Transcript Gentamicin - NHS Networks

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 extendedinterval 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.
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
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).
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
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 concentrationdependent kill.
• Regimen maximises bacterial kill whilst
minimising toxicity.
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.
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
123456
9876641230
Smith
3
5'6"
11/4/50
60kg
Rose Tyler
123456
9876641230
Smith
3
5'6"
11/4/50
60kg
Use the table on
the back of the
prescription
form to
determine ideal
body weight
Rose Tyler
123456
9876641230
Smith
3
5'6"
11/4/50
60kg
58kg
Complete the
allergy/adverse
drug effects box
Rose Tyler
123456
9876641230
Smith
3
5'6"
11/4/50
NKDA
60kg
58kg
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
123456
9876641230
Smith
3
5'6"
11/4/50
NKDA
60kg
58kg
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.
9876641230
5'6"
11/4/50
NKDA
1/5/09
400mg
Smith
3
Rose Tyler
123456
ADr
60kg
58kg
ADr 1/5/09
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.
9876641230
Smith
3
Rose Tyler
123456
5'6"
11/4/50
NKDA
1/5/09
1/5/09
400mg
15.0023.00
ADr
60kg
58kg
ADr 1/5/09
9am
KF AS
The time the
sample is
actually
taken must
be recorded.
9876641230
Smith
3
Rose Tyler
123456
5'6"
11/4/50
NKDA
1/5/09
1/5/09
400mg
15.0023.00
1/5/09
ADr
19.00
10
60kg
58kg
ADr 1/5/09
9am
KF AS
When the
gentamicin
result is
available,
record this
along with
today's
serum
creatinine.
Serum
creatinine
must be
measured
daily.
9876641230
Smith
3
Rose Tyler
123456
5'6"
11/4/50
58kg
NKDA
1/5/09
1/5/09
400mg
15.0023.00
1/5/09
ADr
19.00
10
60kg
Refer to
microbiology
or pharmacy if
serum
creatinine is
rising sharply
ADr 1/5/09
9am
5.5
KF AS
85
Plot the
gentamicin
level against
the hourspost-dose on
the chart on
the back.
This chart
also shows
when the next
level is due.
9876641230
Smith
3
Rose Tyler
123456
5'6"
11/4/50
58kg
NKDA
1/5/09
1/5/09
2/5/09
4/5/09
400mg
15.0023.00
21:00
09:00
1/5/09
400mg
ADr
19.00
ADr
10
60kg
ADr 1/5/09
9am
5.5
KF AS
85
The process
continues until
gentamicin is
no longer
required.
Remember to
review the
need for IV
antibiotics on a
daily basis.
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.
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.
Summary
Initial Dose
Hartford Extended Interval
dosing
Pharmacokinetic Dosing
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
Infusion in 50-100ml Sodium
Administration
Chloride 0.9% over 30
minutes
Blood levels
One sample taken 6-14 hours
taken
after the infusion
commences
Target
No target - use the nomogram
concentrations
to identify the patient's
required dosing interval.
Bolus over at least 3 minutes
Just before the dose (pre-dose sample) and
1 hour (post-dose sample)
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,
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