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.

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 concentration-dependent 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 3 Smith

123456

9876641230

60kg5'6"

11/4/50

Rose Tyler 3 Smith

123456

9876641230

60kg5'6"

11/4/50

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

Rose Tyler 3 Smith

123456

9876641230

60kg5'6"

11/4/50 58kg

Complete the allergy/adverse drug effects box

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)

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.

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.

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.

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.

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.

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.

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.

 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

 

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