The information on the economic burden of infections caused by antibiotic-resistant pathogens can only be obtained from observational cohort studies, which are highly susceptible to bias and confoundings25. So in the process of assessing the economic impact of the production of ESBL, the first thing we need to do is to eliminate the effects of intergroup differences on patients’ characteristics. Therefore, it is crucial to adjust for the relevant confounders when investigating the link between drug resistance and economic burden. In our study,there were no significant differences in baseline characteristics of patients (including patient demographics, comorbidity status, severity of illness, overall hospital length of stay (LOS) and LOS before/after the infection; susceptibility of empirical antimicrobials demographics, mortality) between ESBL-EC and non-ESBL-EC group were found.Therefore, We can directly compare the economic burden of the two groups without considering the confoundings.
Our study found that the production of ESBL did not lead to significant increase in direct costs. The direct cost of a ESBL-EC infection was $8048.68 and a non-ESBL-EC infection was $7476.84, with a difference of $571.84. However, Schwaber et al. 9 found that the average medic cost due to the production of ESBL was $9,620. Tumbarello et al. 8 found that ESBL BSIs were associated with more costly (+ EUR 5,026.00). This difference may be caused by the following reasons: first, in order to control the confounding factors, the previous studies may not have included a large enough sample size to evaluate the economic impact of ESBL infection. Next, there are differences in the inpatient environment, treatment level and test device, price of drugs in different regions and hospitals. Last but not least, Whether the patient caused by E.coli bacteremia had received rapid and effective empirical antibiotic treatment. In our study, before in vitro susceptibility test results were available, BLBLI and carbapenems were administered empirically in 85% of patients with non-ESBL-EC infection while 83.4% of patients with ESBL-EC infection. It shows that whether ESBL or not, BLBLI and carbapenems are mainly used in clinical patients with E. coli bloodstream infection, which makes no significant difference in the direct economic burden between the two groups. While other studies 8; 9 showed that higher hospital costs and longer hospitalization for patients infected E. coli BSIs areassociated with ESBL production and delay in appropriate therapy.
Clinicians should take risk factor for ESBL production into consideration when choosing empirical antimicrobials before in vitro susceptibility test results were available. For patients with low risk of ESBL-EC infection, the third cepholosprins, fuloroquinolones and aminoglygocides were recomded as the treatment choice. And in some studies BLBLI26; 27 and carbapenem28 were the most powerful antibiotics for the treatment of patients with high risk of ESBL-EC infection. However, in our study, for non-ESBL-EC infection group, only 26% of patients used recommended antimicrobials (cepholosprins, fuloroquinolones and aminoglygocides), 85% of patients used BLBLI and carbapenems. The reason why second-line and third-line antibiotics are chosen as empirical treatment drugs can be explained in our previous study10, older age, the presence of comorbidities, intensive care unit (ICU) stay, recurrent urinary tract infections (UTI), previous use of antibiotics, previous colonization with ESBL-producing commensal bacteria, and higher ESBL prevenlence were identified as risk factors for acquisition BSI caused by ESBL-producing Enterobacteriaceae.29; 30; 31; 32. There are many risk factors for ESBL infection in patients with non-ESBL-EC BSI, so clinicians tend to choose antimicrobial agents covering ESBL-producing bacteria as empirical antibiotic therapy 33. In the short term, the use of second and third line antibiotics can improve the cure rate, reduce the direct and indirect costs for individual and society, but in the long term, the use of antibiotics across the ladder will lead to the increase and spread of resistance of advanced antibiotics, so for the rational application of antibiotics, clinicals need to balance individual and societal needs.
For the socio-economic impact, 247 patients infected with ESBL-EC lost 531.05 DALYs in total, with an average of 2.15 DALYs per person.While 333 patients infected with non-ESBL-EC lost 692.64 DALYs in total, with an average of 2.08 DALYs per person. And E.coli bacteremia had a higher burden in women. At present, there are few studies on the calculation of indirect economic burden of E.coli bloodstream infection measure by DALYs combined with human capital method, which are basically used for chronic disease investigation. In 2018, in order to evaluate the burden of communicable diseases, Alessandro Cassini et.al 34 used DALYs to calculate the burden of several selected infectious diseases. For viral infections, the per case burden of influenza, human immunodeficiency virus infection, and hepatitis B was 0.01 DALYs, 6.03 DALYs, 2.79 DALYs respectively. For bacterial infections, the per case burden of invasive pneumococcal disease, tuberculosis, and invasive Haemophilus influenzae disease was 2.74 DALYs, 3.58 DALYs, 3.43 DALYs respectively. Rabies had the highest per case burden (52.1 DALYs) compared to other infectious illness discussed in this study34. In our study, E.coli bloodstream had a significantly lower burden compared to the infctious diseases discussed above (except influenza). We can also infer from these data that the duration of E.coli bloodstream is not as long as that of pneumococcal disease, hepatitis B, Haemophilus influenzae disease, etc. For E.coli bloodstream, 0.07 DALYs were produced due to the production of ESBL, which is seven times the burden of influenza. Hence using DALYs can quantify and compare the burden of different diseases. espically using DALYS to evaluate the burden of antimicrobial resistant pathogens can help decision makers to measure how much resources and energy should be invested to track and control the spread of antimicrobial-resistant organisms.
However, there are still some limitations in our study. At first, this was a retrospective single-center study with inherent biases.The disease prevelence and treatment options in this hospital might have had an impact on the results. Andthe situation inother medical institutions or healthcare systems might be different. Secondly, this was an observational study, not a randomized controlled trial, so our fingdings are susceptible to unmeasured confounding at both the hospital and patient levels.Thirdly, due to difficulties about statistic measurement and calculation, our study ignored direct non-medical costs and intangible economic burden including transportation costs, food costs and others, which may lead the results could not fully represent the socio-economic burden of disease.
In conclusion, patients with BSI due to ESBL-EC did not cost more than patients with BSI due to non-ESBL-EC. This phenomenon may be attributed to timely and effective antibiotic treatment. But the antimicrobial stewardship should be implemented to avoid overaggresive use of second and third line antibiotics in sensitive bacterial infctions.
Notes
Ethics approval and consent to participate:
Ethics approval for this study was submitted and approved through Research Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University. The consent to participate was waived by our institutional review board since this study was retrospective data collection.
Consent to publish:
Not applicable.
Availability of data and materials:
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Potential conflicts of interest:
None of the authors report conflicts of interest.
Financial support
This work was partially supported by grants from The National Key Research and Development Program of China (2017YFC1200203) and National Natural Science Foundation of China (81971984) .