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Flashcards in Antimycobacterial Drugs Deck (108):
1

antimycobacterial drugs are used for the treatment of

1. tuberculosis
2. atypical mycobacteria infections
3. leprosy

2

what First line drugs are used to treat tuberculosis

-Isoniazid, Pyrazinamide, Rifampin, Ethambutol, streptomycin

3

what Second-line Drugs are used to treat tuberculosis

p-Aminosalicylic acid

4

what drugs are used to treat atypical Mycobacteria infections

-Isoniazid, Ethambutol, Rifampin, Erythromycin, Ciprofloxacin, various Cephalosporins

5

late stages of AIDS are associated with what

disseminated M avium complex infection (includes the presence of M. avium and M. intracellular),

6

what drugs are used to treat disseminated M avium complex infections

-clarithromycin plus ethambutol and rifabutin

7

what drugs are used to treat m. leprae

Dapsone, Clofazimine

8

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

9

what is the treatment period for M. infections

treatment for periods of drug therapy longer than that of other infectious diseases

10

all M. Tuberculosisis initial isolates should be tested for what

susceptibility to drugs

11

should drugs be used in combination to treat Tuberculosis

-yes, use combined drug therapy with at least 2 drugs to which organism is susceptible

12

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

13

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

14

what is the prevalence of INH resistant TB

~10%

15

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

16

what are the first line drugs

Based of Efficacy
-isoniazid (INH; generic)
-rifampin (rifadin)
-pyrazinamide (generic)
-ethambuto (myambutol)
-streptomycin (generic)

17

when are the second line drugs used

only if there are resistant organisms to first line drugs or other overriding considerations

18

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

19

Isoniazid (INH) is a hydrazide of what

isonicotinic acid

20

Isoniazid acts only upon

Mycobacteria

21

what is the most active drug available for the treatment of TB casued by M. susceptible strains

Isoniazid

22

Isoniazid is less effective for the treatment of diseases caused by

atypical M. species

23

isoniazid are small molecules, structurally similar to

pyridoxine

24

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

25

resistance to INH has been associated with various mutations, what are they

1. over-expression of inhA gene encoding an NADH-dependent acyl carrier protein reductase
2. mutation or deltion of the katG gene
3. promoter mutations resulting in over-expression of ahpC, a putative virulence gene involved in cell protection from oxidative stress
4. Mutations in kasA

26

inhA overproducers express --- level resistance to INH and cross resistance to ---

low
ethionamide

27

KatG mutants express --- level INH resistance and often are not cross-resistant to ----

high
ethionamide

28

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

29

what converts N-Acetylated to N-acetylisoniazid

liver N-acetyltransferase

30

how are N-acetylizoniazid + isonicotinic acid + little unchanged drugs eliminated

in the urine

31

Acetylisoniazid/isonizaid ratio is genetically determined by what

INH acetylation rate

32

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

33

are there therapetuic consequence of INH when using appropriate daily dosing

no, weekly NIH dosing (rapid acetylators) or malabsorption may result in subtherapetutic levels

34

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

35

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

36

what is the recommended dose of Pyridoxine for those at risk of developing neuropathy (eg. slow acetylators)

25-50mg/d

37

what is the most common major toxic effect occuring with INH

INH-induced clinical hepatitis

38

risk of INH depends on what

age

39

who is at the greatest risk of developing INH-induced clinical hepatitis

alcoholics and possibly during pregnancy and the post-partum period

40

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

41

INH neuropathy is due to what

a relative pyridoxine deficiency

42

INH neuropathy is more likley to occur in

-slow acetylators and patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS and uremia

43

INH promotes the excretion of

pyridoxine
-this is revered by administration of pyridoxine 10 mg/d

44

what are the side effects of pyridoxine adminsitration of 10mg/d

-CNS side effects include memory loss, psychosis and seizures, allergic rxns

45

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

46

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

47

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

48

does human RNA polymerase bind to Rifampin

no! Nor is human RNA polymerase inhibited by in

49

describe the pharmacokinetics of Rifampin

-well absorbed after oral administration, which decreases when taken with meals or PAS acid

50

how is Rifampin excreted

-into bile, undergoes enterohepatic recirculation and eliminated mostly in feces as a deacylated metabolite

51

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

52

Rifampin penetrates mostly

tissues and fluids, including phagocytic cells
-therapeutic CSF levels reached only in the presence of meningeal inflammation

53

in combination with other drugs, rifampin 600 mg/d or twice/w 6 months is effective in treating

some atypical M. infections and leprosy

54

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

55

what color does Rifampin give to urine, feces, saliva, sweat, tears and contact lenses

-a harmless red orange color, producing patients anxiety

56

what are the side effects of Rifampin

light-chain proteinuria and occassionally rash, nephritis, jaundice, and hepatitis

57

intermittent adminstration (>2w) of Rifampin causes

flu-like syndrome
eg. fever, myalgias, thrombocytopenia

58

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

59

what is the antimicrobial activity of ethambutol

bacteriostatic agent

60

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

61

ethambutol resistance is due to what

mutations resulting in over expression of emb gene products or within the embB structural gene

62

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

63

when does rapid resistance to ethambutol occur

if used alone

64

Ethambutol should be combined with

INH or rifampin

65

ethambutol is effective against

M. TB strains
sensitivity of other M. variable

66

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

67

what are contraindications of Ethambutol

-in children too young to permit assessment of visual acuity and red-green color discrimination

68

Ethambutol is a synthetic analog of

nicotinamde
-converted to pyrazinoic acid (active form of the drug) by mycobacterial pyrazinamidase which is encoded by pncA

69

resistance of Ethambutol occurs due to

mutation in pncA, blocking drug conversion to its active form, or by decreasing drug uptake which develops rapidly

70

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

71

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

72

Ethambutol is used together with

INH and rifampin in short course regimes (6 months) as a "sterilizing" agent to prevent relapse

73

TB bacilli rapidly develops resistance to

pyrazinamide

74

Streptomycin is an effective treatment of

M. tuberculosis, M. avium complex and M. kansaii, other M. species are resistant to this drug

75

function of streptomycin

inhibits most tubercle bacilli

76

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

77

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

78

what are the side effects of Streptomycin

dose-related
oto- and nephrotoxicity

79

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

80

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

81

M. Tuberculosis: Second line drugs are considered only if

1. resistance occurs to first-line drugs
2. failure of recommended conventional therapy
3. adverse effects limiting conventional therapy
4. ability to deal with these drugs toxicity

82

function of ethionamide

inhibits mycolic acid synthesis

83

what are the SE of Ethionamide

GI irriation, neurophaties and liver toxicity

84

function of Capreomycin

-protein synthesis inhibitor
-give IM for the treatment of drug-resistant TB

85

what are the SE of Capreomycin

oto-and nephrotoxic

86

function of cycloserine

inhibits cell wall synthesis

87

what are the side effects of Cycloserine

peripheral neuropathies and CNS depression and psychotic rxn

88

what is aminosalicyclic acid (PAS)

folate synthesis antagonist

89

what are the side effects of PAS

GI irritation and hypersensitivity rxn

90

what drugs are used in combination in multidrug resistance M. tuberculosis

Kanamycin, amikacin, Fluoroquinolones (ciprofloxacin, levofloxacin), Linezolid (see slide 32)

91

most mycobacterial infections are due to

"atypical" mycobacteria: M. kansaii, M. marinum, M. avium compex etc

92

are atypical mycobacteria communicable from person to person

NO

93

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

94

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

95

late stages of AIDS are commonly associated with

disseminated M. avium complex infections, which includes the presence of M. avium and M. intracellulare

96

what are the recommended treatments of late stages of AIDS

clarithromycin plus ethambutol and rifabutin

97

leprosy is caused by

M. leprae

98

Leprosy is characterized by

cutaneous lesions causing disfiguration and peripheral nerve damage

99

what is used to treat Leprosy

Dapsone (and other sulfone-like agents) are closely related to sulfonamides and they competitively inhibit folate synthesis

100

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)

101

Dapsone becomes significantly concentrated in the --- of patients with M leprae skin infections

skin

102

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

103

to avoid resistance to Dapsone, treatment should be combined with

rifampin and clofazimine

104

what is an alternative to dapsone

Clofazimine

105

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

106

when is Clofazimine used

in sulfone-resistant leprosy or for sulfone intolerant pts

107

what are the side effects of Clofazimine

skin discolouration from red brown to nearly black

108

see slide 39

see slide 39