AMS Basic Course ESCMID_TDM of antibiotics

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GeneeskundeWOStudiejaar 6

This lesson contains 54 slides, with interactive quizzes and text slides.

time-iconLesson duration is: 45 min

Items in this lesson

Slide 1 - Slide

Slide 2 - Slide

For which antibiotics do you perform TDM?

Slide 3 - Open question

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 - Slide

Why TDM of vancomycin?
A
Optimal Cmin = optimal efficacy
B
Optimal AUC = optimal efficacy
C
Optimal Cmin = optimal efficacy + low risk toxicity
D
Optimal AUC = optimal efficacy + low risk toxicity

Slide 5 - Quiz

Slide 6 - Slide

Why TDM of vancomycin: efficacy
Targets:
  • 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 7 - Slide

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 8 - 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 9 - Slide

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 10 - Slide

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
A
True
B
False

Slide 11 - Quiz

Why TDM of vancomycin: toxicity
  • Lowest toxic concentration: 
        Cmin: >15 mg/L, >20mg/L, 
        AUC0-24: >600, >800, >1300 
        Css: >30 mg/L
  • Bayesian estimated AUC based dosing is associated with lower risk of nephrotoxicity
  • Guideline ASHP/IDSA: AUC0-24/MIC target = 400-600

Rybak AmJHealthSystPharm2020, AnnPharmacother2019, 2022, 2023

Slide 12 - Slide

Slide 13 - Slide

Slide 14 - Slide

Slide 15 - Slide

Apart from the narrow therapeutic window, what's another reason why vancomycin levels must be measured?
A
Pharmacogenetic variability with large effect on PK
B
Large INTERpatient variability in PK
C
Large INTRApatient variability in PK
D
All anserws are correct

Slide 16 - Quiz

Slide 17 - Slide

Slide 18 - Slide

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 19 - Slide

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 20 - Slide

Poll: what's your current practice with regard to sample collection and interpretation when performing TDM of vancomycin?
A
Bayesian estimation of AUC with 1 (Cmin) or 2 samples (also Cmax)
B
Interpretation of Cmin WITH PK model
C
Interpretation of Cmin WITHOUT PK model
D
Interpretation of level under continuous infusion (without PK model)

Slide 21 - Quiz

Slide 22 - Slide

A patient (f, 63 j, 79 kg, eGFR 37) is being treated with iv vancomycin, starting yesterday at 9.00am. Starting dose was 1000 mg/24h continuous iv. The plasma level, drawn at 8.30 am today is 22.9 mg/l. Poll: this is an adequate level for this patient
A
True
B
False

Slide 23 - Quiz

Vancomycin: continuous dosing
  • Target during continuous iv: Css= 17 - 25 mg/l
    (Css=AUC / dosing interval -> 400 / 24 = 17 mg/l)

Slide 24 - Slide

Vancomycin: continuous dosing
  • Target during continuous iv: Css= 17 - 25 mg/l
    (Css=AUC / dosing interval -> 400 / 24 = 17 mg/l)
  • Be aware that steady-state has been reached; otherwise estimate AUC with Baysian estimation


Slide 25 - Slide

Patient (m, 67 j, 73 kg, eGFR 72) starts with vancomycin 1000 mg twice daily at 12.00am and 12.00pm for treatment of a line infection. Sample is drawn on day 2 at 8.00am: 11.1 mg/l. What's next?
A
Stay with 1000 mg twice daily
B
Increase dose to 1250 mg twice daily
C
Switch to 2000 mg continuous infusion
D
I'll ask my TDM consultant

Slide 26 - Quiz

Vancomycin: continuous vs intermittant dosing
  • Target during continuous iv: Css= 17 - 25 mg/l
    (Css=AUC / dosing interval -> 400 / 24 = 17 mg/l)
  • Be aware that steady-state has been reached; otherwise estimate AUC with Baysian estimation

  • TDM is easier with continuous iv dosing (81% of Cmin with intermittant dosing is collected >1 h before new dose, 61% >2 h) [Neely AAC2014])

Slide 27 - Slide

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 28 - Quiz

Slide 29 - Slide

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 gentamicin and tobramycin is 0.1-2 mg/L, so Cmax target is generally 15-20 mg/L
  • Time above MIC not of relevance



Moore et al JInfectDis1987;155:93, Moore et al AmJMed1984;4:657

Slide 30 - Slide

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 31 - Quiz

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 32 - Quiz

Why TDM of aminoglycosides: toxicity
  • The higher Cmin, the higher the risk for nephrotoxicity
  • Target Cmin = <0.5 mg/L (also reported <1 mg/L or <2 mg/L)
  • Long dosing intervals (24 h or longer)
  • Gentamicin may be more nephrotoxic than tobramycin
  • Measure Cmin before 3rd dose, unless eGFR<50 mL/min, than already after 1st dose


Nicolau AAC1995;3:650, Hodiamont ClinPharmacokinet2022;61:1075 

Slide 33 - Slide

Slide 34 - Slide

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 35 - Quiz

A patient is treated with ceftazidime 2 grams three times daily for a pneumonia caused by Pseudomonas aeruginosa (ECOFF 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 36 - Quiz

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 37 - Slide

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 38 - Slide

A patient is treated with ceftazidime 2 grams twice daily for a pneumonia caused by Pseudomonas aeruginosa (ECOFF 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 39 - Quiz

Slide 40 - Slide

Slide 41 - Slide

TDM of beta-lactams: efficacy?
  • ±1/3 of ICU patients doesn't attain 100% of the Time above MIC (T>MIC)
  • TDM should be able to get more patients on 100%T>MIC 
  • 3 RCT's: TDM vs no TDM of beta-lactams:
        2 RCT's indeed showed more patients with 100%T>MIC (DeWaele                          IntensiveCareMed2015; Hagel IntensiveCareMed2022), 1 RCT did not                 (Ewoldt IntensiveCareMed2022)

Slide 42 - Slide

Slide 43 - Slide

Slide 44 - Slide

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 45 - Slide

TDM of beta-lactams: efficacy?
  • ±1/3 of ICU patients doesn't attain 100% of the Time above MIC (T>MIC)
  • TDM should be able to get more patients on 100%T>MIC 
  • 3 RCT's: TDM vs no TDM of beta-lactams:
      2 RCT's indeed showed more patients with 100%T>MIC (DeWaele                      IntensiveCareMed2015; Hagel IntensiveCareMed2022), 1 RCT did not            (Ewoldt IntensiveCareMed2022)
  • May be TDM is only useful in selected (ICU) cases?

Slide 46 - Slide

Slide 47 - Slide

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 48 - Quiz

Why TDM of aminoglycosides: toxicity
  • The higher Cmin, the higher the risk for nephrotoxicity
  • Target Cmin = <0.5 mg/L (also reported <1 mg/L or <2 mg/L)
  • Long dosing intervals (24 h or longer)
  • Gentamicin may be more nephrotoxic than tobramycin
  • Measure Cmin before 3rd dose, unless eGFR<50 mL/min or when the patient is obese, than already after 1st dose 


Nicolau AAC1995;3:650, Hodiamont ClinPharmacokinet2022;61:1075

Slide 49 - Slide

Have you ever requested or measured a beta-lactam serum/plasma level for TDM?
Yes
No

Slide 50 - Poll

Slide 51 - Slide

Slide 52 - Slide

Slide 53 - Slide

Slide 54 - Slide