Multidrug-resistant Gram-negative Organisms Research Articles

Imipenem/Cilastatin/Relebactam for Complicated Infections: A Real-World Evidence.

(1) Background: Infections caused by multidrug-resistant (MDR) bacteria represent one of the major global public health problems of the 21st century. Beta-lactam antibacterial agents are commonly used to treat infections due to Gram-negative pathogens. New β-lactam/β-lactamase inhibitor combinations are urgently needed. Combining relebactam (REL) with imipenem (IMI) and cilastatin (CS) can restore its activity against many imipenem-nonsusceptible Gram-negative pathogens. (2) Methods: we performed a systematic review of the studies reporting on the use of in vivo REAL/IPM/CS. (3) Results: A total of eight studies were included in this review. The primary diagnosis was as follows: complicated urinary tract infection (n = 234), complicated intra-abdominal infections (n = 220), hospital-acquired pneumonia (n = 276), and ventilator-associated pneumonia (n = 157). Patients with normal renal function received REL/IPM/CS (250 mg/500 mg/500 mg). The most frequently reported AEs occurring in patients treated with imipenem/cilastatin plus REL/IPM/CS were nausea (11.5%), diarrhea (9.8%), vomiting (9.8%), and infusion site disorders (4.0%). Treatment outcomes in these high-risk patients receiving REL/IPM/CS were generally favorable. A total of 70.6% of patients treated with REL/IPM/CS reported a favorable clinical response at follow-up. (4) Conclusions: this review indicates that REL/IPM/CS is active against important MDR Gram-negative organisms.

Tackling carbapenem resistance: ceftazidime - avibactam in contemporary clinical scenarios

Antimicrobial resistance poses a formidable challenge in treating severe infections, with the prevalence of extended-spectrum beta-lactamase (ESBL) - producing, Klebsiella pneumoniae carbapenemase (KPC) - producing, and multidrug-resistant (MDR) organisms on the rise. This necessitates careful consideration of various factors, including local resistance patterns, patient-specific characteristics, and drug properties, in treatment decisions for critically ill patients. Ceftazidime-Avibactam demonstrates efficacy against aerobic Gram-negative bacteria and offers a crucial advancement against carbapenem-resistant organisms (CRO) with its effectiveness against key pathogens, including ESBL, AmpC, KPC, and OXA-48-producing Enterobacteriaceae and drug-resistant P. aeruginosa. Ceftazidime-Avibactam emerges as a valuable option for critically ill patients with limited treatment choices. The drug's excellent safety profile demonstrated in clinical trials, further positions it as a crucial addition to antimicrobial treatment options. As the global threat of drug-resistant bacteria grows, Ceftazidime-Avibactam plays a pivotal role in addressing this challenge and offers a promising solution for critically ill patients facing infections caused by antimicrobial-resistant pathogens. The article delves into therapeutic efficacy and the prospective role of Ceftazidime-Avibactam in managing MDR Gram-negative organisms, underscoring the critical role of appropriate antibiotic administration in reducing mortality associated with Gram-negative infections.

Stewardship Prompts to Improve Antibiotic Selection for Urinary Tract Infection

Urinary tract infection (UTI) is the second most common infection leading to hospitalization and is often associated with gram-negative multidrug-resistant organisms (MDROs). Clinicians overuse extended-spectrum antibiotics although most patients are at low risk for MDRO infection. Safe strategies to limit overuse of empiric antibiotics are needed. To evaluate whether computerized provider order entry (CPOE) prompts providing patient- and pathogen-specific MDRO risk estimates could reduce use of empiric extended-spectrum antibiotics for treatment of UTI. Cluster-randomized trial in 59 US community hospitals comparing the effect of a CPOE stewardship bundle (education, feedback, and real-time and risk-based CPOE prompts; 29 hospitals) vs routine stewardship (n = 30 hospitals) on antibiotic selection during the first 3 hospital days (empiric period) in noncritically ill adults (≥18 years) hospitalized with UTI with an 18-month baseline (April 1, 2017-September 30, 2018) and 15-month intervention period (April 1, 2019-June 30, 2020). CPOE prompts recommending empiric standard-spectrum antibiotics in patients ordered to receive extended-spectrum antibiotics who have low estimated absolute risk (<10%) of MDRO UTI, coupled with feedback and education. The primary outcome was empiric (first 3 days of hospitalization) extended-spectrum antibiotic days of therapy. Secondary outcomes included empiric vancomycin and antipseudomonal days of therapy. Safety outcomes included days to intensive care unit (ICU) transfer and hospital length of stay. Outcomes were assessed using generalized linear mixed-effect models to assess differences between the baseline and intervention periods. Among 127 403 adult patients (71 991 baseline and 55 412 intervention period) admitted with UTI in 59 hospitals, the mean (SD) age was 69.4 (17.9) years, 30.5% were male, and the median Elixhauser Comorbidity Index count was 4 (IQR, 2-5). Compared with routine stewardship, the group using CPOE prompts had a 17.4% (95% CI, 11.2%-23.2%) reduction in empiric extended-spectrum days of therapy (rate ratio, 0.83 [95% CI, 0.77-0.89]; P < .001). The safety outcomes of mean days to ICU transfer (6.6 vs 7.0 days) and hospital length of stay (6.3 vs 6.5 days) did not differ significantly between the routine and intervention groups, respectively. Compared with routine stewardship, CPOE prompts providing real-time recommendations for standard-spectrum antibiotics for patients with low MDRO risk coupled with feedback and education significantly reduced empiric extended-spectrum antibiotic use among noncritically ill adults admitted with UTI without changing hospital length of stay or days to ICU transfers. ClinicalTrials.gov Identifier: NCT03697096.

Evaluation of risk factors associated with hard-to-heal wound infection in a tertiary care hospital.

The incidence of hard-to-heal wound infection, especially as a result of multidrug-resistant Gram-negative organisms, has increased in recent years. The reason for the increase is multifactorial and the ability of these pathogenic isolates to form biofilms is one of the important risk factors in wound infection. This study aimed to evaluate the risk factors associated with such cases. This prospective analytical study, conducted over a period of two months, included pus or tissue samples from hospital inpatients with Gram-negative hard-to-heal wound infection. The samples were processed with conventional microbiological techniques. Patient demographic details and the presence of various risk factors were recorded. Biofilm production was detected by tissue culture plate method in the laboratory. The data were analysed using SPSS version 21 (IBM Ltd., US). The experimental cohort comprised 200 patients. Klebsiella spp. was the most common identified organism, followed by Escherichia coli and Pseudomonas spp. Carbapenem resistance was observed in 106 (53%) strains. Almost 66% of the strains showed biofilm formation. On evaluation of associated risk factors, age (p=0.043), presence of biofilms (p=0.0001), diabetes (p=0.002), hypertension (p=0.02) and medical device use (p=0.008) had significant association, whereas sex, previous surgery and prior antibiotic use had no significant impact on the chronicity of the wound. In this study, chronicity of wounds was observed to be associated with multiple risk factors, especially the biofilm-forming ability of the strain. Biofilms are difficult to eradicate and additional measures, such as physical debridement, are important for resolving chronicity. Knowledge about specific risk factors would also allow clinicians a better understanding of the healing process and drive appropriate wound care interventions. A grant was received from the Indian Council of Medical Research (ICMR) for this work (grant ID: 2017-02686). The authors have no conflicts of interest to declare.

Difference in the impact of coinfections and secondary infections on antibiotic use in patients hospitalized with COVID-19 between the Omicron-dominant period and the pre-Omicron period

IntroductionThis study evaluated the effect of coinfections and/or secondary infections on antibiotic use in patients hospitalized with coronavirus disease 2019 (COVID-19). MethodDays of therapy per 100 bed days (DOT) in a COVID-19 ward were compared between 2022 (Omicron period) and 2021 (pre-Omicron period). Antibiotics were categorized as antibiotics predominantly used for community-acquired infections (CAIs) and antibiotics predominantly used for health care-associated infections (HAIs). Bacterial and/or fungal infections which were proved or assumed on admission were defined as coinfections. Secondary infections were defined as infections that occurred following COVID-19. ResultsPatients with COVID-19 during the Omicron period were older and had more comorbidities. Coinfections were more common in the Omicron period than in the pre-Omicron period (44.4% [100/225] versus 0.8% [2/257], respectively, p < 0.001), and the mean DOT of antibiotics for CAIs was significantly increased in the Omicron period (from 3.60 to 17.84, p < 0.001). Secondary infection rate tended to be higher in the Omicron period (p = 0.097). Mean DOT of antibiotics for HAIs were appeared to be lower in the COVID-19 ward than in the general ward (pre-Omicron, 3.33 versus 6.37, respectively; Omicron, 3.84 versus 5.22, respectively). No multidrug-resistant gram-negative organisms were isolated in the COVID-19 ward. ConclusionAntibiotic use for CAIs was limited in the pre-Omicron period but increased in the Omicron period because of a high coinfection rate on admission. With the antimicrobial stewardship, excessive use of antibiotics for HAIs was avoided in the COVID-19 ward during both periods.

Bacterial Resistance in Nephrology

Bacterial resistance to antibiotics (ABR) is a major threat to public health, particularly in nephrology, with far-reaching consequences, including longer hospital stays, higher healthcare costs and increased mortality. Indeed, patients with chronic kidney disease (CKD) are a population at risk of developing infections caused by antibiotic-resistant bacteria (ARBs), given their overexposure to healthcare facilities and the quality of their gut microbiota already damaged by CKD. It is a population with very high rates of colonization and ARB infection worldwide. The mechanisms deployed by these AROs to counteract the effect of antibiotics are multiple. This may include the production of antibiotic-inhibiting enzyme (ATB), waterproofing of the bacterial membrane, or modification of the antibiotic target. They include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) species, and several multidrug-resistant Gram-negative organisms. The emergence and global spread of these ARBs is facilitated by ATB selection pressure, inter-agency transmission of resistance determinants, suboptimal infection control practices, and frequency of international travel, among other factors. The spread of this veritable pandemic highlights the urgent need for new treatment options, the implementation of awareness campaigns to properly prescribe antibiotics and improve infection prevention practices, particularly at hemodialysis centers.

Bring it on again: antimicrobial stewardship in transplant infectious diseases: updates and new challenges.

Advancement in solid organ transplantation and hematopoietic stem cell transplant continues to improve the health outcomes of patients and widens the number of eligible patients who can benefit from the medical progress. Preserving the effectiveness of antimicrobials remains crucial, as otherwise transplant surgeries would be unsafe due to surgical site infections, and the risk of sepsis with neutropenia would preclude stem cell transplant. In this review, we provide updates on three previously discussed stewardship challenges: febrile neutropenia, Clostridioides difficile infection, and asymptomatic bacteriuria. We also offer insight into four new stewardship challenges: the applicability of the "shorter is better" paradigm shift to antimicrobial duration; antibiotic allergy delabeling and desensitization; colonization with multidrug-resistant gram-negative organisms; and management of cytomegalovirus infections. Specifically, data are accumulating for "shorter is better" and antibiotic allergy delabeling in transplant patients, following successes in the general population. Unique to transplant patients are the impact of multidrug-resistant organism colonization on clinical decision-making of antibiotic prophylaxis in transplant procedure and the need for antiviral stewardship in cytomegalovirus. We highlighted the expansion of antimicrobial stewardship interventions as potential solutions for these challenges, as well as gaps in knowledge and opportunities for further research.

The impact of environmental cleaning protocol featuring PX-UV in reducing the incidence of multidrug-resistant gram-negative healthcare-associated infection and colonization in intensive care units in Thailand.

In this quasi-experimental study, implementing PX-UV to the standard environmental cleaning protocol was associated with a reduction in the overall incidence of multidrug-resistant (MDR) gram-negative organisms (P = .01) and MDR Acinetobacter baumannii (P = .001) in intervention intensive care units. However, the intervention did not reduce patient length of stay and 30-day mortality.

1449. Evaluation of Cloud-Based Automated Analytic Pipelines for Whole Genome Sequencing Analysis of Multidrug-Resistant Gram-Negative Organism Outbreaks

Abstract Background Clinical implementation of whole genome sequencing (WGS) has been identified as the optimal approach to identify transmission of multidrug-resistant (MDR) organisms in the healthcare setting. Although WGS capabilities are becoming more common in clinical laboratories, analysis and interpretation of results is still a barrier to implementation. The purpose of this study was to evaluate cloud-based automated analytic pipelines to aid with WGS analysis of MDR gram-negative organisms as part of outbreak investigations. Methods A convenience set of MDR Enterobacterales (n: 142), Acinetobacter baumannii complex (n: 14) and Pseudomonas aeruginosa (n:29) isolates were WGS on Illumina sequencing platforms. The FASTQ files were uploaded to AREScloud (Ares Genetics, an OpGen group company) and to EPISEQ CS (bioMérieux) for whole genome or core genome multi-locus sequence typing (wgMLST/cgMLST) with dendrogram creation. Results were compared to traditional 7 gene MLST schema. Ease-of-use and additional tools were compared between pipelines. Results AREScloud and EPISEQ CS generated similar dendrograms for all organisms evaluated (examples provided in Figures 1 &amp; 2). EPISEQ CS provided preset similarity thresholds based on percent relatedness to define clusters simplifying outbreak analysis, whereas AREScloud allowed users to define allelic difference cutoffs. Although the wgMLST/cgMLST clusters aligned with traditional MLST types, not all isolates assigned to a similar MLST were identified as part of a related cluster demonstrating increased resolution of wgMLST and cgMLST phylogenetic assessments. Table 1 compares the features between the two pipelines. Dendrogram generated for Escherichia coli (EPISEQ CS) Dendrogram generated for Escherichia coli (AREScloud) Comparison of features between EPISEQ CS and AREScloud for phylogenetic analysis Conclusion Both cloud-based tools perform comparably for assessing phylogenetic relatedness compared to traditional MLST. Preset similarity thresholds available with EPISEQ CS provide ease-of-use for cluster assessment. Additional features, such as resistome and virulome analysis, are available by both pipelines. Predictive WGS-AST is an additional asset available with AREScloud. Disclosures Karen C. Carroll, MD, Abbott Diagnostics: Board Member|Co-Diagnostics, Inc.: Board Member|Great Basin: Grant/Research Support|Meridian Diagnostics: Grant/Research Support|Pattern Diagnostics: Advisor/Consultant|Pattern Diagnostics: Stocks/Bonds|Qiagen, Inc.: Grant/Research Support|Scanogen: Advisor/Consultant|Scanogen: Grant/Research Support Patricia J. Simner, PhD, Affinity Biosensors: Grant/Research Support|BD Diagnostics: Advisor/Consultant|BD Diagnostics: Grant/Research Support|Entasis: Advisor/Consultant|GeneCapture: Stocks/Bonds|Merck: Advisor/Consultant|OpGen Inc: Board Member|OpGen Inc: Grant/Research Support|OpGen Inc: Honoraria|Qiagen Sciences Inc: Advisor/Consultant|Qiagen Sciences Inc: Grant/Research Support|Shionogi Inc: Advisor/Consultant|T2 Biosystems: Grant/Research Support

Executive Summary: State-of-the-Art Review: State of the Management of Infections Caused by Multidrug-Resistant Gram-Negative Organisms.

Executive Summary: State-of-the-Art Review: State of the Management of Infections Caused by Multidrug-Resistant Gram-Negative Organisms.

Strategies to combat Gram-negative bacterial resistance to conventional antibacterial drugs: a review.

The emergence of antimicrobial resistance raises the fear of untreatable diseases. Antimicrobial resistance is a multifaceted and dynamic phenomenon that is the cumulative result of different factors. While Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus and Clostridium difficile, were previously the most concerning issues in the field of public health, Gram-negative pathogens are now of prime importance. The World Health Organization's priority list of pathogens mostly includes multidrug-resistant Gram-negative organisms particularly carbapenem-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and extensively drug-resistant Acinetobacter baumannii. The spread of Gram-negative bacterial resistance is a global issue, involving a variety of mechanisms. Several strategies have been proposed to control resistant Gram-negative bacteria, such as the development of antimicrobial auxiliary agents and research into chemical compounds with new modes of action. Another emerging trend is the development of naturally derived antibacterial compounds that aim for targets novel areas, including engineered bacteriophages, probiotics, metal-based antibacterial agents, odilorhabdins, quorum sensing inhibitors, and microbiome-modifying agents. This review focuses on the current status of alternative treatment regimens against multidrug-resistant Gram-negative bacteria, aiming to provide a snapshot of the situation and some information on the broader context.

Polymyxin resistance caused by large-scale genomic inversion due to IS26 intramolecular translocation in Klebsiella pneumoniae.

Polymyxin B and polymyxin E (colistin) are presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms such as carbapenemase-producer Enterobacterales, Acinetobacter baumannii, and Klebsiella pneumoniae. Yet resistance to this last-line drugs is a major public health threat and is rapidly increasing. Polymyxin S2 (S2) is a polymyxin B analogue previously synthesized in our institute with obviously high antibacterial activity and lower toxicity than polymyxin B and colistin. To predict the possible resistant mechanism of S2 for wide clinical application, we experimentally induced bacterial resistant mutants and studied the preliminary resistance mechanisms. Mut-S, a resistant mutant of K. pneumoniae ATCC BAA-2146 (Kpn2146) induced by S2, was analyzed by whole genome sequencing, transcriptomics, mass spectrometry and complementation experiment. Surprisingly, large-scale genomic inversion (LSGI) of approximately 1.1 Mbp in the chromosome caused by IS26 mediated intramolecular transposition was found in Mut-S, which led to mgrB truncation, lipid A modification and hence S2 resistance. The resistance can be complemented by plasmid carrying intact mgrB. The same mechanism was also found in polymyxin B and colistin induced drug-resistant mutants of Kpn2146 (Mut-B and Mut-E, respectively). This is the first report of polymyxin resistance caused by IS26 intramolecular transposition mediated mgrB truncation in chromosome in K. pneumoniae. The findings broaden our scope of knowledge for polymyxin resistance and enriched our understanding of how bacteria can manage to survive in the presence of antibiotics.

Epidemiology and Antimicrobial Resistance Patterns of Urinary Tract Infections: A Cross-Sectional Study from Southwestern Saudi Arabia.

Background: Urinary tract infections (UTIs) are a prevalent form of urinary tract diseases affecting individuals of all ages and genders. In the Kingdom of Saudi Arabia (KSA), UTIs are a significant burden on the healthcare system, comprising 10% of all infections and ranking as the second leading cause of emergency department admissions. Despite this, limited research has been conducted in Saudi Arabia, particularly in Jazan Province, located in the southwestern region. Methods: This retrospective, cross-sectional study encompassed individuals with positive urine cultures who sought care at a tertiary hospital in Jazan between January 2022 and March 2023. A standardized data collection form was utilized to retrieve relevant information from microbiology lab test results and patients' electronic medical records. Variables such as sex, urine sample collection date, bacterial isolates, antibiotic sensitivity, and resistance were collected using the data collection form. Data were analyzed using SPSS software, version 23.0 (IBM Corp., Armonk, NY, USA). Results: A total of 1082 urinary bacterial samples were isolated and identified. Females accounted for more bacterial infections (62.66%) than males (37.34%). Gram-negative bacteria represented 94% of all isolated strains. The most prevalent pathogens associated with UTIs were Escherichia coli (47.97%), Klebsiella pneumoniae (24.58%), and Pseudomonas aeruginosa (11.55%). Antimicrobial resistance patterns indicated the presence of extended-spectrum beta-lactamase (ESBL) (30.13%), carbapenemase-resistant Enterobacter (CRE) (1.94%), methicillin-resistant Staphylococcus aureus (MRSA) (0.74%), and vancomycin-resistant Enterococci (VRE) (0.18%). UTI incidence demonstrated a higher prevalence in September (13%) compared to other months in 2022. Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa were the predominant Gram-negative multidrug-resistant organisms (MDRO), accounting for 34.42%, 13.95%, and 1.63% of the population. Conclusions: The prevalence of UTIs caused by antibiotic-resistant microbes is notable in Jazan. Consistent with findings from other regions, Escherichia coli remains the most common causative pathogen of UTIs, displaying a seasonal pattern that warrants attention. Approximately 35% of reported cases involve MDRO, with ESBLs accounting for 30%. These results should raise concerns among healthcare officials, highlighting the necessity for further investigations into factors contributing to the circulation of MDRO in Jazan.

Successful Use of Cefiderocol to Treat a Multidrug-resistant Stenotrophomonas maltophilia Ventilator-associated Pneumonia in an Extremely Preterm Neonate.

Ventilator-associated pneumonia (VAP) caries a morbidity and mortality risk in the preterm neonate, particularly in the context of rising global antimicrobial resistance driving infections due to multidrug-resistant Gram-negative bacteria. Cefiderocol, a siderophilic cephalosporin, has broad Gram-negative antimicrobial activity and central nervous system penetration and is used for the treatment of hospital-acquired pneumonia or VAP in adults. Scarce data exists on its use in neonates. A female neonate born at 26 + 6 weeks developed VAP at 21 days of life. She was commenced on corticosteroids, vancomycin and ceftazidime but continued to deteriorate. Sputum cultures yielded Stenotrophomonas maltophilia resistant to trimethoprim/sulfamethoxazole, ciprofloxacin and ceftazidime, with potential susceptibility to cefiderocol. Cerebrospinal fluid showed an elevated white cell count. In view of worsening respiratory and hemodynamic status, antibiotic treatment was changed to cefiderocol monotherapy at 30 mg/kg/dose every 8 hours. Within 72 hours of commencing cefiderocol, the neonate was successfully extubated to variable-flow continuous positive airway pressure and showed ongoing clinical improvement. Cefiderocol was integral for the care of our neonate without any immediate adverse safety consequences. We relied on dosing data from a conference abstract, due to the paucity of evidence on the use of novel antimicrobials. This lack of evidence is particularly concerning given preterm neonates are particularly vulnerable to infections with multidrug-resistant Gram-negative organisms due to their immature immune systems, prolonged hospital stay, repeated interventions and antimicrobial exposure.

Hematopoietic stem-cell transplantation in a zoo of multidrug-resistant organisms: Data from a cancer center in eastern India.

Infections by multidrug-resistant organisms (MDRO) are a major hurdle in hematopoietic stem-cell transplants (HSCTs). Conditioning regimens lead to mucosal barrier injury, which in-turn leads to transmigration of gut bacteria and sepsis. Pre-transplant stool and throat surveillance cultures can guide empirical antibiotic policy during the neutropenic period. In this paper, we document colonization with MDRO in pre-transplant surveillance cultures and the correlation with bloodstream infections in HSCT patients and analyze transplant outcomes with respect to these infections. A single-center, retrospective study on HSCT was performed between January 2021 and December 2021. The incidence of bacterial infections, percentage of MDROs, correlation with pre-transplant stool/throat surveillance cultures, and their impact on overall 100-day and post-100-day to 6-month post-transplant survival were analyzed. Sixty-four patients were included in the study. Pre-transplant stool surveillance cultures were positive for MDRO in 85.9% of patients. Almost half (48.5%) of the isolates were positive for carbapenemase-producing genes (mainly New Delhi metallo-beta-lactamase-1 [NDM-1] and oxacillinase-48 [OXA-48]). Eighteen patients (18/64, 28%) had a positive blood culture for MDRO in the peri-engraftment neutropenic period. Correlation between surveillance and blood cultures was seen in 61% (11/18) of patients. All-cause mortality was 14.1% (9/64) and 25% (16/64) in patients at 100 days and 6 months post-HSCT, respectively. The 100-day and post-100-day all-cause mortality rates were higher in patients with Gram-negative MDRO bloodstream infections (p<.012 and <.008, respectively). MDRO infections can adversely affect HSCT outcomes. Pre-transplant stool and throat surveillance cultures may guide empirical antibiotic policy and lead to favorable transplant outcomes.

Clinical Outcome of Cefiderocol for Infections with Carbapenem-Resistant Organisms.

Cefiderocol is a novel cephalosporin recently approved by the FDA to aid clinicians in the fight against multidrug-resistant (including carbapenem-resistant) gram-negative organisms. The primary objective of this study is to evaluate the 14- and 28-day mortality associated with cefiderocol. We performed a retrospective chart review of all adult patients admitted at Stony Brook University Hospital between October 2020 and December 2021 and received cefiderocol for at least 3 days. Patients were excluded if they received more than one course of cefiderocol therapy or remained hospitalized at the time of this study. A total of 22 patients met the inclusion criteria. The all-cause mortality on day 28 for all patients was 13.6%, whereas this rate for patients with BSI was 0%, with cUTI was 0% and with LRTI was 16.7%. The all-cause mortality on day 28 for patients who received the dual antibiotics (in conjunction with cefiderocol) was 0%, compared to 25% for patients who only received cefiderocol (p = 0.25). We noted treatment failure in two patients (9.1%). Our findings suggest that cefiderocol could possibly be associated with lower all-cause mortality than previously thought. In our study, we did not find any significant difference between cefiderocol's use in combination with another antibacterial agent and its use as a monotherapy.

Impact of the cAMP-cAMP Receptor Protein Regulatory Complex on Lipopolysaccharide Modifications and Polymyxin B Resistance in Escherichia coli.

Gram-negative bacteria have a unique cell surface that can be modified to maintain bacterial fitness in diverse environments. A well-defined example is the modification of the lipid A component of lipopolysaccharide (LPS), which promotes resistance to polymyxin antibiotics and antimicrobial peptides. In many organisms, such modifications include the addition of the amine-containing constituents 4-amino-4-deoxy-l-arabinose (l-Ara4N) and phosphoethanolamine (pEtN). Addition of pEtN is catalyzed by EptA, which uses phosphatidylethanolamine (PE) as its substrate donor, resulting in production of diacylglycerol (DAG). DAG is then quickly recycled into glycerophospholipid (GPL) synthesis by the DAG kinase A (DgkA) to produce phosphatidic acid, the major GPL precursor. Previously, we hypothesized that loss of DgkA recycling would be detrimental to the cell when LPS is heavily modified. Instead, we found that DAG accumulation inhibits EptA activity, preventing further degradation of PE, the predominant GPL of the cell. However, DAG inhibition of pEtN addition results in complete loss of polymyxin resistance. Here, we selected for suppressors to find a mechanism of resistance independent of DAG recycling or pEtN modification. Disrupting the gene encoding the adenylate cyclase, cyaA, fully restored antibiotic resistance without restoring DAG recycling or pEtN modification. Supporting this, disruptions of genes that reduce CyaA-derived cAMP formation (e.g., ptsI) or disruption of the cAMP receptor protein, Crp, also restored resistance. We found that loss of the cAMP-CRP regulatory complex was necessary for suppression and that resistance arises from a substantial increase in l-Ara4N-modified LPS, bypassing the need for pEtN modification. IMPORTANCE Gram-negative bacteria can alter the structure of their LPS to promote resistance to cationic antimicrobial peptides, including polymyxin antibiotics. Polymyxins are considered last-resort antibiotics for treatment against multidrug-resistant Gram-negative organisms. Here, we explore how changes in general metabolism and carbon catabolite repression pathways can alter LPS structure and influence polymyxin resistance.

Impact of a real-time diagnostic and antimicrobial stewardship workflow on time to appropriate therapy for infections caused by multidrug-resistant Gram-negative organisms

IntroductionMultidrug-resistant (MDR) Gram-negative organisms cause life-threatening infections, and the incidence is rising globally. Timely therapy for these infections has a direct impact on patient survival. This study aimed to determine the impact of a multidisciplinary diagnostic and antimicrobial stewardship (AMS) workflow on time to appropriate therapy (TAP) for these infections using novel beta-lactam/beta-lactamase inhibitors. MethodsThis was a retrospective quasi-experimental study of adult patients with carbapenem-resistant Enterobacterales (CRE) and multidrug-resistant Pseudomonas (MDR PsA) infections at a 1500 bed university hospital. Included patients who received ≥ 72 hours of ceftazidime-avibactam (CZA) or ceftolozane-tazobactam (C/T) from December 2017 to December 2019. During the pre-intervention period (December 2017 to December 2018), additional susceptibilities (including CZA and C/T) were performed only upon providers’ request. In 2019, reflex algorithms were implemented for faster identification and testing of all CRE/MDR PsA isolates. Results were communicated in real-time to the AMS team to tailor therapy. ResultsA total of 99 patients were included, with no between-group differences at baseline. The median age was 60 years and 56 (56.7%) were in intensive care at the time of culture collection. Identified organisms included 71 (71.7%) MDR PsA and 26 CRE, of which 18 were carbapenemase producers (Klebsiella-producing carbapenemase = 12, New Delhi metallo-β-lactamase = 4, Verona integron-encoded metallo-β-lactamase = 2). The most common infections were pneumonia (49.5%) and bacteraemia (30.3%). A decrease was found in median TAP (103 [IQR 76.0–156.0] vs. 75 [IQR 56–100] hours; P < 0.001). Median time from culture collection to final susceptibility results was shorter in the post-intervention group (123 vs. 93 hours; P < 0.001). ConclusionThis study identified improvement in TAP in MDR PsA and CRE infections with implementation of a reflex microbiology workflow and multidisciplinary antimicrobial stewardship initiatives.

Dexmedetomidine may reduce the risk of acute kidney injury development in critically ill patients during colistin therapy

IntroductionColistin is considered as a last resort therapy for multidrug-resistant gram-negative organisms. It is widely used despite the significant risk of nephrotoxicity. Experimental studies showed the nephroprotective effect of dexmedetomidine, a sedative agent, against colistin toxicity. This study was performed to show the possible nephroprotective effect of dexmedetomidine among critically ill patients who received colistin. MethodsAdult (>17 years) patients who were admitted to our surgical and medical intensive care unit (ICU) from March 2018 through March 2021, and who received colistin were included. Patients who receive Colistin therapy or intensive care unit follow-up of <72 h (discharge or death) and Acute kidney injury (AKI) or need hemodialysis prior to colistin therapy at the same hospitalization were excluded. AKI risk factors were examined by grouping patients with and without AKI. Patients, receiving colistin concomitantly with dexmedetomidine were also evaluated. ResultsOf the 139 patients included, 27 (17.8%) patients received dexmedetomidine. Sixty-five patients (47%) had AKI, at a median 5 (4-7) days after the initiation of colistin. Older age, lower baseline estimated glomerular filtration rate, and vasopressor use were associated with a higher risk of AKI, while dexmedetomidine use was associated with a lower risk. In the multivariate regression model, dexmedetomidine use was independently associated with a lower risk of AKI development (OR 0.20 95% CI 0.07–0.59, p = 0.003). ConclusionIn respect to these findings, dexmedetomidine may provide protection against AKI during colistin therapy in critically ill patients.

Microbiology Clinical Culture Diagnostic Yields and Antimicrobial Resistance Proportions before and during the COVID-19 Pandemic in an Indian Community Hospital and Two US Community Hospitals

Studies comparing the impact of the COVID-19 pandemic on diagnostic microbiology culture yields and antimicrobial resistance proportions in low-to-middle-income and high-income countries are lacking. A retrospective study using blood, respiratory, and urine microbiology data from a community hospital in India and two community hospitals (Hospitals A and B) in St. Louis, MO, USA was performed. We compared the proportion of cultures positive for selected multi-drug-resistant organisms (MDROs) listed on the WHO's priority pathogen list both before the COVID-19 pandemic (January 2017-December 2019) and early in the COVID-19 pandemic (April 2020-October 2020). The proportion of blood cultures contaminated with coagulase-negative Staphylococcus (CONS) was significantly higher during the pandemic in all three hospitals. In the Indian hospital, the proportion of carbapenem-resistant (CR) Klebsiella pneumoniae in respiratory cultures was significantly higher during the pandemic period, as was the proportion of CR Escherichia coli in urine cultures. In the US hospitals, the proportion of methicillin-resistant Staphylococcus aureus in blood cultures was significantly higher during the pandemic period in Hospital A, while no significant increase in the proportion of Gram-negative MDROs was observed. Continuity of antimicrobial stewardship activities and better infection prevention measures are critical to optimize outcomes and minimize the burden of antimicrobial resistance among COVID-19 patients.