gentamicin

introduction

belongs to the aminoglycoside antibiotics which were originally obtained from Streptomyces species
ototoxic & nephrotoxic if high dose or prolonged use
active mainly against enteric Gram -ve bacteria
ATG recommend high dose “once daily” dosing for all indications EXCEPT infective endocarditis (including SBE) in which case “low dose 8 hourly dosing” schedule should be used
iv gentamicin is infused over 30min

chronic renal failure or worsening renal function, particularly if the creatinine clearance is less than 30 ml/min, unless there is consultation with the Infectious Diseases or Renal units
pre-existing hearing problems
pre-existing vestibular problems, including dizziness, vertigo or tinnitus
age greater than 70 years old, other than for stat dose surgical prophylaxis or initial treatment of severe infection for 48 hours, unless no safer, appropriate alternative antibiotic is available

STOP gentamicin if there is new onset or worsening of vertigo, dizziness, balance disturbance, blurred vision, hearing difficulty or tinnitus.

severe acute acute pyelonephritis with 2g iv ampicillin 6hrly
peritonitis (eg. perforated viscus) with 1g ampicillin 6hrly and metronidazole 500g 12hrly
cholecystitis or ascending cholangitis with 1g iv ampicillin 6hrly
severe diverticulitis with 1g ampicillin 6hrly and metronidazole 500g 12hrly
infective endocarditis (including SBE) - 8hrly dosing regime!!!
other Gram negative infections

usual adult dose iv gentamicin 4-5mg/kg calculated to give closest dose to ampoule size (most ED's stock 80mg in 2ml ampoules, thus a common adult once daily dose is 320mg iv)
patients with severe sepsis have higher volumes of distribution and therefore require a higher mg/kg dose.
see elsewhere for infective endocarditis (including SBE) Rx

age	high dose once daily dose of iv gentamicin
neonates < 34wks post-conceptional age	3mg/kg
neonates >= 34wks post-conceptional age	3.5mg/kg
infants and children < 10 yrs age	7.5mg/kg up to max. 320mg
10 - 29 years age	4-6mg/kg up to max. 560mg
30 - 60 years age	4-5mg/kg up to max. 480mg
> 60 years age	4mg/kg up to max. 400mg
> 10 yrs age with severe sepsis	7mg/kg up to max. 640mg

usually should be given in 100ml of comptible fluid and infused over 1 hour
however, prophylactic adult doses up to 120mg can be given over 3-5 minutes as a slow iv bolus

most written product information advise iv gentamicin must be given after at least 1 hour delay following iv penicillin dose if penicillin is being used.
the rationale is that gentamicin is inactivated by penicillin in vivo
unfortunately this advice if heeded may result in unnecessary delays incommencement of antiobiotic Rx in the critically ill patient, and delays in transferring patients from ED to the ward
gentamicin dose does NOT need to be delayed following the FIRST dose of iv penicillin but the line should be flushed with normal saline between the two medications.
the gentamicin dose should be delayed by at least 1 hour if there is a possibility of accumulation of penicillin such as with subsequent penicillin dosing, particularly in the those with renal impairment.

for subsequent dosing in patients on dialysis or in children with renal impairment, seek expert advice
monitoring of aminoglycosides in patients undergoing haemodialysis is difficult. Computerised AUC methods should be used and expert advice is needed. Alternative drugs should be considered.
if the duration of treatment extends beyond 48 hours, the treating doctor should, where possible:
- inform the patient or next of kin/guardian of the rare chance of hearing or balance problems with gentamicin use, while simultaneously explaining the value that gentamicin has as an antibiotic in treating infection
- tell the patient to report any hearing, balance or visual problems immediately.
- document that the above have been done

“high dose once daily dosing” schedule is once daily dosing for patients with normal renal function, but may be less frequent if there is renal impairment with creatinine clearance < 60ml/min.
- in patients with creatinine clearance > 60ml/min, 3 doses may be given at intervals of 24 hours
- in patients with creatinine clearance 40 - 60ml/min, 2 doses may be given at interval of 36 hours
- in patients with creatinine clearance 30 - 40ml/min, 2 doses may be given at interval of 48 hours
- in patients with creatinine clearance < 30ml/min, the 1st empirical dose of gentamicin may be given but then changed to a non-aminoglycoside thereafter.
further dosing may require area under curve (AUC) computations of serial levels:
- one serum level is near peak and the other is taken 6-14 hours after dosing
- Aladdin AUC calculator
- TCIWorks AUC calculator
trough levels cannot be used for monitoring once daily dosing because they are often below lab. detectable threshold, but still high enough to increase risk of toxicity.

creatinine clearance can be approximated in adults using the modified Cockcroft-Gault formula:
- adult males CrCl (mL/min) = [(140-age) x ideal weight in kg] / [0.814 x serum creatinine in micromol/L]
- adult females = adult male calculation x 0.85
- Ideal weight for adult male = 50 kg + 0.9 kg/each cm over 152 cm
- Ideal weight for adult female = 45.5 kg + 0.9 kg/each cm over 152 cm

1 month to 2 years age: CrCl = 40 x height in cm / serum creatinine in micromol/L
2 years to 12 years age: CrCl = 49 x height in cm / serum creatinine in micromol/L
12 years to 21 years age females: CrCl = 49 x height in cm / serum creatinine in micromol/L
12 years to 21 years age males: CrCl = 62 x height in cm / serum creatinine in micromol/L

Recent studies seem to indicate benefit in single daily doses for following reasons:
1. higher concentration results in more rapid & extensive killing
2. selection of resistant mutants during Rx less likely with higher concentration
3. produce significant post-antibiotic growth suppression effects even after brief exposure
4. efficacy determined by area-under-curve of drug exposure, not time concentration exceeds MIC
5. nephrotoxicity & renal accumulation reduced with higher doses administered daily.
However, few studies using gentamicin & limited experience with pts with severe renal impairment (CRN > 300umol/L), febrile neutropenic sepsis, endocarditis or in paediatric pts. In addition, insufficient evidence for risks of ototoxicity.

“low dose 8 hourly dosing” requires close monitoring of TROUGH serum gentamicin levels AND clinical assessment for vestibular and auditory ototoxicity as this may be irreversible.
- in this dosing regime, trough levels should be below 1mg/L to prevent ototoxicity