Fluoroquinolones

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[edit] Description

Fluoroquinolones are derived from quinolones with nalidixic acid as the prototype.
Nalidixic acid is a quinolone without fluorine. It was used as a bacteriostatic agent for UTIs, but was not very effective. The addition of a fluorine group in place of the R6 substituent gave rise to a class of bactericidal agents: fluoroquinolones.

Fluoroquinolones are characterized by a broad spectrum of activity. They can be effective after oral administration because of their wide distribution, but they still do not get to the brain, because they cannot cross the BBB.
Fluoroquinolones may have a long half-life. Resistance to fluoroquinolones does not develop rapidly, but this is increasing because of its more frequent use.
Fluoroquinolones are effective in both hospital and community–acquired infections.

Many fluoroquinolones have been developed and withdrawn from the market because of the many side-effects (Hepatotoxicity, cardiotoxicity and diabetes).

Originally, fluoroquinolones were mainly active against Gram (–) bacteria, but recent modifications have aimed at making it active against Gram (+) bacteria and anaerobes. The different modifications have also made fluoroquinolones with better pharmacokinetics available, such that some of them allow for once a day administration.

The R7 must be a piperazine for fluoroquinolones with a high activity against Pseudomonas.

[edit] Mechanism of action

Fluoroquinolones inhibit gyrase and topo IV in Gram (+) bacteria. Gyrase is a tetrametric enzyme. Two of its subunits are called “gyr A” and the other two “gyr B”.
Gyrase introduces a ds–break in DNA, and reduces the supercoil. This process is typically carried out by the “gyr A” subunit, and it is capable of restoring the integrity of the DNA chain. Conversely, the “gyr B” subunit provides energy by hydrolyzing ATP.
Gyrase is actually the preferred target of fluoroquinolones in Gram (–) bacteria. In Gram (+) bacteria, the preferred target is topo IV. The reason for this might be:

  • Topo IV in Gram (+) is more sensitive to fluoroquinolones.
  • Targeting topo IV results in a more bactericidal activity in Gram (+) cocci.

Although, none of these assumptions have been proven, it is however known that topo IV is the preferred target in S. pneumonia, or S. aureus.
While gyrase is the preferred target in H. influenzae, N. gonorrhoea and proteus.

[edit] Spectrum

Fluoroquinolones have a wide spectrum, but some fluoroquinolones lack activity against Gram (+) cocci, for example, S. pneumoniae.

The spectrum also involves Gram (–) bacteria which cause UTI and G.I. infections like E. coli, proteus, shigella, salmonella, camphylobacter, yersinia and serattsia.

Fluoroquinolones can also be used to treat Chlamydia, Mycobacterium avium complex and some anaerobic infections.

From their spectrum of action, fluoroquinolones can be divided into generations and this classification is also related to when they were developed.

Generation Drug
1st Nalidixic acid, Pipemidic acid
2nd Ciprofloxacin, Lomefloxacin, Norfloxacin, Pefloxacin, Rufloxacin
3rd Levofloxacin
4th Moxifloxacin, Prulifloxacin

Ciprofloxacin is especially active against Gram (–) bacteria but also against P. aeruginosa. Its activity against Gram (+) bacteria is not so high compared with 3rd generation fluoroquinolones. Of this class, it is the most active against Pseudomonas. And it is effective against Chlamydia and Mycoplasma.

Levofloxacin has increased activity against Gram (+) bacteria. This immediately indicates levofloxacin as a drug of choice for community-acquired lung infections.

Levofloxacin is active against S. pneumoniae while ciprofloxacin is not. Physicians have often made the error of assuming these two drugs have the same efficacy, and for UTIs, it is so but for lung infections, it is not so.

Moxifloxacin is active against Gram (+) and Gram (–) bacteria, and anaerobes.


[edit] Mechanism of resistance

  • Overexpression of the efflux pump
  • Mutation of gyrase
  • Reduced penetration of the drug

In hospitals, there has been an increase in resistance of Klebsiella, Pseudomonas and Serratia to fluoroquinolones due to increased use.

In communities, increased resistance is seen in E. coli, Salmonella, N. gonorrhoea.

Modifying the targets are common mechanisms of resistance. The emergence of an amino acid substitution in the gyr A subunit of the bacterial gyrase. Higher resistance depends on the number of mutations and involves both targets of fluoroquinolones. Low resistance occurs when there is only one mutation in the gyr A subunit.

[edit] Contraindications

  • Fluoroquinolones are contraindicated in pregnant women and in children. This is because of its ability to cause damage to cartilage and joints. There is only one exception for using these drugs in children, which is for preventing Pseudomonas infection in Cystic fibrosis. Because in cystic fibrosis, the patients have an increased risk of P. aeruginosa infection due to reduced fluidity of bronchioles.
  • Fluoroquinolones can pass through breast milk and should be contraindicated in breastfeeding women.
  • Important considerations are needed for the cardiotoxicity of levofloxacin and moxifloxacin, which tend to prolong the QT interval and so, increase the risk of arrhythmias. This has actually been the reason for the withdrawal of many fluoroquinolones. However, the incidence of cardiotoxicity with levofloxacin and moxifloxacin is low.

[edit] Interactions

  • Antacids with aluminium and magnesium can reduce the absorption of fluoroquinolones. This is explained by the chelation mechanism. If an antacid has to be used with a fluoroquinolone, the fluoroquinolone must be given 2 – 3 hours after the antacid.
  • Calcium-rich foods can also reduce drug absorption.
  • Fluoroquinolones can reduce the metabolism of warfarin, and increase its concentration. This is significant because warfarin has a low therapeutic index.
  • Fluoroquinolones also interact with theophylline, a drug used to treat bronchial diseases. Despite the fact that theophylline is not a first choice because it is cardiotoxic, fluoroquinolones can alter their metabolism, and this is relevant in elderly patients.
  • Caffeine also interacts with fluoroquinolones.

[edit] Adverse effects

  • Fluoroquinolones are generally well-tolerated for short-term use but the patient may experience some G.I. side effects.
  • It has been recently found that there are CNS side-effects in patients that take fluoroquinolones along with NSAIDs. This seems to be due to displacement of GABA from its receptors.
  • Increased incidence of headache, sleepiness and seizure in at-risk patients.
  • Photosensitivity depending on the fluoroquinolone used.
  • Rash