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Questions and Answers
What is a primary clinical application of inhaled antibiotics for cystic fibrosis patients?
What is a primary clinical application of inhaled antibiotics for cystic fibrosis patients?
Which of the following infections is neomycin indicated for?
Which of the following infections is neomycin indicated for?
What characteristic of neomycin limits its use for parenteral administration?
What characteristic of neomycin limits its use for parenteral administration?
In what manner is netilmicin primarily used in clinical practice?
In what manner is netilmicin primarily used in clinical practice?
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Which bacteria are neomycin and kanamycin generally ineffective against?
Which bacteria are neomycin and kanamycin generally ineffective against?
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Which microorganisms are primarily targeted by aminoglycosides?
Which microorganisms are primarily targeted by aminoglycosides?
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What is a common reason for combining aminoglycosides with β-lactam antibiotics?
What is a common reason for combining aminoglycosides with β-lactam antibiotics?
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What is a potential adverse effect of aminoglycosides when used for more than 5 days?
What is a potential adverse effect of aminoglycosides when used for more than 5 days?
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Which route of administration is preferred for aminoglycosides due to their poor absorption?
Which route of administration is preferred for aminoglycosides due to their poor absorption?
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What treatment monitoring is necessary for patients with renal impairment taking aminoglycosides?
What treatment monitoring is necessary for patients with renal impairment taking aminoglycosides?
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Which of the following aminoglycosides is primarily used as a second-line agent for tuberculosis?
Which of the following aminoglycosides is primarily used as a second-line agent for tuberculosis?
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Concurrent use of aminoglycosides with which type of drug can potentiate nephrotoxicity?
Concurrent use of aminoglycosides with which type of drug can potentiate nephrotoxicity?
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What unique pharmacokinetic property of aminoglycosides affects their tissue concentration levels?
What unique pharmacokinetic property of aminoglycosides affects their tissue concentration levels?
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What is the primary mechanism by which aminoglycosides exert their bactericidal effects?
What is the primary mechanism by which aminoglycosides exert their bactericidal effects?
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Which of the following is a reason for the common resistance to aminoglycosides?
Which of the following is a reason for the common resistance to aminoglycosides?
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Aminoglycosides are primarily effective against which type of bacteria?
Aminoglycosides are primarily effective against which type of bacteria?
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What is the target Cmax for aminoglycosides to achieve optimal efficacy?
What is the target Cmax for aminoglycosides to achieve optimal efficacy?
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What aspect of aminoglycoside treatment can help reduce the risk of nephrotoxicity?
What aspect of aminoglycoside treatment can help reduce the risk of nephrotoxicity?
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Which of the following correctly describes the relationship between the dosage of aminoglycosides and their post-antibiotic effect (PAE)?
Which of the following correctly describes the relationship between the dosage of aminoglycosides and their post-antibiotic effect (PAE)?
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What is a common safety concern associated with aminoglycosides?
What is a common safety concern associated with aminoglycosides?
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In what way can mutations affect the effectiveness of aminoglycosides?
In what way can mutations affect the effectiveness of aminoglycosides?
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What is a significant adverse effect of gentamicin that is likely irreversible?
What is a significant adverse effect of gentamicin that is likely irreversible?
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Which of the following conditions should gentamicin not be used to treat as a single agent?
Which of the following conditions should gentamicin not be used to treat as a single agent?
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Which administration route is NOT indicated for gentamicin?
Which administration route is NOT indicated for gentamicin?
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What is a potential adverse effect associated with prolonged use of gentamicin?
What is a potential adverse effect associated with prolonged use of gentamicin?
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Which of the following antibiotics can be synergistically used with gentamicin?
Which of the following antibiotics can be synergistically used with gentamicin?
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What distinguishes amikacin from gentamicin?
What distinguishes amikacin from gentamicin?
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Which of the following bacteria is amikacin often used to treat?
Which of the following bacteria is amikacin often used to treat?
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Tobramycin is particularly active against which type of bacteria?
Tobramycin is particularly active against which type of bacteria?
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Study Notes
Protein Synthesis Inhibitors
- Targets bacterial ribosomes to inhibit bacterial protein synthesis
- Bacterial ribosomes are composed of 30S and 50S subunits; mammalian ribosomes have 40S and 60S subunits.
- Most are bacteriostatic, broad spectrum and have a common resistance.
- Overuse leads to antibiotic resistance.
Aminoglycosides
- Bactericidal
- Effective against serious infections caused by aerobic gram-negative bacilli, such as bacteremia and sepsis.
- Often used in combination with vancomycin or penicillin for endocarditis and tuberculosis.
- May cause serious toxicities, but have been somewhat replaced by safer antibiotics.
- Examples of safer antibiotics include third and fourth generation cephalosporins, fluoroquinolones, and carbapenems.
- Therapeutic drug monitoring is needed.
Aminoglycoside Mechanism of Action
- Aminoglycosides cross the bacteria cell wall through porin channels and are actively transported across the cell membrane, which is oxygen-dependent, into the cytoplasm.
- Bind to the 30S subunit of the ribosome, causing misreading of the genetic code, resulting in incorrect amino acid incorporation into peptides.
- This results in non-functional or toxic proteins which can lead to the production of dysfunctional proteins, impacting normal bacterial metabolism.
- Bactericidal and concentration dependent.
- Efficacy is dependent on drug concentration above the minimum inhibitory concentration (MIC).
- The target concentration should be 8-10 times greater than the MIC.
- Post-antibiotic effect (PAE) is present, meaning continued suppression of bacterial growth after antibiotic levels fall below the MIC.
- Larger doses lead to longer PAE.
- Extended interval dosing, where a single large dose is given once daily, is preferred over divided daily doses.
- This reduces the risk of nephrotoxicity and increases convenience.
Causes of Aminoglycoside Resistance
- Production of enzymes that inactivate the aminoglycoside
- Decreased uptake due to mutation or deletion of porin or oxygen-dependent transport process
- Increased efflux
- Deletion or alteration of the receptor protein on the 30S ribosomal subunit due to mutation.
Aminoglycoside Antibacterial Spectrum
- Effective against the majority of aerobic gram-negative bacilli, including multidrug resistant strains.
- Examples of strains include Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter sp.
- Often combined with β-lactam antibiotics for a synergistic effect, particularly in the treatment of Enterococcus faecalis and Enterococcus faecium infective endocarditis.
Aminoglycoside Adverse Effects
- Ototoxicity and nephrotoxicity are common adverse effects, particularly with continued treatment over 5 days, high doses, elder patients, and renal insufficiency.
- Concurrent use with ototoxic drugs, such as cisplatin, loop diuretics, vancomycin, or amphotericin, can potentiate nephrotoxicity and should be avoided if possible.
- Vertigo can also occur, especially with streptomycin.
- Neuromuscular paralysis can occur with high doses infused over a short period or concurrent neuromuscular blockers.
Aminoglycoside Pharmacokinetics
- Poor absorption, highly polar, and must be given parenterally.
- Neomycin can cause nephrotoxicity if given parentally.
- Administered as 30-60 minute infusion.
- Due to hydrophilicity, tissue concentrations may be subtherapeutic.
- Concentrations in cerebrospinal fluid (CSF) are inadequate, even with inflamed meninges, and intrathecal administration may be necessary.
- Crosses the placental barrier and can accumulate in fetal plasma and amniotic fluid.
- May cause deafness in the fetus.
- 90% is excreted unchanged in the urine.
- Therapeutic drug monitoring (TDM) is needed for patients with renal impairment.
Streptomycin
- Resistance has emerged, ribosomal resistance to streptomycin develops readily.
- Mainly used as a second-line agent for tuberculosis.
- Should only be used in combination with other drugs to prevent the emergence of resistance.
- Used in combination with tetracycline for plague, tularemia, and sometimes brucellosis.
- Can be used in combination with penicillin for enterococcal endocarditis and viridans streptococcal endocarditis.
- Gentamicin has largely replaced streptomycin for these indications.
- Ototoxicity (irreversible), nephrotoxicity, fetal auditory toxicity, and neuromuscular paralysis are possible adverse effects.
Gentamicin
- Isolated from Micromonospora purpurea.
- Effective against both gram-positive and gram-negative bacteria.
- Used alone or in combination with beta-lactam antibiotics for synergistic effects.
- Effective against Pseudomonas, Proteus, Enterobacter, Klebsiella, Serratia, Stenotrophomonas, and other gram-negative rods that may be resistant to multiple antibiotics.
- Should not be used as a single agent to treat staphylococcal infections, including pneumonia.
- Resistance can develop rapidly, and poor lung tissue penetration is a concern.
- Therapeutic drug monitoring (TDM) is needed.
Gentamicin Administration
- Topical: Creams, ointments, and solutions used for infected burns, wounds, or skin lesions and the prevention of IV catheter infections.
- Intrathecal: Treat meningitis caused by gram-negative bacteria.
Gentamicin Adverse Reactions
- Nephrotoxicity (reversible and mild) occurs in 5–25% of patients receiving gentamicin for longer than 3– 5 days.
- Ototoxicity (likely irreversible) can cause deafness.
Amikacin
- Effective against many gram-negative enteric bacteria.
- Resistant to many enzymes that inactivate gentamicin and tobramycin.
- Often used to treat severe, hospital-acquired infections with multidrug-resistant Gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter, and Enterobacter.
- Liposomal amikacin (inhalation) is under development to treat respiratory diseases like cystic fibrosis, Pseudomonas aeruginosa, and non-tubercular mycobacterial infections.
Tobramycin
- Antibacterial spectrum and pharmacokinetics similar to gentamicin.
- Narrow spectrum of activity and active against Gram-negative bacteria (not active against gram-positive bacteria except for Staphylococcus aureus).
- Used clinically to eliminate Pseudomonas aeruginosa in respiratory tract infections complicating cystic fibrosis patients.
- Good lung penetration, and nephrotoxicity and ototoxicity rarely occur via inhalation due to low systemic absorption.
- Used for life-threatening gram-negative infections, such as meningitis in neonates, brucellosis, pelvic inflammatory disease, and Yersinia pestis infection (plague).
Neomycin & Kanamycin
- Neomycin and kanamycin are closely related.
- Antimicrobial Activity & Resistance: Active against gram-positive and gram-negative bacteria and some mycobacteria. Pseudomonas and streptococci are generally resistant.
- Limited to topical and oral use (Neomycin is too toxic for parenteral use).
- Topical Administration: Ointments (neomycin-polymyxin-bacitracin combination) to treat infected skin lesions.
- Oral Administration: In preparation for elective bowel surgery and hepatic coma.
Netilmicin
- Shares many characteristics with gentamicin and tobramycin (interchangeable).
- Used only for the treatment of serious infections, especially those resistant to gentamicin.
- Dosage and routes of administration are the same as for gentamicin.
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Description
Explore the role of protein synthesis inhibitors in combating bacterial infections, focusing particularly on aminoglycosides. Learn about their mechanisms, uses, and the significance of dosage monitoring. This quiz will also touch upon the issues of antibiotic resistance related to overuse.
