47 antimycobacterial drugs

Lourdes T. M. Dominguez, M.D.

University of Santo Tomas

Faculty of Pharmacy

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?

• 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

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

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

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

USE OF DRUG COMBINATIONS • To delay emergence of resistance • To enhance antimycobacterial efficacy

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 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

DRUGS FOR TUBERCULOSIS• Isoniazid (INH)• Rifampin• Pyrazinamide (PZA)• Ethambutol• Streptomycin

DRUGS FOR TUBERCULOSIS• Bactericidal or bacteriostatic

o Drug concentrationo Strain susceptibility

DRUGS FOR TUBERCULOSIS• Initial treatment

o 3-or 4 drug combination regimens o Known or anticipated rate of resistance

to INH

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

DRUGS FOR TUBERCULOSISA. ISONIAZID2. PHARMACOKINETICS• Well absorbed orally• Acts on intracellular mycobacteria• Liver metabolism is by acetylation

and is under genetic control

DRUGS FOR TUBERCULOSISA. ISONIAZID2. PHARMACOKINETICS• Patients maybe fast (Asians) or slow

inactivators of the drug• Fast acetylators may require higher

dosage

DRUGS FOR TUBERCULOSISA. ISONIAZID3. CLINICAL USE• Single most important drug in TB• Component of most drug regimen

combinations• Latent infection (“prophylaxis”)

DRUGS FOR TUBERCULOSISA. ISONIAZID3. CLINICAL USE• Sole drug treatment

o Latent infection (“prophylaxis”)o Skin test converterso Close contacts of patients with

active disease

DRUGS FOR TUBERCULOSISA. ISONIAZID4. TOXICITY AND DRUG INTERACTIONS• Neurotoxic effects

o Peripheral neuritis, restlessness, muscle twitching, and insomnia

o Pyridoxine (25-50 mg/day)

DRUGS FOR TUBERCULOSISA. ISONIAZID4. TOXICITY AND DRUG INTERACTIONS• Hepatotoxic

o Abnormal liver function testso Jaundice, hepatitiso Rare in children

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

DRUGS FOR TUBERCULOSISB. RIFAMPIN1. MOA• Derivative of rifamycin• Bactericidal against M. tuberculosis• Inhibits DNA-dependent RNA polymerase• Resistance emerges rapidly if used alone

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

DRUGS FOR TUBERCULOSISB. RIFAMPIN3. CLINICAL USES• Used in combination with other drugs• Leprosy

o Given monthly to delay the emergence of resistance to dapsone

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

DRUGS FOR TUBERCULOSISB. RIFAMPIN4. TOXICITY AND INTERACTIONS• Light chain proteinuria• May impair antibody immune responses• Skin rashes, thrombocytopenia, nephritis,

and liver dysfunction

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

DRUGS FOR TUBERCULOSISB. RIFAMPIN4. TOXICITY AND INTERACTIONS• Enhances elimination

Anticonvulsants Contraceptive steroidsCyclosporine KetoconazoleMethadone TerbinafineWarfarin

DRUGS FOR TUBERCULOSISB. RIFAMPIN4. TOXICITY AND INTERACTIONS• Rifabutin

o Less likely to cause drug interaction than rifampin o Equally as effective as antimycobacterial agent

DRUGS FOR TUBERCULOSISB. RIFAMPIN4. TOXICITY AND INTERACTIONS• Rifabutin

o Another rifamycin o Preferred for TB in HIV patients

DRUGS FOR TUBERCULOSISC. ETHAMBUTOL1. MOA• Inhibits arabinoyl transferases

Synthesis of arabinogalactanComponent of mycobacterial cell walls

• Resistance emerges rapidly when used alone

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

DRUGS FOR TUBERCULOSISC. ETHAMBUTOL3. CLINICAL USE• Main use in TB• Used in combination with other

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)

DRUGS FOR TUBERCULOSISC. ETHAMBUTOL4. TOXICITY• Neurotoxic

o Headacheo Confusiono Peripheral neuropathy

DRUGS FOR TUBERCULOSISD. PYRAZINAMIDE1. MOA• Not known• Bacteriostatic

o Require metabolic conversion via pyrazinamidases present in M. tuberculosis

DRUGS FOR TUBERCULOSISD. PYRAZINAMIDE1. MOA• Resistance emerges rapidly when

used alone• Minimal cross-tolerance with other

antimycobacterial drugs

DRUGS FOR TUBERCULOSISD. PYRAZINAMIDE2. PHARMACOKINETICS• Well absorbed orally• Distributed to most tissues, including CNS• Partly metabolized to pyrazinoic acid

DRUGS FOR TUBERCULOSISD. PYRAZINAMIDE2. PHARMACOKINETICS• Parent molecule and metabolite are

excreted in urine• Half-life is increased in hepatic or renal failure

DRUGS FOR TUBERCULOSISD. PYRAZINAMIDE3. CLINICAL USE• Combined use with other drugs

o “Short-course” regimens

DRUGS FOR TUBERCULOSISD. PYRAZINAMIDE4. TOXICITY• 40% develop nongouty polyarthralgia• Asymptomatic hypeuricemia• Myalgia GI irritation• Porphyria Hepatic dysfunction• Maculopapular rash• Photosensitivity reactions

DRUGS FOR TUBERCULOSISE. STREPTOMYCIN• Used more frequently than before

o Prevalence of drug-resistance strains of M. tuberculosis

• Administered intramuscularly

DRUGS FOR TUBERCULOSISE. STREPTOMYCIN• Used in drug combinations for treatment

of life-threatening TB diseaseo Meningitiso Miliary disseminationo Severe organ TB

DRUGS FOR TUBERCULOSISE. STREPTOMYCIN• Pharmacodynamics and kinetics

similar to other aminoglycosides• Kills mainly extracellular tubercle

bacilli

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

DRUGS FOR TUBERCULOSISF. ALTERNATIVE DRUGS

AMIKACIN• Streptomycin-resistant or multi-drug

resistant mycobacterial strains• Used in combination with other drugs

CIPROFLOXACIN and OFLOXACIN• Fluoroquinolones• Mycobacterial strains resistant to

first-line drugs• Used in combination with other drugs

p-AMINOSALICYLIC ACID (PAS)• Rarely used because of primary resistance• GI irritation• Peptic ulceration• Hypersensitivity reactions• Effects on kidney, liver and thyroid function

ETHIONAMIDE• Congener of INH, 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 LEPROSYA. SULFONES

DAPSONE1. MOA• Diaminodiphenylsulfone• Inhibition of folic acid synthesis• Resistance can develop if low doses

are given

DAPSONE2. PHARMACOKINETICS• Well absorbed orally• Penetrates tissues well• Enterohepatic cycling• Eliminated in the urine,

Partly as acetylated metabolites

DAPSONE3. CLINICAL USES• Most active drug against M. leprae• Rarely used alone

DAPSONE4. TOXICITY• GI irritation Fever• Skin rashes Methemoglobinemia• Hemolysis in patients with G-6PD

ACEDAPSONE• Repository form of dapsone• Provides inhibitory plasma concentrations

for several months• Alternative drug for P. carinii pneumonia

in HIV patients

DRUGS FOR LEPROSYA. OTHER AGENTS• Combination of dapsone with rifampin

(or rifabutin) plus or minus clofazimine• Clofazimine

GI irritation Pinkish-brown discoloration of urine

DRUGS FOR ATYPICAL MYCOBACTERIALINFECTIONS• M. marinum• M. avium-intracellulare• M. ulcerans

DRUGS FOR ATYPICAL MYCOBACTERIALINFECTIONS• Sometimes asymptomatic• Antimycobacterial drugs

Ethambutol Rifampin

• Other antibiotics Erythromycin Amikacin

DRUGS FOR ATYPICAL MYCOBACTERIAL INFECTIONSM. avium complex (MAC)• Disseminated infection in HIV patients• Combination of drugs

Clarithromycin or azithromycin With ethambutol and rifabutin

DIRECTLY OBSERVED TREATMENT (DOT)• Noncompliant patients • Drug-resistant tuberculosis

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

DIRECTLY OBSERVED TREATMENT (DOT)• All tb symptomatics must undergo sputum

examination prior to initiation of treatment, with or without x-ray results

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

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

HRE for the next five months during the maintenance

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

47 antimycobacterial drugs

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