Aminoglycosides

Question 1

Structure of aminoglycoside antibiotics

Answer 1

1,3-diaminocyclitol “core structures” that are usually linked to one or more aminoglycoside rings

Question 2

What are the core structures in aminoglycosides?

Answer 2

The core structures are 2-deoxystreptamine, streptidine, and spectinamine

Question 3

What are the clinically important aminoglycosides?

Answer 3

TobramycinKanamycin AAmikacin AGentamicin C2 (Probably most important in terms of use)Neomycin B (skin, usually)StreptomycinSpectinomycin

Question 4

What is the mechanism of action of aminoglycosides?

Answer 4

Inhibit protein biosynthesis by binding to the 30S ribosomeBind to the 16S rRNA forming the A site. This 1. interferes with formation of the initiation complex2. blocks further translation3. elicits premature terminationIt also causes impairment of the proofreading function of the ribosome and formation of “nonsense proteins” resulting from selection of the wrong amino acids during translation. The “nonsense proteins” impair bacterial cell wall function.

Question 5

WRT to aminoglycosides, damaged membranes have altered permeability and this …

Answer 5

actually allows transport of larger amount of aminoglycoside, and protein synthesis ceases altogether

Question 6

Ultimately the aminoglycosides lead to …

Answer 6

Ultimately the aminoglycosides lead to leakage of ions and disruption of the cytoplasmic membrane, resulting in cell death.

Question 7

What is the charge on the backbone of DNA?What does this mean for amino glycosides?

Answer 7

Its negativeThe polycation binds to the polyanion of DNA

Question 8

The initial entry of the positively charged aminoglycosides through the outer membrane involves …

Answer 8

the displacement of Mg++ and Ca++ ions that form salt bridges with phosphates of the phospholipids in the membrane. This makes the membrane more permeable to the aminoglycosides.

Question 9

Passage through the cytoplasmic membrane is …

Answer 9

an active transport process

Question 10

What general bacterial resistance mechanisms to aminoglycosdies are there?

Answer 10

1. metabolic2. altered ribosomes3. altered aminoglycoside uptake

Question 11

Bacteria inactivate amino glycosides by …How does this resistance spread?What does this mean for amino glycoside use?

Answer 11

acetylation, adenylation, and phosphorylationThe genes responsible for metabolism can be transferred to other bacteria Many of the metabolizing enzymes have cross-resistance specificity, so resistance can emerge to aminoglycosides in general

Question 12

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Answer 12

The 16S rRNA binding site can be altered through point mutations. This has been observed clinically with Mycobacterium tuberculosis.

Question 13

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Answer 13

Altered Aminoglycoside Uptake. The rate of emergence is far less than resistance due to metabolism, and the phenotype reverts after the drug is removed.

Question 14

What toxicities can occur with all amino glycosides?

Answer 14

ototoxicity (irreversible) and nephrotoxicity (reversible)

Question 15

The irreversible ototoxicity can result in..

Answer 15

initially in tinnitus and high-frequency hearing loss, or in vestibular damage resulting in vertigo, loss of balance, and ataxia

Question 16

What should we do to monitor ototoxicity?

Answer 16

Serial audiograms

Question 17

When is nephrotoxicity with amino glycosides more likely to occur?

Answer 17

If taken in combination with-loop diuretics (ethacrynic acid and furosamide)-other nephrotoxic antimicrobial drugs (vancomycin or amphotericin)

Question 18

What less common toxic side effect can result from large doses of amino glycosides?What does this cause? Can it be reversed?

Answer 18

Curare-like effects Respiratory paralysis –can usually be reversed by neostigmine or calcium gluconate, but mechanical respiratory assistance may be necessary

Question 19

When is aminoglycoside toxicity is more likely to occur?

Answer 19

1. if there is an extended treatment period2. when higher doses are used3. if renal function is impairs4. in elderly patients

Question 20

Therapeutic uses of aminoglycosides

Answer 20

broad spectrum antibiotic activity against both Gram-(+) and Gram-(–) bacteria (in practice use is almost always reserved for treatment of Gram-(–) bacteria)

Question 21

Aminoglycosides are often administered with …Explain how this should be doneWhen is this combination more commonly used?

Answer 21

They are often used in combination with penicillins in order to take advantage of the synergism between these two classes of antibioticsThey should be administered in different compartments (typically one in each arm) in order to avoid a chemical reaction between the two classesUsed to treat bacterial endocarditis

Question 22

Streptomycin is most often used to …

Answer 22

treat tuberculosis

Question 23

Spetinomycin is used to …

Answer 23

treat gonorrhea

Question 24

Gentamycin is …It is used for …

Answer 24

a mixture of related compounds It is used for urinary tract infections, burns, some pneumonias, and joint and bone infections caused by susceptible Gram-(–) infections.