Hospital Pharmacy - February 2020 - 45

Tullos et al
limited by cost, procurement, timely susceptibility testing,
and minimal clinical experience for a variety of indications.3
Due to their broad spectrum of activity, reservation of these
agents for more resistant infections (e.g. carbapenem-resistant Enterobacteriaceae) is recommended.
Although some ESBL isolates may be categorized as susceptible to beta-lactam/beta-lactamase inhibitors (BL/BLI)
such as piperacillin-tazobactam (PTZ) according to laboratory testing, evidence regarding their in vivo clinical efficacy
is controversial.3 While some studies have shown worse outcomes with PTZ therapy when compared to carbapenems for
treatment of documented ESBL infections,4,5 other studies
have indicated PTZ may be a viable alternative.6-9 A systematic review of carbapenem-sparing therapy against ESBL
bloodstream infections concluded that complete avoidance
of carbapenems cannot be justified and that consideration of
PTZ as an alternative treatment depends heavily on the
source of infection.10 It has been proposed that utilization of
PTZ for treatment of ESBL infections of mild to moderate
severity should be considered, with infections of a urinary
source being a primary area of discussion.3,10,11 Because of
the high proportion of ESBL infections that are of a urinary
source, evidence and guidelines for optimal treatment of
these infections is of the utmost importance to allow for the
preservation of carbapenems.
The purpose of this study is to determine the efficacy of
piperacillin-tazobactam compared with carbapenems for
treatment of nonbacteremic urinary tract infections (UTIs)
caused by ESBL-producing Enterobacteriaceae.

Methods
This was a multicenter, IRB-approved, retrospective cohort
study conducted at three medical centers associated with
one health system in the greater Middle Tennessee area.
The charts reviewed were identified through a microbiology lab report that recognized all inpatient encounters during the time period of January 1, 2014, to June 30, 2016,
that had positive urine cultures with ESBL-producing
Enterobacteriaceae. The researchers were located at one of
the medical centers and were able to access data from the
other medical centers within the same health system via use
of a shared electronic medical record (EMR). IRB approval
was obtained from the health system which covers research
conducted at all three medical centers included in the study.
To be included in the study, patients had to be 18 years of
age or older, admitted to one of three medical centers, have a
UTI due to ESBL-producing Enterobacteriaceae confirmed
by microbiology urine culture reports, and have received at
least 48 hours of treatment with either PTZ or a carbapenem.
Of note, UTI was confirmed by physician documentation
and decision to treat. If asymptomatic bacteriuria was documented by the physician, it was recorded. Formulary carbapenem agents at the medical centers included in the study
were meropenem and ertapenem. Patients were excluded

from the study if the ESBL-producing organism was resistant to the antimicrobial used for treatment or if bacteremia
was present. If a patient had multiple admissions during the
study period, only the first patient encounter that met study
criteria was included in the analysis. Cases were categorized
as one of two groups based on the definitive antimicrobial
therapy received: PTZ or carbapenem. Definitive antimicrobial therapy was defined as the antimicrobial therapy utilized
after organism and susceptibility information was reported.
A pharmacist-led renal dosing protocol was in place for both
PTZ and carbapenems at each of the medical centers included
in this study; dosing strategies were uniform across medical
centers and were reviewed daily. Of note, pharmacodynamic
dosing of PTZ and meropenem was implemented during the
study period at all three medical centers simultaneously and
remained under pharmacist-led dosing.
The primary outcome of the study was to determine the difference in clinical response between PTZ and carbapenems for
the treatment of nonbacteremic UTIs due to ESBL-producing
Enterobacteriaceae. Cases were deemed to have a clinical
response if all of the following criteria were absent: (1) repeat
admission for UTI caused by the same organism within
6 months of initial diagnosis, (2) repeat urine cultures within
6 months of initial diagnosis showed positive growth for the
same organism, or (3) a change in antimicrobial regimen
occurred due to subjective clinical failure as determined by the
ordering provider. Secondary outcomes included duration of
treatment, length of hospital stay, and inpatient mortality.
Minimum inhibitory concentration (MIC) data were collected as determined by Vitek2 on PTZ cases specifically as
the assumption was that MIC data for carbapenem cases
would be inconsequential.
The primary outcome of clinical response, which is a
nominal, dichotomous variable, was analyzed using a Chisquare test. Secondary outcomes and background characteristics were analyzed by appropriate statistical tests, with t
test being used for continuous variables and Chi-square tests
being used for nominal variables. Statistical analyses were
completed by the study authors utilizing JMP® Pro v11.2.0
(SAS Institute Inc., Cary, NC).

Results
A total of 679 patient encounters were screened (Figure 1).
Of these, 180 cases met study criteria. The most common
reasons for exclusion were definitive therapy of less than
48 hours, lack of treatment with PTZ or a carbapenem, or
concomitant bacteremia present. In addition, some patients
had multiple encounters within the study period and according to the study plan, only the first patient encounter meeting inclusion/exclusion criteria was accepted. Of the 180
patient encounters included in the final analysis, 39 received
definitive therapy with PTZ and 141 received definitive
therapy with a carbapenem (105 with meropenem and 36
with ertapenem).

Hospital Pharmacy - February 2020

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