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What is the mechanism of action of protein synthesis inhibitors?
What is the mechanism of action of protein synthesis inhibitors?
Most protein synthesis inhibitors are considered to be _______, with the exception of a few that are _______ against certain organisms.
Most protein synthesis inhibitors are considered to be _______, with the exception of a few that are _______ against certain organisms.
Tetracycline and macrolide resistance are uncommon.
Tetracycline and macrolide resistance are uncommon.
False
Which of the following antibiotics can be administered orally, EXCEPT?
Which of the following antibiotics can be administered orally, EXCEPT?
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Macrolides have a macrocyclic lactone ring attached to deoxy sugars.
Macrolides have a macrocyclic lactone ring attached to deoxy sugars.
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What is the primary reason for the frequent use of macrolides in the outpatient setting?
What is the primary reason for the frequent use of macrolides in the outpatient setting?
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Macrolides are appropriate for infections where bactericidal activity is required, such as meningitis.
Macrolides are appropriate for infections where bactericidal activity is required, such as meningitis.
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Which of the following is NOT a recognized side effect of macrolides?
Which of the following is NOT a recognized side effect of macrolides?
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Which specific macrolide is known to accumulate in macrophages?
Which specific macrolide is known to accumulate in macrophages?
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Which macrolide has the longest half-life and the largest volume of distribution?
Which macrolide has the longest half-life and the largest volume of distribution?
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Azithromycin inhibits cytochrome P450 enzymes, leading to potential drug interactions.
Azithromycin inhibits cytochrome P450 enzymes, leading to potential drug interactions.
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Which macrolide is typically used for a shorter period compared to clarithromycin?
Which macrolide is typically used for a shorter period compared to clarithromycin?
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The 2g extended-release oral suspension of azithromycin should be taken with food.
The 2g extended-release oral suspension of azithromycin should be taken with food.
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Fidaxomicin's mechanism of action is similar to other macrolides.
Fidaxomicin's mechanism of action is similar to other macrolides.
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What is the primary target of fidaxomicin's action?
What is the primary target of fidaxomicin's action?
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Which of the following is NOT a common adverse effect associated with fidaxomicin?
Which of the following is NOT a common adverse effect associated with fidaxomicin?
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Fidaxomicin has a broad spectrum of activity, effectively targeting a wide range of bacterial infections.
Fidaxomicin has a broad spectrum of activity, effectively targeting a wide range of bacterial infections.
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Fidaxomicin is known to cause significant cross-resistance with other macrolides.
Fidaxomicin is known to cause significant cross-resistance with other macrolides.
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Fidaxomicin's primary site of action within the body is the bloodstream.
Fidaxomicin's primary site of action within the body is the bloodstream.
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Telithromycin is considered a first-line treatment for community-acquired pneumonia.
Telithromycin is considered a first-line treatment for community-acquired pneumonia.
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Which macrolide is generally preferred over clarithromycin in treating community-acquired pneumonia in outpatients with comorbidities such as COPD?
Which macrolide is generally preferred over clarithromycin in treating community-acquired pneumonia in outpatients with comorbidities such as COPD?
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Clarithromycin is a primary agent used to treat Mycobacterium avium complex (MAC) infections.
Clarithromycin is a primary agent used to treat Mycobacterium avium complex (MAC) infections.
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Traveler's diarrhea is primarily treated with clarithromycin.
Traveler's diarrhea is primarily treated with clarithromycin.
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Which antibiotic is a key component in treating H. pylori-induced GI ulcer disease?
Which antibiotic is a key component in treating H. pylori-induced GI ulcer disease?
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Which of the following is a common mechanism of resistance to macrolides?
Which of the following is a common mechanism of resistance to macrolides?
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Clarithromycin and azithromycin are known to exhibit cross-resistance with erythromycin.
Clarithromycin and azithromycin are known to exhibit cross-resistance with erythromycin.
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Telithromycin is effective against macrolide-resistant organisms.
Telithromycin is effective against macrolide-resistant organisms.
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Which antibiotic is NOT primarily excreted in the bile?
Which antibiotic is NOT primarily excreted in the bile?
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The dosage of clarithromycin should be adjusted in patients with renal impairment.
The dosage of clarithromycin should be adjusted in patients with renal impairment.
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Telithromycin can prolong the QT interval, increasing the risk of cardiac arrhythmias.
Telithromycin can prolong the QT interval, increasing the risk of cardiac arrhythmias.
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What is the primary concern regarding the use of telithromycin in patients with hepatic dysfunction?
What is the primary concern regarding the use of telithromycin in patients with hepatic dysfunction?
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The use of telithromycin is widely recommended due to its effectiveness and safety profile.
The use of telithromycin is widely recommended due to its effectiveness and safety profile.
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Which of the following is NOT a known drug interaction with macrolides?
Which of the following is NOT a known drug interaction with macrolides?
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What is the primary mechanism by which macrolides interact with digoxin?
What is the primary mechanism by which macrolides interact with digoxin?
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Macrolide use during pregnancy is considered safe for all trimesters.
Macrolide use during pregnancy is considered safe for all trimesters.
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Most antibiotics are considered safe and have no known interactions with other medications.
Most antibiotics are considered safe and have no known interactions with other medications.
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Clarithromycin is considered safe for use during breastfeeding.
Clarithromycin is considered safe for use during breastfeeding.
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Study Notes
Pharmacology 3: Protein Synthesis Inhibitors (Part 1)
-
Introduction
- Mechanism of Action (MOA): Protein synthesis inhibitors bind to and interfere with bacterial ribosomes.
- Most are bacteriostatic, a few are bactericidal against certain organisms.
- Tetracycline and macrolide resistance is common.
- All can be administered orally, except tigecycline and streptogramins.
Macrolides
- Structure: Closely related compounds characterized by a macrocyclic lactone ring attached to deoxy sugars.
- Pharmacological Action: Bacteriostatic drugs.
- Clinical Use: Not appropriate for infections requiring bactericidal activity, such as meningitis and endocarditis.
Macrolide Structure (Chemical Structure)
- Shows the core structure and variable side groups (R1, R2) for erythromycin and clarithromycin
- Different side chains (substituents) determine the specific macrolide.
Macrolides: Clinical Applications
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Azithromycin properties: Widely used outpatient setting due to broad-spectrum and respiratory pathogen coverage.
- Important because of increasing resistance in Streptococcus pneumoniae.
- Ketolide derivatives (like telithromycin) were developed to counter this resistance and provide better coverage of resistant strains.
Examples of Drugs
-
Erythromycin: The first macrolide drug.
- Used orally, parenterally, topically, and often as a penicillin alternative for allergy cases.
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Telithromycin: A semisynthetic derivative of erythromycin, a "ketolide."
- Shown to be effective against resistant organisms, particularly Streptococcus pneumoniae.
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Azithromycin: A semisynthetic macrolide derivative.
- Good for a short duration treatment with once daily dosage, due to its superior intra-cellular half-life.
-
Clarithromycin: Methylated form of erythromycin with improved features.
- Often taken with food.
Mechanism of Action (MOA)
- Bind irreversibly to a site on the bacterial ribosome (50S subunit).
- Interfere with the translocation steps of protein synthesis.
- Can also interfere with other steps, such as transpeptidation.
- Generally considered bacteriostatic, but can be bactericidal at high doses.
Resistance to Macrolides
- Resistance is a growing issue.
- Causes include: inability of the organism to take up the antibiotic, efflux pumps, decreased affinity of the 50S ribosomal subunit for the antibiotic, and plasmid-associated erythromycin esterases.
Administration and Pharmacokinetics
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Erythromycin:
- Base is destroyed by gastric acid, so enteric-coated or esterified forms are used.
- Similar to azithromycin, it's available in IV forms.
- Food interferes with its absorption.
- Absorption: all macrolides except erythromycin are stable in stomach acid. Clarithromycin absorption is higher when taken with food.
- Distribution: Erythromycin is distributed throughout body fluids except CSF, and accumulates in macrophages. All four drugs accumulate in the liver.
- Metabolism: Erythromycin and telithromycin are extensively metabolized hepatically, and can inhibit the oxidation of other drugs, particularly those processed by cytochrome P450.
- Elimination: Erythromycin and azithromycin are primarily concentrated and excreted in the bile. Partial reabsorption occurs through enterohepatic circulation. Clarithromycin, plus metabolites, are eliminated by the kidneys. Dosage adjustments might be needed in renal impairment cases.
Contraindications and Side Effects
- Patients with liver disease should be cautious when using macrolides.
- Severe hepatotoxicity (especially with telithromycin) limits use, as alternatives are often available.
- Macrolides can prolong the QT interval, requiring caution in patients with arrhythmia risk or individuals concurrently using other proarrhythmic drugs.
- Side effects include gastric distress and motility problems, cholestatic jaundice, and ototoxicity.
Drug Interactions
- Macrolides (erythromycin, telithromycin, clarithromycin) can inhibit the hepatic metabolism of certain drugs. This can lead to an accumulation and toxicity.
- Azithromycin drug interaction with digoxin may occur. The antibiotic may eliminate a gut flora that otherwise inactivates the digoxin. This can result in more drug absorption and potentially increased digoxin levels.
Pharmacokinetics of Selected Macrolides (Tables)
- Includes data on oral absorption, half-life, conversion to active metabolites, and urinary excretion for clarithromycin, azithromycin, erythromycin, and telithromycin.
Clinical Indications
- Erythromycin: Drug of choice for corynebacterial infections (diphtheria, sepsis), and erythrasma.
- Azithromycin: Frequently preferred for community-acquired pneumonia in outpatients with comorbidities (i.e., COPD)
- Clarithromycin: A primary treatment agent for Mycobacterium avium complex (MAC) infections.
- Other uses mentioned are: upper/lower respiratory tract infections, traveller's diarrhea, and H.pylori-induced GI ulcer disease, often in combination with other medications.
Ketolides: Telithromycin
- Indications: FDA-approved for mild to moderate community-acquired pneumonia
- Adverse effects: includes fatal hepatotoxicity, potentially fatal myasthenia gravis exacerbations, and visual disturbances
- Interactions: It inhibits the CYP3A4 enzyme system, and prolongs the QT interval.
Other Classes of Antibiotics
- Lincosamides: (incl. clindamycin)
- Streptogramins: (incl. quinupristin/dalfopristin)
- Chloramphenicol
- Oxazolidinones: (incl. linezolid, tedizolid)
- Pleuromutilins: (incl. Lefamulin)
- Specific details on each class and individual antibiotics are available in separate sections of the notes.
Fidaxomicin
- Mechanism of Action (MOA): Acts on the sigma subunit of RNA polymerase in susceptible bacteria for terminating protein synthesis, which leads to bacterial cell death.
- Specificity and Use: Very narrow spectrum, mostly targeting g+ve aerobes and anaerobes such as staphylococci and enterococci. Primary for Clostridium difficile.
- Oral Administration and Gastrointestinal Absorption: Minimally absorbed into the body after oral administration, therefore remaining mostly in the gastrointestinal tract, preventing systemic effects.
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Description
Explore the mechanisms, structures, and clinical applications of protein synthesis inhibitors in this pharmacology quiz. Focused on macrolides and their role in bacterial treatment, you'll learn about their actions, resistance issues, and specific uses. This is part 1 of a comprehensive series on pharmacological agents.
