Transcript Can and should beta-lactams be given by continuous infusion

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