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

1Cubist Pharmaceuticals, Lexington, MA, USA; 2Mapi Group – HEOR & Strategic Market Access, Houten, The Netherlands; 3Royal Hampshire County Hospital, Winchester, UK; 4University of Massachusetts, Amherst, MA, USA; 5EviMed Research Group, LLC, Goshen, MA, USA

Poster# 66385Teresa 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.

REFERENCES1. 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.

ACKNOWLEDGMENTSMedical writing and editorial assistance for this poster was provided by PAREXEL and funded by Merck and Co., Inc., Kenilworth, NJ, USA.

DISCLOSUREST.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 498.00Meropenem 46.20Salvage therapyc 130.17

Benefit discount rate (per annum), % 3 (1-5)aTime to culture results.bIncluding empiric therapy.cMeropenem + 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 -1,570,432Drug costs 7,410,909 861,151 6,549,758

Total costs per patient 15,544 14,517 1027Hospital costs per patient 14,016 14,340 -324Drug costs per patient 1528 178 1350

Total QALYs (discounted) 48,344.3 48,045.7 298.6Incremental cost-effectiveness ratio (cost per discounted QALY saved), $

16,677

Hospitalization days saved 573

25,00070

75

80

85

90

95

100

30,000 35,000 40,000 45,000 50,000

Budget (US$)

Prob

abilit

y (%

)

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/VAPPatient

Initiate AltTherapya

C/T – SSOC – R

C/T – SSOC – S

Gram-

Gram+ Inappropriatea

CureDeath

CureDeath

CureDeath

CureDeath

Inappropriatea

Inap

prop

riate

Appr

opria

te

C/T – RSOC – S

C/T – RSOC – R

ContinueC/T

De-escalateto SOC

Switch toSOC

RescueTherapy

Initiate AltTherapya

Culturenegative

RepeatStructureGram+

Gram-

SOC

C/T

Culturenegative

Figure 1. Model Structure

aOr 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

Duration of empiric therapy

Resistance to meropenem

Resistance to ceftolozane/tazobactam

Mortality rate with inappropriate empiric therapy

Hospital cost per day (average)

Benefit discount rate (per annum)

Health utility for survivors

Mortality rate with appropriate empiric treatment

Total LOS for appropriate therapy (incl. empiric therapy)

Total LOS for inappropriate therapy (incl. empiric therapy)

$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 ValuesClinical 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

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