Fluoroquinolones

Fluoroquinolones are broad-spectrum, bactericidal, concentration-dependent antibiotics that act by inhibiting bacterial DNA gyrase and topoisomerase IV. They are among the most heavily tested antimicrobials in NEET PG because of their unique mechanism, predictable generation-wise spectrum, classic drug interactions (antacid chelation), and a famous cluster of adverse effects (tendinopathy, QT prolongation, cartilage toxicity).

Classification (generation-wise)

The quinolone class began with nalidixic acid (a pure quinolone, gram-negative only, used historically for UTI). Fluorination at position 6 and a piperazine ring at position 7 produced the fluoroquinolones, which markedly broadened the spectrum and improved tissue penetration.

Generation	Drugs	Key spectrum / use
1st (quinolone)	Nalidixic acid	Gram-negative UTI only; not systemic
2nd	Norfloxacin, Ciprofloxacin, Ofloxacin	Gram-negative + some gram-positive; cipro = best anti-Pseudomonas
3rd	Levofloxacin, Sparfloxacin, Gatifloxacin	Added gram-positive (esp. S. pneumoniae) + atypicals → "respiratory FQ"
4th	Moxifloxacin, Gemifloxacin, Trovafloxacin	Above + anaerobes; moxifloxacin used in TB and intra-abdominal cover

High-yield: The two true "respiratory fluoroquinolones" tested for community-acquired pneumonia (CAP) are levofloxacin and moxifloxacin because of reliable pneumococcal and atypical cover. Ciprofloxacin has POOR pneumococcal activity and should NOT be used as monotherapy for CAP.

Mnemonic for respiratory FQs — "Levo–Moxi–Gemi–Gati Save Lungs" (Levofloxacin, Moxifloxacin, Gemifloxacin, Gatifloxacin, Sparfloxacin = enhanced gram-positive/pneumococcal cover).

Mechanism of action

Fluoroquinolones target two bacterial type-II topoisomerases that manage DNA supercoiling during replication:

1. DNA gyrase (topoisomerase II) → primary target in gram-NEGATIVE bacteria. It introduces negative supercoils ahead of the replication fork.
2. Topoisomerase IV → primary target in gram-POSITIVE bacteria. It decatenates (separates) daughter chromosomes after replication.

The drug stabilises the enzyme–DNA cleavage complex, generating lethal double-strand breaks → bactericidal action. They are concentration-dependent killers with a significant post-antibiotic effect (PAE) — efficacy correlates with the AUC/MIC and Cmax/MIC ratios, which justifies once-daily high-dose regimens.

High-yield: Gram-negative target = DNA gyrase; gram-positive target = topoisomerase IV. This is a classic one-line MCQ.

Flow of bactericidal action: FQ enters cell → binds gyrase/topo IV–DNA complex → blocks resealing of DNA strand breaks → accumulation of double-strand breaks → release of free DNA ends → bacterial death.

Spectrum of activity

• Gram-negative aerobes (best activity): E. coli, Klebsiella, Proteus, Enterobacter, Salmonella, Shigella, Campylobacter, Neisseria, Haemophilus.
• Pseudomonas aeruginosa → Ciprofloxacin is the most active oral agent.
• Atypicals: Mycoplasma, Chlamydia, Legionella — well covered (basis for respiratory FQ use).
• Intracellular organisms: Mycobacterium tuberculosis (moxi/levo are key second-line anti-TB drugs), Brucella, Mycobacterium leprae.
• Gram-positive: 3rd/4th gen cover S. pneumoniae and S. aureus (MSSA). FQs are NOT first-line for MRSA.
• Anaerobes: Only moxifloxacin has meaningful anaerobic cover.

Clinical use	Preferred fluoroquinolone
Complicated UTI / pyelonephritis	Ciprofloxacin, Levofloxacin
Pseudomonas infections	Ciprofloxacin
Community-acquired pneumonia	Levofloxacin / Moxifloxacin
Typhoid (enteric fever)	Ciprofloxacin (resistance rising) / Ceftriaxone
Traveller's diarrhoea, bacterial gastroenteritis	Ciprofloxacin (or azithromycin for Campylobacter)
Anthrax (post-exposure prophylaxis)	Ciprofloxacin (drug of choice)
MDR-TB (second line)	Levofloxacin / Moxifloxacin (Group A)
Bacterial conjunctivitis / keratitis	Topical moxifloxacin, ofloxacin
Gonorrhoea	NO longer recommended (widespread resistance) → ceftriaxone

High-yield: Ciprofloxacin is the drug of choice for inhalational anthrax post-exposure prophylaxis and for Pseudomonas UTI. Levofloxacin and moxifloxacin are Group A drugs in the WHO MDR-TB regimen.

Pharmacokinetics

• Excellent oral bioavailability (≈70–95%; levofloxacin and moxifloxacin near 100%) → oral and IV doses are nearly interchangeable.
• Wide tissue penetration — bone, prostate, lung, CSF (moderate). High prostate concentration makes them useful in bacterial prostatitis.
• Elimination: Most are renally excreted (dose-reduce ciprofloxacin/levofloxacin/ofloxacin in renal failure). Moxifloxacin is hepatically metabolised → does NOT need renal dose adjustment and is NOT used for UTI (poor urinary levels).

High-yield: Moxifloxacin = hepatic clearance, so it is NOT used for UTI and needs NO renal adjustment. Ciprofloxacin/levofloxacin = renal clearance, used for UTI.

Key drug interactions

1. Cation chelation (most tested): Di/trivalent cations — antacids (Al³⁺, Mg²⁺), calcium, iron, zinc, sucralfate, dairy products — chelate FQs in the gut and drastically reduce absorption. Give the FQ 2 hours before or 6 hours after these agents.
2. Theophylline & caffeine: Ciprofloxacin inhibits CYP1A2, raising theophylline/caffeine levels → risk of seizures and arrhythmia.
3. Warfarin: Enhanced anticoagulant effect → raised INR.
4. NSAIDs: Increase CNS excitation/seizure risk (GABA-A antagonism by FQ).
5. QT-prolonging drugs (amiodarone, sotalol, macrolides, antipsychotics): additive torsades risk.
6. Sulfonylureas / insulin: Dysglycaemia (notably gatifloxacin — withdrawn).

High-yield: The antacid/iron/calcium chelation interaction is the single most repeated FQ pharmacology MCQ — separate dosing by at least 2 hours before.

Adverse effects

Fluoroquinolones carry an FDA black-box warning for tendinopathy, peripheral neuropathy, and CNS effects, plus a caution to reserve them for situations with no alternative in uncomplicated UTI, acute bronchitis, and sinusitis.

System	Adverse effect	Exam point
Musculoskeletal	Tendinopathy & Achilles tendon rupture	↑ in elderly, renal failure, corticosteroid use
Cartilage	Arthropathy / cartilage erosion in immature animals	Basis of paediatric & pregnancy contraindication
Cardiac	QT prolongation → torsades de pointes	Worst with moxifloxacin; sparfloxacin/gatifloxacin withdrawn
CNS	Headache, dizziness, insomnia, seizures	GABA-A antagonism; worse with NSAIDs/theophylline
GI	Nausea, diarrhoea, C. difficile colitis	High-risk class for pseudomembranous colitis
Skin	Photosensitivity / phototoxicity	Marked with sparfloxacin, lomefloxacin
Metabolic	Dysglycaemia (hypo > hyper)	Gatifloxacin withdrawn for this
Peripheral nerves	Peripheral neuropathy (may be irreversible)	Black-box warning
Eye	Retinal detachment (debated), corneal deposits	—
Vascular	Aortic aneurysm / dissection	Avoid in Marfan, known aneurysm, elderly hypertensives

High-yield: Achilles tendon rupture is the classic tendon lesion; risk multiplies with concomitant corticosteroids, age >60, and renal impairment. Stop the drug at the first sign of tendon pain.

High-yield: Moxifloxacin has the greatest QT-prolonging potential among current FQs; avoid with other QT-prolonging drugs and in hypokalaemia/hypomagnesaemia.

Contraindications & cautions

• Children/adolescents (growing cartilage): relative contraindication due to arthropathy/cartilage toxicity seen in juvenile animals. Used only when benefit outweighs risk (e.g., cystic fibrosis Pseudomonas, MDR-TB, complicated UTI, anthrax).
• Pregnancy: avoid — formerly category C; risk of cartilage damage.
• Lactation: generally avoided.
• Epilepsy / CNS disorders: seizure risk.
• Known QT prolongation / hypokalaemia / hypomagnesaemia.
• Myasthenia gravis: can worsen neuromuscular blockade → exacerbation.
• G6PD deficiency: can precipitate haemolysis.
• Aortic aneurysm or Marfan/Ehlers–Danlos: risk of dissection.

High-yield: In paediatric patients, the contraindication is due to cartilage (arthropathy) toxicity demonstrated in immature animals — a favourite single-line MCQ.

Resistance mechanisms

1. Chromosomal mutations in gyrA / parC (the quinolone resistance-determining region, QRDR) — alter the target enzyme. Most common and clinically important.
2. Efflux pumps (e.g., NorA in S. aureus) and decreased porin uptake in gram-negatives.
3. Plasmid-mediated resistance (PMQR): qnr genes protect gyrase; aac(6′)-Ib-cr acetylates the drug. These transfer resistance horizontally and are increasingly tested.

Investigation / monitoring relevance

• Fluoroquinolones can cause false-positive urine opiate immunoassays.
• Baseline and on-therapy attention to ECG (QTc) in cardiac-risk patients, electrolytes, and blood glucose in diabetics.
• For TB, FQ susceptibility testing (line probe assays — SL-LPA) guides MDR/pre-XDR classification.

Key differentials / "which FQ?" decision aid

Choosing the agent — stepwise:

1. Pseudomonas or complicated gram-negative UTI? → Ciprofloxacin.
2. Community-acquired pneumonia / atypical cover needed? → Levofloxacin or Moxifloxacin.
3. Renal failure but need a FQ? → Moxifloxacin (hepatic, no renal adjustment) — but NOT for UTI.
4. Anaerobic cover wanted (intra-abdominal)? → Moxifloxacin.
5. MDR-TB second-line? → Levofloxacin / Moxifloxacin (Group A).

Compare	Ciprofloxacin	Levofloxacin	Moxifloxacin
Anti-Pseudomonas	Best	Good	Weak
Pneumococcal cover	Poor	Good	Best
Anaerobic cover	No	Minimal	Yes
Renal vs hepatic clearance	Renal	Renal	Hepatic
Use in UTI	Yes	Yes	No
QT prolongation	Low	Moderate	Highest

Recently asked / exam angle

• Mechanism pairing: "Target of fluoroquinolones in gram-negative bacteria?" → DNA gyrase (topoisomerase II); gram-positive → topoisomerase IV.
• Drug interaction: Reduced ciprofloxacin absorption with antacids/iron/calcium/sucralfate (chelation).
• Adverse effect: Achilles tendon rupture; risk factors = steroids, age, renal failure. Also QT prolongation (moxifloxacin) and photosensitivity (sparfloxacin).
• Paediatric contraindication reason: cartilage/arthropathy toxicity.
• DOC questions: Ciprofloxacin for anthrax prophylaxis and Pseudomonas; levo/moxi as Group A anti-TB.
• Which FQ is hepatically cleared / not for UTI? → Moxifloxacin.
• CYP1A2 inhibition by ciprofloxacin → theophylline toxicity / seizures.
• Withdrawn FQs and reasons: gatifloxacin (dysglycaemia), sparfloxacin/grepafloxacin (QT, phototoxicity), temafloxacin (haemolysis/TEMAFLOXACIN syndrome), trovafloxacin (hepatotoxicity).
• WHO MDR-TB Group A = Levofloxacin/Moxifloxacin, Bedaquiline, Linezolid.

Rapid revision

1. FQs are bactericidal, concentration-dependent (AUC/MIC, Cmax/MIC driven) inhibitors of DNA gyrase + topoisomerase IV.
2. Gram-negative target = DNA gyrase; gram-positive target = topoisomerase IV.
3. Ciprofloxacin = best anti-Pseudomonas; levofloxacin/moxifloxacin = respiratory FQs for CAP.
4. Moxifloxacin is hepatically cleared, covers anaerobes, has highest QT risk, and is not used for UTI.
5. Antacids, iron, calcium, sucralfate, dairy chelate FQs → separate by 2 h before / 6 h after.
6. Ciprofloxacin inhibits CYP1A2 → theophylline/caffeine toxicity and seizures.
7. Classic adverse effects: Achilles tendon rupture, QT prolongation, photosensitivity, peripheral neuropathy, C. difficile colitis, aortic dissection.
8. Tendon rupture risk ↑ with corticosteroids, age >60, renal failure.
9. Contraindicated in children/pregnancy due to cartilage (arthropathy) toxicity; caution in myasthenia gravis, epilepsy, G6PD deficiency, prolonged QT.
10. Ciprofloxacin = DOC for anthrax prophylaxis; levo/moxi = Group A MDR-TB drugs.
11. Resistance: gyrA/parC QRDR mutations, efflux pumps, plasmid qnr genes.
12. Withdrawn agents: gatifloxacin (dysglycaemia), sparfloxacin (QT/phototoxicity), trovafloxacin (hepatotoxicity), temafloxacin (haemolysis).