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PDAT6 ID > 16/17 - TB AntiMycobacterials > Flashcards

16/17 - TB AntiMycobacterials Flashcards

1
Q

2nd Line TB Agents
for
Drug-Resistant TB
or
Problems of Tolerance to 1st line agents

A
  • *FLUOROQUINOLONES**
  • *Levo-Moxi-Gati**
  • *OXAZOLIDINONES**
  • *Linezolid**
  • *Diarylquinoline**
  • *BEDAQUILINE**
  • Nitroaromatics = Nitroimidazoles*
  • *Pretomanid & Delamanid**
  • still in trials for LATENT TB*
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2
Q

HIV & TB
Co-Infection

Symptoms & Treatment

A
  • *IRIS**
  • *Immune Reconsititution Inflammatory Syndrome**
  • *Mild –> IBUPROFEN**
  • *SEVERE –> CORTICOSTEROID**

high fevers

  • worsening respiratory symptoms
  • Inflamed lymph nodes
  • new lymphadenopathy
  • expanding CNS lesions,
  • worsening of pulmonary parenchymal infiltrations
  • new/increasing pleural effusions,
  • intra-abdominal or retroperitoneal abscesses
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3
Q

Treatment of
M.Avium Complex

Non-Tuberculous Mycobacteria = NTM

A

REM-A

Rifamycin

Ethambutol

Macrolide

AMINOGLYCOSIDE

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4
Q
  • *Nitroaromatics = Nitroimidazoles**
  • *Pretomanid & Delamanid**

Uses for TB / Toxicities

A

Bacterial PRODRUG
require activation by M. TB

Active vs BOTH:
NON-REPLICATING TB=LATENT TB

likely due to :
multiple molecular targets due to liberation of NA

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5
Q
  • *Rifapentine Uses**
  • in comparison to RIFAMPIN*
A
  • *LONGER HALF LIFE**
  • *intermittent dosing** –> 2x a week for initial phase

ONCE A WEEK in Continuation phase

not active against Rifampin-resistant strains of M. TB

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6
Q

Pyrazinamide Resistance

significant HEPATOTOXICITY
↑ALT / ↑AST

A

Resistance via:
pncA mutations
pyrazinamidase used to activate –> pyrazinoic acid

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7
Q

Is this drug a Bacterial Activated PRODRUG?
What activates it?

PYRAZINAMIDE

A

YES

pncA
pyrazinamidase
VVV
pyrazinoic acid = active agent

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8
Q

Which TB Drug based on Target?

inhibits:
ARABINOSYL TRANSFERASE
affecting the synthesis of:
arabinogalactan & lipoarabinomannan in cell wall

A

ETHAMBUTOL

OPTIC NEURITIS
visual acuity –> red-green differentiation

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9
Q

TB TREATMENT
for
Intensive Phase

A

2 MONTHS DAILY
Kills 99% of bacteria

ISONIAZID = INH

RIFAMPIN

PYRAZINAMIDE

Ethambutol
not used if other 3 are sufficient

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10
Q

​Treatment & Duration for:

HIV & TB Co-infection

A

If Recieving ART –> standard Regimen
CD4 < 50 = start within weeks
CDC > 50 = start within 8-12 weeks

  • If NOT recieving ART*
  • *extend continuation phase for +3 months (7 months)**

RIFABUTIN
may be substituted for rifampin –> reduce CYP450 induction
may need dosage adjustment with some PI’s & NNRTI

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11
Q

Oxazolidinones

Uses for TB / Concerns

A

LINEZOLID
targets the ribosome

Active against MDR & XDR-TB = Resistant TB
but…
BONE MARROW TOXICITY
need for long treatment

myelosuppression / various neuropathies

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12
Q

Fluoroquinolones

Uses for TB / Concerns

A

Moxifloxacin
Gatifloxacin + Levofloxicin

Used for:
DRUG-RESISTANT TB

Inhibit - DNA Gyrase

Resistance:
Mutations in gyrA subunit

AORTIC RUPTURES

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13
Q
  • *Is this drug a Bacterial Activated PRODRUG?**
  • *What activates it?**

ISONIAZID

A

YES

  • *katG**
  • *catalase peroxidase**

also:
Ethionamide = monooxygenase etA

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14
Q

DiarylQuinoline = Bedaquiline

Uses for TB

A

Targets: ATP-SYNTHASE
5 month half life –> single dose

highly potent vs:
NON-REPLICATING M.TB = LATENT TB

FDA approved for MDR-TB when no other options available

Adr:
Prolonged QT Interval + Hepatotoxicities

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15
Q

Ethambutol Resistance

OPTIC NEURITIS

A

very low resistance

OVERexpression of:
embA**+**embB**+**embC

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16
Q

​Treatment & Duration for:

Single-drug resistant ACTIVE TB

A

replace resistant drug with:
FLUOROQUINOLONE
Moxi-Levo-Gati

If RIFAMPIN-Resistant –> extend to 12 months

17
Q

Isoniazid Resistance

PERIPHERAL NEURITIS –> GIVE B6

HEPATOTOXICITY

A

65% in

  • *katG** = activating enzyme
  • *Missense** or Large deletions in catalase peroxidase

20% in

  • *inhA** = final target
  • *mutations in NADH binding site**
18
Q

Diagnosis of TB

A

Definitive Diagnosis:
CULTURE

S/Sx:
Weight Loss / Night Sweats / Cough
HEMOPTYSIS-blood in sputum

CXR

AFB = Acid Fast Bacilli in Sputum

19
Q
  • *Non-Tuberculous Mycobacteria = NTM**
  • *Pulmonary Infection**

TREATMENT

A

“REM” for 12 months of culture-negative sputum

RIFAMPIN

ETHAMBUTOL

MACROLIDE
clarithroycin or azithromycin

  • may consider:*
  • *moxifloxacin**
  • *amikacin - streptomycin**
  • *linezolid - clofazimine - trimethoprim**
20
Q

Impact of NEW TB DRUGS

3 Things

A

↓Treatment Duration
↑Compliance –> ↓drug resistance
↓labor in DOTS
↓cost of treatment

  • *Successful Treatment of MDR/XDR-TB**
  • *↓**transmission of MDR-TB
  • *Cure LATENT TB Infection**
  • *↓**disease reservoir
21
Q

Is this drug a Bacterial Activated PRODRUG?
What activates it?

ETHAMBUTOL

A

NOPE

inhibits arabinosyl transferase –> affects cell wall

22
Q

TB TREATMENT
for
Continuation Phase

A

4 MONTHS DAILY
kills the small% of PERSISTANT bacteria, can come back

ISONIAZID = INH

RIFAMPIN

23
Q

How does M. tb become drug-resistant
(and become progressively more so…)?

A
  • *SPONTANEOUS MUTATIONS**
  • since only confound to lungs, doesnt have a TRANSFER of RESISTANCE*

Target of Drug / Amount of Target

TB Enzymes that activate drug

↑Efflux Pump Activity

↑Cell Wall Permeability

↑Mutation Rates –> DNA REPAIR

24
Q

​Treatment & Duration for:

  • *EXTRAPULMONARY TB**
  • *&**
  • *TB Meningitis**
A

Std Regimen + Continuation Phase = 4 - 7 months

TB Meningitis:
Std Regimen + Continuation Phase = >10months

Dexamethasone** or **Prednisolone
tapered over 6-8 weeks –> ↓mortality

25
Q

Which TB Drug based on Target?

binds to:
beta-subunit rpoB of RNA polymerase
changes conformation -> prevents binding of nucleotides & inhibits initiation of transcription

A

RIFAMYCINS

HEPATITIS + RED URINE
INDUCTION OF CYP450 ENZYMES –> ↓Half-Life of:
steroids / anticoagulants / macrolides / imidazoles
Protease inhibitors / NNRTIs

Rifampin

  • *Rifabutin**
  • less p450 activation –> recommended for HIV/TB co-infection*
  • *Rifapentine**
  • LONG HALF LIFE –> can be dosed WEEKLY in continuation phase*
26
Q

Which TB Drug based on Target?

INHIBIT:
Mycolic Acid Synthesis - C60-90 alpha alkyl
&
target inhA = long chain NAD-dependent enoyl-ACP reductase
INH covalently attaches to nicotinamide ring of NADH@ side of hydride exhange

A
  • *ISONIAZID** = INH
  • *ETHIONAMIDE = ETH**

Hepatotoxicity** & **PERIPHERAL NEURITIS –> give B6

Both are:
Bacterial-Activated Prodrugs

Isoniazid is activated by Catalase Peroxidase = katG

Ethionamide is activated by Monooxygenase = etA

27
Q

Is this drug a Bacterial Activated PRODRUG?
What activates it?

RIFAMPIN

A

NOPE

Just binds to rpoB of RNA poymerase

28
Q
  • *Rifabutin Uses**
  • in comparison to RIFAMPIN*
A
  • LESS ACTIVATION OF P450*
  • rifampin –> strong p450 INDUCER*

Rifamycin of choice for:
HIV/TB Co-infection when using protease inhibitors

Active vs some:
Rifampin-resistant strains of M. TB

use for:
M.AVIUM - intracellulare infection

29
Q

Third Line TB Agents
approved for other disease but have no formal trials to assess efficacy in MDR/XDR TB

A
  • *“I-C-C-T**”
  • order of decreasing evidence*

IMIPENEM

Clofazimine

Clarithromycin

Thioridazine

30
Q

Rifamycin Resistance

HEPATITIS + RED URINE

P450 INDUCER

A

Single AA substitutions in hotspot in:
rpoB
RNA polymerase subunit

31
Q

Treatment & Duration for:

Latent TB Infection = LTBI

A

INH ALONE - 9 months
or
RMP alone - 4 months
or
INH + RifaPENTINE - 3 months
rifapentine = WEEKLY dosage

32
Q

Which TB Drug based on Target?

only active in vitro at low pH <6

Requires:
Pyrazinamide** = **pncA
to generate the active agent = pyrazinoic acid

Sterilizing Activity
treatment 9mo –> 6mo

A

PYRAZINAMIDE

Significant HEPATOTOXICITY
↑ALT ↑AST

MOA IS UNCERTAIN

TB-SPECIFIC DRUG:
TB has deficient efflux compared to some naturally resistant mycobacteria

33
Q

Strategies to Prevent Development of Drug Resistance in TB treatment
DOTS
Directly Observed Therapy Short-course

A

Fixed Dose Combinations:
INH + RIF + PZA
(+/- EMB)
1 drug regimen –> resistance
multiplicative resistance patterns, 2 drugs = less resistance chance

Drug Susceptibility Testing

NEVER ADD 1 DRUG TO A FAILING REGIMEN
fact that they’re failing –> ALREADY RESISTANT

PDAT6 ID (31 decks)

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