Antimicrobial Pharmacology & Resistance Patterns
1. What this chapter covers, and how NEET PG actually tests it
Antimicrobials look like the largest memorisation task in pharmacology, because there are so many drugs.
There are only five targets, and everything about a drug follows from which one it hits.
The target determines the spectrum, because an organism lacking the target is intrinsically resistant.
It determines the resistance mechanism, because bacteria evolve by protecting or altering that specific target.
And it often determines the toxicity, because human cells sometimes carry something structurally similar.
| Target | Drug classes | Consequence of the target |
|---|---|---|
| Cell wall | Beta-lactams, glycopeptides | Useless against organisms with no wall |
| 30S ribosome | Aminoglycosides, tetracyclines | Selective toxicity from ribosomal difference |
| 50S ribosome | Macrolides, clindamycin, chloramphenicol, linezolid | Mostly bacteriostatic |
| Nucleic acid | Fluoroquinolones, rifampicin, metronidazole | Rapid single-step resistance for some |
| Folate synthesis | Sulphonamides, trimethoprim | Humans absorb folate and so are spared |
1.1 Two properties that decide how a drug is dosed
Before the individual drugs, two classifications determine how any antibiotic is used.
Bactericidal agents kill; bacteriostatic agents only halt growth and rely on the host immune system to clear the organism.
That distinction matters clinically in exactly the situations where the immune system cannot help: endocarditis, meningitis, neutropenia and osteomyelitis all require bactericidal therapy.
Beta-lactams, glycopeptides, aminoglycosides, fluoroquinolones, metronidazole and rifampicin are bactericidal; macrolides, tetracyclines, clindamycin, chloramphenicol and sulphonamides are bacteriostatic.
The second classification concerns what drives killing.
Concentration-dependent killing means a high peak matters most, which favours large infrequent doses; aminoglycosides and fluoroquinolones behave this way.
Time-dependent killing means the time spent above the minimum inhibitory concentration matters most, which favours frequent dosing or continuous infusion; beta-lactams and vancomycin behave this way.
This is why aminoglycosides are given once daily while penicillins are given four to six times a day, and it is a mechanistic answer rather than a convention.
The post-antibiotic effect, in which suppression persists after the drug has fallen below the inhibitory concentration, is what makes once-daily aminoglycoside dosing safe.
2. Cell wall agents
2.1 The beta-lactams
All beta-lactams bind penicillin-binding proteins and block peptidoglycan cross-linking, so all are bactericidal and all fail against organisms without a cell wall.
That single fact explains why mycoplasma, which has no cell wall, is intrinsically resistant to every beta-lactam, and why a macrolide is used instead.
| Generation or class | Key coverage |
|---|---|
| Natural penicillin | Streptococci, syphilis, meningococcus |
| Aminopenicillin | Adds some Gram-negative coverage |
| Antipseudomonal penicillin | Piperacillin with tazobactam |
| First-generation cephalosporin | Skin organisms, surgical prophylaxis |
| Third-generation cephalosporin | Good central nervous system penetration |
| Fourth and fifth generation | Cefepime for pseudomonas, ceftaroline for MRSA |
| Carbapenem | Broadest; reserved for resistant Gram-negatives |
Ceftriaxone crosses into cerebrospinal fluid well and is central to bacterial meningitis treatment.
Cephalosporins do not cover enterococci, listeria or MRSA, with the fifth-generation agents as the MRSA exception, and this gap is why ampicillin is added in listeria-risk meningitis.
Aztreonam is the monobactam that is safe in severe penicillin allergy because it lacks the cross-reacting side chain.
Penicillin allergy itself is heavily over-reported, and the cross-reactivity with cephalosporins is far lower than the traditionally quoted figure, particularly for later generations whose side chains differ.
That matters because a mislabelled allergy pushes patients onto broader, more toxic and less effective alternatives for the rest of their lives.
Imipenem is combined with cilastatin, which inhibits renal dehydropeptidase and prevents the drug being degraded in the tubule; meropenem needs no such partner.
Carbapenems lower the seizure threshold, imipenem most of all, which is why meropenem is preferred in central nervous system infection.
2.2 Beta-lactam resistance and the glycopeptides
Resistance to beta-lactams occurs by three routes: beta-lactamase production, altered penicillin-binding proteins, and reduced permeability.
MRSA is resistant through an altered penicillin-binding protein, PBP2a, encoded by mecA, which is why adding a beta-lactamase inhibitor does not help — there is no enzyme to inhibit.
Extended-spectrum beta-lactamases hydrolyse third-generation cephalosporins, and carbapenems are the usual response.
Carbapenemase-producing organisms defeat even those, leaving colistin, tigecycline and newer combinations.
Vancomycin binds the D-alanyl-D-alanine terminus of the peptidoglycan precursor rather than an enzyme, which is why beta-lactamases do not affect it.
Vancomycin resistance in enterococci arises from substituting D-alanyl-D-lactate, removing the binding site altogether.
Rapid vancomycin infusion causes red man syndrome, which is direct histamine release rather than allergy and is managed by slowing the infusion.
3. Protein synthesis inhibitors
3.1 The 30S agents
Aminoglycosides are bactericidal, concentration-dependent, and require oxygen for uptake, which is why they are ineffective against anaerobes.
Their concentration-dependent killing and post-antibiotic effect are why once-daily dosing is both effective and less toxic than divided dosing, since toxicity relates to trough exposure.
They are nephrotoxic and ototoxic, and both risks rise with duration and with concurrent loop diuretics or cisplatin.
Tetracyclines are bacteriostatic, chelate divalent cations so absorption falls with milk, antacids and iron, and deposit in growing teeth and bone.
Doxycycline is the exception that is safe in renal impairment because it is cleared hepatically, and it is the drug of choice for rickettsial infection including scrub typhus.
Tigecycline is a tetracycline derivative retaining activity against many resistant organisms, but it achieves poor blood levels and is therefore unsuitable for bacteraemia.
3.2 The 50S agents
Macrolides inhibit translocation, cover atypical organisms, and prolong the QT interval.
Erythromycin and clarithromycin are potent cytochrome P450 inhibitors; azithromycin is not, which is why azithromycin is preferred when interactions matter.
Clindamycin covers anaerobes above the diaphragm and is strongly associated with Clostridioides difficile colitis.
Chloramphenicol causes dose-related reversible marrow suppression and an idiosyncratic irreversible aplastic anaemia, and grey baby syndrome in neonates from immature glucuronidation.
Linezolid is a reserve agent for resistant Gram-positive infection, causing thrombocytopenia, optic and peripheral neuropathy, and serotonin syndrome with serotonergic drugs because it weakly inhibits monoamine oxidase.
4. Nucleic acid and folate agents
4.1 Fluoroquinolones and others
Fluoroquinolones inhibit DNA gyrase and topoisomerase IV, and are bactericidal with excellent oral bioavailability.
Their adverse effects are distinctive: tendon rupture, QT prolongation, dysglycaemia, aortic aneurysm risk, and central nervous system effects, with cartilage concerns limiting paediatric use.
Absorption falls sharply with divalent cations, so they must be separated from antacids and iron.
Rifampicin inhibits bacterial RNA polymerase, induces cytochrome P450 powerfully, colours secretions orange, and develops resistance rapidly if used alone.
Metronidazole is activated only in anaerobic conditions, which is exactly why its spectrum is restricted to anaerobes and certain protozoa, and it causes a disulfiram-like reaction with alcohol.
Nitrofurantoin concentrates in urine and is used for lower urinary tract infection only, since it achieves no useful tissue levels.
4.2 Folate inhibitors
Sulphonamides block dihydropteroate synthase and trimethoprim blocks dihydrofolate reductase, so the combination blocks sequential steps in the same pathway.
Humans are spared because we absorb preformed folate rather than synthesising it, which is the clearest example of selective toxicity in the whole subject.
Co-trimoxazole causes hyperkalaemia, rash including Stevens-Johnson syndrome, marrow suppression and a rise in creatinine that reflects blocked tubular secretion rather than true renal impairment.
It remains the treatment and prophylaxis of choice for Pneumocystis jirovecii pneumonia.
Trimethoprim alone is also used for uncomplicated urinary infection, and its structural resemblance to potassium-sparing diuretics is what produces the hyperkalaemia.
Sulphonamides displace bilirubin from albumin, which is why they are avoided in neonates, where the freed bilirubin can cross into the brain and cause kernicterus.
The same displacement mechanism explains their interaction with warfarin, whose free fraction rises when it is displaced from albumin.
4.3 Antimalarials and antiparasitics
Malaria pharmacology carries disproportionate weight in an Indian examination and is organised by parasite stage.
Chloroquine acts on the erythrocytic stage by preventing polymerisation of toxic haem into haemozoin, so the parasite is killed by its own digestion products.
Primaquine is the only agent acting on the hepatic hypnozoite stage, which is why it alone prevents relapse in vivax and ovale malaria, and why glucose-6-phosphate dehydrogenase status must be checked before giving it.
Artemisinins act fastest of all antimalarials and are always given in combination to protect against resistance, with artesunate the treatment of choice in severe falciparum malaria.
| Antiparasitic | Principal use |
|---|---|
| Albendazole, mebendazole | Most intestinal nematodes |
| Ivermectin | Strongyloides, onchocerciasis, scabies |
| Diethylcarbamazine | Lymphatic filariasis |
| Praziquantel | Trematodes and most cestodes |
| Metronidazole | Amoebiasis, giardiasis, trichomoniasis |
Diethylcarbamazine is avoided in onchocerciasis because rapid microfilarial killing near the eye can precipitate blindness, and ivermectin is used instead.
Amoebic liver abscess needs metronidazole followed by a luminal agent such as diloxanide, because metronidazole does not reliably clear cysts from the bowel lumen.
5. Tuberculosis, fungi and viruses
5.1 Antitubercular therapy
| Drug | Adverse effect | Note |
|---|---|---|
| Isoniazid | Peripheral neuropathy, hepatitis | Give pyridoxine |
| Rifampicin | Hepatitis, orange secretions | Potent enzyme inducer |
| Pyrazinamide | Hyperuricaemia, hepatitis | Most hepatotoxic |
| Ethambutol | Optic neuritis with red-green loss | Dose-related |
| Streptomycin | Ototoxicity, nephrotoxicity | Now rarely used |
Isoniazid neuropathy occurs because the drug interferes with pyridoxine metabolism, which is why pyridoxine is co-prescribed rather than merely offered.
Combination therapy is used because single-drug resistance emerges rapidly through spontaneous mutation, and multiple simultaneous mutations are vastly less likely.
Drug-resistant tuberculosis treatment in India has changed substantially: the six-month BPaLM regimen — bedaquiline, pretomanid, linezolid and moxifloxacin — has been approved under the National TB Elimination Programme, replacing regimens that previously ran up to twenty months.
Bedaquiline inhibits mycobacterial ATP synthase and prolongs the QT interval, so electrocardiographic monitoring is required.
Latent tuberculosis is treated differently from active disease, and giving a single drug to someone with undiagnosed active disease is how resistance is created.
Rifampicin's enzyme induction has consequences well beyond tuberculosis: it lowers levels of oral contraceptives, warfarin, antiretrovirals and immunosuppressants, and it is the commonest examined cause of contraceptive failure.
Ethambutol's optic neuritis is dose-related and reversible if caught, which is why visual acuity and colour vision are checked at baseline and during treatment.
Pyrazinamide is the most hepatotoxic of the first-line agents, and it is also the one that shortens therapy from nine months to six, so it is retained despite that risk.
5.2 Antifungals
Amphotericin B binds ergosterol and forms membrane pores, causing infusion reactions, nephrotoxicity and potassium and magnesium wasting; liposomal formulations reduce the renal toxicity.
Azoles inhibit ergosterol synthesis at lanosterol 14-alpha-demethylase, and inhibit human cytochrome P450 as a direct consequence of that structural similarity.
Echinocandins inhibit beta-glucan synthesis in the fungal cell wall, a target absent in humans, which is why they are so well tolerated.
Flucytosine is converted to 5-fluorouracil inside the fungus and causes marrow suppression.
5.3 Antivirals
Aciclovir requires viral thymidine kinase for its first phosphorylation, which is precisely why it is selective for infected cells and why thymidine kinase mutation confers resistance.
Ganciclovir treats cytomegalovirus and causes marrow suppression; foscarnet needs no kinase activation and so works against thymidine kinase-mutant virus, but is nephrotoxic.
Oseltamivir inhibits neuraminidase and must be started within 48 hours of symptom onset to be useful.
That narrow window exists because the drug prevents release of new virions from infected cells rather than treating established tissue damage, so it only helps while viral replication is still driving the illness.
Hepatitis C is now curable with direct-acting antivirals in most cases, which was not true a decade ago and is a common source of outdated exam answers.
Antiretroviral therapy combines agents from different classes for the same reason as tuberculosis therapy, and tenofovir causes renal tubular dysfunction while zidovudine causes marrow suppression.
5.4 Resistance mechanisms and stewardship
Resistance arises through a small number of strategies, and every named resistant organism uses one of them.
| Strategy | Example |
|---|---|
| Enzymatic destruction | Beta-lactamases, ESBL, carbapenemase |
| Target alteration | MRSA PBP2a, VRE D-alanyl-D-lactate |
| Reduced permeability | Porin loss in Gram-negatives |
| Efflux pumps | Tetracycline and fluoroquinolone resistance |
| Bypass pathway | Acquiring an alternative folate enzyme |
Recognising the strategy tells you what will and will not work, which is why a beta-lactamase inhibitor rescues an ESBL producer's susceptibility to some agents but does nothing for MRSA.
Resistance is transferred between organisms by plasmids, transposons and integrons, so it spreads far faster than mutation alone would allow.
Antimicrobial stewardship targets the drivers within clinical control: unnecessary prescribing for viral illness, unnecessarily broad empirical cover, excessive duration, and failure to de-escalate once cultures return.
De-escalation is the step most often omitted, and it means narrowing from empirical broad-spectrum therapy to the narrowest effective agent as soon as sensitivities are known.
India carries a particularly heavy resistance burden, driven by over-the-counter availability, incomplete courses and agricultural use, which is why the National Action Plan on Antimicrobial Resistance exists.
6. Worked examples
Example 1
A patient with community-acquired pneumonia has not responded to amoxicillin. Serology suggests Mycoplasma pneumoniae.
The failure is predictable rather than surprising once the target is considered.
Amoxicillin is a beta-lactam, and every beta-lactam works by blocking peptidoglycan cross-linking in the bacterial cell wall.
Mycoplasma has no cell wall at all, so the drug has nothing to act on and the organism is intrinsically resistant.
A macrolide or doxycycline, acting on the ribosome, is effective, and the same reasoning covers the other atypical organisms.
Example 2
A patient with MRSA bacteraemia is treated with piperacillin-tazobactam without improvement.
Tazobactam is a beta-lactamase inhibitor, so the combination defeats resistance mediated by enzyme production.
MRSA resistance is not enzymatic. The mecA gene encodes an altered penicillin-binding protein, PBP2a, with low affinity for beta-lactams.
Since there is no beta-lactamase to inhibit, adding an inhibitor achieves nothing, and the target itself has changed.
Vancomycin, which binds the peptidoglycan precursor rather than the enzyme, is effective.
Example 3
A patient on co-trimoxazole for Pneumocystis pneumonia has a creatinine rise from 80 to 105 micromol/L with normal urine output and no other abnormality.
Trimethoprim competes with creatinine for the organic cation transporter that secretes it in the proximal tubule.
Blocking that secretion raises measured serum creatinine without any change in glomerular filtration.
The rise therefore reflects altered creatinine handling rather than kidney injury, and the drug does not need to be stopped for this reason alone.
A genuine injury would be accompanied by other features, and hyperkalaemia from the same drug is a separate effect that does require attention.
7. Traps the exam sets repeatedly
Adding a beta-lactamase inhibitor for MRSA. Resistance is through an altered binding protein, not an enzyme, so there is nothing for the inhibitor to block.
Using a cephalosporin for enterococcus or listeria. Cephalosporins do not cover either, which is why ampicillin is added in listeria-risk meningitis.
Treating red man syndrome as a vancomycin allergy. It is direct histamine release and is managed by slowing the infusion, not by switching drug.
Stopping co-trimoxazole for a small creatinine rise. Trimethoprim blocks tubular creatinine secretion without reducing filtration.
Using metronidazole for aerobic infection. It requires anaerobic conditions to be activated at all.
Choosing a bacteriostatic agent for endocarditis or meningitis. Those are precisely the sites where host immunity cannot finish the job, so bactericidal therapy is required.
Giving primaquine without checking G6PD status. It is the only agent clearing hypnozoites, but it causes severe haemolysis in deficiency.
Treating an amoebic liver abscess with metronidazole alone. A luminal agent is still needed, because metronidazole does not reliably clear intestinal cysts.
Summary
There are only five antimicrobial targets, and spectrum, resistance and toxicity all follow from which one a drug hits.
Beta-lactams block cell wall cross-linking, so organisms without a wall are intrinsically resistant.
MRSA resistance is an altered penicillin-binding protein, so beta-lactamase inhibitors are useless against it.
Vancomycin binds the peptidoglycan precursor rather than an enzyme, and resistance substitutes the binding terminus.
Aminoglycosides need oxygen for uptake, are concentration-dependent, and are dosed once daily to reduce trough-related toxicity.
Macrolides cover atypicals and prolong QT, and azithromycin is the one that does not inhibit cytochrome P450 significantly.
Metronidazole is activated only anaerobically, which defines its entire spectrum.
Folate inhibitors are selective because humans absorb folate rather than making it.
Tuberculosis is treated in combination because single-drug resistance emerges rapidly, and drug-resistant disease in India now uses the six-month BPaLM regimen.
Aciclovir depends on viral thymidine kinase for activation, which is both the basis of its selectivity and the route to resistance.
Bactericidal therapy is mandatory where host immunity cannot assist: endocarditis, meningitis, neutropenia and osteomyelitis.
Concentration-dependent killing favours large infrequent doses; time-dependent killing favours frequent dosing, which is why aminoglycoside and penicillin schedules differ so sharply.
Primaquine alone clears hepatic hypnozoites and therefore alone prevents relapse, but requires G6PD testing first.
Resistance uses a small number of strategies, and identifying which one an organism uses predicts what treatment will work.
