Accepted Manuscript

Open Forum Infectious Diseases
MAJOR ARTICLE
Clinical Outcomes with Extended versus Intermittent
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Infusion of Anti-pseudomonal Beta-Lactams in Patients with
Gram-Negative Bacteremia
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Nikki N. Tran,1 Ryan P. Mynatt,2 Keith S. Kaye,3 Jing J. Zhao,4 and Jason M. Pogue5
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1
Department of Pharmacy Services, The Ohio State University Wexner Medical Center – The
James Cancer Hospital and Solove Research Institute, Columbus, Ohio, USA; 2Department of
Pharmacy Services, University of Kentucky HealthCare, Lexington, Kentucky, USA;
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3
Department of Medicine, Division of Allergy, Immunology and Infectious Diseases, Rutgers,
Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA; 4Department of
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Pharmacy, Harper University Hospital, Detroit Medical Center, Detroit, Michigan, USA;
5
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Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor,
Michigan, USA
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Background: Administration of doses via an extended infusion (EI) is an important strategy to

optimize beta-lactams. Available data on the impact of EI on outcomes largely focus on clinical
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cure or mortality in critically ill patients or those with resistant pathogens. The potential benefits
of EI extend beyond these populations and outcomes and further study is warranted.
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——————————————————————————————————————
Corresponding author: Nikki N. Tran, PharmD, BCIDP, Specialty Practice Pharmacist,
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Infectious Diseases, Department of Pharmacy, The Ohio State University Wexner Medical
Center, The James Cancer Hospital and Solove Research Institute, 410 W. 10th Ave | 368 Doan
Hall, Columbus OH, 43210, USA, Tel. 614.293.6580, Fax. 614.293.9543, Email.
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nikki.tran@osumc.edu
Alternate corresponding author: Jason M. Pogue, PharmD, BCPS, BCIDP, Clinical Professor,
Infectious Diseases, Department of Clinical Pharmacy, University of Michigan College of
Pharmacy, 428 Church Street | Room 2560A, Ann Arbor, MI 48109, USA, Tel. 734.647.5425,
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Fax. 734.763.4480, Email. jmpogue@med.umich.edu
© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of
America. This is an Open Access article distributed under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial reproduction and distribution of the work, in any medium, provided the
original work is not altered or transformed in any way, and that the work is properly cited. For
commercial re-use, please contact journals.permissions@oup.com
1
DOI: 10.1093/ofid/ofad170
Methods: This was a retrospective cohort study of adult patients who received cefepime,
piperacillin/tazobactam, or meropenem for gram-negative bacteremia via EI or intermittent
infusion (II). Patients were matched 1:1 based on study drug, sepsis severity, ICU status,
bacteremia source, and pathogen. Outcomes assessed included time to clinical stabilization, rates
of treatment failure, mortality, recurrence, and length of stay (LOS).
Results: 268 patients were included. Baseline characteristics were similar between groups. Forty
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two percent of patients were in the ICU at infection onset and the most common pathogen was E.
coli (41%). After adjusting for residual differences between groups, receipt of EI was
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independently associated with shorter time to clinical stability [aOR 0.32, 95% CI 0.22-0.47],
time to defervescence, and time to white blood cell count normalization. Furthermore, EI was
associated with a lower incidence of treatment failure, decreased recurrence of bacteremia, and
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shorter LOS. There was no difference in mortality. These findings were consistent regardless of
patient location (ICU vs. ward), baseline renal function, source of bacteremia, or study drug
received.
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Conclusions: These findings suggest that EI beta-lactams are an important stewardship strategy
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to improve clinical outcomes in patients with Gram-negative bacteremia.
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Keywords: extended infusion, beta-lactams, gram-negative bacteremia, pharmacokinetic-
pharmacodynamic
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INTRODUCTION
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Multidrug resistant Gram-negative pathogens have emerged and proliferated worldwide.

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Infections caused by these pathogens are associated with increased morbidity and mortality when
compared to susceptible strains of these pathogens [1–4]. In 2019, there were an estimated 2.57
million deaths associated with Gram-negative antimicrobial resistance, including more than
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700,000 deaths attributable to Gram-negative antimicrobial resistance [1]. These infections

necessitate assessment of different strategies to enhance the use of existing antibiotics in order to
optimize clinical outcomes and minimize the development of antimicrobial resistance. Such
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strategies include pharmacodynamically dose-optimizing antimicrobial agents [5].
Beta-lactams display time-dependent antibacterial activity, which can be optimized by

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maximizing the amount of time that the free drug concentration is above the minimum inhibitory
concentration (MIC) of the organism (fT > MIC) [6,7]. A strategy for accomplishing this is by
prolonging the infusion time from 30 minutes to an extended infusion over a 3 to 4-hour period.
This strategy improves the probability of achieving the standard pharmacodynamic target of the
beta-lactams, a fT>MIC of 50%, which has been associated with both a 1 log10 reduction in
organisms in preclinical pharmacodynamic models and improvements in both clinical cure and
mortality in patients [8–10].
DOI: 10.1093/ofid/ofad170 2
Most available data assessing the impact of extended infusions on outcomes have targeted
critically ill patients who are most likely to benefit from dose optimization strategies for multiple
reasons [11–18]. First, these patients display alterations in pharmacokinetics which can lead to
unpredictable and often subtherapeutic exposures [8,11,12]. Secondly, they are more likely to be
infected with higher-MIC organisms for which dose optimization schemes are necessary to
reliably achieve standard pharmacodynamic targets [11–15]. Finally, due to their critical illness,
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these patients are most likely to require optimal antimicrobial exposures to achieve desirable

outcomes [11–18]. Importantly, a fT>MIC of 50% may not result in maximal killing, and some
clinical evidence suggests higher fT>MIC targets may be necessary to optimize bacterial killing
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and outcomes [5,11,12,19,20].
Noteworthily, there are other meaningful outcomes that could also be improved by
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pharmacodynamic optimization (and enhanced bacterial killing) that have not been analyzed to
date. These include time to resolution of signs and symptoms of infection (e.g., defervescence,
normalization of leukocytosis), which could impact both the clinical course of the infection and
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length of hospital stay. Furthermore, fully optimized pharmacodynamic exposures could
potentially decrease the likelihood of emergence of resistance [20,21]. Importantly, these
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benefits would be applicable to all patients, not just those who are critically ill.
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In 2013 the Detroit Medical Center (DMC) changed standard practice from intermittent infusions
(over 30-minutes) of anti-pseudomonal beta lactams (cefepime, piperacillin-tazobactam, and
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meropenem) to extended infusions (over 3-hours) to optimize patient outcomes. The purpose of
this study was to assess clinical outcomes in matched patients receiving extended infusions
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compared to intermittent infusions of these agents for the treatment of Gram-negative

bacteremia.
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METHODS
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Study design
This was a retrospective matched cohort study of adult patients within the DMC who received
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empiric treatment with a target antibiotic (cefepime, piperacillin/tazobactam, or meropenem) for

a documented Gram-negative bloodstream infection via a 30-minute intermittent infusion (II) or
a 3-hour extended infusion (EI) from January 1, 2010, through August 31, 2018. Patients were
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matched into each infusion group 1:1 based on the following criteria: (i) severity of illness
(presence or absence of severe sepsis or septic shock) [22], (ii) intensive care unit (ICU) status at
the onset of the index bacteremia (iii) source of bacteremia (urinary tract infection (UTI) vs.
other sources), (iv) causative pathogen (Pseudomonas aeruginosa vs. other Gram-negative
organisms), and (v) anti-pseudomonal beta-lactam received.
Patients were eligible for inclusion if all the following criteria were met: (i) age ≥18 years, (ii)
documented Gram-negative monomicrobial bacteremia with an isolate that was susceptible to
target antibiotic, (iii) treatment with a target antimicrobial with the first dose administered within
24 hours from the of onset of infection (defined as the time of index blood culture collection) and
continued for ≥ 48 hours. Patients were excluded if they met any of the following criteria: (i)
mixed bloodstream infection with a Gram-positive organism or yeast, (ii) presence of additional
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concomitant infection requiring antimicrobial therapy, (iii) receipt of combination therapy with

aminoglycosides or fluoroquinolones for the index infection for > 48 hours, and (iv) receipt of
both EI and II target antimicrobial for treatment of the index infection. Of note, per DMC policy
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the initial dose for all EI antimicrobial was to be given as a bolus infusion as to not delay the
time until therapeutic concentrations, and all renally adjusted doses were administered by the
same infusion strategy as that being used for normal renal function (i.e., 30-minute or 3-hour
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infusion). For instance, dose 1 was given as a bolus and then dose 2 as an EI starting at half the
interval.
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Covariates collected
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Covariates extracted from the electronic medical record included demographics, comorbidities,
severe inflammatory response syndrome (SIRS) criteria, severity of illness [22], duration of
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hospitalization and ICU stay after initiation of antibiotics, use of antipyretics, indwelling lines,
and the need for mechanical ventilation. SIRS criteria, collected daily while on study treatment,
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included temperature >38oC or <36oC, heart rate >90 beats/min, respiratory rate >20 breaths/min,
WBC >12,000 cells/mm3, <4000 cells/mm3, or >10 percent bands. Infection data extracted
included source of bacteremia, which was determined by culture evaluation and physician’s
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clinical assessment in the medical record. For patients with central line-associated bloodstream
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infection (CLABSI), time to line removal was collected. Microbiological data included all
positive blood cultures, collection date, bacteremia clearance date, pathogens identified, and their
susceptibility profiles.
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Treatment data included antibiotics administered, dosage, infusion time, treatment duration,
reason for discontinuation, antibiotics of de-escalation or escalation, and incidence of antibiotic-
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related neurotoxicity. Culture-to-antibiotic time was measured in hours as the difference in time
between when the first positive blood culture was drawn and the documented time of effective
antibiotic administration. Collected daily dose was normalized to the corresponding full renal-
adjusted dose equivalent (Table S1)
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Susceptibility testing
At the onset of the study, the DMC utilized MicroScan for antimicrobial susceptibility testing
(AST). The panel used at the DMC from 2010 – 2014 had limited granularity for providing exact
MIC values, only providing that the MIC was less than or equal to values at or near susceptibility
breakpoints (≤8 for cefepime, ≤8 for piperacillin/tazobactam, and ≤4 for meropenem for all study
pathogens). In 2015, the DMC changed to a new AST platform (Phoenix) which employed
panels that reported lower MIC values (i.e., ≤1 for cefepime, ≤4 for piperacillin/tazobactam, and
≤0.5 for meropenem). Therefore, while the study was always limited to patients who had isolates
“susceptible” to the study drug, the ability to provide with actual MIC values differed in the II
and EI groups. Given these limitations, MIC distributions for actual study pathogens are not
provided in the manuscript. However, to provide insight on how to conceptualize the findings
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with respect to local epidemiology, the MIC distributions of all Enterobacterales susceptible to

the study agents for major study pathogens in 2018 collected at the DMC are provided in the
supplement (Table S2).
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Outcome definitions
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The primary outcome was time to clinical stabilization between patients who received EI and II.
Clinical stabilization was defined as resolution of all SIRS criteria that were present at the onset
of infection. Additionally, time to defervescence and time to white blood cell count (WBC)
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normalization were assessed. For these outcomes, analyses were limited to patients with
abnormal values at the time of study drug initiation. Secondary outcomes included rates of
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treatment failure, bloodstream infection recurrence within 60 days, in-hospital mortality,
infection-related mortality, length of hospitalization (LOS), and ICU-LOS after the initiation of
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study antibiotics. Infection-related mortality was defined as death attributable to the study
bacteremia episode as determined by the primary team physician’s judgment via their
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documentation in discharge notes. Treatment failure was defined as failure to resolve the signs
and symptoms of infection with the study drug requiring an escalation of antibiotics. In patients
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who developed recurrent bloodstream infections, the development of resistance was assessed.
Resistance was defined as isolation of the same pathogen with resistance to a greater number of
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beta-lactams than the initial infection after resolution of the index infection.
Statistical analyses
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All statistics were calculated using SAS version 9.3 (Cary, NC). Bivariate analyses were
conducted using Fisher’s exact test or chi-square tests for unmatched dichotomous variables, and
the Student’s t test and Wilcoxon rank sum test for continuous variables. Matched analyses of
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bivariate variables were conducted using conditional logistic regression modeling. A 2-sided P
value ≤ 0.05 denoted statistical significance. To determine the independent impact of treatment
arm on the primary outcomes, multivariate analyses were performed. Multivariate modeling for
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the time to event (i.e., time to clinical stability, defervescence, and WBC resolution) were
conducted using linear regression model. These outcomes were log transformed into a normally
distributed variable. The inverse log value was calculated for the β coefficients of variables
included in the model for primary outcomes and the associations between the variable of interest
(infusion type) and these outcomes were reported as odds ratios (OR) with 95% confidence
intervals.[22,23] Variables associated with treatment arm in the bivariate analyses at a P value of
< 0.2 were eligible for inclusion into the multivariate model for each outcome along with
treatment arm (EI vs II). The adjusted odds ratio (aOR) for treatment with EI with each outcome
was then determined.
Subgroup analyses:
To further explore the impact of infusion strategy on outcomes of interest, subgroup analyses
were performed. These included assessing outcomes in patients as a function of ICU status at
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onset of bacteremia, baseline renal function, study drug received, and source of bacteremia.
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RESULTS
Description of the Cohort
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A total of 7071 patients with Gram-negative bloodstream infections over the study period were
screened (Figure S1). After the matching process, 268 patients were included in the cohort; 134
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who received EI and 134 who received II. All included patients were matched 1:1 on all five
variables. The median (interquartile range [IQR]) age of the cohort was 64 (55-77) years, and
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116 (43%) were female. The most common comorbidities were diabetes (n=94, 35%), chronic
kidney disease (n=71, 26%), and peripheral vascular disease (n=55, 21%). The median (IQR)
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Charlson Comorbidity Index (CCI) was 3 (1-4). The median baseline creatinine clearance (IQR)
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was 36.4 (19.7-61.3) mL/min (Table 1).
A total of 106 (40%) patients presented with severe sepsis or septic shock, 116 (42%) patients
were in the ICU, and 27 (10%) were mechanically ventilated at infection onset. The most
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common organisms isolated were Escherichia coli (41%), Klebsiella pneumoniae (18%), and
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Pseudomonas aeruginosa (13%). The most common source of bacteremia was the urine (n=136,
51%), followed by intra-abdominal (n=29, 11%), and CLABSI (n=29, 11%) (Table 2).
The two groups were well matched with regards to demographics, comorbidities, severity of
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illness, and infection-related characteristics (Tables 1,2). Patients receiving EI were older (65.5
[58-78] vs. 61.5 [52-73], P = .01), had higher median CCI (3 [2-4] vs 2 [1-3]; P < .001), and had
lower mean weight (78.8 ± 19.2 vs 85.5 ± 27.8, P = .02). Additionally, patients in the EI group
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were less likely to have CLABSI (6% vs 16%; P = .02).
Treatment characteristics
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The most common study antibiotic utilized was cefepime (n=158, 59%), followed by
piperacillin/ tazobactam (n=68, 25%), and meropenem (n=42, 16%). There were no differences
in rate of antibiotic de-escalation, time to appropriate therapy, or the renally adjusted total daily
dose of study drugs between groups (Table 2). Few patients received combination therapy (≤ 48
hours) with an aminoglycoside. The duration of therapy with study drug was significantly longer
in the II group (5.1 ± 4.4 vs. 3.4 ± 2.0; P < .001).
Time to clinical stability (Table 3):
Receipt of the study agent via EI was associated with shorter median (IQR) time to clinical
stability (30.0 hours [10.1-43.0] vs. 52.8 hours [35.6-116.0], P < .001), shorter time to
defervescence (6.5 hours [2.3-15.9] vs. 30.0 hours [15.4-46.4], P < .001), and shorter time to
WBC normalization (39.3 hours [27.7-82.6] vs. 73.6 hours [41.5-176.0], P = .002) compared to
II. After controlling for residual differences between groups, treatment with EI was
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independently associated with shorter time to clinical stability [aOR 0.32, 95% CI 0.22-0.47],
time to defervescence [aOR 0.28, 95% CI 0.16-0.47], and time to WBC normalization [aOR
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0.58, 95% CI 0.44-0.68]).
Secondary outcomes (Table 3):
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Patients that received EI had a lower incidence of treatment failure (0.7% vs. 9.7%, P < .001)
and recurrence of bacteremia (0% vs. 6.7%, P < .001) when compared to those in the II group.
Patients in the EI arm also had a shorter LOS (6 (4-9) days vs. 9 (6-15) days, P = .02), and ICU-
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LOS (3 (3-5) days vs. 5 (3-9) days, P < .001) from study antibiotic initiation until discharge.
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There were no differences between groups with regards to in-hospital mortality, infection-related
mortality, or the development of resistance. There were no cases of antibiotic-associated
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neurotoxicity in the cohort.
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Subgroup analyses:
Overall, results of the subgroup analyses were consistent with the full cohort favoring receipt of
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EI regardless of location within the hospital (floor vs. ICU), baseline renal function (creatinine
clearance (CrCl) < 30, 30 – 49, and ≥ 50 mL/min) (Table 4), study drug utilized, or source of
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bacteremia (urine vs. other) (Table 5). For the primary outcome of time to clinical stabilization,
receipt of study drug via EI was associated with earlier stabilization compared to II groups
among those in the ICU (32.4 hours [7.4-60.2] vs. 67.0 hours [37.0-164.1], P < .001) or on the
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floor (28.7 hours [11.2-38.2] vs. 45.1 hours [32.3-66.8], P = .05) at infection onset (Table 4). A
similar association was also demonstrated between receipt of study agent by EI and time to
clinical stabilization, regardless of baseline renal function, as shown in Table 4. Full results for
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primary and secondary outcomes for all subgroups are listed in Tables 4 and 5.
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DISCUSSION
In this matched comparison, receipt of cefepime, piperacillin-tazobactam, or meropenem by EI

was associated with a significant improvement in time to clinical stability, defervescence, and
leukocytosis resolution compared to II. The quicker resolution, by approximately one day,
appeared to confer multiple clinical and stewardship benefits as patients receiving EI had shorter
lengths of stay, were less likely to be escalated for treatment failure, received nearly two less
days of anti-pseudomonal therapy on average, and were more likely (P = .07) to have antibiotics
de-escalated. Additionally, bacteremia recurrence occurred in 7% of patients in the II group
versus no patients receiving EI. Although no benefit was demonstrated with receipt of EI on
mortality or resistance development, these were infrequent events and highlight the importance
of endpoint selection in analyses assessing the benefit of infusion strategy on outcomes. As this
was a moderately ill cohort where inclusion criteria mandated initiation of active antimicrobial
therapy within 24 hours of infection onset, an overall mortality rate of 1.5% is not surprising.
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Interestingly, the only two patients who had recurrent BSI due to a resistant organism received II

and had subsequent isolation of ESBL producing Enterobacterales. Importantly, a robust blood
culture monitoring and intervention, conducted by antimicrobial stewardship pharmacists, was in
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place for the entire duration of the study, and thus changes in practices do not explain these
findings [22].
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Perhaps the most intriguing findings in this analysis were that the benefits of EI remained in all
subgroup populations, including those where the benefit of EI is less established or questioned.
Previous data on EI mainly targeted critically ill patients because of their PK variability, higher
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likelihood of infections with higher MIC organisms, and/or need for enhanced pharmacodynamic
killing [11,12,19,20]. In the current study, results were similarly in favor of EI regardless of
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whether the patient was in the ICU or floor at the time of BSI onset, with floor patients
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representing nearly 60% of the population in the study. Further, it is notable that median baseline
CrCl was 36 mL/min in this cohort. The benefit of extended infusion in patients with renal
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insufficiency, where prolonged half-life increases fT>MIC, has long been questioned, but results
stratified by renal function demonstrated a similar improvement with receipt of the study drug by
EI for patients with baseline CrCl <30 mL/min, between 30-49 mL/min, and ≥ 50 mL/min.
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Additionally, EI is traditionally employed to target infections caused by higher MIC pathogens,

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most notably P. aeruginosa, to ensure pharmacodynamic targets are met. In the current analysis,
the benefit was demonstrated even though only 13% of patients had P. aeruginosa. In fact, the
most utilized antibiotic in the analysis, cefepime, demonstrated MIC90 values ≤ 1 mg/L for all
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other study pathogens at the DMC. This suggests that the benefit is related to enhanced bacterial
killing as PK/PD data support >90% probability of target attainment with cefepime for standard
pharmacodynamic targets with II at these MIC values [8,19]. The widespread benefit of EI,
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beyond the traditional targets for this dosing strategy, is further supported by the fact that results
were similar in patients with a urinary or non-urinary source of infection.
While these results are encouraging, this study is not without limitations. As mentioned above,
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although all isolates were susceptible to study agents, actual MIC values for isolates collected
prior to 2015 were not available for direct comparison between the two arms nor for assessment
of clinical outcomes based on exact MIC values. While susceptibility data provided from 2018
support that a lack of actual MIC values in the II arm had minimal impact on the findings of the
trial, the exact influence cannot be ascertained. In addition, this was a single center, retrospective
study with a relatively small sample size which is subject to all the biases associated with such
trials. While patients were intentionally matched based on risk factors for poor outcomes, there
may be other confounding factors we could not account for that influenced outcomes. As this is a
pre-post study encompassing an 8-year period, it is important to note that advances of care
during the time of the studied intervention may have influenced outcomes. However, as
previously stated, a robust stewardship program featuring real time monitoring and intervention
by stewardship pharmacists with Gram negative bacteremia was in place throughout the duration
of the study and thus advances in stewardship practices do not explain the improved results.
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Additionally, per the inclusion criteria, patients needed to be on active in vitro therapy within 24

hours. Therefore, advances in care, including within sepsis management, over the time frame
would be unlikely to significantly impact outcomes in patients in this study. Furthermore,
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patients may have been lost to follow-up or readmitted outside of our hospital network which
may have impacted assessment of infection recurrence and resistance development. Finally, as
this study only included monomicrobial gram-negative bloodstream infections, our findings may
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not be generalizable to other infections.
In conclusion, receipt of anti-pseudomonal beta-lactams by EI was associated with faster time to
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resolution of signs and symptoms of infection, lower rates of treatment failure, less recurrence of
infection, and shorter LOS. These data suggest that the benefit of EI is not limited to critically ill
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patients or those infected with high MIC organisms, and consideration should be given to
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broader application of EI.
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NOTES
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Financial support. This work was not supported through a research grant or funding.
Potential conflict of interest. All authors have no conflict of interest related to the work in a
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manuscript. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of
Interest. Conflicts that the editors consider relevant to the content of the manuscript have been
disclosed.
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Patient Consent. The study was approved by the institutional review boards of the DMC. Due to
the retrospective nature of the analysis, written informed consent was exempted.
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Table 1. Baseline Demographics and Comorbidities
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Intermittent Extended
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Infusion Infusion P value
(n = 134) (n = 134)
U
Demographics
Age, years, median (IQR) N 61.5 (52-73) 65.5 (58-78) .01

A
Female, n (%) 63.0 (47.0) 53.0 (39.6) .22
M
33.5 38.6
Baseline creatinine clearance, mL/min, median (IQR) .22
(17.6-60.5) (22.2-61.6)
D
Weight, kg, mean (SD) 85.5 ± 27.8 78.8 ± 19.3 .02

TE
Comorbidities, n (%)
Congestive heart failure 20.0 (14.9) 26.0 (19.4) .42

EP
Chronic kidney disease 40.0 (29.9) 31.0 (23.1) .27

CC
Chronic pulmonary disease 16.0 (11.9) 16.0 (11.9) 1.00
Cerebrovascular disease 20.0 (14.9) 31.0 (23.1) .12

A
Connective tissue disease 9.0 (6.7) 21.0 (15.7) .03
Diabetes mellitus 42.0 (31.3) 52.0 (38.8) .25
Leukemia 0.0 (0.0) 2.0 (1.5) .50
Liver disease 12.0 (9.0) 15.0 (11.2) .69
DOI: 10.1093/ofid/ofad170 11
Malignant lymphoma 0.0 (0.0) 4.0 (3.0) .12
Malignant solid tumor 9.0 (6.7) 27.0 (20.1) .002
Peripheral vascular disease 19.0 (14.2) 36.0 (26.9) .02
Charlson Comorbidity Index 2.0 (1-3) 3.0 (2-4) .001
PT
Abbreviations: IQR, interquartile range; SD, standard deviation.
Table 2. Infection and Treatment-related Characteristics
RI
Intermittent Extended
P value
SC
Infusion Infusion
(n = 134) (n = 134)
U
Febrile, n (%)a 45.0 (33.6) 39.0 (29.1) .51
Leukocytosis, n (%)a N 62.0 (46.3) 52.0 (38.8) .27

A
Hypotension, n (%)a 38.0 (28.4) 43.0 (32.1) .89
M
Tachycardia, n (%)a 95.0 (70.9) 90.0 (67.2) .60
Severe sepsis/septic shock, n (%) 53.0 (39.6) 53.0 (39.6) 1.00

D
ICU care at onset of infection, n (%) 56.0 (41.8) 56.0 (41.8) 1.00
TE
Mechanically ventilated at study drug start, n (%) 10.0 (7.5) 17.0 (12.7) .22
EP
Organisms, n (%)
Escherichia coli 52.0 (38.8) 58.0 (43.3) .54

CC
Klebsiella spp. 20.0 (14.9) 29.0 (21.6) .21
Pseudomonas aeruginosa 17.0 (12.7) 17.0 (12.7) 1.00

A
Proteus spp. 15.0 (11.2) 10.0 (7.5) .40
Enterobacter spp. 15.0 (11.2) 9.0 (6.7) .29
Serratia spp. 9.0 (6.7) 3.0 (2.2) .14
DOI: 10.1093/ofid/ofad170 12
Acinetobacter spp. 3.0 (2.2) 4.0 (2.9) 1.00
Citrobacter spp. 3.0 (2.2) 3.0 (2.2) 1.00
Morganella spp. 0.0 (0.0) 2.0 (1.5) .50
Source of bacteremia, n (%)
PT
Urinary tract 68.0 (50.7) 68.0 (50.7) 1.00
RI
Intra-abdominal 12.0 (9.0) 17.0 (12.7) .43
Central line 21.0 (15.7) 8.0 (6.0) .02
SC
-Time to line removal (hours), median (IQR) 34.0 35.0
.59
(11.0-56.8) (24.0-58.6)
U
Skin and soft tissue 13.0 (9.7) 12.0 (9.0) 1.00
Respiratory
N 8.0 (6.0) 12.0 (9.0) .49
A
Unknown 12.0 (9.0) 17.0 (12.7) .43
M
Study drug, n (%)

D
Cefepime 79.0 (59.0) 79.0 (59.0) 1.00

TE
Piperacillin-tazobactam 34.0 (25.4) 34.0 (25.4) 1.00
Meropenem 21.0 (15.7) 21.0 (15.7) 1.00

EP
Daily dose, gram, median (IQR)b
Cefepime 6.0 (6.0) 6.0 (6.0) 1.00

CC
Piperacillin-tazobactam 18.0 (14.6-18.0) 18.0 (18.0) .39
Meropenem 4.0 (4.0) 4.0 (4.0) 1.00

A
Time to appropriate therapy (hours), median (IQR) 10.4 (4.3-17.7) 13.3 (1.9-20.1) .55
Cefepime 9.4 (2.4-16.6) 14.5 (2.3-20.3) .10
Piperacillin-tazobactam 8.8 (3.8-18.8) 3.2 (1.1-14.6) .08
DOI: 10.1093/ofid/ofad170 13
Meropenem 18.2 (6.6-20.9) 17.3 (10.4-22.9) .46
Duration of study antibiotic, days ± SD 5.1 ± 4.4 3.4 ± 2.0 <0.001
De-escalation off study drug, n (%) 61.0 (45.5) 77.0 (57.5) .07
Completed treatment course with study drug, n (%) 57.0 (42.5) 53.0 (39.6) .71
PT
Study drug transitioned to oral regimen, n (%) 3.0 (2.2) 3.0 (2.2) 1.00
RI
Concomitant aminoglycosides (≤48 hours only), n (%) 6.0 (4.5) 5.0 (3.7) 1.00
Administration of antipyretic, n (%)c 42.0 (93.3) 36.0 (92.3) 1.00
SC
a
Number of patients with fevers, leukocytosis, hypotension, or tachycardia at time of study drug initiation
b
Patients with renal-adjusted doses described as full dose equivalent
c
Limited to patients who had fever at time of study drug initiation
U
Abbreviations: ICU, intensive care unit; IQR, interquartile range; SD, standard deviation.
Table 3. Primary and Secondary Outcomes

N
A
Primary Outcomes Intermittent Extended P Odds Ratio Adjusted
M
hours, median (IQR) Infusion Infusion value (OR) 95% ORa
n = 134 n = 134 CI (aOR)

D
95% CI
TE
Time to clinical stability n = 92 n = 81 <.001 0.33 (0.23- 0.32

EP
52.8 (35.6- 30.0 (10.1- 0.47) (0.22-
116.0) 43.0) 0.47)

CC
Time to defervescence n = 45 n = 39 <.001 0.25 (0.15- 0.28
30.0 (15.4- 6.5 (2.3- 0.41) (0.16-

A
46.4) 15.9) 0.47)
Time to WBC normalization n = 62 n = 52 .002 0.58 (0.40- 0.58
73.6 (41.5- 39.3 (27.7- 0.68) (0.44-
DOI: 10.1093/ofid/ofad170 14
176.0) 82.6) 0.68)
Secondary Outcomes
In hospital mortality, n (%) 0 (0.0) 4 (3.0) 0.12 -- --
Infection-related mortality, n 0 (0.0) 1 (0.7) 1.00 -- --
PT
(%)
RI
Treatment failure, n (%) 13 (9.7) 1 (0.7) <.001 -- --
SC
Recurrence of bloodstream 9 (6.7) 0 (0.0) <.001 -- --
infection, n (%)
U
LOS from study drug start, 9.0 (6.0- 6.0 (4.0- .002 -- --
days, median (IQR) 15.0) N 9.0)

A
n = 56 n = 56 <.001 -- --
M
ICU LOS from study drug start,
5.0 (3.0-9.0) 3.0 (3.0-
days, median (IQR)
D
5.0)
TE
Recurrence due to resistant 2 (1.5) 0 (0.0) .50 -- --
isolate, n (%)
EP
a
aOR adjusted for age, total body weight, CLABSI source of infection, and Charlson Comorbidity Index
Abbreviations: ICU, intensive care unit; IQR, interquartile range; LOS, length of stay; WBC, white blood cell count.
CC
Table 4. Primary and Secondary Outcomes Stratified by ICU Status and Renal Function
Non-ICU ICU
A
II EI P II EI P
n = 78 n = 78 value n = 56 n = 56 value
Time to clinical n = 47 n = 40 .05 n = 45 n = 41 <.001
DOI: 10.1093/ofid/ofad170 15
stability, hours, 45.1 (32.3- 28.7 (11.2- 67.0 (37.0- 32.4 (7.4-60.2)
median (IQR) 66.8) 38.2) 164.1)
Time to n = 29 n = 19 .01 n = 16 n = 20 .002
defervescence, 29.7 (11.7- 8.7 (2.1-19.4) 35.2 (26.9- 6.0 (2.5-16.3)
PT
hours, median (IQR) 43.7) 46.5)
RI
Time to WBC n = 38 n = 30 .07 n = 24 n = 22 .003
SC
normalization, hours, 53.1 (37.9- 32.7 (21.7- 159.5 (65.0- 69.8 (32.2-98.0)
median (IQR) 108.0) 43.5) 250.1)
U
Treatment failure, n 7 (9.0) 0 (0.0) .01 0 (0.0) 1 (1.8) .11
(%) N
A
LOS from study drug 8.0 (5.0-11.8) 5.0 (4.0-8.0) <.001 11.0 (7.0- 8.0 (5.0-11.0) .004
M
start, days, median 17.3)

D
(IQR)
TE
Recurrence of BSI, n 6 (7.7) 0 (0.0) .03 3 (3.8) 0 (0.0) .25
(%)
EP
Outcomes Stratified by Renal Function

CC
CrCl <30 ml/min CrCl 30-49 ml/min CrCl ≥ 50 ml/min
II EI P II EI P II EI P
A
n = 59 n = 47 value n = 31 n = 38 value n = 44 n = 49 value
Time to n = 37 n = 24 .25 n = 24 n = 27 .002 n = 31 n = 30 .03
clinical 53.2 35.4 (16.4- 58.8 33.5 (7.5- 48.6 (26.6- 24.4
DOI: 10.1093/ofid/ofad170 16
stability, (39.4- 69.7) (30.2- 38.9) 98.2) (6.8-
hours, 139.9) 127.4) 34.2)
median
(IQR)
PT
Time to n = 18 n = 11 .06 n = 11 n = 16 .01 n = 17 n = 13 .004
RI
defervesce 28.6 12.1 (2.3- 33.4 9.5 (3.7- 29.8 (12.2- 6.5
SC
nce, hours, (12.7- 24.1) (27.4- 16.7) 51.8) (1.9-
median 37.9) 50.6) 14.5)
U
(IQR)
Time to n = 27 n = 19 .15 n = 19 N n = 15 .06 n = 19 n = 20 .06

A
WBC 138.0 79.9 (22.7- 57.6 37.9 (33- 65.0 (44.3- 29.6
M
normalizati (41.7- 142.3) (31.8- 72.4) 123.8) (22.1-

D
on, hours, 211.9) 157.6) 57.7)

TE
median
(IQR)
EP
Treatment 7 (11.9) 1 (2.1) .07 5 (16.1) 0 (0.0) .02 1 (2.3) 0 (0.0) .47
failure, n
CC
(%)
A
LOS from 9.0 (6.0- 6.0 (4.5- .02 10.0 (6.0- 5.0 (4.3- .001 7.5 (6.0- 7.0 .08
study drug 14.0) 9.0) 15.5) 0.0) 15.0) (4.0-
start, days, 10.0)
median
DOI: 10.1093/ofid/ofad170 17
(IQR)
Recurrence 3 (5.1) 0 (0.0) .25 3 (9.7) 0 (0.0) .09 3 (6.8) 0 (0.0) .10
of BSI, n
(%)
PT
Abbreviations: BSI, bloodstream infection; CrCl, creatinine clearance; EI, extended infusion; ICU, intensive care
unit; II, Intermittent infusion; IQR, interquartile range; LOS, length of stay; WBC, white blood cell count.
RI
Table 5. Subgroup analyses by study drug and source of infection
SC
Cefepime Piperacillin/tazobactam Meropenem
Intermittent Extended P Intermitte Extended P Intermittent Extended P
U
n = 79 n = 79 value nt n = 34 value n = 21 n = 21 value
n = 34
Time to clinical n = 53 n = 44 .05 N

n = 24 n = 21 .02 n = 15 n = 16 .001
A
stability, hours, 47.0 (31.8- 30.2 (10.0- 65.2 (41.2- 23.9 (7.5- 144.5 (60.4- 37.0 (13.8-
M
median (IQR) 66.0) 39.1) 107.7) 43.0) 274.9) 66.0)
Time to n = 33 n = 21 .002 n=9 n = 10 .09 n=4 n=8 .10

D
defervescence, 30.0 (11.9- 5.4 (2.6-14.5) 37.0 (15.4- 3.0 (1.4-17.8) 24.5 (18.8- 13.7 (10.7-
TE
hours, median 46.4) 45.1) 54.0) 20.7)
(IQR)
Time to WBC n = 33 n = 29 .04 n = 17 n = 15 .49 n = 14 n = 10 .004

EP
normalization, 59.1 (40.9- 34.6 (27.5- 67.5 (42.4- 43.0 (22.9- 194.9 (96.4- 51.3 (28.0-
hours, median 150.2) 67.1) 123.8) 124.9) 275.2) 81.9)

CC
(IQR)
Treatment 8 (10.1) 0 (0.0) .01 5 (14.7) 1 (2.9) .20 0 (0.0) 0 (0.0) 1.00
A
failure, n (%)
LOS from study 8.0 (5.0-12.0) 5.0 (4.0-8.0) .001 10.0 (7.0- 8.0 (5-9) .05 12.0 (8.0- 8.0 (6.0-10.0) .01
drug start, days, 16.0) 17.0)
median (IQR)
Recurrence of 7 (8.9) 0 (0.0) .01 1 (2.9) 0 (0.0) 1.00 1 (4.8) 0 (0.0) 1.00
DOI: 10.1093/ofid/ofad170 18
BSI, n (%)
Urine source Non-urine sources
Intermittent Extended P Intermittent Extended P
n = 68 n = 68 value n = 66 n = 66 value
Time to clinical n = 51 n = 39 .02 n = 41 n = 42 .001
PT
stability, hours, 47.3 (32.2-99.5) 31.9 (15.5-42.2) 62.7 (37.9-133.6) 24.0 (7.4-43.3)
median (IQR)
RI
Time to n=28 n = 18 .001 n = 17 n = 21 .02
SC
defervescence, 34.1 (24.3-45.4) 8.7 (5.1-20.3) 29.8 (15.0-46.6) 2.6 (1.5-14.2)
hours, median
(IQR)
U
Time to WBC n = 32 n = 30 .02 n = 30 n = 22 .09
normalization, 62.1 (40.2-168.1) 34.6 (24.1-69.6) N 95.2 (43.0-180.6) 48.9 (30.0-92.1)

A
hours, median
M
(IQR)
Treatment 4 (5.9) 1 (1.5) .37 9 (13.6) 0 (0.0) .003

D
failure, n (%)
LOS from study 8.0 (5.0-12.0) 6.0 (4.0-8.0) .001 10.0 (7.0-17.0) 8.0 (5.0-9.0) .003
TE
drug start, days,
median (IQR)
EP
Recurrence of 7 (10.3) 0 (0.0) .01 2 (3.0) 0 (0.0) .50
BSI, n (%)
CC
Abbreviations: BSI, bloodstream infection; ICU, intensive care unit; IQR, interquartile range; LOS, length of stay;
WBC, white blood cell count.
A
DOI: 10.1093/ofid/ofad170 19

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Open Forum Infectious Diseases

Clinical Outcomes with Extended versus Intermittent

Background: Administration of doses via an extended infusion (EI) is an important strategy to

Fax. 734.763.4480, Email. jmpogue@med.umich.edu

Multidrug resistant Gram-negative pathogens have emerged and proliferated worldwide.

700,000 deaths attributable to Gram-negative antimicrobial resistance [1]. These infections

strategies include pharmacodynamically dose-optimizing antimicrobial agents [5].

Beta-lactams display time-dependent antibacterial activity, which can be optimized by

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compared to intermittent infusions of these agents for the treatment of Gram-negative

empiric treatment with a target antibiotic (cefepime, piperacillin/tazobactam, or meropenem) for

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Description of the Cohort

were less likely to have CLABSI (6% vs 16%; P = .02).

Secondary outcomes (Table 3):

In this matched comparison, receipt of cefepime, piperacillin-tazobactam, or meropenem by EI

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Additionally, EI is traditionally employed to target infections caused by higher MIC pathogens,

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In conclusion, receipt of anti-pseudomonal beta-lactams by EI was associated with faster time to

2019: a systematic analysis. The Lancet 2022; 399:629–655.

Infect Dis Soc Am 2007; 44:357–363.

Antimicrob Agents Chemother 2005; 49:4920–4927.

hospitalized patients with complicated intra-abdominal infection. Antimicrob Agents Chemother

Table 1. Baseline Demographics and Comorbidities

Age, years, median (IQR) N 61.5 (52-73) 65.5 (58-78) .01

Weight, kg, mean (SD) 85.5 ± 27.8 78.8 ± 19.3 .02

Congestive heart failure 20.0 (14.9) 26.0 (19.4) .42

Chronic kidney disease 40.0 (29.9) 31.0 (23.1) .27

Chronic pulmonary disease 16.0 (11.9) 16.0 (11.9) 1.00

Cerebrovascular disease 20.0 (14.9) 31.0 (23.1) .12

Connective tissue disease 9.0 (6.7) 21.0 (15.7) .03

Diabetes mellitus 42.0 (31.3) 52.0 (38.8) .25

Leukemia 0.0 (0.0) 2.0 (1.5) .50

Liver disease 12.0 (9.0) 15.0 (11.2) .69

Malignant solid tumor 9.0 (6.7) 27.0 (20.1) .002

Peripheral vascular disease 19.0 (14.2) 36.0 (26.9) .02

Charlson Comorbidity Index 2.0 (1-3) 3.0 (2-4) .001

Table 2. Infection and Treatment-related Characteristics

Leukocytosis, n (%)a N 62.0 (46.3) 52.0 (38.8) .27

Tachycardia, n (%)a 95.0 (70.9) 90.0 (67.2) .60

Severe sepsis/septic shock, n (%) 53.0 (39.6) 53.0 (39.6) 1.00

Escherichia coli 52.0 (38.8) 58.0 (43.3) .54

Klebsiella spp. 20.0 (14.9) 29.0 (21.6) .21

Pseudomonas aeruginosa 17.0 (12.7) 17.0 (12.7) 1.00

Proteus spp. 15.0 (11.2) 10.0 (7.5) .40

Enterobacter spp. 15.0 (11.2) 9.0 (6.7) .29

Serratia spp. 9.0 (6.7) 3.0 (2.2) .14

Citrobacter spp. 3.0 (2.2) 3.0 (2.2) 1.00

Morganella spp. 0.0 (0.0) 2.0 (1.5) .50

Source of bacteremia, n (%)

Central line 21.0 (15.7) 8.0 (6.0) .02

Study drug, n (%)

Cefepime 79.0 (59.0) 79.0 (59.0) 1.00

Piperacillin-tazobactam 34.0 (25.4) 34.0 (25.4) 1.00

Meropenem 21.0 (15.7) 21.0 (15.7) 1.00

Daily dose, gram, median (IQR)b

Cefepime 6.0 (6.0) 6.0 (6.0) 1.00

Piperacillin-tazobactam 18.0 (14.6-18.0) 18.0 (18.0) .39

Meropenem 4.0 (4.0) 4.0 (4.0) 1.00

Cefepime 9.4 (2.4-16.6) 14.5 (2.3-20.3) .10

Piperacillin-tazobactam 8.8 (3.8-18.8) 3.2 (1.1-14.6) .08