Cost-effectiveness of ceftolozane/tazobactam plus metronidazole versus piperacillin/tazobactam as initial empiric therapy for the treatment of complicated intra-abdominal infections based on pathogen distributions drawn from national surveillance data in the United States
Prabhu et al. Antimicrobial Resistance and Infection Control
Cost-effectiveness of ceftolozane/ tazobactam plus metronidazole versus piperacillin/tazobactam as initial empiric therapy for the treatment of complicated intra-abdominal infections based on pathogen distributions drawn from national surveillance data in the United States
Vimalanand S. Prabhu 0 1
Joseph S. Solomkin 3
Goran Medic 2
Jason Foo 2
Rebekah H. Borse 0
Teresa Kauf 6
Benjamin Miller 5
Shuvayu S. Sen 0
Anirban Basu 4
0 Merck & Co., Inc. , Kenilworth, NJ , USA
1 Center for Observational and Real World Evidence (CORE), Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, NJ 07033 , USA
2 Mapi Group , Houten , The Netherlands
3 University of Cincinnati College of Medicine , Cincinnati, OH , USA
4 Pharmaceutical Outcomes Research and Policy Program, University of Washington , Seattle, WA , USA
5 Shire , Lexington, MA , USA
6 Baxalta US Inc. , Boston, MA , USA
Background: The prevalence of antimicrobial resistance among gram-negative pathogens in complicated intra-abdominal infections (cIAIs) has increased. In the absence of timely information on the infecting pathogens and their susceptibilities, local or regional epidemiology may guide initial empirical therapy and reduce treatment failure, length of stay and mortality. The objective of this study was to assess the cost-effectiveness of ceftolozane/tazobactam + metronidazole compared with piperacillin/tazobactam in the treatment of hospitalized US patients with cIAI at risk of infection with resistant pathogens. Methods: We used a decision-analytic Monte Carlo simulation model to compare the costs and quality-adjusted life years (QALYs) of persons infected with nosocomial gram-negative cIAI treated empirically with either ceftolozane/ tazobactam + metronidazole or piperacillin/tazobactam. Pathogen isolates were randomly drawn from the Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS) database, a surveillance database of non-duplicate bacterial isolates collected from patients with cIAIs in medical centers in the USA from 2011 to 2013. Susceptibility to initial therapy was based on the measured susceptibilities reported in the PACTS database determined using standard broth micro-dilution methods as described by the Clinical and Laboratory Standards Institute (CLSI). Results: Our model results, with baseline resistance levels from the PACTS database, indicated that ceftolozane/ tazobactam + metronidazole dominated piperacillin/tazobactam, with lower costs ($44,226/patient vs. $44,811/patient respectively) and higher QALYs (12.85/patient vs. 12.70/patient, respectively). Ceftolozane/tazobactam + metronidazole remained the dominant choice in one-way and probabilistic sensitivity analyses. (Continued on next page)
(Continued from previous page)
Conclusions: Based on surveillance data, ceftolozane/tazobactam is more likely to be an appropriate empiric therapy for
cIAI in the US. Results from a decision-analytic simulation model indicate that use of ceftolozane/
tazobactam + metronidazole would result in cost savings and improves QALYs, compared with piperacillin/tazobactam.
Intra-abdominal infections (IAIs) represent a wide variety
of pathological conditions caused by inflammation or
perforation of the intra-abdominal organs. In the latter case,
complicated IAIs (cIAIs) arise causing localized or diffuse
]. Gram-negative pathogens, including
resistant pathogens are responsible for over 70% of cIAIs [
Patients at a higher risk of treatment failure due to a
resistant infection include those with health care-associated
infection or prior antibiotic exposure [
]. Studies have
shown that ‘high-risk’ patients are more likely to
experience a delay in the receipt of appropriate therapy,
increased length of hospital stay, more frequent intensive
care unit (ICU) admission, increased cost of care
(including antibiotic costs) and increased mortality [
Treatment guidelines recommend initiation of antibiotic
therapy as soon as a patient is diagnosed or suspected of
an intra-abdominal infection [
]. Since culture and
susceptibility results are not available at diagnosis, empiric
antibiotic therapy is often considered. If the initial empiric
therapy chosen has in vitro activity against the pathogen
isolated it is termed initial appropriate antibiotic therapy
(IAAT), whereas one without in vitro activity is termed
initial inappropriate empiric therapy (IIAT).
Important considerations for choosing empiric therapy
include consideration of the most likely pathogens at the
site of infection, knowledge of any prior colonization,
and finally, local resistance epidemiology [
Surgical Infection Society and Infectious Diseases Society of
America (IDSA) joint guidelines for treatment of cIAI
suggest routine culture and susceptibility studies if there
is significant resistance (10–20% of isolates) of a
common isolate to an antimicrobial regimen in widespread
local use . Improving the chances of IAAT is likely to
improve clinical outcomes and impart economic
benefits. A US study with cIAI patients identified the
additional length of stay (LOS) for IIAT relative to IAAT as
4.6 days (11.6 days vs. 6.9 days total), with additional
hospital costs per patient of $6368 ($16,520 vs. $10,152)
and substantial excess mortality (9.5% vs. 1.3%) [
Given the acute nature of cIAI and the substantial clinical
and economic benefits associated with IAAT, the
antibacterial spectrum of the empiric antibiotic agent considered
should cover the most relevant pathogens to increase the
likelihood of IAAT. The economic benefits that could be
obtained because of improved susceptibility and increased
coverage of IAAT is an important consideration.
A case in point is the comparison of
piperacillin/tazobactam and ceftolozane/tazobactam + metronidazole.
Piperacillin/tazobactam is recommended for empiric therapy for
the treatment of cIAI in various treatment guidelines [
]. Ceftolozane/tazobactam is a novel
cephalosporin/β-lactamase inhibitor combination with activity against
multidrug resistant gram-negative pathogens, including
Enterobacteriaceae and drug-resistant P. aeruginosa . Metronidazole is
an oral synthetic antiprotozoal and antibacterial agent
which may be used for initial empiric treatment of
complicated intra-abdominal infections alongside other agents
including ceftolozane/tazobactam. In this study, we assess
the cost-effectiveness of ceftolozane/tazobactam +
metronidazole compared with piperacillin/tazobactam
(considered standard of care) as empiric therapy in the treatment
of hospitalized US patients with cIAI.
We developed a decision-analytic microsimulation model
to estimate the quality-adjusted life expectancy and cost
of patients admitted to an inpatient facility, diagnosed
with cIAI, and administered empiric antibiotic therapy. A
graphical representation of the model structure with all
treatment pathways is provided in Fig. 1. The
methodology and model structure is similar to the one used to
assess the cost-effectiveness of ceftolozane/tazobactam in
complicated urinary tract infections [
Patients enter the microsimulation model at the time of
cIAI diagnosis, which is assumed to be concurrent with
initiation of empiric antimicrobial therapy. Each patient in
the model receives empiric antibiotic treatment with
ceftolozane/tazobactam + metronidazole in one arm and
piperacillin/tazobactam in another. A specimen is isolated
for culture after diagnosis to determine the pathogen and
its in-vitro susceptibility to different antibiotic therapies.
Pathogen distribution and in-vitro susceptibility was
based on that of a US isolate randomly selected from the
Program to Assess Ceftolozane/Tazobactam
Susceptibility (PACTS) surveillance dataset, an international
antimicrobial surveillance database. Each
intraabdominal pathogen from the PACTS database
represents a single patient in the micro-simulation. The types
of pathogens can be chosen within the model to allow
analyses to be tailored to the underlying pathogens for
specific indications. Further details regarding PACTS are
provided in Additional file 1.
Treatment pathway and disease progression are
estimated using a decision-tree shown in Fig. 1, after the
patient is selected. Patients continue empiric treatment
until culture results are available. Once culture results
are known, patients are switched to the least expensive
therapy to which the causative pathogen is susceptible. If
the pathogen is not susceptible to any of the modeled
comparators, patients are switched to salvage therapy
(combination of meropenem and colistin).
The appropriateness of initial antibiotic therapy
influences each patient’s length of hospital stay and treatment
outcome. Mortality in the model is dependent upon
whether the patient experiences IAAT or IIAT (higher
mortality rate applied for patients experiencing IIAT).
For patients who survive, we assume that they live a
normal length of life based on their life expectancy, and
incur health care expenditure comparable to those of
the average person their age [
Patients with gram-positive pathogens exit the model
because they may not be treated by either comparator
drugs. We assume that patients incur similar outcomes
and costs on either arms if they are gram-positive and
therefore economic incremental impact on ceftolozane/
tazobactam arm is likely to be negligible.
The model allows us to compute undiscounted and
discounted costs and QALYs for each arm, the
incremental costs, incremental QALYs and the incremental
Susceptibility: Customizing PACTS database to represent cIAI patients
The in-vitro surveillance data from the PACTS database
represents the only source of patient-level, real-world
data reflecting IAI patients at risk of resistant infection
in the US, includes isolate susceptibility to ceftolozane/
tazobactam. Isolates obtained from US sites from 2011
to 2013 were included in this analysis. The following
organisms were included in line with the approved label
for ceftolozane/tazobactam and encompass the major
pathogens involved in cIAIs: [
] Enterobacter cloacae,
Escherichia coli, Klebsiella oxytoca, Klebsiella
pneumoniae, Proteus mirabilis and Pseudomonas aeruginosa.
One limitation of the PACTS database is that it does
not differentiate between complicated and uncomplicated
IAI. In order to overcome this limitation, isolates in the
PACTS database were sampled in proportion to the
pathogen distribution for cIAI in a real-world setting
found in the Premier hospital discharge database, [
complete census of inpatients and hospital-based
outpatients from geographically diverse hospitals in the US.
More information regarding Premier database is provided
in Additional file 1. An algorithm based on a set of ICD-9
diagnosis codes and current procedural terminology
(CPT) procedure codes was used to identify cIAI patients
from the Premier database between January 1, 2009 and
March 31, 2013. The cIAI cohort consisted of 10,159
abdominal isolates, the mean age was 55 ± 22 years (median
age: 59 years), and most patients with positive cultures
were above 50 years. The resulting pathogen distribution
used in the model was 26.6% for Escherichia coli, 16.0%
for Klebsiella pneumonia, 13.5% for Pseudomonas
aeruginosa, and 9.0% for Enterobacter cloacae. The
gramnegative pathogens that occurred in less than 5% of
patients were grouped together and made up the remaining
5.8%. The percentage of patients with gram-positive
pathogens in the cohort was 29.1% [
The susceptibility is evaluated using Clinical and Laboratory
Standards Institute (CLSI) breakpoints. A breakpoint of
2 mg/L was used for Enterobacteriaceae and a susceptibility
breakpoint of 4 mg/L was used for Pseudomonas spp. [
Drugs used for the model
The empiric treatments used in the model are ceftolozane/
tazobactam + metronidazole for one arm and piperacillin/
tazobactam for another, which are consistent with the
approved therapies and international cIAI treatment guidelines
]. The following additional drugs were considered for
switching upon pathogen confirmation: aztreonam, cefepime,
ceftazidime, ceftriaxone, ciprofloxacin, doripenem,
imipenem, levofloxacin, meropenem and tigecycline.
The key clinical inputs are summarized in Table 1.
Mortality rates and length of stay were based on Edelsberg et
al., where patients who received IIAT spent 4.6 more days
in the hospital (11.6 vs. 6.9 total days) [
]. Duration of
empiric therapy was assumed to be 3 days. US life-tables
were used for the prediction of life expectancy [
percentage of cIAI patients requiring re-intervention has
been reported at approximately 8–9% [
]. While most
published studies examining the impact of IIAT on
treatment outcomes in cIAI did not report re-intervention
rates, there is evidence from at least one study that IIAT
may increase the risk of re-intervention (relative risk ratio,
5.1; 95% CI, 1.7–15.4) . As the Krobot et al. study [
was relatively small and conducted over a decade ago, the
analysis conservatively assumed that there was no
differential impact of IIAT on re-intervention. Similarly, any
costs associated with re-intervention, such as imaging,
were excluded from the model since those costs did not
vary by empiric treatment option.
An assumed utility value of 0.85 was applied to cured
patients for the remainder of their lives (Table 1). This
was a conservative estimate based on a utility value of
0.9 proposed by Jansen et al. [
]. QALYs were
discounted at a rate of 3% per annum [
Hospitalization costs per day (Table 1) were derived
from the 2013 Healthcare Cost and Utilization Project
] and inflated to 2015 values using the Gross
Domestic Product (GDP) price index [
Hospitalization costs were based on primary diagnoses
for cIAI (ICD-9 code 540.0, 540.1, 567.0, 567.21, 567.22,
567.23, 567.29, 567.31, 567.89, 567.9, and 569.5) [
The average cost per hospital day for cIAI patients,
inflated to 2015 values, was $2558.55.
Daily drug costs (Table 1) were calculated for the
duration of hospitalization based on wholesale acquisition
cost at labeled doses [
For healthy survivors, lifetime health care expenditure
was calculated using average annual age-adjusted values
] inflated to 2015 values using the Gross Domestic
Product (GDP) price index (Table 1) [
Hospitalization and daily drug costs were not discounted
as all costs were incurred within the first year, given the acute
nature of cIAI. A discount rate of 3% per annum was applied
to lifetime health care expenditure for health survivors.
A lifetime time horizon was applied to capture the costs and
utility of healthy survivors over their lifetime. The model
compared ceftolozane/tazobactam + metronidazole with
piperacillin/tazobactam from the healthcare perspective.
To compare the two treatment strategies the following
outcomes were estimated from the model: proportion of
patients appropriately and inappropriately treated
(sensitive/resistant to empiric therapy, cost per QALY saved,
drug costs, hospitalization costs, proportion of cases by
pathogen, total costs, total QALYs). Differences in these
Edelsberg et al. [
Edelsberg et al. [
Edelsberg et al. [
Edelsberg et al. [
on Jansen et al. [
aSalvage therapy consists of meropenem + colistin for cost purposes
LOS Length of stay, IAAT Initial appropriate antibiotic therapy, IIAT Initial inappropriate antibiotic therapy
outcomes of interest were estimated, along with the
incremental cost-effectiveness ratio (ICER) based on
total cost per QALY gained.
One-way sensitivity analyses (OWSA) and probabilistic
sensitivity analysis (PSA) were performed to quantify the
uncertainty in the model outcomes based on the
uncertainty of the input parameters. The model assessed the
sensitivity of the model results to all the input data for
which uncertainty has been defined one parameter at a
time by means of OWSA. The parameters with the
greatest impact were summarized with tornado diagrams.
Ten thousand samples were taken to estimate ranges for
the PSA. Input parameter values were sampled from the
defined distributions for efficacy, safety, and costs.
Lognormal distributions were used for odds ratios, beta
distributions for utilities, and for gamma distributions for
resource use and costs.
For each treatment strategy, the probability of
costeffectiveness was expressed with cost-effectiveness
acceptability curves, calculated as the number of iterations out of
the total number of iterations for which the net monetary
benefit (NMB) was greatest for a given treatment strategy
out of all strategies.
The NMB was calculated as the QALYs multiplied by
a willingness to pay (WTP) ratio minus the costs, where
the WTP is the amount decision makers were willing to
pay per additional QALY gained. An amount of US
$100,000 was used as a WTP threshold [
Risk factors associated with infection due to resistant
pathogens (vs. susceptible pathogens) have been
identified in the literature [
]. Information regarding a
portion of these risk factors for cIAI was available for
patients in the PACTS dataset, including (a) nosocomial
infection, (b) age ≥ 65 years, and (c) ICU stay.
Scenario analyses were performed firstly using all
available isolates for high risk patients aged ≥65 years
and requiring an ICU stay, and secondly using only
nosocomial isolates for high risk patients aged ≥65 years
and requiring an ICU stay.
An additional scenario was also performed excluding
lifetime health care expenditure for healthy survivors.
Base case results
In the cohort of 1000 patients, the average age was
67.1 years ranging from 21 to 100 years.
The key results from the model are summarized in
Table 2. Under the base case scenario,
ceftolozane/tazobactam + metronidazole arm resulted in lower total costs than
the piperacillin/tazobactam arm ($44,226 per patient vs.
$44,811). The ceftolozane/tazobactam + metronidazole
arm also experienced a greater number of QALYs
than the piperacillin/tazobactam arm (12.85 per
patient vs. 12.70 per patient). This resulted in
ceftolozane/tazobactam + metronidazole dominating
piperacillin/tazobactam with 0.63 hospitalization days
saved per patient.
In patients with a gram-negative infection receiving
ceftolozane/tazobactam + metronidazole as empiric
therapy, 6.1% were resistant compared with 19.7% in
patients receiving piperacillin/tazobactam. Since 29.1% of
pathogens were gram-positive, overall, 35.2% were not
susceptible to ceftolozane/tazobactam + metronidazole
compared with 48.8% for piperacillin/tazobactam. There
were 41.8 deaths (4.2%) in the
ceftolozane/tazobactam + metronidazole arm compared with 53.0 (5.3%) in
the piperacillin/tazobactam arm. Amongst those who
died, a larger proportion was resistant to initial therapy
in the piperacillin/tazobactam arm than the ceftolozane/
tazobactam + metronidazole arm.
Ceftolozane/tazobactam + metronidazole reduced overall mortality by 1.1%
When examining the QALY results in more detail, the
ceftolozane/tazobactam + metronidazole arm generated
0.15 more QALYs (discounted) per patient. The average
number of QALYs (discounted) experienced by patients in
the ceftolozane/tazobactam + metronidazole arm were
12.85 and 12.70 for ceftolozane/tazobactam +
metronidazole and piperacillin/tazobactam, respectively.
Lifetime health care expenditure was the largest
contributor to total costs in both treatment arms
followed by hospital costs. The average lifetime health
care expenditure per patient in the
ceftolozane/tazobactam + metronidazole arm was higher than in the
piperacillin/tazobactam arm ($27,940 vs. $27,546). The average
hospital cost per patient in the
ceftolozane/tazobactam + metronidazole arm was lower than in the
piperacillin/tazobactam arm ($15,468 vs. $17,069, respectively).
+ metronidazole - Piperacillin/tazobactam
QALY Quality Adjusted Life Year, IAAT Initial appropriate antibiotic therapy, IIAT Initial inappropriate antibiotic therapy
Per-patient drug costs in the
ceftolozane/tazobactam + metronidazole arm were slightly higher than in
the piperacillin/tazobactam arm ($818 vs. $196,
All of the patients in the
ceftolozane/tazobactam + metronidazole arm who received IAAT were able
to switch to a less expensive therapy after 3 days
(following culture results). For 1.0% of patients in the
piperacillin/tazobactam arm who received IAAT, empiric therapy
with piperacillin/tazobactam was the least expensive
treatment option. In patients who received IIAT, an
equal number of patients in each arm (n = 19, 1.9%)
required salvage therapy with meropenem + colistin.
One-way sensitivity analysis
The results of the one-way sensitivity analysis are
presented in a tornado graph (Fig. 2). Varying the
average cost per hospital day resulted in the largest
impact on the resultant ICER. The other input
parameters which impacted the model results when
varied were: resistance to piperacillin/tazobactam,
resistance to ceftolozane/tazobactam, mortality rate with
IIAT, the utility value applied to survivors, and the
mortality rate with IAAT. Varying the additional
length of stay associated with IIAT had very little
impact on the ICER. In all instances,
ceftolozane/tazobactam + metronidazole remained the dominant
option versus piperacillin/tazobactam.
Probabilistic sensitivity analysis
The distribution of ICER estimates from the PSA show
that in all instances, ceftolozane/tazobactam +
metronidazole is more effective and less costly than piperacillin/
Subsequently, ceftolozane/tazobactam has a 100%
probability of being cost-effective compared with
piperacillin/tazobactam at a willingness-to-pay threshold
of $100,000/QALY gained.
Seventy-four percent of patients from the US PACTS
dataset were aged ≥65 years and 4% of patients required an
ICU stay. Thirty-eight percent of patients had isolates from
nosocomial sources. Amongst these patients, 37% were
aged ≥65 years and 5% of patients required an ICU stay.
Patients could be associated with more than one risk factor.
Results of the scenario analyses are presented in
Table 3. Overall, the cost-effectiveness of ceftolozane/
tazobactam + metronidazole improves versus
piperacillin/tazobactam in high risk patients (≥65 years and
requiring an ICU stay) and high risk patients with
nosocomial infections. Differences in costs and the
number of hospitalization days are larger in both of the
subgroups explored, with a larger difference in total QALYs
(discounted) seen in the high risk patients with
In the scenario where lifetime health care expenditure
was excluded, the total costs per patient were
considerably lower and the incremental cost between
ceftolozane/tazobactam + metronidazole and piperacillin/
tazobactam was larger. Ceftolozane/tazobactam +
metronidazole remained the dominant choice.
The objective of this analysis was to evaluate the use of
ceftolozane/tazobactam + metronidazole compared with
piperacillin/tazobactam in the empiric treatment of US
patients with cIAI at risk of infection due to a resistant
gram-negative pathogen. The ability of either
ceftolozane/tazobactam + metronidazole or
piperacillin/tazobactam to provide appropriate empiric coverage is an
important concept in the model and the source of
economic differentiation between the two therapies.
Ceftolozane/tazobactam + metronidazole provides a greater
degree of appropriate empiric coverage than piperacillin/
tazobactam, as demonstrated by the PACTS data.
We have presented a novel approach utilizing
surveillance data to evaluate the cost-effectiveness of two
empiric therapy options. A similar approach to ours was
used in the study by Sader et al., where they used the
SENTRY Antimicrobial Surveillance Program, a large
multinational data source on pathogen prevalence and
antimicrobial susceptibility, to estimate the effectiveness
of tigecycline in complicated skin and skin structure
]. Although this study only considered
effectiveness and not costs.
The findings of our analysis suggest that the use of
ceftolozane/tazobactam + metronidazole as initial
(empiric) treatment may result in substantial cost-savings
compared to piperacillin/tazobactam. Additionally, use
of ceftolozane/tazobactam + metronidazole may save an
average of 0.63 hospital days per patient.
IIAT is a key driver to the model and contributes to the
differentiation between ceftolozane/tazobactam +
metronidazole and piperacillin/tazobactam. The impact of IIAT
is further emphasized in our two high risk scenarios. In
both scenarios, susceptibility rates to
ceftolozane/tazobactam + metronidazole remain largely unchanged, however,
susceptibility rates to piperacillin/tazobactam are lower
compared to the base case.
Cost savings are a function of several model parameters
including duration of empiric therapy, susceptibility among
comparators, and the increase in length of stay due to IIAT.
Furthermore, differences in costs derive solely from
differences in antimicrobial activity between ceftolozane/
tazobactam + metronidazole and piperacillin/tazobactam.
The inclusion of lifetime health care expenditures in
our base case analysis reduced the incremental costs by
approximately 50%. For our analysis,
ceftolozane/tazobactam + metronidazole remained the dominant option,
however, inclusion of lifetime healthcare expenditure
may have a potential impact on comparisons which are
borderline cost-effective or cost-saving.
We have shown how data from national surveillance
data set can be used to guide the choice of cost-effective
empirical therapy. Clinical trials are often conducted in
a variety of different geographic locations/settings and
the patients enrolled may not necessarily reflect the
specific populations who will receive these treatments in
real life. In practice, patient outcomes can be improved
through improvements in the collection of local
surveillance data and the use of local antibiograms in decision
making and guideline development.
An important limitation is that the model does not
account for further treatment changes after any initial
de-escalation/escalation, with patients assumed to be
fully cured or dead at the end of hospitalization.
Additionally, recurrence and/or re-admission were not
incorporated in this model. For readmission rates, we
assumed that these were the same for patients with IAAT
and IIAT, and subsequently did not have any economic
impact. If patients with IIAT have a higher rate of
readmission, the subsequent analysis would further
improve results favoring the ceftolozane/tazobactam arm.
The model assumes that the duration of therapy,
whilst shorter for IAAT compared with IIAT, is not
directly impacted by the different drugs used following
culture results. In practice, some treatments may shorten/
prolong hospital length of stay.
The PACTS dataset was not designed to focus on resistant
or complicated IAI. Therefore it did not contain enough
information to specifically target complicated IAI (vs.
uncomplicated IAI) patients and may under-represent pathogen
resistance in the target population of cIAI. We attempted to
overcome this limitation by sampling isolates in the PACTS
database in proportion to the pathogen distribution for cIAI
in a real-world setting found in the Premier hospital
discharge database. PACTS is the only source of patient level,
real-world data reflecting IAI patients at risk of resistant
infection in the US that includes isolate susceptibility to
ceftolozane/tazobactam. Our sample had 294 isolates from patients
with IAIs. To conduct an analysis representative of local
settings, more data at a local level may be needed. Also, within
the PACTS database, only one isolate per patient infection
was included in the surveillance whereas in clinical practice
you are likely to encounter more than one isolate per patient.
Additional limitations are the exclusion from the model
of bacterial resistance over time and costs of antibiotic
preparation and administration, monitoring, and adverse
events. These costs were assumed to be similar across
treatments and/or minor. Similarly, dose adjustments were not
The model only considers gram-negative aerobes, when in
practice, gram-positive aerobes and anaerobes (both
grampositive and gram-negative) are frequently implicated. The
proportion of patients with gram-positive infections in our
cohort was based on the distribution of gram-positive
bacteria identified from intraoperative samples reported by
Sartelli et al. [
]. This figure may not be entirely accurate due
to the fact that patients can harbor more than one type of
bacteria, affecting that actual distribution of gram-positive
bacteria amongst patients.
Economic models utilizing surveillance data can help to
identify the appropriate choice of empiric therapy for the
treatment of cIAI. The results of this cost-effectiveness model
indicate that cost-savings and improvements in QALYs may
be achieved by the empiric use of
ceftolozane/tazobactam + metronidazole instead of piperacillin/tazobactam in
US cIAI patients at risk of resistant infection.
Additional file 1: Susceptibility inputs - Program to Assess Ceftolozane/
Tazobactam Susceptibility (PACTS) dataset. (DOCX 25 kb)
cIAI: complicated intra-abdominal infection; CLSI: Clinical and Laboratory
Standards Institute; CPT: Current procedural terminology; GDP: Gross
Domestic Product; HCUP: Healthcare Cost and Utilization Project; IAAT: Initial
appropriate antibiotic therapy; ICD-9: International Classification of Diseases,
Ninth Edition; ICER: Incremental cost-effectivness ratio; ICU: Intensive care
unit; IDSA: Infectious Diseases Society of America; IIAT: Initial inappropriate
antibiotic therapy; LOS: Length of stay; NMB: Net monetary benefit;
PACTS: Program to Assess Ceftolozane/Tazobactam Susceptibility;
QALYs: Quality-adjusted life years; US: United States; WTP: Willingness to pay
Dimitris Kabranis was involved in the development of the original model.
Availability of data and materials
The datasets used and/or analysed during the current study available from
the corresponding author on reasonable request.
VP, JS, GM, RB, TK, BM, SS and AB were involved in the conception and design. VP,
GM, JF, RB, TK, BM and SS were involved in data collection. VP, JS, GM, JF, TK, BM,
SS and AB were involved in data interpretation. VP, JF and TK were involved in
writing the manuscript. All authors read and approved the final manuscript.
Financial support for this study was provided by Merck & Co., Inc. The
funding agreement ensured the authors’ independence in designing the
study, interpreting the data, writing, and publishing the report.
Ethics approval and consent to participate
Consent for publication
VP and SS report other conflicts of interest from Merck & Co., Inc., during the
conduct of the study. JS reports personal fees from Merck & Co., Inc., outside
the submitted work. GM has nothing to disclose. JF reports personal fees
from Merck & Co., Inc., during the conduct of the study. RB reports that she
is an employee of Merck & Co., Inc., and holds stocks in Merck & Co. Inc.,
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