AAC Accepts, published online ahead of print on 31 March 2014 Antimicrob. Agents Chemother. doi:10.1128/AAC.02340-14 Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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Altered pharmacokinetics of piperacillin in febrile neutropenic patients with haematological
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malignancy
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Fekade Bruck Sime,a,b,# Michael S Roberts,a,b Morgyn S Warner,c Uwe Hahn, d Thomas A
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Robertson,a,b Sue Yeend,e Andy Phay, e Sheila Lehman, d Jeffrey Lipman,f,g Sandra L Peake,h
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Jason A Robertsa,f,g
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School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australiaa;
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Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The
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Queen Elizabeth Hospital, Adelaide, Australiab; SA Pathology and the University of Adelaide,
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Adelaide, Australiac; Department of Haematology/Oncology, The Queen Elizabeth Hospital,
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Adelaide, Australiad; Cancer Clinical Trials, The Queen Elizabeth Hospital, Adelaide, Australiae;
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Royal Brisbane and Women’s Hospital, Herston, Brisbane, Queensland, Australiaf; Burns,
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Trauma, and Critical Care Research Centre, University of Queensland, Herston, Brisbane,
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Queensland, Australiag; Department of Intensive Care Medicine, The Queen Elizabeth Hospital,
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Adelaide, Australiaf.
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Running Head: Kinetics of piperacillin in febrile neutropenia
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#Address correspondence to Fekade B. Sime,
[email protected]
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Abstract
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This study assessed the pharmacokinetics and dosing adequacy of piperacillin in febrile
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neutropenic patients after the first dose. Pharmacokinetic analysis was performed using non-
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compartmental methods. We observed elevated volume of distribution (29.7 ± 8.0 L) and
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clearance (20.2 ± 7.5 L/h) compared to data from other patient populations. Antibiotic exposure
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did not consistently achieve therapeutic targets. We conclude that alternative dosing strategies
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guided by therapeutic drug monitoring may be required to optimise exposure.
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Key words: piperacillin, pharmacokinetics, febrile neutropenia, haematological malignancy,
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pharmacodynamics
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26
Febrile neutropenia is a medical emergency associated with high mortality (1). Immediate
27
administration of broad-spectrum antibiotics is crucial to reduce the risk of mortality (2). Beta-
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lactam antibiotics active against Pseudomonas aeruginosa, such as piperacillin–tazobactam, are
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common first line empiric agents for this condition. Emerging data suggest that standard dosing
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regimens of these antibiotics may not provide adequate exposure due to pharmacokinetic (PK)
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alterations emanating from pathophysiological processes associated with neutropenia (3, 4).
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More specifically, the proportion of the dosing interval that the free drug concentration remains
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above the minimum inhibitory concentration (fT>MIC) may be diminished. For beta-lactams,
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fT>MIC is the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with clinical
35
outcome (5).
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Most of the evidence for altered beta-lactam PK and associated poor PK/PD target attainment in
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febrile neutropenic patients is available for other antibiotics such as ceftazidime (6) and
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meropenem (7). Data is meagre for piperacillin in this regard even though it is commonly
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considered the preferred beta-lactam for febrile neutropenia. To our knowledge, there is no well
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described recent study except the works of Drusano et al (8, 9) which reported no PK alterations
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in febrile neutropenic patients, a finding which is contrary to the recent reports of PK alterations
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and variability across many antibiotic classes (3, 4). The aim of this study was, therefore, to
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describe the PK of piperacillin in patients with febrile neutropenia following chemotherapy for
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hematological malignancy as well as assess the adequacy of the standard initial dosing to attain
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recommended pharmacodynamic (PD) target against all possible organisms during the first
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dosing interval.
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Twelve patients with haematological malignancies, aged ≥ 18 years, were enrolled when
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prescribed to receive piperacillin-tazobactam after developing febrile neutropenia.
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neutropenia was defined as the presence of a single oral temperature of ≥ 38.3°C (101°F) or a
Febrile
3
50
temperature of ≥ 38.0°C (100.4°F) for >1 h, with a neutrophil count < 500 cells/mm3; or a count
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< 1,000 cells/ mm3, with a predicted decrease to 500 U/L) or if pregnant. Ethics approval was granted from
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the local Human Research Ethics Committee. All patients received 4.5 g piperacillin-tazobactam
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every eight hours via intravenous bolus infusion over 30 minutes followed by 15 to 20 minutes
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line flushing. In addition all patients received a single gentamicin 7 mg/kg dose.
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Serial blood samples were collected just prior to the first dose, then at the end of line flushing,
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and then at 1hr, 2hr, 3hr, 4hr, 5hr, 6hr, and 7hrs after the start of infusion and a final sample just
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before the second dose. Total plasma concentrations of piperacillin were quantified using a
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validated liquid chromatography tandem mass spectrometry method. Non-compartmental
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pharmacokinetic analysis was performed using PKSolver (10). fT>MIC was estimated after first
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dose from the log-linear elimination phase. First the terminal elimination constant (Kel) was
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estimated with PKSolver software (10). Then, considering 30% protein binding for piperacillin
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(11), fT>MIC was calculated for P. aeruginosa and Enterobacteriaceae based on the break points
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of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (12) and the
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Clinical and Laboratory Standards Institute (CLSI)(13). As this study aims to assess adequacy of
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initial dosing against all possible organisms, we selected P. aeruginosa and Enterobacteriaceae
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which have the highest MIC breakpoints according to EUCAST and CLSI interpretive criteria.
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Demographic characteristics of study participants are given in Table 1. All patients were febrile
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and neutropenic with cell counts too low to perform differential counts. Blood cultures were
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positive in four patients (patient 1, 3, 9 and 10) and organisms isolated were, an organisms
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resembling Staphylococci, Enterobacter aerogenes, P. aeruginosa, and Escherichia coli
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respectively. The plasma concentration-time profile for total piperacillin concentration after a 4
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single dose of 4.5 g piperacillin-tazobactam is depicted in figure 1. Pharmacokinetic parameter
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estimates of individual study participants are given in Table 2.
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We observed elevated volume of distribution (Vd) (29.7 ± 8.0 L) and clearance (CL) (20.2 ± 7.5
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L/h) for the cohort in this study. Different factors may contribute to the expansion of Vd. One
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important factor is alteration of capillary permeability and subsequent extravasation of vascular
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fluid during infection mediated by various factors (14). It could also occur due hypoalbuminemia
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which is common in hematological malignancies and observed for all participants in this study
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(Table 1). Low albumin concentrations reduce plasma oncotic pressure subsequently leading to
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enhanced fluid extravasation. However, the effect of hypoalbuminemia is most prominent for
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highly protein-bound antibiotics and therefore might have limited contribution towards the
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increased piperacillin Vd observed in this study (30% protein binding) (4, 15). Changes in
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glomerular filtration rate (GFR) have been implicated in the variability of antibiotic CL in febrile
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patients with haematological malignancies (6). A very high value of GFR is common in patients
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undergoing chemotherapy (16) and may contribute to elevated CL. Serum creatinine clearance
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(Cockcroft-Gault) was also distinctively high for some participants (Table 1; patient 8 to 12)
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indicating the presence of augmented renal clearance contributing to the significant increase in
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individual piperacillin clearances (Table 2). In fact, drug exposure was moderately correlated
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with creatinine clearance (r = - 0.663, P < 0.05). Augmented renal clearance in febrile patients
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could occur perhaps in a similar way as in critically ill septic patients due to increased renal
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blood flow secondary to a hyperdynamic cardiovascular state (17). However in hyperdynamic
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patients where there is no stable creatinine concentration, predictive equations of creatinine
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clearance as well as GFR are likely to be incorrect for assessment of the rapidly changing renal
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function and hence antibiotic CL (18, 19).
5
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The elevated CL and significant expansion of Vd in our patients explain the very low observed
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trough concentrations (median; 0.5 mg/L). This is far below the clinical susceptibility breakpoint
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of expected pathogens such as Enterobacteriaceae (8mg/L, EUCAST; 16 mg/L, CLSI) and P.
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aeruginosa (16mg/L, CLSI and EUCAST) (12, 13). The fT>MIC achieved for P. aeruginosa after
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the first dose (Figure 2) was sub-optimal as compared to the conventionally recommended PD
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targets of about 50%-60% fT>MIC (20). Similarly, for Enterobacteriaceae fT>MIC was sub-optimal
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for the majority of participants while referring to conventional PD targets, and in all patients
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when considering 100% fT>MIC as a target. There is an emerging understanding that neutropenic
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patients may require higher PK/PD index for successful outcome due to their compromised
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immune response. Ariano et al. (21), for instance, showed that for meropenem, 80% clinical
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response is observed when fT>MIC exceeds 75%, a value much higher than the conventional 40%
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fT>MIC. Similarly, for penicillins and cephalosporins which lack post antibiotic effect against
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Gram negative organisms, previous data from some animal studies have indicated that, in the
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settings of profound neutropenia, free concentrations should be greater than the MIC for 90%–
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100% of the dosing interval to ensure efficacy (22). This is well supported by studies that
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demonstrate the profound effect of host immunity on PD parameters (23-25). In
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immunocompromised hosts, a more aggressive antibiotic action through increased antibiotic
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exposure time may be required to achieve the same response as in immunocompetent ones.
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Considering 100% fT>MIC, our results indicate that the standard bolus dose of 4.5g piperacillin-
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tazobactam every eight hours is unlikely to provide optimal exposure against P. aeruginosa and
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Enterobacteriaceae (figure 2). Optimal exposure should be achieved as early as possible to
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reduce the risk of mortality (26). In the current study, concentrations remained below the MIC of
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P. aeruginosa for about 5 to 6 hours of the first dose interval. Such extended sub-inhibitory
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exposure should be avoided to reduce the risk of selection of resistant organisms (27). 6
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We believe that the present intermittent dosing regimen should be reviewed and replaced with
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new dosing strategies that ensure adequate antibiotic exposure and reduce the risk of emergence
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of antibiotic resistance. Better exposure can be achieved with more frequent administration of the
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dose (e.g. 4.5 g every six hourly) which in effect increases the total daily dose. The mode of
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administration used (i.e 30 minutes bolus infusion) could also be optimized. The use of extended
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(EI) or continuous infusion (CI) is one attractive approach to maximize fT>MIC without
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increasing the total daily dose (28). In combination with a loading dose, EI or CI can be used to
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avoid the initial sub-optimal exposure observed with the intermittent schedule in this study. CI
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may be practically challenging as it requires a dedicated IV line which may not be available
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given patients are often receiving a number of other drugs and perhaps nutrition support. EI is
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more practical in this regard allowing sufficient line access for other purposes. Another challenge
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is that, a fixed EI or CI regimen may not achieve PD target consistently in all patients due to the
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variability in CL as well as Vd. Dose individualization through TDM may be useful to ensure
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optimal exposure in every patient.
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Often culture results are not available initially for use in TDM. We therefore suggest initial
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dosing aiming at organisms with high MIC such as P. aeruginosa and then dosing can be
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readjusted based on the specific organism MIC. Local institutional antibiograms should be
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utilized whenever available as there is geographical and institution-to-institution variability in
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susceptibility. However, in the absence of such data, EUCAST/CLSI breakpoints would provide
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reasonable reference to use for TDM. This has been well demonstrated for piperacillin (and other
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beta-lactam antibiotics) in critically ill patients who exhibit similar PK alterations as observed in
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this study (29). However, it has not yet been described in febrile neutropenic patients. Further
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clinical studies are required to assess the utility of TDM of piperacillin in febrile neutropenic
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patients. 7
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In conclusion, the observed high Vd as well as CL suggest altered PK of piperacillin in febrile
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neutropenic patients. Standard intermittent dosing of 4.5g piperacillin-tazobactam (IV bolus,
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every eight hours) resulted in sub-optimal antibiotic exposure and therefore was not sufficient.
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We recommend TDM guided optimization with EI or adjusted dosing frequency to ensure
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exposure to inhibitory concentrations for the entire dosing interval.
8
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List of Acronyms
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CI
Continuous infusion
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CL
Clearance
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CLSI
Clinical and Laboratory Standards Institute
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EI
Extended infusion
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EUCAST
The European Committee on Antimicrobial Susceptibility Testing
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fT>MIC
Proportion of the dosing interval free drug concentration remains above MIC
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GFR
Glomerular filtration rate
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MIC
Minimum Inhibitory Concentration
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PD
Pharmacodynamic
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PK
Pharmacokinetic(s)
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Vd
Volume of distribution
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Vss
Volume of distribution at steady state
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Competing interests
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None
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Acknowledgments
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None
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Table 1. Characteristics of the study participants
Patient
1 2 3 4 5 6 7 8 9 10 11 12
Heamatological Malignancy
Acute Myeloid Leukaemia Acute Myeloid Leukaemia Acute Myeloid Leukaemia Multiple Myeloma Lymphoma Acute Myeloid Leukaemia Acute lymphoblastic leukaemia Acute lymphoblastic leukaemia Acute Myeloid Leukaemia Multiple Myeloma Multiple Myeloma Multiple Myeloma
Median (Interquartile Range) a
Sex
Age (yr)
Body Weight (Kg)
Height (cm)
Serum Creatinine (µmol/L)
Creatinine Clearancea (ml/min/1.73 m2)
Albumin (g/L)
172 175 164 153 155 173
88 61 57 67 78 95
65.3 73.7 72.6 62.8 55.4 51.4
Liver enzymes (U/L) ALT
AST
27 25 29 28 26 33
50 13 37 16 27 21
23 7 23 24 19 48
M
61
M
74
F
70
F
64
F
74
M
79
82 100 64 53 54 69
M
68
63
175
70
78.6
23
25
15
171 184 174 184 182
44 66 46 61 68
119.6 96.9 109.7 110.4 85.2
27 26 31 30 31
14 142 12 37 53
10 102 14 19 28
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)
F
54
M
63
M
65
M
53
M
59
71 79 100 91 103
64.5 (60.5-71.0)
75.0 (63.7-93.2)
Cockcroft -Gault
253 254 255 256 257 14
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 Median (Interquartile Range)
133.6 ± 42.2 127.6 (96.3-151.8)
1.6 ± 2.1 0.5 (0.3-1.8)
223.4 ± 88 217.5 (148.4 -285.1)
226.9 ±91.6 218.4 (148.8 -291.9)
431.2 ± 257.4 345.1 (244.4 -524.6)
1.6 ± 0.4 1.5 (1.4-1.6)
31.6 ± 9.9 34.1 (23-38.2)
29.7 ± 8.0 30.7 (23.3-35.7)
20.2 ± 7.5 18.5 (13.7-26.9)
1.1 ± 0.3 1.1 (1.0-1.2)
258 259 260 15
261
List of Figures
262
Figure 1. Plasma concentration-time profile for total piperacillin concentration after single
263
dose of 4.5g piperacillin-tazobactam in twelve febrile neutropenic patients with
264
haematological malignancies.
265
Figure 2. Pharmacodynamic target attainment after a single dose of 4.5g piperacillin-
266
tazobactam in twelve febrile neutropenic patients with haematological malignancies
267
(considering EUCAST MIC breakpoints for Entereobacteriaceae and P. aeruginosa.)
16
Total Plasma concentrattion (mg/L) e range) Median (Interquartile
1000
100
10
1
0.1 0
1
2
3
4
5
6
7
8
9
Time (hr)
Figure 1. 1 Plasma concentration-time concentration time profile for total piperacillin concentration after single dose of 44.5g 5g piperacillin-tazobactam in twelve febrile neutropenic patients with haematological malignancies.
100% 90%
P. aeruginosa (16 mg/L)
80%
Enterobacteriaceae (8 mg/L)
ffT>MIC
70% 60% 50% 40% 30% 20% 10% 0% 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.).
