A PowerPoint presentation on Fluoroquinolones suitable for reading by UG level Medical and Nursing students

1. Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

2.  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

3.  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

4. 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)

5.  1st generation: Norfloxacin, Ciprofloxacin,
Ofloxacin and Pefloxacin
 2nd generation: Levofloxacin, Moxifloxacin,
Gemifloxacin, Prulifloxacin, Lomefloxacin and
Sparfloxacin
 Additional Newer: Pazufloxacin and
Balofloxacin

6.  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 ????

7. • 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

8.  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

9.  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

10.  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

11. Source: Textbook of K. D. Tripathi, Jaypee Brothers Medical Publishers, 8th Edition , 2019

12.  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 ????

13. Source: Google images

14.  Theophylline, caffeine, and warfarin conc
increased – inhibition of metabolism – CNS
toxicity
 NSAIDS – enhance CNS toxicity
 Antacids, sucralfate and Iron salts – reduce
absorption

15.  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

16.  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

18.  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

19.  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

20.  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

21.  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

22.  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

23.  FQs are important and widely used as
empirical therapy
 However – should be used rationally and
cautiously

24.  Classification of FQs
 MOA and ADRs of FQs
 Empirical and rational uses and of FQs