Navigating the Current Treatment Landscape of Metallo-ß-Lactamase-Producing Gram-Negative Infections: What are the Limitations?

The spread of carbapenemase-producing gram-negative pathogens, especially those producing metallo-ß-lactamases (MBLs), has become a major health concern. MBLs are molecularly the most diverse carbapenemases, produced by a wide spectrum of gram-negative organisms, including the Enterobacterales, Pseudomonas spp., Acinetobacter baumannii, and Stenotrophomonas maltophilia, and can hydrolyze most ß-lactams using metal ion cofactors in their active sites. Over the years, the prevalence of MBL-carrying isolates has increased globally, particularly in Asia. MBL infections are associated with adverse clinical outcomes including longer length of hospital stay, ICU admission, and increased mortality across the globe. The optimal treatment for MBL infections not only depends on the pathogen but also on the underlying resistance mechanisms. Currently, there are only few drugs or drug combinations that can efficiently offset MBL-mediated resistance, which makes the treatment of MBL infections challenging. The rising concern of MBLs along with the limited treatment options has led to the need and development of drugs that are specifically targeted towards MBLs. This review discusses the prevalence of MBLs, their clinical impact, and the current treatment options for MBL infections and their limitations. Furthermore, this review will discuss agents currently in the pipeline for treatment of MBL infections.

Understanding the rationale and clinical impact of the revised CLSI 2024 minocycline susceptibility breakpoints against Stenotrophomonas maltophilia.

Stenotrophomonas maltophilia is challenging to treat due to the presence of multiple intrinsic and acquired resistance mechanisms. TMP-SMZ is the standard care of therapy for treating S. maltophilia infections; levofloxavin and minocycline are the preferred potential alternatives. Recently, in 2024, CLSI has lowered the susceptibility breakpoints for minocycline against S. maltophilia. Applying the revised minocycline's susceptibility breakpoint of ≤ 1 mg/L, susceptibility to minocycline dropped significantly from 77% (previous breakpoint, ≤ 4 mg/L) to 35% (revised breakpoint of ≤ 1 mg/L). In the wake of this change, minocycline's dependency has been questioned for treating S. maltophilia infections.

Cefiderocol as rescue therapy in a cancer immunosuppressed critically ill child: Case description and literature review.

Severe infections caused by multidrug-resistant bacteria have underscored the urgent need for innovative treatment approaches. Novel antimicrobials like cefiderocol have emerged as effective options, but their use in children remains largely unexplored. In this brief report, we describe a severe case of sepsis in a child with an oncohematological disease, caused by a highly drug-resistant strain of Klebsiella pneumoniae. The addition of cefiderocol to other therapies resulted in a successful outcome. Additionally, we provide a literature review of previously published cases involving children treated with this new antibiotic. In our patient, cefiderocol was both safe and effective in combating the multidrug-resistant pathogen. However, further research is needed to better define the indications and safety profile of this novel antibiotic.

Antimicrobial susceptibility to last-resort antibiotics in carbapenemase-producing bacteria from Ukrainian patients.

Since March 2022, an increase was observed in multidrug-resistant microorganisms (MDRO), associated with the hospital transfer of Ukrainian patients. The goal was to collect phenotypic susceptibility data and assess clinical implications. Carbapenemase-producing Enterobacterales (CPE, n = 96), Pseudomonas aeruginosa (CPPA, n = 20), and carbapenem-resistant Acinetobacter baumannii-calcoaceticus (CRAB, n = 6) from Ukrainian patients were obtained from March to December 2022 from the Dutch MDRO surveillance. Antimicrobial susceptibility testing was performed using broth microdilution (BMD) when available, fosfomycin agar dilution, disk diffusion (DD) for cefiderocol, and diverse gradient strips. All isolates were sequenced with Illumina next-generation sequencing. For meropenem, aminoglycosides, ceftazidime-avibactam, ceftolozane-tazobactam, and imipenem-relebactam, susceptibility rates were low (0%-30%), due to the high number of blaNDM-positive isolates (79/122; 65%). For cefiderocol, results depended on reading with or without microcolonies, applying EUCAST or CLSI breakpoints, and whether DD or BMD was used; e.g., for Klebsiella pneumoniae, 30%-97% were susceptible. For colistin, 103/111 (93%) non-intrinsically resistant CPE/CPPA/CRAB isolates were susceptible. For most CPE, a low minimal inhibitory concentration (MIC) of <0.5 mg/L was measured for tigecycline and ceftazidime-avibactam-aztreonam. For CPPA, cefiderocol tested susceptible in 65%-100% of isolates. For CRAB, ampicillin-sulbactam MICs were ≥128 mg/L; for sulbactam-durlobactam, 1-2 mg/L. Admission in a Ukrainian hospital in the last year was a risk factor for MDRO, and majority were screening isolates (79%). There is extensive phenotypic resistance to last-resort antibiotics in MDRO from Ukrainian patients. Interpretation of cefiderocol susceptibility results depends on several variables. When treating patients recently admitted in Ukraine, suspected for Gram-negative bacterial infection, this should be taken into consideration. IMPORTANCE: Since March 2022, multidrug-resistant microorganisms associated with Ukrainian patients have been detected in national surveillance systems of several European countries. We studied the phenotypic antimicrobial susceptibility to last-resort antibiotics of multidrug-resistant microorganisms from Ukrainian patients in the Netherlands and assessed clinical implications. Our research revealed that there was extensive phenotypic resistance to last-resort antibiotics. Healthcare professionals should be aware of multidrug-resistant microorganisms when treating patients recently admitted in Ukraine, suspected for Gram-negative bacterial infection.

Comparison of cefiderocol and colistin-based regimens for the treatment of severe infections caused by carbapenem-resistant Acinetobacter baumannii: a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: There are multiple antibiotic regimens for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) in clinical practice. We conducted this meta-analysis to compare the efficacy and safety of cefiderocol-based regimens and colistin-based regimens in the treatment of CRAB infections. METHODS: Two authors independently searched the PubMed, Web of Science, Embase, and Cochrane databases from their establishment to April 15, 2024, to search for randomized controlled trials (RCTs) or cohort studies, and compared the clinical efficacy and safety of cefiderocol-based regimens and colistin-based regimens in the treatment of CRAB infections. The Newcastle Ottawa Scale (NOS) checklist was used to evaluate the quality of the included studies. The primary outcome was all-cause mortality, and subgroup analysis was conducted on the basis of the site of infection and the risk of bias in the studies. Trial sequential analysis (TSA) was then conducted. RESULTS: Six observational studies were included, with 251 cases in the cefiderocol-based group and 372 cases in the colistin-based group. Compared to the colistin-based group, the cefiderocol-based group had lower all-cause mortality (RR = 0.71, 95% CI: 0.54-0.92, P = 0.01) and 30-day mortality (RR = 0.64, 95% CI: 0.43-0.95, P = 0.03). However, for the 14-day and 28-day mortality rates, there was no statistically significant difference between two groups. According to the subgroup analysis, among patients with bloodstream infection (BSI), the cefiderocol-based group had lower all-cause mortality, but it did not reduce the mortality of ventilator-associated pneumonia (VAP) patients. The result of TSA showed that our conclusions are reliable. There was no significant statistical difference in the microbiological cure rate, clinical cure rate, or duration of hospitalization. In addition, the cefiderocol-based group did not have an increased incidence of acute kidney injury (AKI). CONCLUSIONS: Compared with the colistin-based regimens, the cefiderocol-based regimens were significantly associated with a lower risk of mortality in CRAB-infected patients, especially for patients with BSI. However, they did not show any advantages in terms of the clinical cure rate or microbiological cure rate, nor did they reduce the incidence of AKI. PROSPERO REGISTRATION NUMBER: CRD42023487213.

Survival of infection with TEM ß-lactamase-producing Escherichia coli with Pan-ß-lactam resistance.

BACKGROUND: Antimicrobial resistance is a critical global health issue, significantly contributing to patient mortality. Recent antibiotic developments have aimed to counteract carbapenemase-producing Enterobacterales; however, the impact of their use on the emergence of antibiotic resistance is unknown. This study investigates the first case of a non-carbapenemase-producing, pan-ß-lactam-resistant Escherichia coli strain from a patient previously treated with ceftolozane-tazobactam and cefiderocol. METHODS: This study describes the clinical progression of a 39-year-old ICU patient who developed multiple infections, culminating in the isolation of a pan-ß-lactam-resistant E. coli strain (EC554). The resistance profile was characterised through MIC determination, whole-genome sequencing, the use of the ß-lactam inactivation method, RT-qPCR, efflux pump inhibition assays, outer membrane protein analysis, and blaTEM transformation. FINDINGS: The EC554 isolate displayed resistance to all tested ß-lactams and ß-lactam-ß-lactamase inhibitor combinations. Whole-genome sequencing revealed four plasmids in EC554, with the only ß-lactamase gene being blaTEM-252 on the pEC554-PBR-X1-X1 plasmid. We found that the extremely resistant phenotype was attributable to a combination of different mechanisms: a high expression of TEM-252, efflux pump activity, porin loss, and PBP3 mutations. INTERPRETATION: The findings illustrate the complex interplay of multiple resistance mechanisms in E. coli, highlighting the potential for high-level resistance even without carbapenemase production. This study underscores the importance of comprehensively characterising resistance mechanisms in order to inform effective treatment strategies and mitigate the spread of resistant strains.

Recent updates in treating carbapenem-resistant infections in patients with hematological malignancies.

INTRODUCTION: Patients with hematological malignancies (PHMs) are at increased risk for infections caused by carbapenem-resistant organisms (CROs) due to frequent exposure to broad-spectrum antibiotics and prolonged hospital stays. These infections result in high mortality and morbidity rates along with delays in chemotherapy, longer hospitalizations, and increased health care costs. AREAS COVERED: Treatment alternatives for CRO infections in PHMs. EXPERT OPINION: The best available treatment option for KPC and OXA-48 producers is ceftazidime/avibactam. Imipenem/cilastatin/relebactam and meropenem/vaborbactam remain as the alternative options. They can also be used as salvage therapy in KPC-positive Enterobacterales infections resistant to ceftazidime/avibactam, if in vitro susceptibility is shown. Treatment of metallo-ß-lactamase producers is an unmet need. Ceftazidime/avibactam plus aztreonam or aztreonam/avibactam seems to be the most reliable option for metallo-ß-lactamase producers. As a first-line option for carbapenem-resistant Pseudomonas aeruginosa infections, ceftolozane/tazobactam is preferable and ceftazidime/avibactam and imipenem/cilastatin/relebactam constitute alternative regimens. Although sulbactam/durlobactam is the most reliable option against carbapenem-resistant Acinetobacter baumannii infections, its utility as monotherapy and in PHMs is not yet known. Cefiderocol can be selected as a 'last-resort' option for CRO infections. New risk score models supported by artificial intelligence algorithms can be used to predict the exact risk of infections in previously colonized patients.

Evaluation and optimization of sample size of neonates and infants for pediatric clinical studies on cefiderocol using a model-based approach.

When planning pediatric clinical trials, optimizing the sample size of neonates/infants is essential because it is difficult to enroll these subjects. In this simulation study, we evaluated the sample size of neonates/infants using a model-based optimal approach for identifying their pharmacokinetics for cefiderocol. We assessed the usefulness of data for estimation performance (accuracy and variance of parameter estimation) from adults and the impact of data from very young subjects, including preterm neonates. Stochastic simulation and estimation were utilized to assess the impact of sample size allocation for age categories in estimation performance for population pharmacokinetic parameters in pediatrics. The inclusion of adult pharmacokinetic information improved the estimation performance of population pharmacokinetic parameters as the coefficient of variation (CV) range of parameter estimation decreased from 4.9%-593.7% to 2.3%-17.3%. When sample size allocation was based on the age groups of gestational age and postnatal age, the data showed 15 neonates/infants would be necessary to appropriately estimate pediatric pharmacokinetic parameters (<20%CV). By using the postmenstrual age (PMA), which is theoretically considered to be associated with the maturation of organs, the number of neonates/infants required for appropriate parameter estimation could be reduced to seven (one and six with <32 and >32 weeks PMA, respectively) to nine (three and six with <37 and >37 weeks PMA, respectively) subjects. The model-based optimal design approach allowed efficient evaluation of the sample size of neonates/infants for estimation of pediatric pharmacokinetic parameters. This approach to assessment should be useful when designing pediatric clinical trials, especially those including young children.

Surveillance of In Vitro Activity of Cefiderocol Against Carbapenem-Resistant Gram-Negative Clinical Isolates in a Tertiary Care Hospital.

INTRODUCTION: Antibiotic resistance among Gram-negative bacterial isolates is increasingly observed. With the emergence of carbapenem-resistant and pan-resistant pathogens, treating these resistant infections is becoming more challenging due to the limited number of effective drugs. There is a desperate need for the discovery of new antibiotics with novel mechanisms of action. Cefiderocol is one such novel antibiotic with a unique siderophore-based mechanism of action, which has been recently approved for clinical use against drug-resistant pathogens. The present study aims to identify the in vitro activity of cefiderocol against major carbapenem-resistant clinical isolates, including those resistant to colistin. MATERIALS AND METHODS: One hundred and one carbapenem-resistant clinical isolates were included in the study. Identification and antibiotic susceptibility testing were performed using the automated VITEK® 2 Compact (bioMérieux SA, Marcy-l'Étoile, France) identification and susceptibility testing system, except for colistin and cefiderocol. Colistin resistance in Enterobacterales and Pseudomonas aeruginosa was assessed using the agar dilution minimum inhibitory concentration method, while for Acinetobacter baumannii, broth microdilution method was employed. Cefiderocol susceptibility testing was conducted using the Kirby-Bauer disc diffusion method with 30 µg discs on standard Mueller-Hinton agar plates. For selected isolates, cefiderocol minimum inhibitory concentration detection was performed using broth microdilution with iron-depleted cation-adjusted Mueller-Hinton broth. RESULTS: Of the total 101 isolates, the majority (75, 74.25%) were Enterobacterales which included Klebsiella pneumonia (42, 41.58%) and Escherichia coli (33, 32.67%), followed by Pseudomonas aeruginosa (13, 12.87%) and Acinetobacter baumannii (10, 9.9%). Only three (2.97%) of the isolates were Stenotrophomonas maltophilia. Most of the isolates were susceptible to cefiderocol, with only four (3.96%) isolates showing resistance. Colistin resistance was observed in six (6.12%) of the isolates. There was a good correlation between disc diffusion testing and broth microdilution testing for the detection of cefiderocol-resistant isolates. No cross-resistance with colistin was observed, as all colistin-resistant isolates were uniformly susceptible to cefiderocol Conclusion: Cefiderocol is highly effective with good in vitro activity against the majority of carbapenem-resistant pathogens. While some isolates do show resistance, it is relatively uncommon. Given its safety profile compared to colistin, cefiderocol can serve as an alternative to colistin to treat carbapenem-resistant infections and it may be considered even for the management of colistin-resistant cases. Disc diffusion testing is a reliable method for identifying cefiderocol-resistant isolates in routine clinical and diagnostic laboratories, especially in resource-limited settings.

Synergistic Activity of Cefiderocol in Combination with Avibactam, Sulbactam or Tazobactam against Carbapenem-Resistant Gram-Negative Bacteria.

We investigated the activity of cefiderocol/ß-lactamase inhibitor combinations against clinical strains with different susceptibility profiles to cefiderocol to explore the potentiality of antibiotic combinations as a strategy to contain the major public health problem of multidrug-resistant (MDR) pathogens. Specifically, we evaluated the synergistic activity of cefiderocol with avibactam, sulbactam, or tazobactam on three of the most "Critical Priority" group of MDR bacteria (carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii). Clinical isolates were genomically characterized by Illumina iSeq 100. The synergy test was conducted with time-kill curve assays. Specifically, cefiderocol/avibactam, /sulbactam, or /tazobactam combinations were analyzed. Synergism was assigned if bacterial grow reduction reached 2 log10 CFU/mL. We reported the high antimicrobial activity of the cefiderocol/sulbactam combination against carbapenem-resistant Enterobacterales, P. aeruginosa, and A. baumannii; of the cefiderocol/avibactam combination against carbapenem-resistant Enterobacterales; and of the cefiderocol/tazobactam combination against carbapenem-resistant Enterobacterales and P. aeruginosa. Our results demonstrate that all ß-lactamase inhibitors (BLIs) tested are able to enhance cefiderocol antimicrobial activity, also against cefiderocol-resistant isolates. The cefiderocol/sulbactam combination emerges as the most promising combination, proving to highly enhance cefiderocol activity in all the analyzed carbapenem-resistant Gram-negative isolates, whereas the Cefiderocol/tazobactam combination resulted in being active only against carbapenem-resistant Enterobacterales and P. aeruginosa, and cefiderocol/avibactam was only active against carbapenem-resistant Enterobacterales.

Predicting early appropriate therapy for patients infected by carbapenem-resistant Gram-negative pathogens in intensive care units in Italy.

BACKGROUND: Antibiotic resistance among Gram-negative bacteria in intensive care units (ICUs) is linked with high morbidity and mortality in patients. In this study, we estimated the therapeutic coverage of various antibiotics, focusing on cefiderocol and comparators, administered empirically against an infection of unknown origin in the ICU. METHODS: In the ARTEMIS surveillance study, susceptibilities of 624 Italian Gram-negative isolates to amikacin, aztreonam-avibactam, cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, colistin, imipenem-relebactam, meropenem, and meropenem-vaborbactam were tested by broth microdilution, and results were interpreted by European Committee on Antimicrobial Susceptibility Testing breakpoints. The susceptibility rates from the ARTEMIS study were extrapolated to Gram-negative isolates obtained from 5,774 patients in Italian ICUs in 2021. The sum of the predicted susceptibilities of individual pathogens represented the overall likelihood of in vitro activity of each antibiotic as early targeted therapy for ICU patients. RESULTS: A total of 624 Italian Gram-negative isolates included 206 Pseudomonas aeruginosa, 138 Acinetobacter baumannii, 187 Klebsiella pneumoniae, and 93 Escherichia coli. Against A. baumannii, K. pneumoniae, P. aeruginosa, and E. coli, the overall susceptibility rates for cefiderocol were 87.7%, 96.8%, 99%, and 100%, respectively; and for comparator agents, 8.7-96.4%, 25.7-100%, 73.3-100%, and 89.2-100%, respectively. Among the subset of meropenem-resistant isolates, susceptibility rates of A. baumannii, K. pneumoniae, and P. aeruginosa to cefiderocol were 86.4%, 96.2% and 100%, respectively. Corresponding susceptibility rates to comparator agents were 0-96.8%, 0-100%, and 6.4-100%, respectively. There were no meropenem-resistant isolates of E. coli. The extrapolation of data to isolates from Italian ICUs showed that the highest likelihood of therapeutic coverage, both overall and among meropenem-resistant isolates, was reported for colistin (96.8% and 72.2%, respectively) and cefiderocol (95.7% and 71.4%, respectively). All other antibiotics were associated with a likelihood below 73% overall and between 0% and 41.4% for meropenem-resistant isolates. CONCLUSIONS: Based on confirmed susceptibility rates and reported ICU prevalence of multiple Gram-negative species, cefiderocol showed a higher predicted therapeutic coverage and utility in ICUs compared with comparator beta-lactam-beta-lactamase inhibitor antibiotics. Cefiderocol may be a promising early treatment option for patients at high risk of carbapenem-resistant Gram-negative bacterial infections in the ICU.

Commercially available tests for determining cefiderocol susceptibility display variable performance in the Achromobacter genus.

BACKGROUND: Cefiderocol is a siderophore-conjugated cephalosporin increasingly used in the management of Achromobacter infections. Testing for cefiderocol susceptibility is challenging with distinct recommendations depending on the pathogens. OBJECTIVES: We evaluated the performance of commercial tests for testing cefiderocol susceptibility in the Achromobacter genus and reviewed the literature. METHODS: Diffusion (disks, MIC gradient test strips [MTS], Liofilchem) and broth microdilution (BMD) methods (ComASP™, Liofilchem; UMIC®, Bruker) were compared with the BMD reference method according to the EUCAST guidelines on 143 Achromobacter strains from 14 species with MIC50/90 of ≤ 0.015/0.5 mg/L. A literature search was conducted regardless of method or species. RESULTS: None of the methods tested fulfilled an acceptable essential agreement (EA). MTS displayed the lowest EA (30.8%) after UMIC® (49%) and ComASP™ (76.9%). All methods achieved an acceptable bias, with MICs either underestimated using MTS (-1.3%) and ComASP™ (-14.2%) or overestimated with UMIC® (+ 9.1%). Inhibition zone diameters ranged from 6 to 38 mm (IZD50/90=33/30 mm). UMIC® and ComASP™ failed to categorize one or the two cefiderocol-resistant strains of this study as resistant unlike the diffusion-based methods. The literature review highlighted distinct performance of the available methods according to pathogens and testing conditions. CONCLUSIONS: The use of MTS is discouraged for Achromobacter spp. Disk diffusion can be used to screen for susceptible strains by setting a threshold diameter of 30 mm. UMIC® and ComASP™ should not be used as the sole method but have to be systematically associated with disk diffusion to detect the yet rarely described cefiderocol-resistant Achromobacter sp. strains.

Hetero-antagonism of avibactam and sulbactam with cefiderocol in carbapenem-resistant Acinetobacter spp.

Cefiderocol, a siderophore-cephalosporine conjugate antibiotic, shows promise as a therapeutic option for carbapenem-resistant (CR) Acinetobacter infections. While resistance has already been reported in A. baumannii, combination therapies with avibactam or sulbactam reduce MICs of cefiderocol, extending its efficacy. However, careful consideration is necessary when using these combinations. In our experiments, exposure of A. baumannii and A. lwoffii to cefiderocol and sulbactam or avibactam led to the selection of cefiderocol-resistant strains. Three of those were subjected to whole genome sequencing and transcriptomic analysis. The strains all possessed synonymous and non-synonymous substitutions and short deletions. The most significant mutations affected efflux pumps, transcriptional regulators, and iron homeostasis genes. Transcriptomics showed significant alterations in expression levels of outer membrane proteins, iron homeostasis, and ß-lactamases, suggesting adaptive responses to selective pressure. This study underscores the importance of carefully assessing drug synergies, as they may inadvertently foster the selection of resistant variants and complicate the management of CR Acinetobacter infections.IMPORTANCEThe emergence of carbapenem-resistant Acinetobacter strains as a serious global health threat underscores the urgent need for effective treatment options. Although few drugs show promise against CR Acinetobacter infections, resistance to both drugs has been reported. In this study, the molecular characterization of spontaneous cefiderocol-resistant variants, a CR A. baumannii strain with antagonism to sulbactam, and an A. lwoffii strain with antagonism to avibactam, provides valuable insights into the mechanisms of resistance to cefiderocol. Some mechanisms observed are associated with mutations affecting efflux pumps, regulators, and iron homeostasis genes. These findings highlight the importance of understanding resistance mechanisms to optimize treatment options. They also emphasize the importance of early evaluation of drug synergies to address the challenges of antimicrobial resistance in Acinetobacter infections.

Cefiderocol-Based Regimen for Acinetobacter NDM-1 Outbreak.

Variable outcomes have been reported with cefiderocol in infections due to carbapenem-resistant Acinetobacter baumannii (CRAB). Nonetheless, it may be the only option for metallo-beta-lactamase-producing strains. We describe an outbreak of NDM-CRAB infections treated with cefiderocol. Thirty-eight patients were colonized and/or infected. Thirteen patients developed a systemic infection. A clinical cure was achieved in 10 (83%) patients, one VAP and 9 BSIs, at day 7. In vitro, the activity of cefiderocol does not appear to match in vivo effectiveness using currently available commercial tests. Despite high clinical cures, overall mortality remains high in severely ill patients. Cefiderocol may be considered in this specific setting, though the implementation of susceptibility tests and infection control measures is mandatory.

Challenges Facing Two Outbreaks of Carbapenem-Resistant Acinetobacter baumannii: From Cefiderocol Susceptibility Testing to the Emergence of Cefiderocol-Resistant Mutants.

Carbapenem-resistant Acinetobacter baumannii (CRAB) infections are associated with poor outcomes depending on patient's conditions, clinical severity and type of infection, and treatment is challenging given the limited therapeutic options available. The aim of this study was to describe the clinical and microbiological characteristics of two outbreaks caused by CRAB in an intensive care unit (ICU). In addition, the mechanisms of resistance detected in these strains and the treatment chosen according to the available therapeutic options were analyzed. Overall, 28 patients were included. Ten patients (35.71%) had ventilator-associated pneumonia (VAP), ten (35.71%) had a bloodstream infection (BSI), and eight (28.57%) were only colonized. Recurrent infection occurred in 25% (5/20) of infected patients. Two different strains of A. baumannii were isolated from the index patient of the first outbreak. The first strain belonged to the ST85 and carried the blaNDM-1 carbapenemase gene, while the second belonged to the ST2 and carried blaOXA-23, and blaOXA-66 carbapenemase genes. The phylogenetic analysis revealed that the ST2 strain was the cause of the major outbreak, and mutations in the AmpC gene were related to progressive increasing minimum inhibitory concentration (MIC) and finally, cefiderocol-resistance in one strain. The CRAB isolates from the second outbreak were also identified as ST2. Cefiderocol-resistant strains tests identified by the disc diffusion method were involved in 24% (6/25) of nosocomial infections. Using broth microdilution (BMD) ComASP® only, 33.3% (2/6) of these strains were cefiderocol-resistant. All-cause ICU mortality was 21.4%. Conclusions: Cefiderocol is the first approved siderophore cephalosporin for the treatment of CRAB infections. Cefiderocol-resistant strains were related with blaNDM-1 carbapenemase and mutations in the AmpC gene. Cefiderocol-resistant strains or that cannot be properly interpreted by disk diffusion, should be retested using BMD for definitive categorization.

Location, Location, Location: Establishing Design Principles for New Antibacterials from Ferric Siderophore Transport Systems.

This review strives to assemble a set of molecular design principles that enables the delivery of antibiotic warheads to Gram-negative bacterial targets (ESKAPE pathogens) using iron-chelating siderophores, known as the Trojan Horse strategy for antibiotic development. Principles are derived along two main lines. First, archetypical siderophores and their conjugates are used as case studies for native iron transport. They enable the consideration of the correspondence of iron transport and antibacterial target location. The second line of study charts the rationale behind the clinical antibiotic cefiderocol. It illustrates the potential versatility for the design of new Trojan Horse-based antibiotics. Themes such as matching the warhead to a location where the siderophore delivers its cargo (i.e., periplasm vs. cytoplasm), whether or not a cleavable linker is required, and the relevance of cheaters to the effectiveness and selectivity of new conjugates will be explored. The effort to articulate rules has identified gaps in the current understanding of iron transport pathways and suggests directions for new investigations.

Cefiderocol and Intraventricular Colistin for Ventriculitis due to an Extensively Drug-Resistant Pseudomonas Aeruginosa.

Rheumatoid arthritis, an inflammatory rheumatic disease predominantly affecting small limb joints, frequently compromises the cervical spine, resulting in spinal instability and the potential surgical necessity. This may result in severe complications, such as ventriculitis, often associated with a high mortality rate and multidrug-resistant organisms. A major challenge lies in achieving therapeutic antimicrobial concentrations in the central nervous system. The authors present a case of a 65-year-old female, with cervical myelopathy due to severe rheumatoid arthritis. Following surgery, the patient developed ventriculitis caused by an extensively drug-resistant Pseudomonas Aeruginosa. Early diagnosis and prompt treatment played a crucial role in facilitating neurological and cognitive recovery.

Unveiling the Secrets of Acinetobacter baumannii: Resistance, Current Treatments, and Future Innovations.

Acinetobacter baumannii represents a significant concern in nosocomial settings, particularly in critically ill patients who are forced to remain in hospital for extended periods. The challenge of managing and preventing this organism is further compounded by its increasing ability to develop resistance due to its extraordinary genomic plasticity, particularly in response to adverse environmental conditions. Its recognition as a significant public health risk has provided a significant impetus for the identification of new therapeutic approaches and infection control strategies. Indeed, currently used antimicrobial agents are gradually losing their efficacy, neutralized by newer and newer mechanisms of bacterial resistance, especially to carbapenem antibiotics. A deep understanding of the underlying molecular mechanisms is urgently needed to shed light on the properties that allow A. baumannii enormous resilience against standard therapies. Among the most promising alternatives under investigation are the combination sulbactam/durlobactam, cefepime/zidebactam, imipenem/funobactam, xeruborbactam, and the newest molecules such as novel polymyxins or zosurabalpin. Furthermore, the potential of phage therapy, as well as deep learning and artificial intelligence, offer a complementary approach that could be particularly useful in cases where traditional strategies fail. The fight against A. baumannii is not confined to the microcosm of microbiological research or hospital wards; instead, it is a broader public health dilemma that demands a coordinated, global response.