Introduction
Clostridium difficile is the most frequent bacterial cause of hospital-acquired diarrhoea [
1]. The annual incidence of CDI in Spain is estimated at 17.1 cases per 10,000 hospitalised patients [
2], ranging from 12.2 to 24.0 cases per 10,000 hospitalisations [
3,
4]. A study from the United Kingdom found that the rate of hospital mortality is much higher for patients with hospital-acquired CDI (15.3%) than for those without CDI (1.9%), with infection also substantially increasing the length of stay [
5].
One study estimated that 7600 episodes of CDI occurred annually in Spain, with an economic burden of €32,157,093 to the National Health System (NHS) [
6]. A study from the USA determined that recurrent CDI was associated with significantly greater likelihood of readmission to hospital (85% vs 41%, respectively;
p < 0.001) and longer length of stay when readmitted (mean 18.6 vs 7.6, respectively;
p < 0.001) than those patients without recurrent CDI [
7]. A recent economic review of published studies reporting CDI-associated burden revealed that in Spain, hospitalisation costs attributable to CDI among all patients were €4265 per patient, rising to €4885 per patient among those aged > 65 years [
8]. Furthermore, there was an incremental rise in the cost of treating an initial CDI episode (€3901), first recurrence (€4875) and second recurrence (€5916), with hospitalisation accounting for 96% of costs [
8].
Patients with CDI should be managed by discontinuing any antibiotic that might have affected the normal microbial ecology of the large intestine and the use of which favours the proliferation of
C. difficile, which releases toxins that induce an inflammatory response [
1,
9]. Guideline-recommended antibiotic treatments for initial, non-severe CDI include fidaxomicin, vancomycin [
10] or metronidazole [
11]. However, recurrent infection is common, occurring in up to 25% of cases treated with vancomycin or metronidazole [
12]. Recurrence may be due, among other reasons, to delayed recovery of the intestinal microbiota previously disrupted by CDI-directed treatment [
13].
Fidaxomicin is a narrow spectrum macrocyclic antibiotic indicated for the treatment of CDI in adults at a dose of 200 mg twice daily for 10 days [
11,
14] and has been associated with greater preservation of the intestinal microbiota than vancomycin [
15]. Fidaxomicin treatment also significantly lowers the incidence of recurrent CDI compared with vancomycin [
16‐
18]. A validated in vitro human gut model showed that an extended-pulsed fidaxomicin (EPFX) regimen enables the persistence of fidaxomicin at concentrations inhibitory to
C. difficile, facilitating intestinal microbiota recovery [
19]. The efficacy and safety of the EPFX regimen (200 mg oral fidaxomicin twice daily on days 1–5, followed by once-daily administration on alternate days on days 7–25), which uses the same number of tablets as the standard fidaxomicin regimen, were compared with standard vancomycin (125 mg orally, four times daily on days 1–10) in the EXTEND randomised, controlled trial of patients 60 years and older with CDI [
20]. The primary endpoint of sustained clinical cure rate 30 days after the end of treatment (day 55 for EPFX and day 40 for vancomycin; defined as clinical response at test of cure and no recurrence of CDI) was significantly higher with EPFX (70%) compared with vancomycin (59%;
p = 0.030). Until day 90, the rate of sustained clinical cure was significantly higher and recurrence was significantly lower in the EPFX than the vancomycin arm (
p ≤ 0.007 and
p ≤ 0.001, respectively) [
20]. An economic analysis of these data found that the reduced recurrence rate with EPFX made this regimen more cost-effective than vancomycin for first-line treatment of CDI in older patients from the perspective of the United Kingdom NHS [
21].
The objective of the present study was to evaluate the cost-effectiveness of EPFX compared with vancomycin for the treatment of CDI in patients aged 60 years and older from the perspective of the NHS in Spain.
Discussion
Our analysis of the treatment of CDI in patients aged 60 years and older revealed that the EPFX regimen was associated with a gain of 0.044 QALYs and a cost saving of €647 per patient compared with vancomycin. The EPFX regimen is a cost-effective treatment in most of the comparative analyses with vancomycin using the range of willingness-to-pay thresholds previously suggested for the NHS in Spain [
36,
37].
Any evaluation of our results must take into account both the strengths and potential limitations. Regarding the limitations, it should be borne in mind that this is a theoretical model which is, by definition, a simplified simulation of reality. Also, assumptions had to be made in the model with respect to second- and third-line treatment sequences, and with regard to recurrences, as there was no follow-up of patients who failed to respond to the initial treatment in the EXTEND study [
20]. In our model, FMT was the third-line treatment, although this practice is not widespread in Spain, highlighting the differences between clinical practice and recommendations in local, national and international treatment guidelines. However, this was regarded as the superior option as it is recommended by ESCMID and IDSA in the case of multi-recurrent CDI [
10,
11]. Owing to the need to complete the model in a way that was fair to both treatment options, two assumptions were applied with regard to third-line treatment: (i) clinical cure would occur in all cases and (ii) there would be no further recurrences. These assumptions were validated by the five clinical experts (authors JMA, BA, JC, SG, MS). Moreover, the same mortality rate was assumed regardless of whether patients received EPFX or vancomycin. In the EXTEND study, one treatment-related death occurred in a patient in the vancomycin treatment arm [
20]. The costs associated with recurrent episodes of CDI were assumed to be the same as those for the initial episode. This assumption was conservative, as recurrent CDI episodes can incur higher hospitalisation costs compared with initial episodes in clinical practice [
38], although a recent study that estimated resource utilisation for the treatment of initial and recurrent CDI was contradictory, finding higher treatment costs for initial compared with recurrent CDI episodes [
39].
The state utilities were not obtained from the EXTEND study, but rather from two published studies: one in patients with CDI, including recurrent CDI [
28], and the other in patients with CDI who developed infected wounds following surgery for bone fractures [
29]. Regarding the validity of performing our model from a Spanish healthcare perspective and sourcing utility data from other countries, it is notable that in a study based on 83,000 assessments of 44 EQ-5D health states from six European countries, including Spain, there was greater variability between individuals than between countries [
40]. All the costs used in our model were taken from Spanish sources [
6,
25‐
27].
The conservative nature of our model did not allow for the inclusion of potential costs associated with reducing the risk of transmission of infection, patient isolation and infection control measures, such as the use of disposable gloves and gowns. As has previously been suggested for standard-regimen fidaxomicin [
23], had these costs been included in our model, the results are likely to have been even more favourable for EPFX owing to the lower recurrence rate compared with vancomycin.
The structure of the current model is the same as the one used in a recently published study from the United Kingdom [
21]. As in our analysis, the study conducted in the United Kingdom concluded that the EPFX regimen would be the dominant treatment—both cost-saving and more effective than vancomycin [
21]—with the cost of a treatment cycle of vancomycin in the United Kingdom being considerably higher than the current regimen in Spain (€214 and €34.50, respectively) [
21,
25]. The probability that first-line EPFX was cost-effective at a willingness-to-pay threshold of £30,000/QALY was 76% for the patients in the United Kingdom [
21].
The EXTEND study demonstrated sustained clinical cure of CDI and significantly lower recurrence rates with EPFX than with vancomycin in a population of patients aged 60 years and older [
20]. The results of this economic model suggest that first-line treatment with EPFX would be cost-effective compared with vancomycin according to the willingness-to-pay thresholds normally considered in Spain.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.