Using an economic model, the authors analyzed the cost-effectiveness of ceftolozane/tazobactam versus piperacillin/tazobactam for the treatment of complicated intra-abdominal infections based on differences in antibiotic resistance. The model found that ceftolozane/tazobactam became cost-effective when resistance to piperacillin/tazobactam was 2% or higher and cost-saving when resistance was 4% or higher. Sensitivity analyses showed the results were sensitive to factors like length of stay, mortality rates, resistance levels, and hospital costs. The authors conclude economic models can help identify optimal initial antibiotic therapy based on local resistance data.

1. Using An Economic Model to
Choose Initial Appropriate Antibiotic
Therapy Based on Differences in
In-vitro Susceptibility to
Ceftolozane/Tazobactam and
Piperacillin/Tazobactam
Vimalanand S. Prabhu, BE, MMgmt, PhD1;
Shuvayu S. Sen, PhD1; Benjamin W. Miller, PharmD1;
Anirban Basu, PhD2; Goran Medic, MSc. Pharm3
1Merck & Co., Inc., Kenilworth, NJ, USA, 2Pharmaceutical
Outcomes Research and Policy Program, Department of Pharmacy,
Departments of Health Services and Economics, University of
Washington, 3MAPI Group, Houten, Netherlands
188116-0001_prabhvim_ISPOR_poster_v1.08 11/06/2015
Meeting name, Output Size: 35” x 47” Scale: 200%
Table 1. Model inputs
Mean Low High Source
Drug costs
Ceftolozane/tazobactam $249.00 — —
Medi-Span database(10)
Piperacillin/tazobactam $39.00 — —
Hospital costs
Hospital cost per day
(average)
$2,698.70 $2,428.83 $2,968.57 Hospital cost per day
derived from 2012
HCUP based on primary
diagnosis of
cIAI.(11) Cost inflated to
2015 $ US using the
medical care component
of Consumer Price
Index.(12)
Re-operation costs
(average per patient)
$3,000.00 $2,700.00 $3,300.00
Mortality rates
Mortality rate with IAAT 0.0130 0.0117 0.0143 Edelsberg et al.(13)
Mortality rate with IIAT 0.0950 0.0855 0.1045 Edelsberg et al.(13)
Duration of therapy
Duration of initial therapy 3 days 1 day 4 days Assumption
Total LOS for IAAT
(including initial therapy)
6.9 days 6.8 days 7.0 days
Edelsberg et al.(13)
Additional LOS associated
with IIAT
4.6 days 4.5 days 4.7 days
Edelsberg et al.(13)
Quality of life
Health utility for survivors 0.83 0.62 1.00 Herrero et al.(14)
Re-operations
Percentage of appropriately
treated patients who require
re-operation
8% — —
Sartelli et al.(15)
Percentage of
inappropriately treated
patients who require
re-operation
8% — —
Sartelli et al.(15)
LOS – Length of stay; IAAT – Initial appropriate antibiotic therapy; IIAT – Initial inappropriate antibiotic therapy.
Table 2. Threshold analysis for differences in resistance to
ceftolozane/tazobactam compared with that for piperacillin/
tazobactam
Resistance modeled in the Piperacillin/tazobactam arm†
0%
resistance
(Baseline)
1%
resistance
(Scenario 2)
2%
resistance
(Scenario 3)
3%
resistance
(Scenario 4)
4%
resistance
(Scenario 5)
5%
resistance
(Scenario 6)
Difference in
susceptibility to
initial therapy
(P/T – C/T
resistance)‡
0.0% 0.8% 1.6% 2.3% 3.1% 3.8%
Difference -
total costs
(C/T – P/T)
$6,083,000 $4,309,551 $2,708,162 $732,011 -$778,337 -$2,758,821
Difference in
total discounted
QALYs
(C/T – P/T)
0.00 78.24 146.22 219.17 289.11 356.46
ICER (Cost per
discounted QALY
saved) (C/T –
P/T)
N/A $55,080 $18,521 $3,340 Cost-
saving
Cost-
saving
Hospitalization
days saved
(C/T – P/T)
0 714 1,333 1,996 2,632 3,243
Deaths avoided
(patients)
(C/T – P/T)
0.0 6.8 12.7 19.0 25.1 30.9
†Resistance modeled in ceftolozane/tazobactam arm is 0%. ‡The resultant difference in susceptibility can be slight
different than the resistance modeled in the P/T arm as the isolates are randomly selected. C/T - ceftolozane/
tazobactam. P/T - piperacillin/tazobactam.
Figure 1. Cost-effectiveness plane ceftolozane/tazobactam vs
piperacillin/tazobactam for 2% difference in modeled resistance
(Scenario 3; Table 1) to all pathogen
$0
$200
$400
$600
Cost-Effectiveness Plane
Ceftolozane/tazobactam versus Piperacillin/tazobactam
X-axis: Additional QALYs saved per patient.
Y-axis: Cost of saved QALYs per patient.
$1,000
-$400
$800
-$200
-0.06 -0.04 -0.02 0.04 0.06 0.08-0.08 0.020.00
Objectives
Gram-negative pathogens are a major cause of hospital-
treated infections and account for 38% of healthcare
associated infections in the US(1-3). An increase in prevalence
of antimicrobial resistance among gram-negative pathogens in
complicated intra-abdominal infections (cIAI) has been noted
recently(4). The yearly cost of antimicrobial -resistant infections
to the US health care system is estimated at between $21 and
$34 billion dollars, accompanied by more than 8 million additional
days in hospital(5).
An increase in the proportion of patients on initial appropriate
antibiotic therapy (IAAT) to treat cIAI is associated with
reduced length of stay (LOS) and mortality compared with initial
inappropriate therapy. New therapies such as ceftolozane/
tazobactam (C/T) have been shown to have a better gram-
negative activity compared to drugs currently used for empiric
therapy for cIAI such as piperacillin/tazobactam (P/T) and are
more likely to succeed as IAAT. (For example, susceptibility to
Escherichia coli was 98.9% for C/T and 96.0% for P/T, and for
Pseudomonas aeruginosa was 96.4% for C/T and 78.5% for P/T
in US hospitals in 2013(6,7)). The economic benefits associated
with new therapies to treat cIAI would depend on the resistance
patterns prevalent in a given hospital. Identifying the resistance
thresholds at which new therapies become cost-effective or cost-
saving can simplify decision-making for hospitals. Once these
thresholds are identified, hospital-specific local antibiograms
could help us identify empiric therapies that make both clinical
and economic sense.
The objective of this research is to utilize an economic model to
establish threshold differences in antibiotic resistance at which
C/T + metronidazole is cost-effective/cost-saving compared with
P/T for the treatment of cIAI.
Methods
We used a decision analytic Monte Carlo patient-level simulation
model to compare costs and QALYs of patients infected
with Gram-negative cIAI and treated empirically with either
C/T+metronidazole or P/T. Each patient with cIAI was randomly
drawn from the Program to Assess Ceftolozane/Tazobactam
Susceptibility (PACTS) database (8), a surveillance database
of non-duplicate bacterial isolates collected from patients
in medical centers in the USA from 2011-2013 infected with
gram-negative pathogens. The database records the minimum
inhibitory concentration (MIC) values of various drugs using
standard broth micro-dilution methods as described by the
Clinical and Laboratory Standards Institute (CLSI)(9). In the
model, susceptibility to empiric therapy is based on the measured
susceptibilities reported in the PACTS.
For simplicity, we restricted the analysis to the four most
commonly isolated gram-negative pathogens: Enterobacter
cloacae, Escherichia coli, Klebsiella pneumoniae, and
Pseudomonas aeruginosa. The distribution of isolates used in
this analysis matched the distribution of isolates in the PACTS
database: Enterobacter cloacae (15%), Escherichia coli (41%),
Klebsiella pneumonia (24%), and Pseudomonas aeruginosa
(20%).
To conduct threshold analysis, we assumed baseline resistance
for both arms for all the bacteria to be equal to zero, and then
gradually increased baseline resistance for all the four pathogens
in the P/T arm in increments of 1%. Threshold differences in
resistance between P/T and C/T at which C/T became either
cost-effective or cost-saving were estimated. After the initial
treatment (post-culture), the cheapest susceptible drug was
chosen until the end of treatment.
We adopted a lifetime horizon to evaluate cost-effectiveness.
A hospital perspective was adopted to evaluate costs. Input
parameters for the model are presented in Table 1. A sensitivity
analysis was performed to evaluate the impact of input
parameters on model outcomes. The analysis was based on a
cohort of 10,000 patients with gram-negative infections.
Results
For the baseline scenario, when resistance levels for both P/T
and C/T were assumed to be equal, C/T was dominated by P/T.
As the resistance for P/T was increased, the hospital days saved
in the C/T arm increased gradually, and C/T was cost-effective
at 2% or more, and eventually cost-saving at 4% or more
(Table 2).
Probabilistic sensitivity analyses were performed on the cost-
effective case and cost-effectiveness plane is shown on
Figure 1.
One-way sensitivity analysis showed that the following factors
have impact on the baseline results: total length of stay for
IIAT, duration of initial therapy, total length of stay for IAAT,
health utility for survivors, resistance to drugs (both C/T and
P/T) mortality rates for IIAT and IAAT and hospital cost per day
(Figure 2 and Figure 3). In addition to the above mentioned
factors, results were also sensitive to changes in the pathogen
distribution.
Conclusions
Economic models can be used to identify IAAT based on in-
vitro resistance data. Ceftolozane/tazobactam is likely to be
cost-effective even when small differences exist in antibiotic
resistance between ceftolozane/tazobactam and piperacillin/
tazobactam, because of savings in hospitalization costs and
mortality reduction. Once threshold differences in antibiotic
resistance that make a comparator drug cost-effective or
cost-saving are established, local antibiograms can be used
to identify optimal IAAT.
Figure 2. One-way sensitivity analysis of factors
influencing difference in total costs for 2% difference in
modeled resistance (Scenario 3; Table 1)
-$2,000,000 $0 $2,000,000 $4,000,000 $6,000,000
Duration of empiric therapy
Total LoS for inappropriate
therapy
(incl. empiric therapy)
Hospital cost per day
(average)
Total LoS for appropriate
therapy
(incl. empiric therapy)
Mortality rate with appropriate
empiric treatment
Mortality rate with
inappropriate
empiric antibiotic
Health utility for survivors
1 day; 4 days
Lower bound;
Upper bound
10 days; 17 days
$2,428.83; $2,968.57
6.8 days; 7.0 days
0.0117; 0.0143
0.0855; 0.1045
0.62; 1.00
Figure 3. One-way sensitivity analysis of factors
influencing ICER for 2% difference in modeled resistance
(Scenario 3; Table 1)
-$80,000 -$60,000 -$40,000 -$20,000 $0 $20,000 $40,000
Resistance to
Piperacillin/tazobactam
Duration of empiric therapy
Resistance to
Ceftolozane/tazobactam
Total LoS for inappropriate
therapy (incl. empiric therapy)
Health utility for survivors
Hospital cost per day (average)
Mortality rate with inappropriate
empiric antibiotic
Mortality rate with appropriate
empiric treatment
Total LoS for appropriate
therapy (incl. empiric therapy)
0.0%; 5.4%
1 day; 4 days
0.0%; 3.7%
10 days; 17 days
0.62; 1.00
$2,428.83; $2,968.57
0.0855; 0.1045
0.0117; 0.0143
6.8 days; 7.0 days
Lower bound;
Upper bound
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ISPOR 18th Annual
European Congress
7-11 November, 2015
MiCo - Milano Congressi
Milan, Italy
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