The document discusses antimycobacterial drugs used to treat tuberculosis and leprosy. It begins by outlining the challenges of treating infections caused by slow-growing mycobacteria, including their intrinsic resistance. It then describes the goals and principles of TB therapy, including using multi-drug regimens to prevent resistance. The first-line drugs for TB, including isoniazid, rifampin, pyrazinamide, and ethambutol are discussed in detail. Treatment regimens for both adults and children are provided. The document also covers definitions and treatment approaches for drug-resistant TB. Finally, it concludes with an overview of drugs used to treat leprosy such as dapsone, rifamp
DR. CALEB OKOTH'S GUIDE TO ANTIMYCOBACTERIAL DRUGS
1. D R . C A L E B O K O T H
U Z I M A U N I V E R S I T Y C O L L E G E
ANTIMYCOBACTE
RIALS
2. ANTIMYCOBACTERIAL DRUGS
INTRODUCTION
Mycobacterial infections are difficult to cure
Slowly growing organisms making them resistant to
antibiotics
Lipid rich mycobacterial cell wall is impermeable to many
drugs
Some organisms are intracellular , residing within
macrophages, and inaccessible to drugs that penetrate poorly
Mycobacteria are notorious for their ability to develop
resistance to a single drug
Combinations of drugs are required to overcome these
obstacles and prevent emergency of resistance during the
course of therapy
3. GOAL OF THERAPY
The overall goals of TB therapy include:
1) Cure patients and therefore prevent suffering.
2) Prevent transmission of the infection.
3) Prevent death.
4) Prevent long-term complications or sequelae of TB.
5) Prevent relapse of the disease.
6) Prevent the development of drug resistant TB.
4. Principles of TB treatment
The principles of TB treatment include the following:
1) Never use single drugs – to avoid resistance.
2) Always use drugs in combinations - to avoid resistance
3) Drug dosage is based on weight
4) Drug intake should be directly observed for all patients -
to ensure adherence, prevent emergence of drug resistance,
assess for medication side effects and to follow clinical
response closely
5) Ensure the entire treatment is taken as recommended
5. First line at- TB drugs
Anti-TB drugs should have one of the following
properties:
A. Bactericidal - the ability to kill the rapidly dividing,
metabolically active bacilli found in the walls of cavities
and in the sputum of patients with microscopy smear-
positive pulmonary tuberculosis. Drugs with high early
bactericidal activity such as Isoniazid will make the
patient non-infectious as early as possible.
B. Sterilization - the ability to kill the persisting,
dormant or intermittently active bacilli, responsible for
relapses. Drugs with rapid sterilization ability such as
Rifampicin and Pyrazinamide will lead to the shortening
of treatment.
7. First line ant-TB drugs
These drugs are given in two phases of treatment:
1. Intensive phase - lasts 2 months and usually
consists of four drugs (RHZE). Aim is to achieve a
rapid killing of actively dividing bacteria, resulting in
the reduction of bacillary load, negativization of
sputum (within two weeks) and eradication of
clinical symptoms.
2. Continuation phase - lasts four months to ten
months and usually consists of two drugs (RH). Aim
is to kill any remaining or dormant bacilli and
preventing subsequent relapse.
11. First line ant-TB drugs
ISONIAZID ( INH)
Most active for treatment of tuberculosis caused by
susceptible strains
Mechanism of action
Inhibit synthesis of mycolic acid which are essential
components of mycobacteria cell wall
Pharmacokinetics
Readily absorbed from GIT
Diffuses readily in all body fluids and tissues
Metabolism by acetylation by N- acetyltrasnferase is
genetically determined, its fast in rapid acetylators than
slow acetylators
Metabolites and unchanged drug are excreted in urine
12. ANTIMYCOBACTERIAL DRUGS
Clinical uses
Part of first line regimen for treatment of active TB infections
Prevention of active tuberculosis in the individuals infected with M.
tuberculosis
Prevention of tuberculosis in close contact of active cases of pulmonary
tuberculosis
Used in individuals who are at greater risk for developing active disease such
as young children, HIV/AIDS patients and other immunocompromised
patients
Adverse reactions
Hypersensitivity reactions –fever, skin rashes and drug induced SLE
Liver hepatitis
Peripheral neuropathy
Hematological abnormalities
Anemia and tinnitus
GIT discomfort
Promotes excretion of pyridoxine, so give with pyridoxine 50 mg OD.
13. ANTIMYCOBACTERIAL DRUGS
RIFAMPICIN
Isolated from Streptomyces mediterranei
Active against gram positive and gram negative
cocci, some enteric bacteria , mycobacteria and
chlamydia.
Mechanism of action
Binds strongly to the beta subunit of bacterial
DNA-dependent RNA polymerase and thereby
inhibits RNA synthesis.
14. ANTIMYCOBACTERIAL DRUGS
Pharmacokinetics
Rifampicin readily penetrates most tissues and into phagocytic cells
It can kill intracellular organisms and those sequestered in abscesses and lung cavities
Well absorbed after oral administration and excreted mainly through the into bile, it
then undergoes enterohepatic recirculation with the bulk excreted as deacylated
metabolites in feces and small amount in urine
Distributed widely in body fluids and tissues
Clinical uses
Mycobacterial infections
Atypical mycobacteria infections and leprosy
Can eliminate meningococcal carriage ; dose 600 mg bd x2/7
Prophylaxis against H influenza in children; dose 20 mg/kg/day for 4 days
Treat of osteomyelitis and prosthetic valve endocarditis due to Staphylococcus
Combined with ceftriaxone or vancomycin to treat meningitis caused by highly
penicillin resistant strains of pneumococcal
Adverse reactions
o Imparts harmless orange colour to urine, sweat, tears and contact lens
o Rashes, thrombocytopenia and nephritis
o Cholelestatic jaundice and occasional hepatitis
o Proteinuria
o Flue like symptoms e.g. fever, chills, myalgia, anemia, thrombocytopenia
o Enzyme inducer
15. ANTIMYCOBACTERIAL DRUGS
ETHAMBUTOL
Synthetic, water soluble, heat-stable compound
Mechanism of action
Its an inhibitor of mycobacterial arabinosyl transferases, which are involved in
the polymerization reaction of arabinoglycan, an essential component of
bacterial cell wall.
Pharmacokinetics
Well absorbed from the gut
Excreted in urine and feces in unchanged form
Crosses blood brain barrier only if the meninges are inflamed
Clinical uses
Treatment of tuberculous meningitis
Adverse reactions
Hypersensivity-rare
Loss of visual acuity and red-green colour blindness
STREPTOMYCIN
Mechanism of action and pharmacological features are typical to those of
aminoglycosides.
16. ANTIMYCOBACTERIAL DRUGS
PYRAZINAMIDE
Stable, slightly soluble in water
It is taken up by macrophages and exerts its activity against intracellular
organisms residing within this acidic environment
Mechanism of action are unknown
Pharmacokinetics
Well absorbed from the GIT and widely distributed in tissues including
inflammed meninges
Mainly used in combination with rifampicin and isoniazid in short course
regimen ( i.e. 6 months) as a sterilizing agent active against residual
intracellular organisms that may cause relapse.
Adverse reaction
Hepatotoxicity
Nausea, vomiting and fever
Hyperuricemia
Second line drugs
Are considered in case of:
Resistance to the drugs of first choice
Failure of clinical response to conventional therapy
When expert guidance is available to deal with the toxic effects
17. MDR TB
Multi-drug resistant TB
Where the mycobacteria is resistant to both Isoniazid
and Rifampicin with or without resistance to other
anti-TB drugs
The MDR TB drugs are classified into a group system
based on efficacy, experience of use and drug class
These groups are very useful for the design of
treatment regimens
18. Classification of drug resistant TB
Presumptive drug-resistant TB case: are
Individuals with a higher risk of getting drug resistant TB
than the general population. They include: smear-
positive previously treated patients such as relapse,
return after default (RAD) and failure
Poly-drug resistance (PDR): Resistance to more than
one first-line anti-TB medicine (other than both
Isoniazid and Rifampicin)
Multi-drug resistance (MDR): Resistance to at least
both Isoniazid and Rifampicin
Rifampicin resistance(RR): Resistance to
Rifampicin detected using phenotypic or genotypic
methods, with or without other anti-TB drugs
19. Classification of drug resistant TB
Isoniazid resistance: Refers to Mycobacterium
tuberculosis strains with resistance to isoniazid and
susceptibility to rifampicin confirmed in vitro
Pre-XDR: Resistance to Isoniazid and Rifampicin
and either a fluoroquinolone or a second-line
injectable agent but not both.
Extensive drug resistance (XDR): Resistance to
any Fluoroquinolone and at least one of three
second-line injectable drugs (Capreomycin,
Kanamycin and Amikacin), in addition to multidrug
resistance
25. Ethionamide/Prothionamide
Are bacteriostaticagents
Mechanism of action of thionamides has not been
fully elucidated, but they appear to inhibit mycolic
acid synthesis
Ethionamide is extensively metabolized, probably in
the liver, to the active sulfoxide and other inactive
metabolites
Are administered in the form of tablets containing
125 mg or 250 mg of active drug. The maximum
optimum daily dose is 15–20 mg/kg/day (max. 1
g/day), usually 500–750 mg.
26. Ethionamide/Prothionamide
100% absorbed but sometimes erratic absorption
caused by gastrointestinal disturbances associated
with the medication.
Rapidly and widely distributed into body tissues and
fluids, with concentrations in plasma and various
organs being approxi- mately equal
Significant concentrations also are present in CSF
27. Para Amino Salicylic Acid(PASA)
Structurally similar to p-aminobenzoic aid (PABA) and to the
sulfonamides
It is active almost exclusively against M tuberculosis.
MOA: inhibit folic acid synthesis
Aminosalicylic acid is readily absorbed from the gastrointestinal
tract
The drug is widely distributed in tissues and body fluids except CSF
It is rapidly excreted in the urine.
Very high concentrations of aminosalicylic acid are reached in the
urine, which can result in crystalluria
Dose :50 mg/kg or 10–12 g daily in 2 divided doses.
Children: 200–300 mg/kg daily in 2–4 divided doses
28. Bedaquiline
Available dosage form: 100 mg tablet, 20mg
(functionally scored)
Mechanism of action
Inhibit mycobacterial ATP synthase, an enzyme essential
for generation of energy in Mycobacterium tuberculosis
Pharmacokinetics
Absorption: bioavailability increased 2 fold whe taken
with standard meal compared with fasted conditions
Peak plasma time: 4-5hours
Distribution: protein binding >99.9%, Vd= 164 L
29. Bedaquiline
Metabolism: metabolized primarily by CYP3A4 to
form N-monodesmethyl metabolite which is 4-6
times les active
Elimination: Half-life 5.5 months. Mainly excreted
in feces
Clinical applications
Multidrug resistant pulmonary tuberculosis in
combination with other ant-TB drugs
Dose: 4oomg PO qDay for 2 weeks THEN from
week 3-24 weeks; 200mg 3 times/week with at least
48 hr between doses.
30. Bedaquiline
Adverse effects
>10% nausea, arthralgia, headache and chest pain
1-10%: anorexia, rash, transaminase increase, serum
amylase increase
QT prolongation
Pregnancy and lactation
Available data insufficient to evaluate risk in
pregnancy
No data available regarding presence in human milk
32. INTRODUCTON
Leprosy is an infectious bacterial disease caused by
Mycobacterium leprae.
It is an Acid-fast-rod shaped bacillus.
It is classified into two:
1. Pauci-bacillary leprosy (PB):
Patients with 1 to 5 hypo pigmented patches
Skin slit smears negative
2. Multibacillary leprosy (MB)
Have more than 6 patches
Skin smear often positive
Incubation period for Pauci-bacillary is between 2-5 years and
Multi-bacillary between 5-10years. It is a slow multiplying bacillus
33. Introduction
Cardinal signs for Leprosy
Hypopigmented/reddish skin patch/ lesion with loss
of sensation
Enlarged one of more peripheral nerve
Presence of acid-fast bacilli in a slit-skin smear.
34. DRUGS USED IN LEPROSY
DAPSONE AND SULFONES
Dapsone is widely used
It inhibits folic acid synthesis
Combination of dapsone, rifampicin and clofazimine is
recommended for initial therapy
Adult dose: 100 mg od
Other clinical applications
Pneumocystis carinnii
Toxoplasmosis
Dermatitis herpetiformis
35. DRUGS USED IN LEPROSY
DAPSONE AND SULFONES
Adverse effects
Slighting itching (Dapsone syndrome)
Anaemia
Exfoliative dermatitis
Fixed reactions
36. DRUGS USED IN LEPROSY
RIFAMPICIN
Used at dosage of 600 mg daily in lepromatous
leprosy
Used in combination with dapsone and other
antileprosy drugs
37. DRUGS USED IN LEPROSY
CLOFAZIMINE
It is a phenazine dye that can be used as an alternative to dapsone
Mechanism of action is not known but may involve binding to
mycobactrial DNA and inhibit mycobacterial replication and growth
Pharmacokinetics
Absorption from the gut is variable
Mainly excreted in feces
Stored widely in reticuloendothelial tissues and skin
Elimination half life is 70 days (at steady state)
Clinical uses
Used in leprosy including sulfone resistant leprosy complicated by
erythema nodosum
Dose: 50-100 mg/day orally
38. DRUGS USED IN LEPROSY
CLOFAZIMINE
Adverse effects
Gastrointestinal disturbances nausea, vomiting, abdominal
pains. Give drugs after a meal.
Red skin/eyes
Hyperpigmentation/darkening of the skin