Pharmacology- Chen Fluoroquinolones Flashcards
What are the 3 strategies employed by antibacterial agents?
- Fight cell wall synthesis (Humans don’t have cell walls)
- Fight nucleic acid synthesis (Humans use the 60S/40S sub-units, while bacterial use 50S/30S)
- Fight protein synthesis (Humans use slightly different enzymes than bacteria)
What are antibiotics?
NATURAL SUBSTANCES synthesized by an organism which can inhibit the growth of another organism
What are antibacterials?
Substances synthesized in a LAB that can inhibit the growth of another organism
How was quinolone discovered?
As a by-product of the anti-malarial agent chloroquine
What is the generation 0 fluoroquinolone?
Nalidixic acid
-This was the byproduct of chloroquine
What was the first antibacterial?
The quinolone ring
What did they do to the quinolone ring to get flouroquinolones?
Added a fluorine atom at position C6
What did this addition of the fluorine atom do?
- Increased DNA gyrase inhibitory activity
- Facilitated penetration into the bacterial cell
- Provided activity against staphylococci
MOA of fluoroquinolones?
Block bacterial DNA synthesis by inhibiting DNA gyrase and Topoisomerase IV
Is the blocking of topoisomeriase II (DNA Gyrase) more specific for gram - or gram + bacteria?
Gram NEGATIVE
What does blocking of DNA gyrase do?
Prevents relaxation of positively supercoiled DNA
Is blocking Topoisomerase IV more specific for gram + or gram - bacteria?
Gram POSITIVE
What does blocking of Topoisomerase IV do?
Interferes with separation of replicated chromosomal DNA into respective daughter cells during cell division
If you increase the dose of fluoroquinolone enough, can you target both enzymes for gram + and gram - bacteria?
YES
-Gram + and gram - have both enzymes and while structural differences determine the selectivity of which enzyme is affected, at high enough doses, fluoroquinolones will block both
Are fluoroquinolones bactericidal or bacteristatic?
Bactericidal
What are the 3 mechanisms of resistance for Fluoroquinolones?
- Mutation that alters drug target
- Mutation that reduces drug accumulation
- Plasmid-Mediated resistance
What are the genes that can be mutated to block fluoroquinolone binding to DNA Gyrase?
GyrA and GyrB which encode GyrA and GyrB proteins
-These make up the subunits for DNA Gyrase
What are the genes that can be mutated to block fluoroquinolone binding Topoisomerase IV?
ParC and ParE which encode ParC and ParE protein
-These make up the subunits for Topoisomerase IV
In gram + bacteria what do fluoroquinolones have to cross to get inside?
The cell wall and cytoplasmic membrane
In gram - bacteria what do fluoroquinolones have to cross to get inside?
Cell wall, cytoplasmic membrane, and the extra outer membrane
What can bacteria mutate to increase fluoroquinolones being pumped out of their cells?
Efflux pumps
What can bacteria mutate to decrease fluroquinolones from entering their cells
Porins
Describe the transfer of plasmids between bacterial cells
- Resistant bacteria comes in close proximity with sensitive bacteria
- Plasmid carrying resistance gene is transferred to sensitive bacteria
- Sensitive bacteria incorporate resistance gene and becomes resistant
What is the resistance gene that can be transferred via plasmid to protect DNA gyrase and topoisomerase IV against fluoroquinolone inhibition?
Plasmid-mediated quinolone resistance gene (gnr)
-This makes a shield for the bacteria
What is another plasmid-transferred gene that can inhibit fluoroquinolone activity?
A variant of aminoglycoside acetyltransferase
How does aminoglycoside acetyltransferase work to block fluoroquinolone activity?
It allows bacteria to transfer an acetyl group to floroquinolone so it can’t bind and thus inhibits it
Is plasmid-mediated resistance low level or high level?
Typically low level, but it can facilitate point mutations that confer high level resistnace
If you increase the dose of the drug, can you inhibit the bacteria?
Typically
What can happen if you increase the drug dose?
You can increase bacterial developing resistance due to gene mutations
What do fluoroquinolones end in?
-floxacin
What is the first generation fluoroquinolone that isn’t used anymore?
Nofloxacin
What drug is an enantiomer of ofloaxacin that has better activity and can be used for gram + and gram - organisms?
Levofloxacin
What type of bacteria is ciprofloxacin most active against?
Gram negatives
-Has moderate activity against gram +, but used more for gram -
Why can’t you use cipro against S. Pneumoniae?
It has a right MIC against this and you would need really high concentrations (gram +)
What are the 3 respiratory fluoroquinolones?
Levofloxacin, Moxifloxacin, and Gemifloxacin
Why are they respiratory fluoroquinolones?
Have low MIC against S. Pneumoniae (can be used against gram + with good activity
What other type of bacteria is Moxifloxacin good for?
Anaerobes
Can you use moxifloxacin against gram -?
Hasn’t been established yet
Do fluoroquinolones have good oral bioavailability?
YES (70-95%)
What can impair oral absorption in floroquinolones?
Divalent or trivalent cations
ANTACIDS
-Form insoluble chelation complexes with cations
Where is moxifloxacin metabolized/eliminated?
LIVER
Do you need to dose adjust moxifloxacin in patients with renal insufficiency?
NO
Is moxifloxacin contraindicated in patients with hepatic failure?
RELATIVELY
What fluoroquinolones are good for use in UTI?
Cipro, Levo, Gemi
-They are eliminated/metabolized in kidneys
Which fluoroquinolones do you have to dose adjust for people with renal insufficiency?
Cipro, Levo, Gemi
Which fluroquinolone is given orally only?
Gemi
All others are oral or IV
What respiratory conditions can fluoroquinolones be used for?
- Community aquired respiratory tract infections
- Nosocomial pneumonia
- Inhalation anthrax
What non-respiratory infections can fluoroquinolones be used for?
- GU infections
- Chronic bacterial prostatitis
- Skin Infections
- Intra-abdominal infections
Which drugs are used for acute bacterial sinusitis?
Cipro, Levo, Moxi
Which drugs are used for CAP?
Levo, Moxi, Gemi
Which drug cannot be used for CAP?
CIPRO… doesn’thave good activity against S. Pneumoniae
Which 2 respiratory conditions are Cipro and Levo good for?
Nosocomial pneumonia and inhalation anthrax
Which 2 non-respiratory conditions are Cipro and Levo good for?
Genito-urinary tract infections and chronic bacterial prostatitis
Remember, moxi is metabolized by liver so it won’t work and gemi is still pending FDA approval
What 2 drugs can be used for skin infections?
Levo and Moxi
Which drug can be used for intra-abdominal infections?
Cipro
What CV AE do fluoroquinolones cause and what is the mechanism?
QT interval prolongation
-Not clear, but has something to do with K channels
What dermatological AE do fluoroquinolones case and what is the mechansim
Photosensitivity and Stevens-Johnson Syndrome
-Due to degradation of the fluoroquinolone ring which makes the skin sensitive to UV light
What GI AE do fluoroquinolones cause?
N/V/D
What MSK AE do fluoroquinolones cause?
Tendonitis, rupture of tendon, and arthropathy
What are the risk factors for tendon rupture?
Being old (already have cartilage damage), renal insufficiency (won’t be clearing drugs from system well), and using steroids (damage cartilage)
Why do we avoid these drugs in patients under 18?
Because of arthropathy… we don’t want to damage their growing cartilage
What neurological AE do fluoroquinolones cause?
Dizzyness, headache, and peripheral neuropathy
How long can the peripheral neuropathy last and how does it present?
Can last months-years (long-term incapacitation) and the onset is QUICK
Are these safe for your preggo patients?
NOPE…caused fetal toxicity in animals so we haven’t tried em on humans yet
Can these drugs be given to nursing mothers?
NOPE… they are excreted in breast milk
What is the prevalence of tendonitis and tendon rupture in patients receiving fluoroquinolones?
1/6000
Which fluoroquinolone seems to have a higher incidence of tendonitis and tendon rupture?
Cipro… although this AE is assocaited with all of them
What is the second most common type of AE reported in floroquinolone?
Neurologic effects
How are fluoroquinolones neurotoxic?
The produce dose-related CNS excitation
What receptors do fluoroqunolones inhibit to produce neurotoxicity?
GABA, NMDA, or adenosine
Which fluoroquinolone is non-respiratory and why?
Cipro, because it lacks activity against S. Pneumoniae
What are the 3 respiratory fluoroquinolones?
Levo, Moxi, Gemi
What classes of bacteria can levo be used against?
Gram - and gram +
What can gemi be used for and how is it given?
UTI/Oral
