Antibiotics: classification; mechanisms, type and spectrum of action. Principles of the rational antibiotic therapy and prophylaxis

01Drug classification

Antimicrobial drugs are classified by site and mechanism of action, then by chemical structure. The cards follow four groups: cell wall synthesis inhibitors, protein synthesis inhibitors, folate synthesis and nucleic acid inhibitors, and cell membrane inhibitors. They name each class and say whether it kills bacteria or holds them back; the topics that follow cover the classes drug by drug.

02Pharmacokinetics

What an antibiotic does depends on how much of it reaches the infection. Four properties decide that: how much is absorbed, where it spreads, how it leaves the body, and what it interacts with.

Many antibiotics are absorbed well by mouth, among them amoxicillin, doxycycline, the fluoroquinolones, linezolid, metronidazole, co-trimoxazole and clindamycin, so a tablet often does the work of a drip once the patient can swallow and the gut works. Others are hardly absorbed, aminoglycosides and vancomycin among them, so they are given into a vein or muscle for an infection in the body; vancomycin by mouth acts only in the gut, which is why it treats C. difficile. The ideal drug for a patient at home is well absorbed and has a long half-life, so that it can be taken once a day, such as azithromycin.

Some sites are hard to reach, and the antibiotic is chosen, and the course lengthened, to suit them.

Most antibiotics leave in the urine, so the dose is lowered in kidney failure; aminoglycosides and vancomycin are the ones where the dose is set by blood levels. A few are cleared in the liver, among them macrolides, clindamycin and rifampicin, and need care in liver disease. Newborns clear chloramphenicol too slowly, so they get a lower dose per kilogram.

Rifampicin switches on liver enzymes and so lowers the levels of many other drugs; macrolides such as clarithromycin and erythromycin switch them off, raising the levels of others. Quinolones and tetracyclines bind calcium, iron, magnesium and aluminium in the gut and are taken apart from antacids and supplements. Several antibiotics, among them metronidazole, macrolides, quinolones and co-trimoxazole, strengthen warfarin, so the INR is watched. Probenecid slows the kidney's removal of penicillins and raises their levels. Each class topic lists its own.

03Pharmacodynamics

Bactericidal and bacteriostatic

A bactericidal drug kills bacteria, and the number alive falls rapidly after exposure. A bacteriostatic drug stops them growing, and the immune system must clear them. As a rule, drugs that block the building of the cell wall (penicillins) or irreversibly block protein synthesis (aminoglycosides) kill, while drugs that reversibly block protein synthesis (tetracyclines) or an enzyme needed for growth (sulfonamides) hold back; some, such as erythromycin, do either, depending on the level and the bacterium.

A bactericidal drug has long been called preferable, as it acts faster and is less likely to invite resistance. A review of 56 randomised trials that compared the two kinds found no significant difference in efficacy in 49, and its authors concluded that bactericidal drugs are not intrinsically more effective. The label comes from laboratory tests, while the dose, the level reached at the site and the patient's defences matter more at the bedside. The review found no such trials in endocarditis or meningitis, and urges caution in applying its result to every infection in an immunocompromised patient, so in practice a killing drug is still the usual choice in these.

Spectrum

The spectrum is the range of bacteria a drug reaches. A narrow-spectrum drug acts on a single species or group, such as benzylpenicillin on streptococci, and a broad-spectrum drug on many, such as piperacillin–tazobactam or a carbapenem; those in between are called extended-spectrum. Narrow drugs are preferred once the cause is known, as they spare the normal flora of the gut and airways, and with them the C. difficile and resistance that follow broad drugs. Broad drugs are used first when the cause is not yet known, then narrowed.

The MIC and the susceptibility report

The minimum inhibitory concentration, the MIC, is the lowest concentration of a drug that stops a bacterium growing in the laboratory. It is read from a tube dilution or an E-test strip, and a disc diffusion test reaches a category without a number. The laboratory then reports one of three categories, from the MIC and the dose that is used. S, susceptible with the standard dose, means treatment is likely to succeed. I, susceptible with increased exposure, means it is likely to succeed if exposure is raised, by a higher dose, a longer infusion or a site where the drug concentrates. R, resistant, means failure is likely even with increased exposure. Breakpoints are set from the MIC of wild-type bacteria, the levels the usual dose reaches and the outcomes seen in patients; for drugs that kill by their peak, the aim is a peak several times the MIC. The urine holds far more drug than the blood, so a drug can work in cystitis that would fail in bacteraemia.

How the pattern of killing sets the dose

Antibiotics fall into patterns, set by which measure best predicts success. The dose and its timing follow.

The groups are a simplification, and some drugs have features of more than one. The post-antibiotic effect is the suppression of growth that goes on after the level has fallen below the MIC. Aminoglycosides and fluoroquinolones have a long one against gram-negative bacilli; penicillins and macrolides have one only against gram-positive cocci. An aminoglycoside kills in proportion to its level and keeps working after the level has gone, so the whole day's dose is given at once.

Combinations

Two drugs can act together in four ways. They are synergistic when the effect exceeds the sum of their separate effects, additive when it equals the sum, indifferent when it is no more than the better drug's alone, and antagonistic when it is less than either alone. A combination is used for four reasons.

1. A mixed infection, such as an abdominal infection from the gut, where aerobic and anaerobic bacteria are both present: a cephalosporin with metronidazole.
2. A severe infection of unknown cause, such as hospital-acquired pneumonia, treated with a combination until the organism is known.
3. Synergy: a cell wall inhibitor lets an aminoglycoside in, so ampicillin with gentamicin kills enterococci faster than either. Aminoglycoside pairs were also used for Pseudomonas and staphylococci, but gentamicin is no longer added for native-valve staphylococcal endocarditis, for its kidney harm, and ampicillin with ceftriaxone is often used for enterococci. Sulfamethoxazole and trimethoprim block two steps of one pathway.
4. Preventing resistance, as in tuberculosis and HIV, where one drug alone fails; the drugs need not be synergistic (see Antituberculosis drugs).

Most infections are caused by a single organism and treated with one drug, which costs less, harms the normal flora less and has fewer side effects. Some pairs are antagonistic, among them an aminoglycoside with chloramphenicol, and a broad-spectrum penicillin with chloramphenicol, though that is their activity in the laboratory, not their results in patients.

Resistance, as it matters at the bedside

A bacterium can be resistant by nature to a drug, or acquire resistance, which the drug then selects for. Resistance grows with the use of antibiotics, above all when they are used for infections that do not need them, at doses too low, for courses longer than they need to be, and as broad drugs where a narrow one will do. The bacteria are named by the drugs they resist: meticillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), the Enterobacterales that make extended-spectrum β-lactamases (ESBL) and those that make carbapenemases, and multidrug-resistant tuberculosis, each with its own drugs, set out in the class topics, which also say how each class is defeated: by enzymes that break the drug, by less drug getting in or more being pumped out, or by a changed target. Laboratories report susceptibility so that the drug can be chosen by the result, and culture confirms the response.

To track use, antibiotics are sorted into three AWaRe groups. Access drugs are first or second choices for common infections, with low resistance potential. Watch drugs have a higher resistance potential and are kept for particular uses and monitored. Reserve drugs are the last resort, for multidrug-resistant bacteria. The United Nations has set a target that Access antibiotics make up at least 70% of human antibiotic use by 2030. In the figures for the burden of resistance, attributable deaths are those that would probably not have happened had the infection been treatable, and associated deaths are those in which a resistant infection played a part.

04Clinical indications

Choosing and using an antibiotic

Every choice rests on the cause, the site and the severity of the infection, the patient (age, pregnancy, allergy, immunity, kidney and liver function, other medicines) and the drug (spectrum, where it reaches, side effects, cost, ease of use). The English approach is called Start Smart, then Focus.

1. 1

   Is it a bacterial infection that needs an antibiotic?

   Many coughs, colds and sore throats are viral and need none. The working diagnosis and its severity are written in the notes.
2. 2

   Take samples, and give the first dose promptly if the patient is ill

   Specimens for culture are taken before the first dose where that causes no delay. In sepsis with a high risk of severe illness or death, an intravenous antibiotic is given within an hour.
3. 3

   Choose the drug empirically, by the likely organisms

   The choice follows the likely bacteria for the site, local resistance and the hospital's guideline, the patient's allergy history, which is taken in detail and sometimes de-labelled, and the factors above. Broad cover is acceptable when the patient is very ill and the cause unknown.
4. 4

   Write down the indication, dose, route and a stop or review date

   An open-ended prescription is a common way for a course to run too long.
5. 5

   Review at 48 to 72 hours, and decide

   There are five choices: cease if there is no infection, amend, ideally to a narrower drug, refer to a non-ward antibiotic service, extend with a new review or stop date, or switch from intravenous to oral once the patient is improving and can take tablets. Culture results are used here to narrow the drug.

Drugs do not replace drainage of an abscess, or removal of an infected catheter or implant, because antibiotics reach pus and the surface of a device poorly.

Common infections take short courses: in the UK, 3 days of nitrofurantoin or trimethoprim for cystitis in a woman who is not pregnant, 5 days of amoxicillin for community-acquired pneumonia of low severity, and 5 to 7 days of flucloxacillin for cellulitis. Longer courses are kept for infections that are hard to reach or hard to clear, such as bone infection, endocarditis and tuberculosis. Therapeutic drug monitoring, a level in the blood, guides aminoglycoside and vancomycin doses.

Prophylaxis

Prevention by drugs is limited to a few situations, because it adds the harms of antibiotics without proof of benefit for most patients. Sterilising instruments and disinfecting skin and mucous membranes before invasive procedures are not antibiotics, but come first.

Prophylaxis for surgery is a single dose, repeated only when the operation is long, not a course. Cefazolin is used for many operations, and a cephalosporin with anaerobic cover, or ertapenem, for the abdomen, though the local formulary decides.

were attributable to antibiotic resistance, and 4.71 million were associated with it

1.14 milliondeaths in 2021were attributable to antibiotic resistance, and 4.71 million were associated with it

are forecast to be attributable to resistance

1.91 milliondeaths a year by 2050are forecast to be attributable to resistance

found no difference in efficacy

49 of 56trials of bacteriostatic against bactericidal drugsfound no difference in efficacy

the UN target for the Access group by 2030

70%of antibiotic usethe UN target for the Access group by 2030

05Adverse drug reactions

The harms specific to each class are in its own topic. These cut across the classes, and are what a prescriber checks for whatever the drug.

• Life-threatening
  Anaphylaxis, most often with β-lactams, the commonest cause of drug allergy among antibiotics, but with any class. Epinephrine (adrenaline) is given at once; the drug is not given again unless the allergy is later ruled out, and the reaction is recorded.
• Life-threatening
  Severe skin reactions: Stevens–Johnson syndrome, toxic epidermal necrolysis and DRESS (drug reaction with eosinophilia and systemic symptoms), most often with sulfonamides, but also with β-lactams, quinolones and others. The drug is stopped at the first blistering rash, sore mouth or eyes, or a rash with fever.
• Life-threatening
  A long QT interval and torsades de pointes with macrolides, fluoroquinolones and some antifungals, above all with other drugs that lengthen the QT, low potassium or magnesium, or heart disease.
• Serious
  Clostridioides difficile colitis. Any antibiotic can bring it on by disturbing the normal gut flora, broad drugs most, and it can start weeks after the course. Severe colitis can kill. Clindamycin, cephalosporins and quinolones are the best known causes.
• Serious
  Kidney damage with aminoglycosides and vancomycin, and ear damage with aminoglycosides; they are given by their levels, and the kidneys are checked.
• Serious
  Reactions of the liver, blood and nerves that are particular to a class, such as hepatitis with co-amoxiclav and flucloxacillin, marrow suppression with linezolid and chloramphenicol, and neuropathy with nitrofurantoin and linezolid. The class topics give the checks.

06Side effects

• Mild
  Nausea, vomiting and diarrhoea, from irritation of the gut or a change in its flora, common with many antibiotics; taking the drug with food helps some.
• Mild
  Thrush of the mouth or vagina, when antibiotics upset the normal flora.
• Mild
  A rash, which is not always an allergy. Most patients labelled penicillin-allergic turn out, when tested, not to be, so a doubtful label is looked into rather than kept.
• Mild
  Pain, redness or a vein that is sore where a drug is given into a vein or muscle.

07Contraindications

• Contraindicated
  A known allergy to the drug, or a severe reaction to a close relative of it, such as anaphylaxis to a β-lactam. Allergy is documented in detail, and tested when it is doubtful.
• Contraindicated
  A drug that caused a severe reaction before, such as a severe skin reaction, tendon rupture or liver injury from the same drug.
• Avoid
  An antibiotic for an infection it does not reach or cannot treat, such as daptomycin for pneumonia, nitrofurantoin for a kidney infection, or any antibiotic for a viral cold.
• Avoid
  A broad-spectrum drug where a narrow one will do.
• Avoid
  Rifampicin with hormonal contraceptives, which it makes fail, and with other drugs whose levels it lowers too far (see Antituberculosis drugs).
• Caution
  Quinolones and tetracyclines taken with antacids, iron or calcium, which bind them in the gut; the doses are spaced apart.
• Caution
  Warfarin with metronidazole, macrolides, quinolones or co-trimoxazole, which strengthen it, and with rifampicin, which weakens it; the INR is watched.
• Caution
  Kidney or liver impairment, for which the dose, the interval or the choice of drug is changed.
• Caution
  Age, newborns and older people above all: newborns clear some drugs slowly and handle others badly, and older people are likelier to be harmed by quinolones, aminoglycosides and co-trimoxazole.
• Caution
  A weak immune system, in diabetes, cancer treatment or HIV, where a bactericidal drug is preferred and the course may need to be longer or reviewed more closely.

08Pregnancy and lactation

The details are in each class topic, which also say where a drug's licence is stricter than the evidence on pregnancy and breastfeeding. As a rule, penicillins and cephalosporins are among the antibiotics used most in pregnancy and breastfeeding, and others are chosen with more care. Most antibiotics cross the placenta.

• Compatible
  Penicillins, cephalosporins and erythromycin or azithromycin in pregnancy. There is no concern that they harm the baby, and they are the antibiotics used when one is needed. They pass into milk in amounts too small to matter, though the baby may get loose stools or thrush; erythromycin in a baby's first month is a caution (see Macrolides).
• Avoid
  Tetracyclines after about 13 weeks of pregnancy, as they stain the baby's teeth; chloramphenicol by mouth or into a vein; and, as a precaution, linezolid, tedizolid and lefamulin.
• Avoid
  Trimethoprim and co-trimoxazole in the first trimester, for the folate antagonist's link with neural tube defects, and sulfonamides near term.
• Avoid
  Streptomycin in pregnancy, the aminoglycoside best known to have deafened babies in the womb.
• Caution
  Other aminoglycosides in pregnancy. They are not known to cause birth defects, and are given for serious infections when the benefit outweighs the risk.
• Avoid
  Fluoroquinolones in pregnancy. There is no good evidence that they harm the baby, but another antibiotic is used where possible; a single dose of ciprofloxacin for a contact of meningococcal disease is possible.
• Caution
  Breastfeeding a baby who is premature, jaundiced or in the first month, with a sulfonamide, the baby watched for jaundice; the class topics name other drugs that call for the same care.