36 ANTIMICROBIALS

# 37 ANTIMICROBIALS

Antimicrobials are among the most heavily examined topics in MRCS Part A. Questions test three things repeatedly: mechanism of action, spectrum and indication, and major side effects. If you can place every drug into one of six mechanism boxes, predict which bugs it covers, and recall one or two killer adverse effects, you will pick up easy marks on this section.

This lesson is built around a single master class table. Learn it cold and the rest of the chapter falls into place.

How antibiotics kill bacteria — six mechanism boxes

Antibacterial drugs attack one of six bacterial targets. Eukaryotic cells lack each of these targets, which is why these agents are selectively toxic.

➡ Cell wall synthesis ➝ β-lactams, glycopeptides

➡ 30S ribosome (protein synthesis) ➝ aminoglycosides, tetracyclines

➡ 50S ribosome (protein synthesis) ➝ macrolides, clindamycin, linezolid, chloramphenicol

➡ DNA gyrase / topoisomerase IV ➝ fluoroquinolones

➡ Folate synthesis ➝ trimethoprim, sulphonamides

➡ DNA strand breaks (anaerobes) ➝ metronidazole

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Master class table

Class	Examples	Mechanism	Spectrum	Killer side effect
Penicillins	Benzylpenicillin, amoxicillin, flucloxacillin, piperacillin	Bind PBPs → inhibit peptidoglycan cross-linking	Gram +ve (broader with later agents); flucloxacillin = anti-staph	Hypersensitivity / anaphylaxis
Cephalosporins	Cefuroxime (2nd), ceftriaxone (3rd), ceftazidime (3rd, anti-pseudomonal)	As penicillins	Broaden with each generation toward Gram −ve	~10% cross-reactivity in penicillin allergy; C. diff
Carbapenems	Meropenem, imipenem, ertapenem	β-lactam, resistant to most β-lactamases	Very broad (Gram +ve, Gram −ve, anaerobes)	Seizures (imipenem); reserve for resistant organisms
Glycopeptides	Vancomycin, teicoplanin	Bind D-Ala-D-Ala terminus → block peptidoglycan elongation	Gram +ve only (too large for Gram −ve outer membrane)	Red man syndrome, nephrotoxicity, ototoxicity
Aminoglycosides	Gentamicin, amikacin, tobramycin	30S subunit → mistranslation	Gram −ve aerobes (synergy with β-lactams vs Gram +ve)	Nephrotoxicity, ototoxicity (irreversible)
Tetracyclines	Doxycycline	30S subunit → block tRNA binding	Intracellular organisms (Chlamydia, Rickettsia, Mycoplasma)	Tooth staining; avoid in pregnancy and children <12
Macrolides	Erythromycin, clarithromycin, azithromycin	50S subunit → block translocation	Gram +ve, atypicals; penicillin alternative	QT prolongation; CYP450 inhibition
Lincosamides	Clindamycin	50S subunit	Gram +ve, anaerobes (good bone/soft tissue penetration)	C. difficile colitis (classic)
Oxazolidinones	Linezolid	50S subunit (early binding)	MRSA, VRE — reserved	Thrombocytopenia, serotonin syndrome with SSRIs
Fluoroquinolones	Ciprofloxacin, levofloxacin	Inhibit DNA gyrase / topoisomerase IV	Gram −ve (cipro is anti-pseudomonal)	Tendon rupture, QT prolongation, C. diff, aortic aneurysm
Folate inhibitors	Trimethoprim, co-trimoxazole, sulphonamides	Block dihydrofolate reductase / dihydropteroate synthase	UTI; PCP prophylaxis	Marrow suppression, hyperkalaemia, teratogenic (1st trimester)
Nitroimidazoles	Metronidazole	Reduced to toxic radicals in anaerobic environment → DNA strand breaks	Anaerobes, protozoa (Giardia, Entamoeba, Trichomonas)	Disulfiram reaction with alcohol; peripheral neuropathy

👩‍⚕️ Two glycopeptide pearls that examiners love: vancomycin is too large to cross the Gram-negative outer membrane, which is why it has no Gram-negative activity; and oral vancomycin is not absorbed, which is exactly why it works for C. difficile (stays in the colonic lumen) but is useless for systemic infection.

Bug coverage at a glance

Think in three buckets when choosing an empirical agent.

Gram-positive cover

Flucloxacillin (staph), benzylpenicillin (strep, clostridia), vancomycin/teicoplanin (MRSA and severe penicillin allergy), linezolid (VRE).

Gram-negative cover

Gentamicin, ciprofloxacin, third-generation cephalosporins (ceftriaxone), piperacillin-tazobactam, carbapenems. Pseudomonas is the awkward Gram-negative — only ceftazidime, ciprofloxacin, piperacillin-tazobactam, aminoglycosides and carbapenems reliably cover it.

Anaerobic cover

Metronidazole (the workhorse), co-amoxiclav, piperacillin-tazobactam, carbapenems, clindamycin. Notably absent: aminoglycosides (need oxygen to enter the cell) and most cephalosporins.

👩‍⚕️ Classic exam trap: gentamicin has no anaerobic activity because aminoglycoside uptake into the bacterium is oxygen-dependent. This is why intra-abdominal sepsis regimens pair gentamicin with metronidazole.

Side effects — the high-yield list

Side effects are where SBAs hide their easy marks. Memorise these pairings.

Penicillins ➝ hypersensitivity. Type I (IgE-mediated anaphylaxis) is the dangerous one. Cross-reactivity with cephalosporins is around 10% historically, though modern data suggests <2% for later generations. With a mild rash, cephalosporins are generally safe; with anaphylaxis, avoid all β-lactams (including carbapenems) and use vancomycin or a macrolide.

Gentamicin ➝ nephrotoxic + ototoxic. Both dose-dependent. Ototoxicity affects the vestibular system first and is irreversible. Monitor trough levels (pre-dose) to ensure clearance between doses, and adjust based on renal function. Avoid in myasthenia gravis (neuromuscular blockade).

Vancomycin ➝ red man syndrome, nephrotoxicity. Red man is a histamine-release reaction to rapid infusion, not a true allergy — slow the infusion. Monitor trough levels (target ~15–20 mg/L for serious infection). Nephrotoxicity is enhanced when co-prescribed with gentamicin.

Fluoroquinolones ➝ tendon rupture, QT prolongation, C. diff, aortic aneurysm/dissection risk. Achilles tendinopathy is the classic. Avoid in children and pregnancy (cartilage toxicity in animal studies).

Clindamycin ➝ C. difficile. Highest C. diff risk of any single agent. The mnemonic "C the 4 Cs" for C. diff offenders: Clindamycin, Ciprofloxacin, Cephalosporins, Co-amoxiclav.

Tetracyclines ➝ tooth staining and impaired bone growth. Chelate calcium in growing teeth and bone. Contraindicated in pregnancy, breastfeeding and children under 12.

Trimethoprim ➝ teratogenic in first trimester (folate antagonist → neural tube defects). Nitrofurantoin replaces it in pregnancy (but avoid nitrofurantoin in the third trimester — neonatal haemolysis).

Metronidazole ➝ disulfiram-like reaction with alcohol. Patient flushes and vomits if they drink. Counsel explicitly.

👩‍⚕️ Two drugs with trough monitoring: gentamicin and vancomycin. Don't confuse with peak levels — troughs reflect whether the drug is clearing between doses and predict toxicity. Peak levels (rarely used now) reflect efficacy.

Resistance — three mechanisms you must know

β-lactamases. Enzymes that hydrolyse the β-lactam ring. Counter-strategy: add a β-lactamase inhibitor (clavulanic acid in co-amoxiclav, tazobactam in piperacillin-tazobactam). Extended-spectrum β-lactamases (ESBLs) hydrolyse cephalosporins too — these organisms (typically E. coli, Klebsiella) require carbapenems.

Altered target — MRSA. Methicillin-resistant Staphylococcus aureus carries the mecA gene, which encodes PBP2a, an altered penicillin-binding protein that β-lactams cannot bind. All β-lactams (including flucloxacillin) are therefore ineffective. Treat with vancomycin or teicoplanin.

Altered target — VRE. Vancomycin-resistant enterococci replace the terminal D-Ala-D-Ala of peptidoglycan with D-Ala-D-Lac, abolishing vancomycin binding. Treat with linezolid or daptomycin.

Other mechanisms tested less often: efflux pumps (tetracyclines), porin loss (Gram-negatives → carbapenems), enzymatic inactivation (aminoglycoside-modifying enzymes).

Common surgical regimens

These are the textbook empirical choices — local hospital policy will vary but MRCS Part A expects the standard answers.

Indication	Regimen
Appendicitis / perforated viscus	Co-amoxiclav (or cefuroxime + metronidazole; or piperacillin-tazobactam)
Acute cholecystitis / cholangitis	Co-amoxiclav ± gentamicin; piperacillin-tazobactam if severe
Diverticulitis	Co-amoxiclav (oral if uncomplicated; IV if systemic)
Necrotising fasciitis	Broad-spectrum: piperacillin-tazobactam + clindamycin (toxin suppression) + IV immunoglobulin
Gas gangrene (C. perfringens)	Urgent debridement + high-dose IV benzylpenicillin + metronidazole
Cellulitis	Flucloxacillin (clarithromycin if penicillin-allergic)
CSF shunt / orthopaedic prosthesis prophylaxis	Cefuroxime ± vancomycin (if MRSA risk)
Bowel surgery prophylaxis	Single-dose co-amoxiclav (or cefuroxime + metronidazole) at induction
Post-splenectomy lifelong prophylaxis	Penicillin V + pneumococcal, HiB, MenACWY, annual influenza vaccines

👩‍⚕️ Surgical prophylaxis principle: give the antibiotic within 60 minutes of skin incision, single dose, only repeat if surgery exceeds two half-lives or significant blood loss. The aim is high tissue concentration at the moment contamination occurs.

MRSA management algorithm

➡ Nasal colonisation (elective surgery): topical mupirocin 5 days + chlorhexidine body wash

➡ Systemic infection / bacteraemia: IV vancomycin or teicoplanin (first-line glycopeptides)

➡ Second-line systemic agents: rifampicin, clindamycin, doxycycline, gentamicin (combination depending on site)

➡ Reserved agents: linezolid, daptomycin, tigecycline (for resistant or refractory cases)

C. difficile management

➡ First episode (mild–moderate): oral vancomycin 125 mg QDS for 10 days (current NICE/IDSA guidance; metronidazole now second-line)

➡ Severe disease: oral vancomycin ± IV metronidazole

➡ Life-threatening (ileus, megacolon): oral vancomycin + IV metronidazole + surgical review

➡ Recurrent: fidaxomicin or faecal microbiota transplant

Note: older textbooks (and some MRCS question banks) still list oral metronidazole as first-line. Current UK guidance is oral vancomycin first-line — know both for the exam.

Antibiotic stewardship — five principles

1. Right drug, right bug — send cultures before starting, narrow spectrum once sensitivities return.

2. Right dose, right route — IV-to-oral switch as early as possible (48–72 h if afebrile and tolerating diet).

3. Right duration — shortest evidence-based course; most surgical infections need 5–7 days, not 14.

4. Document indication and review date in every prescription.

5. Avoid the "Four Cs" where possible — clindamycin, ciprofloxacin, cephalosporins, co-amoxiclav are the highest-risk C. diff drivers.

[Image: MCQs banner]

Test yourself

Patient with nasal MRSA positive, elective surgery. Best management?

• ((Mupirocin nasal ointment for 5 days::☑️ Standard topical decolonisation before elective surgery; add chlorhexidine body wash.))
• ((IV vancomycin::Reserved for systemic MRSA infection, not asymptomatic colonisation.))
• ((Oral vancomycin::Not absorbed systemically — only treats C. difficile in the colonic lumen.))
• ((IV teicoplanin::Glycopeptide for active systemic MRSA, not colonisation.))
• ((Chlorhexidine wash alone::Adjunct for skin only; does not eradicate nasal carriage.))

👩‍⚕️ Colonisation is topical; infection is systemic. Always check the question carefully.

Post-laparotomy patient on an MRSA-colonised ward has blood cultures growing Gram-positive cocci. Best initial therapy?

• ((IV vancomycin or teicoplanin::☑️ Empirical glycopeptide cover for likely MRSA bacteraemia.))
• ((Mupirocin nasal ointment::Topical decolonisation only — useless in bacteraemia.))
• ((Chlorhexidine wash::Skin antiseptic; not systemic therapy.))
• ((Oral vancomycin::Not absorbed from gut — no systemic effect.))
• ((IV benzylpenicillin::Ineffective against MRSA — altered PBP2a from mecA gene.))

80-year-old on day 7 of IV co-amoxiclav develops profuse diarrhoea. Best initial treatment?

• ((Oral vancomycin::☑️ Current first-line for C. difficile colitis — stays in the colonic lumen.))
• ((Oral metronidazole::Previously first-line, now second-line per NICE/IDSA guidance.))
• ((IV metronidazole::Adjunct in severe or ileus-complicated disease, not monotherapy.))
• ((IV meropenem::Broad-spectrum carbapenem worsens dysbiosis.))
• ((Oral clindamycin::Clindamycin is itself a major cause of C. difficile.))

👩‍⚕️ Co-amoxiclav, clindamycin, ciprofloxacin and cephalosporins — the "Four Cs" of C. diff.

Vancomycin belongs to which class?

• ((Glycopeptide::☑️ Binds D-Ala-D-Ala terminus of peptidoglycan precursors, blocking cell wall synthesis.))
• ((Beta-lactam::Penicillins, cephalosporins, carbapenems — all bind PBPs directly.))
• ((Quinolone::DNA gyrase / topoisomerase IV inhibitors (e.g. ciprofloxacin).))
• ((Carbapenem::A subclass of beta-lactams (e.g. meropenem).))
• ((Aminoglycoside::Bind the 30S ribosome (e.g. gentamicin).))

Motorcyclist with a deep wound and gas in the tissues on imaging. Best empirical antibiotics?

• ((Benzylpenicillin and metronidazole::☑️ Gas gangrene = Clostridium perfringens; high-dose penicillin + metronidazole + urgent debridement.))
• ((Flucloxacillin and gentamicin::Anti-staphylococcal — wrong organism.))
• ((Co-amoxiclav alone::Has anaerobic cover but inadequate for clostridial myonecrosis.))
• ((Ciprofloxacin and clindamycin::Not the first-line empirical combination.))
• ((Cefuroxime and metronidazole::Cefuroxime has weaker Gram-positive activity than penicillin for clostridia.))

Which antibiotic is first-line for Bacteroides fragilis?

• ((Metronidazole::☑️ Nitroimidazole — DNA strand breaks in anaerobes; first-line for B. fragilis.))
• ((Gentamicin::Aerobic uptake — no anaerobic activity.))
• ((Ciprofloxacin::Poor anaerobic cover.))
• ((Flucloxacillin::Anti-staph penicillin; no anaerobic activity.))
• ((Erythromycin::Macrolide; limited anaerobic spectrum.))

Post-operative enterocutaneous fistula with sepsis. Most likely organism and treatment?

• ((Bacteroides fragilis treated with metronidazole::☑️ B. fragilis is the predominant anaerobe in intra-abdominal sepsis.))
• ((E. coli treated with ciprofloxacin::E. coli is common but B. fragilis dominates fistula infections.))
• ((Staphylococcus aureus treated with flucloxacillin::Skin pathogen — not typical in GI fistulae.))
• ((Pseudomonas treated with piperacillin-tazobactam::Less likely than Bacteroides as primary organism.))
• ((Clostridium difficile treated with vancomycin::Causes colitis, not fistula sepsis.))

20% chest burn, day 10 post-skin graft, serous discharge and fever. Best antibiotic?

• ((Flucloxacillin::☑️ S. aureus is the commonest graft pathogen; flucloxacillin is anti-staphylococcal first-line.))
• ((Cephalosporin::Broader than required; flucloxacillin is preferred.))
• ((Cephalosporin + metronidazole::Anaerobic cover unnecessary for graft infection.))
• ((Ampicillin::Broad-spectrum but lacks anti-staphylococcal activity.))
• ((Gentamicin::Gram-negative cover; wrong target organism.))

Child with bloody diarrhoea; ova and cysts seen on stool microscopy. Treatment?

• ((Metronidazole::☑️ Amoebic dysentery (Entamoeba histolytica) — metronidazole is first-line.))
• ((Mebendazole::Antihelminthic — not active against protozoa.))
• ((Tinidazole::Alternative nitroimidazole; metronidazole is standard first-line.))
• ((Bithionol::Used for liver flukes, not intestinal amoebiasis.))
• ((Albendazole::Antihelminthic; ineffective against Entamoeba.))

Child with pruritus ani; ova on stool microscopy. Treatment?

• ((Mebendazole::☑️ Enterobius vermicularis (threadworm) — mebendazole first-line, treat whole household, repeat at 2 weeks.))
• ((Metronidazole::Active against anaerobes and protozoa, not helminths.))
• ((Praziquantel::For tapeworms and schistosomiasis.))
• ((Ivermectin::For Strongyloides; mebendazole preferred for pinworm.))
• ((Albendazole::Alternative antihelminthic but mebendazole is first-line.))

Post-splenectomy infection prophylaxis?

• ((Pneumococcal, HiB, MenACWY vaccines + annual influenza vaccine + lifelong penicillin V::☑️ Standard prophylaxis against encapsulated organisms causing OPSI.))
• ((Pneumococcal vaccine alone::Inadequate — need full vaccine schedule plus antibiotic.))
• ((Penicillin V without vaccination::Antibiotic alone is insufficient — vaccination is essential.))
• ((Annual influenza vaccine only::Influenza vaccine is part of the regimen but covers no encapsulated bacteria.))
• ((Co-amoxiclav prophylaxis::Penicillin V is the standard agent — narrower spectrum, lower C. diff risk.))

👩‍⚕️ OPSI mortality approaches 50%. Encapsulated bugs = pneumococcus, HiB, meningococcus.

Endocarditis with a penicillin-sensitive organism in a patient with a previous penicillin rash. Best agent?

• ((Cefuroxime::☑️ Mild penicillin allergy (rash only) allows cephalosporins — cross-reactivity <5%.))
• ((Amoxicillin::Contraindicated by penicillin allergy history.))
• ((Linezolid::Reserved oxazolidinone — not first-line.))
• ((Gentamicin::Synergistic adjunct in endocarditis, not monotherapy.))
• ((Metronidazole::Anaerobic agent; wrong spectrum.))

👩‍⚕️ Rash = mild (cephalosporins safe). Anaphylaxis = severe (avoid all beta-lactams; use vancomycin).

Which class is NOT safe in patients with severe penicillin allergy?

• ((Beta-lactams::☑️ Includes penicillins, cephalosporins and carbapenems — all share the beta-lactam ring and cross-react.))
• ((Macrolides::Different target (50S ribosome) — safe alternative.))
• ((Tetracyclines::30S ribosome — safe.))
• ((Glycopeptides::Vancomycin is the standard alternative in severe penicillin allergy.))
• ((Aminoglycosides::30S ribosome — safe.))

Which adverse effect is most characteristic of gentamicin?

• ((Nephrotoxicity and ototoxicity::☑️ Both dose-dependent; ototoxicity is irreversible — monitor trough levels.))
• ((Tendon rupture::Classic for fluoroquinolones.))
• ((Red man syndrome::Vancomycin infusion reaction.))
• ((Tooth discolouration::Tetracyclines in children under 12.))
• ((Disulfiram-like reaction::Metronidazole with alcohol.))

Which gene confers methicillin resistance in S. aureus?

• ((mecA::☑️ Encodes PBP2a, an altered penicillin-binding protein that beta-lactams cannot bind.))
• ((vanA::Confers vancomycin resistance in enterococci (D-Ala-D-Lac).))
• ((blaZ::Encodes a beta-lactamase — defeated by clavulanic acid, not methicillin resistance.))
• ((ermB::Macrolide resistance via 23S rRNA methylation.))
• ((tetM::Tetracycline resistance via ribosomal protection.))

Revision summary

➡ Six mechanism boxes: cell wall (β-lactams, glycopeptides), 30S (aminoglycosides, tetracyclines), 50S (macrolides, clindamycin, linezolid), DNA gyrase (quinolones), folate (trimethoprim, sulphonamides), DNA breaks in anaerobes (metronidazole).

➡ Vancomycin — glycopeptide, Gram +ve only, oral for C. diff (not absorbed), monitor troughs, red man with rapid infusion.

➡ Gentamicin — Gram −ve aerobes only (no anaerobes), nephro/ototoxic, monitor troughs.

➡ Fluoroquinolones — tendon rupture, QT prolongation, aortic risk, C. diff.

➡ Clindamycin — Gram +ve and anaerobes; biggest single C. diff offender.

➡ Tetracyclines — avoid in pregnancy and children under 12 (teeth).

➡ Trimethoprim — teratogenic in first trimester.

➡ Metronidazole — anaerobes and protozoa; disulfiram reaction with alcohol.

➡ The Four Cs of C. diff: Clindamycin, Ciprofloxacin, Cephalosporins, Co-amoxiclav.

➡ MRSA = mecA → PBP2a (β-lactams useless); treat with vancomycin/teicoplanin.

➡ VRE = D-Ala-D-Lac swap (vancomycin can't bind); treat with linezolid.

➡ ESBL organisms require carbapenems.

➡ Penicillin allergy: rash → cephalosporins safe (<5% cross-react); anaphylaxis → avoid all β-lactams, use vancomycin or macrolide.

➡ C. difficile first-line (current UK): oral vancomycin (metronidazole now second-line).

➡ Gas gangrene: debridement + IV benzylpenicillin + metronidazole.

➡ Post-splenectomy: vaccines (pneumococcal, HiB, MenACWY, annual flu) + lifelong penicillin V.

➡ Surgical prophylaxis: single dose within 60 minutes of incision.