Can and Should ß-lactams be Given byContinuous Infusion?

John TurnidgeJohn Turnidge

Women’s & Children’s HospitalWomen’s & Children’s Hospital

AdelaideAdelaide

24th ICC Manila / ISAP symposium

Why use continuous infusions?

• No requirement for repeated doses in a day, No requirement for repeated doses in a day, especially if drug has short half-lifeespecially if drug has short half-life» one ‘dose’ per day or lessone ‘dose’ per day or less

• Provides measurable & predictable levels in Provides measurable & predictable levels in blood and tissue compartmentsblood and tissue compartments

• Logical for agents where the predictor of Logical for agents where the predictor of efficacy is time that levels exceed the MIC, efficacy is time that levels exceed the MIC, and that do not have significant and that do not have significant concentration killingconcentration killing» i.e. ß-lactamsi.e. ß-lactams

Pharmacodynamic properties of ß-lactams

• Little or no concentration-dependent killingLittle or no concentration-dependent killing• Variable post-antibiotic effectVariable post-antibiotic effect

» Staphylococci – yesStaphylococci – yes» Streptococci and Gram-negative bacilli – noStreptococci and Gram-negative bacilli – no

• Time above MIC best predictor of bacterial Time above MIC best predictor of bacterial killing in animal modelskilling in animal models

Time-kill curves of P. aeruginosa

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8

9

0 1 2 3 4 5 6 7 8 9Time (h)

Log1

0 C

FU/m

L

Control

1/4 MIC

1 MIC

4 MIC

16 MIC

64 MIC

Craig & Ebert; Scan J Infect Dis 1991; Suppl 74:63-70.Craig & Ebert; Scan J Infect Dis 1991; Suppl 74:63-70.

0

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0 1 2 3 4 5 6 7Time (h)

Ticarcillin

Tobramycin

Ciprofloxacin

In Vitro PAE SUMMARY

StaphylococciStaphylococci StreptococciStreptococci ColiformsColiforms PseudomonasPseudomonas

PenicillinsPenicillins ++++ ±± -- --CephalosporinsCephalosporins ++++ ±± -- --CarbapenemsCarbapenems ++ ++ ++VancomycinVancomycin ++++TetracyclinesTetracyclines ++++ ++++ ++++ChloramphenicolChloramphenicol ++++ ++++RifampicinRifampicin ++++++ ++++++MacrolidesMacrolides ++++++ ++++++TrimethoprimTrimethoprim ++ ±±AminoglycosidesAminoglycosides ++ ++++ ++++QuinolonesQuinolones ++ ++ ++

Pharmacokinetic vs Pharmacodynamic Parameters

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0 2 4 6 8 10 12 14

Hours

Pla

sm

aC

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cen

trati

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t½t½

50.....................................................................................................................................................................................................................

Supra-MICEffects

Sub-MIC &Post-antibiotic Effects

MIC

T > MICT > MICT > MICT > MIC

Peak/MICPeak/MICPeak/MICPeak/MIC

AUC/MICAUC/MICAUC/MICAUC/MIC

Pharmacokinetics Pharmacodynamics

PeakPeak

EliminationRate ConstantEliminationRate Constant

PD parameters of ß-lactams

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Peak/MIC ratio

log

cfu

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Cefotaxime vs K. pneumoniae in mouse lung model

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1 10 100 1000 10000

AUC/MIC ratio

log

cfu

per

lu

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PD parameters of ß-lactams

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Time above MIC (%)

log

cfu

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Cefotaxime vs K. pneumoniae in mouse lung model

Hypothetosporin

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11

44

88

1616

3232

6464

128128

256256

22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424

1g dose gives peak of 100mg/L, T½ = 2 hours

1g dose gives peak of 100mg/L, T½ = 2 hours

Time in hoursTime in hours

Co

nce

ntratio

n m

g/L

Co

nce

ntratio

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g/L

1g 8/241g 8/24

Hypothetosporin

22

11

44

88

1616

3232

6464

128128

256256

22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424

1g dose gives peak of 100mg/L, T½ = 2 hours

1g dose gives peak of 100mg/L, T½ = 2 hours

Time in hoursTime in hours

Co

nce

ntratio

n m

g/L

Co

nce

ntratio

n m

g/L

1g 8/241g 8/24

2g 8/242g 8/24

Hypothetosporin

22

11

44

88

1616

3232

6464

128128

256256

22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424

1g dose gives peak of 100mg/L, T½ = 2 hours

1g dose gives peak of 100mg/L, T½ = 2 hours

Time in hoursTime in hours

Co

nce

ntratio

n m

g/L

Co

nce

ntratio

n m

g/L

1g 8/241g 8/24

2g 8/242g 8/24

1g 6/241g 6/24

Hypothetosporin

22

11

44

88

1616

3232

6464

128128

256256

22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424

1g dose gives peak of 100mg/L, T½ = 2 hours

1g dose gives peak of 100mg/L, T½ = 2 hours

Time in hoursTime in hours

Co

nce

ntratio

n m

g/L

Co

nce

ntratio

n m

g/L

1g 8/241g 8/24

2g 8/242g 8/24

1g 6/241g 6/24

500mg 4/24500mg 4/24

Continuous Infusion

Clinical studiesClinical studies

Pharmacokinetic studies

• CephalosporinsCephalosporins» CeftazidimeCeftazidime» CefepimeCefepime» CefotaximeCefotaxime» CefamandoleCefamandole» CefazolinCefazolin» CefpiromeCefpirome

• Other ß-lactamsOther ß-lactams» FlucloxacillinFlucloxacillin» PiperacillinPiperacillin» Piperacillin-Piperacillin-

TazobactamTazobactam» AztreonamAztreonam» MeropenemMeropenem

Efficacy studies

• CeftazidimeCeftazidime» Cystic fibrosisCystic fibrosis

• Vinks et al. J Antimicrob Chemother 1997; 40:125-33Vinks et al. J Antimicrob Chemother 1997; 40:125-33• Rappaz et al. Eur J Pediatr 2000; 159:919-25Rappaz et al. Eur J Pediatr 2000; 159:919-25

» Neutropenic feverNeutropenic fever• Egerer et al. Int J Antimicrob Agents 2000; 15:119-123Egerer et al. Int J Antimicrob Agents 2000; 15:119-123• Marshall et al. Support Care Cancer 2000; 8:198-202Marshall et al. Support Care Cancer 2000; 8:198-202• Egerer et al. Bone Marrow Transplant 2002; 30:427-31Egerer 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 MelioidosisSepticaemic Melioidosis• Angus et al. Br J Clin Pharmacol 2000; 49:445-52Angus et al. Br J Clin Pharmacol 2000; 49:445-52

» Intensive care patientsIntensive care patients• Lipman et al. J Antimicrob Chemother 1999; 43:309-11Lipman et al. J Antimicrob Chemother 1999; 43:309-11• Hanes et al. Am J Surg 2000; 179:436-40Hanes et al. Am J Surg 2000; 179:436-40• McNabb et al. Pharmacotherapy 2001; 21:549-55McNabb et al. Pharmacotherapy 2001; 21:549-55

Efficacy studies

• Other agentsOther agents» Flucloxacillin in staphylococcal sepsisFlucloxacillin in staphylococcal sepsis

• Leder et al. J Antimicrob Chemother 1999; 43:113-8Leder et al. J Antimicrob Chemother 1999; 43:113-8• Howden BP, Richards MJ. J Antimicrob Chemother Howden BP, Richards MJ. J Antimicrob Chemother

2001; 48:311-4.2001; 48:311-4.» Oxacillin in staphylococcal sepsisOxacillin in staphylococcal sepsis

• Leggett. Drugs 2000; 59 Suppl 3:1-8Leggett. Drugs 2000; 59 Suppl 3:1-8» Piperacillin-Tazobactam in a range of infectionsPiperacillin-Tazobactam in a range of infections

• Grant et al. Pharmacotherapy 2002; 22:471-83Grant et al. Pharmacotherapy 2002; 22:471-83» Cefepime in Gram-negative septicaemiaCefepime in Gram-negative septicaemia

• Jaruratanasirikul S et al. J Pharm Pharmacol 2002; Jaruratanasirikul S et al. J Pharm Pharmacol 2002; 54:1693-654:1693-6

491491

Clinical Pharmacokinetics of Continuous Clinical Pharmacokinetics of Continuous Intravenous Administration of PenicillinsIntravenous Administration of Penicillins

L.G Visser, P. Arnouts, * R. van Furth, H. Mattie, and P.J. van den BroekL.G Visser, P. Arnouts, * R. van Furth, H. Mattie, and P.J. van den BroekFromFrom the Department of Infectious Diseases, University Hospital,the Department of Infectious Diseases, University Hospital, Leiden, The NetherlandsLeiden, The Netherlands

Clinical Infectious Diseases 1993; 17: 491-5Clinical Infectious Diseases 1993; 17: 491-5©© 1993 by the University of Chicago. All rights reserved 1993 by the University of Chicago. All rights reserved

10508-4838/93/1702-0025$02.0010508-4838/93/1702-0025$02.00

491491

Clinical Pharmacokinetics of Continuous Clinical Pharmacokinetics of Continuous Intravenous Administration of PenicillinsIntravenous Administration of Penicillins

L.G Visser, P. Arnouts, * R. van Furth, H. Mattie, and P.J. van den BroekL.G Visser, P. Arnouts, * R. van Furth, H. Mattie, and P.J. van den BroekFromFrom the Department of Infectious Diseases, University Hospital,the Department of Infectious Diseases, University Hospital, Leiden, The NetherlandsLeiden, The Netherlands

Clinical Infectious Diseases 1993; 17: 491-5Clinical Infectious Diseases 1993; 17: 491-5©© 1993 by the University of Chicago. All rights reserved 1993 by the University of Chicago. All rights reserved

10508-4838/93/1702-0025$02.0010508-4838/93/1702-0025$02.00

Pharmacokinetics of Continuous IV Benzylpenicillin and Cloxacillin

PenicillinPenicillin CloxacillinCloxacillinDoseDose 7.2 g/d7.2 g/dayay 12 g/d12 g/dayay

No. of patientsNo. of patients 6363 4848

Mean plasma levelMean plasma level 13.713.7 48.848.8 (Range)(Range) (5.2-53.6)(5.2-53.6) (14.5-148.3)(14.5-148.3)

Protein BindingProtein Binding 45%45% 82%82% (Range)(Range) (13-70%)(13-70%) (33-90%)(33-90%)

Visser et al, Clin Infect Dis 1993; 17:491

• 2020 patients patients/21conditions/21conditions» OsteomyelitisOsteomyelitis 1111» Deep abscessDeep abscess 66» EndocarditisEndocarditis 44

• Flucloxacillin DoseFlucloxacillin Dose» 12g12g 1144» 8g8g 33» 8g 8g 12g12g 22» 12g 12g 8g 8g 11

• Concomitant drugs drugs» RifampicinRifampicin

33

• DurationDuration» <10 days<10 days

33» 10-19 days10-19 days

33» 20-29 days20-29 days

33» 30-3930-39 days days

88» 40-60 days40-60 days

33

Leder et al, JAC 1999; 43:113

Continuous Infusion Flucloxacillin for Deep- Seated Staphylococcal

Infection

• OutcomesOutcomes• Initial Initial CureCure 1717• Rash Rash VVancomycinancomycin 22• Readmission Readmission intermittentintermittent 11• Late rLate relapseelapse 33

• Levels Levels (1(133 patients patients receiving flucloxacillin alone receiving flucloxacillin alone))• 8g8g 2929mg/L (Range: mg/L (Range: 8->408->40))• 12g12g 27 27mg/L (Range: mg/L (Range: 11.5->4011.5->40))

Leder et al, JAC 1999; 43:113

Continuous Infusion Flucloxacillin for Deep- Seated Staphylococcal

Infection

Continuous infusion ceftazidime in CF

• 17 adults, treated for 3 weeks, 33 courses17 adults, treated for 3 weeks, 33 courses• All patients had All patients had P. aeruginosaP. aeruginosa infection infection• Dose = 100mg/kg/24h, no other antibioticsDose = 100mg/kg/24h, no other antibiotics• Clinical response 12 patients, 25 coursesClinical response 12 patients, 25 courses

• Excellent Excellent 84%84%• Good Good 8%8%• Moderate Moderate 8%8%

• Microbiological responseMicrobiological response» ~40% ‘eradication’ at end of treatment~40% ‘eradication’ at end of treatment

Vinks et al, JAC 1997; 40:125

Continuous infusion ceftazidime in CF

• PK data from 10 patientsPK data from 10 patientsMeanMeanRangeRange

Clearance (L/h)Clearance (L/h) 9.1 9.1 ± 1.3± 1.3

6.0–11.06.0–11.0CCssss (mg/L) (mg/L) 28.4 28.4 ± 5.0± 5.0

23.3–30.623.3–30.6Sputum conc’n (mg/L)Sputum conc’n (mg/L) 3.9 ± 4.03.9 ± 4.0

0.5–13.10.5–13.1

Vinks et al, JAC 1997; 40:125

Cost comparison studies

• Ceftriaxone 1g bolus versus cefotaxime Ceftriaxone 1g bolus versus cefotaxime 2g/day by continuous infusion2g/day by continuous infusion» Hitt et al. Am J Health-Syst Pharm 1997; 54:1614-8Hitt et al. Am J Health-Syst Pharm 1997; 54:1614-8

• CI cefotaxime 2/3 of costs after after day 1CI cefotaxime 2/3 of costs after after day 1

• Ceftazidime 2g 8-hourly versus 3g/day by CICeftazidime 2g 8-hourly versus 3g/day by CI» McNabb et al. Pharmacotherapy 2001; 21:549-55.McNabb et al. Pharmacotherapy 2001; 21:549-55.

• CI only 60% of costsCI only 60% of costs

Continuous infusion summary

• PK issuesPK issues» Intersubject variation becomes a prominent feature–Intersubject variation becomes a prominent feature–

up to up to 10-fold range10-fold range in C in Cssss

• therefore, need to measure levelstherefore, need to measure levels» Need to account for Need to account for protein binding protein binding due to due to

intersubject variationintersubject variation

• Unanswered PK questionsUnanswered PK questions» How many fold of MIC do levels need to be?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)

Continuous infusion summary 2

• Clinical issuesClinical issues» Limited efficacy dataLimited efficacy data» Few drugs publishedFew drugs published» Particularly suited to outpatient IV therapyParticularly suited to outpatient IV therapy

• Unanswered clinical questionsUnanswered clinical questions» Method of choice for serious infection?Method of choice for serious infection?» Comparative costs? Some data emergingComparative costs? Some data emerging

• Which infections?Which infections?» where (prolonged) IV is essentialwhere (prolonged) IV is essential

• oral agents unavailable, oral not provenoral agents unavailable, oral not proven

» ?not endocarditis and meningitis?not endocarditis and meningitis

Continuous infusion

Practical aspectsPractical aspects

Continuous infusion in practice

• Technological advances have made this Technological advances have made this possiblepossible» PICC linesPICC lines» Affordable pump technologyAffordable pump technology

• with sufficient precisionwith sufficient precision» Drug stability dataDrug stability data

• Given large amount of intersubject variationGiven large amount of intersubject variation» Monitor levels in all patients, principally to avoid Monitor levels in all patients, principally to avoid

under-dosingunder-dosing» Assays established for drugs usedAssays established for drugs used

Peripherally-inserted central lines

• Soft siliconeSoft silicone• Cubital fossaCubital fossa

» safesafe» comfortablecomfortable

• Continuous infusion Continuous infusion reduces risk of clottingreduces risk of clotting

• Insertion not requiring a Insertion not requiring a full surgical procedurefull surgical procedure

Pumps

• For continuous infusion need pumps with a For continuous infusion need pumps with a high degree of precision to avoidhigh degree of precision to avoid» finishing early (treatment gap)finishing early (treatment gap)» running late (underdosing)running late (underdosing)

• Most systems cater for some overage to Most systems cater for some overage to avoid finishing earlyavoid finishing early

Elastomeric pumps

Baxter Intermate®

Syringe pumps

Baxa MicroFuse™

Electronic pumps

Abbott GemstarTM

Drug stability

• Need drugs that are stableNeed drugs that are stable» in high concentrationin high concentration» at body temperature for 24 hoursat body temperature for 24 hours» in fridge/freezer for a week or morein fridge/freezer for a week or more

• in hospital pharmacyin hospital pharmacy• at homeat home

Drug stability

• Adequate 90-100%Adequate 90-100%» FlucloxacillinFlucloxacillin» CefazolinCefazolin» CephalothinCephalothin» CefotaximeCefotaxime» Piperacillin-tazobactamPiperacillin-tazobactam

• Adequate provided ≤ 25°CAdequate provided ≤ 25°C» CefepimeCefepime» MeropenemMeropenem

• IntermediateIntermediate» BenzylpenicillinBenzylpenicillin

• PoorPoor» AmpicillinAmpicillin» ImipenemImipenem

www.opitsourcebook.com

Can We Give ß-lactams by Continuous Infusion?

• YesYes» It is now practical to do so in many settingsIt is now practical to do so in many settings

• Ideal for hospital-in-the-home programsIdeal for hospital-in-the-home programs» Change ‘bag’ dailyChange ‘bag’ daily

• Easily managed in hospitalEasily managed in hospital» Provided a dedicated line or lumen is availableProvided a dedicated line or lumen is available

Should We Give ß-lactams by Continuous Infusion?

• Where prolonged IV ß-lactams are neededWhere prolonged IV ß-lactams are needed» Cystic FibrosisCystic Fibrosis» Serious deep seated infectionsSerious deep seated infections

• e.g. osteomyelitise.g. osteomyelitis• allows discharge to hospital-in-the-home programsallows 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 inPossibly in• neutropenic feverneutropenic fever• ICU infectionsICU infections• patients with pathogens having reduced susceptibilitypatients with pathogens having reduced susceptibility

» Not yet recommended – no dataNot yet recommended – no data• endocarditis, meningitisendocarditis, meningitis