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

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.

6. ANTIMYCOBACTERIAL DRUGS
First line ant-TBs
 Isoniazid (H) 300 mg/d
 Rifampicin (R) 600 mg/d
 Pyrazinamide (Z) 400 mg/d
 Ethambutol (E) 275 mg/d

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.

8. First ant-TB regimen for adults

9. WHO recommended TB regimen in children

10. FDC treatment dosage for adults

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

20. Drugs used in treatment of Drug resistant TB

21. Drugs used in treatment of Drug resistant TB

22. Kenya DR-TB regimen according to resistant
patterns

23. Dosing schedule for DR-TB drugs

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

31. LEPROSY

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