Quinolones

Thorough information about Quinolones as a class of antimicrobial agent

1. Quinolones Prepared by :- Ruchita V Bhavsar 1 st sem M.Pharm Guided by :- Mr. Samaresh Pal Roy HOD of Pharmacology, SDPC, Kim

2. Contents Introduction History Classification Mechanism of Action Resistance Pharmacokinetics Use Adverse Effects Interaction 2

3. Introduction The quinolones are a family of synthetic, broad-spectrum antibiotic with bactericidal activity. The term quinolone refers to potent synthetic chemotherapeutic antibacterial agent. 3

4. History The 1 st generation of the quinolones begins with Nalidixic acid in 1962 for the treatment of Urinary Tract Infections in humans. Nalidixic acid was discovered by George Lesher and co-workers in a distillate during an attempt at chloroquine synthesis. 4

5. Classification Quinolones (1 st generation) Highly protein bound Mostly used in UTI Fluoroquinolones (2 nd , 3 rd , 4 th generation) Modified 1 st generation quinolones Not highly protein bound Wide distribution to urine and other tissues Limited CSF penetration 5

6. Classification Generation Drugs Antibacterial spectrum First Nalidixic acid Cinoxacin Gram – ve bacteria Aerobic Second Norfloxacin Ciprofloxacin Ofloxacin Lomefloxacin Enoxacin Gram + ve bacteria Aerobic Improved activity against Gram – ve bacteria Third Levofloxacin Sparfloxacin Gatifloxacin Gemifloxacin Good activity against Anaerobic Gram + ve bacteria particularly pneumococci Fourth Trovafloxacin Moxifloxacin Clinafloxacin Sitafloxacin Anaerobic Increased activity against pneumococci 6

7. 1 st Generation Quinolones The first-generation agents include cinoxacin and nalidixic acid, which are the oldest and least often used quinolones . Because minimal serum levels are achieved, use of these drugs has been restricted to the treatment of uncomplicated urinary tract infections. They are more susceptible to the development of bacterial resistance. These agents are not recommended for use in patients with poor renal function because of significantly decreased urine concentrations. 7

8. 2 nd Generation Quinolones The second-generation quinolones have increased gram-negative activity, as well as some gram-positive and atypical pathogen coverage. Compared with first-generation drugs, these agents have broader clinical applications in the treatment of complicated urinary tract infections and pyelonephritis , sexually transmitted diseases, selected pneumonias and skin infections. They include ciprofloxacin, lomefloxacin , norfloxacin , ofloxacin and enoxacin . Ciprofloxacin and ofloxacin are the most widely used because of their availability in oral and intravenous formulations. 8

9. 3 rd Generation Quinolones The third-generation quinolones currently include levofloxacin , gatifloxacin , moxifloxacin and sparfloxacin . These agents are separated into a third class because of their expanded activity against gram-positive organisms, particularly penicillin-sensitive and penicillin-resistant  S. pneumoniae , and atypical pathogens such as  Mycoplasma pneumoniae  and  Chlamydia pneumoniae . Although the third-generation quinolones retain broad gram-negative coverage, they are less active than ciprofloxacin against Pseudomonas species. 9

10. 10 Because of their expanded antimicrobial spectrum, they are useful in the treatment of community-acquired pneumonia, acute sinusitis and acute exacerbations of chronic bronchitis. The FDA recommends that all of these drugs should be avoided in patients who are taking drugs that are known to prolong the QT interval, such as tricyclic antidepressants, phenothiazines and class I antiarrhythmics . In contrast, levofloxacin does not affect the QT interval.

11. 4 th Generation Quinolones Trovafloxacin , the current member of the fourth-generation class, adds significant antimicrobial activity against anaerobes while maintaining the gram-positive and gram-negative activity of the third-generation quinolones . It also retains activity against Pseudomonas species comparable to that of ciprofloxacin. Because of concern about hepatotoxicity , trovafloxacin therapy should be reserved for life- or limb-threatening infections requiring inpatient treatment and the drug should be taken for no longer than 14 days. 11

12. In Developement Delafloxacin  (developmental code name  RX-3341 ) is a  fluoroquinolone antibiotic being developed. It is more active than other quinolones against Gram-Positive bacteria.  Phase II clinical trials have been completed and Phase III trial for ACUTE BACTERIAL SKIN AND SKIN STRUCTURE INFECTIONS  (ABSSSI) is due to begin. 12

13. Fluoroquinolones 13

14. Fluoroquinolone The fluoroquinolones are a relatively new group of antibiotics. They were first introduced in 1986, but they are really modified quinolones , a class of antibiotics, whose accidental discovery occured in the early 1960. 14

15. Mechanism of Action 15

16. Mechanism of Action It blocks bacterial DNA synthesis by Inhibition of bacterial Topoisomerase II (DNA Gyrase ) Inhibition of Topoisomerase IV Inhibition of ATP dependent DNA gyrase ; which nicks doule stranded DNA, introduces negative supercoils and then reseals the nicked ends. This is required to prevent excessive positive supercoiling of DNA strands when they seperate to permit replication or transcription. 16

17. 17 Inhibition of DNA gyrase also prevents the relaxation of positively supercoiled DNA. Inhibition of DNA nicking–closing enzyme responsible for DNA elongation, which leads to break in double stranded DNA. Inhibition of topoisomerase IV interferes with the separation of replicated chromosomal DNA into respective daughter cells during cell division.

18. 18 The critical imbalance in cellular metabolism resulting from the inhibition of enzymes precipitates a sequence of cellular events which may lead to : Premature cell division Delayed cell division Total failure of cell division leading to lysis of the cell

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21. Resistance Resistance appears to be the result of : Alteration in the quinolone enzymatic targets (DNA gyrase ), decreased outer membrane permeability or the development of efflux mechanisms. One or more point mutations in the quinolone binding region of the target enzyme ( Topoisomerase ) or from a change in the permeability of the organism. 21

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25. Pharmacokinetics Absorption : Well absorbed orally with bioavailability 80-95% Oral absorption is impaired by divalent cations Distribution : Widely distributed in body fluids and tissues but limited CSF penetration. It can pass the placenta reaching to the foetus Half life : 3-8 hours in serum Elimination : 30-50% from urine by tubular secretion or glomerular filtration and some amount in bile – faeces. 25

26. Uses 26 1. RTI (Respiratory Tract Infection) : EMPYEMA : The collection of pus in a cavity of the body, especially in the pleural cavity (the area between the lungs and the inner surface of the chest wall) PNEUMONIA : Infection of the lungs that caused by bacteria, viruses, fungi or parasites LUNG ABSCESS : Bacterial infection that occurs in the lung tissue causing tissue to die and pus to collect in that space 2. MENINGITIS :   Inflammation of the lining of the brain and spinal cord

27. 27 3 . UTI (Urinary Tract Infection) : PYELONEPHRITIS : A type of urinary tract infection (UTI) that affects one or both kidneys caused by a bacterium mainly   Escherichia coli or virus infection.  It causes the kidneys to swell and may permanently damage them. EPIDIDYMITIS : Inflammation of the epididymis , a tube near the testicles that stores and carries sperm in men PROSTATITIS : Inflammation of the prostate gland due to a urine infection in men CYSTITIS : Inflammation of the bladder usually caused by a urine infection in women

28. 28 4. GIT (Gastro Intestinal Tract) infection : ENTERIC FEVER : A potentially fatal multisystemic illness caused primarily by Salmonella species BACTERIAL DIARRHOEA : Caused by Campylobacter, salmonellae, and shigella organisms 5. Skin & soft tissue infections : INFECTED ULCERS : Shallow  wound that develops on the skin INFECTED BURNS : Red coloured and warm to touch due to an infection

29. 29 6. GONORRHEA : A venereal disease involving inflammatory discharge from the urethra or vagina. 7. CHANCROID : Bacterial infection that causes open sores on or around the genitals of men and women 8. TUBERCULOSIS : Infectious bacterial disease characterized by the growth of nodules (tubercles) in the tissues, especially the lungs 9. CONJUCTIVITIS : Inflammation of the outermost layer of the white part of the eye and the inner surface of the eyelid

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31. Adverse Effects CNS (Central Nervous System) Quinolones may displace the neuroinhibitor GABA, resulting in CNS stimulation Dizziness Headache Insomnia Restlessness Phototoxicity Skin damage after exposure to UV light due to toxic reactions. These included second-degree burns, discoloration and sometimes permanent discoloration and scarring of the skin. 31

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33. 33 Gastrointestinal Depletion of magnesium and disruption of cellular enzyme function Disruption of mitochondrial function and energy production Other common side effects are : Nausea Vomiting Anorexia Diarrhea

34. Interactions NSAIDs : Enhance the CNS toxicity of quinolones Theophylline , Caffeine or Warfirine Plasma concentration is increased by Ciprofloxacin Antacid or Iron salts Reduce the absorption of quinolones 34

35. Ciprofloxacin 2 nd generation fluoroquinolone Most potent fluoroquinolone against  P. aeruginosa Not effective against Gram + ve and anaerobes Mainly effective against Gram – ve bacteria : Enterobacteriacae H. Influenzae Campylobacter M. Catarrhalis Pseudomonas N. Gonorrhea Intracellular Pathogen : M. Tuberculosis Mycoplasma Chlamydia Legionella Brucella 35

36. 36 CLINICAL USE : Urinary Tract Infections Travellers’ diarrhoea Anthrax Diabetic foot infections UNIQUE QUALITIES : It binds to divalent cations which decreases absorption. Because of its good penetration into bone, orally administered ciprofloxacin is a useful alternative to parenterally administered antibiotics for the treatment of osteomyelitis caused by susceptible organisms.

37. 37 MARKETED PREPARATIONS : Ciplox eye drop / Ciloxan eye drop or ointment : Used in conjuctivitis , corneal ulcer and before opthalmic surgery

38. 38 Neocip 500 mg : Cipla C- flox 250 mg : Intas Ciprodac 500 mg : Cadila

39. Levofloxacin 3 rd generation fluoroquinolone Levo -isomer 100% oral bioavailability Effective against Gram + ve and Gram – ve bacteria Also effective against Pathogen : Legionella pneumophila Atypical respiratory pathogens Mycobacterium tuberculosis 39

40. 40 CLINICAL USE : Urinary tract infections Chronic bronchitis Nosocomial pneumonia Intra-abdominal infections UNIQUE QUALITY : It binds to divalent cations which decreases absorption

41. 41 MARKETED PREPARATIONS : Levoslog tablet Levotec tablet Wecure ablet

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