Full title of guideline Author Division & Speciality Scope Gentamicin Prescribing Guideline For Adult Patients Annette Clarkson, Specialist Clinical Pharmacist Antimicrobials and Infection Control All adult specialities (see exclusions within guideline for specific aspects) All adult patients suitable for gentamicin. Excludes paediatrics, neonates. Review date 01/12/2020 Explicit definition of patient group to which it applies (e.g. All adult patients suitable for gentamicin. inclusion and exclusion criteria, diagnosis) Excludes paediatrics, neonates. Changes from previous version Summary of evidence base this guideline has been created from Updated hyperlinks to linked guidelines 1. Drusano G.L. et al., 2007. Back to the Future: Using Aminoglycosides Again and How to Dose Them Optimally. Clinical Infectious Diseases, 45, 753-760. 2. Ariano R.E., Zelenitsky S.A., and Kassum D.A., 2008. Aminoglycoside- Induced Vestibular Injury: Maintaining a Sense of Balance. The Annals of Pharmacotherapy, 42, 1282-1289. 3. Summary of product characteristics for gentamicin. Available at www.medicines.org.uk accessed 11/10/2017 4. Renal drug database online Available at www.renaldrugdatabase.com Accessed 11/10/2017. 5. Micromedex. Thomson Micromedex, Greenwood Village, Colorado accessed via http://www.micromedexsolutions.com/ accessed 11/10/2017 This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using guidelines after the review date. Gentamicin Prescribing Guideline For Adult Patients Page 1 of 11 Review December 2020
ONCE DAILY GENTAMICIN PRESCRIBING GUIDELINES FOR ADULT PATIENTS Contents Page 1. Introduction 3 2. Once daily gentamicin dosing 3 2.1 Dose adjustment in established renal impairment 4 2.1.1 Calculation of creatinine clearance using 4 Cockcroft-Gault equation 2.2 Dosing in haemodialysis, peritoneal dialysis, CVVH/CVVHDF 2.3 Dosing in haematology patients 5 5 2.4 Dose adjustment in obese patients 5 2.3.1 Calculation of dose determining weight for dose adjustment in obese patients 6 2.5 Therapeutic drug monitoring (TDM) of gentamicin levels 6 2.5.1 Interpretation of TDM results 7 3. Multiple daily (conventional) gentamicin dosing 8 3.1 Dose adjustment in established renal impairment 8 3.2 Dose adjustment in obese patients 9 3.3 Therapeutic drug monitoring (TDM) of gentamicin levels 9 3.3.1 Interpretation of TDM results 9 Appendix 1: Gentamicin prescription sticker for once daily gentamicin regimes 11 Gentamicin Prescribing Guideline For Adult Patients Page 2 of 11 Review December 2020
1. Introduction Gentamicin is an aminoglycoside antibiotic with bactericidal effects. It is active against most Gram negative bacteria, including Pseudomonas sp., and also against some Gram positive bacteria, including Staphylococcus aureus (including MRSA). Gentamicin is used synergistically for Enterococcus and Streptococcus sp. Gentamicin is often given as a once daily dose regime, which is easier for the ward staff, it requires pre dose levels only and is generally considered to be less nephrotoxic compared to the conventional multiple daily dosing regime (the effect on ototoxicity remains less clear) 1,2. For certain patients and indications a once daily dose regime is not appropriate, either because of lack of published data or risk of accumulation and toxicity, and the conventional multiple daily dosing regime must be used. These include: Indications where gentamicin is being used for a synergistic effect in combination with another antibiotic most commonly, treatment of endocarditis in combination with a penicillin Pregnancy Abnormal volume of distribution, for example, ascites Major burns (>20% surface area) Therapeutic drug monitoring of gentamicin therapy is necessary to prevent toxicity, notably nephrotoxicity and ototoxicity. Multiple daily dose regimes also require monitoring to ensure efficacy. 2. Once daily gentamicin dosing The standard dose is 5mg/kg once daily to a maximum dose of 500mg see below for dose adjustment in renal impairment and obesity. Doses should be rounded to the nearest 40mg increment and gentamicin should be administered as an infusion. Gentamicin should be prescribed on the designated prescription sticker (see Appendix 1) attached to the antibiotic section of the prescription chart with the exception of haematology, obstetric and paediatric patients and in other cases where a multiple daily dosing gentamicin regime is being Gentamicin Prescribing Guideline For Adult Patients Page 3 of 11 Review December 2020
used. For renal patients being treated with gentamicin for haemodialysis catheter-related sepsis the specific chart should be used. 2.1 Dose adjustment in established renal impairment Dose reduction is required in renal impairment (see Table 1) as gentamicin is excreted into the urine by glomerular filtration. Dose reductions must be based on creatinine clearance (CrCl) calculated using the Cockcroft-Gault equation (see below), rather than the automated MDRD egfr produced by the clinical chemistry laboratory available on NOTIS. There can be a significant difference between the results of the two calculations. Table 1: Once daily gentamicin dosing in renal impairment CrCl 10-40ml/min CrCl <10ml/min 3mg/kg once daily (max 300mg) Check levels 18-24 hours after first dose. Await the result and re-dose only when level <1mg/L. 2mg/kg as a single dose (max 200mg) Check levels 18-24 hours after first dose. Await the result and re-dose only when level <1mg/L. Anuric and oliguric (<500ml/day) patients can be assumed to have a CrCl < 10ml/min. 2.1.1 Calculation of creatinine clearance using Cockcroft-Gault equation The Cockcroft-Gault equation is used to calculate creatinine clearance as an estimate of glomerular filtration rate (GFR) for the purpose of drug dosing in renal impairment: CrCl (ml/min) = F x (140-age) x weight (kg) Serum creatinine (micromol/l) where: F = 1.23 for male patients, F = 1.04 for female patients NOTE: If patient is anuric, morbidly obese or in acute renal failure this equation will not give a true reflection of CrCl. A creatinine clearance calculator is available on the antibiotic intranet site. This can be accessed at: http://nuhnet/diagnostics_clinical_support/antibiotics/pages/calc.aspx. Gentamicin Prescribing Guideline For Adult Patients Page 4 of 11 Review December 2020
2.2 Dosing in haemodialysis, peritoneal dialysis and CVVH/CVVHDF For dosing in haemodialysis refer to page 9 of the Guideline for the Diagnosis and Treatment of Central Venous Catheter Related Infections in Haemodialysis Patients.Further advice can be obtained from the Renal Pharmacist (bleep 780-7078). For peritoneal dialysis patients, if using intravenously give a single 2mg /Kg dose (as for CrCl<10) and only give a further dose when the level is <1mg/L. If using intraperitoneal gentamicin for the treatment of PD peritonitis then refer to the Guideline for the diagnosis and treatment of PD peritonitis and exit site infections or contact the renal team for advice. For dosing in patients on CVVH/CVVHDF, refer to the CVVH/CVVHDF dosing guideline or contact the critical care pharmacist for advice. 2.3 Dosing in haematology patients Refer to separate dosing advice for haematology patients which is available on the antibiotic website or refer to page 9 of the Guideline for management of neutropenic sepsis in haematology. 2.4 Dose adjustment in obese patients If the patient is obese defined as more than 120% of their ideal body weight (IBW) a dose correction is required. It is recommended that in these cases the dosing calculator available on the antibiotic intranet site is used. This calculates a dose determining weight for obese patients based on the patient s ideal body weight and actual body weight and recommends an initial once daily gentamicin dose using CrCl calculated via the Cockcroft-Gault equation. If the online dosing calculator is not available the formulae below can be used. NOTE: This calculator can also be used in non-obese patients. The calculator will not produce reliable results in patients who are anuric or in acute renal failure as it uses CrCl as a measure of renal function. NOTE: No maximum value applies for a dose determining weight, however no dose of gentamicin should exceed 500mg. 2.4.1 Calculation of dose determining weight for dose adjustment in obese patients Calculate ideal body weight (IBW) (kg): o IBW for male patients = 50 + (2.3 x (height in inches - 60)) Gentamicin Prescribing Guideline For Adult Patients Page 5 of 11 Review December 2020
o IBW for female patients = 45 + (2.3 x (height in inches - 60)) Calculate dose determining weight (DDW) (kg) o DDW = IBW + 0.4 (actual body weight (kg) - IBW) Use the dose determining weight to calculate the gentamicin dose required. 2.5 Therapeutic drug monitoring (TDM) of gentamicin levels NOTE: This information relates to TDM associated with the once daily dosing gentamicin regime only. Different monitoring is required for the conventional multiple daily dosing regime. The time and date when levels are to be taken must be clearly annotated on the administration section of the gentamicin prescription sticker (see Appendix 1) including whether the next dose is to be given or withheld until results are available. A trough, or pre-dose, level is required 18-24 hours after the first dose. This should be sent in a gold top serum separator tube to clinical pathology. It is not necessary to do a postdose (or peak) level for once daily dosing. On the sample request form state the date and time of last dose and the date and time level taken and the prescribed dose (without which the results cannot be interpreted). In a patient <65 years of age, if the serum creatinine is normal with good urine output give the second dose without waiting for the result. The result must be checked before the third dose. In a patient >65 years of age or with abnormal renal function or poor urine output, await the result before giving a second dose. Renal function should be checked at least three times a week and levels should be checked twice weekly during a treatment course, provided that renal function and urine output are stable. If renal function deteriorates then renal function should be checked daily and gentamicin levels closely monitored. A dose reduction may be required. All patients who are prescribed more than one dose of gentamicin should have a fluid balance chart completed and urine output should be closely monitored. Gentamicin Prescribing Guideline For Adult Patients Page 6 of 11 Review December 2020
2.5.1 Interpretation of TDM results The pre-dose level must be low to minimise toxicity If the pre-dose level returned is in range (<1mg/L): The current once daily dosing regime can be continued. A further pre-dose level should be performed following 3-4 more doses, provided that renal function is stable. If the pre-dose level returned is between 1-2mg/L and renal function is unchanged: The ongoing need for gentamicin therapy should be reviewed. If gentamicin is still indicated, reduce the dose: Current dosing regime New dosing regime 5mg/kg 3mg/kg 3mg/kg 2mg/kg 2mg/kg Omit dose and repeat level the following day If the pre-dose level returned is >2mg/L or renal function has deteriorated: The ongoing need for gentamicin therapy should be reviewed. Serum creatinine and urine output should be checked. If gentamicin is still required, recheck level after 12-24 hours and only re-dose once a result of <1mg/L is obtained, using the regimen below: Current dosing regime New dosing regime 5mg/kg 3mg/kg 3mg/kg 2mg/kg 2mg/kg Omit dose and repeat level the following day Gentamicin Prescribing Guideline For Adult Patients Page 7 of 11 Review December 2020
3. Multiple daily (conventional) gentamicin dosing Dosing in endocarditis Discuss with microbiology for dosing of gentamicin in endocarditis Dosing in pregnancy The standard dose is 1-1.5mg/kg three times a day see below for dose adjustment in renal impairment. Doses should be rounded to the nearest 10mg increment and can be administered by slow intravenous injection or by infusion. NOTE: The gentamicin prescription sticker is designed for once daily gentamicin regimes only. Multiple daily gentamicin prescriptions should be a handwritten prescription in the antibiotic section of the prescription chart. 3.1 Dose adjustment in established renal impairment Dose reduction is required in renal impairment (see Table 2) as gentamicin is excreted into the urine by glomerular filtration. Dose reductions must be based on creatinine clearance (CrCl) calculated using the Cockcroft-Gault equation (see section 2.1.1), rather than the automated MDRD egfr produced by the clinical chemistry laboratory available on NOTIS. There can be a significant difference between the results of the two calculations. Table 2: Multiple daily gentamicin dosing in renal impairment CrCl (ml/min) Dose 20 50 80mg every 12 hours (60mg if <60kg) 10 20 80mg every 24 hours (60mg if <60kg) <10 80mg every 48 hours (60mg if <60kg) 3.2 Dose adjustment in obese patients If the patient is obese defined as more than 120% of their ideal body weight (IBW) a dose correction is required. A dose determining weight needs to be calculated based on the patient s ideal body weight and actual body weight. For calculation of the dose determining weight Calculate ideal body weight (IBW) (kg): o IBW for male patients = 50 + (2.3 x (height in inches - 60)) Gentamicin Prescribing Guideline For Adult Patients Page 8 of 11 Review December 2020
o IBW for female patients = 45 + (2.3 x (height in inches - 60)) Calculate dose determining weight (DDW) (kg) o DDW = IBW + 0.4 (actual body weight (kg) - IBW) Use the dose determining weight to calculate the gentamicin dose required. NOTE: The dosing calculator available on the antibiotic intranet site recommends a dose for a once daily gentamicin regime and therefore should not be used when calculating doses for multiple daily dose regimes. 3.3 Therapeutic drug monitoring (TDM) of gentamicin levels The time and date when levels are to be taken must be clearly annotated on the administration section of the gentamicin prescription. Levels should be taken around the third or fourth dose. A trough, or pre-dose, level and a one hour post-dose, or peak, level are required. Samples should be sent in gold top serum separator tubes to clinical pathology. On the sample request form state the date and time of last dose and the date and time level taken and the prescribed dose (without which the results cannot be interpreted). Renal function should be checked at least three times a week and levels should be checked twice weekly during a treatment course, provided that renal function and urine output are stable. If renal function deteriorates then renal function should be checked daily and gentamicin levels closely monitored. A dose reduction may be required. All patients who are prescribed more than one dose of gentamicin should have a fluid balance chart completed and urine output should be closely monitored. 3.3.1 Interpretation of TDM results Pre-dose levels The pre-dose level must be low to minimise toxicity For conventional multiple daily dosing regimes the target range is <2mg/L For endocarditis the target range is <1mg/L Note that apparently high levels may be due to mistiming of samples Gentamicin Prescribing Guideline For Adult Patients Page 9 of 11 Review December 2020
If the pre-dose level returned is in range (<2mg/L): The current dosing regime can be continued. Further pre-dose levels should be monitored twice weekly, provided that renal function is stable. If the pre-dose level returned is between 2-3mg/L and renal function is unchanged: The dosing interval should be increased, for example, from three times a day to twice a day. If the pre-dose level returned is >3mg/L or renal function has deteriorated: The ongoing need for gentamicin therapy should be reviewed. Further gentamicin doses should be withheld until discussed with microbiology. Post-dose levels The post-dose level must be adequate to ensure efficacy For most infections the target range is 5-10mg/L For serious pseudomonas infections the target range is 7-10mg/L. This will be on the advice of microbiology. For streptococcal or enterococcal infections, such as endocarditis, the target range is 3-5mg/L. The required post-dose level is lower in these cases as the gentamicin is being used for synergistic effect in combination with another antibiotic. If the post-dose level returned is below the target range: The gentamicin is sub-therapeutic. The dose should be increased. Pre- and post-dose levels If the pre-dose level returned is normal and the post-dose level is above the target range: The gentamicin dose should be reduced. The dosing interval should remain unchanged. If both the pre- and post-dose levels returned are above the target range: The next dose(s) should be omitted. The ongoing need for gentamicin therapy should be reviewed. For further gentamicin therapy the interval between doses must be increased after discussion with microbiology. Gentamicin Prescribing Guideline For Adult Patients Page 10 of 11 Review December 2020
Appendix 1: Gentamicin prescription sticker for once daily gentamicin regimes Gentamicin Prescribing Guideline For Adult Patients Page 11 of 11 Review December 2020