1. Can and Should ß-lactams be Given by Continuous Infusion? John Turnidge Women’s & Children’s Hospital Adelaide 24 th ICC Manila / ISAP symposium

2. Why use continuous infusions? No requirement for repeated doses in a day, especially if drug has short half-life 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 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 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

3. Pharmacodynamic properties of ß-lactams Little or no concentration-dependent killing Little or no concentration-dependent killing Variable post-antibiotic effect Variable post-antibiotic effect »Staphylococci – yes »Streptococci and Gram-negative bacilli – no Time above MIC best predictor of bacterial killing in animal models Time above MIC best predictor of bacterial killing in animal models

4. Time-kill curves of P. aeruginosa Craig & Ebert; Scan J Infect Dis 1991; Suppl 74:63-70. TicarcillinTobramycinCiprofloxacin

5. In Vitro PAE SUMMARY StaphylococciStreptococciColiformsPseudomonas Penicillins++±-- Cephalosporins++±-- Carbapenems+++ Vancomycin++ Tetracyclines++++++ Chloramphenicol++++ Rifampicin++++++ Macrolides++++++ Trimethoprim+± Aminoglycosides+++++ Quinolones+++

6. Pharmacokinetic vs Pharmacodynamic Parameters t½ 50..................................................................................................................................................................................................................... Supra-MIC Effects Sub-MIC & Post-antibiotic Effects MIC T > MIC Peak/MIC AUC/MIC PharmacokineticsPharmacodynamics Peak Elimination Rate Constant

7. PD parameters of ß-lactams Cefotaxime vs K. pneumoniae in mouse lung model

8. PD parameters of ß-lactams Cefotaxime vs K. pneumoniae in mouse lung model

9. Hypothetosporin 2 1 4 8 16 32 64 128 256 24681012141618202224 1g dose gives peak of 100mg/L, T½ = 2 hours Time in hours Concentration mg/L 1g 8/24

10. Hypothetosporin 2 1 4 8 16 32 64 128 256 24681012141618202224 1g dose gives peak of 100mg/L, T½ = 2 hours Time in hours Concentration mg/L 1g 8/24 2g 8/24

11. Hypothetosporin 2 1 4 8 16 32 64 128 256 24681012141618202224 1g dose gives peak of 100mg/L, T½ = 2 hours Time in hours Concentration mg/L 1g 8/24 2g 8/24 1g 6/24

12. Hypothetosporin 2 1 4 8 16 32 64 128 256 24681012141618202224 1g dose gives peak of 100mg/L, T½ = 2 hours Time in hours Concentration mg/L 1g 8/24 2g 8/24 1g 6/24 500mg 4/24

13. Continuous Infusion Clinical studies

14. Pharmacokinetic studies Cephalosporins Cephalosporins »Ceftazidime »Cefepime »Cefotaxime »Cefamandole »Cefazolin »Cefpirome Other ß-lactams Other ß-lactams »Flucloxacillin »Piperacillin »Piperacillin- Tazobactam »Aztreonam »Meropenem

15. Efficacy studies Ceftazidime Ceftazidime »Cystic fibrosis Vinks et al. J Antimicrob Chemother 1997; 40:125-33 Vinks et al. J Antimicrob Chemother 1997; 40:125-33 Rappaz et al. Eur J Pediatr 2000; 159:919-25 Rappaz et al. Eur J Pediatr 2000; 159:919-25 »Neutropenic fever Egerer et al. Int J Antimicrob Agents 2000; 15:119-123 Egerer et al. Int J Antimicrob Agents 2000; 15:119-123 Marshall et al. Support Care Cancer 2000; 8:198-202 Marshall et al. Support Care Cancer 2000; 8:198-202 Egerer et al. Bone Marrow Transplant 2002; 30:427-31 Egerer et al. Bone Marrow Transplant 2002; 30:427-31 Dalle JH et al. J Pedaitr Hematol Oncol 2002; 24:714-6. 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 Angus et al. Br J Clin Pharmacol 2000; 49:445-52 »Intensive care patients Lipman et al. J Antimicrob Chemother 1999; 43:309-11 Lipman et al. J Antimicrob Chemother 1999; 43:309-11 Hanes et al. Am J Surg 2000; 179:436-40 Hanes et al. Am J Surg 2000; 179:436-40 McNabb et al. Pharmacotherapy 2001; 21:549-55 McNabb et al. Pharmacotherapy 2001; 21:549-55

16. Efficacy studies Other agents Other agents »Flucloxacillin in staphylococcal sepsis Leder et al. J Antimicrob Chemother 1999; 43:113-8 Leder et al. J Antimicrob Chemother 1999; 43:113-8 Howden BP, Richards MJ. J Antimicrob Chemother 2001; 48:311-4. Howden BP, Richards MJ. J Antimicrob Chemother 2001; 48:311-4. »Oxacillin in staphylococcal sepsis Leggett. Drugs 2000; 59 Suppl 3:1-8 Leggett. Drugs 2000; 59 Suppl 3:1-8 »Piperacillin-Tazobactam in a range of infections Grant et al. Pharmacotherapy 2002; 22:471-83 Grant et al. Pharmacotherapy 2002; 22:471-83 »Cefepime in Gram-negative septicaemia Jaruratanasirikul S et al. J Pharm Pharmacol 2002; 54:1693-6 Jaruratanasirikul S et al. J Pharm Pharmacol 2002; 54:1693-6

17. 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$02.00491 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

18. Pharmacokinetics of Continuous IV Benzylpenicillin and Cloxacillin PenicillinCloxacillin Dose 7.2 g/day12 g/day No. of patients 6348 Mean plasma level 13.748.8 (Range)(5.2-53.6)(14.5-148.3) Protein Binding 45%82% (Range)(13-70%)(33-90%) Visser et al, Clin Infect Dis 1993; 17:491

19. 20 patients/21conditions 20 patients/21conditions » Osteomyelitis11 » Deep abscess6 » Endocarditis4 Flucloxacillin Dose Flucloxacillin Dose » 12g14 » 8g3 » 8g  12g2 » 12g  8g1 drugs Concomitant drugs »Rifampicin3 Duration Duration »<10 days3 »10-19 days3 »20-29 days3 »30-39 days8 »40-60 days3 Leder et al, JAC 1999; 43:113 Continuous Infusion Flucloxacillin for Deep- Seated Staphylococcal Infection

20. Outcomes Outcomes Initial Cure17 Initial Cure17 Rash Vancomycin 2 Rash  Vancomycin 2 Readmission intermittent1 Readmission  intermittent1 Late relapse3 Late relapse3 Levels (13 patients receiving flucloxacillin alone) Levels (13 patients receiving flucloxacillin alone) 8g29mg/L (Range: 8->40) 8g29mg/L (Range: 8->40) 12g 27mg/L (Range: 11.5->40) 12g 27mg/L (Range: 11.5->40) Leder et al, JAC 1999; 43:113 Continuous Infusion Flucloxacillin for Deep- Seated Staphylococcal Infection

21. Continuous infusion ceftazidime in CF 17 adults, treated for 3 weeks, 33 courses 17 adults, treated for 3 weeks, 33 courses All patients had P. aeruginosa infection All patients had P. aeruginosa infection Dose = 100mg/kg/24h, no other antibiotics Dose = 100mg/kg/24h, no other antibiotics Clinical response 12 patients, 25 courses Clinical response 12 patients, 25 courses Excellent 84% Excellent 84% Good 8% Good 8% Moderate 8% Moderate 8% Microbiological response Microbiological response »~40% ‘eradication’ at end of treatment Vinks et al, JAC 1997; 40:125

22. Continuous infusion ceftazidime in CF PK data from 10 patients PK data from 10 patients MeanRange Clearance (L/h)9.1 ± 1.3 6.0–11.0 C ss (mg/L)28.4 ± 5.0 23.3–30.6 Sputum conc’n (mg/L)3.9 ± 4.0  0.5–13.1 Vinks et al, JAC 1997; 40:125

23. Continuous infusion ceftazidime in critically-ill patients 12 ICU patients, cross-over 12 ICU patients, cross-over »Intermittent:2g 8-hourly 2 days »Continuous:2g bolus + 3g over 24h PK data PK data MeanRange C ss (mg/L)29.7 ± 17.4 10.6–62.4 IntermittentContinuous % of patients with T>MIC 100% 84%100% Benko et al, AAC 1996; 40:691

24. Cost comparison studies Ceftriaxone 1g bolus versus cefotaxime 2g/day by continuous infusion 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 CI cefotaxime 2/3 of costs after after day 1 Ceftazidime 2g 8-hourly versus 3g/day by CI Ceftazidime 2g 8-hourly versus 3g/day by CI »McNabb et al. Pharmacotherapy 2001; 21:549-55. CI only 60% of costs CI only 60% of costs

25. Continuous infusion summary PK issues PK issues »Intersubject variation becomes a prominent feature– up to 10-fold range in C ss therefore, need to measure levels therefore, need to measure levels »Need to account for protein binding due to intersubject variation Unanswered PK questions Unanswered PK questions »How many fold of MIC do levels need to be? most authorities agree on 4-8 fold (for UNBOUND drug) most authorities agree on 4-8 fold (for UNBOUND drug)

26. Continuous infusion summary 2 Clinical issues Clinical issues »Limited efficacy data »Few drugs published »Particularly suited to outpatient IV therapy Unanswered clinical questions Unanswered clinical questions »Method of choice for serious infection? »Comparative costs? Some data emerging Which infections? Which infections? »where (prolonged) IV is essential oral agents unavailable, oral not proven oral agents unavailable, oral not proven »?not endocarditis and meningitis

27. Continuous infusion Practical aspects

28. Continuous infusion in practice Technological advances have made this possible Technological advances have made this possible »PICC lines »Affordable pump technology with sufficient precision with sufficient precision »Drug stability data Given large amount of intersubject variation Given large amount of intersubject variation »Monitor levels in all patients, principally to avoid under-dosing »Assays established for drugs used

29. Peripherally-inserted central lines Soft silicone Soft silicone Cubital fossa Cubital fossa »safe »comfortable Continuous infusion reduces risk of clotting Continuous infusion reduces risk of clotting Insertion not requiring a full surgical procedure Insertion not requiring a full surgical procedure

30. Pumps For continuous infusion need pumps with a high degree of precision to avoid 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 Most systems cater for some overage to avoid finishing early

31. Elastomeric pumps Baxter Intermate®

32. Syringe pumps Baxa MicroFuse™

33. Electronic pumps Abbott Gemstar TM

34. Drug stability Need drugs that are stable 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 in hospital pharmacy at home at home

35. Drug stability Adequate 90-100% Adequate 90-100% »Flucloxacillin »Cefazolin »Cephalothin »Cefotaxime »Piperacillin-tazobactam Adequate provided ≤ 25°C Adequate provided ≤ 25°C »Cefepime »Meropenem Intermediate Intermediate »Benzylpenicillin Poor Poor »Ampicillin »Imipenem

36. www.opitsourcebook.com

37. Can We Give ß-lactams by Continuous Infusion? Yes Yes »It is now practical to do so in many settings Ideal for hospital-in-the-home programs Ideal for hospital-in-the-home programs »Change ‘bag’ daily Easily managed in hospital Easily managed in hospital »Provided a dedicated line or lumen is available

38. Should We Give ß-lactams by Continuous Infusion? Where prolonged IV ß-lactams are needed Where prolonged IV ß-lactams are needed »Cystic Fibrosis »Serious deep seated infections e.g. osteomyelitis e.g. osteomyelitis allows discharge to hospital-in-the-home programs allows discharge to hospital-in-the-home programs remember high-dose oral may work just as well! remember high-dose oral may work just as well! »Possibly in neutropenic fever neutropenic fever ICU infections ICU infections patients with pathogens having reduced susceptibility patients with pathogens having reduced susceptibility »Not yet recommended – no data endocarditis, meningitis endocarditis, meningitis