Chimeric Antigen Receptor T-cell (CAR T-cell) therapy, an innovative form of immunotherapy is becoming the cornerstone of treatment for patients with relapsed and refractory hematologic malignancies such as leukemia, lymphoma, and multiple myeloma [1]. Despite the promises recorded, factors such as early infusion fevers, overlapping inflammatory toxicities and prolonged immune deficits threaten their continued use for treatment [2]. At the end, the physician is faced with a decision; to treat the malignancy (protect the patient) or deal with the consequences of the treatment: confront the case of antimicrobial resistance and microbiome disruption created by the treatment.

The first month after CAR T-cells infusion is the period most frequently associated with infections (Figure 1). In their work, Wittmann Dayagi et al. [3] documented 36 infections out of 88 patients treated with CD28-based CD19 CAR T-cells. Reduced neutrophil count (Neutropenia) and lack of response were cited as major risk factors associated with CAR T-cell treatment. Similarly, Mikkilineni et al. [4] reported that, 32.7% of patients across five trial studies developed infections within 30 days, with bacteremia and bacterial site infections predominating as potential risk factors. The study of Beyar-Katz et al. [5] also observed infections in 45% of the patients with diffuse large B-cell lymphoma, while Garcia-Pouton et al. [6] documented 77 infections among 91 adults. Chimeric Release Syndrome resulting from rapid and massive activation of immune cells has been reported to complicate diagnosis, yet studies by Ng et al . [7] reports that despite the low bacteremia (2.7%) and CRS recorded among patients, they were still given empiric antibiotics. Based on these observations, it has been suggested that biomarkers including C-Reactive Protein (CRP), D-dimer, and ferritin could offer moderate level of discrimination beyond 14 days for monitoring infection and inflammation.

Immune suppression has been reported to persist beyond the acute phase. In their study, Cheng et al. [8] demonstrated that patients with multiple myeloma that received CAR T-cell infusion experienced prolonged CD4⁺ T-cell deficiency and late infections, particularly in bacteremia. In another study, Portuguese et al. [9] showed that, extramedullary disease (EMD) was linked to higher toxicity, prolonged neutropenia, increased bacteremia, and worse survival while Masih et al. [10] reported on the convergence of serious bacterial infections with HLH-like CRS in pediatric patients, underscoring the complexity of overlapping toxicities.

Patients on CAR T-cell therapy are vulnerable to immune suppression and infection, often necessitating antibiotic use. In their review of continuous versus intermittent beta-lactam infusion, Alawyia et al. [11], reported the benefits of extended infusion in sepsis and Febrile Neutropenia (FN) with Mizuno et al. [12] emphasizing adherence to febrile neutropenia (FN) guidelines for better outcome. On the contrary, Lucena et al., [13] reported that cutting back on the use of broad-spectrum antibiotics reduces unnecessary exposure without compromising clinical outcomes. Additionally, studies by Malard and Mohty [14] argued that the use of broad-spectrum antibiotics may impair the efficacy of CAR T-cell therapy, due to the ability of the drugs to disrupt the gut microbiome. Therefore, for effective outcome, only clinically stable patients should be recommended for CAR T-cell therapy while patients already receiving treatment should be managed to mitigate risk of infection [15,16].

The rise in number of antibiotic resistances especially, Extended Spectrum Beta-Lactamase (ESBL) producing and carbapenem resistant gram-negative bacteria, poses a serious global threat to wellbeing of individuals [17]. Fluoroquinolone prophylaxis has been proven to reduce bloodstream infections in immunocompromised patients such as those on CAR T-cell therapy. However, their continuous use increases the risk of resistance, with experts suggesting the selective use of the treatment based on individual assessment. Consequently, Kampouri et al. [18] calls for a harmonized practice involving variation in the use of antibiotics and monitoring across centers.

Microbiome dysregulation is implicated as a risk factor in CAR T-cell therapy. The presence of gut dominant bacteria such as Lactobacillus rhamnosus in the bloodstream indicates their potential role in infection risk [19]. CAR T-cell manufacturing process has also been implicated as a source of infection risk, with a study by Ayala et al. [20] reporting rapid detection of microbial contaminants during CAR T-cell manufacturing. Therefore, experts advise that infection prevention is key to optimizing CAR T cell therapy outcomes. Emerging microbiome focused trials suggest that antibiotic disruption of the microbiome impairs immune recovery and efficacy of CAR T cell therapy.

Novel CAR T cell therapies targeting antigens beyond CD19, B-cell malignancies and natural killer (NK)-based-therapies, offer new treatment options for the management of refractory malignant cancers due to their ability to affect the immune system differently and potentially introduce new risks of infection [21,22]. To that end, the European Society of Blood and Marrow Transplant (EBMT) recommends the harmonization of supportive care, with precision medicine approach promising a refined stewardship and infection prevention [23].

Infections are a frequent ongoing concern after CAR T cell therapy that are influenced by patients’ health status, immune recovery and how antibiotic are used by the patient. Antibiotics use should be highly regulated to avoid risk of resistance development by the organism and protect the gut microbiome. Future strategies including integration of biomarker-guided diagnostics to detect infections more precisely, harmonized prophylaxis (standardized preventive treatments), and microbiome-awareness to protect and preserve beneficial bacteria, thereby optimizing both safety and efficacy.