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Quinolones

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Fluoroquinolones

Ciprofloxacin

Levofloxacin

Mechanism of action

  • inhibit bacterial DNA gyrase (main target in gram -ve bacteria) and topoisomerase IV (main target in gram +ve bacteria)
  • although this major mechanism of action requires cell division quinolones also have other mechanisms of action which result in them being active against bacteria that are not actively replicating
  • cross outer membrane of gram -ve bacteria via porins
  • affinity for bacterial target enzymes is 1000 times that for equivalent human enzymes
  • minimum inhibitory concentration (MIC) is increased in the presence of magnesium and in acid environments (pH <6)

Resistance

  • mutation of target enzymes
  • porin impermeability
  • efflux of drug

Affect all fluoroquinolones although some compounds may remain active against resistant strains due to higher intrinsic activity

Pharmacodynamics

  • concentration dependent killing
    • ratio of area under the concentration-time curve to MIC is thought to be the factor most closely related to clinical efficacy
  • exert a post-antibiotic effect. Duration depends on pathogen, drug concentration and period of exposure to drug

Adverse effects

  • GI complaints: nausea, vomiting, abdominal pain
  • CNS: headaches, vertigo, tremors, fits
  • may exacerbate myasthenia gravis
  • interferes with development of cartilage in experimental animals and therefore not recommended in children, and pregnant and lactating women
  • leucopaenia, anaemia, eosinophilia, thrombocytosis
  • increased transaminases and creatinine

Drug interactions

Drug Effect
Aluminium and magnesium containing antacids, sucralfate ▒ Zn, Fe and Ca salts Decrease absorption of quinolones from GI tract
Xanthines Quinolones interfere with metabolism resulting in higher blood concentrations of theophylline and other xanthines. Effect is absent with ofloxacin and norfloxacin
Probenicid Blocks renal tubular secretion of quinolones
▀ lactams Sometimes synergistic
Chloramphenicol, rifampicin, nitrofurantoin Antagonistic (except with ciprofloxacin, ofloxacin)
Cyclosporin Moderate reduction in clearance of cyclosporin

Ciprofloxacin

Pharmacokinetics

- admin PO/IV. All fluoroquinolones well absorbed from GI tract except in the critically ill, in whom studies of bioavailability have had differing results. Therefore it seems sensible to administer ciprofloxacin intravenously in this group. 
- distribution: all have high volumes of distribution and penetrate intracellularly (thus reach important intracellular organisms such as Legionella, Chlamydia and Mycobacteria. Concentrated in alveolar lining fluid
- elimination: approximately 30% metabolized in the liver, 60% excreted in the urine (20% as metabolites) and 15% in bile

Spectrum of activity

Sensitive micro-organisms include:

  • enterobacteria
  • Pseudomonas aeruginosa
  • Acinetobacter
  • Haemophilus spp.
  • methicillin-sensitive Staph. aureus
  • Neisseria spp.
  • Legionella
  • Brucella spp.
  • Bordatella spp.
  • Corynebacterium spp.

Bacteria with intermediate sensitivity include:

  • Streptococcus spp.
  • Mycoplasma spp.
  • Chlamydia spp.
  • Rickettsia spp.
  • M. tuberculosis

Resistant bacteria include:

  • Xanthomonas maltophilia

Levofloxacin

S-enantisomer of ofloxacin

Pharmacokinetics

  • administration: PO or IV. There are currently no published data on levofloxacin absorption in the critically ill. Absorption in healthy volunteers is good but is reduced by concomitant adminstration of antacids, divalent cations (may be in NG feed) and sucralfate (if administered within 2 hours)
  • elimination: 80% excreted by kidneys unchanged. Dosage should be decreased in patients with significant renal dysfunction
  • Cmax and AUC are at least as high following IV adminstration to critically ill patients as they are in healthy volunteers suggesting that no change in dosing is necessary.

Spectrum of activity

Similar to ciprofloxacin but greater activity against pneumococcus and methicillin sensitive Staph. aureus. Whether levofloxacin is less active than ciprofloxacin against Pseudomonas aeruginosa is controversial.

Moxifloxacin

Further reading

Rovold KA, Neuhauser M. Pharmacokinetics and pharmacodynamics of fluoroquinolones. Pharmacotherapy 2001;21:233S-252S

Van Bambeke F. Mechanisms of action. In Armstrong D, Cohen J. Infectious diseases. Mosby, London, 1999, pp7/1.1-7/1.14

Potential conflict of interest

The Dept of Anaesthesia & Intensive Care, The Chinese University of Hong Kong received funding for research on levofloxacin from Daiichi Pharmaceuticals  in 2002 and 2003


 


ęCharles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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