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Fluoroquinolones

This document provides a comprehensive overview of quinolone antimicrobials, detailing their discovery, structure, mechanism of action, antibacterial spectrum, and resistance mechanisms. It discusses various generations of fluoroquinolones, their clinical uses, pharmacokinetics, and safety profile, highlighting their effectiveness against Gram-negative and Gram-positive bacteria. Additionally, it addresses the side effects and drug interactions associated with these medications, emphasizing the need for rational and cautious use in therapy.

Health & Medicine◦
Related topics:
Urinary Tract Infection• MDR-TB•
Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong
 Synthetic antimicrobials having a quinolone structure  2 ringed nitrogen containing system with a ketone  Primarily against gm-ve bacteria, newer ones gm+also  In 1962 nalidixic acid was discovered by George lesher during synthesis of chloroquine  Limited usefulness – Urinary and GI tract infections – low potency, modest blood and tissue levels, restricted spectrum and high frequency of resistance
 Antibacterial spectrum - against gm –ve bacteria  E. coli, Proteus, Klebsiella, Ebacter, Shigelle – but not Pseudomonas  MOA: Bactericidal, inhibition of bacterial DNA gyrase; Rapid resistance  Kinetics: Orally absorbed, high plasma protein bound, partly metabolized in liver, half life 8 hrs  High conc. In urine and gut lumen – UTI and diarrhoea due to coliforms  ADRs: GIupset, rashes,neurological toxicity (headache, drowsiness, vertigo, visual disturbance), hemolysisin G-6- PD deficiency
General points Structure image  Quinolone antimicrobials with one or more flourine substitution  1980s – flourine substitution at position 6  1990s – flourine at 6 and piperazine moiety at 7  Advantages – Gm+ve bacteria, better tissue penetration, good tolerability, slow development of resistance and anerobes better metabolic stability (longer half-life)
 1st generation: Norfloxacin, Ciprofloxacin, Ofloxacin and Pefloxacin  2nd generation: Levofloxacin, Moxifloxacin, Gemifloxacin, Prulifloxacin, Lomefloxacin and Sparfloxacin  Additional Newer: Pazufloxacin and Balofloxacin
 Unique mechanism of action ◦ Inhibits bacterial  DNA gyrase – nicks double-stranded DNA, removes excess positive supercoiling in the DNA helix and reseals nicked ends  Primary target in gram-negative bacteria  2 subunits – 2 A subunits and 2 B subunits  A subunits – nicking and resealing of strands  B subunit – introduces negative supercoil  Topoisomerase IV – essential for nicking and separation of interlinked daughter DNA molecules  Primary target for many gram-positive bacteria ◦ FQs have greater affinity for Topoisomerase IV ◦ Digestion of DNA by exonucleases ◦ FQs display concentration-dependent bactericidal activity ◦ Topoisomerase II ????
• No plasmid mediated transferable resistance • Reduced affinity – chromosomal mutations in genes that code for DNA gyrase or topoisomerase IV  most important and most common • Altered cell wall permeability – decreased porinexpression • Expression of active efflux – transfers FQs out of cell • Cross-resistance occurs between FQs • Nalidixic acid – single step resistance, FQs not easily selected (long time) – Salmonella, Pseudomonas, Gonococci and Pneumococci
 The most potent first generation FQ – wide range of bacteria  Aerobic gm –ve bacilli, Enterobacteriacae and Neisseria  Highly susceptible: E. coli, N. gonorrhoea, K. pneumoniae, N. meningitidid, Enterobacter, H. influenzae, S. typhi, H. ducrei, N. salmonella, C, jejuni, Shigella, Yersinia, Proteus, V. cholerae  Moderately susceptible: P. aureginosa, Legionella, Brucella, Mycoplasma, Listeria, Chlamydia, Staph. Epidermidis, Bacillus anthracis, B. catarrhalis, M. tuberculosis  Variable susceptibility: Strep pyogenes, Strep fecalis, Strep pneumoniae, MRSA, Mycobact. Kansalis, M. avium  Resistant: Bacteroides fragilis, Clostridia and anaerobic cocci
 Bactericidal and high potency – MBC = MIC  Relatively long post antibiotic effect on Enterobacteriaceae, Pseudomonas and Staph.  Low frequency of mutational resistance  Low frequency of plasmid type resistance  Protective intestinal streptococci and anerobes are spared  Less active iin acidic pH
 Rapidly absorbed orally  Food interferes  Oral absorption impaired by divalent cations(Antacids containg Mg, Ca,or AL )  All FQs attaain bactericidal levels in blood and good tissue penetration – Norfloxacin  Conc. In lungs, sputum, muscle, prostate and phagocytes exceds plasma, but less in CSF  Excreted in urine – gf and ts  Urinary and biliary conc – 10-50 times higher
Source: Textbook of K. D. Tripathi, Jaypee Brothers Medical Publishers, 8th Edition , 2019
 Good safety record – ADRs mild and in 10% withdrawal in 1.5%  GIT: Nausea, vomiting, bad taste, anorexia but no diarrhoea  CNS: dizziness, headache, restlesness, anxiety, insomnia, impairement in conc. and dexterity (???) - tremor and seizure  Tendonitis and tendon rupture – 60+ years  Cartilage damage – children  Pregnancy ????
Source: Google images
 Theophylline, caffeine, and warfarin conc increased – inhibition of metabolism – CNS toxicity  NSAIDS – enhance CNS toxicity  Antacids, sucralfate and Iron salts – reduce absorption
 Extensively used as empirical therapy – careful in minor cases, gm+ve organisms and anerobes  In severe cases IV  Urinary tract Infection: high cure rate – even in complicated cases in catheter – cipro is most active against Pseudomonas  Gonorrhoea: Both non-PPNG and PPNG  Chancroid: Cipro 500 mg BD 2nd line – azithro and ceftriaxone  Bacterial gastroenteritis: Most widely used – careful in cholera  Typhoid: Chloramphenicol, ampicillin, cotrimoxazole – cipro 95% 1st line of drug = 750 mg BD for 10 days or 200 mg IV BD; But now Ceftriaxone or cefoperazone – 2 gm IV BD 2 days and 2 gm IV OD 2 days ◦ Advantages of Cipro: quick defervescence, early releif of symptoms, and prevention of carrier state – carrier 750 mg BD 4 – 6 weeks
 Bone, soft tissue, gynaecological aand wound infections: caused by resistant Staph – osteomyelitis and joint infection – clindamycin and metronidazole in diabetic foot  RTI: Should not be primary drug – strepto and pneumo – Mycoplasma, Legionella, H. influenzae, catarrhalis and chlamydiae; Levo, Gem and Moxi for pneumoniae  Anthrax: DOC inhalational Bioterrorism  TB: Moxi and Levo – 2nd line, Cipro less effective but in MAC  Gm-ve scepticaemia: parenteral cipri  Meningitis: Cipro in gm-ve bacterial meningitis  Prophylaxis: in neutropenic cancer and susceptible patients  Conjunctivitis: gm-ve bacteria
 Less potent FQ – MIC values for gm-ve are 2-8 times higher than Cipro  Many Pseudomonas and gm+ organisms are not inhibited  Lower conc. in plasma  Used in UTI 8-12 weeks, bacterial diarrhoea – anerobic gut flora not disturbed  Pefloxacin: Derivative of Norfloxacin – Lipid soluble, higher plasma conc., more tissue penetration and CSF penetration ◦ Highly metabolized partly to Norfloxacin ◦ Better than other FQs in meningitis ◦ Cumulation on frequent dosing – effective in some systemic infections ◦ Dose reduction in liver disease but not kidney dideases
 Less active than Cipro in gm0ve bacteria  Equally against Strep, pyogens and other gm +ve cocci and anerobes  Good against Chlamydia and Mycoplasma  Useful in nonspecific urethritis, cervicitis, and atypical pneumonia by Clamydia trachmatis  Effective agains M. tuberculosis and M. Lepare – alternative regime in TB and alternative multidrug regime
 Levo isomer of Ofloxacin with better effectivity against M. tuberculosis and Pneumoniae and some gm+ve and gm –ve bacteria  Moderately effective against anerobes  100% oral bioavailability (oral and IV) – given single dose slow elimination  No drug interaction with theophylline,warfarin etc.  Uses: community acquired pneumonia and exacerbation of chronic bronchitis ◦ Sinusitis, pyelonephritis, prostatitis and other UTIs and also STIs ◦ Alternative drug for chlamydial urethritis ◦ 2nd most effective drug in TB and multi drug regime in MDR-TB
 Loong acting 2nd generationFQ – effective aginst Str. Pneumonae and other gm +ve bacteria including beta-lactam and macrolide resistant ones  Also effective against anerobes  Most effective against M. tuberculosis and used MDR-TB  Bacterial Topoisomerase IV major target  Also used in pneumonias, bronchitis, sinusitis and otitis media  Not given in liver diseases  No dose reduction required in renal  Proarrythmic potential – QT prolongation
 Gemifloxacin:  2nd generation  Another broad spectrum FQ effective against gm +ve bacteria (Strep. Pneumoniae, H. influenzae, Mycoplasma, Chlamydia  Diarrhoea, nausea, headache, rise in serum amino transferase, skin rash  Uses: CAP, Chronic Bronchitis Exacerbation  Prulifloxacin  2nd generation effective against gm+ve bacteria, gm –ve including resistant strains  Prodrug of Ulifloxacin excreted unchanged in urine  Broad spectrum  Chronic Bronchitis Exacerbation, UTI
 FQs are important and widely used as empirical therapy  However – should be used rationally and cautiously
 Classification of FQs  MOA and ADRs of FQs  Empirical and rational uses and of FQs
Fluoroquinolones