Abstract
Background
Carbapenem-resistant Enterobacterales (CRE) infections pose a global health concern owing to their increasing incidence and limited treatment options. Ceftazidime–avibactam (CAZ-AVI) has emerged as a promising therapeutic option, with some studies reporting improved outcomes in CRE bacteremia. However, evidence regarding its survival benefit remains unclear, particularly in Korea. In this retrospective cohort study, we compared the effectiveness of CAZ-AVI with the best available therapy (BAT) in patients with CRE bacteremia.
Methods
We included adult patients with CRE bacteremia treated at a tertiary hospital between January 2022 and July 2024. Patients were grouped based on receipt of CAZ-AVI within 5 days of blood culture versus the BAT. The 14-day mortality was compared between the two groups using Pearson’s χ2 test and the log-rank test. Multivariable Cox regression was performed to evaluate the independent association between CAZ-AVI use and 14-day mortality.
Results
Among 194 patients, 32 (16.5%) and 162 (83.5%) received CAZ-AVI and BAT for CRE bacteremia, respectively. The 14-day mortality rate was significantly lower in the CAZ-AVI group than in the BAT group (12.5% vs. 32.1%, P = 0.043). Kaplan–Meier analysis showed improved 14-day survival with CAZ-AVI (log-rank test, P = 0.027). Multivariable analysis showed that CAZ-AVI use (hazard ratio [HR], 0.34; 95% confidence interval [CI], 0.12–0.98; P = 0.046) was significantly associated with reduced mortality, whereas chronic kidney disease (HR, 2.23; 95% CI, 1.09–4.59; P = 0.029), Pitt bacteremia score (HR, 1.10; 95% CI, 1.01–1.20; P = 0.027), and neutropenia (HR, 2.28; 95% CI, 1.00–5.19; P = 0.049) were associated with increased mortality.
Conclusion
CAZ-AVI use was associated with improved survival in CRE bacteremia and can be considered for therapy.
Keywords: Ceftazidime-Avibactam, Bacteremia, Mortality, Survival, Carbapenem-Resistant Enterobacterales
Graphical Abstract
INTRODUCTION
Carbapenem-resistant Enterobacterales (CRE) infections pose a global health threat owing to their increasing incidence. Enterobacterales, a major cause of healthcare-associated infections, account for approximately 30% of all cases.1 Carbapenems have been considered the last-line treatment for multidrug-resistant gram-negative bacterial infections; however, resistance to carbapenems has increased in recent years.2,3,4 In Korea, notified CRE infections increased from 11,954 cases in 2018 to 38,405 cases in 2023, a nearly 3-fold increase.5 Particularly, CRE bacteremia is associated with high morbidity and mortality,6,7 with fatality rates ranging from 42% to 55%.1,8 Patients with CRE bacteremia spend 50 days longer in hospitals and incur $70,000 more in healthcare costs.8 In 2017, the socioeconomic burden of CRE bacteremia in Korea accounted for approximately $46 million.8
Ceftazidime–avibactam (CAZ-AVI) is an effective antibiotic for treating CRE infections. It is a combination of the anti-pseudomonal cephalosporin ceftazidime and novel non-β-lactam β-lactamase inhibitor avibactam.9 Avibactam maintains the activity of ceftazidime by inhibiting a broad spectrum of β-lactamases, including Ambler class A (e.g., TEM-1, CTX-M-15, Klebsiella pneumoniae carbapenemase [KPC]-2, KPC-3), class C (e.g., AmpC), and class D β-lactamases (e.g., OXA-10, OXA-48).10,11 Additionally, CAZ-AVI has demonstrated efficacy against complicated urinary tract and intra-abdominal infections, as well as hospital-acquired pneumonia in several randomized controlled phase 3 clinical trials.12,13,14,15,16,17 Current guidelines recommend CAZ-AVI as the preferred antibiotic for treating CRE infections, except for infections with metallo-β-lactamase (MBL)-producing bacteria.18,19,20
Although several studies have reported improved clinical outcomes with CAZ-AVI in CRE bacteremia, its survival benefit remains unclear.21,22,23,24,25 In particular, no studies have analyzed the effect of CAZ-AVI on CRE bacteremia in Korea. Thus, in this study, we aimed to compare the effects of CAZ-AVI and the best available therapy (BAT) on mortality in patients with CRE bacteremia.
METHODS
Study design and population
In this retrospective cohort study, we compared the effects of CAZ-AVI and BAT on mortality in patients with CRE bacteremia. Conducted at Severance Hospital, a large tertiary teaching hospital with 2,400 beds in Korea, the study included patients diagnosed with CRE bacteremia between January 2022 and July 2024. CAZ-AVI was introduced in Korea in July 2023, and its use expanded following its coverage by the National Health Insurance in February 2024. To ensure an adequate sample size, the study period included the time before the introduction of CAZ-AVI.
CRE bacteremia was defined as the presence of Enterobacterales in blood cultures with in vitro resistance to at least 1 carbapenem class antibiotic. The exclusion criteria were as follows: 1) positive blood cultures from central catheters only, 2) death within 72 hours of diagnosis, 3) polymicrobial infections, 4) not using a predefined BAT regimen, 5) infections with MBL-producing organisms, or 6) delayed CAZ-AVI treatment (> 5 days after blood culture). The BAT regimen comprised combination therapies including colistin, carbapenems, tigecycline, and/or aminoglycosides.19,26 The patients were categorized into 2 groups: those receiving CAZ-AVI and those receiving BAT within 5 days of blood culture.
Variables and outcome measures
Medical records of patients were retrospectively reviewed for the following variables: demographic characteristics (age and sex), comorbidities, laboratory findings, source of infection, mechanical ventilation, renal replacement therapy, Pitt bacteremia score,27 vasopressor administration, microbiological characteristics, and antibiotics used. The Charlson Comorbidity Index was calculated to estimate the severity of comorbid conditions.28 Infection sources were categorized based on the definitions provided in the National Healthcare Safety Network Patient Safety Manual.29 Catheter-related bloodstream infections were considered to be present if the same strain was detected in both the central catheter or catheter tip culture and peripheral blood culture.30 Septic shock was characterized according to the Sepsis-3 definition, which includes a change in the total Sequential Organ Failure Assessment Score of ≥ 2 points, use of vasopressors, and a lactate level > 2 mmol/L.31 Neutropenia was defined as counts < 1,000 cells/μL. Antibiotics included in the analysis were those administered as definitive therapy for 2–5 days following blood culture collection. The outcomes were 14- and 30-day mortality rates, microbiological clearance, and relapse. Microbiological clearance was defined as negative results in all blood cultures collected on the same day following the onset of CRE bacteremia. Relapse was defined as the recurrence of CRE bacteremia at least two weeks after the end of treatment.
Microbiological tests
Bacterial identification was conducted using the Bruker Biotyper matrix-assisted laser desorption ionization-time of flight mass spectrometry (Bruker Daltonics, Bremen, Germany). Antibiotic susceptibility testing was performed using the VITEK 2 automated analyzer system with a VITEK AST2 N212 card (bioMérieux, Marcy l’Etoile, France), and the results were interpreted according to the Clinical and Laboratory Standards Institute guidelines.32 Carbapenemase production and type were determined using the NG-Test Carba 5 (NG-Biotech, Guipry-Messac, France) immunochromatographic assay and disc carbapenemase test.33,34
Statistical analysis
The Shapiro–Wilk test was used to assess normality of continuous variables. Continuous variables were compared using independent t-tests for normally distributed data and Mann-Whitney U tests for non-normally distributed data. Pearson’s χ2 test or Fisher’s exact test was used to analyze categorical variables. Survival analysis was performed using the log-rank test to compare 14-day mortality between the groups. Multivariable Cox regression analysis was performed to determine the independent association between CAZ-AVI use and 14-day mortality. The independent variables included age, sex, comorbidities, source of infection, Pitt bacteremia score, neutropenia, and use of CAZ-AVI. Stepwise variable selection was applied to identify the most relevant predictors, with variables related to immunocompromised status—including solid cancer, hematologic malignancy, solid organ transplantation, stem cell transplantation, and neutropenia—prespecified to remain in the model as clinically important covariates for mortality. A post-hoc analysis was conducted to evaluate the impact of antibiotic regimens potentially suboptimal based on minimal inhibitory concentrations (MICs). A variance inflation factor > 10 indicated multicollinearity. Differences were considered statistically significant at P values < 0.05. All statistical analyses were performed using R v.4.2.2 (The R Foundation for Statistical Computing, Vienna, Austria).
Ethics statement
This study involving human participants was conducted in accordance with the ethical standards of the institutional and national research committee and 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Institutional Review Board of Severance Hospital approved this study and informed consent was waived owing to the retrospective nature of the study (4-2024-1300).
RESULTS
Patient characteristics
Overall, 534 patients with CRE bacteremia were identified (Fig. 1). Among them, we excluded 167 patients with positive cultures only from central catheters, 38 who died within 72 hours, 118 who did not receive the BAT regimen, 9 who received delayed CAZ-AVI treatment, 6 with MBL-producing carbapenemase-producing Enterobacterales (CPE) infections, and 2 with polymicrobial infections. After exclusion, 194 patients were included in the final analysis. Among them, 32 (16.5%) patients received CAZ-AVI, whereas 162 (83.5%) received BAT for the treatment of CRE bacteremia. The overall 14-day and 30-day mortality rates were 28.9% and 40.2%, respectively. In the CAZ-AVI group, the median time from bacteremia onset to CAZ-AVI administration was 3 (interquartile range [IQR], 2–4) days.
Fig. 1. Flowchart illustrating the study design.
CRE = carbapenem-resistant Enterobacterales, BAT = best available therapy, MBL = metallo-β-lactamase.
The median age of the CAZ-AVI and BAT groups was 59.0 (IQR, 47–67.5) years and 62.0 (IQR, 52.0–69.0) years, respectively (Table 1). Compared with the BAT group, the CAZ-AVI group had significantly fewer patients with solid cancers (18.8% vs. 43.8%; P = 0.014), more patients with leukemia (25.0% vs. 9.9%; P = 0.034), and a higher proportion of patients who had undergone stem cell transplantation (21.9% vs. 4.9%; P = 0.004). Additionally, neutropenia was significantly more common in the CAZ-AVI group than in the BAT group (46.9% vs. 21.6%; P = 0.006). No significant differences in the source of infection, disease severity, microorganisms, carbapenemase production, or carbapenemase type were observed between the 2 groups.
Table 1. Clinical and microbiological characteristics of the study population.
| Characteristics | Total (N = 194) | CAZ-AVI (n = 32) | BAT (n = 162) | P value | |
|---|---|---|---|---|---|
| Age, yr | 62.0 (51.0–69.0) | 59.0 (47.0–67.5) | 62.0 (52.0–69.0) | 0.205 | |
| Female, sex | 75 (38.7) | 9 (28.1) | 66 (40.7) | 0.254 | |
| HTN | 75 (38.7) | 10 (31.2) | 65 (40.1) | 0.457 | |
| DM | 52 (26.8) | 10 (31.2) | 42 (25.9) | 0.687 | |
| Chronic liver disease | 47 (24.2) | 9 (28.1) | 38 (23.5) | 0.736 | |
| Chronic kidney disease | 31 (16.0) | 3 (9.4) | 28 (17.3) | 0.394 | |
| Cerebrovascular disease | 24 (12.4) | 6 (18.8) | 18 (11.1) | 0.243 | |
| Solid cancer | 77 (39.7) | 6 (18.8) | 71 (43.8) | 0.014 | |
| Leukemia | 24 (12.4) | 8 (25.0) | 16 (9.9) | 0.034 | |
| Lymphoma | 18 (9.3) | 3 (9.4) | 15 (9.3) | > 0.999 | |
| Solid organ transplantation | 45 (23.2) | 9 (28.1) | 36 (22.2) | 0.621 | |
| Stem cell transplantation | 15 (7.7) | 7 (21.9) | 8 (4.9) | 0.004 | |
| Charlson Comorbidity Index | 3.0 (2.0–5.0) | 2.0 (2.0–3.5) | 3.0 (2.0–5.0) | 0.143 | |
| Source of infectiona | |||||
| Primary bacteremia | 12 (6.2) | 4 (12.5) | 8 (4.9) | 0.115 | |
| Pneumonia | 68 (35.1) | 7 (21.9) | 61 (37.7) | 0.132 | |
| Intra-abdominal infection | 58 (29.9) | 7 (21.9) | 51 (31.5) | 0.382 | |
| Urinary tract infection | 14 (7.2) | 4 (12.5) | 10 (6.2) | 0.254 | |
| CRBSI | 76 (39.2) | 14 (43.8) | 62 (38.3) | 0.702 | |
| Pitt bacteremia score | 2.0 (0.0–5.0) | 2.0 (0.0–3.5) | 2.0 (0.0–6.0) | 0.631 | |
| Septic shock | 53 (27.3) | 7 (21.9) | 46 (28.4) | 0.590 | |
| Renal replacement therapy | 41 (21.1) | 5 (15.6) | 36 (22.2) | 0.550 | |
| Ventilator | 67 (34.5) | 8 (25.0) | 59 (36.4) | 0.299 | |
| Neutropenia | 50 (25.8) | 15 (46.9) | 35 (21.6) | 0.006 | |
| Klebsiella pneumonia | 189 (97.4) | 32 (100.0) | 157 (96.9) | 0.593 | |
| Escherichia coli | 3 (1.5) | 0 (0.0) | 3 (1.8) | > 0.999 | |
| Other organismsb | 2 (1.0) | 0 (0.0) | 2 (1.2) | > 0.999 | |
| Carbapenemase-producing | 188 (96.9) | 32 (100.0) | 156 (96.3) | 0.592 | |
| KPC | 182 (93.8) | 30 (93.8) | 152 (93.8) | > 0.999 | |
| OXA | 6 (3.1) | 2 (6.2) | 4 (2.5) | 0.258 | |
Data are presented as numbers (%) or median (interquartile range).
CAZ-AVI = ceftazidime–avibactam, BAT = best available therapy, HTN = hypertension, DM = diabetes mellitus, CRBSI = catheter-related bloodstream infection, KPC = Klebsiella pneumoniae carbapenemase.
aPatients can have multiple sources of infection; therefore, the combined percentages can exceed 100%.
bOther organisms included K. aerogenes and Serratia marcescens.
The most common source of infection was catheter-related bloodstream infection (CAZ-AVI: 43.8% vs. BAT: 38.3%), followed by pneumonia (CAZ-AVI: 21.9% vs. BAT: 37.7%) and intra-abdominal infections (CAZ-AVI: 21.9% vs. BAT: 31.5%; Table 1). Primary bacteremia occurred in 12.5% and 4.9% of the patients in the CAZ-AVI and BAT groups, respectively. The predominant causative organism was K. pneumoniae, accounting for 100.0% and 96.9% of the isolates in the CAZ-AVI and BAT groups, respectively. Most organisms produced carbapenemases (CAZ-AVI: 100.0% vs. BAT: 96.3%), with KPC being the predominant carbapenemase type (CAZ-AVI: 93.8% vs. BAT: 93.8%). Furthermore, OXA-producing strains accounted for 6.2% and 2.5% in the CAZ-AVI and BAT group, respectively.
We identified the treatment regimens used in the BAT group. The most common regimen was a combination of carbapenem and amikacin, which was administered to 118 (72.8%) patients. A combination therapy consisting of colistin, carbapenem, and amikacin was administered to 34 (21.0%) patients. Additionally, colistin plus carbapenem and colistin plus amikacin were administered to 4 patients (2.5%) each, while carbapenem plus gentamicin, and carbapenem plus tigecycline were administered to 1 patient each.
Outcomes
The 14-day mortality was significantly lower in the CAZ-AVI group than in the BAT group. The 14-day mortality rates were 12.5% and 32.1% in the CAZ-AVI and BAT groups, respectively (P = 0.043; Table 2). The Kaplan–Meier curves showed that the CAZ-AVI group had significantly improved 14-day mortality than the BAT group (log-rank test: P = 0.027; Fig. 2).
Table 2. Comparison of clinical outcomes between CAZ-AVI and BAT in patients with CRE bacteremia.
| Outcomes | Total (N = 194) | CAZ-AVI (n = 32) | BAT (n = 162) | P value |
|---|---|---|---|---|
| 14-day mortality | 56 (28.9) | 4 (12.5) | 52 (32.1) | 0.043 |
| 30-day mortality | 78 (40.2) | 9 (28.1) | 69 (42.6) | 0.184 |
| Microbiological clearance | 153 (78.9) | 29 (90.6) | 124 (76.5) | 0.122 |
| Relapse | 65 (41.9) | 10 (34.5) | 55 (43.7) | 0.488 |
Data are presented as numbers (%).
Relapse was defined as the recurrence of CRE bacteremia after 2 weeks.
CAZ-AVI = ceftazidime–avibactam, BAT = best available therapy, CRE = carbapenem-resistant Enterobacterales.
Fig. 2. Kaplan–Meier survival curves of patients with carbapenem-resistant Enterobacterales bacteremia.
BAT = best available therapy, CAZ-AVI = ceftazidime–avibactam.
The 30-day mortality rate was lower in the CAZ-AVI group (28.1%) than in the BAT group (42.6%); however, the difference was not significant. The microbiological clearance rate was higher in the CAZ-AVI group (90.6%) than in the BAT group (76.5%), and the relapse rate was lower (CAZ-AVI: 34.5% vs. BAT: 43.7%); however, neither difference was significant.
Independent risk factors for mortality
In the univariable analysis, CAZ-AVI use was significantly associated with improved 14-day mortality (hazard ratio [HR], 0.34; 95% confidence interval [95% CI], 0.12–0.93; P = 0.035; Table 3). Other variables significantly associated with 14-day mortality included septic shock and renal replacement therapy. The multivariable analysis showed that CAZ-AVI use was significantly associated with reduced 14-day mortality after adjustment (HR, 0.34; 95% CI, 0.12–0.98; P = 0.046). The other risk factors for mortality were chronic kidney disease (HR, 2.23; 95% CI, 1.09–4.59; P = 0.029), Pitt bacteremia score (HR, 1.10; 95% CI, 1.01–1.20; P = 0.027), and neutropenia (HR, 2.28; 95% CI, 1.00–5.19; P = 0.049).
Table 3. Multivariable Cox regression for 14-day mortality in patients with CRE bacteremia.
| Characteristics | Univariable analysis | Multivariable analysis | |||
|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | ||
| Age, yr | 1.02 (1.00–1.03) | 0.102 | |||
| Female, sex | 1.10 (0.65–1.87) | 0.727 | |||
| HTN | 1.15 (0.68–1.96) | 0.604 | |||
| DM | 1.10 (0.61–1.96) | 0.757 | |||
| Chronic liver disease | 0.89 (0.47–1.69) | 0.730 | |||
| Chronic kidney disease | 1.54 (0.81–2.92) | 0.185 | 2.23 (1.09–4.59) | 0.029 | |
| Cerebrovascular disease | 0.78 (0.34–1.83) | 0.570 | |||
| Solid cancer | 1.47 (0.87–2.48) | 0.152 | 1.72 (0.91–3.26) | 0.094 | |
| Leukemia | 1.39 (0.68–2.84) | 0.362 | 1.73 (0.67–4.49) | 0.261 | |
| Lymphoma | 0.93 (0.37–2.34) | 0.886 | 0.85 (0.28–2.55) | 0.775 | |
| Solid organ transplantation | 0.58 (0.29–1.19) | 0.140 | 0.56 (0.25–1.28) | 0.169 | |
| Stem cell transplantation | 0.65 (0.20–2.08) | 0.470 | 0.82 (0.23–2.92) | 0.764 | |
| Charlson comorbidity index | 1.13 (1.00–1.27) | 0.054 | |||
| Source of infection | |||||
| Primary bacteremia | 0.24 (0.03–1.72) | 0.155 | 0.25 (0.03–1.88) | 0.178 | |
| Pneumonia | 1.58 (0.93–2.68) | 0.088 | |||
| Intra-abdominal infection | 0.90 (0.50–1.62) | 0.715 | |||
| Urinary tract infection | 0.69 (0.22–2.21) | 0.531 | |||
| CRBSI | 0.86 (0.50–1.49) | 0.588 | |||
| Pitt bacteremia score | 1.07 (0.99–1.16) | 0.108 | 1.10 (1.01–1.20) | 0.027 | |
| Neutropenia | 1.31 (0.74–2.31) | 0.356 | 2.28 (1.00–5.19) | 0.049 | |
| CAZ-AVI use | 0.34 (0.12–0.93) | 0.035 | 0.34 (0.12–0.98) | 0.046 | |
Variance inflation factor was set to < 10 in the Cox regression model.
CRE = carbapenem-resistant Enterobacterales, HR = hazard ratio, CI = confidence interval, HTN = hypertension, DM = diabetes mellitus, CRBSI = catheter-related bloodstream infection, CAZ-AVI = ceftazidime–avibactam.
Post-hoc analysis
We identified that the BAT group included a substantial proportion of carbapenem-based regimens. Therefore, we examined the distribution of MICs for imipenem and performed a post-hoc analysis excluding patients who received carbapenems at an MIC ≥ 16 for imipenem. Overall, 80.2% of patients had an MIC ≥ 16 for imipenem, and this proportion was similarly high in the BAT group (78.1%; Supplementary Table 1). After excluding 72 patients meeting this criterion, 102 patients remained for analysis.
Multivariable Cox regression demonstrated that CAZ-AVI use remained significantly associated with reduced 14-day mortality (HR, 0.11; 95% CI, 0.03–0.39; P = 0.001; Supplementary Table 2). Other independent risk factors for 14-day mortality included stem cell transplantation, higher Charlson comorbidity index, higher Pitt bacteremia score, and neutropenia, whereas lymphoma was associated with reduced 14-day mortality.
DISCUSSION
We investigated the effect of CAZ-AVI on survival in patients with CRE bacteremia. The use of CAZ-AVI was significantly associated with reduced 14-day mortality, even after adjusting for other confounders. The CAZ-AVI group showed a trend toward better 30-day mortality, microbiological clearance, and relapse rates compared to the BAT group; however, these differences were not statistically significant. Other independent risk factors for 14-day mortality in patients with CRE bacteremia included chronic kidney disease, higher Pitt bacteremia score, and neutropenia.
This study is significant as it is the first to analyze the efficacy of CAZ-AVI in CRE infections in Korea. Although CRE infections are rapidly increasing in Korea, no studies have been conducted on the effectiveness of CAZ-AVI for the treatment of CRE owing to the delayed introduction of novel β-lactam/β-lactamase inhibitors.5,8 Prior studies on the treatment of CRE bacteremia in Korea have predominantly focused on the efficacy of combination therapies, including colistin, aminoglycosides, carbapenem, and tigecycline.1,35,36 Although these studies demonstrated that the use of at least one in vitro susceptible antibiotic significantly improved survival rates, no significant differences in mortality were observed across different combination regimens. To our knowledge, this is the first study to evaluate the effectiveness of CAZ-AVI for CRE bacteremia after its introduction in Korea. The findings are significant because they show that CAZ-AVI is a treatment associated with improved survival for patients with CRE bacteremia in Korea.
Several studies outside Korea have evaluated the effectiveness of CAZ-AVI in treating CRE bacteremia and reported improved clinical outcomes. Shields et al.21 studied 109 patients with carbapenem-resistant (CR) K. pneumoniae bacteremia (including 13 patients treated with CAZ-AVI) and found that CAZ-AVI significantly improved clinical outcomes compared with those following other antibiotic regimens. Tumbarello et al.25 conducted the largest cohort study on CAZ-AVI use in CRE bacteremia, comparing 104 patients with KPC-producing K. pneumoniae bacteremia who were administered CAZ-AVI to a matched cohort. The 30-day mortality rate in the CAZ-AVI group (36.5%) was significantly lower than that in the control group (55.7%). Karampatakis et al.37 conducted a meta-analysis to evaluate the efficacy of CAZ-AVI for treating CR K. pneumoniae infections and bacteremia and showed that it is more effective than other antimicrobials. Consistent with these results, we found that the use of CAZ-AVI was significantly associated with improved 14-day mortality rates.
The mortality rate observed in patients treated with CAZ-AVI in our study was notably lower than that reported in previous studies. A meta-analysis reported 14- and 30-day mortality rates of 45.1% and 42.9%, respectively, in patients with CRE infections, which were significantly higher than those observed in patients infected with carbapenem-susceptible strains.38 In a multicenter observational study in Korea, the 30-day mortality rate for patients with CRE bacteremia was also high at 50.6%.39 In our study, the 14-day mortality in the BAT group was 32.1%, comparable to previously reported rates, whereas the CAZ-AVI group had a markedly lower 14-day mortality of 12.5%. For 30-day mortality, the CAZ-AVI group had a lower rate (28.1%) compared with the BAT group (42.6%); however, this difference was not statistically significant. A meta-analysis evaluating the effectiveness of CAZ-AVI in patients with CR K. pneumoniae bacteremia reported a 30-day mortality of 28.6% in patients treated with CAZ-AVI versus 44.1% in those receiving other antimicrobial regimens, which is consistent with the 30-day mortality observed in our study.37 These findings support the conclusion that CAZ-AVI is an effective therapy for CRE bacteremia, in accordance with current guideline recommendations.18,19,20
In this study, microbiological clearance did not differ significantly between the CAZ-AVI and BAT groups. Previous studies have also analyzed the effect of CAZ-AVI versus other antibiotic regimens on microbiological clearance, but considerable variability existed across studies in terms of infection sites, comparator regimens, and clearance rate.37 In control groups, clearance rates ranged from 11.2% to 73.9%, whereas in CAZ-AVI-treated patients, clearance rates were consistently higher, ranging from 62.2% to 100%. CAZ-AVI was associated with significantly better outcomes in all studies included in the systematic review.37 Notably, microbiological clearance rates also varied according to the type of infection. Specifically, Tsolaki et al.40 included various infections and stratified patients by bacteremia versus non-bacteremia. In the study, the microbiological clearance rate in the control group was 73.9% for bacteremic patients but only 50% for non-bacteremic patients. Shi et al.41 focused on patients with pneumonia and compared CAZ-AVI with a tigecycline-based regimen, reporting clearance rates of 33.9% and 74.4% in the control and CAZ-AVI groups, respectively. In our study, all patients had CRE bacteremia, and clearance was confirmed solely by negative blood cultures. As a result, the CAZ-AVI group showed a high clearance rate of 90.6%, while the BAT group also demonstrated a relatively high clearance rate of 76.5%, which is comparable to the clearance rate of the bacteremia subgroup in the study by Tsolaki et al.40 Taken together, these findings suggest that microbiological clearance with non-CAZ-AVI regimens may vary depending on the site of infection. In bacteremia, BAT regimens may achieve high microbiological clearance rates, but this does not necessarily translate into clinical treatment success. Further studies are warranted to investigate differences in microbiological clearance with BAT regimens according to infection type.
Although this study included patients with CRE bacteremia, most cases were caused by CP K. pneumoniae, and all patients treated with CAZ-AVI were infected with CPE. In our cohort, K. pneumoniae accounted for 96.0% of causative organisms, with KPC being the predominant carbapenemase type (91.5%). National data on notified CPE cases in Korea indicate that, in 2023, 73.7% of all CRE isolates were CPE, with K. pneumoniae representing 72.4% of cases.5 In addition, Lee et al.42 reported the epidemiological characteristics of CRE bacteremia in Gyeonggi Province, finding that 60.8% of infections were caused by K. pneumoniae and 23.3% by Escherichia coli. Among all CRE cases, 53.1% were CPE, with KPC and NDM accounting for 73.0% and 22.4% of carbapenemase types, respectively. Compared with national epidemiology, our study cohort had a higher proportion of CPE, predominantly KPC, and higher prevalence of K. pneumoniae as the causative pathogen. This may reflect the limitations of single-center data and suggests that generalizing our findings to non-carbapenemase-producing (CP) CRE, other CP organisms, or non-K. pneumoniae species should be done with caution. Nevertheless, considering that KPC-producing K. pneumoniae remains the most common cause of CRE infections in Korea, the results of this study are likely to contribute meaningful evidence regarding the treatment of CRE bacteremia in the local context.
In this study, chronic kidney disease, higher Pitt bacteremia score, and neutropenia were identified as risk factors for mortality in patients with CRE bacteremia. Renal dysfunction has also been recognized as a risk factor for mortality in CRE infections in previous studies.43 This association may reflect increased morbidity due to chronic kidney disease; however, it is also possible that the recommended CAZ-AVI dosage adjustment based on renal impairment is insufficient, resulting in failure to achieve optimal therapeutic goals. Evidence suggests that dose reduction of CAZ-AVI based on renal function is an independent risk factor for mortality in patients with CPE bacteremia.44 Both the duration and severity of neutropenia have been reported as risk factors for mortality in patients with severe infections.45 Neutropenic patients have impaired phagocytic function and other immune deficits, which may further increase their susceptibility to severe infections.46 Additionally, the Pitt bacteremia score is a well-established predictor of mortality in bloodstream infections.47 Therefore, the risk factors identified in our study are consistent with previously reported findings. Further analyses are warranted to assess the impact of standard antibiotic dosing on clinical outcomes in patients with renal dysfunction.
Our study has some limitations. First, this was a single-center retrospective cohort study, with inherent limitations. Second, several baseline characteristics differed significantly between the CAZ-AVI and BAT groups, and unadjusted confounders may have been present. We were unable to evaluate the adequacy of non-antibiotic treatments, such as adequate source control. Antibiotic dosing and appropriateness of treatment based on antimicrobial susceptibility test results were not included in the analysis. Notably, the CAZ-AVI group included a higher proportion of severely immunocompromised patients (hematologic malignancies, stem cell transplantation, or neutropenia) who were at a greater risk of poor outcomes in infectious diseases. To account for this, variables related to immunocompromised status were included in the multivariable analysis regardless of statistical significance, and the results demonstrated a significant association between CAZ-AVI use and reduced 14-day mortality in patients with CRE bacteremia. Third, we evaluated the 14-day all-cause mortality as the outcome, which did not consider the specific cause of death. Fourth, we did not separately analyze the effectiveness of CAZ-AVI for specific infections, although we included patients with different underlying conditions that caused bacteremia. Finally, although this study focused on CRE bacteremia, most patients were infected with KPC-producing K. pneumoniae. In the CAZ-AVI group, all patients were found to have CPE. Therefore, the generalizability of our findings to infections caused by other organisms may be limited. These limitations can be addressed by conducting a multicenter prospective cohort study that evaluates the effectiveness of novel therapeutics, such as CAZ-AVI, to improve patient outcomes in various infectious diseases.
Overall, the use of CAZ-AVI was associated with improved survival in patients with CRE bacteremia. Therefore, CAZ-AVI can be considered for the treatment of CRE bacteremia. Further research is needed to evaluate the extent to which novel antibiotics, such as CAZ-AVI, can improve patient outcomes across different infectious diseases.
Footnotes
Funding: This work was supported by a faculty research grant from Yonsei University College of Medicine (grant number 6-2023-0084).
Disclosure: The authors have no potential conflicts of interest to disclose.
- Conceptualization: Ku NS.
- Data curation: Ahn JY, Lee Y.
- Formal analysis: Lee Y.
- Investigation: Lee Y.
- Methodology: Lee Y, Seong JE, Lee JA, Kim JH, Ahn JY, Jeong SJ, Choi JY, Yeom JS, Ku NS.
- Supervision: Kim JH, Ahn JY, Jeong SJ, Choi JY, Yeom JS, Ku NS.
- Visualization: Lee Y.
- Writing - original draft: Lee Y.
- Writing - review & editing: Lee Y, Seong JE, Lee JA, Kim JH, Ahn JY, Jeong SJ, Choi JY, Yeom JS, Ku NS.
SUPPLEMENTARY MATERIALS
Distribution of minimal inhibitory concentrations for imipenem in patients with CRE bacteremia
Multivariable Cox regression analysis of 14-day mortality in patients with CRE bacteremia after excluding those who received carbapenems with a minimal inhibitory concentration ≥ 16 for imipenem
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Distribution of minimal inhibitory concentrations for imipenem in patients with CRE bacteremia
Multivariable Cox regression analysis of 14-day mortality in patients with CRE bacteremia after excluding those who received carbapenems with a minimal inhibitory concentration ≥ 16 for imipenem