Quinolones Antibiotics

Gafacom March 30, 2023

Quinolones Antibiotics

The quinolones, like the penicillins, are a group of antibiotics that resulted from serendipity flavored with a healthy dose of rational drug design. The discovery of this class of antimicrobial agents can be traced to the observation that a byproduct generated during the synthesis of chloroquine, an antimalarial compound, possessed modest activity against gram-negative bacteria. The subsequent modification of this compound has led to agents with potent activity against aerobic gram-negative, aerobic gram-positive, and even some anaerobic bacteria. Broad spectra of activity, high absorbance when given orally, and favorable toxicity profiles have caused the quinolones to become some of the most commonly used antibiotics today. Of the quinolones, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, and gemifloxacin are the most frequently prescribed.

All commercially available quinolones possess a core dual ring structure. During modification of this core, it was discovered that addition of a fluorine enhanced potency, and, as a result, this alteration has been incorporated into all the quinolones commonly used today. For this reason, these drugs are called fluoroquinolones to distinguish them from older agents such as nalidixic acid that lacked this fluorine.

Quinolones work by inhibiting two topoisomerases, bacterial enzymes that regulate DNA supercoiling. These topoisomerases are named DNA gyrase and topoisomerase IV. Quinolones stabilize the complex that forms between topoisomerases and DNA at the stage of DNA strand breakage but before religation, resulting in the accumulation of double-stranded breaks in the chromosome. These breaks cause arrest of the DNA replication machinery, leading to inhibition of DNA synthesis and eventually bacterial death.

Quinolones Antibiotics


Resistance

Resistance to quinolones results from spontaneous mutations that occur in specific regions of the genes encoding DNA gyrase and topoisomerase IV. Unfortunately, a single mutation in one of these genes is often sufficient to significantly reduce sensitivity to the quinolones. Bacteria with such a mutation are better able to survive in the presence of quinolones, thus allowing for the occurrence of secondary mutations over time that further increase the resistance to the quinolones. Eventually, bacteria with specific mutations in both the DNA gyrase and topoisomerase genes emerge; such bacteria are highly resistant to quinolones. Because a single mutation is capable of starting this process, it is not surprising that quinolone resistance is the major factor limiting the use of these agents. A second mechanism of resistance is the overexpression of efflux pumps in some bacteria. Because these efflux pumps tend to export several different antibiotics in addition to the quinolones, this can lead to cross resistance between quinolones and other classes of antibiotics.

The quinolones have broad activity against various bacteria. Their strength is their activity against aerobic gram-negative bacteria. In general, they are highly active against most members of the Enterobacteriaceae, Haemophilus spp., and Neisseria spp. They are also effective against some staphylococci and streptococci, many atypical bacteria, and even some mycobacteria.

CIPROFLOXACIN

Ciprofloxacin is one of the oldest fluoroquinolones still in common use. Like many of the fluoroquinolones, it contains a piperazine derivative at the R1 side chain, which greatly enhances its activity against aerobic gram-negative bacteria. (Note that addition of a piperazine derivative to the penicillin core structure results in piperacillin, which also has enhanced activity against gram-negative bacteria.) It is the most potent of the quinolones against aerobic gram-negative bacteria and is effective against Pseudomonas aeruginosa. This is balanced by rather weak aerobic gram-positive activity. For example, ciprofloxacin should not be used to treat severe infections caused by Streptococcus pneumoniae. Ciprofloxacin is also active against many atypical bacteria and some mycobacteria.

LEVOFLOXACIN AND OFLOXACIN

Structurally, levofloxacin and ofloxacin are very closely related. Ofloxacin is a racemic mixture of an active and an inactive stereoisomer, whereas levofloxacin is composed solely of the active stereoisomer. Thus, these two agents have the same spectra of activity, but levofloxacin is generally twofold more potent and, as a result, more commonly used. Levofloxacin is not quite as active as ciprofloxacin against aerobic gram- negative bacteria but is still effective against infections caused by most of these bacteria, including P. aeruginosa. Relative to ciprofloxacin, levofloxacin has enhanced activity against aerobic gram-positive bacteria and is effective in the treatment of severe infections caused by S. pneumoniae, including those strains that are penicillin resistant.

MOXIFLOXACIN AND GEMIFLOXACIN

These newer agents, especially gemifloxacin, have enhanced activity against S. pneumonia (including penicillin-resistant strains) and atypical bacteria. This comes at the expense of aerobic gram-negative activity, especially against P. aeruginosa. Moxifloxacin contains a methoxy group at R2, which increases potency against anaerobic bacteria.

Quinolone contraindications

Quinolone antibiotics are a group of antibiotics that are commonly used to treat bacterial infections. While they are generally considered safe and effective, there are some contraindications to their use. Here are some examples:

  • Hypersensitivity to quinolone antibiotics: Individuals who have a history of hypersensitivity or allergic reactions to quinolones should not take these antibiotics.
  • Tendinitis or tendon rupture: Quinolones have been associated with an increased risk of tendinitis (inflammation of a tendon) and tendon rupture (tearing of a tendon). Therefore, quinolones should be used with caution in patients with a history of tendon problems or those taking corticosteroids.
  • Pregnancy and breastfeeding: Quinolones are not recommended for use during pregnancy or breastfeeding because they may harm the developing fetus or infant.
  • Children and adolescents: Quinolones should not be used in children and adolescents under the age of 18, except in special circumstances where other antibiotics are not effective or appropriate.
  • Myasthenia gravis: Quinolones can worsen the symptoms of myasthenia gravis, a neuromuscular disorder that causes muscle weakness and fatigue.
It's important to note that these are not the only contraindications to quinolone antibiotics, and that the specific contraindications can vary depending on the individual and the specific drug being used.

Quinolone or Fluoroquinolone?

Quinolones and fluoroquinolones are both types of antibiotics that are used to treat bacterial infections. The main difference between the two is that fluoroquinolones are a newer generation of quinolones that have been modified to improve their effectiveness and reduce their side effects.

Here are some of the key differences between quinolones and fluoroquinolones:

  1. Chemical structure: Quinolones and fluoroquinolones have a similar chemical structure, but fluoroquinolones have an additional fluorine atom that improves their ability to penetrate bacterial cells.
  2. Spectrum of activity: Fluoroquinolones have a broader spectrum of activity than quinolones, meaning that they can be used to treat a wider range of bacterial infections
  3. Potency: Fluoroquinolones are generally more potent than quinolones, meaning that they can be effective at lower doses.
  4. Side effects: Fluoroquinolones have been associated with more side effects than quinolones, including tendonitis and tendon rupture, central nervous system side effects such as seizures and hallucinations, and an increased risk of aortic aneurysm and dissection.

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