Aminoglycosides Flashcards
Aminoglycosides
gentamycin* tobramycin* amikacin* streptomycin neomycin * used the most
MOA of aminoglycosides
crosses outer bacterial membrane by passive diffusion via porin channels, then binds to 30s ribosomal subunit and thus inhibits protein synthesis
Bactericidal: create fissures in outer cell membrane, resulting in leakage of intracellular contents and enhanced antibiotic uptake
mechanism of resistance
- transferase enzyme inactivates aminoglycoside
- impaired entry of amino glycoside into the cell
- receptor protein on 30s subunit may be altered or deleted
Resistance depends on the amino glycoside: amikacin shows less resistance -> only one locus that may be inactivated
genta and tobra: 6 loci that may be inactivated
Pharmokinetics
poorly distributed (no PO) and poorly protein bound but distribution is increased in pts with ascites, burns, pregnancy
Don’t undergo any significant metabolism
Nearly all administered dose is excreted unchanged in urine
- dose adjustment is required in renal insufficiency
Not required in hepatic disease
Spectrum of activity
most common: serious infections caused by aerobic gram-negative bacilli including pseudomonas, enterobacter, serratia, acinetobacter, and Klebsiella
- also used synergistically w/ other abx in tx of gram + infections
- protozoa
- mycobacterial: tobra, strepto, amikacin
Synergistic with B-lactam against what?
against gram positive cocci
- enterococcus faecalis endocarditis -> ampicillin or penicillin +gentamycin or strept
- staph aureus endocarditis -> quicker killing (naficillin+gentamicin)
-> neglible anaerobic coverage
Concentration dependent killing
dose dependent -> increasing concentrations kill an increasing proportion of bacteria at a more rapid rate
- postantibiotic effect: antibacterial activity persists despite unmeasurable drug concentrations
- may last for several hours
Clinical uses
- serious, life threatening gm - infection
- complicated skin, bone, or soft tissue infection
- complicated UTI
- sepsis
- osteomyelitis
- peritonitis and other sever intra-abdominal infections
- severe pelvic inflammatory disease
- endocarditis
- mycobacterium infection
- neonatal sepsis
- ocular infections (topical)
- otitis externa (topical)
Aminoglycosides combo uses
septicemia, nosocomial RTI, endocarditis, complicated UTI, complicated intraabdominal infections, osteomyelitis caused by aerobic gram - bacilli
- often d/c in favor of less toxic abx once organism identity and susceptibility has been confirmed.
- enterococci in absence of high level resistance
Gentamycin
- most widely used
- both gm - and +(resistance can occur)
- almost always used in combo (beta-lactam)
- IV, IM
- topical and ophthalmic
Tobramycin (Nebcin)
similar coverage as gentamicin, better pseudomonas coverage
- more expensive than gentamicin
- comes in soon for inhalation for cystic fibrosis
- IV, IM, ophthalmic
Amikacin (Amikin)
used for resistant bacteria
IV, IM
Streptomycin
2nd line for TB in combo w/ other agents
used w/ pen or ampicillin for enterococcus faceless endocarditis or viridian’s strep endocarditis (some resistance)
- IM
Neomycin (mycifradin)
limited to topical and oral use (bowel prep for surgery -> colorectal).
Paromomycin
for intestinal amebiasis and hepatic coma/encephalopathy
Aminoglycosides safety
Pregnancy: D (human risk, but benefits may outweigh risks)
Lactation: unknown, probably safe
- enter breast milk but not well absorbed orally
CI’s
previous allergy or hypersensitivity reaction to aminoglycosides
- myasthenia gravis: neuromuscular blockade risk too high
Black box warnings!!
nephrotoxicity ototoxicity neurotoxicity neuromuscular blockade *this is why serum levels are monitored
Nephrotoxicity
reversible, non-oliguric renal failure
- elevated troughs
RFs: old, renal dysfunction, dehydration, hypotension, liver disease, use of other nephrotoxins
Monitor: renal casts, urine output, Cr, BUN
- once daily dosing is less toxic
- most nephrotoxic: neomycin, tobramycin, gentamicin
Ototoxicity
both vestibular and cochlear
vestibular: 2/3-> vertigo, ataxia, loss of balance, tinnitus
cochlear: 1/3 -> high freq hearing loss, deafness unusal
- often irreversible, relationship to peak levels
- neomycin, kanamycin, amikacin: most ototoxic
Neuromuscular blockade
can produce curare-like neuromuscular blockade at very high doses given too fast in resp. paralysis.
- possible w/ any route of admin
- usually reversible w/ Ca gluconate
Drug interactions
Chemotherapy agents- agalsidase Alfa/beta: gentamicin may diminish effect of drugs
loop diuretics: may enhance adverse effect of ahminoglycosides -> nephro and ototoxicity
neuromuscular blocking agents: enhance respiratory depressant effect of NM blocking agents
B-lactam: synergistic effect, cephalosporins can increase risk of nephrotoxicity
Warfarin: enhance anticoag effect
Use of aminoglycosides?
use limited b/c of availability of less toxic agents with comparable efficacy and w/o need for serum [drug] monitoring.
- still impt as 2nd line agent in tx of serious infections due to aerobic gram - and certain gram +
- also impt in multi-drug regimen for certain mycobacterial infections
Instances when mono therapy is adequate therapy
tularemia
plague
uncomplicated UTI caused by drug resistant negative organisms
Why is myasthenia graves a complete CI?
b/c neuromuscular blockade risk is too high -> paralyze diaphragm and die!
