Gentamicin – principles of use and monitoring September 2013 Dr Robert Jackson

E SSENTIAL INFORMATION - GENTAMICIN Gentamicin Policy (adults) Paediatric aminoglycoside policies can be navigated to from: How to do Gentamicin levels

G ENTAMICIN Aminoglycoside antibiotic – same group as Streptomycin, tobramycin, netilmicin, amikacin, neomycin, kanamycin Broad-spectrum vs Gram negative and Gram positive aerobic bacteria Most important activity is against aerobic Gram negative bacilli ie coliforms and pseudomonas Not active against strict anaerobes Synergistic activity vs Streptococci (endocarditis) Only active when used topically or given parenterally Main uses – UTI, intra-abdominal sepsis (combined with eg amoxicillin and metronidazole) and “Gram-negative sepsis” Narrow therapeutic index – dose needs to be carefully calculated and levels monitored to ensure therapeutic and non- toxic levels achieved

G ENTAMICIN AND RENAL FUNCTION Renal impairment – use gentamicin with caution See Gentamicin policy for advice on dose adjustment according to creatinine clearance Creatinine clearance calculated using Cockcroft- Gault equation rather than eGFR All patients on gentamicin need levels monitoring and U+Es monitoring (U+Es every 48 hours) Sepsis can lead to transient renal impairment Acute renal impairment in sepsis – give “full” gentamicin dose initially to avoid undertreatment of more severe sepsis

C ALCULATING THE INITIAL GENTAMICIN DOSE IN RENAL IMPAIRMENT Dose adjustment for impaired renal function Cockroft-Gault equation for estimating creatinine clearance: Creatinine Clearance (GFR) = (140 - Age) x Weight (Kg) x F Serum Creatinine (µmol/litre) Where F = 1.23 (For Men) 1.04 (For Women) Dose adjustment recommendations: Cr Cl (ml/min) Dose mg/kg once-daily mg/kg once-daily 5-102mg/kg every 48 to 72 hours according to levels

G ENTAMICIN ADMINISTRATION Twice and thrice daily dosing with gentamicin used to be the norm – more likely to achieve low peak levels near bacterial MICs and drug accumulation with rising trough (pre-dose) levels – high risk of toxicity Last two decades – once daily dosing has become the most popular way to give gentamicin (can also be used for tobramycin and amikacin)

O NCE DAILY GENTAMICIN Systems available Prinz scheme – 5 mg/kg (3 mg/kg for the elderly or lower if renal impairment) ~ initially used only at GRH but now used across the Trust Hartford scheme – 7 mg/kg ~ used to be used at CGH – adjustment was to dose interval rather than the dose – doses given either every 24, 36 or 48 hours

O NCE DAILY GENTAMICIN Advantages Less likely to cause toxicity Probably more effective (reliably high peak levels well above bacterial MICs and bacteria also affected when serum levels reach trough because of the post- antibiotic effect [high intrabacterial levels when serum levels have dropped]) Easier to administer, cheaper Easier to do levels (no need for the paired pre and 1 hour post-dose levels needed for bd and tds regimes)

E XCLUSIONS FOR USE OF OD G ENTAMICIN Once daily dosing is inappropriate and should not be used in: Endocarditis (lack of experience) Pregnancy (lack of experience) Major Burns Ascites – liver impairment a predisposition to renal impairment – fluid compartment distribution issue Osteomyelitis Myeloma patients (renal amyloid)

H OW OFTEN TO MEASURE LEVELS ? Depends on renal function (particularly baseline renal function) Depends on whether initial gentamicin level is normal or not – if not => dose adjusted => repeat level after first adjusted dose Depends on the regime – od, bd or tds

F REQUENCY OF MONITORING LEVELS OD regime and normal renal function and first level satisfactory => twice weekly gentamicin levels BD or TDS regime – first levels after patient on gentamicin for 48 hours if those levels are satisfactory then repeat every 5-7 days If those levels are unsatisfactory – repeat after dose change when established on altered regime for 48 hours

“N ORMAL RANGE ” Target levels Once daily gentamicin 12 hour post-dose level <2.0 mg/l 18 hour post-dose level <1.0 mg/l BD or TDS gentamicin Pre-dose <2.0 mg/l Post-dose 5-10 mg/l Endocarditis gentamicin regime (bd or tds) Pre-dose <1.0 mg/l Post-dose 3-5 mg/l

I NTERPRETATION OF LEVELS P OST - DOSE LEVEL OF 3.5, REGARDLESS OF TIMING IS WORRYINGLY HIGH

I NTERPRETATION If Serum gentamicin concentration is: < 2mg/L (12 hrs post infusion) or < 1mg/L (18 hrs post infusion) then the present dose is correct for the patient’s existing renal function. This shows no accumulation; therefore continue with the same daily dose. If Serum gentamicin concentration is: > 2mg/L (12 hrs post infusion) or > 1mg/L (18 hrs post infusion) then the present dose is too high for the patient’s existing renal function. Dose reduction to a new dose will be required as per this equation: New Dose = Previous daily dose x Target serum value Actual serum level Serum gentamicin levels should be rechecked 12 to 18 hours after the new dose. If gentamicin levels are within the recommended range with normal renal function then monitor levels and U&Es twice weekly.

I NTERPRETATION AND REGIME MODIFICATION If the level has been taken at the correct time interval and is found to be in the “potentially toxic area” omit the next dose –consider doing a trough (random) level the following morning to see if the level has dropped to a amount where it would be safe to give a further (but reduced) dose of gentamicin Random level should be less than 1 before the patient can have a further dose Review whether gentamicin is still clinically necessary or whether an alternative, less nephrotoxic, antibiotic should be used instead Discuss with ward pharmacist, senior colleague or duty consultant microbiologist if in doubt