Antibiotics

1. Introduction
2. Principles of Antibiotic Therapy
   • Bacteriostatic versus Bactericidal
   • Time-Dependent and Concentration-Dependent Killing
   • MIC and Breakpoints
   • Empirical versus Targeted Therapy
3. Cell Wall Synthesis Inhibitors
   • β-Lactams
   • Glycopeptides
4. Protein Synthesis Inhibitors
   • Aminoglycosides
   • Macrolides
   • Tetracyclines
   • Other Protein Synthesis Inhibitors
5. DNA, RNA and Folate Inhibitors
   • Fluoroquinolones
   • Sulphonamides and Trimethoprim
   • Metronidazole
   • Nitrofurantoin
   • Rifampicin
6. Choosing an Antibiotic by Indication
7. Antibiotic Resistance
8. Antibiotic Stewardship
9. Summary
10. Drug Summary Table
11. Quiz

• Antibiotics are classified by their mechanism of action against bacteria. The four main targets are cell wall synthesis, protein synthesis, nucleic acid synthesis (making DNA by replication, or RNA by transcription, which is copying DNA into RNA) and folate metabolism. Rarely, the target is the cell membrane.
• β-lactams (penicillins, cephalosporins, carbapenems, monobactams) and glycopeptides (vancomycin) inhibit cell wall synthesis and are bactericidal (they kill bacteria).
• Protein synthesis inhibitors: aminoglycosides (gentamicin), macrolides (clarithromycin), tetracyclines (doxycycline), and others.
• DNA, RNA and folate inhibitors: fluoroquinolones (ciprofloxacin), trimethoprim, metronidazole (active against anaerobes, which live without oxygen, and protozoa, which are single-celled parasites), nitrofurantoin (uncomplicated UTI) and rifampicin (tuberculosis, TB, which it treats by blocking RNA synthesis).
• Resistance emerges through chromosomal mutation or horizontal gene transfer (bacteria passing genes to one another by transduction, conjugation or transformation). UK practice prioritises antibiotic stewardship to slow resistance development.

Introduction

Antibiotics are one of the greatest advances in medicine. Drug-resistant bacteria are one of the greatest threats to that advance. The pre-clinical curriculum focuses on understanding antibiotic classes by their mechanism, the spectrum of bacteria they cover, and the rules of stewardship that keep them effective.

The companion infection content is in the SimpleMed Infection subject area. Pharmacodynamics is the study of what a drug does to the body or to a microbe. It underlies the distinction between bacteriostatic drugs (which stop bacteria growing) and bactericidal drugs (which kill them).

Principles of Antibiotic Therapy

Bacteriostatic versus Bactericidal

The simplest division of antibiotics is by what they do to the bacterium:

• Bactericidal drugs kill bacteria. Required where the host immune response is impaired (neutropenia, a low neutrophil count; asplenia, having no working spleen; endocarditis, infection of the heart valves or their lining; meningitis; severe sepsis).
• Bacteriostatic drugs stop bacterial growth and rely on the host immune system to clear them. Adequate in immunocompetent hosts (people whose immune system works normally) with most infections.

The same drug can be bacteriostatic at low doses and bactericidal at higher concentrations; the labels are useful but not absolute.

Time-Dependent and Concentration-Dependent Killing

How antibiotics kill bacteria has direct dosing implications:

• Time-dependent killing: killing depends on how long the drug concentration stays above the minimum inhibitory concentration (MIC, explained in the next section). What matters is the proportion of the dosing interval (the time between doses) spent above the MIC. β-lactams are the classic example, which is why they are dosed multiple times daily.
• Concentration-dependent killing: high peak concentration matters more than time above MIC. Aminoglycosides are the classic example, dosed once daily at high concentration to maximise killing while allowing time for the kidneys and ears to recover.

MIC and Breakpoints

The minimum inhibitory concentration (MIC) is the lowest antibiotic concentration that prevents visible bacterial growth in vitro (in the laboratory, not in the body). Microbiology laboratories measure MICs. They compare each MIC with the breakpoints for that antibiotic. Breakpoints are threshold values that take into account the antibiotic's pharmacokinetics in humans (how the body absorbs, distributes and clears the drug). Breakpoints predict whether the bacterium is susceptible at standard doses (S), susceptible only with increased exposure to the drug (I), or resistant (R).

Empirical versus Targeted Therapy

• Empirical therapy: given before culture results are available, based on the most likely pathogens for the clinical syndrome and on local resistance patterns. The choice should cover the likely organisms without being broader than needed.
• Targeted therapy: narrowed once the organism and its sensitivities are known. The transition from empirical to targeted is a core principle of stewardship.

Cell Wall Synthesis Inhibitors

β-Lactams

The largest and most important antibiotic family. All β-lactams contain a four-membered β-lactam ring. They bind penicillin-binding proteins (PBPs). This stops cross-linking of peptidoglycan. Peptidoglycan is the main structural molecule of the bacterial cell wall, and cross-linking joins its strands together to make the wall strong. Without it the cell undergoes lysis (it bursts). Bactericidal, time-dependent killing.

Four sub-classes:

• Penicillins:
  • Natural: benzylpenicillin (penicillin G, IV), phenoxymethylpenicillin (penicillin V, oral). Mainly streptococcal infections, syphilis, dental infections.
  • Antistaphylococcal (penicillinase-resistant): flucloxacillin. Penicillinase is an enzyme that some bacteria make to destroy penicillins. Flucloxacillin is not inactivated by penicillinase. Flucloxacillin is used for infections caused by penicillin-resistant staphylococci, for example cellulitis (skin and soft tissue infection), osteomyelitis (bone infection) and endocarditis. For MRSA (methicillin-resistant Staphylococcus aureus), see Glycopeptides below.
  • Aminopenicillins: amoxicillin, ampicillin. Broader gram-positive and some gram-negative cover. (Gram-positive bacteria stain purple in the Gram stain. Gram-negative bacteria stain pink.) Co-amoxiclav adds clavulanic acid (a β-lactamase inhibitor, which blocks the enzyme that destroys β-lactams), extending cover to amoxicillin-resistant organisms.
  • Antipseudomonal (active against Pseudomonas, a gram-negative bacterium that resists many antibiotics): piperacillin-tazobactam (Tazocin). Broad cover including Pseudomonas aeruginosa and many gram-negatives. It is one option for hospital sepsis of unknown source. The choice should follow local guidance.
• Cephalosporins: classified by generation. In general, third-generation drugs have more gram-negative activity than second-generation drugs, but are less active than cefuroxime (2nd generation) against gram-positive bacteria, most notably Staphylococcus aureus. The fifth-generation drug ceftaroline has extended gram-positive cover. Examples:
  • 1st (cefalexin): UTI, soft tissue.
  • 2nd (cefuroxime).
  • 3rd (ceftriaxone, cefotaxime): meningitis, severe community-acquired infections.
  • 4th (cefepime).
  • 5th (ceftaroline): some MRSA cover.
  Cephalosporins, along with the related "4 Cs" (Cephalosporins, Ciprofloxacin, Clindamycin, Co-amoxiclav), are major risk factors for Clostridioides difficile infection; UK trusts limit their use accordingly.
• Carbapenems: meropenem, imipenem, ertapenem. The broadest-spectrum β-lactams, reserved for serious infections including those caused by extended-spectrum β-lactamase (ESBL) producers (bacteria that make enzymes which destroy most penicillins and cephalosporins). A penicillin allergy rarely extends to carbapenems, but the British National Formulary (BNF), the UK's standard prescribing reference, advises avoiding meropenem, imipenem and ertapenem if there is a history of immediate hypersensitivity (an allergic reaction soon after a dose, such as anaphylaxis) to any β-lactam, and using them with caution in patients who are sensitive to β-lactams.
• Monobactams: aztreonam. Active only against gram-negative aerobes; useful in penicillin-allergic patients (cross-reactivity, meaning an allergic reaction to a similar drug, is low).

Side effects shared across β-lactams:

• Hypersensitivity: rash to anaphylaxis. Around 10% of UK patients self-report penicillin allergy; true IgE-mediated allergy (an immediate allergy driven by IgE antibodies) is much rarer (closer to 1%). According to the British National Formulary (BNF), the UK's standard prescribing reference, cross-reactivity between penicillins and first-generation or early second-generation cephalosporins has been reported in up to 10% of penicillin-allergic patients, and with third-generation cephalosporins in 2 to 3%. Cross-reactivity with carbapenems is minimal.
• Gastrointestinal (GI) upset, diarrhoea (including C. difficile).
• Reversible neutropenia (low neutrophil count) and thrombocytopenia (low platelet count).
• Cholestatic hepatitis (liver inflammation with blocked bile flow), particularly co-amoxiclav and flucloxacillin (the latter associated with delayed cholestasis up to weeks after stopping).
• Seizures with high-dose carbapenems.

Glycopeptides

Vancomycin and teicoplanin bind the D-alanyl-D-alanine terminus of peptidoglycan precursors. The precursors are the building blocks of the cell wall, and the terminus is their two-amino-acid end. Binding there prevents cross-linking. Active only against gram-positive organisms (the molecule is too large to cross gram-negative outer membranes).

Used for:

• MRSA infection.
• Severe gram-positive infection in penicillin-allergic patients.
• Endocarditis.
• Oral vancomycin, which is not absorbed significantly, for a first episode of C. difficile infection, whether mild, moderate or severe.

Side effects:

• Nephrotoxicity (kidney damage): the dose-limiting toxicity. Plasma levels are routinely monitored.
• Ototoxicity (damage to the ear and hearing).
• "Red man syndrome": histamine release with rapid IV infusion, producing flushing of the upper body. Reversed by slowing the infusion; not a true allergy.

Protein Synthesis Inhibitors

Bacterial ribosomes (70S) are different enough from human ribosomes (80S) for selective targeting. A bacterial ribosome is made of 30S and 50S subunits. The S number is a size measure based on how fast a particle settles in a centrifuge, so S numbers do not simply add up (30S and 50S make 70S).

Aminoglycosides

Gentamicin, amikacin, tobramycin, streptomycin bind the 30S subunit, causing mRNA misreading. Bactericidal, concentration-dependent killing. Active mainly against aerobic gram-negative organisms; synergistic (works better together) with β-lactams against streptococcal endocarditis and listeriosis (infection with Listeria).

Pharmacokinetic features:

• Polar molecules (they carry an uneven electrical charge, so they cross cell membranes poorly): not absorbed orally; given IV or IM.
• Renally excreted; doses must be adjusted for renal function.
• Concentration-dependent killing: once-daily dosing produces high peak (effective) and low trough (less toxic) concentrations. The trough is the lowest level, just before the next dose.
• Therapeutic drug monitoring (measuring drug levels in the blood to adjust the dose) is mandatory. Modern UK extended-interval ("once-daily") regimens use a single timed blood level taken after the dose. The blood level is plotted on a nomogram (a chart used to read off the dosing interval, e.g. Hartford). Serial U&Es (urea and electrolytes, a blood test) are checked for renal function. Traditional multi-dose regimens used peak and trough levels.

Toxicities:

• Nephrotoxicity: classically reversible.
• Ototoxicity: classically irreversible (cochlear damage affects hearing and vestibular damage affects balance).
• Neuromuscular blockade (weakening of the signal between nerve and muscle): rare, can prolong action of muscle relaxants.

Macrolides

Erythromycin, clarithromycin, azithromycin bind the 50S subunit. Bacteriostatic. Active against gram-positives, atypicals (unusual bacteria that β-lactams do not treat, such as Mycoplasma, Chlamydia and Legionella) and some gram-negatives. Useful as alternative to penicillins in allergy.

Indications: community-acquired pneumonia, atypical pneumonia, Helicobacter pylori (H. pylori, a bacterium that infects the stomach lining and can cause ulcers) eradication (clarithromycin), pertussis (whooping cough), and mycobacterial infection (infection with mycobacteria, the group that includes the bacterium that causes TB).

Side effects:

• GI upset and diarrhoea: macrolides are motilin agonists (they activate motilin receptors, which control gut movement) and prokinetic (they speed up movement through the gut).
• QT prolongation (a longer QT interval on the ECG, which can trigger dangerous heart rhythms): clinically important when combined with other QT-prolonging drugs.
• Cholestatic hepatitis.
• Strong CYP3A4 inhibition (CYP3A4 is a liver enzyme that breaks down many drugs, so blocking it raises their levels). This causes clinically important interactions with statins (cholesterol-lowering drugs, with a risk of rhabdomyolysis, the breakdown of muscle), warfarin, ciclosporin, sildenafil and many others. Azithromycin has the weakest effect on CYP3A4.

Tetracyclines

Doxycycline, tetracycline, minocycline, tigecycline bind the 30S subunit. Bacteriostatic. Active against many gram-positives, gram-negatives, atypicals, and some protozoa.

Indications: chest infections (especially with atypical cover), Chlamydia, Lyme disease (a tick-borne infection), acne, malaria prophylaxis (prevention, using doxycycline), MRSA in some regimens.

Side effects and cautions:

• Photosensitivity (the skin burns easily in sunlight).
• Tooth discolouration and bone growth effects (tetracyclines bind calcium in growing teeth and bones): avoid in pregnancy and breastfeeding. Tetracycline is contraindicated in children under 12. For doxycycline, the BNF allows use under 12 only when there is no adequate alternative: in acute or severe infections from 8 to 11 years, and only in severe or life-threatening infections under 8 years.
• GI upset.
• Chelation (the drug binds metal ions such as calcium, magnesium, iron and aluminium, so less is absorbed): reduced absorption with antacids and iron supplements; separate doses by 2 to 3 hours. Dairy products matter mainly for tetracycline itself (see below).
• Benign intracranial hypertension (also called idiopathic intracranial hypertension): a rare cause of raised pressure inside the skull. It causes headache and visual disturbance.
• Dairy products reduce the absorption of tetracycline itself, and the manufacturer advises taking it 1 hour before or 2 hours after them. Milk and other food affect the absorption of doxycycline only slightly.

Other Protein Synthesis Inhibitors

• Clindamycin: binds 50S subunit. Active against gram-positives and anaerobes. Used in necrotising fasciitis (a rapidly spreading, life-threatening infection of the tissue under the skin). It additionally suppresses toxin production. High C. difficile risk.
• Linezolid: an oxazolidinone (a class of antibiotics that bind the 50S subunit); active against MRSA and VRE (vancomycin-resistant enterococci). Side effects include thrombocytopenia, peripheral neuropathy (damage to the nerves of the limbs, causing numbness or tingling), and serotonin syndrome. Linezolid is a weak MAOI (monoamine oxidase inhibitor). It might increase the risk of serotonin toxicity when given with SSRIs (selective serotonin reuptake inhibitors), so check the BNF (the UK prescribing reference) before combining them.
• Chloramphenicol: broad spectrum but rarely used systemically because of two serious adverse effects. Aplastic anaemia is when the bone marrow stops making blood cells; it is rare and can be reversible or irreversible. Grey baby syndrome is a serious reaction in newborn babies, and is a risk if the drug is used in the third trimester of pregnancy. Chloramphenicol eye drops can be used for bacterial conjunctivitis. Most cases get better without treatment, so eye drops are used only when needed.

DNA, RNA and Folate Inhibitors

Fluoroquinolones

Ciprofloxacin, levofloxacin, moxifloxacin inhibit DNA gyrase (topoisomerase II) and topoisomerase IV. Topoisomerases are enzymes that control how bacterial DNA is coiled so that it can be copied. Blocking them prevents DNA supercoiling (the twisting of DNA on itself). Bactericidal, broad-spectrum (gram-positives, gram-negatives including Pseudomonas, atypicals).

Used in: complicated UTI, prostatitis, some gastroenteritis, and anthrax prophylaxis (preventing infection after exposure). Use is restricted (see below). For pyelonephritis (kidney infection), NICE lists ciprofloxacin only if other first-choice antibiotics are unsuitable. For severe community-acquired pneumonia, the NICE first-line antibiotics are co-amoxiclav and clarithromycin, and levofloxacin is only an alternative for people with penicillin allergy.

The MHRA (Medicines and Healthcare products Regulatory Agency, the UK medicines regulator) has issued increasingly stringent restrictions on fluoroquinolones because of:

• Tendinitis and tendon rupture (tendinitis means an inflamed tendon; especially the Achilles tendon), worse in older patients and on corticosteroids.
• Aortic aneurysm and dissection (dissection is a tear in the wall of the aorta): a small increased risk.
• QT prolongation.
• Neurological effects: insomnia, confusion, seizures (lower seizure threshold), peripheral neuropathy.
• C. difficile risk.
• Hypoglycaemia (low blood glucose) and dysglycaemia (unstable blood glucose, high or low).
• Photosensitivity.

As a result, fluoroquinolones must now only be prescribed when other commonly recommended antibiotics are inappropriate.

Sulphonamides and Trimethoprim

These drugs target the bacterial folate pathway. Bacteria (unlike humans) depend on this pathway because they cannot take up preformed folate (folate made elsewhere), so they must make their own. Humans get folate from their diet.

• Sulphonamides (sulfamethoxazole) inhibit dihydropteroate synthase, an early enzyme in the bacterial folate pathway that uses para-aminobenzoic acid (PABA).
• Trimethoprim inhibits dihydrofolate reductase (DHFR), an enzyme in the bacterial folate pathway.
• The combination co-trimoxazole (sulfamethoxazole + trimethoprim) blocks two consecutive steps and is bactericidal. It is used in Pneumocystis jirovecii pneumonia (PCP, a fungal lung infection in people with weakened immunity), for both prophylaxis (prevention) and treatment, and in some MRSA infections.
• Trimethoprim alone is one of the two first-choice oral antibiotics in the UK for lower UTI in non-pregnant women aged 16 or over, but only if there is a low risk of resistance. The other is nitrofurantoin.

Side effects: rash (including Stevens-Johnson syndrome, a severe blistering skin reaction), hyperkalaemia (high blood potassium: trimethoprim blocks the epithelial sodium channel, ENaC, in the kidney, as the diuretic amiloride does), bone marrow suppression, photosensitivity. Trimethoprim carries a teratogenic risk (it can harm the developing fetus) in the first trimester because it is a folate antagonist.

Metronidazole

Metronidazole is reduced inside anaerobic cells to a toxic radical (a highly reactive molecule) that damages DNA. It is active against obligate anaerobes (bacteria that cannot survive in the presence of oxygen, e.g. Bacteroides) and protozoa (single-celled parasites). Examples of protozoa are Giardia and Entamoeba, which infect the gut, and Trichomonas, which infects the genital tract. It is used in intra-abdominal sepsis, pelvic infection, dental infections and amoebic dysentery. It is no longer a first-line treatment for C. difficile (see Choosing an Antibiotic by Indication).

The classic side-effect teaching point is the disulfiram-like reaction with alcohol (disulfiram is a drug used in alcohol dependence that makes alcohol cause unpleasant symptoms): flushing, nausea, palpitations. Patients should be warned to avoid alcohol during treatment and for at least 48 hours after stopping.

Nitrofurantoin

Nitrofurantoin is reduced inside bacteria to several reactive intermediates (short-lived, highly reactive molecules) that damage DNA, ribosomes and other targets. Active against most uropathogens (bacteria that cause urinary tract infection). Concentrates in urine but achieves negligible plasma levels; therefore useful only in uncomplicated lower UTI, not in pyelonephritis or systemic infection.

Side effects: GI upset, brown urine, peripheral neuropathy, pulmonary fibrosis with prolonged use, and haemolysis (breakdown of red blood cells) in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency (an inherited enzyme deficiency, carried on the X chromosome, that leaves red cells unable to cope with oxidative stress, which is damage from reactive oxygen chemicals). Avoid if the estimated glomerular filtration rate (eGFR, a measure of kidney function) is below 45 ml/minute (insufficient urinary concentration); avoid at term in pregnancy (haemolytic anaemia in newborn).

Rifampicin

Rifampicin inhibits bacterial DNA-dependent RNA polymerase (the enzyme that copies DNA into RNA). It is a cornerstone of tuberculosis treatment. For meningococcal contact prophylaxis (preventing infection in close contacts of a person with meningococcal disease), ciprofloxacin is now the recommended first choice and rifampicin is a suitable alternative. Notable for:

• Orange-red discolouration of urine, sweat and tears. Rifampicin also discolours soft contact lenses, so patients should be advised of this.
• Powerful CYP450 inducer (it speeds up the liver enzymes that break down many drugs): reduces plasma levels of many drugs, including hormonal contraceptives such as the combined oral contraceptive pill. Alternative contraceptive advice should be offered.
• Hepatotoxicity.

The standard initial TB regimen is "RIPE": Rifampicin, Isoniazid, Pyrazinamide, Ethambutol, for 2 months, followed by 4 months of rifampicin and isoniazid alone. Each component has memorable toxicities:

• Isoniazid causes peripheral neuropathy and hepatitis. Pyridoxine (vitamin B₆) is given to prevent the neuropathy.
• Pyrazinamide causes hepatitis and hyperuricaemia (high uric acid, which can cause gout).
• Ethambutol causes optic neuritis (inflammation of the optic nerve). Warn patients to report any change in colour vision.

Preview the Antibiotics quiz