive
High
• Used in MDR cases
• low toxicity
(resistant to INH &
rifampin)
• Long duration of
treatment
First line drugs
• Isoniazid (INH)
--- H
• Rifamycin
–Rifampin (rifampicin)--- R
– Rifabutin, Rifapentine)
• Pyrazinamide (PZA)
• Ethambutol
-----
Z
E
Second line drugs
• Streptomycin
--- S
• Aminoglycosides ---- Amikacin, Kanamycin
• Aminosalicylic acid -- PAS
(paraaminosalicylic acid)
• Bedaquiline
• Capreomycin
• Clofazimine
• Cycloserine
Second line drugs
• Ethionamide
• Fluoroquinolones -- Ciprofloxacin,
levofloxacin, sparflxacin, Moxifloxacin
• Linezolid
• Macrolides ---- Azithromycin,
clarithromycin
Second line drugs
•
•
•
•
Rifabutin
Rifapentine
Streptomycin
Thiacetazone
REGIMENS BY Mini kATZUNG
Isoniazid, rifampin, pyrazinamide
(PZA 1ST 2 months only)
Isoniazid, rifampin
Isoniazid, ethambutol
In INH resistant cases:
Rifampin, ethambutol, pyrazinamide
Rifampin, ethambutol, pyrazinamide
(PZA 1ST 6 months only)
All others
Duration in
Months
6
9
18
6
18
24
BIG KATZUNG
REGIMENS
Standard ATT regimens.
• Short course chemotherapy
(6-months treatment)
- Standard unsupervised
- DOTs (Directly observed therapy
short course)
Long term ATT regimens
• Longer term treatment is
needed for patients with
meningitis,
bone/joint involvement or
drug resistant infection
Standard unsupervised
6-months treatment
• Initial phase (intensive phase)--initial 2 months
Rifampicin + INH + PZA +
Ethambutaol
• Continuation phase
Next 4 months
Rifampicin, INH
DOTS
• Directly observed therapy short course –
Health worker physically observes a
patient taking A.T. drugs.
• started by WHO in early 1990s -- using
short-course INH & Rifampin regimens –
recommended in the --------non-compliant patients
DOTS-Plus
• DOTS – Plus ---- which adds the
diagnosis & drugs necessary to
manage the drug resistant disease
• Multi drug resistant (MDR) TB -strains of mycobacterium
tuberculosis resistant to INH &
Rifampicin
ATT – dosing interval
• Daily dose
• Intermittent dose -----------[(Intermittent supervised(DOT)]
- 3 days per week
- 2 days per week
- 5 days per week
Intensive phase
(H+R+Z+E) = 8 weeks
Continuous phase
(H+R)=8 weeks
Dosing interval
Dosing interval
7 days per week
7 days per week
Intensive phase
(H+R+Z+E) = 8 weeks
Continuous phase
(H+R)=8 weeks
Dosing interval
Dosing interval
7 days per week
7 days per week
7 days per week
3 days per week
Intensive phase
(H+R+Z+E) = 8 weeks
Continuous phase
(H+R)=8 weeks
Dosing interval
Dosing interval
7 days per week
7 days per week
7 days per week
3 days per week
3 days per week
3 days per week
Intensive phase
(H+R+Z+E) = 8 weeks
Continuous phase
(H+R)=8 weeks
Dosing interval
Dosing interval
7 days per week
7 days per week
7 days per week
3 days per week
3 days per week
3 days per week
7 days per week × 2 weeks,
then
2 days per week × 6 weeks
2 days per week
Drug
Dose is different
Daily dose
Thrice weekly dose
INH
5 mg/Kg, max 300 mg
15 mg/Kg, max 900 mg
Rifampin
10 mg/Kg, max 600 mg
10 mg/Kg, max 600 mg
PZA
20-25 mg / Kg max 2 g
30-40 mg/Kg, max 3 g
Ethambutol
15-20 mg / Kg
25-30 mg / Kg
Treatment
of
drug resistant tuberculosis
Drug resistance
• Resistance to a particular drug, develop rapidly if
a single drug is used
– INH (in most areas < 4 %)
– Streptomycin
• MDR (multidrug resistant) organisms ----Resistant to INH and rifampin
• XDR (Extensively drug resistant)
– Resistant to first and 2nd line drugs
• TDR --- total drug resistance
MDR TB
• Mycobacteria are resistant to INH
and rifampin
• 2nd line drugs needed for treatment
• Long duration of treatment
• more expensive
• more side effects
MDR
• Initial phase (intensive
phase)---initial 3 months
• Continuation phase
Next 18 months
Resistance
to
Initial phase
Continuation phase
Drugs
Duration
(months)
Drugs
Duration
(months)
INH
Ethionamide
3
Ethionamide
18
Rifampicin
Cycloserine
3
Cycloserine
18
Ethambutol
Fluoroquinolone
3
fluoroquinilines
18
PZA
3
Aminoglycoside
3
Anti TB drugs in renal failure
• Rifampicin, INH and PZA are safe in TB
patients with renal failure
•Avoid ethambutol
and streptomycin
ATT in pregnancy and lactation
• ATT should not be held or
delayed because of
pregnancy or lactation
• Streptomycin should not be
given in pregnancy
• The mechanism of action
and resistance
The mechanism of resistance
Chromosomal mutation / point mutations in genes
• Rifampin – rpoB
• INH --- katG gene, inhA gene
• PZA --- pncA
• Streptomycin -- rpsL gene or rrs
gene
• Ethambutol --- emb gene
INH inhibits synthesis of mycolic acids
• Resistance to INH is associated with several
different chromosomal mutation
– Deletion in the katG gene that codes for a
catalase-peroxidase involved in the
bioactivation of INH
– Mutation/over expression in the inhA gene
that encodes the “target enzyme” as acyl
carrier protein reductase
• Reduced penetration into the bacterium
Rifampin inhibit RNA synthesis
• Inhibits RNA synthesis ---- By binding to the β
subunit of the bacterial DNA-dependent RNA
polymerase
– Human RNA polymerase does not bind rifampin and is
not inhibited by it.
• Resistance results from any one of the several
possible point mutations in rpoB, the gene for
the β subunit of the RNA polymerase
• These mutations result in reduce binding of
rifampin to RNA polymerase
Ethambutol inhibit synthesis of
mycobacterial cell wall
• It inhibits mycobacterial arabinosyl transferse,
which are encoded by the embCAB operon.
• Arabinosyl transferases are involved in the
polymerization reaction of arabinoglycan, an
essential component of mycobacterial cell wall
• Resistance ---- due to mutations resulting in
over expression of emb gene products or
within the emb structural gene
PZA is converted to pyrazinoic acid—the active form of
the drug—by mycobacterial pyrazinamidase, which is
encoded by pncA.
• Pyrazinoic acid disrupts mycobacterial
cell membrane metabolism and
transport functions.
• Resistance may be due to impaired
uptake of PZA or mutations in pncA that
impair conversion of PZA to its active
form.
PZA
• It is inactive at neutral pH, but at pH 5.5 it
inhibits tubercle bacilli
• The drug is taken up by
macrophages and exerts its
activity against mycobacteria
residing within the acidic
environment of lysosomes.
All large populations of the tubercle bacilli
contain some streptomycin resistant mutants
• Resistant is due to a point mutation in either
the rpsL gene encoding the 12S ribosomal
protein gene or the rrs gene encoding 16S
ribosomal RNA, which alter the ribosomal
binding site
• Nontuberculosis species of mycobacteria
other than M avium complex (MAC) & M
kansasii are resistant
Protein synthesis
• Streptomycin
• Rifampin inhibit RNA synthesis
Cell wall
• INH --- inhibits synthesis of mycolic acids
• Ethambutol – inhibit Arabinosyl transferases --- involved in the polymerization reaction of
arabinoglycan, an essential component of
mycobacterial cell wall
• PZA -- cell membrane metabolism and
transport functions.
INDIVIDUAL DRUGS
ISONIAZID
(INH, Isonicotinic hydrazide)
• QUESTION?
What is the rationale of using pyridoxine in a patient of
tuberculosis taking first line antituberculous drugs?
Isoniazid (INH, Isonicotinic hydrazide)
• A synthetic analog of pyridoxine
• Inhibition of mycolic acids
component of mycobacterial cell
wall.
• Narrow spectrum ----- Used
specifically for M. tuberculosis
Antibacterial activity
• It is active against both extracellular &
intracellular bacilli (It penetrates into
macrophages)
• Bactericidal --- For rapidly dividing organisms
• Bacteriostatic --- Halts the growth of resting
organism
• It is less effective against atypical
mycobacteria --- M Kansasii may be
susceptible at higher drug level
Basis of resistance to INH
• Reduced penetration into the bacterium
• Associated with several different chromosomal
mutation
– Deletion in the katG gene that codes for a catalaseperoxidase involved in the bioactivation of INH
– Mutation in the inhA gene that encodes the “target
enzyme” as acyl carrier protein reductase
• Cross resistance does not occur between INH
and other A T drugs
Pharmacokinetics --- INH
• Penetrates well into caseous tuberculous lesion
& CSF
• Well absorbed orally -- Absorption is impaired by
food particularly or alumium containing antacids
• Mtablized in the liver by acetylation
– Fast acteylators – t ½ --- 1 hour
• Higher proportion in Asia (60%)
• May require higher doses
– Slow acetylators --- t ½ --- 3-4 hours
60% of
Asian
(PAK/India)
Require
higher
doses
INH --- Clinical uses
• In the treatment of active disease --- A
component of most drug combination
regimens
• In the treatment of latent infection
(prophylaxis) INH is given as sole drug
– Skin test converters
– Close contacts of patients with active
disease
INH --- Adverse reactions
• Direct toxicity
 Peripheral neuropathy 10-20%
 Hepatitis
– Asymptoma c ↑ in ALT (3-4 times)– seen in 10-20 %. Does
not require cessation of drug
– Clinical hepatitis in <1 %. May be fatal
• Age -- rare under 20, incidence ↑es with ↑ in age
• Greater in alcoholics, pregnancy & postpartum period
• Immunological reactions
– Fever & skin rashes
– Drug induced SLE
– Hemolysis --- With G6PD deficiency
Peripheral neuropathy(10 -20%) & INH
• A synthetic analog of pyridoxine
• INH promotes excretion of pyridoxine, &
induces pyridoxine deficiency
• More rarely anemia & pellagra (in malnourished)
• More likely to occur with high doses, in slow
acetylators, malnutrition, alcohols, diabetics
AIDs & uremia
• Prevented by giving pyridoxine 10 mg (25-50
mg) orally/day
Drug interaction and Toxicity
• Inhibit the hepatic
metaboloism of
carbamazepine,
phenytoin, warfarin
• Hemolysis ---With
G6PD deficiency
• A lupus like
syndrome
RIFAMYCIN
Rifamycin
• Rifamycin --- an antibiotic
produced by streptomyces
mediterranei
• Semisynthetic derivatives ----
Rifampin (Rifampicin) -- R
• Rifabutin, Rifapentine)
Rifampin (Rifampicin)
• Bactericidal against all pools
of the Myco. Tuber. (except
dormant)
Rifampin (Rifampicin)
• It inhibits DNA dependent RNA
polymerase (endcoded by rpo gene)
– (in prokaryotic but not in eukaryotic cells)
Human RNA polymerase does not bind & is
not inhibited by it
• Resistance results from point mutation in
the gene (rpo gene) for the β subunits of
RNA polymerase
Rifampin --- Pharmacokinetics
• Distributed to most
tissues including CNS
(inflammed meninges)
• Enterohepatic cycling
and is partially
metabolized in the liver
• Orange color
– free drug & its metabolites,
are eliminated mainly in
the feces
– Red color to urine
Strong inducer of liver drug
metabolizing enzymes
• ↑ elimina on of many
drugs
• Anticonvulsants,
contraceptives,
cyclosporin,
ketoconazoles,
methadone,
terbinafine, and
warfarin
Rifampin --- Pharmacokinetics
• Dose adjustment for
hepatic or renal
insufficiency is not
necessary
Rifampin Spectrum of activity
• Mycobacteria
• G+ve & G-ve cocci
• Some enteric bacteria
• Chlamydia
Clinical uses of rifampin -- Tuberculosis
• Active disease (tuberculosis)
• Latent infection (prophylaxis)
rifampicin is given as sole drug
–In INH intolerant patients
–In close contacts of the patients with
INH resistance strains of the organism
Clinical uses of rifampin --- Leprosy
• To prevent emergence of resistance.
• Daily dose is highly effective in
leprosy and is given with at least one
other drug (Dapsone, clofazimine)
• Even a dose of 600 mg per month
may be beneficial in combination
therapy
Clinical uses of rifampin --staphylococcal infection
• Rifampin combination therapy (with other
drugs) to
• Eradicate staphylococcal carriage.
• Treatment of serious staphylococcal
infections such as osteomyelitis, prosthetic
joint infections, and prosthetic valve
Endocarditis.
Clinical uses of rifampin
• Used with vancomycin for infections due to
– Resistant staphylococci(MRSA strains) or
– Pneumococci (PRSP strains)
• Treatment of carrier of
– Meningococci --- 600mg twice daily X 2 days
– Staphylococci
• As prophylaxis in contacts of children with
haemophilus influenzae type b disease
– 20 mg/kg/d for 4 days
Toxicity & interactions of rifamipin
• GI upset, Skin rashes
• Hepatitis ---rarely death due to liver
failure -- To be used with caution in
alcoholics, elderly, and CLD
• Cause light chain proteinuria and may
impair antibody response
Toxicity & interactions of rifamipin
• Intermittent or large daily dose (>1.2 g) ---- rifampin may cause flu like syndrome
with fever chills & myalgias
• And sometimes is associated with -Nephritis --- Acute renal failure,
Thrombocytopenia, hemolytic anemia and
shock
Rifabutin --- Another rifamycin
• Equally effective antimycobacterial
• Adverse effects similar to rifampin + uveitis,
skin hyperpigmentation, & neutropenia
• Less likely to cause drug interactions
• Preferred over rifampin in AIDs patients. Less
potent inducer of cytochrome p450 enzyme-- in patients taking protease inhibitors or
nucleoside reverse transcriptase inhibitors
Rifapentin --- Another rifamycin
• Long half life
• For intensive phase (initial 2 months)
-- Twice weekly
• Next 4 months -- Once per week
ETHAMBUTOL
Ethambutol
• Inhibit arabinosyl transferase, involved in
the synthesis of arabinogalactan, a
component of mycobacterial cell wall
• Resistance occurs rapidly via mutation in
the emb gene if the drug is used alone
• Orally and penetrate most body tissues
including CNS
Ethambutol
• A large fraction is eliminated
unchanged in urine
•Dose reduction is
necessary in renal
impairment
Clinical uses
• Has no effect on organisms other than
mycobacteria
– In the treatment of active TB -- It is always given
in combination with other drugs
• Bacteriostatic effect --- Taken up by the
bacteria and exert a bacteriostatic effect after
a period of 24 hours
Toxicity (ethambutol)
• Dose dependent visual disturbances
• ↓ visual acuity
• Red-green color blindness
• Optic neuritis and
• Possible retinal damage (from prolong use at
high doses)
• Most of these effects regress when the drug
is stopped
Toxicity (ethambutol)
• Headache, confusion
• Hyperuricemia
• Peripheral neuritis
PYRAZINAMIDE
(PZA)
PZA
• Tuberculostatic (Bacteriostatic )
against intracellular bacteria
• The drug is taken up by macrophages
and exerts its activity against
mycobacteria residing within the
acidic environment of lysosomes.
• It is inactive at neutral pH, but at pH
5.5 it inhibits tubercle bacilli
Pyrazinamide (PZA)
• PZA is converted to pyrazinoic acid—the active
form of the drug —by mycobacterial
pyrazinamidase, which is encoded by pncA.
• Pyrazinoic acid disrupts mycobacterial cell
membrane metabolism and transport functions.
• Resistance occurs
– Via mutation in gene(pnc A gene) that encodes
enzymes involved in bioactivation of PZA &
– By ↑ expression of drug efflux system / impaired
uptake of PZA
• Minimal cross resistance with other ATT
Pharmacokinetics -- PZA
• Well absorbed orally and penetrate most body
tissues including CNS
• The drug is partially metabolized to pyrazinoic
acid and both the drug and metabolite are
excreted in urine
• The plasma t ½ is ↑ed in hepatic and renal
failure
Clinical use (PZA)
• In the treatment of active disease
• A component of drug combination
regimen
• An important factor in the
success of “ short course”
treatment regimens
Toxicity
• Hyperuricemia –
– Common and is usually
asymptomatic
– Non gouty polyarthralgia
----------- 40 % of patients
• Myalgia, GIT irritation,
maculopapular rash,
hepatic dysfunction,
porpohyria,
photosensitivity
reactions
PZA -- Toxicity
• Hepatotoxicity
– When high doses are used
– Less likely with lower doses/shorter course
regimens
• PZA should be avoided in pregnancy
ND
2
Line
Anti TB Drugs
STREPTOMYCIN
Streptomycin
• Aminoglycoside
• Not absorbed after oral administration and
must be given I/M for systemic effects
• It is used in the treatment of
Tuberculosis
Plague
Tularemia
Rapid development of resistance
to streptomycin
Streptomycin --- Ototoxicity
• Auditory or vestibular damage (or both)with
any aminoglycoside and may be irreversible
• It is proportionate to the plasma levels and
risk ↑ if dose is not adjusted in renal failure
• Ototoxicity may be ↑ by use of loop diure cs
• Aminoglycosides are
contraindicated in PREGNANCY since ototoxicity has
been reported in fetus
Streptomycin --- Nephrotoxicity
•
•
•
•
Acute tubular necrosis
Often reversible
More common in elderly
More common in patients also receiving
amphroteracin B, cephalosporins or
vancomycin
Neuromuscular blockade
• Rarely, a curare-like block may occur at high
doses of aminoglycosides and may result in
respiratory paralysis
• Treated by respiratory support and reversed
by neostigmine and calcium
AMIKACIN
• Indicated in steptomycin or MDR
strains of mycobactrium
tuberculosis
• MDR strain of mycobacterium
tuberculosis that are resistant to
streptomycin may be susceptible
to amikacin
FLUOROQUINOLONES
• Ciprofloxacin and ofloxacin are active against
MDR mycobactial strains resistant to first line
drugs
• Should always be used in
combination regimens with two
or more other active agents
ETHIONAMIDE
• A congener of INH
• Cross resistance does not occur
• Severe GI irritation
• Adverse neurologic effects at doses needed to
achieve effective plasma level
Aminosalicylic acid (PAS)
• It is a bacteriostatic agent
• It act as a competitive inhibitor for paminobenzoic acid (PABA)in folate
biosynthesis
• Rarely used
• Primary resistance is common
• Poorly tolerated --- GIT irritation, peptic
ulceration, Hypersensitivity reactions
• Effects on kidney, liver & thyroid function
Drugs active against
ATYPICAL MYCOBACTERIA
• Nontuberculous or “atypical” mycobacteria
• 10% in USA
• Atypical mycobacteria include
– M. kansasii,
– M. avium complex,
– M. fortuitum,
M. marinum,
M. scrofulaceum,
M. ulcerans M. chelonae.
• Distinct laboratory characteristics, present in the
environment , & are not communicable from
person to person
• less susceptible to ATT
Drugs active against
Atypical Mycobacteria
• Amikacin, clarithromycin, ciprofloxacin,
• Erythromycin, sulfonamides (trimethoprimsulfamethoxazole), or tetracyclines
• Resistance emerges during treatment
• Treated with combinations of drugs
• M Kansasii --- Susceptible to rifampin and
ethambutol, partially resistant to INH, and
completely resistant to PZA
MAC (M. avium complex)
• includes M. avium and M. intracellulare.
• It causes disseminated disease in late stages of AIDS,
usually when CD4 counts < 50/μ L.
• A combination of agents is used to suppress the
disease
– Azithromycin or clarithromycin plus ethambutol,
ciprofloxacin, amikacin , rifabutin.
• Rifabutin may be used for patients with CD4 counts <
200 to reduce the incidence of MAC bacteraemia
• The treatment for this infection is usually life-long.
Antileprosy drugs
• For tuberculoid leprosy
–Dapsone & rifampicin
• For lepromatous leprosy
–Dapsone, rifampicin and
clofazimine
How mycobacterium leprae differs
from other bacteria?
• Mycobacterium leprae has never been grown
in vitro
• Grown in injected mouse footpads
• Increasing resistance to dapsone has been
reported
• Combination of drugs is recommended
Antileprosy drugs
•Dapsone
–Acedapsone (repository form)
•Rifampicin (rifampin)
•Clofazimine
WHO recommendations (1982)
• Tuberculoid --- Paucibacillary leprosy
- Dapsone & rifampin X 6 months
• Lepromatous --- Multibacillary
leprosy(MB)
- Dapsone, rifampin and
clofazimine for at least 2 years
DAPSONE
It inhibit folate synthesis, like sulphonamides
• Orally --- 100 mg daily, Well absorbed, widely
distributed
• Plasma t ½ is 28-48 hours, but some dapsone
persists in certain tissues ---liver, kidney, skin &
muscles for much longer times
• Skin heavily infected with M leprae may contain
several times more drug than normal skin.
• Enterohepatic recycling of the drug
• Both parent drug & metabolites (acetylated) --excreted in urine
Other uses of Dapsone
• In the treatment of pneumonia
caused by pneumocystis jiroveci
in patients infected with HIV
• Dematitis herpatiformis
associated with coeliac disease
Adverse effects(Dapsone)
•
•
•
•
•
Hemolysis -- G6 PD deficiency
Methemoglobinemia
GI intolerance, fever, pruritis, & various rashes
Peripheral neuropathy
During dapsone therapy of lapromatous
leprosy erythema nodosum often develops --- treated by corticosteroids or thalidomide
RIFAMPIN
• 600 mg daily is highly effective in
lepromatous leprosy
• Given in combination with dapsone
• A single monthly dose of 600 mg
may be beneficial in combination
therapy
CLOFAZIMINE
• A phenazine dye that binds to DNA &
prevent it from serving as a template for
future DNA replication
• It is bactericidal to M leprae & has some
activity against M avium intracellular
complex
• It is given for sulfone (dapsone) resistant
leprosy or when patient are intolerant to
sulfone
Clofazimine
• Stored in reticuloendothelial tissues & skin
and its crystal can be seen inside the RE cells,
but it does not enter the CNS
• It is slowly released from these deposits, so
that serum half life may be 2 months
• Dose is 100 mg daily
• The antileprotic effect is delayed and is usually
not evident for 6-7 weeks
Clofazimine
• Some anti-inflammatory activity
• Erytherama nodosum leprosum
does not develop
Adverse effects
• Red brown discoloration of the skin
• Eosinophlic enteritis -- GI intolerance