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AlteredPharmacokineticsofPiperacillininFebrileNeutropenicPatientswithHematologicalMalignancy

ARTICLEinANTIMICROBIALAGENTSANDCHEMOTHERAPY·MARCH2014

ImpactFactor:4.48·DOI:10.1128/AAC.02340-14·Source:PubMed

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MichaelRoberts

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1

Altered pharmacokinetics of piperacillin in febrile neutropenic patients with haematological 1

malignancy 2

Fekade Bruck Sime,a,b,# Michael S Roberts,a,b Morgyn S Warner,c Uwe Hahn, d Thomas A 3

Robertson,a,b Sue Yeend,e Andy Phay, e Sheila Lehman, d Jeffrey Lipman,f,g Sandra L Peake,h 4

Jason A Robertsa,f,g 5

School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australiaa; 6

Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The 7

Queen Elizabeth Hospital, Adelaide, Australiab; SA Pathology and the University of Adelaide, 8

Adelaide, Australiac; Department of Haematology/Oncology, The Queen Elizabeth Hospital, 9

Adelaide, Australiad; Cancer Clinical Trials, The Queen Elizabeth Hospital, Adelaide, Australiae; 10

Royal Brisbane and Women’s Hospital, Herston, Brisbane, Queensland, Australiaf; Burns, 11

Trauma, and Critical Care Research Centre, University of Queensland, Herston, Brisbane, 12

Queensland, Australiag; Department of Intensive Care Medicine, The Queen Elizabeth Hospital, 13

Adelaide, Australiaf. 14

Running Head: Kinetics of piperacillin in febrile neutropenia 15

#Address correspondence to Fekade B. Sime, fekade.sime@mymail.unisa.edu.au 16

AAC Accepts, published online ahead of print on 31 March 2014Antimicrob. Agents Chemother. doi:10.1128/AAC.02340-14Copyright © 2014, American Society for Microbiology. All Rights Reserved.

2

Abstract 17

This study assessed the pharmacokinetics and dosing adequacy of piperacillin in febrile 18

neutropenic patients after the first dose. Pharmacokinetic analysis was performed using non-19

compartmental methods. We observed elevated volume of distribution (29.7 ± 8.0 L) and 20

clearance (20.2 ± 7.5 L/h) compared to data from other patient populations. Antibiotic exposure 21

did not consistently achieve therapeutic targets. We conclude that alternative dosing strategies 22

guided by therapeutic drug monitoring may be required to optimise exposure. 23

Key words: piperacillin, pharmacokinetics, febrile neutropenia, haematological malignancy, 24

pharmacodynamics 25

3

Febrile neutropenia is a medical emergency associated with high mortality (1). Immediate 26

administration of broad-spectrum antibiotics is crucial to reduce the risk of mortality (2). Beta-27

lactam antibiotics active against Pseudomonas aeruginosa, such as piperacillin–tazobactam, are 28

common first line empiric agents for this condition. Emerging data suggest that standard dosing 29

regimens of these antibiotics may not provide adequate exposure due to pharmacokinetic (PK) 30

alterations emanating from pathophysiological processes associated with neutropenia (3, 4). 31

More specifically, the proportion of the dosing interval that the free drug concentration remains 32

above the minimum inhibitory concentration (fT>MIC) may be diminished. For beta-lactams, 33

fT>MIC is the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with clinical 34

outcome (5). 35

Most of the evidence for altered beta-lactam PK and associated poor PK/PD target attainment in 36

febrile neutropenic patients is available for other antibiotics such as ceftazidime (6) and 37

meropenem (7). Data is meagre for piperacillin in this regard even though it is commonly 38

considered the preferred beta-lactam for febrile neutropenia. To our knowledge, there is no well 39

described recent study except the works of Drusano et al (8, 9) which reported no PK alterations 40

in febrile neutropenic patients, a finding which is contrary to the recent reports of PK alterations 41

and variability across many antibiotic classes (3, 4). The aim of this study was, therefore, to 42

describe the PK of piperacillin in patients with febrile neutropenia following chemotherapy for 43

hematological malignancy as well as assess the adequacy of the standard initial dosing to attain 44

recommended pharmacodynamic (PD) target against all possible organisms during the first 45

dosing interval. 46

Twelve patients with haematological malignancies, aged ≥ 18 years, were enrolled when 47

prescribed to receive piperacillin-tazobactam after developing febrile neutropenia. Febrile 48

neutropenia was defined as the presence of a single oral temperature of ≥ 38.3°C (101°F) or a 49

4

temperature of ≥ 38.0°C (100.4°F) for >1 h, with a neutrophil count < 500 cells/mm3; or a count 50

< 1,000 cells/ mm3, with a predicted decrease to <500 cells/ mm3 (2). Patients were excluded if 51

they had known/suspected allergy to beta-lactams, marked renal failure (GFR < 20 ml/min) or 52

hepatic impairment (transaminases > 500 U/L) or if pregnant. Ethics approval was granted from 53

the local Human Research Ethics Committee. All patients received 4.5 g piperacillin-tazobactam 54

every eight hours via intravenous bolus infusion over 30 minutes followed by 15 to 20 minutes 55

line flushing. In addition all patients received a single gentamicin 7 mg/kg dose. 56

Serial blood samples were collected just prior to the first dose, then at the end of line flushing, 57

and then at 1hr, 2hr, 3hr, 4hr, 5hr, 6hr, and 7hrs after the start of infusion and a final sample just 58

before the second dose. Total plasma concentrations of piperacillin were quantified using a 59

validated liquid chromatography tandem mass spectrometry method. Non-compartmental 60

pharmacokinetic analysis was performed using PKSolver (10). fT>MIC was estimated after first 61

dose from the log-linear elimination phase. First the terminal elimination constant (Kel) was 62

estimated with PKSolver software (10). Then, considering 30% protein binding for piperacillin 63

(11), fT>MIC was calculated for P. aeruginosa and Enterobacteriaceae based on the break points 64

of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (12) and the 65

Clinical and Laboratory Standards Institute (CLSI)(13). As this study aims to assess adequacy of 66

initial dosing against all possible organisms, we selected P. aeruginosa and Enterobacteriaceae 67

which have the highest MIC breakpoints according to EUCAST and CLSI interpretive criteria. 68

Demographic characteristics of study participants are given in Table 1. All patients were febrile 69

and neutropenic with cell counts too low to perform differential counts. Blood cultures were 70

positive in four patients (patient 1, 3, 9 and 10) and organisms isolated were, an organisms 71

resembling Staphylococci, Enterobacter aerogenes, P. aeruginosa, and Escherichia coli 72

respectively. The plasma concentration-time profile for total piperacillin concentration after a 73

5

single dose of 4.5 g piperacillin-tazobactam is depicted in figure 1. Pharmacokinetic parameter 74

estimates of individual study participants are given in Table 2. 75

We observed elevated volume of distribution (Vd) (29.7 ± 8.0 L) and clearance (CL) (20.2 ± 7.5 76

L/h) for the cohort in this study. Different factors may contribute to the expansion of Vd. One 77

important factor is alteration of capillary permeability and subsequent extravasation of vascular 78

fluid during infection mediated by various factors (14). It could also occur due hypoalbuminemia 79

which is common in hematological malignancies and observed for all participants in this study 80

(Table 1). Low albumin concentrations reduce plasma oncotic pressure subsequently leading to 81

enhanced fluid extravasation. However, the effect of hypoalbuminemia is most prominent for 82

highly protein-bound antibiotics and therefore might have limited contribution towards the 83

increased piperacillin Vd observed in this study (30% protein binding) (4, 15). Changes in 84

glomerular filtration rate (GFR) have been implicated in the variability of antibiotic CL in febrile 85

patients with haematological malignancies (6). A very high value of GFR is common in patients 86

undergoing chemotherapy (16) and may contribute to elevated CL. Serum creatinine clearance 87

(Cockcroft-Gault) was also distinctively high for some participants (Table 1; patient 8 to 12) 88

indicating the presence of augmented renal clearance contributing to the significant increase in 89

individual piperacillin clearances (Table 2). In fact, drug exposure was moderately correlated 90

with creatinine clearance (r = - 0.663, P < 0.05). Augmented renal clearance in febrile patients 91

could occur perhaps in a similar way as in critically ill septic patients due to increased renal 92

blood flow secondary to a hyperdynamic cardiovascular state (17). However in hyperdynamic 93

patients where there is no stable creatinine concentration, predictive equations of creatinine 94

clearance as well as GFR are likely to be incorrect for assessment of the rapidly changing renal 95

function and hence antibiotic CL (18, 19). 96

6

The elevated CL and significant expansion of Vd in our patients explain the very low observed 97

trough concentrations (median; 0.5 mg/L). This is far below the clinical susceptibility breakpoint 98

of expected pathogens such as Enterobacteriaceae (8mg/L, EUCAST; 16 mg/L, CLSI) and P. 99

aeruginosa (16mg/L, CLSI and EUCAST) (12, 13). The fT>MIC achieved for P. aeruginosa after 100

the first dose (Figure 2) was sub-optimal as compared to the conventionally recommended PD 101

targets of about 50%-60% fT>MIC (20). Similarly, for Enterobacteriaceae fT>MIC was sub-optimal 102

for the majority of participants while referring to conventional PD targets, and in all patients 103

when considering 100% fT>MIC as a target. There is an emerging understanding that neutropenic 104

patients may require higher PK/PD index for successful outcome due to their compromised 105

immune response. Ariano et al. (21), for instance, showed that for meropenem, 80% clinical 106

response is observed when fT>MIC exceeds 75%, a value much higher than the conventional 40% 107

fT>MIC. Similarly, for penicillins and cephalosporins which lack post antibiotic effect against 108

Gram negative organisms, previous data from some animal studies have indicated that, in the 109

settings of profound neutropenia, free concentrations should be greater than the MIC for 90%–110

100% of the dosing interval to ensure efficacy (22). This is well supported by studies that 111

demonstrate the profound effect of host immunity on PD parameters (23-25). In 112

immunocompromised hosts, a more aggressive antibiotic action through increased antibiotic 113

exposure time may be required to achieve the same response as in immunocompetent ones. 114

Considering 100% fT>MIC, our results indicate that the standard bolus dose of 4.5g piperacillin-115

tazobactam every eight hours is unlikely to provide optimal exposure against P. aeruginosa and 116

Enterobacteriaceae (figure 2). Optimal exposure should be achieved as early as possible to 117

reduce the risk of mortality (26). In the current study, concentrations remained below the MIC of 118

P. aeruginosa for about 5 to 6 hours of the first dose interval. Such extended sub-inhibitory 119

exposure should be avoided to reduce the risk of selection of resistant organisms (27). 120

7

We believe that the present intermittent dosing regimen should be reviewed and replaced with 121

new dosing strategies that ensure adequate antibiotic exposure and reduce the risk of emergence 122

of antibiotic resistance. Better exposure can be achieved with more frequent administration of the 123

dose (e.g. 4.5 g every six hourly) which in effect increases the total daily dose. The mode of 124

administration used (i.e 30 minutes bolus infusion) could also be optimized. The use of extended 125

(EI) or continuous infusion (CI) is one attractive approach to maximize fT>MIC without 126

increasing the total daily dose (28). In combination with a loading dose, EI or CI can be used to 127

avoid the initial sub-optimal exposure observed with the intermittent schedule in this study. CI 128

may be practically challenging as it requires a dedicated IV line which may not be available 129

given patients are often receiving a number of other drugs and perhaps nutrition support. EI is 130

more practical in this regard allowing sufficient line access for other purposes. Another challenge 131

is that, a fixed EI or CI regimen may not achieve PD target consistently in all patients due to the 132

variability in CL as well as Vd. Dose individualization through TDM may be useful to ensure 133

optimal exposure in every patient. 134

Often culture results are not available initially for use in TDM. We therefore suggest initial 135

dosing aiming at organisms with high MIC such as P. aeruginosa and then dosing can be 136

readjusted based on the specific organism MIC. Local institutional antibiograms should be 137

utilized whenever available as there is geographical and institution-to-institution variability in 138

susceptibility. However, in the absence of such data, EUCAST/CLSI breakpoints would provide 139

reasonable reference to use for TDM. This has been well demonstrated for piperacillin (and other 140

beta-lactam antibiotics) in critically ill patients who exhibit similar PK alterations as observed in 141

this study (29). However, it has not yet been described in febrile neutropenic patients. Further 142

clinical studies are required to assess the utility of TDM of piperacillin in febrile neutropenic 143

patients. 144

8

In conclusion, the observed high Vd as well as CL suggest altered PK of piperacillin in febrile 145

neutropenic patients. Standard intermittent dosing of 4.5g piperacillin-tazobactam (IV bolus, 146

every eight hours) resulted in sub-optimal antibiotic exposure and therefore was not sufficient. 147

We recommend TDM guided optimization with EI or adjusted dosing frequency to ensure 148

exposure to inhibitory concentrations for the entire dosing interval. 149

9

List of Acronyms 150

CI Continuous infusion 151

CL Clearance 152

CLSI Clinical and Laboratory Standards Institute 153

EI Extended infusion 154

EUCAST The European Committee on Antimicrobial Susceptibility Testing 155

fT>MIC Proportion of the dosing interval free drug concentration remains above MIC 156

GFR Glomerular filtration rate 157

MIC Minimum Inhibitory Concentration 158

PD Pharmacodynamic 159

PK Pharmacokinetic(s) 160

Vd Volume of distribution 161

Vss Volume of distribution at steady state 162

Competing interests 163

None 164

Acknowledgments 165

None 166

10

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piperacillin in febrile neutropenic cancer patients. Clin. Pharmacol. Ther. 45:635-641. 194

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14

Table 1. Characteristics of the study participants

Patient Heamatological Malignancy Sex Age (yr) Body

Weight (Kg)

Height (cm) Serum

Creatinine (µmol/L)

Creatinine Clearancea

(ml/min/1.73 m2)

Albumin (g/L)

Liver enzymes (U/L)

ALT AST

1 Acute Myeloid Leukaemia M 61 82 172 88 65.3 27 50 23

2 Acute Myeloid Leukaemia M 74 100 175 61 73.7 25 13 7

3 Acute Myeloid Leukaemia F 70 64 164 57 72.6 29 37 23

4 Multiple Myeloma F 64 53 153 67 62.8 28 16 24

5 Lymphoma F 74 54 155 78 55.4 26 27 19

6 Acute Myeloid Leukaemia M 79 69 173 95 51.4 33 21 48

7 Acute lymphoblastic leukaemia M 68 63 175 70 78.6 23 25 15

8 Acute lymphoblastic leukaemia F 54 71 171 44 119.6 27 14 10

9 Acute Myeloid Leukaemia M 63 79 184 66 96.9 26 142 102

10 Multiple Myeloma M 65 100 174 46 109.7 31 12 14

11 Multiple Myeloma M 53 91 184 61 110.4 30 37 19

12 Multiple Myeloma M 59 103 182 68 85.2 31 53 28

Median (Interquartile Range)

64.5 (60.5-71.0)

75.0 (63.7-93.2)

173.5 (169.2-176.7)

66.5 (60.0-72.0)

76.1 (64.7-100.1)

27.5 (26.0-30.2)

26 (15.5 -40.2)

21.0 (14.7-25.0)

aCockcroft -Gault

253

254

255

256

257

15

Table 2. Pharmacokinetic parameter estimates of piperacillin after a single dose of 4.5g piperacillin-tazobactam in twelve febrile neutropenic patients with haematological malignancies

Patients Cmax (mg/L)

Cmin (mg/L)

AUC 0-t (mg/L*h)

AUC 0-inf (mg/L*h)

AUMC 0-inf (mg/L*h^2)

MRT (h)

Vz (L)

Vss (L)

CL (L/h)

t1/2 (h)

1 125.7 0.5 174.6 175.5 285.3 1.4 38.3 31.4 22.8 1.2

2 119.5 1.1 196.4 198.1 343.9 1.5 31.6 30.0 20.2 1.1

3 144 0.5 239.0 239.7 409.8 1.5 23.8 24.4 16.7 1.0

4 228 6.1 419.4 433.1 1026.4 2.1 20.7 19.6 9.2 1.6

5 148.5 2.5 292.6 297.2 618.9 1.8 25.0 24.7 13.5 1.3

6 129.5 5.2 283.8 298.1 772.9 2.3 36.6 31.4 13.4 1.9

7 180.5 0.9 288.9 290.2 493.1 1.4 19.8 20.0 13.8 1.0

8 161.5 0.2 238.6 238.8 346.3 1.2 17.9 20.1 16.7 0.7

9 97.5 0.2 150.1 150.4 234.5 1.3 40.7 34.8 26.6 1.1

10 92.65 0.4 143.2 143.8 247.7 1.5 48.6 41.0 27.8 1.2

11 86.6 0.2 124.0 124.3 180.0 1.2 37.9 38.6 32.2 0.8

12 89.8 - 130.1 133.4 215.5 1.4 38.1 41.0 30.0 0.9

Mean ± SD 133.6 ± 42.2 1.6 ± 2.1 223.4 ± 88 226.9 ±91.6 431.2 ± 257.4 1.6 ± 0.4 31.6 ± 9.9 29.7 ± 8.0 20.2 ± 7.5 1.1 ± 0.3 Median

(Interquartile Range) 127.6

(96.3-151.8) 0.5

(0.3-1.8) 217.5

(148.4 -285.1) 218.4

(148.8 -291.9) 345.1

(244.4 -524.6) 1.5

(1.4-1.6) 34.1

(23-38.2) 30.7

(23.3-35.7) 18.5

(13.7-26.9) 1.1

(1.0-1.2)

258

259

260

16

List of Figures 261

Figure 1. Plasma concentration-time profile for total piperacillin concentration after single 262

dose of 4.5g piperacillin-tazobactam in twelve febrile neutropenic patients with 263

haematological malignancies. 264

Figure 2. Pharmacodynamic target attainment after a single dose of 4.5g piperacillin-265

tazobactam in twelve febrile neutropenic patients with haematological malignancies 266

(considering EUCAST MIC breakpoints for Entereobacteriaceae and P. aeruginosa.) 267

1000

100

tion

(mg/

L)e

rang

e)

10

Pla

sma

conc

entr

ated

ian

(Int

erqu

arti

le

0.1

1

0 1 2 3 4 5 6 7 8 9

Tota

lM

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

Figure 1 Plasma concentration time profile for total piperacillin concentration after single dose of 4 5gFigure 1. Plasma concentration-time profile for total piperacillin concentration after single dose of 4.5g piperacillin-tazobactam in twelve febrile neutropenic patients with haematological malignancies.

90%

100%

50%

60%

70%

80%

90%

fT>M

IC

P. aeruginosa (16 mg/L)

Enterobacteriaceae (8 mg/L)

0%

10%

20%

30%

40%

f

P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12

Patients

Figure 2. Pharmacodynamic target attainment after a single dose of 4.5g piperacillin-tazobactam in twelve febrile neutropenic patients with haematological malignancies (considering EUCAST MIC breakpoints for Entereobacteriaceae and P. aeruginosa.).