11/4/2014

1

Continuous and Prolonged Infusions of Beta Lactams

Elizabeth O. Hand, Pharm.D., BCPS Clinical Assistant Professor

The University of Texas at Austin College of Pharmacy Pediatric Infectious Disease Pharmacist

University Hospital, San Antonio TX

Quick Poll…

• How many utilize prolonged or continuous infusion antibiotic regimens at their hospital?

• How many utilize this strategy in ALL patients on select beta lactams? (piperacillin/tazobactam, meropenem, ceftazidime)

Objectives

• Technician Objectives: – Explain the rationale for PI/CI of beta lactams – List 2 antimicrobials that are not ideal for CI – Describe potential downsides of PI/CI of beta lactams

• Pharmacist Objectives:

– Explain the pharmacokinetic and pharmacodynamics benefits of PI/CI of beta lactams

– Evaluate clinical literature related to the use of PI/CI – Describe clinical situations in which PI/CI of beta

lactams may not be ideal

Where to Begin?!

• OVERWHELMING literature

– Improved “target attainment”?

– Improved microbiologic clearance?

– Improved survival?

– No benefit?

– Worse clinical outcomes?

• Important disclaimers….

The Fine Print

• Nothing is exact in infectious disease

• BUG vs. DRUG interactions change when you throw in DOUG

• Beta lactam levels not routinely be utilized, so we’re all guessing

• We don’t always have MIC data

• Must combine what we know with our best clinical judgment – One size likely does NOT fit all

11/4/2014

2

Outline

• Why even extend beta lactam infusions? – Time dependent vs. concentration dependent bacterial

killing

• In vitro, simulated patient, and actual patient data

• Most studied beta lactams

• Practical application – Special populations

Time-Dependent vs. Concentration-Dependent

• f%T>MIC – % of time where free drug concentration exceeds

the MIC • Minimum inhibitory concentration: minimum amount

of drug that inhibits bacterial growth

• Cmax:MIC ratio – Ratio of maximum serum concentration to MIC

• AUC24/MIC – Total drug exposure in 24 hours that exceeds the

MIC

Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Disease. 7th edition. 2010.

Pharmacodynamics

Abdul-Aziz et al. Ann Inten Care 2012; 2: 1-16.

Which is Which?

From Craig WA, Ebert SC. Killing and regrowth of bacteria in vitro: a review. Scand J Infect Dis. 1991;74:63-70.

Examples

• Concentration dependent – Fluoroquinolones

– Daptomycin

– Aminoglycosides

• Time dependent – Metronidazole

– Linezolid

– Tetracyclines

– BETA LACTAMS • Penicillins, cephalosporins, carbapenems

Continuous vs. Intermittent

Abdul-Aziz et al. Ann Inten Care 2012; 2: 1-16.

11/4/2014

3

13

Doripenem: Changes in Infusion Length and Time>MIC

0

2

4

6

8

10

12

14

16

18

0 1 2 3 4 5 6 7 8

Co

nce

ntr

atio

n (

mcg

/mL)

Time (hrs)

1 hr

3 hrs

6 hrs

Bhavnani SM, et al. Antimicrob Agents Chemother 2005;49:3944-47.

How much time > MIC?

• Depends on the beta lactam

– Cephalosporins > penicillins > carbapenems

• Generally ~ 50%

– Some evidence 100% time > MIC may improve clinical and microbiologic outcomes

• Killing maximized at 4-5x MIC

Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Disease. 7th edition. 2010. Roberts JA. Clin Infect Dis 2014; 58: 1072-83.

The DALI Study

• DALI= “Defining Antibiotic Levels in ICU patients”

• 248 infected patients, multicenter – 16% not achieving 50% fT>MIC 32% less likely

to have positive clinical outcome • 7% with prolonged infusion vs. 20% with intermittent

– 100% fT>MIC associated with improved clinical outcome compared to 50%

Roberts JA. Clin Infect Dis 2014; 58: 1072-83.

Achieving Targets in the ICU

Roberts JA. Clin Infect Dis 2014; 58: 1072-83.

Beta Lactams Covered

• Piperacillin-tazobactam – Most clinical data – “Vitamin Z”

• Carbapenems

– Meropenem – Doripenem

• Drugs for the bad bugs

• Ceftazidime – Early data on continuous infusions – Culture directed therapy for Pseudomonas

Why Not ALL Beta Lactams?

• Stability too short – Ampicillin, ceftaroline

• Not necessary due to long half-life – Ertapenem, ceftriaxone

• Other beta lactams given continuously that we won’t cover – Cefazolin, penicillin, oxacillin

11/4/2014

4

Piperacillin-tazobactam

• Workhouse Gram negative antimicrobial

– Standard dosing:

• 3.375 grams IV every 6 hours OR 4.5 grams IV every 8 hours

• 4.5 grams IV every 6 hours (nosocomial pneumonia)

• Infused over 30 minutes

– Cmax following 4.5 gram dose is ~300 mcg/mL (30% protein bound)

– Half life ~1 hour

Zosyn® (piperacillin/tazobactam) package insert. Pfizer. 2012.

Pip/Tazo PK

4

TABLE 1 STEADY STATE MEAN PLASMA CONCENTRATIONS IN ADULTS AFTER

30-MINUTE INTRAVENOUS INFUSION OF PIPERACILLIN/TAZOBACTAM EVERY 6

HOURS

PIPERACILLIN

Plasma Concentrations** (μg/mL)

AUC**

(μg•hr/mL)

Piperacillin/

Tazobactam

Dosea

No. of

Evaluable

Subjects

30

min 1 hr 2 hr 3 hr 4 hr 6 hr AUC0-6

2.25 g 8 134

(14)

57

(14)

17.1

(23)

5.2

(32)

2.5 (35) 0.9

(14)b

131 (14)

3.375 g 6 242

(12)

106

(8)

34.6

(20)

11.5

(19)

5.1 (22) 1.0

(10)

242 (10)

4.5 g 8 298

(14)

141

(19)

46.6

(28)

16.4

(29)

6.9 (29) 1.4

(30)

322 (16)

TAZOBACTAM

Plasma Concentrations** (μg/mL)

AUC**

(μg•hr/mL)

Piperacillin/

Tazobactam

Dosea

No. of

Evaluable

Subjects

30

min 1 hr 2 hr 3 hr 4 hr 6 hr AUC0-6

2.25 g 8

14.8

(14)

7.2

(22)

2.6

(30)

1.1

(35)

0.7 (6)c

<0.5 16.0 (21)

3.375 g 6

24.2

(14)

10.7

(7)

4.0

(18)

1.4

(21)

0.7 (16)b

<0.5 25.0 (8)

4.5 g 8

33.8

(15)

17.3

(16)

6.8

(24)

2.8

(25)

1.3 (30) <0.5 39.8 (15)

** Numbers in parentheses are coefficients of variation (CV%). a

Piperacillin and tazobactam were given in combination. b

N = 4 c

N = 3

Pediatr icsPiperacillin and tazobactam pharmacokinetics were studied in pediatric patients 2 months of age

and older. The clearance of both compounds is slower in the younger patients compared to older

children and adults.

Zosyn® (piperacillin/tazobactam) package insert. Pfizer. 2012.

When is Something Pip/Tazo Susceptible?

• Enterobacteriaceae

– MIC <16 mcg/mL

• Pseudmonas aeruginosa

– MIC <16 mcg/mL

– Previously <64 mcg/mL

• Increased clinical failures for P.aeruginosa isolates with MICs 32-64 mcg/mL

CLSI Performance Standards for Antimicrobial Susceptibility Testing (M100-S24). January 2014.

What Changes with PI?

• 4.5 grams IV every 8 hours as a 4 hour infusion

– 13 hospitalized patients

• 7 ICU

– Age ~50, weight ~80kg

– Cmax- 108.2 mcg/mL (+/- 31.7)

– Cmin- 27.6 mcg/mL (+/- 26.3)

• PD target attainment (50% fT>MIC) rates

– 100% at MICs <16 mcg/mL

Shea KM et al. International Journal of Antimicrobial Agents 2009; 34: 429-33.

Do PIs Improve Outcomes?

• Cohort study of 194 patients

• Pip/tazo 3.375 grams every 4 or 6 hours vs. 3.375 grams every 8 hours as a 4 hour infusion

• 14 day mortality significantly lower with PI for patients with APACHE II >17

• 12.2% vs. 31.6% (p=0.04)

• Shorter median hospital LOS in PI arm

Lodise TP et al. Clin Infect Dis 2007; 44: 357-63.

Achieving PD Targets

Lodise TP et al. Clin Infect Dis 2007; 44: 357-63.

11/4/2014

5

Pip/Tazo: CI vs II in Sepsis

• Retrospective cohort study

• 173 propensity score matched pairs

– 16 grams piperacillin/24 hours

• Similar mortality rates

– ICU

• CI vs. II: 23.7% vs. 20.2% (p=0.512)

– In hospitsl

• CI vs. II: 41.6% vs. 40.5% (p=0.913)

Goncalves-Pereira J et al. PLOS One 2012; 7: 1-7.

Time for a Pause

• TONS of literature on clinical outcome with pip/tazo prolonged/extended/continuous infusions

• No benefit vs. improved outcomes

– Is there a difference or not??

Evaluation of Clinical Trials

Abdul-Aziz et al. Ann Inten Care 2012; 2: 1-16.

Meropenem

• Standard dose= 500 mg- 2 grams every 8 hours • Peak serum concentration after 30 minute

infusion – ~25 mcg/mL for 500 mg dose – ~50 mcg/mL for 1 gram dose

• Very low protein binding • Half life ~ 1 hour • Short stability at room temperature

– ~4 hours (per manufacturer)

• Post antibiotic effect (PAE) seen

Merrem®(meropenem) package insert. AztraZeneca. 2013.

What’s Considered Susceptible?

• Enterobacteriaceae

– <1 mcg/mL

– Based on a dose of 1 gram every 8 hours

• Pseudomonas aeruginosa

– <2 mcg/mL

– 1 gram every 8 hours

• 500 mg every 6 hours appears to be similar to 1 gram every 8 hours

CLSI Performance Standards for Antimicrobial Susceptibility Testing (M100-S24). January 2014. Merrem®(meropenem) package insert. AztraZeneca. 2013.

Mero PI and CI

• Continuous (4 grams/24 hours) – Not so fast… stability issues – Higher clinical cure rates than intermittent infusion in

Gram-negative VAP (90.5% vs 59.6%, OR 6.44, 95% CI 1.97-21.05, p<0.001)

– Similar clinical cure with higher microbiologic clearance in septic patients

• Prolonged – Typically over 3 hours due to stability – Shown to have equal or improved clinical outcomes when

compared to intermittent infusions

Chytra I et al. Critical Care 2012; 16: R113. Lorente L et al. Ann Pharmacother 2006; 40: 219-23.

11/4/2014

6

Mero PI Kinetics

In healthy volunteers!!

Dandekar PK et al. Pharmacotherapy 2003; 23: 988-91.

Practical Uses of Meropenem

• Empiric therapy in patients at high risk of infections with resistant organisms

• Culture-directed therapy

– MDR pathogens

• Pneumonia, bacteremia, intra-abdominal infections… but what about meningitis?

Meropenem PI for CNS Infections

• Effective in cases of severe Gram negative infections in the CNS

• MICs fairly low in all cases

Capitano B et al. Pharmacotherapy 2004; 24: 803-7.

Ceftazidime

• Anti-Pseudomonal cephalosporin

• Commonly utilized agent for pulmonary exacerbations of cystic fibrosis

• Standard dose= 1-2 grams every 8 hours – 8 grams/day has been used in severe Gram

negative infections

• Half life ~2 hours in healthy volunteers

• Largely replaced by cefepime in many institutions

Fortaz®(ceftazidime) package insert. Glaxo Smith Klein. 2007.

Ceftazidime

• What’s susceptible? – Enterobacteriacae

• <4 mcg/mL • Based on a dose of 1 gram every 8 hours

– Pseudomonas aeruginosa • <8 mcg/mL • 1 gram every 6 hours

2

The plastic container for the frozen solution is fabricated from a specially designed multilayer 36

plastic, PL 2040. Solutions are in contact with the polyethylene layer of this container and can 37

leach out certain chemical components of the plastic in very small amounts within the expiration 38

period. The suitability of the plastic has been confirmed in tests in animals according to USP 39

biological tests for plastic containers as well as by tissue culture toxicity studies. 40

CLINICAL PHARMACOLOGY 41

After IV administration of 500-mg and 1-g doses of ceftazidime over 5 minutes to normal adult 42

male volunteers, mean peak serum concentrations of 45 and 90 mcg/mL, respectively, were 43

achieved. After IV infusion of 500-mg, 1-g, and 2-g doses of ceftazidime over 20 to 30 minutes to 44

normal adult male volunteers, mean peak serum concentrations of 42, 69, and 170 mcg/mL, 45

respectively, were achieved. The average serum concentrations following IV infusion of 500-mg, 46

1-g, and 2-g doses to these volunteers over an 8-hour interval are given in Table 1. 47

48

Table 1. Average Serum Concentrations of Ceftazidime 49

Ceftazidime Serum Concentrations (mcg/mL)

IV Dose 0.5 hr 1 hr 2 hr 4 hr 8 hr

500 mg 42 25 12 6 2

1 g 60 39 23 11 3

2 g 129 75 42 13 5

50

The absorption and elimination of ceftazidime were directly proportional to the size of the dose. 51

The half-life following IV administration was approximately 1.9 hours. Less than 10% of 52

ceftazidime was protein bound. The degree of protein binding was independent of concentration. 53

There was no evidence of accumulation of ceftazidime in the serum in individuals with normal 54

renal function following multiple IV doses of 1 and 2 g every 8 hours for 10 days. 55

Following intramuscular (IM) administration of 500-mg and 1-g doses of ceftazidime to normal 56

adult volunteers, the mean peak serum concentrations were 17 and 39 mcg/mL, respectively, at 57

approximately 1 hour. Serum concentrations remained above 4 mcg/mL for 6 and 8 hours after the 58

IM administration of 500-mg and 1-g doses, respectively. The half-life of ceftazidime in these 59

volunteers was approximately 2 hours. 60

The presence of hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in 61

individuals administered 2 g intravenously every 8 hours for 5 days. Therefore, a dosage 62

adjustment from the normal recommended dosage is not required for patients with hepatic 63

dysfunction, provided renal function is not impaired. 64

Approximately 80% to 90% of an IM or IV dose of ceftazidime is excreted unchanged by the 65

kidneys over a 24-hour period. After the IV administration of single 500-mg or 1-g doses, 66

approximately 50% of the dose appeared in the urine in the first 2 hours. An additional 20% was 67

excreted between 2 and 4 hours after dosing, and approximately another 12% of the dose appeared 68

CLSI Performance Standards for Antimicrobial Susceptibility Testing (M100-S24). January 2014. Fortaz®(ceftazidime) package insert. Glaxo Smith Klein. 2007.

Ceftazidime: CI vs II

• 12 critically ill patients

• PK/PD analysis

• 7/12 patients achieved target ceftazidime steady state levels with CI – **4 patients with sub-

therapeutic levels**

• No clinical outcome data

Benko AS et al. Antimicrob Agents Chemother 1996; 40: 691- 5.

11/4/2014

7

A Little More Ceftaz Never Hurt Anyone

• 18 critically ill patients randomized to one of two regimens

• 6 grams/24 hours CI vs. 2 grams every 8 hours

• 8/9 patients in CI arm maintained serum levels 4-5x MIC

Bolus

Continuous

Lipman J et al. J Antimicrob Chemother 1999; 43: 309-11.

Clinical Outcomes > PK/PD

• Ceftazidime II vs. CI in ICU patients with VAP

• II= 2 grams every 12 hours

• CI= 1 gram load followed by 4 grams CI/24 hours

• Average MIC= 2 mcg/mL

• CI associated with greater clinical cure rate (OR 12.2, 95% CI 3.47-43.21; p<0.001)

Lorente L et al. Clin Ther 2007; 29: 2433-9.

Some Take Home Points… So Far

• Know what you’re treating

• Know you’re patient

• Recognize variations in dosing schemes used in clinical trials/reports of prolonged and continuous infusions

CI/PI in Pediatrics

• Differences in children and adults – Larger Vd

– Increased renal elimination • Particularly true in patients with cystic fibrosis

• Similar results to adult studies – Improved target attainment with PI/CI

– Surprisingly poor target attainment with standard doses of many beta lactams

• Loading doses encouraged

• Would not recommend dropping total daily dose

Courter JD et al. Pediatr Blood Cancer 2009; 53: 379-85. Walker MC. Ann Pharmacother 2012; 46: 1537-46.

A Point of Caution?

• Doripenem 1 gram every 8 hours as a 4 hour infusion vs. imipenem 1 gram every 8 hours as a 1 hour infusion

• Stopped prematurely- didn’t mean non-inferiority margin – Lower clinical cure rate in doripenem arm – Higher mortality in patients with VAP due to

P.aeruginosa treated with doripenem

Is It Just Dori?

• Before and after study at Barnes Jewish

• Prolonged (3 hour) infusion vs. intermittent infusion

– Cefepime (51%), meropenem, piperacillin/tazobactam

• NO loading doses given

• No difference in treatment success rates, in hospital mortality, length of stay

– Longer time to mortality in intermittent infusion group (36 vs. 19 days, p <0.001)

Arnold HM et al. Ann Pharmaocther 2013; 47: 170-80.

11/4/2014

8

Implementation of Pip/Tazo PI

• 4.5 grams every 8 hours as a 4 hour infusion

• What’s good for the goose may not be good for the gander…

– Obese patients (>100 kg)

– Young patients with expected rapid renal elimination

• Lower than expected levels with CrCl >100 mL/min

– Critically ill

– Not currently recommended by cystic fibrosis guidelines

Shea KM et al. Int J Antimicrob Ag 2009; 34: 429-33.

Not All Patients Are Created Equally

• Healthy volunteers are not patients

• Critically ill patients are not regular patients – Variations in volumes of distribution

– Alternations in renal clearance

– Decreased protein binding • More free drug to be cleared

• Children are not small adults

Where I Would Use PI/CI

• Critically ill patients

• Culture-directed therapy for pathogens with elevated MICs

• Patients with rapid renal elimination – Be cautious of dropping the total daily dose too much

• First dose should be a load

QUESTIONS? COMMENTS?