2. Antimycobacterial drugs Flashcards
mycobacteria
mycobacterium tuberculosis
non mucobatirume tuberculosis (NMT)
leprosy
mycobacterium tuberculosis & NMT types of treatment treatment
First line & Second lines of treatment
First line treatment drugs
all give in oral administration
Isoniazid (INH)
Rifampin
Pyrazinamide
Ethambutol
First line treatment drug regimen
Initial therapy: isoniazid + rifampin + pyrazinamide + ethambutol/streptomycin for 2 months, then: isoniazid + rifampin for 4 months (4 for 2 and 2 for 4)
Second line treatment drugs
for MDR tuberculosis
more toxic, and less effective
drugs... Streptomycin Para-aminosalicylic acid Capreomycin Cycloserine Ethionamide Fluoroquinolones Macrolide Rifabutin
Fluoroquinolones
for TBC and NTM
drugs …
Levofloxacin
Moxifloxacin
Macrolide
for NTM
drugs
Azithromycin
clarithromycin
Levofloxacin
Fluoroquinolones 3 generation
L- isomer of ofloxacin (2nd gen.)
Spectrum: G-ive aerobe bacteria, Proteus, E.coli, Klebsiella, H, influenzae, Nissera better G+ive (Strep pneumoniae) than 2nd generation but less pseudomonas
Clinical use: respiratory oriented | prostatitis | skin infection
Kinetics: 100% bioavailability | renal excretion
Administration: Oral and IV | ophthalmic
Adverse effect: GI, QT prolongation
Moxifloxacin
Fluoroquinolones 4 generation
Spectrum: G-ive aerobe bacteria, Proteus, E.coli, Klebsiella, H, influenzae, Nissera better G+ive (Strep pneumoniae) than 3nd generation andsome anaerobes as well
Clinical use: respiratory oriented | prostatitis | skin infection | Not for UTI
Kinetics: good absorption | long half life (once a day administration) | liver excretion
Administration: IV | Ophthalmic
Adverse effect: GI, CNS, QT prolongation
Azithromycin
Macrolide
in case of mycobacteria infection it is preferred for patients at greater risk for drug interactions
Spectrum: more potent against G-ive | G+ive Cocci, G-ive Cocci, borrelia burgdorferi | M.avium
Clinical use: Uretritis (chlamydia)
Administration: Oral and IV
Kinetics: longest half life and largest Vd
Distribution: Well | concentrated in neutrophils, macrophages and fibroblasts |
Elimination: Liver
Adverse effect: Less GI, no interactions
clarithromycin
Macrolide
Spectrum: more potent against G+ive | G-ive | H. influenzae, H. Pylori | Chlamydia | M.avium
Kinetics: good bioavailability | renal excretion
Administration: Oral and IV, food increases absorption.
Distribution: Well
Elimination: Kidney
Adverse effect: Less GI, few interactions
Isoniazid (INH)
Prodrug - activated by catalase peroxidase (KatG)
Inhibition of mycolic acid synthesis (needed for the cell wall)
Bactericidal (only for actively growing bacteria)
Spectrum: M. tuberculosis and kansasii (in high concentration)
Absorption: good but reduced with food (high fat)
Distribution: good - also to CNS and caseous material
Metabolism: N-acetylation (fast/slow acetylators) and hydrolysis | inhibits CYP450
Excretion: Glomerular
Adverse effect: Hepatitis (risk increase with age), peripheral neuropathy, SLE
*Give pyridoxine (B6) to avoid neuropathies
pyridoxine
vitemin B6 to avoid adverse effects of neuropathies in isoniazid treatment
Rifampin
Inhibition of RNA polymerase
Bactericidal
Long PAE
Spectrum: M. tuberculosis, NTM (kansasii, avium, leprae), G+ive (staph), G-ive (H.influenzae, N.meningitidis - prophylactic)
Distribution: good | CNS variable
Metabolism: Enterohepatic recycling
Excretion: Bille
Adverse effect: Orange discoloration of body fluid, nusea | drug inducer (CYP450 inducer)
*Always given in combination
Pyrazinamide
Metabolized to pyrazinoic acid which inhibits cell membrane function (resistance by lacking metabolising enzyme)
Spectrum: M. tuberculosis (in acidic lesions and macrophages)
Distribution: good | CNS penetration
Adverse effect: Hepatotoxicity, uric acid retention
Ethambutol
Inhibits arabinosyl-transferase - inhibits cell wall synthesis
Bacteriostatic
Spectrum: Mycobacterium
Distribution: good | CNS minimal
Excretion: Urine
Adverse effect: Optic neuritis (red-green color blindness) | uric acid excretion decreased
Streptomycin
border line - first line in treatment of mycobacterium tuberculosis
Aminoglycoside
Bactericidal
toxic (oto and nephro), acts against extracellular mycobacteria
Para-aminosalicylic acid
Inhibitor of folic acid synthesis
Only against M. tuberculosis
rarely used because of side effects
Capreomycin
inhibits protein synthesis
given IM
AE: nephro and oto-toxicity
Cycloserine
Cell wall synthesis inhibitor
bacteriostatic
given orally
well distributed including CNS
AE: CNS disturbances (seizures)
Ethionamide
Inhibitor of mycolic acid synthesis (as INH)
well distributed including CNS
AE: Neurotoxicity, hepatotoxicity
Inhibitor of mycolic acid synthesis
Ethionamide & Isoniazid (INH)
Rifabutin
A derivative of rifampin
reverse transcriptase inhibitors
Preferred in patients coinfected with HIV and receiving
protease inhibitors or several of the non-nucleoside
Less potent inducer of CYP450 => less interactions
Drugs against leprosy
Dapsone
Rifampin
Clofazimine
Dapsone
Structurally related to sulfonamides
Inhibitor of folic acid synthesis (inhibits dihydropteroate synthetase)
Bacteriostatic (for M. leprae)
Also used in treatment of pneumonia caused by Pneumocystis jirovecii in immunosuppressed patients
Distribution: good GI penetration, well distributed, high concentration in the skin
Adverse effects: Hemolysis (especially in patients with G6PD deficiency), Methemoglobinemia, Erythema nodosum, peripheral neuropathy
Rifampin used for
M. tuberculosis, NTM (kansasii, avium, leprae), G+ive (staph), G-ive (H.influenzae, N.meningitidis - prophylactic)
Clofazimine
A phenazine dye, unknown mechanism (may involve binding to DNA)
Used in case of dapsone resistance
Bactericidal to M. leprae and has potential to be used for M. tuberculosis and atypical mycobacteria
Has some anti-inflammatory and anti-immune activities
This may stop the development of erythema nodosum leprosum in treated patients
Adverse effects: black and brown discoloration of the skin
