We are very happy to share our research with colleagues from around the world in one of the most comprehensive and influential congresses in the field of infection, even if on-site and online components of ECCMID 2020 have been cancelled due to the COVID-19 pandemic.
1. Ducher A, Vehreschild MJGT, Louie T, Cornely OA, Feger C, Dane A, Varastet M, de Gunzburg J, Andremont A, Mentré A, Wilcox MH. DAV132 protects intestinal microbiota of patients treated with quinolones. A European phase II randomized controlled trial. ECCMID 2020, Abstract 9918.
Background: Antibiotic treatments elicit intestinal microbiota dysbiosis with short and long-term deleterious effects. A colon-targeted adsorbent, DAV132, prevents dysbiosis in healthy volunteers and so may protect antibiotic-treated patients.
Materials/methods: An open label, randomized clinical trial targeted hospitalized patients treated with oral/iv fluoroquinolones (FQ) for lower respiratory or urinary infections or febrile neutropenia prophylaxis. Patients were randomised 1:1 to receive DAV132 (7.5g tid orally), or not, during FQ treatment. Central laboratories evaluated plasma concentrations of FQ after 4d by LC-MS/MS, free faecal FQ concentrations, α/β diversity of the intestinal microbiota (16S rRNA gene profiling) at D1, D4, D6, Endof-FQ, 10 days after End-of-FQ, and 30 days after End-of-FQ. Resistance to colonisation by C. difficile (Cd) was assessed ex-vivo [suppression of Cd proliferation]. The primary endpoint (proportion of adverse events (AE) related to DAV132 and/or FQ) was adjudicated by blinded independent experts.
Results: 260 hospitalized patients at 24 sites (median age 71, ≥1 chronic comorbidity: 96%) were treated for 7.5d on average (79% iv) with levofloxacin (43%), ciprofloxacin (40%) or moxifloxacin (17%). Compared with the No-DAV132 arm, faecal FQ levels in DAV132-treated patients were reduced by more than 98.8%, whilst plasma levels did not change significantly. During FQ treatment, significant differences in all metrics of intestinal microbiota diversity were observed between the two arms, such as changes from D1 of the Shannon index at End-of-FQ (∆ mean ± SEM at End-of-FQ: 0.56 ±0.17, p.003). The proportion of patients with DAV132- and/or FQ-related AEs did not differ significantly between arms (14.8 vs. 10.8%, difference of proportions: 4.0%; 95% CI [-4.7; 12.6]). No Cd infection occurred. Ex-vivo resistance to colonisation by Cd was markedly reduced in stool samples of patients receiving FQ only, but was maintained in those co-administered DAV132 (p=0.0003). Faecal carriage of vancomycin-resistant enterococci (VRE) was reduced in DAV132 treated patients (p=0.01).
Conclusions: DAV132 was well tolerated in elderly hospitalized patients with comorbidities. It neither altered antibiotic plasma concentrations nor elicited changes in concomitant drugs regimens. Intestinal microbiota diversity was protected and resistance to colonization by Cd was preserved. DAV132 is a promising, novel product to prevent antibiotic-induced intestinal dysbiosis.
2. Berkell M, Mysara M, Xavier BB, van Werkhoven CH, Monsieurs P, Lammens C, Ducher A, Vehreschild MJGT, Goossens H, de Gunzburg J, Bonten MJ, Malhotra-Kumar S. Increased enterococcal abundance and low microbial diversity are early predictive markers of a microbiota primed for development of Clostridioides difficile infection. ECCMID 2020, Abstract 9817.
Background: Clostridioides difficile infection (CDI) is the most common form of infectious antibiotic-associated diarrhoea (AAD) causing considerable morbidity and mortality in acute-care facilities. Identification of early markers predictive of CDI in hospitalized patients could substantially contribute to decreasing the CDI burden.
Materials/methods: In this European, prospective, longitudinal cohort-study including 1,007 patients aged ≥50 years receiving broad-spectrum antibiotic treatment with penicillins + beta-lactamase inhibitors, other beta-lactam antibiotics, or fluoroquinolones during hospital stay, we characterized faecal samples using high-resolution, single-nucleotide 16S rRNA gene profiling before (D1, n = 945) and after antibiotic treatment (D6, n = 737). CDI was defined according to the ESCMID diagnostic guidelines.
Results: C. difficile carriage was observed in 51/945 (5.4%, D1) and 50/737 (6.8%, D6) patients. Among patients who developed diarrhoea within 90 days, those with CDI (n=14) exhibited significantly lower diversity (p≤0.016) and a distinctly different microbial composition at D1 compared to those with non-C. difficile AAD (n=64) and no diarrhoea (n=669, 198 lost to follow-up, Figure). At D1, the microbiota was enriched for Enterococcus spp. in patients who later developed CDI, for Clostridiales Incertae Sedis XI, Blautia and Ruminococcus spp. in patients developing non-C. difficile AAD, and for Blautia luti, Porphyromonas, Prevotella, and Bifidobacterium spp. in non-diarrheic patients. Antibiotic treatment reduced microbial diversity and induced class-specific dysbiosis; beta-lactam treatment specifically increased enterococcal abundance, and fluoroquinolone treatment depleted Prevotella spp.
Conclusions: Our findings of a distinct, low-diversity CDI-associated microbiota can be exploited for enriching high-risk patients in prospective clinical trials and for the development of predictive, microbiota-based diagnostics for clinical management of patients at high risk of CDI.
3. Duhalde L, Lurienne L, Heimann SM, Guillou L, Buffet R, Bandinelli PA. The economic burden of Clostridioides difficile infection in patients with haematological malignancies: a case-control study. ECCMID 2020, Abstract 395.
Background: The burden of Clostridioides (Clostridium) difficile infection (CDI) is profound and patients with hematological malignancies are at high risk for developing the infection. Very few studies have assessed the economic burden of CDI in this specific population, whereby primarily hospital costs were analyzed. This study aims at describing all direct healthcare costs attributable to CDI (in-hospital and out-of-hospital) in patients suffering from hematological malignancies.
Materials/methods: A retrospective analysis was conducted based on databases of Truven Health Analytics®, part of the IBM Watson HealthTM business. Comprehensive data of hospital stays and services, out-of-hospital services and drug prescriptions of patients newly diagnosed with hematological cancer (acute myeloid leukemia [AML], acute lymphoblastic leukemia, Hodgkin’s lymphoma and non-Hodgkin lymphoma [NHL]) between 01/2014 – 12/2017 were analyzed. Patients with CDI after cancer diagnosis (CDI+ or cases) were matched to patients without CDI (CDI- or controls). Matched cases and controls were compared to identify the CDI-attributable costs and changes in care in the 90 days following the CDI onset (study period).
Results: 622 CDI+ patients were matched with 11,111 controls. NHL and AML were the predominant underlying diseases in the CDI+ group accounting for 41.7% and 30.9% of cases, respectively. Overall, CDI increased costs of care by an average of US$57,159 per patient, an increase of 41.9%, mainly driven by in-hospital costs. Costs data are presented in Table 1.
Conclusions: Findings confirm that CDI treatment results in substantial costs in patients with hematological malignancies, highlighting the need for better treatment and prevention options for this specific patient population.
4. Heimann SM, Lurienne L, Davies K , Benson A, Davis G, Viprey V , Wilcox MH, Bonten MJ, Cornely OA, Vehreschild MJGT. Healthcare resource utilisation for treatment of Clostridioides difficile infection across 12 European countries: health economic results of COMBACTE-CDI. ECCMID 2020, Abstract 3529.
Background: Clostridioides difficile infection (CDI) is one of the leading healthcare associated infections resulting in prolonged hospital length of stay and increased costs. CDI related data of healthcare resource utilization across Europe are scarce.
Materials/methods: A questionnaire to assess current CDI practices and CDI-related costs was sent out in 10/2018 to both hospital and community settings in 12 European countries. Countries were divided into four regions: West (Belgium, France, The Netherlands), North (Ireland, Sweden, United Kingdom), East (Poland, Romania, Slovakia), and South (Greece, Italy, Spain).Bootstrapped CDI related direct costs were expressed in Euro (€), year 2019 values. For international comparison of health expenditures, price level indices published by the Organisation for Economic Co-operation and Development (OECD) were used to ensure comparability of cross-country variations.
Results: Overall, 158 sites participated in the survey, predominantly hospitals (n= 109, 69%) and community physicians (n=40, 25%). Median overall costs for one C. difficile stool sample test was €21.8 (interquartile range (IQR): €13.8 – €37.2), with lowest and highest values in Northern Europe (€15.0; IQR: €11.6 – €22.9) and Western Europe (€31.9; IQR: €16.2 – €37.6; p=0.046), respectively. Across Europe, community physicians reported higher median drug costs for a one-day treatment with metronidazole iv (€14.4; IQR: €9.9 – €52.9 vs. €1.9; IQR: €1.4 – €9.5; p= 0.005) and vancomycin (€15.6; IQR: €7.9 – €22.0 vs. €6.5; IQR: €3.7 – €12.8; p= 0.017) compared to the hospital setting. In the pan-European hospital setting, median costs for severe CDI cases treated in intensive care units ranged from €1,437.5/day (IQR: €1,292.7 – €1,839.9) in Eastern Europe to €2,094.7/day (IQR: €1,063.8 – €3,191.5; p= 0.175) in Western Europe. Median costs for one general ward bed-day with isolation measures due to CDI was 2-fold higher in Southern Europe (€769.2; IQR: €567.9 – €1,623.9) compared to Eastern Europe (€324.0; IQR: €166.8 – €690.0; p= 0.010).
Conclusions: Healthcare costs of CDI diagnostic and treatment measures vary markedly in both hospital and community settings across Europe. The impact of the prevalence of hypervirulent strains, severity of illness, and guideline adherence are subject of future health economic evaluations of COMBACTE-CDI.