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Abstract

Background:

Bloodstream infections (BSI) caused by carbapenemase-producing Enterobacterales (CPE) represent a significant threat to patients with acute leukemia due to their high mortality. Ceftazidime–avibactam (CAZ-AVI) has emerged as a therapeutic alternative against these infections; however, its efficacy in immunocompromised patients remains unclear.

Objective:

To determine the impact of ceftazidime–avibactam on mortality due to BSI caused by CPE in patients with acute leukemia.

Design:

A retrospective cohort study was conducted at the Hospital Nacional Edgardo Rebagliati Martins in Lima, Peru.

Methods:

We included patients diagnosed with acute leukemia who developed BSI due to CPE during their hospital stays. Mortality was assessed for up to 30 days after BSI onset.

Results:

We evaluated 41 patients with a median age of 51 years; 56.1% had acute myeloid leukemia and 43.9% had acute lymphoblastic leukemia. Mortality at 30 days occurred in 60.9% of patients. The most frequent type of chemotherapy administered was induction (51.2%). Empiric antibiotic therapy with meropenem was administered to 97.6% of the patients, and ceftazidime–avibactam was prescribed as a targeted therapy to 48.8%. In the multivariate Cox regression model, the prescription of ceftazidime–avibactam reduced the risk of death (adjusted hazard ratio, 0.29; 95% CI: 0.09–0.92; p = 0.012) compared with those who received other antibiotic therapies, such as colistin.

Conclusion:

In patients with acute leukemia who developed bloodstream infections due to CPE during hospitalization, the prescription of ceftazidime–avibactam reduced 30-day mortality risk.

Keywords

acute leukemia antibiotic resistance bloodstream infection ceftazidime–avibactam death (MeSH)

Introduction

Bloodstream infections (BSI) caused by carbapenemase-producing Enterobacterales (CPE) pose a serious threat to healthcare institutions owing to their high mortality rates and limited treatment options.¹ A particularly vulnerable group includes patients with acute leukemia, who frequently develop febrile neutropenia (FN).² The incidence of FN increases up to 80% in patients with acute myeloid leukemia (AML).³ Although infections are the most common cause of FN, the epidemiology of gram-negative bacteria (GNB) and gram-positive bacteria varies across institutions,⁴ with a growing increase in infections caused by GNB, the most difficult to treat being those resistant to carbapenems.⁴ Initially, therapeutic regimens for these infections relied on the “best available therapies,” such as gentamicin, colistin, amikacin, tigecycline, and fosfomycin, used alone or in combination with each other and carbapenems.^5,6

In this context, ceftazidime–avibactam (CAZ-AVI) was developed, which is active against class A β-lactamases, including KPC carbapenemase in Enterobacterales, class C, and some class D β-lactamases, such as OXA-48.⁷ It is not active against metallo-β-lactamase producers; therefore, in these cases, its combination with aztreonam is recommended.⁸ Although this drug has been approved for the treatment of various CPE infections,^9–12 studies on the efficacy and safety of CAZ-AVI in clinical practice are limited.

Patients with acute leukemia are at a high risk of developing CPE BSI.¹³ Deficiencies in components of the innate immune system resulting from the underlying neoplasm may predispose them to invasive bacterial and fungal infections.¹⁴ Additionally, chemotherapy can lead to neutropenia, a major risk factor for the development of these infections.¹⁵ Mortality associated with BSIs caused by CPE in leukemia patients ranges from 53% to 57%,^4,16,17 but this may increase up to 100% in developing countries.¹⁸ In this complex clinical setting, the use of CAZ-AVI can reduce patient mortality,¹³ but the evidence remains ambiguous.¹⁹ Therefore, this study aimed to assess the impact of CAZ-AVI on 30-day mortality due to CPE BSI in patients with acute leukemia.

Materials and methods

Study design, population, and sample

This was a retrospective cohort study. Eligible patients included adults (⩾18 years) with a confirmed diagnosis of AML or acute lymphoblastic leukemia (ALL) who developed BSI due to CPE during hospitalization between January 2023 and June 2024. All the patients were undergoing active chemotherapy (i.e., induction, reinduction, and consolidation), were not recipients of hematopoietic stem cell transplantation, and were mostly neutropenic at the time of BSI onset. This selection reflects the real-world clinical vulnerability of patients with acute leukemia. We excluded patients who were still hospitalized at the time of data collection and those without microbiological confirmation of BSI caused by CPE.

Hospital Nacional Edgardo Rebagliati Martins (HNERM) belongs to the Social Health Insurance (EsSalud) of Peru. The hospital covers more than 2 million insured individuals.²⁰ Additionally, it has the highest specialization category in Peru (III-2) and performs various types of solid organ and hematopoietic progenitor transplants,²¹ making it the largest referral center in Peru.²²

Given the limited number of patients that met our inclusion criteria, we evaluated all available patients and performed a statistical power calculation. For power estimation, we referenced Herrera et al.²³ In their study, the exposed group (receiving CAZ-AVI) had a mortality rate of 19% compared with 41% in the nonexposed group, with an exposed-to-nonexposed ratio of 1:2 (16/32). Based on this data, a 95% confidence level, and a sample size of 41 participants, the calculated statistical power was 32.5%.

Procedures

After obtaining approval from the Ethics Committee, we requested records of AML or ALL patients treated in the Hematology Department of HNERM. We then reviewed cases of patients who developed CPE BSI during hospitalization. Electronic medical records were accessed through EsSalud’s Intelligent Health Service. In December 2024, two investigators independently extracted data on the variables of interest by using Microsoft Excel (Microsoft 365, Microsoft Corp., Redmond, WA, USA). The datasets were compared after data collection. Discrepancies were resolved through consultation with a third investigator. For the manuscript writing, we followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting observational studies²⁴ (Supplemental Material).

Microbiological samples were analyzed at the HNERM Microbiology Laboratory. Initial identification was performed using conventional microbiological techniques, and susceptibility profiles were determined using the MicroScan WalkAway 96 platform (Beckman Coulter) following the Clinical & Laboratory Standards Institute (CLSI) guidelines and breakpoints.²⁵ Carbapenem resistance was defined as resistance to one or more carbapenems based on the Minimum Inhibitory Concentration (MIC) breakpoints: meropenem MIC ⩾ 4, ertapenem MIC ⩾ 2, and imipenem MIC ⩾ 4. Carbapenemase screening was performed using the modified carbapenem inactivation method, and rapid enzymatic tests (boronic acid and Ethylenediaminetetraacetic acid EDTA) were used for phenotypic detection.²⁶ Lateral flow assay (O. K. N. V. I RESIST-5 Coris) was used to detect the specific carbapenemase determinants (NDM, KPC, OXA-48, VIM, and IMP).

The empirical management of febrile neutropenia at the HNERM follows a locally adapted protocol based on the institution’s microbiological resistance patterns. First-line empirical antibiotic therapy typically includes piperacillin/tazobactam or meropenem, given the high prevalence of extended-spectrum β-lactamase-producing Enterobacteriaceae. In cases of suspected infection due to multidrug-resistant organisms, colistin may be considered based on previous colonization or infection history. The use of advanced antibiotics such as ceftazidime–avibactam requires prior authorization from the hospital antimicrobial stewardship team.

Variables

Outcome variable

The primary outcome was death within 30 days of the follow-up. Follow-up began with the collection of blood cultures at the time of clinical suspicion of BSI²⁷ and ended 30 days after BSI onset.

Independent variables

The primary independent variable was the prescription of CAZ-AVI for at least 72 h as targeted therapy. The prescribed dose was 2 g of ceftazidime and 0.5 g of avibactam intravenously every 8 h, administered as a 2-h infusion. In cases of renal failure, dose adjustments were made based on the estimated creatinine clearance (Cockcroft–Gault equation).²⁸

The remaining independent variables were grouped into the following categories: (1) Clinical characteristics—sex, age, leukemia type, chemotherapy regimen, bacteremia source, and persistent BSI (defined as a positive blood culture despite 48 h of appropriate antibiotic therapy). (2) Assessment Scales—Multinational Association for Supportive Care in Cancer (MASCC) score: Evaluates the risk of complications in febrile neutropenic patients²⁹; Charlson Comorbidity Index: Assesses mortality risk in patients with comorbidities, with low risk defined as a score of 0–2 and a high risk of ⩾3³⁰; Pitt Bacteremia Score (PBS): Evaluates BSI severity, with a score >3 indicating a high risk.³¹ (3) Microbiological characteristics—described the isolated Enterobacterales species and carbapenemase type. (4) Treatment—empirical antibiotics and targeted therapies were also included.

Statistical analysis

The analysis was performed using Stata software (Version 17.0, StataCorp LLC, College Station, TX, USA).For descriptive statistics, categorical variables were presented using frequencies and percentages, whereas numerical variables were described using measures of central tendency (mean or median) and dispersion (standard deviation or interquartile range) depending on the normality of data distribution. For bivariate analysis, the chi-square test was used for categorical variables, while the Mann–Whitney U test was employed for quantitative variables, as the numerical variables followed a nonparametric distribution.

To address this research question, we performed Cox proportional hazards regression to obtain crude and adjusted hazard ratios (HR) with their respective 95% confidence intervals (95% CI). Age, Charlson Comorbidity Index, chemotherapy type, and Pitt Bacteremia Score were included and neutropenia status as adjustment variables in the multivariate model. The proportionality assumptions were assessed using Schoenfeld residuals. Finally, survival was compared between patients who received CAZ-AVI and those who did not using the Kaplan-Meier method, with the differences between the curves evaluated by the log-rank test.

Ethical considerations

This study complied with international standards established by the Declaration of Helsinki and received approval from the Ethics Committee of the Edgardo Rebagliati Martins National Hospital with verification code AUT. No. 135-CE-GHNERM-GRPR-ESSALUD-2024, on November 26, 2024. Confidentiality of extracted data was guaranteed.

Results

Of the 43 medical records reviewed, two did not meet the inclusion criteria (no confirmed isolation of CPE) (Figure 1). Data from 41 patients were analyzed: 58.5% were female, the median age was 51 years (interquartile range (IQR) 37–58), AML was the most frequent hematologic malignancy (56.1%), and 92.7% of patients had neutropenia during BSI development. The mean hospital stay duration was 28 days (IQR 22–46), and death within 30 days of follow-up occurred in 60.9% of patients. CAZ-AVI was prescribed as a targeted therapy in 51.2% of patients. The time to the initiation of CAZ-AVI was 8 days (IQR 5–10).

Figure 1.

Participant selection.

Group comparisons

Death was more frequent among patients with AML, those requiring invasive mechanical ventilation (IMV), those requiring vasopressors, and those with a higher Pitt bacteremia score (Table 1). Regarding CAZ-AVI prescription, this was less frequent in patients with abdominal or respiratory BSI foci, and less frequently prescribed in those requiring vasopressors. No significant differences were found in other characteristics (Table 2).

Table 1.

Baseline Characteristics and Mortality Comparison in Patients with Acute Leukemia and Bloodstream Infection (n = 41).

Characteristic	n (%)	Survival (n = 16)	Nonsurvival (n = 25)	p-Value
Gender				0.375^c
Female	24 (58.5)	8 (50.0)	16 (64.0)
Male	17 (41.5)	8 (50.0)	9 (36.0)
Age^a	51 (37–58)	46.5 (33.5–54)	54 (40–60)	0.117^b
Hematologic malignancy				0.001^c
Acute myeloid leukemia	23 (56.1)	4 (25.0)	19 (76.0)
Acute lymphoblastic leukemia	18 (43.9)	12 (75.0)	6 (24.0)
Disease stage				0.843^c
Relapse	28 (68.3)	10 (62.5)	18 (72.0)
No relapse	13 (31.7)	6 (37.5)	7 (28.0)
Chemotherapy				0.646^d
Induction	21 (51.2)	9 (56.3)	12 (48.0)
Reinduction	16 (39.0)	5 (31.2)	11 (44.0)
Consolidation	4 (9.8)	2 (12.6)	2 (8.0)
Neutropenia status	38 (92.7)	14 (87.5)	24 (96.0)	0.550^d
Focus of BSI				0.158^d
Abdominal	17 (41.5)	3 (18.8)	14 (56.0)
Respiratory	8 (19.5)	4 (25.0)	4 (16.0)
Perianal infection	7 (17.1)	4 (25.0)	3 (12.0)
Undetermined infection	5 (12.2)	2 (12.5)	3 (12.0)
Severe mucositis	3 (7.3)	2 (12.5)	1 (4.0)
Skin and soft tissue	1 (2.4)	1 (6.2)	0 (0.0)
ICU admission within the first 48 h of BSI	2 (4.9)	0 (0.0)	2 (8.0)	0.512^d
Received antibiotics 7 Days before BSI	32 (78.1)	13 (81.3)	19 (76.0)	0.999^d
Hospitalized in the last month	12 (29.3)	7 (43.8)	5 (20.0)	0.161^d
Persistent BSI	4 (9.8)	0 (0.0)	4 (16.0)	0.143^d
Mechanical ventilation requirement	15 (36.6)	1 (6.3)	14 (56.0)	0.001^c
Hemodialysis requirement	2 (4.9)	0 (0.0)	2 (8.0)	0.512^d
Vasopressor use requirement	25 (61.0)	2 (12.5)	23 (92.0)	<0.001^c
Time from admission to BSI development (days)^a	17 (14–23)	18.5 (14–32.5)	17 (14–23)	0.678^b
Length of hospital stay (days)^a	28 (22–46)	51.5 (36–66.5)	24 (19–27)	<0.001^b
Time from BSI to discharge or death (days)^a	9 (4–20)	25.5 (17.5–44.5)	4 (2–8)	<0.001^b
MASCC score^a	10 (6–14)	14 (11–18)	9 (6–10)	<0.001^b
Charlson score^a	3 (2–4)	2.5 (2–3)	3 (2–4)	0.110^b
Pitt score^a	6 (1–9)	0 (0–2)	9 (6–11)	<0.001^b
Enterobacterales isolated in blood culture				0.999^d
Escherichia coli	1 (2.4)	0 (0.0)	1 (4.0)
Klebsiella pneumoniae	40 (97.6)	16 (100.0)	24 (96.0)
Identified resistance mechanism				0.779^d
KPC	36 (87.8)	15 (93.8)	21 (84.0)
OXA-48	2 (4.9)	0 (0.0)	2 (8.0)
NDM	3 (7.3)	1 (6.2)	2 (8.0)
Empirical antibiotic therapy
Meropenem	40 (97.6)	15 (93.8)	25 (100.0)	0.206^d
Colistin	5 (12.2)	2 (12.5)	3 (12.0)	0.962^d
Vancomycin	31 (75.6)	12 (75.0)	19 (76.0)	0.999^d
Targeted antibiotic therapy
Ceftazidime–Avibactam	20 (48.8)	13 (81.3)	7 (28.0)	0.001^c
Ceftazidime–Avibactam + Aztreonam	1 (2.4)	1 (6.3)	0 (0.0)	0.390^d
Meropenem + Colistin	7 (17.1)	1 (6.3)	6 (24.0)	0.215^d
Meropenem	10 (24.4)	0 (0.0)	10 (40.0)	0.003^d
Colistin	4 (9.8)	2 (12.5)	2 (8.0)	0.637^d

KPC, Klebsiella pneumoniae carbapenemasa; NDM, Nueva Delhi metalo-betalactamasa; OXA-48, Oxacilinasa-48.

Infection in the KPC group, 21 isolates were confirmed by immunochromatography and 15 by phenotypic methods.

Median and interquartile range.

Mann–Whitney U statistical test.

Chi-square statistical test.

Fisher’s exact test.

BSI, Bloodstream infections; ICU, Intensive Care Unit.

Table 2.

Differences in ceftazidime–avibactam prescriptions (n = 41).

Characteristic	Did not receive ceftazidime–avibactam (n = 21)	Received ceftazidime–avibactam (n = 20)	p-Value
Gender			0.654^b
Female	13 (61.9)	11 (55.0)
Male	8 (38.1)	9 (45.0)
Age^a	54 (43–60)	44 (28.5–54.5)	0.078^c
Hematologic malignancy			0.043^b
Acute myeloid leukemia	15 (71.4)	8 (40.0)
Acute lymphoblastic leukemia	6 (28.6)	12 (60.0)
Disease stage			0.658^b
Relapse	15 (71.4)	13 (65.0)
Initial diagnosis	6 (28.6)	7 (35.0)
Chemotherapy			0.809^d
Induction	12 (57.2)	9 (45.0)
Reinduction	7 (33.3)	9 (45.0)
Consolidation	2 (9.5)	2 (10.0)
Neutropenia status	20 (95.2)	18 (90.0)	0.606^d
Focus of BSI			0.049^d
Abdominal	13 (61.9)	4 (20.0)
Respiratory	4 (19.1)	4 (20.0)
Perianal infection	1 (4.7)	6 (30.0)
Undetermined infection	2 (9.5)	3 (15.0)
Severe mucositis	1 (4.8)	2 (10.0)
Skin and soft tissue	0 (0.0)	1 (5.0)
ICU admission within the First 48 h of BSI	2 (9.5)	0 (0.0)	0.488^d
Received antibiotics 7 days before BSI	17 (81.0)	15 (75.0)	0.719^d
Hospitalized in the last month	7 (33.3)	5 (25.0)	0.558^d
Persistent BSI	2 (9.5)	2 (10.0)	0.999^d
Mechanical ventilation requirement	9 (42.9)	6 (30.0)	0.393^b
Hemodialysis requirement	0 (0.0)	2 (10.0)	0.232^d
Vasopressor use requirement	17 (81.0)	8 (40.0)	0.007^b
Time from admission to BSI development (days)^a	17 (15–23)	17.5 (14–30)	0.958^c
Length of hospital stay (days)^a	24 (18–27)	44 (32.5–58.5)	<0.001^c
MASCC score^a	10 (6–13)	11 (9.5–15.5)	0.288^c
Charlson score^a	4 (2–4)	2.5 (2–3)	0.084^c
Pitt score^a	8 (2–10)	3 (0–8)	0.067^c
Enterobacterales isolated in blood culture			0.999^d
Escherichia coli	1 (4.8)	0 (0.0)
Klebsiella pneumoniae	20 (95.2)	20 (100.0)
Identified resistance mechanism			0.505^d
KPC	17 (81.0)	19 (95.0)
OXA-48	2 (9.5)	0 (0.0)
NDM	2 (9.5)	1 (5.0)

KPC: Klebsiella pneumoniae carbapenemasa; NDM: Nueva Delhi metalo-betalactamasa; OXA-48: Oxacilinasa-48; Infection in the KPC group, 21 isolates were confirmed by immunochromatography and 15 by phenotypic methods.

Median and interquartile range.

Chi-square statistical test.

Mann–Whitney U statistical test.

Fisher’s exact test.

BSI, bloodstream infections; ICU, Intensive Care Unit.

Ceftazidime–avibactam and its impact on mortality

In the bivariate Cox regression model, CAZ-AVI prescription was associated with a lower mortality risk (crude hazard ratio: 0.16; 95% CI: 0.06–0.45) than other antibiotic treatments. When adjusted for age, Charlson Comorbidity Index, chemotherapy type, and PBS, CAZ-AVI prescription remained associated with lower mortality risk (adjusted hazard ratio: 0.29; 95% CI: 0.09–0.92) compared to other antibiotic therapies such as colistin (Table 3). Figure 2 shows the 30-day survival function through Kaplan–Meier curves comparing patients who received CAZ-AVI versus those who did not.

Table 3.

Crude and adjusted regression model for bloodstream infection mortality.

Characteristic	Crude hazard ratio (95% CI)	p-Value	Adjusted hazard ratio (95% CI)	p-Value
Received Ceftazidime/Avibactam
No	Ref		Ref
Yes	0.16 (0.06–0.45)	<0.001	0.29 (0.09–0.92)	0.012
Age in tertiles
14–40 years	Ref		Ref
41–56 years	1.48 (0.52–4.26)	0.462	12.84 (1.10–149.29)	0.055
57–73 years	3.03 (1.15–7.98)	0.025	14.49 (0.93–225.53)	0.081
Charlson Comorbidity Index
Low comorbidity risk (0 to 2 points)	Ref		Ref
High comorbidity risk (3 or more points)	2.03 (0.87–4.75)	0.102	0.30 (0.03–3.42)	0.307
Chemotherapy type
Induction	Ref		Ref
Reinduction	1.11 (0.49–2.51)	0.809	1.10 (0.34–3.56)	0.837
Pitt bacteremia score
⩽3 points	Ref		Ref
>3 puntos	10.05 (2.97–34.00)	<0.001	12.90 (2.99–55.73)	0.001
Neutropenia status
No	Ref		Ref
Yes	2.68 (0.36–19.87)	0.334	3.45 (0.33–36.36)	0.001

The proportionality of the multivariate model had a p-value of 0.947.

Figure 2.

Kaplan–Meier curves according to ceftazidime/avibactam treatment.

Discussion

Main findings

In this retrospective cohort study of 41 patients with Acute Leukemia, the main findings were as follows: (1) In patients with BSI, CAZ-AVI prescription as targeted therapy was associated with a 71% reduced mortality risk compared with other antibiotics such as colistin. (2) At the 30-day follow-up, death occurred in 60.9% of patients and was more frequent in AML cases. (3) The most frequently isolated pathogen was KPC-producing Klebsiella pneumoniae.

Comparison between studies

In CPE infections, CAZ-AVI prescriptions had a positive impact on mortality reduction.³² The current discussion evaluates the impact of CAZ-AVI in other clinical scenarios, as evidence for oncohematological patients remains unclear. A study conducted in Lebanon, which included 300 patients with Acute Leukemia or undergoing hematopoietic progenitor cell transplantation, showed that CAZ-AVI prescription as an empirical treatment for febrile neutropenia was associated with a higher mortality risk than the best available therapy such as cefepime, piperacillin–tazobactam, meropenem, and aminoglycosides.¹⁹ In contrast, in our study CAZ-AVI was associated with a marked reduction in the mortality risk. The differences may be explained by the small number of patients (n = 4) who had a CPE infection in the Lebanese study and the fact that the CAZ-AVI group had more transplant patients, which could impact mortality differences. Castón et al.¹³ also found no differences in mortality (CAZ-AVI vs best available therapy) when evaluating patients with hematological malignancies. Although their study evaluated patients with CPE infections, their small sample size (n = 31) may have contributed to the low statistical power to identify significant differences between groups. In contrast, Herrera et al.,²³ in a study conducted at a hospital center in Argentina, reported that CAZ-AVI showed a clinical benefit over the best available therapy in patients with CPE BSI, and while their population included all patients with CPE BSI, they also reported that 46% of these had hematological malignancies. Given the results of Herrera et al. and our study, the need for more research to reinforce or refute the findings reported here is evident.

A multicenter study in six hospitals in Chile, Ecuador, and Peru, which included 416 febrile neutropenia episodes in patients with acute leukemia, documented that 38.7% of patients had BSI.³³ The isolates were predominantly gram-negative bacilli and 11% produced carbapenemases, mainly KPC. While they did not describe the empirical and targeted treatment used during febrile neutropenia episodes, they reported that mortality in patients with BSI was 26.7%, which was lower than that reported in our study. The contrast may be because only 11% of patients had CPE BSI; therefore, empirical therapy may have a higher probability of being effective against susceptible Enterobacterales and thus lower mortality. The high mortality in neutropenic patients developing CPE BSI is reflected in another Peruvian study,¹⁸ which reported that in febrile neutropenia patients with OXA-48- and KPC-producing CPE BSI, death occurred in 100% of patients.

Implications

The increase in CPE in Latin America is a serious public health threat³⁴ given the limited efficacy of conventional antibiotics and the associated increase in mortality. Therefore, CAZ-AVI has emerged as a potential therapeutic option. In October 2023, Peru’s Social Health Insurance authorized its use in adult patients with confirmed CPE infections,³⁵ which is a necessary advance. However, its implementation faces logistical barriers because it is not included in the national drug formulary. The lack of inclusion in this national formulary is likely due to the high cost of CAZ-AVI. While its high cost is a limiting factor to consider, when analyzing the cost-effectiveness of CAZ-AVI versus Colistin in the Peruvian context, particularly for the treatment of CRE pneumonia or bacteremia, CAZ-AVI demonstrates greater cost-effectiveness compared to Colistin.³⁶

The evidence, including that of our study, supports the impact of CAZ-AVI as a targeted therapy on 30-day patient survival. However, its usefulness as an empirical antibiotic remains ambiguous¹⁹; therefore, more studies are needed to evaluate this scenario.

Strengths and limitations

This is the first study conducted in Latin America on patients with acute leukemia to evaluate the 30-day mortality impact of CAZ-AVI. Several limitations must be considered. First, despite the small sample size, the number of evaluated cases exceeded that of other studies showing real-world CAZ-AVI use. Second, although our institution lacks access to molecular diagnostic platforms, we used a validated lateral flow immunochromatographic assay (RESIST-5 O.K.N.V.I.) to detect carbapenemases. This test demonstrated excellent performance characteristics, with a sensitivity of 100% and specificity ranging from 95% to 100%, according to previous validation studies. However, this method may not detect novel or coproduced carbapenemases that are not targeted by the assay. Therefore, the absence of molecular confirmation limits the ability to identify less common resistance mechanisms and potential co-expression, which may contribute to the underreporting of mixed carbapenemase producers. Third, the lack of screening for CPE colonization prior to febrile neutropenia episodes and not considering the use of antibacterial prophylaxis during febrile neutropenia episodes are confounding factors that may affect 30-day mortality. Although we considered the neutropenic status in the multivariate adjustment, we did not collect consistent data on the duration of neutropenia, which may be a relevant factor influencing the severity of infection and clinical outcomes. Patients with AML may experience longer neutropenic periods owing to intensive chemotherapy regimens, which could partially explain the higher mortality observed in this group and the lower frequency of CAZ-AVI use. Future studies should include the duration of neutropenia as an adjustment variable to better characterize its prognostic impact. Fourth, the unavailability of CAZ-AVI in the institutional formulary prevents evaluation of its impact if administered early, and the limited number of patients with metallo-β-lactamase-producing Enterobacterales isolates who received ceftazidime/avibactam in combination with aztreonam prevents the assessment of its impact in this scenario. Despite these limitations, our study may serve as a basis for more robust prospective studies to assess the impact of CAZ-AVI in complex clinical scenarios.

Conclusion

In acute leukemia patients with bloodstream infections caused by carbapenemase-producing Enterobacterales, targeted therapy with ceftazidime–avibactam was associated with a 71% reduction in mortality risk compared with other options, such as colistin. These findings reinforce its role in serious CPE infections in oncohematological patients where therapeutic alternatives are limited. Despite the inherent limitations of its retrospective design and sample size, this study provides relevant evidence given the scarcity of data in Latin America. Prospective multicenter studies are required to confirm its impact and define its optimal use in this scenario.

Supplemental Material

sj-docx-1-tai-10.1177_20499361251362955 – Supplemental material for Impact of ceftazidime–avibactam on mortality in bloodstream infections: a cohort study in patients with acute leukemia

Supplemental material, sj-docx-1-tai-10.1177_20499361251362955 for Impact of ceftazidime–avibactam on mortality in bloodstream infections: a cohort study in patients with acute leukemia by Cesar Copaja-Corzo, Susy Bazán-Ruiz, Andre Fuentes-Yufra, Marlies Pizarro-Perea, Marco Montiel-González and Giancarlo Pérez-Lazo in Therapeutic Advances in Infectious Disease

Footnotes

Acknowledgements

None.

Correction (September 2025):

The affiliation of author Cesar Copaja-Corzo was previously incorrect and has now been updated.

Declarations

ORCID iD

Cesar Copaja-Corzo

Supplemental material

Supplemental material for this article is available online.

References

Huang

R-C

Chen

L-Y

Wang

Y-C

, et al. Effectiveness comparison between ceftazidime-avibactam and carbapenem-based regimens in nosocomial carbapenem-resistant Klebsiella pneumoniae bloodstream infections. J Microbiol Immunol Infect. Epub ahead of print 2025. DOI: 10.1016/j.jmii.2025.03.003.

Pal

Othus

Ali

, et al. Identification of factors predicting low-risk febrile neutropenia admissions in adults with acute myeloid leukemia. Blood Adv 2024; 8: 6161–6170.

Schauwvlieghe

Dunbar

Storme

, et al. Stopping antibiotic therapy after 72 h in patients with febrile neutropenia following intensive chemotherapy for AML/MDS (safe study): a retrospective comparative cohort study. eClinicalMedicine. Epub ahead of print 2021. DOI: 10.1016/j.eclinm.2021.100855.

Storhaug

KØ

Skutlaberg

Hansen

, et al. Carbapenem-resistant enterobacteriaceae—implications for treating acute leukemias, a subgroup of hematological malignancies. Antibiotics 2021; 10: 322.

Castón

Cano

Pérez-Camacho

, et al. Impact of ceftazidime/avibactam versus best available therapy on mortality from infections caused by carbapenemase-producing Enterobacterales (CAVICOR study). J Antimicrob Chemother 2022; 77: 1452–1460.

Bassetti

Peghin

How to manage KPC infections. Ther Adv Infect Dis 2020; 7: 2049936120912049.

Zhanel

Lawson

Adam

, et al. Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Drugs 2013; 73: 159–177.

Falcone

Daikos

Tiseo

, et al. Efficacy of ceftazidime-avibactam plus aztreonam in patients with bloodstream infections caused by metallo-β-lactamase-producing enterobacterales. Clin Infect Dis 2021; 72: 1871–1878.

Mazuski

Gasink

Armstrong

, et al. Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: results from a randomized, controlled, double-blind, phase 3 program. Clin Infect Dis 2016; 62: 1380–1389.

10.

Soriano

Montravers

Bassetti

, et al. The use and effectiveness of ceftazidime-avibactam in real-world clinical practice: EZTEAM study. Infect Dis Ther 2023; 12: 891–917.

11.

Wagenlehner

Sobel

Newell

, et al. Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: RECAPTURE, a phase 3 randomized trial program. Clin Infect Dis 2016; 63: 754–762.

12.

Torres

Zhong

Pachl

, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis 2018; 18: 285–295.

13.

Castón

Lacort-Peralta

Martín-Dávila

, et al. Clinical efficacy of ceftazidime/avibactam versus other active agents for the treatment of bacteremia due to carbapenemase-producing Enterobacteriaceae in hematologic patients. Int J Infect Dis 2017; 59: 118–123.

14.

Lyman

Kuderer

NM.

Epidemiology of febrile neutropenia. Support Cancer Ther 2003; 1: 23–35.

15.

Baden

Swaminathan

Angarone

, et al. Prevention and treatment of cancer-related infections, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw 2016; 14: 882–913.

16.

Satlin

Calfee

Chen

, et al. Emergence of carbapenem-resistant Enterobacteriaceae as causes of bloodstream infections in patients with hematologic malignancies. Leuk Lymphoma 2013; 54: 799–806.

17.

Pagano

Caira

Trecarichi

, et al. Carbapenemase-producing Klebsiella pneumoniae and hematologic malignancies. Emerg Infect Dis 2014; 20: 1235–1236.

18.

Pérez-Lazo

del Valle-Mendoza

Sandoval-Ahumada

, et al. Impact of adding a rapid PCR-based blood culture identification panel to the antimicrobial stewardship program of patients with febrile neutropenia in a Peruvian Referral Hospital. Antibiotics 2023; 12: 648.

19.

Abi Frem

Khazzeka

Allaw

, et al. Ceftazidime-avibactam for the treatment of febrile neutropenia in HSCT recipients and acute leukemia patients post induction chemotherapy. Sci Rep 2024; 14: 31322.

20.

Estudios SS de S (EsSalud) GC de P y PG de G de la ISG de A y. Perfil de la población asegurada de EsSalud, I trimestre 2023, https://repositorio.essalud.gob.pe/handle/20.500.12959/4201 (2023, accessed 27 March 2025).

21.

Aranda-Gomero

Pichardo-Rodriguez

Fernandez-Vertíz

, et al. Trasplante de células madre hematopoyéticas en el Perú: experiencia y desafíos del centro de trasplante más grande del Perú. Rev Fac Med Hum 2022; 22(2): 225–227.

22.

EsSalud. Hospital Rebagliati de EsSalud logra recategorización por su alta especialidad y capacidad, https://www.gob.pe/institucion/essalud/noticias/1036566-hospital-rebagliati-de-essalud-logra-recategorizacion-por-su-alta-especialidad-y-capacidad (2024, accessed 27 March 2025).

23.

Herrera

Rearte

Mejía

, et al. Ceftazidima/avibactam frente a otros antimicrobianos para el tratamiento de bacteriemias por Enterobacterales productores de carbapenemasa KPC: datos de la vida real de un hospital universitario de Argentina. Rev Chil Infectol; 40, https://www.revinf.cl/index.php/revinf/article/view/1820 (2023, accessed 15 March 2025).

24.

von Elm

Altman

Egger

, et al. Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ 2007; 335: 806–808.

25.

CLSI. Clinical & Laboratory Standards Institute: CLSI Guidelines. https://clsi.org/ (2024, accessed 17 November 2024).

26.

Ministerio de Salud. Instituto de Salud Pública de Chile, https://www.ispch.gob.cl/biomedico/documentos-tecnicos-de-referencia/gestion-tecnica-calidad-y-bioseguridad/ (2023, accessed 17 November 2024).

27.

Viscoli

Bloodstream infections: the peak of the iceberg. Virulence 2016; 7: 248–251.

28.

Jorgensen

SCJ

Trinh

Zasowski

, et al. Real-world experience with ceftazidime-avibactam for multidrug-resistant gram-negative bacterial infections. Open Forum Infect Dis 2019; 6: ofz522.

29.

Gayol

MdC

Font

Casas

, et al. Utilidad de la escala de MASCC en el tratamiento de la neutropenia febril inducida por quimioterapia en pacientes con neoplasia sólida. Med Clínica 2009; 133: 296–299.

30.

Rius

Pérez

Martínez

, et al. An adaptation of Charlson comorbidity index predicted subsequent mortality in a health survey. J Clin Epidemiol 2004; 57: 403–408.

31.

Henderson

Luterbach

Cober

, et al. The pitt bacteremia score predicts mortality in nonbacteremic infections. Clin Infect Dis 2020; 70: 1826–1833.

32.

Chen

Huang

H-B

Peng

J-M

, et al. Efficacy and safety of ceftazidime-avibactam for the treatment of carbapenem-resistant enterobacterales bloodstream infection: a systematic review and meta-analysis. Microbiol Spectr 2022; 10: e0260321.

33.

Rabagliati

Salazar

Pérez-Lazo

, et al. An emergent change in epidemiologic and microbiological characteristics of bloodstream infections in adults with febrile neutropenia resulting from chemotherapy for acute leukemia and lymphoma at reference centers in Chile, Ecuador, and Peru. Open Forum Infect Dis 2024; 11: ofae052.

34.

García-Betancur

Appel

Esparza

, et al. Update on the epidemiology of carbapenemases in Latin America and the Caribbean. Expert Rev Anti Infect Ther 2021; 19: 197–213.

35.

IETSI. Dictamen N° 048-DETS-IETSI-2023. IETSI, https://ietsi.essalud.gob.pe/dictamenes/dictamen-n-048-dets-ietsi-2023/ (2023, accessed 27 March 2025).

36.

Bolaños-Díaz

Angles-Yanqui

Pérez-Lazo

, et al. Cost-effectiveness of ceftazidime/avibactam for infections due to carbapenem-resistant bacteria in Peru. J Pharm Health Serv Res 2022; 13: 2–8.

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