A systematic review and meta-analysis evaluating the impact of antibiotic use on the clinical outcomes of cancer patients treated with immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) have considerably improved patient outcomes in various cancer types, but their efficacy remains poorly predictable among patients. The intestinal microbiome, whose balance and composition can be significantly altered by antibiotic use, has recently emerged as a factor that may modulate ICI efficacy. The objective of this systematic review and meta-analysis is to investigate the impact of antibiotics on the clinical outcomes of cancer patients treated with ICIs. Methods: PubMed and major oncology conference proceedings were systematically searched to identify all studies reporting associations between antibiotic use and at least one of the following endpoints: Overall Survival (OS), Progression-Free Survival (PFS), Objective Response Rate (ORR) and Progressive Disease (PD) Rate. Pooled Hazard Ratios (HRs) for OS and PFS, and pooled Odds Ratios (ORs) for ORR and PD were calculated. Subgroup analyses on survival outcomes were also performed to investigate the potential differential effect of antibiotics according to cancer types and antibiotic exposure time windows. Results: 107 articles reporting data for 123 independent cohorts were included, representing a total of 41,663 patients among whom 11,785 (28%) received antibiotics around ICI initiation. The pooled HRs for OS and PFS were respectively of 1.61 [95% Confidence Interval (CI) 1.48-1.76] and 1.45 [95% CI 1.32-1.60], confirming that antibiotic use was significantly associated with shorter survival. This negative association was observed consistently across all cancer types for OS and depending on the cancer type for PFS. The loss of survival was particularly strong when antibiotics were received shortly before or after ICI initiation. The pooled ORs for ORR and PD were respectively of 0.59 [95% CI 0.47-0.76] and 1.86 [95% CI 1.41-2.46], suggesting that antibiotic use was significantly associated with worse treatment-related outcomes. Conclusion: As it is not ethically feasible to conduct interventional, randomized, controlled trials in which antibiotics would be administered to cancer patients treated with ICIs to demonstrate their deleterious impact versus control, prospective observational studies and interventional trials involving microbiome modifiers are crucially needed to uncover the role of microbiome and improve patient outcomes. Such studies will reduce the existing publication bias by allowing analyses on more homogeneous populations, especially in terms of treatments received, which is not possible at this stage given the current state of the field. In the meantime, antibiotic prescription should be cautiously considered in cancer patients receiving ICIs. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42019145675.

Prognostic Associations of Concomitant Antibiotic Use in Patients with Advanced NSCLC Treated with Atezolizumab: Sensitivity Analysis of a Pooled Investigation of Five Randomised Control Trials.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been a significant milestone for the treatment of advanced non-small cell lung cancer (NSCLC). However, the efficacy of ICIs can vary substantially between patients, with disparities in treatment outcomes being potentially driving by changes in the microbiome. Antibiotics can cause dysbiosis and are hypothesised to impact the efficacy of ICIs Methods: Data were pooled from five randomised clinical control trials, IMpower130, IMpower131, IMpower150, OAK, and POPLAR, assessing atezolizumab in advanced NSCLC. Cox proportional hazard models were used to determine whether antibiotic use within 6-weeks before and after randomisation was associated with progression-free survival (PFS) and overall survival (OS) outcomes, with data further stratified by programmed death ligand-1 (PD-L1) status. RESULTS: Antibiotic use was significantly associated with worsened PFS (hazard ratio (HR) = 1.19 [1.08-1.30], p ≤ 0.001) and OS (HR = 1.27 [1.13-1.42], p ≤ 0.001) in patients treated with atezolizumab and those not treated with atezolizumab (PFS, HR = 1.21 [1.08-1.36] p < 0.001, OS, HR = 1.33 [1.16-1.51] p < 0.001). These associations were relatively consistent in both PD-L1 positive and PD-L1 negative. CONCLUSIONS: Antibiotic use within a ±6-week window was significantly associated with worse PFS and OS.

Clostridioides difficile infection (CDI): A pan-European multi-center cost and resource utilization study, results from the Combatting Bacterial Resistance in Europe CDI (COMBACTE-CDI).

OBJECTIVES: Clostridioides difficile infection (CDI) is one of the leading nosocomial infections worldwide, resulting in a significantly increasing burden on the healthcare systems. However, Pan-European data about cost and resource utilization of CDI treatment do not exist. METHODS: A retrospective analysis within the Combatting Bacterial Resistance in Europe CDI project was conducted based on resource costs for inpatient treatment and productivity costs. Country-specific cost values were converted to EURO referred to 1 January, 2019 values. Differences in price levels for healthcare services among the participating countries were adjusted by using an international approach of the Organisation for Economic Co-operation and Development. As the study focused on patients with recurrent CDI, the observed study population was categorized into (a) patients with CDI but without CDI recurrence (case group), (b) patients with CDI recurrence (recurrence group), and (c) patients without CDI (control group). RESULTS: Overall, 430 hospitalized patients from 12 European countries were included into the analysis between July 2018 and November 2018. Distribution of mean hospital length of stay and mean overall costs per patient between the case group, recurrence group, and control group were as follows: 22 days (95% CI 17-27 days) vs. 55 days (95% CI 17-94 days) vs. 26 days (95% CI 22-31 days; p 0.008) and € 15 242 (95% CI 10 593-19 891) vs. € 52 024 (95% CI 715-103 334) vs. € 21 759 (95% CI 16 484-27 035; p 0.010), respectively. The CDI recurrence rate during the observational period was 18%. Change escalation in CDI medication (OR 3.735) and treatment in an intensive care unit (OR 5.454) were found to be the most important variables associated with increased overall costs of patients with CDI. CONCLUSIONS: Treatment of patients with recurrent CDI results in a significant burden. Prevention of CDI recurrences should be in focus of daily patient care to identify the most cost-effective treatment strategy.

Spare and repair the gut microbiota from antibiotic-induced dysbiosis: state-of-the-art.

Homeostasis of the intestinal microbiota is currently recognized as a major contributor to human health. Furthermore, intestinal dysbiosis is associated with a multitude of consequences, including intestinal colonization by antibiotic-resistant or pathogenic bacteria, such as Clostridioides difficile, and reduced efficacy of promising anticancer immunotherapies. By far, the most immediate and drastic exposure leading to dysbiosis is antibiotic treatment. Many attempts have been made to prevent or repair antibiotic-associated dysbiosis. Here, we review these innovations and the difficulties associated with their development.

The economic burden of Clostridioides difficile infection in patients with hematological malignancies in the United States: A case-control study.

OBJECTIVE: The primary study aim was to describe all direct healthcare costs associated with Clostridioides difficile infection (CDI), both in and out of the hospital, in patients with hematologic malignancies in the United States. DESIGN: A retrospective analysis was conducted utilizing data from US databases of Truven Health Analytics. PATIENTS: We analyzed health insurance claims between January 2014 and December 2017 of patients diagnosed with hematological cancer: acute myeloid leukemia (AML), acute lymphoblastic leukemia, Hodgkin's lymphoma, and non-Hodgkin's lymphoma (NHL). METHODS: Patients with CDI after cancer diagnosis (CDI+, cases) were matched with patients without CDI reported (CDI-, controls). Matched cases and controls were compared to identify the CDI-associated costs in the 90 days following the onset of CDI. RESULTS: We matched 622 CDI+ patients with 11,111 CDI- patients. NHL (41.7%) and AML (30.9%) were the predominant underlying diseases in the CDI+ groups. During study period, the average time in-hospital of CDI+ patients was 23.1 days longer than for CDI- patients (P < 2×10-16). Overall, CDI onset increased costs of care by an average of US$57,159 per patient (P = 6×10-12), mainly driven by hospital costs. CONCLUSIONS: This study confirms the significant economic burden associated with CDI in the United States, especially in patients with hematological malignancies. These findings highlight the need for prevention of CDI in this specific patient population.

NSCLC Immunotherapy Efficacy and Antibiotic Use: A Systematic Review and Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have dramatically improved patient outcomes in a variety of tumor types, but with variable efficacy. Recent research has suggested that antibiotic-induced disruption of the microbiota may impact ICI efficacy. We performed a systematic review and meta-analysis of studies that assessed the impact of antibiotic use on the survival of patients diagnosed with NSCLC and treated with ICI. We systematically searched Medline, the Cochrane Library, and major oncology conferences proceedings. Eligible studies mentioned hazard ratio or Kaplan-Meier curves for progression-free survival (PFS) or overall survival (OS) based on antibiotic exposure before or during ICI treatment. We identified 23 eligible studies. The impact of antibiotics was then evaluated in 2208 patients for PFS and 5560 for OS. For both PFS and OS meta-analyses, the between-study heterogeneity was high (Higgins and Thompson I2 of 69% and 80%, respectively). The pooled hazard ratio was 1.47 (95% confidence interval [CI]: 1.13-1.90) for PFS and 1.69 (95% CI: 1.25-2.29) for OS revealing a significantly reduced survival in patients with NSCLC exposed to antibiotics. The median OS was reduced on average by 6.7 months (95% CI: 5.1-8.4) in the patients exposed to antibiotics. The effect seems to depend on the time window of exposure with stronger effects reported when the patients took antibiotics [-60 days; +60 days] around ICI initiation. In patients with NSCLC, the findings of the meta-analysis indicate that antibiotic use before or during treatment with ICI leads to a median OS decreased by more than 6 months. Specifically, exposure shortly before or after ICI initiation seems to be particularly detrimental, whereas antibiotic use later during disease course does not seem to alter survival. Because PFS and OS were difficult to compare between studies owing to heterogeneity and the multiple confounding factors identified, further studies are needed to strengthen the understanding of this phenomenon.

Perception of quality of life in people experiencing or having experienced a Clostridioides difficile infection: a US population survey.

BACKGROUND: Although the incidence, severity and mortality of Clostridioides (Clostridium) difficile infection (CDI) have been increasing, patients' quality of life changes resulting from CDI have not been studied thoroughly. This study aimed at exploring the consequences of CDI on quality of life through patients' perspective. METHODS: An observational, cross-sectional study involving 350 participants with a self-reported CDI diagnosis was conducted through an online self-administered survey. Participants were grouped into those who had active disease ("Current CDI") and those who had a history of CDI ("Past CDI"). RESULTS: One hundred fifteen participants (33%) reported Current CDI and 235 (67%) reported Past CDI. A large majority of participants admitted that their daily activities were impacted by the infection (93.9% and 64.7% of Current and Past CDI respondents respectively, p < 0.05). Physical and psychological consequences of CDI were experienced by 63.5% and 66.1% of participants with active CDI. Despite the infection being cleared, these consequences were still frequently experienced in Past CDI cohort with similar rates (reported by 73.2% of respondents for both, physical consequences p = 0.08; psychological consequences p = 0.21). After the infection, 56.6% of respondents noted that post-CDI symptoms remained; 40.9% believed they would never get rid of them. CONCLUSIONS: While the societal burden of CDI is well described in the literature, our study is one of the first aimed at understanding the major burden of CDI on quality of life. Our results highlight the long-lasting nature of CDI and further reinforce the need for enhanced therapeutics in the prevention and treatment of this devastating infection.

Burden of Clostridium difficile Infections in French Hospitals in 2014 From the National Health Insurance Perspective.

OBJECTIVE To describe the hospital stays of patients with Clostridium difficile infection (CDI) and to measure the hospitalization costs of CDI (as primary and secondary diagnoses) from the French national health insurance perspective DESIGN Burden of illness study SETTING All acute-care hospitals in France METHODS Data were extracted from the French national hospitalization database (PMSI) for patients covered by the national health insurance scheme in 2014. Hospitalizations were selected using the International Classification of Diseases, 10 th revision (ICD-10) code for CDI. Hospital stays with CDI as the primary diagnosis or the secondary diagnosis (comorbidity) were studied for the following parameters: patient sociodemographic characteristics, mortality, length of stay (LOS), and related costs. A retrospective case-control analysis was performed on stays with CDI as the secondary diagnosis to assess the impact of CDI on the LOS and costs. RESULTS Overall, 5,834 hospital stays with CDI as the primary diagnosis were included in this study. The total national insurance costs were €30.7 million (US $33,677,439), and the mean cost per hospital stay was €5,267±€3,645 (US $5,777±$3,998). In total, 10,265 stays were reported with CDI as the secondary diagnosis. The total national insurance additional costs attributable to CDI were estimated to be €85 million (US $93,243,725), and the mean additional cost attributable to CDI per hospital stay was €8,295±€17,163, median, €4,797 (US $9,099±$8,827; median, $5,262). CONCLUSION CDI has a high clinical and economic burden in the hospital, and it represents a major cost for national health insurance. When detected as a comorbidity, CDI was significantly associated with increased LOS and economic burden. Preventive approaches should be implemented to avoid CDIs. Infect Control Hosp Epidemiol 2017;38:906-911.

Tissue extracellular matrix nanoparticle presentation in electrospun nanofibers.

Biomaterials derived from the decellularization of mature tissues retain biological and architectural features that profoundly influence cellular activity. However, the clinical utility of such materials remains limited as the shape and physical properties are difficult to control. In contrast, scaffolds based on synthetic polymers can be engineered to exhibit specific physical properties, yet often suffer from limited biological functionality. This study characterizes composite materials that present decellularized extracellular matrix (DECM) particles in combination with synthetic nanofibers and examines the ability of these materials to influence stem cell differentiation. Mechanical processing of decellularized tissues yielded particles with diameters ranging from 71 to 334 nm. Nanofiber scaffolds containing up to 10% DECM particles (wt/wt) derived from six different tissues were engineered and evaluated to confirm DECM particle incorporation and to measure bioactivity. Scaffolds containing bone, cartilage, and fat promoted osteogenesis at 1 and 3 weeks compared to controls. In contrast, spleen and lung DECM significantly reduced osteogenic outcomes compared to controls. These findings highlight the potential to incorporate appropriate source DECM nanoparticles within nanofiber composites to design a scaffold with bioactivity targeted to specific applications.