Gentamicin Training for junior doctors and pharmacists.
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Transcript of Gentamicin Training for junior doctors and pharmacists.
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Gentamicin
Training for junior doctors and pharmacists
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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.
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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.
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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.
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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
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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.
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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).
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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
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Pharmacokinetics
• Study of how drugs pass through the body:– Includes; absorption, distribution, metabolism and
excretion.
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Absorption
• Gentamicin is not readily absorbed from GI tract, so is given via intravenous route (may also be given IM).
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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.
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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.
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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.
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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.
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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.
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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.
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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
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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
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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)
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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.
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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.”
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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
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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.
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An example of how to complete the Yorkshire Hartford
Gentamicin Regimen drug chart
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Complete the patient details at
the top of the chart
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Rose Tyler 3 Smith
123456
9876641230
60kg5'6"
11/4/50
Rose Tyler 3 Smith
123456
9876641230
60kg5'6"
11/4/50
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Rose Tyler 3 Smith
123456
9876641230
60kg5'6"
11/4/50 Use the table on the back of the
prescription form to
determine ideal body weight
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Rose Tyler 3 Smith
123456
9876641230
60kg5'6"
11/4/50 58kg
Complete the allergy/adverse drug effects box
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Rose Tyler 3 Smith
123456
9876641230
60kg5'6"
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)
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Rose Tyler 3 Smith
123456
9876641230
60kg5'6"
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.
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Rose Tyler 3 Smith
123456
9876641230
60kg5'6"
11/4/50 58kg
NKDA ADr 1/5/09
400mg ADr1/5/09
The first dose is administered to the patient. It is important that the time the
infusion starts starts is recorded. The
first blood test is due 6-14 hours after this time.
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Rose Tyler 3 Smith
123456
9876641230
60kg5'6"
11/4/50 58kg
NKDA ADr 1/5/09
400mg ADr1/5/09 9am KF AS
1/5/09 15.00-23.00
The time the sample is actually
taken must be recorded.
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Rose Tyler 3 Smith
123456
9876641230
60kg5'6"
11/4/50 58kg
NKDA ADr 1/5/09
400mg ADr1/5/09 9am KF AS
1/5/09 15.00-23.00
1/5/09 19.00 10
When the gentamicin
result is available, record this along with
today's serum
creatinine. Serum Serum
creatinine creatinine must be must be
measured measured daily.daily.
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1/5/09
Smith
60kgRose Tyler 3
123456
9876641230
5'6"
11/4/50 58kg
NKDA ADr
400mg ADr1/5/09 9am KF AS
1/5/09 15.00-23.00
1/5/09 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.
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1/5/09
Smith
60kgRose Tyler 3
123456
9876641230
5'6"
11/4/50 58kg
NKDA ADr
400mg ADr1/5/09 9am KF AS
1/5/09 15.00-23.00
1/5/09 19.00 10 5.5 85
2/5/094/5/09
21:0009:00 400mg ADr
The process continues until gentamicin is
no longer required.
Remember to review the need for IV
antibiotics on a daily basis.
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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.
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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.
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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.
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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.
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SummaryHartford Extended Interval
dosingPharmacokinetic 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
AdministrationInfusion in 50-100ml Sodium
Chloride 0.9% over 30 minutes
Bolus over at least 3 minutes
Blood levels
takenOne sample taken 6-14 hours
after the infusion commences
Just before the dose (pre-dose sample) and 1 hour (post-dose sample)
Target
concentrationsNo 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
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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