Macrolides, Tetracyclines & Chloramphenicol
Pharmacology · Antimicrobials · lean revision notes
Macrolides, Tetracyclines & Chloramphenicol
These three classes are the classic bacteriostatic protein-synthesis inhibitors of the pharmacology paper. They share a common theme — interference with bacterial ribosomes — yet each targets a distinct step, carries signature toxicities, and answers a predictable cluster of NEET PG questions. Master the site of action, the signature adverse effect, and the drug of choice indications, and most stems become one-liners.
Where they act: the ribosome roadmap
Bacterial ribosome = 70S (= 50S large subunit + 30S small subunit). Protein synthesis inhibitors are split by the subunit they bind.
| Subunit | Drugs | Step inhibited | Cidal/Static |
|---|---|---|---|
| 30S | Aminoglycosides, Tetracyclines | Tetracyclines block aminoacyl-tRNA binding to A-site | Tetra = static; AG = cidal |
| 50S | Macrolides, Chloramphenicol, Clindamycin, Linezolid, Streptogramins | Translocation / peptidyl transferase | Mostly static |
High-yield: Mnemonic for 30S inhibitors = "At 30, buy AT" (Aminoglycoside, Tetracycline). Everything else acts on 50S. Among 30S binders, aminoglycosides are bactericidal while tetracyclines are bacteriostatic — a frequently flipped option.
Flow of where each one hits the 50S/30S: Tetracycline → 30S A-site (blocks aminoacyl-tRNA) → Macrolide → 50S, blocks translocation (P→E site movement) → Chloramphenicol → 50S, inhibits peptidyl transferase (blocks peptide bond formation).
Macrolides
Members & classification
- Erythromycin — prototype (14-membered ring).
- Clarithromycin — 14-membered.
- Azithromycin — 15-membered (an azalide); the exam favourite.
- Roxithromycin, Fidaxomicin (narrow-spectrum, for C. difficile), Telithromycin (a ketolide).
Mechanism
Bind reversibly to the 50S subunit (23S rRNA of the peptidyl transferase centre) → block translocation of peptidyl-tRNA from the A-site to the P-site → chain elongation stalls. Predominantly bacteriostatic.
High-yield: Macrolides, clindamycin and chloramphenicol all bind the 50S near the same site → they compete and are antagonistic if combined. This overlapping binding also underlies MLS_B resistance (Macrolide–Lincosamide–Streptogramin B) via erm-gene methylation of 23S rRNA.
Spectrum / clinical uses
- Atypical respiratory pathogens — Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella, Chlamydia trachomatis.
- Pertussis (Bordetella pertussis) — azithromycin is DOC.
- Diphtheria carrier state / when penicillin allergic — erythromycin.
- Campylobacter enteritis — azithromycin DOC.
- Atypical mycobacteria (MAC) — clarithromycin/azithromycin (prophylaxis & treatment).
- H. pylori triple therapy — clarithromycin.
- Penicillin-allergic patients with strep pharyngitis, mild pneumonia, syphilis (azithromycin alt).
- Gastroparesis / prokinetic — erythromycin is a motilin receptor agonist (low dose).
High-yield: Azithromycin has a huge volume of distribution and concentrates intracellularly / in tissues (released slowly) → very long half-life (~68 h) → allows the famous single-dose or 3-day regimens (e.g. single-dose for chlamydial urethritis, chancroid, trachoma). It is NOT cleared renally — eliminated mainly in bile/faeces → no dose adjustment in renal failure.
Pharmacokinetics & interactions
- Erythromycin & clarithromycin are potent CYP3A4 inhibitors → ↑ levels of warfarin, theophylline, carbamazepine, statins, ergot, cyclosporine.
- Azithromycin does NOT inhibit CYP3A4 → fewer interactions (exam discriminator).
- Erythromycin estolate salt is the most hepatotoxic form.
Adverse effects
- GI intolerance — erythromycin is a motilin agonist → cramps, diarrhoea (commonest reason for non-compliance).
- Cholestatic hepatitis — esp. erythromycin estolate.
- QT prolongation / torsades — class effect (erythromycin > clarithromycin > azithromycin), worse with CYP inhibition.
- Reversible ototoxicity at high IV doses.
- Infantile hypertrophic pyloric stenosis — erythromycin in neonates.
High-yield: Erythromycin given to a neonate → risk of hypertrophic pyloric stenosis. Erythromycin used as a prokinetic in gastroparesis = motilin receptor agonism. Both are classic single-best-answer facts.
Tetracyclines
Members & classification
| Generation / Group | Drugs | Notable feature |
|---|---|---|
| Short-acting | Tetracycline, Oxytetracycline | t½ ~6–8 h |
| Intermediate | Demeclocycline | causes nephrogenic DI → used for SIADH |
| Long-acting | Doxycycline, Minocycline | t½ ~16–18 h; doxy is the workhorse |
| Glycylcycline | Tigecycline | active vs MRSA, VRE, ESBL; not for bloodstream/UTI |
Mechanism
Enter the bacterium by active transport (energy-dependent), then bind the 30S subunit → block binding of aminoacyl-tRNA to the A-site → no new amino acids added → bacteriostatic.
High-yield: Selective toxicity comes from active uptake into bacteria (not human cells). Resistance is chiefly by efflux pumps and ribosomal protection proteins — and resistance is largely cross-class within tetracyclines (tigecycline often escapes efflux).
Spectrum / clinical uses (very broad — "the rickettsia/atypical drug")
- Rickettsial diseases — scrub typhus, Rocky Mountain spotted fever, Q fever → doxycycline is DOC, even in children & pregnancy when life-threatening.
- Scrub typhus — doxycycline DOC.
- Brucellosis — doxycycline + rifampicin/streptomycin.
- Cholera — doxycycline (adjunct to rehydration).
- Chlamydia, Mycoplasma, Ureaplasma, atypical pneumonia.
- Lyme disease — doxycycline DOC.
- Plague, tularaemia, anthrax prophylaxis.
- Acne vulgaris — doxy/minocycline (anti-inflammatory + anti-P. acnes).
- Leptospirosis prophylaxis (doxycycline weekly).
- Malaria prophylaxis — doxycycline (and partner in treatment).
- H. pylori quadruple therapy.
- SIADH — demeclocycline (induces nephrogenic DI).
High-yield: Doxycycline = DOC for scrub typhus, Lyme disease, rickettsiae, and (with rifampicin) brucellosis. Remember "rickettsia, relapsing, rat-bite, brucella, cholera, chlamydia" tetracycline territory.
Pharmacokinetics — the chelation rule
- Chelate divalent/trivalent cations (Ca²⁺, Mg²⁺, Al³⁺, Fe²⁺) → absorption ↓↓ with milk, antacids, iron, sucralfate.
- Doxycycline & minocycline absorption is least affected by food and they are safe in renal failure (eliminated by gut, not kidney) — doxy is the tetracycline of choice in renal impairment.
High-yield: All tetracyclines are nephrotoxic in renal failure (anti-anabolic, worsen azotaemia) EXCEPT doxycycline, which is the safe choice. Outdated/expired tetracycline → Fanconi-like syndrome (proximal renal tubular damage) — a classic toxicology MCQ.
Adverse effects (signature)
- Teeth & bone deposition — chelate Ca²⁺ in growing teeth/bone → permanent yellow-brown discolouration of teeth, enamel hypoplasia, depressed bone growth. → Contraindicated in pregnancy, lactation, and children < 8 years.
- Hepatotoxicity — acute fatty liver, esp. high IV doses in pregnancy.
- Phototoxicity / photosensitivity — exaggerated sunburn (demeclocycline, doxycycline).
- Oesophagitis / oesophageal ulcers — take with water, stay upright (doxycycline).
- Vestibular toxicity — minocycline (dizziness, vertigo); minocycline also → blue-black pigmentation of skin/sclera/thyroid.
- Benign intracranial hypertension (pseudotumour cerebri) — esp. in children.
- Fanconi syndrome with expired drug.
High-yield: Tetracyclines in a 5-year-old → permanent tooth staining → contraindicated < 8 years. The "developing teeth and bone" answer is repeatedly tested.
Mnemonic for tetracycline toxicity — "TETRA": Teeth discolouration, Enteric upset/oEsophagitis, Teratogenic/hepatotoxic in pregnancy, Renal (Fanconi with expired drug), Azotaemia + phototoxicity.
Chloramphenicol
Mechanism
Binds 50S subunit → inhibits peptidyl transferase → blocks peptide bond formation. Bacteriostatic (cidal vs H. influenzae, N. meningitidis, S. pneumoniae). Broad-spectrum (Gram +/−, anaerobes, rickettsiae).
High-yield: Chloramphenicol = the classic peptidyl transferase inhibitor. It can also inhibit human mitochondrial ribosomes (which resemble 70S) → explains its dose-dependent bone marrow suppression.
Clinical uses (now reserved — toxicity limits it)
- Bacterial meningitis in penicillin-allergic / resource-limited settings.
- Typhoid fever — historically DOC (now ceftriaxone/azithro/fluoroquinolones preferred); still asked.
- Rickettsial disease in pregnancy/young children when doxycycline is unsuitable.
- Anaerobic infections, brain abscess (good CNS/CSF penetration even without inflamed meninges).
- Topical — bacterial conjunctivitis (eye drops/ointment).
Adverse effects (the two classic marrow + neonatal hits)
| Toxicity | Mechanism | Features |
|---|---|---|
| Dose-dependent marrow suppression | Inhibits mitochondrial protein synthesis (ferrochelatase) | Reversible anaemia, ↓retics, ↑serum iron; resolves on stopping |
| Idiosyncratic aplastic anaemia | Not dose-related, often after therapy ends; possibly via nitroso metabolite | Irreversible, frequently fatal; ~1:25,000–40,000 |
| Grey baby syndrome | Neonatal deficiency of UDP-glucuronyl transferase + immature renal excretion → drug accumulates | Vomiting, ashen-grey cyanosis, hypotension, abdominal distension, vasomotor collapse |
High-yield: Grey baby syndrome mechanism = neonate cannot glucuronidate chloramphenicol (immature hepatic conjugation) and has poor renal excretion → accumulation → circulatory collapse. This exact mechanism is a repeat NEET PG question. Distinguish the two marrow effects: dose-dependent (reversible) vs idiosyncratic aplastic anaemia (dose-independent, irreversible).
- Inhibits CYP enzymes → ↑ warfarin, phenytoin, sulfonylureas, tolbutamide.
- Gray syndrome can also occur in adults given massive doses.
Putting them side by side
| Feature | Macrolides | Tetracyclines | Chloramphenicol |
|---|---|---|---|
| Ribosomal target | 50S (23S rRNA), translocation | 30S, A-site aminoacyl-tRNA | 50S, peptidyl transferase |
| Cidal/Static | Static | Static | Static (cidal vs HiB/meningo/pneumo) |
| Star drug | Azithromycin | Doxycycline | (reserved) |
| Renal-safe member | Azithromycin (biliary) | Doxycycline | needs care |
| CYP3A4 inhibition | Erythro/clarithro (azithro no) | No | Yes |
| Signature toxicity | QT prolongation, GI, pyloric stenosis (neonate) | Teeth/bone deposition, Fanconi (expired) | Aplastic anaemia, grey baby |
| Key CI | — | Pregnancy, <8 yrs | Neonates |
| Pregnancy | Azithro/erythro (NOT estolate) — relatively safe | Contraindicated | Avoid near term |
Pregnancy-safe quick recall: Macrolides (erythromycin base/azithromycin) are among "safe" antibiotics in pregnancy; tetracyclines and chloramphenicol are not.
Key differentials & "which drug" discriminators
- Atypical pneumonia (Mycoplasma/Chlamydophila/Legionella) → macrolide or doxycycline (both cover); add for Legionella → macrolide/fluoroquinolone.
- Scrub typhus / rickettsiae → doxycycline (not macrolide as first line; azithro is the pregnancy alternative for scrub typhus).
- Whooping cough / pertussis → azithromycin.
- Acne → doxycycline/minocycline.
- SIADH → demeclocycline.
- Gastroparesis prokinetic → erythromycin (motilin agonist).
- Antibiotic-associated diarrhoea / C. difficile → fidaxomicin (a macrolide) or oral vancomycin.
High-yield: When the stem says "single dose" for an STI (chlamydia, chancroid) or trachoma → azithromycin. When it says "weekly prophylaxis in flood/leptospirosis" → doxycycline.
Recently asked / exam angle
- Site of action match — Tetracycline → 30S A-site; Macrolide → 50S translocation; Chloramphenicol → 50S peptidyl transferase. (Pairing/assertion-reason format.)
- Grey baby syndrome mechanism — deficient glucuronyl transferase + poor renal excretion in neonates. Repeatedly asked as a mechanism question, not just recognition.
- Tetracycline contraindication in children < 8 yrs — teeth and bone deposition (chelation of calcium).
- Azithromycin tissue/intracellular concentration advantage + long half-life enabling short courses; biliary (not renal) elimination.
- Erythromycin = motilin agonist (prokinetic) and neonatal pyloric stenosis risk.
- Demeclocycline → nephrogenic DI → SIADH treatment.
- Expired tetracycline → Fanconi syndrome.
- Chloramphenicol — two distinct bone marrow effects (dose-dependent reversible vs idiosyncratic irreversible aplastic anaemia).
- Drug interaction angle — clarithromycin/erythromycin inhibit CYP3A4 (statin myopathy, raised warfarin INR); azithromycin spares CYP.
- Doxycycline DOC for scrub typhus, Lyme, brucellosis (with rifampicin), cholera, and as the renal-safe tetracycline.
- MLS_B resistance by erm methylase explaining macrolide–lincosamide–streptogramin cross-resistance and the D-test for inducible clindamycin resistance.
- Tigecycline — glycylcycline, covers MRSA/VRE/ESBL but poor blood & urine levels (not for bacteraemia/UTI).
Rapid revision
- 30S = Aminoglycosides + Tetracyclines; everything else = 50S. Only aminoglycosides among these are bactericidal.
- Tetracycline blocks aminoacyl-tRNA at the A-site (30S); chloramphenicol blocks peptidyl transferase; macrolides block translocation (both 50S).
- Macrolides, clindamycin, chloramphenicol bind overlapping 50S sites → mutually antagonistic.
- Azithromycin = huge Vd, intracellular concentration, long t½ (single-dose regimens), biliary elimination, no CYP3A4 inhibition.
- Erythromycin/clarithromycin inhibit CYP3A4 → statin myopathy, ↑warfarin, ↑theophylline.
- Erythromycin is a motilin agonist (gastroparesis) and causes neonatal pyloric stenosis; QT prolongation is a class effect.
- Doxycycline = DOC for scrub typhus, rickettsiae, Lyme, cholera, brucellosis (+rifampicin); the only renal-safe tetracycline.
- Tetracyclines chelate Ca/Mg/Al/Fe → avoid milk, antacids, iron; cause tooth/bone deposition → contraindicated in pregnancy, lactation and children < 8 yrs.
- Demeclocycline → nephrogenic DI → treats SIADH; minocycline → vestibular toxicity + blue-black pigmentation; expired tetracycline → Fanconi syndrome.
- Chloramphenicol = peptidyl transferase inhibitor; dose-dependent reversible marrow suppression vs idiosyncratic irreversible aplastic anaemia.
- Grey baby syndrome = deficient neonatal glucuronyl transferase + immature renal excretion → drug accumulates → ashen-grey, vasomotor collapse.
- Tigecycline (glycylcycline) covers MRSA/VRE/ESBL but is useless for bloodstream or urinary infections (low serum/urine levels).