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Lourdes T. M. Dominguez, M.D.
University of Santo Tomas
Faculty of Pharmacy
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
• Mycobacterium tuberculosis• Mycobacterium leprae• Mycobacterium avium
HOW 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
HOW IS TB SPREAD?
HOW 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• Hematologic abnormalities
HISTORY AND PHYSICAL EXAMINATION
• Lungs: 71% Extrapulmonary: 20% Both: 9%• Cough (for 2-3 weeks is the most common)• Pleuritic pain• Pneumothorax• Dyspnea• Hemoptysis
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•Sputum is initial specimen of choice•3 specimens, early morning specimen
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
Types of TB Cases
Definition of Terms
New A patient who has never had treatment for TB or who has taken anti-tuberculosis drugs for less than one month.
Relapse A patient previously treated for tuberculosis who has been declared cured or treatment completed, and is diagnosed with bacteriologically positive (smear or culture) tuberculosis.
Failure A patient who, while on treatment, is sputum smear positive at five months or later during the course of treatment.
Return after Default (RAD)
A patient who returns to treatment with positive bacteriology (smear or culture), following interruption of treatment of treatment for two months or more.
Transfer-In A patient who has been transferred from another facility with proper referral slip to continue treatment.
Other All cases that do not fit into any of the above definitionsThis 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 smear—positive during the treatment.
3. Chronic case: a patient who is sputum positive at the end of a re-treatment regimen.
Location of Lesion
Definition of Terms
Extra-Pulmonary
TB
1. A patient with at least one mycobacterial smear/culture positive from an extra-pulmonary site (organs other than the lungs: pleura, lymph nodes, genito-urinary tract, skin, joints and bones, meninges, intestines, peritoneum and pericardium, among others), or
2. A patient with histological and/or clinical evidence consistent with active TB and there is a decision by a 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 infection
A person with Active TB disease
Usually has a skin test or blood test result indicating TB infection
Usually has a skin test or blood test result indicating TB infection
Has a normal chest x-ray and a negative sputum test
May have an abnormal chest x-ray, or positive sputum smear or culture
Has TB bacteria in his/her body that are alive, but inactive
Has active TB bacteria in his/her 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 others
May spread TB bacteria to others
Needs treatment for latent TB infection to prevent TB disease
Needs treatment to treat active TB disease
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
USE OF DRUG COMBINATIONS • To delay emergence of resistance • To enhance antimycobacterial efficacy
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
COMPLICATIONS OF CHEMOTHERAPY• Limited information about the MOA• Development of resistance• Intracellular location of mycobacteria• Chronic nature of the disease
(protracted therapy and drug toxicities)• Patient compliance
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
ANTIMYCOBACTERIAL DRUGS
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
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSIS• Isoniazid (INH)• Rifampin• Pyrazinamide (PZA)• Ethambutol• Streptomycin
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSIS• Bactericidal or bacteriostatic
o Drug concentrationo Strain susceptibility
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSIS• Initial treatment
o 3-or 4 drug combination regimens o Known or anticipated rate of resistance
to INH
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISA. ISONIAZID1. 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
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISA. ISONIAZID2. PHARMACOKINETICS• Well absorbed orally• Acts on intracellular mycobacteria• Liver metabolism is by acetylation
and is under genetic control
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISA. ISONIAZID2. PHARMACOKINETICS• Patients maybe fast (Asians) or slow
inactivators of the drug• Fast acetylators may require higher
dosage
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISA. ISONIAZID3. CLINICAL USE• Single most important drug in TB• Component of most drug regimen
combinations• Latent infection (“prophylaxis”)
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISA. ISONIAZID3. CLINICAL USE• Sole drug treatment
o Latent infection (“prophylaxis”)o Skin test converterso Close contacts of patients with
active disease
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISA. ISONIAZID4. TOXICITY AND DRUG INTERACTIONS• Neurotoxic effects
o Peripheral neuritis, restlessness, muscle twitching, and insomnia
o Pyridoxine (25-50 mg/day)
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISA. ISONIAZID4. TOXICITY AND DRUG INTERACTIONS• Hepatotoxic
o Abnormal liver function testso Jaundice, hepatitiso Rare in children
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISA. ISONIAZID4. TOXICITY AND DRUG INTERACTIONS• Inhibits the metabolism of other drugs
(eg, phenytoin)• Hemolysis in patients with G-6PD
(Glucose 6-phosphate deficiency)• Lupus-like syndrome
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISB. RIFAMPIN1. MOA• Derivative of rifamycin• Bactericidal against M. tuberculosis• Inhibits DNA-dependent RNA polymerase• Resistance emerges rapidly if used alone
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISB. RIFAMPIN2. PHARMACOKINETICS• Well absorbed orally• 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
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISB. RIFAMPIN3. CLINICAL USES• Used in combination with other drugs• Leprosy
o Given monthly to delay the emergence of resistance to dapsone
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISB. RIFAMPIN3. CLINICAL USES• Sole drug therapy
o Latent TB in INH-intolerant patientso Close contacts of patients with INH-
resistant strains• Meningococcal and staphylococcal
carrier states
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISB. RIFAMPIN4. TOXICITY AND INTERACTIONS• Light chain proteinuria• May impair antibody immune responses• Skin rashes, thrombocytopenia, nephritis,
and liver dysfunction
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISB. RIFAMPIN4. TOXICITY AND INTERACTIONS• If given less often than twice weekly
o Flu-like syndrome and anemia
• Induces liver drug-metabolizing enzymes
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISB. RIFAMPIN4. TOXICITY AND INTERACTIONS• Enhances elimination
Anticonvulsants Contraceptive steroidsCyclosporine KetoconazoleMethadone TerbinafineWarfarin
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISB. RIFAMPIN4. TOXICITY AND INTERACTIONS• Rifabutin
o Less likely to cause drug interaction than rifampin o Equally as effective as antimycobacterial agent
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISB. RIFAMPIN4. TOXICITY AND INTERACTIONS• Rifabutin
o Another rifamycin o Preferred for TB in HIV patients
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISC. ETHAMBUTOL1. MOA• Inhibits arabinoyl transferases
Synthesis of arabinogalactanComponent of mycobacterial cell walls
• Resistance emerges rapidly when used alone
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISC. ETHAMBUTOL2. PHARMACOKINETICS• Well absorbed orally• Distributed to most tissues, including CNS• Large fraction is excreted unchanged in urine• Dose reduction necessary in renal failure
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISC. ETHAMBUTOL3. CLINICAL USE• Main use in TB• Used in combination with other
drugs
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISC. ETHAMBUTOL4. TOXICITY• Dose-dependent visual disturbances
o Increased visual acuityo Red-green color blindnesso Optic neuritiso Possible retinal damage (prolonged use at high
doses)
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISC. ETHAMBUTOL4. TOXICITY• Neurotoxic
o Headacheo Confusiono Peripheral neuropathy
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISD. PYRAZINAMIDE1. MOA• Not known• Bacteriostatic
o Require metabolic conversion via pyrazinamidases present in M. tuberculosis
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISD. PYRAZINAMIDE1. MOA• Resistance emerges rapidly when
used alone• Minimal cross-tolerance with other
antimycobacterial drugs
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISD. PYRAZINAMIDE2. PHARMACOKINETICS• Well absorbed orally• Distributed to most tissues, including CNS• Partly metabolized to pyrazinoic acid
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISD. PYRAZINAMIDE2. PHARMACOKINETICS• Parent molecule and metabolite are
excreted in urine• Half-life is increased in hepatic or renal failure
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISD. PYRAZINAMIDE3. CLINICAL USE• Combined use with other drugs
o “Short-course” regimens
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISD. PYRAZINAMIDE4. TOXICITY• 40% develop nongouty polyarthralgia• Asymptomatic hypeuricemia• Myalgia GI irritation• Porphyria Hepatic dysfunction• Maculopapular rash• Photosensitivity reactions
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISE. STREPTOMYCIN• Used more frequently than before
o Prevalence of drug-resistance strains of M. tuberculosis
• Administered intramuscularly
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISE. STREPTOMYCIN• Used in drug combinations for treatment
of life-threatening TB diseaseo Meningitiso Miliary disseminationo Severe organ TB
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISE. STREPTOMYCIN• Pharmacodynamics and kinetics
similar to other aminoglycosides• Kills mainly extracellular tubercle
bacilli
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISF. ALTERNATIVE DRUGS• Cases that are resistant to first-line drugs• Second-line drugs• Not more effective than first-line drugs• Toxicities are more serious
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISF. ALTERNATIVE DRUGS
AMIKACIN• Streptomycin-resistant or multi-drug
resistant mycobacterial strains• Used in combination with other drugs
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISF. ALTERNATIVE DRUGS
CIPROFLOXACIN and OFLOXACIN• Fluoroquinolones• Mycobacterial strains resistant to
first-line drugs• Used in combination with other drugs
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISF. ALTERNATIVE DRUGS
p-AMINOSALICYLIC ACID (PAS)• Rarely used because of primary resistance• GI irritation• Peptic ulceration• Hypersensitivity reactions• Effects on kidney, liver and thyroid function
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISF. ALTERNATIVE DRUGS
ETHIONAMIDE• Congener of INH, cross-resistance does
not occur• Severe GI irritation and adverse neurologic
effects at doses needed to achieve effective plasma levels
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISF. ALTERNATIVE DRUGS
CAPREOMYCIN• Limited use because of toxicity• Ototoxicity and renal dysfunction
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR TUBERCULOSISF. ALTERNATIVE DRUGS
CYCLOSERINE• Limited use because of toxicity• Peripheral neuropathy and CNS
dysfunction
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR LEPROSYA. SULFONES
DAPSONE1. MOA• Diaminodiphenylsulfone• Inhibition of folic acid synthesis• Resistance can develop if low doses
are given
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR LEPROSYA. SULFONES
DAPSONE2. PHARMACOKINETICS• Well absorbed orally• Penetrates tissues well• Enterohepatic cycling• Eliminated in the urine,
Partly as acetylated metabolites
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR LEPROSYA. SULFONES
DAPSONE3. CLINICAL USES• Most active drug against M. leprae• Rarely used alone
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR LEPROSYA. SULFONES
DAPSONE4. TOXICITY• GI irritation Fever• Skin rashes Methemoglobinemia• Hemolysis in patients with G-6PD
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR LEPROSYA. SULFONES
ACEDAPSONE• Repository form of dapsone• Provides inhibitory plasma concentrations
for several months• Alternative drug for P. carinii pneumonia
in HIV patients
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR LEPROSYA. OTHER AGENTS• Combination of dapsone with rifampin
(or rifabutin) plus or minus clofazimine• Clofazimine
GI irritation Pinkish-brown discoloration of urine
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR ATYPICAL MYCOBACTERIALINFECTIONS• M. marinum• M. avium-intracellulare• M. ulcerans
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR ATYPICAL MYCOBACTERIALINFECTIONS• Sometimes asymptomatic• Antimycobacterial drugs
Ethambutol Rifampin
• Other antibiotics Erythromycin Amikacin
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DRUGS FOR ATYPICAL MYCOBACTERIAL INFECTIONSM. avium complex (MAC)• Disseminated infection in HIV patients• Combination of drugs
Clarithromycin or azithromycin With ethambutol and rifabutin
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DIRECTLY OBSERVED TREATMENT (DOT)• Noncompliant patients • Drug-resistant tuberculosis
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DIRECTLY OBSERVED TREATMENT (DOT)• Direct sputum smear microscopy
o Primary diagnostic toolo Definitive diagnosis of active TBo Simple and economicalo Microscopy center would be organized
even in remote areas
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DIRECTLY OBSERVED TREATMENT (DOT)• All tb symptomatics must undergo sputum
examination prior to initiation of treatment, with or without x-ray results
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DIRECTLY OBSERVED TREATMENT (DOT)• Contraindication to examination is massive
hemoptysis• No diagnosis of TB shall be made based
on the result of x-ray examinations alone
ANTIMYCOBACTERIAL DRUGSANTIMYCOBACTERIAL DRUGS
DIRECTLY OBSERVED TREATMENT (DOT) H = ISONIAZID R = RIFAMPICIN Z = PYRAZINAMIDE E = ETHAMBUTOL S = STREPTOMYCIN
TB Diagnostic Category
TB Patients To Be Given Treatment
Tuberculosis Treatment Regimen & Duration of
Treatment
Category I • New pulmonary smear (+) cases• New pulmonary smear (-) cases with extensive parenchymal involvement and as assessed by the TBDC• Extra-pulmonary TB cases
2HRZE / 4 HR:HRZE for two months during
the intensive phase
HR for 4 months during the maintenance phase
Category II • Failure cases• Relapse cases• RAD• Other (smear +)• Other (smear -)
2HRZES / 1HRZE / 5HRE:HRZES for the first two
months, then HRZE for the third month during intensive
phase
HRE for the next five months during the maintenance
phase
Category III • New smear (-) but with minimal pulmonary TB on radiography and as assessed by the TBDC
2HRZE / 4HR:HRZE for 2 months during the
intensive phase
HR for 4 months during the maintenance phase