Antibacterial prophylaxis and antimicrobial stewardship in the era of innovative therapies for haematological malignancies: transplantation, cellular therapies and new drugs.

Introduction

Minimizing antibiotic exposure is the cornerstone of preventing emergence of antibiotic resistance, and therefore an important aspect of rational antimicrobial stewardship (AMS). According to the joint definition of the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), AMS encompasses coordinated strategies aimed at optimizing antimicrobial use in terms of drug choice, dosing, duration, and route of administration, with the dual goal of improving clinical outcomes while minimizing toxicity and limiting the emergence of antimicrobial resistance. 1

Given these premises, antimicrobial prophylaxis in haematological patients represents a highly relevant field of application for AMS strategies; indeed, it has long been studied as a strategy to prevent severe infections and reduce mortality. In 2012, Gafter-Gvili and colleagues published an updated meta-analysis on afebrile neutropenic patients following chemotherapy. 2 Consistent with their earlier analyses, 3 , 4 they confirmed that antibiotic prophylaxis reduces all-cause mortality, infection-related mortality, fever, and both clinically and microbiologically documented infections. It has to be noted that this meta-analysis was conducted in a setting of low quinolone resistance. Following this and other studies, 5–7 guideline recommendations were revised over the years to endorse antibiotic prophylaxis in high-risk haematological patients with an expected duration of neutropenia longer than 7 days. 8–10

More recent meta-analyses and reviews, however, have failed to show a consistent benefit in terms of overall mortality, even though fluoroquinolones (FQ) remain effective in reducing bloodstream infections (BSI). 11 , 12 The lack of consistent benefit in more recent studies indicates that these findings may have limited applicability in contemporary epidemiological settings characterised by higher resistance rates.

The advent of novel cellular and immune-based therapies, including chimeric antigen receptor (CAR) T cells, bispecific antibodies (BsAbs) and bispecific T-cell engagers (BiTEs), has highlighted the need to reassess antibacterial prophylaxis within an antimicrobial stewardship framework. The widespread use of FQ is increasingly challenged by rising global resistance and their potential to select resistant pathogens. Moreover, FQ are associated with clinically relevant toxicities, such as neurological and musculoskeletal, whose risk is influenced by patient- and treatment-related factors and may be amplified in haematological patients receiving multiple concomitant therapies and Clostridioides difficile infection, which is already common in patients with haematological malignancies. Therefore, any potential benefit in reducing febrile neutropenia (FN) or BSI must be carefully balanced against both patient-level harms and population-level consequences. As a result, some institutions have revised their protocols, omitting routine prophylaxis and instead initiating empiric therapy once patients develop fever. 13 Nonetheless, the most recent international guidelines have not substantially changed their recommendations 12 , 14–16 and notwithstanding the increasing uncertainty regarding its benefit in the current resistance landscape, FQ prophylaxis is still routinely adopted in most centres.

The joint ASCO/IDSA guideline ‘Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression’ recommends antibacterial and antifungal prophylaxis for patients expected to have ‘profound, protracted neutropenia’. In that high-risk population prophylaxis with a FQ is recommended. Levofloxacin is often favoured in patients at increased risk of mucositis and viridans group streptococcal infections. 10

This review aims to summarize current considerations regarding infection prophylaxis in adult patients not only in the context of traditional chemotherapy regimens but also in patients receiving newly therapeutic approaches such as targeted agents, immunotherapies, and cellular therapies. By outlining how prophylactic strategies evolve according to treatment modality and risk profile, this review tries to give practical considerations useful for everyday practice before addressing specific guideline recommendations.

Fluoroquinolones as antibacterial prophylaxis in haematological patients

FN is defined as an oral temperature of >38.3°C or two consecutive readings of >38.0°C for 2 h and an absolute neutrophil count (ANC) of <0.5 × 10 9 /L, or expected to fall below 0.5 × 10 9 /L. 17 It is a common complication in haematological malignancy patients undergoing high dose chemotherapy, haematopoietic stem cell transplantation (HSCT) and cellular therapies such as CAR-T cell therapy, as well as novel therapeutic modalities including BiTEs and BsAbs. Given the different mechanisms of action, these emergence novel cellular therapies have further highlighted the need to reassess the role of antibiotic prophylaxis within the broader network of antimicrobial stewardship.

In acute myeloid leukaemia (AML) patients, FN is the main cause of non-relapse mortality, especially during induction chemotherapy. However, recent real life evidence does not confirm a detrimental impact of omitting FQ prophylaxis on the incidence of infections. 18

According to recent guidelines, antibacterial prophylaxis should not be routinely used but should be reserved for individuals with prolonged and profound neutropenia (commonly ANC <0.5 × 10 9 /L for 7 or more days), prior colonization with multidrug-resistant organisms (MDR), or in centres with high rates of Gram-negative bloodstream infection, and always aligned with local resistance patterns and AMS principles. 19 , 20

HSCT

In allogeneic HSCT, antibacterial prophylaxis was historically a cornerstone of supportive care as patients inevitably experience a period of profound and prolonged neutropenia during conditioning and the early post-transplant phase. 21

Three Italian studies evaluated Gram negative bacteraemia during pre-engraftment in HSCT that is strongly associated with increased early mortality, underlining the importance of careful risk stratification, preventive measures (including possibly prophylaxis and colonization monitoring that is itself a risk factor even if not directly associated with worsening outcomes), and prompt interventions in case of fever or bacteraemia. 22–24

Some studies challenged the long-held paradigm that all allogenic-HSCT patients require universal antibiotic prophylaxis. Neuerburg et al. 25 found that discontinuing prophylaxis did not worsen survival, graft versus host disease, relapse, or transplant-related mortality, although severe infections were slightly more frequent. Notably, the no-prophylaxis cohort showed a trend toward better outcomes, possibly reflecting reduced microbiota disruption or lower selective pressure for resistant organisms. However, in this setting, prophylaxis increased C. difficile infections. In contrast, Stern et al. 26 showed that stopping FQ prophylaxis led to more early Gram-negative BSI, but this did not translate into higher mortality or greater need for therapy.

In a single-centre retrospective study of Clerici et al., 13 levofloxacin prophylaxis was adopted during pre-engraftment neutropenia with a subsequent no-prophylaxis policy in the setting of HSCT. Notably, antimicrobial susceptibility improved after discontinuation of FQ prophylaxis (e.g. higher susceptibility to piperacillin–tazobactam, FQ, and carbapenems in pathogens isolated during the no-prophylaxis period), underscoring a trade-off between fewer early Gram-negative BSI and selection pressure for resistance with routine levofloxacin.

This suggests that in a modern haematology ward, with rapid diagnostics, early empiric therapy, and close monitoring, the clinical consequences of these additional infections may be mitigated. FQ resistance was far more common among Gram negative isolates from patients who received prophylaxis.

Together, these studies suggest that routine prophylaxis reduces early infections but may promote resistance and microbiota disruption, whereas withholding prophylaxis is feasible with close monitoring and rapid empiric therapy, supporting a shift towards risk-adapted, centre-specific prophylaxis strategies rather than universal use. 25–28

CAR-T

CAR T-cell therapy is an approved treatment that has markedly improved clinical outcomes across several haematological malignancies, such as B-cell lymphoma, leukaemia, and multiple myeloma (MM). This strategy is expanding also to non-malignant indications. FN is common after CAR-T therapy, with reported incidences between 20% and 40% in both CD19- and BCMA-targeted products. 29 Most episodes that occur within the first 30 days are attributed to lymphodepleting chemotherapy as well as early haematological toxicity related to cytokine release syndrome (CRS). Prolonged or late cytopenias, described as immune effector cell-associated haematotoxicity (ICAHT), extend infectious risk beyond day +30. 30 In the first month, there is predominance of bacterial BSI and pneumonia. 31 , 32

Recent publications confirm that infections remain frequent and may represent a major cause of non-relapse mortality, especially early after CAR-T infusion, but can also occur long after. Infection risk varies by CAR-T target antigen, prior therapies, and patient-specific factors, emphasizing that prophylaxis, monitoring, and supportive care should be individualized rather than applied uniformly. 33 , 34

Indeed, guidelines emphasize that all patients developing FN after CAR-T should undergo a standard diagnostic workup, as fever must not be attributed to CRS until infection is reasonably excluded.

The role of levofloxacin prophylaxis in afebrile neutropenic patients after CAR-T therapy remains controversial. Current ASTCT best-practice recommendations consider FQ prophylaxis a selective option, principally for patients with anticipated prolonged neutropenia, substantial comorbidity burden, or colonization with MDR Gram-negative organisms—while discouraging routine use. 29 , 35

The EBMT/EHA CAR-T Cell Handbook 36 recommends using the CAR-HEMATOTOX score before the treatment, to estimate the risk and duration of neutropenia in order to guide prophylaxis decisions. Expert opinion supports an individualized strategy guided by patient-specific risk factors. In a single retrospective single-centre cohort of 50 adults receiving CD19 CAR-T therapy, Walker et al. 37 described the use of levofloxacin prophylaxis during periods of severe neutropenia as institutional practice without comparing levofloxacin versus no prophylaxis and therefore cannot determine its efficacy. Overall, the study supports a risk-adapted rather than routine approach to antibacterial prophylaxis, consistent with contemporary stewardship principles. In a retrospective multicentric analysis, Rejeski et al. 38 found that the antibiotic prophylaxis with FQ (and in particular with levofloxacin) was associated with a lower risk of severe bacterial infections in high-risk patients with high CAR-HEMATOTOX, while no benefit was observed in low-risk subjects, supporting a risk-adapted approach rather than a universal approach.

Conversely, Yin et al. 39 observed that FQ prophylaxis adversely affected progression-free survival but not overall survival, in a cohort of relapsed/refractory MM patients treated with CAR-T cells.

Similarly, Mikkilineni et al. 40 found no significant difference in bacterial infection rates between patients who did or did not receive prophylaxis.

Thus, the role of FQ prophylaxis in CAR-T therapy remains unsettled. AMS programs should ensure that FQ prophylaxis is not automatically extended from traditional HSCT indications to CAR-T recipients without robust local data supporting its benefit, and expected duration and depth of neutropenia, local resistance epidemiology, and colonisation status.

BiTEs and BsAbS therapy

Data on infection prevention and prophylaxis in this setting are even more limited given their recent approval. BiTEs and BsAbs are emerging therapies across different haematological malignancies: blinatumomab (CD19×CD3) in acute lymphoblastic leukaemia (ALL), mosunetuzumab (CD20×CD3) in follicular lymphoma, epcoritamab and glofitamab (CD20×CD3) in diffuse large B-cell lymphoma (DLBCL); in MM, teclistamab and elranatamab (BCMA × CD3) alongside talquetamab (GPRC5D × CD3). A recent review demonstrates that the impressive response rates of BsAbs in MM come at the cost of more than 50% patients with infections during treatment. Indeed, these engineered antibodies co-bind CD3 on T lymphocytes and a tumour antigen (e.g. CD19, CD20, BCMA, GPRC5D), thereby redirecting T cells to kill targets via MHC-independent cytotoxicity. These off-the-shelf agents are delivered either by continuous infusion or, increasingly, with step-up subcutaneous dosing to mitigate CRS.

Some parallels can be drawn from CAR-T experience, but important differences exist, most notably the prolonged or continuous treatment course of BsAbs compared with the one-time administration of CAR-T therapy and the profound depletion of immunoglobulin and cytopenia related to some type of BsAbs, 41 even though in general CAR-T compared to BsAbs is associated with a more profound and prolonged neutropenia.

In the largest systematic review and meta-analysis to date, van Besien et al. compared infection rates in patients treated with CAR-T versus BsAbs. While pooled rates of all-grade and grade ≥3 infections were similar between groups, BsAbs-treated patients experienced higher infection rates per patient month, reflecting the chronic treatment exposure and associated cumulative risk. Unfortunately, this analysis did not evaluate the impact of antibacterial prophylaxis. 42 In a multicentre study of 229 MM patients treated with BsAbs, Jourdes et al. 43 observed an association between antibacterial prophylaxis and reduced infection risk, although this was not confirmed in multivariate analysis.

Mohan et al. 44 proposes a risk-adapted prophylaxis framework for MM patients receiving CAR-T or BsAbs. Antibacterial prophylaxis is not universal and should be considered only for anticipated prolonged severe neutropenia, aligned with local epidemiology and stewardship principles. Similar prophylaxis has been proposed by Raje et al. 45 with selective (non-routine) use of antibacterial (including levofloxacin) according to individual risk. Lesokhin et al. 46 focuses on elranatamab in relapsed/refractory patients with MM: antibacterial prophylaxis (FQ in particular) use was selective and infrequent, reflecting a risk-adapted approach informed by local epidemiology and institutional practice.

In the phase I/II MajesTEC-1 study, 47 a high early burden of infections driven by hypogammaglobulinaemia and cytopenias highlights the need of supporting proactive prevention, close monitoring, and prompt management throughout therapy.

Given the limited robust evidence, current recommendations for antibiotic prophylaxis in BiTEs/BsAbs therapies are largely based on expert opinion (Table 1 ), underscoring the need for an individualized approach that considers both local epidemiology and patient-specific factors. BsAbs are a chronic immunosuppressive therapy, requiring the same careful preventive mindset reserved for transplantation or long-term immunomodulation. Personalized prophylaxis, immunological monitoring, and possibly immunoglobulin support should become standard in many patients receiving these agents. 54

The antibacterial prophylaxis remains selective and reserved for patients with prolonged or profound neutropenia or other high-risk features, and should be implemented within antimicrobial-stewardship programs, evaluating local resistance epidemiology and colonisation status, without endorsing routine use of oral antibiotics.

Other innovative therapies

Other treatment options are also rapidly emerging, accompanied by growing data on infection risk, although specific recommendations for antibacterial prophylaxis are still lacking.

Antibody–drug conjugates are associated with a non-negligible risk of infection, primarily due to myelosuppression. Targeted therapy has become more common in haematological malignancies, including monoclonal antibodies (mAbs) reshape standards in DLBCL, classic Hodgkin lymphoma ALL, AML, and MM. They are directed against specific antigens expressed on the surface of different cell types, mediating different mechanisms of actions. 55 Among these, gemtuzumab ozogamicin and inotuzumab ozogamicin are particularly associated with higher rates of sepsis and infection-related mortality compared with other molecules such as belantamab mafodotin or polatuzumab vedotin, frequently contributing to prolonged neutropenia. 56 , 57 A recent retrospective study analysed the incidence of infection in inotuzumab ozogamicin treated patient. The authors showed that significant infectious adverse events were uncommon. 58

Immune checkpoint inhibitors alone typically carry a favourable infection risk profile; however, the use of high-dose corticosteroids or other immunosuppressants for immune-related adverse events substantially increases the risk of serious infections. 48 , 59

Natural killer (NK) cell therapies generally pose a lower infection risk than other T-cell-based therapies, given the lower incidence of CRS and the absence of graft versus host disease risk. Nonetheless, infections do occur and are often attributable to prior therapies or the underlying malignancy rather than NK therapy itself, and real-world data remain limited. 60–62

From an AMS perspective, FQ prophylaxis in patients receiving these novel cellular or immune-based therapies should be reserved for those with significant or prolonged neutropenia, mirroring the criteria applied in traditional chemotherapy or transplant settings.

Most monoclonal antibodies—such as rituximab, obinutuzumab, daratumumab, and elotuzumab—alter specific components of the immune system but rarely cause significant neutropenia on their own. In MM, agents such as daratumumab and isatuximab are often combined with corticosteroids, which contribute to immunosuppression. Although infections are common in MM, routine antibacterial prophylaxis is still not universally recommended. Instead, the decision is individualized and usually reserved for patients with repeated bacterial infections, severe hypogammaglobulinaemia, or concomitant neutropenia related to the treatment regimen 63 , 64 (Table 2 ).

Alternatives to levofloxacin in antibacterial prophylaxis

Alternative antibacterial prophylaxis strategies beyond levofloxacin are increasingly explored in high-risk patients undergoing treatment for haematological malignancies, HSCT, or cellular therapies. This shift is driven by rising FQ resistance, safety concerns, and evolving resistance patterns. 65 , 66 As no survival advantage has been demonstrated, these findings reflect a changing infection landscape, marked by increasing Gram-positive bacteraemia and the emergence of MDR Gram-negative organisms, including extended spectrum beta lactamases (ESBL)-producing Enterobacterales and carbapenem-resistant Pseudomonas aeruginosa . 65 , 67

Although these limitations apply to FQ as a class, a substantial proportion of the available evidence concerning agents other than levofloxacin arises from the use of another FQ, ciprofloxacin. Ciprofloxacin shows activity against a broad range of Gram negative bacteria, including Pseudomonas aeruginosa , and is generally well tolerated. However, its limited activity against Gram-positive pathogens has emerged as a key drawback. Comparative evidence highlights this limitation: a meta-analysis of five studies including 1202 HSCT recipients demonstrated that while ciprofloxacin and levofloxacin showed similar efficacy in preventing FN and Gram-negative infections, levofloxacin was significantly more effective in preventing BSI, particularly those due to Gram-positive organisms. 68 Similarly, Copeland et al. 69 reported a higher incidence of Gram-positive BSI among ciprofloxacin-treated patients (15.6%) compared with levofloxacin (7.0%), primarily due to viridans group Streptococci.

Among non-FQ regimens, oral third-generation cephalosporins (OTGCs), such as cefpodoxime, cefixime, and cefdinir, represent the most frequently evaluated alternatives. 70 Data from leukaemia and HSCT cohorts show comparable rates of FN, Gram-negative BSI, and infection related mortality relative to levofloxacin. 71 , 72 OTGCs are generally well tolerated and free from major drug interactions, offering a safer profile in patients with organ dysfunction. However, their limited activity against Pseudomonas aeruginosa and anaerobes, together with the frequent isolation of Enterobacter and AmpC-producing organisms, raises concern for resistance. 70 Clinical evidence remains limited to small observational studies and a single randomised trial. At the Mayo Clinic, cefpodoxime prophylaxis after chemotherapy for haematological malignancies was associated with high rates of breakthrough FN (85%) and culture-positive infections (60%). 72 A subsequent study from the same centre comparing OTGCs (mostly cefdinir, with some cefpodoxime) to levofloxacin found similar rates of FN and mortality, though intensive care admissions were numerically higher in the OTGC group. 70 Likewise, a small RCT in allogeneic HSCT recipients comparing levofloxacin to cefpodoxime showed no significant differences in prophylaxis failure, C. difficile , or MDR infections, though overall mortality was higher in the cefpodoxime arm. 71

Trimethoprim–sulfamethoxazole (TMP–SMX) has been shown to be effective in reducing bacteraemia in comparison with no prophylaxis among patients with haematological malignancies and HSCT. 73 However, international guidelines do not recommend its routine use for antibacterial prophylaxis in adult HSCT recipients, except when FQ or alternative agents are unavailable or contraindicated. 19 , 66 Clinicians should remain vigilant to the potential adverse effects of TMP-SMX, which include myelosuppression, rash, and renal toxicity. 74 They should also be aware of the risk of resistance among Gram-negative pathogens. Accordingly, its current use is mainly confined to prophylaxis against Pneumocystis jirovecii and Toxoplasma gondii , usually given three times per week following allogeneic HSCT. 75

Fosfomycin has emerged as a potential alternative for patients intolerant to FQ or beta-lactams. Its broad-spectrum activity against multi drug resistant Enterobacterales and favourable safety profile make it an appealing option, although evidence remains limited. Retrospective data indicate low breakthrough infection rates, good tolerability, and minimal resistance. In a Yale–New Haven cohort, oral fosfomycin used for prophylaxis in FQ-intolerant patients yielded a 19% infection rate, mainly due to Klebsiella spp., Streptococcus mitis / viridans , and Pseudomonas aeruginosa . 76 The ongoing FOVOCIP trial is comparing oral fosfomycin with ciprofloxacin for FN prevention in acute leukaemia and HSCT. Data from this trial are awaited. 77 Overall, fosfomycin appears safe and well tolerated, but prospective validation is lacking and current guidelines do not yet support its routine use. Moreover, fosfomycin blood pharmacokinetics at doses used for systemic prophylaxis is still a point of debate.

As discussed earlier in this review, the selective omission of antibacterial prophylaxis has been explored in specific clinical settings and have shown only modest increases in Gram-negative bacteraemia, with no increase in infection-related mortality and even a reduction in antimicrobial resistance in Gram-negative organisms. 13 , 78

Although FQ remain the most extensively studied agents, emerging evidence supports a more cautious, individualised approach, including the use of non-FQ options, such as oral third-generation cephalosporins, or, in selected settings, the omission of routine prophylaxis. The optimal approach should ultimately be guided by local epidemiology, patient-specific factors and robust antimicrobial stewardship principles.

Antimicrobial stewardship

In patients with haematological malignancies, particularly in the era of novel immunotherapeutic strategies, AMS should provide the framework for the rational use of FQ prophylaxis. Rather than being universally implemented, prophylaxis should be reserved for patients at highest risk of prolonged and profound neutropenia and tailored to local resistance epidemiology. Effective stewardship requires robust measurement of antimicrobial consumption and clinical outcomes, supported by microbiological surveillance, standardized antibiotic-use metrics, and validated quality indicators. Screening for intestinal colonization with resistant organisms, such as rectal swabs for resistant Enterobacterales, may further refine patient selection and support a truly individualized approach. Satlin and colleagues suggested using a carbapenem or omitting antibacterial prophylaxis when the screening isolate was an ESBL producer. The authors had shown that, in all cases of bacteraemia, the bloodstream and gastrointestinal ESBL-producing Enterobacterales displayed identical profiles, suggesting that the BSI originated from the colonizing strains. 79 The utility of surveillance cultures is contingent upon the resistance landscape. In low-prevalence FQ-resistance scenarios, screening serves to exclude patients harbouring resistant isolates from ineffective prophylaxis. In contrast, where multi-drug resistant organisms are endemic, these data transition into a clinical tool for personalized pre-emptive regimens.

Stewardship policies should remain responsive to evolving resistance patterns, clinical outcomes, and the incidence of C. difficile infection, with periodic reassessment embedded within institutional practice. Close multidisciplinary collaboration and strong institutional support are essential for sustainable implementation. Within this framework, AMS does not aim to eliminate prophylaxis but to optimize its use, ensuring an appropriate balance between infection prevention and the long-term containment of antimicrobial resistance. The proposed stewardship algorithm is illustrated in Figure 1 .

Conclusions

Antibiotic prophylaxis remains a cornerstone in traditional haematology to prevent infections during prolonged neutropenia, but its role is increasingly nuanced in the era of novel therapies such as CAR T cells and BsAbs. While prophylaxis can reduce early bacterial infections in neutropenic phases of treatment, it may promote antimicrobial resistance, microbiota disruption, and other complications. Emerging evidence supports a risk-adapted, individualized approach based local epidemiology and colonisation status, balancing infection prevention with long-term safety, close monitoring, and rapid intervention strategies tailored to the patient’s immune status and type of therapy.

Funding

None declared.

Transparency declarations

None to declare.

References

1 Fishman N . Policy statement on antimicrobial stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS) . Infect Control Hosp Epidemiol 2012 ; 33 : 322 – 7 . 10.1086/665010 22418625

2 Gafter-Gvili A , Fraser A , Paul M et al Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy . Cochrane Database Syst Rev 2018 ; 1 CD004386 . 10.1002/14651858.CD004386.pub3 16235360

3 Gafter-Gvili A , Fraser A , Paul M et al Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients . Ann Intern Med 2005 ; 142 : 979 – 95 . 10.7326/0003-4819-142-12_part_1-200506210-00008 15968013

4 Gafter-Gvili A , Fraser A , Paul M et al Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy . Cochrane Database Syst Rev 2005 ; 4 CD004386 . 10.1002/14651858.CD004386.pub2 16235360

5 Cullen M , Steven N , Billingham L et al Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas . N Engl J Med 2005 ; 353 : 988 – 98 . 10.1056/NEJMoa050078 16148284

6 Leibovici L , Paul M , Cullen M et al Antibiotic prophylaxis in neutropenic patients: new evidence, practical decisions . Cancer 2006 ; 107 : 1743 – 51 . 10.1002/cncr.22205 16977651

7 Bucaneve G , Micozzi A , Menichetti F et al Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia . N Engl J Med 2005 ; 353 : 977 – 87 . 10.1056/NEJMoa044097 16148283

8 Bucaneve G , Castagnola E , Viscoli C et al Quinolone prophylaxis for bacterial infections in afebrile high risk neutropenic patients . Eur J Cancer 2007 ; 5 : 5 – 12 . 10.1016/j.ejcsup.2007.06.002

9 Flowers CR , Seidenfeld J , Bow EJ et al Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American society of clinical oncology clinical practice guideline . J Clin Oncol 2013 ; 31 : 794 – 810 . 10.1200/JCO.2012.45.8661 23319691

10 Freifeld AG , Bow EJ , Sepkowitz KA et al Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America . Clin Infect Dis 2011 ; 52 : e56 – 93 . 10.1093/cid/cir073 21258094

11 Douglas AP , Stohs E , Mikulska M . The role of antibacterial prophylaxis in high-risk neutropenia: benefits, risks, and current perspectives . Curr Opin Infect Dis 2025 ; 38 : 281 – 9 . 10.1097/QCO.0000000000001114 40314335

12 Mikulska M , Averbuch D , Tissot F et al Fluoroquinolone prophylaxis in haematological cancer patients with neutropenia: ECIL critical appraisal of previous guidelines . J Infect 2018 ; 76 : 20 – 37 . 10.1016/j.jinf.2017.10.009 29079323

13 Clerici D , Galli L , Greco R et al Levofloxacin prophylaxis vs no prophylaxis in patients with neutropenia within an endemic country for carbapenem-resistant GNB . Blood Adv 2023 ; 7 : 1621 – 34 . 10.1182/bloodadvances.2022008226 36409602 PMC10182274

14 Baden LR , Bensinger W , Angarone M et al Prevention and treatment of cancer-related infections . J Natl Compr Canc Netw 2012 ; 10 : 1412 – 45 . 10.6004/jnccn.2012.0146 23138169

15 Baden LR , Swaminathan S , Almyroudis NG et al Prevention and treatment of cancer-related infections, version 3.2024 . J Natl Compr Canc Netw 2024 ; 22 : 617 – 44 . 10.6004/jnccn.2024.0056 39536464

16 Verlinden A , Mikulska M , Knelange NS et al Current antimicrobial practice in febrile neutropenia across Europe and Asia: the EBMT infectious disease working party survey . Bone Marrow Transplant 2020 ; 55 : 1588 – 94 . 10.1038/s41409-020-0811-y 32047286 PMC7391284

17 Klastersky J , De Naurois J , Rolston K et al Management of febrile neutropaenia: ESMO clinical practice guidelines . Ann Oncol 2016 ; 27 : v111 – 8 . 10.1093/annonc/mdw325 27664247

18 Santoni A , Malchiodi M , Papayannidis C et al Incidence of infectious complications in acute myeloid leukemia patients undergoing induction chemotherapy with or without fluoroquinolone prophylaxis in real-life: results from INFLUENCER study . Blood 2025 ; 146 993 . 10.1182/blood-2025-993

19 Taplitz RA , Kennedy EB , Bow EJ et al JOURNAL OF CLINICAL ONCOLOGY antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA clinical practice guideline update . J Clin Oncol 2018 ; 36 : 3043 – 54 . 10.1200/JCO.18.00374 30179565

20 Averbuch D , Orasch C , Cordonnier C et al European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European conference on infections in leukemia . Haematologica 2013 ; 98 : 1826 – 35 . 10.3324/haematol.2013.091025 24323983 PMC3856957

21 Tomblyn M , Chiller T , Einsele H et al Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective . Bone Marrow Transplant 2009 ; 44 : 453 – 5 . 10.1038/bmt.2009.254 19861977

22 Girmenia C , Bertaina A , Piciocchi A et al Incidence, risk factors and outcome of pre-engraftment gram-negative bacteremia after allogeneic and autologous hematopoietic stem cell transplantation: an Italian prospective multicenter survey . Clin Infect Dis 2017 ; 65 : 1884 – 96 . 10.1093/cid/cix690 29020286

23 Forcina A , Lorentino F , Marasco V et al Clinical impact of pretransplant multidrug-resistant gram-negative colonization in autologous and allogeneic hematopoietic stem cell transplantation . Biol Blood Marrow Transplant 2018 ; 24 : 1476 – 82 . 10.1016/j.bbmt.2018.02.021 29501780

24 Patriarca F , Cigana C , Massimo D et al Risk factors and outcomes of infections by multidrug-resistant gram-negative bacteria in patients undergoing hematopoietic stem cell transplantation . Biol Blood Marrow Transplant 2017 ; 23 : 333 – 9 . 10.1016/j.bbmt.2016.11.005 27826061

25 Neuerburg CK , Schmitz F , Schmitz MT et al Antibiotic prophylaxis during allogeneic stem cell transplantation—a comprehensive single center retrospective analysis . Transplant Cell Ther 2024 ; 30 : 1195.e1 – e13 . 10.1016/j.jtct.2024.09.011 39299503

26 Stern A , Henig I , Cohen M et al Impact of discontinuing routine fluoroquinolone prophylaxis in neutropenic allogeneic haematopoietic stem cell transplant recipients: an observational study . J Antimicrob Chemother 2024 ; 79 : 3289 – 96 . 10.1093/jac/dkae360 39397650

27 Malagola M , Turra A , Signorini L et al Results of an innovative program for surveillance, prophylaxis, and treatment of infectious complications following allogeneic stem cell transplantation in hematological malignancies (BATMO protocol) . Front Oncol 2022 ; 12 874117 . 10.3389/fonc.2022.874117 35785189 PMC9247274

28 Baltas I , Kavallieros K , Konstantinou G et al The effect of ciprofloxacin prophylaxis during haematopoietic cell transplantation on infection episodes, exposure to treatment antimicrobials and antimicrobial resistance: a single-centre retrospective cohort study . JAC Antimicrob Resist 2024 ; 6 dlae010 . 10.1093/jacamr/dlae010 38304723 PMC10833646

29 Hill JA , Seo SK . How I prevent infections in patients receiving CD19-targeted chimeric antigen receptor T cells for B-cell malignancies . Blood 2020 ; 136 : 925 – 35 . 10.1182/blood.2019004000 32582924 PMC7441168

30 Rejeski K , Subklewe M , Aljurf M et al Immune effector cell-associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations . Blood 2023 ; 142 : 865 – 77 . 10.1182/blood.2023020578 37300386

31 Park JH , Romero FA , Taur Y et al Cytokine release syndrome grade as a predictive marker for infections in patients with relapsed or refractory b-cell acute lymphoblastic leukemia treated with chimeric antigen receptor T cells . Clin Infect Dis 2018 ; 67 : 533 – 40 . 10.1093/cid/ciy152 29481659 PMC6070095

32 Hill JA , Li D , Hay KA et al Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy . Blood 2018 ; 131 : 121 – 30 . 10.1182/blood-2017-07-793760 29038338 PMC5755046

33 Rejeski K , Hill JA , Dahiya S et al Noncanonical and mortality-defining toxicities of CAR T cell therapy . Nat Med 2025 ; 31 : 2132 – 46 . 10.1038/s41591-025-03813-5 40670774

34 Kampouri E , Little JS , Rejeski K et al Infections after chimeric antigen receptor (CAR)-T-cell therapy for hematologic malignancies . Transpl Infect Dis 2023 ; 25 e14157 . 10.1111/tid.14157 37787373

35 Shahid Z , Jain T , Dioverti V et al Best practice considerations by the American society of transplant and cellular therapy: infection prevention and management after chimeric antigen receptor t cell therapy for hematological malignancies . Transplant Cell Ther 2024 ; 30 : 955 – 69 . 10.1016/j.jtct.2024.07.018 39084261 PMC12826105

36 Kröger N , Gribben J , Chabannon C et al The EBMT/EHA CAR-T Cell Handbook . Springer , 2022 . 36121969

37 Walker B , Zimmer AJ , Stohs EJ et al Infectious complications among CD19 CAR-T cell therapy recipients: a single-center experience . Transpl Infect Dis 2023 ; 25 e14191 . 10.1111/tid.14191 37987114

38 Rejeski K , Perez A , Iacoboni G et al The CAR-HEMATOTOX risk-stratifies patients for severe infections and disease progression after CD19 CAR-T in R/R LBCL . J Immunother Cancer 2022 ; 10 e004475 . 10.1136/jitc-2021-004475 35580927 PMC9114843

39 Yin L , Lv B , Ge J et al The impact of antibiotic use on outcomes of relapsed/refractory multiple myeloma patients treated with CAR-T therapy . Front Immunol 2025 ; 16 1566016 . 10.3389/fimmu.2025.1566016 40313953 PMC12043596

40 Mikkilineni L , Yates B , Steinberg SM et al Infectious complications of CAR T-cell therapy across novel antigen targets in the first 30 days . Blood Adv 2021 ; 5 : 5312 – 22 . 10.1182/bloodadvances.2021004896 34619768 PMC9153053

41 Klein C , Brinkmann U , Reichert JM et al The present and future of bispecific antibodies for cancer therapy . Nat Rev Drug Discov 2024 ; 23 : 301 – 19 . 10.1038/s41573-024-00896-6 38448606

42 van Besien H , Easwar N , Demetres M et al Comparative infection risk in CAR T vs bispecific antibodies in B-cell lymphoma: a systematic review and meta-analysis . Blood Adv 2025 ; 9 : 6063 – 75 . 10.1182/bloodadvances.2025016291 40590871 PMC12686707

43 Jourdes A , Cellerin E , Touzeau C et al Characteristics and incidence of infections in patients with multiple myeloma treated by bispecific antibodies: a national retrospective study . Clin Microbiol Infect 2024 ; 30 : 764 – 71 . 10.1016/j.cmi.2024.02.023 38432433

44 Mohan M , Chakraborty R , Bal S et al Recommendations on prevention of infections during chimeric antigen receptor T-cell and bispecific antibody therapy in multiple myeloma . Br J Haematol 2023 ; 203 : 736 – 46 . 10.1111/bjh.18909 37287117 PMC10700672

45 Raje N , Anderson K , Einsele H et al Monitoring, prophylaxis, and treatment of infections in patients with MM receiving bispecific antibody therapy: consensus recommendations from an expert panel . Blood Cancer J 2023 ; 13 116 . 10.1038/s41408-023-00879-7 37528088 PMC10394080

46 Lesokhin AM , Tomasson MH , Arnulf B et al Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results . Nat Med 2023 ; 29 : 2259 – 67 . 10.1038/s41591-023-02528-9 37582952 PMC10504075

47 Nooka AK , Rodriguez C , Mateos MV , et al Incidence, timing, and management of infections in patients receiving teclistamab for the treatment of relapsed/refractory multiple myeloma in the MajesTEC-1 study . Cancer 2024 ; 130 : 886 – 900 . 10.1002/cncr.35107 37960969

48 Los-Arcos I , Aguilar-Company J , Ruiz-Camps I . Riesgo de infección asociada a nuevas terapias para el tratamiento de los síndromes linfoproliferativos . Med Clín 2020 ; 154 : 101 – 7 . 10.1016/j.medcli.2019.07.026 31771856

49 Maus MV , Alexander S , Bishop MR et al Society for immunotherapy of cancer (SITC) clinical practice guideline on immune effector cell-related adverse events . J Immunother Cancer 2020 ; 8 e001511 . 10.1136/jitc-2020-001511 33335028 PMC7745688

50 Bupha-Intr O , Haeusler G , Chee L et al CAR-T cell therapy and infection: a review . Expert Rev Anti Infect Ther 2021 ; 19 : 749 – 58 . 10.1080/14787210.2021.1855143 33249873

51 Hayden PJ , Roddie C , Bader P et al Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European society for blood and marrow transplantation (EBMT) and the joint accreditation committee of ISCT and EBMT (JACIE) and the European haematology association (EHA) . Ann Oncol 2022 ; 33 : 259 – 75 . 10.1016/j.annonc.2021.12.003 34923107

52 Ludwig H , Terpos E , Van De Donk N et al Prevention and management of adverse events during treatment with bispecific antibodies and CAR T cells in multiple myeloma: a consensus report of the European myeloma network . Lancet Oncol 2023 ; 24 : e255 – 69 . 10.1016/S1470-2045(23)00159-6 37269857

53 Rodriguez-Otero P , Usmani S , Cohen AD et al International myeloma working group immunotherapy committee consensus guidelines and recommendations for optimal use of T-cell-engaging bispecific antibodies in multiple myeloma . Lancet Oncol 2024 ; 25 : e205 – 16 . 10.1016/S1470-2045(24)00043-3 38697166

54 Alshammari F , Alrajhi AM , Howaidi J . Risk of infections in bispecific antibody therapy for multiple myeloma: a comprehensive review of literature . Hematology 2025 ; 30 2448898 . 10.1080/16078454.2024.2448898 39789980

55 Ghosh K , Ghosh K . Monoclonal antibodies used for management of hematological disorders . J Hematol Allied Sci 2021 ; 1 : 12 – 21 . 10.25259/JHAS_2_2021

56 Taylor RP , Lindorfer MA . Antibody-drug conjugate adverse effects can be understood and addressed based on immune complex clearance mechanisms . Blood 2024 ; 144 : 137 – 44 . 10.1182/blood.2024024442 38643493

57 Wu H , Fan X , Wu S et al Pharmacovigilance insights into antibody–drug conjugates: a multi-database analysis of adverse events in leukemia treatment . Expert Opin Drug Saf 2025 . 10.1080/14740338.2025.2521365 40522479

58 Candoni A , Piciocchi A , Fianchi L et al First report of the GIMEMA INO-first multicenter observational study analyzing infective and non-infective complications in patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with inotuzumab ozogamicin . Blood 2025 ; 146 5102 . 10.1182/blood-2025-5102

59 Fishman JA , Hogan JI , Maus MV . Inflammatory and infectious syndromes associated with cancer immunotherapies . Clin Infect Dis 2019 ; 69 : 909 – 20 . 10.1093/cid/ciy1025 30520987

60 Lamb MG , Rangarajan HG , Tullius BP et al Natural killer cell therapy for hematologic malignancies: successes, challenges, and the future . Stem Cell Res Ther 2021 ; 12 211 . 10.1186/s13287-021-02277-x 33766099 PMC7992329

61 Merino A , Maakaron J , Bachanova V . Advances in NK cell therapy for hematologic malignancies: NK source, persistence and tumor targeting . Blood Rev 2023 ; 60 101073 . 10.1016/j.blre.2023.101073 36959057 PMC10979648

62 Lin C , Horwitz ME , Rein LAM . Leveraging natural killer cell innate immunity against hematologic malignancies: from stem cell transplant to adoptive transfer and beyond . Int J Mol Sci 2023 ; 24 204 . 10.3390/ijms24010204 PMC9820370 36613644

63 Raje NS , Anaissie E , Kumar SK et al Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group . Lancet Haematol 2022 ; 9 : e143 – 61 . 10.1016/S2352-3026(21)00283-0 35114152

64 Kannan A , Jeffrey K , Misbah S et al Practical guidance on the prevention and management of infection in multiple myeloma patients: a case-based approach . Blood Rev 2025 ; 72 101287 . 10.1016/j.blre.2025.101287 40240231

65 Er AG , Aslan AT , Mikulska M et al Prevention and treatment of bacterial infections in patients with haematological cancers and haematopoietic stem cell transplantation: headways and shortcomings . Clin Microbiol Infect 2025 ; 31 : 24 – 8 . 10.1016/j.cmi.2024.09.015 39332598

66 Lehrnbecher T , Fisher BT , Phillips B et al Guideline for antibacterial prophylaxis administration in pediatric cancer and hematopoietic stem cell transplantation . Clin Infect Dis 2020 ; 71 : 226 – 36 . 10.1093/cid/ciz1082 31676904 PMC7312235

67 Baccelli F , Aguilar-Guisado M , Vidal CG et al Epidemiology of resistant bacterial infections in patients with hematological malignancies or undergoing hematopoietic cell transplantation in Europe: a systematic review by the European conference on infections in leukemia (ECIL) . J Infect 2025 ; 91 106571 . 10.1016/j.jinf.2025.106571 40812455

68 Albalawi MA , Al-Sayaghi KM , Hegazy SM et al Prophylactic fluoroquinolones in hematopoietic stem cell transplant recipients: a meta-analytic comparison of ciprofloxacin and levofloxacin . Medicine 2025 ; 104 e42317 . 10.1097/MD.0000000000042317 40355203 PMC12074066

69 Copeland V , McLaughlin M , Trifilio S . Ciprofloxacin vs levofloxacin for prophylaxis during hematopoietic stem-cell transplantation . Clin Transplant 2018 ; 32 e13145 . 10.1111/ctr.13145 29080369

70 Yemm KE , Barreto JN , Mara KC et al A comparison of levofloxacin and oral third-generation cephalosporins as antibacterial prophylaxis in acute leukaemia patients during chemotherapy-induced neutropenia . J Antimicrob Chemother 2018 ; 73 : 204 – 11 . 10.1093/jac/dkx338 29040595

71 Doan VP , Yeh JC , Gulbis AM , et al Levofloxacin versus cefpodoxime for antibacterial prophylaxis in allogeneic stem cell transplantation . Biol Blood Marrow Transplant 2019 ; 25 : 1637 – 41 . 10.1016/j.bbmt.2019.04.013 31002991

72 Wojenski DJ , Barreto JN , Wolf RC et al Cefpodoxime for antimicrobial prophylaxis in neutropenia: a retrospective case series . Clin Ther 2014 ; 36 : 976 – 81 . 10.1016/j.clinthera.2014.04.013 24832560

73 Egan G , Robinson PD , Martinez JP et al Efficacy of antibiotic prophylaxis in patients with cancer and hematopoietic stem cell transplantation recipients: a systematic review of randomized trials . Cancer Med 2019 ; 8 : 4536 – 46 . 10.1002/cam4.2395 31274245 PMC6712447

74 Preyra R , Eddin LE , Ahmadi F et al Safety of sulfamethoxazole–trimethoprim for the treatment of bacterial infection in outpatient settings: a systematic review and meta-analysis with active comparator disproportionality analysis . Br J Clin Pharmacol 2025 ; 91 : 1632 – 48 . 10.1002/bcp.70051 PMC12272531 40129122

75 Tverdek F , Escobar ZK , Liu C et al Antimicrobials in patients with hematologic malignancies and recipients of hematopoietic cell transplantation and other cellular therapies . Transpl Infect Dis 2023 ; 25 e14129 . 10.1111/tid.14129 37594221

76 Zapolskaya T , Perreault S , McManus D et al Utility of fosfomycin as antibacterial prophylaxis in patients with hematologic malignancies . Support Care Cancer 2018 ; 26 : 1979 – 83 . 10.1007/s00520-017-4040-x 29322242

77 Moreno AF , Lavín-Alconero L , de Ugarriza PL et al FOVOCIP study: a multicenter randomized trial of fosfomycin versus ciprofloxacin for febrile neutropenia in hematologic patients—efficacy and microbiologic safety . Trials 2023 ; 24 694 . 10.1186/s13063-023-07702-5 37891616 PMC10612155

78 Ehrlich S , Eufinger J , Tahiri N et al Infections during AML induction chemotherapy in a contemporary cohort without fluoroquinolone prophylaxis . Infection 2026 ; 54 : 243 – 52 . 10.1007/s15010-025-02651-4 41032191 PMC12864249

79 Satlin MJ , Chen L , Douglass C et al Colonization with fluoroquinolone-resistant enterobacterales decreases the effectiveness of fluoroquinolone prophylaxis in hematopoietic cell transplant recipients . Clin Infect Dis 2021 ; 73 : 1257 – 65 . 10.1093/cid/ciab404 33956965 PMC8492119