Fluoroquinolone Prophylaxis Remains Effective in Transplant Patients Despite High Resistance Rates

Could Fluoroquinolone Prophylaxis Enhance HCT Outcomes Amidst High Resistance?

In a healthcare landscape increasingly challenged by antimicrobial resistance, a recent study from Lebanon provides valuable insights into the effectiveness of fluoroquinolone (FQ) prophylaxis among hematopoietic cell transplantation (HCT) recipients, even in settings with high endemic resistance. The research, conducted at the Middle East Institute of Health between 2017 and 2022, examined 156 adult patients undergoing autologous or allogeneic stem cell transplantation, with particular attention to the impact of FQ prophylaxis on neutropenic fever and pre-engraftment bacteremia in patients with and without baseline colonization by fluoroquinolone-resistant Enterobacterales (FQRE).

The study reveals strikingly high baseline colonization rates, with nearly 40% of patients testing positive for FQRE and 50% for third-generation cephalosporin-resistant Enterobacterales (3GCRE) on admission screening. These figures substantially exceed previously reported rates from studies in the United States (23%) and Japan (16%), reflecting the endemic nature of antimicrobial resistance in the region. Despite this challenging backdrop, FQ prophylaxis demonstrated noteworthy benefits. Among patients receiving levofloxacin prophylaxis (73.1% of the cohort), there was a significant reduction in the frequency of neutropenic fever (80.7% versus 100% in the non-prophylaxis group) and a delay in fever onset (median 3 days versus 1.5 days). Kaplan-Meier analysis confirmed this protective effect with a hazard ratio of 0.47 (p<0.001), indicating that prophylaxis halved the risk of early febrile episodes.

Does Colonization Alter the Impact of FQ Prophylaxis?

Perhaps most intriguing was the finding that FQ prophylaxis retained efficacy even in patients already colonized with FQRE. While the magnitude of protection was somewhat attenuated in this subgroup, prophylaxis still reduced the likelihood of fever with comparable hazard ratios in both FQRE-positive (HR: 0.35) and FQRE-negative patients (HR: 0.42). This challenges the notion that prior colonization with resistant organisms necessarily negates the clinical utility of prophylaxis. Similar patterns emerged for pre-engraftment bacteremia, which occurred in 39.1% of evaluable patients. Those receiving prophylaxis experienced lower bacteremia rates (35.7% versus 62.5%) and delayed onset (median 6.5 days versus 2 days), with a significant reduction confirmed by survival analysis (HR: 0.31, p=0.02). Again, the protective effect extended to FQRE-colonized patients, albeit with a trend toward earlier onset compared to non-colonized recipients.

The microbiological findings further illuminate the complex interplay between prophylaxis and resistance. Among patients who developed bacteremia, 60% of cases involved Gram-negative bacteria, with Escherichia coli being the predominant pathogen (28% of cases). As might be expected, FQ resistance was common among isolates, particularly in the prophylaxis group where all Enterobacterales from bacteremic patients were FQ-resistant. However, this did not translate into worse clinical outcomes, as the overall bacteremia rate remained lower with prophylaxis. Interestingly, the prophylaxis group had a lower proportion of Gram-negative bacteremia (55% versus 80%) and a higher proportion of Gram-positive infections (65% versus 20%), suggesting a selective effect on the microbiological spectrum of breakthrough infections.

Can Secondary Endpoints Inform Clinical Practice?

Beyond fever and bacteremia, the study examined several secondary endpoints with clinical relevance. Pre-engraftment pneumonia occurred in 5.1% of patients, with numerically lower rates in the prophylaxis group (4.4% versus 7.1%). Contrary to concerns about FQ-associated Clostridioides difficile infection (CDI), the study found lower CDI rates with prophylaxis (1.8% versus 7.1%), potentially due to reduced exposure to broad-spectrum empiric antibiotics. All-cause in-hospital mortality was also lower in the prophylaxis group (2.6% versus 7.1%), though these secondary endpoints did not reach statistical significance due to the limited sample size. Importantly, FQ prophylaxis did not significantly increase the rate of conversion from FQRE-negative to positive status during admission (22.9% versus 16.7%), suggesting that prophylaxis may not substantially exacerbate colonization dynamics in this population.

How Do Local Resistance Trends Shape Prophylactic Strategies?

These findings carry significant implications for clinical practice, particularly in regions with high endemic resistance. The data suggest that FQ prophylaxis may retain value in preventing infectious complications among HCT recipients, even when background resistance is substantial. This aligns with previous research by Caro et al., who reported reduced neutropenic fever in acute myeloid leukemia patients receiving prophylaxis despite high background resistance. However, the study's retrospective single-center design introduces important limitations, including potential selection bias, as prophylaxis was prescribed at the treating oncologist's discretion rather than by randomization. Additionally, the analysis was restricted to inpatient outcomes and did not capture long-term complications or resistance evolution.

The high baseline colonization rates observed in this study reflect the broader public health challenge of antimicrobial resistance in Lebanon and similar regions. According to WHO Global Antimicrobial Resistance and Use Surveillance System data, third-generation cephalosporin resistance in E. coli bloodstream infections in Lebanon ranged from 50% to 58.8%, while FQ resistance increased from 50.7% in 2020 to 56.4% in 2021. This epidemiological context underscores the importance of tailoring antimicrobial strategies to local resistance patterns rather than adopting a one-size-fits-all approach based on guidelines developed in regions with different resistance profiles.

What Future Directions Will Advance Antimicrobial Stewardship?

The study's findings invite deeper reflection on several critical questions in transplant infectious disease management. How should clinicians balance the potential benefits of prophylaxis against concerns about further selecting for resistance? Could routine screening for colonization help personalize prophylactic strategies, reserving FQs for patients without documented resistance? What alternative prophylactic approaches might be considered in settings where FQ resistance exceeds a certain threshold? These questions become increasingly relevant as antimicrobial resistance continues to rise globally, challenging established infection prevention paradigms. Could novel approaches such as microbiome-sparing narrow-spectrum agents or non-antibiotic preventive strategies eventually replace our current reliance on broad-spectrum prophylaxis?

While this study provides valuable real-world evidence on the persistent utility of FQ prophylaxis in a high-resistance setting, larger multicenter prospective studies are needed to validate these findings and develop more nuanced, evidence-based approaches to infection prevention in vulnerable transplant populations. The complex interplay between colonization, prophylaxis, and clinical outcomes observed here highlights the need for personalized approaches to antimicrobial management that consider not only guideline recommendations but also local epidemiology and individual patient factors. As antimicrobial stewardship continues to evolve in the face of increasing resistance, such context-specific evidence becomes increasingly valuable for optimizing patient outcomes while minimizing ecological impact.

Summary

A retrospective study from Lebanon examined fluoroquinolone prophylaxis effectiveness in 156 hematopoietic cell transplantation recipients between 2017 and 2022, revealing that levofloxacin prophylaxis significantly reduced neutropenic fever incidence and delayed fever onset even in a setting with high endemic antimicrobial resistance. Nearly 40% of patients showed baseline colonization with fluoroquinolone-resistant Enterobacterales, yet prophylaxis halved the risk of early febrile episodes and reduced pre-engraftment bacteremia rates. The protective effect persisted even among patients colonized with resistant organisms, challenging assumptions that prior colonization negates prophylaxis benefits. While prophylaxis shifted the microbiological spectrum toward more Gram-positive infections and universal fluoroquinolone resistance among breakthrough Gram-negative cases, overall bacteremia rates remained lower in the prophylaxis group. Secondary outcomes showed numerically lower rates of pneumonia, Clostridioides difficile infection, and mortality with prophylaxis, though these did not reach statistical significance. The findings suggest that fluoroquinolone prophylaxis retains clinical value in high-resistance settings, supporting tailored antimicrobial strategies based on local epidemiology rather than universal guidelines, while highlighting the need for larger prospective studies to optimize personalized infection prevention approaches in transplant populations.