In total, 226 hospitalized patients with blood cultures positive for CRE were screened for this study, with 187 non-duplicate patients ultimately being enrolled in our analysis (Fig. 1), including 164, 21, 1, and 1 CRE-BSI cases caused by K. pneumoniae,E. coli, Enterobacter cloacae, and Citrobacter freundii, respectively.
Analyzed patients exhibited a mean age of 67.0 years old (SD: 14.5), and were 61.5% (115/187) male . The most prevalent comorbid conditions in these individuals were cardiovascular disease (26.2%, 49/187), cerebrovascular disease (21.4%, 40/187), and chronic obstructive pulmonary disease (19.8%, 37/187), and 27.8% (52/187) of these individuals were immunocompromised. The most common suspected sources of CRE-BSIs were central venous catheter (CVC)-related infections (28.3%, 53/187), lower respiratory tract (LRT) infections (24.1%, 45/187) and abdominal infections (23.0%, 43/187). Of these patients, 33.2% (62/187) were hospitalized in the intensive care unit (ICU) at the time of BSI development, while just 4.3% (8/187) of cases were community-onset healthcare-associated infections. Appropriate empirical antimicrobial treatments were administered to 13.9% (26/187) of patients within 48 h following BIS onset, as detailed in Supplementary Material 4. The all-cause 30-day mortality rate for these patients was 41.7% (78/187), and the 30-day clinical failure rate was 61.0% (114/187) (Table 1).
Antimicrobial susceptibility testing results
Susceptibility rates of tested isolates to tigecycline and polymyxin B were excellent at over 90%, whereas just 73 isolates were tested for CAZ-AVI susceptibility, revealing a 78.1% (57/73) susceptibility rate. Respective rates of isolate susceptibility to sulfamethoxazole, amikacin, and gentamicin were 30.5% (57/187), 54.5% (102/187), and 26.7% (50/187), respectively. Resistance rates to other tested antimicrobial agents were over 90% (Supplementary Material 3).
Risk factors associated with CRE-BSI patient 30-day mortality
Relative to surviving CRE-BSI patients, those that were deceased at the end of the 30-day period exhibited higher APACHE II scores (median, 13.0 vs 10.0, P < 0.001) and Pitt scores (median, 3.0 vs 1.5, P < 0.001) at the time of BSI. Deceased patients also exhibited higher incidence of immunocompromising conditions (42.3%, vs 17.4%, P < 0.001), primary BSI (11.5% vs 2.8%, P = 0.016), and ICU hospitalization at time of BSI onset 42.3% vs 26.6%, P = 0.025). The number of days of appropriate antimicrobial treatment was also decreased for deceased patients relative to survivors (median, 10.0 vs 12.0, P = 0.049) (Table 1).
Multivariate backward stepwise logistic regression analysis indicated that Pitt score [odds ratio (OR) 5.313, 95% confidence interval (CI) 3.209 - 8.797, P < 0.001], immunocompromised status (OR 4.605, 95% CI 1.629 - 13.020, P = 0.004), and a meropenem MIC ≥ 8 mg/L (OR 3.736, 95% CI 1.091 - 12.795, P = 0.036) were positively associated with 30-day mortality, whereas source control of infection (OR 0.316, 95% CI 0.117 - 0.854, P = 0.023) and appropriate empirical therapy (OR 0.129, 95% CI 0.027 - 0.625, P = 0.011) were negatively correlated with 30-day mortality in these CRE-BSI pateints (Table 2).
The impact of definitive antimicrobial treatment on CRE-BSI patient mortality
After controlling for Pitt scores, meropenem MICs ≥ 8 mg/L, immunocompromised status, source control of infection, and the administration of appropriate empirical therapy, an additional multivariate backward stepwise logistic regression analysis revealed that definitive therapy with CAZ-AVI alone, CAZ-AVI + tigecycline (OR 1.645, 95% CI 0.106 - 25.422, P = 0.722), and CAZ-AVI + tigecycline + polymyxin B sulfate (OR 0.606, 95% CI 0.016 - 23.056, P = 0.788) were related to a comparable 30-day mortality risk in CRE-BSI patients. Other definitive regimens not containing CAZ-AVI (OR 12.407, 95% CI 1.684 - 31.430, P = 0.011), in contrast, were associated with a higher 30-day mortality risk, including specific regimens composed of tigecycline + polymyxin B sulfate (OR 13.674, 95% CI 1.160 - 26.148, P = 0.040), carbapenem + tigecycline + polymyxin B sulfate (OR 8.295, 95% CI 1.041 - 16.123, P = 0.046), carbapenem + polymyxin B sulfate + aminoglycoside (OR 13.564, 95% CI 1.160 - 26.148, P = 0.038), carbapenem + tigecycline (OR 29.810, 95% CI 1.835 - 69.751, P = 0.037), tigecycline (OR 33.121, 95% CI 3.322 - 69.322, P = 0.005), and carbapenem + aminoglycoside (OR 24.250, 95% CI 1.989 - 52.579, p = 0.012) (Table 3 and Fig. 2).
After controlling for potential confounding variables, definitive CAZ-AVI therapy (OR 0.088, 95% CI 0.020 - 0.379, P = 0.001) was associated with a lower risk of 30-day mortality relative to definitive therapy without CAZ-AVI. Regimens containing carbapenems (OR 2.281, 95% CI 0.874 - 5.956, P = 0.092), tigecycline (OR 1.139, 95% CI 0.410 - 3.166, P = 0.802), polymyxin B sulfate (OR 1.020, 95% CI 0.394 - 2.642, P = 0.968), and aminoglycosides (OR 2.259, 95% CI 0.741 - 7.143, P = 0.165) exhibited similar 30-day mortality risk profiles relative to regimens not including these respective drugs (Supplementary Material 5).
The impact of definitive antimicrobial regimens on clinical failure rates in CRE-BSI patients
Multivariate backward stepwise logistic regression analyses additionally indicated that relative to definitive therapy with CAZ-AVI alone, CAZ-AVI + tigecycline (OR 2.044, 95% CI 0.324 - 12.900, P = 0.447) and CAZ-AVI + tigecycline + polymyxin B sulfate (OR 0.899, 95% CI 0.099 - 8.170, P = 0.925) were related to a comparable risk of clinical failure, whereas other definitive regimens n to containing CAZ-AVI (OR 8.047, 95% CI 1.896 - 34.151, p = 0.005) were associated with a higher risk of clinical failure even after adjustment for Pitt score, meropenem MIC ≥ 8 mg/L, immunocompromised status, source control of infection, appropriate empirical therapy, possible source of BSI, and days of appropriate antimicrobial therapy (Supplementary Material 6).
The impact of monotherapy and combination therapy regimens on CRE-BSI patient mortality
After adjusting for Pitt score, meropenem MIC ≥ 8 mg/L, immunocompromised status, source control of infection, and appropriate empirical therapy administration, an additional multivariate backward stepwise logistic regression analysis indicated that compared with definitive CAZ-AVI monotherapy, treatment with combination therapies containing CAZ-AVI (OR 1.287, 95% CI 0.124 - 13.403, P = 0.833) was linked to comparable 30-day mortality risk among CRE-BSI patients. In contrast, when patients were administered definitive antimicrobial regimens not containing CAZ-AVI, combination therapy (OR 0.240, 95% CI 0.077 - 0.745, p = 0.014) was related to a lower 30-day mortality risk relative to monotherapy (Table 4).
Consistent with the above data, Cox regression survival curves indicated that CAZ-AVI monotherapy-treated patient 30-day mortality rates were similar to those of patients treated with a combination of antimicrobial agents including CAZ-AVI, whereas the 30-day mortality for patients that underwent monotherapy treatment was significantly higher than that of patients administered combination therapies not containing CAZ-AVI (Fig.3).