Antibiotic therapy in febrile neutropenia in haematological patients: current considerations and future challenges

Abstract

The management of febrile neutropenia (FN) in oncohematological patients is undergoing a paradigm shift driven by a deeper understanding of patients’ pathophysiological heterogeneity, the increasing speed and accuracy of microbiological diagnostics, the emergence of new antibiotics, and the incorporation of predictive artificial intelligence (AI) as a tool to support clinical decision-making. Our objective is to provide an updated and comprehensive overview of the factors influencing antibiotic treatment in FN. We propose that its management should be based on three essential pillars. First, accurate risk stratification for bacterial infection. Second, ensuring that patients receive appropriate empirical antibiotic therapy, tailoring the initial choice according to the results of surveillance cultures from oropharyngeal and/or fecal microbiota. Finally, prioritizing antibiotic choices that preserve intestinal microbiota eubiosis as much as possible. Reducing colonization and overgrowth of facultative aerobic/anaerobic flora (Enterobacteriaceae, non-fermenting Gram-negative bacilli, and Enterococcus spp.) while preserving strict anaerobic flora decreases the risk of bacterial translocation and complications such as graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or loss of CAR-T functionality. This decision model, grounded in objective criteria, aims to balance the need for effective empirical coverage with responsible antibiotic use.

Introduction

Febrile neutropenia (FN) is a common medical emergency in patients with hematologic malignancies receiving chemotherapy. It is defined by a single oral temperature of ≥38.3°C or a temperature of ≥38.0°C sustained for more than one hour, in the setting of an absolute neutrophil count (ANC) of <500 cells/μL, or <1000 cells/μL with an expected decline below this threshold within the next 48 hours. This condition represents a clinically significant risk due to the impaired immune response, which can transform seemingly mild infections into potentially life-threatening events. Accordingly, early recognition and prompt, appropriate management are essential to reduce morbidity and mortality. Empirical antibiotic therapy constitutes a cornerstone of FN management. Subsequent treatment adjustment according to microbiological findings is critical both for the patient’s clinical course and for its influence on the composition of the microbiota.

In recent years, substantial changes have occurred in the FN patient population. The introduction of novel therapies, many of them based on immunotherapy, has created new pathophysiological scenarios. Likewise, shifts in the epidemiology of infection, including changes in causative pathogens and their antimicrobial susceptibility profiles, have further complicated decisions regarding empirical antibacterial therapy. At the same time, new antibiotic options have become available to address these challenges. Moreover, growing evidence on the role of intestinal microbiota dysbiosis in the development of endogenous bacteremia and in the response to various hematologic treatments highlights the need to integrate these findings into clinical management. Within this context, the analysis of large-scale datasets using artificial intelligence algorithms may offer valuable opportunities to improve bacteremia risk stratification. Concurrently, major advances in clinical microbiology have been achieved, both through the introduction of novel molecular diagnostic tools and through improvements in diagnostic yield and turnaround time. Together, these developments enable a more timely and precise antibiotic strategy tailored to different clinical scenarios. Finally, the availability of new antibiotics active against resistant GNB but lacking anaerobicidal effects allows for greater preservation of the colonic microbiota.

In this review, we provide an updated and comprehensive overview of the main factors that influence clinical decision-making regarding antibiotic therapy in FN, with particular focus on the pathophysiological heterogeneity across patient profiles; the potential of microbiological testing and artificial intelligence to support appropriate, individualized empirical strategies; and the importance of preserving intestinal microbiota eubiosis.

Clinical manifestations and physical examination in patients with febrile neutropenia

Fever in neutropenic patients should be interpreted as a potential marker of severe infection, as the inflammatory response is blunted and the classic signs of localized infection may be absent or subtle. Additional indicators suggestive of possible infection include the appearance of cutaneous lesions, localized erythema or pain (particularly in the perianal region), hypotension, signs of hypoperfusion or organ dysfunction, hyperventilation, decreased oxygen saturation, subtle alterations in mental status, or any other new clinical change without an evident cause.

A careful, system-based history should be obtained, together with a thorough physical examination that may need to be repeated every few hours. This comprehensive assessment enables the identification of otherwise inconspicuous foci of infection that may guide empirical therapy, as well as the recognition of potential non-infectious causes of fever. Particular attention should be paid to the skin, including the periungual region; venipuncture and biopsy sites; vascular catheter insertion sites, with evaluation for signs of infection or malfunction; the oral cavity and oropharynx; the lung fields, where findings may be minimal even in cases of pneumonia; the abdomen, to assess for neutropenic enterocolitis; and the perianal region.

Most infections without an apparent focus in neutropenic patients are of endogenous origin, resulting from bacterial translocation from the gastrointestinal microbiota [1,2]. Significant oropharyngeal mucositis increases the risk of bloodstream infection caused by viridans group streptococci, whereas intestinal mucositis favors the translocation of aerobic GNB and Enterococcus spp. In addition, vascular catheters represent a relatively common source of infection, which is often clinically silent and usually caused by coagulase-negative Staphylococcus or GNB [3].

Limitations of current antibiotic recommendations for the empirical treatment of febrile neutropenia

Current clinical guidelines recommend the immediate initiation of empirical antibiotic therapy in hematologic patients with FN using an intravenous broad-spectrum β-lactam active against Pseudomonas aeruginosa. This approach is supported by studies showing that delays in the administration of appropriate therapy are associated with a significant increase in mortality, even when the delay is less than 30 minutes from fever onset [4,5]. Most contemporary FN treatment guidelines include meropenem, piperacillin–tazobactam, and cefepime as first-line agents [6–9]. However, this strategy presents important limitations in contemporary clinical practice. First, major changes in the treatment of hematologic malignancies, including the adoption of better-tolerated regimens and the introduction of immunotherapy, together with improvements in vascular catheter management, have altered both patients’ susceptibility to bacterial infection and the underlying causes of fever. When the concept of FN emerged alongside the expanding use of intensive chemotherapy in hematology in the 1970s, infection by P. aeruginosa was among the leading causes of fever in patients with FN [10]. In contemporary clinical practice, an increasing proportion of patients present with fever unrelated to infection [11,12]. A bacterial cause is identified in approximately one third of patients with FN, with GNB accounting for nearly half of these infections. Second, when fever is of bacterial origin, it is essential to consider that the epidemiology of bacterial infections in neutropenic patients, particularly GNB, has undergone substantial shifts, with a sustained increase in antimicrobial resistance documented across multiple series [13,14]. The majority of GNB currently isolated in these infections exhibit susceptibility profiles that challenge the empirical use of the aforementioned β-lactams. Indeed, recent studies conducted in Spain show that up to one third of neutropenic patients with bacteremia receive inadequate empirical therapy despite high adherence to clinical guidelines [2,15–18]. Inappropriate empirical therapy, defined as the administration of an antibiotic lacking activity against the identified pathogen, has been consistently associated with increased mortality and represents the principal modifiable factor for improving outcomes in this population [2,19]. These considerations underscore that FN should be regarded as a true medical emergency.

Lastly, current guidelines offer only limited guidance on the use of newly available β-lactam/β-lactamase inhibitor combinations, the role of combination therapy, and the identification of patients who may benefit from narrower-spectrum agents during initial empirical treatment. This information is nonetheless essential to balance the need for adequate empirical coverage with the imperative to avoid prolonged and unnecessary exposure to broad-spectrum antimicrobials, a practice associated with the selection of multidrug-resistant bacteria and an increased risk of Clostridioides difficile infection. Furthermore, emerging evidence has associated disruption of the gut microbiota, characterized by the overgrowth of facultative anaerobes, with an increased risk of bacteremia, the development of GVHD, and reduced CAR T-cell functionality [20–24].

In this context, antibiotic management of FN should rest upon three essential principles: first, accurate stratification of the risk of bacterial infection; second, selection of initial empirical therapy that ensures appropriate coverage of likely pathogens; and third, prioritization of antibiotics with minimal anaerobic activity with the aim of preserving intestinal microbiota eubiosis.

Risk stratification of bacterial infection in febrile neutropenia in hematologic patients

The risk of bacterial infection in hematologic patients with FN is primarily determined by three factors: a) disruption of epithelial barriers, particularly the gastrointestinal mucosa and the skin, which facilitates pathogen translocation into the bloodstream; b) the density of potentially pathogenic bacterial populations dominating the colonic microbiota; and c) the reduction in neutrophil count and potential neutrophil dysfunction, which compromises the ability of the immune system to contain and eliminate microorganisms translocating from the microbiota.

Patients with acute leukemia and recipients of hematopoietic stem cell transplantation (HSCT) undergoing conventional treatments exhibit substantial alterations in these three fundamental factors. Contemporary chemotherapy regimens continue to induce significant mucosal injury. By contrast, advances in vascular catheter insertion and management, including the use of aseptic technique, ultrasound guidance, and, in selected cases, additional preventive measures such as taurolidine lock therapy, have markedly reduced the incidence of catheter-related sepsis. Prolonged cytopenias, however, remain common and impair the function of neutrophils and macrophages, which under normal conditions are responsible for clearing bacteria that translocate from their ecological niches. In addition, a large proportion of patients receive prophylactic or therapeutic antibiotics, often with marked activity against anaerobic microorganisms. This leads to profound alterations in the colonic microbiota, characterized by a progressive decline in strict anaerobes, mostly belonging to the Firmicutes and Bacteroidetes phyla, and their replacement by Proteobacteria, which include facultative anaerobic Enterobacterales that are highly prone to acquiring and disseminating antibiotic resistance determinants.

However, there is a growing population of hematologic patients treated with targeted therapies or immunotherapy who, despite presenting with significant neutropenia, do not share other characteristics classically associated with infection risk. The available evidence on the epidemiology of bacterial infections in these emerging FN populations remains limited. This issue is particularly relevant in patients receiving immunotherapy, in whom non-infectious inflammatory fever is common, and its clinical distinction from infection-related fever is especially challenging, even with imaging and biomarker support.

CAR-T cell recipients provide a representative example. Many develop prolonged neutropenia and, in a substantial proportion of cases, experience fever of inflammatory origin in the days after infusion without a documented infectious etiology. Nevertheless, most receive broad-spectrum antibiotics [25]. Moreover, these patients often require potent immunosuppressive treatments such as high-dose dexamethasone (up to 20 mg every 6 hours) and/or IL-6 inhibitors like tocilizumab, generating a clinical scenario of markedly increased infection risk. Paradoxically, both fever and increases in inflammatory biomarkers, including C-reactive protein, may be attenuated by the effects of immunosuppressive treatment, further challenging the classical definition of FN. Another common scenario of fever unrelated to infection is observed after haploidentical allogeneic hematopoietic stem cell transplantation. In this setting, fever occurring during the first days after stem cell infusion reflects cytokine release syndrome secondary to intense early immune activation and resolves with cyclophosphamide administration [24,26].

Taken together, these considerations call for a critical reassessment of the classical concept of FN, both in its pathophysiological foundations and in its ability to adequately reflect the clinical complexity of emerging scenarios. In this context, risk stratification for bacterial infection represents the first essential step toward rational antibiotic management in hematologic patients with FN.

Machine learning for bacterial infection risk stratification

Traditionally, FN has been stratified using tools such as the MASCC score to distinguish between low- and high-risk scenarios for severe complications, including infectious complications, based on the severity and duration of neutropenia, the clinical presentation, and the underlying disease [27]. However, in the current landscape, it is worth questioning to what extent this classical classification remains fully applicable to identifying patients at the highest risk of infection. Patients receiving CAR-T cell therapy, those treated with bispecific monoclonal antibodies for multiple myeloma or other hematologic malignancies, or those with acute leukemia receiving targeted therapies against specific molecular pathways (such as BCL-2 inhibitors or FLT-3 inhibitors), all meet criteria for high-grade FN according to current scales. Yet this classification likely does not adequately reflect their true bacterial infection risk.

A recent study employed unsupervised machine-learning algorithms to predict the probability that neutropenic hematologic patients presenting with fever would have bacteremia [28]. The analysis was based on a large database of hematologic patients treated with contemporary therapies. In a cohort of patients with FN with an overall bacteremia incidence of 25%, the algorithm stratified patients into three risk groups: low risk (4% bacteremia, none caused by GNB), intermediate risk (27%, 55% GNB), and high risk (38%, 47% GNB). Factors associated with a lower risk of bacterial infection included fever following CAR-T infusion, fever in patients with lymphoma, and fever occurring in cases with absolute neutrophil counts between 100 and 500 cells/μL. Conversely, patients with more than 10 days of hospitalization, a diagnosis of acute leukemia, systolic blood pressure below 95 mmHg, cyclophosphamide use, neutrophil counts below 100 cells/μL, and higher transfusion requirements exhibited a significantly increased risk of bacteremia. The algorithm underwent internal validation at the same center and external validation in cohorts from several hospitals in Spain and France. It is available for online consultation in certain antibiotic-treatment guideline applications and on the web platform of the research group at Hospital Clínic de Barcelona [29].

Recommended empirical antibiotic therapy in patients with febrile neutropenia

Patients at low risk of bacteremia. In patients with FN without an apparent clinical focus who can currently be classified as having a low risk of bacteremic infection, empirical antibiotic therapy may be initiated with a β-lactam lacking anaerobic activity and with potential efficacy against GNB identified in surveillance cultures. During the subsequent 24–48 hours, clinical reassessment is essential, and if the patient remains stable and microbiological tests are negative, narrowing the antibacterial spectrum, switching to oral therapy, or even discontinuing antibiotic treatment should be considered. Advances in microbiology allow us to affirm that if blood cultures remain negative during the first 24 hours after collection, the likelihood of subsequent positivity is very low [30]. The necessity of empirical antibiotic therapy in this population may therefore be questioned, although future studies are needed to better identify alternative causes of fever and validate this strategy.

Patients at intermediate or high risk of bacteremia. The presence of an identifiable infectious focus, sepsis, or shock should guide the initial use of combination antibiotic therapy, following the recommendations in Figure 1. Patients with FN without an apparent clinical focus but with a risk of bacteremic infection should receive β-lactam monotherapy providing adequate coverage of endogenous GNB (Figure 2).

Figure 1. Recommended treatment in specific clinical scenarios for patients with FN.

GNB: Gram-negative bacilli; MDR: multidrug-resistant.

Figure 2. Recommended approach to empirical β-lactam selection for gram-negative bacillary coverage in high-risk FN.

ATM-AVI: aztreonam-avibactam; CAZ-AVI: ceftazidime-avibactam; CRO: ceftriaxone; CTX: cefotaxime; ESBL: extended-spectrum β-lactamase; FDC: cefiderocol; FEP-ENM: cefepime-enmetazobactam; GNB: gram-negative bacilli; IMI-REL: imipenem-relebactam; MBL: metallo-β-lactamase; MDR: multidrug-resistant; MER-VAB: meropenem-vaborbactam; TOL-TAZ: ceftolozane-tazobactam.

*Obtain rectal and pharyngeal swabs and initiate empirical antibiotic therapy.

**Its use is recommended only when no other alternatives are available according to the susceptibility profile of the isolate.

Historically, empirical antibiotic therapy for nosocomial infections, including FN, has been selected based on the epidemiology of multidrug-resistant GNB (MDR-GNB) prevalent in a given hospital. However, while hospital-level data help estimate the overall risk of infections caused by specific resistant pathogens, they are imprecise when applied to individual patients. A major recent advance is the ability to determine each patient’s rectal colonization status for resistant microorganisms, enabling a personalized and more accurate approach to antimicrobial selection.

Table 1 describes the positive and negative predictive values of rectal swab cultures in anticipating the etiology of bacteremia in hematologic patients [31]. Approximately 10% of patients colonized with extended-spectrum β-lactamase (ESBL)-producing GNB, 25% of those carrying carbapenemase-producing GNB, and up to 40% of those colonized with difficult-to-treat P. aeruginosa develop bacteremia caused by these organisms [31]. Accordingly, the most recent guidelines on empirical antibiotic therapy in hospitalized patients with FN incorporate this evidence as a key element of clinical decision-making [32].

Table 1.

Positive and negative predictive values of rectal surveillance cultures for predicting the causative pathogens of bacteremia in patients with FN

Microorganism	PPV (%) [95% CI]	NPV (%) [95% CI]
Third-generation cephalosporin-resistant Enterobacterales	14.6% [10.2%-20.5%]	99.0% [97.8%-99.6%]
Escherichia coli	18.4% [12.1%-27.0%]	99.7% [98.8%-99.9%]
Klebsiella pneumoniae complex	13.9% [6.1%-28.7%]	100.0% [99.4%-100.0%]
Carbapenem-resistant Enterobacterales	25.0% [12.7%-43.4%]	99.9% [99.2%-100.0%]
Escherichia coli	33.3% [6.1%-79.2%]	100.0% [99.5%-100.0%]
Klebsiella pneumoniae complex	28.6% [11.7%-54.6%]	100.0% [99.4%-100.0%]
Pseudomonas aeruginosa	20.0% [9.5%-37.3%]	97.9% [96.5%-98.7%]
Difficult-to-treat Pseudomonas aeruginosa	36.4% [15.2%-64.6%]	99.9% [99.2%-100.0%]

PPV: positive predictive value; NPV: negative predictive value; CI: confidence interval.

Even more relevant is the high negative predictive value of rectal surveillance cultures for MDR-GNB. Among non-colonized patients, infection caused by these pathogens is exceptionally rare. These findings provide a strong basis for individualizing empirical antibiotic therapy and for adopting a more precise and rational approach to treatment selection. Their implications extend beyond current guideline recommendations and directly challenge the traditional paradigm whereby all patients with FN are considered candidates for standard empirical therapy with routine antipseudomonal coverage.

This recommendation originated in the 1960s and 1970s, when P. aeruginosa was the leading pathogen in documented bacteremia and early administration of antipseudomonal therapy was shown to significantly reduce mortality [33,34]. However, as discussed above, changes in patient characteristics and hematologic therapies have substantially reshaped the epidemiology of infection. Currently, the incidence of bacteremia caused by P. aeruginosa is markedly lower than in previous decades. Recent studies have shown that among patients with a rectal surveillance culture obtained within the preceding 7 days that was negative for MDR-GNB and/or P. aeruginosa, no infections caused by these pathogens were documented [31,35–40].

In this context, maintaining universal antipseudomonal coverage in empirical antibiotic therapy appears neither necessary nor readily justifiable in the current era of multidrug resistance. Rather, we support the implementation of systematic microbiological surveillance based on rectal swab cultures in all patients with hematologic malignancies, both at hospital admission and weekly during hospitalization. The high negative predictive value of rectal swab cultures obtained within the preceding 5 days for P. aeruginosa infection and within the preceding 3 days for other Enterobacterales provides a strong rationale for the use of narrower-spectrum empirical therapy, such as a third-generation cephalosporin without antipseudomonal activity [31].

Figure 2 summarizes the proposed approach to selecting empirical β-lactam therapy for coverage of GNB in high-risk FN. In the absence of a recent rectal swab culture, this test should be included in the initial evaluation of every febrile episode, together with a complete blood count, serum biochemistry, and blood cultures. In most centers, results are available within 24–48 hours. When rectal colonization status is unknown, initial empirical antibiotic therapy for FN should rely on a broad-spectrum β-lactam, preferably a cephalosporin combined with a β-lactamase inhibitor, selected to provide initial coverage of at least 95% of potentially relevant pathogens according to the local epidemiology. Ceftazidime-avibactam, administered at 2/0.5 g intravenously every 8 hours as a 3-hour infusion, may be used as the preferred therapeutic option. Treatment should be reassessed and adjusted after 24–48 hours based on the results of blood cultures and rectal swab cultures. Figure 2 details the preferred antibiotic approach when a recent rectal swab culture is positive for specific microorganisms.

Prioritizing the use of antibiotics with minimal anaerobic activity

There is growing scientific evidence that exposure to antibiotics with potent activity against anaerobic microorganisms (such as piperacillin–tazobactam or carbapenems) induces a rapid loss of the Firmicutes and Bacteroidetes phyla, as well as a critical reduction in intestinal bacterial diversity. This ecological disruption favors the overgrowth of the Proteobacteria phylum, including Enterobacteriaceae and other aerobic GNB. This phenomenon has several collateral effects: (a) an increased likelihood of bacterial translocation and subsequent GNB bacteremia [41–43]; (b) a greater probability of horizontal transfer of resistance-associated genetic material within the fecal microbiota, including plasmids carrying genes encoding β-lactamases or carbapenemases, sometimes together with additional determinants of cross-resistance or co-resistance; (c) increased incidence and mortality of acute GVHD in transplant recipients [24,44,45]; and (d) reduced CAR-T cell functionality and persistence, together with an increased risk of complications such as cytokine release syndrome and neurotoxicity [22,23,46].

In clinical practice, these observations support the use of empirical regimens that, whenever feasible, avoid anti-anaerobic agents in patients with FN who have no apparent infectious focus and no clinical suspicion of complicated intra-abdominal infection, such as typhlitis, persistent abdominal pain, or a rectal phlegmon/abscess. This strategy entails relevant shifts that align with the concept of “ecological” antibiotics and promote replacing carbapenems and piperacillin–tazobactam with cephalosporins combined with β-lactamase inhibitors such as ceftazidime–avibactam, ceftolozane-tazobactam, or cefepime-enmetazobactam, as well as with siderophore cephalosporins such as cefiderocol. Recent data suggest that these “ecological” antibiotics are not only effective in the treatment of infections in patients with hematologic malignancies but may also contribute to intestinal eradication of MDR-GNB in colonized patients, either through a direct antibacterial effect or by preserving the anaerobic microbiota, thereby favoring sustained intestinal decolonization [31,47]. Nonetheless, the extent to which this ecological effect applies to ceftriaxone remains uncertain, particularly given its substantial biliary excretion.

Future challenges

This document on the management of FN in hematologic patients introduces several significant innovations. Among them, the need to define the risk of bacteremic infection and characterize its epidemiology in emerging hematologic patient populations stands out. As a first step in clinical decision-making, we propose objective stratification of bacteremia risk using an unsupervised machine-learning algorithm developed from recent hematologic patient cohorts [29]. In the future, new algorithms should incorporate additional outcomes such as non-bacteremic bacterial infections and/or provide greater predictive accuracy through supervised learning models or neural networks.

Another major advance lies in the central role of individualized risk assessment for infection due to MDR-GNB or P. aeruginosa based on recent rectal swab culture results, considering not only their positive predictive value but also their high negative predictive value.

A key challenge for future research will be to refine the interpretation of positive rectal swab cultures and to identify strategies capable of improving their diagnostic predictive performance [48,49]. At present, the positive predictive value of rectal swab cultures remains limited, as detection of MDR-GNB or P. aeruginosa in the fecal microbiota does not necessarily indicate that these organisms are responsible for the ongoing infection. Our hypothesis is that primary bacteremia in FN occurs when the burden of aerobic bacteria translocating across the intestinal mucosa exceeds the capacity of granulocytes to clear them. The clinical relevance of bacterial translocation is intrinsically related, on the one hand, to intestinal barrier permeability, reflecting the degree of mucositis, and, on the other, to the density of aerobic microorganisms per unit of surface area in the fecal microbiota. This raises the question of whether a critical threshold of bacterial density within the fecal microbiota may exist beyond which the risk of bacteremia rises substantially. To elucidate this, the use of semiquantitative culture methods for rectal swabs is essential, enabling estimation of P. aeruginosa and MDR Enterobacteriaceae growth using a graded scale: sparse (+), moderate (++), abundant (+++), or very abundant (++++).

If such a critical threshold is confirmed, future research should focus on two key questions. First, whether this threshold is specific to clinically relevant pathogens such as P. aeruginosa and MDR Enterobacterales, which would provide a rationale for personalized targeted antibiotic strategies in FN. Second, whether bacteremia can be prevented by reducing bacterial burden below the identified threshold through the use of non-absorbable antibiotics with selective activity against aerobic flora. The objective would not be decolonization, but rather containment of bacterial growth, that is, reduction of bacterial burden or inoculum, during the high-risk phase associated with neutropenia and mucositis. In this scenario, prophylactic treatment should be administered for a limited period and directed toward the predominant microorganism in the microbiota.

Another aspect requiring clarification in the coming years is the time window beyond which the predictive value of a rectal swab becomes unreliable. It is evident that a rectal swab obtained on the same day as the febrile episode best reflects the recent microbiota from which infection may have originated. However, given that obtaining results in under 24 hours is not always feasible across all centers and circumstances, it is essential to determine the validity of swabs collected several days before FN onset to guide empirical treatment. Our studies suggest that a window of 3–5 days may represent the upper limit of validity [31], but this remains an important line of future investigation.

Conclusion

In conclusion, we are witnessing a timely paradigm shift in the approach to febrile neutropenia, both in its definition and in the incorporation of risk-stratification strategies based on artificial intelligence and individualized knowledge of the patient’s colonic microbiota through rectal swabs. These advances enable a truly personalized therapeutic approach. The integration of these developments, together with a deeper understanding of the importance of intestinal eubiosis, should now guide clinical practice in the antimicrobial management of FN. Initial empirical antibiotic therapy for patients with FN without an apparent focus should include a β-lactam without anaerobic activity and with potential efficacy against the colonizing flora. In cases where an infectious focus exists or the patient meets criteria for sepsis or shock, combination therapy including agents active against Gram-positive microorganisms is recommended. All treatments must be reassessed at 24–48 hours, considering antibiotic withdrawal or transition to oral therapy if the patient falls into the low-risk bacteremia group, remains clinically stable, and microbiological results are negative or an alternative cause of fever is identified.

Funding Statement

A.G.-P. has received funding through a Río Hortega contract (CM25/00065), awarded by Resolution of the Director of the Instituto de Salud Carlos III dated 10 December 2025 and co-financed by the European Union. C.G.-V. (FIS PI24/01776) has received research funding from the Spanish Ministry of Health and Consumer Affairs and the Instituto de Salud Carlos III. Project PI24/01776 was funded by the Instituto de Salud Carlos III (ISCIII) and co-financed by the European Union. The funders had no specific role in the conception or writing of the manuscript, or in the decision to submit it for publication.

Funding

A.G.-P. has received funding through a Río Hortega contract (CM25/00065), awarded by Resolution of the Director of the Instituto de Salud Carlos III dated 10 December 2025 and co-financed by the European Union. C.G.-V. (FIS PI24/01776) has received research funding from the Spanish Ministry of Health and Consumer Affairs and the Instituto de Salud Carlos III. Project PI24/01776 was funded by the Instituto de Salud Carlos III (ISCIII) and co-financed by the European Union. The funders had no specific role in the conception or writing of the manuscript, or in the decision to submit it for publication.

Conflicts of interest

A.G.-P. has received support from Gilead Sciences and MSD for registration fees and travel expenses to attend scientific meetings, and honoraria for lectures on behalf of AstraZeneca. T.F.-A. has received support from Gilead Sciences, Pfizer, and PharmaMar for registration fees and travel expenses to attend scientific meetings. J.M. has received honoraria for lectures on behalf of Merck Sharp & Dohme, Pfizer, Novartis, and Angelini. A.S. has received honoraria for lectures on behalf of Merck Sharp & Dohme, Pfizer, Novartis, Angelini, Menarini, and Gilead Sciences, as well as research grants from Pfizer and Gilead Sciences. C.G.-V. has received honoraria for lectures on behalf of Gilead Sciences, MSD, Pfizer, Janssen, Novartis, Basilea, GSK, Shionogi, AbbVie, and Advanz Pharma, as well as research grants from Gilead Sciences, Pfizer, GSK, MSD, and PharmaMar.