-lactamen door continu-infuus: van farmacodynamische en rationele aspecten tot mogelijke toepassingen bij longinfecties Beta-lactams-CI-GSK 12-02-01

-lactamen door continu-infuus: van farmacodynamische en rationele aspecten tot mogelijke toepassingen bij longinfecties Hoe is dat mogelijk ? Beta-lactams-CI-GSK 12-02-01

P.M. Tulkens, Dr med., H. Servais, Apoth., -lactamen door continu-infuus: van farmacodynamische en rationele aspecten tot mogelijke toepassingen bij longinfecties P.M. Tulkens, Dr med., H. Servais, Apoth., H. Chanteux, Apoth., E. Viaene, Lic. Wet., Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, Brussel; in medewerking met I. Dab, Dr Med. (Kinderpneumologie, AZ Vrije Universiteit Brussel), P.F. Laterre, Dr Med. (Soins Intensifs, Clin. Univ. St-Luc, Brussel) en verschillende Intensieve Zorgen Diensten in België Beta-lactams-CI-GSK 12-02-01

Antibiotische behandelingen: Wat verlangt de clinicus ? Beste therapeutische effecten “The” drug Geen toxische effecten Beta-lactams-CI-GSK 12-02-01

therapeutische effecten Waar werkt nijverheid ? Beste therapeutische effecten “The” drug Geen toxische effecten Beta-lactams-CI-GSK 12-02-01

The ideal antibiotic ... patient’s the molecule cure microbiology brilliant and clear solutions the molecule chemistry patient’s cure therapy Beta-lactams-CI-GSK 12-02-01

Is the molecule always ideal ? microbiology brilliant and clear solutions the ideal molecule chemistry patient’s cure therapy Beta-lactams-CI-GSK 12-02-01

Main causes of antibiotic failures. Adapted from Pechère J. C False failures erroneous diagnosis underlying disease uninfluenced by antibiotics unjustified lack of patience inactivation of the antibiotic Patient related failures compliance failure (broadly speaking) inappropriate administration route (broadly speaking) immunodepressed hosts Pharmacological failures insufficient amount or drug inappropriately administered no attention paid to pharmacodynamic parameters in situ inactivation or lack of drainage Micro-organism related failures wrong pathogen resistance acquired during treatment insufficient bactericidal activity inoculum effect Beta-lactams-CI-GSK 12-02-01

Farmacokinetiek Concentratie op de infectiehaard Therapeutische effecten Serumconcen- tratie variërend in de tijd Dosering Concentratie in de andere weefsels Toxische effecten Beta-lactams-CI-GSK 12-02-01

Farmacodynamie Concentratie op de infectiehaard Therapeutische effecten Serumconcen- tratie variërend in de tijd Dosering Concentratie in de andere weefsels Toxische effecten Beta-lactams-CI-GSK 12-02-01

Farmacokinetiek parameters Serumconcentratie variërend in de tijd Piek Dal Oppervl. /o. de curve (AUC) Beta-lactams-CI-GSK 12-02-01

Farmacokinetiesche parameters en microbiologie ... Piek / Dal / AUC Min. Remmende Conc. (MIC) Beta-lactams-CI-GSK 12-02-01

Pharmacokinetics / Pharmacodynamics Parameters controlling efficacy concentration  peak / MIC time above the MIC  time > MIC area under the curve / MIC  AUC24h / MIC or AUIC post-antibiotic and other persistent effects sub-MIC effects; post-exposure sub-MIC effects; post-antibiotic (leukocyte enhancement effects) Beta-lactams-CI-GSK 12-02-01

PK/PD patterns of antimicrobial activity (3 of 3) (after WA PK/PD patterns of antimicrobial activity (3 of 3) (after WA. Craig, 2000) 1. Antibiotics with concentr. -dependent killing and prolonged persistent effects (post-antibiotic effects) Drugs aminoglycosides fluoroquinolones daptomycin ketolides amphotericin B PK/PD parameter Peak and AUC24h / MIC Goal Optimize concentrations and drug amount Beta-lactams-CI-GSK 12-02-01

PK/PD patterns of antimicrobial activity (1 of 3) (after WA PK/PD patterns of antimicrobial activity (1 of 3) (after WA. Craig, 2000) 3. Antibiotics with time-dependent killing, no or little effect of concentration, minimal to moderate persistent effects Drugs beta-lactams clindamycin oxazolidinones macrolides flucytosine PK/PD parameter Time above MIC Goal Optimize the duration of exposure to drug Beta-lactams-CI-GSK 12-02-01

Pharmacokinetics / Pharmacodynamics in action ... What can (and must ) the clinician know ? Beta-lactams-CI-GSK 12-02-01

Farmacodynamie Invloed van de concentratie op de werking van de antibiotica Uitgesproken effect Zwak effect aminoglycosiden  -lactamen (alles) fluorochinolonen glycopeptiden (alles) metronidazole macroliden (alles) clindamycine tetracyclinen Beta-lactams-CI-GSK 12-02-01

Wat te doen voor de aminoglycosiden ? 1. Adequate toedieningswijze i.v. toediening 2. De dosering berekenen (a) piek/MIC = 8 (b) piek = dosis / Vd dosis = MIC x 8 x Vd Beta-lactams-CI-GSK 12-02-01

Pharmacokinetics / Pharmacodynamics in action ... Aminoglycosides : increase the unit dose to get the appropriate peak MIC = 1 mg/L 3 mg/kg MIC = 2 mg/L 6 mg/kg MIC = 4 mg/L 15 mg/kg dose limit of G, T, N dose limit of A, I Beta-lactams-CI-GSK 12-02-01

Wat voor de fluorochinolonen ? Minimale AUC24h / MIC = 125 piek /MIC = 10 de MIC kennen de noodzakelijke AUC en peak berekenen de dosis bepalen in functie van het product (halfwaardetijd en Vd ) de patiënt (klaring) Beta-lactams-CI-GSK 12-02-01

Pharmacokinetics / Pharmacodynamics in action ... PK/PD Bkpts (mg/L) Drug Dosage AUC/MIC peak / MIC NCCLS (mg/24h) (24h) Bkpts* norfloxacin 800 0.1 0.2 < 4 ciprofloxacin 500 0.1 0.2 < 1 ofloxacin 400 0.2-0.4 0.3 - 0.4 < 2 levofloxacin 500 0.4 0.4 - 0.5 < 2 gatifloxacin 400 0.3 0.4 < 2 moxifloxacin 400 0.4 0.4 < 2 * US prescrib. inf. (adult of 60 kg) of NOROXIN®, CIPRO®, FLOXIN®, LEVAQUIN®, TEQUIN® and AVELOX® Beta-lactams-CI-GSK 12-02-01

Wat voor  - lactamen ? aanvaardbare termijn tussen Het interval berekenen tijdens hetwelke de concentratie blijft > MIC Ct = C0 x e-kt aanvaardbare termijn tussen 2 toedieningen: rechtstreeks proport. met de dosis omgekeerd proport. met de klaring Beta-lactams-CI-GSK 12-02-01

Typical pharmacokinetics of a model -lactam * time concentration for (hours) 0.5 g 1 g 2 g 2 25 50 100 4 12.5 25 50 6 6 12 25 8 3 6 12 10 1.5 3 6 12 0.75 1.5 3 * single administration; 2h half-life; Vd = 0.2 l/kg Beta-lactams-CI-GSK 12-02-01

 - lactamen in de pratijk: 1 g / 50 kg in bolus ... tijd spiegel t > MIC voor een MIC van (uren) (voor 100 mg/L op t=0h) 16 8 4 2 1 2 50 ok ok ok ok ok 4 25 ok ok ok ok ok 6 12 ! ok ok ok ok 8 6 !! ! ok ok ok 12 3 !!! !! ! ok ok * halfwaardetijd van 2u; Vd = 0.2 l/kg Beta-lactams-CI-GSK 12-02-01

Hoelang moet U over de MIC blijven met dieren ? 50 % Beta-lactams-CI-GSK 12-02-01

Maar hoelang met patiënten ? 50 % Beta-lactams-CI-GSK 12-02-01

Maar met Gram (-) bacteriën in moelijke situaties ? cefotaxime neutropenic mice K. pneumoniae lung infection) 66 % Beta-lactams-CI-GSK 12-02-01

Typical pharmacokinetics of a model -lactam * time concentration for (hours) 0.5 g 1 g 2 g 2 25 50 100 4 12.5 25 50 6 6 12 25 8 3 6 12 10 1.5 3 6 12 0.75 1.5 3 * single administration; 2h half-life; Vd = 0.2 l/kg if given every 12h 50 % coverage 66 % coverage 100 % coverage Beta-lactams-CI-GSK 12-02-01

Pharmacokinetics / Pharmacodynamics in action ... - lactams: if you have reached the limits ... increase the frequency of administration to get enough time > MIC efficacy high peaks are unnecessary and may cause toxicity Beta-lactams-CI-GSK 12-02-01

Typical pharmacokinetics of a model -lactam * time concentration for (hours) 0.5 g 1 g 2 g 2 25 50 100 4 12.5 25 50 6 6 12 25 8 3 6 12 10 1.5 3 6 12 0.75 1.5 3 * single administration; 2h half-life; Vd = 0.2 l/kg if given every 6 h 50 % coverage 66 % coverage 100 % coverage Beta-lactams-CI-GSK 12-02-01

 - lactams * in clinical practice : influence of the schedule on potential breakpoint continuous infusion 8 x 4 x 3 x 2 x 1 x Beta-lactams-CI-GSK 12-02-01

PK / PD in actie … continu infuus of 4 g / dag Css = Ko / Cl 40 [µg/ml] = { 2.77 [mg/min] / 69.3 [ml/min] } x 103 serum spiegel Klaring * infusie rate * half-eliminatie tijd: 2 u Beta-lactams-CI-GSK 12-02-01

Continu infuus van  - lactamen in de praktijk: doeltreffenheid ... Probleem: Hoe hoog moet de bloedspiegel staan ? voorstel : 4 x het MIC reden : (a) effect is bijna maximaal (b) AUC / MIC is 96  vermindering van risicos van resistentie Beta-lactams-CI-GSK 12-02-01

4 X the MIC is optimal for -lactams Beta-lactams-CI-GSK 12-02-01

Continu infuus van  - lactamen in de praktijk: farmaceutische aspecten ... Probleem: Is de molecule stabiel genoeg ? antwoord : u moet specifiek testen reden : de -lactame ring is spontaan breekbaar ! Beta-lactams-CI-GSK 12-02-01

chemische instabiliteit De -lactame ring is zeer reageerbaar R R C N C HN O O COOH OH COOH chemische instabiliteit Beta-lactams-CI-GSK 12-02-01

De -lactame ring is zeer reageerbaar O COOH R HOOC The attack of one molecule of -lactam by another is favored in CONCENTRATED solutions ! Beta-lactams-CI-GSK 12-02-01

Continu infuus in de praktijk: veiligheid Probleem: Zijn er voorzienbare neveneffecten ? antwoord : Ja, convulsies reden : als het -lactam in het CZS zou gaan! Beta-lactams-CI-GSK 12-02-01

Is continu-infuus mogelijk ? Elk  - lactame moet individueel bestudeerd worden ! Beta-lactams-CI-GSK 12-02-01

Continu-infuus van  - lactamen in mucoviscidose Farmacokinetiesche / clinische studie met aztreonam (AZACTAM®) opgericht in samenwerking met AZ-VUB bedoeling: huis-therapie midden: infusie-pompen van 125 ml (te vernieuwen één keer per dag) programma: stabiliteit van de molecule "phase I" studie met vrijwilligers clinische studie met patiënten in progress Beta-lactams-CI-GSK 12-02-01

Continu-infuus van  - lactamen in mucoviscidose: stabiliteitsstudies Stabiliteit van aztreonam aan 37°C 80,00 85,00 90,00 95,00 100,00 105,00 110,00 5 10 15 20 25 30 35 Incubatietijd (uren) % van recuperatie 10% 8% 6% 4% H. Chanteux, 1999 Beta-lactams-CI-GSK 12-02-01

Continu-infuus van  - lactamen in intensieve zorgen: een amerikaanse studie…(4g/dag) 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 3.2 (2.5) (h) 777.4 (474.6) 419.7 (141.5) AUC 0-24h 142.5 (58.7) 133.2 (37.0) Cl (ml/min) t Pharmacokinetocs and Pharmacodynamics of continuous and intermittent ceftazidime during the treatment of nosocomiale pneumonia. D.P. Nicolau et al. Clin Drug Invest 1999:18(2):133-139. Beta-lactams-CI-GSK 12-02-01

bedoeling: ziekenhuis gebruik Continu-infuus van  - lactamen in intensieve zorgen in België : eerste stappen Farmacokinetieshe / clinische studie met ceftazidime (GLAZIDIM®) opgericht in samenwerking met UCL-St Luc en verschillende centra in België bedoeling: ziekenhuis gebruik midden: infusie-pompen van 48 ml (te vernieuwen één keer per dag) programma: stabiliteit van de molecule comptabiliteit met anderen geneesmiddelen clinische studie met patiënten in progress Beta-lactams-CI-GSK 12-02-01

Ceftazidime stability studies ... 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 Beta-lactams-CI-GSK 12-02-01

Ceftazidime stability studies ... 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 Beta-lactams-CI-GSK 12-02-01

Ceftazidime stability studies ... At 25°c, ceftazidime is stable during 24 hours caution must be exercised if the temperature gets higher thah 25°C temperature may certainly not reach 37°C since significant degradation occurs risk of ring opening and generation of haptens risk of appearance of toxic products Beta-lactams-CI-GSK 12-02-01

Degradation products of ceftazidime cefazidime [(2–amino–4-thiazolyl) (1–carboxy–1–methyletoxy) imino] acetyl–ethanal. 2-isomer Beta-lactams-CI-GSK 12-02-01

Degradation pathways of ceftazidime cefazidime 2-isomer 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 Beta-lactams-CI-GSK 12-02-01

Wy do you need to study compatibility ? R C N O COOH the -lactam could be attacked by other drugs… Beta-lactams-CI-GSK 12-02-01

Compatibility studies: principles mimic the intended clinical use to examine in details the stability HPLC the lack of physical interaction Viewer the lack of chemical interaction HPLC Beta-lactams-CI-GSK 12-02-01

Compatibility studies: methods Ceftazidime 8 g % Drug X as in infusion set 1st contact at 37°C and at high concentration (10 min) 2d contact at 37°C in more diluted conditions (V= 3 L) for 1 h Beta-lactams-CI-GSK 12-02-01

Compatibility studies: results Compatible antinfectives aminoglycosides macrolides (diluted) fluconazole sedatives / anticonvulsivants ketamin valproic acid antihypertensives / diuretics uradipil furosemide miscellaneous aminoacid solution (VAMIN) Non-compatible vancomycin (precipitation) macrolides (if concentrated) propofol (trapping in emulsion) midazolam (precipitation) nicardipin (precipitation) N-acetylcystein (chemical react.) Beta-lactams-CI-GSK 12-02-01

Clinical study: overall design empiric treatment of nosocomial, lower respiratory tract infections in Intensive Care Units two arms continuous infusion conventional administration prospective randomized but not double-blind clinical and microbiological assessment of efficacy, safety and pharmacoeconomics on an "intent to treat" basis total no. of patients: 2 x 60 pharmacokinetic studies in 2 x 12 patients Beta-lactams-CI-GSK 12-02-01

Clinical study: patient population must be in Intensive Care Units infection: must be nosocomial pneumonia > 4 days in ICU, or coming from another ward with an infection, or >1 week in hospital positive signs of sepsis: 3 criteria among: temperature <36°C or > 38°C heart rate > 90 leucocyte count < 4,000 or > 12,000 respiratory rate > 20/min) or need of mechanical ventilation 2 out of the 3 following symptoms: new lung infiltrate (RX) postive endotracheal aspirate need to increase fiO2 by > 15% within 24 h Beta-lactams-CI-GSK 12-02-01

Clinical study: exclusion criteria < 18 year of age pregnant women known allergy to -lactam antibiotics (penicillins or cephalosporins) moribund patients (therapy limitation) known resistance to the ceftazidime prior treatment with ceftazidime prior treatment with antibiotic combinations with demonstrated activity Beta-lactams-CI-GSK 12-02-01

Clinical study: patient description and treatment Patient description at enrolment (in addition to the population criteria: organ dysfunction SAPS score Treatment Ceftazidime plus amikacin or isepamicin amikacin can be discontinued if microbiological investigations at day 3 do not justify its maintenance Beta-lactams-CI-GSK 12-02-01

Clinical study: cefatzidime CI treatment modalities aim at 27 µg/ml loading dose should ideally be determined on the basis of the patient's weight and his/her volume of distribution of ceftzidime  D=Vd * Css Vd (L/kg): 0.2 0.3 0.4 0.5 ... loading dose (mg/kg): 5.4 8.1 10.8 13.5 ... Beta-lactams-CI-GSK 12-02-01

Cefatzidime CI: loading dose in practice patient’s weight Vd (L/kg) (kg) 0.2 0.4 40 216 432 50 270 540 60 324 648 70 378 756 80 432 864 90 486 972 100 540 1080 Beta-lactams-CI-GSK 12-02-01

Cefatzidime CI : infusion 4 g / day (2 x 2 g in 48 ml -- 2 ml/h) if abnormal renal fuction: > 50 ml/min: no adjustment 50 ml/min to 30 ml/min: 2g / day < 30 ml/min to 15 ml/min: 1g /day < 15 ml/min to 5 ml/min: 0.5 g /day < 5 ml/min: 0.25 g /day Beta-lactams-CI-GSK 12-02-01

Ceftazidime : conventional administration 6 g / day tid (2 g every 8 h) if abnormal renal fuction: > 50 ml/min: no adjustment 50 ml/min to 30 ml/min: 3 g / day tid (1g every 8 h < 30 ml/min to 15 ml/min: 1.5 g /day tid (0.5 g every 8 h) < 15 ml/min to 5 ml/min: 0.75 g /day tid (0.25 g every 8h) < 6 ml/min: 0.39 g /day tid (0.13 g every 8 h) Beta-lactams-CI-GSK 12-02-01

Amikacin / isepamicin : dosages 15 mg / day qd (once-a-day) if abnormal renal function: > 50 ml/min: no adjustment 50 ml/min to 30 ml/min: 15 g every 48 h < 30 ml/min to 15 ml/min: 7.5 g every 48 h < 15 ml/min: discontinue or do not start treatment Beta-lactams-CI-GSK 12-02-01

Assessment of results (all patients) 1. Clinical criteria at days 7, 14 and every week until leaving the ICU changes in sepsis signs radiologic changes changes in PaO2 changes in organ dysfunction levels changes in SAPS score drug-related side effects Beta-lactams-CI-GSK 12-02-01

Assessment of results (all patients) 2. microbiological criteria (at days 0, 4, and 7) isolation and MIC estimation of AUC24h to MIC ratios 3. pharmacokinetic criteria (at days 1, 4, and 7) (population pharmacokinetics) continuous infusion  one sample at any time conventional administration  peak (1h) and trough (7.5h) levels Beta-lactams-CI-GSK 12-02-01

Assessment of results (all patients) 4. side effects: every day… blood sample must be taken for assay of ceftazidime in case of suspected drug-related side-effect (CNS…) Beta-lactams-CI-GSK 12-02-01

Assessment of results (all patients) 5. pharmacoeconomics direct saving costs  amount of drug used indirect saving costs length of stay other antibiotics if faillure failure nursing care Beta-lactams-CI-GSK 12-02-01

Assessment of results: pharmacokinetic investigations (2 x 12 patients w/o renal failure) At days 0, 4 and 7 Cmax, Cmin, t1/2, clearance AUC and AUC24h / MIC ratio time > MIC Beta-lactams-CI-GSK 12-02-01

Central organization Data collection: 1 pharmacist [based at UCL]: stability studies and “on demand” compatibility studies sample collection and assay pharmacokinetics and AUC / MIC calculations clinical data collection and regular contact with all centers Progress reports by E-mail by password-protected WEB site Center for severe side effects alert P.F. Laterre P.M. Tulkens in progress not necessary so far ... Beta-lactams-CI-GSK 12-02-01

Where in Belgium ... Beta-lactams-CI-GSK 12-02-01

Patients’enrollement: status report February 12th, 2001 Bruxelles - Saint-Luc 6 Arlon 5 Ottignies - St Pierre 4 Brussel - AZ-VUB 3 Hornu 1 Namur - Ste Elisabeth 1 Turnhout - OCMW 1 Aalst - Onze Lieve Vrouw Antwerpen-Stuyvenberg Antwerpen-St Vincencius Brussel - H. Elizabetha Bruxelles -Brugmann Bruxelles - Etterneek Brussel - St Jan Charleroi - Fabiola / N. Dame Duffel Gent - UZ Haine-St Pierre (Jolimont) Mons - St Joseph total no. of patients enrolled: 21 Beta-lactams-CI-GSK 12-02-01

-lactamen door continu-infuus: But don’t let you fool your self... It ‘s a brilliant idea…. Beta-lactams-CI-GSK 12-02-01

Continu-infuus van  - lactamen Work must continue... Beta-lactams-CI-GSK 12-02-01

Farmacokinetiek / Farmacodynamie van antiinfectieusen weefsel- concentraties tolerantie / doeltreffenheids- ratio farmacokinetiek postantibiotisch effect en -lactamen continu infusie AUIC piek/mic http://www.isap.org Beta-lactams-CI-GSK 12-02-01

Farmacokinetiek / Farmacodynamie van antiinfectieusen Een hartelijk danken aan - H. Chanteux 1 (UCL) - B. Byl 3 (Erasme) - M.C. Cambier 1,4 (UCL) - I. Dab 1 (AZ VUB) - Th. Ghobert 4 (GSK) - P.F. Laterre 4 (UCL) - M.L. Leto 3 (UCL) - F. Renoird 1,4 (UCL) - H. Servais 4 (UCL) - E. Viaene 1 (UCL) - F. Van Bambeke 2 (UCL) 1 mucoviscidose; 2 concepten en algemene hulp; 3 farmacokinetische parameters van CF patiënten 4 ceftazidime studie Beta-lactams-CI-GSK 12-02-01