Journal of Medical Economics ISSN: 1369-6998 (Print) 1941-837X (Online) Journal homepage: https://www.tandfonline.com/loi/ijme20 Economic analysis of ceftaroline fosamil for treating community-acquired pneumonia in Spain Antoni Torres, Matteo Bassetti, Tobias Welte, Simone Rivolo, Edit Remak, Carmen Peral, Claudie Charbonneau, Jennifer Hammond, Wajeeha Ansari & Santiago Grau To cite this article: Antoni Torres, Matteo Bassetti, Tobias Welte, Simone Rivolo, Edit Remak, Carmen Peral, Claudie Charbonneau, Jennifer Hammond, Wajeeha Ansari & Santiago Grau (2020) Economic analysis of ceftaroline fosamil for treating community-acquired pneumonia in Spain, Journal of Medical Economics, 23:2, 148-155, DOI: 10.1080/13696998.2019.1688819 To link to this article: https://doi.org/10.1080/13696998.2019.1688819 © 2019 Pfizer Inc. Published by Informa UK Limited, trading as Taylor & Francis Group. Published online: 26 Nov 2019. Submit your article to this journal Article views: 1844 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ijme20 JOURNAL OF MEDICAL ECONOMICS 2020, VOL. 23, NO. 2, 148–155 https://doi.org/10.1080/13696998.2019.1688819 Article 0146-RT.R1/1688819 ORIGINAL RESEARCH Economic analysis of ceftaroline fosamil for treating community-acquired pneumonia in Spain Antoni Torresa, Matteo Bassettib,c, Tobias Welted, Simone Rivoloe, Edit Remakf, Carmen Peralg, Claudie Charbonneauh, Jennifer Hammondi, Wajeeha Ansarij and Santiago Grauk a Hospital Clınic of Barcelona, Spain University of Barcelona, CIBERES, IDIBAPS, Barcelona, Spain bUniversity of Udine and Santa Maria Misericordia University Hospital, Udine, Italy; cUniversity of Genoa, Genoa, Italy; dHannover Medical School, Hannover, Germany; eEvidera, London, UK; fEvidera, Budapest, Hungary; gPfizer, Madrid, Spain; hPfizer, Paris, France; iPfizer, Collegeville, PA, USA; jPfizer, New York, NY, USA; kHospital del Mar Universitat Autonoma de Barcelona, Barcelona, Spain ABSTRACT ARTICLE HISTORY Background: Adults admitted to hospital with community-acquired pneumonia (CAP) impose signifi- Received 25 July 2019 cant burden upon limited hospital resources. To achieve early response and possibly early discharge, Revised 11 October 2019 thus reducing hospital expenditure, the choice of initial antibiotic therapy is pivotal. Accepted 31 October 2019 Methods: A cost-consequences model was developed to evaluate ceftaroline fosamil (CFT) as an alter- KEYWORDS native to other antibiotic therapies (ceftriaxone, co-amoxiclav, moxifloxacin, levofloxacin) for the Ceftaroline fosamil; empiric treatment of hospitalized adults with moderate/severe CAP (PORT score III–IV) from the per- community-acquired pneu- spective of the Spanish National Health System (NHS). monia; cost-consequences Findings: Compared with ceftriaxone, the model predicted an increase in the number of CFT-treated economic analysis; Spanish patients discharged early (PDE) (30.6% vs. 26.1%) while decreasing initial antibiotic failures (3.8% vs. National Health System; 7.6%). For patients with pneumococcal pneumonia, CFT was cost-saving vs. ceftriaxone (by 1.2%) and early discharge significantly increased PDE (32.1% vs. 24.6%). CFT resulted in cost-saving vs. levofloxacin, due lower initial antibiotic therapy costs and increased PDE (30.6% vs. 14.9%). Moxifloxacin and co-amoxiclav JEL CLASSIFICATION CODES early response rate of 53.63% and 54.24% resulted in cost neutrality vs. CFT, with direct comparison I10; I19 hampered by the significantly different early response criteria utilized in the literature. Conclusions: Despite a higher unit cost, CFT is a reasonable alternative to other agents for adults hos- pitalized with moderate/severe CAP, given the projected higher PDE achieved with similar or lower total costs. Introduction associated with each episode of inpatient care for CAP was estimated to exceed $18,000 in the US in 2012, which equa- Community-acquired pneumonia (CAP) remains an acute ted to an overall annual burden above $13 billion5,6. infection with significant associated morbidity, mortality and Similarly, in Europe, the estimated inpatient care direct costs economic burden1–4, particularly prevalent in the elderly. amount to e5.7 billion per year with a further estimated e3.6 Indeed, within an estimated European incidence of 0.2–242 billion of indirect costs due to productivity loss3. Given that per 1,000 adults/year, significantly higher rates are observed the main determinants of overall costs are in-patient treat- in the elderly population3,4. Accordingly, in the US, 1.3 mil- ment, hospital length of stay and the need for intensive lion cases of CAP were estimated to have occurred in adults care3,9, effective treatment which can achieve rapid clinical 65 years in 20125. With the globally aging population, the cure and enable early discharge are therefore highly desir- incidence and burden of CAP is therefore set to increase able. Furthermore, the rising concern of antibiotic resistance, even further3,6,7. One study in primary care showed an inci- which has been observed in all pathogens associated with dence of CAP in Spain that was in the range 4.63/1,000 peo- CAP3, also necessitates alternative effective treatments. ple/year4. The incidence in people older than 65 years was A series of well-established guidelines govern the treat- higher in men, with a range of 7.06–36.93 compared to ment strategy, with the aim of reducing unnecessary hospi- 5.43–19.62 in women. talization and readmissions, length of hospital stays, Although mild disease can be managed in the commu- mortality and in turn cost10–12. Upon admission, most nity, a significant proportion of patients with comorbidities, patients are treated empirically with antibiotics selected such as metabolic or cardiovascular disease, or more severe according to disease severity, local patterns of bacterial CAP will require hospitalization8. The medical costs resistance and safety profiles1. As initial antibiotic treatment CONTACT Wajeeha Ansari wajeeha.ansari@pfizer.com Pfizer, 235 E. 42nd Street, 5th Floor, Room 43, New York, NY 10017, USA ß 2019 Pfizer Inc. Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. www.tandfonline.com/ijme ECONOMIC ANALYSIS OF CEFTAROLINE FOSAMIL FOR CAP IN SPAIN 149 failure has been shown to prolong hospital stay, increase hospitalized patients with moderate/severe CAP from the antibiotic usage and add to hospital expenditure, this is a perspective of the Spanish National Health System. pivotal decision13. The most common antibiotic approach involves monotherapy with a respiratory fluoroquinolone or combination therapy with a macrolide plus a b-lactam14,15. Methods Ceftaroline fosamil (CFT) is a fifth-generation cephalo- sporin with a broad spectrum of antibacterial activity. In an Model structure integrated analysis of the two pivotal, multicenter, phase III A decision-tree model was developed in Microsoft Excel 2016 RCTs trials (FOCUS 1 and FOCUS 2), CFT treatment was non- (Microsoft Corporation, Redmond, WA), to simulate the clin- inferior to ceftriaxone in adults with CAP (Pneumonia ical pathway of a hypothetical cohort of adult patients Outcomes Research Team (PORT) risk class III or IV)16. admitted to hospital in Spain with moderate/severe CAP Specifically, CFT demonstrated numerically higher clinical (PORT score III–IV) tracking the costs and consequences of cure rates than ceftriaxone in the clinically evaluable popula- treatments as shown in Figure 1. Upon admission, the initial tion both in the individual trials (FOCUS 1: 86.6% vs. 78.2%, decision was to either treat with CFT 600 mg every 12 h FOCUS 2: 82.1% vs. 77.2%) and in the combined analysis (q12hr) or an alternative antibiotic. The alternative antibiotics (84.3% vs. 77.7%)16. Furthermore, when the trials data were included in the analysis were ceftriaxone 1–2 g every 24 h analyzed focusing on the early response (Day 4, 72–96 h, CFT (q24h), co-amoxiclav 1.2 g every 8 h (q8h), moxifloxacin appeared to provide clinical benefit over ceftriaxone at Day 400 mg q24h or levofloxacin 0.5–1 g q24h, based on CAP 4, with Day 4 clinical response rates of 69.5% vs. 59.4%17. In guidelines and clinical expert consultation10–12. addition, real-world studies have shown CFT to be effective, Patients initially receive intravenous (IV) antibiotic therapy irrespective of whether it was used as monotherapy or con- for four days before clinical and microbiological assessment. current therapy18, first- or second-line therapy18,19, in elderly patients18,20 or in patients with significant comorbidities20. After 4 days, responding patients17 will either switch to a As newer agents, such as CFT, become available, the num- 5-day course of oral antibiotics and be discharged early, or ber of treatment options open to clinicians, will increase. remain in hospital due to conditions unrelated to pneumonia However, given the rising concern of national health system (e.g. unable to swallow), and continue to receive IV antibiotic expenditures, decisions need to be made based on economic therapy22. Non-responders after 4 days will either remain value as well as clinical benefit. Focusing on Spain, between on IV therapy until clinical cure and discharge or switch to a 2004 and 2013, the hospitalization rates for CAP in Spain second-line antibiotic (e.g. ceftriaxone) until clinical cure increased significantly from 142.4 to 163.87 cases/100,000 and discharge23. The non-responders switched to a second- inhabitants21. This study was therefore undertaken to evalu- line antibiotic could either be treated in the general ward ate intravenous (IV) CFT (600 mg q12hr) as an alternative to or in an intensive care unit (ICU) and then switched to the available IV antibiotic therapies for the empiric treatment of general ward. Figure 1. Schematic visualization of the decision-tree model. Over each branch, a brief description of the corresponding patient pathway has been summarized. Abbreviations. CAP, community-acquired pneumonia; ICU, intensive care unit; IV, intravenous. 150 A. TORRES ET AL. Table 1. Clinical inputs for the cost-effectiveness analysis. Description Base-case SE Distribution Source 16 Probability of clinical cure with CFT 0.843 0.0170 Beta Probability of clinical cure with CFT in pneumococcal pneumonia 0.855 0.042 Beta 16 Relative risk clinical cure CFT vs. ceftriaxone 1.10 0.028 LogNormal 25 Probability of clinical cure with ceftriaxone in pneumococcal pneumonia 0.686 0.052 Beta 25 Relative risk clinical cure CFT vs. co-amoxiclav 1.18 0.05 LogNormal 25 Relative risk clinical cure CFT vs. levofloxacin 1.05 0.05 LogNormal 25 Relative risk clinical cure CFT vs. moxifloxacin 1.08 0.04 LogNormal 17 Probability of Day 4 clinical response for CFT 0.695 0.0371 Beta 17 Probability of Day 4 clinical response for CFT in pneumococcal pneumonia 0.73 0.0516 Beta 17 Probability of Day 4 clinical response for ceftriaxone 0.594 0.0394 Beta 17 Probability of Day 4 clinical response for ceftriaxone in pneumococcal pneumonia 0.56 0.0567 Beta Probability of Day 4 clinical response for co-amoxiclav NA NA NA Probability of Day 4 clinical response for moxifloxacin NA NA NA 26 Probability of Day 4 clinical response for levofloxacin 0.34 0.046 Beta Abbreviations. CFT, ceftaroline fosamil; NA, not applicable; SE, standard error. This model structure was considered most appropriate comparators are summarized in Table 1 along with the corre- since costs and clinical outcomes (resolution of signs and sponding references. symptoms of the infection) occur over a relatively short It is important to notice that the moxifloxacin early period of time, typically <3 weeks from hospital admission to response criteria utilized in the literature were significantly discharge24. different to those utilized for CFT, with early response defined as just body temperature <37.5  C27. Similarly, early response criteria for co-amoxiclav were less stringent than Model inputs the criteria used for CFT (improvement in two out of four Clinical efficacy inputs CAP symptoms, clinical stability not required)28. Therefore, The clinical inputs used in the cost-effectiveness analyses are comparison against moxifloxacin and co-amoxiclav was ham- summarized in Table 1. The clinical cure rate for CFT was pered by the lack of comparable early response data in the obtained from an integrated analysis of phase III trials16, and literature. Nevertheless, threshold analysis was performed for in the absence of head-to-head data, the clinical cure rates both co-amoxiclav and moxifloxacin to assess the level of for the other antibiotics were estimated from a published early response rate at which cost-neutrality could be network meta-analysis (NMA)25. Accordingly, the relative risk achieved with respect to CFT. (RR) of CFT versus ceftriaxone, co-amoxiclav, levofloxacin and moxifloxacin were reported to be 1.10 (95% confidence inter- Economic inputs vals [Cl] 1.04–1.16), 1.18 (95% Cl 1.06–1.3), 1.05 (95% Cl Health care resource use and costs are shown in Table 2. The 0.96–1.15) and 1.08 (95% Cl 0.99–1.16) respectively. average hospital length of stay (LOS) for patients both Day 4 clinical response was based on criteria set by the responding to and failing on initial antibiotic therapy, as well FDA and was defined as meeting criteria for both clinical sta- as the associated admission rates to and duration of stays in bility and clinical improvement on Day 4: ICU for the latter patients was obtained from a large obser- vational study of CAP management in hospitalized patients23.  Clinical stability was defined according to the Infectious A prospective observational study of 200 patients with CAP Diseases Society of America/American Thoracic Society admitted to hospital provided the proportion of treatment guidelines as temperature <37.8  C, heart rate <100 responders (44%) eligible for iv-to-oral switch and early hos- beats/min, respiratory rate <24 breaths/min, systolic pital discharge22. The duration of first-line antibiotic treat- blood pressure >90 mmHg, oxygen saturation >90% and ment was assumed as 6.6 days for CFT and all comparators, confusion/disorientation (recorded as absent). consistent with the duration observed in the CFT trials16.  Clinical improvement was defined as improvement of at Ceftriaxone monotherapy was selected as the second line least one of four symptoms present at baseline (i.e. antibiotic of choice for patients treated in general wards, fol- cough, dyspnea, pleuritic chest pain, sputum production) lowing clinical experts’ consultation, while a combination with worsening of none. therapy (ceftriaxone þ azithromycin) was deemed more suit- able for ICU patients. The duration of second line antibiotic Patients who did not meet both criteria were considered treatment was assumed to be 7 days, due to lack of reliable non-responders. sources found in the literature but varied during the sensitiv- Day 4 clinical response rates, sourced from a post hoc ity analysis. analysis of the FOCUS trials in the CE population17, were Ceftriaxone 1 g q24hr and levofloxacin 500 mg q24hr dos- 69.5% for CFT and 59.4% for the ceftriaxone. Focusing on ages were used for the base case as these were the doses the pneumococcal pneumonia confirmed group, the clinical used in the source clinical trials. However, higher doses are response rates at Day 4 were 73.0% in the CFT group and routinely needed in real life to achieve similar efficacy to 56.0% in the ceftriaxone group. The values for the other that observed in clinical trials. Additional scenarios with ECONOMIC ANALYSIS OF CEFTAROLINE FOSAMIL FOR CAP IN SPAIN 151 Table 2. Economic inputs for the cost-consequences analysis. Health care resource use Average value (SE) Distribution Reference 23 Mean hospital LOS (95% CI) initial antibiotic treatment success (days) 11.3 (0.24) Normal 23 Mean hospital LOS (95% CI) initial antibiotic treatment failure (days) 15.3 (0.5) Normal 23 Proportion of treatment failures admitted to ICU 19.8% (1.57%) Beta 23 Duration of ICU stay (days) 10.9 (0.51) Normal 22 Proportion of patients eligible for IV-to-oral therapy 44% (3.51%) Beta 16 Duration of antibiotic treatment (days) 6.6 1 Duration of second-line antibiotic treatment (days) 7 1 Assumption Unit costs Value (e 2017) Reference Hospital day stay (per day) 553.90 Spanish National Price List30 ICU stay (per day) 1,456.52 Drug Acquisition Costs (per unit/per day) Ceftaroline 600 mg q12hr 60.00/120.00 Ceftriaxone 1 g q24hr 3.89/3.89 Co-amoxiclav 1.2 g q8hr 4.0/12.0 Moxifloxacin 400 mg q24hr 31.2/31.2 Levofloxacin 500 mg q24hr 12.15/12.15 Oral Step-down Antibiotic (co-amoxiclav) 4.0/12.0 Second-line antibiotic in general ward (ceftriaxone) 3.89/3.89 Second-line antibiotic in ICU (ceftriaxone þ azithromycin) 10.86/10.86 Abbreviations. CI, confidence interval; ICU, intensive care unit; IV, intravenous; LOS, length of stay; q8hr, every eight hours; q12hr, every 12 hours; q24hr, every 24 hours; SE, standard error. ceftriaxone 2 g q24hr and levofloxacin 1 g q24hr were simu- pneumococcal pneumonia confirmed group was performed lated to reflect the doses most commonly used in clinical for CFT versus ceftriaxone, given the high-mortality associ- practice. Drug and hospital resource costs were sourced from ated with this specific causative organism3. Due to lack of the Spanish national price list 2017. data a pneumococcal subgroup analysis was not possible for the other comparators. Deterministic one-way sensitivity analysis was performed Model assumptions to identify the primary sources of uncertainty in the model’s When building the decision-tree model, multiple assumptions estimates of treatment costs and clinical outcomes. The had to be made to simplify the clinical pathways and allow model base-case inputs were varied within their 95% CIs, data from multiple sources to be integrated. Firstly, the early obtained from assigned statistical distributions as specified in response rate across trials was assumed to be comparable. Tables 1 and 2 (beta-distribution for probabilities, and log- Secondly, the duration of IV treatment in patients remaining normal distribution for relative risks) while the costs were varied by ±25%. in hospital beyond 4 days was assumed to be the same for In additional, probabilistic sensitivity analysis (PSA) was CFT and all the comparators considered, due to the lack of undertaken to assess the impact of simultaneously varying treatment specific data published in the literature16. Thirdly, clinical outcomes and health care resource use with respect as the costs of initial microbiological testing, and concomi- to the model outcomes, using Monte Carlo simulation (1,000 tant antibiotics providing coverage against atypical patho- simulations were performed). gens were assumed to be the same in both treatment arms, these were not considered in the model in the base case (consistent with the clinical trial protocols from which the Results efficacy inputs have been derived). Nevertheless, one add- Compared to ceftriaxone-treated patients, a higher percent- itional scenario was tested adding concomitant macrolide age of CFT-treated patients were predicted by the model to therapy (azithromycin 500 mg q24h – first 3 days IV then oral be eligible for early discharge (30.6% vs. 26.1%; Figure 2), formulation for a daily cost of e7.31) to each beta-lactam and fewer were projected to experience initial antibiotic fail- treatment (ceftaroline fosamil, ceftriaxone, co-amoxiclav) as ure (3.8% vs. 7.6%) or require ICU treatment (0.9% vs. 1.9%) recommended in the latest clinical guidelines and likely hap- (see Table 3). The predicted total average costs of CFT were pening in clinical practice14,15. e286.10 per patient higher than ceftriaxone (1 g q24hr), resulting in a 5% increase (Table 4 and Figure 2). Specifically, Model analyses CFT patients were projected to have higher initial antibiotic drug costs and oral step-down costs versus ceftriaxone. The model predicted health outcomes such as percentage of Similar results were obtained when ceftriaxone 2 g q24hr patients discharged at Day 4, percentage of patients experi- dosage was compared, but the marginal increase in total encing antibiotic treatment failure, and percentage of costs between CFT and ceftriaxone was reduced to 4.6%. patients treated in the ICU, as well as incremental costs of Simulating the combination of CFT and ceftriaxone with a CFT versus each of the comparators were included in the macrolide marginally increased the total costs per patient analysis. Furthermore, sub-group analysis focusing on the (e5,917.13 and e5,684.98 respectively) compared to the base 152 A. TORRES ET AL. Figure 2. Comparison of total costs per patient (left side) and the percentage of patients discharged early (right side) for CFT, Ceftriaxone, and Levofloxacin. Abbreviations. CFT, ceftaroline fosamil; q12hr, every 12 hours; q24hr, every 24 hours Table 3. Total and incremental percentage of patients, for each treatment pathway (according to Figure 1), predicted by the model. All pneumonias Pneumococcal pneumonia CFT Ceftriaxone Levofloxacin CFT Ceftriaxone Total Total Incremental Total Incremental Total Total Incremental (%) (%) vs. CFT (%) vs. CFT (%) (%) vs. CFT (%) Initial antibiotic treatment success. Patient remains on initial 64.63 64.38 0.25 72.03 7.4% 63.97 61.54 2.43 antibiotic to complete IV course of therapy. (Pathway A þ Pathway C) Initial antibiotic treatment success. Clinical response achieved 30.58 26.14 4.44 14.96 15.62% 32.12 24.64 7.48 at Day 4. Patients switched to oral antibiotic and discharged early (Pathway B) Initial antibiotic treatment failure. Patients switched to 3.84 7.61 3.77 10.44 6.6% 3.14 11.08 7.94 second-line antibiotic and managed in general ward (Pathway D) Initial antibiotic treatment failure. Patients switched to 0.95 1.88 0.93 2.58 1.63 0.78 2.74 1.96 second-line antibiotic and managed in ICU (Pathway E) Abbreviations. CFT, ceftaroline fosamil; ICU, intensive care unit; IV, intravenous. Table 4. Total and incremental hospital costs per patient by antibiotic regimen and pneumonia type. All Pneumonias (e 2017) Pneumococcal pneumonia (e 2017) CFT Ceftriaxone Levofloxacin CFT Ceftriaxone Total Total Incremental vs. CFT Total Incremental vs. CFT Total Total Incremental vs. CFT Total average hospital cost e5,929.59 e5,643.49 e286.10 e6,283.92 e2354.33 e5,829.77 e5,884.40 e254.63 Initial antibiotic therapy e681.65 e22.07 e659.58 e71.36 e610.29 e679.57 e21.78 e657.79 Oral antibiotic step-down e24.22 e20.70 e3.52 e11.85 e12.37 e25.44 e19.51 e5.92 Second-line antibiotic e1.77 e3.50 e1.73 e4.80 e3.03 e1.44 e5.10 e3.65 Hospital stay (general ward) e5,071.43 e5,299.04 e227.61 e5,786.91 e715.48 e5,000.25 e5,403.71 e403.46 Hospital stay (ICU) e150.52 e298.18 e147.65 e409.01 e258.48 e123.07 e434.30 e311.23 Abbreviations. CFT, ceftaroline fosamil; ICU, intensive care unit. case results (see Table 4) without impacting the incremental early discharged than ceftriaxone (32.1% versus 24.6%). total costs per patient (since the same macrolide treatment Considering a higher dosage of ceftriaxone (2 g q24hr) was added to both comparators). resulted in higher cost-savings of e74.62 per patient while When the analysis was restricted to patients with adding macrolide concomitant therapy to CFT and ceftriax- pneumococcal pneumonia, CFT was estimated to be cost- one did not impact the per-patient costs savings. saving versus ceftriaxone (1 g q24hr), with a total cost reduc- CFT was also predicted to be cost-saving overall versus tion of e54.63 per patient (Table 4). Despite higher projected levofloxacin 500 mg q24hr (e354.33 per patient), mainly initial antibiotic and oral antibiotic step-down costs, those ascribable to the relatively high Day 4 response rate which associated with hospitalization and second-line antibiotics resulted in reduced length of hospital stay (Table 4). Indeed, were predicted to be lower with CFT. More patients achieved in comparison with levofloxacin, CFT increased the percent- initial antibiotic treatment success with CFT than ceftriaxone age of early discharges (30.6% vs. 14.96%) and decreased ini- (63.97% versus 61.54%), and more CFT patients would be tial antibiotic failures (4.8% vs. 13%) and number of patients ECONOMIC ANALYSIS OF CEFTAROLINE FOSAMIL FOR CAP IN SPAIN 153 Figure 3. Deterministic sensitivity analysis results: CFT 600 mg q12hr versus Ceftriaxone 1 g q24hr (a); CFT 600 mg q12hr versus Levofloxacin 500 mg q24hr (b). Abbreviations. ABT, antibiotic therapy; CFT, ceftaroline fosamil; LOS, length of stay; q12hr, every 12 hours; q24hr, every 24 hours. treated in ICU (0.9% vs. 2.6%) (see Table 3). Increasing levo- lower and upper bound of the confidence interval is pre- floxacin dosage (1 g q24hr) increased total cost savings per sented in Figure 3(a) with respect to ceftriaxone and in patient, predicted by the model, to e425.68 while adding Figure 3(b) with respect to levofloxacin. concomitant macrolide therapy to CFT reduced the cost sav- Threshold analysis was repeated for moxifloxacin and co- ings per patient to e312.79. amoxiclav using the lower and upper bounds of the risk ratio Threshold analysis indicated that total cost neutrality with confidence intervals (see Table 1). Varying the moxifloxacin respect to CFT was achieved with an early response rate of and co-amoxiclav risk ratios to the lower and upper bounds 53.63% and 54.24% for moxifloxacin and co-amoxiclav of the confidence interval resulted in an early response rate respectively. Considering concomitant macrolide therapy of 48–57.2% and 48.3–58.1%, respectively, for achieving cost- with the beta-lactams (CFT and co-amoxiclav) marginally neutrality with respect to CFT. reduced moxifloxacin early response rate for achieving cost The probabilistic sensitivity analysis, during which the cost neutrality to 52.1% while had no impact on CFT/co-amoxiclav and clinical inputs were simultaneously varied by random comparison. sampling from the input distributions (see Tables 1 and 2) Finally, consistently with the literature, the model demon- demonstrated that CFT reduced the total cost in 90.9% of strated that antibiotic costs represent a small proportion of the cases compared with levofloxacin and in 3% of the cases overall hospital costs (<11% of total costs), the main driver compared with ceftriaxone. being hospital length of stay (>85% of total costs). Discussion Sensitivity analyses With an aging population, the incidence of CAP and in turn The deterministic sensitivity analyses, where each input par- the associated economic burden will continue to rise in the ameter was varied separately as the lower and upper bound coming years3. Given the rising amount of treatments avail- of the corresponding confidence interval (see Table 1), dem- able to clinicians and the fact that treatment decisions will onstrated that day 4 responses, clinical cure rates and anti- be based upon both clinical and economic factors, this mod- biotic treatment duration were the key drivers of total costs, elling study was undertaken to compare the cost and conse- when comparing CFT with ceftriaxone (see Figure 3(a)). quences of using CFT in hospitalized adults with moderate Similarly, the top-three parameters generating the most vari- to severe CAP with respect to alternative antibiotics com- ation in total costs when comparing CFT with levofloxacin monly used. were day 4 responses and the risk ratio of clinical cure rates, The greater early treatment success with CFT compared as highlighted in Figure 3(b). The full list of per patient incre- with ceftriaxone was associated with a reduction in costs for mental cost obtained setting each model parameter to the second line antibiotic and hospitalization. However, these 154 A. TORRES ET AL. cost savings were insufficient to offset the higher CFT drug different types of causative organisms for CAP would have acquisition and infusion costs; resulting in a marginal (<5%) different susceptibility patterns with respect to each of the increase in total costs versus ceftriaxone (1–2 g q24hr). antimicrobial agents commonly used29, in turn affecting the Nevertheless, the model predicted that in responding clinical efficacy of each treatment. On one hand, this would patients more would be discharged early with CFT than cef- require additional data regarding country-specific susceptibil- triaxone. Furthermore, in the pneumococcal pneumonia sub- ity patterns along with organism-specific clinical inputs for group analysis, CFT treatment resulted cost-saving while each comparator included in the analysis, thus significantly significantly increasing the number of patients achieving ini- increasing the complexity of the analysis. On the other hand, tial antibiotic treatment success and early discharge. This this could be of significant interest for future analyses, given would suggest that CFT may be preferred to ceftriaxone in that the diverse nature of resistance across Europe highlights hospitalized adults with suspected pneumococcal pneumo- the need of developing national guidelines to provide opti- nia, which is one of the main causative organisms of CAP3. mal treatment3. When compared against levofloxacin, the model demon- strated that CFT would result in significant cost savings per patient, due to greater clinical efficacy resulting in decreased Conclusion initial antibiotic treatment failures and increased percentage In conclusion, despite a higher unit cost, ceftaroline fosamil of early discharges. is a reasonable alternative to other agents in the treatment The sensitivity analysis demonstrated that early response, of adults hospitalized with moderate/severe CAP, given the treatment duration and length of hospitalization are the key projected higher rate of patients discharged early achieved drivers of total costs, which is consistent with what has been with similar or lower total costs than the alternative treat- previously described in the literature13. Furthermore, the ments considered. model demonstrates that antibiotic costs represent a small proportion of overall hospital costs, the main driver being hospital LOS3,13. This may be of benefit in focusing payers’ Transparency attention away from pharmacy spend alone towards a review Declaration of funding of the overall economic burden of managing patients with moderately severe CAP in their hospital. Funding for this project was provided by Pfizer International Operations, The developed model has multiple limitations. Firstly, Paris, France. except for ceftriaxone, there are no head to head clinical tri- als comparing CFT with the other antibiotics; thus, the clin- Declaration of financial/other interests ical inputs were based on available literature (see Table 1) and indirect comparison (NMA)25 validated by clinical expert Carmen Peral, Claudie Charbonneau, Jennifer Hammond, and Wajeeha Ansari are employees of Pfizer. Evidera received consulting fees from opinion. Furthermore, significantly different criteria used to Pfizer for undertaking this economic analysis. JME peer reviewers on this measure early response data (Day 4) were observed in the manuscript have no relevant financial or other relationships to disclose. literature, which hampered comparisons with moxifloxacin and co-amoxiclav (see Section 2.2.1). Secondly, the treatment length has been assumed equal between CFT and all the Author contributions comparators (see Table 2), given the lack of evidence in lit- All authors have made substantial contributions to the development of erature. Given that this parameter is one of the key driver of the manuscript and have approved the final version submitted. total costs, especially when comparing CFT with ceftriaxone (see Figure 3(a)), further studies leveraging real-world evi- dence regarding average length of treatment for each of the Acknowledgements considered comparators might be of interest. Thirdly, anti- We thank Julia Donnelly (on behalf of Evidera) for medical writ- biotic dosage used in the clinical trials differs to the dosage ing assistance. used in clinical practice. Multiple scenarios with increased antibiotic dosage demonstrated a limited impact of the dos- Data sharing statement age variations with respect to the model outcomes and con- clusions. However, the clinical efficacy was assumed to Upon request, and subject to certain criteria, conditions and exceptions remain constant due to the lack of literature evidence. see (https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identi- Fourthly, the unit costs used in the analysis (see Table 2) fied participant data from Pfizer-sponsored global interventional clinical could change in the future due to the introduction of studies conducted for medicines, vaccines and medical devices (1) for generics and do not take into considerations confidential dis- indications that have been approved in the United States and/or counts provided by the manufacturers. Therefore, these two European Union or (2) in programs that have been terminated (i.e. aspects along with other considerations (e.g. changes in rec- development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical ana- ommended dosages) will dictate modified cost-consequences lysis plan. Data may be requested from Pfizer trials 24 months after results. Finally, susceptibility rates were not considered in the study completion. The de-identified participant data will be made avail- analysis, which might be a critical factor in countries with able to researchers whose proposals meet the research criteria and other high levels of emerging antibiotic resistance3,29. Specifically, conditions, and for which an exception does not apply, via a secure ECONOMIC ANALYSIS OF CEFTAROLINE FOSAMIL FOR CAP IN SPAIN 155 portal. To gain access, data requestors must enter into a data access [18] Ramani A, Udeani G, Evans J, et al. Contemporary use of ceftaro- agreement with Pfizer. line fosamil for the treatment of community-acquired bacterial pneumonia: CAPTURE study experience. J Chemother. 2014;26(4): 229–234. 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