BRISTOL-MYERS SQUIBB SPA
BRISTOL-MYERS SQUIBB SPA
The quinolones are a family of broad-spectrum antibiotics. The parent of the group is nalidixic acid. The majority of quinolones in clinical use belong to the subset of fluoroquinolones, which have a fluoro group attached the central ring system, typically at the 6-position.
Quinolones and fluoroquinolones are bactericidal drugs, actively killing bacteria. Quinolones inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription. Quinolones can enter cells easily via porins and therefore are often used to treat intracellular pathogens such as Legionella pneumophila and Mycoplasma pneumoniae. For many gram-negative bacteria DNA gyrase is the target, whereas topoisomerase IV is the target for many gram-positive bacteria. Eukaryotic cells do not contain DNA gyrase or topoisomerase IV.
In the fall of 2004, the Food and Drug Administration upgraded the warnings found within the package inserts for quinolones regarding potentially serious adverse reactions. It is important to note, however, that the incidence of the following is quite rare, with occurrences at less than one per ten thousand person-years:
Side effects from fluoroquinolones can be mild and short lived or they can be severe and long lasting after therapy has been discontinued. If side effects effecting the central nervous system, peripheral nervous system or muscular system occur the patient should discontinue therapy and consult with their doctor. The side effects from fluoroquinolones include tingling, anxiety, numbness, twitching, joint pain, muscle pain, tendinitis, fear, blurred vision, memory loss, diarrhea, severe panic attacks, insomnia, tear of achilles tendon, confusion, impaired concentration, burning pain, carpal tunnel syndrome, nightmares, confusion, tachycardia, nausea, palpitations, hyperesthesia, fatigue, depersonalisation, pins and needles sensation, muscular spasms, tremors, headaches, agitation, hallucinations, psychosis, tinnitus, skin rash, hair loss, abdominal pain, visual disturbances.
Peripheral neuropathy (nerve damage): "Rare cases of sensory or sensor motor axonal polyneuropathy affecting small and or large axons resulting in paresthesias, hypoaesthesias, dysesthesias, and weakness have been reported in patients taking quinolones. Therapy should be discontinued if the patient experiences symptoms of neuropathy, including pain, burning, tingling, numbness and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition."
Tendon damage: "Ruptures of the shoulder, hand, Achilles tendon, or other tendons that require surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially the elderly. Fluoroquinolone therapy should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until diagnosis of tendinitis or tendon rupture had been excluded. Tendon rupture can occur during or after therapy with quinolones." On July 8, 2008, the FDA requested manufacturers to include a black box warning for tendon damage.
Kidney stones due to loss of Oxalobacter formigenes
Caffeine, nonsteroidal antiinflamatory drugs, Theophylline and corticosteroids enhance the toxicity of fluoroquinolones.
Other drugs which interact with fluoroquinolones include Antacids, Sucralfate, Probenecid, Cimetidine, Probenecid, Warfarin, Antiviral agents, phenytoin, cyclosporine, rifampin, pyrazinamide, and cycloserine.
Resistance to quinolones can evolve rapidly, even during a course of treatment. Numerous pathogens, including Staphylococcus aureus, enterococci, and Streptococcus pyogenes now exhibit resistance worldwide. Widespread veterinary usage of quinolones, in particular in Europe, has been implicated.
There are three known mechanisms of resistance. Some types of efflux pumps can act to decrease intracellular quinolone concentration. In gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind to DNA gyrase, protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or topoisomerase IV can decrease their binding affinity to quinolones, decreasing the drug's effectiveness.
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