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.

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