47 Antimycobacterial Drugs

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ANTIMYCOBACTERIAL DRUGS
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£OW IS TB SPREAD?
_ Spread through the air from one person to

another
_ Most likely to spread to people who are close
contacts (people they spend time with every day,
family, friends, co-workers, schoolmates)
_ Transmitted through airborne droplets when
person with active TB of the lungs (PTB) or throat
(laryngeal TB) coughs, sneezes, speaks or sings
_ TB of the lung or throat can be infectious
£OW IS TB SPREAD?
£OW IS TB SPREAD?
_ TB of the lungs or throat can be infectious

_ Extra-pulmonary TB is usually not infectious
CLINICAL MANIFESTATIONS
_ Fever
_ Weight loss
_ Weakness
_ Night sweats
_ Malaise
_ £ematologic abnormalities
£ISTORY AND P£YSICAL
EXAMINATION
_ Lungs: 71%
Extrapulmonary: 20%
Both: 9%
_ Cough (for 2-3 weeks is the most common)
_ Pleuritic pain
_ Pneumothorax
_ Dyspnea
_ £emoptysis
DIAGNOSTIC EXAMS
Chest radiograph
_ Usually the first diagnostic study done
_ May be negative in some patients with positive sputum
cultures
_ Cannot provide a definitive diagnosis of TB
_ Activity cannot be determined from a single radiographic
examination
DIAGNOSTIC EXAMS
Bacteriologic Evaluation
_ Sputum examination
_ Sampling of gastric contents
_ Broncho-alveolar lavage, Transbronchial lung
biopsy
_ Needle aspiration biopsy
SPUTUM AFB SMEAR
_

_

MTB CULTURE
_ More sensitive than microscopy

_ Sensitivity of 80-85%; specificity of 98%
_ Growth of organisms is necessary for precise
species identification
_ Required for drug susceptibility testing
DRUG SUSCEPTIBILITY TESTING
_ Performed on initial isolates from all patients in

order to identify what should be an effective
regimen
_ Repeated if patient continues to produce culture-

positive sputum after 3 months of treatment or
becomes positive after a negative culture
PPD
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A patient who has never had treatment for TB or who has taken anti-
tuberculosis drugs for less than one month.
A patient previously treated for tuberculosis who has been declared cured
or treatment completed, and is diagnosed with bacteriologically positive
(smear or culture) tuberculosis.
A patient who, while on treatment, is sputum smear positive at five months
or later during the course of treatment.
A patient who returns to treatment with positive bacteriology (smear or

culture), following interruption of treatment of treatment for two months or

more.
à A patient who has been transferred from another facility with proper
referral slip to continue treatment.
All cases that do not fit into any of the above definitions
This group includes:
1. A patient who is starting treatment again after interrupting
treatment for more than two months and has remained or become
smear-negative.
2. A sputum smear negative patient initially before starting treatment
and became sputum smear²positive during the treatment.
3. Chronic case: a patient who is sputum positive at the end of a re-
treatment regimen.
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1. A patient with at least two

Smear positive sputum specimens positive for
AFB, with or without radiographic
abnormalities consistent with
active TB, or
2. A patient with one sputum
specimen positive for AFB and
with radiographic abnormalities
consistent with active TB as
determined by a clinician, or
3. A patient with one sputum
ulmonary specimen positive for AFB with
TB (TB) sputum culture positive for a

A patient with at least three sputum

Smear negative specimens negative for AFB with
radiographic abnormalities consistent
with active TB, and there has been no
response to a course of antibiotics
and/or symptomatic medications, !
there is a decision by a Medical Officer
to treat the patient with anti-TB drugs.
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1. A patient with at least one mycobacterial smear/culture

positive from an e tra-pulmonary site (organs other
than the lungs: pleura, lymph nodes, genito-urinary
tract, skin, joints and bones, meninges, intestines,
þ tra- peritoneum and pericardium, among others), or
ulmonary 2. A patient with histological and/or clinical evidence
consistent with active TB and there is a decision by a
TB Medicla Officer to treat the patient with anti-TB drugs.
LATENT TB
_ Not infectious; cannot transmit the

organism
_ Approximately 10% who acquire TB
infection and not treated will develop
active TB
_ Risk is highest in the first 2 year of infection
A person with latent TB A person with Active TB
infection disease
Usually has a skin test or blood Usually has a skin test or blood
test result indicating TB infection test result indicating TB infection
Has a normal chest -ray and a May have an abnormal chest -

negative sputum test ray, or positive sputum smear or
culture
Has TB bacteria in his/her body Has active TB bacteria in his/her

that are alive, but inactive body
Does not feel sick Usually feels sick and may have
symptoms such as coughing,
fever, and weight loss
Cannot spread the TB bacteria to May spread TB bacteria to others

others
Needs treatment for latent TB Needs treatment to treat active
infection to prevent TB disease TB disease
USE OF DRUG COMBINATIONS

_ To delay emergence of resistance
_ To enhance antimycobacterial efficacy
COMPLICATIONS OF C£EMOT£ERAPY
_ Limited information about the MOA
_ Development of resistance
_ Intracellular location of mycobacteria
_ Chronic nature of the disease
(protracted therapy and drug toxicities)
_ Patient compliance
Drugs used in Drugs used Drugs used for

tuberculosis in leprosy atypical mycobacteria
First-line Alternative Drugs for Drugs for

drugs drugs major infections minor
infections
DRUGS FOR TUBERCULOSIS
_ Isoniazid (IN£)
_ Rifampin
_ Pyrazinamide (PZA)
_ Ethambutol
_ Streptomycin
_ Bactericidal or bacteriostatic
o Drug concentration
o Strain susceptibility
_ Initial treatment
o 3-or 4 drug combination regimens
o Known or anticipated rate of resistance
to IN£
A. ISONIAZID
1. MOA
_ Structural congener of pyridoxine
_ Inhibition of enzymes required for the
synthesis of mycolic acid and mycobacterial
cell walls
_ Resistance can emerge rapidly if used alone
A. ISONIAZID
2. P£ARMACOKINETICS
_ Well absorbed orally
_ Acts on intracellular mycobacteria
_ Liver metabolism is by acetylation
and is under genetic control
A. ISONIAZID
_ Patients maybe fast (Asians) or slow
inactivators of the drug
_ Fast acetylators may require higher
dosage
A. ISONIAZID
3. CLINICAL USE
_ Single most important drug in TB
_ Component of most drug regimen
combinations
_ Latent infection (͞prophylaxis͟)
A. ISONIAZID
3. CLINICAL USE
_ Sole drug treatment
o Latent infection (͞prophylaxis͟)
o Skin test converters
o Close contacts of patients with
active disease
A. ISONIAZID
4. TOXICITY AND DRUG INTERACTIONS
_ Neurotoxic effects
o Peripheral neuritis, restlessness,
muscle twitching, and insomnia
o Pyridoxine (25-50 mg/day)
A. ISONIAZID
_ £epatotoxic
o Abnormal liver function tests
o Jaundice, hepatitis
o Rare in children
A. ISONIAZID
_ Inhibits the metabolism of other drugs
(eg, phenytoin)
_ £emolysis in patients with G-6PD
(Glucose 6-phosphate deficiency)
_ Lupus-like syndrome
B. RIFAMPIN
1. MOA
_ Derivative of rifamycin
_ Bactericidal against a
_ Inhibits DNA-dependent RNA polymerase
_ Resistance emerges rapidly if used alone
B. RIFAMPIN
_ Distributed to most body tissues, including
CNS
_ Enterohepatic cycling, partly metabolized by
the liver
_ Free drug and metabolites (orange colored)
are excreted in the feces
B. RIFAMPIN
3. CLINICAL USES
_ Used in combination with other drugs
_ Leprosy
o Given monthly to delay the emergence
of resistance to dapsone
B. RIFAMPIN
3. CLINICAL USES
_ Sole drug therapy
o Latent TB in IN£-intolerant patients
o Close contacts of patients with IN£-
resistant strains
_ Meningococcal and staphylococcal
carrier states
B. RIFAMPIN
4. TOXICITY AND INTERACTIONS
_ Light chain proteinuria
_ May impair antibody immune responses
_ Skin rashes, thrombocytopenia, nephritis,
and liver dysfunction
B. RIFAMPIN
_ If given less often than twice weekly
o Flu-like syndrome and anemia
_ Induces liver drug-metabolizing enzymes
B. RIFAMPIN
_ Enhances elimination
Anticonvulsants Contraceptive steroids
Cyclosporine Ketoconazole
Methadone Terbinafine
Warfarin
B. RIFAMPIN
_ Rifabutin
o Less likely to cause drug interaction than
rifampin
o Equally as effective as antimycobacterial agent
B. RIFAMPIN
_ Rifabutin
o Another rifamycin
o Preferred for TB in £IV patients
C. ETHAMBUTOL
1. MOA
_ Inhibits arabinoyl transferases
Synthesis of arabinogalactan
Component of mycobacterial cell walls
_ Resistance emerges rapidly when used
alone
C. ETHAMBUTOL
_ Distributed to most tissues, including CNS
_ Large fraction is excreted unchanged in urine
_ Dose reduction necessary in renal failure
C. ETHAMBUTOL
3. CLINICAL USE
_ Main use in TB
_ Used in combination with other
drugs
C. ETHAMBUTOL
4. TOXICITY
_ Dose-dependent visual disturbances
o Increased visual acuity
o Red-green color blindness
o Optic neuritis
o Possible retinal damage (prolonged use at high
doses)
C. ETHAMBUTOL
4. TOXICITY
_ Neurotoxic
o £eadache
o Confusion
o Peripheral neuropathy
D. PYRAZINAMIDE
1. MOA
_ Not known
_ Bacteriostatic
o Require metabolic conversion via pyrazinamidases
present in a
D. PYRAZINAMIDE
1. MOA
_ Resistance emerges rapidly when
used alone
_ Minimal cross-tolerance with other
antimycobacterial drugs
D. PYRAZINAMIDE
_ Distributed to most tissues, including CNS
_ Partly metabolized to pyrazinoic acid
D. PYRAZINAMIDE
_ Parent molecule and metabolite are
excreted in urine
_ £alf-life is increased in hepatic or renal failure
D. PYRAZINAMIDE
3. CLINICAL USE
_ Combined use with other drugs
o ͞Short-course͟ regimens
D. PYRAZINAMIDE
4. TOXICITY
_ 40% develop nongouty polyarthralgia
_ Asymptomatic hypeuricemia
_ Myalgia ^ GI irritation
_ Porphyria ^ £epatic dysfunction
_ Maculopapular rash
_ Photosensitivity reactions
E. STREPTOMYCIN
_ Used more frequently than before
o Prevalence of drug-resistance
strains of a
_ Administered intramuscularly
E. STREPTOMYCIN
_ Used in drug combinations for treatment
of life-threatening TB disease
o Meningitis
o Miliary dissemination
o Severe organ TB
E. STREPTOMYCIN
_ Pharmacodynamics and kinetics
similar to other aminoglycosides
_ Kills mainly extracellular tubercle
bacilli
F. ALTERNATIVE DRUGS
_ Cases that are resistant to first-line drugs
_ Second-line drugs
_ Not more effective than first-line drugs
_ Toxicities are more serious
AMIKACIN
_ Streptomycin-resistant or multi-drug
resistant mycobacterial strains
CIPROFLOXACIN and OFLOXACIN
_ Fluoroquinolones
_ Mycobacterial strains resistant to
first-line drugs
-AMINOSALICYLIC ACID (PAS)
_ Rarely used because of primary resistance
_ GI irritation
_ Peptic ulceration
_ £ypersensitivity reactions
_ Effects on kidney, liver and thyroid function
ETHIONAMIDE
_ Congener of IN£, cross-resistance does
not occur
_ Severe GI irritation and adverse neurologic
effects at doses needed to achieve
effective plasma levels
CAPREOMYCIN
_ Limited use because of toxicity
_ Ototoxicity and renal dysfunction
CYCLOSERINE
_ Limited use because of toxicity
_ Peripheral neuropathy and CNS
dysfunction
DRUGS FOR LEPROSY
A. SULFONES
DAPSONE
1. MOA
_ Diaminodiphenylsulfone
_ Inhibition of folic acid synthesis
_ Resistance can develop if low doses
are given
DRUGS FOR LEPROSY
A. SULFONES
DAPSONE
_ Penetrates tissues well
_ Enterohepatic cycling
_ Eliminated in the urine,
Partly as acetylated metabolites
DRUGS FOR LEPROSY
A. SULFONES
DAPSONE
3. CLINICAL USES
_ Most active drug against a
_ Rarely used alone
DRUGS FOR LEPROSY
A. SULFONES
DAPSONE
4. TOXICITY
_ GI irritation ^ Fever
_ Skin rashes ^ Methemoglobinemia
_ £emolysis in patients with G-6PD
DRUGS FOR LEPROSY
A. SULFONES
ACEDAPSONE
_ Repository form of dapsone
_ Provides inhibitory plasma concentrations
for several months
_ Alternative drug for P pneumonia
in £IV patients
DRUGS FOR LEPROSY
A. OTHER AGENTS
_ Combination of dapsone with rifampin
(or rifabutin) plus or minus clofazimine
_ Clofazimine
GI irritation
Pinkish-brown discoloration of urine
DRUGS FOR ATYPICAL MYCOBACTERIAL
INFECTIONS
_ a

_ a

_ a
INFECTIONS
_ Sometimes asymptomatic
_ Antimycobacterial drugs
Ethambutol Rifampin
_ Other antibiotics
Erythromycin Amikacin
INFECTIONS
a
complex (MAC)
_ Disseminated infection in £IV patients
_ Combination of drugs
Clarithromycin or azithromycin
With ethambutol and rifabutin
DIRECTLY OBSERVED TREATMENT (DOT)
_ Noncompliant patients
_ Drug-resistant tuberculosis
_ Direct sputum smear microscopy
o Primary diagnostic tool
o Definitive diagnosis of active TB
o Simple and economical
o Microscopy center would be organized
even in remote areas
_ All tb symptomatics must undergo sputum
examination prior to initiation of treatment,
with or without x-ray results
_ Contraindication to examination is massive
hemoptysis
_ No diagnosis of TB shall be made based
on the result of x-ray examinations alone
H = ISONIAZID
R = RIFAMPICIN
Z = PYRAZINAMIDE
E = ETHAMBUTOL
S = STREPTOMYCIN
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" _ New pulmonary smear (+) cases 2HRZþ / 4 HR:

_ New pulmonary smear (-) cases HRZþ for two months during
with e tensive parenchymal the intensive phase
involvement and as assessed by
the TBDC HR for 4 months during the
_ þ tra-pulmonary TB cases maintenance phase
" _ Failure cases 2HRZþS / 1HRZþ / 5HRþ:

_ Relapse cases HRZþS for the first two
_ RAD months, then HRZþ for the
_ Other (smear +) third month during intensive
phase
_ Other (smear -)
HRþ for the ne t five months

during the maintenance
phase
" _ New smear (-) but with minimal 2HRZþ / 4HR:
pulmonary TB on radiography and HRZþ for 2 months during the
as assessed by the TBDC intensive phase
HR for 4 months during the

maintenance phase

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47 Antimycobacterial Drugs

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_ Spread through the air from one person to

_ TB of the lungs or throat can be infectious

_ More sensitive than microscopy

_ Performed on initial isolates from all patients in

_ Repeated if patient continues to produce culture-

A patient who returns to treatment with positive bacteriology (smear or

1. A patient with at least two

A patient with at least three sputum

1. A patient with at least one mycobacterial smear/culture

_ Not infectious; cannot transmit the

Has a normal chest -ray and a May have an abnormal chest -

Has TB bacteria in his/her body Has active TB bacteria in his/her

Cannot spread the TB bacteria to May spread TB bacteria to others

USE OF DRUG COMBINATIONS

Drugs used in Drugs used Drugs used for

First-line Alternative Drugs for Drugs for

" _ New pulmonary smear (+) cases 2HRZþ / 4 HR:

" _ Failure cases 2HRZþS / 1HRZþ / 5HRþ:

HRþ for the ne t five months

HR for 4 months during the

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47 Antimycobacterial Drugs

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47 Antimycobacterial Drugs

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

_ Spread through the air from one person to

_ TB of the lungs or throat can be infectious

_ More sensitive than microscopy

_ Performed on initial isolates from all patients in

_ Repeated if patient continues to produce culture-

    A patient who returns to treatment with positive bacteriology (smear or

1. A patient with at least two

A patient with at least three sputum

1. A patient with at least one mycobacterial smear/culture

_ Not infectious; cannot transmit the

Has a normal chest -ray and a May have an abnormal chest -

Has TB bacteria in his/her body Has active TB bacteria in his/her

Cannot spread the TB bacteria to May spread TB bacteria to others

USE OF DRUG COMBINATIONS

Drugs used in Drugs used Drugs used for

First-line Alternative Drugs for Drugs for

 "  _ New pulmonary smear (+) cases 2HRZþ / 4 HR:

 "  _ Failure cases 2HRZþS / 1HRZþ / 5HRþ:

HRþ for the ne t five months

HR for 4 months during the

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A patient who returns to treatment with positive bacteriology (smear or

" _ New pulmonary smear (+) cases 2HRZþ / 4 HR:

" _ Failure cases 2HRZþS / 1HRZþ / 5HRþ: