Antimycobacterial Drugs Flashcards
antimycobacterial drugs are used for the treatment of
- tuberculosis
- atypical mycobacteria infections
- leprosy
what First line drugs are used to treat tuberculosis
-Isoniazid, Pyrazinamide, Rifampin, Ethambutol, streptomycin
what Second-line Drugs are used to treat tuberculosis
p-Aminosalicylic acid
what drugs are used to treat atypical Mycobacteria infections
-Isoniazid, Ethambutol, Rifampin, Erythromycin, Ciprofloxacin, various Cephalosporins
late stages of AIDS are associated with what
disseminated M avium complex infection (includes the presence of M. avium and M. intracellular),
what drugs are used to treat disseminated M avium complex infections
-clarithromycin plus ethambutol and rifabutin
what drugs are used to treat m. leprae
Dapsone, Clofazimine
what are the general considerations for the drug treatment of mycobacteria infections
- M. infections intrinsically resistant to most antibiotics
- notorious ability to develop resistance
- slow growth rate: can also be dormant
- intracellular location
- lipid-rich cell wall is impermeable to many drugs
what is the treatment period for M. infections
treatment for periods of drug therapy longer than that of other infectious diseases
all M. Tuberculosisis initial isolates should be tested for what
susceptibility to drugs
should drugs be used in combination to treat Tuberculosis
-yes, use combined drug therapy with at least 2 drugs to which organism is susceptible
TB therapy requires use of
- a multi-drug regiment with agents active against the clinical isolate
- susceptibility test of initial isolates should always be obtained
what does the American Thoracic Society and the CDCP recommend for the initial treatment of TB
- give 4 drugs: isoniazid, rifampin (or other rifamycin), pyrazinamide and ethambutol or streptomycin
- after susceptibility of the clinical isolate has been determined, patients with drug-susceptible isolates can be treated with isoniazid and rifampin
what is the prevalence of INH resistant TB
~10%
what is the treatment of TB in HIV patients
use of rifampin-based regimes given clinical responses similar to that obtained in HIV-free TB patients
what are the first line drugs
Based of Efficacy
- isoniazid (INH; generic)
- rifampin (rifadin)
- pyrazinamide (generic)
- ethambuto (myambutol)
- streptomycin (generic)
when are the second line drugs used
only if there are resistant organisms to first line drugs or other overriding considerations
what is the primary reason for the use of drug combinations in the treatment of TB
-to delay the emergency of resistance to INDIVIDUAL drugs
Isoniazid (INH) is a hydrazide of what
isonicotinic acid
Isoniazid acts only upon
Mycobacteria
what is the most active drug available for the treatment of TB casued by M. susceptible strains
Isoniazid
Isoniazid is less effective for the treatment of diseases caused by
atypical M. species
isoniazid are small molecules, structurally similar to
pyridoxine
Isoniazid is a prodrug, what does that mean
After activation (by mycobacterial catalase peroxidase KatG), has lethal effect by forming a covalent complex with an acyl carrier protein (AcpM) and a beta-ketoacyl carrier protein synthetase (KasA), blocking mycolic acid synthesis killing the cell
resistance to INH has been associated with various mutations, what are they
- over-expression of inhA gene encoding an NADH-dependent acyl carrier protein reductase
- mutation or deltion of the katG gene
- promoter mutations resulting in over-expression of ahpC, a putative virulence gene involved in cell protection from oxidative stress
- Mutations in kasA
inhA overproducers express — level resistance to INH and cross resistance to —
low
ethionamide
KatG mutants express — level INH resistance and often are not cross-resistant to —-
high
ethionamide
what are the pharmacokinetics of Isoniazid
- well absorbed after oral administration, reaching peak plasma levels within 1-2 hrs
- widespread distribution in body fluids and tissues, including brain, CSF, caseous TB lesions and phagocytic cells
- active against intra- and extracellular organisms
what converts N-Acetylated to N-acetylisoniazid
liver N-acetyltransferase
how are N-acetylizoniazid + isonicotinic acid + little unchanged drugs eliminated
in the urine
Acetylisoniazid/isonizaid ratio is genetically determined by what
INH acetylation rate
INH average plasma conc. in rapid acetylators is
~1/3 to 1/2 of that in slow acetylators, with average t1/2 of >1hr and 3hr, respectively
are there therapetuic consequence of INH when using appropriate daily dosing
no, weekly NIH dosing (rapid acetylators) or malabsorption may result in subtherapetutic levels
when is INH the drug of choice (DOC)
when single agent used a chemoprophylaxis in individuals at greatest risk for developing active disease after being infected
what is the typical adult dose of INH
300 mg/once/d
- should be adjusted in serious infection (single 900 mg twice/w) in combination with a second agent (600 mg rifampin)
- dose modified in malabsorption of use of drug combinations
what is the recommended dose of Pyridoxine for those at risk of developing neuropathy (eg. slow acetylators)
25-50mg/d
what is the most common major toxic effect occuring with INH
INH-induced clinical hepatitis
risk of INH depends on what
age
who is at the greatest risk of developing INH-induced clinical hepatitis
alcoholics and possibly during pregnancy and the post-partum period
peripheral neuropathy caused by INH is seen in what % of patients
10-20% pts given dosages > 5 mg/kg/d
infrequent with standard 300 mg/d adult dose
INH neuropathy is due to what
a relative pyridoxine deficiency
INH neuropathy is more likley to occur in
-slow acetylators and patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS and uremia
INH promotes the excretion of
pyridoxine
-this is revered by administration of pyridoxine 10 mg/d
what are the side effects of pyridoxine adminsitration of 10mg/d
-CNS side effects include memory loss, psychosis and seizures, allergic rxns
Rifampin is a semisynthetic analog of what
the antibiotic rifamycin, present cross-resistance to other rifamycin derived drugs
eg. rifabutin, but not to other classes of antibiotics
rifampin is effective against what
- various bacteria, including bactericidal against M
- binds to the beta subunit of bacterial DNA dependent RNA polymerase, inhibiting RNA synthesis
resistance to Rifampin results from
one of several point mutations in rpoB, the gene for the beta subunit of RNA polymerase, resulting in reduced rifampin binding to RNA polymerase
does human RNA polymerase bind to Rifampin
no! Nor is human RNA polymerase inhibited by in
describe the pharmacokinetics of Rifampin
-well absorbed after oral administration, which decreases when taken with meals or PAS acid
how is Rifampin excreted
-into bile, undergoes enterohepatic recirculation and eliminated mostly in feces as a deacylated metabolite
what dose of Rifampin should be administered to patients with active TB
600 mg/d + INH or other anti-TB drugs to prevent emergence of drug resistant mycobacteria
Rifampin penetrates mostly
tissues and fluids, including phagocytic cells
-therapeutic CSF levels reached only in the presence of meningeal inflammation
in combination with other drugs, rifampin 600 mg/d or twice/w 6 months is effective in treating
some atypical M. infections and leprosy
Rifampin is a single drug alternative to
INH prophylactic treatment in patients with latent TB unable to take INH or when exposed to a case of active TB caused by INH-resistant, rifampin-susceptible M. strain
what color does Rifampin give to urine, feces, saliva, sweat, tears and contact lenses
-a harmless red orange color, producing patients anxiety
what are the side effects of Rifampin
light-chain proteinuria and occassionally rash, nephritis, jaundice, and hepatitis
intermittent adminstration (>2w) of Rifampin causes
flu-like syndrome
eg. fever, myalgias, thrombocytopenia
what does Rifampin strongly induce
most cytochrome P450 isoforms increasing the elimination rate, this lowering serum levels or numerous drugs
eg. methadone, oral anticoagulants, some anticonvulsants
what is the antimicrobial activity of ethambutol
bacteriostatic agent
MOA of ethambutol
inhibits mycobacterial arabinosyl transferases enzymes, encoded by the embCAB operon, which are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell
ethambutol resistance is due to what
mutations resulting in over expression of emb gene products or within the embB structural gene
what are the pharmacokinetic properties of ethambutol
- well absorbed from GI, peak plasma levels reached within 2 hr, excreted in feces and urine
- it accumulates in renal; can cause renal failure
- reaches CSF only if menigeal inflammation
when does rapid resistance to ethambutol occur
if used alone
Ethambutol should be combined with
INH or rifampin
ethambutol is effective against
M. TB strains
sensitivity of other M. variable
what is the most common serious side effect of Ethambutol
- is dose-related retrobulbar neuritis resulting in loss of visual acuity and red-green color blindness
- it disappears after drug discontinuation
what are contraindications of Ethambutol
-in children too young to permit assessment of visual acuity and red-green color discrimination
Ethambutol is a synthetic analog of
nicotinamde
-converted to pyrazinoic acid (active form of the drug) by mycobacterial pyrazinamidase which is encoded by pncA
resistance of Ethambutol occurs due to
mutation in pncA, blocking drug conversion to its active form, or by decreasing drug uptake which develops rapidly
what are the pharmacokineics of Ethambutol
- well absorbed from GI, widely distributed including inflamed meninges and macrophages
- peak serum levels reached within 1-2 hrs and t1/2 ~ 10 hrs
what are the major adverse effects of Ethambutol
- effects include hepatotoxicity
- GI disturbance and hyperuricemia (common)
*this is not a reason to stop therapy unless patients suffers acute gout attack
Ethambutol is used together with
INH and rifampin in short course regimes (6 months) as a “sterilizing” agent to prevent relapse
TB bacilli rapidly develops resistance to
pyrazinamide
Streptomycin is an effective treatment of
M. tuberculosis, M. avium complex and M. kansaii, other M. species are resistant to this drug
function of streptomycin
inhibits most tubercle bacilli
what are the pharmacokinetic properties of streptomycin
- poor penetration into cells and is effective mainly against extracelllular tubercle bacilli
- used when injectable (IV or IM) therapy is recommended
eg. meningitis (crosses the BBB achieving therapeutic levels with inflamed meninges) and disseminated infection, or when TB is resistant to other drugs
resistance to streptomycin is due to
- a point mutation in the rpsL gene, encoding the S12 ribosomal protein gene
- or the rrs gene encoding the 16S ribosomeal rRNA, this altering the ribosomal binding site
what are the side effects of Streptomycin
dose-related
oto- and nephrotoxicity
what are the common SE of Streptomycin
- vertigo and hearing loss, may become permanent
- risk increasing in the elderly and in patients with impaired renal functions
what regime must be given with Streptomycin
- a multidrug regime to prevent emergency of resistance
- treatment continue for several months and dosage should be adjusted during the course of therapy
M. Tuberculosis: Second line drugs are considered only if
- resistance occurs to first-line drugs
- failure of recommended conventional therapy
- adverse effects limiting conventional therapy
- ability to deal with these drugs toxicity
function of ethionamide
inhibits mycolic acid synthesis
what are the SE of Ethionamide
GI irriation, neurophaties and liver toxicity
function of Capreomycin
- protein synthesis inhibitor
- give IM for the treatment of drug-resistant TB
what are the SE of Capreomycin
oto-and nephrotoxic
function of cycloserine
inhibits cell wall synthesis
what are the side effects of Cycloserine
peripheral neuropathies and CNS depression and psychotic rxn
what is aminosalicyclic acid (PAS)
folate synthesis antagonist
what are the side effects of PAS
GI irritation and hypersensitivity rxn
what drugs are used in combination in multidrug resistance M. tuberculosis
Kanamycin, amikacin, Fluoroquinolones (ciprofloxacin, levofloxacin), Linezolid (see slide 32)
most mycobacterial infections are due to
“atypical” mycobacteria: M. kansaii, M. marinum, M. avium compex etc
are atypical mycobacteria communicable from person to person
NO
M. species are less responsive to M. tuberculosis to
anti-TB drugs (isoniazid, ethambutol, rifampin); however, they may respond to antibiotics not active against M. tuberculosis
eg. erythromycin, ciprofloxacin, various cephalosporins
active infection of TB should be treated with
a multidrug regime to achieve optimal results in the shortest period of time, while minimizing the development of resistance
late stages of AIDS are commonly associated with
disseminated M. avium complex infections, which includes the presence of M. avium and M. intracellulare
what are the recommended treatments of late stages of AIDS
clarithromycin plus ethambutol and rifabutin
leprosy is caused by
M. leprae
Leprosy is characterized by
cutaneous lesions causing disfiguration and peripheral nerve damage
what is used to treat Leprosy
Dapsone (and other sulfone-like agents) are closely related to sulfonamides and they competitively inhibit folate synthesis
what are the pharmacokinetic properties of Dapsone
- well absorbed from the GI
- widely distributed in the body t1/2 of 1-2d, eliminated in the urine (use with dose adjustment in kidney failure)
Dapsone becomes significantly concentrated in the — of patients with M leprae skin infections
skin
what are the side effects of Dapsone
- hemolysis, particularly in G-6-PD deficiency pts
- erythema nodosum leprosum responds to corticosteroids
- FDA approved thalidomide for the treatment of this condition
- may cause irreversible neuropathy
to avoid resistance to Dapsone, treatment should be combined with
rifampin and clofazimine
what is an alternative to dapsone
Clofazimine
what are the pharmacokinetic properties of Clofazimine
-has a erractic absorption rate
-stored in skin and reticuloendothelial tissues from were it is slowly released
t1/2~2 months
when is Clofazimine used
in sulfone-resistant leprosy or for sulfone intolerant pts
what are the side effects of Clofazimine
skin discolouration from red brown to nearly black
see slide 39
see slide 39
