Antimycobacterial

Drugs
Chapter 41
Lippincott Pharmacology (6th Edition)

Faisal Gulzar
Assistant Professor
Faculty of Pharmacy
The University of Lahore, Lahore
Contents
• What is mycobacterium
• Its characteristics
• Acid fast staining
• Types of mycobacterium
• Diseases caused by mycobacterium
• Symptoms of T.B
Overview
• Mycobacteria are rod-shaped aerobic bacilli

• Slightly curve or straight

• Non motile

• Multiple slowly, 18 to 24 hours in vitro

• Their cell walls contain mycolic acids, which give the genus its name.

• Mycolic acids are very long-chain, β-hydroxylated fatty acids.

Video link: https://www.youtube.com/watch?v=yuHUikQy2vk
Cell wall of mycobacterium tuberculosis

The cell envelope glycoconjugates of Mycobacterium tuberculosis

https://www.researchgate.net/publication/262977054_The_cell_envelope_glycoconjugates_of_Mycobacterium_tuberculosis/figures?lo=1
Overview (continue)
• Mycobacteria produce highly lipophilic cell walls that stain poorly
with Gram stain.

• Once stained, the bacilli are not decolorized easily by acidified organic
solvents. Hence, the organisms are called “acid-fast bacilli.”

• Mycobacterial infections classically result in the formation of slow

growing, granulomatous lesions that cause tissue destruction
anywhere in the body.
Acid-Fast Staining

1. Carbol fuchsin
• When the smear is stained with carbol fuchsin

• It solubilizes the lipoidal material present in the Mycobacterial cell wall

• By application of heat, carbol fuchsin further penetrates through

lipoidal wall and enters into cytoplasm.

• Then after all cell appears red.

https://microbiologyinfo.com/acid-fast-stain-principle-procedure-interpretation-and-examples/
2. Decolorizing agent

• Then the smear is decolorized with

decolorizing agent
• (3% HCl in 95% alcohol)

• The acid fast cells are resistant to

decolorizing agent

• Due to the presence of large amount of

lipoidal material in their cell wall which
prevents the penetration of
decolorizing solution.
3. Counterstain (methylene blue)

• The non-acid fast organism lack the lipoidal material in their cell wall
due to which they are easily decolorized, leaving the cells colorless.

• Then the smear is stained with counterstain, methylene blue.

• Only decolorized cells absorb the counter stain and take its color and
appears blue while acid-fast cells retain the red color.
Summary of Acid Fast Staining
Granulomatous infection?
• A granuloma is a small area of inflammation.

• Granulomas are often found incidentally on an X-ray or other imaging

test done for a different reason.

• Typically, granulomas are noncancerous (benign). ...

• Common causes include an inflammatory condition called sarcoidosis

and infections such as histoplasmosis or tuberculosis
Mycobacterium
• Mycobacterium tuberculosis (T.B)

• Mycobacterium leprae (leprosy)

Mycobacterium tuberculosis
• It can cause latent tuberculosis infection (LTBI) and the disease known
as tuberculosis (TB).

• [Note: In LTBI, the patient is infected with M. tuberculosis but does

not have any signs or symptoms of active TB disease.]

• TB is the leading infectious cause of death worldwide

• Over 2 billion people already have been infected (roughly 10 million

are in the United States).
Atypical mycobacteria

Nontuberculosis mycobacteria (NTM). Symptoms

• Increasing in frequency are • Fever.
diseases caused by These • Weight loss.
species include
• Cough.
1. M. avium-intracellulare • Lack of appetite.
2. M. chelonae • Night sweats.
3. M. abscessus • Blood in the sputum (hemoptysis)
4. M. kansasii • Loss of energy.
5. M. fortuitum • Shortness of breath (dyspnea)
 Links for further detail

1. Preparation of smear
https://www.youtube.com/watch?v=c2BPE7wIK20

2. Procedure of acid fast staining

https://www.youtube.com/watch?v=vJB4i_14qBw
T.B cases in Pakistan
• http://www.emro.who.int/pak/programmes/stop-tuberculosis.html
• https://www.who.int/en/news-room/fact-sheets/detail/tuberculosis
Antimycobacterial therapy
Complication factors
1. Limited information about the mechanisms of antimycobacterial
drug actions
2. Development of resistance
3. Intracellular location of mycobacteria
4. Chronic nature of mycobacterial disease, which requires
protracted drug treatment and is associated with drug toxicities
5. Patient compliance
Antimycobacterial therapy
• Chemotherapy of mycobacterial infections almost always involves the
use of drug combinations
1. To delay the emergence of resistance

2. To enhance antimycobacterial efficacy

Antimycobacterial agents
Drugs for tuberculosis
• The major drugs used in tuberculosis are
1. Isoniazid (INH)
2. Rifampin
3. Ethambutol
4. Pyrazinamide
5. Streptomycin
• Actions of these agents on M tuberculosis are bactericidal or
bacteriostatic depending on drug concentration and strain
susceptibility.
• Appropriate drug treatment involves antibiotic susceptibility testing of
mycobacterial isolates from that patient.

• Initiation of treatment of pulmonary tuberculosis usually involves a 3 or 4

drug combination regimen depending on the known or anticipated
resistance to isoniazid (INH).

• Directly observed therapy (DOT) regimens are recommended in

noncompliant patients and in drug-resistant tuberculosis.

• DOT is used to ensure the person receives and takes all medications as
prescribed and to monitor response to treatment.
Antibiotic susceptibility testing
• Video link
• https://www.youtube.com/watch?v=sx1uDYSfINA

• https://labtestsonline.org/tests/antibiotic-susceptibility-testing
A. Isoniazid
• Isoniazid (INH) is a structural congener of pyridoxine.

• Its mechanism of action involves inhibition of the synthesis of

mycolic acids.

• Resistance can emerge rapidly if the drug is used alone.

• Bactericidal or bacteriostatic?

Pyridoxine: Vitamin B₆
Pharmacokinetics
• INH is well absorbed orally.
• Penetrates cells to act on intracellular mycobacteria.
• The liver metabolism of INH is by acetylation and is under genetic control.
• Patients may be fast or slow inactivators of the drug.

• INH half-life in fast acetylators is 60–90 min;

• Slow acetylators it may be 3–4 h.

• The proportion of fast acetylators is higher among people of Asian origin

(and Native Americans) than those of European or African origin.
We need to adjust the dose in
fast acetylators or in slow
acetylators????
• Fast acetylators may require higher dosage than slow acetylators for
equivalent therapeutic effects.
Clinical uses
• INH is the single most important drug used in tuberculosis and is a
component of most drug combination regimens.

• In the treatment of latent infection including skin test converters and

for close contacts of patients with active disease, INH is given as the
sole drug.
Tuberculin Skin Test
• Tuberculin Skin Test (TST) Conversion.

• TST conversion refers to the situation where an individual's TST result

changes from “negative” (typically 0-4mm diameter induration)

• to “positive” (typically equal to or >10mm diameter induration)

within a 24 month period.
Toxicity and interactions
• Neurotoxic effects are common and include

• Peripheral neuritis, restlessness, muscle twitching and insomnia.

• These effects can be alleviated by administration of pyridoxine (25–50

mg/d orally).

• INH is hepatotoxic and may cause abnormal liver function tests,

jaundice and hepatitis. Fortunately, hepatotoxicity is rare in children.
Drug interactions
• INH may inhibit the hepatic • A lupus-like syndrome has also
metabolism of drugs been reported that develops in
• Carbamazepine temporal relation to exposure to
• Phenytoin a drug and resolves after
• Warfarin cessation of the drug exposure.

• Hemolysis has occurred in

patients with glucose-6-
phosphate dehydrogenase
(G6PDH) deficiency.
B. Rifampin
• It is a derivative of rifamycin

• It is bactericidal against M tuberculosis.

• MoA: The drug inhibits DNA-dependent RNA polymerase (encoded by

the rpo gene) in M tuberculosis and many other microorganisms.

• Resistance: via changes in drug sensitivity of the polymerase often

emerges rapidly if the drug is used alone.
Pharmacokinetics
• When given orally, rifampin is well absorbed and is distributed to
most body tissues, including the central nervous system (CNS).

• The drug undergoes enterohepatic cycling and is partially metabolized

in the liver.

• Both free drug and metabolites, which are orange-colored, are

eliminated mainly in the feces.
Clinical uses
• Treatment of tuberculosis in combination with other drugs.

• However, rifampin can be used as the sole drug in treatment of latent

tuberculosis

• In INH-intolerant patients

• In close contacts of patients with INH-resistant strains of the organism.

Other uses
• In leprosy, rifampin given • Rifampin may be used with
monthly delays the emergence Vancomycin for infections
of resistance to dapsone. • Resistant staphylococci
(methicillin-resistant
Staphylococcus aureus [MRSA]
• It also used for meningococcal strains).
and staphylococcal carrier
states. • Pneumococci (penicillin-resistant
Streptococcus pneumoniae [PRSP]
strains).
Toxicity
• Light-chain proteinuria and may impair antibody responses.
• Occasional adverse effects include
• Skin rashes
• Thrombocytopenia
• Nephritis
• Liver dysfunction

• Rifampin may cause a flu-like syndrome and anemia (If given less often
than twice weekly)
Drug interactions
• Rifampin strongly induces liver drug-metabolizing enzymes and
enhances the elimination rate of many drugs
• Anticonvulsants
• Contraceptive steroids
• Cyclosporine
• Ketoconazole
• Methadone
• Terbinafine
• Warfarin
Other rifamycins
i. Rifabutin

ii. Rifaximin
i. Rifabutin
• Equally effective as an • For treatment of tuberculosis
antimycobacterial agent • other mycobacterial infections in
AIDS patients
• Less drug interactions as
compared to rifampin • especially those treated with
cytochrome P450 substrates
including
• It is usually preferred over • Protease inhibitors
rifampin • Efavirenz
ii. Rifaximin
• Rifampin derivative that not absorbed from the gastrointestinal
tract

• Used in traveler’s diarrhea

C. Ethambutol (ETB)
• MoA: It inhibits arabinosyl transferases (encoded by the embCAB
operon) involved in the synthesis of arabinogalactan, a component of
mycobacterial cell walls.

• Resistance: occurs rapidly via mutations in the emb gene if the drug is
used alone.
Pharmacokinetics
• The drug is well absorbed orally and distributed to most tissues,
including the CNS.

• A large fraction is eliminated unchanged in the urine.

• Dose reduction is necessary in renal impairment.

Clinical uses
• The main use of ethambutol is in tuberculosis and is always given in
combination with other drugs
Toxicity

• The most common adverse effects are dose-dependent

• Visual disturbances
• Most of these effects regress when the drug is stopped.

Retinal damage
Optic neuritis
Visual acuity Red-green color blindness
Other adverse effects
• Headache

• Confusion

• Hyperuricemia

• Peripheral neuritis
D. Pyrazinamide
• It is a prodrug and pyrazinamidases (encoded by the pncA gene)
present in M tuberculosis convert it in active form.

• It inhibit the growth of M. tuberculosis (mean bacteriostatic drug)

Pyrazinamide
• MoA:
• Exact mechanism of action of pyrazinamide is not known.

• Resistance:
1. Mutations in the gene that encodes enzymes involved in the
bioactivation of pyrazinamide

2. Increased expression of drug efflux systems.

D. Pharmacokinetics
• Pyrazinamide is well absorbed orally and penetrates most body
tissues, including the CNS.

• The drug is partly metabolized to pyrazinoic acid, and both parent

molecule and metabolite are excreted in the urine.

• The plasma half-life of pyrazinamide is increased in hepatic or renal

failure
Clinical uses
• In combination with other antituberculous drugs is an important
factor in the success of short course treatment regimens.
Toxicity
• Approximately 40% of patients develop non-gouty polyarthralgia.

• Hyperuricemia occurs commonly but is usually asymptomatic.

• Pyrazinamide should be avoided in pregnancy.

Other adverse effects
• Gastrointestinal irritation
• Hepatic dysfunction

Photosensitivity reactions

Maculopapular rash
E. Streptomycin
• This aminoglycoside is now used more frequently than before
because of the growing prevalence of strains of M. tuberculosis
resistant to other drugs.
• Streptomycin is used principally in drug combinations for the
treatment of life-threatening tuberculous disease e.g.
1. Meningitis
2. Miliary dissemination (widespread dissemination of M. tuberculosis via
blood)
3. Severe organ tuberculosis (the condition in which many organ get
infected with M. tuberculosis)
• The pharmacodynamics and pharmacokinetic properties of
streptomycin are similar to those of other aminoglycosides as
discussed in chapter 38 Lippincott .
Alternative drugs
• Several drugs with antimycobacterial activity are used in cases that
are resistant to first-line agents.

• They are considered second-line drugs because

1. They are no more effective
2. Their toxicities are often more serious than those of the major first
line drugs
Alternative drugs (continue)
1. Aminoglycosides (Amikacin)
2. Fluoroquinolones (Ciprofloxacin & ofloxacin)
3. Ethionamide
4. p-Aminosalicylic acid (PAS)
5. Others
1. Capreomycin
2. Cycloserine
1. Amikacin

• It is indicated for the treatment of tuberculosis suspected to be

caused by streptomycin-resistant or multi drug resistant
mycobacterial strains.

• To avoid emergence of resistance, amikacin should always be used in

combination drug regimens.
2. Ciprofloxacin & Ofloxacin

• These are often active against strains of M. tuberculosis resistant to

first-line agents.

• The Fluoroquinolones should always be used in combination

regimens with two or more other active agents.
3. Ethionamide

• is a *congener of INH, but cross-resistance does not occur.

• The major disadvantage of ethionamide is

• Severe gastrointestinal irritation
• Adverse neurologic effects at doses needed to achieve effective plasma levels.

*Pyridoxine or Vitamin B₆
4. p-Aminosalicylic acid (PAS)

• It is rarely used because primary resistance is common.

• In addition, its toxicity includes
• Gastrointestinal irritation
• Peptic ulceration
• Hypersensitivity reactions
• Effects on kidney, liver, and thyroid function
5. Other drugs

• Have limited use because of • Cycloserine

their toxicity include • Peripheral neuropathy
• Capreomycin • CNS dysfunction
• Ototoxicity
• Renal dysfunction
Antitubercular Drug Regimens
1. Standard regimens
2. Alternative regimens
3. Resistance regimens
4. Multidrug resistance regimens
1. Standard regimens

• For empiric treatment of pulmonary TB (in most areas of <4% INH

resistance),
• An initial 3-drug regimen of isoniazid (INH), rifampin, and pyrazinamide

• If the organisms are fully susceptible (Patient HIV-negative)

• Pyrazinamide can be discontinued after 2 mo
• treatment continued for a further 4 mo with a 2-drug regimen
• [isoniazid (INH), rifampin]
2. Alternative regimens

• Alternative regimens in cases of fully susceptible organisms include

INH + rifampin for 9 mo
• or INH + ethambutol for 18 mo
• Intermittent (2 or 3 × weekly) high-dose 4-drug regimens are also
effective.
3. Resistance regimens

• If resistance to INH is higher than 4%, the initial drug regimen should
include ethambutol or streptomycin.
• Tuberculosis resistant only to INH (the most common form of
resistance) can be treated for 6 mo with a regimen

• rifampin + pyrazinamide + ethambutol or streptomycin.

4. Multidrug-resistant TB (MDR-TB) regimens

• Multidrug-resistant organisms (resistant to both INH and rifampin)

should be treated with 3 or more drugs to which the organism is
susceptible for a period of more than 18 mo, including 12 mo after
sputum cultures become negative.
4. MDR-TB regimens (continue)

• Fluoroquinolones (moxifloxacin or gatifloxacin), clofazimine, ethambutol and

pyrazinamide throughout the treatment period supplemented by prothionamide,
kanamycin, and high-dose isoniazid during an intensive phase.
Drugs for leprosy
Drugs for leprosy
A. Sulfones

B. Acedapsone

C. Other Agents (Clofazimine)

A. Sulfones
• Dapsone (diaminodiphenylsulfone) remains the most active drug
• against M leprae.
• MoA: of sulfones may involve inhibition of folic acid synthesis
• Resistance: Because of increasing reports of resistance, it is
recommended that the drug be used in combinations with rifampin
and/or clofazimine.
Pharmacokinetics
• Dapsone can be given orally
• Penetrates tissues well
• Undergoes enterohepatic cycling
• Eliminated in the urine
• partly as acetylated metabolites.

Enterohepatic circulation refers to the circulation of biliary acids, bilirubin, drugs or other
substances from the liver to the bile, followed by entry into the small intestine, absorption by the
enterocyte and transport back to the liver.
Toxicity
• Common adverse effects include
• Gastrointestinal irritation
• Fever
• Skin rashes
• Methemoglobinemia
• Hemolysis (may occur, especially in patients with G6PDH deficiency).
Methemoglobinemia
B. Acedapsone
• It is a repository form of dapsone that provides
• inhibitory plasma concentrations for several months. In addition to
• its use in leprosy, dapsone is an alternative drug for the treatment
• of Pneumocystis jiroveci pneumonia in AIDS patients.
C. Other Agents (Clofazimine)
• Drug regimens usually include combinations of dapsone with rifampin
(or rifabutin, see prior discussion) with or without clofazimine.
• Clofazimine
• MoA: A phenazine dye that may interact with DNA
• Toxicity: causes
• Gastrointestinal irritation
• Skin discoloration (ranging from red-brown to nearly black).
Drugs for atypical mycobacterial infections
Drugs for atypical mycobacterial infections
• Mycobacterium avium complex (MAC) is a cause of disseminated
infections in AIDS patients.
• Currently, clarithromycin or azithromycin with or without rifabutin is
recommended for primary prophylaxis in patients with CD4 counts
less than 50/μL.
• Treatment of MAC infections requires a combination of drugs, one
favored regimen consisting of azithromycin or clarithromycin with
Ethambutol and rifabutin.
• Infections resulting from other atypical mycobacteria (e.g, M
marinum, M ulcerans), though sometimes asymptomatic

• May be treated with the described antimycobacterial drugs

(ethambutol, INH, rifampin) Or

• Other antibiotics (amikacin, cephalosporins, fluoroquinolones,

macrolides, or tetracyclines).