TDM Vancomycin and Gentamicin

Question 1

What type of antibiotic and coverage is Vancomycin?

Answer 1

Vancomycin is a glycopeptide antibiotic and covers both aerobic and anaerobic gram-positive infections including methicillin-resistant S. aureus (MRSA).

Question 2

When is Vancomycin indicated?

Answer 2

Usually severe staphylococcal infections (skin and soft tissue are often common) that cannot or have failed to respond to penicillins and cephalosporins.

Indications include:
Diabetic foot infections and leg ulcers
Infected leg ulcers
Complicated skin infections
Infective endocarditis
CAP/HAP

Clostridium difficile infections also

Question 3

What formulation of Vancomycin is used?

Answer 3

Vancomycin is always administered intravenously unless it is indicated for use in treating C. diff infections whereby oral administration is used. This is because the drug has poor oral absorption within the gastrointestinal tract making it ideal for treating a GI infection due to the prolonged exposure.
If oral Vancomycin is prescribed for any other indication this should be queried.

Question 4

Is Vancomycin dosing based on renal function?

Answer 4

Vancomycin dosing is split into a loading and a maintenance dose.
Loading dosing which are given as an infusion calculated only on actual body weight
Maintenance dosing, which is initiated after the correct interval following the loading doses are based on creatinine clearance.

Question 5

How should CrCl be calculated in obese patients?

Answer 5

Creatinine clearance in obese patients should be calculated from using their adjusted body weight:
Adjusted BW = IBW + 0.4(ABW – IBW)

Question 6

In patients with low creatinine which value should be used?

Answer 6

In patients with low creatinine (<60micromol/L), use 60micromol/L. Do not
use eGFR

Question 7

Why is TDM required for Vancomycin?

Answer 7

Drug level monitoring of Vancomycin is required both to maintain efficacy but also to reduce toxicities. Vancomycin has a minimum inhibitory concentration of 5mg/L, which is the lowest concentration of antibiotic which inhibits bacterial growth. But also Vancomycin at high levels can cause nephrotoxicity and otoxicity.

Question 8

What percentage of Vancomycin is renally excreted?

Answer 8

About 80-90% of the drug is excreted unchanged in the urine within 24 h in patients with normal renal function.
Lecture slides state over 90%.

Question 9

When should Vancomycin levels be taken?

Answer 9

Vancomycin levels should be taken as a trough level taken at the maximum amount of time since the last was given and just before the next, therefore known as a pre-dose level.
When they should be taken depends on the regimen patients are taking:
- Before 4th dose if on BD dosing
- Before 3rd dose if on OD dosing
- Before 2nd dose if on 48-hourly dosing
- Before each dose if on STAT dosing

Question 10

How should Vancomycin levels be recorded?

Answer 10

Record the time that the last dose was given and the time that the blood sample was
taken on the request form, and record the sample time on the sample tube.

Question 11

What are the target therapeutic ranges for Vancomycin?

Answer 11

Trough levels of:
10-15mg/L for general infections
15-20mg/L severe infections and bone and joint infections

Question 12

List some of the severe infections in which a target Vancomycin level of 15-20 mg/L is required.

Answer 12

Bacteraemia,
Infective endocarditis
Osteomyelitis
Meningitis
Pneumonia
Severe skin and soft tissue infections e.g. necrotising fasciitis

Question 13

If the patient is within the target therapeutic range for Vancomycin what is their ongoing monitoring?

Answer 13

If the patient is in range having had their trough level taken, monitor the patient’s pre-dose levels every 2-3 days.

Note this is different than pre 2nd/3rd dose as the patient may be on a twice daily regimen.

Or is this 3/4 days - this is what I think Uni said - check. NNUH guidelines says 2/3 days.

Question 14

What is the significance of Vancomycin’s pharmacokinetics?

Answer 14

Vancomycin has linear pharmacokinetics, otherwise known as first order. This means that the exposure is proportional to the dose. By doubling the dose, you will double the level; by halving the dose you will halve the level.

Question 15

What would the most appropriate actions to take if a pre-dose trough level is less than 10mg/L?

Answer 15

Increase dose by 50% and consider reducing the dosage interval or
seek advice (for doses above 2g bd discuss with pharmacy/microbiology for advice)

Question 16

What would the most appropriate actions to take if a pre-dose trough level is between 10-15mg/L?

Answer 16

If the patient is responding, maintain the present dosing regimen
If the patient is seriously ill, consider increasing the dose amount or reducing the dosage interval to achieve a trough level of 15-20mg/L

Question 17

What would the most appropriate actions to take if a pre-dose trough level is between 15-20mg/L?

Answer 17

Within target range for treatment of severe infections (bacteraemia, infective endocarditis, osteomyelitis, meningitis, pneumonia and severe skin and soft tissue infections e.g. necrotising fasciitis).
Maintain present dosage regimen. If treating less severe infections, a
pre-dose level of 15-20mg/L is acceptable to then administer the next dose

Question 18

What would the most appropriate actions to take if a pre-dose trough level is greater than 20mg/L?

Answer 18

To summary, you would consider reducing the dose or increasing the dosing interval. An reduction of how much is dependent upon pre-existing level and therapeutic target but may look at reducing it by about 50%.
However before administering another dose stop until < 20mg/L then seek advice.

Question 19

Should you wait to receive the trough level of Vancomycin from microbiology before administering the next dose?

Answer 19

If the renal function is stable, give the next dose before the trough result is
available. If the renal function is deteriorating, withhold until the result is
available and follow advice in table.

Question 20

Following a dose/regimen adjustment what is the ongoing monitoring?

Answer 20

Resumes at taking a pre-dose trough level before 3rd or 4th dose.
Remember if the dose is particularly high and you’ve had to hold therapy in order for the level to drop, another pre-dose level should be taken before recommencing therapy.
If renal function is unstable, Vancomycin levels should be taken daily alongside CrCl

Question 21

What considerations should be made if the level is unexpectedly high or low?

Answer 21

Were the dose and sample times recorded accurately?
Was the correct dose administered?
Was the sample taken from the line used to administer the drug?
Was the sample taken during drug administration?
Has renal function declined or improved?
Does the patient have oedema or ascites?

Question 22

What is the Vancomycin dosing regimen for patients with renal failure?

Answer 22

STAT doses to be given, calculated using the patient’s actual body weight.
No loading doses are required in these patients (those with a CrCl below 20mL/min or on haemodialysis or peritoneal dialysis).
1g Vancomycin in 200mL 0.9% sodium chloride over 100 minutes. Vancomycin may be dialysed out so should be given in the last 100 minutes of dialysis.

Question 23

When should Vancomycin levels be taken for patients with renal failure?

Answer 23

A blood sample for a Vancomycin serum concentration should be taken after 24 hours for non-dialysis/peritoneal dialysis patients and at the start of each subsequent haemodialysis sessions for haemodialysis patients before administering another dose.

Question 24

What is the target Vancomycin level for patients with renal failure (CrCl less than 20mL/min)?

Answer 24

Target Vancomycin range for those with renal failure is less than 15mg/L

Question 25

What would be the most appropriate action to take if a pre-dose Vancomycin level for a renal patient was received at 14mg/L?

Answer 25

Patients with a Vancomycin level equal to or below 15mg/L:

Give a further dose of Vancomycin. Recheck levels in 24 hours for non-dialysis/PD patients

Recheck levels just before the start of the next dialysis session for haemodialysis patients

Question 26

What would be the most appropriate action to take if a pre-dose Vancomycin level for a renal patient was received at 17.6mg/L?

Answer 26

Patients with a Vancomycin levels between 15 and 25mg/L:

Do not give a further dose.

Recheck levels in 24 hours for non-dialysis/PD patients and at each dialysis session for HD patients

Question 27

What would be the most appropriate action to take if a pre-dose Vancomycin level for a renal patient was received at 28.7mg/L?

Answer 27

Patients with a Vancomycin levels greater than 25mg/L:

Do not give a further dose.
Recheck levels in 48 hours for nondialysis/PD patients and at each dialysis session for HD patients

Question 28

What is the equation which helps to dictate new maintenance doses of Vancomycin?

Answer 28

New dose is equal to:
Target levels at a steady state x old dose/current level at steady state

Question 29

Which type of hypersensivity reaction should you monitor for with Vancomycin?

Answer 29

Red man syndrome, an anaphylactoid reaction related to the amount and rate of Vancomycin infusion. This can cause flushing and erythema and itching of the upper body including the neck and face.

Question 30

When is red man syndrome likely to occur (in relation to the rate of infusion)?

Answer 30

When the rate of infusion exceeds 10mg/min.

Question 31

What type of antibiotic and coverage is Gentamicin?

Answer 31

Gentamicin is an aminoglycoside antibiotic which is considered effective against aerobic Gram-negative organisms, some Gram-positive organisms (such as Staphylococcus aureus) and Pseudomonas aeruginosa.

Question 32

When is Gentamicin indicated?

Answer 32

Gentamicin is used in severe infections caused by usually gram negative bacterium. Gentamicin is commonly used to treat urinary tract infections, sepsis, intra-abdominal infections, endocarditis, pelvic inflammatory disease and complicated skin, bone and soft tissue infections.

Question 33

Describe the mechanism of action of Gentamicin.

Answer 33

Aminoglycosides display concentration-dependent bactericidal activity against “most gram-negative aerobic and facultative anaerobic bacilli” but not against gram-negative anaerobes and most gram-positive bacteria. Aminoglycosides work by inhibiting protein synthesis by binding to specifically the A-site on the 16S ribosomal RNA of the 30S ribosome.

Question 34

What are some of the limitations to use of Gentamicin and other aminoglycosides?

Answer 34

The mechanism of action of aminoglycosides is oxygen dependent and therefore this class of antibiotics work poorly in anaerobic environments, such as abscesses.
Furthermore the antibiotics itself efficacy is limited by poor penetration into the bacterial membrane. Therefore efficacy is increased with co-administration of B-lactams, such increase in efficacy is seen with Tazocin.

Question 35

Describe the activity of Gentamicin.

Answer 35

Gentamicin has concentration dependent activity which means The magnitude by which the peak concentration exceeds the MIC (typically expressed as the peak-to-MIC ratio) best correlates with antimicrobial activity. Essentially the greater the peak, the greater the bactericidal activity.
Gentamicin also has a post antibiotic effect meaning that after administration the trough level can drop below the minimum inhibitory concentration and still have bactericidal activity.

Question 36

Describe the distribution of Gentamicin in different body compartments.

Answer 36

The drug itself is hydrophilic and therefore mainly distributed in body water rather than in adipose tissue. This can mean however conditions where there are alters in body compartments such as pregnancy and ascites can affect the distribution of the drug and should be taken into consideration.

Question 37

Describe the clearance of Gentamicin.

Answer 37

Gentamicin is almost entirely renally excreted with the median clearance (CL) of gentamicin in adult patients with normal renal function (creatinine clearance [CLCR] >60 mL/min) is 4.58 L/h/70 kg (range 4.31–5.12), averaged for those with a weight of 70kg. This is a similar rate to the CrCl.
Non-renal clearance is roughly 0.002 L/hr/kg/

Question 38

In which conditions may the non-renal excretion of Gentamicin be exemplified?

Answer 38

When a patient has poor renal function, either acutely in AKI or in CKD where the patient is on dialysis, clearance of the drug relies on other routes of elimination.

Non-renal excretion of drugs also occurs in cystic fibrosis, where bile acid malabsorption increases the excretion of drugs in bile as well as within bronchial secretions, a result of acute pulmonary infections.

Question 39

Describe the toxic monitoring parameters for Gentamicin.

Answer 39

Nephrotoxicity:
This should be closely monitored by assessing renal function with creatinine should be monitored daily whilst patient is on this antibiotic therapy

Ototoxicity:
Drug can cause irreversible damage and patient should monitored for tinnitus, dizziness, poor balance and hearing loss. Therapy should be stopped if suspected

Question 40

How would a decline in renal function be detected?

Answer 40

A temporary elevation in creatinine level (ref. range is 0.7 to 1.3 mg/dL for men and 0.6 to 1.1 mg/dL women), which suggests the kidneys aren’t working as effectively in excreting the waste product meaning there is a decrease in creatinine clearance and eGFR. A decline in renal function would also be detected by a reduced urine output/oligouria.

Question 41

When should you seek advice regarding changes in creatinine levels following initiation of Gentamicin?

Answer 41

If renal function unstable (e.g. change in creatinine of > 15‐20%), or if patient becomes oliguric (less than 400mL of urine in 24 hours).

Question 42

What other factors exacerbate risk of Gentamicin induced nephrotoxicity?

Answer 42

Concurrent administration with other nephrotoxic drugs - NSAIDS, ACEI, ARBs
Prior exposure
Age - elderly have a naturally declined renal function
Co-existing CKD/Renal disease
Prolonged Gentamicin therapy

Question 43

Is Gentamicin ototoxicity concentration dependent?

Answer 43

It is independent of concentration used however it is associated with prolonged use of greater than 10 days but can occur after 72 hours and is secondary to drug accumulation within the inner ear.

Question 44

How should suspected Gentamicin induced ototoxicity be dealt with?

Answer 44

Stop treatment if ototoxicity is suspected and refer to microbiology or an
infection specialist for advice on future therapy

Question 45

When should an audiology assessment take place if the patient is receiving a longer course of Gentamicin?

Answer 45

If gentamicin continues for > 7 days, consider referring to audiology for
assessment.

Question 46

What are the contraindications to Gentamicin therapy?

Answer 46

Hypersensivity to Gentamicin or any of the excipients
Pregnancy
Myasthenia Gravis

Question 47

What are the cautions to Gentamicin therapy?

Answer 47

• Patients with decompensated liver disease ‐ aminoglycosides are associated with an increased risk of renal failure
• Chronic Kidney Disease (CKD) Stage 4+
• Known or suspected acute kidney injury in the previous 48 hours (50% increase in baseline serum creatinine or oliguria > 6 hours

Question 48

Co-administration of which other drugs aside from nephrotoxics cautions use of Gentamicin therapy?

Answer 48

Neuromuscular blockers
Potent diuretics
Other aminoglycosides

Question 49

What are the two dosing regimens of Gentamicin?

Answer 49

Either once daily or once every 48 hours

Question 50

Is once daily or every 48 hourly therapy preferential?

Answer 50

It is dependent really on the patient however 48 hourly dosing is at least as efficient as 24 hourly dosing if not perhaps more due to the greater peaks.
Also shown to have reduced nephrotoxicity due to shorter exposure time however there is an increased risk of undetected declines in renal function as won’t be monitored as closely.
Ototoxicity prevalence shows no difference between the two dosing regimens.

Question 51

What are the contraindications to once daily dosing of Gentamicin?

Answer 51

Under 16 years old
Pregnancy
Renal disease/impairment
Cystic fibrosis
Endocarditis
Ascites
Major burns
Obese patients

• Most of these are due to increased ECF or in obese patients they are easier to over or underdose

Question 52

What determines the dose and dosing interval decided regarding Gentamicin therapy?

Answer 52

Estimated creatinine clearance and actual body weight are used to dictate dose and dosing interval except in pregnancy where the booking weight should be used.

If creatinine is not known, use actual body weight to determine the dose. 5mg/kg should be administered initially (max 400mg), unless CKD stage 5 where 2.5mg/kg should be given.

Question 53

Provide an overview of the dose and dosing intervals for different weights and creatinine clearances in Gentamicin therapy.

Answer 53

Creatinine clearance is used to dictate the dosing interval so essentially all those with CrCl between 21-50 mL/min are on 48 hourly dosing regimens.
Those with a CrCl over 51 mL/min are on a 24 hourly dosing regimen.

Question 54

What is the dosing regimen for Gentamicin in those with a CrCl below 21 mL/min?

Answer 54

2.5mg/kg (max 180mg) - assume this is once daily but need to check

Question 55

What is the dosing regimen for Gentamicin if the patient weighs < 40 kg and CrCl is ≥ 21 mL/min?

Answer 55

Give a single dose of 5mg/kg then take a sample 6 – 14 hours after the dose

Question 56

When should Gentamicin levels be taken if creatinine clearance is greater than 21mL/min, in once daily dosing*?

Answer 56

A blood sample should be taken 6‐14 hours after the start of the first gentamicin infusion, which provides the peak levels
Record on a sample form with the exact times the levels were taken and then plot on nomogram and evaluate appropriately

Question 57

When should Gentamicin levels be taken if creatinine clearance is less than 21mL/min?

Answer 57

A blood sample 24 hours after the start of the first gentamicin infusion for a trough level.
Again record the exact time of all gentamicin samples on the sample request form.
If therapy is to continue, take additional blood samples at least every 24 hours and give a further dose once the measured concentration is < 1 mg/L

Question 58

How frequent should levels of Gentamicin be taken?

Answer 58

Regarding ongoing therapy, levels should be repeated at least every 2 days.
If the gentamicin concentration is unexpectedly high or if renal function alters, daily sampling may be necessary.

Question 59

What is the therapeutic ranges for Gentamicin?

Answer 59

Gentamicin has a narrow therapeutic range in serum of 5 to 10 mg/l (10.5 to 20.9 µmol/l) for peak levels and 1 to 2 mg/l (2.1 to 4.2 µmol/l) for trough levels

Question 60

What are the possible interpretations from the Gentamicin nomogram?

Answer 60

Continue on current regimen
Adjustment to the dosing interval - give same dose every 24 hours or 48 hours
Withholding until level is less than 1mg/L and seek advice, resample 24 hours later

Question 61

What is the usual duration of Gentamicin therapy?

Answer 61

To minimise the risk of toxicity, duration of treatment should normally be
limited to 72 hours. All gentamicin prescriptions that continue beyond 3 days
of treatment must be discussed with microbiology. Consider switching to an
oral alternative as appropriate.

Question 62

Which clinical condition requires a different dosing regimen and monitoring for Gentamicin therapy?

Answer 62

Infective endocarditis due to gram-positive organisms due to Gentamicin working synergistically with other antibiotics

Question 63

Describe the dosing regimen of Gentamicin for infective endocarditis.

Answer 63

Again doses are guided by actual body weight and CrCl however they are significantly lower; about only 25% of the total dose compared to other indications. This is according to the Doncaster formulary however on the BNF it states that doses are given as 1mg/kg.
Doses are to be given as a multiple daily dosing regimen every 12 hours (BD).

Question 64

When should Gentamicin levels be taken when indicated for infective endocarditis?

Answer 64

Aiming for trough (taken just before next dose due) of <1mg/L AND peak (taken EXACTLY one hour post-dose) of 3-5mg/L.
First levels should be taken one hour after dose 3 (peak) and immediately before dose 4
(trough). Do NOT delay giving the fourth gentamicin dose while waiting for the trough
concentration to be reported, unless there are concerns over deteriorating renal function

Question 65

When should the first levels of Gentamicin be taken for infective endocarditis?

Answer 65

First levels should be taken one hour after dose 3 (peak) and immediately before dose 4 (trough).
Do NOT delay giving the fourth gentamicin dose while waiting for the trough concentration to be reported, unless there are concerns over deteriorating renal function.

*This is taken from Doncaster formulary

Question 66

What is the ongoing monitoring of Gentamicin levels for infective endocarditis?

Answer 66

If levels AND renal function are stable, levels can then be monitored twice weekly.

If renal function OR levels are unstable, check both daily until levels AND renal function are stable

*This is taken from Doncaster formulary

Question 67

What are the initial most appropriate actions to take if Gentamicin levels are outside the range for infective endocarditis?

Answer 67

Check if level taken at the correct time with respect to dose.
Check that renal function has not changed enough to require an alteration in dose
frequency

Question 68

Most appropriate action to take in I.E if pre-dose is in range and the post-dose is low?

Answer 68

If the post dose is less than 3mg/L but the pre dose is in range, consider increasing the dose.
Dosing interval may need to be increased?

Question 69

Most appropriate action to take in I.E if pre-dose is high and the post-dose is low?

Answer 69

If the post-dose is less than 3mg/L consider increasing the dose, which will increase the peak concentration for efficacy.
In regard to the high pre-dose, the dosing interval will need to be increased/dosing frequency reduced (e.g. from 12-
hourly to 24-hourly)
Recheck trough level when next dose is due and do not re-dose until <1mg/L

Question 70

Most appropriate action to take in I.E if pre-dose is high and the post-dose is in range?

Answer 70

Reduce frequency of dosing (e.g. from 12-
hourly to 24-hourly)
Recheck trough level when next dose is due and do not re-dose until <1mg/L
Do not need to adjust the dose

Question 71

Most appropriate action to take in I.E if the pre dose is in range and the post-dose is high?

Answer 71

If the post dose is greater than 5mg/L but the pre-dose is in range consider reducing the dose appropriately

Question 72

Most appropriate action to take in I.E if the pre dose is high and the post-dose is high?

Answer 72

Screencasts state only to reduce the dose however on the formulary for Doncaster it states to OMIT the next dose
Discuss with Microbiologist before
recommencing therapy