Training for junior doctors and pharmacists Gentamicin Training for junior doctors and pharmacists

About this presentation This e-Learning package is in two parts. The first part will give you some background on gentamicin and the dosing regimens used to ensure safe and effective therapy. The second part looks at the version of the Hartford extended-interval regimen adopted by many trusts across Yorkshire.

Learning Objectives After viewing this presentation, you should Understand the mechanism of action, indications and contra-indications of gentamicin Understand basic pharmacokinetics, as they apply to Gentamicin Be able to apply the above to use the Yorkshire Hartford Gentamicin regimen. Understand the principles of pharmacokinetic and synergistic gentamicin regimens.

Pharmacology Gentamicin is a member of the aminoglycoside family of antibiotics.  Aminoglycosides are bactericidal antibiotics active against many aerobic gram-negative bacteria and some aerobic gram-positive bacteria. Aminoglycosides act by disrupting protein synthesis at the bacterial ribosome. First aminoglycoside (streptomycin) discovered in 1943. Produced by species of Streptomyces and Micromonospora. Those derived from the latter e.g. gentamicin have an ‘i’ in the ‘mycin’ suffix. Composed of linked ring of amino sugars and aminoosubstituted cyclic polyalcohol (aminocyclitol). This moiety usually consists of 1 of 2 streptamine derivatives; streptidine or deoxystreptidine. The latter may be subdivided into the neomycin and kanamycin groups. The latter includes gentamicin, tobramycin and netilmicin. Gentamicin is active against staphylococci, and gram-negative bacilli including pseudomonas spp. Aminoglycosides penetrate poorly into mammalian cells, so of limited value in infections caused by intracellular bacteria.

Pharmacology Aminoglycosides are believed to act by binding to the 30S ribosomal sub-unit causing Misreading of the mRNA codon, leading to errors in amino-acid sequencing Disruption of polysomes, reducing the efficiency of protein synthesis Inhibition of the translocation of tRNA between A and P ribosomal binding sites Cause misreading of mRNA codons, producing defective proteins which may affect cell membrane integrity, may cause formation of non-functioning initiation complexes, or inhibition of translocation during formation of polypeptides. None of these theories fully explains potent bactericidal activity of aminoglycosides compared with other protein synthesis inhibitors. Enter bacteria by active transport involving respiratory quinones. These are absent in streptococci, explaining their resistance, but action against them may be improved by synergy with penicillins.

Side-effects of Gentamicin Damage to the cochlear and vestibular apparatus  loss of balance, tinnitus, loss of hearing.  May cause renal damage - risk of nephrotoxicity is increased with prolonged treatment.  Concurrent use of other nephrotoxic drugs may exacerbate renal damage.  Use with ototoxic diuretics, e.g. furosemide, may increase risk of ototoxicity and nephrotoxicity. May cause allergic reactions, nausea, vomiting and rashes.

Cautions and Contra-indications Gentamicin is contra-indicated in severe renal impairment and pregnancy. It is contra-indicated in myasthenia gravis (due to its effects on nerve cells). It may increase the activity of neuromuscular blocking agents (although rarely clinically significant). May cause neuromuscular blockade and respiratory paralysis with curare-type muscle relaxants.

So why use Gentamicin? Because it is very effective when used correctly. If levels are monitored appropriately, severe renal impairment and ototoxicity rarely occur. Low incidence of provoking Clostridium difficile infections Indicated in urinary-tract infections, chest infections, bacteraemia, septicaemia, and other systemic infections due to sensitive organisms. Usually active against most strains of : Escherichia coli, Klebsiella spp., Proteus spp. (indole positive and indole negative), Pseudomonas aeruginosa, Staphylococci, Enterobacter spp., Citrobacter spp and Providencia spp. Local guidelines recommend use in: Acute, hospital acquired UTIs; Pyelonephritis; Acute prostatitis; Severe diabetic foot; Listeria meningitis (with amoxicillin); Peritonitis (with Vanc and Met); Pelvic inflammatory disease; Pueperal sepsis or TOP; Infective endocarditis (with fluclox or benpen); Septicaemia (with Taz, vanc or dapto); Neutropenic sepsis; Surgical, orthopaedic and head and neck prophylaxis.

Pharmacokinetics Study of how drugs pass through the body: Includes; absorption, distribution, metabolism and excretion.

Absorption Gentamicin is not readily absorbed from GI tract, so is given via intravenous route (may also be given IM).

Distribution Gentamicin is highly hydrophilic, i.e. not distributed into body fat and minimally distributed into tissue fluids. When calculating an appropriate dose, consider using the patient's lean mass (mass without excess fat = ideal body weight). Usually calculate dose using lower of actual or ideal body weight.

Elimination Gentamicin is excreted unmodified, by the kidneys and so follows "first order kinetics". i.e. drug is cleared from blood at a rate proportional to it's concentration. After a dose, level in the blood decays exponentially.

Elimination Gentamicin is excreted unmodified, by the kidneys and so follows "first order kinetics". i.e. drug is cleared from blood at a rate proportional to it's concentration. After a bolus dose, level in the blood decays exponentially. Kidneys continuously removing a constant fraction of gentamicin in the blood. As level goes down with time, less is excreted. If patient’s renal function compromised, excretion less efficient, so must be considered before commencing a course.

Dosing Regimens Two types of regimens commonly used in UK: Pharmacokinetic Extended Interval. A 1996 paper (1) looked at meta-analyses comparing these regimens and found: Both regimens had equivalent efficacy, but; Extended Interval gentamicin had reduced nephrotoxicity. 1Mega-analysis of meta-analysis: an examination of meta-analysis with an emphasis on once-daily aminoglycoside comparative trials. Pharmacotherapy. 1996 Nov-Dec;16(6):1093-1102.

Extended Interval Dosing May also be known as: Once daily dosing/administration Hartford dosing Pioneered at Hartford hospital (Connecticut, USA) incorporating pharmacodynamic concepts of post-antibiotic effect and concentration-dependent kill. Regimen maximises bacterial kill whilst minimising toxicity. Post antibiotic effect is the apparent continuation of bacterial kill after the drug is cleared. Gentamicin is a concentration-dependant killer.

Hartford Regimen – key points Hartford regimen is based on a consistent dose of 7mg/kg gentamicin calculated from the lower of the ideal body weight or actual body weight. Serum level is measured 6-14 hours after first dose to determine dosage interval. Nomogram is used to determine whether patient should receive gentamicin every 24 hours, 36 hours or 48 hours.

Unless specifically recommended by microbiology Patient suitability Do NOT use Hartford regimen for Pregnant women Children < 16 years Urology surgery prophylaxis Any patient who has Ascites Cystic fibrosis Endocarditis (unless requested by microbiology consultant) Major burns Renal transplant Renal impairment – creatinine clearance <30mL/min Unless specifically recommended by microbiology

Calculating creatinine clearance Don’t used automated eGFR Use a Cockcroft-Gault estimate: Men: (140 – age) x Weight (kg) x 1.23 Serum creatinine (micromol/L) Women: (140 – age) x Weight x 1.04 Serum creatinine

Dose calculations Ideal body weight calculations: Female IBW = 45kg + (2.3kg x no. of inches over 5 feet) Male IBW = 50kg + (2.3kg x no. of inches over 5 feet) If patient is < 5 feet tall, use IBW = 45kg (females) or 50kg (males)

Administration Dilute gentamicin dose in 50-100mL sodium chloride 0.9% and give by intravenous infusion over 1 hour. Record exact start time of the infusion on drug chart.

Measurement of levels Look at your local policy for when your lab can receive gentamicin assays Do not take blood sample from the IV line used for gentamicin administration! Take one blood sample (ideally 10mL) between 6 and 14 hours after the start of first infusion in a plain tube (clotted blood). Document on microbiology request form EXACT time and date infusion was set up and EXACT time and date sample was taken in addition to patient details and “Hartford Gentamicin Regimen.”

Selecting dose interval If level falls in area designated 24 hours, 36 hours or 48 hours, dosing interval is 24, 36 or 48 hourly respectively. If level falls on a line between dosing intervals, choose longer interval. If level is above 48 hour line then STOP the treatment. If gentamicin is to be continued, take daily levels, but do not give any more gentamicin until level falls below 2mg/L

Repeat monitoring Check U & Es and creatinine daily to monitor renal function. If serum creatinine is rising significantly (≥20%) and time is within 6-14 hours of infusion, measure level ASAP, otherwise contact Microbiologist for advice.

An example of how to complete the Yorkshire Hartford Gentamicin Regimen drug chart

Complete the patient details at the top of the chart

Rose Tyler 3 Smith 123456 9876641230 60kg 5'6" 11/4/50 Rose Tyler 3 Smith 123456 9876641230 60kg 5'6" 11/4/50

Rose Tyler 3 Smith 123456 9876641230 60kg 5'6" 11/4/50 Use the table on the back of the prescription form to determine ideal body weight

Complete the allergy/adverse drug effects box Rose Tyler 3 Smith 123456 9876641230 60kg 5'6" 11/4/50 58kg Complete the allergy/adverse drug effects box

Rose Tyler 3 Smith 123456 9876641230 60kg 5'6" 11/4/50 58kg NKDA ADr 1/5/09 Check the patient is not excluded. Calculate the Cockroft and Gault estimate of creatinine clearance to ensure that the patient has sufficient renal function to receive this regimen. (For this patient, they have a serum of creatinine of 90micromol/L and a creatinine clearance of 56ml/min)

Rose Tyler 3 Smith 123456 9876641230 60kg 5'6" 11/4/50 58kg NKDA ADr 1/5/09 Use the lower of the Actual Weight or Ideal Body Weight to calculate the 7mg/kg dose, rounded to the nearest 40mg. Alternatively, use the table on the reverse of the chart to determine the dose.

Rose Tyler 3 Smith 123456 9876641230 60kg 5'6" 11/4/50 58kg NKDA ADr 1/5/09 400mg The first dose is administered to the patient. It is important that the time the infusion starts is recorded. The first blood test is due 6-14 hours after this time.

The time the sample is actually taken must be recorded. Rose Tyler 3 Smith 123456 9876641230 60kg 5'6" 11/4/50 58kg NKDA ADr 1/5/09 400mg 9am KF AS 15.00- 23.00 The time the sample is actually taken must be recorded.

Rose Tyler 3 Smith 123456 9876641230 60kg 5'6" 11/4/50 58kg NKDA ADr 1/5/09 400mg 9am KF AS 15.00- 23.00 19.00 10 When the gentamicin result is available, record this along with today's serum creatinine. Serum creatinine must be measured daily.

This chart also shows when the next level is due. 1/5/09 Smith 60kg Rose Tyler 3 123456 9876641230 5'6" 11/4/50 58kg NKDA ADr 400mg 9am KF AS 15.00- 23.00 19.00 10 5.5 85 Refer to microbiology or pharmacy if serum creatinine is rising sharply Plot the gentamicin level against the hours-post-dose on the chart on the back. This chart also shows when the next level is due.

1/5/09 Smith 60kg Rose Tyler 3 123456 9876641230 5'6" 11/4/50 58kg NKDA ADr 400mg 9am KF AS 15.00- 23.00 19.00 10 5.5 85 The process continues until gentamicin is no longer required. Remember to review the need for IV antibiotics on a daily basis. 2/5/09 4/5/09 21:00 09:00 400mg ADr

Pharmacokinetic Dosing Also known as: Traditional dosing Multiple-dose-per-day dosing Tailored dosing Conventional dosing Use for patients excluded from Hartford. Bolus doses calculated according to estimated measures of distribution and excretion of gentamicin. Most preparations only licensed for multiple-dose per day administration.

Pharmacokinetic dosing Discuss with microbiology or pharmacy appropriate doses Measure levels after 3 – 5 doses. Need to monitor both peak (post-dose) and trough (pre-dose) levels. Take pre-dose sample immediately (1 hour) before next dose, post-dose 1 hour after dose is finished.

Synergistic Dosing Form of pharmacokinetic dosing, used in treatment of endocarditis, and other streptococcal or enterococcal infections. Usually gentamicin plus cell wall inhibitor (e.g. benzylpenicillin, flucloxacillin or vancomycin). Combination synergistic, so lower serum concentrations of gentamicin needed - typically peak of 3-5mg/L and trough of less than 1mg/L. Synergy only occurs when both gentamicin and cell wall inhibitor given together – hence multiple doses per day.

Synergistic Dosing Endocarditis usually requires a minimum of 2 weeks aminoglycoside therapy, so lower serum concentrations minimise nephrotoxicity and ototoxicity. In young patients without renal impairment, start synergistic dosing with a dose of 1mg/kg 8 hourly. For elderly patients / patients with poor renal function contact Pharmacist or Microbiologist for advice.

Hartford Extended Interval dosing Pharmacokinetic Dosing  Summary Hartford Extended Interval dosing Pharmacokinetic Dosing Initial Dose 7mg/kg, with dose frequency altering according to nomogram based upon gentamicin serum concentration Adults: 2mg/kg loading dose, then refer to pharmacy or microbiology for maintenance dose Synergistic dosing for endocarditis 1mg/kg TDS (or less frequently) Paediatrics: 2.5mg/kg TDS Adjust dose and frequency based upon gentamicin serum concentration Administration Infusion in 50-100ml Sodium Chloride 0.9% over 30 minutes Bolus over at least 3 minutes Blood levels taken One sample taken 6-14 hours after the infusion commences  Just before the dose (pre-dose sample) and 1 hour (post-dose sample) Target concentrations No target - use the nomogram to identify the patient's required dosing interval. Standard: Pre-dose <2mg/L, Post-dose 6-10mg/L  Synergistic dosing for endocarditis: Pre-dose <1mg/L, Post-dose 3-5mg/L  

Credits Yorkshire Hartford Gentamicin developed with the assistance of the Yorkshire and Humber Antimicrobial Pharmacist network In particular: Pam Garnett, Peter Taylor, Alison Haigh, Andy Karvot and Philip Howard Regimen developed from Nicolau et al Experience with a Once-Daily Aminoglycoside Program Administered to 2,184 Adult Patients. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1995; 39(3): 650–655 This Yorkshire Hartford regimen protocol and associated materials can be used, without guarantee or warranty by other healthcare professionals providing it is on a not-for-profit basis and any resulting materials are shared on a similar basis