Selective Antibiotics Research Articles

Investigating the feasibility and potential of combining industry AMR monitoring systems: a comparison with WHO GLASS.

Efforts to estimate the global burden of antimicrobial resistance (AMR) have highlighted gaps in existing surveillance systems. Data gathered from hospital networks globally by pharmaceutical industries to monitor antibiotic efficacy in different bacteria represent an underused source of information to complete our knowledge of AMR burden.. We analysed available industry monitoring systems to assess to which extent combining them could help fill the gaps in our current understanding of AMR levels and trends. We analysed six industry monitoring systems (ATLAS, GEARS, SIDERO-WT, KEYSTONE, DREAM, and SOAR) obtained from the Vivli platform and reviewed their respective isolates collection and analysis protocols. Using the R software, we designed a pipeline to harmonise and combine these into a single dataset. We assessed the reliability of resistance estimates from these sources by comparing the combined dataset to the publicly available subset of WHO GLASS for shared bacteria-antibiotic-country-year combinations. Combined, the industry monitoring systems cover 18 years (4 years for GLASS), 85 countries (71), 412 bacterial species (8), and 75 antibiotics (25). Although all industry systems followed a similar centralised testing approach, the patient selection protocol and associated sampling period were unclear. Over all reported years and countries, E.coli, K. pneumoniae and S. aureus resistance rates were in >65% of cases within 0.1 of the corresponding estimate in GLASS. We did not identify systemic bias towards resistance in industry systems compared to GLASS. High agreement values for available comparisons with GLASS suggest that data for other bacteria-antibiotic-country-year combinations only present in industry systems could complement GLASS; however, for this purpose patient and isolate selection criteria must first be clarified to understand the representativeness of industry systems. This additional source of information on resistance levels could help clinicians and stakeholders prioritize testing and select appropriate antibiotics in settings with limited surveillance data.

Effectiveness of selective antibiotics use in ESBL-related UTIs

BackgroundUrinary tract infections (UTIs) are the second most common infection, affecting 150 million people each year worldwide. Enterobacteriaceae species expressing extended-spectrum β-lactamases (ESBLs) are on the rise across the globe and are becoming a severe problem in the therapeutic management of clinical cases of urinary tract infection. Knowledge of the prevalence and antibiogram profile of such isolates is essential to develop an appropriate treatment methodology. This study aimed to investigate the prevalence of Enterobacteriaceae isolates exhibiting ESBL and their selective oral antibiogram profile at the district general hospital, Polonnaruwa.ResultsA total of 4386 urine specimens received to the Microbiology Laboratory during the study period. Among them, 1081 (24.6%) showed positive results for urine culture while 200/1081 specimens showed ESBL isolates. Out of the selected 200 specimen’s majority (67.5%) of samples received from the In-Patient Department. There were 200 patients and reported that 115 (57.5%) were females and 85 (42.5%) were males. The majority (51%) of the patients belong to the age group of 55–74 years. Among the ESBLs positive specimens, the majority 74.5% (n = 149) identified organisms were E. coli followed by Klebsiella spp.17.5% (n = 35), Enterobacteriaceae 7% (n = 14) and only1% (n = 2) isolate of Proteus spp. Mecillinam (87.92%) and Nitrofurantoin (83.2%) showed higher effectiveness against E. coli. Nitrofurantoin showed the highest effectiveness against Klebsiella spp. (40%), other Enterobacteriaceae spp. (100%). Proteus spp. showed 100% effectiveness and resistance respectively against Ciprofloxacin, Cotrimoxazole and Nitrofurantoin.ConclusionThe most predominant ESBLs producing uro-pathogen was the E. coli in the study setting and E. coli had higher sensitivity rate against Mecillinam. Among currently used oral antibiotics Nitrofurantoin was the best choice for UTIs caused by ESBL producers.

Impact of causative organism identification on clinical outcomes after minimally invasive posterior fixation for thoracolumbar pyogenic spondylitis: multicenter retrospective cohort study.

This study aimed to evaluate the difference in treatment duration and unplanned additional surgeries between patients with unidentified causative organisms on empiric antibiotics and those with identified organisms on selective antibiotics in treating thoracolumbar pyogenic spondylitis with minimally invasive posterior fixation. This multicenter retrospective cohort study included patients with thoracolumbar pyogenic spondylitis refractory to conservative treatment who underwent minimally invasive posterior fixation. Patients were divided into the identified (known causative organism) and unidentified groups (unknown causative organism). We analyzed data on demographics, antibiotic use, surgical outcomes, and infection control indicators. We included 74 patients, with 52 (70%) and 22 (30%) in the identified and unidentified groups, respectively. On admission, the identified group had higher C-reactive protein (CRP) levels and more iliopsoas abscesses. The duration to postoperative CRP negative was similar in the identified and unidentified groups (7.13 vs. 6.48 weeks, p = 0.74). Only the identified group had unplanned additional surgeries due to poor infection control, affecting 6 of 52 patients (12%). Advanced age and causative organism identification increased the additional surgery odds (odds ratio [OR], 8.25; p = 0.033 and OR, 6.83; p = 0.034, respectively). The use of empiric antibiotics in minimally invasive posterior fixation was effective without identifying the causative organism and did not prolong treatment duration. In patients with identified organisms, 12% required unplanned additional surgery, indicating a more challenging infection control. Causative organism identification was associated with the need for additional surgery, suggesting a more cautious treatment strategy for these patients.

Contribution of gut microbiota to biodegradation of polystyrene in Tenebrio molitor larvae: Microbiome under antibiotic suppression of Gram-positive, Gram-negative, and fungal microbes

The discovery of plastic biodegradation by insects such as Tenebrio molitor larvae has been well known, however, understanding of the roles of larval gut microorganisms is still very limited. The contribution of the gut microbes belonging to respective Gram-positive (G+), Gram-negative (G−), and fungal (F) groups remains unclear. In this study, we tested polystyrene (PS) biodegradation by T. molitor larvae under three selective antibiotics i.e., gentamicin sulfate (GMS) against G− bacteria, ampicillin (AMP) against G+ bacteria and nystatin (NS) against fungi. The larvae consumed and biodegraded PS foams with Mn 86.381 kDa and Mw 181.176 kDa under antibiotic suppressions at reduced rates versus control (CK) with a sequence of CK>GMS>AMP>NS group. Specifically, only NS group showed a significant decreased in consumption compared to the control. The gut microbial counts decreased with GMS, AMP, or NS addition during the PS feeding. The respective gut microbial counts decreased by 103 to 104 with GMS, AMP, or NS addition PS feeding. Analyses of DSC, TGA, FTIR confirmed oxidation and biodegradation in the presence of antibiotics. The ingested PS polymers were depolymerized and mass reduction with negative influence in the order of NS<AMP<GMS. The negative impact of antibiotic suppression on PS biodegradation process was as follows: anti-fungi reagent > anti-G+ bacteria > anti- G− bacteria. Changes in chemical functional groups are probably related to certain gut microbes, such as the fungal genus of Candida, and bacterial genera of unclassified Enterobacteriaceae and Lactobacillus. Our findings provided new insights into the mechanisms of the biodegradation of plastics in insects.

In vitro evolution of ciprofloxacin resistance in Neisseria commensals and derived mutation population dynamics in natural Neisseria populations.

Commensal Neisseria are members of a healthy human oropharyngeal microbiome; however, they also serve as a reservoir of antimicrobial resistance for their pathogenic relatives. Despite their known importance as sources of novel genetic variation for pathogens, we still do not understand the full suite of resistance mutations commensal species can harbor. Here, we use in vitro selection to assess the mutations that emerge in response to ciprofloxacin selection in commensal Neisseria by passaging 4 replicates of 4 different species in the presence of a selective antibiotic gradient for 20 days; then categorized derived mutations with whole genome sequencing. 10/16 selected cells lines across the 4 species evolved ciprofloxacin resistance (≥ 1 ug/ml); with resistance-contributing mutations primarily emerging in DNA gyrase subunit A and B (gyrA and gyrB), topoisomerase IV subunits C and E (parC and parE), and the multiple transferable efflux pump repressor (mtrR). Of note, these derived mutations appeared in the same loci responsible for ciprofloxacin reduced susceptibility in the pathogenic Neisseria, suggesting conserved mechanisms of resistance across the genus. Additionally, we tested for zoliflodacin cross-resistance in evolved strain lines and found 6 lineages with elevated zoliflodacin minimum inhibitory concentrations. Finally, to interrogate the likelihood of experimentally derived mutations emerging and contributing to resistance in natural Neisseria, we used a population-based approach and identified GyrA 91I as a substitution circulating within commensal Neisseria populations and ParC 85C in a single gonococcal isolate. Small clusters of gonococcal isolates had commensal-like alleles at parC and parE, indicating recent cross-species recombination events.

Review on anti-microbial resistance patterns of staphylococcus aureus isolated from mastitic cow’s milk: Ethiopian context

Aim of this paper is to review antimicrobial resistance profile of Staphylococcus aureus (S. aureus) isolated from mastitic cow milk in Ethiopia between 2013- 2023. S. aureus causes chronic intramammary infections, causing financial losses and challenging antimicrobial therapy globally. In Ethiopia meta-analysis of the pooled prevalence of bovine mastitis was 47.6% showing S. aureus as the major isolates accounting for 13.4% and 16.5% of clinical and subclinical mastitis. In Ethiopia, there are indication of the misuse of antibiotics coupled with the rapid spread of resistant bacterial nature and inadequate surveillance, which contributed to the problem. According to this review resistance profile of S. aureus studied in Ethiopia, the bulk of tested isolates showed alarmingly high levels of resistance to widely used antimicrobial drugs for the treatment of mastitis, particularly penicillin G and tetracycline. Variuos studies warned low susceptibility of S. aureus to commonly used antimicrobials such as penicillin G and tetracycline as a great concern because this antibiotic represents the main antibiotic group recommended for staphylococcal mastitis infection in Ethiopia. If essential steps to stop the indiscriminate use of antibiotics are not implemented, the prevalence of antibiotic-resistant S. aureus could rise posing major risks to both animal and human health. Therefore, conducting regular antimicrobial sensitivity testing before treatment helps select effective antibiotics which reduce the development of resistance to commonly used antibiotics. Further studies should be conducted to detect antimicrobial resistant strains, continiuos surveillance and monitoring of S. aureus to prevent the spread of milk-borne drug-resistant strains throughout communities.

Coordination Number Regulation of Iron Single‐Atom Nanozyme for Enhancing H2O2 Activation and Selectively Eliminating Cephalosporin Antibiotics

AbstractNanozymes present promising alternatives to natural enzymes, but controlling nanozymes' performance and employing them for selectively removing antibiotics are extremely challenging. Employing theoretical calculations to design the coordination environments of mental and coordination atoms for directing single‐atom nanozymes synthesis emerges as a promising strategy to enhance their efficiency and selectivity in antibiotic elimination. In this study, the peroxidase‐like specificity of iron single‐atom nanozymes (FeSA‐Nx, x = 2,3, and 4) with specific Fe–N coordination numbers is demonstrated based on theoretical calculations. These calculations guide the synthesis of corresponding ultra‐thin FeSA‐Nx, achieving a high degree of consistency between theoretical predictions and experimental results. FeSA‐N3 with a Fe─N3 coordination number proves to be the most effective. The efficient electron transfer from Fe─N3 site to H2O2 reduces the free energy required for •OH generation. Quantitative structure‐activity relationship (QSAR) analysis reveals a strong positive correlation between degradation efficiency of cephalosporins and their electron‐donating capabilities (R2 = 0.820–0.929), realizing selectively eliminating cephalosporins. Integration FeSA‐N3 into ceramic membrane (FeSA‐N3/CM) improves hydrophilicity, achieving continuous and stable removal of cephalosporin. This study provides valuable insights into coordination number regulating nanozyme properties for selective antibiotics removal and offers novel perspectives for FeSA‐N3 application in integrated systems.

Pharmacist review of discharge antibiotics for urinary tract infections in the emergency department

AbstractEmergency medicine (EM) pharmacists provide high‐quality patient care in a fast‐paced environment by optimizing pharmacotherapy regimens and reducing medication errors. Current literature demonstrates higher rates of medication errors with antibiotics compared with other medication classes. The aim of this quality improvement (QI) project was to reduce medication errors by 25% from baseline for antibiotic discharge prescriptions for urinary tract infections (UTIs). This QI initiative utilized the Institute for Healthcare Improvement Model for Improvement to implement a UTI stewardship intervention and prospective pharmacist review of discharge prescriptions. Patients discharged from the adult ED with an electronic prescription for UTI treatment with select antibiotics were included. The primary outcome metric was the percent of medication errors, defined as a composite of appropriate antibiotic agent, dose, frequency, and treatment duration based on our local treatment algorithm. The balancing metric was time spent per order reviewed. Data over time were assessed using statistical process control charts. A total of 534 antibiotic prescriptions were reviewed from January 9, 2022 to May 31, 2023. The most common indication was cystitis (70%), followed by pyelonephritis (17.4%) and asymptomatic bacteriuria (12.5%). Composite error rate decreased from 64.2% to 5%. Duration of therapy was the most common baseline error and was reduced from 45.3% to 11.6%. Errors in agent, dose and frequency decreased from 19.7% to 3.5%, 10.3% to 0.8% and from 5.7% to 0%, respectively. The aim of this QI initiative was achieved through a series of interventions, including prospective review of discharge antibiotics for UTIs by EM pharmacists, which reduced medication errors. This project demonstrates EM pharmacists have a positive impact in optimization of antimicrobial therapy for the treatment of UTIs.

Prophylactic Intracameral Antibiotics and Endophthalmitis After Cataract Surgery

Although the effectiveness of intracameral antibiotics to prevent postoperative endophthalmitis is described, selective use of antibiotics combined with 1% povidone iodine disinfection might be equally effective and could lead to cost reduction and avoidance of unnecessary use of antibiotics. To compare the incidence of postoperative endophthalmitis when 1% povidone iodine disinfection is applied in combination with selective intracameral antibiotics with the incidence after routine use of intracameral antibiotics in combination with 5% povidone iodine. This was a retrospective cohort study using incidence data from the ongoing endophthalmitis register of the Rotterdam Eye Hospital, a specialized hospital providing both secondary and tertiary ophthalmological care, when intracameral antibiotics were used only during cataract procedures with occurrence of a posterior capsular tear in comparison with results from cohorts described in the literature where routine antibiotics were used. All patients who had cataract (phacoemulsification) surgery at the Rotterdam Eye Hospital between 1993 and 2022 were included. No cataract surgical procedures combined with other intraocular procedures were included. Povidone iodine disinfection and intracameral antibiotics during cataract surgery either routinely or only in case of posterior capsular tears. Postoperative endophthalmitis incidence. Postoperative endophthalmitis incidence after 56 598 cataract (phacoemulsification) surgical procedures in the Rotterdam Eye Hospital between 2016 and 2022 was 0.000 (95% CI, 0.000-0.000). A PubMed literature search until September 2023 with respect to the incidence of postoperative endophthalmitis after routine antibiotic prophylaxis yielded 37 publications with an overall postoperative endophthalmitis incidence of 0.000 (95% CI, 0.000-0.000). No difference was observed between the postoperative endophthalmitis incidence during the last 7 years in the Rotterdam Eye Hospital and the overall postoperative endophthalmitis incidence after routine intracameral antibiotics prophylaxis as described in the literature. Disinfection with 1% povidone iodine in combination with selective antibiotic prophylaxis may be equally effective as routine antibiotic use and 5% povidone iodine.

Antibiotic treatment to prevent pediatric acute otitis media infectious complications: A meta-analysis.

Most US children with acute otitis media [AOM] receive prompt antibiotic treatment, though guidelines encourage watchful waiting. Previous systematic reviews of antibiotics versus watchful waiting have focused on symptom resolution and RCTs, limiting the assessment of serious, rare complications. We sought to evaluate these complications by including observational studies. RCTs and observational studies that compared antibiotics to placebo or watchful waiting for pediatric clinician diagnosed AOM were identified [PubMed/MEDLINE, Embase, Cochrane Database of Systematic Reviews, Central Register of Controlled Trials, and Web of Science] and reviewed for meta-analysis. Two reviewers independently extracted study characteristics, patient characteristics, and outcomes. We assessed publication bias, study bias with ROBINS-1 and RoB-2 and used random-effects models to assess treatment effects. 24 studies were included. Antibiotics decreased the risk of acute mastoiditis [incidence 0.02%, RR 0.48, 95% CI 0.40-0.59; NNT 5,368]. This protective effect may be underestimated because of misclassification of non-suppurative conditions as AOM. Intracranial complications remained too rare to assess. Antibiotics markedly increased the risk of adverse effects [incidence 10.5%, RR 1.49, 1.27-1.73; NNH 23]. Studies used non-specific criteria for acute mastoiditis, potentially underestimating treatment effects. Prompt antibiotic therapy reduces the risk for some AOM complications. The NNT to prevent serious, rare complications is high, while the NNH is relatively low. Large-scale population-based observational studies using real-world datasets with validated measures of severe complications are needed to improve understanding of risk factors for serious AOM complications, facilitate more selective antibiotic therapy, and optimize individual outcomes and public health.

First report of isolation of Fusobacterium varium from liver abscesses and ruminal and colonic epithelial tissues of feedlot cattle*

ObjectiveOur objective was to isolate and determine prevalence of Fusobacterium varium in liver abscesses and the corresponding ruminal and colonic epithelial tissues and ruminal and colonic contents of feedlot cattle. Materials and MethodsA total of 96 intact liver abscess samples and matched ruminal and colonic tissues and contents from cattle, originating from feedlots that did not receive in-feed tylosin, were collected at slaughter. Liver abscesses and ruminal and colonic tissue were ho- mogenized and then plated, before and after enrichment in lactate or lysine medium with selective antibiotics, onto blood agar and selective lactate or lysine agar for isolation of Fusobacterium and to determine prevalence and concentration. Putative colonies were tested by a quantitative PCR assay targeting the hgdA gene for species confirma- tion. Results and DiscussionNone of the liver abscess samples yielded F. varium by direct plating; however, F. varium was isolated from 3 of 96 (3.1%) following enrich- ment of the homogenate in lactate or lysine medium. In contrast to liver abscesses, F. varium was isolated by direct plating from 27.1% (26/96) of ruminal epithelial and 3.1% (3/96) of colonic epithelial tissue homogenates. Overall, 10.1%, 77.1%, 44.8%, 86.5%, and 70.1% of liver abscess, ruminal, and colonic epithelial tissues and ruminal and colonic contents were positive for F. varium, respectively. Implications and ApplicationsThe increased fre- quency of isolation and high prevalence of F. varium in ruminal tissue and, to a lesser extent, in the colonic tissue confirms its ability to invade tissues and possibly cause bacterial ruminitis. However, the relatively low frequency of F. varium isolation and low prevalence in liver abscesses suggest that it is unlikely to be an etiologic agent. Inter- estingly, there is some evidence that ruminal strains of F. varium were resistant to tylosin; therefore, it would be of interest to determine the prevalence in cattle receiving in-feed tylosin.

Comparative Retrospective Assessment of the Effectiveness and Risk Factors of Fluoroquinolones, Cephalosporines, and Selective Antibiotic Prophylaxis for Transrectal Prostate Biopsy

Introduction: Despite increasing resistance of enterobacteria against fluoroquinolones (FLU), they are still widely used during transrectal prostate biopsy (TRPB). This study was designed to analyse infectious complications and risk factors between FLU, cephalosporines (CEPH) and selective other antibiotics (O-AB) used during TRPB. Methods: 664 patients were included retrospectively (152 FLU, 452 CEPH and 60 O-AB). Infectious complications were defined as fever >38.0°C, the in-house definition of complicated urinary tract infection (cUTI) (if all applied: fever >38.0°C, leucocytosis >11.000/µL and positive urine dipstick) or postinterventional bacteriuria. Hospitalisation rate, duration and comorbidities were also assessed. χ2 and Fisher’s exact test were used for group comparison. Multivariate regression analysis assessed the association of comorbidities with infectious complications. Results: FLU and CEPH were indifferent regarding infectious complications, however in the O-AB group significantly more common compared to FLU and CEPH (11.6, 13.3, 25%, p < 0.05). Duration of hospital stay in CEPH was significantly shorter compared to FLU and O-AB (4.1 vs. 6.3 vs. 8.2 days, p < 0.05). Arterial hypertension showed increased association with fever (OR 6.002 (1.178; 30.597) p = 0.031) and cUTI (OR 6.006 (1.207; 29.891) p = 0.029). Conclusion: Infectious complications were low and indifferent between FLU and CEPH but significantly more frequent in O-AB. Arterial hypertension was significantly associated with postinterventional fever and cUTI.

Investigating the feasibility and potential of combining industry AMR monitoring systems: a comparison with WHO GLASS

Background Efforts to estimate the global burden of antimicrobial resistance (AMR) have highlighted gaps in existing surveillance systems. Data gathered from hospital networks globally by pharmaceutical industries to monitor antibiotic efficacy in different bacteria represent an additional source to track the temporal evolution of AMR. Here, we analysed available industry monitoring systems to assess to which extent combining them could help fill the gaps in our current understanding of AMR levels and trends. Methods We analysed six industry monitoring systems (ATLAS, GEARS, SIDERO-WT, KEYSTONE, DREAM, and SOAR) obtained from the Vivli platform and reviewed their respective isolates collection and analysis protocols. Using the R software, we designed a pipeline to harmonise and combine these into a single dataset. We assessed the reliability of resistance estimates from these sources by comparing the combined dataset to the publicly available subset of WHO GLASS for shared bacteria-antibiotic-country-year combinations. Results Combined, the industry monitoring systems cover 18 years (4 years for GLASS), 85 countries (71), 412 bacterial species (8), and 75 antibiotics (25). Although all industry systems followed a similar centralised testing approach, the criteria for isolate collection were unclear (patients selection, associated sampling periods…). For E.coli, K. pneumoniae and S. aureus, at least 65% of comparable resistance proportions were within 0.1 of the corresponding estimate in GLASS. We did not identify systemic bias towards resistance in industry systems compared to GLASS. Conclusions Combining industry monitoring systems can substantially strengthen our knowledge of global AMR burden across bacterial species and countries. High agreement values for available comparisons with GLASS suggest that data for other bacteria-antibiotic-country-year combinations only present in industry systems could complement GLASS, particularly for Priority Pathogens currently not covered. This valuable information on resistance levels could help clinicians and stakeholders prioritize testing and select appropriate antibiotics in settings with limited surveillance data.

Characteristics and Evolution of Microbial Drug Resistance in Burned Patients.

Wound infection is a serious complication in burn injury, which is a common form of trauma and an important public health issue. We investigated samples from burn and nonburn wounds for microbial characteristics and temporal trends of antibiotic resistance. Wound samples were collected from 369 burned patients and 927 non-burned individuals admitted from 2007 to 2017. Higher frequency of Acinetobacter baumannii, Klebsiella pneumonia, and Pseudomonas aeruginosa was observed in samples from burned individuals when compared to those from non-burned. The prevalence of different groups of bacteria varied when the samples were stratified according to age and sex. The antimicrobial resistance profiles showed a significant difference between burned and non-burned patients. The different temporal trends of antimicrobial resistance rates were also found, which may be critical for the proper selection of antibiotics in burn treatment. The present study suggested that frequent pathogens and antibacterial resistance evolution could differ between burn wounds and other wounds. Therefore, periodic surveillance of antibiotic resistance patterns in the burn unit might help physicians properly select antibiotics for treatment.

Functional domains of Acinetobacter bacteriophage tail fibers.

A rapid increase in antimicrobial resistant bacterial infections around the world is causing a global health crisis. The Gram-negative bacterium Acinetobacter baumannii is categorized as a Priority 1 pathogen for research and development of new antimicrobials by the World Health Organization due to its numerous intrinsic antibiotic resistance mechanisms and ability to quickly acquire new resistance determinants. Specialized phage enzymes, called depolymerases, degrade the bacterial capsule polysaccharide layer and show therapeutic potential by sensitizing the bacterium to phages, select antibiotics, and serum killing. The functional domains responsible for the capsule degradation activity are often found in the tail fibers of select A. baumannii phages. To further explore the functional domains associated with depolymerase activity, tail-associated proteins of 71 sequenced and fully characterized phages were identified from published literature and analyzed for functional domains using InterProScan. Multisequence alignments and phylogenetic analyses were conducted on the domain groups and assessed in the context of noted halo formation or depolymerase characterization. Proteins derived from phages noted to have halo formation or a functional depolymerase, but no functional domain hits, were modeled with AlphaFold2 Multimer, and compared to other protein models using the DALI server. The domains associated with depolymerase function were pectin lyase-like (SSF51126), tailspike binding (cd20481), (Trans)glycosidases (SSF51445), and potentially SGNH hydrolases. These findings expand our knowledge on phage depolymerases, enabling researchers to better exploit these enzymes for therapeutic use in combating the antimicrobial resistance crisis.

Identification of a 2-Aminobenzimidazole Scaffold that Potentiates Gram-Positive Selective Antibiotics Against Gram-Negative Bacteria.

The development of novel therapeutic approaches is crucial in the fight against multi-drug resistant (MDR) bacteria, particularly gram-negative species. Small molecule adjuvants that enhance the activity of otherwise gram-positive selective antibiotics against gram-negative bacteria have the potential to expand current treatment options. We have previously reported adjuvants based upon a 2-aminoimidazole (2-AI) scaffold that potentiate macrolide antibiotics against several gram-negative pathogens. Herein, we report the discovery and structure-activity relationship (SAR) investigation of an additional class of macrolide adjuvants based upon a 2-aminobenzimidazole (2-ABI) scaffold. The lead compound lowers the minimum inhibitory concentration (MIC) of clarithromycin (CLR) from 512 to 2 μg/mL at 30 μM against Klebsiella pneumoniae 2146, and from 32 to 2 μg/mL at 5 μM, against Acinetobacter baumannii 5075. Preliminary investigation into the mechanism of action suggests that the compounds are binding to lipopolysaccharide (LPS) in K. pneumoniae, and modulating lipooligosaccharide (LOS) biosynthesis, assembly, or transport in A. baumannii.

A FtsZ Inhibitor That Can Utilize Siderophore-Ferric Iron Uptake Transporter Systems for Activity against Gram-Negative Bacterial Pathogens.

The global threat of multidrug-resistant Gram-negative bacterial pathogens necessitates the development of new and effective antibiotics. FtsZ is an essential and highly conserved cytoskeletal protein that is an appealing antibacterial target for new antimicrobial therapeutics. However, the effectiveness of FtsZ inhibitors against Gram-negative species has been limited due in part to poor intracellular accumulation. To address this limitation, we have designed a FtsZ inhibitor (RUP4) that incorporates a chlorocatechol siderophore functionality that can chelate ferric iron (Fe3+) and utilizes endogenous siderophore uptake pathways to facilitate entry into Gram-negative pathogens. We show that RUP4 is active against both Klebsiella pneumoniae and Acinetobacter baumannii, with this activity being dependent on direct Fe3+ chelation and enhanced under Fe3+-limiting conditions. Genetic deletion studies in K. pneumoniae reveal that RUP4 gains entry through the FepA and CirA outer membrane transporters and the FhuBC inner membrane transporter. We also show that RUP4 exhibits bactericidal synergy against K. pneumoniae when combined with select antibiotics, with the strongest synergy observed with PBP2-targeting β-lactams or MreB inhibitors. In the aggregate, our studies indicate that incorporation of Fe3+-chelating moieties into FtsZ inhibitors is an appealing design strategy for enhancing activity against Gram-negative pathogens of global clinical significance.

Efficacy and Durability of Intravenous Ertapenem Therapy for Recalcitrant Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a debilitating follicular skin disorder in which bacterial colonization is typical. Oral antibiotic efficacy can be unreliable; however, selective intravenous antibiotics, specifically ertapenem, may provide favorable clinical outcomes. To explore optimal course duration, efficacy, and patient satisfaction associated with intravenous ertapenem for HS. This retrospective review of the medical records of 98 patients with HS between 2018 and 2022 measured and evaluated patient outcomes before and after treatment with intravenous ertapenem. Participants were followed up in a telephone survey assessing patient perspectives and satisfaction. All of those included in this study received medical care from the Albert Einstein College of Medicine's Montefiore HS Center. Patients were treated with 1 g of ertapenem that was self-administered at home through a peripheral intravenous central catheter using an elastomeric pump for 12 to 16 weeks. Antiandrogens and immunomodulatory biologic therapies initiated prior to ertapenem were maintained throughout the treatment course. The primary outcomes, encompassing clinical severity (evaluated through the HS Physician Global Assessment score [a 6-point scale ranging from clear to very severe] and a numerical rating scale for pain [an 11-point scale in which a score of 0 indicates no pain and a score of 10 indicates the worst possible pain]) and markers of inflammation (such as leukocytes, erythrocyte sedimentation rate, C-reactive protein, and interleukin-6), were measured at baseline, the midcourse of intravenous ertapenem treatment, at the end of the course, and posttherapy. Bacterial abundance was also examined at these 4 points, and patient satisfaction was assessed during follow-up. A total of 98 patients (mean [SD] age, 35.8 [13.0] years; 61 [62.2%] female) with HS were treated with intravenous ertapenem. The self-reported racial distribution included 3 individuals identifying as Asian (3.1%), 59 as Black/African American (60.2%), 13 as White (13.3%), and 23 as either other or unknown (23.5%). Additionally, 24 participants (24.5%) reported Spanish/Hispanic/Latino ethnicity. The mean (SD) treatment duration spanned 13.1 (4.0) weeks, with posttherapy follow-up occurring after 7.8 (3.6) weeks. From baseline to posttherapy follow-up, significant reductions were found in the mean (SD) HS Physician Global Assessment scores (3.9 [1.0] vs 2.7 [1.2]; P < .001) and the numerical rating scale for pain (4.2 [3.3] vs 1.8 [2.7]; P < .001), C-reactive protein (5.4 [11.4] vs 2.4 [2.0] mg/dL; P < .001), interleukin-6 (25.2 [21.1] vs 13.7 [13.9]; P < .001), and leukocytes (11.34 [3.9] vs 10.0 [3.4]; P < .001). At follow-up, 76 patients (78.0%) participated in the telephone survey, where 63 (80.3%) reported medium to high satisfaction; further, 69 (90.8%) would recommend ertapenem to other patients. In this retrospective review of medical records and telephone survey, treating HS with intravenous ertapenem, administered for a mean of 13 weeks, was associated with improvement in clinical and inflammatory markers, as well as heightened patient satisfaction. Nonetheless, this approach should be monitored for the emergence of antimicrobial resistance given a longer than standard treatment course.

Oral Probiotic Supplementation in Pregnancy to Reduce Group B Streptococcus Colonisation (OPSiP trial): study protocol for a double-blind parallel group randomised placebo trial

IntroductionGroup B streptococcus (GBS), or Streptococcus agalactiae, remains a leading cause of neonatal morbidity and mortality. Canadian guidelines advise universal maternal screening for GBS colonisation in pregnancy in conjunction with...

The gut microbiota modulate locomotion via vagus-dependent glucagon-like peptide-1 signaling

Locomotor activity is an innate behavior that can be triggered by gut-motivated conditions, such as appetite and metabolic condition. Various nutrient-sensing receptors distributed in the vagal terminal in the gut are crucial for signal transduction from the gut to the brain. The levels of gut hormones are closely associated with the colonization status of the gut microbiota, suggesting a complicated interaction among gut bacteria, gut hormones, and the brain. However, the detailed mechanism underlying gut microbiota-mediated endocrine signaling in the modulation of locomotion is still unclear. Herein, we show that broad-spectrum antibiotic cocktail (ABX)-treated mice displayed hypolocomotion and elevated levels of the gut hormone glucagon-like peptide-1 (GLP-1). Blockade of the GLP-1 receptor and subdiaphragmatic vagal transmission rescued the deficient locomotor phenotype in ABX-treated mice. Activation of the GLP-1 receptor and vagal projecting brain regions led to hypolocomotion. Finally, selective antibiotic treatment dramatically increased serum GLP-1 levels and decreased locomotion. Colonizing Lactobacillus reuteri and Bacteroides thetaiotaomicron in microbiota-deficient mice suppressed GLP-1 levels and restored the hypolocomotor phenotype. Our findings identify a mechanism by which specific gut microbes mediate host motor behavior via the enteroendocrine and vagal-dependent neural pathways.