Cette leçon contient 42 diapositives, avec quiz interactifs et diapositives de texte.
La durée de la leçon est: 45 min
Éléments de cette leçon
Slide 1 - Diapositive
Slide 2 - Diapositive
For which antibiotics do you perform TDM?
Slide 3 - Question ouverte
Dutch guideline on AMS (2016)
Strong recommendation to perform TDM in patients treated with aminoglycosides, glycopeptides, posaconazole or voriconazole
Yet, quality of evidence is low (TDM reduces length of hospital stay) to very low (TDM reduces mortality, therapy failure, (nephro)toxicity, costs)
https://swab.nl/exec/file/download/81
Slide 4 - Diapositive
Patient (m, 79 kg, 1.78 m, eGFR 82 ml/min) starts with gentamicin 7 mg/kg once daily for treatment of sepsis. Which levels would you want to measure and when?
A
Peak and trough before 3rd dose
B
Trough before 3rd dose.
C
Peak and trough after 1st dose.
D
Trough after 1st dose
Slide 5 - Quiz
Slide 6 - Diapositive
Why TDM of aminoglycosides: efficacy
Killing rate of aminoglycosides correlates in vitro with Cmax
Concentration-dependent killing
PKPD target = Cmax/MIC 8-10
MIC of Gram - bacteria for genta/tobra: 0.1-2 mg/L
Time above MIC not of relevance
Moore et al JInfectDis1987;155:93, Moore et al AmJMed1984;4:657
Slide 7 - Diapositive
What is your current practice: in which situations do you measure aminoglycoside peak levels?
A
All patients
B
Only ICU patients
C
Only in selected cases
D
Never
Slide 8 - Quiz
Slide 9 - Diapositive
Slide 10 - Diapositive
TDM is of added value when:
Interpatient variability in PK is high
Therapeutic window is narrow (small difference between lowest effective conc and lowest toxic conc)
Slide 11 - Diapositive
TDM is of added value when:
Interpatient variability in PK is high
Therapeutic window is narrow (small difference between lowest effective conc and lowest toxic conc)
Interpatient variability in PK in ICU patients (much) higher than in non-ICU patients -> (likely) no added value of peak level monitoring in non-ICU patients
Slide 12 - Diapositive
Slide 13 - Diapositive
TDM is of added value when:
Interpatient variability in PK is high AND intrapatient variability in PK is low
Therapeutic window is narrow (small difference between lowest effective conc and lowest toxic conc)
Measurement of drug concentration is not (too) complex
Efficacy/toxicity of the drug can not be easily measured/predicted in another way
Slide 14 - Diapositive
Patient (m, 79 kg, 1.78 m, eGFR 31 ml/min) starts with gentamicin 7 mg/kg once daily for treatment of sepsis. Which levels would you want to measure and when?
A
Peak and trough before 3rd dose
B
Trough before 3rd dose
C
Peak and trough after 1st dose
D
Trough after 1st dose
Slide 15 - Quiz
What do you notice about this question?
Patient (m, 79 kg, 1.78 m, eGFR 31 ml/min) starts with gentamicin 7 mg/kg once daily for treatment of sepsis. Which levels would you want to measure and when?
Slide 16 - Diapositive
Why TDM of aminoglycosides: toxicity
The higher Cmin, the higher the risk for nephrotoxicity
Gentamicin may be more nephrotoxic than tobramycin
Measure Cmin before 3rd dose, unlesseGFR<50 mL/min, than already after 1st dose
Nicolau AAC1995;3:650, Hodiamont ClinPharmacokinet2022 in press
Slide 17 - Diapositive
Patient (m, 120 kg, 1.78 m, eGFR 82 ml/min) starts with gentamicin 7 mg/kg ABW once daily for treatment of sepsis. Which levels would you want to measure and when?
A
Peak and trough before 3rd dose
B
Trough before 3rd dose
C
Peak and trough after 1st dose
D
Trough after 1st dose
Slide 18 - Quiz
Why TDM of aminoglycosides: toxicity
The higher Cmin, the higher the risk for nephrotoxicity
Gentamicin may be more nephrotoxic than tobramycin
Measure Cmin before 3rd dose, unlesseGFR<50 mL/min or when the patient is obese, than already after 1st dose
Nicolau AAC1995;3:650, Hodiamont ClinPharmacokinet2022 in press
Slide 19 - Diapositive
What is the availability regarding a TDM service for aminoglycosides and vancomycin at your institution?
A
<24h between sample collection and TDM result
B
>24h, but <72h between sample collection and result
C
No service available locally, samples go to nearby center
D
No TDM service available at all
Slide 20 - Quiz
Patient (m, 67 j, 73 kg, eGFR 72) starts with vancomycin 1000 mg twice daily at 12.00am and 12.00pm fo treatment of a line infection. Sample is drawn on day 2 at 8.30am: 11.1 mg/l. What's next?
AUC0-24 / MIC > 400 (=AUC0-24 > 400 at MIC of 1 mg/l or smaller)
Cmin as surrogate for AUC0-24: 10 - 20 mg/l
Slide 24 - Diapositive
What is your current practice: which vancomycin target is applied in your institution?
A
Cmin between 15 and 20 mg/l
B
Cmin between 10 and 15 mg/l
C
AUC > 400
D
Something else
Slide 25 - Quiz
Why TDM of vancomycin: efficacy
Targets:
AUC0-24 / MIC > 400 (= AUC0-24 > 400 at MIC of 1 mg/l or smaller)
Before 2020: Cmin as surrogate for AUC0-24: 10 - 20 mg/l
Since 2020: estimate AUC0-24 with 1 (Cmin) or 2 (Cmin+Cmax) samples and Bayesian estimation or 1st order PK equations
Rybak AmJHealthSystPharm2020;77:835
www.tdm-monografie.org/vancomycine
Slide 26 - Diapositive
Why TDM of vancomycin: efficacy
Targets (Rybak, AmJHealthSystPharm2020;77:835):
AUC0-24 / MIC > 400
Estimate AUC0-24 with 1 (Cmin) or 2 (Cmin+Cmax) samples and Bayesian estimation or 1st order PK equations
Samples to be collectes within 48 h after start of vancomycin; already after 1st dose when eGFR<50 ml/min
NB Target is based on evidence on MRSA bacteremia
Slide 27 - Diapositive
Poll: when treating an infection with Staph. epidermidis with an MIC of 2 mg/l, the vancomycin dose should be increased to target an AUC of 800 (e.g. 2 gram twice daily) as the risk for nephrotoxicity is still acceptable at that AUC
Recent meta-analysis: dosing based on Bayesian estimation is associated with lower risk of nephrotoxicity
Guideline ASHP/IDSA: AUC0-24/MIC target = 400-600
Rybak AmJHealthSystPharm2020, He AnnPharmacother2019
Slide 29 - Diapositive
Patient is discharged home with iv vancomycin (outpatient parenteral therapy). Based on TDM, the patient is dosed 750 mg once daily. At home this is switched to continuous infusion 750 mg/24h. The plasma level, 24 h after switching is 24 mg/l. Poll: this is an adequate level for this patient
Be aware that steady-state has been reached; otherwise estimate AUC with Baysian estimation
No difference regarding efficacy (continuous might be less toxic)
Advantages of continuous iv dosing: - Target is attained faster - Easier for outpatient parenteral therapy - Easier TDM (81% of Cmin with intermittent dosing is collected >1 h before new dose, 61% >2 h)[Neely AAC2014])
Slide 32 - Diapositive
A patient is treated with ceftazidime 2 grams twice daily for a pneumonia caused by Pseudomonas aeruginosa, with an MIC of 8 mg/L. The patient has a eGFR of 55 ml/min. Would you recommend performing TDM in this case?
A
Yes, collect a Cmin after 4th dose
B
Yes, collect a sample 4h after 4th dose
C
No
D
Something else
Slide 33 - Quiz
Slide 34 - Diapositive
Slide 35 - Diapositive
A patient is treated with ceftazidime 2 grams twice daily for a pneumonia caused by Pseudomonas aeruginosa, with an MIC of 8 mg/L. The patient has a eGFR of 160 ml/min. Would you recommend performing TDM in this case?
A
Yes, collect a Cmin after 4th dose
B
Yes, collect a sample 4h after 4th dose
C
No
D
Something else
Slide 36 - Quiz
Slide 37 - Diapositive
Slide 38 - Diapositive
TDM of beta-lactams: efficacy?
Which T>MIC target to use: 50% or 100%; 1xMIC or 4xMIC?
(depending on target population)
Total or unbound concentration? fT>MIC
Which sample to collect then?
Cmid if 50%(f)T>(4x)MIC
Cmin of 100%(f)T>(4x)MIC Css when continuous infusion Model based TDM?
Slide 39 - Diapositive
Slide 40 - Diapositive
Have you ever requested or measured a beta-lactam serum/plasma level for TDM?