Fluoroquinolones

crop_square Key points

  • check_circle Bactericidal antibiotics, analogs of nalidixic acid
  • check_circle Disrupt DNA synthesis by binding to DNA gyrase and topoisomerase IV
  • check_circle Excellent activity against gram-negatives
  • check_circle Newer generations: broad spectrum of activity
  • check_circle May cause QT prolongation and tendon rupture in adults

crop_square Background and biochemistry

Quinolone antibiotics are chemical analogs of nalidixic acid, which was discovered by scientists experimenting with the antimalarial drug chloroquine. Since then, several generations of quinolone antibiotics have been developed. Nalidixic acid and first-generation quinolone antibiotics were of limited usefulness due to low oral absorption. The breakthrough happened with the development of fluoroquinolones, which have an additional fluorine atom in their core structure. All quinolone antibiotics in clinical use today are fluroquinolones. They have become some of the most widely used antibiotics in the world.

crop_square Mechanism of action

Quinolone antibiotics penetrate cell walls easily through porin channels. They bind to and inhibit two enzymes, DNA gyrase and topoisomerase IV. DNA gyrase is the main drug target in gram-negative bacteria whereas in gram-positive bacteria, it is topoisomerase IV. Both enzymes belong to the group of type II topoisomerases which are crucial for the unwinding of bacterial DNA during cell replication. Enzyme inhibition by fluoroquinolones and subsequent disruption of DNA synthesis leads to bacterial cell death. Fluoroquinolones are bactericidal. Resistance to fluoroquinolones develops due to mutations at binding sites of DNA gyrase and topoisomerase IV, efflux pumps reducing intracellular antibiotic concentrations, and the expression of resistance genes protecting enzymes from antibiotic activity.

crop_square Drugs and spectrum of activity

Second-generation fluoroquinolones
  • Cipro­floxacin
  • Ofloxacin
  • Nor­floxacin
Third-generation fluoroquinolones
  • Levo­floxacin
Fourth-generation cephalosporins
  • Moxi­floxacin
  • Gati­floxacin

Second-generation fluoroquinolones provide excellent coverage against gram-negative organisms, which makes ciprofloxacin one of the most commonly used antibiotics in urinary tract infections, prostatitis and bacterial diarrhoea. Later generation fluoroquinolones are somewhat less active against gram-negatives: Moxifloxacin is not sufficiently active against Pseudomonas aeruginosae. Third- and fourth-generation fluoroquinolones cover against a range of gram-positive organisms, including methicillin-susceptible Staphylococcus aureus (MRSA), as well as mycobacteria.

crop_square Pharmacokinetics

Fluoroquinolones show good bioavailability after oral administration. They are usually given once or twice over 24h as their elimination half-life varies between 4-8h. Tissue penetration is excellent. Fluoroquinolones cross the blood-brain barrier, but it is contested if sufficient CNS drug levels can be achieved. They are hepatically metabolised and primarily cleared by the kidneys.

crop_square Adverse drug effects

The most often reported side effects of fluoroquinolone therapy are nonspecific and no major concern. These include headache, nausea, insomnia, and dizziness. Impaired liver function and skin rashes are also seen. The possibly best-known severe adverse effects are tendinitis and tendon rupture in adults. Other rare but potentially serious side effects are cardiac arrhythmia and QT interval prolongation.