L22- Mycobacterial Antibiotics Flashcards
Mycobacteria is difficult to treat because of:
- (1) location
- (2) intrinsic property
- (3) required therapy
1- intracellular location
2- resistance to most antibiotics + ability to develop resistance quickly
3- combination therapy for mos-yrs
Tb is caused by (1), described as a (2- size, shape, respiration, motility) type bacteria. TB is a serious infection of the (3) organs.
1- mycobacterium tuberculosis
2- small, aerobic, non-motile, bacillus (divides every 16-20 hrs)
3- lungs, GUT, skeleton, meninges
Note- believed 1/3 of population is infected, latent or active
list the 1st line Tb drugs (hint- 5)
- isoniazid
- rifampin
- rifabutin* (1st line in HIV pts)
- ethambutol
- pyrazinamide
list the 2nd line Tb drugs (hint- 4)
- streptomycin
- ethionamide
- levofloxacin
- amikacin
list the 3 goals of Tb therapy (include generally what it takes to accomplish them)
1) kill bacilli
2) prevent emergence of drug resistance
3) eliminate persistent bacilli from host tissue –> prevent relapse
-multiple drugs for a significant period in time is required to meet these goals
Tb therapy:
- (1) is required before therapy
- (2) is required in therapy
- (3) is recommended for difficult patients
1- antibiotic susceptibility testing
2- 3-4 drug combination regimen
3- DOT, directly observed therapy: for non-compliant Pts or highly resistant strains
what are the 2 categories of high risk Tb patients (Latent Tb, since it effects recommended therapy)
- recently infected Tb patients
- Pts with medical conditions that weaken the immune system
what are the criteria for high risk Tb patients for those that have been recently infected
- close contact with infected Tb person
- person who has emigrated from an area with high Tb rate
- children <5y/o w/ +Tb test
- groups with high Tb transmission rates
what are the common conditions that weaken the immune system and put a person at high risk for Tb
- HIV+
- substance abuse
- DM
- organ transplants
- severe kidney disease
(1) is a synthetic agent of pyridoxine. It is a (1st/2nd)-line Tb drug for (mono-/combination) therapy in active infections and (mono-/combination) therapy in latent infections.
1- Isoniazid
2- 1st line
3- combination (active)
4- monotherapy (latent)
______ is the sole drug of choice for latent Tb infections
isoniazid
Isoniazid is a pro-drug activated by (1). It aims to target (2) and (3) enzymes which function to (4).
1- myobacterial catalase peroxidase (KatG)
2- enoyl acyl carrier protein reductase (InhA)
3- β-ketoacyl-ACP synthase (KasA)
4- mycolic acid synthesis
Isoniazid uses:
- (1) effects against bacilli in stationary phase
- (2) effects against rapidly dividing bacilli
- specific for (3)
- if used alone for (3), (4) is almost guarantee to occur
1- bacteriostatic effects (prevents growth, stagnant)
2- bacteriocidal effects (destroys bacteria)
3- M. tuberculosis (active infection)
4- resistant organisms rapidly emerges
Isoniazid Resistance results from one of the following…. (discuss its tendency for cross-resistance)
Chromosomal mutations:
- deletion of KatG
- mutation of acyl carrier proteins
- InhA overexpression
Note- no cross-resistance for other Anti-Tb drugs developed
discuss administration and distribution of Isoniazid
- oral, IV, IM
- diffuses into all body fluids, cells, *caseous material
list the AEs for isoniazid
- peripheral neuritis (correct with pyridoxine supplementation)
- hepatotoxicity (clinical idiosyncratic hepatitis)
- CYP450 inhibitor (inc effect of other drugs)
- lupus-like syndrome, rare
discuss Isoniazid use in pregnancy
-generally safe
- hepatitis risk is inc
- pyridoxine supplementation use is recommended (prevent peripheral neuritis)
Rifamycins:
- (1) list the drugs
- (1st/2nd) line therapy for active Tb
- (1st/2nd) line therapy for latent Tb
1- rifampin, rifabutin
2- 1st line, in combination
3- 2nd line, monotherapy (isoniazid is 1st)
Rifampin uses:
- (1) type effects against bacilli
- if used alone for Tb, (2) is almost guarantee to occur
1- bactericidal (antimicrobial, antimycobacterial)
2- resistant strains rapidly emerge (therefore usually given in combination)
Rifampin MOA
-binds β-subunit of bacterial DNA-dependent RNA polymerase
–> blocks transcription // inhibition of RNA synthesis
list the organisms Rifampin is used against in therapy
- Intracellular and Extracellular Mycobacteria: M. tuberculosis, M. kansasii
- Gram+/- organisms
- MRSA
Rifampin resistance:
-(1) mutation is required in (2) gene of (3) protein, causing (4)
OR
-decrease in (5) in bacteria
1- point mutation
2- rpoB gene
3- β-subunit of bacterial DNA-dependent RNA polymerase
4- dec affinity of β-subunit for Rifampin
5- dec permeability
Rifampin clinical applications:
- (1) discuss uses in Tb
- (2) discuss its use in Leprosy
- prophylaxis use in (3) and (4) patients
- used in (5) infections along with (6); hint- a very common highly resistant infection
1- 1st line combination for active infections, 2nd line (for isoniazid intolerant Pts) for latent infections
2- delays resistance to Dapsone
3- those exposed to Menigintis
4- those in contact with H. influenza (children)
5- MRSA
6- vancomycin
Rifampin pharmacokinetics:
- (1) route of administration
- (2) distribution
- (3) excretion mechanism
- (4) other metabolism effects
1- oral, parenteral
2- well distributed, including CSF
3- feces mainly
4- strong CYP450 inducer (dec levels of other drugs)
Rifampin AEs:
- (1) are common effects
- (2) are occasional effects
- (3) noticeable harmless effect
- (4) metabolism effect
- (5) use in pregnancy
1- light chain proteinuria, GI distress
2- thrombocytopenia, rashes, nephritis, liver dysfunction
3- orange-red body fluid colors (urine mainly noticed)
4- strong CYP450 inducer (dec levels of other drugs)
5- safe in pregnancy
Rifabutin:
- (1) and (2) are why it would be used over Rifampin
- (3) are its recommendations during pregnancy
1- preferred for HIV Pts b/c less CYP induction
2- Pts intolerant to Rifampin
3- no data for use in pregnancy
Ethambutol is used to treat (1) in combination with (2). If used in monotherapy for (1), (3) is almost guaranteed to occur due to mutations in (4).
1- all susceptible forms of Tb
2- (ethambutol), isoniazid, pyrazinamide, rifampin
3- acquired resistance
4- emb gene
Ethambutol MOA
- inhibits arabinosyltransferase
- decreased carbohydrate polymerization of cell wall
Ethambutol AEs:
- (1) is an important dose-dependent effect, therefore not is used in (2) patients
- (3) are the observed AEs
- (4) use in pregnancy
1- visual disturbances, e.g. red-green color blindness
2- children too young for vision testing
3- HA, confusion, hyperuricemia, (rarely peripheral neuritis)
4- safe in pregnancy
Pyrazinamide is activated by (1) process into (2). It is used as (1st/2nd) line treatment for Tb.
1- hydrolyzed
2- pyrazinoic acid
3- 1st line Tb Tx in combination (RIPE drugs)
list the methods mycobacteria have for Pyrazinamide resistance
- lack pyrazinamidase
- inc drug efflux
Pyrazinamid pharmacokinetics:
- (1) discuss absorption and distribution
- dose adjustments are needed in (2) patients
1- well absorbed (high F), well distributed (including CSF)
2- renal or hepatic insufficient patients
Pyrazinamide AEs:
- (1) is the common AE
- (2) is a similar AE to (1) because (3) is also an AE, but rare because it usually requires a predisposition
- (4) are the other AEs
- (5) use in pregnancy
1- nongouty polyarthralgia (40% Pts)
2- acute gouty arthritis
3- hyperuricemia
4- hepatotoxicity, myalgia, GI irritation, porphyria, rash, photosensitivity
5- only used in pregnancy if the benefits outweigh the risks
Streptomyocin is a (1) type antibiotic, with a (2) MOA.
1- aminoglycoside
2- binds ribosome –> inhibits protein synthesis
Streptomyocin AEs (include use in pregnancy)
- ototoxicity
- nephrotoxicity
-category D for pregnancy: only used if benefits outweigh the risks
Streptomyocin is used for (1) type bacteria, usually in a (2) regimen for the following diseases, (3).
1- drug-resistant 2- combination 3: (life-threatening Tb disease) -meningitis -miliary dissemination -severe organ tuberculosis
Levofloxacin is a (1) type antibiotic, with a (2) MOA.
1- fluoroquinolone
2- inhibits bacterial DNA replication
Levofloxacin AEs (include use in pregnancy)
- Connective Tissue problems: avoid in pregnancy, nursing mothers <18 y/o – Black Box Warning
- photosensitivity
2nd line Tb drugs:
- (1) are aminoglycosides used for (2) situations
- Levofloxacin is always is used in combination for (3) situations
- Ethionamide is similar to (4) drugs, has (5) AEs
-Note- all have significant (6) effects
1- streptomycin, amikacin
2- MDR strains (+ streptomycin resistance for amikacin use)
3- 1st-line drug resistant strains
4- isoniazid
5- GI irritation, neurological effects, hepatotoxicity, endocrine effects
6- **teratogenic
describe the Drug Regimens for Latent Tb
1st line) Isoniazid, 6-9 mos
2nd line) rifampin, 4 mos
discuss the standard Drug Regimens for Active Tb (hint- 2 regimens)
1:
i) initial phase 8 wks: RIPE combination (rifampin, isoniazid, pyrazinamide, ethambutol)
ii) continuation phase 18 wks: rifampin, isoniazid
2:
i) initial phase, 8 wks: rifampin, isoniazid, ethambutol
ii) continuation phase 31 wks: rifampin, isoniazid
Leprosy, aka (1) disease, is caused by (2). It mainly causes (3). Most cases are found in (4) part of the world.
1- Hansen’s disease
2- Mycobacterim leprae, M. lepromatis
3- primary granulomatous disease of peripheral nerves and URT mucosa
4- India, 70% cases
what is the pharmacological recommendation for Leprosy (by the WHO)
- dapsone
- clofazimine
- rifampin
(1) is a Leprosy drug structurally related to sulfonamides. It has a (2) effect on mycobacterium growth. Besides leprosy treatment, it also is used to treat (3) infections.
1- dapsone
2- bacteriostatic (prevents growth –> stagnant)
3- pneumonia due to P. jiroveci in HIV pts
dapsone MOA
- inhibits dihydropteroate synthertase
- -> inhibits folate synthesis
Dapsone pharmacokinetics:
- (1) discuss absorption and distribution
- (2) is respiratory form of dapsone
1- well absorbed (high F), well distributed (high levels in skin)
2- acedapsone
Dapsone AEs:
- (1) is key effect, especially in susceptible patients
- (2) other AEs
- (3) metabolism effects
1- hemolysis (especially in G6PD deficiency)
2- GI irritation, fever, hepatitis, methemoglobinemia
3- CYP450 inhibitor (elevated levels of other drugs)
Clofazimine AEs:
- (1) properties allow it to generate (2)
- (3) hallmark AE
- (4) other AEs
1- redox properties
2- cytotoxic oxygen radicals
3- Red-Brown discoloration of skin
4- GI irritation, eosinophillic enteritis
Describe Leprosy Tx recommendations based on type
Pauci-bacillary (PB): 1-5 skin lesions
-2 drug regimen, dapsone + rifampin for 6 mos
Multi-bacillary: >5 skin lesions
-3 drug regimen, dapsone + rifampin + clofazimine for 12 mos
Describe Leprosy Tx recommendations based on type
Pauci-bacillary (PB): 1-5 skin lesions
-2 drug regimen, dapsone + rifampin for 6 mos
Multi-bacillary: >5 skin lesions
-3 drug regimen, dapsone + rifampin + clofazimine for 12 mos
Atypical Mycobacteria:
- (1) communicability
- drug susceptibility is in relation to (2) disease
- (3) therapy is requires (include why)
1- not transmission person-to-person, although present in environment
2- M. tuberculosis drugs
3- combination therapy b/c of drug resistance
