Chapter 178 - Fluoroquinolones Flashcards
How do you qualify the enteral absorption, volume of distribution and elimination half-lives of fluoroquinolones?
Fluoroquinolones are well absorbed after oral and parenteral administration, have a large volume of distribution, and have extended elimination half-lives
Are fluoroquinolones bactericidal or bacteriostatic?
Bactericidal
What properties make fluoroquinolones good antibiotics for infectious prostatitis?
Weak acids
Lipophilic
Low protein binding
Are fluoroquinolones soluble in alkaline, acidic solutions or both?
Both (amphoteric molecule)
What is the generation of enrofloxacin, ciprofloxacin and marbofloxacin?
2nd-generation
What is the percentage of enrofloxacin metabolized in ciprofloxacin?
40%
What is the percentage of marbofloxacin excreted unchanged in the urine?
40%
Give one antibiotics from the third generation of fluoroquinolones
Pradofloxacin
What properties did these additions bring to the fluoroquinolones?
- Fluorine at position 6
- Piperazine at position 7
- Pyrrolidine group at position 7
- Halide, fluorine, or methoxy group at position 8
- Fluorine at position 6: enhanced drug penetration into the bacterial cell as well as increased efficacy against gram-negative bacteria
- Piperazine at position 7: increased antipseudomonal activity
- Pyrrolidine group at position 7: improves activity against gram-positive organisms.
- Halide, fluorine, or methoxy group at position 8: increase the drug’s half-life, absorption,
and efficacy against anaerobic bacteria
What is the activity of third generation fluoroquinolones?
Third-generation drugs (e.g., pradofloxacin) have the activity of the 2nd generation against aerobic gram-negative, and expanded activity against gram-positive bacteria, atypical pathogens, and some anaerobes
What is the mechanism of fluoroquinolones?
Inhibition of two bacterial enzymes of the topoisomerase class: DNA gyrase (formerly called topoisomerase II) responsible for the opening of the 2 strands of duplex DNA (primarily gram negative), and topoisomerase IV, responsible for the removal of the interlinking of daughter chromosomes (primarily gram positive) –> inhibiting normal bacterial DNA synthesis
What is the minimal bactericidal concentrations
of quinolones in relation to the minimum inhibitory concentration (MIC)
Minimal bactericidal concentrations of quinolones are usually within 2-fold to 4-fold of the minimum inhibitory concentration (MIC)
T/F Most fluoroquinolones are effective against Streptococcus spp
F - Only a small subset of the newer agents
What are the effects of oral antacids containing polyvalent cations (magnesium, aluminum,
calcium, iron, and zinc) on Fluoroquinolones?
Oral antacids containing polyvalent cations (magnesium, aluminum, calcium, iron, and zinc) decrease absorption
What are the effects of administration of food on Fluoroquinolones?
Food does not tend to decrease total serum concentrations of fluoroquinolones, but may lengthen the time to peak serum concentrations
T/F: Quinolone concentrations achieved in bile and urine are often 10 to 20 times greater than those in serum
T
T/F: Quinolone concentrations achieved in saliva, prostatic fluid, bone, and cerebrospinal fluid are often 10 to 20 times greater than those in serum
F: Concentrations of quinolones in saliva, prostatic fluid, bone, and cerebrospinal fluid are usually lower than drug concentrations in serum, although they are often adequate for killing susceptible organisms, particularly in the presence of inflammation
What is the recommended AUC/MIC24hr ratios for gram-positive and gram-negative bacteria
Streptococcus pneumoniae and most other gram-positive bacteria are rapidly killed by quinolones at a
24-hour AUC/MIC (AUC/MIC24hr) ratio of 30 to 40 or higher, whereas others, like P. aeruginosa and most other aerobic gram- negative bacteria, require much greater exposure over time to quinolones (AUC/MIC24hr ratios of ≥100 to 125).
For how long does the postantibiotic effect last after elimination?
Fluoroquinolones exhibit a marked postantibiotic
effect (PAE) in which they continue to inhibit bacterial growth for up to 8 hours after elimination from the body
What are the 3 bacteria most likely to be resistant to fluoroquinolones?
Staphylococcus, Pseudomonas, and E. coli
What are the mechanisms of fluoroquinolones bacterial resistance?
- Chromosomal point mutations in the genes encoding DNA gyrase and topoisomerase IV
- Expression of energy-dependent efflux systems that prevent the accumulation of effective intracellular concentrations of quinolones via active pumping of drug across the cell membrane (ex. multidrug efflux system AcrA-AcrB-TolC).
- Gram-negative bacteria can regulate membrane permeability by altering the levels of outer
membrane porins that form the channels responsible for passive diffusion.
Why are fluoroquinolones of later generation less prone to bacterial resistance?
Later-generation fluoroquinolone compounds with equal activity against DNA gyrase and topoisomerase IV would require simultaneous mutations in the bacteria at both sites to be rendered ineffective (double mutation rarely happens)
How is fluoroquinolone resistance transmitted to other antibiotics?
Via the transmission of plasmids
T/F:
Plasmid-mediated mechanisms typically confer high levels of resistance to fluoroquinolones
F - Plasmid-mediated mechanisms typically confer low levels of resistance to fluoroquinolones, but importantly, they favor the selection of bacteria possessing additional chromosome-encoded resistance mechanisms.
What were the dose and duration of the HDSD (high dose, short duration) protocol used to treat uncomplicated urinary tract infection?
18 to 20 mg/kg
orally q24h for 3 days
What is the most common adverse effects of fluoroquinolones administered too rapidly?
Seizures
What is the effects of fluoroquinolones on P-450 metabolism?
Inhibition
What are the mechanisms behind the neurological side effects of fluoroquinolones?
Fluoroquinolones directly inhibit γ-aminobutyric acid (GABA) receptors and stimulate N-methyl-d-aspartate (NMDA) receptors in the central nervous system.
What are the mechanisms behind the cartilagenous defects in juvenile patients after fluoroquinolones administration?
Inhibition of proteoglycan synthesis, chelation of magnesium, and inhibition of mitochondrial dehydrogenase activity
In patients of what age are fluoroquinolones contraindicated?
Young, growing dogs between the ages of 2 and 8 months and up to 18 months in large breed dogs
What is the most common adverse effect of fluoroquinolones in cats when administered at a dose greater than 5mg/kg every 24 hours?
Irreversible retinal degeneration and blindness
Fluoroquinolones are concentration-dependent bactericidal antibiotics and all of them are synthetic. Yes/No
Yes
Enrofloxacin belongs to which generation of fluoroquinolones? Name 2 other fluoroquinolones that belongs to this generation.
Second-generation
Marbofloxacin, ciprofloxacin
What is the mechanism of action of fluoroquinolones’ bactericidal effect?
They inhibit DNA gyrase (formerly called topoisomerase II), and topoisomerase IV -> inhibit normal bacterial DNA synthesis and cause bacterial cell death
** Topoisomerase IV is the primary target for fluoroquinolone in gram-positive bacteria, and DNA gyrase is the primary target in gram-negative organisms
The fluoroquinolones are highly effective against aerobic gram-negative bacteria. They have limited activity against gram-positive and anaerobic bacteria, and do not have any effect against intracellular pathogen (e.g. mycoplasma). Yes/No
No
(Fluoroquinolones have activity against many intracellular pathogens, including Mycoplasma, Mycobacteria, Chlamydia, and Brucella.)
What are the mechanisms of fluoroquinolones resistance in bacteria?
1) Chromosomal point mutations in the genes encoding DNA gyrase and topoisomerase IV -> decreased drug affinity for the altered enzyme-DNA complex
2) Increase the expression of energy-dependent efflux systems -> pump more drug out of the cells and prevent reaching the effective intracellular concentration
3) Gram-negative bacteria can reduce the levels of outer membrane porins that are responsible for passive diffusion -> decrease membrane permeability
4) Plasmid-mediated fluoroquinolone resistance
There was a study evaluating the efficacy of high-dose, short-duration (HDSD) enrofloxacin treatment (18-20 mg/kg PO q24h for 3 days) in dogs with uncomplicated UTI compared with a 14-day course of amoxicillin-clavulanate. What is the conclusion of that study?
HDSD enrofloxacin to be non-inferior to a 14-day course of amoxicillin-clavulanate.
** There were 35 dogs in enro group and 33 in amo group. The microbiologic cure rate was 77.1 and 81.2% for groups 1 and 2, respectively. The clinical cure rate was 88.6 and 87.9% for groups 1 and 2, respectively.
What are the fluoroquinolones that have been reported to cause retinal degeneration and blindness in cats?
Enrofloxacin, orbifloxacin, marbofloxacin
What are the adverse effects that may be seen when giving fluoroquinolones IV rapidly?
Seizures, neurologic signs, local tissue reactions, thrombophlebitis
Fluoroquinolones can cause cartilaginous defect in juvenile animals. What are the pathogeneses?
Inhibition of proteoglycan synthesis
Chelation of magnesium
Inhibition of mitochondrial dehydrogenase activity
Where are the fluroquinolones and their metabolites excreted?
Urine, bile
