Prolonged Antibiotic Exposure Research Articles

The use of long-term antibiotics for suppression of bacterial infections.

Suppressive antibiotic therapy is prescribed when a patient has an infection that is presumed to be incurable by a defined course of therapy or source control. The cohort receiving suppressive antibiotic therapy is typically highly comorbid and the infections often involve retained prosthetic material. In part due to a lack of clear guidelines regarding the use of suppressive antibiotics, and in part due to the complex nature of the infections in question, patients are often prescribed suppressive antibiotics for extremely long, if not indefinite, courses. The risks of prolonged antibiotic exposure in this context are not fully characterised, but they include adverse drug effects ranging from mild to severe, the development of antibiotic resistant organisms and perturbations of the gastrointestinal microbiome. In this narrative review we present the available evidence for the use of suppressive antibiotic therapy in four common indications, examine the gaps in the current literature and explore the known and potential risks of this therapy. We also make suggestions for improving the quality of evidence in future studies, particularly by highlighting the need for a standardised term to describe the use of long-courses of antibiotics to suppress hard-to-treat infections.

Antibiotic duration and gastric dysmotility in preterm neonates.

Prolonged antibiotic use after birth is associated with neonatal feeding intolerance and functional gastrointestinal disorders (FGIDs). A gastric dysrhythmia (tachygastria) with frequencies >4-9 cycles per minute, measured by electrogastrography (EGG), is associated with FGIDs. The relationship between prolonged antibiotic use and % time spent in tachygastria is unknown in preterm infants. We aimed to compare weekly changes in % tachygastria between preterm infants receiving long (>48 h) versus short (≤48 h) courses of antibiotics for early onset sepsis evaluation (initiated at <3 days of life). This was a longitudinal, prospective cohort study of 88 preterm infants (<34 weeks' gestation) with weekly EGG recordings from the first week of life until 40 weeks' post-menstrual age, discharge, or death. We calculated % of EGG recording time in tachygastria and determined the mean across weekly sessions. A mixed effects model assessed variance in % tachygastria between the short- and long-antibiotic exposure groups across all weeks. Baseline characteristics were similar between the two groups. There was no difference in % tachygastria between short and long antibiotic exposure groups across nine postnatal weeks (p = 0.08). Early, prolonged antibiotic exposure among preterm infants may not lead to significant gastric dysrhythmia. Future studies including larger sample sizes and a "no antibiotic" exposure arm are essential in elucidating this potential relationship.

Prolonged Antibiotic Use in Gulf War Chronic Multisymptom Illness Induces Renal Fibrosis-Like Pathology Associated with microRNA-21-Mediated PTEN Inhibition

Gulf War veterans afflicted with chronic multisymptom Illness (GWI) often experience unexplained, debilitating symptoms, including microbiome dysbiosis, gastrointestinal and neuroinflammation. Prolonged antibiotic treatments, especially of fluoroquinolone class are commonly employed in these veterans, raising concerns about their potential side effects. To date, no studies have investigated the effects of Gulf War (GW) chemicals- Pyridostigmine bromide (PB) and insecticide, permethrin exposures on renal dysfunction in the veterans. Therefore, this study aimed to investigate the impact of prolonged antibiotic exposure on renal pathology in GWI and to elucidate the underlying molecular mechanisms leading to renal dysfunction. In this study, we used a persistent Gulf War Illness (GWI) mouse model to study the combined effect of prolonged antibiotic regimen involving Neomycin and Enrofloxacin treatment for 5 months (20 weeks). Our results showed that prolonged antibiotic treatment exacerbated renal inflammation leading to elevated levels of pro- inflammatory cytokines and significant activation of NF-κB signaling over Gulf war chemicals treated (GWI) mice (GWI). Further, we hypothesized the involvement of HMGB1 mediated RAGE activation leading to the inflammatory phenotype in the kidneys of GWI+ AB mice. We observed that prolonged antibiotic exposure in GWI- induced mice led to significant increased HMGB1-mediated RAGE activation compared to GWI mice, which was associated with increased TGF-β production in GWI+ AB mice. Furthermore, miR-21, whose expression is reported to be regulated by TGF-β is widely linked to renal fibrosis, was also significantly upregulated in antibiotic-treated GWI-induced mice. This upregulation was associated with decreased PTEN expression, a direct target of miR-21 in GWI+ AB mice over GWI- mice, resulting in the activation of the AKT signaling pathway and increased extracellular matrix (ECM) deposition in GWI+ AB mice. Furthermore, we examined the involvement of AKT signaling activation in the induction of Epithelial-Mesenchymal Transition (EMT) by assessing the immunoreactivity of α-SMA. The renal tissue of GWI+AB mice exhibited an elevated immunoreactivity of α-SMA, suggesting that the cells were undergoing transition from an epithelial to a mesenchymal state. In contrast, GWI- mice displayed no significant expression of α-SMA or increased fibronectin deposition, indicating that exposure to Gulf War chemicals alone was insuffcient to induce renal fibrosis-like pathology. These findings highlight the complex interplay between GWI, antibiotics, and renal pathology, emphasizing that prolonged antibiotic treatment in Gulf War Chronic Multisymptom Illness leads to renal fibrosis like- pathology by activating TGF- β dependent miR-21/ PTEN/ AKT signaling. This study was supported by VA Merit Award I01CX001923-01 awarded to Dr. Saurabh Chatterjee. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Prolonged Antibiotic Use in a Preclinical Model of Gulf War Chronic Multisymptom-Illness Causes Renal Fibrosis-like Pathology via Increased micro-RNA 21-Induced PTEN Inhibition That Is Correlated with Low Host Lachnospiraceae Abundance.

Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse renal pathology and its association with gut bacterial species abundance in underlying GWI and aims to uncover the molecular mechanisms leading to possible renal dysfunction with aging. Using a GWI mouse model, administration of a prolonged antibiotic regimen involving neomycin and enrofloxacin treatment for 5 months showed an exacerbated renal inflammation with increased NF-κB activation and pro-inflammatory cytokines levels. Involvement of the high mobility group 1 (HMGB1)-mediated receptor for advanced glycation end products (RAGE) activation triggered an inflammatory phenotype and increased transforming growth factor-β (TGF-β) production. Mechanistically, TGF-β- induced microRNA-21 upregulation in the renal tissue leads to decreased phosphatase and tensin homolog (PTEN) expression. The above event led to the activation of protein kinase-B (AKT) signaling, resulting in increased fibronectin production and fibrosis-like pathology. Importantly, the increased miR-21 was associated with low levels of Lachnospiraceae in the host gut which is also a key to heightened HMGB1-mediated inflammation. Overall, though correlative, the study highlights the complex interplay between GWI, host gut dysbiosis, prolonged antibiotics usage, and renal pathology via miR-21/PTEN/AKT signaling.

A Family of Antibiotics That Evades Resistance by Binding Polyprenyl Phosphates.

Cilagicin is a Gram-positive active antibiotic that has a dual polyprenyl phosphate binding mechanism that impedes resistance development. Here we bioinformatically screened predicted non-ribosomal polypeptide synthetase encoded structures to search for antibiotics that might similarly avoid resistance development. Synthesis and bioactivity screening of the predicted structures that we identified led to three antibiotics that are active against multidrug-resistant Gram-positive pathogens, two of which, paenilagicin and virgilagicin, did not lead to resistance even after prolonged antibiotic exposure.

Short-Course Empiric Antibiotics in Children Undergoing Allogeneic Hematopoietic Cell Transplantation

Fever is common in children undergoing hematopoietic cell transplantation (HCT). Empiric antibiotic (EA) therapy is initiated and often continued until neutrophil engraftment. Prolonged antibiotic exposure reduces microbiome diversity and causes overgrowth of pathogenic organisms, leading to such complications as infections from antibiotic-resistant organisms and Clostridium difficile colitis. Shorter courses of EA therapy have been studied in adults undergoing HCT without significant safety concerns, but data in children are lacking. We instituted a single-center preintervention/ postintervention quality improvement (QI) project to assess the feasibility of short-course EA therapy for first fever in patients undergoing HCT. We aimed to reduce the median duration of broad-spectrum antibiotic use in eligible patients from 20 days in 2020 to 10 days in 2021. Patients were eligible for the intervention, limiting EAs to 7 days for first fever, if they were admitted for their first allogeneic HCT, were afebrile for >24 hours, had no infection requiring systemic treatment, and were hemodynamically stable. Outcome measures included days of EA therapy for first fever and total broad-spectrum antibiotic use during the period of hospitalization, defined as the time from the start of conditioning to 30 days after HCT or hospital discharge, whichever occurred first. Balancing measures included bloodstream infection (BSI), fever, and intensive care (ICU) admission within 3 days of stopping EA therapy. Project criteria were applied retrospectively to patients who underwent HCT in 2020 to construct a preintervention short-course-eligible cohort. During the intervention period, 41 patients underwent allogeneic HCT, of whom 17 (41%) were eligible for short-course EA therapy. Among eligible patients, the median age was 5.3 years, 47% had an underlying malignancy, and 88% received myeloablative conditioning. There were no differences in demographic or HCT characteristics between patients eligible for short-course EA during the intervention and preintervention period (n=24). The short-course EA schedule was adhered to by 14 of the 17 eligible patients (82%). The duration of EA for first fever and total broad-spectrum antibiotic use was significantly decreased in the short-course EA-eligible patients compared to the preintervention cohort, from a median of 17 days to 8 days and from 20 days to 10 days, respectively (P < .01). Of the 14 patients adhering to short-course EA, 2 experienced a balancing measure of recurrent fever requiring resumption of EA, but no infection was identified. There were no BSIs, ICU admissions, or deaths during the hospitalization period in patients who received short-course EA. In this single-center QI project, short-course EA for initial fever was successfully applied to children undergoing allogeneic HCT using strict criteria and led to a significant decrease in broad-spectrum antibiotic use during hospitalization. These results should be validated in a prospective clinical trial to include the impact of short-course EA on antibiotic-resistant organisms, the intestinal microbiome, and HCT outcomes.

Case Commentary: The hidden side of oxacillin resistance in Staphylococcus aureus.

Acquisition of PBP2a (encoded by the mec gene) is the key resistance mechanism to β-lactams in Staphylococcus aureus. The mec gene can be easily detected by PCR assays; however, these tools will miss mec-independent oxacillin resistance. This phenotype is mediated by mutations in cell wall metabolism genes that can be acquired during persistent infections under prolonged antibiotic exposure. The complex case presented by Hess et al. (Antimicrob Agents Chemother 67:e00437-23, 2023, https://doi.org/10.1128/aac.00437-23) highlights the diagnostic and therapeutic challenges in the management of mec-independent oxacillin resistance.

RISK FACTORS ASSOCIATED WITH PROLONGED MECHANICAL VENTILATION IN VERY LOW BIRTH WEIGHT INFANTS

Introduction. Mechanical ventilation (MV) remains a life-saving intervention for the sickest very low birth weight (VLBW) neonates. Despite the widespread use of non-invasive respiratory support, many VLBW neonates require some duration of MV during their initial hospitalization. As prolonged exposure to MV is associated with adverse outcomes in VLBW infants, it is important to identify the factors that influence the duration of this intervention.The study aimed to determine the factors affecting the duration of MV in VLBW infants.Material and methods. Data from a prospectively created computerized database were used in a retrospective cohort study. The database included information on 1086 VLBW infants &lt; 32 weeks' gestation who were ventilated at any time during their hospitalization at the tertiary care hospital between January 2010 and December 2020. Factors that potentially influenced the duration of MV were examined.The research was carried out in compliance with the requirements of bioethics as part of the planned scientific work of the department (state registration number 0117U001083).The data obtained were analyzed using descriptive and comparative statistics, as well as Spearman's rank correlation coefficient and one-way analysis of covariance (ANCOVA). Measurements with normal distribution are presented as mean (standard deviation). Non-parametric continuous data are presented as median (interquartile range). All values were considered significant when p &lt;0.05.The study was carried out as a part of the planned scientific work of the department "Clinical-laboratory and instrumental substantiation of differential approaches to diagnosis, treatment and prevention of childhood diseases" (state registration number 0122U000164) without external sources of funding.Results. According to univariant analysis, bronchopulmonary dysplasia (BPD) (rS=0.32, p&lt;0.05), severe BPD (rS=0.418, p&lt;0.05), pneumothorax (rS=0.06, p=0.05), severe intraventricular hemorrhages (IVH) (rS=0.255, p&lt;0.05), periventricular leukomalacia (PVL) (rS=0.15, p&lt;0.05), sepsis (rS=0.087, p&lt;0.05), necrotizing enterocolitis (rS=0.088, p&lt;0.05), longer duration of antibiotic therapy (rS=0.168, p&lt;0.05), and a lower gestational age (rS=-0.118, p&lt;0.05) were associated with longer duration of MV in VLBW infants. At the same time, BPD (F=18.544, p&lt;0.0001), severe BPD (F=109.810, p&lt;0.0001), severe IVH (F=23.859, p&lt;0.0001), PVL (F=15.031, p&lt;0.0001), and more days of antibiotic therapy (F=13.173, p&lt;0.0001) significantly and independently affected the duration of MV based on the results of one-way ANCOVA.Conclusion. Severe lung and brain injury and prolonged antibiotic exposure were the main risk factors that significantly and independently prolonged MV in VLBW infants.

Prolonged Antibiotic Exposure during Adolescence Dysregulates Liver Metabolism and Promotes Adiposity in Mice

Antibiotic administration during early life has been shown to have lasting effects on the gut microbiota, which have been linked to sustained alterations in liver metabolism and adiposity. Recent investigations have discerned that the gut microbiota continues to develop toward an adult-like profile during adolescence. However, the impact of antibiotic exposure during adolescence on metabolism and adiposity is unclear. Herein, a retrospective analysis of Medicaid claims data was performed, which indicated that tetracycline class antibiotics are commonly prescribed for the systemic treatment of adolescent acne. The purpose of this was to discern the impact of a prolonged tetracycline antibiotic exposure during adolescence on the gut microbiota, liver metabolism, and adiposity. Male C57BL/6T specific pathogen-free mice were administered a tetracycline antibiotic during the pubertal/postpubertal adolescent growth phase. Groups were euthanized at different time points to assess immediate and sustained antibiotic treatment effects. Antibiotic exposure during adolescence caused lasting genera-level shifts in the intestinal bacteriome and persistent dysregulation of metabolic pathways in the liver. Dysregulated hepatic metabolism was linked to sustained disruption of the intestinal farnesoid X receptor-fibroblast growth factor 15 axis, a gut-liver endocrine axis that supports metabolic homeostasis. Antibiotic exposure during adolescence increased subcutaneous, visceral, and marrow adiposity, which intriguingly manifested following antibiotic therapy. This preclinical work highlights that prolonged antibiotic courses for the clinical treatment of adolescent acne may have unintended deleterious effects on liver metabolism and adiposity.

Early Empirical Antibiotics and Adverse Clinical Outcomes in Infants Born Very Preterm: A Population-Based Cohort.

The objective of this study was to evaluate the association between empirical antibiotic therapy in the first postnatal week in uninfected infants born very preterm and the risk of adverse outcomes until discharge. Population-based, nationwide registry study in Norway including all live-born infants with a gestational age <32weeks surviving first postnatal week without sepsis, intestinal perforation, or necrotizing enterocolitis (NEC) between 2009 and 2018. Primary outcomes were severe NEC, death after the first postnatal week, and/or a composite outcome of severe morbidity (severe NEC, severe bronchopulmonary dysplasia [BPD], severe retinopathy of prematurity, late-onset sepsis, or cystic periventricular leukomalacia). The association between empirical antibiotics and adverse outcomes was assessed using multivariable logistic regression models, adjusting for known confounders. Of 5296 live-born infants born very preterm, 4932 (93%) were included. Antibiotics were started in first postnatal week in 3790 of 4932 (77%) infants and were associated with higher aOR of death (aOR 9.33; 95% CI: 1.10-79.5, P=.041), severe morbidity (aOR 1.88; 95% CI: 1.16-3.05, P=.01), and severe BPD (aOR 2.17; 95% CI: 1.18-3.98; P=.012), compared with those not exposed. Antibiotics ≥ 5days were associated with higher odds of severe NEC (aOR 2.27; 95% CI: 1.02-5.06; P=.045). Each additional day of antibiotics was associated with 14% higher aOR of death or severe morbidity and severe BPD. Early and prolonged antibiotic exposure within the first postnatal week was associated with severe NEC, severe BPD, and death after the first postnatal week.

The impact of early empirical antibiotics treatment on clinical outcome of very preterm infants: a nationwide multicentre study in China

BackgroundInfants with rule-out infections are responsible for the majority of empirical antibiotics treatment (EAT) in neonatal intensive care units (NICUs), particularly very preterm infants (VPIs). Antibiotic overuse has been linked to adverse outcomes. There is a paucity of data on the association between EAT and clinical outcomes (containing the nutritional outcomes) of VPIs without infection-related morbidities.MethodsClinical data of VPIs admitted in 28 hospitals in 20 provinces of China from September 2019 to December 2020 were collected. EAT of VPIs was calculated as the number of days with initial usage in the first week after birth, and then categorized into 3 groups (antibiotic exposure: none, 1-4 days, and > 4 days). Clinical characteristics, nutritional status , and the short-term clinical outcomes among 3 groups were compared and analyzed.ResultsIn total, 1834 VPIs without infection-related morbidities in the first postnatal week were enrolled, including 152 cases (8.3%) without antibiotics, 374 cases (20.4%) with EAT ≤4 days and 1308 cases (71.3%) with EAT > 4 days. After adjusting for the confounding variables, longer duration of EAT was associated with decreased weight growth velocity and increased duration of reach of full enteral feeding in EAT > 4 days group (aβ: -4.83, 95% CI: − 6.12 ~ − 3.53; aβ: 2.77, 95% CI: 0.25 ~ 5.87, respectively) than those receiving no antibiotics. In addition, the risk of feeding intolerance (FI) in EAT > 4 days group was 4 times higher than that in non-antibiotic group (aOR: 4.14, 95%CI: 1.49 ~ 13.56) and 1.8 times higher than that in EAT ≤4 days group (aOR: 1.82, 95%CI: 1.08 ~ 3.17). EAT > 4 days was also a risk factor for greater than or equal to stage 2 necrotizing enterocolitis (NEC) than those who did not receive antibiotics (aOR: 7.68, 95%CI: 1.14 ~ 54.75) and those who received EAT ≤4 days antibiotics (aOR: 5.42, 95%CI: 1.94 ~ 14.80).ConclusionsThe EAT rate among uninfected VPIs was high in Chinese NICUs. Prolonged antibiotic exposure was associated with decreased weight growth velocity, longer duration of reach of full enteral feeding, increased risk of feeding intolerance and NEC ≥ stage 2. Future stewardship interventions to reduce EAT use should be designed and implemented.

Ampicillin and Gentamicin Treatment for Early Onset Neonatal Sepsis: When One Size Does Not Fit All.

Based on in vitro susceptibilities and the concern for emergence of resistance and long-term safety, ampicillin plus gentamicin remains the recommended antibiotic regimen for early onset neonatal sepsis. Our objective was to identify potential limitations of this regimen based on clinical and pathogen characteristics while minimizing risks associated with prolonged antibiotic exposure. We identified 43 gram-negative pathogens in 42 patients. Escherichia coli (E coli) occurred in 50% and Streptococcus agalactiae in 23.8% of patient. Ampicillin resistance was common, particularly in E coli (85.7%). Mortality was 23.8%, all due to E coli. We found that E coli is the most frequent pathogen and has a high mortality particularly in neonates < 1500 g; mortality is high with the current dosing strategy when E coli is resistant to ampicillin even when sensitive to gentamicin; resistance to gentamicin remains low but seems to be increasing while resistance to third-generation cephalosporins remains very low.

565. Pilot Study of Prolonged Post-Discontinuation Antibiotic Exposure (PDAE) to Ampicillin Among Low Birthweight Preterm Infants

Abstract Background In the United States, 75% of preterm infants receive ampicillin after birth for evaluation of early onset sepsis. Excess antibiotic exposure in preterm infants is associated with morbidity and mortality. Pharmacokinetic (PK) simulations suggest that very low birthweight (&amp;lt; 1500g) infants receiving ampicillin may experience excess and prolonged therapeutic exposures to ampicillin after drug discontinuation, called post-discontinuation antibiotic exposures (PDAE). It is unknown if low birthweight ( &amp;gt; 1500g to &amp;lt; 2500g) infants that receive ampicillin experience prolonged PDAE. Methods We conducted a pilot prospective PK clinical trial at a single tertiary care center. We enrolled infants with gestational age (GA) &amp;lt; 36 weeks and birthweight (BW) &amp;gt; 1500g and &amp;lt; 2500g who received ampicillin 200 mg/kg/day per standard of care. All infants received 6 ampicillin 66mg/kg doses administered Q8H within 24 hours following birth. Post-discontinuation PK samples were collected between 8-120 hours after the last dose of ampicillin. We performed descriptive statistics on patient characteristics, and graphically displayed ampicillin plasma concentrations following discontinuation. We defined therapeutic exposures as concentrations above the minimum inhibitory concentration (MIC) for Group B Streptococcus (0.25mcg/mL). Results We analyzed 20 PK samples from 12 infants with median (IQR) GA of 32 weeks (31, 34) and BW of 1838g (1730, 2060). See Table 1 for clinical characteristics. All infants (N=8) with post-discontinuation samples collected within 48 hours of last dose had continued therapeutic ampicillin exposures, only 25% of infants had continued therapeutic exposures between 48 and 72 hours post last dose (N=4), and none had therapeutic ampicillin exposures beyond 72 hours post-dose (Figure 1). Samples (n=5) within 24 hours of last dose had median (IQR) ampicillin concentration of 13.2mcg/mL (9.2, 18.7); those within 25-48 hours (n=3) had median concentration of 0.9 mcg/mL (0.6, 2.2). TABLE 1.Enrolled Patient Characteristics and Plasma Ampicillin ConcentrationsFigure 1.Ampicillin Post-Discontinuation Antibiotic Exposures in Low Birthweight Infants (1500g-2500g)MIC = minimum inhibitory concentration. GBS = Group B Streptococcus. Each individual symbol represents one sample collected. MICs based on European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (8 for E. coli, 0.25mcg/mL for Group B Streptococcus). Conclusion In this small cohort of premature infants, exposures of ampicillin remained therapeutic for at least 24 hours post drug discontinuation and suggests that shorter duration of empirical ampicillin treatments may be warranted in this population. Disclosures Daniel Benjamin, Jr., MD PhD MPH, Allergan: Advisor/Consultant|Melinta Therapuetics: Advisor/Consultant|Syneos Health: Advisor/Consultant Rachel Greenberg, MD, MB, MHS, Provepharm Inc: Advisor/Consultant|Tellus Therapeutics: Advisor/Consultant.

Engineering a "detect and destroy" skin probiotic to combat methicillin-resistant Staphylococcus aureus.

The prevalence and virulence of pathogens such as methicillin-resistant Staphylococcus (S.) aureus (MRSA), which can cause recurrent skin infections, are of significant clinical concern. Prolonged antibiotic exposure to treat or decolonize S. aureus contributes to development of antibiotic resistance, as well as depletion of the microbiome, and its numerous beneficial functions. We hypothesized an engineered skin probiotic with the ability to selectively deliver antimicrobials only in the presence of the target organism could provide local bioremediation of pathogen colonization. We constructed a biosensing S. epidermidis capable of detecting the presence of S. aureus quorum sensing autoinducer peptide and producing lysostaphin in response. Here, we demonstrate in vitro activity of this biosensor and present and discuss challenges to deployment of this and other engineered topical skin probiotics.

Comparison between Short Therapy and Standard Therapy in Pediatric Patients Hospitalized with Urinary Tract Infection: A Single Center Retrospective Analysis.

There is marked heterogeneity in clinicians' choice of antibiotic duration for pediatric urinary tract infections (UTIs). Most patients with bacterial UTIs still receive between 7 and 10 days of antibiotics. Prolonged antibiotic exposure drives the emergence of resistance and increases the occurrence of adverse effects. There is increasing evidence that shorter antibiotic regimens may be equally effective compared with longer ones. However, studies evaluating shorter therapies in children hospitalized with urinary tract infections have not yet been performed. We performed a retrospective study comparing children hospitalized with UTIs treated with a short antibiotic (&lt;7 days) or standard antibiotic treatment. The primary aim of our study was to assess the efficacy of a shorter antibiotic therapy for children with UTIs, compared with an historical group of children treated with a standard 7-14 days course. 112 patients, 46 of which were females (41.1%) with a median age 6 months were enrolled. A total of 33 patients (29.5%) underwent a short therapy. All patients were successfully discharged from the acute episode, independently from antibiotic duration. Short therapy was associated with a lower risk of urinary tract relapse (22 relapses (95.6%) in the standard group, 1 (4.4%) in the short group; OR 0.081; 95%CI 0.01-0.63). Short antibiotic therapy was equivalent to standard duration therapy for the cure of UTIs in hospitalized children and was also associated with a lower rate of recurrences. This study provides the basis for a larger prospective randomized study to address the role of short antibiotic therapies in children with UTIs requiring hospitalization.

Yersinia pseudotuberculosis doxycycline tolerance strategies include modulating expression of genes involved in cell permeability and tRNA modifications.

Antibiotic tolerance is typically associated with a phenotypic change within a bacterial population, resulting in a transient decrease in antibiotic susceptibility that can contribute to treatment failure and recurrent infections. Although tolerant cells may emerge prior to treatment, the stress of prolonged antibiotic exposure can also promote tolerance. Here, we sought to determine how Yersinia pseudotuberculosis responds to doxycycline exposure, to then verify if these gene expression changes could promote doxycycline tolerance in culture and in our mouse model of infection. Only four genes were differentially regulated in response to a physiologically-relevant dose of doxycycline: osmB and ompF were upregulated, tusB and cnfy were downregulated; differential expression also occurred during doxycycline treatment in the mouse. ompF, tusB and cnfy were also differentially regulated in response to chloramphenicol, indicating these could be general responses to ribosomal inhibition. cnfy has previously been associated with persistence and was not a major focus here. We found deletion of the OmpF porin resulted in increased antibiotic accumulation, suggesting expression may promote diffusion of doxycycline out of the cell, while OsmB lipoprotein had a minor impact on antibiotic permeability. Overexpression of tusB significantly impaired bacterial survival in culture and in the mouse, suggesting that tRNA modification by tusB, and the resulting impacts on translational machinery, promotes survival during treatment with an antibiotic classically viewed as bacteriostatic. We believe this may be the first observation of bactericidal activity of doxycycline under physiological conditions, which was revealed by reversing tusB downregulation.

A6 MECHANISMS UNDERLYING GUT DYSFUNCTION FOLLOWING C. DIFFICILE INFECTION AND IMPLICATIONS FOR TREATMENT

BackgroundRecent evidence suggests an increasing prevalence of gut dysfunction following C. difficile infection (CDI). The accompanying prolonged antibiotic (AB) exposure likely contributes to chronic gut dysfunction and our ability to induce gut dysfunction in germ free (GF) mice colonized with microbiota from a patient with severe slow transit post CDI (PCDI) supports this notion (10.1093/jcag/gwz047.117). Furthermore, we were able to restore gut function following fecal microbial transfer from healthy murine donors. Our studies have implicated a role for macrophages in the destruction of the Interstitial Cell of Cajal (ICC) network underlying slow colonic transit in the humanized mouse model. These findings prompted us to evaluate microbiota-directed therapy in normalising gut function in this model.Aims 1)To investigate whether dietary psyllium rescues the development of slow colonic transit (SCT) through modulating host function via microbiota mediated immune mechanisms; and 2)To evaluate the mechanisms underlying the beneficial effects of psylliumMethodsGF mice were colonized with either microbiota from the PCDI patient or healthy control (HC) for 3 weeks following which PCDI mice were treated with either a control diet or a 15% psyllium diet (PSY). Colonic motility was assessed before and after the diet intervention using the bead expulsion test. Stool samples were collected for microbial profiling, and short and branched-chain fatty acids (SCFA/BCFA) analysis. Colonic muscle layers encompassing myenteric plexus (MP) were collected for gene expression analysis and to evaluate activated macrophages and ICC degeneration using immunohistochemistry.ResultsMicrobiota from a PCDI patient induced a SCT phenotype in GF mice (n=13) as compared to mice colonized with HC microbiota (p=0.0002). Psyllium rescued this SCT phenotype in mice (PCDI(n=7) vs.PSY(n=6):p=0.0014). The psyllium-induced rescue was accompanied by normalization of the ICC network and morphological alterations in infiltrating macrophages. This was supported by changes in immune-related gene expression in the MP including CD11b, NOS, Myd88, Mapk1 and NF-κB. Additionally, bacterial composition was different between PCDI and PSY group (p=0.003). SCFAs like acetic and propionic acid were increased, while BCFA like isobutyric and isovaleric acid were decreased following PSY treatment. These alterations in SCFA/BCFA were supported by fluctuations in specific bacteria like Butyricimonas, Phascolarctobacterium and Allistipes.ConclusionsOur results provide evidence that chronic gut dysfunction following CDI and AB exposure is microbiota-driven. Furthermore, microbiota-directed therapy using psyllium could serve as a novel therapeutic strategy to normalize gut function via microbiota-mediated restoration of immune homeostasis in these patients.Funding AgenciesW. Garfield Weston Foundation

Hidden No More: Capturing the Full Picture of Prolonged Perioperative Antibiotic Prophylaxis.

Hidden No More: Capturing the Full Picture of Prolonged Perioperative Antibiotic Prophylaxis.

Microbiome Resilience despite a Profound Loss of Minority Microbiota following Clindamycin Challenge in Humanized Gnotobiotic Mice.

ABSTRACTAntibiotics are known to induce gut dysbiosis and increase the risk of antibiotic resistance. While antibiotic exposure is a known risk factor leading to compromised colonization resistance against enteric pathogens such as Clostridioides difficile, the extent and consequences of antibiotic perturbation on the human gut microbiome remain poorly understood. Human studies on impacts of antibiotics are complicated by the tremendous variability of gut microbiome among individuals, even between identical twins. Furthermore, antibiotic challenge experiments cannot be replicated in human subjects for a given gut microbiome. Here, we transplanted feces from three unrelated human donors into groups of identical germfree (GF) Swiss-Webster mice, and examined the temporal responses of the transplanted microbiome to oral clindamycin challenge in gnotobiotic isolators over 7 weeks. Analysis of 177 longitudinal fecal samples revealed that 59% to 81% of human microbiota established a stable configuration rapidly and stably in GF mice. Microbiome responses to clindamycin challenge was highly reproducible and microbiome-dependent. A short course of clindamycin was sufficient to induce a profound loss (∼one third) of the microbiota by disproportionally eliminating minority members of the transplanted microbiota. However, it was inadequate to disrupt the global microbial community structure or function, which rebounded rapidly to resemble its pre-treatment state after clindamycin discontinuation. Furthermore, the response of individual microbes was community-dependent. Taken together, these results suggest that the overall gut microbiome structure is resilient to antibiotic perturbation, the functional consequences of which warrant further investigation.IMPORTANCE Antibiotics cause imbalance of gut microbiota, which in turn increase our susceptibility to gastrointestinal infections. However, how antibiotics disrupt gut bacterial communities is not well understood, and exposing healthy volunteers to unnecessary antibiotics for research purposes carries clinical and ethical concerns. In this study, we used genetically identical mice transplanted with the same human gut microbiota to control for both genetic and environmental variables. We found that a short course of oral clindamycin was sufficient to eliminate one third of the gut bacteria by disproportionally eliminating minority members of the transplanted microbiota, but it was inadequate to disrupt the overall microbial community structure and function, which rebounded rapidly to its pre-treatment state. These results suggest that gut microbiome is highly resilient to antibiotic challenge and degradation of the human gut ecosystem may require repeated or prolonged antibiotic exposure.

Gut Dysbiosis, Bacterial Colonization and Translocation, and Neonatal Sepsis in Very-Low-Birth-Weight Preterm Infants.

Gut dysbiosis may precede neonatal sepsis, but the association is still not well-understood. The goal of this study is to investigate the association between gut microbiota and neonatal sepsis, and to seek the evidence of colonization of pathogenic bacteria in the gut before evolving into an invasive infection. A prospective cohort study examined fecal microbiota composition in preterm infants with and without sepsis. Thirty-two very-low-birth-weight (VLBW) preterm infants and 10 healthy term infants as controls were enrolled. The fecal samples collected from the participants at the first, fourth, and seventh weeks of life underwent 16S rRNA amplicon sequencing for measurement of the diversity and composition of the microbiota. The bacterial isolates causing neonatal sepsis were genome sequenced. PCR was performed to confirm the translocation of the bacteria from the gut to the blood. The results showed that VLBW preterm infants with sepsis had lower microbial diversity in the gut at birth compared to preterm infants without sepsis and term infants. The composition of gut microbiome in preterm infants was similar to healthy terms at birth but evolved toward dysbiosis with increasing Proteobacteria and decreasing Firmicutes weeks later. The strain-specific PCR confirmed the presence of causative pathogens in the gut in 4 (40%) out of 10 VLBW preterms with sepsis before or at onset of sepsis, and persistence of the colonization for weeks after antibiotic treatment. The same bacterial strain could horizontally spread to cause infection in other infants. Prolonged antibiotic exposure significantly reduced beneficial Bifidobacterium and Lactobacillus in the gut. In conclusion, preterm infants with gut dysbiosis are at risk for neonatal sepsis, and the causative pathogens may be from the gut and persist to spread horizontally. The association of increased Proteobacteria abundance and decrease in microbiome diversity suggests the need for interventions targeting the gut microbiome to prevent dysbiosis and sepsis in VLBW preterm infants.