Antimycobacterial agents

Chemotherapy of
Mycobacterial Diseases
Dr. J.N. Chaturvedi

Introduction
 Mycobacteria have caused epic diseases: TB and leprosy have terrorized
humankind since antiquity.
 “Mycos” means wax.
 Although the burden of leprosy has decreased, TB is still the most important
infectious killer of humans.
 Mycobacterium abscessus has now been called a new “antibiotic” nightmare
because of-
 Its tenacity,
 Lack of response to combination antibiotics, and
 A nearly universal propensity to develop acquired drug resistance
 Mycobacterium avium-intracellulare (or MAC) infection continues to be difficult to
treat.

Classification of Mycobacteria
Typical Atypical/ Non-Tubecular
Slow Grower Rapid Grower
M.Tuberculosis Runyon I: Photochromogens
Mycobacterium kansasii
Mycobacterium marinum
Runyon IV
Mycobacterium fortuitum complex
Mycobacterium smegmatis group
Mycobacterium abscessus
M. Leprae Runyon II: Scotochromogens
Mycobacterium scrofulaceum
Mycobacterium szulgai
Mycobacterium gordonae
Runyon III: Nonchromogens
Mycobacterium avium complex
Mycobacterium haemophilum
Mycobacterium xenopi

Classification of Antimycobacterial agents
• Based on the primary mechanism of action:
1. Cell wall synthesis inhibitors
a) Isoniazid
b) Ethambutol
c) Ethionamide
d) Cycloserine
2. Cell membrane disruptors
a) Clofazimine
3. RNA synthesis inhibitors
a) Rifamycins: Rifampicin, Rifapentine & Rifabutin
4. DNA synthesis inhibitors
a) Fluoroquinolones: ofloxacin, moxifloxacin, gatifloxacin, levofloxacin and
ciprofloxacin

Classification of Antimycobacterial agents
5. Protein synthesis inhibitors
a) Oxazolidinones: Linezolid, Tedizolid, and Sutezolid
b) Aminoglycosides: Streptomycin, Amikacin, and Kanamycin
c) Capreomycin
d) Macrolides: Azithromycin and Clarithromycin
6. Folate synthesis inhibitors
a) Para-aminosalicylic acid
b) Dapsone
7. Cellular energetics inhibitors
a) Pyrazinamide
b) Bedaquiline
8. Free radical producers
a) Bicyclic Nitroimidazole: Delaminid and Pretomanid

Important gene & gene products of
mycobacteria
1. InhA: enoyl acyl carrier protein reductase
2. KasA: β-ketoacyl-acyl carrier protein synthase
3. KatG: catalase peroxidase
4. NAT2: N-acetyltransferase type 2
5. ahpC: Alkyl hydroperoxide reductase C peptide
6. embAB: Arabinosyl transferases
7. EthaA: NADPH-specific, FAD-containing monooxygenase.

Cell wall synthesis inhibitors- Isoniazid
• Isoniazid (isonicotinic acid hydrazide), also called INH.
• It is an important drug for the chemotherapy of drug-susceptible
TB.
• The use of combination therapy (isoniazid + pyrazinamide +
rifampin) provides the basis for short-course therapy and
improved cure rates.

• Mechanism of Action:
Enters in bacilli by passive diffusion
Activated by KatG to toxic form isonicotinoyl radical & other free radical
Formation of nicotinoyl-NAD isomer mycobactericidal effects
of INH
Inhibits the activities of enoyl acyl carrier protein reductase (InhA) and
KasA
Inhibits synthesis of mycolic acid

• Antibacterial Activity
• M. tuberculosis
• Mycobacterium bovis and
• Mycobacterium kansasii
• Mechanisms of Resistance
1. Mutation or deletion of KatG.
2. Overexpression of the genes for InhA and ahpC.
3. Mutations in the ahpC.
4. Efflux pump induction.

• Pharmacokinetics:
A= Very well absorbed orally (Bioavailability=100%).
D= Widely distributed.
M= Undergoes acetylation in liver.
E= Metabolites are excreted in urine.
• Microbial Pharmacokinetics-Pharmacodynamics:
• Isoniazid’s microbial kill, as well as resistance emergence, is best explained by the
ratios of AUC0/MIC and CPmax/MIC.
• Therapeutic Uses & Dosage:
• Available as pill, as an elixir, and for parenteral administration.
• 5 mg/kg (max. 300 mg) daily or 10 mg/kg (range 10–15 mg/ kg; max. 900
mg) two or three times a week.

• Untoward Effects:
1. Hepatotoxicity- Elevated serum aspartate and alanine
transaminases
2. Peripheral neuritis
3. Other neurological toxicities- convulsions, optic neuritis and
atrophy, muscle twitching, dizziness, ataxia, paresthesias, stupor,
and toxic encephalopathy.
4. Mental abnormalities- euphoria, transient impairment of memory,
loss of self-control, and florid psychoses.
5. Hypersensitivity reactions
6. Immune reactions- Vasculitis associated with antinuclear
antibodies, Drug induced lupus.
7. Anemia

• Isoniazid Overdose
• Seizures refractory to treatment with phenytoin and barbiturates
• Metabolic acidosis with an anion gap that is resistant to treatment with
sodium bicarbonate
• Coma
• M/m of Isoniazid Overdose:
• Intravenous pyridoxine is administered over 5–15 min on a gram-to-
gram basis with the ingested isoniazid.
• Benzodiazepines for seizures.

Cell wall synthesis inhibitors- Ethambutol
• Mechanism of Action
Inhibition of arabinosyl transferase III
Disrupting the transfer of arabinose into arabinogalactan
biosynthesis
Disrupts the assembly of mycobacterial cell wall

• Antibacterial Activity:
• M. tuberculosis,
• M. marinum,
• M. kansasii,
• M. gordonae,
• M. scrofulaceum,
• M. szulgai, and
• M. avium

• Mechanisms of Resistance:
1. Mutations in the embB gene.
2. Enhanced efflux pump activity.
A= Oral bioavailability is about 80%.
D= Widely distributed, 10-40% plasma protein bound.
M= 20% by liver (aldehyde dehydrogenase)
E= 80% by kidney.

• Microbial kill of M. tuberculosis is optimized by AUC/MIC.
• Against disseminated MAC is optimized by Cmax/MIC.
• TB,
• Disseminated MAC, and
• M. kansasii infection
• 20 mg/kg (15–25 mg/kg) per day for both adults and children.

1. Optic neuritis- diminished visual acuity and loss of red-green
discrimination
2. Hyperuricemia

Cell wall synthesis inhibitors- Ethionamide
Ethionamide sulfoxide 2-ethyl-4-aminopyridine
Inhibiting the activity of the inhA gene product, the enoyl-ACP
reductase of fatty acid synthase II
inhibition of mycolic acid biosynthesis
impairment of cell wall synthesis.
FAD-containing
monooxygenase

• M. tuberculosis
• Photochromogens
• Mechanism of Resistance:
• Mutation in EthaA decreased activation.
• Mutations in the inhA gene decreased action.

A=oral bioavailability approaches 100%.
D= Widely distributed
M= Hepatic
E= Renal
• Resistant tuberculosis
• Adult dose: 250 mg twice daily; it is increased by 125 mg/d every 5 days until a dose of 15–
20 mg/kg/d is achieved (max. 1g/d).
• Best taken with meals in divided dose to minimize gastric irritation.
• Children should receive 10–20 mg/kg/d in two divided doses, not to exceed 1 g/d.

1. GI upset: anorexia, nausea and vomiting, gastric irritation.
2. Neurologic symptoms: olfactory disturbances, blurred vision,
diplopia, dizziness, paresthesias, headache, restlessness, and
tremors.
3. Severe postural hypotension.
4. mental depression, drowsiness, and asthenia.
5. Hepatitis
6. Allergic reactions.

Cell wall synthesis inhibitors- Cycloserine
• It is a broad-spectrum antibiotic produced by Streptococcus
orchidaceous.
• Mechanism of Action
1. Inhibition alanine racemase Inhibition of l-alanine to d-
alanine.
2. Inhibition of D-alanine: d-alanine ligase inhibition of d-
alanine incorporation into bacterial cell wall.
Cell wall synthesis inhibition

• M. tuberculosis
• MAC,
• enterococci,
• E. coli,
• S. aureus,
• Nocardia species, and
• Chlamydia.
• Mechanisms of Resistance
• Loss-of-function mutations in ald gene.
• Nonsynonymous SNPs in alr gene.

A= Almost complete oral absorption.
D= well distributed throughout body
M= 30 % metabolized
E= 70% unchanged in urine.
• Resistant Tuberculosis
• The usual dose for adults is 250–500 mg twice daily.
• Neuropsychiatric symptoms are common and occur in 50% of patients on 1 g/d
“psych-serine.”
• Symptoms range from headache and somnolence to severe psychosis, seizures, and
suicidal ideas.

Clofazimine
• The biochemical basis for the antimicrobial actions of clofazimine remains to be
established.
• Possible mechanisms of action-
1. Membrane disruption,
2. Inhibition of mycobacterial phospholipase A2,
3. Inhibition of microbial K+ transport,
4. Generation of hydrogen peroxide,
5. Interference with the bacterial electron transport chain, or
6. Efflux pump inhibition
• Has both antibacterial activity and anti-inflammatory effects via inhibition of
macrophages, T cells, neutrophils, and complement.

Clofazimine
• M. tuberculosis,
• M. avium,
• Mycobacterium ulcerans,
• S. aureus,
• Coagulase-negative staphylococci,
• Streptococcus pyogenes, and
• Listeria monocytogenes
• Mutation in the gene encoding a transcription repressor for efflux pump
MmpL;
• This is associated with cross resistance to bedaquiline

Clofazimine
• A= oral bioavailability is 45%–60%; it is increased 2-fold by high-fat meals and
decreased 30% by antacids
• Prolonged absorption phase (Tmax- 5 to 8 hr)
• D= good penetration into many tissues.
• M= Liver
• Elimination T1/2= 70 days.
1. Leprosy
• Adults: 300 mg once a month and 50 mg daily
• Children (10–14 years): 150 mg once a month, 50 mg on alternate days
• Children <10 years or <40kg body wt: 100 mg once a month, 50 mg twice weekly
2. MDR-TB
• Adults: 100–200 mg daily
• Children: 1 mg/kg/day

Clofazimine
• Abdominal pain (MC)
• Reddish-black discoloration body secretion, eye and skin.
• Crystal deposition in intestinal mucosa, liver, spleen, and abdominal lymph
nodes.

Rifamycins- Rifampin, Rifapentine, and
Rifabutin
Binds to the β subunit of DNA-dependent RNA polymerase (rpoB) to
form a stable drug-enzyme complex.
Drug binding suppresses chain formation in RNA synthesis.

Rifabutin
Gram-positive bacteria Gram-negative bacteria Mycobacteria
• Staphylococcus
aureus and
• coagulase-
negative
staphylococci.
• Escherichia coli,
• Pseudomonas,
• Indole-positive and indole-negative
Proteus,
• Klebsiella
• Neisseria meningitidis and
• Haemophilus influenzae.
• M. tuberculosis
• Mycobacterium leprae
• Mycobacterium kansasii
• Mycobacterium
scrofulaceum,
• Mycobacterium
intracellulare, and
• Mycobacterium avium

Rifabutin
• Mechanism of Bacterial Resistance:
1. Alteration of the target of this drug, rpoB.
2. Efflux pump induction
• A= Variable absorption
• Food decreases the rifampin CPmax by one-third; a high-fat meal increases the AUC of
rifapentine by 50%. Food has no effect on rifabutin absorption.
• D= Widely distributed
• M= Hepatic CYP3A4.
• E= 2/3 biliary & 1/3 renal.

Rifabutin
• Bactericidal and sterilizing effect activity are best optimized by high AUCs and
a high AUC/MIC ratio
• Resistance suppression and rifampin’s enduring postantibiotic effect are best
optimized by high CPmax/ MIC.

Rifabutin
• Therapeutic Uses & Dosage (Rifampicin):
1. Tuberculosis:
• Adults: 600 mg, given once daily, either 1 h before or 2 h after a meal.
• Children: 15 mg/kg (range 10–20 mg/kg), with the maximum dose 600 mg/d, given in the same
way.
2. Prophylaxis of meningococcal disease and H. influenzae meningitis.
• Adult: 600 mg twice daily for 2 days or 600 mg once daily for 4 days.
• Children >1month: 10–15 mg/kg, to a maximum of 600 mg daily.
3. Staphylococcal endocarditis or osteomyelitis: Along with beta lactam or
Vancomycin.
4. Eradication of the staphylococcal nasal carrier state in patients with chronic
furunculosis.
5. Brucellosis: 900 mg/d in combination with doxycycline for 6 weeks.

Rifabutin
• Rifampicin is generally well tolerated
1. Hepatitis
2. Hypersensitivity reactions.
3. Flu like symptoms: particularly at high dose and less frequent administration.
• fever, chills, and myalgias.
• eosinophilia, interstitial nephritis, acute tubular necrosis, thrombocytopenia, hemolytic anemia,
and shock.
4. Orange-tan discoloration of skin, urine, feces, saliva, tears, and contact lenses,
• Unique ADRs associated with Rifabutin:
1. polymyalgia,
2. pseudojaundice, and
3. anterior uveitis.

Rifabutin
• Drug Interactions:
• Because of microsomal enzyme induction, t 1/2 decreases for a number of
compounds that are metabolized by these CYPs.
• Enzyme inducing property of Rifampin>Rifapentine>Rifabutin.

DNA Synthesis inhibitors- Fluoroquinolones
• Ofloxacin, ciprofloxacin moxifloxacin, gatifloxacin, and levofloxacin
• Mechanism of action:
• DNA gyrase inhibition
• Microbial Pharmacokinetics-Pharmacodynamics Relevant to TB:
• Fluoroquinolone microbial kill is best explained by the AUC0–24/MIC ratio.
• Therapeutic Uses in Treatment of TB:
• Pulmonary MDR-TB and
• Treatment of TB meningitis.

Protein synthesis inhibitors
• Oxazolidinones: Linezolid, Tedizolid, and Sutezolid
• MDR-TB
• Aminoglycosides: Streptomycin, Amikacin, and Kanamycin
• Antimicrobial spectrum:
• M. tuberculosis
• M. kansasii
• M. avium
• Macrolides: Azithromycin and clarithromycin
• Used for the treatment of MAC.

Protein synthesis inhibitors
• Capreomycin:
• An antimycobacterial cyclic peptide.
• Antimycobacterial activity and adverse effects is similar to that of
aminoglycosides.
• Given for MDR-TB.
• Recommended daily dose is 1 g (no more than 20 mg/kg) per day for 60–120
days, followed by 1 g two or three times a week.

Folate synthesis inhibitors- Dapsone
• Broad-spectrum agent with antibacterial, antiprotozoal, and
antifungal effects.
• Structural analogue of PABA and a competitive inhibitor of dihydropteroate
synthase (folP1/P2) in the folate pathway,
• The anti-inflammatory effects by inhibition of neutrophil myeloperoxidase
activity and respiratory burst, and it inhibits activity of neutrophil lysosomal
enzymes.

• Antimicrobial Effects:
• Antibacterial-
• Bacteriostatic against M. leprae.
• MAC and M. kansasii
• Antiparasitic-
• Toxoplasma gondii tachyzoites.
• Plasmodium falciparum
• Antifungal-
• Pneumocystis jiroveci.
• Mechanism of Drug Resistance:
• Mutations in genes encoding dihydropteroate synthase

A= Complete oral absorption
D= Widely distributed
M= Undergoes N-acetylation by NAT2
• Therapeutic Uses:
1. Leprosy
2. Falciparum malaria (along with chlorproguanil)
3. P. jiroveci prophylaxis
4. Prophylaxis for T.gondii
5. Pemphigoid, dermatitis herpetiformis, linear IgA bullous disease, relapsing
chondritis,

• Hemolysis in G6PD deficiency. Doses of 100 mg or less in healthy persons and
50 mg or less in healthy individuals with a G6PD deficiency do not cause
hemolysis.
• Methemoglobinemia.
• Neurological reactions: headache, nervousness, insomnia, blurred vision,
paresthesias, reversible peripheral neuropathy.
• Infectious mononucleosis-like syndrome

Folate synthesis inhibitors- PAS
• Para-aminosalicylic acid, discovered by Lehman in 1943, was the first
effective treatment of TB.
• PAS is thought to be a competitive inhibitor folP1, but in vitro the inhibitory
activity against folP1 is very poor
• Bacteriostatic against M. tuberculosis.
• Mechanism of Bacterial Resistance
• Mutations in thyA, folC, dfrA and ribD.

Folate synthesis inhibitors- PAS
A= oral bioavailability is more than 90%.
The Cmax increases 1.5-fold and AUC 1.7-fold with food compared to fasting
D= Widely distributed, Protein binding is 50%–60%.
M= N-acetylated in the liver.
E= Both metabolites and active drug excreted in urine.
• MDR-TB
• Adults: daily dose of 12 g divided in 3 doses.
• Children: 150–300 mg/kg/d in three or four divided doses.
• GI problem
• Hypersensitivity reactions

Cellular energetics inhibitors- Pyrazinamide
pyrazinamide passively diffuses into mycobacterial cells
Pyrazinoic acid (POA−, in its dissociated form)
Passive diffusion of the POA− to the extracellular milieu
In an acidic extracellular milieu, a fraction of POA– is protonated to the uncharged form, POAH
Reenters the bacillus and accumulates due to a deficient efflux pump
The acidification of the intracellular milieu is believed to inhibit enzyme function and collapse the
transmembrane proton motive force, thereby killing the bacteria.
Pyrazinamidase

• Mechanisms of Resistance:
1. Production of pyrazinamidase with reduced affinity for pyrazinamide.
2. Mutations in the genes encoding proposed pyrazinamide targets.
3. Increased efflux rate of POA.
A= oral bioavailability >90%.
D= concentrated 20-fold in lung epithelial lining fluid.
M= By microsomal deamidase & hydroxylases.

• Microbial Pharmacokinetics-Pharmacodynamics
• Pyrazinamide’s sterilizing effect is closely linked to AUC0–24/MIC
• Tuberculosis
• 35 mg/kg (30–40) mg/kg/d.
• The coadministration of pyrazinamide with isoniazid or rifampin has led to-
• one-third reduction in the duration of anti-TB therapy and a
• two-thirds reduction in TB relapse.
• Hepatotoxicity
• Hyperuricemia

Cellular energetics inhibitors- Bedaquiline
Binds to subunit c of the ATP synthase of M. tuberculosis,
Inhibition of the proton pump activity of the ATP synthase
Inhibition of energy metabolism.

• M. tuberculosis.
• MAC,
• M. leprae,
• M. bovis,
• M. marinum,
• M. kansasii,
• M. ulcerans,
• M. fortuitum,
• M. szulgai, and
• M. abscessus

• Mechanism of Bacterial Resistance:
• Mutation in gene encoding ATP synthase c subunit.
• Increased expression of efflux pump.
A= Slow absorption (Tmax- 5hr)
D= Large aVd but poor CNS penetration
M= Hepatic CYPs
The terminal t 1/2 is about 5.5 months, mainly driven by redistribution from the
tissues

• Microbial kill of bedaquiline is believed to be linked to AUC/MIC ratios.
• Efficacy and Therapeutic Use:
• MDR-TB:
• 400 mg daily for 2 weeks followed by 200 mg three times a day thereafter added to a background second-line
regimen of either kanamycin or amikacin, ofloxacin with or without ethambutol.
• Nausea and diarrhoea (MC)
• Arthralgia, pain in extremities, and hyperuricemia.
• major concern with this drug is cardiovascular toxicity and death.

Bicyclic Nitroimidazoles: Delaminid and
Pretomanid
• Mechanisms of Action:
• Pretomanid & delaminid are a prodrug that requires activation by the bacteria
via a nitroreduction step.
• Has two mechanisms of action:
• First, under aerobic conditions it inhibits M. tuberculosis mycolic acid and protein
synthesis at the step between hydroxymycolate and ketomycolate
• Second, generates reactive nitrogen species such as NO via its des-nitro metabolite,
• M. tuberculosis
• Changes in structure of FGD, due to point mutations in the fgd gene
decreased activation.

Bicyclic Nitroimidazoles: Delaminid and
Pretomanid
• T>MIC
• MDR TB
• Delaminid is currently dispensed in 50-mg tablets at 100 mg twice daily, with food.
• Pretomanid is administered at 200 mg a day and is undergoing phase III trials in
combination with other drugs.
• Delamanid is associated with QT segment prolongation

Principles of Antituberculosis,
MAC & Antileprosy chemotherapy.

Principles of Antituberculosis Chemotherapy
• Introduction
• Mycobacterium tuberculosis is not a single species, but a complex of species
with 99.9% similarity at the nucleotide level.
• The complex includes M. tuberculosis (typus humanus), M. canettii, M.
africanum, M. bovis, and M. microti.
• They all cause TB, with M. microti responsible for only a handful of human
cases.

• Antituberculosis Therapy: General Points
1. Traditionally, isoniazid (H), pyrazinamide (Z), rifampin (R), and ethambutol (E)
have been considered first-line anti-TB agents.
2. Second-line drugs included ethionamide, PAS, cycloserine, amikacin,
kanamycin, and capreomycin.
3. However, the concept of specific drugs as first line is being replaced with
focus on regimens to be ranked by faster sterilizing effect.
4. Traditionally, first-line agents were more efficacious and better tolerated
relative to second-line agents.

• Antituberculosis Therapy: General Points
5. The mutation rates to anti-TB drugs are between 10-6 and 10-10 so that the
likelihood of resistance is high to any single anti-TB drug in patients with
cavitary TB who have about 109 CFU of bacilli in a 3-cm pulmonary lesion.
6. However, the likelihood that bacilli would develop mutations to two or more
different drugs is the product of two mutation rates (between 1 in 1014 and
1 in 1020), which makes the probability of resistance emergence to more
than two drugs acceptably small.
7. Thus, only combination anti-TB therapy is currently recommended.
8. Multidrug therapy has led to a reduction in length of therapy.

• Types of Antituberculosis Therapy: Prophylaxis
• After infection with M. tuberculosis, about 10% of people will develop active disease over a
lifetime.
• The highest risk of reactivation TB is in patients with Mantoux tuberculin skin test reaction
5mm or greater but ≤ 10 mm, who also fall into one of the following categories:
a) Recently exposed to TB,
b) HIV coinfection,
c) Fibrotic changes on chest radiograms, Or
d) Immunosuppressed due to HIV infection or posttransplantation or are taking immunosuppressive medications
for any reason.
• Any person with a skin test greater than 10 mm is also at high risk of disease.
• In these patients at high risk of active TB, prophylaxis is recommended to prevent active
disease.

• Types of Antituberculosis Therapy: Prophylaxis
• Prophylaxis consists of either of following regimens:
1. Shortest-duration regimen that is effective consists of isoniazid 15 mg/kg (maximum 900
mg) and weight band–based rifapentine doses administered orally once a week for 12
weeks.
• The weight bands for rifapentine are 300 mg for 10–14 kg, 450 mg for 14.4–25 kg, 600 mg for
25.1–32 kg, 750 mg for 32.1–49.9 kg, and 900 mg for above 50 kg.
2. The traditional regimens consist of oral isoniazid, 300 mg daily or twice weekly, for 6
months in adults.
• In children, isoniazid 10–15 mg/kg daily (maximum 300 mg) is administered, or 20–30 mg/kg
two times a week directly observed, for 9 months.
3. Those who cannot take isoniazid should be given rifampin, 10 mg/kg daily, for 4 months.
• In children who cannot tolerate isoniazid, rifampin 10–20 mg/kg daily for 6 months is
recommended.

• Types of Antituberculosis Therapy: Definitive Therapy of
Drug-Susceptible TB
• All active TB cases should be confirmed by culture or rapid diagnostic methods such as
nucleic acid amplification tests (e.g., Xpert MTB/RIF) and have antimicrobial susceptibilities
determined.
Population Initial/ Intensive Phase Continuation Phase
Adult Isoniazid (5 mg/kg, Max. 300 mg/d),
Rifampin (10 mg/kg, max. 600 mg/d), and
Pyrazinamide (15–30 mg/kg, max. of 2 g/d)
for 2 months
Isoniazid (15mg/kg) and Rifampicin (10-mg/kg) two
or three times a week
for 4 months
Rifapentine (10 mg/kg once a week) may be
substituted for rifampin in patients with no evidence
of HIV infection or cavitary TB.
If there is resistance to isoniazid, initial therapy also may
include ethambutol (15–20 mg/kg/d) or streptomycin (1
g/d) until isoniazid susceptibility is documented
Paediatric Isoniazid 10–15 mg/kg at a max. 300 mg/d.
Rifampin 10–20 mg/kg at a max. 600 mg/d,and
Pyrazinamide 30–40 mg/kg/d,.
Ethambutol doses are 20 mg/kg/d (maximum 1 g) or 50
mg/kg twice weekly (2.5 g).
Rifabutin 5 mg/kg/d can be used as preferred rifamycin for the entire 6 months of therapy in adult HIV-infected patients

Drug-Susceptible TB
• Pyridoxine, vitamin B6, (10–50 mg/d) should be administered with isoniazid to
minimize the risks of neurological toxicity.
• To ensure compliance, therapy is administered as DOT.
• The duration of therapy of drug-susceptible pulmonary TB is 6 months.
• A 9-month duration should be used for patients with cavitary disease who are
still sputum culture positive at 2 months.

Drug-Susceptible TB
• HIV-infected patients with CD4+ lymphocyte cell counts less than 100/mm3
are at increased risk of developing rifamycin resistance.
• Therefore, daily therapy is recommended during the continuation phase.
• Most cases of extrapulmonary TB are treated for 6 months, TB meningitis is an
exception that requires a 9- to 12-month duration.
• The optimal regimen for treatment of TB pericarditis remains to be identified.

Drug-Susceptible TB
• RNTCP Guidelines (2018)
Type of TB Case Intensive Phase Continuation Phase**
New (2) HRZE (4) HRE
Previously Treated (2) HRZE (4) HRE
** May be extended for 3-6 months in extrapulmonary TB of CNS, skeleton or disseminated TB
Weight Band
(Adults)
No. of Tablets (FDC) Inj. Streptomycin
(in gm)Intensive Phase- HRZE
(75/150/400/275)
Continuation Phase-
HRE (75/150/275)
25-39 kg 2 2 0.5
40-54 kg 3 3 0.75
55-69 kg 4 4 1.0
>/= 70 kg 5 5 1.0
For pts. >50 years of age max. dose of streptomycin in 0.75 gm

Drug-Resistant TB
• Multi Drug resistant TB (MDR-TB):
• Resistance to both Isoniazid (H) and Rifampin (R) with or without
resistance to other first line anti-tubercular drugs.
• Extensive Drug resistant TB (XDR-TB):
• MDR-TB also resistant to fluoroquinolones and at least one of three injectable
second-line drugs (i.e., amikacin, kanamycin, or capreomycin).

Drug-Resistant TB
• The exact regimens to use are still unknown.
• Thus, in documented drug resistance, therapy should be based on evidence of
susceptibility and should include:
a) At least three drugs to which the pathogen is susceptible, with at least one of the
injectable anti-TB agents.
b) In the case of MDR-TB, a prolonged course (24 months) of 5 to 7 agents, except a
shorter 9-12 month regimen if there is no resistance to fluoroquinolones and second-
line injectable agents.
c) The addition of a fluoroquinolone and surgical resection of the main lesions have been
associated with improved outcome.

Principles of Therapy Against Mycobacterium
avium Complex
• Introduction
• The MAC is made up of at least two species: M. intracellulare and M. avium.
• Mycobacterium intracellulare causes pulmonary disease often in
immunocompetent individuals.
• Mycobacterium avium is further divided into a number of subspecies:
• M. avium subsp. hominissuis causes disseminated disease in immunocompromised
patients,
• M. avium subsp. Paratuberculosis has been implicated in the etiology of Crohn disease,
and
• M. avium subsp. avium causes TB of birds.

avium Complex
• Therapy of MAC Pulmonary Infection:
• Criteria in favor of therapy includes:
1. Bacteriological evidence, which consists of positive cultures from at least two
sputums or one positive culture from bronchoalveolar lavage or pulmonary
biopsy with a positive culture or histopathological features, and
2. Clinical evidence of infection, and
3. Radiological evidence of infection such as pulmonary cavitation, nodular lesions,
or bronchiectasis.
• In newly diagnosed patients with MAC pneumonia, triple-drug therapy
is recommended.
• These drugs include a rifamycin, ethambutol, and a macrolide.

avium Complex
• Therapy of MAC Pulmonary Infection:
• For nodular and bronchiectatic disease:
• Clarithromycin, 1000 mg, or azithromycin, 500 mg, + ethambutol, 25 mg/kg, +
rifampin, 600 mg, and administered three times a week.
• For cavitary disease:
• Azithromycin, 250 mg, + ethambutol, 15 mg/kg, + rifampin, 600 mg, and
administered three times a week.
• Parenteral streptomycin or amikacin at 15 mg/kg is recommended as a fourth
drug.
• Advanced pulmonary disease or during re-treatment:
• Rifabutin 300 mg daily may replace rifampin.
• Therapy is continued for 12 months after the last negative
culture.

avium Complex
• Therapy of Disseminated M. avium Complex:
• Disseminated MAC disease is caused by M. avium in 95% of patients.
• This is a disease of the immunocompromised patient, especially with
reduced cell-mediated immunity.
• MAC usually occurs in patients whose CD4 cell count is less than 50/mm3.
• The symptoms and laboratory findings of disseminated disease are
nonspecific and include fever, night sweats, weight loss, elevated serum
alkaline phosphates, and anemia at the time of diagnosis.
• However, when disease occurs in patients already on antiretroviral therapy, it
may manifest as a focal disease of the lymph nodes, osteomyelitis,
pneumonitis, pericarditis, skin or soft-tissue abscesses, genital ulcers, or
CNS infection

avium Complex
• Therapy of Disseminated M. avium Complex: Prophylactic
Therapy
• Monotherapy with either oral azithromycin 1200 mg once a week or
clarithromycin 500 mg twice a day is started when patients present with a CD4
count below 50/mm3.
• For patients intolerant to macrolides, rifabutin 300 mg a day is administered.
• Once the CD4 count is greater than 100 per mm3 for 3 months or longer, MAC
prophylaxis should be discontinued.

avium Complex
• Therapy of Disseminated M. avium Complex: Definitive &
Suppressive Therapy
• Goals of therapy include:
• Suppression of symptoms and
• Conversion to negative blood cultures.
• The infection itself is not completely eradicated
until immune reconstitution.

avium Complex
Suppressive Therapy
• Therapy is divided into initial therapy and chronic suppressive therapy.
Clarithromycin 500 mg twice a day
+
ethambutol 15 mg/kg daily
±
rifabutin 300 mg/d
±
Amikacin, 10–15 mg/kg intravenously daily OR streptomycin, 1 g intravenously or
intramuscularly daily OR ciprofloxacin, 500–750 mg orally twice daily OR levofloxacin,
500 mg orally daily OR moxifloxacin, 400 mg orally daily.

avium Complex
Suppressive Therapy
• Patients should be continued on suppressive therapy until
all three of the following criteria are met:
• Therapy duration of at least 12 months
• CD4 count greater than 100/mm3 for at least 6 months
• Asymptomatic for MAC infection

Principles of Antileprosy Therapy
• Introduction:
• Mycobacterium leprae was discovered by Armauer Hansen in 1873.
• M. leprae is difficult to culture on synthetic media, an impediment to basic
research on the disease.
• The global prevalence of leprosy has markedly declined, largely due to the
global initiative of the WHO to eliminate leprosy (Hansen disease) as a public
health problem by providing multidrug therapy (rifampin, clofazimine, and
dapsone) free of charge.
• Four major clinical types of leprosy:
1. Tuberculoid
2. borderline (dimorphous) tuberculoid.
3. Indeterminate.
4. Lepromatous.

• Therapy of leprosy is based on multidrug regimens using rifampin, clofazimine, and
dapsone.
• The reasons for using combinations of agents include:
1. Reduction in the development of resistance,
2. The need for adequate therapy when primary resistance already exists, and
3. Reduction in the duration of therapy.
• The most bactericidal drug in current regimens is rifampin.
• Because of high kill rates and massive release of bacterial antigens, rifampin is not
often given during a “reversal” reaction or in patients with erythema nodosum
leprosum.
• Clofazimine is only bacteriostatic against M. leprae. However, it also has anti-
inflammatory effects and can treat reversal reactions and erythema nodosum
leprosum.

• Types of Antileprosy Therapy: Definitive Therapy; Standard
Therapy
• Paucibacillary Leprosy (1-5 skin lesion± Nerve involvement):
• The WHO regimen consists of a single dose of oral rifampin, 600 mg + dapsone, 100 mg,
administered under direct supervision once every month for 6 months, and dapsone,
100 mg a day, in between for 6 months
• Multibacillary Leprosy (>5 skin lesion + > or =1 Nerve involvement) :
• The WHO recommends the same regimen as for paucibacillary leprosy, with two major
changes:
1. Clofazimine, 300 mg once a month f/b 50 mg daily, is added for the entirety of therapy.
2. Regimen lasts 1 year instead of 6 months.

• Types of Antileprosy Therapy: Treatment of reactions in leprosy
• Reversal reactions:
• Seen in Patients with tuberculoid leprosy.
• Manifestations of delayed hypersensitivity to antigens of M. leprae.
• Cutaneous ulcerations and deficits of peripheral nerve function may occur.
• Early therapy with corticosteroids or clofazimine is effective.
• Erythema Nodosum Leprosum (ENL):
• Reactions in the lepromatous form of the disease.
• Characterized by the appearance of raised, tender, intracutaneous nodules, severe constitutional
symptoms, and high fever.
• It is thought to be an Arthus-type reaction.
• Treatment with clofazimine or thalidomide is effective.

Therapy of Other Nontuberculous
Mycobacteria

Antimycobacterial agents

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