Rifapentine Uses in comparison to RIFAMPIN

_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_

16/17 - TB AntiMycobacterials Flashcards by Karlo Sison

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

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

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HIV & TB
Co-Infection

Symptoms & Treatment

*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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Treatment of
M.Avium Complex

Non-Tuberculous Mycobacteria = NTM

REM-A

Rifamycin

Ethambutol

Macrolide

AMINOGLYCOSIDE

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*Nitroaromatics = Nitroimidazoles**
*Pretomanid & Delamanid**

Uses for TB / Toxicities

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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*Rifapentine Uses**
in comparison to RIFAMPIN*

*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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Pyrazinamide Resistance

significant HEPATOTOXICITY
↑ALT / ↑AST

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

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

PYRAZINAMIDE

YES

pncA
pyrazinamidase
VVV
pyrazinoic acid = active agent

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Which TB Drug based on Target?

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

ETHAMBUTOL

OPTIC NEURITIS
visual acuity –> red-green differentiation

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TB TREATMENT
for
Intensive Phase

2 MONTHS DAILY
Kills 99% of bacteria

ISONIAZID = INH

RIFAMPIN

PYRAZINAMIDE

Ethambutol
not used if other 3 are sufficient

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Treatment & Duration for:

HIV & TB Co-infection

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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Oxazolidinones

Uses for TB / Concerns

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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Fluoroquinolones

Uses for TB / Concerns

Moxifloxacin
Gatifloxacin + Levofloxicin

Used for:
DRUG-RESISTANT TB

Inhibit - DNA Gyrase

Resistance:
Mutations in gyrA subunit

AORTIC RUPTURES

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

ISONIAZID

YES

*katG**
*catalase peroxidase**

also:
Ethionamide = monooxygenase etA

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DiarylQuinoline = Bedaquiline

Uses for TB

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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Ethambutol Resistance

OPTIC NEURITIS

very low resistance

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

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Treatment & Duration for:

Single-drug resistant ACTIVE TB

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replace resistant drug with:
FLUOROQUINOLONE
Moxi-Levo-Gati

If RIFAMPIN-Resistant –> extend to 12 months

Isoniazid Resistance

PERIPHERAL NEURITIS –> GIVE B6

HEPATOTOXICITY

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65% in

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

20% in

*inhA** = final target
*mutations in NADH binding site**

Diagnosis of TB

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Definitive Diagnosis:
CULTURE

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

CXR

AFB = Acid Fast Bacilli in Sputum

*Non-Tuberculous Mycobacteria = NTM**
*Pulmonary Infection**

TREATMENT

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“REM” for 12 months of culture-negative sputum

RIFAMPIN

ETHAMBUTOL

MACROLIDE
clarithroycin or azithromycin

may consider:*
*moxifloxacin**
*amikacin - streptomycin**
*linezolid - clofazimine - trimethoprim**

Impact of NEW TB DRUGS

3 Things

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↓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

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

ETHAMBUTOL

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NOPE

inhibits arabinosyl transferase –> affects cell wall

TB TREATMENT
for
Continuation Phase

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

ISONIAZID = INH

RIFAMPIN

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

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*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

Treatment & Duration for:

*EXTRAPULMONARY TB**
*&**
*TB Meningitis**

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Std Regimen + Continuation Phase = 4 - 7 months

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

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

**Which TB Drug based on Target?** binds to: **beta-subunit** **_rpoB_** of **RNA polymerase** changes conformation -\> *prevents binding of nucleotides & inhibits initiation of transcription*

**_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*

**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*

* *_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_**

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

***_NOPE_*** Just binds to **rpoB** of **RNA poymerase**

* *Rifabutin Uses** * in comparison to RIFAMPIN*

* **_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**

**_Third Line TB Agents_** approved for other disease but have no formal trials to assess efficacy in MDR/XDR TB

* *"I-C-C-T**" * order of decreasing evidence* ## Footnote **_IMIPENEM_** **_Clofazimine_** **_Clarithromycin_** ***_Thioridazine_***

**Rifamycin Resistance** HEPATITIS + RED URINE P450 INDUCER

**Single AA substitutions in hotspot in: _rpoB_** RNA polymerase subunit

**Treatment & Duration for:** **Latent TB Infection = LTBI**

**_INH ALONE_** - **9 months** or **RMP alone** - **4 months** or **INH + RifaPENTINE - 3 months** rifapentine = WEEKLY dosage

**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

**_PYRAZINAMIDE_** **Significant _HEPATOTOXICITY_** ↑**ALT ↑AST** *MOA IS UNCERTAIN* TB-SPECIFIC DRUG: **TB has *_deficient efflux_*** **compared to some naturally resistant mycobacteria**

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

**_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

16/17 - TB AntiMycobacterials Flashcards

(33 cards)