Clostridioides difficile is a Gram-positive bacteria that causes nosocomial infections, significantly impacting public health. In the present study, we aimed to describe the clinical characteristics, outcomes, and relationship between antibiotic exposure and Clostridioides difficile infection (CDI) in patients based on reports from two databases. Thus, we conducted a retrospective study of patients diagnosed with CDI from Sibiu County Clinical Emergency Hospital (SCCEH), Romania, followed by a descriptive analysis based on spontaneous reports submitted to the EudraVigilance (EV) database. From 1 January to 31 December 2022, we included 111 hospitalized patients with CDI from SCCEH. Moreover, 249 individual case safety reports (ICSRs) from EVs were analyzed. According to the data collected from SCCEH, CDI was most frequently reported in patients aged 65-85 years (66.7%) and in females (55%). In total, 71.2% of all patients showed positive medical progress. Most cases were reported in the internal medicine (n = 30, 27%), general surgery (n = 26, 23.4%), and infectious disease (n = 22, 19.8%) departments. Patients were most frequently exposed to ceftriaxone (CFT) and meropenem (MER). Also, in the EV database, most CDI-related ADRs were reported for CFT, PIP/TAZ (piperacillin/tazobactam), MER, and CPX (ciprofloxacin). Understanding the association between previous antibiotic exposure and the risk of CDI may help update antibiotic stewardship protocols and reduce the incidence of CDI by lowering exposure to high-risk antibiotics.

BACKGROUND: Preterm neonates often receive a variety of duration of antibiotic exposure during admission. The aim of the study was to evaluate whether neonatal antibiotic exposure is relevant with longitudinal growth problems in preterm-birth children.
METHODS: This prospective study enrolled 481 infants who were born <32 weeks of gestation, discharged, and longitudinally followed from corrected age (CA) 6-60 months. After excluding 153 infants with blood culture-confirmed bacteremia, necrotizing enterocolitis, severe cerebral palsy, intestinal ostomy, and congenital anomaly, 328 infants were included for analysis. Covariates included perinatal demographics, neonatal morbidities, extrauterine growth restriction, and antibiotic exposure accumulated by term equivalent age. The primary outcome was the anthropometric trajectories in z-score of bodyweight (zBW), body height (zBH), and body mass index (zBMI) from CA 6-60 months.
RESULTS: Antibiotic exposure duration was significantly negatively associated with zBW and zBH at CA 6, 12, and 60 months, and zBMI at CA 60 months. Multivariate generalized estimating equation analyses showed antibiotic exposure duration had significantly faltering z-score increment from CA 6 to 60 months in zBW and zBH (adjusted mean [95% CI]; ΔzBW: -0.021 [-0.041 to -0.001], p = 0.042; ΔzBH: -0.019 [-0.035 to -0.002], p = 0.027) after adjustment. Children with neonatal antibiotic exposure duration >15 days were significantly lower in the mean anthropometric zBW, zBH, and zBMI at CA 6, 12, 24, and 60 months compared with children with neonatal antibiotic exposure ≤15 days (all p < 0.01).
CONCLUSIONS: Growth increments were negatively associated with antibiotic exposure duration in preterm neonates implicating that antibiotic stewardship and growth follow-up for preterm neonates are thus warranted.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has significantly improved the prognosis of some patients with advanced urothelial carcinoma (UC), but it does not provide high therapeutic efficacy in all patients. Therefore, identifying predictive biomarkers is crucial in determining which patients are candidates for ICI treatment. This study aimed to identify the predictors of ICI treatment response in patients with platinum-refractory advanced UC treated with pembrolizumab.
METHODS: Patients with platinum-refractory advanced UC who had received pembrolizumab at two hospitals in Japan were included. Univariate and multivariate analyses were performed to identify biomarkers for progression-free survival (PFS) and overall survival (OS).
RESULTS: Forty-one patients were evaluable for this analysis. Their median age was 75 years, and the vast majority of the patients were male (85.4%). The objective response rate was 29.3%, with a median overall survival (OS) of 17.8 months. On multivariate analysis, an Eastern Cooperative Oncology Group performance status (ECOG-PS) ≥ 2 (HR = 6.33, p = 0.03) and a baseline neutrophil-to-lymphocyte ratio (NLR) > 3 (HR = 2.79, p = 0.04) were significantly associated with poor OS. Antibiotic exposure did not have a significant impact on either PFS or OS.
CONCLUSIONS: ECOG-PS ≥ 2 and baseline NLR > 3 were independent risk factors for OS in patients with platinum-refractory advanced UC treated with pembrolizumab. Antibiotic exposure was not a predictor of ICI treatment response.

Chronic pancreatitis (CP) is a progressive and irreversible fibroinflammatory disorder, accompanied by pancreatic exocrine insufficiency and dysregulated gut microbiota. Recently, accumulating evidence has supported a correlation between gut dysbiosis and CP development. However, whether gut microbiota dysbiosis contributes to CP pathogenesis remains unclear. Herein, an experimental CP was induced by repeated high-dose caerulein injections. The broad-spectrum antibiotics (ABX) and ABX targeting Gram-positive (G+) or Gram-negative bacteria (G-) were applied to explore the specific roles of these bacteria. Gut dysbiosis was observed in both mice and in CP patients, which was accompanied by a sharply reduced abundance for short-chain fatty acids (SCFAs)-producers, especially G+ bacteria. Broad-spectrum ABX exacerbated the severity of CP, as evidenced by aggravated pancreatic fibrosis and gut dysbiosis, especially the depletion of SCFAs-producing G+ bacteria. Additionally, depletion of SCFAs-producing G+ bacteria rather than G- bacteria intensified CP progression independent of TLR4, which was attenuated by supplementation with exogenous SCFAs. Finally, SCFAs modulated pancreatic fibrosis through inhibition of macrophage infiltration and M2 phenotype switching. The study supports a critical role for SCFAs-producing G+ bacteria in CP. Therefore, modulation of dietary-derived SCFAs or G+ SCFAs-producing bacteria may be considered a novel interventive approach for the management of CP.

Antibiotic therapy is the standard of care for urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC). However, previous antibiotic therapy may impart a selective pressure that influences the population structure and pathogenic potential of infecting UPEC strains. Here, we conducted a 3-year study using whole-genome-sequencing analysis and retrospective medical record review to characterize how antibiotic exposure influenced the phenotypic antibiotic resistance, acquired resistome, virulome, and population structure of 88 UTI-causing E. coli strains from dogs. A majority of UTI-associated E. coli strains were from phylogroup B2 and clustered within sequence type 372. Previous antibiotic exposure was associated with a population shift toward UPEC from phylogroups other than the typical urovirulent phylogroup B2. The specific virulence profiles within the accessory virulome that were associated with antibiotic use were elicited by the effect of antibiotics on UPEC phylogenetic structure. Among phylogroup B2, antibiotic exposure increased the quantity of genes within the resistome and the odds of developing reduced susceptibility to at least one antibiotic. Non-B2 UPEC strains harbored a more diverse and greater resistome that conferred reduced susceptibility to multiple antibiotic classes following antibiotic exposure. Collectively, these data suggest that previous antibiotic exposure establishes an environment that provides a selective edge to non-B2 UPEC strains through their diverse and abundant antibiotic resistance genes, despite their lack of urovirulence genes. Our findings highlight the necessity for judicious use of antibiotics as we uncover another mechanism by which antibiotic exposure and resistance can influence the dynamics of bacterial infectious disease. IMPORTANCE Urinary tract infections (UTIs) are one of the most common infections of dogs and humans. While antibiotic therapy is the standard of care for UTIs and other infections, antibiotic exposure may influence the pathogenic profile of subsequent infections. We used whole-genome sequencing and retrospective medical record review to characterize the effect of systemic antibiotic therapy on the resistance, virulence, and population structure of 88 UTI-causing UPEC strains isolated from dogs. Our results indicate that antibiotic exposure alters the population structure of infecting UPEC strains, providing a selective edge for non-B2 phylogroups that harbor diverse and abundant resistance gene catalogues but fewer urovirulence genes. These findings highlight how antibiotic resistance can influence pathogen infection dynamics and have clinical implications for the judicious use of antibiotics for bacterial infections.

OBJECTIVE: We aim to evaluate the adherence rate to an Antimicrobial Stewardship Program (ASP) in an Intensive Care Unit (ICU), and to assess its effect on the use of antibiotics, quality indicators and clinical outcomes.
METHODS: Retrospective description of the interventions proposed by the ASP. We compared antimicrobial use, quality and safety indicators in an ASP versus a non-ASP period. The study was performed in a polyvalent ICU of a medium-size University Hospital (600 beds). We studied patients admitted to the ICU for any cause during the ASP period, provided that a microbiological sample aiming to diagnose a potential infection has been drawn, or antibiotics have been started. We elaborated and registered of non-mandatory recommendations to improve antimicrobial prescription (audit and feedback structure) and its registry during the ASP period (15 months, October 2018-December 2019). We compared indicators in a period with ASP (April-June 2019) and without ASP (April-June 2018).
RESULTS: We issued 241 recommendations on 117 patients, 67% of them classified as de-escalation type. The rate of adherence to the recommendations was high (96.3%). In the ASP period, the mean number of antibiotics per patient (3.3±4.1 vs 2.4±1.7, p=0.04) and the days of treatment (155 DOT/100 PD vs 94 DOT/100 PD, p <0.01) were reduced. The implementation of the ASP did not compromise patient safety or produce changes in clinical outcomes.
CONCLUSIONS: The implementation of an ASP is widely accepted in the ICU, reducing the consumption of antimicrobials, without compromising patient safety.

To investigate the relationship between antibiotic exposure and asthma in adults in the United States.
Data was obtained from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2018. A total of 51,124 participants were included, excluding those who were aged < 20 years, female participants who were pregnant, and individuals who did not complete the prescription medications questionnaire and the medical conditions questionnaire regarding asthma status. Antibiotic exposure was defined as the utilization of antibiotics within the past 30 days, categorized based on the Multum Lexicon Plus therapeutic classification system. Asthma was defined as having a history of asthma or having an asthma attack or wheezing symptoms in the past year.
The risk of asthma was found to be 2.557 (95% CI: 1.811, 3.612), 1.547 (95% CI: 1.190, 2.011) and 2.053 (95% CI: 1.344, 3.137) times greater in participants who had used macrolide derivatives, penicillin and quinolones in the past 30 days, respectively, compared with those not using antibiotics. After adjusting for demographic covariates and asthma-related factors, only macrolides derivatives were significantly associated with asthma in the 20-40 and 40-60 age groups. For individuals over 60 years old, quinolones were significantly associated with asthma. The effect of different types of antibiotic with asthma varied in male and female populations. Moreover, higher socioeconomic status, greater BMI, younger age, smoking habits, history of infection, chronic bronchitis, emphysema, and family history of asthma were all identified as risk factors for asthma.
Our study indicated that three types of antibiotics were significantly associated with asthma in different subgroups of the population. Therefore, the use of antibiotics should be more strictly regulated.

Gastrointestinal mucositis could potentially compromise drug absorption due to functional loss of mucosa and other pathophysiological changes in the gastrointestinal microenvironment. Little is known about this effect on commonly used anti-infectives. This study aimed to explore the association between different stages of gastrointestinal mucositis, drug exposure, and gut microbiota. A prospective, observational pilot study was performed in HSCT patients aged ≥ 18 years receiving anti-infectives orally. Left-over blood samples and fecal swabs were collected from routine clinical care until 14 days after HSCT to analyze drug and citrulline concentrations and to determine the composition of the gut microbiota. 21 patients with a median age of 58 (interquartile range 54-64) years were included with 252 citrulline, 155 ciprofloxacin, 139 fluconazole, and 76 acyclovir concentrations and 48 fecal swabs obtained. Severe gastrointestinal mucositis was observed in all patients. Due to limited data correlation analysis was not done for valacyclovir and fluconazole, however we did observe a weak correlation between ciprofloxacin and citrulline concentrations. This could suggest that underexposure of ciprofloxacin can occur during severe mucositis. A follow-up study using frequent sampling rather than the use of left-over would be required to investigate the relationship between gastrointestinal mucositis, drug exposure, and gut microbiome.

Oxytetracycline, a widely produced and administered antibiotic, is uncontrollably released in low concentrations in various types of environments. However, the impact of exposure to such low concentrations of antibiotics on the host remains poorly understood. In this study, we exposed zebrafish to a low concentration (5,000 ng/L) of oxytetracycline for 1 month, collected samples longitudinally (Baseline, and Days 3, 6, 9, 12, 24, and 30), and elucidated the impact of exposure on microbial composition, antibiotic resistance genes, mobile genetic elements, and phospholipid metabolism pathway through comparison of the sequenced data with respective sequence databases. We identified Pseudomonas aeruginosa, a well-known pathogen, to be significantly positively associated with the duration of oxytetracycline exposure (Adjusted P = 5.829e-03). Several tetracycline resistance genes (e.g., tetE) not only showed significantly higher abundance in the exposed samples but were also positively associated with the duration of exposure (Adjusted P = 1.114e-02). Furthermore, in the exposed group, the relative abundance of genes involved in phospholipid metabolism had also decreased. Lastly, we characterized the impact of exposure on zebrafish intestinal structure and found that the goblet cell counts were decreased (~82%) after exposure. Overall, our results show that a low concentration of oxytetracycline can increase the abundance of pathogenic bacteria and lower the abundance of key metabolic pathways in the zebrafish gut microbiome that can render them prone to bacterial infections and health-associated complications.

We aimed to evaluate the effect of procalcitonin (PCT) guided therapy on antibiotic exposure in pediatric patients with infectious disease.
We performed an updated systematic review and meta-analysis of randomized controlled trials (RCTs) identified in systematic searches of MEDLINE, Embase, the Cochrane Database, Google Scholar, and SinoMed (through July 2021). The primary outcome was the length of the antibiotic therapy. Required information size (RIS) was calculated using trial sequential analysis (TSA).
Four RCTs with 1,313 patients with infectious disease were included. Overall, after a mean 22-day follow-up, PCT-guided antibiotic therapy was associated with a significantly shorter length of antibiotic therapy compared with the control group (WMD, -2.22 days; 95% CI, -3.41 to -1.03; P <0.001) and a decreased rate of antibiotic adverse events (RR, 0.25; 95% CI, 0.11-0.58; P <0.001). However, the length of hospital stay (WMD, -0.39 days; 95% CI, -0.84 to 0.07; P = 0.094), rates of antibiotic prescription (RR, 1.10; 95% CI, 0.97-1.25; P = 0.122), hospital readmission (RR, 1.03; 95% CI, 0.92-1.16; P = 0.613) and mortality (RR, 0.73; 95% CI, 0.17-3.19; P = 0.674) were comparable between the PCT-guided antibiotic and control groups. TSA showed that the RIS was 2,340, indicating a statistically significantly shorter length of antibiotic therapy between PCT-guided antibiotic and control groups (P <0.05).
PCT-guided management seems to be able to decrease antibiotic exposure in patients with infectious disease. However, much larger prospective clinical studies are warranted to confirm these findings.