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Classification and Uses of Fluoroquinolone Antimicrobials
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 ????
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
17.
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