Carbapenem Exposure Research Articles

P-1470. Single-dose Aminoglycosides versus Carbapenems for the Treatment of Uncomplicated Urinary Tract Infections caused by Extended-spectrum Beta-lactamase-phenotype Enterobacterales

Abstract Background Carbapenems are often used for treatment of infections caused by extended-spectrum β-lactamase-producing (ESBL) Enterobacterales. Over utilization has led to carbapenem resistance and these infections can be difficult to treat. Limiting unnecessary carbapenem exposure has been shown to decrease the risk of carbapenem resistance and a 2023 Infectious Disease Society of America guidance document recommends non-carbapenem alternatives for the treatment of uncomplicated urinary tract infections (uUTI). A single dose of an aminoglycoside (AG) can be considered, however clinical trial data is lacking, especially for those with infections caused by drug-resistant pathogens. Methods A retrospective, multi-center, cohort study over 60-months evaluated hospitalized patients within the NYU Langone Health System ≥18 years of age who received a single dose of an AG for the treatment of an uUTI caused by an AG-susceptible, ESBL-phenotype (defined as ceftriaxone MIC ≥2 mcg/mL) gram-negative bacilli (GNB). Patients who received MEM for ≥72 hours were the active comparator. Clinical success, a composite of the following, was assessed at Day 7 (±2 days) post-therapy or at discharge, whichever occurred sooner: clinical cure, defined as complete resolution or significant improvement of baseline uUTI signs/symptoms; microbiological response, defined as reduction in baseline uropathogen to < 103 CFU/mL. To demonstrate non-inferiority, 352 patients were needed to achieve 90% power. Results Baseline characteristics can be found in Table 1. Clinical success occurred in 97% (N=37) vs. 86% (N=129) of patients treated with an AG vs. MEM, respectively (p=0.052). Non-inferiority was met with a 0.11 proportion difference in clinical success (90% confidence interval [-0.011, 0.25]) within the predefined non-inferiority limit. No statistically significant differences in secondary outcomes were observed (Table 2). Diarrhea was more common in those treated with MEM (p=0.049; Table 3). Conclusion Single dose AG demonstrated comparable clinical success and recurrence rates to MEM for the treatment of uUTI caused by ESBL-producing GNB. The study was underpowered, increasing the chance for type II error. A future prospective study is warranted to justify preliminary findings. Disclosures Michael Bosco, PharmD, BCIDP, AAHIVP, Shionogi Inc: Advisor/Consultant|Shionogi Inc: Grant/Research Support

Carbapenem-Resistant E. coli Adherence to Magnetic Nanoparticles.

Carbapenem-resistant Enterobacterales (CRE) is an emerging global concern. Specifically, carbapenemase-producing (CP) E. coli strains in CRE have recently been found in clinical, environmental, and food samples worldwide, causing many hospitalizations and deaths. Their rapid identification and characterization are paramount in control, management options, and treatment choices. Thus, this study aimed to characterize the cell surface properties of carbapenem-resistant (R) E. coli isolates and their interaction with glycan-coated magnetic nanoparticles (gMNPs) compared with carbapenem-susceptible (S) E coli. This study used two groups of bacteria: The first group included E. coli (R) isolates harboring carbapenemases and had no antibiotic exposure. Their initial gMNP-cell binding capacity, with cell surface characteristics, was assessed. In the second group, one of the E. coli (R) isolates and E. coli (S) had long-term serial antibiotic exposure, which we used to observe their cell surface characteristics and gMNP interactions. Initially, cell surface characteristics (cell morphology and cell surface charge) of the E. coli isolates were evaluated using confocal laser scanning microscope (LSCM) and a Zetasizer, respectively. The interaction of gMNPs with the E. coli isolates was assessed through LSCM and transmission electron microscope (TEM). Further, the gMNP-cell attachment was quantified as a concentration factor (CF) through the standard plating method. The results showed that the CF values of all E. coli (R) were significantly different from those of E. coli (S), which could be due to the differences in cell characteristics. The E. coli (R) isolates displayed heterogeneous cell shapes (rod and round cells) and lower negative zeta potential (cell surface charge) values compared to E. coli (S). Further, this research identified the differences in the cell surface characteristics of E. coli (S) under carbapenem exposure, compared to unexposed E. coli (S) that impact their attachment capacity. The gMNPs captured more E. coli (S) cells compared to carbapenem-exposed E. coli (S) and all E. coli (R) isolates. This study clearly found that differences in cell surface characteristics impact their interaction with magnetic nanoparticles. The gained insights aid in further understanding adhesion mechanisms to develop or improve bacterial isolation techniques and diagnostic and treatment methods for CRE.

Development and validation of a nomogram-based risk prediction model for carbapenem-resistant Klebsiella pneumoniae in hospitalized patients.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses one of the major challenges in clinical anti-infective therapy worldwide. This retrospective cohort study at a tertiary general hospital in Wuhan aimed to identify risk factors for hospital-acquired CRKP infections among 1,113 patients. All participants were aged 18 years and above, and had confirmed positive cultures for KP isolated within 48 hours post-hospitalization. Independent risk factors were identified using LASSO logistic regression and incorporated into a predictive nomogram. The factors included in the nomogram were prior carbapenem exposure, prior β-lactams-β-lactamase inhibitor combination (BLBLI) exposure, prior intensive care unit (ICU) stay, and prior mechanical ventilation. The areas under the receiver operating characteristic curve (AUC) for the nomogram were 0.793 in the training group (70% of patients) and 0.788 in the validation group (30% of patients), demonstrating its discriminatory power and predictive accuracy. The P values for the Hosmer-Lemeshow test were 0.333 and 0.684, indicating good calibration. The clinical utility of the nomogram was further supported by decision curve analysis (DCA) and clinical impact curve (CIC), demonstrating its potential to guide clinical decision-making. Our retrospective analysis identified key risk factors for CRKP infection and developed a nomogram that could effectively predict CRKP infections in hospitalized patients. Although the single-center nature of this study limits generalizability, the nomogram provides a foundation for future prospective, multicenter validations.IMPORTANCEWe established a nomogram scoring system that incorporates four key risk factors: prior carbapenem exposure, prior β-lactams-β-lactamase inhibitor combination (BLBLI) exposure, prior intensive care unit (ICU) stay, and prior mechanical ventilation. This nomogram demonstrated strong discriminatory power, excellent calibration, and significant clinical utility. This study highlights the critical risk factors associated with hospital-acquired carbapenem-resistant Klebsiella pneumoniae (CRKP) infections, providing valuable insights for clinicians to identify high-risk patients.

Comprehensive Assessment of Initial Adaptation of ESBL Positive ST131 Escherichia coli to Carbapenem Exposure.

It remains unclear how high-risk Escherichia coli lineages, like sequence type (ST) 131, initially adapt to carbapenem exposure in their progression to carbapenem resistance. Carbapenem mutation frequency was measured in multiple subclades of extended-spectrum β-lactamase (ESBL) positive ST131 clinical isolates using a fluctuation assay followed by whole genome sequencing (WGS) characterization. Genomic, transcriptomic, and porin analyses of ST131 C2/H30Rx isolate, MB1860, under prolonged, increasing carbapenem exposure was performed using two experimental evolutionary platforms to measure fast vs. slow adaptation. All thirteen ESBL positive ST131 strains selected from a diverse (n=184) ST131 bacteremia cohort had detectable ertapenem (ETP) mutational frequencies with a positive correlation between initial ESBL gene copy number and mutation frequency (r = 0.87, P-value <1e-5). WGS analysis of mutants showed initial response to ETP exposure resulted in significant increases in ESBL gene copy numbers or mutations in outer membrane porin (Omp) genes in the absence of ESBL gene amplification with subclade specific associations. In both experimental evolutionary platforms, MB1860 responded to initial ETP exposure by increasing blaCTX-M-15 copy numbers via modular, insertion sequence 26 (IS26) mediated pseudocompound transposons (PCTns). Increased transcript levels of genes present within the PCTn was a conserved expression signal in both experimental evolutionary platforms. Stable mutations in Omp encoding genes were detected only after prolonged increasing carbapenem exposure consistent with clinical observations. ESBL gene amplification is a conserved response to initial carbapenem exposure, especially within the high-risk ST131 C2/H30Rx subclade. Targeting such amplification could assist with mitigating carbapenem resistance development.

Impact of universal contact precautions and chlorhexidine bathing on the acquisition of carbapenem-resistant enterobacterales in the intensive care unit: a cohort study

BackgroundFor the prevention of carbapenem-resistant Enterobacterales (CRE) acquisition in the intensive care unit (ICU), the effectiveness of universal contact precautions (UCP) and chlorhexidine gluconate (CHG) bathing is controversial.MethodsWith the aim of evaluating the effectiveness of UCP and CHG on CRE acquisition, this study was conducted in an ICU at a university-affiliated hospital in Seoul. Beginning in April 2017, all patients admitted to the ICU underwent weekly CRE screening and surveillance tests, and beginning in January 2018, UCP and CHG bathing were implemented for all patients. The pre-intervention period spanned from April to December 2017; the post-intervention period spanned from January 2018 to December 2019. The pre- and post-intervention CRE acquisition rates were subsequently compared using Kaplan–Meier analysis and log-rank tests, and independent risk factors for CRE acquisition were analysed using Cox proportional hazard modelling.ResultsOf 1,747 patients, 35 acquired CRE during their ICU stay. The CRE acquisition rate was 1.94 and 1.45 per 1,000 patient-days before and after the intervention, respectively, with no significant difference (p = 0.357). The incidence rate of multidrug-resistant organism (MDRO) colonisation decreased from 19.33 to 13.57 per 1,000 patient-days, with Poisson regression analysis showing a relative risk of 0.85 (95% confidence interval [CI] 0.738–0.945, p = 0.004). Additionally, multivariable Cox regression revealed that CRE acquisition was significantly associated with carbapenem exposure (adjusted hazard ratio [aHR] 2.555, 95% CI 1.208–5.405, p = 0.013) and the presence of more than four patients colonised with CRE during their ICU stay (aHR 2.639, 95% CI 1.157–5.243, p = 0.019). However, UCP and CHG bathing were not significantly associated with CRE acquisition (aHR 0.657, 95% CI 0.301–1.433; p = 0.291).ConclusionsUCP and CHG bathing did not affect the CRE acquisition rate in the ICU of a low-prevalence area. A multimodal strategy including antibiotic stewardship is necessary for controlling the nosocomial spread of MDROs.

Antimicrobial Stewardship: A Game Changer in the Fight against Carbapenem-Resistant Enterobacteriaceae (CRE) among Children with Cancer

Abstract Background Carbapenem-resistant Enterobacteriaceae (CRE) is an emerging threat among pediatric cancer patients, with a high mortality rate. A previous study in our center reported that 254 patients with CRE BSI were diagnosed from (2013-2018) with mortality from CRE BSI being 30%. Previous colonization was reported in 35% of those patients. Time to start adequate antibiotics is an independent prognostic factor for patients with CRE BSI, (48%) of patients started active treatment after 48h from culture and associated with higher mortality when compared to patients who started treatment earlier. Our recommendations include antimicrobial stewardship for early detection through routine screening and timely adequate therapy that may impact the outcome for such high-risk patient groups. Methods This prospective study included all pediatric cancer patients with (CRE) bloodstream infections (BSI) at a children’s cancer hospital in Egypt (2020–2022) with adopting antimicrobial stewardship program goals by (1) applying routine screening by rectal swab for high-risk patients and starting active treatment for patients colonized by CRE. (2) Introduction of PCR-based method (Cepheid XpertCarba-R assay) is developed for detecting carbapenemase genes with the availability of results within one hour which can allow for rapid time to start active treatment in less than 48h. Results One hundred and fifty pediatric cancer patients with CRE BSI were identified; 83% had hematological malignancies, and 17% had solid tumors. Acute myeloid leukemia was the most common hematological malignancy (47%). The main clinical features for acquiring CRE-BSI were prolonged neutropenia &amp;gt; 7 days (62%), previous Carbapenem exposure (82%), Quinilone prophylaxis (44%), central venous catheter use (40%), previous colonization with a resistant pathogen (35%) and ICU admission within 90 days (18%). E. coli was the most common isolated pathogen (65%), followed by Klebsiella pneumoniae (31%). Documented site of infection was reported with pneumonia in (32%), typhlitis in 15% skin soft tissue infection (57%), CNS infection (18%), and urinary tract infection in (10%). Time to start active antibiotics in less than 48h was reported in 89% with clinical cure reported in 71% and microbiological clearance was reported in in less than 7 days in 70% of patients. The need for ICU admission as sepsis related to CRE was reported in 29/150 (19%). The Gentopyic profile for CRE in our study reported that class B (69%) with NDM reported in 98/150 (65%) and VIM 6/150 (4%) was the most common carbanamases followed by Oxa-48 in 89/150(59%) of patients while KPC enzyme reported only in 6/150(4%). Day 30 mortality was reported in 23/150(15%). Upon multivariate analysis, patients with Klebsiella pneumoniae BSI, NDM genotype carbapenemases, CRE with aminoglycosides resistance or associated with pneumonia, and CRE patients who developed septic shock with the need for ICU admission were predictors of poor outcome. Conclusion CRE-BSI is a major threat among pediatric cancer patients in limited-resource countries and is considered a barrier against better outcomes. Antimicrobial stewardship through routine screening for colonization detection and Rapid diagnosis by using gene expert with rapid time to start adequate active antibiotics treatment is associated with improvement of outcome and decreasing mortality. Table 1: Comparison between retrospective study and prospective study (after adopting antimicrobial stewardship goals)

Clinical Characteristics and Molecular Insights of Carbapenem-Resistant Klebsiella pneumoniae Isolates from Patients in Intensive Care Units.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP), a significant worldwide public health threat, is common in patients in intensive care units. Methods: A retrospective study was conducted over a period of 22 months to assess the risk factors associated with infection caused by CRKP isolates. Strain identification was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and antimicrobial sensitivity was assessed using the micro broth dilution method and Kirby-Bauer test. The genes blaKPC, blaOXA-48, blaNDM, blaVIM, and blaGES were amplified using polymerase chain reaction (PCR), followed by sequencing of the PCR products. The polymerase hypermucoviscosity phenotype was determined using the string test. Capsular serotypes (K1, K2) and presence of the virulence gene (rmpA) in positive isolates were investigated using phenotypic tests followed by PCR. Results: Length of hospitalization and use of carbapenems were associated with CRKP infection. CRKP isolates exhibited extensive drug resistance, but retained sensitivity to colistin and ceftazidime-avibactam (CZA). The main gene detected in 35 CRKP isolates was blaKPC-2. In addition, 11 strains were positive in the string test, and two of these strains carried rmpA. Conclusions: Prolonged hospitalization and carbapenem exposure increased the risk of CRKP infection in intensive care unit (ICU) patients. The prevalence of CRKP carrying the blaKPC-2 gene was high, and suspected hypervirulent carbapenem-resistant K. pneumoniae isolates were scattered.

Prior carbapenem exposure increases the incidence of ventilator-associated pneumonia in critically Ill children

BackgroundPrior antibiotic exposure has been identified as a risk factor for VAP occurrence, making it a growing concern among clinical practitioners. But there is a lack of systematic research on the types of antibiotics and the duration of exposure that influence VAP occurrence in children at current.MethodsWe retrospectively reviewed 278 children admitted to the Pediatric Intensive Care Unit (PICU) and underwent invasive mechanical ventilation (MV) between January 2020 and December 2022. Of these, 171 patients with MV duration ≥ 48 h were included in the study, with 61 of them developing VAP (VAP group) and the remaining 110 as the non-VAP group. We analyzed the relationship between early antibiotic exposure and VAP occurrence.ResultsThe incidence of VAP was 21.94% (61/278). The VAP group had significantly longer length of hospital stay (32.00 vs. 20.00 days, p<0.001), PICU stay(25.00 vs. 10.00 days, p<0.001), and duration of mechanical ventilation(16.00 vs. 6.00 days, p<0.001) compared to the non-VAP group. The mortality in the VAP group was significantly higher than that in the non-VAP group (36.07% vs. 21.82%, p = 0.044). The VAP group had a significantly higher rate of carbapenem exposure (65.57% vs. 41.82%, p = 0.003) and duration of usage (9.00 vs. 5.00 days, p = 0.004) than the non-VAP group. Vancomycin and/or linezolid exposure rates (57.38% vs. 40.00%, p = 0.029) and duration (8 vs. 4.5 days, p = 0.010) in the VAP group were significantly higher than that in the non-VAP group, either. Multivariate logistic regression analysis identified the use of carbapenem (≥ 7 days) (OR = 5.156, 95% CI: 1.881–14.137, p = 0.001), repeated intubation (OR = 3.575, 95% CI: 1.449–8.823, p = 0.006), and tracheostomy (OR = 5.767, 95% CI:1.686–19.729, p = 0.005) as the independent risk factors for the occurrence of VAP, while early intravenous immunoglobulin (IVIG) was a protective factor against VAP (OR = 0.426, 95% CI: 0.185–0.98, p = 0.045).ConclusionPrior carbapenem exposure (more than 7 days) was an independent risk factor for the occurrence of VAP. For critically ill children, reducing carbapenem use and duration as much as possible should be considered.

Comprehensive Assessment of Initial Adaptation of ESBL Positive ST131 Escherichia coli to Carbapenem Exposure.

It remains unclear how high-risk Escherichia coli lineages, like sequence type (ST) 131, initially adapt to carbapenem exposure in their progression to becoming carbapenem resistant. Carbapenem mutation frequency was measured in multiple subclades of extended-spectrum β-lactamase (ESBL) positive ST131 clinical isolates using a fluctuation assay followed by whole genome sequencing (WGS) characterization. Genomic, transcriptomic, and porin analyses of ST131 C2/ H 30Rx isolate, MB1860, under prolonged, increasing carbapenem exposure was performed using two distinct experimental evolutionary platforms to measure fast vs. slow adaptation. All thirteen ESBL positive ST131 strains selected from a diverse (n=184) ST131 bacteremia cohort had detectable ertapenem (ETP) mutational frequencies with a statistically positive correlation between initial ESBL gene copy number and mutation frequency (r = 0.87, P -value <1e-5). WGS analysis of mutants showed initial response to ETP exposure resulted in significant increases in ESBL gene copy numbers or mutations in outer membrane porin (Omp) encoding genes in the absence of ESBL gene amplification with subclade specific associations. In both experimental evolutionary platforms, MB1860 responded to initial ETP exposure by increasing bla CTX-M-15 copy numbers via modular, insertion sequence 26 (IS 26 ) mediated pseudocompound transposons (PCTns). Transposase activity driven by PCTn upregulation was a conserved expression signal in both experimental evolutionary platforms. Stable mutations in Omp encoding genes were detected only after prolonged increasing carbapenem exposure consistent with clinical observations. ESBL gene amplification is a conserved response to initial carbapenem exposure, especially within the high-risk ST131 C2/ H 30Rx subclade. Targeting such amplification could assist with mitigating carbapenem resistance development.

Clinical risk factors and outcomes of carbapenem-resistant Escherichia coli nosocomial infections in a Chinese teaching hospital: a retrospective study from 2013 to 2020.

The emergence of carbapenem-resistant Escherichia coli strains poses a considerable challenge to global public health, and little is known about carbapenemase-producing E. coli strains in Tianjin, China. This study aimed to investigate the risk factors for infections with carbapenem-resistant E. coli (CREC) strains. This retrospective case-control study was conducted at a tertiary teaching hospital. A total of 134 CREC clinical isolates were collected from the General Hospital of Tianjin Medical University between 2013 and 2020. The control group was selected at a ratio of 1:1 from patients with nosocomial carbapenem-susceptible E. coli infection. Risk factors for nosocomial CREC infection and clinical outcomes were analyzed using univariate and multivariate analyses. Multivariate analysis revealed that cephalosporin exposure (odd ratio OR = 2.01), carbapenem exposure (OR = 1.96), glucocorticoid exposure (OR = 32.45), and surgical history (OR = 3.26) were independent risk factors for CREC infection. The in-hospital mortality rate in the CREC group was 29.1%, and age >65 years (OR = 3.19), carbapenem exposure (OR = 3.54), and central venous catheter insertion (OR = 4.19) were independent risk factors for in-hospital mortality in patients with CREC infections. Several factors were identified in the development of nosocomial CREC infections. The CREC isolates were resistant to most antibiotics. Reducing CREC mortality requires a comprehensive consideration of appropriate antibiotic use, underlying diseases, and invasive procedures.IMPORTANCEEscherichia coli is an opportunistic pathogen that causes severe hospital-acquired infections. The spread of carbapenem-resistant E. coli is a global threat to public health, and only a few antibiotics are effective against these infections. Consequently, these infections are usually associated with poor prognosis and high mortality. Therefore, understanding the risk factors associated with the causes and outcomes of these infections is crucial to reduce their incidence and initiate appropriate therapies. In our study, several factors were found to be involved in nosocomial carbapenem-resistant E. coli (CREC) infections, and CREC isolates were resistant to most antibiotics. Reducing CREC mortality needs a comprehensive consideration of whether antibiotics are used appropriately, underlying diseases, and invasive interventions. These findings provide valuable evidence for the development of anti-infective therapy, infection prevention, and control of CREC-positive infections.

The identification of risk factors and outcomes of cerebrospinal fluid shunt infections caused by carbapenem-resistant gram-negative bacteria in children: a retrospective cohort.

Cerebrospinal fluid (CSF) shunt infections caused by gram-negative bacteria are difficult to treat given the limited treatment options and the emergence of carbapenem-resistant (CR) strains. This study aimed to evaluate the demographic and clinical characteristics of children with CSF shunt and external ventricular drain (EVD) infections caused by gram-negative bacteria, to identify the risk factors for acquiring CR CSF shunt infections, and to report on the clinical outcomes of these infections. A retrospective cohort study was designed to evaluate pediatric patients with CSF shunt and EVD infections caused by gram-negative bacteria between January 2013 and February 2023. A total of 64 episodes in 50 patients were evaluated. There were 45 (70.3%) CSF shunt infections and 19 (29.7%) EVD infections. The median (range) ages were 1.4 years (9 months-17.5 years) for CSF shunt infection patients and 4.2 years (1 month-17 years) for EVD infection patients. The most common isolated gram-negative bacteria species in CSF shunt infections were Pseudomonas spp. (12, 26.7%), followed by Escherichia coli (11, 24.4%), Klebsiella pneumoniae (9, 20%), and Enterobacter cloacae (5, 11.1%). In EVD infections, the most common isolated gram-negative bacteria species were Acinetobacter spp. (6, 31.6%), followed by Pseudomonas spp. (4, 21.1%) and E. coli (3, 15.8%). The carbapenem resistance rate was 26.3% (n = 5) in EVD infections and 26.2% (n = 11) in CSF shunt infections. When risk factors for carbapenem resistance were evaluated for CSF shunt infections, prior carbapenem treatment and a prolonged hospital stay > 7 days were risk factors for the CR group (p = 0.032 and p = 0.042, respectively). In definitive treatment, colistin was statistically more commonly used in the CR group (p = 0.049). When outcomes were evaluated, the 30-day mortality rate (18.2% vs 0%) was higher in the CR group, without a significant difference (p = 0.064). A prolonged hospital stay > 7 days and prior carbapenem exposure within 30 days were associated with CR shunt infections caused by gram-negative bacteria.

Evaluating Clinical Sequelae of the Carbapenem-Valproate Interaction: A Retrospective Analysis.

Previous studies identified a rapid decrease in valproate serum concentrations when coadministered with a carbapenem; however, the specific consequences and subsequent therapy adjustments are not well described. We aimed to investigate the clinical and therapeutic implications of the carbapenem-valproate drug-drug interaction. This retrospective analysis included data from 2 large academic medical centers during January 2017 to June 2022. The primary outcome was incidence of seizures or behavioral events stratified by valproate indication. All adult patient encounters with concomitant administration of any carbapenem antimicrobial and valproate were included. Patients without prolonged exposure to valproate prior to hospitalization, without valproate levels pre- and post-carbapenem administration, with an admitting diagnosis of seizure, with exposure to other agents that decrease valproate concentrations, or who had a seizure during the hospitalization prior to carbapenem exposure were excluded. Two hundred fifty-eight episodes of concomitant use among 78 unique adult patients were included. Valproate was used for seizure control in 41 patients (52.6%) and for mood-related disorders in 37 (47.4%). In those prescribed valproate for its antiepileptic properties, seizures occurred following carbapenem administration in 46.3% of encounters. In those taking valproate for mood-related disorders, 50.8% met the primary endpoint of behavioral disturbance. Our study demonstrates significant clinical implications of the carbapenem-valproate interaction. Clinicians should be aware of this interaction and consider alternative antimicrobial and/or antiepileptic agents whenever possible. Adding or increasing doses of antiepileptic agents and/or consultation with a neurologist prior to concomitant use should be considered when this combination cannot be avoided.

A role for diet and gut microbiota metabolites in autologous hematopoietic cell transplant recipients.

The gut microbiome has an established role in allogeneic hematopoietic cell transplantation (allo-HCT), but not in an auto-HCT setting. We have hypothesized that fecal short-chain fatty acids (SCFA) and urinary 3-indoxyl sulfate (3-IS), which are metabolites derived from the action of the gut microbiome on dietary fiber, play a role in auto-HCT outcomes. This was a single-center prospective study involving auto-HCT recipients. Baseline patient and disease details, diet diaries, and antibiotic exposure were recorded in consenting patients. Serial (pre-HCT, week two, and week four post-HCT) SCFA and urine 3-IS levels were measured using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). HCT outcomes were correlated with these metabolites. Thirty patients (myeloma, n=13; lymphoma, n=17) were analyzed. The levels of urinary 3-IS, fecal acetate, propionate, and butyrate were found to be decreased at week two and were recovered by week four post-HCT. Those with low median nadir fecal butyrate levels at week two also had significantly lower pre-HCT and week four butyrate levels. Recipients with low butyrate levels had more grade ≥2 mucositis (80% vs. 33%, p=0.01) and low fiber intake (10.4 g vs. 13.6 g, p=0.04). They also had more carbapenem exposure (93% vs. 47%, p=0.005) and prolonged antibiotics (11 days vs. 8 days, p=0.008). There were no differences in the time to neutrophil or platelet engraftment, mortality, or disease response. Low pre-HCT fecal butyrate levels tend to persist post-HCT and they are associated with mucositis, dietary fiber intake, and antibiotic exposure. The gut microbiome and its modulation may play a role in auto-HCT settings.

The prognostic value of neutrophil-to-lymphocyte ratio in adult carbapenem-resistant Klebsiella pneumoniae infection: a retrospective cohort study.

Systemic inflammatory indicators such as neutrophil-to-lymphocyte ratio (NLR) can effectively predict the prognosis of various inflammatory diseases. However, its prognostic effect on patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) infection is little known. The objective of this study was to investigate the risk factors for mortality associated with CRKP infection and the clinical value of NLR in predicting prognosis in these patients. A total of 190 inpatients with CRKP infection from 1 January 2023 to 31 December 2023 were enrolled in this study, namely, 73 fatal cases and 117 survival cases in hospital. The medical data and examination results of these patients were collected. A logistic regression analysis was performed to assess the association between the NLR on the day of CRKP infection onset and all-cause mortality in hospital. The overall mortality rate of patients with CRKP infection was 38.42% (73/190). Of the 190 patients, 91 were co-infected with carbapenem-resistant Acinetobacter baumannii/carbapenem-resistant Pseudomonas aeruginosa (CRAB/CRPA). Multifactor regression analysis confirmed that carbapenem exposure in the past 14 days, central line insertion, and chronic Foley catheter requirement were independent risk factors for carbapenem-resistant bacteria co-infection. The multivariate analysis shows that admission to an ICU, co-infection with CRAB/CRPA, and higher NLR were independent risk factors for the mortality in hospital, while appropriate treatment within 3 days was an independent protective factor. The area under the curve (AUC) of the NLR was 0.696, and the cutoff value of the NLR was 10.73. The NLR on the day of CRKP infection onset, admission to an ICU, and co-infection with CRAB/CRPA were identified as independent risk factors for all-cause mortality of patients with CRKP infection, while appropriate treatment within 3 days was recognized as an independent protective factor. The NLR serves as a conveniently accessible and independent prognostic biomarker for patients with CRKP infection.

Insights into the epidemiology, risk factors, and clinical outcomes of carbapenem-resistant Acinetobacter baumannii infections in critically ill children.

Carbapenem-resistant Acinetobacter baumannii (CRAB) has become a leading cause of nosocomial infections with an increasing impact on critically ill patients, yet there is limited data on contributing factors. This study was aim to evaluate the prevalence and risk factors, and clinical outcomes of CRAB infections among critically ill children in a tertiary university teaching hospital in China. From January 2016 to December 2021, all children diagnosed with nosocomial Acinetobacter baumannii (A. baumannii) infections in the pediatric intensive care unit (PICU) were identified through the computerized microbiology laboratory databases. Among them, children suffering from CRAB infection were designated as a case group, while children with carbapenem susceptible A. baumannii (CSAB) infection were assigned to a control group. This retrospective case-control study was based on two groups of patients to determine potential clinical factors contributing to CRAB infection and death among critically ill children via univariate and multivariate analyses. During the 6-year study period, a total of 372 episodes of nosocomial A. baumannii infection in the PICU were eligible and included in the study. These isolates displayed moderate or high rates of resistance to all tested antimicrobials except colistin. The overall prevalence of CRAB and MDRAB (multidrug-resistant A. baumannii) was 78.0% and 80.9%, respectively. Several risk factors found to significantly increase CRAB infection included receiving invasive operation (OR = 9.412, p = 0.001), gastric intubation (OR = 2.478, p = 0.026), prior carbapenems exposure (OR = 2.543, p = 0.003), severe pneumonia (OR = 3.235, p = 0.001), and hemoglobin <110g/L (OR = 3.049, p = 0.005). Of 372 patients with CRAB infection, the mortality rate was 30.9% (115/372) and mortality did not differ between children with CRAB and CSAB infections. Septic shock (OR = 2.992, p = 0.001), AST > 46U/L (OR = 2.015, p = 0.005), bone marrow aspiration (OR = 2.704, p = 0.008), lymphocyte <20 % (OR = 1.992, p = 0.006) and age (OR = 1.094, p = 0.002) were independent risk factors for the death of A. baumanni infection. This study highlights considerable incidence rate and remarkable mortality of children with A. baumanni (especially CRAB) infections, and identifies age-specific risk factors for CRAB infection and mortality in critically ill children. These risk factors should be taken into account in pediatric hospitals in order to establish early intervention and rational treatment to improve clinical outcomes.

Individualized Antibiotic Plans as a Quality Improvement Initiative to Reduce Carbapenem Use for Hematopoietic Cell Transplant Patients at a Freestanding Pediatric Hospital.

Providers must balance effective empiric therapy against toxicity risks and collateral damage when selecting antibiotic therapy for patients receiving hematopoietic cell transplant (HCT). Antimicrobial stewardship interventions during HCT are often challenging due to concern for undertreating potential infections. In an effort to decrease unnecessary carbapenem exposure for patients undergoing HCT at our pediatric center, we implemented individualized antibiotic plans (IAPs) to provide recommendations for preengraftment neutropenia prophylaxis, empiric treatment of febrile neutropenia, and empiric treatment for hemodynamic instability. We compared monthly antibiotic days of therapy (DOT) adjusted per 1000 patient-days for carbapenems, antipseudomonal cephalosporins, and all antibiotics during two 3-year periods immediately before and after the implementation of IAPs to measure the impact of IAP on prescribing behavior. Bloodstream infection (BSIs) and Clostridioides difficile (CD) positivity test rates were also compared between cohorts. Last, providers were surveyed to assess their experience of using IAPs in antibiotic decision making. Overall antibiotic use decreased after the implementation of IAPs (monthly reduction of 19.6 DOT/1000 patient-days; P = .004), with carbapenems showing a continuing decline after IAP implementation. BSI and CD positivity rates were unchanged. More than 90% of providers found IAPs to be either extremely or very valuable for their practice. Implementation of IAPs in this high-risk HCT population led to reduction in overall antibiotic use without increase in rate of BSI or CD test positivity. The program was well received by providers.

Relationship between antibiotic exposure and carbapenem-resistant Klebsiella pneumoniae infection within four types of control patients: A systematic review and meta-analysis

This study attempted to identify the relationship between antibiotic exposure and carbapenem-resistant Klebsiella pneumoniae (CRKP) infection. Antibiotic exposure were chosen as the risk factors for CRKP infection, which were extracted from research articles indexed in PubMed, EMBASE and Cochrane Library. Relevant studies published until January 2023 were reviewed, and a meta-analysis was conducted on antibiotic exposure within the four types of control groups, which comprised of 52 studies. The meta-analysis was performed within four types of control groups: patients infected with carbapenem-susceptible Klebsiella pneumoniae (comparison 1), other infection especially without CRKP infection (comparison 2), CRKP colonization (comparison 3) and no infection (comparison 4). The two risk factors were common to the four comparisons according to Carbapenem and Aminoglycoside exposure. Compared to Carbapenem-susceptible Klebsiella pneumoniae (CSKP) infection, Tegacyclin exposure in bloodstream infection and Quinolone exposure within 30 days were associated with increased risk for CRKP infection. However, Tegacyclin exposure in MIX infection (MIX infection included two or more different infection sites) and Quinolone exposure within 90 days possessed a similar risk for both CRKP and CSKP infection. Carbapenem and Aminoglycoside exposure serve as likely risk factors for CRKP infection. Meanwhile, antibiotic exposure time as continuous variables was not relatedtoCRKP infection compared to CSKP infection. Tigecycline exposure in MIX infection and Quinolone exposure within 90 days may not increase the risk of CRKP infection.

Clinical impact and early prediction of carbapenem-resistant Pseudomonas aeruginosa bacteraemia in allogeneic hematopoietic stem cell transplantation recipients

Although antipseudomonal agents are administered in high-risk patients, no reports have focused on the risk of carbapenem-resistant (CR) Pseudomonas aeruginosa bacteremia in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. We retrospectively studied a cohort of adult allo-HSCT recipients with P. aeruginosa bacteremia, focusing on a comparison between carbapenem-sensitive (CS) and CR P. aeruginosa after initiating conditioning chemotherapy at our institute between January 2005 and December 2020. The incidence, all-cause 30-day mortality of P. aeruginosa bacteremia, and risk factors for carbapenem resistance among patients with P. aeruginosa bacteremia in allo-HSCT recipients were evaluated. Forty-eight patients with P. aeruginosa bacteremia were included, with an incidence of 3.84/100 recipients (CS 1.92 vs. CR 1.92). The all-cause 30-day mortality was significantly higher in CR P. aeruginosa bacteremia (CS 4.2% vs. CR 39.1%; p = 0.003). The factor significantly associated with CR P. aeruginosa bacteremia was carbapenem use for at least three days within 30 days before the onset of bacteremia (odds ratio: 9.23, 95% confidence interval: 2.52-33.67). Inappropriate antimicrobial selection was significantly more frequent in CR P. aeruginosa bacteremia (CS 4.2% vs. CR 66.7%; p ˂ 0.001). Empirical combination therapy with reference to antimicrobial susceptibility profiles in each institution should be considered when CR P. aeruginosa bacteremia is suspected in allo-HSCT recipients based on the risk of carbapenem exposure.

Risk factors for acquisition of carbapenemase-producing versus non-carbapenemase-producing enterobacterales: a case-control study

ObjectivesWe aimed to assess the association between carbapenem-resistant Enterobacterales (CRE) colonization pressure and carbapenem exposure and acquisition of carbapenemase-producing Enterobacterales (CPE) and non-carbapenemase-producing carbapenem-resistant Enterobacterales (non-CP-CRE). MethodsWe conducted a parallel 1:2 matched case-control study at Rambam Health Care Campus, Israel, from January 2014 to June 2017. The cases included all adults who acquired CPE or non-CP-CRE in hospital. The controls were hospitalized patients who were negative for CRE on screening and matched by age, hospitalization division and the number of hospitalization days 90 days prior to CRE screening. The exposures of interest were high CRE colonization pressure, defined as a higher-than-median proportion of CRE carriers in the concurrent patient's department before acquisition, and carbapenem exposure, assessed as days of treatment. Conditional logistic regression was used for analyses of CPE and non-CP-CRE. ResultsIn total, 1058 patients were included: 278 CPE and 75 non-CP-CRE cases, matched to 556 and 149 controls, respectively. High CRE colonization pressure was associated with CPE acquisition (adjusted odds ratio [aOR], 2.6; 95% CI, 1.69–4.02); however, the duration of carbapenem treatment was not (aOR, 1.004; 95% CI, 0.98–1.03; 1-day increment). The duration of carbapenem treatment was significantly associated with non-CP-CRE acquisition (aOR per day, 1.07; 95% CI, 1.03–1.11). A source patient was identified significantly more frequently in epidemiological acquisition investigations of CPE than in those of non-CP-CRE (107/240, 44.6% vs. 18/64, 28.1%, respectively; p 0.017). ConclusionsCPE acquisition was associated with horizontal transmission, whereas non-CP-CRE was associated with carbapenem exposure. Differences in the drivers of acquisition mandate tailored infection prevention efforts.

Clinical Risk Factors and Microbiological and Intestinal Characteristics of Carbapenemase-Producing Enterobacteriaceae Colonization and Subsequent Infection.

Gastrointestinal colonization with carbapenem-resistant Enterobacteriaceae (CRE) is always a prerequisite for the development of translocated infections. Here, we sought to screen for fecal carriage of CRE and identify the risk factors for CRE colonization as well as subsequent translocated pneumonia in critically ill patients admitted to the intensive care unit (ICU) of a university hospital in China. We further focused on the intestinal flora composition and fecal metabolic profiles in CRE rectal colonization and translocated infection patients. Animal models of gastrointestinal colonization with a carbapenemase-producing Klebsiella pneumoniae (carbapenem-resistant K. pneumoniae [CRKP]) clinical isolate expressing green fluorescent protein (GFP) were established, and systemic infection was subsequently traced using an in vivo imaging system (IVIS). The intestinal barrier, inflammatory factors, and infiltrating immune cells were further investigated. In this study, we screened 54 patients hospitalized in the ICU with CRE rectal colonization, and 50% of the colonized patients developed CRE-associated pneumonia, in line with the significantly high mortality rate. Upon multivariate analysis, risk factors associated with subsequent pneumonia caused by CRE in patients with fecal colonization included enteral feeding and carbapenem exposure. Furthermore, CRKP colonization and translocated infection influenced the diversity and community composition of the intestinal microbiome. Downregulated propionate and butyrate probably play important and multiangle roles in regulating immune cell infiltration, inflammatory factor expression, and mucus and intestinal epithelial barrier integrity. Although the risk factors and intestinal biomarkers for subsequent infections among CRE-colonized patients were explored, further work is needed to elucidate the complicated mechanisms. IMPORTANCE Carbapenem-resistant Enterobacteriaceae have emerged as a major threat to modern medicine, and the spread of carbapenem-resistant Enterobacteriaceae is a clinical and public health problem. Gastrointestinal colonization by potential pathogens is always a prerequisite for the development of translocated infections, and there is a growing need to assess clinical risk factors and microbiological and intestinal characteristics to prevent the development of clinical infection by carbapenem-resistant Enterobacteriaceae.