Pharmacology chapters
Antibiotic resistance and major adverse effects
How bacteria resist antibiotics (enzymes, altered targets, reduced entry, efflux pumps), the resistant organisms that matter in Pakistan (MRSA, ESBL, carbapenem-resistant organisms, XDR typhoid, MDR-TB), how resistance spreads, antimicrobial stewardship, and a one-table summary of the major adverse effects of each antibiotic class.
- Bacteria resist antibiotics by enzymatic destruction (β-lactamases, ESBLs, carbapenemases such as NDM-1; aminoglycoside-modifying enzymes), altered targets (MRSA: mecA → PBP2a; VRE: D-Ala-D-Lac; mutated DNA gyrase in quinolone resistance), reduced entry (porin loss) and efflux pumps (tetracyclines, macrolides); resistance genes spread between bacteria mainly by plasmids through conjugation.
- Pakistan faces ESBL-producing Gram-negatives, carbapenem-resistant organisms, MRSA, MDR-TB and the XDR typhoid outbreak that began in Sindh in 2016 (resistant to ampicillin, chloramphenicol, co-trimoxazole, fluoroquinolones and third-generation cephalosporins; treated with azithromycin or carbapenems).
- Antimicrobial stewardship means the right drug, dose, route and duration, guided by culture; misuse also causes superinfection, notably C. difficile colitis (clindamycin, cephalosporins, quinolones, co-amoxiclav).
On this page
Types of resistance
- Intrinsic (natural): the organism has never been susceptible (Gram-negatives to vancomycin; anaerobes to aminoglycosides; Mycoplasma to β-lactams, as it lacks a cell wall).
- Acquired: a previously sensitive organism becomes resistant through:
- Mutation (chromosomal), selected by antibiotic exposure (rifampicin and isoniazid in TB; quinolone resistance).
- Gene transfer between bacteria:
| Mechanism | How | Notes |
|---|---|---|
| Conjugation | Direct transfer through a sex pilus, usually of plasmids (R factors) | The commonest and most important route; can cross species (Gram-negatives in the gut) |
| Transduction | Transfer by a bacteriophage | Important in staphylococci (penicillinase) |
| Transformation | Uptake of free DNA from the environment | Pneumococci, Neisseria, Haemophilus |
| Transposons | "Jumping genes" moving between plasmid and chromosome | Spread multiple resistance genes together |
Biochemical mechanisms
| Mechanism | Examples |
|---|---|
| Enzymes that destroy or modify the drug | β-lactamases (penicillinase of S. aureus), ESBLs (resist third-generation cephalosporins), carbapenemases (NDM-1, KPC, OXA-48); aminoglycoside-modifying enzymes; chloramphenicol acetyltransferase |
| Altered target | MRSA: mecA gene → PBP2a with low affinity for β-lactams; penicillin-resistant pneumococci (altered PBPs); VRE: D-Ala-D-Lac instead of D-Ala-D-Ala; quinolones: mutated DNA gyrase; rifampicin: mutated RNA polymerase (rpoB); macrolides: ribosomal methylation (erm) |
| Reduced permeability | Loss of porins in Gram-negatives (carbapenem resistance in Pseudomonas) |
| Efflux pumps | Tetracyclines, macrolides, fluoroquinolones |
| Bypass pathways | Sulphonamide and trimethoprim resistance (altered or extra folate enzymes) |
MRSA = mecA → PBP2a. VRE = D-Ala-D-Lac. ESBL = β-lactamase against third-generation cephalosporins → carbapenems.
Resistance in Pakistan
- ESBL-producing E. coli and Klebsiella are common in hospitals and the community, so third-generation cephalosporins often fail in serious Gram-negative infections.
- Carbapenem-resistant Enterobacterales (including NDM-1) limit options to drugs such as colistin and newer agents.
- MRSA is common in hospital infections.
- XDR typhoid: an outbreak of extensively drug-resistant Salmonella Typhi began in Sindh in 2016, resistant to ampicillin, chloramphenicol, co-trimoxazole, fluoroquinolones and third-generation cephalosporins. Uncomplicated cases are treated with azithromycin; severe cases with carbapenems (meropenem). Typhoid conjugate vaccine was added to the national immunisation programme in response.
- MDR-TB: resistant to at least isoniazid and rifampicin; XDR-TB adds resistance to fluoroquinolones and other second-line drugs.
Resistance rates change from year to year; check local antibiograms and the latest national guidance.
Why resistance develops and how to prevent it
Drivers: over-the-counter antibiotic sales, antibiotics for viral illnesses (colds, most diarrhoea), incomplete courses or under-dosing, poor-quality drugs, broad-spectrum empirical use without cultures, antibiotics in livestock, poor infection control and sanitation.
Antimicrobial stewardship:
- Give antibiotics only when there is a likely bacterial infection.
- Take cultures before starting where possible; de-escalate to a narrow-spectrum drug when results arrive.
- Correct drug, dose, route and duration; switch IV to oral when appropriate.
- Combination therapy where resistance emerges easily (TB, HIV).
- Infection control: hand hygiene, isolation of MRSA and CRE carriers.
- Vaccination (typhoid conjugate, pneumococcal, Hib) reduces antibiotic need.
Superinfection
Antibiotics destroy normal flora, allowing other organisms to overgrow:
- Clostridioides difficile colitis (pseudomembranous colitis): diarrhoea, fever, raised white cells, toxic megacolon. Classic culprits: clindamycin, cephalosporins, fluoroquinolones, co-amoxiclav. Treat: stop the culprit, oral vancomycin or fidaxomicin (metronidazole for mild cases where others are unavailable), fluids; isolation and hand washing with soap (spores resist alcohol gel).
- Candidiasis (oral, vaginal) after broad-spectrum antibiotics.
Major adverse effects at a glance
| Drug or class | Signature adverse effects |
|---|---|
| Penicillins | Hypersensitivity (rash to anaphylaxis), diarrhoea; amoxicillin rash in EBV; co-amoxiclav and flucloxacillin: cholestatic jaundice |
| Cephalosporins | Hypersensitivity (some cross-reactivity with penicillins), C. difficile; ceftriaxone: biliary sludge |
| Carbapenems | Seizures (imipenem), C. difficile |
| Vancomycin | Red man syndrome (fast infusion), nephrotoxicity, ototoxicity |
| Aminoglycosides | Nephrotoxicity, ototoxicity, neuromuscular blockade, teratogenic |
| Tetracyclines | Teeth and bone (children, pregnancy), photosensitivity, oesophagitis; outdated drug: Fanconi syndrome |
| Macrolides | Gut upset, QT prolongation, cholestatic hepatitis, CYP3A4 inhibition |
| Chloramphenicol | Aplastic anaemia, grey baby syndrome |
| Clindamycin | C. difficile colitis |
| Linezolid | Thrombocytopenia, optic neuropathy, serotonin syndrome |
| Fluoroquinolones | Tendon rupture, QT prolongation, seizures, neuropathy, cartilage (children), C. difficile |
| Metronidazole | Metallic taste, disulfiram-like reaction, neuropathy |
| Sulphonamides / co-trimoxazole | Stevens-Johnson syndrome, G6PD haemolysis, kernicterus, marrow suppression, hyperkalaemia (trimethoprim) |
| Nitrofurantoin | Pulmonary fibrosis, neuropathy, haemolysis |
| Polymyxins (colistin) | Nephrotoxicity, neurotoxicity |
| Isoniazid | Peripheral neuropathy (pyridoxine), hepatitis |
| Rifampicin | Orange-red secretions, hepatitis, enzyme induction |
| Pyrazinamide | Hepatotoxicity, gout (hyperuricaemia) |
| Ethambutol | Optic neuritis (red-green colour vision) |
| Streptomycin | Ototoxicity (vestibular), nephrotoxicity |
Expect: intrinsic vs acquired resistance, conjugation, transduction and transformation, β-lactamase and ESBL, MRSA (mecA, PBP2a), VRE (D-Ala-D-Lac), efflux pumps and porins, XDR typhoid and its treatment, MDR-TB definition, stewardship principles, C. difficile and its treatment, and signature adverse effects of each class.
Quick revision
- Resistance: enzymes, altered target, less entry, efflux.
- Spread: plasmids by conjugation (main), transduction (staphylococci), transformation.
- MRSA: mecA → PBP2a; vancomycin. ESBL: carbapenems. VRE: D-Ala-D-Lac.
- XDR typhoid (Sindh, 2016): azithromycin or meropenem.
- MDR-TB: isoniazid + rifampicin resistance.
- C. difficile: clindamycin and others; oral vancomycin.
- Grey baby: chloramphenicol. Red man: vancomycin. Tendons: quinolones. Disulfiram reaction: metronidazole.
Written by The House Job from standard pharmacology and microbiology references (Katzung's Basic and Clinical Pharmacology; Levinson's Review of Medical Microbiology).
FAQ
How does MRSA resist methicillin?
It carries the mecA gene, which codes for an altered penicillin-binding protein (PBP2a) that beta-lactams bind poorly.
How do resistance genes spread between bacteria?
Mainly on plasmids passed by conjugation; also by bacteriophages (transduction), uptake of free DNA (transformation) and transposons.
What is XDR typhoid?
Typhoid caused by Salmonella Typhi resistant to the older first-line drugs, fluoroquinolones and third-generation cephalosporins; an outbreak began in Sindh in 2016 and is treated with azithromycin or carbapenems.
Which antibiotics most often cause C. difficile colitis?
Clindamycin, cephalosporins, fluoroquinolones and co-amoxiclav.