Gentamicin Title of Guideline (must include the word Guideline (not protocol, policy, procedure etc) Contact Name and Job Title (author) Directorate & Speciality Date of submission May 2017 Date on which guideline must be May 2020 reviewed (one to five years) Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis) Abstract Key Words Guideline for the treatment of children and young people with intravenous gentamicin Dr Mamatha Mallya SpR Paediatrics Andrew Wignell, Senior Clinical Pharmacist, Paediatrics Dr Meeta Mallik, Consultant Paediatric Nephrologist Directorate: Family Health Children Speciality: Therapeutics Children and young people aged 0-18 yrs requiring intravenous gentamicin treatment Gentamicin, intravenous antibiotics monitoring, nephrotoxic, ototoxic, TDM Statement of the evidence base of the guideline has the guideline been peer reviewed by colleagues? 1a meta analysis of randomised controlled trials 2a at least one well-designed controlled study without randomisation 2b at least one other type of well-designed quasi-experimental study 3 well designed non-experimental descriptive studies (ie comparative / correlation and case studies) 4 expert committee reports or opinions and / or clinical experiences of respected authorities 5 recommended best practise based on the clinical experience of the guideline developer Consultation Process Clinicians and healthcare professionals caring for children and young people (0-18yrs) who require treatment with intravenous gentamicin Target audience Paediatric Clinical Guidelines Group 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.
Document Control Document Amendment Record Version Issue Date Author V1 Dec 2010 V2 Jun 2014 Andy Lunn V3 May 2017 Peter Foxon General Notes: Summary of changes for new version: 1) Table 4: Change in egfr ranges to fit in with CKD staging 2) Table 4: Removal of dose ranges for reduced GFR. Replacement with definitive values 3) Removal of sample timing recommendations due to 24 hour lab availability
Gentamicin Introduction Background Gentamicin is a broad spectrum aminoglycoside antibiotic. It is active against some gram positive and many gram negative organisms: Staphylococcus aureus (including MRSA), Escherichia coli, Pseudomonas aeruginosa and Klebsiella sp. It is inactive against anaerobes and has poor activity against Haemolytic Streptococci, Pneumococci, Enterococcus and H.influenza. Once daily dosing (ODD) is an easier and possibly superior alternative to multiple daily dosing (MDD) and is recommended for most paediatric patients Benefits of ODD include, enhanced concentration- dependent bactericidal activity, post antibiotic effect (PAE), decreased risk of adaptive resistance and less accumulation in the renal tubules and inner ear. Extended dosing profile is recommended for neonates Post Antibiotic Effect (PAE) This refers to suppression of bacterial growth even when no extracellular drug is present, allowing continued efficacy even when serum concentrations fall below the expected minimum inhibitory concentration (MIC). The PAE is longer with a higher aminoglycoside peak serum concentration and in the presence of neutrophils. Toxicity Excretion of Gentamicin is principally via the kidney. The two most important adverse effects are nephrotoxicity and ototoxicity. Both relate to serum drug concentration and duration of therapy. The rate of uptake of gentamicin into the renal tissue is related to the time of exposure to higher levels rather than the absolute concentration. Therefore, giving high doses less frequently may reduce toxicity Monitoring of serum gentamicin levels, renal function (urea, electrolytes and creatinine) and fluid balance is essential
Once Daily Gentamicin Regimen Indications Meningitis/Sepsis in neonates Febrile Neutropenia (stat dose then review see oncology guideline in addition) Surgical conditions- perforated or gangrenous appendicitis (on microbiology advice) Urosepsis- see Paediatric UTI Guideline Exclusion Criteria 1) Multiple daily gentamicin dosing regimens are still recommended for patients in the following categories (please refer to the BNFc for dosing and monitoring recommendations and liaise with pharmacist) Endocarditis Extensive burns Concurrent pregnancy Ascites/excessive third-space volume Where intramuscular gentamicin is necessary (i.e. where intravenous access is not possible) 2) Increased risk of gentamicin toxicity. Patients in the categories below are at increased risk of gentamicin toxicity. The use of gentamicin should be discussed with the patient s consultant and where appropriate an alternative antibiotic should be considered. The gentamicin dosing and monitoring regimen will need to be adjusted (see dosing in renal impairment section later). Patients with acute kidney injury or chronic renal impairment (egfr < 90 ml/min/1.73 m 2 1 ). Renal transplant patients Dialysis patients 3) 4) Patients with myasthenia gravis - gentamicin may impair neuromuscular transmission and must not be given in myasthenia gravis. Neonates with a postmenstrual age of less than 32 weeks - please refer to Neonatal Service clinical guideline (no. 27), the interval between doses is increased to 36 hours. Cautions Renal function and gentamicin levels should be monitored very carefully in patients who are receiving additional nephrotoxic drugs such as: Cyclosporine Tacrolimus Aciclovir Amphotericin NSAIDs. Gentamicin should preferably not be given with other ototoxic drugs (e.g. Furosemide). If concomitant use cannot be avoided, administration should be staggered. 1 egfr (ml/min/1.73 m2) = (height in cm x k) / Creatinine (µmol/l) where k=36 in males 13 years or over and 30 in all other cases (Local modification of Schwartz-Haycock formula)
Dosing Once daily dose regimen Most side effects are dose related, therefore care must be taken with dosage and whenever possible treatment should not exceed 7 days. Table 1: Once daily gentamicin recommended dosages and administration Age Once Daily Dose Administration Neonates 4 mg/kg Slow bolus over 3 mins or (< 28 days) intravenously infusion over 30 mins Children 7 mg/kg Infusion over at least 30 (1 month- 18 years) intravenously mins (maximum 500mg) When prescribing gentamicin - o Round doses down to the nearest 0.5 mg for neonates and to the nearest 1mg for older children o Use the 24 hour clock and avoid midday and midnight o Indicate the timing of levels clearly on the drug chart o Initially prescribe the first 3 doses only to ensure that levels are checked Dosing in obese patients Aminoglycosides distribute poorly into adipose tissue. Ideal body weight (IBW) should be used if the child is obese (extrapolate estimated IBW from the height centiles on growth chart) Administration Parenteral gentamicin should be administered via the intravenous route where possible. Interruptions during the preparation and administration of gentamicin should be minimised, staff should not be disturbed A double checking prompt should be used during the preparation and administration of gentamicin The prescribed dose of gentamicin should be given within 1 hour of the prescribed time. If the dose given is delayed, the prescription chart should be re-written with the exact time of the dose given
Monitoring All patients with normal baseline renal function receiving once daily gentamicin should have: Measurement of renal function (creatinine, urea and electrolytes) at baseline and at least twice weekly thereafter. Measurement of a pre-dose gentamicin level taken before the 2nd dose. Measurement of fluid balance and daily weight where possible. Sampling o o o o Take a blood sample (minimum of 0.5 ml in gold top serum separator tubes (preferred) or red top) 18 to 24 hours after the first dose If sampling from a central venous line, do not sample from the same lumen through which gentamicin was administered, peripheral venous/ finger prick sampling may therefore be required instead This sample should be labelled as a "Pre-dose" Post-dose samples are NOT required for those on once daily dosing Request cards These must include the following information to allow accurate interpretation of the assay result: Patient Details Drug Details Sample Details Name Antibiotic Date and time of sample Hospital number Dose Date and time of last Date of birth Frequency dose Last creatinine and date Indication Type of sample (random, pre-dose, post-dose) Failure to provide this information may result in the sample being rejected by the lab, or incorrect interpretation of the assay result. Target Gentamicin Levels (once daily dose regimen) Table 2: Target pre-dose levels Neonates <28 days Age Children 1month- 18 years Target Pre-Dose (trough) Level < 2 mg/l < 1 mg/l In children with normal renal function (egfr >90 ml/min/1.73m 2 ) and good urine output, measure gentamicin pre-dose level before the 2rd dose and the dose can be given without waiting for the result. If renal function deteriorates (10 point rise in creatinine in µmol/l from baseline), then further doses of gentamicin should be withheld until the trough level is available for review (see below). If pre dose level is within target range Continue current regimen. Further pre-dose levels must be performed every 3-4 days so long as renal function is stable. Adjustments required for higher levels are summarised in the table below.
Table 3: Management of pre-dose gentamicin level results Age Neonate <28 days Child 1month 18 years Gentamicin Pre-Dose Level and Response < 2mg/L 2-3 mg/l >3 mg/l < 1mg/L 1-2 mg/l >2 mg/l Action Continue current regimen. Repeat level after 3-4 days provided renal function stable If renal function stable, increase dosing interval to 36 hourly and repeat levels with the next dose (giving the dose). Review the need for gentamicin therapy, assess renal function. Withhold further doses until discussed with microbiology and levels within target trough range (repeat after 24 hours). Renal Function Monitoring All children should have creatinine and U+Es checked at least thrice weekly- ideally at baseline, at the same time as the first level and once thereafter. The egfr should also be calculated to ensure normal renal function on each occasion. Measure fluid balance and daily weight (where possible) in all children. If any acute deterioration in renal function (10 µmol/l or greater rise in creatinine from baseline) occurs a pre-dose level should be taken before the next dose is due and the dose withheld. o The result must be reviewed before any further gentamicin is given (unless on the direct advice of the patient s consultant, usually in discussion with microbiology). o The requirement for gentamicin should be reassessed and further doses should only be given once the serum level is <1mg/L. Renal Impairment In patients with renal impairment, give a one-off dose according to egfr, as below. egfr (ml/min/1.73m 2 ) Table 4: Gentamicin dosing in patients with renal impairment 60-90 5 mg/kg 30-60 4 mg/kg 15-30 3 mg/kg <15 / Dialysis patient 2 mg/kg One-off Gentamicin Dose Check gentamicin levels 24 hours after the first dose and await the result. If the level is 1 mg/l, recheck levels after 12-24 hours. Do not give any further doses of gentamicin until the level is <1 mg/l. Gentamicin is removed by dialysis. In haemodialysis patients the dose should be given after dialysis.
Indications for Hearing Test New onset Nephrotoxicity Subsequent gentamicin dose administration despite high trough level Longer duration of therapy (> than 7 days) Family history of ototoxicity Concomitant use of Furosemide or other ototoxic drugs Audit Criteria Aminoglycoside fluid balance audit (attached) Gentamicin care bundle compliance chart (attached) Standard: All patients on an aminoglycoside will have their renal function checked at least three times a week and their fluid intake and output accurately monitored to allow early detection of nephrotoxicity. Exceptions to strict fluid balance monitoring include: Oncology patients who leave the ward between doses of antibiotics providing they are well and have normal renal function (must be agreed with registrar or consultant). Cystic fibrosis patients who are well and receiving planned treatment and have normal renal function (must be agreed with registrar or consultant). Breast fed babies whose intake cannot be measured in which case recording all wet nappies is sufficient rather than weighing nappies. Haemodialysis patients who are well enough to be at home between dialysis sessions Patients in the above groups should have their weight measured daily or each time they come to the hospital. References BNF for children 2016-2017 Safer use of intravenous gentamicin for neonates: National Patient Safety Agency Once daily Gentamicin in adults Trust Guidelines Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. Smyth AR, Bhatt J, Cochrane Database Syst. Rev. 2010 Jan 20;(1):CD002009 Extended Interval Aminoglycoside administration for children :A meta-analysis. Contopoulos- Ioannidis et al. Pediatrics 2004 114(1) e111-8 Nottingham Neonatal Service Clinical Guideline No. 27 - Gentamicin Use The Renal Drug Database, accessed via renaldrugdatabase.com on 9 th Mat 2017