Aminoglycosides and Quinolones

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What are the chemical properties of aminoglycosides?

-They have a hexose ring (either streptidine, in streptomycin or 2-deoxystreptamine) to which various amino sugars are attached via glycoside linkages
-They are highly polar and do not enter cells readily

What are the physical properties of aminoglycosides?

-They are water soluble
-They stabile in solution
-They are more active in alkaline solutions than in acidic solutions

What is the general mechanism of action of aminoglycosides?

They are irreversible inhibitors of protein synthesis.

How does the drug enter the bacteria it is used against?

1. Passive diffusion via porin channels across the outer membrane
2. It is transported across the cell membrane via an O2 dependent process
3. This transport is coupled to a proton pump

Do aminoglycosides work better in low or high pH environments? Why?

-Aminoglycosides work better in high pH environments
-This is because transport of the drug across the membrane is coupled to a proton pump

Do aminoglycosides work better in aerobic or anaerobic environments? Why?

-Aminoglycosides work better in aerobic environments
-This is because transport of the drug across the membrane is an oxygen dependent process

How do aminoglycosides carry out their mechanism of action?

They bind to a specific 30s subunit of ribosomal proteins and inhibit protein synthesis by:
1. Interference with the initiation complex of peptide formation
2. Misreading of mRNA (which can cause incorrect peptide insertion, yielding nonfunctional or toxic proteins)
3. Breakup of polysomes into nonfunctional monosomes

What are the three principle mechanisms of resistance to aminoglycosides?

1. Production of a transferase enzyme(s) that inactivate aminoglycosides via adenylation, acetylation or phosphorylation
2. Impaired entry of aminoglycoside into the cell
3. Deletion or alteration of the receptor protein on the 30s subunit

What is the most common mechanism of resistance to aminoglycosides, worldwide?

Production of a transferase enzyme that inactivates the aminoglycoside via adenylation, acetylation or phosphorylation

How is entry of an aminoglycoside into a cell inhibited?

Genotypic cause: Mutation or deletion in the gene that codes for the porin proteins responsible for transport and maintenance of the electrochemical gradient
Phenotypic cause: Anaerobic growth conditions, or other growth conditions which would inhibit the oxygen dependent transport process

How are aminoglycosides absorbed when taken orally?

They are very poorly absorbed in the intestinal tract. Almost the entire dose is excreted in the feces.

What are the best ways to administer aminoglycosides?

Intramuscularly or intravenously

What is the normal half-life of aminoglycosides?

2-3 hours in healthy patients, 24-48 hours in patients with impaired renal function

Do aminoglycosides enter the CNS?

No. Aminoglycosides do not enter the CNS or the eye.

Under what conditions might aminoglycosides by found in the CNS?

In the presence of inflammation, aminoglycoside levels of 20% can be reached in the CSF, more in the case of neonatal meningitis.

What is concentration-dependent killing?

Concentration dependent killing is essentially the dependance of a drugs ability to be bactericidal on it's concentration in the system.

What is the post-antibiotic effect?

The effect of an antibiotic that remains after it's concentration in the body has diminished.

How long does the post antibiotic effect of aminoglycosides last?

Several hours.

What is the synergistic effect?

It is the effect that two drugs have in synergy that is greater than each of them individually, and the combined effect is more than additive.

What drugs do aminoglycosides synergize well with?

Cell wall active drugs.

Aminoglycoside clearance is directly proportional to ___ clearance.

creatine

What are the potential toxic effects of aminoglycosides?

Ototoxicity and nephrotoxicity

Aminoglycosides are most often used against what pathogen?

Gram-negative enteric bacteria, when used in synergy with Beta-lactam drugs, it can be used against gram-positive bacteria.

What is most severely limiting the usefulness of streptomycin?

Existing resistance to the drug, and the rate at which resistance is developed.

How is streptomycin most commonly used?

As a main line defense against tuberculosis.

What pathogens are gentamicin effective against?

Gentamicin is effective against both gram-positive and gram-negative bacteria

Can gentamicin be used for aerobic organisms? Anaerobic organisms?

Gentamicin, like all aminoglycosides, can only be used against aerobic organisms, as transport of the medication into the cell requires oxygen.

Which organisms have been shown to have a relative resistance to gentamicin?

Streptococci and enterococci, because of failure of the drug to penetrate the cell wall.

Under which conditions would gentamicin be effective against streptococci or enterococci?

When gentamicin is used in synergy with cell wall active drugs, like Beta-lactam medications or vancomycin. It's activity is due to the uptake of the drug when cell wall synthesis is inhibited.

What problem might be encountered when treating a staphylococci with gentamicin?

The staphylococci developing resistance due to mutations in permeability.

What is the most common cause of resistance to gentamicin by gram-negative bacteria?

Plasmid-encoded aminoglycoside-modifying enzymes.

How is gentamicin mainly used?

It is used for the treatment of serious gram-negative bacterial infections, when these organisms are likely to be resistant to other drugs.

Is gentamicin effective for infections in the urinary tract? In the GI tract?

Gentamicin is effective for infections in the Urinary tract due to it's tendency to remane in high concentrations there. It is not as effective elsewhere in the body, and should be used synergistically with cell-active medications.

Are aminoglycosides, as a mono-therapy, effective in the lung tissues? Why or why not?

No, they are not effective due to local areas of low O2 perfusion and lower pH. They can be effective if they are used synergistically with another medication.

Are topical preparations of gentamicin effective?

It is unclear if these applications are effective. Purulent exudate will tend to inactivate gentamicin.

Can gentamicin be used for ocular infections?

Yes, ten mg of gentamicin can be injected subconjunctivally.

How can gentamicin be administered for patients with meningitis? Is gentamicin effective for meningitis?

It can be delivered intrathecally or intraventricularly. It's effectiveness is in question.

In neonates, can gentamicin be used to treat meningitis?

No, intrathecal injection of gentamicin is not effective, and intraventricular injection is toxic in neonates.

What are the potential toxic effects of gentamicin?

Nephrotoxicity and ototoxicity

How likely is nephrotoxicity to occur in patients taking gentamicin?

Nephrotoxicity occurs in as low as 5% and as high as 25% of patients who have been receiving gentamicin for longer then 3 - 5 days.

What drug is tobramycin similar to?

Gentamicin

How do gentamicin and tobramycin differ?

Tobramycin is more effective for the treatment of Pseudomonas aeruginosa.

What medication can be used as an inhalation treatment for pseudomonas aeruginosa lower respiratory tract infections?

Tobramycin

When would amikacin be used?

It can be used for organisms that are resistant to gentamicin and tobramycin. Amikacin is resistant to many of the enzymes that will inactivate the above mentioned drug.

What type of drug is amikacin?

It is an aminoglycoside.

How is netilmicin different from gentamicin?

The addition of an ethyl group on netilmicin protects it from enzymatic degradation that gentamicin would be vulnerable to.

In the case of resistance, what drugs could sometimes be used in place of gentamicin?

-Amikacin
-Netilmicin
-Neomycin
-Kanamycin

(neomycin and kanamycin will be given orally)

What organisms can neomycin and kanamycin be used against?

Gram negative, gram positive and some mycobacteria

Can neomycin be used against gram-positive organisms?

Yes. So can kanamycin.

Can neomycin be used against streptococci?

No, they are resistant to neomycin and kanamycin.

Can kanamycin be used against Pseudomonas aeruginosa?

No, pseudomonas aeruginosa are resistant to kanamycin and neomycin

What is the greatest drawback to the use of neomycin and kanamycin?

They are to toxic to be given parentally, so they are only given orally. Their bioavailability after oral administration is low.

What is spectinomycin?

An antibiotic that is structurally related to aminoglycosides.

What organisms can spectinomycin be used to treat?

Any gram positive bacteria, but is almost always used to as an alternative treatment for gonorrhea in patients with allergies to penicillin, or in patients infected with drug resistent gonorrhea.

What is topoisomerase II?

Topoisomerase II as a bacterial protein that relaxes positively supercoiled DNA. It is often referred to as DNA gyrase.

What is DNA gyrase?

DNA gyrase as a bacterial protein that relaxes positively supercoiled DNA. It is often referred to as Topoisomerase II.

What is topoisomerase IV?

Topoisomerase IV is involved with the separation of replicated chromosomal DNA.

What is the mechanism of action of the quinolone drugs?

They inhibit the action of topoisomerase II (DNA gyrase) and topoisomerase IV

What kind of drug is norfloxacin?

It is a quinolone.

What types of organisms is norfloxacin used to treat?

It is active against both gram-positive and gram-negative organisms. It is the least active of all the fluoroquinolones.

What were the disadvantages to early quinolones? How were they improved upon?

The early quinolones were not able to achieve systemic concentrations and were therefore only used for treatment of lower urinary tract infections. The advent of fluoroquinolones improved on quinolones and allowed for bactericidal levels in blood and tissues.

What type of drug is ciprofloxacin? What is it used for?

It is a quinolone. It has excellent activity against gram-negative bacteria and good activity against gram-positive bacteria.

What type of drug is enoxacin? What is it used for?

It is a quinolone. It has excellent activity against gram-negative bacteria and good activity against gram-positive bacteria.

What type of drug is lomefloxacin? What is it used for?

It is a quinolone. It has excellent activity against gram-negative bacteria and good activity against gram-positive bacteria.

What type of drug is levofloxacin? What is it used for?

It is a quinolone. It has excellent activity against gram-negative bacteria and good activity against gram-positive bacteria.

What type of drug is ofloxacin? What is it used for?

It is a quinolone. It has excellent activity against gram-negative bacteria and good activity against gram-positive bacteria.

What type of drug is pefloxacin? What is it used for?

It is a quinolone. It has excellent activity against gram-negative bacteria and good activity against gram-positive bacteria.

How is the activity of fluoroquinolones against methicillin-resistant streptococcus pneumoniae?

Methicillin-resistant streptococcus pneumoniae are generally resistant to the fluoroquinolones.

Of all of the fluoroquinolones, which is the most active against gram-negative bacteria?

Ciprofloxacin

What organism is ciprofloxacin most active against?

Pseudomonas aeruginosa

Which of the quinolones has the best activity against gram-positive bacteria (Other than the latest quinolones, gatifloxacin, gemifloxacin and moxifloxacin)?

Levofloxacin

What type of drug is gatifloxacin? What is it used for?

It is a fluoroquinolone that has been modified for improved activity against gram-positive bacteria.

What type of drug is gemifloxacin? What is it used for?

It is a fluoroquinolone that has been modified for improved activity against gram-positive bacteria.

What type of drug is moxifloxacin? What is it used for?

It is a fluoroquinolone that has been modified for improved activity against gram-positive bacteria.

What s the bioavailability of fluoroquinolones if taken orally?

80-95%, distributed widely in the blood and tissues.

What is the T1/2 of the fluoroquinolones?

3 - 10 hours

What is the advantage to using fluoroquinolones with regard to patient compliance?

Fluoroquinolones can be taken once daily.

What might impaire the absorption of fluoroquinolones?

Divalent and trivalent cations, found commonly in antacids.

How are fluoroquinolones eliminated from the body?

Tubular secretion or renal filtration.

When might a fluoroquinolone, that is not cleared renally, be contraindicated?

In patients with hepatic failure.

What are the most common side effects of fluoroquinolones?

Nausea, vomiting and diarrhea.

Less common: Headache, dizziness, insomnia, skin rash and abnormal liver function.

What are the less common side effects of fluoroquinolones?

Less common: Headache, dizziness, insomnia, skin rash and abnormal liver function.

Most common: Nausea, vomiting and diarrhea.

Which quinolones have been known to cause photophobia?

Lomefloxacin and pefloxacin.

Which quinolones have been known to cause elongation of the QT interval?

Gatifloxacin, levofloxacin, gemifloxacin and moxifloxacin

Why are fluoroquinolones not recommended for adolescent patients?

Because fluoroquinolones are known to damage growing cartilage

In what patients would you not recommend fluoroquinolones?

In patients who are under 18 or who are pregnant.

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