Q1 LONG ANSWER 10M ★ High-yield

Describe the general principles of antimicrobial therapy including selective toxicity, classification, pharmacodynamic patterns and combination therapy.

Pharmacology · 2nd Professional — Para-Clinical

Definitions and the Principle of Selective Toxicity

An antimicrobial is a substance that kills or inhibits micro-organisms. selective toxicity — the ability to harm the pathogen while sparing the host — is the principle on which all chemotherapy rests.

Basis of selectivity	Explanation	Drugs
A target absent in man	The bacterial cell wall (peptidoglycan) has no human counterpart — hence these are the safest antibiotics	Penicillins, cephalosporins, vancomycin
A target that differs	The bacterial 70S ribosome differs from the human 80S	Aminoglycosides, tetracyclines, macrolides, chloramphenicol
A pathway man does not use	Bacteria synthesise folate; man absorbs it preformed	Sulphonamides, trimethoprim
Selective activation	The drug is activated only inside the organism	Metronidazole (reduced by anaerobes); aciclovir (phosphorylated by viral thymidine kinase); isoniazid (activated by mycobacterial catalase)
Selective accumulation	Concentrated by the organism	Tetracyclines in bacteria

Selectivity is weakest where the target is most similar — which is why antifungal and antiviral drugs are more toxic than antibacterials: fungi are eukaryotes and viruses use host machinery, leaving fewer differences to exploit

Classification

Basis	Groups
By mechanism	(1) cell wall synthesis — penicillins, cephalosporins, vancomycin, bacitracin, cycloserine. (2) protein synthesis — 30S: aminoglycosides, tetracyclines; 50S: macrolides, chloramphenicol, clindamycin, linezolid. (3) nucleic acid — fluoroquinolones (DNA gyrase), rifampicin (RNA polymerase). (4) folate — sulphonamides, trimethoprim. (5) cell membrane — polymyxins, daptomycin
By spectrum	Narrow (benzylpenicillin, vancomycin) against broad (tetracyclines, chloramphenicol, carbapenems)
By action	Bactericidal — penicillins, cephalosporins, aminoglycosides, fluoroquinolones, vancomycin, metronidazole, rifampicin, isoniazid. Bacteriostatic — tetracyclines, chloramphenicol, macrolides, sulphonamides, clindamycin, ethambutol
By source	Natural (penicillin), semisynthetic (amoxicillin), synthetic (fluoroquinolones)

Pharmacodynamic Patterns

Pattern	Meaning	Drugs	Dosing consequence
Concentration-dependent killing	Killing increases with peak concentration; a marked post-antibiotic effect persists after levels fall	Aminoglycosides, fluoroquinolones, metronidazole	Once-daily large dose — a high peak for efficacy and a low trough for safety
Time-dependent killing	Killing depends on the time the concentration stays above the MIC; little post-antibiotic effect	Beta-lactams, vancomycin, clindamycin	Frequent dosing or continuous infusion; raising the dose adds little

MIC (minimum inhibitory concentration) — the lowest concentration preventing visible growth; MBC (minimum bactericidal concentration) — the lowest killing 99.9%
Once-daily aminoglycoside dosing follows directly from the pharmacodynamics — efficacy tracks the peak, toxicity tracks the trough, so one large dose is both more effective and less toxic than three small ones

CLINICAL PEARL

Whether a drug is bactericidal or bacteriostatic matters far less than students are led to believe. For most infections in an immunocompetent host the two perform equally, because host defences finish the job. The distinction becomes genuinely important only where those defences cannot reach or do not work — endocarditis, meningitis, osteomyelitis and neutropenia — where a bactericidal drug is required.

Combination Therapy

Justification	Example
To achieve synergy	Penicillin with an aminoglycoside in enterococcal endocarditis — the penicillin damages the wall and lets the aminoglycoside in; trimethoprim with sulphamethoxazole (sequential blockade of folate)
To prevent resistance	Tuberculosis, leprosy, HIV — the probability of simultaneous resistance to several drugs is the product of the individual probabilities, so combination makes it vanishingly small
To cover polymicrobial infection	Intra-abdominal sepsis, aspiration pneumonia, diabetic foot
Empirical therapy in severe illness	Febrile neutropenia, septic shock, meningitis — before the organism is known
To reduce toxicity	Lower doses of each; less relevant in practice

Disadvantages of combination — cost, added toxicity, superinfection, selection of resistance, and antagonism
Classical antagonism — a bacteriostatic drug given with a bactericidal one may reduce killing, because beta-lactams need actively dividing organisms; the historical example is tetracycline reducing the efficacy of penicillin in pneumococcal meningitis

Choosing and Monitoring Therapy

Take cultures before the first dose wherever possible — a single dose can render blood cultures sterile and leave the patient without a diagnosis for the rest of the illness
Start empirically in serious infection, guided by the likely organisms at that site and by local resistance patterns; then DE-escalate to a narrow-spectrum agent when the culture is back
Consider host factors — age, renal and hepatic function, pregnancy and lactation, allergy, immune status, G6PD deficiency, and the site of infection (does the drug penetrate cerebrospinal fluid, bone, prostate, abscess?)
An abscess must be drained; antibiotics penetrate pus poorly, and the acidic anaerobic environment inactivates aminoglycosides. Source control outranks drug choice
Duration should be defined at the start; shorter courses are as effective as longer ones for most common infections, and cause less resistance

Failure of Antimicrobial Therapy

Reason	Explanation
Wrong diagnosis	The illness is viral, or is not infective at all — malignancy, connective tissue disease, drug fever
Wrong organism assumed	Empirical choice did not cover the actual pathogen
Resistance	Pre-existing or emerging during treatment
The drug does not reach the site	Abscess, empyema, prosthetic material, biofilm, CSF, prostate, bone, eye
Inadequate dose or duration	Under-dosing in obesity, or stopping early
Poor adherence	The commonest reason in outpatient practice; cost, side effects and complexity all contribute
Impaired absorption	Chelation with antacids or iron; vomiting; malabsorption
Host factors	Neutropenia, HIV, diabetes, foreign body, obstruction — no antibiotic succeeds against an undrained collection or an obstructed system
Superinfection	A new organism causing continued fever

Before escalating an antibiotic, ask whether the problem is the drug at all — in practice, source control and diagnosis are more often the answer than a broader agent

Adverse Effects Common to Antimicrobials

Category	Examples
Hypersensitivity	Penicillins (anaphylaxis), sulphonamides (Stevens–Johnson syndrome)
Direct toxicity	Aminoglycosides (ototoxic and nephrotoxic), chloramphenicol (marrow aplasia), tetracyclines (teeth and bone)
Superinfection	Suppression of normal flora allows overgrowth — oral and vaginal candida, and clostridioides difficile colitis, classically after clindamycin, cephalosporins and fluoroquinolones
Nutritional	Suppression of gut flora reduces vitamin K and B synthesis
Masking of infection	Partial treatment obscures the diagnosis, as in partially treated meningitis
Jarisch–herxheimer reaction	Fever, rigors and worsening after the first dose in syphilis, leptospirosis and relapsing fever — from massive release of antigen as organisms are killed; not an allergy

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