Pharmacology chapters
Antibacterial drugs by mechanism of action
The antibacterial drugs grouped by how they work: cell wall inhibitors (penicillins, cephalosporins, carbapenems, vancomycin), protein synthesis inhibitors (aminoglycosides, tetracyclines, macrolides, chloramphenicol, clindamycin, linezolid), DNA and folate inhibitors (fluoroquinolones, metronidazole, sulphonamides, trimethoprim), with their spectrum and drugs of choice.
- Cell wall inhibitors (bactericidal): β-lactams (penicillins, cephalosporins, carbapenems) bind penicillin-binding proteins and block transpeptidation; vancomycin binds D-Ala-D-Ala (Gram-positive only, including MRSA; oral for C. difficile).
- Protein synthesis inhibitors: 30S: aminoglycosides (bactericidal; Gram-negatives; ototoxic, nephrotoxic) and tetracyclines (doxycycline: atypicals, rickettsiae, cholera; avoid in children and pregnancy); 50S: macrolides (azithromycin, clarithromycin: atypical pneumonia), chloramphenicol (typhoid in the past; grey baby, aplastic anaemia), clindamycin (anaerobes above the diaphragm; C. difficile), linezolid (MRSA, VRE).
- DNA and folate: fluoroquinolones inhibit DNA gyrase and topoisomerase IV (ciprofloxacin: Gram-negatives, typhoid; tendon rupture, QT), metronidazole damages DNA in anaerobes and protozoa (disulfiram-like reaction with alcohol), sulphonamides + trimethoprim block two steps of folate synthesis (co-trimoxazole: Pneumocystis, UTI).
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Basic concepts
- Bactericidal drugs kill bacteria (β-lactams, vancomycin, aminoglycosides, fluoroquinolones, metronidazole); preferred in endocarditis, meningitis and neutropenic patients.
- Bacteriostatic drugs stop growth (tetracyclines, macrolides, clindamycin, chloramphenicol, sulphonamides, linezolid); immunity clears the infection.
- Time-dependent killing: effect depends on time above the MIC (β-lactams, vancomycin): frequent doses or infusions.
- Concentration-dependent killing: effect depends on peak level (aminoglycosides, fluoroquinolones): once-daily high doses; aminoglycosides also have a post-antibiotic effect.
- Synergy: β-lactam + aminoglycoside (cell wall damage lets the aminoglycoside in), e.g. in enterococcal endocarditis.
Summary by mechanism
| Target | Drugs |
|---|---|
| Cell wall synthesis | β-lactams (penicillins, cephalosporins, carbapenems, monobactams), glycopeptides (vancomycin, teicoplanin), fosfomycin, bacitracin |
| Cell membrane | Polymyxins (colistin), daptomycin |
| Protein synthesis: 30S | Aminoglycosides, tetracyclines |
| Protein synthesis: 50S | Macrolides, chloramphenicol, clindamycin, linezolid, streptogramins |
| DNA | Fluoroquinolones (DNA gyrase, topoisomerase IV), metronidazole (DNA strand breaks), nitrofurantoin |
| RNA polymerase | Rifampicin |
| Folate synthesis | Sulphonamides (dihydropteroate synthase), trimethoprim (dihydrofolate reductase) |
Protein synthesis: "buy AT 30, CCEL at 50": Aminoglycosides and Tetracyclines at 30S; Chloramphenicol, Clindamycin, Erythromycin (macrolides), Linezolid at 50S.
Cell wall inhibitors
Penicillins
β-lactam ring binds penicillin-binding proteins (PBPs) → blocks transpeptidation (cross-linking of peptidoglycan) → cell lysis. Bactericidal; time-dependent.
| Group | Drugs | Spectrum and uses |
|---|---|---|
| Natural | Benzylpenicillin (IV, IM), phenoxymethylpenicillin (oral), benzathine penicillin (depot IM) | Streptococci, pneumococci (sensitive), meningococci, syphilis (benzathine), rheumatic fever prophylaxis, diphtheria, tetanus, gas gangrene, leptospirosis |
| Anti-staphylococcal (β-lactamase stable) | Flucloxacillin, cloxacillin | Staphylococcus aureus (not MRSA): cellulitis, osteomyelitis |
| Broad-spectrum (aminopenicillins) | Amoxicillin, ampicillin | Also H. influenzae, E. coli, enterococci, Listeria; destroyed by β-lactamase; rash in glandular fever (EBV) |
| With β-lactamase inhibitor | Co-amoxiclav (amoxicillin + clavulanic acid), piperacillin-tazobactam | Wider cover including β-lactamase producers and anaerobes; piperacillin-tazobactam covers Pseudomonas |
Adverse effects: hypersensitivity (rash; anaphylaxis in a small minority; about 10% cross-reaction with cephalosporins is often quoted but true cross-reaction is lower), diarrhoea, C. difficile, seizures (very high doses), cholestatic jaundice (co-amoxiclav, flucloxacillin), interstitial nephritis. Probenecid delays excretion.
Cephalosporins
| Generation | Examples | Spectrum |
|---|---|---|
| First | Cefalexin, cefazolin | Gram-positive cocci; some Gram-negatives; surgical prophylaxis |
| Second | Cefuroxime, cefaclor | More Gram-negative (H. influenzae) |
| Third | Ceftriaxone, cefotaxime, ceftazidime (Pseudomonas), cefixime (oral) | Strong Gram-negative; meningitis, typhoid, gonorrhoea; ceftazidime covers Pseudomonas |
| Fourth | Cefepime | Broad, including Pseudomonas |
| Fifth | Ceftaroline | MRSA cover |
Cephalosporins do not cover enterococci, Listeria, atypicals or (except ceftaroline) MRSA ("LAME": Listeria, Atypicals, MRSA, Enterococci).
Ceftriaxone: biliary sludge; do not give with calcium-containing IV fluids in neonates.
Carbapenems and monobactams
- Meropenem, imipenem (+ cilastatin to prevent renal breakdown), ertapenem (no Pseudomonas): broadest spectrum β-lactams; reserved for ESBL producers and serious hospital infections; imipenem can cause seizures.
- Aztreonam (monobactam): Gram-negatives only; safe in penicillin allergy.
Glycopeptides
Vancomycin binds D-alanyl-D-alanine of cell wall precursors. Gram-positive only (too large for Gram-negative porins).
- Uses: MRSA, serious Gram-positive infections in penicillin allergy, oral for Clostridioides difficile colitis (not absorbed).
- Adverse effects: red man syndrome (flushing from histamine release with fast infusion; slow the rate), nephrotoxicity, ototoxicity; monitor trough levels.
- Resistance: VRE (D-Ala-D-Lac).
Protein synthesis inhibitors
Aminoglycosides (30S)
Gentamicin, amikacin, streptomycin, tobramycin, neomycin.
- Bind 30S, cause misreading of mRNA; bactericidal; concentration-dependent with post-antibiotic effect.
- Enter bacteria by an oxygen-dependent transport, so no activity against anaerobes.
- Gram-negative aerobes (E. coli, Klebsiella, Pseudomonas), synergy in endocarditis; streptomycin and amikacin for TB; neomycin orally (bowel preparation, hepatic encephalopathy).
- Adverse effects: nephrotoxicity (reversible), ototoxicity (vestibular and cochlear, often irreversible; worse with loop diuretics), neuromuscular blockade (avoid in myasthenia gravis), teratogenic (deafness). Monitor levels; once-daily dosing; reduce in renal impairment.
Tetracyclines (30S)
Doxycycline, tetracycline, minocycline.
- Bacteriostatic; broad spectrum including intracellular organisms.
- Uses: Chlamydia, Mycoplasma, rickettsiae (typhus), cholera, brucellosis (with rifampicin or streptomycin), Lyme disease, acne, malaria prophylaxis (doxycycline), leptospirosis, MRSA skin infections.
- Adverse effects: tooth discolouration and bone growth problems (avoid in children under 8–12 years and pregnancy), photosensitivity, oesophageal ulceration (take upright with water), gut upset; outdated tetracycline: Fanconi syndrome; minocycline: vestibular effects, pigmentation.
- Absorption reduced by calcium (milk), iron, magnesium and antacids.
Macrolides (50S)
Erythromycin, clarithromycin, azithromycin.
- Bacteriostatic; Gram-positives and atypicals.
- Uses: atypical pneumonia (Mycoplasma, Legionella, Chlamydophila), penicillin allergy (streptococcal infections), whooping cough, H. pylori (clarithromycin), chlamydia (azithromycin single dose), typhoid (azithromycin), Campylobacter, MAC (clarithromycin, azithromycin).
- Adverse effects: gut upset (erythromycin acts on motilin receptors, used as a prokinetic), QT prolongation, cholestatic hepatitis (erythromycin estolate), ototoxicity; CYP3A4 inhibition (erythromycin, clarithromycin) raises warfarin, statins, theophylline, carbamazepine; azithromycin has fewer interactions.
Chloramphenicol (50S)
- Bacteriostatic (bactericidal against H. influenzae, N. meningitidis, S. pneumoniae); crosses into CSF.
- Uses: eye drops (conjunctivitis); systemic use is now limited (bacterial meningitis in some settings, rickettsiae, once typhoid).
- Adverse effects: dose-related marrow suppression; idiosyncratic, often fatal aplastic anaemia; grey baby syndrome in neonates (cannot glucuronidate).
Clindamycin (50S)
- Anaerobes (above the diaphragm: aspiration pneumonia, lung abscess, dental infections), Gram-positives (staphylococci, streptococci), toxin suppression in necrotising fasciitis and toxic shock, toxoplasmosis (with pyrimethamine), malaria (with quinine), bacterial vaginosis.
- Adverse effect: C. difficile (pseudomembranous) colitis: the classic association.
Linezolid (50S)
Oxazolidinone; prevents formation of the initiation complex. MRSA and VRE. Adverse effects: thrombocytopenia (marrow suppression with longer use), optic and peripheral neuropathy, serotonin syndrome (weak MAO inhibitor).
DNA and folate inhibitors
Fluoroquinolones
Ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin.
- Inhibit DNA gyrase (topoisomerase II) (main target in Gram-negatives) and topoisomerase IV (Gram-positives); bactericidal.
- Ciprofloxacin: Gram-negatives including Pseudomonas, typhoid (resistance now widespread in Pakistan), UTIs and prostatitis, gonorrhoea (resistance common), travellers' diarrhoea, anthrax.
- Levofloxacin, moxifloxacin ("respiratory quinolones"): pneumococcus, atypicals; MDR-TB.
- Adverse effects: tendinitis and tendon rupture (Achilles; older people, steroids), QT prolongation, seizures (lower threshold; with NSAIDs), peripheral neuropathy, dysglycaemia, aortic aneurysm risk, C. difficile, photosensitivity; cartilage damage in animal studies, so avoided in children and pregnancy unless needed.
- Absorption reduced by calcium, iron, magnesium, antacids; ciprofloxacin inhibits CYP1A2 (raises theophylline).
Metronidazole (and tinidazole)
- Activated inside anaerobes and protozoa → free radicals → DNA damage.
- Uses: anaerobic infections (intra-abdominal, below the diaphragm), C. difficile (mild cases, oral, where vancomycin is unavailable), amoebiasis, giardiasis, Trichomonas, bacterial vaginosis, H. pylori regimens, dental infections, tetanus.
- Adverse effects: metallic taste, nausea, disulfiram-like reaction with alcohol (avoid alcohol during and for 48 hours after), peripheral neuropathy (long courses), dark urine; enhances warfarin.
Sulphonamides and trimethoprim
- Sulphonamides (sulfamethoxazole) block dihydropteroate synthase (PABA analogue); trimethoprim blocks bacterial dihydrofolate reductase. Together (co-trimoxazole) they cause sequential blockade (synergistic and bactericidal).
- Uses: Pneumocystis jirovecii pneumonia (treatment and prophylaxis in HIV), UTIs (trimethoprim alone), toxoplasmosis prophylaxis, Nocardia, MRSA skin infections, Stenotrophomonas.
- Adverse effects: rashes including Stevens-Johnson syndrome, haemolysis in G6PD deficiency, marrow suppression and folate deficiency (megaloblastic anaemia), hyperkalaemia (trimethoprim), crystalluria, kernicterus in neonates (avoid near term), raised creatinine (trimethoprim blocks secretion), raises warfarin and methotrexate toxicity.
Nitrofurantoin
Damages bacterial DNA; concentrates in urine. Uncomplicated lower UTI (including pregnancy, but avoid at term). Avoid when kidney function is poor (ineffective, toxic). Adverse effects: nausea, pulmonary fibrosis and neuropathy with long use, haemolysis in G6PD deficiency, brown urine.
Drugs of choice in common situations
These follow standard teaching; local resistance patterns and current guidelines decide actual prescribing.
| Infection or organism | Usual choices |
|---|---|
| Streptococcal pharyngitis, rheumatic fever prophylaxis | Penicillin V or benzathine penicillin |
| Syphilis | Benzathine penicillin |
| S. aureus (MSSA) | Flucloxacillin |
| MRSA | Vancomycin, teicoplanin, linezolid |
| Bacterial meningitis (adults, empirical) | Ceftriaxone or cefotaxime (+ amoxicillin for Listeria in older people; + dexamethasone) |
| Typhoid | Ceftriaxone, azithromycin; meropenem for XDR typhoid (Pakistan has had XDR outbreaks) |
| Atypical pneumonia | Macrolide or doxycycline |
| Pseudomonas | Piperacillin-tazobactam, ceftazidime, ciprofloxacin, meropenem, aminoglycosides |
| Anaerobes | Metronidazole, clindamycin, co-amoxiclav, carbapenems |
| Pneumocystis | Co-trimoxazole |
| C. difficile | Oral vancomycin or fidaxomicin |
| Cholera | Doxycycline (single dose) or azithromycin; rehydration is the key |
| Chlamydia | Doxycycline or azithromycin |
| Gonorrhoea | Ceftriaxone (IM) |
| Leptospirosis | Penicillin or doxycycline |
| Brucellosis | Doxycycline + rifampicin (or streptomycin) |
Expect: bactericidal vs bacteriostatic, time- vs concentration-dependent killing, β-lactam mechanism, penicillin groups and uses, cephalosporin generations and gaps (LAME), carbapenems for ESBL, vancomycin mechanism and red man syndrome, 30S vs 50S drugs, aminoglycoside toxicity and lack of anaerobic activity, tetracycline contraindications and chelation, macrolide interactions and QT, chloramphenicol grey baby, clindamycin and C. difficile, linezolid, fluoroquinolone mechanism and tendon rupture, metronidazole disulfiram reaction, co-trimoxazole sequential blockade and Pneumocystis, and drugs of choice.
Quick revision
- Cell wall: β-lactams (PBPs), vancomycin (D-Ala-D-Ala, MRSA).
- 30S: aminoglycosides, tetracyclines. 50S: chloramphenicol, clindamycin, macrolides, linezolid.
- DNA: fluoroquinolones (gyrase), metronidazole. Folate: sulphonamides + trimethoprim.
- Aminoglycosides: ototoxic, nephrotoxic; no anaerobes.
- Tetracyclines: teeth; avoid in children and pregnancy; chelated by calcium.
- Macrolides: atypicals; CYP3A4 inhibition; QT.
- Clindamycin: C. difficile. Fluoroquinolones: tendon rupture. Metronidazole: no alcohol.
- Co-trimoxazole: Pneumocystis.
Written by The House Job from standard pharmacology references (Katzung's Basic and Clinical Pharmacology).
FAQ
How do beta-lactam antibiotics kill bacteria?
They bind penicillin-binding proteins and block the cross-linking (transpeptidation) of peptidoglycan in the cell wall, so the bacteria burst.
Which antibiotic is used for MRSA?
Vancomycin (or teicoplanin or linezolid, depending on the infection).
Which antibiotics act on DNA gyrase?
Fluoroquinolones such as ciprofloxacin and levofloxacin.
Why are aminoglycosides ineffective against anaerobes?
Their entry into bacteria depends on an oxygen-requiring transport system.