Macrolides and Ketolides Overview
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Questions and Answers

What is the primary mechanism of action for macrolides and ketolides?

  • Binding to the 50S subunit of the bacterial ribosome (correct)
  • Inhibition of cell wall synthesis
  • Blocking RNA polymerase activity
  • Interference with DNA replication

    • Which of the following antibiotics is considered a ketolide?

  • Azithromycin
  • Telithromycin (correct)
  • Clarithromycin
  • Erythromycin

    • Which antibiotic is typically used as an alternative for individuals allergic to penicillin?

  • Telithromycin
  • Erythromycin (correct)
  • Clarithromycin
  • Azithromycin

    • Clarithromycin has enhanced activity against which of the following organisms compared to erythromycin?

    <p>Haemophilus influenzae</p> Signup and view all the answers

    Which of the following statements about azithromycin is true?

    <p>Has led to increased resistance in Streptococcus pneumoniae</p> Signup and view all the answers

    What is the antibacterial spectrum of telithromycin compared to azithromycin?

    <p>Similar spectrum to azithromycin</p> Signup and view all the answers

    How do macrolides typically function against bacterial infections?

    <p>Bacteriostatic, may be bactericidal at higher doses</p> Signup and view all the answers

    Which of the following antibiotics has the least effectiveness against streptococci?

    <p>Azithromycin</p> Signup and view all the answers

    What mechanism contributes to resistance against macrolides?

    <p>Decreased affinity of the 50S ribosomal subunit</p> Signup and view all the answers

    Which of the following statements is true regarding the pharmacokinetics of erythromycin?

    <p>Erythromycin requires enteric-coated forms for adequate absorption.</p> Signup and view all the answers

    How is clarithromycin primarily excreted from the body?

    <p>In the urine</p> Signup and view all the answers

    Which ketolide is likely to be effective against macrolide-resistant organisms?

    <p>Telithromycin</p> Signup and view all the answers

    What effect does food have on the absorption of azithromycin?

    <p>Food decreases its absorption.</p> Signup and view all the answers

    Which of the following kinetics is associated with telithromycin?

    <p>Concentrates in neutrophils and macrophages</p> Signup and view all the answers

    What distinguishes azithromycin from erythromycin regarding pharmacokinetics?

    <p>Azithromycin has a larger volume of distribution.</p> Signup and view all the answers

    What mechanism can render macrolides ineffective?

    <p>Presence of erythromycin esterases in certain organisms</p> Signup and view all the answers

    What is the most common adverse effect associated with macrolides?

    <p>Gastrointestinal upset</p> Signup and view all the answers

    Which macrolide has been specifically associated with irreversible hearing loss?

    <p>Azithromycin</p> Signup and view all the answers

    What effect does erythromycin have at higher doses related to gastric function?

    <p>Induces smooth muscle contractions</p> Signup and view all the answers

    Which of the following can lead to toxic accumulation of drugs when interacting with erythromycin?

    <p>Inhibition of hepatic metabolism</p> Signup and view all the answers

    Which adverse effect is most commonly related to the estolate form of erythromycin?

    <p>Cholestatic jaundice</p> Signup and view all the answers

    In which condition should macrolides be used cautiously due to their effects on the QTc interval?

    <p>Proarrhythmic conditions</p> Signup and view all the answers

    What is the primary mechanism of action of fidaxomicin?

    <p>Disruption of bacterial transcription</p> Signup and view all the answers

    Which condition further limits the use of telithromycin due to its adverse effects?

    <p>Severe hepatotoxicity</p> Signup and view all the answers

    What type of anemia is characterized by the body's inability to produce new blood cells and can occur independently of dosage?

    <p>Aplastic anemia</p> Signup and view all the answers

    Which antibiotic can cause gray baby syndrome due to the neonate's low capacity to glucuronidate the drug?

    <p>Chloramphenicol</p> Signup and view all the answers

    What is a common metabolic effect of chloramphenicol that affects the metabolism of warfarin?

    <p>Inhibits hepatic mixed-function oxidases</p> Signup and view all the answers

    Which of the following is a potential adverse effect associated with clindamycin use?

    <p>Diarrhea leading to pseudomembranous colitis</p> Signup and view all the answers

    Which specific bacteria are primarily targeted when using clindamycin?

    <p>Staphylococcus and Streptococcus</p> Signup and view all the answers

    What is a major reason for the limited clinical utility of oral clindamycin?

    <p>Gastrointestinal intolerance</p> Signup and view all the answers

    What is the distribution issue faced by clindamycin concerning central nervous system treatment?

    <p>Poor entry into the CSF</p> Signup and view all the answers

    What is the ratio of streptogramins in the mixture quinupristin/dalfopristin?

    <p>30:70</p> Signup and view all the answers

    What is the primary mechanism of resistance seen in oxazolidinones?

    <p>Reduced binding at the target site</p> Signup and view all the answers

    Which of the following accurately describes the pharmacokinetics of linezolid?

    <p>Well absorbed and widely distributed after oral administration.</p> Signup and view all the answers

    What is the most common gastrointestinal adverse effect associated with oxazolidinones?

    <p>Nausea</p> Signup and view all the answers

    Which of the following oxazolidinones has a notable risk of causing irreversible peripheral neuropathies?

    <p>Linezolid with prolonged use greater than 28 days</p> Signup and view all the answers

    Which adverse effect is associated with concurrent use of oxazolidinones and large quantities of tyramine-containing foods?

    <p>Serotonin syndrome</p> Signup and view all the answers

    How is tedizolid primarily metabolized and eliminated from the body?

    <p>Via sulfation with fecal excretion</p> Signup and view all the answers

    What are the inactive metabolites of linezolid primarily formed through?

    <p>Oxidation</p> Signup and view all the answers

    Which of the following is a serious adverse effect that can arise from using oxazolidinones for more than 28 days?

    <p>Optic neuritis leading to blindness</p> Signup and view all the answers

    Study Notes

    Macrolides and Ketolides

    • Macrolides are antibiotics with a macrocyclic lactone structure with attached deoxy sugars.
    • Erythromycin was the first macrolide used clinically, as both a first choice and an alternative to penicillin for penicillin allergies.
    • Clarithromycin and azithromycin have similarities to erythromycin but have improvements.
    • Telithromycin is a semi-synthetic derivative of erythromycin, a “ketolide” antimicrobial agent.
    • Macrolides and ketolides bind irreversibly to the 50S subunit of the bacterial ribosome, inhibiting protein synthesis translocation steps.
    • They may also interfere with bacterial protein synthesis transpeptidation.
    • They are generally considered bacteriostatic but may be bactericidal at higher doses.
    • Their binding site is either identical to or in close proximity to clindamycin and chloramphenicol.

    Antibacterial spectrum

    • Erythromycin is effective against many of the same organisms as penicillin G.
    • Clarithromycin has activity similar to erythromycin but is effective against Haemophilus influenzae and has greater activity against intracellular pathogens such as Chlamydia, Legionella, Moraxella, Ureaplasma species, and Helicobacter pylori.
    • Azithromycin is less active than erythromycin against streptococci and staphylococci but is more active against respiratory pathogens such as H. influenzae and Moraxella catarrhalis.
    • Telithromycin has an antimicrobial spectrum similar to azithromycin.
    • Ketolides neutralize the most common resistance mechanisms that make macrolides ineffective.

    Resistance

    • The inability of the organism to take up the antibiotic.
    • Presence of efflux pumps.
    • Decreased affinity of the 50S ribosomal subunit for the antibiotic in gram-positive organisms.
    • Presence of erythromycin esterases in gram-negative organisms such as the Enterobacteriaceae.
    • Erythromycin has limited clinical use because of increasing resistance.
    • Clarithromycin and azithromycin share some cross-resistance with erythromycin.
    • Telithromycin may be effective against macrolide-resistant organisms.

    Pharmacokinetics

    • Erythromycin base is destroyed by gastric acid, requiring enteric-coated tablets or esterified forms for oral administration.
    • Clarithromycin, azithromycin, and telithromycin are stable in stomach acid and are readily absorbed.
    • Food interferes with the absorption of erythromycin and azithromycin but can increase the absorption of clarithromycin.
    • Telithromycin is administered orally without regard to meals.
    • Erythromycin and azithromycin are available in IV formulations.

    Distribution

    • Erythromycin distributes well to all body fluids except the CSF.
    • It is one of the few antibiotics that diffuses into prostatic fluid and accumulates in macrophages.
    • All four drugs concentrate in the liver.
    • Clarithromycin, azithromycin, and telithromycin are widely distributed in the tissues.
    • Azithromycin concentrates in neutrophils, macrophages, and fibroblasts, and serum concentrations are low.
    • Azithromycin has the largest volume of distribution of the four drugs.

    Elimination

    • Erythromycin, azithromycin, and telithromycin undergo hepatic metabolism.
    • Erythromycin, azithromycin, and telithromycin are excreted in the bile.
    • Partial reabsorption occurs through the enterohepatic circulation.
    • Clarithromycin is hepatically metabolized, and the active drug and its metabolites are excreted in the urine.
    • Clarithromycin dosages should be adjusted in patients with renal impairment.
    • They can inhibit the oxidation of many drugs through their interaction with the cytochrome P450 system.
    • Clarithromycin can interfere with the metabolism of theophylline, statins, and numerous antiepileptics.

    Adverse Effects

    • Gastric distress and motility: Gastrointestinal upset is most common, possibly leading to poor patient compliance.
    • Cholestatic jaundice: More common with the estolate form of erythromycin and reported with other formulations and agents in this class.
    • Ototoxicity: Transient deafness has been associated with erythromycin, especially at high doses. Azithromycin has also been associated with irreversible hearing loss.
    • QTc prolongation: Macrolides and ketolides may prolong the QTc interval, requiring caution in individuals with proarrhythmic conditions or concomitant use of proarrhythmic agents.

    Contraindications

    • Patients with hepatic dysfunction should be treated cautiously with erythromycin, telithromycin, or azithromycin.
    • Severe hepatotoxicity with telithromycin has limited its use due to alternative therapies.

    Drug interactions

    • Erythromycin, telithromycin, and clarithromycin can inhibit the hepatic metabolism of various drugs, leading to toxic accumulation.
    • An interaction with digoxin may occur. One theory suggests the antibiotic eliminates intestinal flora that ordinarily inactivates digoxin, resulting in greater reabsorption of digoxin from the enterohepatic circulation.

    Fidaxomicin

    • Fidaxomicin is a macrocyclic antibiotic with a structure similar to the macrolides.
    • Fidaxomicin acts on the sigma subunit of RNA polymerase, disrupting bacterial transcription and terminating protein synthesis, leading to cell death in susceptible organisms.
    • Fidaxomicin has a narrow spectrum of activity limited to gram-positive aerobes and anaerobes.

    Chloramphenicol

    • Chloramphenicol inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit.
    • It is an effective broad spectrum antibiotic especially against gram-negative bacterial infections.
    • It is used to treat serious infections such as meningitis, typhoid fever, and Rocky Mountain spotted fever.
    • Chloramphenicol can cross the placenta and is excreted in breast milk, making it a common choice for treating neonatal infections.
    • It is commonly administered intravenously.
    • Although it is not a preferred antibiotic, it is still used for certain infections, particularly when other options are less effective.

    Adverse Effects

    • Hematopoietic toxicity: The classic adverse effect is dose-related bone marrow suppression, manifesting as anemia, leukopenia, and thrombocytopenia. It's a rare but serious adverse effect.
    • Gray baby syndrome: Neonates have limited capacity for glucuronidation of the antibiotic and underdeveloped renal function, leading to drug accumulation.
    • This accumulation interferes with mitochondrial ribosome function, causing poor feeding, depressed breathing, cardiovascular collapse, cyanosis, and death.
    • Adults receiving very high doses of chloramphenicol may also exhibit this toxicity.

    Drug interactions

    • Chloramphenicol inhibits some hepatic mixed-function oxidases, preventing the metabolism of drugs like warfarin and phenytoin and potentiating their effects.

    Clindamycin

    • Clindamycin (lincosamides) has a mechanism of action similar to macrolides.
    • Clindamycin is used primarily for gram-positive organisms, including MRSA, streptococcus, and anaerobic bacteria.
    • Resistance mechanisms are the same as for erythromycin, and cross-resistance has been described.
    • C. difficile is resistant to clindamycin.
    • Clindamycin is available in both intravenous and oral formulations, but oral use is limited by gastrointestinal intolerance.
    • It distributes well into all body fluids but has poor entry into the CSF.
    • Clindamycin undergoes extensive oxidative metabolism and is excreted into bile and urine.
    • Accumulation has been reported in patients with severe renal impairment or hepatic failure.
    • Low urinary excretion of active drug limits its clinical utility for urinary tract infections.
    • The most common adverse effect is diarrhea, which may represent a serious pseudomembranous colitis caused by overgrowth of C. difficile.

    Quinupristin/Dalfopristin

    • Quinupristin/dalfopristin is a mixture of two streptogramins.

    Oxazolidinones

    • Oxazolidinones are synthetic antibiotics with a unique mechanism of action.
    • They inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit.
    • Oxazolidinones are effective against gram-positive bacteria, including MRSA and vancomycin-resistant enterococcus (VRE).
    • Linezolid and tedizolid are the two currently available oxazolidinones.
    • They are frequently used to treat serious infections, particularly those caused by drug-resistant organisms.

    Resistance

    • Resistance primarily occurs via reduced binding at the target site.
    • Reduced susceptibility and resistance have been reported in S. aureus and Enterococcus sp.

    Pharmacokinetics

    • Linezolid and tedizolid are well-absorbed after oral administration, and IV formulations are also available.
    • They distribute widely throughout the body.
    • Linezolid is metabolized via oxidation to inactive metabolites.
    • It is excreted by renal and nonrenal routes
    • Tedizolid is metabolized by sulfation, and the majority of elimination occurs via the liver.
    • It is excreted in the feces
    • No dose adjustments are required for either agent for renal or hepatic dysfunction.

    Adverse effects

    • Gastrointestinal upset, nausea, diarrhea, headache, and rash are the most common adverse effects.
    • Thrombocytopenia has been reported, usually in patients taking the drug for more than 10 days.
    • Irreversible peripheral neuropathies and optic neuritis causing blindness have been associated with greater than 28 days of use.
    • Linezolid and tedizolid possess nonselective monoamine oxidase inhibitory activity.
    • They can lead to serotonin syndrome if given concomitantly with tyramine-containing foods, selective serotonin reuptake inhibitors, or monoamine oxidase inhibitors.
    • The condition is reversible upon drug discontinuation.

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    Description

    Explore the key features of macrolides and ketolides, including their structures, mechanisms of action, and clinical applications. Learn about the crucial differences between erythromycin, clarithromycin, azithromycin, and their semi-synthetic derivative, telithromycin. This quiz offers insights into their antibacterial spectrum and modes of action.

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