Multicenter study on clinical outcomes and poor prognostic factors in patients with Klebsiella pneumoniae bacteremia receiving cefoperazone/sulbactam treatment

Background Infections caused by Klebsiella pneumoniae are common and result in high mortality rates. In vitro studies demonstrated the potency of cefoperazone/sulbactam (CPZ/SUL) against Klebsiella pneumoniae. However, the clinical efficacy of CPZ/SUL for the treatment of K. pneumoniae bacteremia has not been studied. Objectives This study aimed to associate the clinical outcomes of patients with bacteremia with the minimal inhibitory concentrations (MICs) of CPZ/SUL against the causative K. pneumoniae isolates. Methods This multicenter, retrospective study was conducted in Taiwan between July 2017 and April 2021. Patients with K. pneumoniae bacteremia treated with CPZ/SUL were enrolled in this study. CPZ/SUL MICs were determined using the agar dilution method. Data on the patients’ clinical outcomes and characteristics were collected and analyzed. Results In total, 201 patients were enrolled. Among the causative K. pneumoniae isolates, 180 (89.5%) were susceptible to CPZ/SUL. Most patients (n = 156, 77.6%) had favorable outcomes. The 30-day mortality rate was 11.9% (n = 24). Multivariate risk analyses showed that higher APACHE II score (Odds Ratio [OR], 1.14; Confidence Interval [CI], 1.07–1.21; p < 0.001), metastatic tumors (OR, 5.76; CI, 2.31–14.40; p < 0.001), and causative K. pneumoniae CPZ/SUL MICs > 16 µg/ml (OR, 4.30; CI, 1.50–12.27; p = 0.006) were independently associated with unfavorable outcomes. Conclusion Patients with K. pneumoniae bacteremia treated with CPZ/SUL at a ratio 1:1 had favorable outcomes when the CPZ/SUL MICs were ≤ 16 µg/ml. Patients with higher APACHE II scores and metastatic tumors had unfavorable outcomes. Supplementary Information The online version contains supplementary material available at 10.1007/s10096-024-04892-x.


Introduction
Klebsiella pneumoniae is a common and life-threatening community-acquired, healthcare-associated, and hospitalacquired pathogen.K. pneumoniae can cause pneumonia, urinary tract infections, intra-abdominal infections, liver abscesses, bacteremia, and other invasive infections [1][2][3].The mortality rates of patients with K. pneumoniae bacteremia differed from 20 to 50%, depending on the infected population, and the rates became higher when the severity of the infection increased and the presence of carbapenem acid sulfone with activity against Ambler class A enzymes, broadened the antimicrobial spectrum of CPZ [13,14].
Over the past, the emergence of ESBL-producing K. pneumoniae has caused a serious clinical burden [7][8][9].The Taiwan Surveillance of Antimicrobial Resistance program conducted from 2002 to 2012 reported that the prevalence of ESBL-producing K. pneumoniae increased from 4.8 to 11.9% in Taiwan [15].According to the SENTRY antimicrobial surveillance program data, the prevalence of multidrugresistant (MDR) Enterobacterales-associated bloodstream infections increased from 6.2 to 15.8% between 1997 and 2016 [9].
We conducted a multicenter, retrospective study to correlate the MIC values of a 1:1 ratio of CPZ/SUL against K. pneumoniae and the clinical outcomes of patients with K. pneumoniae bacteremia.The enrolled patients were > 20 years of age had monomicrobial bacteremia caused by K. pneumoniae and were initially treated using antimicrobial monotherapy with a 1:1 ratio of CPZ/SUL within 24 h of bacteremia onset with treatment lasting for more than 72 h.The onset of bacteremia was defined as the date of index blood culture collected [25,28].CPZ/SUL was given intravenously every 12 h at a standard dosage of 2/2 g, with dosage modification as the manufacturer's guidelines, according to the estimated creatinine clearance using the Cockroft-Gault equation [29].Patients receiving additional antimicrobial therapies exceeding 48 h were excluded, except those treatments were targeting GPCs, virus or fungi.This study was approved by the Institutional Review Board (IRB) of the TSGH (No. 1-106-05-116) and the IRBs of all other participating hospitals.

Variable definition and assessment of the treatment efficacy
The Charlson Comorbidity Index [30] was used to assess comorbidities.Immunosuppressant therapy indicated those patient receiving prednisolone for at least10mg per day (or equivalent potency agents) from 2 days before bacteremia onset till 30 days post the event.The Acute Physiology and Chronic Health Evaluation II (APACHE II) [31] was used to assess disease severity.The source of bacteremia was classified as respiratory tract infection/pneumonia, urinary tract infection, soft-tissue infections, intraabdominal infection, or primary bloodstream infection, according to the definitions of the Centers for Disease Control and Prevention [32].Clinical outcomes were assessed at 30 days.The clinical outcomes were recorded and divided into four categories: cure, improvement, lack of efficacy, and death.A cure was defined as the absence of symptoms and signs of infection without the requirement for additional antibiotic therapy and a negative result in the subsequent blood culture within a week of the onset of bacteremia.Improvement indicated that the symptoms and signs subsided with or without laboratory improvement, based on clinical judgment, and further antibiotic treatment was required.Lack of efficacy was defined as clinical progression or persistent bacteremia at the end of CPZ/SUL treatment [33].Regarding the correlation between treatment efficacy and the MICs of CPZ/SUL, cure and improvement were defined as favorable outcomes.In contrast, a lack of efficacy and death were defined as unfavorable outcomes.

Statistical analyses
Descriptive statistics were used to present the demographic characteristics of enrolled patients.The demographic characteristics of the two groups (MIC ≤ 16 and MIC > 16) were compared using the Fisher's exact test for categorical variables.Continuous variables are presented as the mean ± standard deviation and compared using Student's t-test.Statistical significance was set at p < 0.05.A multivariate analysis was performed for all variables that were statistically significant in the univariate analysis.Odds ratios (ORs) with 95% confidence intervals (CIs) and p-values were calculated.All statistical analyses were performed using SPSS version 20 (IBM Corp., Armonk, NY, USA).

Results
During the study period, 201 patients with K. pneumoniae bacteremia were enrolled based on the patient selection criteria (Fig. 1).The patient demographic data were presented in Table 1.The majority of patients were male.The most prevalent comorbidities included diabetes mellitus, impaired liver function, and impaired renal function.The primary cause of bacteremia was intra-abdominal infection, followed by primary bacteremia, respiratory tract infection, and urinary tract infections.Antimicrobial susceptibility results for K. pneumoniae are detailed in Table 2.
The MIC of CPZ alone and the 1:1 combination of CPZ/ SUL against K. pneumoniae are shown in Table 3.The MIC ranges and MIC 50 values for CPZ and CPZ/SUL were similar.However, the MIC 90 values were lower for CPZ/ SUL (MIC 90 : 32 ug/ml) than for CPZ (MIC 90 : >64 ug/ml) alone.Among the 201 isolates, 180 (89.55%) were susceptible, six (2.99%) were intermediate, and 15 (7.46%) were resistant to CPZ/SUL.For isolates that were not susceptible to CPZ, the addition of SUL restored the susceptibility rate from 0 to 53.33% and reduced the resistance rate from 82.22 to 33.33% (Table 3).Distribution of the cefoperazone/sulbactam MIC values among those K. pneumoniae isolates were showed in Fig. 2. Most of those K. pneumoniae isolates in this study exhibited MIC values of less than 8 µg/ml (< 8 µg/ml, n = 157, 78.11%) (Fig. 2).
Outcome evaluations revealed that 77.61% exhibited favorable outcomes (cure and improvement) and 22.39% showed unfavorable outcomes (death and lack of treatment efficacy).(Table 1).The clinical outcomes correlated with CPZ/SUL MIC values were showed in Fig. 2. As the MIC value increased, the rate of favorable outcomes decreased, and the 30-days mortality rate increased.
Comparing the patient characteristics and outcomes in causative K. pneumoniae isolates with CPZ/SUL MIC ≤ 16 µg/ml and > 16 µg/ml in

Discussion
This is the first multicenter study to investigate the effects of CPZ/SUL therapy in patients with K. pneumoniae bacteremia and to provide reference clinical breakpoints and prognostic factors for outcomes.The correlation analysis of that unfavorable outcomes were more frequent in those with MIC > 16 µg/ml than those with MIC ≤ 16 µg/ml.Those infected by isolates with MIC > 16 µg/ml had a higher APACHE II scores and higher prevalence of impaired renal function.There were no significant differences in sex, age, or source of infection between the two groups.producers, which is important in antimicrobial stewardship [27].However, in areas where the prevalence of carbapenem resistance is significant, the empirical use of CPZ/SUL should be approached with caution [38,39].
The addition of SUL effectively restored the efficacy of CPZ from 77.6 to 89.6%.Even in isolates that were not susceptible to CPZ, the addition of SUL to CPZ restored antimicrobial susceptibility from 0 to 53% in the current study (Table 3).In most previous studies, the ratio of CPZ to SUL was 2:1 [40][41][42][43].Recent studies have established that CPZ/ SUL ratio of 2:1 and 1:1 significantly increased the efficacy against ESBL strains and MDR GNB compared with CPZ alone [25].Moreover, CPZ/SUL at a 1:1 ratio produced better activity against MDR GNB than that at a 2:1 ratio [26].
the MIC values of CPZ/SUL against K. pneumoniae with the clinical outcomes revealed that most patients (81.1%) infected by isolates with MIC ≤ 16 µg/ml had favorable outcomes.MIC values > 16 µg/ml were independently associated with unfavorable outcomes.In addition, higher APACHE II scores and metastatic tumors were associated with unfavorable outcomes in patients with K. pneumoniae bacteremia.
The major mechanism underlying third-generation cephalosporin resistance in K. pneumoniae in Taiwan and worldwide is the presence of ESBL genes [34,35].The consumption of carbapenems has increased, which has promoted the spread of carbapenem-resistant K. pneumoniae [36,37].Therefore, CPZ/SUL may offer a valuable carbapenem-sparing alternative for effectively covering ESBL  bacteremia [45,46].Therefore, judicious antimicrobial treatment is crucial for patients with such risk factors.When the MICs ≤ 16 µg/ml, CPZ/SUL could be confidently used to treat K. pneumoniae bacteremia.It is also important to follow the results of antimicrobial susceptibilities and following antimicrobial stewardship principles.This study had some limitations.The major limitations are its retrospective design with potential intrinsic selection bias, and the fact that the detailed treatment course cannot be controlled.Further randomized controlled studies are required to confirm these findings.The strengths of this study include the inclusion of a relatively large number of patients from multiple medical centers located in representative regions of Taiwan using stringent inclusion criteria.Our findings provide clinicians with useful information regarding the outcomes and risk factors of patients with K. pneumoniae bacteremia treated with CPZ/SUL.
In the current study, we observed that the APACHE score and the presence of metastatic tumors were significant risk factors for unfavorable outcomes.These findings were consistent with prior investigations on K. pneumoniae ** Immunosuppressant therapy: patients receiving prednisolone for at least10mg per day (or equivalent potency agents) from 2 days before bacteremia onset till 30 days post the event *** Others, other sources, included six cases of catheter-related blood stream infection (CRBSI) and five cases of soft tissue or wound infection adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons. org/licenses/by/4.0/.

Conclusion
Patients with K. pneumoniae bacteremia treated with CPZ/ SUL at a ratio of 1:1 had a favorable outcome when the CPZ/SUL MICs were ≤ 16 µg/ml.Higher APACHE II scores and metastatic tumors were associated with unfavorable outcomes.

aFig. 2
Fig. 2 Distribution of the cefoperazone/sulbactam minimum inhibitory concentration (MIC) values and clinical outcomes correlated with cefoperazone/sulbactam minimum MIC values among the 201 Klebsiella pneumoniae isolates

Table 1 ,
we observed

Table 2
The antimicrobial susceptibilities of 201 Klebsiella pneu-

Table 3
The minimal inhibitory concentrations and the susceptibilities of cefoperazone alone and in combination with sulbactam (1:1) against

Table 4
Univariate and multivariate logistic analyses of factors associated with unfavorable outcomes in patients with Klebsiella pneumoniae bacteremia.
** Data are n (%) unless otherwise stated