Antimycobacterials Questions Flashcards
What is tuberculosis caused by?
Mycobacterium tuberculosis
-formidable infection
How do mycobacteria replicate compared to “typical bacteria”?
Replicate more slowly
- pharmacotherapy more difficult
- rapidly dividing cells are most metabolically active and therefore susceptible to antibiotic therapy
What state can mycobacteria exist in?
Dormant state
-makes them resistant to nearly all antibiotics
Where do mycobacteria live in the host?
Inside human cells
-antimicrobials that have poor intracellular penetration are ineffective
What does the outermost layer of mycobacteria consist of?
Phospholipids and mycolic acids
- make a waxy layer
- resists penetration from antibiotics
What are components of the mycobacterial cell wall?
Arabinogalactan and peptidoglycan
- are polysaccharide components of the cell wall
- peptidoglycan not accessible to beta-lactams: are poorly active
Why are combinations of drugs always given for active mycobacterial disease?
- minimize the development of resistance
- shorten the duration of therapy
What is one common characteristic of mycobacterial drugs?
Pharmacokinetic drug interactions
-many immunocompromised patients are very susceptible to mycobacterial disease and are usually on drugs with many interactions
How long does standard susceptibility testing take for mycobacteria?
Takes weeks instead of days
- mycobacteria grow slowly
- empiric regimens often given for extended durations
What is the standard of care for active tuberculosis?
Four drug regimen
- compliance important
- careful monitoring for drug interactions
Which antibacterials also have antimycobacterial properties?
- fluoroquinolones (moxifloxacin is particularly active)
- macrolides
- AMG
Name the rifamycins.
- Rifampin (known as rifampicin in Europe)
- Rifabutin
- rifapentine
- rifaximin
Which rifamycin is not used for mycobacterial disease?
Rifaximin
What diseases are rifamycins the cornerstones of therapy for?
- tuberculosis
- Mycobacterium avium-intracellulare complex (MAC)
What are rifamycins?
Protein synthesis inhibitors
-inhibit transcription of DNA to bacterial mRNA
How do rifamycins affect the cytochrome P450 system?
Are potent inducers
-patients receiving them should always be screened for drug interactions
Besides mycobacteria, what are rifamycins also active against?
Active against many “typical” bacteria
-sometimes added to other therapies (particularly to treat difficult MRSA infections)
What is the MOA of rifamycins?
Protein synthesis inhibitors
- inhibit RNA polymerase
- prevent transcription by blocking the production of mRNA
How are rifamycins different from other protein synthesis inhibitors?
Others inhibit translation
What organisms do rifamycins have GOOD activity against?
-most mycobacteria
What organisms do rifamycins have MODERATE activity against?
- Staphylococcus
- Acinetobacter
- Enterobacteriaceae
What organisms do rifamycins have POOR activity against?
- “typical” bacteria as monotherapy
- some very rare mycobacteria
How are rifamycins tolerated?
Generally well-tolerated
What are rifamycins most notorious for?
Potent CYP450-inducing effects
- anticonvulsants (loss of seizure control)
- organ rejection (antirejection agents)
What adverse effect of rifampin do patients appreciate knowing about?
Characteristically colors secretions orange-red
- urine
- tears
- can stain contact lenses (do not wear during rifampin therapy)
- is nonpermanent and not harmful
What are some other adverse effects of rifamycins?
- rash
- nausea
- vomiting
- hypersensitivity (often fever)
- can cause hepatotoxicity
Which rifamycin is preferred for tuberculosis?
Rifampin
Which rifamycin is preferred for MAC? Why?
Rifabutin
- MAC most common in HIV patients
- rifabutin has somewhat less-potent CYP450 inducing effects than rifampin (antiretroviral therapy often metabolized by CYP450)
Which rifamycin has somewhat less potent CYP450-inducing effects than rifampin?
Rifabutin
-still a potent inducer
What are the two most important drugs for tuberculosis?
- rifampin (or rifabutin)
- isoniazid
If an isolate of M. tuberculosis is resistant to rifampin, more complicated regimens must be used for longer durations
Which rifamycins induce CYP450 enzymes?
All of them
- can induce the metabolism of drugs through other hepatic pathways as well
- always screen for drug interactions
What is rifapentine?
A second line rifamycin
- given once weekly
- if an isolate is resistant to other rifamycins, it is resistant to rifapentine as well
When is rifapentine used?
In combination with isoniazid for latent tuberculosis
-given once weekly
What is rifaximin used for?
Treatment or prevention of GI conditions
-is a nonabsorbed rifamycin
Is rifaximin used for mycobacterial diseases?
No
Can rifamycins be used as monotherapy for tuberculosis?
NOT for treatment of active tuberculosis
When can rifampin be used as monotherapy?
To treat latent tuberculosis
What are rifamycins good for?
In combination with other agents for treatment of:
- active tuberculosis
- MAC
Latent tuberculosis
Selected bacterial infections:
-most notably bacterial infections involving prosthetic material (in combination with standard antibacterials): ex: artificial hip or heart valve
What side effect of rifamycins may be a surprise to most patients?
Urine and other secretions may turn orange or red
What type of mycobacteria is isoniazid active against?
Both active growing and dormant
-used in treatment of both active and latent tuberculosis
What mycobacteria is isoniazid active against?
Only:
- M. tuberculosis
- M. kansasii
What is the MOA of isoniazid?
Prevents the synthesis of mycolic acids in the cell wall
-inhibits enzymes that catalyze their production
What adverse effect does isoniazid share with several other antituberculosis medications?
Hepatotoxicity
Describe isoniazid hepatotoxicity.
Early in therapy
- many patients will experience asymptomatic elevations in liver transaminases
- will resolve on their own in most cases and patient can complete therapy
When does isoniazid need to be stopped to prevent severe liver damage?
Enzyme levels are many times the ULN
and/or
Patient experiences symptoms of hepatitis
- nausea
- abdominal pain
- jaundice
What is isoniazid’s characteristic adverse effect?
Peripheral neuropathy
How can isoniazid-induced peripheral neuropathy be prevented?
By administering pyridoxine (vitamin B6)
For which patients is pyridoxine recommended while on isoniazid?
Those at risk for developing neuropathy
- diabetic
- pregnant women
- alcohol abusers
There’s no downside to recommending it to all patients receiving isoniazid
What are other neurotoxicities of isoniazid?
- optic neuritis (less common)
- seizures (rarely)
What possible adverse effect of isoniazid abates with cessation of therapy?
Drug-induced lupus
How does isoniazid hypersensitivity present?
Can be seen most commonly as:
- rash
- drug fever
List the categories of isoniazid toxicities.
- hepatotoxicity
- peripheral neuropathy
- other neurotoxicities
- drug-induced lupus
- hypersensitivity
What is a drug of choice for treatment of latent tuberculosis?
Isoniazid
Which form of tuberculosis as isoniazid be used as monotherapy?
Latent
-burden of organisms is much lower than in active
Can isoniazid be used as monotherapy for active tuberculosis?
NO
-resistance can develop
Which tuberculosis drug has variable pharmacogenomic metabolism?
Isoniazid
Describe isoniazid variable pharmacogenomic metabolism.
- rapid acetylators metabolize it more quickly than slow acetylators
- clinical significance is unknown
- genetic testing before starting therapy is NOT routinely performed
Is isoniazid bactericidal or bacteriostatic?
- bactericidal against growing mycobacteria
- bacteriostatic against dormant mycobacteria
What should patients avoid while on isoniazid?
Do not drink alcohol while on therapy
- to prevent additive risk of hepatotoxicity
- myth: alcohol decreases antibiotic effectiveness
What is isoniazid good for?
Drug of choice for:
- active TB (must be combined with other drugs)
- latent TB
What drugs are recommended for the consolidation phase of non-MDR-TB?
Combination of:
-isoniazid
and
-rifampin
Which drug allows the overall duration of TB therapy to be shortened from 9 months to 6 months?
Pyrazinamide
What does the initial four drug regimen for active TB consist of?
RIPE
- rifampin
- isoniazid
- pyrazinamide
- ethambutol
What type of activity does pyrazinamide have against M. tuberculosis?
Bactericidal
-even against slow growing M. tuberculosis
During what part of TB therapy is pyrazinamide used?
Generally only during the first 2 months of therapy
What is the MOA of pyrazinamide?
Pro-drug; unclear MOA
In its active form, thought to:
- prevents production of mycolic acids
- inhibits the enzyme fatty acid synthetase 1
- likely has other effects as well
What organisms is pyrazinamide active against?
Only:
-M. tuberculosis
What are the key adverse effects for pyrazinamide?
- hyperuricemia
- hepatotoxicity
Describe pyrazinamide hepatotoxicity.
- chiefly hepatitis
- dose dependent
- less common at the lower doses given today than higher ones previously used
Describe pyrazinamide hyperuricemia.
- predictable
- can precipitate gout (rarely)
- leads to withdrawal from regimen and extension of duration of TB therapy
What is another adverse effect of pyrazinamide?
Arthralgias can occur
- separate from hyperuricemia
- can be managed with OTC pain medications
In what environment is pyrazinamide active in?
Active only in acidic environments
- pH < 6
- would be problematic for some disease states
- perfect for the caseous granulomas that active TB forms
Also works intracellularly in phagocytes
Which two drugs with similar names should not be confused for active TB?
- pyrazinamide
- pyridoxine
What is pyrazinamide good for?
Only use:
-initial phase of active TB treatment
What symptoms should patients report while on pyrazinamide or any first line TB therapy?
Any signs of hepatitis
- dark urine
- abdominal pain
- loss of appetite
What is ethambutol?
EMB
- first line drug for both active TB and MAC infections
- used in initial four drug phase of active TB
- given for the duration of MAC therapy
What is the MOA of ethambutol?
Inhibits the enzyme aribinosyl transferase III
- blocks production of arabinogalactan
- arabinogalactan is a component of the cell wall of mycobacteria but not “typical” bacteria
- so activity limited to mycobacteria
What is the spectrum of activity of ethambutol?
- M. tuberculosis
- M. avium-intracellularare complex
- M. kansasii
What is the characteristic adverse effect of ethambutol?
Optic neuritis
- often manifests as decreased visual activity or inability to differentiate red from green
- dependent on both dose and duration of therapy
- generally reversible
- monitoring required
Why is ethambutol NOT recommended in children younger than 5 years old?
Generally not able to reliably perform the vision tests needed for monitoring
What adverse effects occur uncommonly with ethambutol?
- rash
- drug fever
Which TB drug is not associated with hepatotoxicity?
Ethambutol
Which drug can be used as a substitute for rifampin in patients unable to take it during the continuation phase (after 2 months) of active TB?
Ethambutol
-duration has to be extended relative to what it would be with rifampin and isoniazid
What drug is a primary first line drug for treating MAC infections?
Ethambutol
-along with a macrolide and rifabutin
What is ethambutol good for 1st line?
- active TB
- MAC
What is ethambutol good for 2nd line?
In patients unable to tolerate rifampin during the continuation phase
What organ system does Ethambutol affect?
Eyes
-optic neuritis
