Mechanism of Action of Fluoroquinolones (DNA Gyrase and Topoisomerase Inhibitors)

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Introduction

Fluoroquinolones are a powerful class of bactericidal antibiotics that inhibit bacterial DNA replication. They are widely used to treat urinary tract infections (UTIs), respiratory infections, gastrointestinal infections, and sexually transmitted diseases. Common agents include ciprofloxacin, levofloxacin, and moxifloxacin. They exhibit broad-spectrum activity against Gram-positive, Gram-negative, and atypical organisms.

Because of their unique mechanism of action and clinical importance, fluoroquinolones are frequently tested in USMLE, NCLEX, GPAT, and NEET-PG.

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Stepwise Mechanism of Action of Fluoroquinolones

1. Inhibition of DNA gyrase (Topoisomerase II) in Gram-negative bacteria
   Fluoroquinolones bind to and inhibit DNA gyrase, which is essential for introducing negative supercoils into bacterial DNA during replication and transcription.
2. Inhibition of Topoisomerase IV in Gram-positive bacteria
   In Gram-positive organisms, they inhibit topoisomerase IV, which is crucial for decatenation (separation) of daughter DNA strands during cell division.
3. Stabilization of DNA-enzyme complex
   They stabilize the complex between DNA and these enzymes, preventing re-ligation of DNA strands, leading to DNA fragmentation.
4. Bacterial cell death
   Disruption of replication and transcription leads to irreversible DNA damage and bactericidal activity.

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Pharmacokinetic Parameters of Fluoroquinolones (e.g., Ciprofloxacin)

Parameter	Value
Bioavailability	~70% (oral)
Half-life	3–7 hours (varies by drug)
Protein binding	20–40%
Metabolism	Hepatic (partial)
Excretion	Renal (major), biliary (minor)
CNS penetration	Moderate

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Clinical Uses of Fluoroquinolones

• Urinary tract infections (UTIs)
• Prostatitis
• Gastroenteritis (Shigella, Salmonella, Campylobacter)
• Typhoid fever
• Respiratory tract infections (levofloxacin, moxifloxacin)
• Anthrax prophylaxis (ciprofloxacin)
• STIs (e.g., Chlamydia)
• Bone and joint infections
• Tuberculosis (second-line)

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Adverse Effects of Fluoroquinolones

• Tendinitis and tendon rupture
• QT interval prolongation
• CNS toxicity (seizures, dizziness, insomnia)
• GI upset – nausea, diarrhea
• Photosensitivity
• Dysglycemia (hypo/hyperglycemia)
• Arthropathy in children (contraindicated in growing age)
• C. difficile superinfection

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Comparative Analysis: Ciprofloxacin vs Levofloxacin

Feature	Ciprofloxacin	Levofloxacin
Spectrum	Gram– > Gram+	Broad (better Gram+ & atypicals)
Respiratory coverage	Poor	Excellent
Half-life	Short (~4 h)	Longer (~7 h)
Dosing frequency	Twice daily	Once daily

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Practice MCQs

Q1. Fluoroquinolones inhibit which bacterial enzyme in Gram-negative organisms?
a. Topoisomerase IV
b. DNA polymerase
c. DNA gyrase ✅
d. RNA polymerase

Q2. What is the primary mechanism of fluoroquinolones?
a. Ribosomal inhibition
b. DNA replication inhibition ✅
c. Cell wall synthesis inhibition
d. Folic acid inhibition

Q3. Which of the following is a major adverse effect?
a. Hepatic failure
b. Tendon rupture ✅
c. Stevens-Johnson Syndrome
d. Pancytopenia

Q4. Fluoroquinolones are contraindicated in:
a. Elderly
b. Pregnant women
c. Children with open growth plates ✅
d. All of the above

Q5. Which fluoroquinolone is best for pneumonia?
a. Ciprofloxacin
b. Norfloxacin
c. Levofloxacin ✅
d. Ofloxacin

Q6. Fluoroquinolones cause QT prolongation by blocking:
a. Na⁺ channels
b. K⁺ channels ✅
c. Ca²⁺ channels
d. HCN channels

Q7. Which fluoroquinolone is preferred for anthrax?
a. Moxifloxacin
b. Ciprofloxacin ✅
c. Levofloxacin
d. Gatifloxacin

Q8. Which adverse effect is seen with fluoroquinolones in diabetics?
a. Dysglycemia ✅
b. Ketoacidosis
c. Hypokalemia
d. Hypocalcemia

Q9. Fluoroquinolones are time- or concentration-dependent killers?
a. Time-dependent
b. Concentration-dependent ✅
c. Both
d. Neither

Q10. Which is a second-line use of fluoroquinolones?
a. Tuberculosis ✅
b. Malaria
c. Gonorrhea
d. MRSA

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FAQs

Q1: Are fluoroquinolones safe in pregnancy?
No, they are contraindicated due to risk of cartilage damage in the fetus.

Q2: Why avoid fluoroquinolones in athletes?
Because of the risk of tendinitis and tendon rupture.

Q3: Can fluoroquinolones cause QT prolongation?
Yes, especially levofloxacin and moxifloxacin.

Q4: What’s the difference between generations of fluoroquinolones?
Later generations have improved Gram+ and atypical coverage.

Q5: Do they work on anaerobes?
Minimal to no activity against strict anaerobes like Bacteroides.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Sparsh Gupta – Review of Pharmacology
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK537038/