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 Mini-Symposium April 7th, 2005 1
What did the textbooks say about antibiotic dosages and schedules in the 70’s ? 1. Stay above the MIC... but how much ? 2. Remain around for a while… but how long ? 3. Hope it works... against everything ? 4. Hope it is not toxic… Sorry, but I can’t do much ... PK-PD Mini-Symposium April 7th, 2005 2
How long do you need to remain above the MIC for a beta-lactam ? 50 % • cefotaxime 66 % • neutropenic mice • K. pneumoniae • lung infection) or 100 % ? W.A. Craig, ECCMID-ISAP workshop 2001 PK-PD Mini-Symposium April 7th, 2005 3
Continuous infusion of ceftazidime in ICU (3 g/day) Intermittent Continuous (n=17) (n=17) C max (mg/ml) 106.5 (34.6) 18.2 (6.5) C min (mg/ml) 10.3 (16.0) 16.5 (5.7) C mean (mg/ml) 17.4 (6.1) T ½ (h) 3.2 (2.5) 777.4 (474.6) 419.7 (141.5) AUC 0-24h 142.5 (58.7) 133.2 (37.0) Cl t (ml/min) 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. PK-PD Mini-Symposium April 7th, 2005 4
Continuous infusion: a bunch of other studies... • suspected Gram (-) infections in critically-ill patients Benko et al., AAC 1996 • severe infections in Intensive Care patients (5 studies) Domenig et al., Transplantation, 2000 • septicemia (2) Angus et al., Brit. J. Clin. Pharmacol. 2000 • severe sepsis Leder et al., JAC, 1999 • cystic Fibrosis (3 25). Rapaz et al., Eur. J. Ped. 2000 PK-PD Mini-Symposium April 7th, 2005 5
But is it safe ? Ceftazidime stability studies … 25°C Ceftazidime stability at 25°c 110 105 Range o f 100 tolerance 95 present ceftazidime 90 4% 85 6% 80 8% 10% 75 12% 70 0 5 10 15 20 25 30 Time (hours) Servais & Tulkens, AAC, 2001 PK-PD Mini-Symposium April 7th, 2005 6
But is it safe ? Ceftazidime stability studies … 37°C ... Ceftazidime stability at 37°c 110 105 Range of 100 tolerance 95 90 85 Present ceftazidime 80 4% 75 6% 70 8% 65 10% 60 12% 55 50 0 5 10 15 20 25 30 Time (hours) Servais & Tulkens, AAC, 2001 PK-PD Mini-Symposium April 7th, 2005 7
Degradation products of ceftazidime cefazidime [(2–amino–4-thiazolyl) ∆ 2 -isomer (1–carboxy–1– methyletoxy) imino] acetyl–ethanal. Servais & Tulkens, 11th ECCMID, 2001 PK-PD Mini-Symposium April 7th, 2005 8
Degradation pathways of ceftazidime (24h in aqueous media) > 25 °C ∆ 2 -isomer cefazidime 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 PK-PD Mini-Symposium April 7th, 2005 9
PK / PD in action … continuous infusion of β -lactams: the case of ceftazidime (4g / day) in Intensive Care Units C ss = K o / Cl serum Clearance * concentration Infusion rate 27 [µg/ml] = { 2.77 [mg/min] / 102 [ml/min] } x 10 3 Targeted level for MIC’s up to 6-8 mg/L … PK-PD Mini-Symposium April 7th, 2005 10
PK / PD in action … continuous infusion of β -lactams: the case of ceftazidime (4g / day) in Intensive Care Units observed serum concentration (mg/L) mean : 26.6 ± 15.0 (n = 93; min = 7.6; max = 62.4) 60 40 target mean 20 0 Servais, Laterre & Tulkens, unpublished PK-PD Mini-Symposium April 7th, 2005 11
Variaties in ceftazidime concentraties bij ICU-patiënten werden niet alleen in Brussel waargenomen ... 100 concentratie mg/L 10 5 10 15 20 time h From Mouton, 8th ISAP symposium, Nijmegen, 2001 PK-PD Mini-Symposium April 7th, 2005 12
Variaties in ceftazidime concentraties bij ICU-patiënten werden niet alleen in Brussel waargenomen ... 100 concentratie mg/L Maar de variatie is even groot voor pieken en T>MIC met conventionele toedieningen 10 5 10 15 20 time h From Mouton, 8th ISAP symposium, Nijmegen, 2001 PK-PD Mini-Symposium April 7th, 2005 13
Variaties in ceftazidime concentraties bij ICU-patiënten werden niet alleen in Brussel waargenomen ... 100 concentratie mg/L Maar de variatie is even groot voor pieken en T>MIC met conventionele toedieningen 10 5 10 15 20 time h β -lactamen bloedspiegels opvolgen ? From Mouton, 8th ISAP symposium, Nijmegen, 2001 PK-PD Mini-Symposium April 7th, 2005 14
And now, en route to the future ... Using "old" drugs for their best … to a bright future ! PK-PD Mini-Symposium April 7th, 2005 15
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