2. LEARNING OBJECTIVES
• What are aminoglycosides and their distinctive features?
• Which drugs are included in this class?
• How do they act?
• What organisms are they effective against and their clinical uses?
• What are their adverse effects?
• What are the precautions to follow while administering these drugs?
3. INTRODUCTION
• Consist of 2 or more amino sugars attached by
glycoside linkage to hexose nucleus
• Streptomycin was the first to be discovered in 1944 by
Schatz, Bugie and Waksman
• Actinomycetes – Streptomyces griseus
4.
5. CHEMICAL STRUCTURE
• Amino sugars linked through
glycosidic bonds
• Polycations: Partly responsible
for many of their shared
pharmacokinetic properties
7. Common properties
• Chemical structure
• Used to treat aerobic Gram –ve bacteria, with NO ACTION against
anaerobes
• Bactericidal and Inhibit bacterial protein synthesis
• Highly polar compounds, more active at alkaline pH and they are used as
sulphate salts
• Solutions remain stable for months
• Mainly distributed into ECF with poor penetration in CSF
Buzz: (1 min)
What is the characteristic of their absorption from GIT?
Route of administration?
8. Common properties
• Not metabolised
• Excreted unchanged via kidney
• Narrow safety margin
• Common toxicities – Ototoxicity (auditory and vestibular), nephrotoxicity,
neuromuscular blockade
• Partial cross resistance
9. Dosing considerations
• Concentration dependent killing (>> conc. = >> bacteria are killed rapidly)
• Significant Post-antibiotic effect (Definition?)
• Single daily dosing at least as effective, convenient and no more toxic than
multiple dosing, except in case of bacterial endocarditis
• Multiple daily dosing regimen (2-3 equally divided doses)
• Dose adjustment according to BW and creatinine clearance
10. Mechanism of action
• Initially they penetrate
bacterial cell wall, to reach
periplasmic space through
porin channels (passive
diffusion)
• Further transport across
cytoplasmic membrane takes
place by active transport by
proton pump; an oxygen-
dependent process
11. Mechanism of Action
• Bind with 30S
ribosomal subunits
and interfere with
initiation complex
• Induce misreading of
genetic code on
mRNA
• Breakup of polysomes
into monosomes
12. Mechanism of action
• Premature termination of protein synthesis
+
• Incorporation of incorrect AA into the growing polypeptide chains
= Formation of Defective or non-functional proteins
• Incorporation of these defective proteins into bacterial cell membrane
• Altered permeability and disruption of cell membrane
17. Mechanism of resistance
• Synthesis of plasmid mediated bacterial transferase
enzyme: Inactivate aminoglycosides
• ↓ transport into bacterial cytosol
• Deletion/alteration of receptor protein on 30 S
ribosomal unit by mutation: prevents attachment
18. ANTIMICROBIAL SPECTRUM
• Not effective against Gm +ve bacilli, Gm-ve cocci and anaerobes
• Some are active against Mycobacteria
19. ADVERSE EFFECTS
• Ototoxicity
- tinnitus, deafness (cochlear)
- Intense headache, dizziness, nausea, vomiting, nystagmus, ataxia
(vestibular)
Reversible if discontinued early
If used during pregnancy, may cause ototoxicity in foetus
• Buzz: 1 min
Risk factors?
20. Risk factors for ototoxicity with
aminoglycosides
• Elderly
• Repeated courses
• Persistently increased concentration of drug in plasma
• Pre-existing auditory impairment
• Concurrent use of other ototoxic drugs - Vancomycin, Minocycline,
Loop diuretics (Furosemide)
21. Adverse effects
• Nephrotoxicity
- Concentrated in renal cortex
- Risk factors are elderly, vancomycin, amphotericin B, cyclosporine,
cisplatin
• Neuromuscular blockade due to inhibition of Ach release from motor
nerve
- apnoea, muscular paralysis
- Risk factors: Disease?, Drugs?
• Hypersensitivity (skin rashes, drug fever rarely)
22. Precautions and contraindications
• Pregnancy
• Elderly (>60y)
• Renal dysfunction
• Avoid concurrent use of other nephrotoxic and ototoxic drugs
• Muscle relaxants
• DO NOT MIX aminoglycosides with any drug in the same syringe/infusion
bottle
23. Therapeutic uses
• Severe G –ve bacillary infections (Pseudomonas, Klebsiella, E.coli,
Proteus)
- UTI with pyelonephritis
- Pneumonia
- Meningitis
- Osteomyelitis
- Septicemia
- Peritonitis
- Infected burns
24. Therapeutic uses
• Bacterial endocarditis (S. viridans, Enterococcus)
Gentamicin + a Penicillin/Vancomycin
• Tuberculosis
Streptomycin, amikacin, kanamycin
• Other G –ve infections
Plague, Brucellosis, Tularaemia (Streptomycin/gentamicin)
Skin, eye, ear infections (gentamicin, tobramycin, neomycin, sisomicin,
Framycetin for topical application)
25. Individual drugs
• Streptomycin:
First aminoglycoside discovered in 1944
Obtained from Streptomyces griseus
First line drug for tuberculosis, plague
<< activity against E.coli, Klebsiella, Shigella, Enterococci, V.cholera,
H.influenza
NO ACTIVITY against Pseudomonas
Least Nephrotoxic aminoglycoside
Inj site pain, paresthesias occasionally
Q. What is Streptomycin dependence?
26. Individual drugs
• Gentamicin:
Most commonly used
Obtained from Micromonospora purpurea in 1964
More potent than streptomycin, kanamycin, amikacin, but equally
potent as tobramycin, sisomicin, netilmicin
>> activity against:
G –ve aerobic bacilli (E.coli, Klebsiella, Proteus, Enterobacter, P.
aeruginosa, H.influenza)
G +ve cocci (Enterococci, S. viridans, Staph)
27. Individual drugs
• Neomycin
- Obtained from S.fradiae
- Only topical use
- >> nephrotoxic
- For skin, eye, ear infections
- Orally (for local action) in case of hepatic encephalopathy (reduces blood
NH3 level by destroying colonic bacteria)
- Preparation of bowel for surgery
Q. Which drug apart from the aminoglycoside group is more preferred for
hepatic encephalopathy nowadays?
28. Individual drugs
• Framycetin (soframycin)
- Topical use only
- >> nephrotoxic
- Skin, eye, ear infections
• Amikacin
- Broadest spectrum among aminoglycosides
- Resistant to aminoglycoside-inactivating enzymes
- G-ve nosocomial infections
- Tuberculosis
29. Individual drugs
• Kanamycin
- Similar to streptomycin but >> ototoxic and nephrotoxic
- 2nd line drug for tuberculosis
• Tobramycin
- >> activity against Pseudomonas compared to gentamicin
• Sisomicin
Similar to gentamicin with >> activity against Pseudomonas
• Netilmicin
- Resistant to aminoglycoside-inactivating enzymes
- Useful for gentamicin-resistant bacteria
30. Individual drugs
• Paromomycin
- Chemically related to neomycin
- Similar antibacterial spectrum with neomycin
- Additionally, active against parasites (E.histolytica, G.lamblia,
T.vaginalis, Cryptosporidium, Leishmania)
- Oral formulation for local use similar to neomycin in hepatic
encephalopathy
- Parenteral formulation for visceral leishmaniasis
31. QUESTIONS
• What synergistic combinations of drugs with aminoglycosides are
used for treating serious nosocomial infections due to G –ve bacilli?
• Which aminoglycosides are effective against P.aeruginosa?
All are sulfate salts which are highly water soluble; solutions are stable for months
They ionize in solution are not absorbed orally, distribute only extracellularly, do not penetrate brain or csf.
More active in alkaliner ph.
There is only partial cross resistance among them.
Streptomycin – 1944
Actinomycetes – Streptomyces griseus
Antibacterial activity of aminoglycosides, fluoroquinolones and metronidazole is conc dependent. While that of beta lactums and vancomycin is time dependent.
Conc dependent killing: more effective if higher blood conc are reached periodically.
Time dependent killing: more effective if blood levels are maintained above the MIC for as long duration as possible.
Post antibiotic effect: A persistant supression of bacterial growth. After brief a brief exposure of an antimicrobial agent. Inhibiton of bacterial growth is even seen when Conc of drug falls below MIC. REFLECTS time required by bacteria to return to normal growth. PAE is most significant with drugs that act by inhibiting bacterial protein synthesis or DNA synthesis. (Amino, Fluro, tetracycline, chloramphenicol, rifampicin.
Post antibiotioc effect explains why these drugs can be given in a single daily dose even though they have a short half life (1-3) Hrs.
That is why beta lactum antibiotics which weaken or inhibit bacterial cell wall synthesis facilitate passive diffusion of aminoglycosides if given together- synergistic action. Subsequently further transport of aminoglycosides across the cytoplasmic membrane takes place by energy dependent and oxygen dependent active transport . As such transport cannot take place in anaerobic conditions, aminoglycosides are inactive against anaerobic bacteria.
These drugs then bind to 30 S ribosomal units of bacteria and prevent formation of initiation complex. Which is prerequisite for peptide synthesis. Lack of formation of initiation complex causes 30 S subunit to misread genetic code on mRNA. Incorrect aminoacids are thus incorporated into growing peptide chain which are of no use for bacterial growth. The formation of improper initiation complex also blocks the movement of ribosomes, resulting in mRNA chain attached with single ribosomes (Monosomes). Thus aminoglycosides also interfere with in the assembly of polysomes which result in accumulation of nonfunctional ribosomes.
Penetration is favoured by high pH. Aminoglycosides are 20 times more active in alkaline than acidic pH.
Cidal action: secondary changes in integrity of bacterial cell membrane, because other antibiotics which inhibit protein synthesis are bacteriostatic. After exposure to aminoglycosides , sensitive bacteria become more permeable ; ions aminoacids and even protein leak out followed by cell death. This probably results from incorporation of faulty proteins into cell membrane.one of the consequences of aminoglycoside induced alteration of cell membrane is augmentation of carrier mediated entry of the antibiotic. This reinforces the lethal action.
The cidal action of aminoglycosides is concentration dependentand they also exert prolonged post antibiotic effect.
This complex moves along mrna so that sucessive codons of mRNA pass along ribosome from a site to p site
Codon is triplet of 3 nucleotides which codes for specific amino acid needed for protein synthesis
Bacterial transferase enzymes are: phosphotransferases, acetyl tranferases and adenyl transferases. Which inactivate aminoglycosides by acetylatuion, adennylkation and phosphorylation.
Decreased transport may result from mutation or deletion of porin channels or protein involved in transportor by makink o2+ energy dependent transport system non functional.
