M5: Antibacterials Flashcards
Antibiotic:
Natural, e.g.
Synthetic, e.g.
Semi-synthetic, e.g.
a substance which kills bacteria or inhibits their growth
substance produced by organisms to kill/inhibit other organisms (aminoglycosides)
substances produced and discovered artificially (fluoroquinolones)
substances modified from those found naturally (beta-lactams)
Resistance to antibiotics threatens their success, speaking to the importance of:
Use antibiotics only _
Choose antibiotics _
Choose effective drugs with the _ once an organism has been identified (start _ -> de-escalate to _)
_ appropriately
Limit _ of therapy
when necessary (esp for viral infections)
appropriately
narrowest spectrum of activity
broad
narrow
Dose
durations
Points to Consider When Choosing an Antibiotic:
Identify the _ (or identify which _ to target empirically)
Match to _
_
_ / _
organism
organisms
antibiotic spectrum of activity
Sensitivity
Pharmacokinetics / Pharmacodynamics
Process of Starting Antibiotics (3)
empiric therapy
de-escalation
targeted therapy
Process of Starting Antibiotics:
Empirical Therapy
De-escalation
Targeted Therapy
choose antibiotics to cover a broad spectrum of possible organisms
culture & sensitivity data becomes available
choose antibiotics to cover a single pathogen
Antibiotic Classes:
Inhibitors of _ synthesis
Inhibitors of _ synthesis
Inhibitors of _ synthesis
_ damaging agents
_ damaging agents
cell wall
protein
DNA & RNA
DNA
cell membrane
Minimum Inhibitory Concentration (MIC):
Determines _
The (highest / lowest) concentration of antibiotic that results in _ (_)
Interpretation: _, _, or _
sensitivity
lowest
no visible growth (turbidity)
sensitive, intermediate, or resistant
Pharmacokinetics:
Definition
4 parts
the ways the body manipulates a drug
absorption
distribution
metabolism
excretion
Pharmacokinetics:
Absorption:
Bioavailability
Fluoroquinolones are (very / poorly) bioavailable
Vancomycin is (very / poorly) bioavailable
Level of drug in blood when given orally/given intraveneously X 100%
very
poorly
Pharmacokinetics:
Distribution:
Measured by _.
Good indicator is to assess concentrations in _ sites (_, _, _, _, etc.)
_ is an unique site, drug penetration depends on a number of factors including _, _, _, and _
Tobramycin: (good / poor) CNS distribution
Rifampin: (good / poor) CNS distribution
Volume of Distribution (L/kg)
sequestered
Cerebrospinal fluid, prostate, bone, abscess, etc.
Blood-brain barrier
molecular weight, lipophilicity, plasma protein binding, and active transport mechanisms
poor
good
Pharmacokinetics:
Metabolism:
Aminoglycosides: drugs that are (heavily / minimally) metabolized before being excreted unchanged
Moxifloxacin: drugs that are (heavily / minimally) metabolized
minimally
heavily
Pharmacokinetics:
Excretion:
_ vs. _ (e.g., biliary, feces, etc.)
_ eliminated drugs require dosage adjustment in renal failure (_) to avoid toxicity
_ eliminated drugs may not (_)
Renal vs. non-renal
Renally
penicillin
Non-renally
moxifloxacin
Pharmacodynamics:
Aspects (3)
the biochemical and physiologic effects of the drug and its mechanism of action (effects of the drug on the organism and body)
mechanism of action
toxicities
indices associated w/ optimal activity (concentration vs. time vs. exposure dependent)
Concentration-dependent killing:
The rate of cell killing increases with _
More effective: (400 mg once daily / 100mg four times daily)
Concentration dependent drugs (4)
each increase in peak concentration of antibiotic.
400 mg once daily
aminoglycosides
daptomycin
metronidazole
fluoroquinolones
Time-dependent killing:
The rate of cell killing increases with _
More effective: (400 mg once daily / 100mg four times daily)
Time Dependent drugs (3)
increasing amount of time that the concentration of antibiotic remains above a certain threshold (the MIC of the organism) for a majority of the dosing interval.
100mg four times daily
beta-lactams
linezolid
trimethoprim/sulfamethoxazole
Exposure Dependent killing:
Based
Exposure dependent drugs
neither entirely on peak concentration or time above MIC, rather based on total daily exposure
all other drugs (e.g. vancomycin)
Bactericidal vs. Bacteristatic Antibiotics:
Especially important for _ infections (_and _)
In most infections, _ is sufficient to allow the host immune system to eradicate infection.
life-threatening
meningitis and endocarditis
inhibition of growth
Bacteristatic:
An antibiotic which _ at usual achievable concentrations.
For (life-threatening / most) infections
Ex. (5)
inhibits growth
most
tetracyclines macrolides (azithromycin, erythromycin) clindamycin linezolid tigecycline
Bactericidal:
An antibiotic which _ at usual achievable serum concentrations.
For (life-threatening / most) infections
E.g. (7)
kills organism
life-threatening
penicillins cephalosporins aminoglycosides vancomycin fluoroquinolones monobactams daptomycin
Inhibitors of cell wall synthesis (3)
beta-lactam antibiotics
vancomycin
fosfomycin
Inhibitors of cell wall synthesis:
Beta-lactam antibiotics:
E.g. (4)
penicillins
cephalosporins
carbapenems
monobactams
Inhibitors of cell wall synthesis:
Beta-lactam antibiotics:
Mechanism of action:
The bacterial cell wall is composed of _, assembled in a series of enzymatic steps
The last step is the formation of these cross-links, catalyzed by _
Beta-lactams bind to and inhibit _, thus inhibiting _
This mechanism is part of a pathway that ultimately results in (bacteristatic / bactericidal) activity (except against _)
cross-linked peptidoglycans
cross-links
penicillin-binding proteins (PBPs)
PBPs
cell wall synthesis
bactericidal
Enterococcus
Inhibitors of cell wall synthesis:
Beta-lactam antibiotics:
Mechanisms of resistance (gram+):
Altered _, which have (increased / decreased) affinity for beta-lactam drug
Mechanism of resistance in gram + organisms (beta-lactam resistance in _, _, and _)
_ (in _ only)
PBPs
decreased
Staphylococcus, Enterococcus, and Streptococcus
Β-lactamases
Staphylococcus
Inhibitors of cell wall synthesis:
Beta-lactam antibiotics:
Mechanisms of resistance (gram-):
Overexpression of _
Loss of _
_
- PBPs that catalyze _
- Location is critical to activity
i. _ space of gram-negatives
ii. _ cell wall in gram-positives
This renders the antibiotic _ before it reaches the PBP target
efflux pumps
porins
β-lactamases
hydrolysis of the β-lactam ring
Periplasmic
Outside
inactive
Inhibitors of cell wall synthesis:
Vancomycin:
Mechanism of action:
Vancomycin binds to _, interrupting the chain of events necessary to synthesize _ (occurs one step earlier in pathway than that of the _ mechanism).
D-Ala
peptidoglycan
beta-lactam
Inhibitors of cell wall synthesis:
Vancomycin:
Mechanism of resistance:
Via : D-alanyl-D- binding site changes to D-alanyl-D-_ or D-alanyl-D-_
Via _, which prevents vancomycin from _
an altered binding site
alanine
lactate or serine
a thickened cell wall
reaching its target site
Inhibitors of cell wall synthesis:
Fosfomycin:
Mechanism of action:
Inhibits the first step in _ synthesis by binding to the enzyme which catalyzes the formation of _ (a precursor)
Mechanism of resistance:
Decreased _, _ modification and _ inactivation
peptidoglycan
N-acetylmuramic acid
drug uptake
target site
enzymatic
Inhibitors of protein synthesis:
Mechanism of action:
_ to create proteins
As such, _ results in impaired protein synthesis
e.g. (6)
Ribosomes “read” mRNA
inhibition of ribosomal function
aminoglycosides macrolides tetracyclines linezolid clindamycin tigecycline
Inhibitors of protein synthesis:
50S inhibitors block either:
Initiation of _ (_)
Translocation of _ - inhibits reaction which elongates the peptide chain (_, _)
protein translation
linezolid
peptidyl rRNAs
macrolides, clindamycin
Inhibitors of protein synthesis:
30S inhibitors:
Block access of _ to ribosome (_, _)
Bind _ component of the ribosome, which leads to protein _ (_)
tRNAs
tetracyclines, tigecycline
16S rRNA
mistranslation
aminoglycosides
Inhibitors of DNA/RNA synthesis (4)
Trimethoprim/Sulfamethoxazole
Rifamycins (rifampin)
Fluoroquinolones (FQ’s)
Fidaxomicin
Inhibitors of DNA/RNA synthesis:
Trimethoprim/Sulfamethoxazole:
Mechanism of action:
In combination, act synergistically to _.
TMP is 50-100k times (more / less) active against bacterial enzyme than human
inhibit nucleic acid synthesis
more
Inhibitors of DNA/RNA synthesis:
Rifamycins (rifampin):
Mechanism of action: inhibits _ (thus inhibiting RNA synthesis)
Mechanism of resistance: _ mutation
DNA-dependent RNA polymerase
Target site
Inhibitors of DNA/RNA synthesis:
Fluoroquinolones (FQ’s):
Mechanism of action:
_ catalyze reactions which are vital for DNA replication, transcription, recombination, and repair.
FQ’s (enhance / inhibit) the function of these enzymes
Topoisomerases
inhibit
Inhibitors of DNA/RNA synthesis:
Fidaxomicin:
Mechanism of action:
Inhibiting transcription of _
bacterial RNA polymerase
DNA damaging agents (2)
Nitrofurantoin
Metronidazole
DNA damaging agents:
Nitrofurantoin:
Mechanism of action: unclear, but appears that parent compound is reduced to form _
Mechanism of resistance: Mutations resulting in _
DNA damaging oxygen radicals
inhibition of reductase activity
DNA damaging agents:
Metronidazole:
Mechanism of action: Pro-drug, (aerobic / anaerobic) nitro-reduction to _ that bind to and perturb DNA function
Mechanism of resistance: (common / rare) outside of intrinsically-resistant organisms, multiple mechanisms postulated
anaerobic
radical metabolites
rare
Cell membrane damaging agents (2)
Daptomycin
Polymyxins (Colistin or colistimethate)
Cell membrane damaging agents:
Daptomycin:
Mechanism of action:
The antibacterial target of daptomycin in Staphylococcus aureus and other Gram-positive bacteria is the _.
Daptomycin inserts into the CM in a Ca2+-dependent manner, resulting in _ and subsequent _, including K+,Mg2+, and ATP
Mechanism of resistance:
Multiple, and still being studied. Possibly includes _ and _
cytoplasmic membrane (CM)
membrane depolarization
loss of intracellular components
thickened cell wall
altered binding site
Cell membrane damaging agents:
Polymyxins (Colistin or colistimethate):
Mechanism of action: inserts into membranes, interacting with _; acts as _
Mechanism of resistance: Still being studied. Possibly includes _
phospholipids
cationic detergent
altered binding site
