Nitrofurantoin, daptomycin, polymyxins and other antibacterials

01Drug classification

Five "other antibacterial agents", nitrofurantoin, daptomycin, polymyxin B, rifaximin and fidaxomicin, have no single mechanism in common, so the cards sort them by where and how they work. Three more join them: colistin, the polymyxin given into a vein across Europe, and nitroxoline and methenamine, two drugs for cystitis.

Most of them are old, and some were nearly lost. Nitrofurantoin was patented in 1952 and has been prescribed since 1953; in England its prescriptions doubled between 2015 and 2020. The polymyxins were found in 1947 in Paenibacillus polymyxa, and colistin, found in Japan, proved to be polymyxin E. Approved in the late 1950s, they fell out of use in the 1970s because they harmed the kidneys, and came back as a last resort against gram-negatives that resist almost everything else. Daptomycin, isolated in the 1980s from Streptomyces roseosporus, was shelved when high doses damaged muscle; with a new way of dosing it, it was approved in the United States in 2003. Fidaxomicin was authorised in the EU in 2011.

02Pharmacokinetics

Where each drug goes decides what it treats.

Nitrofurantoin passes from the blood into the urine so fast that the blood never holds much, which is why it treats the bladder and nothing else. Food raises its absorption, and the larger macrocrystals dissolve slowly, which eases nausea. It needs working kidneys to reach the urine: its UK licence rules it out below an eGFR of 45 ml/minute, and allows a short course at 30 to 44 only against resistant bacteria. It turns the urine yellow or brown.

Methenamine works only in acid urine, where it slowly gives off formaldehyde; the hippuric acid it comes with helps keep the urine acid. Nitroxoline is absorbed almost completely and quickly joined to glucuronide and sulphate, and its licence doesn't promise an effect once the serum creatinine is over 2 mg/dL.

Daptomycin stays mostly in the blood and the fluid around cells, about 90% bound to protein. It is given once a day because a long gap keeps the trough level low, which spares muscle. When the creatinine clearance is under 30 ml/minute it is given every 48 hours, after dialysis on dialysis days.

Colistimethate is a prodrug: about 30% of it turns into colistin in the body, slowly, so colistin peaks up to 7 hours after the first dose, which is why the critically ill get a loading dose. European labels give doses in million international units: 1 million units is about 80 mg of colistimethate, or about 34 mg of colistin base activity, the unit American labels use. Mixing the units up has caused dosing errors. Polymyxin B is given as itself, not as a prodrug, and isn't cleared by the kidneys, so its dose isn't lowered as they fail.

Rifaximin reaches the blood more in liver disease, its exposure about 10 times higher in mild and 20 times in severe, and ciclosporin raised its peak level 83-fold. Fidaxomicin reaches high levels in the stool and barely any in the blood.

03Pharmacodynamics

Polymyxins: breaking the outer membrane

The outer membrane of a gram-negative bacterium has lipopolysaccharide on its outer face, anchored by lipid A. Magnesium and calcium ions bridge the negatively charged phosphates of neighbouring lipid A molecules and hold the face together.

1. 1

   Drawn to the outer membrane

   The positively charged diaminobutyric acid (Dab) residues of a polymyxin bind the negatively charged phosphates of lipid A.
2. 2

   The bridges come apart

   The polymyxin pushes out the magnesium and calcium that bridge the lipid A molecules, and its fatty tail slips into the membrane and loosens it.
3. 3

   The cell leaks

   More polymyxin passes through the gaps it has made, its self-promoted uptake, and disrupts the inner membrane, so the cell leaks and dies. The higher the level, the faster it kills.

The polymyxins reach aerobic gram-negative bacilli: Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella, E. coli and Haemophilus influenzae. They miss gram-positives and anaerobes. Proteus, Providencia, Serratia, Morganella, Neisseria and Burkholderia cepacia resist them by nature; in Proteus and Burkholderia every lipid A phosphate already carries ethanolamine or aminoarabinose, which blunts its negative charge. Colistin and polymyxin B differ by a single amino acid, and a bacterium that resists one is expected to resist the other.

Other bacteria acquire the same change. Mutations in their two-component sensors, PmrAB and PhoPQ, or in Klebsiella pneumoniae in mgrB, switch on enzymes that add phosphoethanolamine or aminoarabinose to lipid A. Resistance can emerge during treatment with a polymyxin alone, one reason a second drug is often added. In 2015 came mcr-1, the first polymyxin resistance gene carried on a plasmid, which can spread between bacteria: in China it was found in E. coli from 21% of farm animals and 15% of raw meat sampled, and from 1% of samples from patients with infections, after years of colistin use in farming.

Daptomycin and the gram-positive membrane

Daptomycin is a cyclic lipopeptide that works only with calcium. Bound to calcium, it seeks out phosphatidylglycerol, a negatively charged lipid plentiful in gram-positive membranes, and inserts its fatty tail. The classic account is that it then depolarises the membrane, potassium leaks out, and DNA, RNA and protein synthesis stop. Studies in living bacteria find the depolarisation comes late, after most cells have died, and point instead to daptomycin crowding into fluid patches of the membrane where the cell wall is built and driving off the enzymes there, MurG among them; how it kills is still debated. Either way it kills quickly, without bursting the cell.

It reaches S. aureus, MRSA among it and strains less susceptible to vancomycin, coagulase-negative staphylococci, streptococci of groups A, B, C and G, and some gram-positive anaerobes. It misses gram-negatives. Against enterococci it is unproven: its licence finds too little evidence that it works, and reports failures. It is given all the same, at 10 to 12 mg/kg with a β-lactam or fosfomycin, for enterococci that resist vancomycin. S. aureus can become less susceptible during a long course by changing its membrane, making less phosphatidylglycerol or adding lysine to it, which turns the surface positive and repels the calcium–daptomycin complex.

Nitrofurantoin: many targets at once

Inside bacteria, nitroreductases (NfsA and NfsB in E. coli) reduce nitrofurantoin to reactive products that attack many things at once: protein synthesis, enzymes of the citric acid cycle, and DNA and RNA. Bacteria that lack these enzymes resist it by nature, Pseudomonas among them, as do most Proteus and Serratia. It reaches E. coli, Enterococcus faecalis, Staphylococcus saprophyticus and many Klebsiella and Enterobacter, though some strains of those two resist it.

In E. coli, clinical resistance usually needs both nitroreductase genes to be lost, and rarely travels on plasmids, though a pump carried on one, OqxAB, can make the step easier. That, and its many targets, is why resistance stays rare: about 2.5% of E. coli and other coliforms from the community in England resisted it from 2015 to 2023, though its use had doubled.

Methenamine and nitroxoline

Methenamine, also called hexamine, is a prodrug: in acid urine it slowly breaks down to formaldehyde, which kills bacteria, and its partner, hippuric acid, also slows their growth. It is antiseptic prophylaxis: it prevents infection rather than treating an acute one.

Nitroxoline, an 8-hydroxyquinoline, binds metal ions. It pulls the magnesium and calcium that hold the outer membrane together out of it, which makes it leaky, takes iron and zinc from biofilms, and carries copper and zinc into the cell, where the excess appears to damage the iron–sulphur clusters its enzymes need. Older accounts add a block of RNA polymerase, for which the evidence is thin. It mostly stops bacteria growing rather than killing them, and well below that level it keeps them from sticking to the bladder wall. It reaches E. coli, Klebsiella and the other Enterobacterales that cause cystitis, Acinetobacter, and gram-positives such as S. aureus; Pseudomonas resists it by nature. Resistance is still rare after decades of use, and it has a breakpoint for E. coli in uncomplicated cystitis only.

Rifaximin and fidaxomicin: RNA polymerase in the gut

Both block bacterial RNA polymerase, the enzyme that copies DNA into RNA, at different sites. Rifaximin, a rifamycin like rifampicin, binds its β subunit. Bacteria resist it through mutations in rpoB, but the resistant strains are unstable and vanish once it is stopped, and the data suggest that treating carriers of M. tuberculosis or meningococci with it won't select resistance to rifampicin.

Fidaxomicin binds a site of its own, so it shares no resistance with the rifamycins or any other class, and blocks the RNA polymerase of clostridia at a twentieth of the level the E. coli enzyme needs. It kills C. difficile, stops it forming spores in the laboratory, and leaves Bacteroides and the other main bowel bacteria largely untouched.

04Clinical indications

from the community in England resisted nitrofurantoin from 2015 to 2023, though its use doubled

2.5%of E. coli and coliformsfrom the community in England resisted nitrofurantoin from 2015 to 2023, though its use doubled

get kidney injury on a polymyxin into a vein

20 to 50%of seriously ill patientsget kidney injury on a polymyxin into a vein

against 25% after vancomycin, in its first trial

15%relapsed after fidaxomicinagainst 25% after vancomycin, in its first trial

within 6 months on rifaximin, against 46% on placebo

22%had hepatic encephalopathy againwithin 6 months on rifaximin, against 46% on placebo

05Adverse drug reactions

• Life-threatening
  Lung reactions to nitrofurantoin. Acute ones, with fever, cough, breathlessness, chest pain and eosinophilia, come mostly in the first week, and a death after a 10-day course led to a renewed UK warning in 2023; chronic fibrosis and interstitial pneumonitis creep in over months of continuous use, mostly in older people. The drug is stopped at the first sign.
• Serious
  Hepatitis and cholestatic jaundice with nitrofurantoin, rarely, and autoimmune hepatitis. Long courses need the liver checked from time to time, and the drug is stopped if hepatitis appears.
• Life-threatening
  Chronic active hepatitis and liver necrosis with nitrofurantoin, which can begin quietly during long courses; deaths have been reported.
• Life-threatening
  Peripheral neuropathy with nitrofurantoin, which can become severe or permanent. Caution is needed in anaemia, diabetes, electrolyte imbalance, vitamin B deficiency and debility, and the drug is stopped at the first pins and needles.
• Life-threatening
  Aplastic anaemia and agranulocytosis with nitrofurantoin: aplastic anaemia rarely, agranulocytosis at an unknown rate. The drug is stopped for any unexplained blood disorder.
• Serious
  Other blood disorders with nitrofurantoin: haemolysis in G6PD deficiency and in newborns, whose red cell enzymes are immature; and rarely a low platelet count and megaloblastic anaemia.
• Serious
  Muscle damage with daptomycin: a raised creatine kinase (CPK), myositis and rhabdomyolysis. CPK is measured at the start and at least weekly, every 2 to 3 days in those at risk, and the drug is stopped when unexplained muscle symptoms come with a CPK over five times normal.
• Life-threatening
  Eosinophilic pneumonia with daptomycin, mostly after two weeks: fever, breathlessness with too little oxygen in the blood, and diffuse shadows on the chest film. It is stopped and steroids are given; it can come back if the drug is given again.
• Serious
  Peripheral neuropathy, kidney impairment and tubulointerstitial nephritis with daptomycin.
• Serious
  Kidney injury with colistimethate into a vein, in a fifth to a half of seriously ill patients, about 20% in its licence and higher by today's definitions, under 1% in cystic fibrosis, more with high doses, dehydration and other drugs that harm the kidneys. It usually recovers when the drug is stopped; the kidneys are checked throughout.
• Life-threatening
  Nerve toxicity and apnoea with colistimethate, from high levels: tingling around the mouth and in the limbs, the sign to watch for, vertigo, slurred speech, confusion, and muscle weakness that can stop breathing, more likely with failing kidneys and neuromuscular blockers.
• Serious
  Bronchospasm with inhaled colistimethate, prevented or treated with a β2-agonist.
• Life-threatening
  Anaphylaxis and severe skin reactions: anaphylaxis with daptomycin, nitrofurantoin and rifaximin, and severe angioedema with fidaxomicin; DRESS and Stevens–Johnson syndrome with daptomycin and nitrofurantoin; Stevens–Johnson syndrome and toxic epidermal necrolysis with daptomycin and with rifaximin, mostly in liver disease. A drug that caused one is never given again.
• Serious
  Clostridioides difficile colitis with daptomycin and colistimethate, and possibly with rifaximin.
• Serious
  A low platelet count with nitroxoline, rarely, from an allergy.

06Side effects

• Mild
  Nausea, vomiting, loss of appetite and diarrhoea, above all with nitrofurantoin, less with the macrocrystals and with food; and stomach upset with nitroxoline and methenamine.
• Mild
  Coloured urine: yellow or brown with nitrofurantoin, an intense yellow with nitroxoline, which can rarely tint the skin, hair and nails, and reddish with rifaximin.
• Mild
  Headache, dizziness and drowsiness, and with daptomycin insomnia and anxiety.
• Mild
  Rash and itching with daptomycin, methenamine and nitroxoline, and bladder irritation with methenamine.
• Mild
  With daptomycin, soreness where the drip goes in, fungal infections, raised liver enzymes, and a falsely long prothrombin time with some reagents.
• Mild
  Cough, a sore throat or mouth, and thrush with inhaled colistimethate.
• Mild
  Nausea, vomiting and constipation with fidaxomicin, each in 1 to 3% of patients; rifaximin's side effects matched placebo's in trials.
• Mild
  A false positive urine glucose with nitrofurantoin, by the tests that detect reducing sugars.

07Contraindications

• Contraindicated
  An allergy to the drug or its family: to any nitrofuran with nitrofurantoin; to colistin or polymyxin B with either; to any rifamycin with rifaximin; and to the soya oil or the dye Ponceau 4R in nitroxoline capsules.
• Contraindicated
  Nitrofurantoin below an eGFR of 45 ml/minute, in its UK licence, which allows a short course at 30 to 44 only against resistant bacteria; and in G6PD deficiency, acute porphyria and infants under 3 months.
• Contraindicated
  Methenamine in liver disease, infection of the kidney itself, severe dehydration, metabolic acidosis, a GFR under 10 ml/minute or gout; and with sulfonamides, which can crystallise in the urine, or with drugs that make the urine alkaline, such as potassium citrate.
• Contraindicated
  Nitroxoline in severe kidney or liver impairment.
• Contraindicated
  Rifaximin when the bowel is obstructed.
• Contraindicated
  Ear drops with neomycin and polymyxin B when the eardrum is or may be perforated, as neomycin can harm hearing for good.
• Avoid
  Nitrofurantoin for pyelonephritis, a kidney abscess or prostatitis, where it isn't shown to work.
• Avoid
  Methenamine with acetazolamide, which makes the urine alkaline.
• Avoid
  Daptomycin for pneumonia, in which it doesn't work.
• Avoid
  Daptomycin with statins, fibrates or ciclosporin, which also harm muscle; they are paused if possible, and otherwise CPK is checked more than weekly.
• Avoid
  Daptomycin under the age of one, for harm to muscle and nerves seen in newborn dogs.
• Avoid
  Colistimethate in myasthenia gravis, as it blocks the release of acetylcholine; only if clearly needed, with the greatest caution.
• Avoid
  Colistimethate with aminoglycosides or other drugs that harm the kidneys or nerves.
• Avoid
  Rifaximin for diarrhoea with fever or blood, for more than 3 days, as a second course, or with another rifamycin.
• Avoid
  Fidaxomicin with strong P-glycoprotein inhibitors, which raise its level: ciclosporin, ketoconazole, erythromycin, clarithromycin, verapamil, dronedarone and amiodarone.
• Caution
  Nitrofurantoin in lung, liver or nerve disease, allergy, anaemia, diabetes, electrolyte imbalance, vitamin B deficiency or debility, which can hide or add to its harms; long courses are watched for lung and liver reactions, mostly in older people. Probenecid slows its passage into the urine, magnesium trisilicate cuts its absorption, and drugs that make the urine alkaline weaken it.
• Caution
  Daptomycin when the kidneys are impaired already, with regular kidney tests; with NSAIDs and other drugs that slow its filtration or harm the kidneys; and with warfarin, whose INR is watched in the first days.
• Caution
  Colistimethate when the kidneys are impaired, with the dose lowered by the creatinine clearance; in porphyria, with extreme caution; in infants under one; and with non-depolarising muscle relaxants, whose effect it prolongs.
• Caution
  Rifaximin with warfarin, whose INR has both risen and fallen; with ciclosporin; and in severe liver disease, Child–Pugh C or a MELD score over 25.
• Caution
  Fidaxomicin after an allergy to macrolides, in severe kidney or moderate to severe liver impairment, and in fulminant C. difficile infection, where it is little studied.
• Caution
  Nitroxoline for long courses, with liver tests; high doses of mineral supplements may weaken it.

08Pregnancy and lactation

• Compatible
  Nitrofurantoin in the first and second trimesters. It has been used in pregnancy for decades and isn't known to harm the baby, and it is given for 7 days for cystitis in pregnancy.
• Avoid
  Nitrofurantoin late in pregnancy. It tends to be avoided in the third trimester for a possible effect on the baby's red cells, though it can be used if tests show it is the best choice. It is avoided at term, and its licence rules it out at term and in labour, for the risk of haemolysis in the newborn.
• Compatible
  Breastfeeding with nitrofurantoin, which passes into milk in amounts too small to matter.
• Avoid
  Breastfeeding a premature baby, one under two weeks old, or a baby with jaundice or G6PD deficiency, with nitrofurantoin, for the risk of haemolysis.
• Avoid
  Methenamine in pregnancy. It has been widely used without apparent harm, but there is too little evidence of safety, so its licence prefers to avoid it, and specialist advice is sought.
• Caution
  Breastfeeding with methenamine, probably compatible: little passes into milk and no harm has been seen, but the baby is watched, and waiting three hours after a dose lowers its share further. Its licence allows breastfeeding.
• Avoid
  Nitroxoline in pregnancy and breastfeeding. In pregnancy, harm to the baby's nervous system can't be ruled out, so it is given only when tests leave no alternative; it isn't given while breastfeeding, as nothing is known of its passage into milk.
• Avoid
  Daptomycin and colistimethate in pregnancy, used only when clearly needed. There are no human data on daptomycin, though animal studies showed no harm; colistimethate crosses the placenta, and repeated doses could harm the baby.
• Compatible
  Breastfeeding with daptomycin or colistimethate, which pass into milk in amounts too small to matter, and are barely absorbed from the baby's gut. Their licences are stricter: daptomycin's says to stop breastfeeding, colistimethate's to give it only when clearly needed.
• Compatible
  Eye and ear drops with neomycin and polymyxin B in pregnancy, from which too little reaches the baby to matter. Their licences are stricter and don't recommend them, for the neomycin and, in the eye drops, the corticosteroid.
• Compatible
  Breastfeeding with polymyxin B on the skin, eye or ear, from which almost none reaches the blood; creams are kept off the nipple. Here too the licences are stricter: the ear drops aren't recommended, and the eye drops weigh stopping the drug against stopping breastfeeding.
• Avoid
  Rifaximin and fidaxomicin in pregnancy. There are few or no human data. Rifaximin had passing effects on the developing bones of animal fetuses and isn't recommended; fidaxomicin showed no harm in animals but is best avoided as a precaution, and vancomycin by mouth is preferred in pregnancy.
• Compatible
  Breastfeeding with rifaximin, of which almost none is absorbed.
• Compatible
  Breastfeeding with fidaxomicin, of which almost none is absorbed, so little is likely to reach the baby. Its licence is stricter, and weighs stopping breastfeeding against stopping the drug.