Anti-Mycobacterial Agents Flashcards
Mycobacterium tuberculosis-Mtb causes
TB
Mycobacterium leprae causes
leprosy
Slow-growing, slender, rod- shaped aerobic bacteria with a unique lipid-rich (waxy, acid-fast)) cell wall. May remain dormant in the host for long periods.
Mycobacterium tuberculosis
Mycobacterium tuberculosis is transmitted by
inhalation of airborne droplets that can remain aloft for minutes to hours
Why are antimicrobials for TB treatment combined?
To decrease emergence of resistant strains.
TB bacteria can become active if
immune system
doesn’t prevent growth
Latent TB infection
Exposure to bacteria, but bacteria become inactive
Latent TB symptoms
no symptoms or physical findings suggestive of TB
In LTBI, respiratory smear and culture are
negative
Symptoms of pulmonary TB disease
fever,cough, nightsweats,weight loss,fatigue,hemoptysis,
decreasedappetite
Pulmonary TB disease respiratory specimens and culture are
positive
5 Principles of Active TB Treatment
- Multiple drugs MUST be used.
- Drug sensitivity testing is mandatory.
- Single daily dosing of drugs is preferred.
- Prolonged therapy is necessary (generally >6 months).
- Monitoring for patient compliance and toxicity is
required (DOT, Directly observed therapy or VOT, Video
Observed Treatmen
First line agents for TB
Rifamycins: Rifampin (RIF), Rifabutin, Rifapentine
Isoniazid (INH)
Pyrazinamide (PZA) Ethambutol (EMB)
Second line agents for TB
Streptomycin Amikacin Quinolones (Moxifloxacin) Cycloserine P-Aminosalicyclic Acid Ethionamide
Second line drugs used for TB treatment considered if
a) Resistance to first-line agents
b) Clinical failure of first-line therapy
c) Serious adverse drug reactions that limit treatment
Initiation phase treatment of TB
isoniazid, rifampin, pyrazinamide and ethambutol
(the 4 first –line agents) administered for 2 months.
Continuation phase treatment of TB
At two months, treatment with isoniazid and rifampin
are continued for 4 months - or 7 months w/ the
following:
• cavitation on chest X-ray
• positive acid fast bacillus smear
• positive culture
What inhibits synthesis of mycolic acids
Isoniazid (INH)
What is a pro-drug activated inside the mycobacterium
Isoniazid (INH)
Isoniazid (INH) resistance
Mutations in katG or inhA promoter region (increased expression)
Isoniazid is metabolized in
liver by acetylation
Isoniazid ADME
-Oral absorption
-Aluminum containing antacids can interfere with absorption
(take on empty stomach, 2 hours from taking antacids)
- penetrates CSF
Isoniazid is hepatotoxic so monitor
for signs of hepatic dysfunction/ hepatitis (LFTs)
inhibits mycobacterial cell wall synthesis but primarily enhances activity of lipophilic drugs
Ethambutol (Myambutol®
Ethambutol (Myambutol® ADME
-Oral absorption
-Aluminum containing antacids can
interfere with absorption
-Hepatic metabolism
most important toxicity associated with use of Ethambutol
Optic neuritis
- The pro-drug enters M. tuberculosis by passive diffusion
- Converted to pyrazinoic acid (POA) by nicotinamidase/pyrazinamidase (PZase).
- Disrupts intracellular pH and membrane transport (may effect metabolism- energy production…exact MOA unresolved)
Pyrazinamid
Pyrazinamid ADME
- Well absorbed
- Wide tissue distribution, CSF
- Hepatic metabolism
Pyrazinamid ADE
-Liver injury (15%) with jaundice (2-3%),
rarely fatal
-Do not use with decreased liver function
-Monitoring: LFTs
Binds to the β-subunit of bacterial DNA-dependent RNA polymerase. Inhibits RNA synthesis
Rifamycins (Rifampin, Rifabutin, Rifapentine)
Use Rifabutin instead of Rifampin in
HIV patients on ART therapy (to avoid drug interactions)
causes orange staining of host secretions
Rifampin
Rifampin ADME
- Oral administration (food/antacids decrease absorption)
- Distributes to all body fluids and organs, including CNS
- Induces hepatic mixed-function oxidases increasing its own metabolism as well as other drugs. (i.e. oral contraceptives)
- Eliminated via feces and urine
TB that is resistant to
at least two of the best anti-TB drugs, isoniazid and
rifampicin
Multidrug-resistant TB (MDR TB)
relatively
rare type of MDR TB. XDR TB is defined as TB that is
resistant to isoniazid and rifampin, plus resistant to any
fluoroquinolone and at least one of three injectable
second-line drugs (i.e., amikacin, kanamycin, or
capreomycin)
Extensively drug-resistant TB (XDR TB)
Inhibits proton pump for mycobacterial ATP
synthase
Bedaquiline (Sirturo®)
approved for combination use against XDR TB
Pretomanid
