Classes Of Antibiotics Research Articles

P-1565. Antimicrobial Resistance among Gram-negative Urinary Isolates from Kidney Transplant Recipients: Implications for Precision Antimicrobial Stewardship

Abstract Background Urinary tract infections (UTI) in kidney transplant recipients (KTR) can lead to chronic allograft dysfunction, progression to sepsis, graft loss, and death. With such morbidity and even mortality, it is important to determine if this population has similar antimicrobial resistance (AMR) patterns to those of the general patient population in the same community, to determine the need for dedicated antibiograms, formulate empiric protocols for treatment, and optimize antimicrobial stewardship (AMS) interventions. Methods We captured positive urine cultures between 1/1/09 and 11/4/19 in KTR at Brown-University affiliated hospitals. We compared resistance rates to preferred oral antibiotics for the management of UTI and for ceftriaxone (CTX, marker of extended-spectrum beta-lactamase production) to those reported in our institutional antibiogram. The study was approved by the Lifespan Institutional Review Board. Results We studied 236 isolates from 294 KTR. 122 (42%) were females; 57 (19%) were Black. Median age at transplant was 55 (range: 10-82) years old. The most common causes of end-stage renal disease included hypertension (n=93, 32%) and diabetes (n=55, 19%). Of 187 Gram-negative organisms isolated, the most common were E. coli (n=112), K. pneumoniae (n=59), K. oxytoca (n=10), and E. cloacae (n=6). Compared to our general population, those isolates were more frequently resistant to ciprofloxacin (29% vs. 16%), nitrofurantoin (NTF, 29% vs. 16%), trimethoprim/sulfamethoxazole (TMS 65% vs. 19%) and CTX (12% vs. 7%) (Table, P< 0.05). Conclusion KTR are at high risk for the development of AMR, not only to TMPS, which they receive as Pneumocystis jirovecii prophylaxis, but other antibiotic classes as well. KTR-specific institutional antibiograms and targeted AMS interventions, such as provider education against treatment of asymptomatic bacteriuria in KTR, could help improve clinical outcomes and mitigate AMR. Disclosures Dimitrios Farmakiotis, M.D., Astra Zeneca: Grant/Research Support|Viracor: Advisor/Consultant|Viracor: Honoraria

P-1679. Discrepancies in antibiotic prescribing: revealing inappropriate use patterns

Abstract Background Inappropriate antibiotic prescribing fuels antimicrobial resistance (AMR) and compromises patient outcomes. This study aimed to elucidate the prevalence and factors associated with inappropriate antibiotic use across various agents and antibiotic groups.Table 1.Assessment of Inappropriate Antibiotic Prescribing Patterns by Antibiotic Type Methods A retrospective analysis of 1647 cases evaluated antibiotic prescribing patterns. We assessed both prescription rates and prevalence ratios (PR) to examine the appropriateness of antibiotic choice within and across groups.Table 2.Comparative analysis of prevalence factors for various antimicrobial groups Results Prescription rates indicated higher rates of inappropriate use for meropenem (22.8%) and carbapenems (20%) compared to other agents and groups. Conversely, PR analysis revealed a significantly lower likelihood of inappropriate prescribing for cephalosporins compared to carbapenems (adjusted PR: 0.43, 95%CI 0.29-0.66, p < 0.001). Glycylcyclines exhibited a markedly higher risk of inappropriate use (adjusted PR: 3.00, 95%CI 1.44-6.24, p=0.003), while glucopeptides also demonstrated a propensity for inappropriate prescribing (adjusted PR: 1.46, 95%CI: 1.12-1.89, p=0.004). Conclusion our study reveals notable discrepancies in the appropriateness of antibiotic prescriptions across different agents and antibiotic groups. While the analysis based on prescription rates demonstrated higher rates of inappropriate use for meropenem and carbapenems overall, prevalence ratio analysis highlighted specific trends within antibiotic classes. Cefalosporins consistently demonstrated a lower likelihood of inappropriate prescribing compared to carbapenems, suggesting their preferential use in clinical practice. However, caution is warranted with glicylcyclines, which exhibited a higher risk of inappropriate prescription. These findings underscore the importance of tailored interventions to optimize antibiotic prescribing practices, mitigate antimicrobial resistance, and improve patient outcomes. Disclosures All Authors: No reported disclosures

P-1211. Early Infections Predict Weight Gain and Obesity in US Children

Abstract Background An unexplained link between early viral infection and later weight gain has been observed in the US and internationally. In our population of children at Kaiser Permanente Southern California, we seek to confirm this association and determine the magnitude of the absolute weight increase. Methods In a retrospective cohort of children born 2008 – 2012, frequency of infection in infancy (≤12m), timing of first infection (< 6m vs 6-12m), and antibiotic use, class, timing, and frequency were assessed relative to absolute weight and body mass index (BMI) at age 4-6 and 10 years. Patients with low birthweight and prematurity were excluded. Maternal BMI, breastfeeding, birthweight, delivery type, and race/ethnicity were included in multivariable regression; height was also included when absolute weight was the outcome variable. Weight outcomes were compared in uninfected vs infected without antibiotic treatment in infancy (IWOT); and IWOT vs those infected who received antibiotic treatment (IWAT), using logistic regression analysis for obesity outcomes and linear regression for absolute weight. Results We identified N=66,687 children at 4-6y and N= 46,462 at 10y for analysis. Of the latter, 7,918 had been uninfected, 18,144 had IWOT, and 20,400 had IWAT. The IWOT group had higher rates of obesity vs uninfected (24% vs 19% at 10y; see figure 1), reflected in multivariable analysis at 4-6y (OR 1.11 [1.03-1.2]; p=0.004) and 10y (OR 1.14 [1.06-1.22]; p < 0.001), in a "dose-dependent" manner (Figure 2). The corresponding absolute weight increase (+0.55 kg [+0.3-0.8] at 10y; p< 0.001) was also dose-dependent (Figure 3). Compared to untreated infections, the additional contribution of antibiotic use to future obesity was minimal (OR 1.05 [0.99-1.1]; p=0.09) and not dose-dependent. Of the 10 year olds, most had upper respiratory infections (27,562 patients had at least one URI; 59%), ear infections (16,404 patients; 35%), or infections without a specified site (including viral syndromes; 11,822; 25%) in infancy. Conclusion A significant (14% at 10y) increase in obesity after early infection is confirmed, with a small (+0.55kg) corresponding increase in average weight. Prospective study in specific subgroups or with specific viruses of interest would be warranted. Disclosures All Authors: No reported disclosures

P-1657. Antibiotics in hospice and the patients who receive them

Abstract Background At the time of hospice enrollment, patients are asked whether they would potentially want antibiotics. This is little information regarding which patients are more likely to receive these antibiotics or the impact on comfort or longevity. To help guide discussions with patients and families and target future stewardship interventions, we sought to characterize the use of antibiotics in the outpatient hospice setting. Methods We performed a retrospective review of patients enrolled in hospice with the Mayo Clinic Health System -Midwest from 1/1/2017 through 1/1/2023. For those with documented Hospice Qualifying Condition (HQC), we assessed age at enrollment, gender, survival time (ST), and Charleston Comorbidity Index (CCI). We documented which antibiotics were prescribed and compared the rate of prescription based on the above characteristics. Results We identified 6452 patients with identifiable HQC. Of these, 1281 patients (19.8%) received 4173 antibiotic prescriptions. After removing refilled prescriptions, there were 2037 new prescriptions. Cephalosporins were the most common class of antibiotics prescribed (24.4% of antibiotics prescribed), followed by fluoroquinolones (19.9%), penicillin derivatives (14.4%), and trimethoprim (10.4%) (fig 1). Pulmonary (28.6%) and GI (31.9%) HQCs were most likely to receive antibiotics, neurologic was least likely (fig 2). There was no difference of age for those receiving antibiotics (80.6 yr) vs those not receiving (80.3 yr [p=0.53]), or for gender (male vs female OR 0.97 [0.86-1.10). CCI was higher in those patients who received antibiotics (4.3) than those not receiving (3.93, p< 0.001). Patients were more likely to receive antibiotics the longer they survived on hospice (4.7% surviving < 7d, 47.7% surviving >6mo – fig 3). Conclusion Antibiotics are an important pharmaceutical tool in the hospice setting. Nearly 20% of patients in hospice will receive antibiotics during their hospice course, with higher chance in those surviving longer periods and those enrolled for GI or pulmonary reasons. Discussions of antibiotic are crucial for these groups, and antimicrobial steward efforts should consider focusing on these patients. Disclosures All Authors: No reported disclosures

P-1339. Navigating Antibiotic Susceptibility Testing: The Antibiotic Breakpoint Explorer (ABE 1.0)

Abstract Background The landscape of antibiotic susceptibility testing has evolved significantly, with constant revisions to antibiotic breakpoint definitions by key standard-setting bodies: the Clinical and Laboratory Standards Institute (CLSI), the Food and Drug Administration (FDA), and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). These changes reflect advances in scientific understanding, emerging resistance patterns, and the need for harmonization across international guidelines. However, staying abreast of these evolving breakpoints can be challenging for healthcare professionals. The Antibiotic Breakpoint Explorer 1.0 (ABE 1.0) is an innovative tool that simplifies antibiotic susceptibility testing interpretation with current 2024 breakpoint interpretive criteria. Methods Antibiotic breakpoints for minimum inhibitor concentration (MIC) were consolidated from the CLSI, FDA and EUCAST websites for current 2024 breakpoint interpretative criteria for 15 Gram-negative pathogens and 30 antibiotics from 10 antibiotic classes (Table 1). ABE 1.0 was programmed using Python 3.12.2 and the Streamlit package. ABE 1.0 is hosted as a web-based tool hosted at www.petrifiedbugs.com. The initial beta version of the program is accessible at https://newbreak-hxdfezfsrkpuusfjpfkrby.streamlit.app/ Results By consolidating breakpoint information from CLSI, FDA, and EUCAST guidelines for the top 15 Gram-negative pathogens, ABE 1.0 provides a simple user-friendly web-based tool to help users make informed decisions regarding antibiotic therapy and resistance management for 30 key clinically used antibiotics (Figure 1). Conclusion ABE 1.0 addresses the challenge of navigating antibiotic breakpoints by offering a user-friendly platform that consolidates antibiotic breakpoint information from CLSI, FDA, and EUCAST guidelines into a single, easily accessible resource. Disclosures Arryn Craney, PhD D(ABMM), MiraVista Diagnostics: Employee; Salary

P-1545. Evaluation of Clinical Efficacy of Systemic Antibiotics for Treatment of Acute Pyelonephritis in Adults: A Network Meta-Analysis of Randomized Controlled Trials

Abstract Background Acute pyelonephritis, a severe form of urinary tract infection (UTI), poses significant health risks including kidney damage and urosepsis. Current clinical guidelines, last updated in 2010, primarily focus on women with uncomplicated UTIs, leaving a gap in recommendations for broader cases. Our study aims to bridge this gap by conducting an updated literature review to evaluate the efficacy of various antibiotics for acute pyelonephritis. Figure 1: Flow diagram of study selection Methods We conducted a systematic review of PubMed and Embase databases from inception to July 2023. We included randomized controlled trials (RCTs) involving adults (≥18 years) treated for acute pyelonephritis across various care settings. Our review focused on English-language articles examining intravenous (IV), oral, and IV-to-oral antibiotic treatments. Studies reporting outcomes specifically for pyelonephritis were eligible. We performed a frequentist network meta-analysis to evaluate clinical success, microbiological cure, and composite clinical or microbiological cure of different antibiotic therapies.Figure 2:Network plot of RCTs evaluating A) clinical cure, B) microbiological cure, and C) composite outcome of clinical cure or microbiological cure Results We included 37 RCTs (Figure 1). Due to data limitations, we assessed antibiotic classes rather than individual antibiotics (Figure 2). For clinical cure (n=1290, 11 RCTs), both fluoroquinolones (Odds Ratio [OR]: 3.71, 95% confidence interval [CI]: 1.30-10.55; P-score: 0.8215) and cephalosporins (OR: 3.45, 95% CI: 1.30-10.55; P-score: 0.7420) outperformed trimethoprim-sulfamethoxazole (TMP-SMX), with fluoroquinolones ranking highest in efficacy. For microbiological cure (n=1270, 11 RCTs), aminoglycosides (OR: 19.85, 95% CI: 1.62-243.61; P-score: 0.8373), fluoroquinolones (OR: 13.69, 95% CI: 1.73-108.03; P-score: 0.7785), cephalosporins (OR: 10.33, 95% CI: 1.20-88.73; P-score: 0.5395), and carbapenems (OR: 9.92, 95% CI: 1.14-86.61; P-score: 0.5394) were superior to TMP-SMX. Aminoglycosides ranked highest in efficacy. Regarding composite outcomes (n=2164, 6 RCTs), cephalosporins (P-score: 0.9898) and fluoroquinolones (0.7377) ranked highest in efficacy.Figure 3:Efficacy of systemic antibiotics in A) clinical cure, B) microbiological cure, and C) composite outcome of clinical cure or microbiological cure in adult patients with acute pyelonephritis.League tables display the results [OR (95% CI)] of pairwise meta-analysis in the upper right half, when available, and the results of the network meta-analysis in the left lower half. CI, confidence interval; OR, odds ratio; TMP-SMX, trimethoprim-sulfamethoxazole. Conclusion In adults with acute pyelonephritis, fluoroquinolones and cephalosporins demonstrate the highest efficacy probability, while TMP-SMX exhibits the lowest. Further studies are warranted to validate these findings. Disclosures All Authors: No reported disclosures

P-1835. Evolution of Antibiotic Resistance Patterns in Acinetobacter baumannii Clinical Isolates in Response to Bleach Exposure

Abstract Background Acinetobacter baumannii (Ab) is a common cause of drug-resistant infections. Ab rapidly acquires antibiotic resistance and can survive exposure to numerous antiseptics such as bleach. Prior research has demonstrated increased antibiotic resistance in Ab following exposure to antiseptics, likely due to increased expression of efflux pumps, but the relationship between antiseptic resistance and antibiotic resistance is not well known. In this study, we describe the evolution of antibiotic resistance in two Ab isolates following exposure to bleach.Table 1:Antibiotic Susceptibilities for Evolved Strains of ACB3 Antibiotic susceptibilities for the evolved strains of ACB3 are depicted. For each strain, antibiotic susceptibilities were determined based on Clinical & Laboratory Standards Institute (CLSI) reference standards, and were classified as susceptible (S) or non-susceptible (NS). Non-susceptible values were those that were determined to be either intermediate or resistant. ACB3 was initially susceptible to most antibiotics at G0, and developed increased resistance to all antibiotic classes by G450. Methods Two Ab clinical isolates, ACB3 and ACB9, were exposed to sublethal (0.01%) concentrations of bleach and grown in triplicate, with strains selected at baseline (G0), the 450th generation (G450), and the 1000th generation (G1000) for further analysis. Antibiotic susceptibility profiles for each strain were established by determining minimum inhibitory concentration (MIC) values against 24 standard-of-care antibiotics using broth microdilution assays. Whole genome sequencing (WGS) of each strain was performed to evaluate for the emergence of new alleles to affecting antibiotic resistance.Table 2:Antibiotic Susceptibilities for Evolved Strains of ACB9 Antibiotic susceptibilities for the evolved strains of ACB9 are depicted. For each strain, antibiotic susceptibilities were determined based on Clinical & Laboratory Standards Institute (CLSI) reference standards, and were classified as susceptible (S) or non-susceptible (NS). Non-susceptible values were those that were determined to be either intermediate or resistant. NS* denotes strains with MIC values that were decreased, but not enough to be classified as susceptible. ACB9 was initially PDR at G0 but developed increased susceptibility to all aminoglycoside and tetracycline drugs by G1000. Results The ACB3 line was susceptible to most antibiotics at G0, but developed increased resistance to various antibiotics by G450, particularly against aminoglycoside and beta-lactam drugs (Table 1). Conversely, the ACB9 line was pan-drug resistant (PDR) at G0 but developed increased susceptibility to all aminoglycoside and tetracycline drugs by G1000 (Tables 2, 3). WGS of ACB9 G1000 demonstrated mutations in uvrA and uvrB, which encode nucleotide excision repair proteins, with concomitant mutations in the ABC transporter TssG, and type IV secretion system (T4SS) proteins TssC and VgrG. Mutations were observed in numerous other unidentified genes with close homology to ABC transporters, MFS efflux pumps, and OprD porins.Table 3:Minimum Inhibitor Concentration (MIC) Values for Aminoglycoside and Tetracycline Drugs Against Evolved Strains of ACB9 MIC values for aminoglycoside and tetracycline drugs against evolved strains of ACB9 are depicted. All three triplicates of ACB9 were initially resistant to all aminoglycoside and tetracycline drugs tested at G0. By G1000, all three triplicates demonstrated increased susceptibility to all aminoglycoside and tetracycline drugs, as indicated by decreased MIC values. Conclusion We describe the evolution of antibiotic resistance in Ab after exposure to bleach. ACB3 was initially susceptible to most antibiotics but developed increased resistance. ACB9 was initially PDR but developed increased susceptibility to aminoglycoside and tetracycline drugs, likely due to mutations in hypermutators uvrA and uvrB, enabling mutations in genes which may confer resistance to these drugs. Disclosures All Authors: No reported disclosures

P-124. Ongoing Infections with Extensively Drug-Resistant Campylobacter jejuni Linked to Pet Store Puppies

Abstract Background Campylobacter is the leading cause of enteric bacterial infections in the United States, causing an estimated 1.5 million illnesses annually. Antimicrobial therapy can reduce the duration of illness and limit complications; macrolides and fluoroquinolones are typically recommended as first- and second-line treatment, respectively. The Centers for Disease Control and Prevention (CDC) investigates emerging resistance in Campylobacter strains to identify potential sources and collaborate on approaches to reduce its spread. Here, we describe extensively drug-resistant (XDR) strains linked to pet store puppies. Methods State public health departments perform whole genome sequencing on Campylobacter isolates as resources allow and submit sequence data to CDC. CDC assesses isolate relatedness using core genome multilocus sequence typing (cgMLST) and screens isolate sequences for resistance determinants to predict antimicrobial resistance (older isolates sequenced retroactively are also screened). We considered isolates to be XDR if they showed predicted resistance to macrolides, fluoroquinolones, and ≥ 3 additional antibiotic classes. Persons with XDR isolates were interviewed about exposures when possible. Results We identified three strains of XDR C. jejuni; the oldest isolates were from 2007. Although these strains are not highly related phylogenetically ( > 200 allele differences between strains by cgMLST), cases share epidemiological and clinical characteristics. As of June 30, 2023, CDC received reports of 274 cases associated with these strains. Affected individuals had a median age of 36 years (interquartile range, 20–52); 66% were female, and 23% were hospitalized. Of those affected, 97% reported contact with a dog before becoming ill, among whom 78% reported contact with a puppy from a pet store. Conclusion Clinicians should be aware that strains of XDR Campylobacter are circulating in the United States and should consider XDR infection when patients fail to respond to routine treatment, particularly if they have recently had contact with pet store puppies. Carbapenem antibiotics may be used for severe infections that are resistant to recommended treatment agents. Disclosures All Authors: No reported disclosures

P-1650. Clinical Outcomes among Patients Prescribed Suboptimal Antibiotic Therapy on Discharge to Nursing Homes

Abstract Background Little is known regarding outcomes for patients prescribed antibiotics on discharge from the hospital to nursing homes (NHs). We quantified the association between suboptimal antibiotic prescribing and clinical outcomes at discharge to NHs. Methods This was a multicenter, retrospective cohort study of adult (age >18 years) patients prescribed systemic antibiotics on discharge from 9 acute care hospitals in Oregon, Washington, and Wisconsin to a NH from 2016 – 2018. Study data were electronically extracted from hospital and NH electronic health records and supplemented with chart review. Suboptimal antibiotic therapy was determined by an infectious disease pharmacist or physician using clinical information (e.g., antibiotic regimen, indication, and culture results) available at discharge. Outcomes included emergency department (ED) visits, hospital readmissions, or Clostridioides difficile infection (CDI) within 30 days of hospital discharge. Comparison of outcomes between patients with suboptimal and non-suboptimal antibiotic therapy were tested by chi-squared tests. Results Among 280 included patients, mean (SD) age was 76.0 (11.5) years, 35.7% (n=100) were male, and median (IQR) inpatient length of stay was 6 (4-9) days. The most prevalent antibiotic indications were urinary tract infections (n =109, 38.9%), lung indications (n=60, 21.4%), and prophylaxis (n=29, 10.4%). Among 317 antibiotic prescriptions, the most frequently prescribed antibiotic classes were cephalosporins (n=83, 29.6%), fluoroquinolones (n=57, 20.4%), and beta-lactam/beta-lactamase-inhibitors (n=40, 14.3%). Fifty-eight patients (20.7%) were prescribed suboptimal antibiotic therapy on hospital discharge. There were no significant differences in the frequency of 30-day ED visits (14% vs 11%, p=0.76) or hospital readmission (19% vs 18%, p=0.94) between patients prescribed and not prescribed suboptimal antibiotics; however, suboptimal antibiotics were significantly associated with CDI within 30 days of discharge (10% vs 2%, p=0.01). Conclusion Suboptimal antibiotic prescribing on discharge to NHs was associated with increased risk of CDI within 30 days of discharge. This finding may inform interventions to improve antibiotic prescribing on discharge to NHs. Disclosures YoungYoon Ham, PharmD, Gilead: Honoraria Jon P. Furuno, PhD, Merck & Co., Inc: Grant/Research Support

P-1792. Impact of Integrated Interventions of Prescriber Education and De-escalation Strategies on Implementing WHO Access: Watch Targets: Insights from a South Indian Tertiary Care Setting

Abstract Background The study aims to determine the Access: Watch ratio, as recommended by the WHO AWaRE guide 2022, to regulate antimicrobial prescribing practices, highlighting the importance of educational sessions for successful AMS interventions.Table 1:Quantification of antibiotic use during the study periodBased on Days of therapy (DOT), an AMS metric. Methods The study analyzed antimicrobial usage data from 360 patients from March to July 2023. It quantified DOT by comparing Access and Watch group antibiotics. The first three months focused on auditing antimicrobial prescribing practices, followed by a session on rational prescribing and an educational survey. The second two months focused on feedback on the impact of educational interventions.Figure 1:Trend of Access:Watch ratio of antibiotics during the study period Results The use of Cefoperazone + Sulbactam, a broad-spectrum watch class antibiotic, was high in April and May (48.7 and 50.7, respectively) but decreased to 19.3 and 18.1 in the subsequent months following educational interventions. Optimization of de-escalation practices through audit and feedback strategies, emphasized in the continuing medical education sessions, contributed to this reduction. The Access: Watch Ratio increased from 0.45 to 0.52 over the study period, indicating a reduction in Watch antibiotic use. Pre-survey results showed 88.9% of prescribers considered de-escalation safer, increasing to 100% post-intervention. Various case-scenarios presented to prescribers showed improved understanding and adoption of rational antibiotic prescribing and de-escalation strategies after the educational session. Conclusion Integrated interventions, including prescriber education and de-escalation strategies, were effective in achieving the WHO Access: Watch target in our South Indian tertiary care setting. The reduction in Watch antibiotic use and the increase in the Access: Watch ratio demonstrate the impact of these interventions on antimicrobial prescribing practices. Ongoing education and support for rational antibiotic use are critical in addressing antimicrobial resistance. Disclosures All Authors: No reported disclosures

Clinical considerations on antimicrobial resistance potential of complex microbiological samples.

Antimicrobial resistance (AMR) is one of our greatest public health challenges. Targeted use of antibiotics (ABs) can reduce the occurrence and spread of AMR and boost the effectiveness of treatment. This requires knowledge of the AB susceptibility of the pathogens involved in the disease. Therapeutic recommendations based on classical AB susceptibility testing (AST) are based on the analysis of only a fraction of the bacteria present in the disease process. Next and third generation sequencing technologies allow the identification of antimicrobial resistance genes (ARGs) present in a bacterial community. Using this metagenomic approach, we can map the antimicrobial resistance potential (AMRP) of a complex, multi-bacterial microbial sample. To understand the interpretiveness of AMRP, the concordance between phenotypic AMR properties and ARGs was investigated by analyzing data from 574 Escherichia coli strains of five different studies. The overall results show that for 44% of the studied ABs, phenotypically resistant strains are genotypically associated with a 90% probability of resistance, while for 92% of the ABs, the phenotypically susceptible strains are genotypically susceptible with a 90% probability. ARG detection showed a phenotypic prediction with at least 90% confidence in 67% of ABs. The probability of detecting a phenotypically susceptible strain as resistant based on genotype is below 5% for 92% of ABs. While the probability of detecting a phenotypically resistant strain as susceptible based on genotype is below 5% for 44% of ABs. We can assume that these strain-by-strain concordance results are also true for bacteria in complex microbial samples, and conclude that AMRP obtained from metagenomic ARG analysis can help choose efficient ABs. This is illustrated using AMRP by a canine external otitis sample.

Fish epidermal mucus-derived antimicrobial peptides: Classification, structure, biological activities, and potential biotechnological applications

Abstract In recent years the advent and spread of diverse multidrug-resistant bacteria has become a serious concern not only in the medical field but also in public health. The dissemination of drug-resistant pathogens has been considerably hastened by human activities in the clinical practice, livestock, and aquaculture sectors. Therefore, there is an urgent need to explore novel classes of antimicrobial agents against resistant bacterial pathogens. Antimicrobial peptides (AMPs), or host defense peptides, are synthesized by ribosomal or non-ribosomal mechanisms, which are vital components of the innate immune system in fish. Fish epidermal mucus can serve as a sources of unique peptides with a broad range of biological activities including antimicrobial activity towards multidrug-resistant pathogens, anticancer, wound healing, etc. AMPs derived from epidermal mucus are recognized as a novel class of antibiotics owing to their inimitable and multidimensional effects, including the low possibility for developing antimicrobial resistance, minimal cytotoxicity towards mammalian cells, high selective cytotoxicity against pathogens, low residual flesh, and the capacity to modulate the host immune responses. Additionally, the mucosal composition varies among fish species and is influenced by both endogenous and exogenous factors, which could be leveraged to identify new drugs in the future. This review investigates the AMPs produced by aquatic fish, their unique properties as potent therapeutic agents as well as classifications and biological activities.

Identification of NDM-1 producing and colistin resistant Klebsiella pneumoniae ST11: A highly drug-resistant strain detected in intensive care unit of a Greek tertiary care hospital.

The spread of NDM-1-harboring Klebsiella pneumoniae is a worldwide concern. In this study the whole-genome sequence (WGS) of a carbapenem- and colistin-resistant K. pneumoniae 838Gr strain is presented. This strain was isolated from a urine sample of a patient in the Intensive Care Unit (ICU) at Volos Hospital, Greece. The initial assembly produced 224 contigs with a combined genome size of 5,561,803 bp and a GC content of 57.21%. The K. pneumoniae strain carried IncR, IncFIA, IncC, and repB (R1701) replicons. Multilocus sequence typing (MLST) analysis revealed that the isolate belonged to the sequence type 11 (ST11) and serogroup KL24 and O2a. The WGS analysis identified several beta-lactamase genes (blaTEM-1B, blaCTX-M-15, blaNDM-1, blaOXA-1, blaVEB-1, blaOXA-10, and blaSHV-11) alongside resistance genes for other antibiotic classes, including floR2, cmlA1, cmlA5, catB3, arr-3, aph(6)-Id, aadA2. Colistin resistance was attributed to specific point mutations in pmrB (R256G, T140P). This is the first report of a carbapenem- and colistin-resistant K. pneumoniae ST11 strain in Greece. The findings of this study highlight the urgent need for increased surveillance and stringent infection control.

Evaluation of multidrug resistance in the Gram-negative microbiome of cancer patients and the adverse effects of their metabolites on albino rats and epithelial or fibroblasts cell lines

BackgroundCancer is a significant global health issue due to its high incidence and mortality rates. In recent years, the relationship between the human microbiota and cancer has garnered attention across various medical fields. This includes research into the microbial communities that influence cancer development, tumor-associated microorganisms, and the interactions between the microbiome and tumor, collectively referred to as the oncobiome.MethodsThe negative effects of secondary metabolites extracted from selected multidrug-resistant Gram-negative bacteria within the cancer microbiota were evaluated. These effects included carcinogenicity, mutagenicity, hepatotoxicity, nephrotoxicity, and sperm deformities observed in albino rats after one month of oral ingestion of these microbial extracts.ResultsOur findings in the present investigation revealed that among the bacterial community derived from the microbiota, Gram-negative bacteria accounted for 74.87% the total microbiota (146 out of 195) and their spectrum including Escherichia sp. (n = 36, 24.66%) followed by Acinetobacter sp. (n = 34, 23.29%), Stenotrophomonas sp. (n = 29, 19.86%), Pseudomonas sp. (n = 26, 17.81%) and Serratia sp. (n = 21, 14.38%), as the most prevalent pathogens. All isolates derived from the cancer microbiome exhibited multidrug resistance to a large number of conventional therapies. Out of them Serratia sp. Esraa 1, Stenotrophomonas sp. Esraa 2, Acinetobacter sp. Esraa 3, Escherichia sp. Esraa 4 and Pseudomonas sp. Esraa 5 strains showed multidrug resistant profile against all antibiotic classes under study including penicillins, cephalosporins, carbapenems, fluoroquinolones, β-lactamase inhibitors combinations, folate synthesis pathway inhibitors, phosphonic, aminoglycosides, polymyxins, tetracyclines, macrolides, and chloramphenicol antibiotics. The adverse effects of oral ingestion of their metabolites were evaluated in albino rats. They induced pronounced carcinogenesis along with severe raise in the inflammatory cytokines, hepatotoxicity, nephrotoxicity, mutagenicity along with sperm deformities in treated animals. Moreover, all metabolites showed marked cytotoxicity against human normal cell lines; human mammary epithelial (MCF10A), human lung fibroblasts (WI38) and human dermal fibroblasts (HDFs).ConclusionThese bacterial strains isolated from the cancer microbiome may play significant roles in inducing cancer, inflammation, mutagenesis, hepatotoxicity, nephrotoxicity, and sperm abnormalities, along with histopathological changes in the treated animal groups by orally administrated metabolites in compared to the untreated group.Graphical

Clostridioides difficile colonization is not mediated by bile salts and utilizes Stickland fermentation of proline in an in vitro model.

Treatment with antibiotics is a major risk factor for Clostridioides difficile infection, likely due to depletion of the gastrointestinal microbiota. Two microbiota-mediated mechanisms thought to limit C. difficile colonization include the conversion of conjugated primary bile salts into secondary bile salts toxic to C. difficile growth and competition between the microbiota and C. difficile for limiting nutrients. Using a continuous flow model that simulates the nutrient conditions of the distal colon, we investigated how treatment with 6 clinically used antibiotics influenced susceptibility to C. difficile infection in 12 different microbial communities cultivated from healthy individuals. Antibiotic treatment reduced microbial richness; disruption varied by antibiotic class and microbiota composition, but did not correlate with C. difficile susceptibility. Antibiotic treatment also disrupted microbial bile salt metabolism, increasing levels of the primary bile salt, cholate. However, changes in bile salt did not correlate with increased C. difficile susceptibility. Furthermore, bile salts were not required to inhibit C. difficile colonization. We tested whether amino acid fermentation contributed to the persistence of C. difficile in antibiotic-treated communities. C. difficile mutants unable to use proline as an electron acceptor in Stickland fermentation due to disruption of proline reductase (prdB-) had significantly lower levels of colonization than wild-type strains in four of six antibiotic-treated communities tested. The inability to ferment glycine or leucine as electron acceptors, however, was not sufficient to limit colonization in any communities. The data provide further support for the importance of bile salt-independent mechanisms in regulating the colonization of C. difficile.IMPORTANCEClostridioides difficile is one of the leading causes of hospital-acquired infections and antibiotic-associated diarrhea. Several potential mechanisms through which the microbiota can limit C. difficile infection have been identified and are potential targets for new therapeutics. However, it is unclear which mechanisms of C. difficile inhibition represent the best targets for the development of new therapeutics. These studies demonstrate that in a complex in vitro model of C. difficile infection, colonization resistance is independent of microbial bile salt metabolism. Instead, the ability of C. difficile to colonize is dependent upon its ability to metabolize proline, although proline-dependent colonization is context dependent and is not observed in all disrupted communities. Altogether, these studies support the need for further work to understand how bile-independent mechanisms regulate C. difficile colonization.

Phenotypic and Transcriptomic Changes in Acinetobacter baumannii in Rich and Minimal Growth Mediums.

Acinetobacter baumannii is an opportunistic pathogen that is often studied in commonly used rich media in laboratories worldwide. Due to the metabolic versatility of A. baumannii, it can be cultured in different growth mediums; however, this can lead to genotypic and phenotypic variations. In this study, we compared phenotypic and transcriptomic changes in A. baumannii ATCC17978 VUcultured in M9 minimal media supplemented with 20 mM sodium succinate and rich lysogeny broth media. Phenotypically, growth was significantly slowed, virulence in Galleria mellonella was attenuated, and susceptibility to a variety of antibiotic classes was reduced when A. baumannii ATCC17978 VU was grown in minimal media versus rich media. Transcriptomic analysis showed differential regulation of >700 genes-including those associated with energy production and ribosomal function-when the two growth conditions were compared, with the majority of the upregulated genes seen in minimal media of unknown function. This study showed that culture media has a profound effect on the phenotype and cellular workings of a bacteria, highlighting the need for more studies of pathogens like A. baumannii ATCC17978 VU in minimal media.

Synthesis of mutual prodrug of mefenamic acid and fluroquinolones

A novel strategy in medicinal chemistry to increase the therapeutic efficacy and reduce the side effects of separate medications is the creation of mutual prodrugs. The production and pharmacological assessment of a mutual prodrug including the broad-spectrum antibiotic class fluoroquinolones and the nonsteroidal anti-inflammatory drug (NSAID) mefenamic acid are the main topics of this paper. The justification for this combination is its ability to reduce the gastrointestinal and other systemic side effects that are frequently linked to NSAIDs and fluoroquinolones, while also potentially enhancing anti-inflammatory and antibacterial activity in a synergistic manner. The chemical characteristics, production pathways, and modes of action of mefenamic acid and fluoroquinolones are thoroughly covered in this work. The design strategies for mutual prodrugs are further examined, emphasising the need to optimise reaction conditions and choose appropriate chemical linkers in order to produce a stable and potent prodrug. By contrasting the mutual prodrug with its parent molecules, a review of in vitro and in vivo research is conducted to assess the pharmacokinetic and pharmacodynamic advantages of this strategy. The paper also discusses the difficulties that arise during the synthesis and development of mutual prodrugs, such as problems with stability, bioavailability, and regulatory barriers. Future perspectives on the potential of mutual prodrugs in drug development are discussed in the paper's conclusion, which highlights the need for more study to get past present obstacles and fully realise the therapeutic benefits of this exciting approach.

Isolation and Characterization of Colistin-Resistant Enterobacteriaceae from Foods in Two Italian Regions in the South of Italy.

The emergence of colistin-resistant Enterobacteriaceae in food products is a growing concern due to the potential transfer of resistance to human pathogens. This study aimed to assess the prevalence of colistin-resistant Enterobacteriaceae in raw and ready-to-eat food samples collected from two regions of Italy (Apulia and Basilicata) and to evaluate their resistance phenotypes and genetic characteristics. A total of 1000 food samples were screened, with a prevalence of 4.4% of colistin-resistant Enterobacteriaceae. The majority of the isolates belonged to Enterobacter spp. (60%), followed by Moellerella wisconsensis, Atlantibacter hermannii, Klebsiella pneumoniae, and Escherichia coli, among others. Genomic sequencing and antimicrobial susceptibility testing revealed high levels of resistance to β-lactams, with most isolates exhibiting multidrug resistance (MDR). Notably, seven isolates harbored mcr genes (mcr-1, mcr-9, and mcr-10). Additionally, in four of them were predicted the IncHI2 plasmids, known to facilitate the spread of colistin resistance. Furthermore, 56 antimicrobial resistance genes were identified, suggesting the genetic mechanisms underlying resistance to several antibiotic classes. Virulence gene analysis showed that E. coli and other isolates carried genes linked to pathogenicity, increasing the potential risk to public health. This study emphasizes the role of food as a potential reservoir for colistin-resistant bacteria and the importance of monitoring the spread of AMR genes in foodborne pathogens.

Chloramphenicol-mobilized Bacillus subtilis transiently expresses resistance to multiple antibiotics, including the glycopeptides phleomycin and bleomycin.

Antibiotic resistance is a global crisis that stems from the use of antibiotics as an essential part of modern medicine. Understanding how antibiotic resistance is controlled among cells in bacterial populations will provide insights into how antibiotics shape microbial communities. Here, we describe patterns of B. subtilis gene expression that arise from growth on a surface either in isolation or under subinhibitory chloramphenicol exposure. We identified elevated expression of genes encoding five different antibiotic resistance functions. The expression of four of the five resistance functions is controlled by a combination of terminator attenuation and transcriptional regulation. Two of these, vmlR and tlrB provide resistance to lincosamides and tylosin, respectively. We found that bmrCD promotes resistance to glycopeptides, including phleomycin and bleomycin. Promoter fusions to luciferase were used to follow expression of bmrCD, vmlR, and tlrB. Subinhibitory chloramphenicol exposure induces sliding motility of B. subtilis, wherein the three antibiotic resistance functions are expressed heterogeneously in spatiotemporally segregated pattern. We found that their expression is transiently elevated even in the absence of antibiotic exposure. The data suggest that for some antibiotics, intrinsic resistance genes are entrained to changes in growth and metabolism. Antibiotic exposure amplifies their expression, potentially providing a subpopulation of cells elevated protection to multiple classes of antibiotic.

Antibiotic Use and Subsequent Cognitive Decline and Dementia Risk in Healthy Older Adults.

Antibiotics rapidly reduce intestinal bacterial diversity, leading to dysbiosis that persists for months to years. Although emerging evidence from retrospective and claims-based studies has linked dysbiosis to cognitive function, prospective data are lacking. We aim to examine the prospective association of antibiotics with cognitive aging among initially healthy older adults. We leveraged data from prospective follow-up and observational extension of ASPirin in Reducing Events in the Elderly, a completed randomized trial of community-based Australian older adults. Among participants whose prescription records were available and without dementia during the first 2 years of follow-up, we identified any or repeated antibiotic use based on the Anatomical Therapeutic Chemical code (J01). We assessed the associations of antibiotic use during the first 2 years with longitudinal changes in standardized composite and domain-specific cognitive scores (global cognition, episodic memory, language and executive function, and psychomotor speed) using linear mixed models, and with incident, clinically adjudicated dementia (Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition criteria) and incident cognitive impairment, no dementia (CIND, without a dementia trigger but with significant, nontransient decline), using Cox proportional hazard models. Over a median of 4.7 years after the second follow-up visit, we documented 461 dementia and 2,576 CIND cases among 13,571 participants (mean age ± SD 75.0 ± 4.1 years, 54.3% female). Compared with nonuse, antibiotic use was not associated with increased risks for dementia (hazard ratio [HR] 1.03; 95% CI 0.84-1.25), CIND (HR 1.02; 95% CI 0.94-1.11), or subsequent declines in cognitive scores, after adjusting for sociodemographic, lifestyle factors, family history of dementia, baseline cognitive function, and medications known to affect cognition. There were also no associations according to the cumulative frequency of antibiotic use, long-term use, specific antibiotic classes (e.g., beta-lactams, tetracyclines, and sulfonamides), and subgroups defined by risk factors. Among initially healthy older adults, any or repeated antibiotic use was not associated with incident dementia, CIND, or accelerated cognitive decline. Although prescription data may not reflect the actual use, we examined the frequency of antibiotics within a defined period to capture the extent and duration of antibiotic exposure. Our results do not support an association between antibiotic-associated gut microbiome disruption and dementia risk.