Aminoglycosides

Aminoglycosides are bactericidal antibiotics that bind the 30S ribosomal subunit, cause mRNA misreading, and kill chiefly aerobic gram-negative bacilli. They are concentration-dependent killers with a post-antibiotic effect, hence the modern once-daily dosing. Their fame in exams rests on two toxicities — nephrotoxicity (reversible) and ototoxicity (irreversible) — and their synergy with beta-lactams.

Members and classification

The clinically relevant aminoglycosides are products or semi-synthetic derivatives of Streptomyces and Micromonospora species. A quick spelling clue: drugs from Streptomyces end in "-mycin" (streptomycin, neomycin, tobramycin, kanamycin), whereas those from Micromonospora end in "-micin" (gentamicin, sisomicin, netilmicin). Amikacin is a semisynthetic derivative of kanamycin.

Drug	Source / origin	Principal clinical use
Gentamicin	Micromonospora purpurea	First-line gram-negative cover; endocarditis synergy
Amikacin	Semisynthetic (from kanamycin)	Gentamicin-resistant organisms; broadest, most resistant to inactivating enzymes
Tobramycin	Streptomyces tenebrarius	Pseudomonas (esp. cystic fibrosis); inhaled/ophthalmic
Streptomycin	Streptomyces griseus	Second-line anti-TB; plague, tularaemia, brucellosis
Neomycin	Streptomyces fradiae	Topical; oral bowel prep (hepatic encephalopathy) — too toxic systemically
Netilmicin	Semisynthetic	Least ototoxic of the group
Paromomycin	Streptomyces	Intestinal amoebiasis, Cryptosporidium, leishmaniasis
Spectinomycin	Streptomyces	An aminocyclitol (not a true aminoglycoside) — gonorrhoea

High-yield: Amikacin is the most resistant to bacterial aminoglycoside-inactivating enzymes (it has only one site vulnerable to acetylation), so it is the agent of choice when gentamicin/tobramycin resistance is suspected.

Mechanism of action

Aminoglycosides are highly polar polycationic molecules. Their bactericidal action is a multistep process:

1. Passive diffusion through porins across the outer membrane → 2. Oxygen-dependent active transport across the cytoplasmic membrane (the energy-dependent phase, requires a transmembrane electrochemical gradient) → 3. Irreversible binding to the 30S subunit (specifically the 16S rRNA of the aminoacyl site) → 4. Three downstream effects: (a) blockade of formation of the initiation complex, (b) misreading of the mRNA codon causing incorporation of wrong amino acids → abnormal/non-functional proteins, (c) premature termination/breakup of polysomes → 5. Damaged membrane proteins enhance further drug uptake → cell death.

High-yield: The transport step is oxygen-dependent. This explains why aminoglycosides are inactive against anaerobes, ineffective in abscesses (low O₂, low pH), and antagonised by an acidic/hypoxic environment.

Aminoglycosides are unusual among protein-synthesis inhibitors in being bactericidal (most 30S/50S inhibitors such as tetracyclines, macrolides, clindamycin and chloramphenicol are bacteriostatic). This is attributed to irreversible binding and membrane damage.

High-yield: Mnemonic for the 30S inhibitors = "AT 30" — Aminoglycosides and Tetracyclines act at the 30S. Aminoglycosides are the bactericidal exception among ribosomal inhibitors.

Pharmacokinetics

• Absorption: Negligible oral absorption (highly polar) — must be given parenterally (IM/IV) for systemic effect. Oral neomycin/paromomycin act locally in the gut.
• Distribution: Poor penetration into CSF (even inflamed meninges), bronchial secretions, bile and prostate; do not cross into cells well. Volume of distribution approximates extracellular fluid.
• Special accumulation: Concentrate in the renal cortex and the endolymph/perilymph of the inner ear — the basis of their two signature toxicities.
• Metabolism: Not metabolised.
• Excretion: Almost entirely by glomerular filtration, unchanged. Half-life ~2–3 h with normal renal function but markedly prolonged in renal failure → dose adjustment mandatory.
• Placenta: Cross the placenta → ototoxic to the foetus (pregnancy category D); streptomycin is classically implicated in congenital deafness.

Pharmacodynamics — why once-daily dosing

Two PK/PD properties dominate dosing strategy:

Property	Meaning	Clinical consequence
Concentration-dependent killing	Killing rate rises as peak concentration rises; the higher the C_max/MIC ratio (target ≥ 8–10), the better	Favours large single daily doses to maximise peak
Post-antibiotic effect (PAE)	Bacterial suppression persists for hours after drug levels fall below MIC	Allows a drug-free trough interval without losing efficacy
Adaptive resistance	Transient down-regulation of drug uptake after first exposure	A drug-free interval lets transporters "reset" → restores killing

These combine to justify extended-interval (once-daily) dosing — e.g. gentamicin 5–7 mg/kg once daily.

High-yield — once-daily (pulse) dosing advantages: (1) higher peak → better concentration-dependent kill; (2) low trough between doses reduces nephrotoxicity (toxicity is driven by sustained drug accumulation in the renal cortex, not by the peak); (3) exploits PAE and reverses adaptive resistance; (4) cheaper, fewer levels to monitor.

Exceptions where once-daily extended-interval dosing is NOT used / used cautiously: pregnancy, extensive burns, ascites/large fluid shifts, endocarditis (synergy regimens use divided low doses), severe renal impairment, paediatric/neonatal patients, and gram-positive synergy indications.

Therapeutic drug monitoring

For traditional multiple-daily dosing, monitor:

• Peak (drawn ~30–60 min after IV dose): reflects efficacy (target gentamicin/tobramycin peak ~5–10 µg/mL; amikacin ~20–30 µg/mL).
• Trough (just before next dose): reflects accumulation/toxicity (gentamicin trough should be < 2 µg/mL; amikacin < 5–10 µg/mL). A high trough warns of impending nephro/ototoxicity.

High-yield: Trough level correlates with toxicity; peak level correlates with efficacy. With once-daily dosing, a single mid-interval level plotted on a Hartford nomogram guides the dosing interval.

Spectrum and clinical uses

Spectrum: Primarily aerobic gram-negative bacilli — E. coli, Klebsiella, Enterobacter, Proteus, Serratia, Pseudomonas aeruginosa (tobramycin most active), Acinetobacter. Limited gram-positive activity alone; ineffective against anaerobes, streptococci and intracellular organisms when used as monotherapy.

Key indications:

1. Gram-negative sepsis / serious infections — combined with a beta-lactam or carbapenem for synergy and broadened cover (febrile neutropenia, hospital-acquired pneumonia, complicated UTI, intra-abdominal sepsis).
2. Infective endocarditis — gentamicin + a cell-wall agent for synergy: enterococcal endocarditis (penicillin/ampicillin + gentamicin), and for Staphylococcus/Streptococcus in selected regimens.
3. Tuberculosis — streptomycin (second-line, injectable) and amikacin/kanamycin in MDR-TB regimens.
4. Plague & tularaemia — streptomycin is the historical drug of choice (gentamicin an alternative).
5. Brucellosis — streptomycin or gentamicin + doxycycline.
6. Cystic fibrosis — inhaled tobramycin for chronic Pseudomonas.
7. Topical / local — neomycin (skin, bowel prep, hepatic encephalopathy ammonia reduction), tobramycin/gentamicin eye drops.
8. Protozoa — paromomycin for intestinal amoebiasis and cryptosporidiosis.

High-yield — synergy: Beta-lactams damage the cell wall, which enhances aminoglycoside uptake across the membrane → true bactericidal synergy. This is the basis of penicillin + gentamicin in enterococcal endocarditis. Caution: do not mix in the same syringe/IV bag — penicillins chemically inactivate aminoglycosides in vitro (so check levels separately).

Mechanisms of resistance

Mechanism	Notes
Plasmid-mediated drug-inactivating enzymes (acetyltransferases, phosphotransferases, nucleotidyltransferases)	Most common and clinically important mechanism; amikacin least affected
Decreased uptake / altered porins	Reduced membrane transport
Altered ribosomal binding site (16S rRNA mutation)	Important for high-level streptomycin resistance
Efflux pumps	Contributes in Pseudomonas

High-yield: Enzymatic inactivation is the predominant resistance mechanism; amikacin resists most of these enzymes, making it the agent of choice for resistant gram-negatives.

Adverse effects

The two board-favourite toxicities:

Toxicity	Mechanism / site	Key features	Reversibility
Nephrotoxicity	Accumulation in proximal tubule cells (renal cortex); acute tubular necrosis	Non-oliguric rising creatinine, ↓GFR; usually after several days	Reversible (tubular cells regenerate)
Ototoxicity	Damage to hair cells of cochlea & vestibule (accumulates in endolymph)	Cochlear → tinnitus, high-frequency hearing loss; vestibular → vertigo, ataxia	Irreversible (hair cells do not regenerate)
Neuromuscular blockade	Inhibit presynaptic ACh release + block postsynaptic receptors	Apnoea, weakness — risk with myasthenia gravis, anaesthesia, hypocalcaemia	Reversed by calcium gluconate / neostigmine
Contact dermatitis	Topical neomycin	Common allergen	—

High-yield: Nephrotoxicity is reversible; ototoxicity is irreversible. This single contrast is among the most repeatedly tested aminoglycoside facts.

Organ-specific tendencies (commonly asked):

• Neomycin — most nephrotoxic (hence never given systemically).
• Streptomycin — most vestibulotoxic (vertigo, ataxia).
• Amikacin / kanamycin — more cochlear (auditory) toxicity.
• Netilmicin — least ototoxic.
• Gentamicin — both vestibular and cochlear; commonly tested as nephrotoxic.

Risk factors for toxicity: prolonged therapy (> 5–7 days), high trough levels, pre-existing renal impairment, advanced age, hypovolaemia, and concurrent nephrotoxins. Avoid combining with:

• Loop diuretics (furosemide) → additive ototoxicity.
• Vancomycin, amphotericin B, cisplatin, cyclosporine, contrast → additive nephrotoxicity.

High-yield mnemonic — "NOT" for aminoglycoside toxicity: Nephrotoxicity, Ototoxicity, Teratogenicity (+ neuromuscular blockade). Remember "Mean GNATS canNOT kill anaerobes" — Gentamicin, Neomycin, Amikacin, Tobramycin, Streptomycin; toxicities = Nephro, Oto, Teratogen; and they cannot kill anaerobes.

Contraindications and cautions

• Pregnancy — risk of foetal ototoxicity/deafness (category D); streptomycin classically.
• Myasthenia gravis — neuromuscular blockade can precipitate crisis.
• Pre-existing renal failure or deafness — relative contraindication; dose-adjust and monitor.
• Avoid with botulism, in the very elderly with borderline renal function, and during concurrent neuromuscular blocker use in anaesthesia.

Key differentials / comparisons

Aminoglycoside vs other 30S/protein-synthesis agents: Tetracyclines also bind 30S but are bacteriostatic and reversible; aminoglycosides are bactericidal and irreversible. Macrolides, clindamycin, linezolid and chloramphenicol act at the 50S subunit.

Choosing among aminoglycosides: Use gentamicin as the default for gram-negative synergy; switch to amikacin for resistant organisms; choose tobramycin for Pseudomonas (CF); reserve streptomycin for TB, plague, tularaemia, brucellosis and enterococcal endocarditis synergy; netilmicin when ototoxicity must be minimised.

Recently asked / exam angle

• "Which aminoglycoside is most resistant to inactivating enzymes?" → Amikacin.
• "Ototoxicity of aminoglycosides is — reversible or irreversible?" → Irreversible (nephrotoxicity is reversible).
• "Mechanism of action" → bind 30S, cause misreading of mRNA, bactericidal.
• "Why are aminoglycosides ineffective against anaerobes?" → oxygen-dependent uptake.
• "Rationale of once-daily dosing" → concentration-dependent killing + post-antibiotic effect + reduced trough-related nephrotoxicity.
• "Which level reflects toxicity?" → trough; efficacy → peak.
• "Drug + gentamicin in enterococcal endocarditis" → ampicillin/penicillin (synergy via enhanced uptake).
• "Most vestibulotoxic aminoglycoside" → streptomycin; "most nephrotoxic" → neomycin; "least ototoxic" → netilmicin.
• "Aminoglycoside-induced neuromuscular blockade is reversed by?" → calcium gluconate (± neostigmine).
• "Second-line injectable anti-TB aminoglycosides" → streptomycin, amikacin, kanamycin.
• Image/clinical vignette: post-op patient on gentamicin + furosemide developing tinnitus/hearing loss → additive ototoxicity.

Rapid revision

1. Bind 30S subunit → mRNA misreading + faulty initiation → bactericidal (unique among ribosomal inhibitors).
2. Uptake is oxygen-dependent → useless against anaerobes and in abscesses/acidic environments.
3. Concentration-dependent killing + post-antibiotic effect → rationale for once-daily dosing.
4. Trough = toxicity, peak = efficacy; target gentamicin trough < 2 µg/mL.
5. Nephrotoxicity is reversible; ototoxicity is irreversible.
6. Amikacin = most enzyme-resistant → drug of choice for resistant gram-negatives.
7. Neomycin = most nephrotoxic (topical/oral only); streptomycin = most vestibulotoxic; netilmicin = least ototoxic.
8. Gentamicin + ampicillin synergy in enterococcal endocarditis; never mix in same syringe (penicillin inactivates aminoglycoside).
9. Avoid with furosemide (oto-) and vancomycin/amphotericin/cisplatin (nephro-); contraindicated in myasthenia gravis and pregnancy (foetal deafness).
10. Excreted unchanged by glomerular filtration → dose-adjust in renal failure.
11. Streptomycin/amikacin = second-line injectable anti-TB; streptomycin = DOC for plague & tularaemia.
12. Neuromuscular blockade (apnoea) reversed by IV calcium gluconate.