Aminoglycosides

Question 1

What is the chemical structure of aminoglycosides?

Answer 1

Two or three sugars attached through glycosidic linkages to an aminocyclitol

Question 2

What are the admixture incompatibilities?

Answer 2

Admixture with penicillins can cause precipitation (insoluble salt complex) and inactivation of both drugs

Question 3

What aminoglycosides are most susceptible to admixture incompatibilities?

Answer 3

• Gentamicin
• Tobramycin
• Amikacin

Question 4

What beta-lactam antibiotics are the most problematic in admixture incompatibilities?

Answer 4

• Ticarcillan, Carbenicillin–no longer available
• Piperacillin/tazobactam

Question 5

How do you avoid admixture incompatibilities?

Answer 5

If giving two drugs, then administer into different tissue compartments (one drug on each arm)

Question 6

What is the MOA?

Answer 6

Inhibition of protein synthesis
* Binds to the bacterial 30S ribosomal unit which:
* Interferes with initiation of protein synthesis
* Blocks 30S-50S ribosomal complex from forming at the start codon of 16S mRNA
* Blocks further translation of the message
* Causes misreading of mRNA which leads to
* Production of nonfunctional proteins
* Incompletely synthesized protein

Question 7

What is the SOA of aminoglycosides?

Answer 7

Serious systemic infections due to gram-negative bacilli (rods) that can grow aerobically
* Strict aerobes
* Facultative aerobes
* Ex: Pseudomonas, enterobacterales

Question 8

What is aminoglycosides less susceptible to?

Answer 8

• Aerobic gram-positive cocci (synergism with beta-lactams for Enterococci)
• Aerobic gram-negative cocci

Question 9

What are aminoglycosides resistant to?

Answer 9

• Anaerobes
• Stentrophomonas
• Burkholderia

Question 10

What are aminoglycosides pharmacodynamic properties?

Answer 10

• Bactericidal
• Rate and extent of killing is concentration dependent

Question 11

Post antibiotic effect

Answer 11

• Residual bactericidal activity persist after serum concentration has fallen below the MIC

Question 12

What are the special patient populations with altered PK?

Answer 12

• Burn patients
• Critically ill
• Obesity
• CF
• Ascites
• Overhydration
• Dialysis

Question 13

What are the pharmacokinetics?

Answer 13

• Very poor oral bioavailability due to high polar cations
• Wide to extracellular fluid (ECF)
• Highly polar nature excludes many cells
• Negligible protein binding

Question 14

What is the elimination of aminoglycosides?

Answer 14

• Almost entirely via glomerular filtration as unchanged drug
• Do NOT require metabolism
• Elimination rate increases in proportion with CrCl
• Half-life: 2-3 hrs in patients with normal renal function (anephric patients: half-life is 20-40x that of those with normal renal function)
• Regimen MUST be adjusted with impaired renal function (to avoid nephrotoxicity)
• Pharmacokinetic/Therapeutic Drug Monitoring (TDM) is required

Question 15

Nephrotoxicity

Answer 15

• Toxicity due to accumulation and retention in the proximal renal tubular cells
• Consequence = reduced excretion and additional risk of other toxicities

Question 16

What are the two types of ototoxicity?

Answer 16

• Cochlear
• Vestibular

Question 17

What are the risks of getting cochlear ototoxicity?

Answer 17

• Genetic predisposition
• Preexisting hearing problems
• Loop diuretics co-admin

Question 18

Vestibular ototoxicity

Answer 18

• Manifest as vertigo or ataxia
• Most common with streptomycin

Question 19

What are the risk factor of ototoxicity?

Answer 19

• Frequent or very high doses
• Very high blood levels of the drug
• Long duration of therapy ( > 3 days)
• Older age

Question 20

Neuromuscular toxicity

Answer 20

• Rare
• Prolongs neuromuscular blocker effect (typically with higher doses)
• Can worsen weakness in disorders affecting neuromuscular transmission (ex: myasthenia gravis)

Question 21

What are some contraindications?

Answer 21

• Pregnancy
• Hypersensitivity

Question 22

When should aminoglycosides be used in caution in?

Answer 22

• Vertigo
• Tinnitus
• Hearing loss
• Renal disease
• Neuromuscular disease

Question 23

What are some drug interactions?

Answer 23

• Vancomycin (nephrotoxicity)
• Loop diuretics (nephrotoxicity, ototoxicity)
• Polypeptide antibiotics (nephrotoxicity, neuromuscular toxicity)

Question 24

Which aminoglycosides are used to treat Pseudomonas?

Answer 24

• Tobramycin preferred for urinary tract
• Amikacin for urinary infections

Question 25

Which aminoglycoside is used to treat Enterobacterales?

Answer 25

Gentamicin

Question 26

Which aminoglycoside is used to treat MDR organism?

Answer 26

Plazomicin

Question 27

What is the 4 types of bacterial resistance?

Answer 27

• Bacterial enzymes modify the antibiotic–> prevents it from binding to the ribosome (Aminoglycoside Modifying Enzymes)
• Production of 16S rRNA methyltransferase–> alteration of ribosomal target
• Upregulation of efflux pumps–> decreased accumulation within the bacterium
• Loss of outer membrane proteins–> reduced permeability into bacterial cells

Question 28

Aminoglycosides Modifying Enzymes

Answer 28

Strains carrying R factors synthesize enzymes capable of reacting with amino or hydroxyl groups:
* Aminoacetyltransferases (AAC)–> acetylation
* Aminoglycoside acetyltransferase
* Phosphotransferase (APH)–> phosphorylation
* Aminoglycoside phosphotransferase
* Nucleotidyltransferase (ANT)–> adenylation
* Aminoglycoside nucleotidyltransferase