Quinolones

01Drug classification

The first quinolone, nalidixic acid, was described in 1962, from work on antimalarial drugs. It was used mainly for urinary infections, as it reached useful levels in the urine but little in the blood. A fluorine atom, and then a piperazine ring, made the fluoroquinolones, norfloxacin and ciprofloxacin among the first, far more active and spread through the body; later drugs reached gram-positives better. In 2019 the EU suspended nalidixic acid and the other old quinolones still sold, pipemidic acid, cinoxacin and flumequine. The fluoroquinolones fall into two groups, around ciprofloxacin and around levofloxacin.

02Pharmacokinetics

Fluoroquinolones are absorbed well, levofloxacin completely, so a tablet often does the work of a drip: 500 mg of ciprofloxacin by mouth gives the same exposure as 400 mg into a vein. They spread widely and enter cells, into lung, kidney, prostate, bile and the female genital tract, often at two to five times the level in plasma, and into the neutrophils and macrophages that carry intracellular bacteria. Levofloxacin reaches the cerebrospinal fluid poorly.

In the gut they bind magnesium, aluminium, iron and zinc into complexes that aren't absorbed. Antacids, iron and zinc supplements, sucralfate and phosphate binders are spaced from the dose by the interval each product gives: 1 to 2 hours before or at least 4 hours after ciprofloxacin, 2 hours either side of levofloxacin, about 6 hours for moxifloxacin. Calcium matters mostly for ciprofloxacin: milk or yoghurt taken alone, or a calcium supplement, cuts its absorption, while the calcium in a meal hardly does. For levofloxacin and moxifloxacin calcium makes little difference.

03Pharmacodynamics

Trapped on cut DNA

Most bacteria have two type II topoisomerases; Mycobacterium tuberculosis has only gyrase. DNA gyrase undoes the twisting that builds up ahead of a replication fork, and topoisomerase IV untangles the two new chromosomes once they are copied. Both work by cutting both strands of the DNA, passing another stretch of the double helix through the gap, and sealing it again.

1. 1

   The enzyme cuts both strands

   Gyrase or topoisomerase IV holds the cut ends while another stretch of DNA passes through.
2. 2

   The drug wedges into the cut

   A fluoroquinolone binds where enzyme meets DNA and slips into the DNA at each cut, two drug molecules to a double break. A magnesium ion, bridged by water to a serine and an acidic residue of the enzyme, holds it in place. Now the enzyme can't reseal the break.
3. 3

   Trapped cuts become breaks

   When a replication fork or RNA polymerase runs into a trapped enzyme, the cut becomes a lasting double-strand break. More breaks than the cell can repair kill it, so the drugs are bactericidal.

In gram-negatives the main target is usually gyrase, in gram-positives topoisomerase IV, though it varies with the species and the drug. Our own type II topoisomerases lack the residues that hold the water–metal bridge, which is part of why the drugs spare us.

Their killing is concentration-dependent: the higher the peak level, and the larger the area under the curve, against the bacterium's minimum inhibitory concentration, the better they work. The best effect comes with a peak at least ten times the MIC. They also hold bacteria back for 2 to 6 hours after levels have fallen, a long post-antibiotic effect, which, with their half-lives, lets them be given once or twice a day.

What they reach

• Ciprofloxacin and ofloxacin: Enterobacterales (E. coli, Klebsiella, Proteus, Salmonella, Shigella), Campylobacter, Haemophilus, Moraxella, Neisseria, Legionella and Pseudomonas aeruginosa, ciprofloxacin more strongly than ofloxacin. Ciprofloxacin is not recommended for streptococcal infections, pneumococci among them.
• Levofloxacin and moxifloxacin add pneumococci and reach the atypical Mycoplasma pneumoniae and Chlamydia pneumoniae better, and moxifloxacin some anaerobes; all of them reach Legionella. Moxifloxacin doesn't reach Pseudomonas.
• Mycobacteria: Mycobacterium tuberculosis, against which levofloxacin and moxifloxacin are core drugs when it resists rifampicin.
• Not reliably: MRSA, except with delafloxacin, enterococci, and most anaerobes.

How bacteria resist

• Changed targets. Mutations in the genes for gyrase (gyrA) and topoisomerase IV (parC), often at the serine that holds the water–metal bridge, lower the drug's grip. They come step by step, each raising the level of resistance.
• Less drug inside. Gram-negatives make fewer porins and pump more out through their own efflux pumps, which can raise resistance to several classes at once.
• Plasmid genes. Qnr proteins shield the enzymes, a variant of an aminoglycoside enzyme, aac(6')-Ib-cr, acetylates ciprofloxacin and norfloxacin, and some plasmids carry pumps. Each gives only a little resistance, but it makes higher-level mutants easier to select.

Heavy use has made resistance common. In 2023, 24.0% of invasive E. coli across the EU and EEA resisted fluoroquinolones, from 10.1% to 42.9% between countries, with 33.7% of Klebsiella pneumoniae and 17.9% of Pseudomonas aeruginosa. ESBL producers commonly resist them too, and resistance to ciprofloxacin is rising in Campylobacter jejuni and Salmonella Enteritidis from patients in over half the European countries that report it. Most Campylobacter already resist it: 72% of C. jejuni from patients in a German series, 2018 to 2023.

04Clinical indications

at least, have reactions that can disable for months or for good

1 to 10in 10,000 treatedat least, have reactions that can disable for months or for good

after the first dose a tendon can tear, or months after the last

48hoursafter the first dose a tendon can tear, or months after the last

in Europe resisted ciprofloxacin in 2022

65.9%of gonococciin Europe resisted ciprofloxacin in 2022

in the EU and EEA resisted fluoroquinolones in 2023

24%of invasive E. coliin the EU and EEA resisted fluoroquinolones in 2023

05Adverse drug reactions

• Life-threatening
  Long-lasting, disabling reactions of tendons, muscles, joints, nerves, mind and senses, among them a peripheral neuropathy that can be permanent. They occur at any age, with or without risk factors. The drug is stopped at the first symptom, and fluoroquinolones are avoided from then on.
• Serious
  Tendinitis and tendon rupture, mostly of the Achilles tendon, sometimes on both sides, from 48 hours after the first dose to months after the last. The risk is higher over 60, with corticosteroids, kidney disease and organ transplants. At the first pain the drug is stopped and the limb rested.
• Life-threatening
  Aortic aneurysm and dissection, a small added risk, mostly in older people. Sudden pain in the abdomen, chest or back is an emergency.
• Serious
  Leaking heart valves: aortic and mitral regurgitation, a small added risk. Sudden breathlessness, palpitations or swelling of the legs or abdomen send the patient to a doctor.
• Life-threatening
  A long QT interval and torsades de pointes, mostly with other risks: other drugs that lengthen it, low potassium or magnesium, heart disease, older age and female sex.
• Life-threatening
  Worsening of myasthenia gravis, which has needed ventilation and caused deaths.
• Serious
  A low or high blood sugar, mostly in diabetics on insulin or a sulfonylurea; hypoglycaemic coma has occurred. The blood sugar is watched.
• Serious
  Seizures, status epilepticus among them, more likely with epilepsy, NSAIDs or theophylline.
• Life-threatening
  Psychiatric reactions, even after the first dose: agitation, confusion, hallucinations, psychosis and depression, which can lead to suicidal thoughts and suicide. The drug is stopped.
• Serious
  Clostridioides difficile colitis: severe or lasting diarrhoea, even weeks after the course. Outside hospital, fluoroquinolones are among the antibiotics most likely to bring it on.
• Serious
  Liver injury: hepatitis and jaundice. The drug is stopped at jaundice, dark urine, itching or a tender abdomen.
• Life-threatening
  Liver necrosis and liver failure, rare, sometimes fatal, reported with each of them.
• Life-threatening
  Anaphylaxis, which can follow the first dose, and severe skin reactions: Stevens–Johnson syndrome, toxic epidermal necrolysis and DRESS.

06Side effects

• Mild
  Nausea and diarrhoea, the commonest.
• Mild
  Headache, dizziness, restlessness and poor sleep; ciprofloxacin makes coffee more stimulating, as it slows the breakdown of caffeine.
• Mild
  Sensitivity to sunlight, rare, so strong sun and sunbeds are avoided during the course.
• Mild
  Crystals in the urine with ciprofloxacin, rare, mostly in an alkaline urine, so patients drink enough.
• Mild
  Thrush, in the mouth or vagina.

07Contraindications

• Contraindicated
  An allergy to any quinolone.
• Contraindicated
  A tendon disorder from a fluoroquinolone before, in the licences of levofloxacin, moxifloxacin, ofloxacin and delafloxacin; ciprofloxacin's says it should generally not be used.
• Contraindicated
  Ciprofloxacin with tizanidine, duloxetine or agomelatine. Tizanidine's exposure rises about tenfold, with a fall in blood pressure and drowsiness. Duloxetine's and agomelatine's own licences rule ciprofloxacin out, as it blocks the CYP1A2 that clears them.
• Contraindicated
  Moxifloxacin with a long QT or a risk of one: a long QT from birth or acquired, uncorrected low potassium, a slow heart rate that matters, heart failure with a low ejection fraction, past symptomatic arrhythmias, or other drugs that lengthen the QT. Also in severe liver disease, Child–Pugh C, or liver enzymes over five times normal.
• Contraindicated
  Epilepsy, with levofloxacin and ofloxacin, which lower the seizure threshold.
• Avoid
  Any other serious reaction to a quinolone before. Another is given only when there is no alternative.
• Avoid
  Children and growing adolescents, for the cartilage harm seen in young animals. Ciprofloxacin is the exception, licensed for Pseudomonas in cystic fibrosis, complicated urinary infections and anthrax, and given as a single dose to meningococcal contacts. The licences of levofloxacin, moxifloxacin, ofloxacin and delafloxacin rule them out.
• Avoid
  Corticosteroids, which add to the risk of tendon rupture and of aortic dissection.
• Avoid
  An aortic aneurysm, heart valve disease, or a risk of either: a family history of aneurysm, Marfan or Ehlers–Danlos syndrome, Turner syndrome, Behçet's disease, high blood pressure, rheumatoid arthritis, giant cell or Takayasu arteritis, Sjögren's syndrome, known atherosclerosis, or for the valves congenital valve disease or endocarditis. Other antibiotics are considered first.
• Avoid
  G6PD deficiency, in which quinolones can cause haemolysis. Ciprofloxacin is avoided unless the benefit outweighs the risk, ofloxacin's licence rules it out, and levofloxacin and moxifloxacin are used with caution, watching for haemolysis.
• Avoid
  Ciprofloxacin with methotrexate, whose levels it raises.
• Avoid
  Myasthenia gravis, which can worsen dangerously. Levofloxacin's and ofloxacin's licences advise against them; ciprofloxacin and moxifloxacin are used with caution.
• Caution
  Drugs cleared by CYP1A2, with ciprofloxacin: theophylline, whose level is checked and dose cut, clozapine, olanzapine, ropinirole and caffeine.
• Caution
  Other drugs that lengthen the QT, with ciprofloxacin and levofloxacin, and low potassium or magnesium, heart disease and older age.
• Caution
  Warfarin and the other vitamin K antagonists, whose effect can rise, so the INR is checked often.
• Caution
  Insulin and sulfonylureas, so the blood sugar is watched.
• Caution
  Antacids, iron, zinc, sucralfate and phosphate binders, and calcium with ciprofloxacin, spaced from the dose.
• Caution
  Conditions that lower the seizure threshold, with ciprofloxacin and moxifloxacin, and NSAIDs or theophylline, which lower it further.
• Caution
  Age over 60, kidney disease and organ transplants, for the tendons; the dose of ciprofloxacin, ofloxacin and levofloxacin is lowered as the kidneys fail.

08Pregnancy and lactation

• Avoid
  Pregnancy. There is no good evidence that a quinolone harms the baby: the worry about growing cartilage comes from young animals. A different antibiotic is usually tried first, because of the drugs' own harms, but one can be given when it is the best treatment. The licences are stricter: levofloxacin's, moxifloxacin's, ofloxacin's and delafloxacin's rule them out, and ciprofloxacin's prefers to avoid it.
• Compatible
  A single dose of ciprofloxacin in pregnancy, to prevent meningococcal disease in a close contact.
• Compatible
  Breastfeeding with ciprofloxacin or ofloxacin, which pass into the milk in tiny amounts, and the calcium in milk may keep the baby from absorbing much of it; long courses are best avoided. The licences are stricter: ciprofloxacin's and ofloxacin's say not to breastfeed.
• Caution
  Breastfeeding with levofloxacin or moxifloxacin, probably compatible, though ciprofloxacin or ofloxacin is preferred, above all for a newborn or a premature baby. Their licences rule breastfeeding out.