Aminoglycosides

Introduction

Pharmacokinetic properties

Mechanism of action

Medications

Clinical use

Dose and administration

Interactions

Monographs

Introduction

• Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar).The term can also refer more generally to any organic molecule that contains amino sugar substructures. 

• Aminoglycoside antibiotic display bactericidal activity against Gram-negative aerobes and some anaerobic bacilli where resistance has not yet arisen but generally not against Gram-positive and anaerobic Gram-negative bacteria.

Pharmacokinetic properties

1. Absorption:

   • Aminoglycosides are poorly absorbed from the gastrointestinal tract due to their high polarity and lack of lipophilicity.

   • They are usually administered intravenously or intramuscularly to ensure adequate systemic exposure.

2. Distribution:

   • After administration, aminoglycosides distribute rapidly into extracellular fluids.

   • They tend to accumulate in the renal cortex and inner ear, which is relevant to their nephrotoxicity and ototoxicity.

   • Their distribution is also influenced by their binding to plasma proteins and tissue uptake, which is relatively low.

3. Metabolism:

   • Aminoglycosides are not significantly metabolized in the body.

   • Their structure remains unchanged, which is why they can be recovered in active form in the urine.

4. Excretion:

   • The primary route of excretion for aminoglycosides is through glomerular filtration in the kidneys.

   • Patients with impaired renal function may require dose adjustments due to reduced clearance of the drug.

Mechanism of action

Aminoglycosides are potent bactericidal antibiotics that work by disrupting bacterial protein synthesis. Here’s how they do it:

1. Transport into the Bacterial Cell:

   • Aminoglycosides are actively transported into the bacterial cell through oxygen-dependent uptake mechanisms. This is why they are particularly effective against aerobic bacteria.

2. Binding to the Ribosome:

   • Once inside, aminoglycosides bind irreversibly to specific nucleotides in 16S rRNA of the 30S ribosomal subunit. This binding interferes with the initiation complex of peptide formation and causes misreading of mRNA.

3. Interference with Protein Synthesis:

   • The misreading leads to the incorporation of incorrect amino acids into the polypeptide, resulting in nonfunctional or toxic proteins.

   • The drugs also cause the breakdown of polysomes into nonfunctional monosomes.

4. Inhibition of Translocation:

   • Aminoglycosides block the translocation step of protein synthesis, where the ribosome moves along the mRNA to the next codon. This further hinders protein synthesis.

5. Membrane Damage:

   • The faulty proteins can get incorporated into the bacterial cell membrane, altering its permeability and leading to cell death.

6. Post-Antibiotic Effect:

   • Aminoglycosides have a post-antibiotic effect, meaning they continue to suppress bacterial growth even after the drug concentration has fallen below the minimum inhibitory concentration.

7. Resistance Mechanisms:

   • Resistance to aminoglycosides can occur through various mechanisms, such as enzymatic modification of the drug, mutations in the ribosomal target, or efflux pumps expelling the drug from the cell.

Clinical use

• Sepsis: A life-threatening response to infection that can lead to tissue damage, organ failure, and death.

• Bacteremia: When bacteria have entered the bloodstream, potentially leading to sepsis.

• Urinary Tract Infections (UTIs): Especially those that are complicated or hospital-acquired.

• Hospital-Acquired Respiratory Tract Infections: Including pneumonia, which is a common infection in hospitalized patients.

• Cystic Fibrosis: To treat lung infections caused by Pseudomonas aeruginosa and other bacteria.

• Osteomyelitis: A severe bone infection that can be difficult to treat due to poor penetration of antibiotics into bone tissue.

• Intra-Abdominal Infections: Such as peritonitis, often in combination with other antibiotics.

• Endocarditis: Infection of the heart valves, typically caused by bacteria.

It’s important to note that while aminoglycosides are effective, they must be used cautiously due to potential side effects

Dose and administration

• Traditional Dosing: Typically involves a weight-based dose divided two to three times daily for patients with normal renal function. The dose is adjusted for patients with decreased renal function or based on measured serum drug concentrations.

• Extended-Interval Dosing: Also known as once-daily dosing, this method uses a higher weight-based dose administered at an extended interval (every 24 hours for those with normal renal function and longer for those with renal dysfunction). This approach aims to maximize drug concentration at the site of infection while minimizing toxicity.

• Dose Calculation: For non-obese and underweight patients, total body weight (TBW) is used. In obese patients, an adjusted body weight (ABW) formula may be used: IBW + 0.4 (TBW - IBW), where IBW is the ideal body weight.

• Creatinine Clearance: It’s important to calculate creatinine clearance, often using the Cockcroft-Gault equation, to adjust dosing in patients with renal impairment.

• Monitoring: Serum concentration monitoring is recommended to adjust therapy and ensure efficacy while minimizing toxicity.

• Combination Therapy: Aminoglycosides are often used in combination with other agents for treating various infection

•  Dosing of aminoglycosides is complex and requires careful monitoring to avoid toxicity. The dosing and administration are discussed in detail in resources like UpToDate 

Interactions

Synergistic Effects:

• Aminoglycosides can have a synergistic effect when used with other antibiotics, such as beta-lactams or vancomycin. This combination can enhance the bactericidal activity, especially against certain gram-positive organisms.

Ototoxicity and Nephrotoxicity:

• These antibiotics can cause ototoxicity (ear toxicity) and nephrotoxicity (kidney toxicity), which can be exacerbated by interactions with other drugs. For example, using aminoglycosides with loop diuretics like furosemide can increase the risk of hearing loss.

• Concurrent use with other nephrotoxic drugs, such as NSAIDs, can increase the risk of kidney damage.

Neuromuscular Blockade:

• Aminoglycosides can potentiate the effects of neuromuscular blocking agents, which could lead to increased muscle relaxation and even paralysis during surgery.

Metabolic Enzyme Induction/Inhibition:

• Unlike many other drugs, aminoglycosides are not significantly affected by the induction or inhibition of metabolic enzymes, which means their activity remains consistent regardless of the presence of other drugs that might affect enzyme activity.

Resistance:

• Bacterial resistance to aminoglycosides can occur, and it’s often due to the modification of the target site, enzymatic inactivation, or efflux mechanisms. However, newer aminoglycosides like plazomicin have been developed to overcome common resistance mechanisms.

Dosing Considerations:

• Aminoglycosides require careful dosing to avoid toxicity. Therapeutic drug monitoring is often employed to ensure appropriate serum levels are maintained.

Renal Function Monitoring:

• Due to the risk of nephrotoxicity, renal function must be monitored closely whewhenn patients are on aminoglycosides, especially when used in combination with other nephrotoxic drugs.