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Aminoglycosides are used for the treatment of serious infections due to what type of bacilli?
Aminoglycosides are used for the treatment of serious infections due to what type of bacilli?
The utility of aminoglycosides is limited by serious toxicities.
The utility of aminoglycosides is limited by serious toxicities.
True
What is the structure of aminoglycosides?
What is the structure of aminoglycosides?
-two amino sugars joined by a glycosidic linkage to a central hexose nucleus
Aminoglycosides are derived from:
Aminoglycosides are derived from:
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What are the two hexose rings found in aminoglycoside structure?
What are the two hexose rings found in aminoglycoside structure?
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Which of the following is NOT an aminoglycoside?
Which of the following is NOT an aminoglycoside?
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The drugs described in this chapter are bacteriostatic inhibitors of protein synthesis.
The drugs described in this chapter are bacteriostatic inhibitors of protein synthesis.
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How do aminoglycosides reach their target inside bacterial cells?
How do aminoglycosides reach their target inside bacterial cells?
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What is the primary site of action for aminoglycosides in bacterial cells?
What is the primary site of action for aminoglycosides in bacterial cells?
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In addition to interfering with the assembly of the ribosomal apparatus, how else do aminoglycosides disrupt protein synthesis?
In addition to interfering with the assembly of the ribosomal apparatus, how else do aminoglycosides disrupt protein synthesis?
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Aminoglycosides can inhibit protein synthesis in bacterial cells in at least three ways. Which of the following is NOT one of these ways?
Aminoglycosides can inhibit protein synthesis in bacterial cells in at least three ways. Which of the following is NOT one of these ways?
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Antibiotics that disrupt protein synthesis are generally bacteriostatic.
Antibiotics that disrupt protein synthesis are generally bacteriostatic.
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Aminoglycosides are unique in being irreversible bactericidal.
Aminoglycosides are unique in being irreversible bactericidal.
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The bactericidal effect of aminoglycosides is NOT concentration-dependent.
The bactericidal effect of aminoglycosides is NOT concentration-dependent.
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What is the target Cmax for aminoglycosides, compared to the MIC?
What is the target Cmax for aminoglycosides, compared to the MIC?
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Aminoglycosides exhibit a post antibiotic effect (PAE) which is continued bacterial suppression after drug levels fall below the MIC
Aminoglycosides exhibit a post antibiotic effect (PAE) which is continued bacterial suppression after drug levels fall below the MIC
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Due to the PAE effect, aminoglycosides are best administered in divided daily doses.
Due to the PAE effect, aminoglycosides are best administered in divided daily doses.
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What is a potential drawback of administering a single large dose of aminoglycosides?
What is a potential drawback of administering a single large dose of aminoglycosides?
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Aminoglycosides are effective against a majority of aerobic g-ve bacilli, including multidrug-resistant strains.
Aminoglycosides are effective against a majority of aerobic g-ve bacilli, including multidrug-resistant strains.
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Aminoglycosides are best administered alone for treatment of infections.
Aminoglycosides are best administered alone for treatment of infections.
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What is the specific example of synergistic effect that aminoglycosides are commonly used with?
What is the specific example of synergistic effect that aminoglycosides are commonly used with?
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Low extracellular pH and anaerobic conditions enhance the transport of aminoglycosides across the bacterial cell membrane.
Low extracellular pH and anaerobic conditions enhance the transport of aminoglycosides across the bacterial cell membrane.
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What type of drugs can enhance the transport of aminoglycosides into bacterial cells?
What type of drugs can enhance the transport of aminoglycosides into bacterial cells?
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Tularemia is a rare lymphoid disease that can be effectively treated with gentamicin.
Tularemia is a rare lymphoid disease that can be effectively treated with gentamicin.
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Pseudomonas aeruginosa is a common cause of infection, easily affecting healthy individuals.
Pseudomonas aeruginosa is a common cause of infection, easily affecting healthy individuals.
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Aminoglycosides are commonly used as monotherapy in the treatment of infections.
Aminoglycosides are commonly used as monotherapy in the treatment of infections.
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Resistance to aminoglycosides can occur via:
Resistance to aminoglycosides can occur via:
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Each of the enzymes involved in aminoglycoside resistance has its own specificity, meaning that cross-resistance can be presumed.
Each of the enzymes involved in aminoglycoside resistance has its own specificity, meaning that cross-resistance can be presumed.
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Aminoglycosides are easily absorbed following oral administration.
Aminoglycosides are easily absorbed following oral administration.
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Which aminoglycoside is the exception to the rule of parenteral administration?
Which aminoglycoside is the exception to the rule of parenteral administration?
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What is the reason for Neomycin not being administered parenterally?
What is the reason for Neomycin not being administered parenterally?
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Neomycin is administered topically for skin infections and orally for bowel preparation prior to colorectal surgery.
Neomycin is administered topically for skin infections and orally for bowel preparation prior to colorectal surgery.
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Once daily dosing of aminoglycosides is generally considered safe and effective, especially if creatinine clearance is > 60 mL/min.
Once daily dosing of aminoglycosides is generally considered safe and effective, especially if creatinine clearance is > 60 mL/min.
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After intramuscular injection, what is the range of time for peak concentrations of aminoglycosides in the blood?
After intramuscular injection, what is the range of time for peak concentrations of aminoglycosides in the blood?
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Aminoglycosides are generally dosed based on actual body weight, regardless of body fat percentage.
Aminoglycosides are generally dosed based on actual body weight, regardless of body fat percentage.
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Aminoglycosides are highly hydrophilic, meaning they easily penetrate into most body fluids.
Aminoglycosides are highly hydrophilic, meaning they easily penetrate into most body fluids.
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Concentrations of aminoglycosides are often inadequate in the cerebrospinal fluid (CSF), even when the meninges are inflamed
Concentrations of aminoglycosides are often inadequate in the cerebrospinal fluid (CSF), even when the meninges are inflamed
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For central nervous system (CNS) infections, the intrathecal route of administration may be considered for aminoglycosides.
For central nervous system (CNS) infections, the intrathecal route of administration may be considered for aminoglycosides.
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Aminoglycosides do not readily cross the placental barrier.
Aminoglycosides do not readily cross the placental barrier.
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More than 90% of parenteral aminoglycosides are excreted unchanged in the urine.
More than 90% of parenteral aminoglycosides are excreted unchanged in the urine.
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Aminoglycosides are commonly used in patients with renal dysfunction while maintaining the same dosage.
Aminoglycosides are commonly used in patients with renal dysfunction while maintaining the same dosage.
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Traditionally, aminoglycosides were given in two or three equally divided doses per day in patients with normal renal function.
Traditionally, aminoglycosides were given in two or three equally divided doses per day in patients with normal renal function.
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Administering the entire daily dose of aminoglycosides in a single injection is generally preferred in modern practice.
Administering the entire daily dose of aminoglycosides in a single injection is generally preferred in modern practice.
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Therapeutic drug monitoring of aminoglycoside plasma levels is not routinely performed.
Therapeutic drug monitoring of aminoglycoside plasma levels is not routinely performed.
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What is the primary purpose of therapeutic drug monitoring of aminoglycosides?
What is the primary purpose of therapeutic drug monitoring of aminoglycosides?
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Which adverse effect is most likely associated with aminoglycosides?
Which adverse effect is most likely associated with aminoglycosides?
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Aminoglycoside-induced deafness is always reversible with appropriate treatment.
Aminoglycoside-induced deafness is always reversible with appropriate treatment.
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Aminoglycoside ototoxicity is a risk for both adults and developing fetuses.
Aminoglycoside ototoxicity is a risk for both adults and developing fetuses.
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Tobramycin has a higher risk of causing vestibular toxicity than gentamicin and streptomycin.
Tobramycin has a higher risk of causing vestibular toxicity than gentamicin and streptomycin.
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Nephrotoxicity caused by aminoglycosides is always reversible with appropriate treatment.
Nephrotoxicity caused by aminoglycosides is always reversible with appropriate treatment.
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Individuals with renal insufficiency are at a decreased risk of developing nephrotoxicity from aminoglycosides.
Individuals with renal insufficiency are at a decreased risk of developing nephrotoxicity from aminoglycosides.
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Concomitant use of aminoglycosides and loop diuretics is generally safe and poses no additional risk of toxicity.
Concomitant use of aminoglycosides and loop diuretics is generally safe and poses no additional risk of toxicity.
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Which aminoglycoside is considered the most nephrotoxic?
Which aminoglycoside is considered the most nephrotoxic?
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What is the most common allergic reaction to topically applied neomycin?
What is the most common allergic reaction to topically applied neomycin?
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Neuromuscular paralysis, a side effect associated with aminoglycosides, is only a risk when the drug is administered in combination.
Neuromuscular paralysis, a side effect associated with aminoglycosides, is only a risk when the drug is administered in combination.
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Patients with myasthenia gravis are at a higher risk of developing neuromuscular paralysis when given aminoglycosides.
Patients with myasthenia gravis are at a higher risk of developing neuromuscular paralysis when given aminoglycosides.
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Prompt administration of calcium gluconate or neostigmine can reverse the neuromuscular block caused by aminoglycosides.
Prompt administration of calcium gluconate or neostigmine can reverse the neuromuscular block caused by aminoglycosides.
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Aminoglycosides are recommended for use in patients with myasthenia gravis.
Aminoglycosides are recommended for use in patients with myasthenia gravis.
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Aminoglycosides easily penetrate into the central nervous system (CNS).
Aminoglycosides easily penetrate into the central nervous system (CNS).
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Spectinomycin is an aminoglycoside antibiotic.
Spectinomycin is an aminoglycoside antibiotic.
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Spectinomycin is mainly used for treating infections caused by Gram-negative bacteria.
Spectinomycin is mainly used for treating infections caused by Gram-negative bacteria.
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Spectinomycin is considered a first-line treatment for Gonorrhea.
Spectinomycin is considered a first-line treatment for Gonorrhea.
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Aminoglycosides bind to the 30S site of ribosomal RNA, disrupting bacterial peptide elongation.
Aminoglycosides bind to the 30S site of ribosomal RNA, disrupting bacterial peptide elongation.
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Aminoglycosides are generally bactericidal against susceptible aerobic gram-negative bacteria.
Aminoglycosides are generally bactericidal against susceptible aerobic gram-negative bacteria.
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The antimicrobial activity of aminoglycosides is independent of pH.
The antimicrobial activity of aminoglycosides is independent of pH.
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Gentamicin and Tobramycin are considered less effective than amikacin against Pseudomonas.
Gentamicin and Tobramycin are considered less effective than amikacin against Pseudomonas.
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Amikacin is typically chosen for treating infections caused by pathogens resistant to gentamicin and Tobramycin.
Amikacin is typically chosen for treating infections caused by pathogens resistant to gentamicin and Tobramycin.
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Streptomycin has a broad range of applications in modern clinical practice.
Streptomycin has a broad range of applications in modern clinical practice.
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Aminoglycosides are more frequently used in combination with other antibiotics rather than on their own.
Aminoglycosides are more frequently used in combination with other antibiotics rather than on their own.
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Gentamicin is rarely used in combination therapy.
Gentamicin is rarely used in combination therapy.
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Netilmicin shares many characteristics with gentamicin and tobramycin, including its effectiveness against gentamicin-resistant bacteria.
Netilmicin shares many characteristics with gentamicin and tobramycin, including its effectiveness against gentamicin-resistant bacteria.
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Neomycin is considered ideal for treating infections due to its low toxicity and broad spectrum of activity.
Neomycin is considered ideal for treating infections due to its low toxicity and broad spectrum of activity.
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After oral administration, neomycin mainly acts by targeting the susceptible intestinal flora.
After oral administration, neomycin mainly acts by targeting the susceptible intestinal flora.
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Kanamycin, neomycin, and paromomycin all have similar properties; kanamycin is commonly used for multi-drug resistant tuberculosis.
Kanamycin, neomycin, and paromomycin all have similar properties; kanamycin is commonly used for multi-drug resistant tuberculosis.
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Paromomycin is considered to be effective against visceral leishmaniasis.
Paromomycin is considered to be effective against visceral leishmaniasis.
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Gentamicin is considered less effective against gram-positive bacteria compared to gram-negative bacteria.
Gentamicin is considered less effective against gram-positive bacteria compared to gram-negative bacteria.
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Gentamicin's effectiveness against susceptible bacteria is dependent on the concentration of the drug.
Gentamicin's effectiveness against susceptible bacteria is dependent on the concentration of the drug.
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Gentamicin's post-antibiotic effect, also known as PAE, is negligible.
Gentamicin's post-antibiotic effect, also known as PAE, is negligible.
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Spectinomycin is readily available in the USA.
Spectinomycin is readily available in the USA.
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Tobramycin is more active than gentamicin against Pseudomonas aeruginosa.
Tobramycin is more active than gentamicin against Pseudomonas aeruginosa.
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Tobramycin may have less nephrotoxic potential compared to gentamicin.
Tobramycin may have less nephrotoxic potential compared to gentamicin.
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Amikacin is resistant to many enzymes that inactivate gentamicin and tobramycin, making it a valuable option for treating infections caused by multidrug-resistant bacteria.
Amikacin is resistant to many enzymes that inactivate gentamicin and tobramycin, making it a valuable option for treating infections caused by multidrug-resistant bacteria.
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Study Notes
Pharmacology 3 - Protein Synthesis Inhibitors (Part 2)
- Aminoglycosides are used to treat serious infections caused by aerobic gram-negative bacilli.
- Their utility is limited by serious toxicities.
- Structurally, aminoglycosides consist of two amino sugars linked to a central hexose nucleus via a glycosidic linkage.
- They are derived from Streptomyces species (ending in "-mycin") or Micromonospora species (ending in "-micin").
- Aminoglycoside structure includes a 1-hexose ring (streptidine in streptomycin) and a 2-hexose ring (deoxystreptamine in other aminoglycosides). Various amino sugars are attached via glycosidic linkages.
- Examples of aminoglycoside agents include Streptomycin, Neomycin, Kanamycin, Amikacin, Gentamicin, Tobramycin, Sisomicin, Netilmicin, and Plazomicin, among others.
- These drugs are bactericidal protein synthesis inhibitors that interfere with ribosomal function.
- They diffuse through porin channels and are transported across the cytoplasmic membrane.
- Inside the cell, they irreversibly bind to the 30S ribosomal subunit.
- This binding interferes with ribosomal assembly and function.
- The 30S subunit of the ribosome misreads the genetic code.
- Aminoglycosides inhibit protein synthesis in at least three ways:
- Interference with initiation complex formation.
- Misreading of mRNA.
- Breakup of polysomes into nonfunctional monosomes.
- Antibiotics that disrupt protein synthesis are generally bacteriostatic. However, aminoglycosides are unique in their irreversible bactericidal action.
- Bactericidal effect is concentration-dependent.
- Dependent on Cmax (peak drug concentration) above MIC (minimum inhibitory concentration) of the target organism.
- Aminoglycosides exhibit a post-antibiotic effect (PAE), which is continued bacterial suppression after drug levels fall below the MIC.
- Single large doses given once daily are more common than divided daily doses, with the advantage of convenience but increasing the risk of nephrotoxicity.
- Aminoglycosides are often combined with a β-lactam antibiotic for a synergistic effect, particularly in treating infective endocarditis of Enterococcus species.
- Low extracellular pH and anaerobic conditions inhibit transport by reducing the gradient.
- Transport can be enhanced by cell wall-active drugs (e.g., penicillin, vancomycin).
- The major spectrum of activity is against aerobic gram-negative bacilli, often including multidrug-resistant species (e.g., Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species).
- Resistance to aminoglycosides can occur through various mechanisms, including efflux pumps, altered uptake (porins), and enzymatic modification/inactivation of the drug. Cross-resistance isn't fully predictable due to the unique specificity of the enzymes.
Pharmacokinetics
- High polarity prevents adequate oral absorption.
- All aminoglycosides (except neomycin) require parenteral administration for adequate serum levels.
- Neomycin is administered topically or orally for bowel preparation prior to surgery due to its severe nephrotoxicity.
- Peak concentrations in the blood, following intramuscular injection, reach their maximum between 30-90 minutes after administration.
- Once-daily dosing is safe and effective if creatinine clearance is >60 mL/min (5-7 mg/kg gentamicin/tobramycin; 15 mg/kg amikacin).
- Traditional dosing (divided doses) may be preferred for patients with lower creatinine clearance (<60 mL/min).
Distribution
- Aminoglycosides have similar pharmacokinetic properties.
- Tissue concentrations can be subtherapeutic due to their hydrophilicity and variable penetration into body fluids.
- Distribution into fatty tissue is low; dosing is based on lean body mass, not total body weight.
- Concentrations in cerebrospinal fluid (CSF) are often inadequate, even in cases of inflamed meninges, necessitating intrathecal administration when indicated.
- Aminoglycosides cross the placental barrier. They can accumulate in fetal plasma and amniotic fluid.
Elimination
- More than 90% of parenteral aminoglycosides are excreted unchanged in the urine.
- Dose adjustments are required for those with renal dysfunction.
- Traditional dosing involves equally divided doses daily for patients with normal renal function.
- Single daily high-dose administrations are increasingly preferred when clinically indicated.
Adverse Effects
- Monitoring plasma levels is important (e.g., gentamicin, tobramycin, amikacin) to ensure adequacy and minimize dose-related toxicities.
- Ototoxicity: Vestibular and auditory issues, including deafness (potentially irreversible). Vertigo is sometimes reported, particularly with streptomycin.
- Nephrotoxicity: Includes mild reversible renal impairment to severe, potentially irreversible acute tubular necrosis. Elderly patients and those with renal impairment are particularly susceptible.
- Concurrent Use with Other Nephrotoxic Agents: Concurrent use with loop diuretics (e.g., furosemide, ethacrynic acid) or other nephrotoxic antimicrobials (vancomycin, amphotericin B) can potentiate nephrotoxicity; concurrent use should be avoided. Neomycin, tobramycin, and gentamicin are the most nephrotoxic in this group.
- Allergic Reactions: Contact dermatitis (rash) is a common reaction, particularly with topically applied neomycin.
- Neuromuscular Paralysis: Associated with rapid increases in drug concentrations or concurrent administration with neuromuscular blocking agents. This is especially a risk factor to patients with myasthenia gravis. Using calcium gluconate or neostigmine (ACh-esterase inhibitor) can reverse the neuromuscular paralysis.
Spectinomycin
- Spectinomycin is an aminocyclitol antibiotic.
- Structurally, it's related to the aminoglycosides group but lacks amino sugars and glycosidic bonds.
- It's active in vitro against many gram-positive and gram-negative organisms.
- Primarily used as an alternative treatment for drug-resistant gonorrhea or penicillin-allergic patients.
Clinical Uses
- Aminoglycosides are typically used against gram-negative enteric bacteria.
- This includes situations when the isolate is drug-resistant or if there is suspicion of sepsis.
- They are often combined with β-lactam antibiotics to extend coverage to include gram-positive pathogens, and take advantage of a synergistic effect.
- Frequently used in combination therapy, particularly with gentamicin for empiric therapy.
- For certain infections and specific pathogens (e.g., Pseudomonas, Klebsiella), different aminoglycosides may be preferred based on efficacy and/or reduced toxicity.
- Monotherapy with aminoglycosides is occasionally indicated (e.g., tularemia and plague).
Empiric Use
- Aminoglycosides are often used initially as empiric therapy in combination with other antibacterial agents to cover a wide range of potential pathogens.
- Once the pathogen is identified and sensitivities determined, a less toxic antibiotic can be substituted to complete the treatment course.
Netilmicin, Neomycin and Others
- Netilmicin shares characteristics with gentamicin and tobramycin and may be efficacious against some resistant strains.
- Neomycin is generally limited to topical or oral use due to toxicity associated with parenteral use and higher resistance in enteric flora after oral administration.
- Neomycin, kanamycin, and paromomycin have similar pharmacologic properties. Kanamycin's clinical uses are limited to treating multi-drug-resistant tuberculosis; paromomycin shows efficacy against visceral leishmaniasis.
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Description
This quiz focuses on aminoglycosides, a class of protein synthesis inhibitors used to treat serious infections. You will learn about their structure, mechanism of action, examples, and associated toxicities. Prepare to test your knowledge on this essential pharmacological topic!
