Infections caused by drug resistant gram-negative bacteria, particularly CRE, are becoming increasingly prevalent and constitute a serious threat to public health worldwide because they are difficult to treat and are associated with higher morbidity and mortality rates . The incidence of CRE infection in China was reported to be 4.0 per 10,000 discharges , and the mortality rates from CRE bacteremia have ranged from approximately 19–70% [27, 28]. Infection with carbapenem-resistant gram-negative bacteria may also increase medical costs . To better understand the burden of CRE infection, our study explored the direct economic costs and indirect economic loss of CRE-BSI infection and its dynamic changes in recent years.
The most important finding of this study was that carbapenem resistance had major effects on patient outcomes and socioeconomic burden of Enterobacteriaceae BSI. Compared with patients in the CSE-BSI group, those in the CRE-BSI group were more likely to have nosocomial infections, undergo organ transplantation, be admitted to the ICU, and have more severe disease (APACHEII and Pitt scores) and more comorbidities (Charlson score). To eliminate potential confounding factors for outcomes, the two groups of patients were subjected to PSM, minimizing possible sources of bias, such as demographic characteristics and disease severity. This study found that the median per capita total direct medical costs ($24940.1 vs. 16864.0, P = 0.017) and indirect economic loss ($3848.5 vs. 1139.9, P = 0.304) were higher in patients with CRE-BSI than with CSE-BSI, confirming that carbapenem resistance increased the economic burden of disease. This finding was consistent with studies showing that carbapenem resistance was associated with higher medical costs in patients infected with K. pneumoniae  and E. coli . In addition, the median economic burden for hospitals of a single patient infected with CRE was about $59366.2, far more than the average person in China can afford.
The differences in direct economic burden between the two groups was caused primarily by the higher costs of antibiotics in the CRE group. Similarly, the cost of antibiotics, especially broad-spectrum antibiotics, has been reported to contribute to the high direct medical expenses in patients with CRE . Another study, however, reported that the cost of antibacterial drugs accounted for a small part of the total cost of hospitalization . However, we found that the cost of medicine was the largest single direct medical cost, with antibiotics accounting for 23.7% ($5904.9/$24940.1) of all direct medical costs in CRE infected patients. Thus, although other factors were more responsible for direct medical costs in these patients, the contribution of antibiotics to all costs should not be underestimated. Implementation of antibiotic stewardship practices may therefore reduce the economic burden on individuals, hospitals, and society.
The indirect loss analyzed in this study consisted primarily of reduced working time and socially creative productivity resulting from a patient's illness, disability, or death. Although these costs are frequently determined using a capital- or output-accounting approach, this method has certain limitations . The indirect economic loss due to disease in this study was analyzed by determining DALY, a new disease burden index. The present study found that DALY and indirect economic loss were higher in patients infected with CRE than with CSE, but the differences were not statistically significant. Analysis of indirect economic loss in different age groups showed that this loss was highest in patients aged 16–29 years, which may be related to different productivity weights. In addition, indirect economic loss in this group increased yearly. Combined with the increasing incidence of CRE, these findings suggest that the indirect economic loss caused by CRE infection may continue to increase over time.
Similar to previous findings , the present study found that mortality rates were significantly higher in patients with CRE-BSI than with CSE-BSI (P < 0.05), emphasizing the clinical effects of carbapenem resistance. Although hospital LOS was greater in the CRE-BSI than in the CSE-BSI group, the difference was not statistically significant. PSM that included LOS as a potential confounding variable resulted in a similar median LOS in the two groups, indicating that the effect of carbapenem-resistance on hospital LOS was due to longer hospital LOS before infection . These findings suggest that hospital LOS was unrelated to the increase in medical costs.
This study had several limitations. First, this study was a retrospective analysis, which has certain selection and recall biases. Although PSM was performed to control for potential confounding factors, some unmeasured confounders remained present. Second, the socioeconomic burden of disease also includes indirect medical expenses and intangible economic burdens such as psychosocial costs. Because these costs are difficult to estimate, they were omitted from the cost estimates in this study. Finally, this single center study only included patients infected with K. pneumoniae and E. coli. Thus, our findings may not represent the economic burden of infection with other types of Enterobacteriaceae.
In conclusion, infection with carbapenem-resistant bacteria resulted in higher direct and indirect economic costs. Although CRE-BSI did not significantly affect hospital LOS, mortality rates were higher in patients with CRE-BSI than with CSE-BSI. Medicines accounted for the largest proportion of direct medical expenses in both groups, suggesting the need for stricter regulation of antibiotic use. Indirect economic loss differed among age groups, likely due to differences in productivity weights.