Clinical management of CRE infections is complex, especially when the evidence in this population is limited. To unify the evidence of the economic value of treatments together with clinical efficacy, a simplified decision tree was developed and validated by clinicians with extensive clinical experience in the management of these infections and critically ill patients, in this way, ensure that the economic model developed reflects the clinical practice of the country. The structure, temporary horizon and assumptions used are detailed below.
Model Structure
The decision tree was designed in Microsoft Office Excel version 1908. The model was based on data derived mainly from Van Duin et al. (11). This included the 30-day hospital follow-up with hospital discharge, mortality rate, duration of initial therapy, percentage of patients who develop renal failure, and the likelihood of receiving additional antibiotics.
Figure 1. Model structure
In the model, patients begin treatment with CAZ-AVI or COL + MEM. Colistin alone was excluded as a monotherapy comparator since, in the opinion of experts, it does not reflect clinical practice where combination therapies are usually the most appropriate treatment strategies (2). Moreover, the results of the clinical study by Paul et al., showed that the combination therapy, COL + MEM, generates similar clinical outcomes compared to colistin monotherapy (17), unfortunately, the low number of patients impaired the statistical power subgroups (18), different to A baumannii infections, and there is not another study to provide conclusive evidence.
In this model, therapeutic failure is supposed to occur between 48 and 72 hours, which represents an extension of treatment (19). This failure has been defined as the addition of other antibiotics (tigecycline or fosfomycin). Patients who respond and do not require a second antibiotic will be discharged home according to the probability of occurrence of it reported by Van Duin et al. (11), and the treatment length will be 10 days as was observed in the same study. Among those who do not respond, a second antibiotic is added after 2–3 days; after this, a new 10-day course of treatment begins. Polymyxin and tigecycline would be as add-on treatment for CAZ-AVI and COL + MEM, in the proportions reported by Van Duin et al. (11). Renal failure probability used was the reported in the observational study after the 30-days of follow up.
Effectiveness
Effectiveness was expressed as quality-adjusted life years (QALY), where cohort survival is calculated after 30 days of follow-up. The life years saved were calculated by multiplying the percentage of patients alive at the end of the follow-up by the life expectancy of this type of patient. The life expectancy reported in the National Administrative Department of Statistics (DANE) (20) was adjusted to relative risk of death for survivors of 0.51, according to a study by Garcia-Hernandez and Mayrhofer (21).
The model included two health state utilities, for patients who a clinical response 0.92, according to a study by Song et al.(22), and for patients who had therapeutic failure 0.61, according to the publication by Delate et al.(23).
Costs
All costs are reported in dollars (USD) 2019. The exchange rate used was COP$3,282 per dollar (24). The costs of medications were obtained from the January to March 2019 reports of the Drug Price Information System (i.e. SISMED). For dose determination, he average weight of 65 kg was assumed. The daily dosage was derived for colistin from the study by Van Duin study (11); meropenem, from the study by Paul et al. (17); and the other antibiotics, including CAZ-AVI, from the study by Morrill et al. (2).
Table 1. Total treatment costs
Table 1
| | Daily dose | Mean cost per unit |
Treatments | | | |
Meropenem, g | | 6 | $ 6.53 |
Colistin, million unit (MIU) | Loading dose | 3* | $ 11.83 |
Maintenance dose | 4.5* |
CAZ-AVI, g | | 7.5 | $ 40.23 |
Additional treatments | | | |
Tigecycline, mg | | 100 | $ 21,61 |
Fosfomycin, g | | 12 | $ 2,29 |
*Average weight 60 kg | | | |
The fees in the Mandatory Traffic Accident Service (i.e. SOAT) (25) and Tariff Manual ISS 2001 (26) manuals were used for hospital costs, and include the monitoring costs and stays in ward and in the Intensive Care Unit (ICU).
The cost associated with the adverse event of treatment-related renal failure was extracted from the published literature (27), and from the Electronic System for Public Procurement (i.e. SECOP)(28). To update prices, the Consumer Price Index (CPI) reported by the Central Bank was used (29).
Table 2. Costs inputs
Table 2
| | Mean | | SD |
Hospitalization | | | | |
Ward | | $ 35 | | $ 32 |
ICU | | $ 313 | | $ 207 |
Adverse event | | | | |
Renal failure | | $ 426 | | $ 145 |
Dialysis | | $ 1,197 | | $ 189 |
Paraclinics | | | |
Colistin-meropenem | | $ 15 | | $ 11 |
CAZ-AVI | | $ 5 | | $ 4 |
Sensitivity analyses
To assess the robustness of the study findings, univariate sensitivity analyzes were performed to examine the impact of the key variables on the incremental cost-effectiveness ratio (ICER). The data of utilities, costs, proportion of patients who developed renal failure, treatment length and failure, and the dose of colistin were the variables selected for this analysis. Furthermore, mortality observed in the Paul study in patients with Enterobacteriaceae treated in Colistin plus meropenem was evaluated.
The probabilistic sensitivity analysis (PSA) was carried out assuming distributions for the model parameters. For clinical parameters and utilities, it was assumed that they followed Beta or Uniform distributions and, in terms of cost parameters, Gamma distribution. The results of this analysis are presented in the acceptability curve.