Abstract
The role of antibacterial prophylaxis in non-Hodgkin lymphoma (NHL) patients undergoing Rituximab-Cyclophosphamide-Doxorubicin-Vincristine-Prednisolone (R-CHOP) chemotherapy with granulocyte-colony stimulating factor (G-CSF) support remains uncertain. This study evaluates the efficacy of levofloxacin in preventing febrile episodes in these patients. A randomized, single-blind, placebo-controlled trial was conducted, enrolling NHL patients receiving R-CHOP every 21-day cycle between January 2023 and June 2024. Patients were randomized to receive levofloxacin 500 mg once daily or placebo from day 1 to day 7 post-chemotherapy. All patients received G-CSF support. The primary outcome was the occurrence of febrile episodes within 120 days. Eighty participants were equally randomized into two groups. The median age was 64 years. In the intention-to-treat analysis, the first febrile episode was documented in 3 (7.5%) and 12 (30%) participants in the levofloxacin and placebo groups, respectively (P = 0.010). Levofloxacin prophylaxis significantly reduced febrile neutropenia (2.5% vs. 20%, P = 0.029) and the composite of febrile episodes, septic shock, all-cause mortality and chemotherapy dose reduction (10% vs. 30%, P = 0.025). The hazard ratio (HR) for fever-free survival with levofloxacin prophylaxis was 0.23 (95% CI 0.06–0.80; P = 0.012). Multivariate analysis showed levofloxacin was associated with a lower risk of febrile episodes (adjusted HR 0.17, 95% CI, 0.05–0.66; P = 0.01). No differences in mortality or serious adverse events were observed. Levofloxacin prophylaxis is an effective, well-tolerated strategy to reduce febrile episodes, febrile neutropenia and composite adverse outcomes after R-CHOP chemotherapy, despite concurrent G-CSF support. Long-term antibiotic resistance monitoring is warranted.
Trial registration: This trial is registered at Thai Clinical Trials Registry (TCTR), number TCTR20230719005.
Keywords: Levofloxacin, Prophylaxis, Febrile episode, Non-Hodgkin lymphoma, R-CHOP
Subject terms: Medical research, Oncology
Introduction
Non-Hodgkin lymphoma (NHL) comprises a heterogeneous group of lymphoid malignancies characterized by the abnormal proliferation of lymphocytes. Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of newly diagnosed NHL cases1–3. The combination of rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone, administered every 21-day cycle (R-CHOP-21), has been the cornerstone of DLBCL treatment for over two decades4,5. Despite its notable efficacy, R-CHOP-21 is associated with a significant risk of febrile episodes, neutropenia and infectious complications, which can adversely affect patient outcomes, including increased hospitalization rates, infection-related morbidity and mortality, and interruption or dose reductions in chemotherapy6–11.
Current guidelines recommend primary granulocyte-colony stimulating factor (G-CSF) prophylaxis for chemotherapy regimens with a febrile neutropenia risk of ≥ 20%. R-CHOP-21 is generally classified as an intermediate-risk regimen, with a 10–20% risk of febrile neutropenia. Therefore, the decision to provide G-CSF prophylaxis after R-CHOP-21 is often based on individual patient risk factors for febrile neutropenia12–14. However, in clinical practice, the incidence of febrile neutropenia after R-CHOP-21 in real clinical practice ranges from 13% to 41%, even with G-CSF prophylaxis used in up to half of patients6–11. At our institution, the rate of febrile neutropenia among patients receiving G-CSF support was 26.7%11. These findings highlight the need for more effective strategies to mitigate the risk of febrile neutropenia and optimize the overall success of NHL treatment.
The role of antibacterial prophylaxis following R-CHOP chemotherapy remains uncertain, particular in patients receiving concurrent G-CSF support, due to the lack of harmonized recommendations15–19. Previous studies, including a meta-analysis, have suggested that fluoroquinolones effectively prevent bacterial infections in neutropenic patients following chemotherapy, significantly reducing febrile episodes, all-cause mortality and infection-related mortality20–24. However, these studies excluded patients receiving routine G-CSF support23,24. Thus, the benefits of quinolone prophylaxis in patients receiving concurrent G-CSF support remain unclear. Furthermore, most of the patients in these studies had solid tumors, with only approximately 10% having lymphoma and receiving CHOP-based chemotherapy24. The efficacy of levofloxacin in preventing febrile neutropenia within this specific subgroup was either not reported or inadequately defined. To date, no randomized controlled trials have specifically evaluated the efficacy of antibacterial prophylaxis in NHL patients undergoing R-CHOP-21, particularly those receiving concurrent G-CSF support. Concerns also persist regarding potential side effects and the emergence of quinolone-resistant bacteria20–22.
To address these uncertainties, we conducted a single-blind, randomized controlled trial to evaluate the efficacy of levofloxacin, an extended-spectrum fluoroquinolone with activity against both Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa. The trial focused on preventing febrile episodes in NHL patients receiving R-CHOP-21 chemotherapy with universal G-CSF support.
Methods
Trial design and oversight
We conducted a randomized, single-blind, placebo-controlled trial at King Chulalongkorn Memorial Hospital in Bangkok, Thailand, from January 1, 2023, to June 30, 2024. The study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University (IRB No. 0788/65) and adhered to the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants. The trial was registered with the Thai Clinical Trials Registry (TCTR20230719005) on 19/07/2023 and funded by the Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University.
Patients
Eligible patients were adults aged 18 years or older who were newly diagnosed with NHL and scheduled to receive R-CHOP chemotherapy every 21 days. All participants underwent screening prior to randomization. Exclusion criteria included active infection or documented fever (core temperature ≥ 38 °C), a history of fluoroquinolone allergy, epilepsy, QT prolongation, prior serious adverse events related to fluoroquinolones, inability to adhere to follow-up protocols, recent antibiotic use within 5 days before enrollment and pregnancy.
Randomization and treatments
Patients were randomly assigned in a 1:1 ratio to receive either levofloxacin 500 mg once daily, administered at least 30 min before a meal or a matching placebo for 7 days, beginning one day after chemotherapy. This timing was chosen to coincide with the period of early mucosal barrier disruption and initial neutrophil decline, during which bacterial translocation commonly occurs. A 7-day course was selected to target this high-risk window while minimizing antibiotic exposure, in accordance with antimicrobial stewardship principles. The randomization process utilized a block size of 4. Both patients and the hematologists overseeing chemotherapy and patient care were blinded to the treatment allocation. Neither was aware of whether the patient was receiving levofloxacin or placebo during the study period. The investigator, who conducted the statistical analysis, was unblinded to the treatment assignment; however, the investigator had no direct involvement in the clinical management of patients or decisions related to chemotherapy administration.
All patients were scheduled to undergo R-CHOP treatment in six 21-day cycles. The R-CHOP therapeutic protocol consisted of intravenous rituximab (375 mg/m2), vincristine (1.4 mg/m2, with a maximum dose of 2 mg), cyclophosphamide (750 mg/m2) and doxorubicin (50 mg/m2) administered on Day 1, along with prednisolone at a dosage of 100 mg/day for 5 consecutive days. In this clinical trial, G-CSF support was administered routinely to all participants. The type of G-CSF used was at the discretion of the primary physicians. Filgrastim was administered for 7 days, starting 24 h after cytotoxic chemotherapy, while pegfilgrastim was administered as a single dose, starting 24 h after chemotherapy. Prophylaxis for varicella zoster reactivation using acyclovir and Pneumocystis jiroveci pneumonia (PJP) using sulfamethoxazole-trimethoprim were routinely provided to all participants unless there was a history of allergy to these medications.
Randomized subjects were provided with a standardized thermometer to record their daily temperatures, and participant were monitored for 120 days from enrollment.
Outcomes
The primary endpoint was the occurrence of the first febrile episodes, defined by an axillary temperature of ≥ 38.3 °C once or ≥ 38.0 °C sustained for more than 1 h, as well as fever-free survival. Secondary endpoints included febrile neutropenia-free survival, defined as the time from randomization to the first episode of febrile neutropenia (fever accompanied by an absolute neutrophil count [ANC] < 500/µL or < 1000/µL with a decreasing trend)19, the rate of febrile neutropenia, septic shock, infection-related mortality, all-cause mortality, chemotherapy dose reduction rate and relative dose intensity. The onset of the initial febrile episode and a composite outcome consisting of febrile episodes, septic shock, all-cause mortality and chemotherapy dose reduction were also assessed. Additional secondary outcomes included hospitalization rates, microbiological findings and safety profiles. Upon diagnosis of infection, patients underwent comprehensive assessment and treatment in accordance with clinical findings and local protocols. Chemotherapy dose adjustments were made at the discretion of the primary physician. Detailed definitions and criteria for these outcomes are provided in the supplementary protocol.
Statistical analysis
Power calculations were conducted using Freedman’s method25, with assumptions based on survival probabilities derived from the cumulative likelihood of a febrile episode occurring over six cycles of R-CHOP in the control group (65%). This implies febrile episode-free survival probabilities of 0.3. The estimation of probabilities and sample sizes aimed at achieving a hazard ratio of 0.36, reflecting a 64% reduction in the risk of febrile episodes in the levofloxacin arm compared to the control arm. We anticipated that a sample size of 72 patients would provide the trial with 80% power at a 2-sided significance level of 5%, accounting for a 5% withdrawal rate. All efficacy endpoints were assessed on an intention-to-treat basis.
Categorical data were presented as numbers and percentages, while continuous variables were presented as means (± standard deviation, SD) or medians with interquartile ranges (IQR), as appropriate. Chi-square or Fisher exact tests were applied to compare differences between groups for categorical data. Survival analysis was performed using the Kaplan-Meier method and compared using the log-rank test. Potential influential factors for febrile episodes were analyzed through univariate analysis, and multivariate analysis was conducted using the Cox proportional hazards model. A p-value of < 0.05 was considered statistically significant. All analyses were conducted using IBM SPSS Statistics version 29.0 (Chicago, SPSS Inc.).
Results
Enrollment and baseline characteristics
Between January 2023 and June 2024, a total of 86 participants were screened, of whom 80 were randomized, with 40 assigned to each group. Reasons for screening failure included 5 patients with documented fever and recent antibiotic use within the previous 5 days, and one patient who declined to participate. The intention-to-treat analysis included all 80 randomized participants (Fig. 1). All participants were followed for 120 days from enrollment, with the data cutoff date on August 31, 2024.
Fig. 1.
Consort diagram shows study enrolment and outcome.
The demographic and clinical characteristics of the participants were generally well balanced between the treatment groups, except for a significantly higher proportion of males in the placebo group (Table 1). The median age was 64 years (IQR, 54.5–70.5), and 57.5% had advanced-stage disease (Ann Arbor stage III-IV). A pathological subtype of DLBCL was identified in 90% of participants. The levofloxacin group included a non-significantly higher proportion of patients with advanced-stage disease and elevated IPI scores, whereas the placebo group had a greater proportion of patients with bone marrow involvement. Baseline neutrophil counts prior to chemotherapy were comparable between the groups. The proportion of participants receiving pegfilgrastim was higher in the levofloxacin group; however, there were no statistically significant differences in the type of G-CSF used between the two groups.
Table 1.
Baseline characteristics of enrolled participants.
| Total (N = 80) |
Levofloxacin (N = 40) |
Placebo (N = 40) |
p-value | |
|---|---|---|---|---|
| Age (years), median (IQR) |
64 (54.5, 70.5) |
65.5 (55, 71) |
64 (53.5, 69) |
0.668 |
| Sex | ||||
| Male, N (%) | 35 (43.8%) | 13 (32.5%) | 22 (55%) | 0.043 |
| Female, N (%) | 45 (56.3%) | 27 (67.5%) | 18 (45%) | |
| BMI (kg/m2), mean ± SD | 22.79 ± 2.88 | 22.83 ± 2.83 | 22.75 ± 2.96 | 0.894 |
| BSA (m2), mean ± SD | 1.60 ± 0.18 | 1.57 ± 0.16 | 1.63 ± 0.19 | 0.105 |
| Comorbidities | ||||
| Diabetes mellitus, N (%) | 7 (8.8%) | 3 (7.5%) | 4 (10%) | 1 |
| Hypertension, N (%) | 17 (21.3%) | 8 (20%) | 9 (22.5%) | 0.785 |
| Chronic kidney disease, N (%) | 2 (2.5%) | 1 (2.5%) | 1 (2.5%) | 1 |
| Chronic liver disease, N (%) | 1 (1.3%) | 0 (0%) | 1 (2.5%) | 1 |
| HIV infection, N (%) | 1 (1.3%) | 0 (0%) | 1 (2.5%) | 1 |
| Others, N (%) | 10 (12.5%) | 4 (10%) | 6 (15%) | 0.499 |
| Performance status (ECOG) | ||||
| 0–1, N (%) | 75 (93.8%) | 36 (90%) | 39 (97.5%) | 0.359 |
| 2–4, N (%) | 5 (6.3%) | 4 (10%) | 1 (2.5%) | |
| Pathological subtype | ||||
| DLBCL, N (%) | 72 (90%) | 36 (90%) | 36 (90%) | 0.766 |
| Follicular lymphoma, N (%) | 5 (6.3%) | 3 (7.5%) | 2 (5%) | |
| Other, N (%) | 3 (3.8%) | 1 (2.5%) | 2 (5%) | |
| Ann Arbor stage | ||||
| 1–2, N (%) | 34 (42.5%) | 14 (35%) | 20 (50%) | 0.175 |
| 3–4, N (%) | 46 (57.5%) | 26 (65%) | 20 (50%) | |
| IPI score | ||||
| 0–2, N (%) | 44 (55%) | 20 (50%) | 24 (60%) | 0.369 |
| 3–5, N (%) | 36 (45%) | 20 (50%) | 16 (40%) | |
| BM involvement, N (%) | 9 (11.3%) | 2 (5%) | 7 (17.5%) | 0.154 |
| Baseline neutrophil count (x106/L) before R-CHOP, median (IQR) |
4555 (3195, 5820) |
4620 (3370, 5835) |
4520 (2960, 5820) |
0.551 |
| Types of G-CSF | ||||
| Filgastrim, N (%) | 51 (63.75%) | 22 (55%) | 29 (72.5%) | 0.104 |
| Pegfilgastrim, N (%) | 29 (36.25%) | 18 (45%) | 11 (27.5%) | |
| VZV prophylaxis, N (%) | 80 (100%) | 40 (100%) | 40 (100%) | 1 |
| PJP prophylaxis, N (%) | 79 (98.75%) | 40 (100%) | 39 (97.5%) | 1 |
IQR interquartile range, G-CSF granulocyte-colony stimulating factor, PJP Pneumocystis jiroveci pneumonia, VZV varicella zoster virus.
Primary outcome
In the intention-to-treat analysis, the first febrile episode was documented in 3 participants (7.5%) in the levofloxacin group and 12 participants (30%) in the placebo group (P = 0.010). Most initial febrile episodes occurred during the first cycle of R-CHOP chemotherapy. Fever-free survival was significantly improved in the levofloxacin group, with a hazard ratio (HR) of 0.23 (95% confidence interval [CI], 0.06 to 0.80; P = 0.012 by log-rank test) (Fig. 2A).
Fig. 2.
Kaplan-Meier survival estimates of fever-free survival (a) and febrile neutropenia-free survival (b) during the 120-day trial. The hazard ratio for febrile events in the levofloxacin group versus the placebo group was 0.23 (95% CI: 0.06 to 0.80), with a statistically significant difference between the two groups (log-rank test, P = 0.012). The hazard ratio for febrile neutropenia in the levofloxacin group versus the placebo group was 0.11 (95% CI: 0.01 to 0.91), with a statistically significant difference between the two groups (log-rank test, P = 0.013).
Secondary outcomes
Levofloxacin prophylaxis significantly reduced the incidence of febrile neutropenia compared to placebo (1 of 40 [2.5%] vs. 8 of 40 [20%], P = 0.029). Febrile neutropenia-free survival was significantly higher in the levofloxacin group, with a HR of 0.11 (95% CI, 0.01 to 0.91; P = 0.013) (Fig. 2B). Levofloxacin maintained a higher relative dose intensity of chemotherapy (99.59 ± 2.53 vs. 96.05 ± 8.77, P = 0.023) and significantly reduced the composite outcome of febrile episodes, septic shock, all-cause mortality and chemotherapy dose reduction (4 of 40 [10%] vs. 12 of 40 [30%], P = 0.025) (Table 2). Among the 15 patients who experienced a febrile episode, 13 (86.7%) underwent complete blood count (CBC) testing at the onset of fever. Of these, 9 patients met the diagnostic criteria for febrile neutropenia.
Table 2.
Efficacy outcomes.
| Levofloxacin (n = 40) | Placebo (n = 40) |
p-value | |
|---|---|---|---|
| Febrile episode, n (%) | 3 (7.5%) | 12 (30%) | 0.010 |
| Cycle of initial febrile episode, n (%) | |||
| 1 | 1 (2.5%) | 5 (12.5%) | |
| 2 | 1 (2.5%) | 2 (5%) | |
| 3 | 0 (0%) | 2 (5%) | |
| 4 | 1 (2.5%) | 0 (0%) | |
| 5 | 0 (0%) | 3 (7.5%) | |
| 6 | 0 (0%) | 0 (0%) | |
| Febrile neutropenia, n (%) | 1 (2.5%) | 8 (20%) | 0.029 |
| Hospitalization, n (%) | 3 (7.5%) | 9 (22.5%) | 0.116 |
| Septic shock, n (%) | 1 (2.5%) | 4 (10%) | 0.06 |
| Infection-related mortality, n (%) | 0 (0%) | 1 (2.5%) | 0.359 |
| All-cause mortality, n (%) | 2 (5%) | 1 (2.5%) | 1 |
| Chemotherapy dose reduction, n (%) | 0 (0%) | 5 (12.5%) | 1 |
| Relative dose intensity,1 mean ± SD | 99.59 ± 2.53 | 96.05 ± 8.77 | 0.055 |
| Composite of febrile episodes, septic shock, all-cause mortality, chemotherapy dose reduction, n (%) | 4 (10%) | 12 (30%) | 0.023 |
1Relative dose intensity was calculated based on the total administered dose of doxorubicin.
The reduction in febrile episodes associated with levofloxacin prophylaxis also led to decreased rates of chemotherapy dose reduction (0 of 40 [0%] vs. 5 of 40 [12.5%], P = 0.055), hospitalization (3 of 40 [7.5%] vs. 9 of 40 [22.5%], P = 0.06), septic shock (1 of 40 [2.5%] vs. 4 of 40 [10%], P = 0.359) and infection-related mortality (0 of 40 [0%] vs. 1 of 40 [2.5%], P = 1.0); however, these reductions were not statistically significant (Table 2). All-cause mortality (2 of 40 [5%] vs. 1 of 40 [2.5%], P = 1.0) did not differ significantly between the two groups. In the levofloxacin group, two deaths were attributed to progressive disease, whereas in the placebo group, one death resulted from sepsis.
Microbiological outcomes
Among patients with febrile episodes, microbiologically documented infections were identified in 1 of 3 patients (33.3%) in the levofloxacin group and 8 of 12 patients (66.7%) in the placebo group (Table 3). Gram-negative bacteria remained the predominant bacterial pathogens identified in this cohort. Notably, no quinolone resistance was detected in any of the 4 patients with documented bacterial infections. In the levofloxacin group, a single case of urinary tract infection caused by Klebsiella pneumoniae was observed among the 3 febrile episodes. In the placebo group, two Gram-negative infections and one Gram-positive infection were documented. Among the 12 febrile episodes in the placebo group, 4 were attributed to COVID-19. Additionally, one case of PJP occurred in a patient who had not received PJP prophylaxis due to a known sulfa allergy.
Table 3.
Microbiological outcomes.
| Levofloxacin (N = 3) |
Placebo (N = 12) |
|
|---|---|---|
| Microbiological documented infection, n (%) | 1 (33.3%) | 8 (66.7%) |
| Bacteria | ||
| Gram negative pathogen | 1 (33.3%) | 2 (16.7%) |
| Gram positive pathogen | 0 | 1 (8.3%) |
| Polymicrobial | 0 | 0 |
| Fungus | ||
| Pneumocystis jiroveci | 0 | 1 (8.3%) |
| Virus | ||
| SARS-CoV-2 | 0 | 4 (33.3%) |
Factors associated with febrile episodes
A univariate analysis demonstrated that a high IPI of 3–5 was associated with an increased risk of febrile episodes (HR 3.89, 95% CI, 1.24 to 12.21; P = 0.02). Conversely, levofloxacin prophylaxis was associated with a reduced risk of febrile episodes (HR 0.23, 95% CI, 0.06 to 0.8; P = 0.021). In a multivariate Cox regression analysis, a high IPI remained a significant factor associated with an increased risk of febrile episodes (adjusted HR 10.45, 95% CI, 1.15 to 94.47; P = 0.037), while levofloxacin prophylaxis continued to be significantly associated with a reduced risk (adjusted HR 0.17, 95% CI, 0.05 to 0.66; P = 0.01) (Table 4).
Table 4.
Univariate and multivariate Cox regression for febrile episodes.
| Univariate | Multivariate | |||
|---|---|---|---|---|
| HR (95%CI) | p-value | Adjusted HR (95%CI) | p-value | |
| Age | ||||
| < 65 | Reference | 1 | Reference | 1 |
| ≥ 65 | 0.97 (0.35, 2.67) | 0.948 | 0.62 (0.19, 2.04) | 0.434 |
| Performance status (ECOG) | ||||
| 0–1 | Reference | 1 | Reference | 1 |
| 2–4 | 2.87 (0.65, 12.74) | 0.165 | 2.89 (0.53, 15.74) | 0.22 |
| Ann Arbor stage | ||||
| 1–2 | Reference | 1 | Reference | 1 |
| 3–4 | 2.19 (0.7, 6.87) | 0.18 | 0.51 (0.05, 4.75) | 0.553 |
| IPI score | ||||
| 0–2 | Reference | 1 | Reference | 1 |
| 3–5 | 3.89 (1.24, 12.21) | 0.02* | 10.45 (1.15, 94.47) | 0.037* |
| BM involvement | ||||
| No | Reference | 1 | Reference | 1 |
| Yes | 2.1 (0.59, 7.45) | 0.251 | 0.67 (0.14, 3.22) | 0.615 |
| Baseline absolute neutrophil count (x106/L) | ||||
| < 3000 | Reference | 1 | Reference | 1 |
| ≥ 3000 | 1.02 (0.29, 3.61) | 0.978 | 0.66 (0.16, 2.72) | 0.561 |
| Antimicrobial prophylaxis | ||||
| Placebo | Reference | 1 | Reference | 1 |
| Levofloxacin | 0.23 (0.06, 0.8) | 0.021* | 0.17 (0.05, 0.66) | 0.01* |
Safety outcome
Mild gastrointestinal symptoms were reported in 3 patients (7.5%) in the levofloxacin group, all of which were grade 1 in severity. No such symptoms were reported in the placebo group. No unexpected adverse events were observed.
Discussion
Several cohorts, including our hospital, have demonstrated that the rate of febrile neutropenia after R-CHOP treatment remains over 20%, even with concurrent G-CSF support8–11. This underscores the need for an effective strategy to reduce the risk of febrile neutropenia following R-CHOP chemotherapy.
In this single-center, randomized controlled trial, we evaluated the effectiveness of levofloxacin prophylaxis in preventing febrile episodes in NHL patients undergoing R-CHOP chemotherapy with routine G-CSF support. The selection of clinically documented febrile episodes as the primary outcome was based on the recognition that infections can occur without neutropenia after chemotherapy. Levofloxacin, a broad-spectrum antibiotic with potent activity against both Gram-positive and Gram-negative bacteria, offers the potential to prevent febrile illnesses post-chemotherapy, regardless of neutrophil counts. The study population consisted of NHL patients with a median age of 64 years, predominantly diagnosed with DLBCL, reflecting the epidemiological characteristics commonly observed in clinical practice1–3. The rate of febrile neutropenia in patients receiving concurrent G-CSF support without levofloxacin was 20%, consistent with our previous report11. This result reaffirms that primary G-CSF support alone is insufficient to prevent febrile neutropenia in NHL patients undergoing R-CHOP chemotherapy.
Our study demonstrated that levofloxacin prophylaxis was highly effective in significantly reducing febrile episodes and febrile neutropenia. Notably, levofloxacin prophylaxis decreased the incidence of febrile episodes from 30% to 7.5% and febrile neutropenia from 20% to 2.5%. Survival analysis showed a 77% reduction in the rate of febrile episodes and an 89% reduction in the rate of febrile neutropenia. Furthermore, levofloxacin prophylaxis maintained chemotherapy intensity and showed a trend toward reducing chemotherapy dose reduction, hospitalization, septic shock and infection-related mortality. These findings highlight the potential benefits of levofloxacin prophylaxis in improving clinical outcomes and reducing the burden on healthcare resources.
Importantly, prophylaxis was initiated on day 1 following chemotherapy and limited to 7 days to coincide with the anticipated onset of mucosal barrier injury and the early phase of neutrophil decline—periods during which bacterial translocation is most likely to occur. As supported by the SIGNIFICANT trial24, targeting this early neutropenic window is sufficient to reduce systemic pathogen burden and subsequent infectious complications. Although neutropenia frequently extends beyond Day 8, the efficacy of this regimen is attributed to its preemptive mitigation of early microbial translocation. Furthermore, the abbreviated course supports antimicrobial stewardship principles by limiting unnecessary antibiotic exposure and reducing the selective pressure for fluoroquinolone resistance.
In this study, all NHL patients treated with R-CHOP received routine primary G-CSF support. Additionally, PJP prophylaxis using trimethoprim/sulfamethoxazole was routinely prescribed for all included patients. Multiple Cox regression analysis identified levofloxacin prophylaxis as the only independent factor associated with preventing febrile episodes. Other factors, including age, performance status, disease stage, bone marrow involvement and baseline neutrophil counts, were not significantly associated with the development of febrile episodes. This finding underscores the robust effectiveness of levofloxacin prophylaxis in preventing febrile episodes in NHL patients treated with R-CHOP and concurrent G-CSF support.
Safety outcomes from this trial were favorable, with only mild gastrointestinal symptoms reported by a small proportion of patients in the levofloxacin group. Importantly, no unexpected adverse events were observed, supporting the overall safety profile of levofloxacin in this clinical setting.
The significant benefit of levofloxacin prophylaxis in preventing febrile episodes without causing serious adverse events must be carefully weighed against the risk of developing antibiotic resistance. In this context, local fluoroquinolone resistance patterns are critical for assessing the broader applicability of our findings. Data from the National Antimicrobial Resistance Surveillance Center (NARST), Thailand, based on isolates from 68 sentinel hospitals in 2022, reported fluoroquinolone resistance rates of 39% in Escherichia coli, 53.7% in Klebsiella pneumoniae and 71.9% in Pseudomonas aeruginosa26. These rates reflect a substantial baseline resistance burden that may limit generalizability to regions with similar or higher resistance profiles. Notably, no fluoroquinolone-resistant bacteria were identified among the 4 patients with documented bacterial infections in this cohort, suggesting that short-course prophylaxis may remain clinically beneficial even in settings with moderate resistance prevalence. A breakthrough urinary tract infection caused by fluoroquinolone-sensitive Klebsiella pneumoniae occurred in one patient in the levofloxacin group during the first cycle of R-CHOP. This infection was likely due to preexisting bacterial colonization prior to the initiation of prophylaxis and may have been influenced by the patient’s history of neurogenic bladder.
Interestingly, 4 cases of SARS-CoV-2 infection were documented exclusively in the placebo group. Although this finding may be attributable to chance given the small sample size, it raises the intriguing possibility that levofloxacin could have antiviral properties, potentially inhibiting SARS-CoV-2 cell entry and replication, as suggested by in vitro studies27,28. Further research is warranted to explore this potential antiviral effect and its clinical applications.
While the findings of this study are promising, several limitations must be acknowledged. The relatively small sample size and the specific characteristics of the study population may limit the generalizability of the results to a broader patient population. Furthermore, the small number of isolated pathogens and the short duration of follow-up may hinder the ability to effectively monitor the emergence of drug-resistant bacteria. These limitations highlight the need for extended follow-up and continuous surveillance if levofloxacin prophylaxis is to be widely implemented in clinical practice.
Conclusion
Levofloxacin prophylaxis is an effective and well-tolerated strategy for reducing the incidence of febrile episodes and febrile neutropenia while maintaining chemotherapy intensity in NHL patients undergoing R-CHOP chemotherapy with concurrent G-CSF support. These findings complement previous research on antibiotic prophylaxis in hematologic malignancies and provide a foundation for evidence-based strategies to mitigate the risk of infections during neutropenia in NHL patients. By addressing a critical gap in infection prevention, levofloxacin prophylaxis has the potential to enhance clinical outcomes, reduce healthcare resource utilization and improve the overall management of febrile episodes in this high-risk population.
Acknowledgements
The authors would like to thank Prof. Stephen John Kerr from the Research Affairs, Faculty of Medicine, Chulalongkorn University, for his assistance with the statistical analysis.
Author contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Mutita Surakijboworn and Noppacharn Uaprasert. The first draft of the manuscript was written by Mutita Surakijboworn and was edited by Chantana Polprasert, Kitsada Wudhikarn, Ponlapat Rojnuckarin and Noppacharn Uaprasert. All authors read and approved the final manuscript.
Funding
Grant support for this research was received from the Ratchadapiseksompotch Research Affairs, Faculty of Medicine, Chulalongkorn University. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Data availability
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.
Declarations
Competing interests
The authors declare no competing interests.
Ethics approval
The study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University (IRB No. 0788/65) and adhered to the principles of the Declaration of Helsinki.
Consent to participate
Written informed consent was obtained from all participants.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.