Quinolones & Fluoroquinolones
Introduction
- Quinolones are synthetic antimicrobials having a quinolone structure.
Classification
Quinolones are classified as following :
1. Nalidixic acid
- Nalidixic acid is the first member of quinolones thus, it is the predecessor to all fluoroquinolones.
2. Fluoroquinolones : Fluoroquinolones are newer fluorinated quinolones.
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Mechanism of action
Fluoroquinolones enter bacteria through porin channels and exhibit antimicrobial effects on DNA gyrase (bacterial topoisomerase II) and bacterial topoisomerase IV.
- Inhibition of DNA gyrase results in relaxation of supercoiled DNA, promoting DNA strand breakage.
- Inhibition of topoisomerase IV impacts chromosomal stabilization during cell division, thus interfering with the separation of newly replicated DNA
In gram-negative organisms, the inhibition of DNA gyrase is more significant than that of topoisomerase IV, whereas in gram-positive organisms, the opposite is true; thus, greater affinity for topoisomerase IV may confer higher potency against gram-positive bacteria.
Mammalian cells possess an enzyme topoisomerase II which has very low affinity for FQs, hence low toxicity to host cells.
The bactericidal action probably results from digestion of DNA by exonucleases whose production is signalled by the damaged DNA
Antibacterial spectrum
Quinolones are bactericidal & active primarily against gram-negative bacteria.
- Nalidixic acid is active against gram-negative bacteria.
- Fluoroquinolones inhibit gram-negative bacteria & many gram-positive bacteria.
Fluoroquinolones are typically not used for the treatment of Staphylococcus aureus or enterococcal infections. They are not effective against syphilis and have limited utility against Neisseria gonorrhoeae due to disseminated resistance worldwide.
Resistance
Because of the unique mechanism of action, plasmid mediated transferable resistance probably does not occur.
- Resistance noted so far is due to chromosomal mutation producing a DNA gyrase or topeisomerase IV with reduced affinity for FQs, or due to reduced permeability I increased efflux of these drugs across bacterial membranes.
- In contrast to nalidixic acid which selects single step resistant mutants at high frequency, FQ-resistant mutants are not easily selected. Therefore, resistance to FQs has been slow to develop. However, increasing resistance has been reported among Salmonella, Pseudomonas, staphylococci, gonococci and pneumococci.
- Cross-resistance exists among the quinolones.
Therapeutic usage
Fluoroquinolones can be employed in the management of
- Urinary tract infections,
- Gonorrhoea,
- Chancroid,
- Bacterial gastroenteritis,
- Typhoid,
- Bone, soft tissue, gynaecological and wound infections,
- Respiratory infections,
- Tuberculosis,
- Gram-negative septicaemias,
- Meningitis,
- Conjunctivitis etc.
Drug Interactions
- Plasma concentration of theophylline, caffeine and warfarin are increased by ciprofloxacin, norfloxacin and pefloxacin due to inhibition of metabolism : toxicity of these drugs can occur.
- NSAIDs may enhance the CNS toxicity of FQs; seizures are reported.
- Antacids, sucralfate and iron salts given concurrently reduce absorption of FQs.
Adverse Effects
In general, these agents are well tolerated. But following side effects may be observed :
- Like most antibiotics, the most common adverse effects of fluoroquinolones are nausea, vomiting, and diarrhea.
- Headache and dizziness or lightheadedness may occur. Thus, patients with central nervous system (CNS) disorders, such as epilepsy, should be treated cautiously with these drugs.
- Peripheral neuropathy and glucose dysregulation (hypoglycemia and hypoglycemia) have also been noted.
- Fluoroquinolones can cause phototoxicity, and patients taking these agents should be advised to use sunscreen and avoid excess exposure to sunlight. If phototoxicity occurs, discontinuation of the drug is advisable.
- Articular cartilage erosion (arthropathy) has been observed in immature animals exposed to fluoroquinolones. Therefore, these agents should be avoided in pregnancy and lactation and in children under 18 years of age. [Note: Careful monitoring is indicated in children with cystic fibrosis who receive fluoroquinolones for acute pulmonary exacerbations.]
- An increased risk of tendinitis or tendon rupture may also occur with systemic fluoroquinolone use.
- Moxifloxacin and other fluoroquinolones may prolong the QTc interval and, thus, should not be used in patients who are predisposed to arrhythmias or those who are taking other medications that cause QT prolongation.
- Ciprofloxacin can increase serum levels of theophylline by inhibiting its metabolism.
- Quinolones may also raise the serum levels of warfarin, caffeine, and cyclosporine.
Contraindications
- Quinolones are contraindicated if a patient has epilepsy, QT prolongation, pre-existing CNS lesions, or CNS inflammation, or the patient has suffered a stroke.
- They are best avoided in the athletes.
- Safety concerns exist for fluoroquinolone use during pregnancy, so they are contraindicated unless no other safe alternative antibiotic exists.
- They are also contraindicated in children (under age of 18 due to the risks of damage to the musculoskeletal system. Their use in children is not absolutely contraindicated, however. For certain severe infections where other antibiotics are not an option, their use can be justified.
- Quinolones should also not be given to people with a known hypersensitivity to the drug.
