Possible Role of the Antibiotic-Modified Microbiome in the Development of Hematological Malignancies in European Countries

Hematological malignancies are considered the fifth most common cancer in the world. Several risk factors and probable etiological agents have been suspected in the pathomechanism of those malignancies as infections, chemicals, irradiation, etc., and recently, the contribution of the altered gut flora, dysbiosis, was identified also as a possible additional factor to the existing ones. Host, and external factors, like antibiotics, which were identified as a major disruptor of the "normal" gut flora, influence the composition of the microbiome. Considering the several-fold differences in antibiotic consumption patterns and the incidence of hematological malignancies in European countries, the hypothesis was raised that the dominant consumption of certain antibiotic classes might influence the incidence of different hematological malignancies through the modification of gut flora. Comparisons were performed between the average antibiotic consumption databases reported yearly by ECDC (2009-2019) and the incidence rate of Hodkin lymphoma (HL), non-Hodgkin lymphoma (NHL), multiple myeloma (MM), and leukemia (LEU) estimated for 2020 in 30 European countries. Applying Spearman calculations, significant positive correlation has been found between the incidence of HL and tetracycline (J01A) consumption (r = 0.399, p = 0,029), NHL and narrow spectrum, beta-lactamase resistant penicillin (J01CF) (r = 0.580, p = 0,001), MM and tetracycline (r = 0.492, p = 0.006), penicillin (J01C) (r = 0.366, p = 0.047), narrow spectrum, beta-lactamase resistant penicillin (J01CF) (r = 0.574, p = 0.001), while strong, significant negative correlation has been recorded between NHL and cephalosporin (r = -0,460, p = 0,011), and quinolone (r = -0,380, p = 0,038). The incidence of LEU did not show any positive or negative association with any antibiotic classes. It is concluded that certain antibiotic classes, in addition to other putative factors, might promote or inhibit the development of different hematological malignancies.

Short- and Long-Term Impact of a Multifaceted Approach Targeting Fluoroquinolone use in a Tertiary, Non-Teaching Hospital

Background. While various strategies for antibiotic restrictions have been validated, their impacts are not well described in smaller, non-teaching facilities. Fluoroquinolones are an appropriate target for restriction based on their propensity for overuse and potential for causing “collateral damage.” Aim. Evaluate the impact of a multifaceted approach to decreasing fluoroquinolone use on fluoroquinolones and alternative antibiotics at a smaller, non-teaching facility. Method. Retrospective, interrupted time series analysis conducted at a single 288-bed, tertiary, non-teaching hospital with 71 adult ICU beds comparing antibiotic consumption measured monthly by defined daily doses per 1000 adjusted patient days (DDD/1000 APD) prior to intervention (January 2011 to August 2014) to short-term (October 2014 to December 2015) and long-term (January 2018 to December 2019) periods following intervention. Results. An increase in downward trends of fluoroquinolone use was observed from prior to intervention (-0.49 DDD/1000 APD) to the short-term period (-1.13 DDD/1000 APD) and to a greater extent in the long-term period following the intervention (-1.32 DDD/1000 APD). Fluoroquinolone consumption decreased from 100.20 DDD/1000 APD in August 2014 to 73.96 DDD/1000 APD in the short-term and 14.89 DDD/1000 APD in the long-term intervention period. Levofloxacin susceptibility for Pseudomonas aeruginosa increased from 61% in 2014 to 83% in 2018. No deleterious effects on Pseudomonas aeruginosa susceptibilities were observed for alternative antibiotics. Conclusion. A multifaceted approach to decreasing fluoroquinolone use at a smaller, tertiary, non-teaching hospital led to a sustained decrease in consumption and a substantial increase in levofloxacin susceptibility to Pseudomonas aeruginosa.

Dysbiosis in Alzheimer’s Disease Might be Triggered by Certain Classes of Antibiotics with Time-lapse: New Insights in the Pathogenesis?

Background and objectives: Alzheimer's disease (AD) is a progressive neurodegenerative illness, responsible for 60-70% of all dementias, affecting over 50 million people worldwide, and nearly 11 million in European countries. Several putative factors are identified in the literature as causative agents or risk factors for the development of AD. The amyloid cascade hypothesis has been the main hypothesis about the pathophysiology of AD for decades. Recent studies raised the possible role of dysbiosis in the development of AD which prevents memory loss. The amyloid-β (Aβ) deposition might be considered as an inflammatory reaction to certain molecular products arising from the altered microbiome. Based on the above observations, it has been suspected, that antibiotic consumption patterns of different antibiotic classes might be associated with the prevalence of AD in European countries. Methods: Antibiotic consumption (ECDC) for 1997-2007, 2008-2018, and as the whole 1997-2018 period, have been compared to the AD prevalence for 2018 expressed in percentage of the population and statistically analyzed by Pearson calculation. Results: A significant positive correlation has been found between the AD prevalence (2018) and the average quinolone consumption for the year 1997-2007 (p: 0.044). A similar association was not observed for the entire 22 years (1997-2018) of the average quinolone consumption, and the years 2008-18, indicating 10-20 years of time-lapse between the antibiotic exposure and the development of AD. The ratio of broad-spectrum and narrow-spectrum antibiotics (B/N) estimated in the ECDC database for the years of 2008-2018 showed a strong positive association with AD prevalence (2018) (p: 0.026) and a positive correlation tendency for the entire 22 years 1997-2018 (p: 0.063), but none for the years 1997-2007 (p: 0.241). Broad-spectrum, beta-lactamase sensitive penicillin (J01CA) consumption showed a positive (non-significant) correlation with the prevalence of AD for the years 2008-2018 (p:0.080).Discussion: Our study indicated the possible sequential role of certain classes of antibiotics in the development of dysbiosis leading to amyloid deposits of AD, which strengthen the possible role of different mediator molecules (short-chain fatty acids, lipopolysaccharides, etc.) produced by the altered microbiome in the development of AD.

Long-Term Outcomes in Patients on Life-Long Antibiotics: A Five-Year Cohort Study

Background: Little is known about the impacts at an individual level of long-term antibiotic consumption. We explored health outcomes of long-term antibiotic therapy prescribed to a cohort of patients to suppress infections deemed incurable. Methods: We conducted a 5-year longitudinal study of patients on long-term antibiotics at Monash Health, a metropolitan tertiary-level hospital network in Australia. Adults prescribed antibiotics for >12 months to suppress chronic infection or prevent recurrent infection were included. A retrospective review of medical records and a descriptive analysis was conducted. Results: Twenty-seven patients were followed up during the study period, from 29 patients originally identified in Monash Health in 2014. Seven of the 27 patients (26%) died from causes unrelated to the suppressed infection, six (22%) ceased long-term antibiotic therapy and two (7%) required treatment modification. Fifteen (56%) were colonised with multiresistant microorganisms, including vancomycin resistant Enterococci, methicillin resistant Staphylococcus aureus, and carbapenem resistant Enterobacteriaciae. Conclusions: This work highlights the potential pitfalls of long-term antibiotic therapy, and the frailty of this cohort, who are often ineligible for definitive curative therapy.

Safety & efficacy of antibiotic de-escalation and discontinuation in high-risk haematological patients with febrile neutropenia: a single-centre experience

Background There is currently no consensus on optimal duration of antibiotic treatment in febrile neutropenia. We report on the clinical impact of implementation of antibiotic de-escalation and discontinuation strategies based on the 4th European Conference on Infections in Leukaemia (ECIL-4) recommendations in high-risk haematological patients. Methods We studied 446 admissions after introduction of an ECIL-4 based protocol (= ECIL-4 group) in comparison to a historic cohort of 512 admissions. Primary clinical endpoints were the incidence of infectious complications including septic shock, infection-related intensive care unit (ICU) admission and overall mortality. Secondary endpoints included the incidence of recurrent fever, bacteraemia and antibiotic consumption. Results Bacteraemia occurred more frequently in the ECIL-4 group [46.9% (209/446) vs 30.5% (156/512); p<0.001], without an associated increase in septic shock [4.7% (21/446) vs 4.5% (23/512); p=0.878] or infection-related ICU admission [4.9% (22/446) vs 4.1% (21/512); p=0.424]. Overall mortality was significantly lower in the ECIL-4 group [0.7% (3/446) vs 2.7% (14/512); p=0.016], resulting mainly from a decrease in infection-related mortality [0.4% (2/446) vs 1.8% (9/512); p=0.058]. Antibiotic consumption was significantly reduced by a median of 2 days on antibiotic therapy (12 versus 14; p=0.001) and 7 daily antibiotic doses (17 versus 24; p<0.001) per admission period. Conclusions Our results support implementation of ECIL-4 recommendations to be both safe and effective based on real world data in a large high-risk patient population. We found no increase in infectious complications and total antibiotic exposure was significantly reduced.

Oral antibiotic use and early-onset colorectal cancer: findings from a case-control study using a national clinical database

Background Antibiotic-induced gut dysbiosis has been associated with colorectal cancer (CRC) in older adults. This study will investigate whether an association exists between antibiotic usage and early-onset colorectal cancer (CRC), and also evaluate this in later-onset CRC for comparison. Methods A case-control study was conducted using primary care data from 1999–2011. Analysis were conducted separately in early-onset CRC cases (diagnosed < 50 years) and later-onset cases (diagnosed ≥ 50 years). Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (CI) for the associations between antibiotic exposure and CRC by tumour location, adjusting for comorbidities. Results Seven thousands nine hundred and three CRC cases (445 aged <50 years) and 30,418 controls were identified. Antibiotic consumption was associated with colon cancer in both age-groups, particularly in the early-onset CRC cohort (<50 years: adjusted Odds Ratio (ORadj) 1.49 (95% CI 1.07, 2.07), p = 0·018; ≥50 years (ORadj (95% CI) 1.09 (1.01, 1.18), p = 0·029). Antibiotics were not associated with rectal cancer (<50 years: ORadj (95% CI) 1.17 (0.75, 1.84), p = 0.493; ≥50 years: ORadj (95% CI) 1.07 (0.96, 1.19), p = 0.238). Conclusion Our findings suggest antibiotics may have a role in colon tumour formation across all age-groups.

Impact and Sustainability of Antibiotic Stewardship on Antibiotic Prescribing in Visceral Surgery

Background: Antibiotic stewardship (AS) ward rounds are a core element in clinical care for surgical patients. Therefore, we aimed to analyze the impact of surgical AS ward rounds on antibiotic prescribing, and the sustainability of the effect after the AS interventions are no longer provided. Methods: On four wards of the department of visceral surgery, we conducted two independent retrospective prescribing analyses (P1, P2) over three months each. During the study periods, the level of AS intervention differed for two of the four wards (ward rounds/no ward rounds). Results: AS ward rounds were associated with a decrease in overall antibiotic consumption (91.1 days of therapy (DOT)/100 patient days (PD) (P1), 70.4 DOT/100PD (P2)), and improved de-escalation rates of antibiotic therapy (W1/2: 25.7% (P1), 40.0% (P2), p = 0.030; W3: 15.4 (P1), 24.2 (P2), p = 0.081). On the ward where AS measures were no longer provided, overall antibiotic usage remained stable (71.3 DOT/100PD (P1), 74.4 DOT/100PD (P2)), showing the sustainability of AS measures. However, the application of last-resort compounds increased from 6.4 DOT/100PD to 12.1 DOT/100PD (oxazolidinones) and from 10.8 DOT/100PD to 13.2 DOT/100PD (carbapenems). Conclusions: Antibiotic consumption can be reduced without negatively affecting patient outcomes. However, achieving lasting positive changes in antibiotic prescribing habits remains a challenge.

Antibiotic prescribing patterns among patients admitted to an academic teaching hospital for COVID-19 during the first wave of the pandemic in Toronto: A retrospective, controlled study

Background: Empirical antibiotics are not recommended for coronavirus disease 2019 (COVID-19). Methods: In this retrospective study, patients admitted to Toronto General Hospital’s general internal medicine from the emergency department for COVID-19 between March 1 and August 31, 2020 were compared with those admitted for community-acquired pneumonia (CAP) in 2020 and 2019 in the same months. The primary outcome was antibiotics use pattern: prevalence and concordance with COVID-19 or CAP guidelines. The secondary outcome was antibiotic consumption in days of therapy (DOT)/100 patient-days. We extracted data from electronic medical records. We used logistic regression to model the association between disease and receipt of antibiotics, linear regression to compare DOT. Results: The COVID-19, CAP 2020, and CAP 2019 groups had 67, 73, and 120 patients, respectively. Median age was 71 years; 58.5% were male. Prevalence of antibiotic use was 70.2%, 97.3%, and 90.8% for COVID-19, CAP 2020, and CAP 2019, respectively. Compared with CAP 2019, the adjusted odds ratio (aOR) for receiving antibiotics was 0.23 (95% CI 0.10 to 0.53, p = 0.001) and 3.42 (95% CI 0.73 to 15.95, p = 0.117) for COVID-19 and CAP 2020, respectively. Among patients receiving antibiotics within 48 hours of admission, compared with CAP 2019, the aOR for guideline-concordant combination regimens was 2.28 (95% CI 1.08 to 4.83, p = 0.031) for COVID-19 and 1.06 (95% CI 0.55 to 2.05, p = 0.856) for CAP-2020. Difference in mean DOT/100 patient-days was –24.29 ( p = 0.009) comparing COVID-19 with CAP 2019, and +28.56 ( p = 0.003) comparing CAP 2020 with CAP 2019. Conclusions: There are opportunities for antimicrobial stewardship to address unnecessary antibiotic use.