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Section IVOther important drugssubunits are smaller than mammalian subunits and this difference is utilized by
anumber of antimicrobials that interfere with protein synthesis. Once bound to
ribosomal RNA, aminoglycosides block tRNA attachment and mRNA is either not
transcribed or totally misread (depending on aminoglycoside concentration). Ente-
rococcal resistance in the UK is low and likely to be caused by enzyme-mediated
deactivation. Altered cell permeability and altered ribosomal binding have also been
found in resistant strains.Kinetics
Owing to their low lipid solubility, aminoglycosides are not absorbed from the gut
and must be given parenterally; aminoglycoside concentration being directly pro-
portional to the rate of bacterial killing. They have low protein binding (20–30%),
distribute predominantly in extracellular fluid and penetrate cells, CSF and spu-
tum poorly. They are not metabolized and are excreted unchanged in the urine by
filtration. Owing to their narrow therapeutic index, blood assays should be checked
before and 1 hour after a dose to determine the most appropriate dose and the
adequacy of its clearance.Side effects
Ototoxicity (vestibular and rarely auditory dysfunction) occurs when a significant
amount of drug accumulates in the inner ear perilymph and is usually perma-
nent. Perilymph penetration is related to peak aminoglycoside concentration and
decreased removal due to high trough levels. This risk is increased in renal failure
and with simultaneous use of furosemide.
Nephrotoxicity is seen in up to 37% of intensive care patients treated with amino-
glycosides and tends to be reversible on discontinuing treatment. Accumulation
of the drug in the renal cortex leads to acute tubular necrosis that manifests within
the first week of treatment. Synergistic toxicity is seen with some cephalosporins
but the most likely independent risk factor is patient age. Netilmicin is the least
toxic in this respect.
Muscle weakness – aminoglycosides decreases the pre-junctional release of
acetylcholine; reduces post-junctional sensitivity to acetylcholine and as a result
increases non-depolarizing muscle relaxant potency. While intravenous calcium
may reverse this effect, their use is still cautioned in myasthenia gravis.Quinolones
Nalidixic acidis a synthetic 4-quinolone that is used for urinary tract infections.
Itprovides no gram-positive or anaerobic cover and although it has a wide gram-
negative spectrum, Pseudomonas is known to be resistant. Fluoroquinolones rep-
resent a much more significant category of antimicrobials. When compared to
the 4-quinolones, this group has increased gram-positive cover and also includes
Legionella, Mycoplasma, Rickettsia and Chlamydia. Pseudomonas aeruginosa