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Unraveling Quinolones: Antimicrobial Class Review

Delve into the world of quinolones with a succinct and detailed lecture by Dr. Logan Atkins on the history, mechanism of action, pharmacokinetics, and antimicrobial activities of these antibiotics. Discover the generations, routes of administration, and clinical uses of quinolones.

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Unraveling Quinolones: Antimicrobial Class Review

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  1. Quinolones Class Review Logan Atkins, MD

  2. Why This Lecture? • We don’t get a lot of antimicrobial lectures. • The ones we get are usually very broad. • This makes a succinct drug class for lecture. • If you guys like this, I (or we) can make more lectures on specific antibiotic classes, or make this one less crappy. • This (and any others) can be put up on TigerDocs.org for a quick reference.

  3. Objectives • Get uncomfortably familiar with quinolones. • Make Dr. McLemore proud. • Get dat deep knowledge, son. • Does it matter? No one ever reads the objectives anyway.

  4. History • 2000 B.C. – Here, eat this root • 1000 A.D. – That root is heathen. Here, say this prayer. • 1850 A.D. – That prayer is superstition. Here, drink this potion. • 1920 A.D. – That potion is snake oil. Here, swallow this pill. • 1945 A.D. – That pill is ineffective. Here, take this penicillin. • 1955 A.D. – Oops....bugs mutated. Here, take this tetracycline. • 1962-1999 – 39 more "oops"...Here, take this more powerful antibiotic. • 2000 A.D. – The bugs have won... Here, eat this root.

  5. History • Nalidixic Acid • 1st generation • Introduced in 1962 • Modifications since have resulted in 2nd, 3rd, 4th generation drugs used today

  6. Generations

  7. Quiz Time What is the mechanism of action of quinolone antibiotics? A) Binding of PBP B) Inhibit DNA gyrase C) Inhibit DNA topoisomerase IV D) A & C E) B & C F) Giraffe

  8. Mechanism of Action • Enter the cell through porins (passive diffusion) • Binds DNA gyrase & topoisomerase IV • These remove positive coils that occur during replication • In gram negatives (E. coli), binds gyrase preferentially • In gram positives (S. aureus), binds topoisomerase preferentially • Stops replication, transcription, repair, recombination • This is a Bactericidal Drug

  9. Pharmacokinetics • Available: Ciprofloxacin, Ofloxacin, Levafloxacin, Moxifloxacin • Cipro, Levaquin, Avelox available both PO & IV • Cipro & Ofloxacin available as drops • Bioavailability: 70-90+ % • Postantibiotic effect of 1-2 hours • Elimination half lives 1.5-16 hours

  10. Quiz Time Which is a more effective route of administration? A) Oral B) Intravenous C) Both are equally effective

  11. Pharmacokinetics • IV & Oral routes are equally effective, with a few caveats • Oral doses can chelate with cations like aluminum, magnesium, calcium, iron, and zinc • Oral doses slowed with food - peak levels delayed by up to an hour

  12. Pharmacokinetics • Effects are concentration-dependent • Bactericidal activity improves as serum drug concentration reach up to 30x the MIC • At high concentration, can disintegrate inner/outer bacterial membranes

  13. Pharmacokinetics • Quinolones have very good tissue penetration • Kidney • Lung • Gallbladder • Genital tract • Prostate • NOT blood-brain barrier • Exceptional intracellular activity in neutrophils, macrophages • Bone, prostatic fluid, saliva, cerebrospinal fluid levels do not exceed serum levels

  14. Pharmacokinetics • Eliminated by renal or hepatic metabolism • Hydrophilic (renal clearance) • Cipro, Levaquin, Ofloxacin • Lipophilic (hepatic clearance) • Sparfloxacin, Gatifloxacin, Moxifloxacin • Dose accordingly for renal/hepatic failure

  15. Antimicrobial Activity • Can be classified into four generations based on activity: • 1st - Nalidixic acid • Moderate G(-) activity with minimal systemic distribution • 2nd - Cipro, Ofloxacin • Expanded G(-) & atypical coverage, with limited G(+) activity • 3rd - Levaquin, Moxifloxacin, Gatifloxacin • Improved G(+) coverage • 4th - Moxifloxacin, Trovafloxacin • Improved G(+) coverage, some anaerobe coverage

  16. Antimicrobial Activity • Again, the only 4 readily-available quinolones at this time are: • Ciprofloxacin • Ofloxacin • Levofloxacin • Moxifloxacin • So let’s focus on what we use the most in our practice.

  17. Quiz Time Which of the following are “respiratory” quinolones? A) Cipro B) Levaquin C) Avelox (Moxifloxacin) D) Gentamicin

  18. Antimicrobial Activity • 2nd Generation • Ciprofloxacin (Cipro) & Ofloxacin (Floxin) • Various Gram negative cocci & bacilli • N. gonorrhea, P. aeruginosa, H. influenza, L. pneumophila • GI tract bugs • E. coli, Salmonella spp., Shigella spp., Vibrio spp., Yersinia enterocolitica • Atypicals - Chlamydia, Mycoplasma • M. tuberculosis? • Good for UTI, gastroenteritis, prostatitis, STDs, Otitis externa • Cipro is the most active against Pseudomonas • Cipro is NOT a “respiratory quinolone” • Clinical experiences & studies show association with pneumococcal bacteremia & meningeal seeding due to poor susceptibility

  19. Antimicrobial Activity • 3rd Generation • Levofloxacin (Levaquin) • Similar Gram negative coverage • Similar atypical coverage • Improved Gram positive coverage • Streptococcus pneumoniae - This & its atypical coverage are why it can be used as a first-line pneumonia treatment • Staphylococcus aureus • Enterococcus spp.

  20. Antimicrobial Activity • 4th Generation • Moxifloxacin (Avelox) • Similar Gram negative coverage • Similar atypical coverage • Improved Gram positive coverage • Improved S. aureus (MRSA) coverage - • S. pneumoniae - Avelox is 4-8x more active in vitro • Added anaerobic coverage • Actinomyces spp, Bacteroides spp, Clostridium perfringens, Lactobacillus, etc. • Now approved for treatment of complicated intra-abdominal infections • Otherwise, not approved for treatment of anaerobic infections

  21. Resistance • Kind of a Big Fat Deal • 3 Mechanisms • 1) Mutation of DNA gyrase or topoisomerase IV • 2) Expression of efflux mechanisms • 3) Protective proteins attached to gyrase • Encoded on a plasmid that can be horizontally transferred • Check your antibiogram • <70% susceptible E. coli to Cipro/Levaquin • <70% susceptible Pseudomonas • MRSA - Resistant.

  22. Adverse Effects • Keep quinolones from being first-line in many situations • C. difficile colitis - one of the most-associated classes (up to 55% in one study)

  23. Adverse Effects • GI effects • Most frequent (3-17%) • Anorexia, nausea, vomiting, discomfort, diarrhea • Nervous system • Occur in 0.9-11% • Most common - mild headache, dizziness, insomnia • Rare - hallucinations, seizure, delirium • Rash & allergy • Occur in 0.4-2.2% • Unspecified rash most frequent • Urticaria, angioedema, anaphylaxis very rare

  24. Adverse Effects • Arthropathy • Mostly in juvenile cases (thanks to our CF patients) • Leukopenia & Eosinophilia • <1%, usually not severe enough to warrant cessation of therapy

  25. Adverse Effects • And now for the big test items: • Tendinopathy & Rupture (Black Box Warning) • Uncommon in adults • Majority at Achilles, but also reported at rotator cuff, hand, biceps, thumb • Stronger risk if age >60, obese, using oral glucocorticoids, or female • STOP taking at first sign of tendon swelling, pain, and call physician

  26. Adverse Effects • Myasthenia Gravis (Black Box Warning) • Quinolones have neuromuscular blocking activity (remember the K+ channels) and can exacerbate myasthenia gravis symptoms • Some of these cases have resulted in full-blown respiratory failure, so there’s a black box warning now

  27. Adverse Effects • QT Prolongation • Due to inhibition of potassium channels (KCNH2 gene) • Moxifloxacin > Cipro/Levaquin/Ofloxacin • Use with caution in those at risk for Torsades • QT prolongation • Hypokalemia • Hypomagnesemia • Use of class IA (quinidine, procainamide) or III (amiodarone, sotalol) antiarrhythmics

  28. Adverse Effects • Dysglycemia • Risk highest for Moxifloxacin > Levaquin > Cipro • Liver Injury • Moxifloxacin & Levaquin associated with increased chance of acute liver injury within 30 days • Cipro shows no signs of this • Trovafloxacin was taken off the market for this

  29. Drug Interactions • May potentiate effect of warfarin • May increase caffeine/theophylline levels • May prolong QT if used with Class IA & III antiarrhythmics • May lead to hypo/hyperglycemia with antidiabetic agents • Absorption decreased if taken within 2 hours of multivalent cations

  30. Quick Review Class: Quinolones Mechanism: Binding DNA gyrase/topoisomerase IV (Bactericidal) Tissue Penetration: Great (except non-urine fluids & bone) Bioavailability: 70-90+ % (PO & IV) Clearance: Hepatic (Moxi), Renal (Cipro/Leva) Adverse Effects: GI effects, CNS effects, Tendinopathy, QT prolongation, Dysglycemia, Myasthenia exacerbation

  31. Quick Review • Can be classified into four generations based on activity: • 1st - Nalidixic acid • Moderate G(-) activity with minimal systemic distribution • 2nd - Cipro, Ofloxacin • Expanded G(-) & atypical coverage, with limited G(+) activity • 3rd - Levaquin, Moxifloxacin, Gatifloxacin • Improved G(+) coverage • 4th - Moxifloxacin, Trovafloxacin • Improved G(+) coverage, some anaerobe coverage

  32. More questions?

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