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Cefiderocol is a last resort option for carbapenem-resistant (CR) Gram-negative bacteria, especially metallo-β-lactamase-producing Pseudomonas aeruginosa and CR Acinetobacter baumannii. Monitoring global levels of cefiderocol non-susceptibility (CFDC-NS) is important. To systematically collate and examine studies investigating in vitro CFDC-NS and estimate the global prevalence of CFDC-NS against major Gram-negative pathogens. PubMed and Scopus, up to May 2023. Eligible were studies reporting CFDC-NS in Enterobacterales , P. aeruginosa , A. baumannii , or Stenotrophomonas maltophilia clinical isolates. Two independent reviewers extracted study data and assessed the risk of bias on the population, setting, and measurement (susceptibility testing) domains. Binomial-Normal mixed-effects models were applied to estimate CFDC-NS prevalence by species, coresistance phenotype, and breakpoint definition (EUCAST, CLSI, and FDA). Sources of heterogeneity were investigated by subgroup and meta-regression analyses. In all, 78 studies reporting 82 035 clinical isolates were analysed (87% published between 2020 and 2023). CFDC-NS prevalence (EUCAST breakpoints) was low overall but varied by species (S. maltophilia 0.4% [95% CI 0.2–0.7%], Enterobacterales 3.0% [95% CI 1.5–6.0%], P. aeruginosa 1.4% [95% CI 0.5–4.0%]) and was highest for A. baumannii (8.8%, 95% CI 4.9–15.2%). CFDC-NS was much higher in CR Enterobacterales (12.4%, 95% CI 7.3–20.0%) and CR A. baumannii (13.2%, 95% CI 7.8–21.5%), but relatively low for CR P. aeruginosa (3.5%, 95% CI 1.6–7.8%). CFDC-NS was exceedingly high in New Delhi metallo-β-lactamase-producing Enterobacterales (38.8%, 95% CI 22.6–58.0%), New Delhi metallo-β-lactamase-producing A. baumannii (44.7%, 95% CI 34.5–55.4%), and ceftazidime/avibactam-resistant Enterobacterales (36.6%, 95% CI 22.7–53.1%). CFDC-NS varied considerably with breakpoint definition, predominantly among CR bacteria. Additional sources of heterogeneity were single-centre investigations and geographical regions. CFDC-NS prevalence is low overall, but alarmingly high for specific CR phenotypes circulating in some institutions or regions. Continuous surveillance and updating of global CFDC-NS estimates are imperative while cefiderocol is increasingly introduced into clinical practice. The need to harmonize EUCAST and CLSI breakpoints was evident. [ABSTRACT FROM AUTHOR]

Background: Infections caused by gram-negative carbapenemase-producing organisms (CPO) have become a global phenomenon. Screening of patients for CPO that was carried out at 48-h intervals enables early detection of carriers for infection control purposes and planning therapy. Methods: We investigated the bacterial flora detected on screening, the enzymes that conferred resistance and the proportion of patients who developed bacteraemia with CPO and their therapy. Results: In all, 27 patients had a positive screen for CPO. A small but significant (7.5%) proportion of patients were not detected on initial screening. Escherichia coli and Klebsiella were predominant. New-Delhi metallo β-lactamase and oxacillin carbapenemases were the main enzymatic mechanisms of resistance. Four (14.8%) patients developed bacteraemia with CPO (30- and 90-day survival 100% and 75%, respectively). Conclusion: A single negative screen does not rule out colonisation. A significant proportion of patients colonised with CPO develop bacteraemia. Vigilance is needed to prevent the nosocomial spread of CPO. [ABSTRACT FROM AUTHOR]

Background Cefiderocol and ceftazidime-avibactam plus aztreonam (CZA-ATM) are preferred treatment regimens for New Delhi metallo-β-lactamase (NDM)-producing infections. Methods We report the case of a US patient who traveled to India to receive a renal transplant. He subsequently experienced pyelonephritis by an NDM-producing Escherichia coli. Broth microdilution and the broth disk elution method indicated resistance to all β-lactams, including cefiderocol and CZA-ATM. Whole-genome sequencing investigations were undertaken to identify resistance mechanisms. Results An E. coli isolate belonging to sequence type (ST) 167 containing a bla NDM-5 gene was identified on a plasmid of the IncFIA/IncFIB/IncFIC replicon groups. When compared with the genome of another ST167 E. coli clinical isolate containing bla NDM-5 and exhibiting susceptibility to cefiderocol and CZA-ATM, a 12–base pair insertion in ftsI , translating to a 4–amino acid duplication in PBP3, was identified. Moreover, a bla CMY-59 gene was harbored on an IncI-γ replicon type, and frameshift mutations were identified in the cirA iron transport gene. Conclusions This is the first clinical case of a US patient harboring an NDM-producing isolate exhibiting resistance to all available β-lactam agents. The isolate's unexpected resistance to cefiderocol and CZA-ATM was likely due to a combination of (1) a modified PBP3 (increased MICs to both regimens), (2) truncated iron-binding protein (increased cefiderocol MIC), and (3) a bla CMY gene (reduced CZA-ATM activity). E. coli ST167 clinical isolates harboring bla NDM-5 genes are a recognized international high-risk clone. When coupled with the additional mechanisms identified in our patient's isolate, which is not uncommon for this high-risk clone, pan-β-lactam resistance may occur. [ABSTRACT FROM AUTHOR]

• We identified multiple New Delhi metallo-beta-lactamase 1 Klebsiella pneumoniae isolates in Ukrainian patients. • We detected isolates co-carrying OXA-48 and New Delhi metallo-beta-lactamase-1 carbapenemases. • Treatment choices were limited by the occurrence of multiresistant co-infections. • Sequencing results suggest partial transmission during primary care in Ukraine. We analyzed consecutive clinical cases of infections due to carbapenemase-producing gram-negative bacteria detected in war-wounded patients from Ukraine who were treated at one university medical center in southwest Germany between June and December 2022. The isolates of multiresistant gram-negative bacteria were subjected to a thorough microbiological characterization and whole genome sequencing (WGS). We identified five war-wounded Ukrainian patients who developed infections with New Delhi metallo-β-lactamase 1-positive Klebsiella pneumoniae. Two isolates also carried OXA-48 carbapenemases. The bacteria were resistant to novel antibiotics, such as ceftazidime/avibactam and cefiderocol. The used treatment strategies included combinations of ceftazidime/avibactam + aztreonam, colistin, or tigecycline. WGS suggested transmission during primary care in Ukraine. We conclude that there is an urgent need for thorough surveillance of multiresistant pathogens in patients from war zones. [ABSTRACT FROM AUTHOR]

Cefiderocol is a novel synthetic siderophore-conjugated antibiotic that hijacks the bacterial iron transport systems facilitating drug entry into cells, achieving high periplasmic concentrations. This systematic review analyzed the currently available literature on cefiderocol. It summarized in vitro susceptibility data, in vivo antimicrobial activity, pharmacokinetics/pharmacodynamics (PK/PD), clinical efficacy, safety and resistance mechanisms of cefiderocol. Cefiderocol has potent in vitro and in vivo activity against multidrug-resistant (MDR) Gram-negative bacteria, including carbapenem-resistant isolates. But New Delhi Metallo-β-lactamase (NDM)- positive isolates showed significantly higher MICs than other carbapenemase-producing Enterobacterales , with a susceptible rate of 83.4% for cefiderocol. Cefiderocol is well-tolerated, and the PK/PD target values can be achieved using a standard dose regimen or adjusted doses according to renal function. Clinical trials demonstrated that cefiderocol was non-inferiority to the comparator drugs in treating complicated urinary tract infection and nosocomial pneumonia. Case reports and series showed that cefiderocol was a promising therapeutic agent in carbapenem-resistant infections. However, resistant isolates and reduced susceptibility during treatment to cefiderocol have already been reported. In conclusion, cefiderocol is a promising powerful weapon for treating MDR recalcitrant infections. [ABSTRACT FROM AUTHOR]