Antibiotics

Core

Introduction

Antibiotics are arguably the single greatest pharmacological advance in medicine. Drug-resistant bacteria are equally arguably the single greatest threat 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. The principles of pharmacodynamics underlie the bacteriostatic-versus-bactericidal distinction.

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, asplenia, endocarditis, meningitis, severe sepsis).
• Bacteriostatic drugs stop bacterial growth and rely on the host immune system to clear them. Adequate in immunocompetent hosts 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 the proportion of the dosing interval that drug concentration exceeds 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. Microbiology laboratories measure MICs and compare them to breakpoints: threshold values that take into account the antibiotic's pharmacokinetics in humans, predicting whether the bacterium will be susceptible (S), intermediate (I) or resistant (R) to that antibiotic at standard doses.

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. Always broad enough to cover likely organisms.
• 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 and act by binding penicillin-binding proteins (PBPs), inhibiting peptidoglycan cross-linking and producing bacterial cell lysis. 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. First-line for Staphylococcus aureus infection (skin, soft tissue, bone, endocarditis).
  • Aminopenicillins: amoxicillin, ampicillin. Broader gram-positive and some gram-negative cover. Co-amoxiclav adds clavulanic acid (a β-lactamase inhibitor) extending cover to amoxicillin-resistant organisms.
  • Antipseudomonal: piperacillin-tazobactam (Tazocin). Broad cover including Pseudomonas aeruginosa and many gram-negatives; standard for hospital sepsis of unknown source.
• Cephalosporins: classified by generation, increasing gram-negative cover and decreasing gram-positive activity in higher generations:
  • 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 extended-spectrum β-lactamase (ESBL) producers.
• Monobactams: aztreonam. Active only against gram-negative aerobes; useful in penicillin-allergic patients (low cross-reactivity).

Side effects shared across β-lactams:

• Hypersensitivity: rash to anaphylaxis. Around 10% of UK patients self-report penicillin allergy; true IgE-mediated allergy is much rarer (closer to 1%). Cross-reactivity between penicillins and cephalosporins is around 1-5%; lower with later generations and minimal with carbapenems.
• GI upset, diarrhoea (including C. difficile).
• Reversible neutropenia and thrombocytopenia.
• Cholestatic hepatitis, 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, preventing 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 (not absorbed) for severe C. difficile infection.

Side effects:

• Nephrotoxicity: the dose-limiting toxicity. Plasma levels are routinely monitored.
• Ototoxicity.
• "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, made of 30S and 50S subunits) are different enough from human ribosomes (80S) for selective targeting.

Aminoglycosides

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

Pharmacokinetic features:

• Polar molecules: 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.
• Therapeutic drug monitoring is mandatory: modern UK extended-interval ("once-daily") regimens use a single timed post-dose concentration plotted on a nomogram (e.g. Hartford), plus serial U&Es for renal function. Traditional multi-dose regimens used peak and trough levels.

Toxicities:

• Nephrotoxicity: classically reversible.
• Ototoxicity: classically irreversible (cochlear and vestibular).
• Neuromuscular blockade: rare, can prolong action of muscle relaxants.

Macrolides

Erythromycin, clarithromycin, azithromycin bind the 50S subunit. Bacteriostatic. Active against gram-positives, atypicals (Mycoplasma, Chlamydia, Legionella) and some gram-negatives. Useful as alternative to penicillins in allergy.

Indications: community-acquired pneumonia, atypical pneumonia, H. pylori eradication (clarithromycin), pertussis, mycobacterial infection.

Side effects:

• GI upset and diarrhoea: macrolides are motilin agonists and prokinetic.
• QT prolongation: clinically important when combined with other QT-prolonging drugs.
• Cholestatic hepatitis.
• Strong CYP3A4 inhibition: classic clinically important interactions with statins (rhabdomyolysis), warfarin, ciclosporin, sildenafil and many others. Azithromycin is the least CYP-active.

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, acne, malaria prophylaxis (doxycycline), MRSA in some regimens.

Side effects and cautions:

• Photosensitivity.
• Tooth discolouration and bone growth effects: contraindicated in children under 12, in pregnancy and breastfeeding.
• GI upset.
• Chelation with calcium, magnesium, iron and aluminium: reduced absorption with dairy products, antacids and iron supplements; separate doses by 2 hours.
• Benign intracranial hypertension (rare).

Other Protein Synthesis Inhibitors

• Clindamycin: binds 50S subunit. Active against gram-positives and anaerobes. Used in necrotising fasciitis (additionally suppresses toxin production). High C. difficile risk.
• Linezolid: an oxazolidinone; active against MRSA and VRE. Side effects include thrombocytopenia, peripheral neuropathy, and serotonin syndrome (linezolid is a weak MAOI; avoid with SSRIs).
• Chloramphenicol: broad spectrum but rarely used systemically because of aplastic anaemia (an idiosyncratic, often fatal failure of all three bone marrow lineages) and grey baby syndrome. Topical eye drops are still common for bacterial conjunctivitis.

DNA and Folate Inhibitors

Fluoroquinolones

Ciprofloxacin, levofloxacin, moxifloxacin inhibit DNA gyrase (topoisomerase II) and topoisomerase IV, preventing DNA supercoiling. Bactericidal, broad-spectrum (gram-positives, gram-negatives including Pseudomonas, atypicals).

Used in: complicated UTI, prostatitis, severe community-acquired pneumonia (especially with atypicals), some gastroenteritis, anthrax prophylaxis.

The MHRA has issued increasingly stringent restrictions on fluoroquinolones because of:

• Tendinitis and tendon rupture (especially Achilles), worse in older patients and on corticosteroids.
• Aortic aneurysm and dissection: small but real signal.
• QT prolongation.
• Neurological effects: insomnia, confusion, seizures (lower seizure threshold), peripheral neuropathy.
• C. difficile risk.
• Hypoglycaemia and dysglycaemia.
• Photosensitivity.

Consequently restricted to use only when other antibiotics are inappropriate.

Sulphonamides and Trimethoprim

These drugs target the bacterial folate pathway, on which bacteria (unlike humans) are dependent because they cannot take up preformed folate.

• Sulphonamides (sulfamethoxazole) inhibit dihydropteroate synthase.
• Trimethoprim inhibits dihydrofolate reductase.
• The combination co-trimoxazole (sulfamethoxazole + trimethoprim) blocks two consecutive steps and is bactericidal: used in Pneumocystis jirovecii pneumonia (PCP) prophylaxis and treatment, and in some MRSA infections.
• Trimethoprim alone is the first-line UK drug for uncomplicated UTI.

Side effects: rash (including Stevens-Johnson syndrome), hyperkalaemia (trimethoprim mimics amiloride at the ENaC channel), bone marrow suppression, photosensitivity. Trimethoprim is teratogenic in the first trimester (folate antagonism).

Metronidazole

Metronidazole is reduced inside anaerobic cells to a toxic radical that damages DNA. Active against obligate anaerobes (e.g. Bacteroides) and protozoa (Giardia, Trichomonas, Entamoeba). Used in intra-abdominal sepsis, pelvic infection, dental infections, C. difficile (as alternative to vancomycin), and amoebic dysentery.

The classic side-effect teaching point is the disulfiram-like reaction with alcohol: flushing, nausea, palpitations. Patients should be warned to avoid alcohol during and for 48 hours after treatment.

Nitrofurantoin

Nitrofurantoin is reduced inside bacteria to multiple reactive intermediates that damage DNA, ribosomes and other targets. Active against most uropathogens. 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 in patients with G6PD deficiency (an X-linked enzyme deficiency that makes red cells unable to handle oxidative stress). Avoid if eGFR < 45 (insufficient urinary concentration); avoid at term in pregnancy (haemolytic anaemia in newborn).

Rifampicin

Rifampicin inhibits bacterial DNA-dependent RNA polymerase. The cornerstone of tuberculosis and meningococcal contact prophylaxis. Notable for:

• Orange-red discolouration of urine, sweat, tears (and contact lenses).
• Powerful CYP450 inducer: reduces plasma levels of many drugs, including the combined oral contraceptive pill (additional contraception is required).
• 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 (give pyridoxine/B₆) and hepatitis; pyrazinamide hepatitis and hyperuricaemia; ethambutol optic neuritis (warn about colour vision).

Choosing an Antibiotic by Indication

UK first-line empirical regimens (confirm with local microbiology guidance, which always trumps national):

• Uncomplicated UTI in non-pregnant women: nitrofurantoin 3 days first-line where eGFR permits (per NICE NG109); trimethoprim is an alternative where local resistance is low.
• Pyelonephritis: cefalexin first-choice oral; co-amoxiclav as alternative; ciprofloxacin only if other options unsuitable (per NICE NG111).
• Community-acquired pneumonia: CURB-65 score guides severity. Mild: amoxicillin. Severe: co-amoxiclav + clarithromycin.
• Hospital-acquired pneumonia: co-amoxiclav or piperacillin-tazobactam, depending on local guidance.
• Cellulitis: flucloxacillin (clarithromycin if penicillin-allergic).
• Necrotising fasciitis: benzylpenicillin + flucloxacillin + clindamycin + gentamicin (regimens vary).
• Bacterial meningitis: ceftriaxone (add amoxicillin in over-50s and immunocompromised for Listeria cover; add dexamethasone).
• Sepsis of unknown source: broad-spectrum cover (e.g. piperacillin-tazobactam ± gentamicin), within 1 hour as part of the "Sepsis Six".
• C. difficile infection: oral vancomycin first-line; fidaxomicin for recurrence (per NICE NG199). Metronidazole is now reserved for severe, life-threatening cases (intravenously) and is not first-line.
• Tonsillitis (severe, FeverPAIN/CENTOR positive): phenoxymethylpenicillin.
• Helicobacter pylori: PPI + amoxicillin + clarithromycin (or metronidazole), 7 days.
• TB: RIPE regimen (see above).

Antibiotic Resistance

Bacteria become resistant by two routes:

• Chromosomal mutation: spontaneous changes that confer resistance.
• Horizontal gene transfer:
  • Conjugation: transfer of plasmids by direct cell-cell contact.
  • Transduction: transfer via bacteriophage.
  • Transformation: uptake of free DNA from the environment.

The mechanisms by which bacteria become resistant fall into four broad categories:

• Drug-inactivating enzymes: β-lactamases, carbapenemases, aminoglycoside-modifying enzymes.
• Target modification: altered penicillin-binding proteins (MRSA), altered ribosomal target (macrolide resistance), altered D-Ala-D-Ala (VRE).
• Reduced drug uptake or active efflux: tetracycline resistance, fluoroquinolone resistance.
• Bypass of the affected pathway.

Resistant organisms of particular UK concern:

• MRSA: methicillin-resistant Staph aureus; treat with vancomycin, teicoplanin, linezolid, or daptomycin.
• VRE: vancomycin-resistant enterococci.
• ESBL: extended-spectrum β-lactamase-producing gram-negatives; treated with carbapenems.
• CRE / CPE: carbapenem-resistant / carbapenemase-producing Enterobacteriaceae; few options remain (e.g. colistin, ceftazidime-avibactam).

Antibiotic Stewardship

The Start Smart, Then Focus approach is the standard UK framework:

• Start smart: use empirical antibiotics promptly when bacterial infection is likely, but only when likely; document indication, dose and duration; obtain cultures before starting where possible; avoid antibiotics for self-limiting viral infections.
• Then focus: review at 48-72 hours: stop, switch IV-to-oral, change to a narrower-spectrum agent, continue with documented duration, or refer.

Five key prescribing rules (the WHO "AWaRe" classification and similar UK frameworks):

• Always use the narrowest-spectrum agent that will work.
• Use the shortest effective duration: UK courses are now generally shorter than they were a decade ago.
• Switch IV to oral as soon as the patient can tolerate oral and is improving.
• Document indication, dose, route, duration and stop date on every prescription.
• Avoid the "4 Cs" (cephalosporins, ciprofloxacin, clindamycin, co-amoxiclav) where alternatives exist, because of C. difficile risk.

Summary

• Antibiotics are classified by the bacterial process they target: cell wall, protein synthesis, DNA/folate.
• Cell wall: β-lactams (penicillins, cephalosporins, carbapenems, monobactams) and glycopeptides (vancomycin, teicoplanin): bactericidal, time-dependent.
• Protein synthesis: aminoglycosides (concentration-dependent, nephro/ototoxic, monitor), macrolides (CYP3A4 inhibitors, QT), tetracyclines (avoid in pregnancy and children), clindamycin (anaerobes, C. diff), linezolid (MRSA/VRE, MAOI).
• DNA/folate: fluoroquinolones (now restricted), trimethoprim (UTI, hyperkalaemia), co-trimoxazole (PCP), metronidazole (anaerobes, alcohol), nitrofurantoin (uncomplicated UTI), rifampicin (TB, orange urine, CYP inducer).
• Resistance arises by chromosomal mutation or horizontal gene transfer (conjugation, transduction, transformation); MRSA, VRE, ESBL and CPE are the main UK concerns.
• The "4 Cs" (cephalosporins, ciprofloxacin, clindamycin, co-amoxiclav) carry the highest C. difficile risk.
• Standard TB regimen RIPE: rifampicin (orange urine, CYP), isoniazid (neuropathy: give B₆), pyrazinamide (gout, hepatitis), ethambutol (optic neuritis).
• Antibiotic stewardship: Start Smart, Then Focus; narrow spectrum, short duration, IV-to-oral switch.

Drug Summary Table

Antibiotics organised by mechanism of action.

Reviewed by: Dr. Marcus Judge

Quiz

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