This study used a cost-utility model to compare the cost-effectiveness of ceftolozane/tazobactam versus meropenem for empiric treatment of nosocomial pneumonia (NP) patients at risk of drug-resistant infections. The model structure considered mortality, length of stay, costs, and quality-adjusted life years based on appropriate or inappropriate initial empiric therapy. Based on pathogen susceptibility data, ceftolozane/tazobactam resulted in 17.6 fewer deaths, 573 fewer hospital days, and 0.06 more quality-adjusted life years compared to meropenem, with an incremental cost per quality-adjusted life year of $16,677, below the accepted cost-

1. Use of Surveillance Data to Examine the Cost-effectiveness of Alternative Approaches
to Empiric Antibiotic Therapy in Gram-negative Nosocomial Pneumonia
T. L. Kauf1
, G. Medic2
, M. Dryden3
, P. Xu1
, M. D. Zilberberg4,5
1
Cubist Pharmaceuticals, Lexington, MA, USA; 2
Mapi Group – HEOR & Strategic Market Access, Houten, The Netherlands; 3
Royal Hampshire County Hospital, Winchester, UK;
4
University of Massachusetts, Amherst, MA, USA; 5
EviMed Research Group, LLC, Goshen, MA, USA
Poster# 66385
Teresa Kauf
Merck and Co., Inc.
Kenilworth, NJ, USA
E-mail: teresalkauf@gmail.com
This study was funded by Merck and Co., Inc., Kenilworth, NJ, USA. Presented at ATS International Conference 2015 May 15-20, 2015, Denver, CO, USA
■ Although ceftolozane/tazobactam in comparison with meropenem was associated with
higher average patient costs, primarily due to increased drug costs, the incremental
cost of ceftolozane/tazobactam compared with meropenem was well below accepted
thresholds for cost-effectiveness.
■ If safety and efficacy are confirmed by clinical studies, this model suggests that ceftolozane/
tazobactam may be a cost-effective approach to empiric coverage of NP patients at risk for
multidrug-resistant infection.
CONCLUSIONS
INTRODUCTION
■ Nosocomial pneumonia (NP), comprising hospital-acquired pneumonia and
ventilator-associated pneumonia (VAP), is the most common hospital-acquired infection in
the United States.1
VAP is a substantial burden to the US healthcare system and is responsible
for more than half of all intensive care unit antibiotic utilization.1-3
■ NP is often caused by Gram-negative pathogens, most notably Pseudomonas aeruginosa and
Enterobacteriaceae. Selecting appropriate empiric therapy for these infections is becoming
increasingly difficult because of rising antimicrobial resistance.4,5
Patients with NP due to
resistant pathogens are more likely to receive inappropriate initial antimicrobial therapy (IIAT)
than patients with NP due to susceptible pathogens, which results in longer length of stay,
greater hospitalization cost, and higher mortality.6
Along with more diligent efforts to reduce
unnecessary and inappropriate use of antimicrobial agents to curtail the rise of resistance,
new agents that effectively treat bacterial NP infections and avoid the clinical and economic
consequences of IIAT are needed.7
■ Ceftolozane/tazobactam is a novel β-lactam/β-lactamase inhibitor with in vitro activity
against P. aeruginosa, including drug-resistant strains, and other common Gram-negative
pathogens including most extended-spectrum β-lactamase–producing Enterobacteriaceae.8
It is currently approved for the treatment of complicated intra-abdominal infections when
used in combination with metronidazole and for the treatment of complicated urinary tract
infections, including pyelonephritis.9
A Phase 3 clinical trial for treatment of nosocomial
pneumonia is underway (NCT02070757).
LIMITATIONS
■ Because the PACTS data are at the isolate level and not the patient level, it was not possible to
consider dual Gram-positive/Gram-negative infection within the context of the model;
therefore, only monomicrobial infection was examined.
■ The development of antibiotic resistance over time was not taken into account; ongoing
surveillance will be important to ascertain the impact of antimicrobial resistance on the
cost-effectiveness of empiric therapy in NP.
REFERENCES
1. Magill S, et al. N Engl J Med. 2014;370:1198-1208.
2. American Thoracic Society; Infectious Diseases Society of America. Am J
Respir Crit Care Med. 2005;171:388-416.
3. Safdar N, et al. Crit Care Med. 2005;33:2184-2193.
4. Sievert DM, et al. Infect Control Hosp Epidemiol. 2013;34:1-14.
5. Jones RN. Clin Infect Dis. 2010;51(suppl 1):S81-S87.
6. Tumbarello M, et al. Intensive Care Med. 2013;39:682-692.
7. Infectious Diseases Society of America. Infectious Diseases Society
of America. Bad Bugs, No Drugs. Alexandria, VA: IDSA; 2004.
8. Farrell DJ, et al. Int J Antimicrob Agents. 2014;43:533-539.
9. Zerbaxa [prescribing information]. Cubist Pharmaceuticals; Lexington,
MA; 2014.
10. Labelle AJ, et al. Chest. 2010;137:1130-1137.
11. Kollef MH, et al. Chest. 2005;128:3854-3862.
12. Raman G, et al. ISPOR 17th Annual European Congress; November 8th-12th,
2014; Amsterdam, The Netherlands. Poster # PIN20.
13. Zilberberg MD, et al. Surg Infect (Larchmt). 2010;11:409-417.
14. Candrilli S, Mauskopf J. Value in Health. 2006;9:A56-A56.
15. US Bureau of Labor Statistics. Consumer price index. http://www.bls.gov/
cpi/home.htm. Accessed June 18, 2014.
16. Wolters Kluwer Health. Medi-Span database. https://pricerx.medispan.
com/. Accessed June 1, 2014.
17. Academy of Managed Care Pharmacy. AMCP Format for Formulary
Submission. Version 3.1, December 2012.
http://amcp.org/practice-resources/amcp-format -formulary-submisions.
pdf. Accessed November 18, 2013.
ACKNOWLEDGMENTS
Medical writing and editorial assistance for this poster was provided by PAREXEL and funded by Merck and Co., Inc., Kenilworth, NJ, USA.
DISCLOSURES
T.L. Kauf and P. Xu are now employees of Merck and Co., Inc., Kenilworth, NJ. M. Dryden and M. D. Zilberberg have received consulting
fees from Merck and Co., Inc., Kenilworth, NJ.
RATIONALE: Nosocomial pneumonia (NP) remains a formidable clinical challenge.
Antimicrobial resistance makes it difficult to predict appropriate empiric therapy so critical
to survival. Furthermore, common nosocomial pathogens such as Pseudomonas aeruginosa
are becoming resistant to traditional antipseudomonals. Ceftolozane/tazobactam, an
antipseudomonal cephalosporin with a β-lactamase inhibitor, is currently undergoing clinical
trials in the setting of NP. One concern with novel agents, however, is cost. To assess the
cost-effectiveness of ceftolozane/tazobactam compared with standard empiric treatment,
we developed a decision-based mathematical model for NP patients at risk for drug-resistant
infection from the perspective of the US healthcare system.
METHODS: We designed a cost-utility model with NP treated empirically with either
ceftolozane/tazobactam or meropenem, in which we compared mortality, length of
stay, hospital costs, and quality-adjusted life years (QALY) for NP survivors based on the
empiric regimen. Proportions of Gram-negative pathogens, Gram-positive pathogens, and
culture-negative cases were derived from published literature. Susceptibility profiles of
Gram-negative organisms were obtained from a large surveillance database reporting in vitro
susceptibilities. We randomly sampled US NP isolates from 2011-2012 (n = 4849) from this
database to represent individual patients and assessed MIC values against CLSI breakpoints
for meropenem and a breakpoint of 8 mg/L for ceftolozane/tazobactam to determine
pathogen susceptibility to initial therapy. From a meta-analysis of available literature,
absolute mortality rates of 27.0% with appropriate and 47.0% with inappropriate treatment
were derived. We assumed 72 hours until culture availability, and, once available, that a
switch would be made to the cheapest available drug to which the organism was susceptible.
Alternatively, if the isolate was pan-resistant, a switch to salvage therapy (meropenem plus
colistin) would be made. We used the daily listed meropenem cost of $46.20 and projected
daily ceftolozane/tazobactam cost to meet cost-effectiveness thresholds.
RESULTS: Initial treatment with ceftolozane/tazobactam resulted in an avoidance of 17.6
deaths and 573 hospital days and gained on average an additional 0.06 QALYs compared with
meropenem. The total difference in costs was $4,979,326 and the difference in total QALYs
was 298.58, resulting in an incremental cost-effectiveness ratio of $16,677. These results
were most sensitive to hospital costs, time to culture results, and assumed ceftolozane/
tazobactam breakpoints.
CONCLUSIONS: If safety and efficacy are confirmed by clinical studies, this model suggests
cost thresholds at which ceftolozane/tazobactam may be a cost-effective approach to empiric
treatment of NP patients at risk for multidrug-resistant infection.
AMENDED ABSTRACT RESULTS
Table 1. Model Inputs
Input Values
Mortality rates, mean (range)
Appropriate empiric treatment, % 27 (23-32)
Inappropriate empiric treatment, % 47 (40-53)
Length of stay (LOS), days, mean (range)
Duration of empiric therapy,a
days 3 (1-4)
Total LOS for appropriate therapy,b
days 9 (7-14)
Total LOS for inappropriate therapy,b
days 16 (10-17)
Health utility for survivors, mean (range) 0.83 (0.62-1.00)
Hospital cost per day, $, mean (range) 2745.51 (0-4458.54)
Drug cost per day, $
Ceftolozane/tazobactam 498.00
Meropenem 46.20
Salvage therapyc
130.17
Benefit discount rate (per annum), % 3 (1-5)
a
Time to culture results.
b
Including empiric therapy.
c
Meropenem + colistin.
Table 2. Cost-effectiveness Model Results (US$)
Ceftolozane/
Tazobactam
Meropenem
Difference
(Ceftolozane/
Tazobactam –
Meropenem)
Costs, $
Total costs 75,374,636 70,395,310 4,979,326
Hospital costs 67,963,727 69,534,159 -1,570,432
Drug costs 7,410,909 861,151 6,549,758
Total costs per patient 15,544 14,517 1027
Hospital costs per patient 14,016 14,340 -324
Drug costs per patient 1528 178 1350
Total QALYs (discounted) 48,344.3 48,045.7 298.6
Incremental cost-effectiveness ratio
(cost per discounted QALY saved), $
16,677
Hospitalization days saved 573
25,000
70
75
80
85
90
95
100
30,000 35,000 40,000 45,000 50,000
Budget (US$)
Probability(%)
55,000 60,000 65,000 70,000 75,000
Figure 3. CEAC - Cost per Additional QALY Saved, Ceftolozane/Tazobactam vs Meropenem
METHODS
METHODS (cont’d)
NP/VAP
Patient
Initiate Alt
Therapya
C/T – S
SOC – R
C/T – S
SOC – S
Gram-
Gram+ Inappropriatea
Cure
Death
Cure
Death
Cure
Death
Cure
Death
Inappropriatea
InappropriateAppropriate
C/T – R
SOC – S
C/T – R
SOC – R
Continue
C/T
De-escalate
to SOC
Switch to
SOC
Rescue
Therapy
Initiate Alt
Therapya
Culture
negative
Repeat
Structure
Gram+
Gram-
SOC
C/T
Culture
negative
Figure 1. Model Structure
a
Or discontinue C/T if coverage is provided via adjunctive therapy at treatment initiation.
Alt = alternate; C/T = ceftolozane/tazobactam; R = resistant; S = susceptible; SOC = standard of care.
$5000 $10,000 $15,000 $20,000 $25,000 $30,000 $35,000
Durationofempirictherapy
Resistancetomeropenem
Resistancetoceftolozane/tazobactam
Mortalityratewithinappropriateempirictherapy
Hospitalcostperday(average)
Benefitdiscountrate(perannum)
Healthutilityforsurvivors
Mortalityratewithappropriateempirictreatment
TotalLOSforappropriatetherapy(incl.empirictherapy)
TotalLOSforinappropriatetherapy(incl.empirictherapy)
$0
Figure 2. One-way Sensitivity Analysis of Model Results: Ceftolozane/Tazobactam vs Meropenem:
Influence of Variables on Incremental Cost-effectiveness Ratio (Cost per Discounted QALY)
Blue refers to: Upper bound; Orange refers to: lower bound.
OBJECTIVES
■ Evaluate the cost-effectiveness of ceftolozane/tazobactam compared with standard empiric
treatment (meropenem) for NP patients at risk for drug-resistant infection from the
perspective of the US healthcare system.
Model Structure
■ A cost-utility model was developed to compare the mortality, length of stay, hospital costs,
and quality-adjusted life-years (QALY) for NP patients treated empirically with either
ceftolozane/tazobactam or meropenem (Figure 1). Specifically, the model considered NP
patients at high risk for drug-resistant infection. To compare treatment strategies, differences
in these outcomes of interest were estimated, along with the incremental cost-effectiveness
ratio (ICER) based on total cost per QALY gained.
■ In the model, a patient is treated empirically with either ceftolozane/tazobactam or
meropenem. After 3 days, initial therapy is re-evaluated based on the results of susceptibility
testing, and a decision on definitive treatment is made (either continuation of empiric therapy,
escalation or de-escalation of therapy, or commencement of salvage therapy [defined for
modeling purposes as meropenem plus colistin]).
■ The model assumes that patients at risk for resistant infection would receive empiric coverage
against both Gram-positive and Gram-negative pathogens. If the infection is Gram-positive,
the model does not make any determination or assumption of appropriate or inappropriate
therapy and assumes that Gram-negative coverage is discontinued. Similarly, under either
empiric treatment scenario, culture-negative cases are assumed to either discontinue empiric
therapy or de-escalate coverage. The proportions of Gram-positive pathogens (42.5%) and
culture-negative cases (25.7%) were derived from the published literature.10,11
■ Cost and outcomes from a US payer perspective were calculated based on whether the initial
empiric therapy was appropriate or inappropriate.
Utility and Economic Inputs (Table 1)
■ Health utility estimates were obtained from the literature and applied to cured patients for
the remainder of their lives.13
■ Hospital cost per day was derived from the 2012 Healthcare Cost and Utilization Project
database for patients with a principal diagnosis of NP.14
Costs were inflated to 2013 US dollars
using the medical care component of the US consumer price index.15
Drug costs per day were
retrieved from the Medi-Span database.16
■ QALYs were discounted at a rate of 3% per annum.17
Costs were not discounted since they
accrued only during the hospitalization period, which occurred during the first year.
Model Validation—Output Values
■ One-way and probabilistic sensitivity analyses were performed to quantify the effect of
uncertainty in the input parameters on model outcomes.
■ For the one-way sensitivity analysis, input parameters were varied by the ranges listed in
Table 1. The 10 parameters with the greatest impact on model results were summarized with
a tornado diagram.
■ The probabilistic sensitivity analysis used Monte Carlo simulation to evaluate the model over
a series of 1000 draws of relevant input parameters from their corresponding probability
distributions. Model probabilities were generally modeled using beta distributions, and costs
were assumed to follow log-normal distributions. Results of the simulations were used to
calculate the probability of net monetary benefit for a given treatment strategy at various values
of willingness to pay for a QALY and displayed as a cost-effectiveness acceptability curve.
■ The PACTS database included 1542 patients with Gram-negative NP. Including patients with a
Gram-positive or a culture-negative infection (n = 3307), the modeled cohort numbered 4849
NP patients.
■ For the modeled cohort, empiric treatment with ceftolozane/tazobactam resulted in
avoidance of 17.6 deaths (0.4% reduction in mortality rate) and 573 hospital days and an
average gain of 0.06 QALYs per patient compared with meropenem.
■ Empiric treatment with ceftolozane/tazobactam was more effective but also more costly
compared with meropenem. The total increase in costs associated with the use of
ceftolozane/tazobactam in comparison with meropenem was $4,979,326 and the gain in total
QALYs was 298.6, resulting in an ICER (cost per discounted QALY saved) of $16,677 (Table 2).
■ One-way sensitivity analysis showed that the ICER model results were most sensitive to the
duration of empiric therapy, excess mortality associated with IIAT, and hospital costs (Figure 2).
■ The probabilistic sensitivity analysis generated a 95% confidence interval for the ICER compared
with meropenem of $13,961 to $54,212, suggesting that the results are quite stable to input
parameter uncertainty. However, it should be noted that the probabilistic sensitivity analysis
was conducted using the base case breakpoint of 8 mg/L for ceftolozane/tazobactam. The
cost-effectiveness acceptability curve (probability of ceftolozane/tazobactam to be accepted vs
meropenem) derived from the probabilistic sensitivity analysis is provided in Figure 3.
Model Parameters – Input Values
Clinical Parameters (Table 1)
■ US NP/VAP isolates from 2011-2013 (n = 4849) were sampled from the Program to Assess
Ceftolozane/Tazobactam Susceptibility (PACTS) database.8
The susceptibility evaluation used
Clinical Laboratory Standards Institute (CLSI) breakpoints (minimum inhibitory concentration
required to inhibit the growth of 90% of organisms [MIC90
]) for all antibiotics, with the
exception of ceftolozane/tazobactam. A breakpoint of ≤8 mg/L was assumed for ceftolozane/
tazobactam because at the time this analysis was conducted clinical breakpoints for
ceftolozane/tazobactam were not available from the CLSI or US Food and Drug Administration
(FDA). The model assumed that any pathogen with an MIC above the breakpoint was resistant.
■ Excess mortality associated with IIAT (odds ratio, 3.3) was based on a recent network
meta-analysis.12
■ Patients were assumed to receive therapy for the duration of their hospital stay. Duration of
empiric therapy was assumed to be 3 days. Length of stay (including the period of empiric
therapy) was set to 9 days for appropriate therapy and 16 days for inappropriate therapy.13
GW0071 Cubist ATS_NP economic S03.indd 1 5/4/15 5:19 PM