Continuous infusion of beta-lactams: a Belgian experience P.F. - - PowerPoint PPT Presentation

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Continuous infusion of beta-lactams: a Belgian experience P.F. - - PowerPoint PPT Presentation

Jan 14, 2023 242 likes •402 views

Continuous infusion of beta-lactams: a Belgian experience P.F. Laterre Intensive Care Department, University Clinics St-Luc, Brussels P.M. Tulkens Cellular and Molecular Pharmacology Unit Catholic University of Louvain, Brussels PK-PD

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SLIDE 1

April 7th, 2005 PK-PD Mini-Symposium 1

Continuous infusion of beta-lactams: a Belgian experience

P.F. Laterre Intensive Care Department, University Clinics St-Luc, Brussels P.M. Tulkens Cellular and Molecular Pharmacology Unit Catholic University of Louvain, Brussels

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SLIDE 2

April 7th, 2005 PK-PD Mini-Symposium 2

What did the textbooks say about antibiotic dosages and schedules in the 70’s ? but how much ?

  • 1. Stay above the MIC...

but how long ?

  • 2. Remain around for a while…

against everything ?

  • 3. Hope it works...

Sorry, but I can’t do much ...

  • 4. Hope it is not toxic…
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SLIDE 3

April 7th, 2005 PK-PD Mini-Symposium 3

How long do you need to remain above the MIC for a beta-lactam ?

  • cefotaxime
  • neutropenic mice
  • K. pneumoniae
  • lung infection)
  • r 100 % ?

50 % 66 %

W.A. Craig, ECCMID-ISAP workshop 2001

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SLIDE 4

April 7th, 2005 PK-PD Mini-Symposium 4

Continuous infusion of ceftazidime in ICU (3 g/day)

Intermittent

(n=17)

Continuous

(n=17)

C max (mg/ml) C min (mg/ml) C mean (mg/ml) T½(h) AUC

0-24h

Cl

t(ml/min)

106.5 (34.6) 10.3 (16.0) 3.2 (2.5) 777.4 (474.6) 142.5 (58.7) 18.2 (6.5) 16.5 (5.7) 17.4 (6.1) 419.7 (141.5) 133.2 (37.0)

Pharmacokinetocs and Pharmacodynamics of continuous and intermittent ceftazidime during the treatment of nosocomial

  • pneumonia. D.P. Nicolau et al. Clin Drug Invest 1999:18(2):133-139.
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SLIDE 5

April 7th, 2005 PK-PD Mini-Symposium 5

Continuous infusion: a bunch of

  • ther studies...
  • suspected Gram (-) infections in critically-ill patients
  • severe infections in Intensive Care patients (5 studies)
  • septicemia (2)
  • severe sepsis
  • cystic Fibrosis (3 25).

Benko et al., AAC 1996 Domenig et al., Transplantation, 2000 Angus et al., Brit. J. Clin. Pharmacol. 2000 Leder et al., JAC, 1999 Rapaz et al., Eur. J. Ped. 2000

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SLIDE 6

April 7th, 2005 PK-PD Mini-Symposium 6

But is it safe ? Ceftazidime stability studies … 25°C

Ceftazidime stability at 25°c

70 75 80 85 90 95 100 105 110 5 10 15 20 25 30 Time (hours) present ceftazidime

4% 6% 8% 10% 12%

Range of tolerance

Servais & Tulkens, AAC, 2001

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SLIDE 7

April 7th, 2005 PK-PD Mini-Symposium 7

But is it safe ? Ceftazidime stability studies … 37°C ...

Ceftazidime stability at 37°c

50 55 60 65 70 75 80 85 90 95 100 105 110 5 10 15 20 25 30 Time (hours) Present ceftazidime

4% 6% 8% 10% 12%

Range of tolerance

Servais & Tulkens, AAC, 2001

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SLIDE 8

April 7th, 2005 PK-PD Mini-Symposium 8

Degradation products of ceftazidime

cefazidime

[(2–amino–4-thiazolyl) (1–carboxy–1– methyletoxy) imino] acetyl–ethanal. ∆2-isomer

Servais & Tulkens, 11th ECCMID, 2001

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SLIDE 9

April 7th, 2005 PK-PD Mini-Symposium 9

Degradation pathways of ceftazidime

(24h in aqueous media)

∆2-isomer

cefazidime

> 25 °C

Ring opening

Pyridine *

[(2–amino–4-thiazolyl) (1– carboxy–1–methyletoxy) imino] acetyl–ethanal. * < 50 mg from an amount of 4 g in 24h at temp < 25°C

Servais & Tulkens, AAC, 2001

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SLIDE 10

April 7th, 2005 PK-PD Mini-Symposium 10

PK / PD in action … continuous infusion of β-lactams:

the case of ceftazidime (4g / day) in Intensive Care Units

Css = Ko / Cl

27 [µg/ml] = { 2.77 [mg/min] / 102 [ml/min] } x 103

serum concentration Clearance * Infusion rate Targeted level for MIC’s up to 6-8 mg/L …

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SLIDE 11

April 7th, 2005 PK-PD Mini-Symposium 11

PK / PD in action … continuous infusion of β-lactams:

the case of ceftazidime (4g / day) in Intensive Care Units

20 40 60

mean : 26.6 ± 15.0 (n = 93; min = 7.6; max = 62.4)

  • bserved serum concentration (mg/L)

target mean

Servais, Laterre & Tulkens, unpublished

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SLIDE 12

April 7th, 2005 PK-PD Mini-Symposium 12

Variaties in ceftazidime concentraties bij ICU-patiënten werden niet alleen in Brussel waargenomen ...

5 10 15 20 10 100

concentratie mg/L time h

From Mouton, 8th ISAP symposium, Nijmegen, 2001

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SLIDE 13

April 7th, 2005 PK-PD Mini-Symposium 13

Variaties in ceftazidime concentraties bij ICU-patiënten werden niet alleen in Brussel waargenomen ...

5 10 15 20 10 100

concentratie mg/L

Maar de variatie is even groot voor pieken en T>MIC met conventionele toedieningen

time h

From Mouton, 8th ISAP symposium, Nijmegen, 2001

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SLIDE 14

April 7th, 2005 PK-PD Mini-Symposium 14

Variaties in ceftazidime concentraties bij ICU-patiënten werden niet alleen in Brussel waargenomen ...

5 10 15 20 10 100

concentratie mg/L

Maar de variatie is even groot voor pieken en T>MIC met conventionele toedieningen

time h

From Mouton, 8th ISAP symposium, Nijmegen, 2001

β-lactamen bloedspiegels opvolgen ?

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SLIDE 15

April 7th, 2005 PK-PD Mini-Symposium 15

And now, en route to the future ...

… to a bright future ! Using "old" drugs for their best