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

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

2. Essential information - gentamicin • Gentamicin Policy (adults) http://intranet/en/Trust-Staff/Antibiotic-Guidelines/Gentamicin-Protocol/ • Paediatric aminoglycoside policies can be navigated to from: http://intranet/en/Trust-Staff/Antibiotic-Guidelines/Paediatric-Guidelines/ • How to do Gentamicin levels http://intranet/en/Your-Division/Diagnostic-Specialties-Division/Pathology1/Gentamicin-Assay/

3. Gentamicin • 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

4. Gentamicin 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

5. Calculating 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 30-70 3-5mg/kg once-daily 10-30 2-3mg/kg once-daily 5-10 2mg/kg every 48 to 72 hours according to levels

6. Gentamicin 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)

7. Once 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

8. Once 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)

9. Exclusions for use of OD Gentamicin 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)

10. How 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

11. Frequency 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

12. “Normal 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

13. Interpretation of levelsPost-dose level of 3.5, regardless of timing is worryingly high

14. Interpretation • 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.

15. Interpretation 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