Cerebrospinal fluid drain infection caused by pandrug-resistant Staphylococcus epidermidis successfully treated with ceftaroline in combination with fosfomycin and vancomycin.

External ventricular drain-related cerebrospinal fluid infection represents a fearsome complication of neurosurgical interventions. Although vancomycin represents the standard of care for methicillin-resistant CoNS healthcare-associated ventriculitis, resistance phenomena have been described. We reported a case of a persistent external ventricular fluid drain infection after device removal by pandrug-resistant Staphylococcus epidermidis successfully treated with intravenous ceftaroline in combination with fosfomycin and vancomycin. No evidence regarding pandrug-resistant S. epidermidis therapy currently exists to our knowledge. In this case, the S. epidermidis phenotype emerged during the therapy course, possibly due to initial device retention, biofilm formation and the host immune impaired response. Despite being poorly studied in vivo, ceftaroline may be considered an option when other alternatives are unavailable, thanks to its described activity against CoNS in vitro. This case extends the experience with ceftaroline for central nervous system infections suggesting it could also be used in high antimicrobial resistance settings for immunocompromised people.

Aetiology and use of antibiotics in pregnancy-related infections: results of the WHO Global Maternal Sepsis Study (GLOSS), 1-week inception cohort.

BACKGROUND: Pregnancy-related infections are important contributors to maternal sepsis and mortality. We aimed to describe clinical, microbiological characteristics and use of antibiotics by source of infection and country income, among hospitalized women with suspected or confirmed pregnancy-related infections. METHODS: We used data from WHO Global Maternal Sepsis Study (GLOSS) on maternal infections in hospitalized women, in 52 low-middle- and high-income countries conducted between November 28th and December 4th, 2017, to describe the frequencies and medians of maternal demographic, obstetric, and clinical characteristics and outcomes, methods of infection diagnosis and causative pathogens, of single source pregnancy-related infection, other than breast, and initial use of therapeutic antibiotics. We included 1456 women. RESULTS: We found infections of the genital (n = 745/1456, 51.2%) and the urinary tracts (UTI) (n = 531/1456, 36.5%) to be the most frequent. UTI (n = 339/531, 63.8%) and post-caesarean skin and soft tissue infections (SSTI) (n = 99/180, 55.0%) were the sources with more culture samples taken and microbiological confirmations. Escherichia coli was the major uropathogen (n = 103/118, 87.3%) and Staphylococcus aureus (n = 21/44, 47.7%) was the commonest pathogen in SSTI. For 13.1% (n = 191) of women, antibiotics were not prescribed on the same day of infection suspicion. Cephalosporins (n = 283/531, 53.3%) were the commonest antibiotic class prescribed for UTI, while metronidazole (n = 303/925, 32.8%) was the most prescribed for all other sources. Ceftriaxone with metronidazole was the commonest combination for the genital tract (n = 98/745, 13.2%) and SSTI (n = 22/180, 12.2%). Metronidazole (n = 137/235, 58.3%) was the most prescribed antibiotic in low-income countries while cephalosporins and co-amoxiclav (n = 129/186, 69.4%) were more commonly prescribed in high-income countries. CONCLUSIONS: Differences in antibiotics used across countries could be due to availability, local guidelines, prescribing culture, cost, and access to microbiology laboratory, despite having found similar sources and pathogens as previous studies. Better dissemination of recommendations in line with antimicrobial stewardship programmes might improve antibiotic prescription.

Are changes in antibiotic prophylaxis recommendations responsible for an increased risk of cefazolin allergy?

BACKGROUND: The first line of prevention of surgical site infection relies on the timely administration of antibiotic prophylaxis. First- and second-generation cephalosporins are the most recommended antibiotics in elective surgery. The incidence of cefazolin allergy has increased worldwide over the years. The sensitization mechanism of cefazolin is currently unknown, and data supporting cross-reactivity between penicillins and cephalosporins are lacking. Sensitization could occur through previous exposure either to cefazolin or to structurally related chemical agents. The objective of this study was to evaluate sensitization agents towards cefazolin. METHODS: The OpenBabel chemoinformatics toolbox was used to search for similarities between cefazolin and other molecules in an extensive drug database. Using the pholcodine-rocuronium similarity score as a threshold, we selected drugs with the most similar structure to that of cefazolin. Exposure to those drugs and cefazolin was assessed in a cohort of patients with skin test-proven cefazolin allergy at a specialized allergy centre via a self-administered anonymous questionnaire. RESULTS: Using the pholcodine-rocuronium similarity score as a threshold (score≥0.7), 42 molecules were found to be similar to cefazolin (all cephalosporins). Only 8 were marketed in France. None of the 14 cefazolin-allergic patients who answered the questionnaire (65% female, median age 56 years) reported exposure to any identified antibiotics. In contrast, 11 (78%) had at least one previous surgery requiring cefazolin before the index case. CONCLUSION: Direct previous cefazolin exposure was identified in 78% of cefazolin-allergic patients. Cefazolin started to take a central place in antibiotic prophylaxis after 2010, when cefamandole usage decreased drastically. Changes in antibiotic prophylaxis over the past 14 years in France could have been the turning point for the increased incidence of cefazolin allergy.

Early picc-line infections in non-neutropenic patients are mainly due to E. coli suggesting that third-generation cephalosporin may be used as a first-line antibiotic therapy.

PURPOSE: To describe the rate of peripherally inserted central catheter (PICC) -associated bloodstream infections, and the pathogens involved. METHODS: We prospectively analyzed data collected from all adult patients with a PICC insertion in a hematology unit in a tertiary care center between January 1, 2017 and June 30, 2020. RESULTS: A total of 370 PICCs were inserted in 275 patients with hematological malignancies: 54 (15 %) confirmed cases of central-line associated bloodstream infection (CLABSI) were identified. Enterobacteria were the most frequent bacteria identified, involved in 35 % of CLABSIs. Group 1 enterobacteria bacteremia occurred a much shorter time after insertion (median time to CLABSI 16 days) than group 2 or group 3 enterobacteria (median time to CLABSI 64 days, p-value = 0.049). CONCLUSION: Among Gram-negative bacilli CLABSI among non-neutropenic patients, E. coli identification was the most frequent and occurred earlier after insertion, suggesting that third-generation cephalosporin may be used as a first-line antibiotic therapy for enterobacteria bacteremia among non-neutropenic patients.

Impact of pH on the activity of novel cephalosporin cefiderocol in human urine.

BACKGROUND: Antimicrobial activity of antibiotics can be impacted by pH, enhancing or reducing their bactericidal properties. Cefiderocol, a novel cephalosporin antibiotic that is among others indicated for the treatment of complicated urinary tract infections (cUTIs), lacks data on activity in urine. METHODS: Pooled human urine (iron levels ∼0.05 mg/L/24 h), CAMHB and iron-depleted CAMHB (ID-CAMHB) at pH 5, 7 and 8 served as media. MIC testing was done according to EUCAST with the broth microdilution method for 17 clinical isolates of Escherichia coli and ATCC 25922 (including isolates with ESBL activity), 17 clinical isolates of Klebsiella pneumoniae and ATCC 700603 (also with ESBL), and 6 clinical isolates of Pseudomonas aeruginosa and ATCC 27853. Time-kill curves (TKCs) were performed for selected strains at pH 5, 7 and 8 in urine. RESULTS: MIC values in urine, CAMHB and ID-CAMHB exhibited isolate-specific variations when assessed under identical pH conditions, ranging from a 1-fold dilution to changes of up to 4-fold dilutions in either direction. Median MICs of cefiderocol were up to 50-fold higher in pH 5 than in pH 7 for P. aeruginosa isolates and 32-fold higher in E. coli and K. pneumoniae isolates. TKCs with 650 and 1300 mg/L cefiderocol in urine showed that ATCC strains were efficiently eradicated despite the pH set. CONCLUSIONS: Acidic pH had a significant negative impact on cefiderocol activity. Yet, after a recommended IV administration of 2 g cefiderocol every 8 h, a concentration of approximately 1300 mg/L can be achieved in urine, suggesting that efficient killing of all tested pathogens could have been possible even under acidic conditions in vivo.

Moving towards a standardized definition of antimicrobial resistance: a comparison of the antimicrobial susceptibility profile of difficult-to-treat resistance (DTR) versus multidrug-resistant (MDR) Pseudomonas aeruginosa clinical isolates (CANWARD, 2016-2021).

Pseudomonas aeruginosa clinical isolates demonstrating difficult-to-treat resistance (DTR) and multidrug-resistant (MDR) phenotypes were evaluated by broth microdilution. Susceptibility was lower for all antimicrobials versus DTR relative to MDR isolates. Ceftazidime-avibactam, ceftolozane-tazobactam, and imipenem-relebactam susceptibility was 35.9%, 64.5%, and 47.0% for DTR isolates and 60.5%, 80.6%, and 71.5% for MDR isolates.

In vitro activity of cefiderocol and other newly approved antimicrobials against multi-drug resistant Gram-negative pathogens recovered in intensive care units in Spain and Portugal.

OBJECTIVE: The antimicrobial resistance is a significant public health threat, particularly for healthcare-associated infections caused by carbapenem-resistant Gram-negative pathogens which are increasingly reported worldwide. The aim of this study was to provide data on the in vitro antimicrobial activity of cefiderocol and that of commercially available comparator antibiotics against a defined collection of recent clinical multi-drug resistant (MDR) microorganisms, including carbapenem resistant Gram-negative bacteria collected from different regions in Spain and Portugal. METHODS: A total of 477 clinical isolates of Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia were prospectively (n=265) and retrospectively (n=212) included (2016-2019). Susceptibility testing was performed using standard broad microdilution and results were interpreted using CLSI-2021 and EUCAST-2021 criteria. RESULTS: Overall, cefiderocol showed a good activity against Enterobacterales isolates, being 99.5% susceptible by CLSI and 94.5% by EUCAST criteria. It also demonstrated excellent activity against P. aeruginosa and S. maltophilia isolates, all being susceptible to this compound considering CLSI breakpoints. Regarding A. baumannii (n=64), only one isolate was resistant to cefiderocol. CONCLUSIONS: Our results are in agreement with other studies performed outside Spain and Portugal highlighting its excellent activity against MDR gram-negative bacteria. Cefiderocol is a therapeutic alternative to those available for the treatment of infections caused by these MDR bacteria.

Pharmacokinetic Analysis of Intravenous Push Cefepime in Burn Patients with Augmented Renal Clearance.

Patients with augmented renal clearance (ARC) are a subset of critically ill patients including burn patients that exhibit increased renal elimination of medications beyond that of similarly injured patients. Currently approved maximum regimens of medications primarily eliminated by the kidney, such as cefepime (>90% unchanged in the urine), may be inadequate (eg, compromising the bactericidal activity of cefepime) in patients with ARC. Due to recent resource limitations, centers have changed infusion practices of commonly prescribed medications to intravenous push (IVP), potentially exacerbating the problem of maintaining bactericidal cefepime concentrations. The hypothesis of the study was patients with ARC are not currently achieving adequate target attainment, when receiving cefepime 2 g every 8 h IVP. Eight blood samples were collected from each patient, and concentrations measured via LC-MS/MS. WinNonlin (version 8.3) was used to estimate the pharmacokinetic parameters of cefepime and simulate plasma concentrations of cefepime in each of the ten subjects. Simulations of cefepime plasma concentrations produced by a 2 g dose given every 8 h and a 1 g dose given every 4 h were performed and the time above a MIC of 4 mg/L, 8 mg/L, and 16 mg/L compared. The 2 g every 8 h regimen remained above the breakpoints for 92%, 85%, and 71% of the dosing interval, respectively. The 1 g every 4 h regimen remained above the same breakpoints at a frequency of 100%, 99%, and 92% of the dosing interval. Giving cefepime 1 g every 4 h is a simple approach to increase the likelihood of maintaining the optimal bactericidal activity of cefepime in patients with ARC.

Real-life use of ceftobiprole for severe infections in a French intensive care unit.

Ceftobiprole (CBP) is an anti-methicillin-resistant Staphylococcus aureus (MRSA) cephalosporin with a wide spectrum of activity. We aimed to describe our experience of real-life use of CBP for the treatment of severe infections of critically ill patients with multiple infected sites and related trough CBP concentrations. We performed a retrospective, observational, monocentric study in our intensive care unit (ICU) that included all patients treated with CBP for documented infections between January 2016 and December 2021. We collected demographic, clinical, and microbiological data. When available, we report the CBP trough concentrations. The primary endpoint was clinical cure at the end of treatment. The secondary endpoints were in-hospital mortality and documentation of the carriage of multidrug-resistant (MDR) bacteria not present before CBP treatment. Between January 2016 and December 2021, 47 patients were treated in the ICU with CBP. The main indication for treatment was pneumonia (51%) and most patients presented with associated bacteremia (72%). All infections were polymicrobial. A clinical cure was achieved for nearly 80% of the patients. Only five patients presented new carriage of MDR bacteria. In-hospital mortality was 32%. Out of 21 strains of Enterobacterales for which the MIC was available, 33% were considered to be resistant to CBP according to the EUCAST 2023 clinical breakpoint. Trough CBP concentrations were reported for 16 patients. In our real-life experience, treatment of ICU patients with CBP for polymicrobial severe infections resulted in most cases in a clinical cure. Monitoring of trough concentrations is critical, especially in cases of high MIC.

Prescribing Pattern and Efficacy of Oral Antibiotics for Pediatric Urinary Tract Infections in Japan: A Descriptive Study Using a Nationwide Claims Database.

BACKGROUND: Pediatric urinary tract infections are often treated with third-generation cephalosporins; however, the increasing prevalence of Escherichia coli resistant to cephalosporins has reduced their effectiveness. Although resistance is prevalent in Asia, the prescribing patterns and clinical effectiveness of antibiotics have mostly been reported in the United States. This study aimed to describe the prescription patterns and effectiveness of oral antibiotics for treating pediatric urinary tract infections in Japan. METHODS: This descriptive study used data from a nationwide Japanese claims database. We identified patients <6 years old with urinary tract infections who received oral antibiotics between January 2016 and December 2020. Descriptive analyses were performed to assess prescription patterns. Moreover, logistic regression analyses were conducted to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for treatment failure among the commonly prescribed antibiotics and patient characteristics. Treatment failure was defined as the prescription of different antibiotics within 7 days of the primary prescription. RESULTS: Of the 4,127 patients, 2,766 (67.0%) were prescribed third-generation cephalosporins, and 347 (8.4%) were prescribed amoxicillin. Trimethoprim-sulfamethoxazole and amoxicillin-clavulanate were prescribed to 63 (1.5%) and 50 (1.2%) patients, respectively. Treatment failure was observed in 118 (2.9%) patients and more often in amoxicillin-treated patients than in cefcapene pivoxil-treated patients [OR, 2.18 (95% CI: 1.04-4.58)]. CONCLUSIONS: Third-generation cephalosporins are the most commonly prescribed antibiotics for the initial therapy of pediatric urinary tract infections in Japan. Third-generation cephalosporins are still effective in Japan, despite the high prevalence of resistance against cephalosporins.

A Process Improvement Project to Increase Compliance With Cephalosporin-based Surgical Antimicrobial Prophylaxis in Children With Non-severe Penicillin Allergies.

BACKGROUND/PURPOSE: Cephalosporins are considered safe and first-line prophylaxis in children with non-severe penicillin allergies. However, use of second-line agents is common and is primarily driven by poor allergic response documentation and misunderstanding of cross-reactivity risk. The goal of this project was to improve compliance with cephalosporin prophylaxis through improved documentation and targeted educational efforts. METHODS: A multidisciplinary working group including representatives from allergy, surgery, infectious disease, and pharmacy developed staged interventions to facilitate compliance with cephalosporin prophylaxis. These included: (1) caregiver outreach to clarify incomplete allergy documentation, (2) a decision-support algorithm for prophylaxis use in penicillin-allergic patients, (3) standardized educational resources for surgical faculty and rotating trainees, (4) email reminders with prophylaxis recommendations sent out prior to scheduled cases, and (5) EMR-based decision support during antibiotic ordering. Rates of complete allergy documentation and cephalosporin utilization were compared for general surgery procedures between a 12-month pre-intervention and 14-month post-intervention period. RESULTS: 578 patients with penicillin allergies recorded in the EMR were included (301 pre-intervention and 277 post-intervention), 54.0% of which received prophylaxis. Compared to the pre-intervention period, complete documentation of allergic reactions increased from 57.1% to 84.2% (p < 0.001) following implementation of all interventions. Appropriate prophylaxis utilization increased from 34.5% to 88.5% following implementation of all interventions (p < 0.001), and evidence of a stepwise increase in appropriate utilization was evident with each intervention stage. Persistent compliance failures during the post-implementation period were most commonly associated with urgent and emergent add-on cases. No adverse events or allergic responses were reported before or after project implementation. CONCLUSIONS: Compliance with cephalosporin prophylaxis significantly improved following a multidisciplinary effort targeting education, allergy documentation, and clinical support at the point of care. Ongoing efforts include postoperative audits within 24 h for noncompliant cases in order to identify barriers and improve compliance for urgent and emergent add-on cases. LEVEL OF EVIDENCE: III. TYPE OF STUDY: Prospective.

Cephalosporin resistance, tolerance, and approaches to improve their activities.

Cephalosporins comprise a ß-lactam antibiotic class whose first members were discovered in 1945 from the fungus Cephalosporium acremonium. Their clinical use for Gram-negative bacterial infections is widespread due to their ability to traverse outer membranes through porins to gain access to the periplasm and disrupt peptidoglycan synthesis. More recent members of the cephalosporin class are administered as last resort treatments for complicated urinary tract infections, MRSA, and other multi-drug resistant pathogens, such as Neisseria gonorrhoeae. Unfortunately, there has been a global increase in cephalosporin-resistant strains, heteroresistance to this drug class has been a topic of increasing concern, and tolerance and persistence are recognized as potential causes of cephalosporin treatment failure. In this review, we summarize the cephalosporin antibiotic class from discovery to their mechanisms of action, and discuss the causes of cephalosporin treatment failure, which include resistance, tolerance, and phenomena when those qualities are exhibited by only small subpopulations of bacterial cultures (heteroresistance and persistence). Further, we discuss how recent efforts with cephalosporin conjugates and combination treatments aim to reinvigorate this antibiotic class.

Clinical outcomes of intensive care unit patients infected with multidrug-resistant gram-negative bacteria treated with ceftazidime/avibactam and ceftolozane/tazobactam.

In intensive care units (ICUs), infection rates range from 18 to 54%, which is five to ten times higher than those observed in other hospital units, with a mortality rate of 9% to 60%. In recent decades, the susceptibility pattern has changed and Gram-Negative Bacteria (GNB) have become a threat due to their high frequency of multidrug resistance associated with a scarcity of therapeutic options. However, the drugs Ceftolozane/Tazobactam (C/T) and Ceftazidime/Avibactam (C/A) are demonstrating good clinical and microbiological response in the treatment of severe nosocomial infections. Therefore, this study aims to evaluate the clinical outcome of patients with severe infections caused by Multidrug-Resistant (MDR) GNB treated with C/T and C/A. Our study evaluates a total of 131 patients who received treatment with C/T and C/A due to infections caused by MDR GNB within the period from 2018 to 2021. The main infections were urinary tract (46,6%) and respiratory (26,7%) infections. Pseudomonas aeruginosa was the prevailing agent in the sample evaluation (34.3%), followed by Klebsiella pneumoniae (30,1%). About 54,9% of patients showed a favorable response, with culture negativation in 66,4% of the samples, with no discrepancy in negativations when comparing ages: 67,7% in young and 66% in elderly patients. Among the patients, 62,6% received monotherapy with C/T and C/A with a better response observed with monotherapy compared to combination therapy (58,6% vs 41,4%). The overall mortality rate was 45%, with MDR GNB infections responsible for 33,9% of these deaths, and the others (66,1%) due to factors such as oncological, hematological, and degenerative neurological diseases. In regards to hematological aspect, 35,1% of patients showed changes, with 28,2% of them presenting anemia, 4,5% thrombocytopenia, and 2,5% thrombocytosis. Concerning the use of invasive devices, higher mortality was observed in patients on mechanical ventilation (52%). In this manner, it was possible to observe that therapy with C/T and C/A yielded a favorable clinical outcome in patients with severe infections caused by MDR GNB in the study. These drugs also demonstrated good tolerability regardless of age or the presence of preexisting comorbidities and were deemed safe when assessing adverse effects. Our data also demonstrate the importance of determining the mechanism of resistance to carbapenems so that these drugs can be used more effectively and rationally.

Cefiderocol: Clinical application and emergence of resistance.

Antibacterial drug resistance of gram-negative bacteria (GNB) results in high morbidity and mortality of GNB infection, seriously threaten human health globally. Developing new antibiotics has become the critical need for dealing with drug-resistant bacterial infections. Cefiderocol is an iron carrier cephalosporin that achieves drug accumulation through a unique "Trojan horse" strategy into the bacterial periplasm. It shows high antibacterial activity against multidrug-resistant (MDR) Enterobacteriaceae and MDR non-fermentative bacteria. The application of cefiderocol offers new hope for treating clinical drug-resistant bacterial infections. However, limited clinical data and uncertainties about its resistance mechanisms constrain the choice of its therapeutic use. This review aimed to summarize the clinical applications, drug resistance mechanisms, and co-administration of cefiderocol.

MDR/XDR/PDR or DTR? Which definition best fits the resistance profile of Pseudomonas aeruginosa?

PURPOSE OF REVIEW: The aim of this narrative review is to compare the prognostic utility of the new definition of difficult-to-treat resistance (DTR) vs. established definitions in patients with Pseudomonas aeruginosa infection to understand the therapeutic implications of resistance classification and its impact on clinical outcome. RECENT FINDINGS: Among Gram-negative bacteria (GNB), P. aeruginosa (PA) is associated with high rates of morbidity and mortality, mostly related to its intrinsic capacity of developing antibiotic resistance. Several classifications of antibiotic resistance have been proposed in the last 15 years. The most common used is that from Magiorakos et al. including multidrug resistance (MDR), extensively drug-resistant (XDR) and pan drug resistance (PDR) according to the number of antibiotic classes showing in vitro activity. A further classification based on the resistance to specific antibiotic classes (i.e. fluoroquinolones, cephalosporins, carbapenem resistance) was also proposed. However, both of them have been criticized because of limited usefulness in clinical practice and for poor correlation with patient outcome, mainly in infections due to PA. More recently the new definition of difficult-to-treat resistance (DTR) has been proposed referring to nonsusceptibility to all first-line agents showing high-efficacy and low-toxicity (i.e. carbapenems, ß-lactam-ß-lactamase inhibitor combinations, and fluoroquinolones). Studies including large cohorts of patients with GNB bloodstream infections have confirmed the prognostic value of DTR classification and its clinical usefulness mainly in infections due to PA. Indeed, in the recent documents from the Infectious Diseases Society of America (IDSA) on the management of antibiotic resistant GNB infections, the DTR classification was applied to PA. SUMMARY: DTR definition seems to identify better than MDR/XDR/PDR and single class resistant categories the cases of PA with limited treatment options. It requires periodic revision in order to remain up-to-date with the introduction of new antibiotics and the evolving pattern of resistance.

Divergent veterinarian and cat owner perspectives are barriers to reducing the use of cefovecin in cats.

OBJECTIVE: To understand veterinarian and cat owner perspectives on antimicrobial use in cats, reasons for prescribing cefovecin, and barriers to improving antimicrobial stewardship, including veterinarian and cat owner perspectives of giving oral medication to cats. SAMPLE: 21 New York veterinarians and 600 cat owners across the US. METHODS: Cat owners were surveyed about their preferences for and experiences in giving oral medications to cats and their experiences with antimicrobials specifically. Veterinarians were interviewed about antimicrobial use decisions in cats, benefits and drawbacks of cefovecin, and their perspectives on antimicrobial resistance. RESULTS: Many veterinarians reported feeling pressure to prescribe antimicrobials, while 41% of cat owners reported requesting antimicrobials. Although veterinarians are aware of the downsides of prescribing cefovecin, many prescribed cefovecin in situations where an antimicrobial was not needed or cefovecin may not have been the best choice. Veterinarians thought that 20% of cat owners could not give oral medications, but < 10% of cat owners had a cat that was impossible to medicate. CLINICAL RELEVANCE: The disconnect between veterinarians' assessment of and cat owners' reported abilities in administering oral medication may contribute to cefovecin use. Demonstrating for cat owners how to give oral medication may help improve compliance and reduce the use of parenteral long-acting formulations. Structural and educational interventions are needed to address other contributors to inappropriate antimicrobial use. This research provides the specific considerations about barriers and motivations for cat owners and veterinarians that are required to guide strategic, tailored interventions for both audiences to advance stewardship.

Extreme resistance to the novel siderophore-cephalosporin cefiderocol in an extensively drug-resistant Klebsiella pneumoniae strain causing fatal pneumonia with sepsis: genomic analysis and synergistic combinations for resistance reversal.

Cefiderocol (CFDC) is the first-in-class siderophore-cephalosporin. Klebsiella pneumoniae strain that is extremely resistant to CFDC (MIC: 256 µg/ml) was isolated for the first time in the United Arab Emirates from a patient with pneumonia and sepsis. It belonged to sequence-type 14 (ST14), with a novel core genome ST. Resistance was driven by the co-expression of ß-lactamases (blaNDM-1, blaOXA-232 and blaCTX-M-15) and a mutation in catecholate-siderophore receptor, utilized by CFDC to enter the bacterial cell. Synergistic combinations (ß-lactamase inhibitors, aztreonam plus CFDC) re-sensitized the bacteria to CFDC. Although CFDC resistance is multifactorial, the combination with ß-lactamase inhibitors represents a promising approach in resistance reversal for fighting superbugs.