The document discusses various generations of quinolone antibiotics, including fluoroquinolones. It describes their mechanisms of action, spectrum of activity against different bacteria, mechanisms of resistance, pharmacokinetics, indications, adverse effects, and comparisons of common fluoroquinolones including ciprofloxacin, levofloxacin, and moxifloxacin. Specific details are provided on the absorption, distribution, metabolism and excretion of these drugs.

1. • QUINOLONES
 BY :- DR MAYUR PATEL

2. • The fluoroquinolones are a family of broad spectrum,
systemic antibacterial agents that have been used widely
as therapy of respiratory and urinary tract infections.
Fluoroquinolones are active against a wide range of
aerobic gram-positive and gram-negative organisms.

3. • The first member Nalidixic acid introduced in mid-1960s had
usefulness limited to urinary and g.i. tract infections because of low
potency, modest blood and tissue levels, restricted spectrum and
high frequency of bacterial resistance. A breakthrough was achieved
in the early 1980s by fluorination of the quinolone structure at
position 6 and introduction of a piperazine substitution at position 7
resulting in derivatives called fluoroquinolones with high potency,
expanded spectrum, slow development of resistance, better tissue
penetration and good tolerability.

4. • FLUOROQUINOLONES
• The ‘first generation’
fluoroquinolones (FQs)
introduced in 1980s have
one fluoro substitution.
In the 1990s, compounds
with additional fluoro
and other substitutions
have been developed—
further extending
antimicrobial activity to
gram-positivecocci and
anaerobes, and
confering metabolic
stability (longer t½).
These are referred to as
‘second generation’ FQs

5. First generation fluoroquinolone
1. Norfloxacin (no longer clinically used)
Second generation fluoroquinolone
1.Ciprofloxacin
2. Ofloxacin
Third generation fluoroquinolone
1.Levofloxacin 3.Gemifloxacin
2. Moxifloxacin
Fourth generation fluoroquinolone
1. Delafloxacin

6. SPECTRUM OF ACTIVITY
• Fluoroquinolones are considered broad-spectrum antibiotics: Ciprofloxacin
covers gram-negative rods the best
• Levofloxacin and moxifloxacin provide excellent coverage of most potential
respiratory pathogens
• Delafloxacin covers both P. aeruginosa and MRSA.

7. MECHANISM OF ACTION
• Fluoroquinolones directly inhibit bacterial DNA synthesis by binding to:
• Topoisomerase II (DNA gyrase) in gram-negative organisms.
• Topoisomerase IV in gram-positive organisms.
• Topoisomerase enzymes:
• Unwind DNA prior to replication
• Have both nuclease (DNA cleaving) and ligase (DNA repairing) activity
•

8. • Fluoroquinolone binding to enzymes results in:
• Inhibition of ligase activity only
• DNA cleavage without the ability to repair the DNA
• Cessation of DNA replication with broken DNA strands
• Cell death → fluoroquinolones are Bactericidal

10. MECHANISMS OF RESISTANCE
The dominant mechanisms of fluoroquinolone resistance:
• ↓ Accumulation of the drug within bacterial cells:
• ↓ Expression of porin channels → ↓ entry of the drug into cells
• ↑ Expression of efflux pumps
• ↓ Affinity of the drug to the target:
• Chromosomal point mutations change the structure of the topoisomerase
and affect the binding site.
• The mutations are drug and bug specific (e.g.,
gyrA genes in Neisseria gonorrhoeae)
• Plasmid-mediated resistance (typically a low-level resistance)

11. CLINICALLY IMPORTANT RESISTANCE PATTERNS
• As resistance to fluoroquinolones becomes more common, fluoroquinolone
use may be limited for the following indications:
• Neisseria gonorrhoeae
• Pseudomonas aeruginosa
• Urinary tract infections (UTIs)
• Typhoid

12. • PHARMACOKINETICS
• Absorption
• Well absorbed in the upper GI tract
• Good oral bioavailability:
• Levofloxacin (99%) > moxifloxacin (90%) > gemifloxacin/ciprofloxacin
(70%) > delafloxacin (60%)
• Ingestion with dairy, mineral supplements, and most antacids can
significantly ↓ bioavailability
• Peak concentrations: 1–3 hours after an oral dose

13. • Distribution
• Large volumes of distribution (VD): most exceed the total body water volume
→ the drug accumulates in the tissue
• Drugs concentrate in:
• Prostate tissue
• Bile and stool
• Lungs
• Kidneys (except moxifloxacin)
• Neutrophils and macrophages

14. METABOLISM
• < 15% of drug concentrations undergo hepatic metabolism (except moxifloxacin)
• Moxifloxacin:
• Approximately 50% of the drug is metabolized in the liver.
• Metabolized via glucuronidation and sulfate conjugation rather than CYP450
mechanisms
• Ciprofloxacin:
• Inhibits CYP1A2 → can ↑ the levels of drugs metabolized by CYP1A2
• Some affected drugs include:
• Clozapine
• Theophylline
• Tizanidine

15. EXCRETION
• Elimination:
• Primarily via renal tubular secretion (except moxifloxacin)
• Some fecal excretion for ciprofloxacin, moxifloxacin, gemifloxacin, and
delafloxacin
• Moxifloxacin:
• Hepatic clearance
• May be used in renal failure
• Should not be used for UTIs
• Half-life: 3–9 hours (typically dosed twice daily

16. INDICATIONS
• Compared to other antibiotics, fluoroquinolones are associated
with a higher risk of potentially permanent and disabling adverse
events. Therefore, fluoroquinolones are generally not used for
uncomplicated infections and should only be used against
susceptible bacteria.

17. COMPLICATED INFECTIONS
• Abdominal infections:
• Complicated intra-abdominal infections (in combination
with metronidazole for anaerobic coverage)
• Peritonitis and infection related to a peritoneal dialysis catheter
• Genitourinary infections:
• Complicated UTIs and pyelonephritis
• Prostatitis (acute and chronic)
• Pelvic inflammatory disease
• May be used in uncomplicated cystitis when no alternative options exist

18. • Respiratory infections:
• Hospital-acquired pneumonia
• Pneumonia caused by multidrug-resistant (MDR) S. pneumoniae
• Atypical pneumonia
• Tuberculosis (levofloxacin and moxifloxacin (2nd-line agents))
• May be used in uncomplicated infections when no alternative options exist:
• Bacterial sinusitis
• Chronic obstructive pulmonary disease (COPD) exacerbations
• Nervous system infections:
Bacterial meningitis

19. • Skin, soft tissue, and musculoskeletal infections:
• Bone and joint infections (including prosthetic joint infections)
• Diabetic foot infections
• Skin infections
• Surgical prophylaxis in patients allergic to 1st-line agents
(e.g., cephalosporins)
• Infections from bite wounds

20. ADVERSE EFFECTS
• Neurologic effects:
• Common mild effects:
• Headache
• Dizziness
• Insomnia (transient)
• Less common, more serious effects:
• Peripheral neuropathy (may be permanent)
• Delirium, psychosis, and/or hallucinations
• Seizures
• Exacerbation of myasthenia gravis

21. • Musculoskeletal effects (especially in growing children and teenagers):
• Tendinopathy, including tendon rupture:
• Most often the Achilles tendon
• Advise individuals to stop taking fluoroquinolone
if pain and/or swelling develop.
• Arthropathy:
• Cartilage erosions
• Noninflammatory effusions

22. • GI effects:
• Nausea, vomiting, and/or abdominal discomfort
• Diarrhea (less common)
• Cardiovascular effects:
• QT prolongation
• Aortic aneurysm and dissection
• Other effects:
• Skin rashes
• Phototoxicity
• Dysglycemia (highest risk is with moxifloxacin in diabetic individuals

23. CONTRAINDICATIONS
• Hypersensitivity to fluoroquinolones
• Pregnancy
• Growing children and teenagers
• Concurrent use with other medications prolonging the QT interval
• Myasthenia gravis
• Use with caution with:
Diabetes
Rheumatoid arthritis
Aortic aneurysm/dissection

24. CIPROFL NORFL PEFLXACI
N
OFL LEVOFL GEMI PRULI MOXI
Oral
bioavailability
60–80 35–45 90–100 85–95 ~100 70 90 85
Plasma protein
binding
20–35 15 20–30 25 25 55–73 45 40
Vol. of
distribution (L/kg)
3-4 2 2 1.5 1.3 - - 2
Percent
metabolized
20 25 85 5–10 5 >90 70-80
Elimination t½
(hr)
3–5 4-6 8-14 5-8 8 7 10-12 10-15
Routes of
administration
oral, i.v oral oral, i.v oral, i.v oral, i.v oral oral oral, i.v

25. Routes of
administration
oral, i.v oral oral, i.v oral,
i.v
oral, i.v oral oral oral, i.v
Dose (mg) :
oral
250–750
BD
400
BD
400
BD
200-400
BD
500
OD
320
OD
600
OD
400
OD
IV: 100–200 - 400 200 500 - - 400
CIPROFL NORFL PEFLXACI
N
OFL LEVOFL GEMI PRULI MOXI
DOSES OF FLUOROQUINOLONE

26. COMPARISON BASED ON COVERAGE
• Different antibiotics have varying degrees of activity against different bacteria.
The table below outlines the antibiotics with activity against 3 important
classes of bacteria: gram-positive cocci, gram-negative bacilli, and anaerobes.

28. NORFLOXACIN
• Norfloxacin is primarily used for urinary and genital tract infections. Given for
8–12 weeks,it can treat chronic UTI. It is also good for bacterial diarrhoeas,
because high concentrations are present in the gut, and anaerobic flora of the
gut is not disturbed. Norfloxacin is not recommended for respiratory and
other systemic infection.
• NORBACTIN, NORFLOX 200, 400, 800 mg tab,
• 3 mg/ml eye drops;
• UROFLOX, NORILET 200, 400 mg tab. BACIGYL 400mg tab, 100 mg/5 ml susp.

29. LEVOFLOXACIN
• It is the active levo(s) isomer of ofloxacin having improved activity against
Strep. pneumoniae and some other gram-positive and gram-negative bacteria.
Anaerobes are moderately susceptible. Oral bioavailability of levofloxacin is
nearly 100%; oral and i.v. doses are similar. It is mainly excreted unchanged,
and a single daily dose is sufficient because of slower elimination and higher
potency. Theophylline, warfarin, cyclosporine and zidovudine
pharmacokinetics has been found to remain unchanged during levofloxacin
treatment.

30. The primary indication of levofloxacin is community acquired pneumonia
and exacerbations of chronic bronchitis in which upto 90% cure rted in
sinusitis, pyelonephritis, prostatitis and other UTI, as well as skin/soft
tissue infections.
• TAVANIC, GLEVO 500 mg tab, 500 mg/100 ml inj.
• LOXOF, GLEVO, LEVOFLOX, LEVODAY 250, 500, 750 mg tabs,
• 500 mg/100 ml inj;
• VELOXIN-750/100 INJ
• GLEVO 0.5% eye drops.
• Routes of administration:-oral, i.v.
• Dose (mg);-Oral500 (OD)
IV (500)