Effectiveness and Safety of High-Dose versus Standard-Dose Cefoperazone-Sulbactam in Severe Infections: A Multicenter Retrospective Study

Introduction

Cefoperazone-sulbactam, a combination of third-generation cephalosporins and beta-lactamase inhibitors, is widely used to treat various severe bacterial infections.^1–5 However, the emergence of resistant pathogens and complex pharmacokinetics observed in critically ill patients have raised concerns about the adequacy of standard dosing regimens in achieving optimal therapeutic outcomes. Importantly, recent clinical evidence has shown that in infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales, treatment outcomes with cefoperazone-sulbactam progressively worsen as minimum inhibitory concentrations (MICs) values increase, underscoring the risk of suboptimal exposure when standard dosing is applied.¹ This finding highlights the need to optimize dosing strategies.⁶ Consequently, higher antibiotic doses have been proposed as a potential solution. High-dose cefoperazone-sulbactam regimens have been reported for managing severe infections and multidrug-resistant organisms, such as extended-spectrum β-lactamase (ESBL)-producing Escherichia coli, Klebsiella pneumoniae, and carbapenem-resistant Acinetobacter baumannii.^7–10 This strategy is particularly relevant in specific patient populations, including those with altered drug metabolism, impaired renal function, or impaired hepatic function, where standard doses may be insufficient to achieve therapeutic concentrations.^11,12 The standard cefoperazone-sulbactam dose is 2 g-2 g, administered every 12 h. Increasing the dose to 2 g-2 g every 8 h may enhance the time above the minimum inhibitory concentration (MIC) and improve clinical and microbiological efficacy. Additionally, physiological changes in critically ill patients, such as increased volume of distribution, augmented renal clearance, and altered protein binding, can significantly affect drug concentrations, potentially necessitating higher doses to achieve therapeutic targets.¹³

Despite the theoretical advantages of high-dose regimens, comparative data on the effectiveness and safety of high-dose versus standard-dose cefoperazone-sulbactam remain limited. Uncertainty persists regarding the optimal dosing strategy that balances maximal therapeutic effect with minimal adverse events. Moreover, the cost implications and practical considerations of implementing high-dose regimens in routine clinical practice require systematic evaluation. This study aimed to compare the effectiveness and safety profiles of high- and standard-dose cefoperazone-sulbactam in patients with severe bacterial infections. Multiple outcome parameters will be assessed, including clinical cure rates, microbiological eradication, and mortality rates. Safety outcomes will also be monitored, focusing on liver function abnormalities, coagulation disorders, and renal function changes. This study aimed to compare the effectiveness and safety profiles of high- and standard-dose cefoperazone-sulbactam in patients with severe bacterial infections.

Materials and Methods

Study Design and Population

This multicenter, retrospective cohort study was conducted at four hospitals within the Chi Mei Medical System and E-Da Hospital between January 2020 and October 2024. The study protocol was reviewed and approved by the Institutional Review Board of Chi Mei Medical Center (IRB No. 11312–013) and the Institutional Review Board of E-Da Hospital (IRB No. EMRP-113-127).

The requirement for informed consent was waived by both ethics committees due to the retrospective nature of the study involving anonymized patient data. All procedures were carried out in accordance with institutional guidelines and the ethical standards of the responsible committees, as well as the principles outlined in the Declaration of Helsinki.

Patient Selection

Adult patients aged ≥20 years who received cefoperazone–sulbactam for the treatment of severe infections, defined as admission to the intensive care unit (ICU), requirement for mechanical ventilation, or an increase in Sequential Organ Failure Assessment (SOFA) score of more than 2, or for infections caused by multidrug-resistant organisms (MDROs), excluding carbapenem-resistant Pseudomonas aeruginosa (CRPA), were eligible for inclusion. Infections caused by CRPA were excluded due to evidence indicating that the addition of sulbactam does not enhance the in vitro antibacterial activity of cefoperazone against carbapenem-resistant P. aeruginosa.⁸ The type of infection was defined according to internationally recognized criteria. Pneumonia was defined based on the American Thoracic Society (ATS)/Infectious Disease Society of America (IDSA) guidelines.¹⁴ Urinary tract infection was defined according to the IDSA guidelines.¹⁵ Catheter-related bloodstream infection was diagnosed according to the IDSA 2009 update.¹⁶ Primary bacteremia was defined as bloodstream infection without an identifiable primary focus of infection. Skin and soft tissue infections were defined based on the IDSA 2014 guidelines.¹⁷ Intra-abdominal infection was defined according to the Surgical Infection Society and IDSA guidelines.¹⁸ To ensure adequate assessment of drug exposure, patients must have received cefoperazone-sulbactam treatment for a minimum of 72 h. Additionally, the study population included patients with documented treatment failure of other antibiotics and those with MDROs who subsequently switched to cefoperazone-sulbactam therapy.

Exclusion criteria included patients under 20 years, individuals with HIV infection, pregnant or lactating women, those with creatinine clearance ≤30 mL/min, and patients with Child-Pugh class B or C liver cirrhosis. Additional exclusions were concurrent anticoagulant therapy (warfarin or heparin), prolonged prothrombin time (INR >1.5), history of anaphylactic shock to cefoperazone-sulbactam, and documented allergies to cephalosporin antibiotics.

Intervention

Based on the clinical judgment of the treating physician, patients were categorized into two treatment groups. The standard-dose group received cefoperazone-sulbactam 2g-2 g every 12 hours, while the high-dose group received cefoperazone-sulbactam 2g-2 g every 8 hours. All other aspects of patient care followed the standard institutional protocols.

Data Collection

Comprehensive medical records were reviewed retrospectively to extract the patient data. Demographic and clinical characteristics included age, sex, underlying conditions or comorbidities, Charlson comorbidity index, and specific sites of infection. Laboratory parameters included comprehensive liver function tests, renal function profiles, coagulation parameters, and other clinically relevant biochemical markers. Disease severity was assessed using the Sequential Organ Failure Assessment (SOFA) score, while Pneumonia severity was evaluated using the CURB-65 score. The index date was defined as the first day of cefoperazone-sulbactam administration.

Microbiological Procedures

All clinical isolates were processed according to the standard operating procedures of each participating hospital. Using aseptic techniques, the samples were inoculated onto appropriate culture media and incubated at 37 °C in a 5% CO₂ atmosphere. After 18–24 hours of incubation, colony morphology, quantity, pigmentation, and odor were examined. Species identification was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS; MALDI Biotyper Microflex LT/SH, Bruker) with the Bruker MBT 8468 MSP Library. All clinical isolates underwent available cefoperazone-sulbactam antimicrobial susceptibility testing (AST) using the disk diffusion method after species identification. Antibiotic disks were purchased from BD BBL™ Sensi-Disc™. Owing to the absence of specific Clinical and Laboratory Standards Institute (CLSI) interpretive criteria, the CLSI criteria for cefoperazone alone were temporarily used to define the breakpoints for cefoperazone-sulbactam susceptibility.¹⁹ However, routine antimicrobial susceptibility testing for cefoperazone-sulbactam was not performed at one of the participating institutions.

Outcomes

The primary outcome measure was the clinical cure rate on day 14, defined as complete resolution or significant improvement in infection signs and symptoms without the need for additional antibiotic therapy after discontinuation of cefoperazone-sulbactam. This endpoint was selected because our primary aim was to evaluate the clinical effectiveness of high-dose versus standard-dose cefoperazone–sulbactam, in line with prior retrospective studies of antibiotic therapy.²⁰ Secondary outcomes included microbiological eradication (elimination of the causative pathogen in follow-up cultures), all-cause mortality, and adverse events (AEs). Mortality was defined as in-hospital mortality within 28 days, and all patients were followed until discharge, with mortality status determined during the index hospitalization. Patients discharged alive before day 28 were classified as survivors. As such, no right-censored data were present for either outcome, and logistic regression was applied for statistical analysis. In cases where no follow-up culture was available, but the patient demonstrated clinical cure, eradication was classified as presumed. Presumed eradication was included in the overall microbiological eradication outcome. The AEs assessed included elevation of liver enzymes, bilirubin, serum creatinine, and coagulation abnormalities as indicated by prothrombin time (PT) and activated partial thromboplastin time (aPTT).

Statistical Analysis

Continuous variables were expressed as means and standard deviations, while categorical variables were presented as numbers and percentages. Differences between cefoperazone-sulbactam dosage groups were analyzed using chi-square tests for categorical variables and two-sample t-tests for continuous variables. Logistic regression analyses were conducted to evaluate the associations between study outcomes (ie, clinical cure rate, microbiological eradication, and in-hospital mortality) and cefoperazone-sulbactam dosage, with the standard-dose control group defined as the reference group. A multivariate logistic model was established by selecting variables with p-values <0.05 in the univariate analysis. Subgroup analyses were performed according to sociodemographic and clinical characteristics. The association between microbiological eradication and cefoperazone-sulbactam dosage for specific microbial pathogens was evaluated using logistic regression. Changes in safety profiles on Day 7 and 14 compared to Day 0, were presented as means ± standard deviations and analyzed using two-sample t-test for each laboratory measure. All analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA). Statistical significance was set at P <0.05.

Results

Clinical Characteristics of Included Patients

During the study period, 383 patients were included: 141 in the high-dose group and 242 in the standard-dose control group. Table 1 summarizes the clinical features of the patients. There were no significant differences between the groups in terms of age (73.7 ± 15.0 vs 74.3 ± 14.8 years, p = 0.719), sex, height, or body weight (all p > 0.05). Although the high-dose group included more ICU patients than the standard-dose group, the difference was not significant (51.1% vs 44.2%; p = 0.195). Furthermore, the Charlson Comorbidity Index, type of infection, and disease severity according to the SOFA and CURB-65 scores for patients with pneumonia did not differ significantly (all p > 0.05). Compared with the standard-dose group, the high-dose group had significantly more patients with acute respiratory failure (41.8% vs 24.8%, p < 0.001), but treatment duration was similar (7.7±5.6 vs 7.8±3.7, p = 0.875).

Table 1 Baseline Characteristics of Included Patients According to Cefoperazone/Sulbactam Dosage

In the high-dose group, E. coli (n = 18) was the most common pathogen, followed by P. aeruginosa (n = 14), K. pneumoniae (n = 13), and A. baumannii (n = 11). The most common pathogens in the standard-dose group were E. coli (n = 26) and K. pneumoniae (n = 26), followed by P. aeruginosa (n = 21) and A. baumannii (n = 18), this distribution did not differ significantly between the groups. Details of all cases with positive pathogen cultures, along with their corresponding infection types and specimen sources, are provided in Supplementary Table 1. The prevalence of carbapenem-resistant Enterobacterales (CRE) (defined as non-susceptibility to at least one carbapenem) was significantly higher in the high-dose group (n=20, 14.2%) compared with the standard-dose group (n=10, 4.1%; p < 0.001). In contrast, the number of patients with carbapenem-resistant A. baumannii (CRAB) was comparable between the two groups (n=8 [5.7%] vs n=15 [6.2%]; p = 0.835). Regarding the available susceptibility to cefoperazone-sulbactam, in the high-dose group, the susceptibility rates were 92.9% for E. coli, 42.9% for K. pneumoniae, 30.0% for carbapenem-resistant Enterobacterales, and 100% for A. baumannii. In the Q12H group, the corresponding rates were 85.7%, 69.6%, 42.9%, and 87.5%, respectively (Supplementary Table 2).

Primary Outcomes

The clinical cure rates on day 14 were 49.7% (70/141) and 38.8% (94/242) in the high-dose and standard-dose groups, respectively (Table 2). Compared with the standard-dose group, the high-dose group had a significantly higher clinical cure rate (adjust odds ratio [OR]: 1.55; 95% CI, 1.03–2.39) (Table 3). This trend persisted after multivariate adjustment for age, sex, acute respiratory failure, and infection with CRE (aOR: 1.61; 95% CI, 1.05–2.50). In subgroup analysis, higher clinical cure rate in the high-dose group were observed in patients with pneumonia (aOR: 2.10, 95% CI: 1.23–3.58, p=0.007), acute respiratory failure (aOR: 2.80, 95% CI: 1.30–6.07, p=0.009), those admitted to the ICU (aOR: 2.39, 95% CI: 1.24–4.61, p=0.009), and those with higher Charlson Comorbidity Index (CCI >4) (aOR: 1.76, 95% CI: 1.05–2.96, p=0.032) (Table 4). A higher clinical cure rate in the high-dose group was also observed in patients with high SOFA scores (≥10), although this difference was not statistically significant (aOR: 1.89, 95% CI: 0.71–5.05, p=0.206).

Table 2 Characteristics of Study Outcomes by Cefoperazone/Sulbactam Dosage

Table 3 Association of Cefoperazone/Sulbactam Dosage with Clinical and Microbiology Outcomesa

Table 4 Stratified Analyses for Association of Dose of Cefoperazone-Sulbactam on Clinical and Microbiology Outcomes by Patients’ Clinical Characteristics

Secondary Outcomes

Microbiological eradication rates were also significantly higher in the high-dose group (46.1% vs 20.3%; OR, 3.37; 95% CI, 2.14–5.32). All-cause in-hospital mortality was lower in the high-dose group, although this difference was not statistically significant (17.7% vs 21.1%; OR, 0.81; 95% CI, 0.48–1.37) (Tables 2 and 3). After adjustment for age, sex, acute respiratory failure, and infection with CRE, significantly higher microbiological eradication rate (aOR: 3.85; 95% CI, 2.37–6.26) and a trend toward a lower in-hospital mortality rate (aOR: 0.71; 95% CI, 0.41–1.25) remained (Table 3). In subgroup analyses, a higher eradication rate was observed in the CR-Gram-negative bacillus (GNB) group, although this difference was not statistically significant (aOR: 2.20; 95% CI, 0.58–8.42) (Table 5). A trend toward lower in-hospital mortality was also observed in the pneumonia, acute respiratory failure, and high CCI score subgroups and was statistically significant in the group with a lower SOFA score (Table 4).

Table 5 Subgroup Analyses for Association Between Cefoperazone-Sulbactam Dosage and Microbiological Eradication

Regarding laboratory examinations, the changes in PT, aPTT, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, and albumin levels from day 0 to day 7 or 14 did not differ between the groups (all p > 0.05) (Table 6).

Table 6 Evaluation of Safety Profiles by Cefoperazone-Sulbactam Dosage

Discussion

This study compared the clinical effectiveness and safety of high-dose cefoperazone-sulbactam in treating patients with severe bacterial or MDRO infections. The results demonstrate that high-dose cefoperazone-sulbactam offers enhanced clinical effectiveness without compromising safety. First, patients treated with high-dose cefoperazone-sulbactam exhibited a significantly higher clinical cure rate than those treated with the standard dose, despite the greater proportion of patients with respiratory failure in the high-dose group. Second, the high-dose group achieved a superior microbiological eradication rate. These findings remained robust even after adjusting for potential confounders. Third, in subgroup analysis, a higher clinical cure rate was observed in patients with pneumonia, acute respiratory failure, ICU admission, and a high CCI score. A trend towards higher microbiological eradication rates was also observed in the CR-GNB group. These findings are consistent with those of a previous study that compared cefoperazone-sulbactam 2 g-2 g twice daily with a dose adjusted according to renal function in patients with chronic kidney diseases (CKD).¹² The group receiving a higher dose demonstrated a higher clinical response rate (80.0% vs 65.0%) and a lower treatment failure rate (4.0% vs 23.8%).¹² In summary, these findings suggest a potential role for high-dose cefoperazone-sulbactam in the treatment of severe bacterial or MDRO infections.

The findings of this study can be attributed to the pharmacodynamic advantage of higher doses, which results in sustained concentrations of the free drug above the minimum inhibitory concentration (%fT > MIC).^11,21 This effect may be due to the increased daily dose of sulbactam, which enhances its activity against multidrug-resistant pathogens. The 2024 IDSA guidelines recommend a sulbactam dose of 9 g daily for the treatment of carbapenem-resistant A. baumannii (CRAB).²² Higher sulbactam doses have been associated with improved microbiological eradication rates and reduced mortality during the treatment of CRAB infections.²³ For multidrug-resistant Enterobacterales, an elevated sulbactam-to-cefoperazone ratio reduces the MIC of ESBL-producing and CRE.⁹ Additionally, in vitro studies have demonstrated that formulations with higher sulbactam content exhibit improved susceptibility to high-inoculum ESBL-producing K. pneumoniae and E. coli.⁷ Collectively, these mechanisms explain the enhanced efficacy of high-dose cefoperazone-sulbactam in clinical settings.

This study also evaluated the safety profile of high-dose cefoperazone-sulbactam and found no significant differences in the prolongation of PT, APTT, liver function, or renal function compared with the standard-dose regimen. These results align with the findings of previous studies, including those involving patients with CKD.^12,24 These studies compared the adverse effects of 2 g-2 g every 12 h and 1 g-1 g every 12 h in patients with CKD and renal replacement therapy and found no significant between-group differences in AEs, including prolonged PT.^12,24 Although an association between cefoperazone use and coagulopathy has been reported,²⁵ the administration of vitamin K1 effectively mitigates coagulation abnormalities.²⁶ At our institution, prophylactic vitamin K1 was administered to patients receiving cefoperazone-sulbactam, resulting in no significant prolongation of PT or evidence of bleeding. In summary, our findings demonstrate that high-dose cefoperazone-sulbactam is well tolerated in patients with sepsis and MDRO infections, and can be safely used in critically ill patients without raising additional safety concerns.

This study has several limitations. First, the number of included patients was limited; therefore, a significant difference was observed only in the overall population and not in all subgroup analyses. Accordingly, our findings should be interpreted not only in terms of statistical significance but also by considering the effect sizes and the possibility of both type I and type II errors. Although subgroup analyses were underpowered, the overall sample size (n=383) was adequate to detect clinically meaningful differences between high-dose and standard-dose groups, consistent with prior studies that reported similar effect estimates with comparable sample sizes.² Second, because antimicrobial susceptibility tests for cefoperazone-sulbactam was not consistently available across all centers, resulting in missing susceptibility data, which may limit the generalizability of the susceptibility analysis. Third, because this was a retrospective study, the inability to control for biases and confounding variables may have compromised the validity of our findings, such as time to appropriate therapy and immune status. Fourth, we acknowledge that mortality is often considered a primary endpoint in retrospective studies; however, given the study aim to evaluate treatment effectiveness beyond survival, we selected clinical cure rate as the primary endpoint, consistent with prior observational studies.²⁰ Further large-scale studies are required to clarify this issue.

Conclusion

High-dose cefoperazone-sulbactam demonstrated superior clinical effectiveness and microbiological eradication compared with the standard dose, without additional safety concerns. These findings suggest that high-dose regimens may be beneficial for selected patients with severe infections or MDROs, but prospective trials are warranted to validate these observations.