QUINOLONES

Overview

• Quinolones -- not new
  • General spectrum -- gram(-)
  • nalidixic acid (NegGram^R)
    • UTI only
    • Rapid resistance a problem
  • oxolinic acid (UtiBID^R)
• FLUOROquinolones -- relatively new - 1990s
  • General spectrum -- broad
  • Veterinary Medicine
    • enrofloxacin (Baytril^R) -- companion animals
    • sarafloxacin (Saraflox^R) -- poultry
    • FDA/CVM -- Banned extralabel use in food animals, Fall '95
    • CDC opposed to use of this group in animals!
  • Human Medicine
    • norfloxacin (Noroxin^R)
    • ciprofloxacin (Cipro^R)
• Act on DNA

Structure and Chemical Characteristics

• Zwitterions -- so no easy prediction of ion trapping
• Piperazinyl group
  • Increases activity against Pseudomonas spp.
• Fluorine atom
  • Increases activity agaisnt some gram(+) bacteria
• Incompatibilities
  • Large inocula
  • Bivalent cations (e.g., Mg⁺⁺)
  • Acidic pH
  • Urine

Mechanism of Action

• Cidal at 1 to 4-fold MIC
• Inhibits relaxation of supercoiled (packed) DNA needed for DNA replication
• Increases double-strand DNA breakage
• Inhibit the A subunit of DNA gyrase, a type II topoisomerase
• The type II topoisomerase --
  • nicks & seals DNA during replication
  • needed for DNA to uncoil and recoil
• Gyrase required for plasmid replication
  • Fluoroquinolones may reduce plasmid mediated resistance in other drugs
• Bacteria DO become resistant to these drugs
  • MAJOR CONCERN of Center for Disease Control & Prevention!!!!
  • Don't believe the salesmen and ads
• AUC is crucial to killing**
  • Enrofloxacin experiments in animal models [Meinen et al., '95]
    • Dogs & mice /w Staph and E. coli
    • Found Peak and AUC crucial, not time above MIC
    • Killing concentration dependent, not time dependent

Resistance

• Major problem with nalidixic acid -- compliance (q6h)
• Develops slowly by mutation
• Reduction of gyrase affinity for gyrase
• Decreased penetration due to loss of key membrane proteins
• Cross resistance among fluoroquinolones

Pharmacokinetics

Absorption/administration

• Injectable
• Oral
  • F= >70% (humans)
  • F= >80% dogs -- enrofloxacin

Distribution

• Nalidixic acid -- only UTI
  Insufficient conc. elsewhere
• Fluoroquinolones
  • Cross membranes well
  • Wide distribution
    • respiratory tract
    • prostate
    • bone
    • cartilage
    • CSF

Elimination

• Renal excrection - active drug
• Probenecid sensitive
• Half-life
  • Dog -- enrofloxacin = >3 hr
  • Humans -- ciprofloxacin and norfloxacin = 3-4 hr
    • Renal failure =5 - 10 hr

Adverse effects

Allergies

• Hypersensitivity can occur
• Contraindicates use

Biological effects

• Not important problem

Direct toxicity

• Generally low toxicity -- recommended doses
• PO enrofloxacin rarely causes vomition (0.7%)
• Crystallization in acid urine
  • Keep water intake high
• Avoid in pregnant animals
  • Monkeys -- embryonic loss, vomiting, anorexia
• Arthropathies / cartilage deterioration
  • Avoid severe exercise
  • Avoid dogs <1 yr old
  • Young dogs
    • Lameness observed w/in 2 days
    • Typically resolved by 8 wks after stop
    • Erosion of articular cartilage
    • Contraindicated
      • Small dogs & medium -- before 2 to 8 months
      • Large dogs -- up to 18 months
  • Cats -- also sensitive
• High doses
  • CNS, etc.
• Humans
  • < 3% & mild
  • nausea
  • upper GI discomfort
  • dizziness
  • rarely cause cessation
  • Joint toxicity
    • Contraindicated up to 18 yrs

Drug interaction

• May interfere with hepatic biotransformation
  • theophylline
  • warfarin

Indications

• Inactive vs anaerobes
• Claims for enrofloxacin (Baytril^R) Dogs
  • Dermal infections -- wounds and abscesses
    • Susceptible strains of E. coli, Klebsiella pneumoniae, Proteus mirabilis, and Staphylococcus aureus,
    • Pseudomonas aeruginosa if increase dose
      (Bowersock'95)
  • Respiratory infections -- pneumonia, tonsilitis, rhinitis
    • caused by susceptible strains of E. coli and Staphylococcus aureus
  • Urinary cystitis
    • caused by susceptible strains of E. coli, Proteus mirabilis, and Staphylococcus aureus.
• Claims for enrofloxacin -- cats
  • Dermal infections -- wounds and abscesses
    • caused by susceptible strains of Pasteurella multocida, Staphylococcus aureus, Staphylococcus epidermidis
• Claims for sarafloxacin (Saraflox^R) -- poultry only
  • Water soluble powder for PO
  • Injectable
  • NOT USE EXTRA-LABEL in Food animals
• Humans
  • Norfloxacin better for UTI
  • Ciprofloxacin -- wide range of infections
    • pneumonias, bone infections, diarrhea, skin infections and urinary tract infections.
• Extra-label
  • Dogs -- norfloxacin -- Enterococcus spp. infections
  • Dogs -- norfloxacin -- better than enrofloxacin or ciprofloxacin for enteric Streptococci
    (Bowersock'95)

References

• USPDI91: USP Drug Information for the Health Care Professional, 11th edition, 1991. U.S. Pharmacopeial Convention, Inc., Rockville, MD.
• Walker, R.C. and A.J. Wright. The Quinolones. Mayo Clin Proc 62:1007-1-12, 1987.
• Mobay/Haver promotional material for Baytril[R], December 1988.
• News article -- CVM Bans Extra-label Fluoroquinolone, JAVMA 208(1):11, 1996
• Barragry'94 -- Tetracyclines, Chloramphenicol, and Quinolones, Chapter 11, in Barragry, Thomas B., Veterinary Drug Therapy, Lea & Febiger, Philadelphia, 1994. Chapter 11.
• Meinen, J.B., J.T. McClure, E. Rosin, 1996, Pharmacokinetics of enrofloxacin in clinically normal dogs and mice and drug pharmacodynamics in neutropenic mice with Eschericia coi and staphylococcal infections. Am J Vet Res 56(9):1219-1224.

Study Questions

1. How does the spectrum of action of nalidixic acid differ from those of the newer fluoroquinolones?
2. How does the tendency for bacteria to develop of resistance to fluroquinolones compare with nalidixic acid?
3. How do the sites of susceptible infections compare for nalidixic acid versus the fluoroquinolones?
4. What tissue is most susceptible to quinolone toxicity? Are fluoroquinolones usually very toxic otherwise?
5. Should quinolone derivatives be used in rapidly growing animals and humans?
6. On what is the manufacturer's claim based that fluoroquinolones cannot be cross-resistant with other antiinfective agents?
7. Can fluoroquinolones be used "extra-label" in food producing animals?
8. What does it mean that killing of Staphylocci and E. coli is "concentration" dependent and not "time" dependent?

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   Gordon L. Coppoc, DVM, PhD
   Professor of Veterinary Pharmacology
   Head, Department of Basic Medical Sciences
   School of Veterinary Medicine
   Purdue University
   West Lafayette, IN 47907-1246
   Tel: 317-494-8633Fax: 317-494-0781
   Email: coppoc@vet.purdue.edu
   
   Last modified
   9:32 AM on 4/17/96
   GLC