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Aminoglycosides - Coggle Diagram
Aminoglycosides
Therapeutic uses
Kanamycin
- Limited spectrum & toxicity - less use
- Kanamyxin sulfate for oral use & injection
- Parental dose: Adult - 15mg/kg OD, max. 1.5g/day; Children - 15mg/kg
- Treat tuberculosis - combination with other drug
- no therapeutic advantages over Streptomycin, Amikacin
- probably more toxic
Amikacin
- Broad spectrum
- Resistant to many aminoglycside-inactivating enzymes
- Active against aerobic gram-ve bacilli
- Against Serratia, Proteus, P. aeruginosa, Klebsiella, Enterobacter, E. coli - these are resistant to gentamicin and tobramycin
- Active against M. tuberculosis - including streptomycin-resistant strains and atypical mycobacteria
- Disseminated atypical mycobacterial infection in AIDS patients
- Less active against enterococci
- Not for gram+ve anaerobes
Tobramycin
- superior activity against P. aeruginosa
- administered with an antipseudomonal B-lactam
- poor activity in combination with penicillin against enterococci
- Most E. faecium are highly resistant
- Ineffective against mycobacteria
Neomycin
- broad-spectrum
- Widely used for topical in various skin and mucous membrane infections - burns, wounds, ulcers, infected dermatoses
- Oral administered with Erythromycin - before bowel surgery
- Hepatic encephalopathy / Hepatic coma - 4-12g/day
Gentamicin
- Treat serious gram-ve bacillary infections
- First choice of aminoglycosides - lower cost & reliable activity
- Dosage forms: parenteral, opthalmic, topical
- Complicated UTI
- Hospital-acquired pneumonia - combined with B-lactam antibiotic
- Meningitis - combined with 3rd generation cephalosporin
- except infections caused by gram-ve organisms that resistance to B-lactam antibiotics
- Peritoneal dialysis-associated peritonitis
- Bacterial endocarditis
- Sepsis
Netilmicin
- the latest aminoglycside
- Treat serious infections - Enterobacteriaceae
- Active against aerobic gram-ve bacilli
- Effective against getamicin-resistant pathogens, except enterococci
Common properties
- used as sulfate salts, which are highly water-soluble
- ionize in solution
- not absorbed orally
- distribute only in extracellular
- do not penetrate brain or CSF
- excreted unchanged in urine by glomerular filtration
- bactericidal, more active at alkaline pH
- interfering with bacterial protein synthesis
- active primarily against aerobic gram-ve bacilli, but do not inhibit anaerobes
- partial cross resistance
- relatively narrow margin of safety
- exhibit ototoxicity and nephrotoxicity
MOA
- Gram-ve organisms:-
- allow aminoglycosides to diffuse through poring channels in their outer-membrane
- have an oxygen-dependent system that transports the drug across the cytoplasmic membrane
- Once inside the bacterial cell, streptomycin bind to 30S ribosomes;
other aminoglycosides bind to additional sites on 50S subunit and 30S-50S interface
- freeze initiation of protein synthesis
- prevent polysome formation and promote their disaggregation to monosomes
- Binding of aminoglycoside to 30S-50S structure causes distortion of mRNA codon recognition resulting in misreading of the code
- One or more wrong amino acids are entered in the peptide chain and peptides of abnormal lengths are produced
- aminoglycosides synergize with B-lactam antibiotics because of the latter's action on cell wall synthesis, which enhances diffusion of the aminoglycosides into the bacterium
Resistance
- Different aminoglycosides cause misreading at different levels, it is depending upon their selective affinity for specific ribosomal proteins
- Resistance mechanisms:
- inactivation by microbial enzymes
- Amikacin - poor substrate for enzymes, but some organisms have developed enzymes that inactivation this agent as well
- resistance result of failure of penetration can be largely overcome by the concomitant use of penicillin and/or vancomycin
Antibacterial spectrum
- bactericidal and show post-antibiotic effect
- effective in empirical treatment of infections due to aerobic gram-ve bacilli, includes Pseudomonas aeruginosa
- often combination with B-lactam antibiotic or vancomycin or drug active against anaerobic bacteria
- the exact mechanism of their lethality is unknown because other antibiotics that affect protein synthesis are generally bacteriostatic
- the aminoglycosides are effective only against aerobic organisms because strict anaerobes lack the oxygen-requiring drug transport system
Pharmacokinetics
- polycations and highly polar
- Not absorbed in GIT
- Given in im or iv
- Cross placenta but not BBB
- Penetrate vitretous humour of eye, or into most secretions and body fluids
- High conc. attained in joint and pleural fluid
- Short plasma half-life: 2-3 hours
- Elimination is entirely by glomerular filtration in the kidney
- 50-60% of a dose being excreted unchanged within 24 hours
- Impaired renal function - rapid accumulation of drug leads to toxic effects
- Poorly metabolized - do not penetrate most cell, where metabolizing-enzymes are present in cell
Adverse effects
- Ototoxicity
- Direct related to high peak plasma level & duration of treatment
- accumulation in the endolymph & perilymph - toxicity correlates with the number of destroyed hair cells in the organ of corti
- Deafness - irreversible, and may affect the fetus
- Vertigo & Loss of balance - Streptomycin
- Nephrotoxicity
- Drug retention by proximal tubular cells disrupts calcium-mediated transport processes, resulting kidney damage
- Allergic reactions
- Contact dermatitis - common in applied neomycin
- Neuromuscular paralysis
- occurs in direct intrapleural administer in large dose
- Decrease the release of acetylcholine from pre-junctional nerve endings & the sensitivity of postsynaptic site
- Patient with myasthenia gravis are particularly at risk
- Prompt administration of calcium gluconate or neostigmine can reverse the block
- Treat injections due to aerobic Gram-ve bacilli
- used associated with serious toxicity
- have been replaced to some extend by safer antibiotics - 3rd and 4th generation cephalosporins, FQs, carbapenems
- mycin - derived from Streptomyces; micin - derived from Micromonospora
- polycations - ease passage across tissue membranes
- inhibits bacterial protein synthesis
- produced by soil actinomycetes
- mainstay for treatment of serious infections due to aerobic gram-ve bacilli
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