Aminoglycoside AB Flashcards
Aminoglycosides: in general
•Very toxic (maybe most toxic AB known, but most effective)
•Amino groups in a glycoside structure (like in sugars)
•Soluble in water – hydrophilic (not lipophilic = not good due to poor pharmacokinetic behaviour, cannot cross special barriers)
•Amino groups have positive charge
•Neomycin & Gentamicin
•Spectinomycin – no glycoside bond & no positive charge (not considered an AG – an aminocyclitol)
•Produced by bacteria: Streptomyces spp. & Micromonospora spp.
o Streptomyces: Streptomycin, neomycin, spectinomycin and kanamycin –> Amikacin (synthetic, best AG known), tobramycin
o Micromonospora: Gentamicin
Aminoglycosides: Mechanism of action
•Inhibition of protein synthesis on 30S ribosome subunit –> bacteriocidal
•Aminoglycoside will not stop protein synthesis, but force ribosome to insert incorrect aminoacid to peptide chain –> mistranslation of genetic code –> synthesis of useless «non sense» proteins –> incorporated into cell membrane –> death of bacterium.
•Bacteria will voluntarily take up AG w- active transport! Energy demand maintained in the presence of O2 (aerobic conditions) - only against aerobic bacteria! – potentiation!
•+ other mechanisms (one of the most active drugs available, very fast killers of bacteria)
o Cell membrane toxicity
o RNA-structure damage
Aminoglycosides: Mode of action
- Concentration dependent bactericidal! (Spectinomycin = exception – bacteriostatic): the more that is given the faster the killing
- PAE (post-antibiotic effect) – always given once per day because of this
- Synergistic with the beta-lactams (penicillins, cephalosporins) (used very frequently together) – can help the penetration of the AG inside the cell, the AG will help the beta-lactam by inhibiting protein synthesis (decrease production of beta-lactamase)
Aminoglycosides: Resistance
•Ab ovo – Anaerobic bacteria e.g. Clostridia, Bacterioides, Fusobacterium etc. – can’t treat foot rot, oral cavity infections, necrotic enteritis
o Streptococcus is also resistant
•Plasmids!!! – resistance can spread very quickly
•Production of altering enzymes by bacterium which will acetylate or adenylate, so it is not active anymore – E. coli & Pseudomonas aeruginosa
•Reduced permeability of the cell wall (don’t let antibiotic in) by blocking active transport mechanisms
•Cross resistance (one-way) – Streptomycin resistant E. coli can be sensitive to neomycin. If it is resistant to neomycin, can use gentamycin. If resistant to gentamycin too, can use tobramycin & amikacin.
o If resistant to tobramycin & amikacin then it will definitely be resistance to streptomycin, neomycin & gentamycin.
Aminoglycosides: Antibacterial spectrum
•Slight differences
•Gr- aerobic are the primary targets! – E. coli, Salmonella, Pseudomonas, fastidious Gr- (pasteurella, haemophilus, actinobacillus, mannheimia): respiratory tract infections, proteus, leptospira
o Pseudomonas: treated with Amikacin (best), Tobramycin (second best) or Gentamycin
o Mycoplasma: pig & poultry pneumonia – treat with Spectinomycin
•Gr+ bacteria are usually not sensitive apart from Staphylococcus spp. (skin, ear, mastitis)
o Mycobacterium: tuberculosis – treat with Streptomycin (human)
•Anaerobic bacteria are resistant!
Aminoglycosides: Pharmacokinetics
Poor (hydrophilic, not lipophilic)
•Absorption:
o Oral absorption is negligible (almost not abs) -Used orally against intestinal infections only – not absorbed, concentrated in the intestine.
o IM & SC = perfectly absorbed, can also be given IV
o Intra-mammary infusion, intra-uterine tablet, cleaning abscess etc. – can be a slight absorption (1-2%) - will require a WP! (meat & milk)
•Distribution = poor, don’t cross the special barriers, can’t enter the cells, accumulation in the kidney cortex – mastitis only (intramammary infusion)
•Metabolism: (hydrophilic drug) minimal - absolutely not hepatotoxic.
•Excretion: almost 100% by kidney (excreted in active form) – not for kidney failure patiens! And reach high cc. in urine - UTI (E.coli) BUT because of toxicity – only for multiresistant cases (Amoxicillin nr.1)
o 3 compartment model:
Alpha: distribution phase (through tissues) – t1/2 = mins
Beta: elimination phase (urine/bile) – t1/2 = hours
Gamma: very long phase = t1/2 = days (bind to kidney cortex & eliminated very slowly)
o Long withdrawal period! – 2 months (up to 75 days) due to accumulation in the kidneys.
Aminoglycosides: Side effects
•Toxicity – one of the most toxic antibiotic groups
•Ototoxic: primary sensory neurones sensitive - irreversible deafness & vestibular problems (check tympanic membrane!)
o Used against Staphylococcus & Pseudomonas (Tobramycin, Gentamycin)
•Nephrotoxic: renal tubular cells sensitive (carefull with injections!) - irreversible
•Duration of treatment should not be more than one week - if we have to: check the kidneys regularely!
•Safe orally (not absorbed) – no toxic effect
•AG very pos. charged - ear & kidney highly neg. charged phosphatidyl-inositol (pos. – neg. attraction)
o Cells take up AG resulting in oxidative stress inside the cell (ROS) – kills the cell
o More positive charge - more toxic
•Neomycin most toxic, given orally & topically only; Streptomycin less toxic; safest drug = Spectinomycin
•Amikacin = best drug known, second safest drug
•Companion animals more sensitive, cats more than dogs
•Reptiles are very sensitive!
•Predisposing factors!
o Pre-existing kidney disease – DON’T apply AG
o Don’t use in dehydrated patients & during operations (circulation of the kidney is impaired)
•Long term app. not recommended (max 7-10 days – except Amikacin (2 wks) & Spectinomycin (3 wks)) –> injection
o Orally can be given for as long as wish
o Preferring SID in high dose IV– minimize the time of effect
•Can cause neuromuscular blockade
o Inhibit Ach release
o Muscle relaxants can enhance this effect & lead to muscle weakness & paralysis (imp. in breathing!), DON’T apply in animals w. myasthenia gravis!
Aminoglycosides: Indications
•Respiratory infections - injection
•GI infections – orally (E. coli and Salmonella – Neomicin, Gentamicin, Spectinomicin)
•UTI – injection only (multiresistant)
•Mastitis – intra-mammary infusion only (E. Coli, Strep. And Staph – penicillins or cephalosporins together with AG)
•Dermatitis – topical (multiresistant skin infection)
•Ear & eye drops (check tympanic membrane – one drop can cause deafness)
•Septicaemia (combination) – quick healing action, synergistic with beta-lactams
o Penicillin (amoxiclav) + cephalosporin = good combination
Aminoglycosides: Drugs
- Streptomycin/dihydro-streptomycin
o Not used alone – resistance very widespread
o Combination with penicillins (TTC)
o IM, SC, duration = 3 days - Neomycin
o Much more active than Streptomycin.
o Usually used alone
o Combination with penicillins
o Per os, parenteral (not recommended), topical (skin, ear, eye)
o Very toxic
• Gentamycin
o Alone or combination with penicillins
o Orally (eg. For E. coli) & topically (eye drops, ear drops, skin) more active than neomycin
o Per os, parenteral (inj.), topical
o Very ototoxic. Not used more than one week (inj.). - Spectinomycin
o Exception - resistance common
o Bacteriostatic, Mycoplasma spp. (Swine, poultry, Ru)
o Also alone & in combination with Lincomycin (inj. to reach the lung – not used in poultry)
o Per os, parenteral - Apramycin
o Bioavailability is better orally – other drugs have no absorption
o Used in swine – intestinal infection & respiratory (E. coli diarrhoea)
o Per os - Tobramycin
o Best AG, 2nd most active - but: Toxic!
o Topical, parenteral, eye drop
o Human drugs, only used in small animals, not large
o Combination w. beta-lactams in life threatening infection - Amikacin
o (Best AG). Most active.
o Combination w. beta-lactams in life threatening infection
o Slightly toxic (least toxic) – can be given for a longer time
o Parenteral.
o Resistance is very uncommon - Treat MRSA/MRSB
