For MBBS Students

1. AMINOGLYCOSIDES
DR. J.N CHATURVEDI
ASSOC. PROF. (DESIG.)
S.S. MEDICAL COLLEGE, REWA (M.P.)

2. Aminoglycosides- Origin & Structure
■ Natural/ semi-synthetic derivatives of products derived from soil actinomycetes.
■ Streptomycin was first isolated from Streptomyces griseus.
■ Gentamicin & netilmicin derived from micromonospora.
■ Tobramycin produced by streptomyces tenebrarius.
AminosugarAminocyclitol
Glycosidic linkage

3. Aminoglycosides- Agents
■ Natural:
– Streptomycin
– Gentamicin
– Tobramycin
– Kanamycin
– Sisomicin
– Paromomycin
– Neomycin
■ Semisynthetic:
– Amikacin (derived from Kanamycin)
– Netilmicin (derived from Sisomicin)

4. Aminoglycosides- Mechanism of Action
■ Diffuses through aqueous porin channel (outer membrane)
■ Transport across cytoplasmic (inner) membrane depends upon transmembrane
electrical gradient coupled to electron transport.
■ Bind to polysomes (30s subunit) and interfere with protein synthesis by:
– Interfering with formation of initiation complex.
– Incorporation of incorrect amino acid in growing polypeptide chain.
– Misreading & premature termination of mRNA translation.

5. Aminoglycosides- Antimicrobial
Spectrum
■ Aerobic gram –ve bacilli:
– E.coli
– Klebsiella
– Enterobacter
– Serratia
– Pseudomonas (Gentamicin, amikacin, tobramycin)
■ Mycobacteria (Streptomycin, Amikacin, Kanamycin)
■ Protozoa (Paromomycin)
– Leishmania spp.
– Entamoeba histolytica
– Giardia Lamblia
– Cryptosporidium Parvum
 Not active against gram +ve alone but along with cell wall active agents synergistic action against:
 Staphylococci, streptococci (incl. viridians & enterococci) & listeria.

6. Aminoglycosides- Mechanism of
Resistance
1. Production of aminoglycoside modifying enzymes. (MC)
– Amikacin is most resistant.
– Streptomycin is effective against enterococcal infection not responding to other
aminoglycosides
2. Decreased entry of antibiotics.
3. Production of low affinity bacterial ribosomes.

7. Aminoglycosides- Pharmacokinetics
■ Absorption:
– All aminoglycosides are polar polycationic compounds.
– Not absorbed via intact GI tract/ skin.
– Absorbed rapidly from intramuscular injection sites.
■ Distribution
– Do not cross lipid bilayer.
– Do not significantly binds to plasma proteins.
– Vol. of distributions roughly equals to ECF volume.
– High conc. is found in renal cortex; endolymph & perilymph of inner ear.
– Aminoglycosides given in late pregnancy may cross placenta and results in fetal
toxicity (streptomycin & tobramycin)

8. Aminoglycosides- Pharmacokinetics
■ Metabolism:
– Not significantly metabolized.
■ Excretion:
– Excreted entirely by glomerular filtration.
 PlasmaT1/2 (adults & children >6mo. with normal renal function)= 2-3 hrs.
 PlasmaT1/2 (early neonate <2kg) = 8-11 hrs.
 PlasmaT1/2 (early neonate >2kg) = 5 hrs.
 PlasmaT1/2 is reduced in pts. with Cystic Fibrosis, burn.

9. Aminoglycosides- Dosing & Monitoring
■ High dose, extended interval (total 24 hr dose once a day) is preferred because:
– Conc. dependent kill.
– Significant Post antibiotic effect.
– Associated with less toxicity (ototoxicity & Nephrotoxicity).
■ High dose, extended interval is not preferred in:
– Pregnancy
– Neonates
– Paediatric population.
– Pts. with renal dysfunction (CLcr <25 ml/min)
– Combination therapy for endocarditis treatment.
 Administered in two or three divided doses.

10. Aminoglycosides- Dosing & Monitoring
■ Therapeutic dose range:
■ Therapeutic Drug Monitoring (plasma) is done either:
– Single sample taken between 6-14 hrs after start of infusion. OR,
– Two samples taken well apart (e.g 2 & 12 hrs) after start of infusion.
Agent Peak concentration Trough Concentration
Gentamicin, netilmicin &
tobramycin
4-8 µg/ml 1-2 µg/ml
Tobramycin 20-35 µg/ml <10 µg/ml

11. Aminoglycosides- Pharmacological
Properties of Individual Agents
1. Streptomycin:
– Less active againstGr-ve aerobic bacilli as compared to other members.
– Not active against pseudomonas & enterococci.
– Active against Mycobacteria.
– Administered by deep i.m or i.v.
– Dose 15-25 mg/kg/d (single or divided doses)
– Usually combined with agents of other class.
– Use is replaced by Gentamicin because of lesser toxicity.

12. Aminoglycosides- Pharmacological
Properties of Individual Agents
2. Gentamicin:
– Important agent for treatment of many serious gram –ve bacillary infections.
– Aminoglycoside of first choice because of cost & reliable activity.
– Available for parenteral, ophthalmic & topical use.
– Typical i.v. dose= 5-7mg/kg daily over 30-60 mins.
– Periodic therapeutic drug monitoring is required for more successful therapy.

13. Aminoglycosides- Pharmacological
Properties of Individual Agents
3. Tobramycin:
– Antimicrobial spectrum, P/K properties, Dosage & toxicity profile similar to
gentamicin.
– Available for parenteral, ophthalmic & inhalational use.
– Superior activity against pseudomonas. (Typically combined with anti-
pseudomonal β lactam).
– Poor activity against enterococci & Mycobacteria.

14. Aminoglycosides- Pharmacological
Properties of Individual Agents
4. Amikacin:
– Antimicrobial spectrum is broadest among aminoglycosides.
– Resistant against aminoglycosides modifying enzymes.
– Less active against enterococci (as compared to gentamicin)
– Recommended Dose= 15mg/kg/d (single or divided)

15. Aminoglycosides- Pharmacological
Properties of Individual Agents
5. Netilmicin:
– Similar to gentamicin in P/K properties & dosage.
– Like amikacin, resistant to aminoglycoside modifying enzymes.
– Not active against pseudomonas, mycobacteria & enterococci.
6. Neomycin:
– Broad spectrum.
– Not effective against pseudomonas.
– Not used for systemic effect due to high nephrotoxicity.
– Available for oral & topical (alone or in combination with polymyxin, bacitracin &
other antibiotics) use: Non systemic.

16. Aminoglycosides- Pharmacological
Properties of Individual Agents
7. Paromomycin:
– Notable antiparasitic activity: Leishmania spp., Entamoeba, Giardia,
Cryptosporidium.
– Available for oral, topical & parenteral Use.
– Oral Dose= 25-35 mg/kg in three divided doses.
8. Kanamycin:
– Most toxic.
– Reserved for XDR-TB.

17. Aminoglycosides-Therapeutic Uses
■ General Points:
– Gentamicin, amikacin, tobramycin & netilmicin are used interchangeably for most of
infections.
– For most infections gentamicin is preferred among above mentioned
aminoglycosides.
– Due to serious toxicity, prolong use of aminoglycosides are restricted to life
threatening infections.
– Used frequently with other cell wall active agents (β-lactam & glycopeptides):
■ To expand spectrum for empirical use.
■ To achieve synergy.
■ To prevent emergence of drug resistance.
– Combination therapy is useful in:
■ Healthcare associated pneumonia or sepsis.
■ Endocarditis.

18. Aminoglycosides-Therapeutic Uses
1. UrinaryTract Infection:
– Not responding toTMP-SMX, β-lactam & fluroquinolones.
– Gentamicin 5mg/kg single i.m. injection for uncomplicated cystitis.
– Gentamicin/tobramycin 10-14 day course for pyelonephritis.
2. Pneumonia:
– Hospital acquired pneumonia d/t multidrug resistant gr-ve bacteria.
– Aminoglycoside + β- lactam is standard empiric regimen.
3. Meningitis:
– Due to gr-ve bacteria resistant to β- lactam.
– Effective when directly instilled into CSF (intrathecal).

19. Aminoglycosides-Therapeutic Uses
4. Peritonitis
– In the settings of peritoneal dialysis.
– Direct instillation of aminoglycosides in peritoneal fluid
5. Bacterial Endocarditis
– Low dose gentamicin (3mg/kg) + penicillins/vancomycin.
6. Sepsis
– Limited use
– Broad spectrum β-lactam (carbapenems and antipseudomonal cephalosporins)
are preferred.

20. Aminoglycosides-Therapeutic Uses
7. Tularemia
– Streptomycin (or gentamicin) is the drug of choice.
– 1-2g (15-25mg/kg)/ day in divided doses for 10-14 days.
8. Plague
– Streptomycin/ gentamicin for 10 days in severe forms of plague.
9. Mycobacterial Infections
– Streptomycin, amikacin or kanamycin
– Mycobacterium tuberculosis & atypical mycobacteria infection.

21. Aminoglycosides-Therapeutic Uses
10. Cystic Fibrosis
– Recurrent gr-ve bacilli infection esp. pseudomonas.
– Higher dose than standard is commonly used.
– Tobramycin is used inhalational to improve lung function & reduce exacerbation.
11. Topical Use
– Neomycin & paromomycin used topically for skin and mucus membrane.
– Oral aminoglycosides are used:
■ To prepare bowel for surgeries. (Neomycin)
■ Hepatic encephalopathy. (Neomycin)
■ GI protozoal infections. (paromomycin)

22. Aminoglycosides- Adverse Drug
Reactions
1. Ototoxicity:
– Vestibular & auditory dysfunction in the form of b/l high frequency hearing loss.
– Degeneration of hair cells and neurons in cochlea.
– High pitch tinnitus is the first symptom.
– Vestibular toxicity manifest earliest as headache, nausea, vomiting.The
prominent symptom is vertigo in upright position.
Agents Ototoxicity
Streptomycin, gentamicin Vestibular
Kanamycin, amikacin, netilmicin Auditory
Tobramycin Both

23. Aminoglycosides- Adverse Drug
Reactions
2. Nephrotoxicity:
– Accumulation and retention in PCT.
– Manifest initially as excretion of enzymes of renal tubular brush border f/b mild
proteinuria and appearance of hyaline & granular casts.
– Renal dysfunction is almost always reversible.
– GFR reduction takes several days additional.
– Sever ATN may occur but rare.
– Toxicity corelates with dose & duration of therapy.
– Neomycin most nephrotoxic, streptomycin is least.

24. Aminoglycosides- Adverse Drug
Reactions
3. Neuromuscular Blockade:
– By decreasing Ach release at NMJ & reducing post synaptic receptor sensitivity.
– Pts. with myasthenia gravis are more susceptible.
– Neomycin>kanamycin>amikacin>gentamicin>tobramycin.
– Reversed by i.v. Calcium salts.
4. Hypersensitivity reactions
– Less allergenic potential.

25. ThankYou