TDM - Gentamicin & Vancomycin

Question 1

Difference between pharmacokinetics and pharmacodynamics

Answer 1

Pharmacokinetics focuses on measurement of the time course of the drug concentrations in serum and tissues (ADME).

Pharmacodynamics focuses on what the drug does to the body.

Question 2

What is MIC?

Answer 2

The lowest concentration of an antibiotic that completely inhibits the growth of a microorganism in vitro.

Question 3

What are the 3 pharmacodynamic properties of antibiotics that best describe killing activity?

Answer 3

1. Time dependence
2. Concentration dependence
3. Persistent effects

Question 4

Name 5 antibiotics that are concentration dependent

Answer 4

• Aminoglycosides (gentamycin)
• Metronidazole
• Quinolones
• Daptomycin

Question 5

In concentration dependent antibiotics, which ratio on the pk/pd graph is the most important predictor in antibiotic efficacy?

Answer 5

Cmax : MIC

Question 6

For aminoglycosides like gentamicin, what is the best Cmax:MIC ratio to prevent antibacterial resistance?

Answer 6

8 - 10

Question 7

Name 3 time dependent antibiotics

Answer 7

• Vancomycin
• Beta Lactams
• Clindamycin

Question 8

What is the difference between time-dependent and concentration-dependent antibiotics?

Answer 8

Time dependent antibiotics exert optimal bactericidal effect when drug concentrations are maintained above the minimum inhibitory concentration (MIC).

Concentration-dependent antibiotics exert optimal bactericidal effect with increasing levels of drug.

Question 9

In time dependent antibiotics, which ratio on the pk/pd graph is the most important predictor in antibiotic efficacy?

Answer 9

T > MIC

Question 10

Which 2 antibiotics can be seen exerting maximum killing when their time above MIC is 70% of the dosing interval?

Answer 10

Beta lactams and erythromycin

Question 11

Which antibiotic has mixed properties of time-dependent killing and moderate persistent effect?

Answer 11

Vancomycin

Question 12

In practical terms, how can we avoid toxicity when giving drugs that we want at high peak levels?

Answer 12

• Give short term of high peak levels
• Maximise the time above MIC, so have steady levels with reduced peaks and higher troughs. This can be achieved by giving antibiotics by continues infusion.

Question 13

List when TDM is useful

Answer 13

• When drugs have a narrow therapeutic index
• When multiple doses of aminoglycosides and glycopeptides are given
• When giving itraconazole, posaconazole and voriconazole
• TB meds if GI absorption is impairment
• ARVs for treatment of HIV
• Severe infection with renal impairment e.g. Daptomycin

Question 14

For aminoglycosides like gentamicin, why is there no need for GI absorption?

Answer 14

Because it is given intravenously or intramuscularly or topically via ear drops.

Question 15

Does Gentamicin target Gram-positive or Gram-negative bacteria?

Answer 15

Gram-negative

Question 16

Is gentamicin water soluble?

Answer 16

yes

Question 17

1. Why is the volume of distribution of gentamicin less in adults than in children?
2. Which other two groups have altered volume of distribution?

Answer 17

1. Because children have a higher proportion of water per kg of body weight.
2. Patients with ascites and pregnant women.

Question 18

When do we use a patient’s adjusted body weight when dealing with gentamicin?

Answer 18

For very obese patients because gentamicin does not penetrate fat well.
So when the patient’s body weight is 20-30% over their ideal body weight, we use their adjusted body weight.

Question 19

Where does gentamicin distribute?

Answer 19

Gentamicin is distributed in the biliary tract and the epithelial lining fluid which is a thin layer of fluid that covers the mucosa of the alveoli, the small airways and the large airways.

Question 20

Can you give gentamicin to a pregnant woman?

Answer 20

It should be avoided unless it is ESSENTIAL!!
This is because gentamicin crosses the placenta and cause ototoxicity (when a person develops hearing or balance problems due to a medicine) of the foetus.
If gentamicin is given to pregnant women, serum-aminoglycoside concentration monitoring is essential.

Question 21

Gentamicin is given to treat Gram-negative UTI because…

Answer 21

…they concentrate well in urine.

Question 22

What is the half-life of gentamicin in a normal renal function compared to an End-Stage Renal Failure?

Answer 22

2 - 3 hours in normal renal function

24 - 86 hours in ESRF

Question 23

Toxicity of gentamicin

Answer 23

• Gentamicin can cause irreversible ototoxicity. It is rare (0.5 - 3% of patients develop ototoxicity).
• Some people are more genetically prone to ototoxicity and it is thought to be due to a mitochondrial gene that confers the increased risk.
• Patients with a family history of deafness should not be given gentamicin due to the irreversible ototoxicity even when the drug is within therapeutic range.
• The half-life in the perilymph and endolymph of the inner ear is 5-6 times greater than in plasma and therefore progressive accumulation occurs.
• Nephrotoxicity is usually reversible. In Acute Tubular Necrosis, there is no reduction in urinary output but creatinine clearance is reduced. Gentamicin levels will increase as the renal function decreases so if no dose adjustment is made, toxicity can worsen.
• Gentamicin should be avoided in myasthenia gravis as it can impair neuromuscular transmission and cause clinically significant muscle weakness resulting in respiratory depression.

Question 24

Describe the administration of a single-dose or once-daily (OD) Gentamicin

Answer 24

5mg/kg infused over 60 minutes once daily

Single dose or once daily administration in patients without pre-existing renal impairment is as effective as multiple daily dosing.

A pre-dose level should be taken 18-24 hours before the next dose and aim for a trough level of < 1mg/L

Question 25

Advantages of single-dose / once daily administration of Gentamicin

Answer 25

- High peaks are more effective in achieving bacterial kill. - There's a long post-antibiotic effect and therefore it is not necessary to have levels above the MIC all day - There is a reduced risk of nephrotoxicity due to a wash-out period allowed by infrequent dosing. - There's no greater risk of ototoxicity - Monitoring of levels is simpler - Less nursing time is required to administer the antibiotic

Question 26

What antibiotic can you give in combination with Gentamicin to treat Enterococci and Streptococci?

Answer 26

Beta-lactams

Question 27

Multiple Dose (MD) Gentamicin

Answer 27

3-5mg/kg per day every 8-12 hours intravenously infused over 20-30minutes. Less commonly used unless given to pregnant patients, cystic fibrosis patients, patients with severe burns and patients with endocarditis. Both pre- and post- dose levels are required. Take a pre-dose sample which will give the trough level before giving the 3rd or 4th dose after commencement of gentamicin. Post-dose sample which gives the peak level should be taken 1 hour after the end of the infusion.

Question 28

Who should you not give Once-daily Gentamicin to?

Answer 28

- In significant renal impairment (CrCl < 30ml/min) - In burns that cover more than 15-20% of their body surface area. - In ascites greater than 10% of body weight. - In pregnancy - In cystic Fibrosis Consult local guidelines for paediatrics.

Question 29

What information do you include in a protocol concerning antibiotic dosing and monitoring?

Answer 29

``` When to use/not use OD Calculations for obese patients Calculating renal function Dosing table How to administer dose When to take levels What levels to aim for What to do if levels are too low / too high References / Review date ```

Question 30

Clinical case: Miss LC is 46 years old. Treated for abdominal sepsis. (Weight = 95kg, Height = 5ft 4”, SrCr = 74). Given amoxicillin 1g IV tds, Metronidazole 500mg IV tds, gentamicin 360mg OD. First dose was given 2pm yesterday. No levels were taken this morning. The nursing staff are asking whether they can give the second dose at 2pm today? can you?

Answer 30

You can give a 2nd dose without waiting for level results in patients who are less than 65 years old with good renal function.

Question 31

What is Vancomycin?

Answer 31

Vancomycin is a glycopeptide antibiotic with activity against gram-positive infections.

Question 32

What can vancomycin treat?

Answer 32

``` MRSA sepsis Intravascular catheter-related bloodstream infections Skin and soft tissue infection Pneumonia Infective endocarditis ``` Vancomycin is also an alternative to penicillin for patients who have a history of serious penicillin allergy.

Question 33

Why is vancomycin available as capsules?

Answer 33

Oral vancomycin is used for its local effect to treat c diff infections (Clostridioides difficile-associated diarrhea (also called C diff)). C diff is a type of bacteria that causes severe diarrhea.

Question 34

Is vancomycin water soluble?

Answer 34

Yes

Question 35

Metabolism of Vancomycin?

Answer 35

Vancomycin is poorly metabolised and is primarily eliminated unchanged.

Question 36

What is the most common adverse reaction caused by rapid infusion of Vancomycin?

Answer 36

Red Man Syndrome (also known as Red Neck Syndrome)

Question 37

What should the infusion rate of Vancomycin not exceed?

Answer 37

10mg/minute

Question 38

Do you give a loading dose when giving vancomycin?

Answer 38

Yes. | A loading dose is always given to all patients who are starting on Vancomycin.

Question 39

Why is a loading dose given in vancomycin?

Answer 39

To reach the therapeutic range quicker.

Question 40

Vancomycin monitoring

Answer 40

- Trough levels (0-60 minutes pre-dose) should be taken before giving the 3rd or 4th dose to ensure they are taken at steady state - The dose can be given after trough levels are taken providing serum creatinine is normal with good urine output. - Do not wait for levels to come back before giving dose unless it is for dialysis patient/severe renal impairment. - If levels are normal and patients renal function is stable, twice weekly monitoring of pre dose levels is recommended. Routine peak level monitoring is unnecessary for vancomycin.

Question 41

What is the loading dose and maintenance dose in vancomycin based on?

Answer 41

The loading dose is based on Body weight. The initial maintenance dose is base on renal function.

Question 42

Clinical case: ``` Male patient given Vancomycin for cellulitis caused by MRSA. Age: 76 Weight: 75kg Height: 5ft 10 SrCl: 105 (stable) CrCl: 56l/min Loading dose: 1.5g two days ago Maintenance dose : 750mg bd started yesterday. ``` It is now 10pm. The vancomycin levels taken this morning were 36mg/L. The nurse says "I am not going to give the next dose. Is that okay?" Is it okay?

Answer 42

Since the morning levels were 36mg/L, the nurse needs to contact the pharmacy. Think it through: - What levels being aimed for? - Why could the level be high? Look for errors, Look for changes in the patients clinical condition. If there has been no errors made - request for urgent repeat vancomycin levels to confirm if possible - Repeat level in morning; if the level comes back <20mg/L, we would then give a dose.