Next Article in Journal
Antibiotic Use in Beekeeping: Implications for Health and Environment from a One-Health Perspective
Previous Article in Journal
Antibiotics Use for Dental or Oral Cavity Infections in Pediatric Dentistry: Knowledge and Prescribing Practices Between Italian Dentists
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Antibiotics
Volume 14
Issue 4
10.3390/antibiotics14040358
antibiotics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Optimizing Antibiotic Treatment Duration for ESBL-Producing Enterobacteriaceae Bacteremia in ICU: A Multicentric Retrospective Cohort Study

by
Camille Le Berre
1,
Maxime Degrendel
2,
Marion Houard
3,
Lucie Benetazzo
1,
Anne Vachée
4,
Hugues Georges
1,
Frederic Wallet
5,
Pierre Patoz
6,
Perrine Bortolotti
7,
Saad Nseir
2,
Pierre-Yves Delannoy
1 and
Agnès Meybeck
1,*
1
Service de Réanimation et Maladies Infectieuses, Centre Hospitalier de Tourcoing, 135 Rue du Président Coty, 59200 Tourcoing, France
2
Unité de Recherche, Centre Hospitalier de Tourcoing, 135 Rue du Président Coty, 59200 Tourcoing, France
3
Service de Réanimation Médicale, CHRU de Lille, 2 Avenue Oscar Lambret, 59000 Lille, France
4
Laboratoire de Microbiologie, Centre Hospitalier de Roubaix, 11 Boulevard Lacordaire, 59100 Roubaix, France
5
Laboratoire de Microbiologie, CHRU de Lille, 2 Avenue Oscar Lambret, 59000 Lille, France
6
Laboratoire de Microbiologie, Centre Hospitalier de Tourcoing, 135 Rue du Président Coty, 59200 Tourcoing, France
7
Service de Réanimation, Centre Hospitalier de Roubaix, 11 Boulevard Lacordaire, 59100 Roubaix, France
*
Author to whom correspondence should be addressed.
Antibiotics 2025, 14(4), 358; https://doi.org/10.3390/antibiotics14040358
Submission received: 20 February 2025 / Revised: 24 March 2025 / Accepted: 25 March 2025 / Published: 1 April 2025
(This article belongs to the Special Issue Antibiotic Stewardship and Infection Control Strategies in Critical Care)
Browse Figures
Versions Notes

Abstract

:
Background: The optimal duration of antibiotic treatment for extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) bloodstream infections (BSI) in intensive care unit (ICU) is not established. We aim to evaluate the frequency and clinical outcomesof a short appropriate antibiotic treatment (≤7 days) (SAT) for ESBL-E BSI acquired in the ICU. We specifically assessed the rate of ESBL-E BSI relapse, and in-ICU mortality. Method: All patients who acquired ESBL-E BSI in three ICU in Northern France between January 2011 and June 2022 were included in a multicenter retrospective cohort study. The factors associated with prescribing short (SAT, ≤7 days) versus long (LAT, >7 days) antibiotic treatment were analyzed. To evaluate the impact of SAT on mortality in the ICU, an estimation was applied using a Cox model with a time-dependent co-variable adjusted by inverse weighting of the propensity score. Results: In total, 379 patients were included. The proportion of patients receiving a SAT was 40% in the entire cohort and 25% in survivors beyond 7 days. In bivariate analysis, the factors associated with prescribing a SAT in survivors were shorter pre-bacteremia ICU stay (p = 0.005), lower proportion of chronic renal failure history (p = 0.034), cancer (p = 0.042), or transplantation (p = 0.025), less frequent exposure to carbapenem within 3 months (p = 0.015). There was a higher proportion of septic shock (p = 0.017) or bacteremia secondary to pneumonia (p = 0.003) in the group of survivors receiving a LAT. After adjustment, no difference in survival was found between the two groups (HR: 1.65, 95%CI: 0.91–3.00, p = 0.10). Conclusion: In our cohort, one quarter of patients with ESBL-E bacteremia acquired in the ICU surviving beyond 7 days were treated with a SAT. SAT did not appear to affect survival. Patients who could benefit from a SAT need to be better identified.

1. Introduction

Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) bloodstream infections (BSI) are associated with high rates of treatment failure and mortality, especially when initial probabilistic antimicrobial therapy is inappropriate [1,2]. The standard of care of severe ESBL-E infections is carbapenem. Butits overuse has promoted the emergence of carbapenemase-producing Enterobacteriaceae [3,4]. Reducing antibiotic overuse, including reducing antibiotic treatment duration, is an important target of antibiotic stewardship. Long antibiotic courses favor the emergence of antimicrobial resistance [5]. Multiple studies have evaluated different durations of antibiotic therapy in case of Gram-negative bacteremia to define an equally effective shorter treatment [6]. Recently, several randomized controlled trials showed the non-inferiority of 7 days vs. 14 days antibiotic courses for Gram-negative bacteremia [7,8,9]. These studies were not designed to assess shorter antibiotic course in specific subgroups of patients, especially intensive-care patients. The first two studies included only uncomplicated bacteremia. Patients with hemodynamic instability 48 h prior to randomization were excluded. The third one included both hospitalized patients and outpatients. A recent systematic review and meta-analysis showed that 7 days of antibiotic treatment resulted in a similar outcome as 14 days for patients with controlled Enterobacteriaceae bacteremia [10]. Of note, multidrug-resistant bacteria were involved in 8 to 18% of the cases included in the various studies retained in the meta-analysis. These limitations prevent a strong conclusion on the duration of antibiotic treatment for ESBL-E bacteremia, especially in critically ill patients. The current guidelines state that the duration of therapy should not differ for infections caused by resistant organisms compared to infections caused by susceptible organisms [11,12]. According to French guidelines, the recommended duration of antibiotic treatment for uncomplicated bacteremia is 7 days [13]. We therefore defined short treatment as a duration of antibiotic treatment of ≤7 days. While prior studies suggest a short treatment of 7-day is non-inferior to longer durations in the case of Gram-negative bacteremia, none focus specifically on intensive care unit (ICU) patients. We conducted a multicentric retrospective cohort study in critically ill patients to assess the prescription of short (≤7 days) antibiotic treatment (SAT) versus long (>7 days) antibiotic treatment (LAT) for ESBL-E BSI acquired in the ICU. The retrospective design allowed us to include all the ICU patients suffering from ESBL-E BSI. It avoided recruitment difficulties inherent to prospective studies conducted in the ICU [14]. Finally, we aimed to evaluate the prognosis impact of a reduced antibiotic treatment duration.

2. Results

2.1. Study Cohort

Figure 1 represents the flowchart of our study. During the study period, we identified 507 critically ill patients with at least one blood culture yielding ESBL-E. We excluded 128 patients because of ESBL-E BSI onset preceding the ICU admission or missing data about the antibiotic treatment. Finally, 379 patients with ESBL-E BSI acquired in the ICU were included.
Table 1 summarized the characteristics of our patients and clinical data. The patients were mainly male (66%) with a median age of 61 years (51–70). Among our patients, 275 (73%) suffered from at least one comorbidity. The most frequent comorbidity was diabetes, observed in 28% of patients. The majority of our patients entered ICU for medical admission (84%). The median SAPS II value on ICU admission was 50 (38–62). The most common sources of bacteremia were pneumonia (n = 212, 56%), a catheter infection (n = 102, 27%), an abdominal infection (n = 47, 12%), and a urinary tract infection (n = 20, 5%). In our cohort, the primary source of infection was pneumonia. The proportion of bacteremia from respiratory source was especially high during the COVID-19 pandemic, reaching 81% of the infections from 2020 to 2022. In the previous years, the proportion of pneumonia was 51.4%.
The most frequently ESBL-E identified were Klebsiella sp.(66%), Enterobacter sp. (20%), and Escherichia coli (9%).
In our cohort, 169 (45%) patients suffered from a septic shock. The mortality rate in the ICU was 49%. Fifty-two patients (14%) experienced relapse. Persistent colonization with multidrug-resistant bacteria was observed in 26% of patients, including colonization with carbapenem-resistant enterobacteriaceae in 6% of patients.

2.2. Antibiotic Regimen

Figure 2 summarizes the initial empirical and definitive antibiotic prescriptions. Empirical treatment contained carbapenem in 232 of cases (61%). Other betalactams prescribed were mainly piperacillin-tazobactam in 63 patients (17%), ceftazidime in 21 patients (6%), ceftazidime-avibactam in 13 patients (3%), andcefepime in 11 patients (3%). Among our patients, 232 (61%) received an empirical combination therapy, mainly with an aminoglycoside in 136 cases (36%), colistine in 56 cases (15%) or a fluoroquinolone in 35 cases (9%). A total of 293 patients (77%) received an appropriate empirical antibiotic treatment. Of note, the effect of an inappropriate empirical antibiotic therapy on mortality was not significant, OR: 1.35, 95 CI: 0.83–2.2, (p = 0.22).
The definitive antibiotic regimen contained carbapenem in 276 cases (73%), piperacillin-tazobactam in 35 cases (9%), ceftazidime-avibactam in 22 patients (6%), ceftazidime in 11 patients (3%), andcefepime in 7 patients (2%). Besides betalactams, the definitive antibiotic regimen contained aminoglycoside (n = 71, 19%), colistine (n = 49, 13%), or fluoroquinolone (n = 17, 4%).

2.3. Duration of Antibiotic Treatment and Prognostic Impact

Table 2 summarizes the characteristics and clinical data of all patients included and those who survived beyond 7 days in the ICU based on the duration of appropriate antibiotic treatment received (SAT vs. LAT).
In our cohort, the median duration of appropriate antibiotic treatment was 10 days (5–14) with a maximum prescribed duration of 50 days. A total of 153 patients out of 379 (40%) received SAT. Among the survivors, 48 patients out of 194 (25%) received SAT. The mean duration of bacteremia was similar in both treatment groups (1.46 days in SAT group vs. 1.54 days in LAT group, p = 0.41).
In patients surviving beyond 7 days, the factors associated with the prescription of a SAT compared to a LAT were a shorter length of stay in the ICU prior to bacteremia (15 (10–25) vs. 19 (12–32) days, p = 0.005), a lower proportion of patients with a history of chronic renal failure (3% vs. 11%, p = 0.034) of cancer (5% vs. 14%, p = 0.042) or transplantation (0 vs. 6%, p = 0.025), less frequent exposure to carbapenem in the last 3 months (13% vs. 30%, p = 0.015), and a lower proportion of patients with septic shock (24% in the SAT group vs. 40% in the LAT group, p = 0.017). Pneumonia was associated with the prescription of LAT (57% in LAT group vs. 31% in SAT group, p = 0.0021). Finally, among survivors, the proportion of appropriate initial antibiotic therapy was higher in the LAT group (83% vs. 62%, p = 0.0001).
Regarding the post-bacteremia outcome, no difference was found regarding the duration of vasoactive amine treatment between the 2 groups in survivors beyond 7 days. But survivors receiving LAT had more prolonged mechanical ventilation with a median of 14 days in LAT group vs. 7 days in SAT group (p = 0.0001). They experienced more frequently a persistent colonization with multidrug-resistant bacteria (36% vs. 16%, p = 0.0021), or a recurrence of ESBL-E bacteremia (26% vs.10%, p = 0.03).In the absence of adjustment, the mortality rate in the ICU in the global cohort was 69% in the SAT group compared to 35% in the LAT group (p < 0.0001).
After adjusting for immortal time bias and non-random allocation of antibiotic duration, no difference in survival was found between the two groups of antibiotic duration. Indeed, the Cox time-dependent model which allowed control for confounding factors present at treatment initiation and considered treatment duration as a time dependent covariate found HR of 1.65 with, 95% CI: 0.91–3.00 (p = 0.10). The sensitivity analysis performed with SAT defined as a duration of antibiotic treatment of ≤10 days found similar results with HR of 1.38 and 95% IC: 0.79–2.42 (p = 0.26).

3. Discussion

In our cohort of patients suffering from ESBL-E BSI acquired in the ICU, the median duration of antibiotic treatment was 10 days. The proportion of SAT was 40% in the total population, and 25% among survivors beyond 7 days. Our study demonstrated a high mortality among patients who acquired ESBL-E BSI in the ICU. However, after adjustment, the prescription of SAT was not associated with a higher mortality.
An empirical carbapenem-containing regimen was prescribed in 61% of our patients, while almost three quarters of our patients received a definitive carbapenem-containing regimen. For patients with BSI or severe infection due to ESBL-E, the French and international guidelines maintain carbapenem as the preferred treatment [11,12,15]. Prescription of the shortest possible antibiotic therapy will save carbapenems. It will limit the pressure of selection of resistant bacteria and the complications emanating from them [5,16]. The use of carbapenems particularly promotes the emergence of carbapenemase-producing Enterobacteriaceae [3,4]. In our cohort, persistent colonizations with multidrug-resistant bacteria were more frequent in patients who received LAT.
When taking into account only patients surviving beyond 7 days, the proportion of our patients receiving SAT was 25%. The absence of strong recommendations on the duration of treatment for bacteriemia, especially in the most severe patients, leads to disparities in management. A national survey of Canadian infectious diseases and critical-care specialists regarding antibiotic treatment duration for bloodstream infections in critically ill patients showed significant variations amongst clinicians’ recommended durations [17]. However, a majority of clinicians advocated for 10 days of treatment. A similar study was conducted more recently in Australia and New Zealand [18]. Depending on the scenario proposed, one third to almost 60% of the clinicians interviewed suggested the prescription of a short (≤7 days) antibiotic treatment. In these two practice surveys, patient characteristics such as age and comorbidities did not affect the duration of the antibiotic treatment chosen. Similarly, participants reported that they would not change the duration of treatment based on clinical response. The factors considered were the type of infection and the bacteria involved.
In our real-life study, the proportion of SAT appeared lower than that reported in the surveys. The duration of antibiotic treatment seemed to be influenced by patient characteristics. In bivariate analysis, the factors associated with prescribing LAT in survivors beyond 7 days were a history of chronic renal failure, cancer or transplantation, more frequent exposure to carbapenems in the last 3 months, and a longer ICU stay prior to ESBL-E bacteremia. The initial severity and type of infection also seemed to be taken into account in the choice of antibiotic treatment duration. The presence of septic shock at diagnosis and a pulmonary origin of the bacteremia were associated with the prescription of LAT. Inappropriate initial antibiotic therapy did not extend the duration of antibiotic treatment and was even associated with prescription of SAT.
Pulmonary infections are the most frequent infectious complications in the ICU, accounting for up to 50% of ICU-acquired infections [19]. European and French guidelines recommend against a duration longer than 7days of antibiotic therapy for pulmonary infections in most patients [20,21]. The HAS and IDSA recommend not to change the treatment duration for infections caused by a resistant organism [11,12]. However, the association of bacteremia with pneumonia may have motivated the prescription of a longer treatment in our cohort. A recent retrospective study analyzing episodes of nosocomial bacteriaemic pneumonia reported a median duration of antibiotic treatment of 14 days [22]. The presence of bacteremia has been identified as an independent risk factor for mortality in nosocomial pneumonia [23].
An expert opinion recommends that the duration of treatment for uncomplicated bacteremia in the ICU can be matched to that of the source of infection and the causative pathogen [24]. In the absence of a specific risk factor, septic shock, and when the control of the source of infection is appropriate, a short antibiotic treatment of 7 days should be preferred to a longer one. Thus, space is left for a long antibiotic treatment, especially in case of septic shock.
In our study, the mortality rate in the ICU was 49%. This result is concordant with the 44% mortality rate reported by Russo et al. in their cohort of patients with severe sepsis or septic shock due to ESBL-E infection [25]. The reluctance of the ICU physicians to prescribe SAT for ESBL-E BSI can be explained by the potential prognostic impact of the reduction inantibiotic treatment duration. Recently, several randomized controlled trials compared SAT with LAT for the treatment of Gram-negative bacterial infections. Yahav et al. conducted a randomized controlled non-inferiority trial comparing 7 days vs. 14 days of antibiotic treatment in uncomplicated Gram-negative bacteremia [7]. Non-inferiority was demonstrated. The subgroup analysis of resistant pathogens included mainly ESBL-E. Of note, the patients should be afebrile and hemodynamically stable for at least 48 h at baseline. The randomized controlled trial conducted by Molina et al. showed no difference in clinical cure rate of BSI by Enterobacterales between 7-day and 14-day of antibiotic treatments [9]. Only 13% of included patients had sepsis or septic shock and 11% had ESBL-E BSI. Von Dach E. et al. compared a fixed duration of 7 days or CRP-guided antibiotic therapy to 14 days for the treatment of uncomplicated Gram-negative bacteremia [8]. The cure rate was similar in both groups of reduced treatment duration to that observed in the 14-day treatment group. But the median SOFA score was low, and the source of infection was mainly urinary, preventing result extension to critically ill patients and other source of infection. A recent systematic review and meta-analysis showed that 7 days of antibiotic treatment resulted in a similar outcome as 14 days for patients with uncomplicated and controlled Enterobacteriaceae bacteremia, even in the case of hypotension on initial presentation [10]. It should be noted that multidrug-resistant bacteria were involved in only 8 to 18% of the patients included in the various studies. Finally, the recently published BALANCE trial showed that a 7-day antibiotic treatment was non-inferior to a 14-day antibiotic treatment in hospitalized patients with BSI including ICU patients [26]. In the ICU-enrolled patients, the main source of bacteremia was urinary tract infection, and the proportion of resistant organisms was not reported. Moreover, the trial encountered recruitment difficulties, with physicians declining to participate as the main reason for non-randomization. Deviations from protocol were frequent. A pilot randomized trial preparing the BALANCE trial and conducted exclusively in the ICU anticipated these difficulties [14].These limitations prevent solid conclusions from being drawn about the duration of antibiotic treatment in critically ill patients with various source of bacteremia or resistant microorganisms. Our study contributed to bridging existing knowledge gaps concerning the duration of antibiotic treatment of Gram-negative bacteremia. Indeed, it focused on resistant microorganisms, namely, ESBL-E, and on ICU-acquired bacteremia. In our retrospective cohort study including 379 patients treated for ESBL-E BSI acquired in the ICU, after adjustment of the immortality time bias and the biases related to non-random allocation of antibiotic treatment duration, no difference in survival was found between the SAT and LAT groups.
Our study has several limitations. It is a multicenter retrospective observational study. Data collection, although multicentric, was carried out in three ICUs in Northern France, potentially applying an antibiotic strategy different from that used in other regions of the world. This reduces its external validity. However, prescriptions of carbapenems were in accordance with national and international guidelines. The median duration of antibiotic treatment was consistent with that stated by several surveys conducted in different regions of the world. Conversion from IV to oral antibiotic therapy was not recorded. Its impact on in-ICU mortality could not be assessed. Our study, like any observational study assessing the impact of duration of treatment on patient outcomes, is limited by survivor bias (patients must survive long enough to be classified as receiving longer treatment) and indication bias (clinicians select sicker patients to receive longer-duration treatment). The immortal time bias was addressed by the use of a Cox model. The application of a weighted inverse propensity score (IPTW) method reduced the bias related to non-random allocation of treatment duration. Despite our efforts to correct these biases, relevant data to take into account some confounding factors were missing. The criteria used by clinicians to make decisions, differences in physician prescribing behavior, variations in the ICU protocols or infection control measures were not collected. Finally, despite a large sample size, a lack of statistical power in the model cannot be ruled out. However, our results are consistent with the literature.Despite its limitations, our study remains an alternative to randomized trials. Indeed, randomized trials concerning the duration of treatment in the ICUface with recruitment difficulties and frequent deviations from the protocol. Large studies would be needed to assess the prognostic impact of duration of treatment in critically ill patients with ESBL-E BSI.

4. Patients and Methods

4.1. Setting and Patients

We conducted a multicenter retrospective cohort study in the ICU of two general hospitals (Roubaix and Tourcoing Hospitals) and one academic hospital (Lille Hospital) in the North of France from 1 January 2011 to1 June 2022.
Inclusion criteria:
-
Adult patients;
-
Admitted to one of the participating ICUs during the study period;
-
With at least one blood culture yielding ESBL-E after 48 h of ICU stay.
Exclusion criteria:
-
Positive blood culture before 48 h of ICU stay;
-
Missing data on antibiotic treatment.
Patients with multiple episodes were included only once in the analysis, and subsequent episodes were considered recurrences or re-infections. Cases were identified using a laboratory and ICU data base query. Enterobacteriaceae identifications, in vitroantimicrobial susceptibility testing and ESBL diagnosis were performed with a Vitek 2 system (bioMérieux®, Marcy l’Etoile, France) following the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines [27].

4.2. Ethical Approval and Consent to Participate

Our study was carried out in accordance with national guidelines concerning a retrospective observational study conducted on collected data (article R.1121-1-1, Décret No. 2017-884 du 9 May 2017). It obtained approval from the local ethics committee of Dron Hospital and from the National Data Processing and freedoms Commission (No. CHT/URC/2023/06) on 10 June 2023.

4.3. Data Collection

The following data were collected on ICU admission: demographic data, indication(s) of ICU admission, underlying clinical conditions, factors of immunodeficiency, and severity of illness. The underlying clinical conditions were classified following McCabe and Jackson criteria [28]. Neoplasia, neutropenia, treatment with glucocorticosteroids, and/or other immunosuppressive therapy, and AIDS were defined as factors of immunodeficiency. Severity of illness was assessed by the Simplified Acute Physiology Score II (SAPS II) and Sepsis-related Organ Failure Assessment (SOFA) score [29,30].
The following data were collected on ESBL-E BSI onset: prior antimicrobial therapy within three months, duration of hospital and ICU stay, severity of illness, presence of shock, and ongoing antibiotic treatment. Empirical antibiotic treatment was defined as the prescription of antibiotics before culture results were available. It was considered appropriate when the isolated bacteria weresusceptible in vitro to at least one of the initial administered antibiotics according to the EUCAST breakpoints. The timing of empirical antibiotic treatment was considered appropriate when it was started during the first 24 h after BSI onset. No specific protocol for antibiotic treatment was applied and the choice of empirical and documented antibiotic treatment wasleft to the clinician in charge of the patient.

4.4. Objectives and Definitions

The main objective of our study was to assess the antibiotic duration in patients suffering from ICU-acquired ESBL-E BSI. The primary judgement criterion was the proportion of short antibiotic treatment (SAT), defined as a duration of appropriate antibiotic treatment of 7 days or less. The secondary objectives were to determine factors associated with the prescription of SAT and to assess its prognostic impact. To evaluate the prognostic impact of the antibiotic duration, the rate of ESBL-E BSI relapse, emergence of resistance, C. difficile colitis, and in-ICU mortality were recorded.

4.5. Statistical Analysis

Continuous variables were expressed as mean values ± standard deviation or as median (interquartile range), depending on the normality of their distribution. They were compared using Student’s test or the Mann–Whitney U test, as appropriate. Categorical variables were expressed as percentages. They were compared using the chi-square test and Fisher’s test when appropriate. Differences between groups were considered to be significant for variables yielding a p value ≤ 0.05.
To address the immortal time bias, the treatment duration group was considered a time-dependent covariate within a Cox model. After 7 days of antibiotic treatment, the patients were transferred to the long (>7 days) antibiotic treatment (LAT) group until the end of follow-up. To correct the bias related to non-random allocation of treatment duration, we used a weighted inverse propensity score (IPTW) method. The absence of randomized treatment allocation could introduce confounding bias. The IPTW method aims to simulate a randomized trial by weighting observations according to the probability of receiving the treatment actually observed, thus minimizing the impact of confounding factors. We performed a logistic regression to identify factors associated with short antibiotic treatment (SAT). The covariates included in the model were age, the sum of comorbidities (calculated from the presence of chronic heart failure, diabetes, COPD, cirrhosis, chronic alcoholism, chronic renal failure, solid cancer, malignant hemopathy, asplenia, HIV infection, solid organ transplantation, and neutropenia), and the severity score at ICU admission (SAPS II and SOFA).
After adjustment, a Kaplan–Meier survival analysis was performed to determine in-ICU survival probability depending on the antibiotic treatment duration. Of note, 9 patients were excluded from the analysis due to missing data. A sensitivity analysis was performed defining SAT as a duration of antibiotic treatment of ≤10 days.

5. Conclusions

In our cohort, one quarter of patients with ESBL-E BSI acquired in the ICU surviving beyond 7 days were treated with a SAT. Short duration of antibiotic therapy did not appear to affect survival in patients with ESBL-E BSI acquired in the ICU. The authors recommend the prescription of SAT in the ICU patients with ESBL-E BSI regardless of the source of infection or initial severity. Exceptions should be inappropriate control of the source of infection or at-risk patients, such as transplanted patients or neutropenic patients. Additional studies are needed to assess the best duration of treatment for these specific populations.

Author Contributions

C.L.B., A.V., L.B., P.-Y.D. and A.M. built the design of this study; C.L.B., M.H., A.V., F.W., P.P., P.-Y.D., A.M. and M.D. collected, analyzed and interpreted the data; M.D. conducted statistical analysis; H.G., P.B., S.N. and A.M. were responsible for drafting the manuscript. All authors were involved in the interpretation of findings and revising the manuscript critically. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Our study was carried out in accordance with National guidelines concerning a retrospective observational study conducted on collected data (article R.1121-1-1, Décret No. 2017-884 du 9 May 2017). It obtained approval from the local ethics committee of Dron Hospital and from the National Data Processing and freedoms Commission (n° CHT/URC/2023/06) on 10 June 2023.

Informed Consent Statement

In accordance with French Law, a non-opposition statement was obtained from all patients, except for deceased patients.

Data Availability Statement

Data are available under request by email to the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Rodríguez-Baño, J.; Navarro, M.D.; Romero, L.; Muniain, M.A.; de Cueto, M.; Ríos, M.J.; Hernandez, J.R.; Pascual, A. Bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli in the CTX-M era: A new clinical challenge. Clin. Infect. Dis. 2006, 43, 1407–1414. [Google Scholar] [CrossRef] [PubMed]
  2. Tumbarello, M.; Sanguinetti, M.; Montuori, E.; Trecarichi, E.M.; Posteraro, B.; Fiori, B.; Citton, R.; D’Inzeo, T.; Fadda, G.; Cauda, R.; et al. Predictors of mortality in patients with bloodstream infections caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae: Importance of inadequate initial antimicrobial treatment. Antimicrob. Agents Chemother. 2007, 51, 1987–1994. [Google Scholar]
  3. Nordmann, P.; Naas, T.; Poirel, L. Global spread of carbapenemase-producing enterobacteriaceae. Emerg. Infect. Dis. 2011, 17, 1791–1798. [Google Scholar] [PubMed]
  4. Jean, S.S.; Harnod, D.; Hsueh, P.R. Global threat of carbapenem-resistant Gram-negative bacteria. Front. Cell. Infect. Microbiol. 2022, 12, 823684. [Google Scholar]
  5. Bell, B.G.; Schellevis, F.; Stobberingh, E.; Goossens, H.; Pringle, M. A systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance. BMC Infect. Dis. 2014, 14, 13. [Google Scholar]
  6. Reyes, S.; Morel, M.D.P.; Kostka, J.; Nicolau, D.P. Duration of antibiotic therapy for Enterobacterales and Pseudomonas aeruginosa: A review of recent evidence. Curr. Opin. Infect. Dis. 2021, 34, 693–700. [Google Scholar]
  7. Yahav, D.; Franceschini, E.; Koppel, F.; Turjeman, A.; Babich, T.; Bitterman, R.; Neuberger, A.; Ghanem-Zoubi, N.; Santoro, A.; Eliakim-Raz, N.; et al. Seven versus 14 Days of antibiotic therapy for uncomplicated gram-negative bacteremia: A noninferiority randomized controlled trial. Clin. Infect. Dis. 2019, 69, 1091–1098. [Google Scholar]
  8. von Dach, E.; Albrich, W.C.; Brunel, A.S.; Prendki, V.; Cuvelier, C.; Flury, D.; Gayet-Ageron, A.; Huttner, B.; Kohler, P.; Lemmenmeier, E.; et al. Effect of C-reactive protein-guided antibiotic treatment duration, 7-day treatment, or 14-day treatment on 30-day clinical failure rate in patients with uncomplicated gram-negative bacteremia: A randomized clinical trial. JAMA 2020, 323, 2160–2169. [Google Scholar] [CrossRef]
  9. Molina, J.; Montero-Mateos, E.; Praena-Segovia, J.; León-Jiménez, E.; Natera, C.; López-Cortés, L.E.; Valiente, L.; Rosso-Fernández, C.M.; Herrero, M.; Aller-García, A.I.; et al. Seven-versus 14-day course of antibiotics for the treatment of bloodstream infections by Enterobacterales: A randomized, controlled trial. Clin. Microbiol. Infect. 2022, 28, 550–557. [Google Scholar] [CrossRef]
  10. Turjeman, A.; von Dach, E.; Molina, J.; Franceschini, E.; Koppel, F.; Yelin, D.; Dishon-Benattar, Y.; Mussini, C.; Rodriguez-Bano, J.; Cisneros, J.M.; et al. Duration of antibiotic treatment for Gram-negative bacteremia. Systematic review and individual participant data (IPD) meta-analysis. Eclininal Med. 2022, 55, 101750. [Google Scholar] [CrossRef]
  11. HAS. Antibiothérapie des Infections à Entérobactéries et à Pseudomonas aeruginosa Chez l’Adulte: Place des Carbapenèmes et de Leurs Alternatives. Mai 2019, mis à jour Mars 2023. Available online: https://www.has-sante.fr/jcms/c_2968915/fr/antibiotherapie-des-infections-a-enterobacteries-et-a-pseudomonas-aeruginosa-chez-l-adulte-place-descarbapenemes-et-de-leurs-alternatives (accessed on 1 January 2024).
  12. Tamma, P.D.; Aitken, S.L.; Bonomo, R.A.; Mathers, A.J.; van Duin, D.; Clancy, C.J. Infectious Diseases Society of America 2022 Guidance on the Treatment of Extended-Spectrum β-lactamase Producing Enterobacterales (ESBL-E), Carbapenem-Resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with Difficult-to-Treat Resistance (DTR-P. aeruginosa). Clin. Infect. Dis. 2022, 75, 187–212. [Google Scholar] [PubMed]
  13. Gauzit, R.; Castan, B.; Bonnet, E.; Bru, J.P.; Cohen, R.; Diamantis, S.; Faye, A.; Hitoto, H.; Issa, N.; Lebeaux, D.; et al. Anti-infectious treatment duration: The SPILF and GPIP French guidelines and recommendations. Infect. Dis. Now 2021, 52, 114–139. [Google Scholar]
  14. Daneman, N.; Rishu, A.H.; Pinto, R.; Aslanian, P.; Bagshaw, S.M.; Carignan, A.; Charbonney, E.; Coburn, B.; Cook, D.J.; Detsky, M.E.; et al. 7 versus 14 days of antibiotic treatment for critically ill patients with bloodstream infection: A pilot randomized clinical trial. Trials 2018, 19, 111. [Google Scholar] [PubMed]
  15. Paul, M.; Carrara, E.; Retamar, P.; Tangden, T.; Bitterman, R.; Bonomo, R.A.; de Waele, J.; Daikos, G.L.; Akova, M.; Harbarth, S.; et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European Society of intensive care medicine). Clin. Microbiol. Infect. 2022, 28, 521–547. [Google Scholar]
  16. Cassini, A.; Högberg, L.D.; Plachouras, D.; Quattrocchi, A.; Hoxha, A.; Simonsen, G.S.; Colomb-Cotinat, M.; Kretzschmar, M.E.; Devleesschauwer, B.; Cecchini, M.; et al. Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: A population-level modelling analysis. Lancet Infect. Dis. 2019, 19, 56–66. [Google Scholar]
  17. Daneman, N.; Shore, K.; Pinto, R.; Fowler, R. Antibiotic treatment duration for bloodstream infections in critically ill patients: A national survey of Canadian infectious diseases and critical care specialists. Int. J. Antimicrob. Agents 2011, 38, 480–485. [Google Scholar]
  18. Alwan, M.; Davis, J.S.; Daneman, N.; Fowler, R.; Shehabi, Y.; Rogers, B. Duration of therapy recommended for bacteraemic illness varies widely amongst clinicians. Int. J. Antimicrob. Agents 2019, 54, 184–188. [Google Scholar]
  19. He, Y.; Xu, J.; Shang, X.; Fang, X.; Gao, C.; Sun, D.; Yao, L.; Zhou, T.; Pan, S.; Zou, X.; et al. Clinical characteristics and risk factors associated with ICU-acquired infections in sepsis: A retrospective cohort study. Front. Cell. Infect. Microbiol. 2022, 12, 962470. [Google Scholar]
  20. Torres, A.; Niederman, M.S.; Chastre, J.; Ewig, S.; Fernandez-Vandellos, P.; Hanberger, H.; Kollef, M.; Li Bassi, G.; Luna, C.M.; Martin-Loeches, I.; et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: Guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT). Eur. Respir. J. 2017, 50, 1700582. [Google Scholar]
  21. Leone, M.; Bouadma, L.; Bouhemad, B.; Brissaud, O.; Dauger, S.; Gibot, S.; Hraiech, S.; Jung, B.; Kipnis, E.; Launey, Y.; et al. Brief summary of French guidelines for the prevention, diagnosis and treatment of hospital-acquired pneumonia in ICU. Ann. Intensive Care 2018, 8, 104. [Google Scholar]
  22. Bouza, E.; Guillen-Zabala, H.; Rojas, A.; Canada, G.; Cercenado, E.; Sanchez-Carrillo, C.; Diez, C.; Puente, L.; Munoz, P.; Galar, A. Comparative study of the etiology of nosocomial bacteremic pneumonia in ventilated and non ventilated patients: A 10-year experience in an institution. Microbiol. Spectr. 2023, 11, e0151723. [Google Scholar] [CrossRef]
  23. Magret, M.; Lisboa, T.; Martin-Loeches, I.; Manez, R.; Nauwynck, M.; Wrigge, H.; Cardellino, S.; Koulenti, D.; Rello, J.; for EU-VAP/CAP Study Group. Bacteremia is an independent risk factor for mortality in nosocomial pneumonia: A prospective and observational multicenter study. Crit. Care 2011, 15, 2–8. [Google Scholar]
  24. Timsit, J.F.; Ruppé, E.; Barbier, F.; Tabah, A.; Bassetti, M. Bloodstream infections in critically ill patients: An expert statement. Intensive Care Med. 2020, 46, 266–284. [Google Scholar] [CrossRef] [PubMed]
  25. Russo, A.; Falcone, M.; Gutierrez-Gutierrez, B.; Calbo, E.; Almirante, B.; Viale, P.L.; Oliver, A.; Ruiz-Garbajosa, P.; Gasch, O.; Gozalo, M.; et al. Predictors of outcome in patients with severe sepsis or septic shock due to extended-spectrum B-lactamase-producing Enterobacteriaceae. Int. J. Antimicrob. Agents 2018, 52, 577–585. [Google Scholar] [CrossRef] [PubMed]
  26. The BALANCE Investigators. Antibiotic treatment for 7 versus 14 days in patients with bloodstream infections. N. Engl. J. Med. 2025, 392, 1065–1078. [Google Scholar]
  27. European Committee on Antimicrobial Susceptibility Testing (EUCAST 2012). Breakpoint Tables for Interpretation of MICs and Zone Diameters. Version 2.0. Available online: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/v_15.0_Breakpoint_Tables.pdf (accessed on 1 August 2020).
  28. McCabe, W.R.; Jackson, C.G. Gram-negative bacteremia: Etiology and ecology. Arch. Intern. Med. 1962, 110, 847–855. [Google Scholar]
  29. Le Gall, J.R.; Lemeshow, S.; Saulnier, F. A new simplified acute physiology score (SAPS II) based on a European/North American multicenter study. JAMA 1993, 270, 2957–2963. [Google Scholar] [CrossRef]
  30. Vincent, J.L.; Moreno, R.; Takala, J.; Willatts, S.; De Mendonça, A.; Bruining, H.; Reinhart, C.K.; Suter, P.M.; Thijs, L.G. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfonction/failure. Intensive Care Med. 1996, 22, 707–710. [Google Scholar] [CrossRef]
Antibiotics 14 00358 g001
Figure 1. Flow chart of the study population.
Figure 1. Flow chart of the study population.
Antibiotics 14 00358 g001
Antibiotics 14 00358 g002
Figure 2. Empirical and definitive antibiotic treatment in patients treated for an ICU-acquired ESBL-E bacteremia.
Figure 2. Empirical and definitive antibiotic treatment in patients treated for an ICU-acquired ESBL-E bacteremia.
Antibiotics 14 00358 g002
Table 1. Demographic and clinical characteristics of our patients.
Table 1. Demographic and clinical characteristics of our patients.
CharacteristicsPatients
n = 379
Male sex250 (66%)
Age (years)61 (51–70)
McCabe ≥ 2191 (50%)
SOFA score6 (3–9)
Comorbidities
      Diabetes106 (28%)
      COPD and respiratory insufficiency82 (22%)
      Renal insufficiency39 (10%)
      Solid cancer44 (12%)
      Hematological malignancy29 (8%)
Immunodeficiency
      Immunosuppressive therapy < 3 months40 (11%)
      Transplantation22 (6%)
      Neutropenia13 (3%)
Medical admission317 (84%)
Source:
      Respiratory212 (56%)
      Catheter related infection102 (27%)
      Intra-abdominal47 (12%)
      Urinary tract20 (5%)
Microorganisms:
      Klebsiella sp.169 (45%)
      Enterobacter sp.82 (22%)
      Escherichia coli37 (10%)
      Serratia marcescens8 (2%)
Complications
      Septic shock169 (45%)
      Acute respiratory distress syndrome41 (29%)
      Acute renal failure85 (22%)
      Disseminated intravascular coagulation36 (9%)
      Fungemia26 (7%)
      Clostridium difficile colitis5 (1%)
      Colonization with multidrug-resistant bacteria98 (26%)
      Colonization with carbapenem-resistant bacteria24 (6%)
Outcome
      Relapse52 (14%)
      In-ICU mortality185 (49%)
Table 2. Bivariate analysis comparing SAT (≤7-day antibiotic treatment) and LAT (>7-day antibiotic treatment) groups in the entire cohort and in survivors beyond 7 days.
Table 2. Bivariate analysis comparing SAT (≤7-day antibiotic treatment) and LAT (>7-day antibiotic treatment) groups in the entire cohort and in survivors beyond 7 days.
CharacteristicsTotal PopulationSurvivors Beyond 7 Days
SAT
n = 153		LAT
n = 226		pSAT
n = 74		LAT
n = 174		p
Age62 (53–71)60 (49–69)0.5961 (50–69)60 (49–69)0.640
Male gender105 (69%)145 (64%)0.3755 (74%)143 (64%)0.10
Mc Cabe ≥ 286 (56%)105 (46%)0.06333 (45%)105 (47%)0.73
SOFA at admission8 (5–11)6 (4–10)<0.058 (4–10)6 (4–10)0.086
Comorbidities
      Diabetes43 (28%)63 (28%)0.9619 (26%)63 (28%)0.68
      COPD, respiratory insufficiency26 (17%)56 (25%)0.07112 (16%)55 (25%)0.14
      Dhronic renal insufficiency15 (9.8%)24 (11%)0.802 (3%)24 (11%)<0.05
      Solid cancer12 (7.8%)32 (14%)0.0604 (5%)32 (14%)<0.05
      Malignant hemopathy18 (12%)11 (5%)<0.052 (3%)11 (5%)0.53
Immunodeficiency
      Immunosuppressive therapy < 3 months14 (9%)26 (12%)0.4612 (16%)14 (6%)0.58
      Transplantation8 (5%)14 (6%)0.690 (0)14 (6%)<0.05
      Neutropenia8 (5%)5 (2%)0.110 (0)5 (2%)0.34
Carbapenem < 3 months40 (26%)72 (32%)0.2512 (16%)71 (32%)<0.05
Duration of ICU stay before BSI15 (10–26)19 (12–30)<0.0515 (10–25)19 (12–32)<0.05
SOFA at BSI onset7 (4–11)5 (3–8)<0.055 (2–7)5 (3–8)0.49
qPitt score at BSI onset4 (2–6)3 (2–4)<0.053 (0–5)3 (2–4)0.37
Septic shock at BSI onset77 (50%)90 (40%)<0.0518 (24%)89 (40%)<0.05
Source of BSI
      Pneumonia79 (52%)133 (59%)0.1729 (39%)133 (59%)<0.05
      Catheter related38 (25%)64 (28%)0.4528 (38%)64 (29%)0.13
      Intra-abdominal21 (14%)26 (12%)0.525 (7%)25 (11%)0.28
      Urinary tract9 (6%)11 (5%)0.663 (4%)11 (5%)>0.99
Secondary localization2 (1%)13 (6%)0.0292 (3%)13 (6%)0.37
Antibiotic treatment
      Appropriate initial treatment105 (69%)188 (83%)<0.0546 (62%)187 (83%)<0.05
      Duration of appropriate treatment4 (2–7)14 (10–15)<0.057 (4–7)14 (10–15)<0.05
Evolution
      Amines > 48 h46 (31%)74 (33%)0.5917 (23%)73 (33%)0.11
      Duration of mechanical ventilation4 (1–9)14 (7–31)<0.057 (0–17)14 (7–31)<0.05
      Relapse7 (5%)45 (20%)<0.057 (10%)45 (26%)<0.05
      Death in ICU105 (69%)80 (35%)<0.0526 (35%)79 (35%)0.98
      C. difficile colitis0 (0)5 (2%)0.0860 (0)5 (3%)0.34
      Fungemia4 (3%)22 (10%)<0.053 (4%)18 (8%)0.25
      Colonization with MDR bacteria18 (12%)80 (36%)<0.0512 (16%)79 (45%)<0.05
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Le Berre, C.; Degrendel, M.; Houard, M.; Benetazzo, L.; Vachée, A.; Georges, H.; Wallet, F.; Patoz, P.; Bortolotti, P.; Nseir, S.; et al. Optimizing Antibiotic Treatment Duration for ESBL-Producing Enterobacteriaceae Bacteremia in ICU: A Multicentric Retrospective Cohort Study. Antibiotics 2025, 14, 358. https://doi.org/10.3390/antibiotics14040358

AMA Style

Le Berre C, Degrendel M, Houard M, Benetazzo L, Vachée A, Georges H, Wallet F, Patoz P, Bortolotti P, Nseir S, et al. Optimizing Antibiotic Treatment Duration for ESBL-Producing Enterobacteriaceae Bacteremia in ICU: A Multicentric Retrospective Cohort Study. Antibiotics. 2025; 14(4):358. https://doi.org/10.3390/antibiotics14040358

Chicago/Turabian Style

Le Berre, Camille, Maxime Degrendel, Marion Houard, Lucie Benetazzo, Anne Vachée, Hugues Georges, Frederic Wallet, Pierre Patoz, Perrine Bortolotti, Saad Nseir, and et al. 2025. "Optimizing Antibiotic Treatment Duration for ESBL-Producing Enterobacteriaceae Bacteremia in ICU: A Multicentric Retrospective Cohort Study" Antibiotics 14, no. 4: 358. https://doi.org/10.3390/antibiotics14040358

APA Style

Le Berre, C., Degrendel, M., Houard, M., Benetazzo, L., Vachée, A., Georges, H., Wallet, F., Patoz, P., Bortolotti, P., Nseir, S., Delannoy, P.-Y., & Meybeck, A. (2025). Optimizing Antibiotic Treatment Duration for ESBL-Producing Enterobacteriaceae Bacteremia in ICU: A Multicentric Retrospective Cohort Study. Antibiotics, 14(4), 358. https://doi.org/10.3390/antibiotics14040358

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop