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  1. 1. Quinolones Nucleic Acid Synthesis Inhibitors Dr. Salman Khan
  2. 2. Quinolones <ul><li>Quinolones </li></ul><ul><li>Nalidixic acid </li></ul><ul><li>cinoxacin </li></ul><ul><li>Fluoroquinolones </li></ul><ul><li>Ciprofloxacin </li></ul><ul><li>Ofloxacin </li></ul><ul><li>Sparfloxacin </li></ul><ul><li>Lomefloxacin </li></ul><ul><li>Norfloxacin </li></ul><ul><li>Enoxacin </li></ul><ul><li>Fleroxacin </li></ul><ul><li>Pefloxacin </li></ul><ul><li>Levofloxacin </li></ul><ul><li>Trovafloxacin </li></ul>
  3. 3. Generational Classification <ul><li>First Generation </li></ul><ul><ul><li>Cinoxacin </li></ul></ul><ul><ul><li>Nalidixic Acid </li></ul></ul><ul><ul><li>Oxolinic acid </li></ul></ul><ul><li>Second Generation </li></ul><ul><ul><li>Ciprofloxacin </li></ul></ul><ul><ul><li>Enoxacin </li></ul></ul><ul><ul><li>Fleroxacin </li></ul></ul><ul><ul><li>Lomefloxacin </li></ul></ul><ul><ul><li>Levofloxacin </li></ul></ul><ul><ul><li>Norfloxacin </li></ul></ul><ul><ul><li>Ofloxacin </li></ul></ul><ul><ul><li>rulfloxacin </li></ul></ul><ul><li>Third Generation </li></ul><ul><ul><li>Gatifloxacin </li></ul></ul><ul><ul><li>Grepafloxacin </li></ul></ul><ul><ul><li>Pazufloxacin </li></ul></ul><ul><ul><li>Sparfloxacin </li></ul></ul><ul><ul><li>Tosufloxacin </li></ul></ul><ul><li>Fourth Generation </li></ul><ul><ul><li>Clinafloxacin </li></ul></ul><ul><ul><li>Gemfloxacin </li></ul></ul><ul><ul><li>Moxifloxacin </li></ul></ul><ul><ul><li>Trovafloxacin </li></ul></ul>
  4. 4. Nucleic acid synthesis inhibitors <ul><li>Older members of this class of synthetic antimicrobial agents, particularly nalidixic acid, have been available for the treatment of urinary tract infections for many years. These drugs are of relatively minor significance because of their limited therapeutic utility and the rapid development of bacterial resistance. </li></ul><ul><li>more recent introduction of fluorinated 4-quinolones, such as ciprofioxacin (CIPRO) and ofloxacin (FLOXIN), represents a particularly important therapeutic advance, since these agents have broad antimicrobial activity and are effective after oral administration for the treatment of a wide variety of infectious diseases. Relatively few side effects appear to accompany the use of these fluoroquinolones, and mi­crobial resistance to their action does not develop rapidly </li></ul>
  5. 5. Mechanism of action: <ul><li>The quinolone antibiotics target bacterial DNA gyrase and topoisomerase IV. For many gram-positive bacteria (such as S. aureus), topoisomerase IV is the primary activity inhibited by the quinolones. In contrast, for many gram-negative bacteria (such as E. coli) DNA gyrase is the primary quinolone target. </li></ul>
  6. 7. Spectrum of activity <ul><li>The fluoroquinolones are potent bactericidal agents against: </li></ul><ul><li>E. coli and various species of Salmonella, Shigella, Enterobacter, Campylobacter, and Neisseria </li></ul><ul><li>Ciprofloxacin is more active than norfioxacin against P. aeruginosa </li></ul><ul><li>Fluoroquinolones also have good activity against staphylococci, including methicillin­resistant strains </li></ul><ul><li>Several intracellular bacteria are inhibited by fluoroquinolones these include species of Chlamydia, Mycoplasma, Legionella, Brucella, and Mycobacterium (including Mycobacterium tuberculosis) </li></ul>
  7. 8. Mechanism of resistance <ul><li>Resistance to quinolones may develop during therapy via mutations in the bacterial chromosomal genes encoding DNA gyrase or topoisomerase IV, or by active transport of the drug out of the bacteria </li></ul>
  8. 10. Pharmacokinetics <ul><li>The quinolones are well absorbed after oral administration and are widely distributed in body tissues, The volume of distribution of quinolones is high Quinolone concentrations in cerebrospinal fluid, bone, and prostatic fluid are lower than in serum </li></ul><ul><li>Routes of elimination differ among the quinolones. Renal clearance predominates for ofloxacin, lomefloxacin, and cinoxacin; pefloxacin, nalidixic acid, sparfloxacin, grepafloxacin, and trovafloxacin are predominantly elim­inated nonrenally. Dose adjustments in patients with renal insufficiency are required for cinoxacin, norfloxacin, ciprofloxacin, ofloxacin, enoxacin, and lomefloxacin but not for nalidixic acid, grepafloxacin, trovafloxacin, and pefloxacin. None 'of the agents is efficiently' removed by peritoneal or hemodialysis. A fluoroquinolone other than trovafloxacin, grepafloxacin, or pefloxacin should be used in patients with hepatic failure. </li></ul>
  9. 11. Adverse effects: <ul><li>Quinolones and fluoroquinolones are generally well tolerated; the most common adverse reactions involve the gastrointestinal tract, mostly mild nausea, vomiting, and/or abdominal discomfort. </li></ul><ul><li>Diarrhea and antibiotic-associated colitis have been unusual </li></ul><ul><li>Central nervous system side effects, predominately mild headache and dizziness </li></ul><ul><li>Rarely, hallucinations, delirium, and seizures, predominantly in patients who also receive theophylline or a nonsteroidal antiinflammatory drug </li></ul><ul><li>Rashes, including photosensitivity reactions. </li></ul><ul><li>All of these agents can produce arthropathy in several species of immature animals. Traditionally, the use of'quinolones in children has been contraindicated for that reason. However, children with cystic fibrosis given ciprofloxacin, norfloxacin, and nalidixic acid have had few, and reversible, joint symptoms. Therefore, in some cases the benefits may outweigh the risks of quinolone therapy in children. </li></ul>
  10. 12. <ul><li>Arthralgias and joint swelling have developed in children receiving fluoroquinolones; therefore, these drugs are not generally recommended for use in prepubertal children or pregnant women. </li></ul><ul><li>Serious hepatic damage, including liver failure resulting in death, observed with patients receiving trovafloxacin. For this reason, the use of trovafloxacin has been restricted to serious or life-threatening in­fections where the benefits of therapy outweigh the risk </li></ul>
  11. 13. Therapeutic indications: <ul><li>Urinary Tract Infections. </li></ul><ul><ul><li>Nalidixic acid and cinoxacin are useful only for urinary tract infections caused by susceptible microorganisms. The fluoroquinolones are sig­nificantly more potent and have a much broader spectrum of antimicrobial activity. </li></ul></ul><ul><li>Prostatitis. </li></ul><ul><ul><li>Norfloxacin, ciprofloxacin, and ofloxacin all have been effective in uncontrolled trials for the treatment of pros­tatitis caused by sensitive bacteria. </li></ul></ul><ul><li>Sexually Transmitted Diseases. </li></ul><ul><li>Pelvic inflammatory disease </li></ul><ul><li>Gastrointestinal and Abdominal Infections </li></ul>
  12. 14. <ul><li>Respiratory Tract Infections. </li></ul><ul><ul><li>The major limitation of the use of quinolones for the treatment of community-acquired pneumonia and bronchitis had been the poor in vitro activity of ciprofloxacin, ofloxacin, and norfloxacin against S. pneumoniae ­ </li></ul></ul><ul><li>Bone, joints and soft tissue infections   </li></ul><ul><li>Other Infections. </li></ul><ul><ul><li>The quinolones may be used as part of multiple-drug regimens for the treatment of multidrug-resistant tuberculosis and for the treatment of atypical mycobacterial infections as well as Mycobacterium avium complex infections in AIDS </li></ul></ul>
  13. 15. <ul><li>In neutropenic cancer patients with fever, the combination of a quinolone with an aminoglycoside is comparable to ,B-Iactam aminoglycoside combinations but is less effective when used as a single drug. </li></ul><ul><li>Ciprofloxacin plus amoxicillin-clavulanate recently has been shown to be effective as an oral empiric therapy for fever in low-risk patients with granulocytopenia secondary to cancer chemotherapy </li></ul>