Quinolone antibiotic ( inflammation treatments )

The quinolones are a family of antibiotics containing a bicyclic core structure related to the compound 4-quinolone .
Since their discovery in the early 1960s, they have gained increasing importance as key therapies to treat both community-acquired and severe hospital-acquired infections.
During the 1970s–1980s, the coverage of the quinolone class was expanded by the breakthrough development of fluoroquinolones, which show a much broader spectrum of activity and improved pharmacokinetics compared to the first-generation quinolone.
Those fluoroquinolones, such as ciprofloxacin, are active against both Gram-negative and Gram-positive pathogens; importantly, they are also active against the causative agent of tuberculosis, Mycobacterium tuberculosis.
Quinolones are widely prescribed for several different types of human infections. With side effects including gastrointestinal reactions, CNS reactions, and some minor adverse effects.

1. Quinolone antibiotic

2. Pharmacological research supervised by : Dr. Faris E. Mohammed Dr. Amjed N. Alatrushi Prepared by students of group C4 : 1- علي ابراهيم جبار 2- حنا انور حنا 3- محمد صلاح الدين 4- حسن وعدالله 5- رشا رضوان 6- افنان طلال

3. Introduction The quinolones are a family of antibiotics containing a bicyclic core structure related to the compound 4-quinolone  . Since their discovery in the early 1960s, they have gained increasing importance as key therapies to treat both community-acquired and severe hospital-acquired infections . During the 1970s–1980s, the coverage of the quinolone class was expanded by the breakthrough development of fluoroquinolones, which show a much broader spectrum of activity and improved pharmacokinetics compared to the first-generation quinolone . Those fluoroquinolones, such as ciprofloxacin, are active against both Gram-negative and Gram-positive pathogens; importantly, they are also active against the causative agent of tuberculosis,  Mycobacterium tuberculosis . Quinolones are widely prescribed for several different types of human infections. With side effects including gastrointestinal reactions, CNS reactions, and some minor adverse effects.   Core structure of quinolone antibiotics.

4. Source of Quinolones Quinolones are molecules structurally derived from the heterocyclic aromatic compound quinolone, the name of which originated from the oily substance obtained after the alkaline distillation of quinine . Since the isolation of quinine from  Cinchona  bark in 1811, many other quinolones derivatives have been isolated from natural sources  and form the core structure of many alkaloids, were isolated from plant sources. Several different animal and bacterial species also produce compounds of the quinolone class. These differ not only in the varied substitutions in the carbocyclic and heteroaromatic rings but also have other rings fused to the quinolone nucleus.  alkaline plant

5. Pharmacokinetics Absorption : Fluoroquinolones are well absorbed after oral administration, with levofloxacin and moxifloxacin having a bioavailability that exceeds 90%. Ingestion of fluoroquinolones with sucralfate, aluminum- or magnesium-containing antacids, or dietary supplements containing iron or zinc can reduce the absorption. Calcium and other divalent cations also interfere with the absorption of these agents. Distribution : Binding to plasma proteins ranges from 20% to 84%. Fluoroquinolones distribute well into all tissues and body fluids. Concentrations are high in bone, urine (except moxifloxacin), kidney, prostatic tissue (but not prostatic fluid), and lungs as compared to serum. Penetration into cerebrospinal fluid is good, and these agents may be considered in certain central nervous system (CNS) infections. Accumulation in macrophages and polymorphonuclear leukocytes results in activity against intracellular organisms such as Listeria, Chlamydia, and Mycobacterium. Elimination : Most fluoroquinolones are excreted renally. Therefore, dosage adjustments are needed in renal dysfunction. Moxifloxacin is metabolized primarily by the liver, and while there is some renal excretion, no dose adjustment is required for renal impairment

6. Pharmacodynamics Fluoroquinolone antimicrobial agents are highly active against aerobic or facultative gram-negative bacilli. The fluoroquinolones have been shown to be very concentration dependent in their rates of killing and also have a post antibiotic effect against most gram-negative pathogens . These properties resemble those of aminoglycosides more than those of the beta-lactam antibiotics . Studies in patients, most often with ciprofloxacin, demonstrated that the area under the concentration-time curve (AUC)/MIC ratio (AUIC) is the most important predictor of both clinical and microbiological cure.

7. Mechanism of action Most bacterial species maintain two distinct type II topoisomerases that assist with deoxyribonucleic acid (DNA) replication, DNA gyrase, and topoisomerase IV. DNA gyrase is responsible for reducing torsional stress ahead of replicating forks by breaking double-strand . DNA and introducing negative supercoils. Topoisomerase IV assists in separating daughter chromosomes once replication is completed. Following cell wall entry through porin channels, fluoroquinolones bind to these enzymes and interfere with DNA ligation. This interference increases the number of permanent chromosomal breaks, triggering cell lysis. In general, fluoroquinolones have different targets for gram-negative (DNA gyrase) and gram-positive organisms (topoisomerase IV), resulting in rapid cell death.

8. Bacterial Resistance to Quinolones Like other antibiotics, quinolones face resistance from infectious bacteria due to their widespread use and this resistance is a major clinical issue. Bacterial resistance to quinolones is increasing and it is common reported throughout the world. Most vancomycin-resistant enterococcus (VRE) and methicillin-resistant  Staphylococcus aureus  (MRSA) are also cross-resistant to fluoroquinolones. Bacterial resistance to quinolones can be classified into three categories. Resistance to quinolone antibiotics can also result from the acquisition of plasmid-borne determinants. Quinolone Resistance As discussed earlier, quinolone resistance is becoming a prevalent clinical issue that is threatening the use of these drugs. Resistance mechanisms are grouped into three distinct categories that are discussed below . The cellular alterations associated with each mechanism are not mutually exclusive and can accumulate to create strains that exhibit very high levels of quinolone resistance.

9. Avelox moxifloxacin Cipro ciprofloxacin Levaquin levofloxacin Noroxen norfloxacin Baxdela delafloxacin Floxin ofloxacin Zagam sparfloxacin Trovan trovafloxacin Cinobac cinoxacin Quinolones and fluoroquinolones Brand | Generic names

10. quinolone antibiotics in dentistry Fluoroquinolones are broad-spectrum bactericidal antibiotics that mostly act against Gram-negative bacilli, Gram-positive aerobic cocci, and anaerobic organisms, by preventing the synthesis of DNA. Fluoroquinolones are commonly prescribed for nonodontogenic infections, such as respiratory, genitourinary tract, joint, and bone infections . These agents have a higher capacity of penetration into tissue in comparison with other commonly prescribed antibiotics in dental practice . ciprofloxacin is among the second generation of fluoroquinolone antibiotics and is active against Gram-positive and Gram-negative pathogens . This antibiotic showed excellent antibacterial potency, whilst having minimum side effects . The drug is usually administered orally with a dosage of 500 mg every 12 hours to treat odontogenic infections Moxifloxacin (Avelox), a fluoroquinolone, may be more appropriate for treatment of a dental abscess after failure of first line antibiotics as compared to clindamycin. Broad spectrum antibiotics such as the fluoroquinolones may be used after unsuccessful treatment with a

11. Quinolone and Fluoroquinolones antibiotic adverse effects The most commonly reported side effects include diarrhea, nausea, abnormal liver function tests, vomiting, and rash. Fluoroquinolones may also cause anxiety, insomnia, psychotic reactions, nerve pain or a loss of feeling in the extremities, electrocardiogram (ECG) abnormalities, increased sensitivity to light, and other effects. In people with myasthenia gravis, they may exacerbate muscle weakness and may trigger seizures or increase the risk of having a seizure. In people with diabetes, fluoroquinolones may affect blood glucose levels requiring extra monitoring. Fluoroquinolones are not suitable for people with myasthenia gravis, certain heart rhythm disturbances, or children and adolescents under the age of 18 (unless the infection cannot be treated by another antibiotic).

12. Quinolones interactions Products containing multivalent cations, such as aluminum- or magnesium-containing antacids, and products containing calcium, iron, or zinc invariably result in marked reduction of oral absorption of fluoroquinolones. Other drugs that interact with fluoroquinolones include sucralfate, probenecid, cimetidine, theophylline, warfarin, antiviral agents, phenytoin, cyclosporine, rifampin, pyrazinamide, and cycloserine. Administration of quinolone antibiotics to a benzodiazepine-dependent individual can precipitate acute benzodiazepine withdrawal symptoms due to quinolones displacing benzodiazepines from their binding sites. Fluoroquinolones have varying specificity for cytochrome P450, so may have interactions with drugs cleared by those enzymes; the order from most P450-inhibitory to least, is enoxacin > ciprofloxacin > norfloxacin > ofloxacin, levofloxacin, trovafloxacin, gatifloxacin, moxifloxacin.

13. Quinolones Contraindications Quinolones are not recommended in people with epilepsy, Marfan's syndrome, Ehlers Danlos Syndrome, QT prolongation, pre-existing CNS lesions, or CNS inflammation, or who have had a stroke. They are best avoided in the athlete population. Safety concerns exist for fluoroquinolone use during pregnancy, so they are contraindicated unless no other safe alternative antibiotic exists.

14. Summary Quinolones are one of the most important classes of antibacterial available for the treatment of infectious diseases in humans. However, the clinical utility of these drugs is being impacted by the growing number of resistant bacterial strains. Although several resistance mechanisms have been described, the most common and significant form of resistance is caused by specific mutations in gyrase and topoisomerase IV that disrupt the water–metal ion bridge interaction. Quinolones have been in the clinics since the 1960s, but the molecular details of how these drugs interact with their topoisomerase targets and how mutations cause resistance have only recently been described. Hopefully, this new information can be used to direct the discovery of a new generation of quinolones with improved activity against wild-type and mutant gyrase and topoisomerase IV to extend the clinical use of these drugs well into the future.

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