* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Can and should beta-lactams be given by continuous infusion
Survey
Document related concepts
Psychopharmacology wikipedia , lookup
Pharmacognosy wikipedia , lookup
Drug discovery wikipedia , lookup
Discovery and development of cephalosporins wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Drug interaction wikipedia , lookup
Plateau principle wikipedia , lookup
Prescription costs wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Transcript
24th ICC Manila / ISAP symposium Can and Should ß-lactams be Given by Continuous Infusion? John Turnidge Women’s & Children’s Hospital Adelaide Why use continuous infusions? • No requirement for repeated doses in a day, especially if drug has short half-life » one ‘dose’ per day or less • Provides measurable & predictable levels in blood and tissue compartments • Logical for agents where the predictor of efficacy is time that levels exceed the MIC, and that do not have significant concentration killing » i.e. ß-lactams Pharmacodynamic properties of ß-lactams • Little or no concentration-dependent killing • Variable post-antibiotic effect » Staphylococci – yes » Streptococci and Gram-negative bacilli – no • Time above MIC best predictor of bacterial killing in animal models Time-kill curves of P. aeruginosa Ticarcillin 9 9 8 7 7 7 6 6 Ciprofloxacin 10 8 8 Log10 CFU/mL Tobramycin 9 6 5 5 5 4 4 Control 4 3 1/4 MIC 3 1 MIC 3 2 4 MIC 2 16 MIC 2 1 1 0 0 64 MIC 1 0 1 2 3 4 5 6 Time (h) 7 8 9 0 1 2 3 4 Time (h) 5 6 7 Craig & Ebert; Scan J Infect Dis 1991; Suppl 74:63-70. 0 1 2 3 4 Time (h) 5 6 7 In Vitro PAE SUMMARY Penicillins Cephalosporins Carbapenems Vancomycin Tetracyclines Chloramphenicol Rifampicin Macrolides Trimethoprim Aminoglycosides Quinolones Staphylococci Streptococci ++ ++ + ++ ++ ++ +++ +++ + + + ± ± + ++ ++ ++ +++ +++ Coliforms Pseudomonas ± ++ + + ++ + Pharmacokinetic vs Pharmacodynamic Parameters Pharmacokinetics 1000 Peak/MIC Peak Plasma Concentration Pharmacodynamics 100 50 Elimination Rate Constant 10 t½ 1 0 2 4 .. ......... ................ ........................ AUC/MIC MIC .............................. ...................................... ............................................ T > MIC .................................................. 6 Hours Supra-MIC Effects 8 10 12 Sub-MIC & Post-antibiotic Effects 14 PD parameters of ß-lactams 11 11 10 10 log cfu per lung at 24h log cfu per lung at 24h Cefotaxime vs K. pneumoniae in mouse lung model 9 8 7 9 8 7 6 6 5 5 0.1 1 10 100 Peak/MIC ratio 1000 10000 1 10 100 AUC/MIC ratio 1000 10000 PD parameters of ß-lactams Cefotaxime vs K. pneumoniae in mouse lung model 11 log cfu per lung at 24h 10 9 8 7 6 5 0 20 40 60 Time above MIC (%) 80 100 Hypothetosporin 1g dose gives peak of 100mg/L, T½ = 2 hours 256 1g 8/24 128 Concentration mg/L 64 32 16 8 4 2 1 2 4 6 8 10 12 14 Time in hours 16 18 20 22 24 Hypothetosporin 1g dose gives peak of 100mg/L, T½ = 2 hours 256 1g 8/24 2g 8/24 128 Concentration mg/L 64 32 16 8 4 2 1 2 4 6 8 10 12 14 Time in hours 16 18 20 22 24 Hypothetosporin 1g dose gives peak of 100mg/L, T½ = 2 hours 256 1g 8/24 2g 8/24 128 Concentration mg/L 1g 6/24 64 32 16 8 4 2 1 2 4 6 8 10 12 14 Time in hours 16 18 20 22 24 Hypothetosporin 1g dose gives peak of 100mg/L, T½ = 2 hours 256 1g 8/24 2g 8/24 128 Concentration mg/L 1g 6/24 64 500mg 4/24 32 16 8 4 2 1 2 4 6 8 10 12 14 Time in hours 16 18 20 22 24 Continuous Infusion Clinical studies Pharmacokinetic studies • Cephalosporins » » » » » » Ceftazidime Cefepime Cefotaxime Cefamandole Cefazolin Cefpirome • Other ß-lactams » » » » » Flucloxacillin Piperacillin PiperacillinTazobactam Aztreonam Meropenem Efficacy studies • Ceftazidime » » » » Cystic fibrosis • Vinks et al. J Antimicrob Chemother 1997; 40:125-33 • Rappaz et al. Eur J Pediatr 2000; 159:919-25 Neutropenic fever • Egerer et al. Int J Antimicrob Agents 2000; 15:119-123 • Marshall et al. Support Care Cancer 2000; 8:198-202 • Egerer et al. Bone Marrow Transplant 2002; 30:427-31 • Dalle JH et al. J Pedaitr Hematol Oncol 2002; 24:714-6. Septicaemic Melioidosis • Angus et al. Br J Clin Pharmacol 2000; 49:445-52 Intensive care patients • Lipman et al. J Antimicrob Chemother 1999; 43:309-11 • Hanes et al. Am J Surg 2000; 179:436-40 • McNabb et al. Pharmacotherapy 2001; 21:549-55 Efficacy studies • Other agents » Flucloxacillin in staphylococcal sepsis • Leder et al. J Antimicrob Chemother 1999; 43:113-8 • Howden BP, Richards MJ. J Antimicrob Chemother 2001; 48:311-4. » Oxacillin in staphylococcal sepsis • Leggett. Drugs 2000; 59 Suppl 3:1-8 » Piperacillin-Tazobactam in a range of infections • Grant et al. Pharmacotherapy 2002; 22:471-83 » Cefepime in Gram-negative septicaemia • Jaruratanasirikul S et al. J Pharm Pharmacol 2002; 54:1693-6 491 Clinical Pharmacokinetics of Continuous Intravenous Administration of Penicillins L.G Visser, P. Arnouts, * R. van Furth, H. Mattie, and P.J. van den Broek From the Department of Infectious Diseases, University Hospital, Leiden, The Netherlands Clinical Infectious Diseases 1993; 17: 491-5 © 1993 by the University of Chicago. All rights reserved 10508-4838/93/1702-0025$02.00 Pharmacokinetics of Continuous IV Benzylpenicillin and Cloxacillin Dose No. of patients Mean plasma level (Range) Protein Binding (Range) Penicillin Cloxacillin 7.2 g/day 63 13.7 12 g/day 48 48.8 (5.2-53.6) (14.5-148.3) 45% 82% (13-70%) (33-90%) Visser et al, Clin Infect Dis 1993; 17:491 Continuous Infusion Flucloxacillin for DeepSeated Staphylococcal Infection • • 20 patients/21conditions » Osteomyelitis » Deep abscess » Endocarditis 11 6 4 Flucloxacillin Dose » » » » 12g 8g 8g 12g 12g 8g Leder et al, JAC 1999; 43:113 14 3 2 1 • Concomitant drugs » Rifampicin 3 • Duration » » » » » <10 days 10-19 days 20-29 days 30-39 days 40-60 days 3 3 3 8 3 Continuous Infusion Flucloxacillin for DeepSeated Staphylococcal Infection • Outcomes • • • • Initial Cure Rash Vancomycin Readmission intermittent Late relapse 17 2 1 3 • Levels (13 patients receiving flucloxacillin alone) • 8g • 12g 29mg/L (Range: 8->40) 27mg/L (Range: 11.5->40) Leder et al, JAC 1999; 43:113 Continuous infusion ceftazidime in CF • • • • 17 adults, treated for 3 weeks, 33 courses All patients had P. aeruginosa infection Dose = 100mg/kg/24h, no other antibiotics Clinical response 12 patients, 25 courses • Excellent 84% • Good 8% • Moderate 8% • Microbiological response » ~40% ‘eradication’ at end of treatment Vinks et al, JAC 1997; 40:125 Continuous infusion ceftazidime in CF • PK data from 10 patients Clearance (L/h) Css (mg/L) Sputum conc’n (mg/L) Vinks et al, JAC 1997; 40:125 Mean 9.1 ± 1.3 28.4 ± 5.0 3.9 ± 4.0 Range 6.0–11.0 23.3–30.6 0.5–13.1 Cost comparison studies • Ceftriaxone 1g bolus versus cefotaxime 2g/day by continuous infusion » Hitt et al. Am J Health-Syst Pharm 1997; 54:1614-8 • CI cefotaxime 2/3 of costs after after day 1 • Ceftazidime 2g 8-hourly versus 3g/day by CI » McNabb et al. Pharmacotherapy 2001; 21:549-55. • CI only 60% of costs Continuous infusion summary • PK issues » Intersubject variation becomes a prominent feature– up to 10-fold range in Css • therefore, need to measure levels » Need to account for protein binding due to intersubject variation • Unanswered PK questions » How many fold of MIC do levels need to be? • most authorities agree on 4-8 fold (for UNBOUND drug) Continuous infusion summary 2 • Clinical issues » Limited efficacy data » Few drugs published » Particularly suited to outpatient IV therapy • Unanswered clinical questions » Method of choice for serious infection? » Comparative costs? Some data emerging • Which infections? » where (prolonged) IV is essential • oral agents unavailable, oral not proven » ?not endocarditis and meningitis Continuous infusion Practical aspects Continuous infusion in practice • Technological advances have made this possible » PICC lines » Affordable pump technology • with sufficient precision » Drug stability data • Given large amount of intersubject variation » Monitor levels in all patients, principally to avoid under-dosing » Assays established for drugs used Peripherally-inserted central lines • Soft silicone • Cubital fossa » safe » comfortable • Continuous infusion reduces risk of clotting • Insertion not requiring a full surgical procedure Pumps • For continuous infusion need pumps with a high degree of precision to avoid » finishing early (treatment gap) » running late (underdosing) • Most systems cater for some overage to avoid finishing early Elastomeric pumps Baxter Intermate® Syringe pumps Baxa MicroFuse™ Electronic pumps Abbott GemstarTM Drug stability • Need drugs that are stable » in high concentration » at body temperature for 24 hours » in fridge/freezer for a week or more • in hospital pharmacy • at home Drug stability • Adequate 90-100% » » » » » Flucloxacillin Cefazolin Cephalothin Cefotaxime Piperacillin-tazobactam • Adequate provided ≤ 25°C » Cefepime » Meropenem • Intermediate » Benzylpenicillin • Poor » Ampicillin » Imipenem www.opitsourcebook.com Can We Give ß-lactams by Continuous Infusion? • Yes » It is now practical to do so in many settings • Ideal for hospital-in-the-home programs » Change ‘bag’ daily • Easily managed in hospital » Provided a dedicated line or lumen is available Should We Give ß-lactams by Continuous Infusion? • Where prolonged IV ß-lactams are needed » Cystic Fibrosis » Serious deep seated infections • e.g. osteomyelitis • allows discharge to hospital-in-the-home programs • remember high-dose oral may work just as well! » Possibly in • neutropenic fever • ICU infections • patients with pathogens having reduced susceptibility » Not yet recommended – no data • endocarditis, meningitis