Aminoglycosides

overview

· discovered in 1940's

· derived from soil bacteria

· effective against vast majority of gram-negative bacilli

mechanism of activity

· multifactorial bacteriocidal effect

· bind to gram-negative bacterial cell wall and affect permeability

· actively taken up and concentrated by bacteria

· bind to bacterial ribosomes and affect protein synthesis

in vitro activity

Time course

· concentration-dependent killing

· one single bolus dose works better than divided doses in 24 hrs

Postantibiotic effect

· persistent suppression of bacterial growth after short antimicrobial exposure

· continues for 2-3 hrs after exposure to aminoglycoside removed

· concentration-dependent

Antimicrobial synergy

· synergy between aminoglycoside and cell wall active microbial (penicillin, cephalosporin) for gram-positive cocci

pharmacology

· administered IV over 30 min or IM (completely absorbed in 30-90 min)

· minimal absorption from GIT

· wide volume of distribution

· poorly protein bound and very water soluble

· cross membranes poorly

· traverse blood-brain barrier poorly

· exception is renal tubular and inner ear cells

· enters synovial fluid easily

· not metabolised

· 99% excreted unchanged in kidney

toxicity

· allergies rare

· can cause

· injury to renal proximal convoluted tubules

· damage to cochlea and vestibular apparatus

· appears to be less with once-daily dose

clinical indications

· aerobic G- bacillus

· Klebsiella

· Enterobacter

· Serratia

· Pseudomonas aeruginosa (tobramicin)

· aerobic G+ cocci

· Strep viridans

· Staph aureus (methicillin sensitive)

· Staph epidermidis

· Enterococcus

· with penicillin or cephalosporin

· resistance rare

dosage

Multiple daily dose

· loading dose of 2 mg/kg and then 1.7 mg/kg q8h

· aim for peak of 4-10 and trough of < 2

Once daily dose

· clinical data not adequate to support unqualified endorsement

Premise

· nephrotoxicity and ototoxicity less severe

· PAE demonstrated which is peak concentration-dependent

· antibacterial efficacy enanced with high peak drug concentration

Dosing

· dose is 4-5 mg/kg over 60 min

· peak levels not required

· level at 18 hrs to check trough