Abstract
Introduction
Oxacillinase-48 (OXA-48)-producing carbapenem-resistant Klebsiella pneumoniae (CRKP) infections have been increasingly reported in Taiwan. Real-world studies regarding effective treatments for these infections are limited, and recommendations from international guidelines are controversial. The aim of this study was to compare clinical outcomes of OXA-48-producing CRKP bacteremia between patients treated with ceftazidime/avibactam (CZA) and those receiving other active therapies.
Methods
Unique adult patients with OXA-48-producing CRKP bacteremia who received CZA or other therapies in vitro for at least 3 days between June 2017 and December 2024 at Taipei Veterans General Hospital were enrolled. Clinical characteristics and outcomes were compared among the treatment groups. OXA-48 strains were detected using polymerase chain reaction (PCR) followed by Sanger sequencing.
Results
Of 45 patients included in this study, 18 were treated with CZA, and 27 were treated with other active therapies. Four patients received combination therapy. Most strains were OXA-48 producers (n = 42), and the rest were OXA-181 producers. No significant difference in 30-day mortality rate was observed between the treatment groups (22.2% versus 33.3%, p = 0.420), and even in critically ill patients (28.6% versus 43.8%, p = 0.389). Acute Physiology and Chronic Health Evaluation II (APACHE II) score (hazard ratio [HR] 1.07, 95% confidence interval [CI] 1.01–1.15, p = 0.028) was an independent risk factor for 30-day mortality, and colistin-based therapy (HR 3.02, 95% CI 1.00–9.13, p = 0.050) showed marginal significance with 30-day mortality. CZA use was not associated with 30-day mortality.
Conclusions
Our findings revealed that CZA and other active therapies showed similar outcomes, but colistin-based regimens should be used cautiously.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40121-025-01210-6.
Keywords: Bacteremia, Carbapenem-resistant Klebsiella pneumoniae, Ceftazidime/avibactam, OXA-48
Key Summary Points
| Why carry out this study? |
| Previous studies on the optimal treatment for oxacillinase-48 (OXA-48)-producing carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are limited and only available in endemic regions. |
| We aimed to compare clinical features and outcomes of OXA-48-producing CRKP bacteremia between patients treated with ceftazidime/avibactam (CZA) and those treated with other active therapies in Taiwan. |
| What was learned from the study? |
| The 30-day mortality and microbiological eradication rates were similar between patients treated with CZA and those treated with other active therapies, even among critically ill patients. |
| Active monotherapy other than CZA was appropriate for OXA-48-producing CRKP bacteremia, but colistin should be used cautiously. |
Introduction
Carbapenemase-producing Enterobacterales (CPE) infections have become a global threat, with oxacillinase-48 (OXA-48) β-lactamases being a common class of carbapenemases worldwide [1]. The first OXA-48 enzyme was identified in a Klebsiella pneumoniae isolate in 2004, and OXA-48-producing Enterobacterales are now considered endemic in the Middle East and North Africa [2, 3]. Nosocomial infections caused by OXA-48-produing K. pneumoniae have been reported in several European countries, Australia, Mexico, China, Taiwan, and South Africa [2, 4, 5]. In Taiwan, OXA-48 has emerged as the second most prevalent carbapenemase [5]. However, clinical information on OXA-48-producing K. pneumoniae bacteremia remains limited. Nonetheless, a recent report revealed a high 30-day mortality of 20% among affected patients [6].
OXA-48 enzymes efficiently hydrolyze penicillins, poorly hydrolyze extended-spectrum cephalosporins, and show weak activity against carbapenems [1, 2]. Therefore, some OXA-48-producing Enterobacterales have low-level meropenem minimal inhibitory concentrations (MIC) (≤ 2 μg/mL) [3]. Treatment recommendations for OXA-48-producing Enterobacterales infections are inconsistent between American and European guidelines. The Infectious Disease Society of America (IDSA) recommends ceftazidime/avibactam (CZA) as the preferred treatment for OXA-48-producing Enterobacterales infections [7]. Further, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommends new β-lactam/β-lactamase inhibitors for severe infections caused by carbapenem-resistant Enterobacterales (CRE), as well treatments involving multiple drugs active in vitro, such as polymyxins, aminoglycosides, tigecycline, or fosfomycin [8].
Studies comparing the effectiveness of CZA versus other traditional antibiotics for infections caused by OXA-48 producers are limited and exclusive to endemic regions [6, 9–11]. Therefore, the aim of this study was to compare the clinical outcomes of OXA-48-producing carbapenem-resistant K. pneumoniae (CRKP) bacteremia between patients treated with CZA and those who received other available therapies, and to identify risk factors for 30-day mortality in these patients in Taiwan.
Methods
Study Design and Setting
Patients with OXA-48-producing CRKP bacteremia who were hospitalized at Taipei Veterans General Hospital, a tertiary medical center in northern Taiwan, between June 2017 and December 2024 were enrolled. The inclusion criteria were adult patients (≥ 20 years old) whose first blood culture yielded OXA-48-producing CRKP during their index hospitalization and who received antibiotics with in vitro activity against CRKP for at least 72 h. OXA-48-producing isolates co-harboring other classes of carbapenemase were excluded.
Patient data were retrospectively collected through chart reviews, including demographics, preexisting medical conditions, source of infection, disease severity, antibiotic regimens, antibiotic susceptibility, and clinical outcomes. The Charlson comorbidity index (CCI) was used to evaluate chronic conditions. Disease severity was assessed using the Acute Physiology and Chronic Health Evaluation II (APACHE II), the Pitt bacteremia score, and INCREMENT-CPE score, all calculated on the day of the index culture. Outcomes of interest included microbiological eradication, recurrence, clinical success, 30-day mortality, and in-hospital mortality.
Ethical Approval
The study protocol was approved by the Institutional Review Board of Taipei Veterans General Hospital (2025-07-009BC). As a retrospective observational study, the study posed minimal risk to participants, thus the requirement for informed consent was waived. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki of 1964 and its later amendments.
Definition of Treatment Category
The enrolled patients were categorized into two groups: CZA therapy group and other active therapy group. Other active therapy was defined as any antibiotic with in vitro activity against the index CRKP isolate, including cephamycins, third- and fourth-generation cephalosporins, meropenem, tigecycline, and colistin. Tigecycline monotherapy was allowed for the treatment of non-urinary tract bacteremia when the isolate exhibited an MIC ≤ 0.5 μg/mL [12, 13].
Empirical antibiotics were administered at the clinician’s judgment before antimicrobial susceptibility test (AST) results became available. Definitive treatment was defined as antibiotic administration after AST results became available. Appropriate therapy was defined as the administration of an active drug against a blood isolate for at least 72 h, within 5 days of the index infection. If the active drug was started within 2 days, it was considered an appropriate early therapy [14]. Combination therapy was defined as the concurrent use of two active antibiotics, administered for ≥ 72 h.
Definition of Outcomes
Outcomes of interest, including 30-day mortality, in-hospital mortality, clinical success, microbiological eradication, and recurrence, were compared between the two treatment groups. Clinical success was defined as survival without recurrence 30 days after the onset of infection, resolution of signs and symptoms of infection, and sterilization of blood cultures within 7 days of treatment initiation [15]. Microbiological eradication was defined as the absence of CRKP in subsequent blood cultures at 7–30 days after the initiation of antimicrobial therapy. Recurrent infection was defined as the reappearance of CRKP bacteremia 28 days after the end of treatment in a patient who had previously achieved clinical cure and microbiological response [16].
Microbiological Methods
Bacterial identification was performed using matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS) (bioMérieux SA, Marcy l’Etoile, France) for each blood isolate. Antimicrobial susceptibility was determined using the Vitek2 System (bioMérieux, Marcy l’Etoile, France). Results were interpreted according to Clinical and Laboratory Standards Institute (CLSI) guidelines [17]. Interpretation of tigecycline MIC was based on the recommendations of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) [13]. Susceptibility was defined as tigecycline MIC ≤ 0.5 μg/mL and colistin MIC ≤ 2 μg/mL. Polymerase chain reaction (PCR) amplification was performed on DNA extracted from CRKP isolates. Genes coding for carbapenemases, including K. pneumoniae carbapenemase, New Delhi metallo-β-lactamase, Imipenemase metallo-β-lactamase, Verona integron-encoded metallo-β-lactamase, and OXA-48, were detected using PCR and characterized by Sanger sequencing, as previously described [18].
Statistical Analysis
Categorical variables are presented as numbers and percentages, and continuous variables are expressed as mean and standard deviation (SD). Comparisons between the treatment groups were conducted using the chi-squared and Fisher’s exact tests for categorical data, and the Student’s t test for continuous data. Univariate and multivariate Cox regression analyses were performed to identify independent variables associated with 30-day mortality. Variables with a p-value < 0.1 in the univariate analysis were included in the multivariate models. A backward selection method was used for multivariate Cox regression analysis. All p-values were two-sided, with a p-value < 0.05 considered statistically significant. All the statistical analyses were performed using SPSS version 26 (SPSS, Armonk, NY, USA).
Results
Clinical and Microbiological Characteristics
During the study period, a total of 58 cases with OXA-48-producing CRKP bacteremia were identified, but 13 cases were excluded in this study because they did not receive appropriate antibiotics. Finally, a total of 45 OXA-48-producing CRKP isolates were collected in this study, including 42 (93.3%) OXA-48 producers and 3 (6.7%) OXA-181 producers. AST results are presented in Supplementary Table S1. Most patients (n = 35, 77.8%) had nosocomial bacteremia, while the remaining ten (22.2%) had community-onset bacteremia, of whom eight had a history of hospitalization within the 3 months prior to the bacteremia episode.
All 45 patients received antibiotics with in vitro activity against CRKP for at least 72 h. Table 1 presents their clinical characteristics and outcomes. Pneumonia (n = 13, 28.9%) was the most common cause of bacteremia, followed by primary bacteremia (n = 10, 22.2%) and intraabdominal infection (n = 9, 20%). A total of 18 (40%) patients received CZA as the main therapy, and 27 (60%) patients were treated with other available therapies, including cephalosporins (n = 11), colistin (n = 10), meropenem (n = 4), and tigecycline (n = 2). The cephalosporins used were cefepime (n = 7), ceftazidime (n = 2), flomoxef (n = 1), and cefmetazole (n = 1). Combination therapy was administered to only four patients, with regimens including CZA plus aminoglycoside, colistin plus aminoglycoside, meropenem plus tigecycline, and flomoxef plus tigecycline.
Table 1.
Comparison of clinical characteristics and outcomes between patients with OXA-48-producing CRKP bacteremia treated with ceftazidime/avibactam (CZA) and those who received other active therapies
| Overall, n = 45 | CZA, n = 18 (40%) | Other active therapies, n = 27 (60%) | p-Value | |
|---|---|---|---|---|
| Male sex | 32 (71.1) | 14 (77.8) | 18 (66.7) | 0.420 |
| Age | 72.1 ± 15.1 | 69.8 ± 18.0 | 73.6 ± 13.0 | 0.416 |
| Comorbidities | ||||
| CCI | 6.7 ± 3.9 | 5.3 ± 3.7 | 7.7 ± 3.8 | 0.041 |
| Malignancy | 19 (42.2) | 9 (50) | 10 (37) | 0.388 |
| Solid tumor | 15 (33.3) | 5 (27.8) | 10 (37) | 0.519 |
| Metastases | 8 (17.8) | 3 (16.7) | 5 (18.5) | 1.000 |
| Hematological malignancy | 5 (11.1) | 4 (22.2) | 1 (3.7) | 0.141 |
| Diabetes mellitus | 18 (40) | 5 (27.8) | 13 (48.1) | 0.172 |
| Chronic kidney diseasea | 20 (44.4) | 6 (33.3) | 14 (51.9) | 0.221 |
| End-stage renal disease | 11 (24.4) | 3 (16.7) | 8 (29.6) | 0.482 |
| Heart failure | 13 (28.9) | 5 (27.8) | 8 (29.6) | 0.893 |
| Coronary artery disease | 12 (26.7) | 2 (11.1) | 10 (37) | 0.086 |
| Cirrhosis | 6 (13.3) | 1 (5.6) | 5 (18.5) | 0.377 |
| Cerebrovascular accident | 11 (24.4) | 1 (5.6) | 10 (37) | 0.031 |
| Chronic obstructive pulmonary disease | 7 (15.6) | 2 (11.1) | 5 (18.5) | 0.684 |
| Chronic ventilator use | 18 (40) | 8 (44.4) | 10 (37) | 0.619 |
| Connective tissue disease | 2 (4.4) | 0 | 2 (7.4) | 0.509 |
| Solid organ transplantation | 3 (6.7) | 1 (5.6) | 2 (7.4) | 1.000 |
| Immunocompromised statusb | 17 (37.8) | 10 (55.6) | 7 (25.9) | 0.045 |
| At the time of index bacteremia | ||||
| APACHE II score | 22.8 ± 9.8 | 23.1 ± 11.4 | 22.6 ± 8.8 | 0.869 |
| Pitt bacteremia score | 3.2 ± 2.6 | 3.3 ± 2.2 | 3.1 ± 2.8 | 0.222 |
| INCREMENT-CPE score | 7.4 ± 3.9 | 6.7 ± 3.1 | 7.8 ± 4.4 | 0.383 |
| Shock | 16 (35.6) | 5 (27.8) | 11 (40.7) | 0.373 |
| ICU acquisition | 19 (42.2) | 9 (50) | 10 (37) | 0.388 |
| Initiation of mechanical ventilator | 6 (13.3) | 3 (16.7) | 3 (11.1) | 0.670 |
| Acute kidney injuryc | 15 (33.3) | 7 (38.9) | 8 (29.6) | 0.519 |
| Initiation of renal replacement therapy | 4 (8.9) | 2 (11.1) | 2 (7.4) | 1.000 |
| Source | ||||
| Pneumonia | 13 (28.9) | 6 (33.3) | 7 (25.9) | 0.591 |
| Primary | 10 (22.2) | 3 (16.7) | 7 (25.9) | 0.716 |
| Intraabdomen | 9 (20) | 4 (22.2) | 5 (18.5) | 1.000 |
| Urinary tract | 8 (17.8) | 1 (5.6) | 7 (25.9) | 0.119 |
| Catheter-related | 4 (8.9) | 3 (16.7) | 1 (3.7) | 0.286 |
| Skin and soft tissue | 1 (2.2) | 1 (5.6) | 0 | 0.400 |
| Polymicrobial | 7 (15.6) | 3 (16.7) | 4 (14.8) | 1.000 |
| Treatment | ||||
| Appropriate early therapy | 37 (82.2) | 15 (83.3) | 22 (81.5) | 1.000 |
| Combination therapy | 4 (8.9) | 1 (5.6) | 3 (11.1) | 0.640 |
| Duration of therapy | 13.6 ± 7.4 | 14.4 ± 7.6 | 13.2 ± 7.4 | 0.572 |
| Outcomes | ||||
| Clinical success | 22 (48.9) | 9 (50) | 13 (48.1) | 0.903 |
| Microbiological eradication | 34 (75.6) | 14 (77.8) | 20 (74.1) | 1.000 |
| Recurrence | 4 (8.9) | 1 (5.6) | 3 (11.1) | 0.640 |
| 14-day mortality | 10 (22.2) | 4 (22.2) | 6 (22.2) | 1.000 |
| 30-day mortality | 13 (28.9) | 4 (22.2) | 9 (33.3) | 0.420 |
| In-hospital mortality | 22 (48.9) | 9 (50) | 13 (48.1) | 0.903 |
Data are presented as mean ± standard deviation for continuous variables, and number (percent) for categorical variables. Statistically significant p-values are highlighted in bold
aChronic kidney disease was defined as estimated glomerular filtration rate < 60 mL/min/1.73 m2 for ≥ 3 months
bImmunocompromised status was defined as neutropenia, receiving prednisolone over 20 mg/day for more than 7 days, immunosuppressants, or cancer-related therapy
cAcute kidney injury was defined by modified Kidney Disease Improving Global Outcomes (KDIGO) guidelines as a 1.5 × increase in baseline serum creatinine levels within 7 days of treatment initiation
Figure 1 shows 30-day mortality rates across different antibiotic regimens. Twenty-two (48.9%) patients achieved clinical success, and 34 (75.6%) patients achieved microbiological eradication on day 30. Recurrence was observed in only four (8.9%) patients after treatment completion. The 30-day mortality and in-hospital mortality were 28.9% and 48.9%, respectively.
Fig. 1.
The 30-day mortality rates across different antibiotic regimens
Comparison between Patients with OXA-48-Producing CRKP Bacteremia Treated with CZA and Those Who Received Other Active Therapies
Table 1 presents the comparison of the clinical characteristics and treatment outcomes between patients treated with CZA and those who received other active therapies. CCI was significantly higher in the other active therapy group than in the CZA group (7.7 ± 3.8 versus 5.3 ± 3.7, p = 0.041), while disease severity was similar between the two groups.
No significant differences were observed between the groups in terms of clinical success, microbiological eradication, or recurrence. The 30-day mortality rate was numerically higher in the other active therapy group than in the CZA group (33.3% versus 22.2%), but no statistical significance was noted (p = 0.42). In-hospital mortality rate was also similar between the groups (50% in the CZA group versus 48.1% in the other active therapy group, p = 0.903).
CZA (n = 18), cephalosporins (n = 11), and colistin-based therapy (n = 10) were the most frequently used regimens. Further comparison of clinical outcomes between patients treated with CZA and those who received cephalosporins (Supplementary Table S2) revealed a similar 30-day mortality rate (22.2% in the CZA group versus 9.1% in the cephalosporin group, p = 0.622). A comparison of clinical outcomes between patients treated with CZA and those who received colistin-based therapy (Supplementary Table S3) revealed that patients treated with CZA had a numerically lower 30-day mortality rate (22.2% versus 60%, p = 0.097).
Comparison of Clinical Characteristics of 30-Day Survivors and Non-survivors Treated with Appropriate Antimicrobial Therapy
Table 2 presents the clinical characteristics of 30-day survivors and non-survivors. Non-survivors more frequently had chronic respiratory failure with mechanical ventilator dependence and chronic kidney disease. They also had significantly higher mean APACHE II score (27.2 ± 7.7 versus 20.4 ± 9.4, p = 0.008), Pitt bacteremia score (4.7 ± 2.0 versus 2.7 ± 2.4, p = 0.004), and INCREMENT-CPE score (9.3 ± 3.5 versus 6.8 ± 3.8, p = 0.021), as well as a higher proportion of intensive care unit (ICU)-acquired bacteremia (69.2% versus 31.3%, p = 0.019).
Table 2.
Comparison of clinical features between 30-day survivors and 30-day non-survivors with OXA-48-producing CRKP bacteremia
| Survivors, n = 32 (71.1%) | Non-survivors, n = 13 (28.9%) | p-Value | |
|---|---|---|---|
| Male sex | 22 (68.8) | 10 (76.9) | 0.725 |
| Age | 72.1 ± 16.1 | 71.9 ± 15.9 | 0.959 |
| Comorbidities | |||
| CCI | 6.4 ± 3.7 | 8.2 ± 4.0 | 0.114 |
| Malignancy | 12 (37.5) | 7 (53.8) | 0.314 |
| Solid tumor | 9 (28.1) | 6 (46.2) | 0.304 |
| Metastases | 4 (12.5) | 4 (30.8) | 0.202 |
| Hematological malignancy | 3 (9.4) | 2 (15.4) | 0.617 |
| Diabetes mellitus | 12 (37.5) | 6 (46.2) | 0.591 |
| Chronic kidney diseasea | 11 (34.4) | 9 (69.2) | 0.033 |
| End-stage renal disease | 6 (18.8) | 5 (38.5) | 0.251 |
| Heart failure | 10 (31.3) | 3 (23.1) | 0.725 |
| Coronary artery disease | 9 (28.1) | 3 (23.1) | 1.000 |
| Cirrhosis | 5 (15.6) | 1 (7.7) | 0.656 |
| Cerebrovascular accident | 7 (21.9) | 4 (30.8) | 0.704 |
| Chronic obstructive pulmonary disease | 6 (18.8) | 1 (7.7) | 0.654 |
| Chronic ventilator use | 9 (28.1) | 9 (69.2) | 0.011 |
| Connective tissue disease | 2 (6.3) | 0 | 1.000 |
| Solid organ transplantation | 3 (9.4) | 0 | 0.546 |
| Immunocompromised statusb | 11 (34.4) | 6 (46.2) | 0.511 |
| At the time of index bacteremia | |||
| APACHE II score | 20.4 ± 9.4 | 27.2 ± 7.7 | 0.008 |
| Pitt bacteremia score | 2.7 ± 2.4 | 4.7 ± 2.0 | 0.004 |
| INCREMENT-CPE score | 6.8 ± 3.8 | 9.3 ± 3.5 | 0.021 |
| Shock | 11 (34.4) | 5 (38.5) | 1.000 |
| ICU acquisition | 10 (31.3) | 9 (69.2) | 0.019 |
| Initiation of mechanical ventilator | 4 (12.5) | 2 (15.4) | 1.000 |
| Acute kidney injuryc | 10 (31.3) | 5 (38.5) | 0.732 |
| Initiation of renal replacement therapy | 2 (6.3) | 2 (15.4) | 0.567 |
| Source | |||
| Pneumonia | 8 (25) | 5 (38.5) | 0.473 |
| Primary | 6 (18.8) | 4 (30.8) | 0.441 |
| Intraabdomen | 7 (21.9) | 2 (15.4) | 1.000 |
| Urinary tract | 7 (21.9) | 1 (7.7) | 0.405 |
| Catheter-related | 3 (9.4) | 1 (7.7) | 1.000 |
| Skin and soft tissue | 1 (3.1) | 0 | 1.000 |
| Polymicrobial | 3 (9.4) | 4 (30.8) | 0.168 |
| Treatment | |||
| Appropriate early therapy | 27 (84.4) | 10 (76.9) | 0.672 |
| Regimens | |||
| CZA-based | 14 (43.8) | 4 (30.8) | 0.420 |
| Cephalosporins-based | 10 (31.3) | 1 (7.7) | 0.136 |
| Colistin-based | 4 (12.5) | 6 (46.2) | 0.022 |
| Meropenem-based | 2 (6.3) | 2 (15.4) | 0.567 |
| Tigecycline-based | 2 (6.3) | 0 | 1.000 |
| Combination therapy | 4 (12.5) | 0 | 0.308 |
Data are presented as mean ± standard deviation for continuous variables, and number (percentage) for categorical variables. Statistically significant p-values are highlighted in bold
aChronic kidney disease was defined as estimated glomerular filtration rate < 60 mL/min/1.73 m2 for ≥ 3 months
bImmunocompromised status was defined as neutropenia, receiving prednisolone over 20 mg/day for more than 7 days, immunosuppressants, or cancer-related therapy
cAcute kidney injury was defined by modified KDIGO guidelines as a 1.5 × increase in baseline serum creatinine levels within 7 days of treatment initiation
Patients treated with colistin-based regimen had a higher tendency of 30-day mortality (p = 0.022). Table 3 presents univariate and multivariate analyses of risk factors associated with 30-day mortality. APACHE II score (hazard ratio [HR] 1.07; 95% confidence interval [CI] 1.01–1.15; p = 0.028) was an independent risk factor, and colistin-based therapy (HR 3.02; 95% CI 1.00–9.13; p = 0.050) was a marginally statistically significant independent risk factor. CZA therapy was not independently associated with 30-day mortality.
Table 3.
Univariate and multivariate analysis for risk factors associated with 30-day mortality
| Risk factors | Univariate | Multivariate | ||
|---|---|---|---|---|
| HR (95% CI) | p-Value | HR (95% CI) | p-Value | |
| Chronic kidney disease | 2.98 (0.92–9.68) | 0.070 | ||
| Chronic ventilator use | 3.76 (1.16–12.22) | 0.027 | ||
| APACHE II score | 1.07 (1.01–1.14) | 0.026 | 1.07 (1.01–1.15) | 0.028 |
| Pitt bacteremia score | 1.24 (1.02–1.52) | 0.035 | ||
| ICU acquisition | 3.48 (1.07–11.30) | 0.038 | ||
| Colistin-based therapy | 2.84 (0.95–8.46) | 0.061 | 3.02 (1.00–9.13) | 0.050 |
| CZA-based therapy | 0.69 (0.21–2.25) | 0.539 | ||
Statistically significant p-values are highlighted in bold
Subgroup Analysis of Critically Ill Patients
A total of 30 critically ill patients had Pitt bacteremia score ≥ 2 and received appropriate antibiotics against CRKP for at least 72 h. Among them, patients in the other active therapy group had a numerically higher 30-day mortality than those in the CZA group (43.8% versus 28.6%), but no statistical significance was noted (p = 0.389) (Supplementary Table S4). Multivariate analysis showed that primary bacteremia (HR 5.55, 95% CI 1.27–24.23, p = 0.023) and ICU-acquired infection (HR 5.22, 95% CI 1.02–26.81, p = 0.048) were independently associated with 30-day mortality (Supplementary Tables S5 and S6). CZA therapy was not independently associated with 30-day mortality.
Discussion
The overall 30-day mortality rate in patients with OXA-48-producing CRKP bacteremia was 28.9%. Although no significant difference was observed between the CZA and other active therapy groups, the CZA group exhibited a numerically lower mortality rate compared with the other active therapies group (22.2% versus 33.3%). CZA therapy was not associated with improved clinical or microbiological outcomes. However, colistin-based therapy may not be the optimal choice for treating OXA-48-producing CRKP bacteremia.
Recommendations from international guidelines for OXA-48-producing CRE infections are controversial [7, 8]. IDSA guidance supports CZA as the preferred therapy for OXA-48-producing Enterobacterales infections and cefiderocol as an alternative treatment option [7]. In contrast, ESCMID guideline does not specifically recommend antibiotics for OXA-48-producing CRE. However, for severe CRE infections, in addition to novel β-lactams, treatments involving multiple drugs with in vitro activity, such as polymyxins, aminoglycosides, tigecycline, or fosfomycin, are recommended [8].
Previous studies regarding the clinical outcomes of OXA-48-producing CRE infections treated with CZA or other regimens have been limited to endemic regions [6, 9–11]. A multicenter retrospective study conducted in Turkey included 106 patients with CZA-susceptible bacteremia who were treated with CZA between 2017 and 2021 [9]. The overall 30-day mortality rate was 33%, lower in those who received CZA as first-line treatment than in those who switched treatment to CZA (14.3% versus 37.7%) [9]. However, this study did not compare the effectiveness of CZA with that of other active regimens and did not detail the source of bacteremia.
A Spanish study included 76 patients with OXA-48-producing K. pneumoniae bacteremia treated with CZA or best available therapy (BAT) [6]. BAT included aminoglycoside monotherapy for urinary sources, and a combination of carbapenem (MIC ≤ 8 μg/mL) and another in vitro active drug (aminoglycoside, colistin, or fosfomycin) for non-urinary sources. Approximately half of the patients (51%) received combination therapy. The major source of bacteremia was urine (48.7%), followed by catheters (27.6%). The CZA group had a lower, though not statistically significant, 30-day mortality rate than the BAT group (12% versus 26%, p = 0.244), but had a significantly higher clinical success rate (91% versus 58%, p = 0.002) [6].
Another multicenter Spanish study included 339 patients with CPE infections, comparing the effectiveness of CZA (n = 189) with that of BAT (n = 150) [10]. The median Pitt bacteremia score was 1 in each group. Combination therapy was administered to 56 patients (29.6%) in the CZA group and 99 (66%) in the BAT group. The most common BAT combination was tigecycline plus gentamicin, followed by imipenem plus colistin. The most frequent infection was urinary tract infection (38.1%), followed by bacteremia (32.7%). Patients in the CZA group had a significantly lower 30-day mortality rate than those in the BAT group (13.7% versus 22%, p = 0.04) [10].
A study from Saudi Arabia was conducted to compare CZA with other active therapies in 28 patients with OXA-48-producing CRE infections, most of which were caused by K. pneumoniae isolates (24/28, 85.7%) [11]. Outcomes including 30-day mortality, clinical cure, relapse, and microbiological clearance were similar between patients in the CZA and other active therapy groups [11].
These three comparative studies show inconsistent results regarding the beneficial effects of CZA. Our study showed similar outcomes between the CZA and other active therapy groups, even in critically ill patients. Notably, our study focused on bacteremia, included a higher proportion of patients with pneumonia and primary bacteremia, and involved more patients with severe disease as indicated by higher APACHE II and Pitt bacteremia scores, compared with previous studies. In addition, most patients in our study received monotherapy, contrasting with the regimens in previous studies. The current findings provide further insights into treatment strategies for high-severity cases. However, colistin-based therapy was associated with a higher mortality rate in our study, suggesting that, while active monotherapy other than CZA is appropriate for OXA-48-producing CRKP bacteremia, colistin should be used with caution.
In our study, cephalosporins including cefepime, ceftazidime, and cephamycins were the most commonly used active agents other than CZA. However, the CLSI criteria recommends caution when prescribing third-generation cephalosporins and cefepime, even if their MICs are in the susceptible range, as current clinical and laboratory evidence remains insufficient to confirm their efficacy against CPE strains [17]. A recent French study conducted by Bonnin et al. revealed that 75% and 58% of OXA-48-producing Enterobacterales strains remained susceptible to cefepime and ceftazidime, respectively, in 1000 isolates [19]. Another recent study from the UK showed that 62.2% (153/246 isolates) of OXA-48-producing Enterobacterales strains had in vitro susceptibility to flomoxef ≤ 0.5 μg/mL [20]. In our study, patients treated with CZA and those treated with cephalosporins had similar 30-day mortality rates. Further studies on the effectiveness of cephalosporins against OXA-48-producing CRE are required.
Our study has some limitations. First, the small sample size and single-center study design may limit the statistical power and generalizability of the results. Future studies with larger or multicenter cohorts are recommended to validate these results and provide more robust evidence to guide clinical practice. Second, confounding factors, including baseline differences in comorbidities and clinical characteristics between the treatment groups, and heterogeneity of regimens within the other active therapy group, could not be completely eliminated because of the retrospective nature of the study and may influence clinical outcomes. Future prospective study or propensity score matching method are warranted to minimize these confounders to allow for more accurate assessment of treatment effectiveness. Third, the number of patients who received combination therapy was relatively small in our study, making it difficult to draw meaningful conclusions regarding its potential benefits compared with monotherapy. Finally, we did not further investigate other associated resistance mechanisms in these strains, such as co-production of extended-spectrum β-lactamase/AmpC β-lactamase or reduced porin expression. Given OXA-48 enzymes poorly hydrolyze extended-spectrum cephalosporins and show weak activity against carbapenems, the aforementioned mechanisms would result in higher MIC of cephalosporins and carbapenems and affected treatment choices. Despite the limitations in this study, to our knowledge, ours is the first study conducted to investigate the choice of treatment for OXA-48-produing CRKP bacteremia in Asia.
Conclusions
We found that 30-day mortality rate in patients with OXA-48-producing CRKP bacteremia was high outside endemic regions. Clinical outcomes were similar between patients treated with CZA and those treated with other active therapies; however, caution should be exercised when using colistin-based therapies.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We sincerely thank the participants of the study and Medical Science and Technology Building of the Taipei Veterans General Hospital for providing experimental space and facilities.
Medical Writing, Editorial, and Other Assistance
The authors would like to thank Editage (https://www.editage.com.tw/) for the English language editing. This assistance was funded by Y.L. Lin Hung Tai Education Foundation.
Author Contributions
Szu-Yu Liu performed the data analysis and wrote the original draft of the manuscript. Sheng-Hua Chou, Chien Chuang, Chih-Han Juan, Yi-Ru Huang, and Hsiang-Ling Ho performed data collection. Yi-Tsung Lin contributed to study design, data collection, funding acquisition, and revising the manuscript. Wan Chin, Yu-Chien Ho, and Szu-Yu Liu directly accessed and verified the underlying data. All authors reviewed and approved the final manuscript.
Funding
This work was supported by grants from the Ministry of Science and Technology (MOST 111-2314-B-A49-044), Taipei Veterans General Hospital (V112C-102, V113C-073, and V114C-047), and National Science and Technology Council (NSTC 112-2314-B-A49-029 and NSTC 114-2314-B-A49-079-MY3) in Taiwan, which included journal’s rapid service fee. The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.
Data Availability
The datasets generated and analyzed during the current study are not publicly available due to privacy concerns related to patient data.
Declarations
Conflicts of Interest
Szu-Yu Liu, Chien Chuang, Chih-Han Juan, Yu-Chien Ho, Sheng-Hua Chou, Yi-Ru Huang, Wan Chin, Hsiang-Ling Ho, and Yi-Tsung Lin declare no competing interests. Dr. Chih-Han Juan acquires an additional affiliation with the Taiwan Centers for Disease Control, Ministry of Health and Welfare, Taipei, Taiwan, starting 31 July 2025. Dr. Yi-Tsung Lin has held an additional affiliation with the Center for Infection Control, Taipei Veterans General Hospital, Taipei, Taiwan, since 16 July 2025.
Ethical Approval
This study protocol was approved by the Institutional Review Board of Taipei Veterans General Hospital (2025-07-009BC) As a retrospective observational study, the study posed minimal risk to participants, thus the requirement for informed consent was waived. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki of 1964 and its later amendments.
Footnotes
Publisher’s Note
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and analyzed during the current study are not publicly available due to privacy concerns related to patient data.