ORIGINAL ARTICLE
Retrospective Study of Prolonged Versus Intermittent
Infusion Piperacillin-Tazobactam and Meropenem in
Intensive Care Unit Patients at an Academic Medical Center
Rebekka J. Dow, PharmD,* Warren E. Rose, PharmD,Þ Barry C. Fox, MD,þ Joshua M. Thorpe, PhD, MPH,§
and Jeffrey T. Fish, PharmD||
Background: Prolonged infusions of A-lactams are increasingly being
utilized because of increased antimicrobial resistance and a lack of new
antibiotics in the pipeline.
Methods: A retrospective, observational study evaluated adult patients
who received at least 72 hours of piperacillin-tazobactam or meropenem
in a medical and surgical intensive care unit (ICU) at an academic
medical center. In the first 6 months of the study, all patients received
conventional intermittent dosing; in the second 6 months, all patients
received these antibiotics by prolonged infusions. The main outcome
comparisons between groups were duration of ventilator support, duration of ICU and hospital length of stay, and in-hospital mortality.
Results: A total of 121 patients were included: 54 patients in the intermittent (67% piperacillin-tazobactam, 33% meropenem) and 67 patients
in the prolonged group (81% piperacillin-tazobactam, 19% meropenem).
The prolonged group demonstrated a significant decrease in ventilator
days (j7.2 days; 95% confidence interval [CI], j12.4 to j2.4), ICU
length of stay (j4.5 days; 95% CI, j8.3 to j1.4), and hospital length of
stay (j8.5 days; 95% CI, j18.7 to j1.2) compared with the intermittent
group. The risk of in-hospital mortality was 12.4% in the prolonged infusion group and 20.7% in the intermittent infusion group corresponding
to an odds ratio of 0.54 (0.18Y1.66).
Conclusions: The results of this study show that the use of prolonged infusions of piperacillin-tazobactam and meropenem could potentially improve clinical outcomes in critically ill populations. As
antibiotic resistance continues to increase in gram-negative pathogens,
these A-lactam dosing strategies will be important for appropriate
treatment.
Key Words: piperacillin-tazobactam, meropenem, intensive care unit,
A-lactams
(Infect Dis Clin Pract 2011;00: 00Y00)
B
ecause of increased antimicrobial resistance and a shortage
of novel antimicrobial development, new dosing strategies
have been proposed to optimize the pharmacodynamics of
From the *Department of Pharmacy, Froedtert & The Medical College of
Wisconsin; †Pharmacy Practice Division, University of Wisconsin School
of Pharmacy; ‡Department of MedicineYInfectious Diseases, University
of Wisconsin Hospital and Clinics; §Social and Administrative Sciences
Division, University of Wisconsin School of Pharmacy; and ||Department
of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, WI.
Correspondence to: Jeffrey T. Fish, PharmD, University of Wisconsin
Hospital and Clinics, Pharmacy Services, 600 Highland Ave,
F6/133-1530, Madison, WI 53792. E-mail: jfish@uwhealth.org.
This study has no sources of support.
Presented in part at the Great Lakes Pharmacy Residency Conference,
West Lafayette, IN, April 29YMay 1, 2009.
Dr Fox was previously on the speaker’s bureaus of Wyeth (which makes
piperacillin-tazobactam) and Cubist (which markets meropenem).
Dr Rose has received research funding and is on the speaker’s bureau
for Cubist. All other authors have no competing interests to disclose.
Copyright * 2011 by Lippincott Williams & Wilkins
ISSN: 1056-9103
Infectious Diseases in Clinical Practice
&
existing antimicrobials. The application of pharmacodynamic
principles can aid in the preservation of antibiotic efficacy,
impede the emergence of resistance, and potentially provide
a pharmacoeconomic benefit.1 A-Lactams are time-dependent
killing antibiotics and demonstrate maximum efficacy when the
percentage of time during which the free drug concentration
exceeds the minimum inhibitory concentration (%f T 9 MIC) is
optimized. In general, a bactericidal effect occurs when the free
drug concentration exceeds the MIC for 40%, 50%, and 60%
to 70% of the dosing interval for the carbapenems, penicillins,
and cephalosporins, respectively.2,3 Piperacillin-tazobactam and
meropenem both exhibit time-dependent killing and are often
used in the treatment of multidrug-resistant bacterial infections.1,2,4 Prolonged infusions of these A-lactams increase the
time of antimicrobial exposure above the MIC and should as a
result improve their efficacy.1,2,4Y6
Population pharmacokinetic modeling and Monte Carlo
simulations have been used to generate new dosing strategies,
such as the prolonged infusion of A-lactam antibiotics, and
have been applied directly into clinical practice.4 Piperacillintazobactam as a prolonged infusion of 3.375 g in Monte Carlo
simulations demonstrates a greater probability of attaining 50%
f T 9 MIC in isolates of reduced susceptibility and has corresponded to improved outcomes in critically ill patients.2,4
The pharmacodynamic profile of meropenem has been
evaluated as a prolonged infusion administration.6 Although less
outcome data in the literature are available for meropenem use
with this dosing strategy, prolonged infusions of meropenem
have greater %f T 9 MIC and potentially reduced morbidity and
mortality compared with standard infusions.7
Based on the above evidence, the University of Wisconsin
Hospital and Clinics instituted a guideline that was approved by
the Pharmacy and Therapeutics Committee for the prolonged
infusions of both piperacillin-tazobactam and meropenem for
patients receiving this therapy in a medical and surgical intensive
care unit (ICU), on August 1, 2008.
This study was conducted after the guideline was instituted
to further evaluate the efficacy of prolonged infusion regimens.
The objective of our study was to compare the clinical and
pharmacoeconomic outcomes of conventional intermittent dosing of piperacillin-tazobactam and meropenem to the prolonged
infusions in critically ill patients, with a proactive focus on reducing ventilator days in ventilated patients, length of stay in
both the ICU and hospital, and patient mortality.
MATERIALS AND METHODS
This study was approved by the University of Wisconsin
Hospital and Clinics Health Sciences institutional review board.
Data were collected by conducting a retrospective chart review
of all patients 18 to 89 years of age admitted to the medical and
surgical ICU who received at least 72 hours of therapy with
piperacillin-tazobactam or meropenem from February 1, 2008,
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1
Infectious Diseases in Clinical Practice
Dow et al
to January 31, 2009. Cystic fibrosis patients, those receiving
continuous renal replacement therapy, or those who were receiving therapy in the ICU from July 31 to August 1 and had
their regimen changed per the new protocol were excluded. The
first dose of each antibiotic is infused over 30 minutes to rapidly
obtain therapeutic concentrations. Each subsequent dose is
given per prolonged infusion while the patient is in the ICU.
According to the guideline, a patient’s regimen may change
when transferred out of this ICU. For patients with a pathogen
with an MIC of 2 Hg/mL or greater, the same dosage, interval,
and infusion rate continued on the intermediate care or general
care unit for both piperacillin-tazobactam and meropenem. For
those pathogens with MICs of less than 2 Hg/mL, or if there is
no recovered organism, the piperacillin-tazobactam or meropenem regimen is changed to intermittent infusion dosing
and is adjusted based on renal function upon transfer from the
ICU.4 The intermittent group (February 1 to July 31, 2008) included patients who received conventional intermittent dosing (piperacillin-tazobactam 3.375 g intravenously [IV] every
6 hours or meropenem 500 mg IV every 6 hours) with the
30-minute bolus infusions. The prolonged group (August 1,
2008, to January 31, 2009) included patients who received
prolonged infusion (piperacillin-tazobactam 3.375 g IV every
8 hours infused over 4 hours or meropenem 500 mg IV every
6 hours infused over 3 hours). The dosing intervals are adjusted based on renal function (Table 1). The piperacillintazobactam and meropenem dosing in patients with normal renal
function was adopted from Lodise et al.4 To verify the meropenem renal dosing, a Monte Carlo simulation revealed that
500 mg IV every 6 hours infused over 3 hours attained 40% f T 9
MIC for 99% of isolates with MIC of 2 or less and 92%
of isolates with an MIC of 4 for patients with an estimated
creatinine clearance of 40 mL/min (personal communication,
G. Drusano, MD, March 24, 2008). The choice of antibiotics
was decided by the prescriber based on patient history and risk
factors for resistant pathogens. If a patient was admitted to this
ICU more than once during a single hospital admission, only the
patient’s initial ICU stay was included in the study. Also, any
patient whose Acute Physiology and Chronic Health Evaluation
II (APACHE II) score could not be determined based on the
medical record data available was excluded from the study
analysis.
Data were collected from patients’ medical records using a
structured data collection tool to document age, sex, primary
type of critical care patient (medical or surgical), APACHE II
score, ICU length of stay, hospital length of stay, in-hospital
TABLE 1. Prolonged Infusion Dose Adjustments Based
on Renal Function
Estimated CrCl
Piperacillin-tazobactam infused over 4 h
Q20 mL/min
G20 mL/min
Hemodialysis/peritoneal dialysis
Meropenem infused over 3 h
Q36 mL/min
26Y35 mL/min
10Y25 mL/min
G10 mL/min
Hemodialysis/peritoneal dialysis
CrCl indicates creatinine clearance.
2
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Dose
3.375 g IV every 8 h
3.375 g IV every 12 h
3.375 g IV every 12 h
500 mg IV every 6 h
500 mg IV every 8 h
500 mg IV every 12 h
500 mg IV every 24 h
500 mg IV every 24 h
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Volume 00, Number 00, Month 2011
mortality, patient ventilator days, duration of therapy with
piperacillin-tazobactam or meropenem, and other concomitant
antibiotics and their duration of therapy. Data on all cultures
during the time frame of piperacillin-tazobactam or meropenem
treatment (3 days before treatment initiation to 7 days after
treatment discontinuation), organism susceptibility to the study
agent used, and site of infection (determined from positive culture or clinical assessment) were collected. The defined daily
dose (DDD) per 1000 patient days in this ICU was collected
before and after implementation of prolonged infusion for both
study antimicrobials. The APACHE II score was defined as the
worst physiological score calculated during the initial 24 hours
after admission to the ICU. Susceptibility testing was performed
by in vitro Kirby-Bauer testing with zone size interpreter (BIOMIC V3 System; Giles Scientific, Santa Barbara, Calif).8
The main outcomes assessed in this study were assigned
before study implementation and included duration of ventilator
support in intubated patients, ICU length of stay, hospital length
of stay, and in-hospital mortality. A pharmacoeconomic assessment of antibiotic costs was also performed and was based on the
July 2009 average wholesale price of the antibiotic used.
Statistical Analysis
Multiple linear regression analysis was used to compare
mean hospital length of stay, ICU length of stay, and ventilator
days across study groups, adjusting for potential confounding
associated with differences in underlying patient risk characteristics between study groups. The estimates for these comparisons were adjusted for age, severity of illness (APACHE II),
site of infection, other antibiotics while on study therapy, and
organisms recovered during treatment that were not amenable
to primary therapy. Similarly, multiple logistic regression was
used to analyze in-hospital death, adjusting for these potential
confounders. Total hospital length of stay, ICU length of stay,
and ventilator days may be nonnormal and right-skewed, thereby
violating the underlying distributional assumptions of classic
statistical approaches (eg, ordinary least squares). To account
for possible violations of distributional assumptions, therefore,
we estimated standard errors and confidence intervals (CIs)
using a nonparametric bootstrapping approach with bias correction and acceleration.9 Nonparametric bootstrapping does not
rely on assumptions about the sampling distribution of the estimate and has favorable small sample properties resulting in
more accurate type I error rates and greater power for identifying small effects.10,11 Descriptive statistical analyses were performed using SPSS (version 16.0; SPSS Inc, Chicago, Ill), and
multivariate analyses were performed using Stata (version 11;
StataCorp, LP, College Station, Tex). Two-sided P G 0.05 was
regarded as statistically significant.
RESULTS
The 183 evaluated patients were identified through billing
records as having received study medications for at least
72 hours in the ICU. Seventy-eight patients were in the intermittent group and 105 patients in the prolonged group. Evaluated patients were excluded for the following reasons: 31 were
receiving continuous renal replacement therapy; 2 received both
regimens; none were cystic fibrosis patients; 6 were readmitted
to the ICU; in 4, we were unable to obtain their medical records;
and 19 were still in the hospital at the time of study conclusion.
A total of 121 patients were included in the study, with 54 in
the intermittent group and 67 in the prolonged group. In the
intermittent group, 18 patients (33%) received meropenem,
whereas 36 patients (67%) received piperacillin-tazobactam.
Thirteen patients (19%) received meropenem in the prolonged
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Infectious Diseases in Clinical Practice
&
group, and 54 patients (81%) received piperacillin-tazobactam.
Demographic characteristics were similar between both study
groups (Table 2). The average patient APACHE II scores were
25.6 T 6.8 and 24.4 T 6.5 for the intermittent infusion and the
prolonged infusion patients (P = 0.237), respectively. After
adjusting for confounding variables by linear regression, the
intermittent group received therapy for an average total of
8.97 days compared with 9.14 days in the prolonged group
($ 0.17, 95% CI, j1.85 to 2.39). In contrast, the patients in the
prolonged group had a reduced number of days of antibiotic
therapy in the ICU (6.31 days) when compared with the patients
in the intermittent group (7.16 days; $ j0.85; 95% CI, j2.14
to 0.28) (Table 3).
In the multiple linear regression analysis of ventilated
patients, time spent on the ventilator was reduced by 7.2 days
(95% CI, 2.4Y12.4) in the patients receiving prolonged infusion
compared with those in the intermittent group (Table 3). A reduction in total ICU length of stay of 4.5 days (95% CI, 1.4Y8.3)
as well as a reduction in the total hospital length of stay of
8.5 days (95% CI, 1.2Y18.7) was associated with the prolonged
infusion group. The risk of in-hospital mortality compared between the two groups by multiple logistic regression resulted in
a 12.4% mortality risk with prolonged infusion versus 20.7%
with intermittent infusion (odds ratio, 0.54; 95% CI, 0.18Y1.66).
Although this was not significant, the odds of dying in patients
from the prolonged group were 0.54 times lower than those in
the intermittent group (Table 3).
A similar percentage of culture proven (prolonged, 45%,
vs intermittent, 44%) and clinically documented (prolonged,
55%, vs intermittent, 56%) infections were found in both groups.
TABLE 2. Demographic Characteristics
Intermittent
Age, average (SD)
(range), y
Males, n (%)
Patient type, %
Medical
Surgical
APACHE II score,
mean (SD) (range)
Intubated patients
Presumed site of
infection, %
Pulmonary
Intra-abdominal
Blood
Pancreas
Urine
Gram-negative
isolates, n
Pseudomonas
aeruginosa
E. coli
Klebsiella spp
Citrobacter spp
Enterobacter spp
Haemophilus spp
Other
Prolonged vs Intermittent A-Lactam Infusions
Volume 00, Number 00, Month 2011
Prolonged
n = 54
n = 67
P
60.4 (16.4) (18Y89)
58.4 (17.2) (18Y88)
0.527
33 (61)
46 (69)
0.444
61
39
25.6 (6.8) (11Y39)
69
31
24.4 (6.5) (8Y41)
0.565
51
60
40
25
10
9
7
53
17
11
4
6
15
13
23
9
3
3
0
2
5
0
5
4
2
2
0.237
TABLE 3. Outcomes
Difference $ Means
(95% CI)
Intermittent Prolonged
Total days of
therapy,*
mean days
Days of therapy
in ICU,*
mean days
Ventilator days,*
mean days
ICU length
of stay,*
mean days
Hospital length
of stay,*
mean days
Mortality,* %
8.97
9.14
0.17 (j1.85 to 2.39)
7.16
6.31
j0.85 (j2.14 to 0.28)
16.8
9.6
j7.2 (j12.4 to j2.4)†
15.3
10.7
j4.5 (j8.3 to j1.4)†
30.9
22.4
j8.5 (j18.7 to j1.2)†
20.7%
12.4%
Odds ratio, 0.54 (0.18Y1.66)
Adjusted for age, severity of illness (APACHE II), site of infection,
other antimicrobials while on study therapy, and organisms recovered
during treatment not amenable to primary therapy.
*Includes 121 evaluable patients.
†Significant difference.
There were a total of 162 documented infections at multiple sites
that were comparable between groups (Table 2). Table 2 depicts
the gram-negative organisms isolated from culture. Sixty-nine
isolates had MICs performed to piperacillin-tazobactam and/or
meropenem, with 65 isolates (94%) found to be susceptible to
either agent (median MIC = 0.5; range, G0.25Y14). Sixty-four
percent (44/69) of our isolates had an MIC of 1 or less to both
agents. Four isolates (6%) were found to be nonsusceptible to
piperacillin-tazobactam, and none of the isolates were found to
be nonsusceptible to meropenem, according to the established
MIC breakpoints for each antibiotic during the study period.8
Three of these isolates (Pseudomonas aeruginosa, Enterobacter
cloacae, and Escherichia coli) were from the intermittent group,
whereas 1 isolate (Enterobacter aerogenes) was from the prolonged group. Patients with resistant isolates had their therapy
changed to appropriate antibiotics to cover the infecting organism. Vancomycin (79%), ciprofloxacin (66%), and metronidazole (11%) were the most common concomitant antibiotics
used with either piperacillin-tazobactam or meropenem, and
there were no statistical differences in use between treatment
groups. Twelve patients (10%) did not receive any concomitant
antibiotics.
There was a decrease in the DDD per 1000 patient days of
piperacillin-tazobactam in the ICU from 128.3 in the 6 months
of intermittent infusion therapy to 115.4 during the first 6 months
of the prolonged infusion in the ICU. There was also a decrease
in the meropenem DDD per 1000 patient days from 58.6 during
the intermittent infusion period to 34.5 in the prolonged infusion
period.
DISCUSSION
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The prolonged infusions of piperacillin-tazobactam and
meropenem were adopted into clinical practice in the medical
and surgical ICU after promising results in Monte Carlo simulations were followed by improved outcomes in critically ill
patients.2,4 In this retrospective analysis of a newly implemented prolonged infusion strategy, we demonstrated significantly improved outcomes in reduced ventilator days and ICU
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Infectious Diseases in Clinical Practice
Dow et al
and hospital length of stay, as well as a trend toward lower
mortality with prolonged infusion.
In Monte Carlo simulation, the probability of attaining
50% f T 9 MIC for the prolonged infusion of piperacillintazobactam was 92% at an MIC of 16 mg/L and 100% at MICs
of less than 16 mg/L.4 When piperacillin-tazobactam was
dosed as a 30-minute bolus infusion every 6 hours, the probability of attaining 50% f T 9 MIC was greater than 90% only
for an MIC of 1 mg/L. Lodise and colleagues2 reported that
critically ill patients with only P. aeruginosa infections who
had APACHE II scores of 17 or greater receiving the prolonged infusion of piperacillin-tazobactam had a significantly
lower 14-day mortality rate when compared with those who received the bolus intermittent infusion (12.2% vs 31.6%, respectively; P = 0.04), as well as a significantly lower median
duration of hospital stay (21 vs 38 days, respectively; P = 0.02).
Differences in duration of ventilation and ICU length of stay
outcomes between the 2 groups were not reported.2
Meropenem was also included in the prolonged infusion
protocol based on promising but limited clinical data. A 500-mg
dose of meropenem administered by prolonged infusion over 3
hours has been shown to result in mean drug exposures (%f T 9
MIC) above the MICs of 4 and 1 mg/L of 47.27% and 71.44% of
the dosage interval, respectively. This was significantly greater
than that obtained with a 1000-mg bolus dose at the same MICs,
42.5% and 67.04%, respectively (P G 0.05).6
A study by Nicasio and colleagues7 compared
pharmacodynamic-based antibiotic dosing in patients treated
for ventilator-associated pneumonia (VAP) with historical controls. In 21.3% of these patients, meropenem 2 g IV every 8 hours
infused over 3 hours was given. The pharmacodynamic-based
dosing regimens significantly decreased infection-related mortality by 13.1%, infection-related length of stay by 14.4 days,
and superinfections by 19.1%. There was no difference in
28-day mortality, ICU days after VAP, ventilator duration after
VAP, or total hospital length of stay for the historical versus
pharmacodynamic-based dosing patients. The primary prolonged
infusion A-lactam in this study was cefepime in approximately
75% of patients, which was not evaluated in our study.
The results of our study support the use of the prolonged
infusions of piperacillin-tazobactam and meropenem in critically
ill patients. Time spent on the ventilator, total ICU length of
stay, and hospital length of stay were also significantly decreased in this study. A potential theory as to why the prolonged infusion strategy may be beneficial in critically ill
patients may be due to changes in pharmacokinetics in this
population. These physiological changes that can occur in these
patients may lead to inadequate concentrations of A-lactam
antibiotics and decreased efficacy.12,13 In sepsis, patients often
have an increased volume of distribution due to leaky capillaries and altered protein binding, as well as an increased clearance
due to an increased cardiac index.12 The increased clearance of
A-lactam antibiotics has been demonstrated in this population.12
Hypoalbuminemia is also common in critically ill patients,
resulting in lower than anticipated concentrations of drug in the
blood. This can create an increase in the free drug concentration,
which in turn may reduce the half-life of the drug.13 Although a
statistically significant difference in in-hospital mortality was
not shown in this study, the lower risk of mortality in patients
who received the prolonged infusion may represent a promising
trend. We did not find a significant difference in total days of
therapy or days of therapy in the ICU as a result of reliance on
evidence-based guidelines for duration of therapy, such as when
treating VAP.14 We believe the large difference in ventilator
days to be secondary to the above explained change in phar-
4
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Volume 00, Number 00, Month 2011
macokinetics in critically ill patients, which may give the prolonged infusion strategy of A-lactams an advantage over the
intermittent infusion in this population.
Relatively few studies have evaluated the clinical outcomes
of the prolonged infusion of piperacillin-tazobactam and meropenem. This study is a preprotocol and postprotocol study that
validates the previously reported positive outcomes in this
population.2 Although we did not demonstrate a significant
difference in mortality in our patient population, several differences in our study should be discussed. First, we did not limit
our study only to patients with culture-proven P. aeruginosa
infections. Only 11 patients (6 in intermittent group and 5 in
the prolonged group) had documented P. aeruginosa infections. Only 1 of these 11 patients, from the intermittent group,
had a P. aeruginosa isolate that was reported to be resistant to
piperacillin-tazobactam. In this medical and surgical ICU for
2008, 13% of all the gram-negative isolates (not just from our
study) were nonsusceptible to meropenem (all P. aeruginosa),
whereas 21% were nonsusceptible to piperacillin-tazobactam
(Acinetobacter baumannii, E. cloacae, E. coli, Klebsiella oxytoca,
Klebsiella pneumoniae, and P. aeruginosa). We included
patients with both documented and suspected infections, consistent with clinical practice in patients admitted to the ICU.
The patients with suspected infections had their antibiotics
continued by their attending physicians secondary to clinical
signs and symptoms.
The findings of our study differ from those reported by
Patel and colleagues,15 which did not observe a significant difference in 30-day mortality or median length of hospital stay
by comparing patients receiving intermittent infusion to prolonged infusion piperacillin-tazobactam. Contrary to this previous study, our investigation focused solely on critical care
patients, who may benefit from improved coverage with prolonged infusions due to the discussed changes in antimicrobial
pharmacokinetics and pharmacodynamics that occur in this
complex population. This may account for the difference in
outcomes. Overall, disease severity was low in their study
population. The mean APACHE II scores were only 10.5 and
10.9 for the intermittent and prolonged patients, respectively.
Only 4% (intermittent group) and 7% (prolonged group) of
their patients were in the ICU at the time of culture collection,
and their overall mortality was much lower (intermittent group,
5%; prolonged group, 4%), as was their median hospital length
of stay (8 days for both groups).
The prolonged infusion of piperacillin-tazobactam is associated with the benefit of cost savings by reducing the dosing
frequency from every 6 hours to every 8 hours. Based on average wholesale price, the 54 patients who received the prolonged infusion of piperacillin-tazobactam during the 6-month
period of the study, and assuming a 7- to 10-day treatment
period, $8765 to $12,522 were saved by using the prolonged
infusion dosing in this ICU. The reduction in the DDD for
piperacillin-tazobactam was despite an increase in the actual
days of use by 76 days, which reflects significant cost savings with the use of the prolonged infusion of piperacillintazobactam. In addition, our study also demonstrates cost
savings due to the reduction in ventilator days and both ICU and
total hospital length of stay. Based on previously published
literature on the estimated cost of an ICU day, the approximate
4-day decrease in ICU length of stay in our study resulted in
cost savings of $14,000 per patient in ICU stay alone.16 The
reduction in DDD for meropenem can be accounted for by a
decrease in the total days of use in the ICU during this period
(115 days), as the meropenem dosing regimen did not change,
just the infusion time.
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Infectious Diseases in Clinical Practice
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Volume 00, Number 00, Month 2011
Several limitations of the study should be discussed. The
study was retrospective in nature, and data are limited to the
depth and the accuracy of the documented medical record.
The study population was confined to a single-center medical/
surgical ICU. A relatively small number of patients received
meropenem, which consequently makes it difficult to draw conclusions on the efficacy of prolonged infusion of meropenem
individually. Patients were included with documented as well as
suspected infections, and it was not limited to patients with
only documented, culture-proven gram-negative infections. This
may give the study improved external validity as piperacillintazobactam or meropenem is often used as empiric broadspectrum coverage in critically ill patients and then continued
despite the absence of a culture-proven infection as the patient
may still show clinical signs of infection. There was also a relative
lack of gram-negative bacteria with high MICs during our study
period. However, this is consistent with our local ICU antimicrobial susceptibility patterns over several years. Antibiotic regimens used before the initiation of piperacillin-tazobactam and
meropenem were not collected. This could have influenced outcomes if patients were not treated appropriately, although only
9% of the intermittent group and 7% of the prolonged group
had positive cultures drawn 48 hours or more before the initiation
of study antibiotics.
The length of the study period was also limited and therefore may have had insufficient power to detect a difference in
overall mortality. We do acknowledge that other threats to validity cannot be ruled out by the study design, such as regression
to mean and the Hawthorne effect in the prolonged period.
In conclusion, this study shows that the use of the prolonged infusions of piperacillin-tazobactam or meropenem
could potentially improve clinical and pharmacoeconomic outcomes in critically ill populations. More rigorous scientific
studies in critically ill patients in a prospective manner, especially further studies with meropenem, at other institutions
may support our findings and promote further implementation
of this strategy.
REFERENCES
1. Mattoes HM, Kuti JL, Drusano GL, et al. Optimizing antimicrobial
pharmacodynamics: dosage strategies for meropenem. Clin Ther.
2004;26:1187Y1198.
2. Lodise TP, Lomaestro B, Drusano GL. Piperacillin-tazobactam for
Pseudomonas aeruginosa infection: clinical implications of an
extended-infusion dosing strategy. Clin Infect Dis. 2007;44:
357Y363.
* 2011 Lippincott Williams & Wilkins
Prolonged vs Intermittent A-Lactam Infusions
3. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale
for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26:1Y10.
4. Lodise TP, Lomaestro BP, Drusano GL. Application of antimicrobial
pharmacodynamic concepts into clinical practice: focus on Q-lactam
antibiotics. Insights from the Society of Infectious Diseases Pharmacists.
Pharmacotherapy. 2006;26(9):1320Y1332.
5. Kim A, Sutherland CA, Kuti JL, et al. Optimal dosing of
piperacillin-tazobactam for the treatment of Pseudomonas aeruginosa
infections: prolonged or continuous infusion? Pharmacotherapy.
2007;27:1490Y1497.
6. Jaruratanasirikul S, Sriwiriyajan S. Comparison of the
pharmacodynamics of meropenem in healthy volunteers following
administration by intermittent infusion or bolus injection.
J Antimicrob Chemother. 2003;52:518Y521.
7. Nicasio AM, Eagye KJ, Nicolau DP, et al. Pharmacodynamic-based
clinical pathway for empiric antibiotic choice in patients with
ventilator-associated pneumonia. J Crit Care. 2010;25:69Y77.
8. Clinical and Laboratory Standards Institute. Performance Standards for
Antimicrobial Susceptibility Testing. Nineteenth Informational
Supplement. CLSI Document M100-S19. Wayne, PA: Clinical and
Laboratory Standards Institute; 2009.
9. Efron B. Better bootstrap confidence intervals. J Am Stat Assoc.
1987;82(397):171Y185.
10. Yung Y, Chan W. Statistical analyses using bootstrapping: concepts
and implementation. In: Hoyle R, ed. Statistical Strategies for Small
Sample Research. Thousand Oaks, CA: Sage Publications; 1999.
11. Barber JA, Thompson SG. Analysis of cost data in randomized trials:
an application of the non-parametric bootstrap. Stat Med.
2000;19(23):3219Y3236.
12. Roberts JA, Lipman J. Antibacterial dosing in intensive care:
pharmacokinetics, degree of disease and pharmacodynamics of sepsis.
Clin Pharmacokinet. 2006;45:755Y773.
13. Diaz E, Ulldemolins M, Lisboa T, et al. Management of
ventilator-associated pneumonia. Infect Dis Clin N Am. 2009;23:
521Y533.
14. American Thoracic Society. Infectious Diseases Society of America.
Guidelines for the management of adults with hospital-acquired,
ventilator-associated, and healthcare-associated pneumonia.
Am J Respir Crit Care Med. 2005;171:388Y416.
15. Patel GW, Patel N, Lat A, et al. Outcomes of extended infusion
piperacillin/tazobactam for documented gram-negative infections.
Diagn Microbiol Infect Dis. 2009;64:236Y240.
16. Dasta JF, McLaughlin TP, Mody SH, et al. Daily cost of an
intensive care unit day: the contribution of mechanical ventilation.
Crit Care Med. 2005;33:1266Y1271.
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