Widespread cefiderocol heteroresistance in carbapenem-resistant Gram-negative pathogens

Choby, Jacob E.; Ozturk, Tugba; Satola, Sarah W.; Jacob, Jesse T; Weiss, David S.

doi:10.1016/s1473-3099(21)00194-8

Cited by 78 publications

(82 citation statements)

References 5 publications

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“…In addition, there was no investigation of potential heteroresistance, which has been recently reported, 32 but the clinical significance of this phenomenon has not been established. Although no increase in cefiderocol MIC was seen with the expression of mutant OXA-23 enzyme in the isogenic E. coli cloning experiments, the enzyme may not have been fully functional or fully expressed on this genetic background.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Reduced Susceptibility to Cefiderocol Among Isolates from the CREDIBLE-CR and APEKS-NP Clinical Trials

Nordmann

Shields

Doi

et al. 2022

Microbial Drug Resistance

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The objective of this study was to characterize isolates with reduced susceptibility to cefiderocol in patients receiving cefiderocol for nosocomial pneumonia or carbapenem-resistant infections in the Phase 3 APEKS-NP and CREDIBLE-CR studies. Susceptibility testing of isolates was conducted at a central laboratory, and post-treatment changes were evaluated according to available breakpoints for cefiderocol. Whole-genome sequencing and multilocus sequence typing were performed for isolates to confirm their origin and identify mutations. Five (APEKS-NP) and nine (CREDIBLE-CR) isolates demonstrated a ≥ 4-fold minimum inhibitory concentration (MIC) increase compared with genetically related baseline isolates; most remained susceptible to cefiderocol despite the ≥4-fold MIC increase. Mutations in β-lactamases or penicillin-binding protein (PBP) were identified in 4/14 isolates: one Enterobacter cloacae (amino acid [AA] substitution [A313P] in ACT-17); two Acinetobacter baumannii (one PBP3 AA substitution [H370Y], one with OXA-23 substitutions [N85I and P225S]); and one Pseudomonas aeruginosa (PDC-30 [4AA deletion “TPMA” position 316–319]). Cloning experiments using isogenic Escherichia coli strains containing wild-type and those mutant cephalosporinase enzymes show that the mutant enzymes may contribute to decreased susceptibility to cefiderocol. Pharmacokinetic data were available for nine patients, for whom cefiderocol exposures exceeded 100% f T > 4 × MIC . No clear pattern between mutations and development or extent of MIC increases was observed. No mutations were identified in genes related to iron transport, including fiu , cirA , piuA/C , and pirA , among recovered Gram-negative isolates. APEKS-NP: NCT03032380; CREDIBLE-CR: NCT02714595.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of Reduced Susceptibility to Cefiderocol Among Isolates from the CREDIBLE-CR and APEKS-NP Clinical Trials

Nordmann

Shields

Doi

et al. 2022

Microbial Drug Resistance

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“…In addition, treatment with this agent resulted in higher mortality rates as compared to best available therapy in patients with A. baumannii bloodstream infections or nosocomial pneumonia in the recent CREDIBLE-CR Phase 3 trial (Bassetti et al, 2021). These findings have recently been proposed to be related to liabilities associated with siderophore-mediated uptake leading to heteroresistance (Choby et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Durlobactam, a New Diazabicyclooctane β-Lactamase Inhibitor for the Treatment of Acinetobacter Infections in Combination With Sulbactam

et al. 2021

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Durlobactam is a new member of the diazabicyclooctane class of β-lactamase inhibitors with broad spectrum activity against Ambler class A, C, and D serine β-lactamases. Sulbactam is a first generation β-lactamase inhibitor with activity limited to a subset of class A enzymes that also has direct-acting antibacterial activity against Acinetobacter spp. The latter feature is due to sulbactam’s ability to inhibit certain penicillin-binding proteins, essential enzymes involved in bacterial cell wall synthesis in this pathogen. Because sulbactam is also susceptible to cleavage by numerous β-lactamases, its clinical utility for the treatment of contemporary Acinetobacter infections is quite limited. However, when combined with durlobactam, the activity of sulbactam is effectively restored against these notoriously multidrug-resistant strains. This sulbactam-durlobactam combination is currently in late-stage development for the treatment of Acinectobacter infections, including those caused by carbapenem-resistant isolates, for which there is a high unmet medical need. The following mini-review summarizes the molecular drivers of efficacy of this combination against this troublesome pathogen, with an emphasis on the biochemical features of each partner.

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“…A gradual decrease in the number of CFU instead of a single-step loss of survival indicates the presence of a resistant subpopulation ( Figure 1 a). Unfortunately, due to the duration and complexity of the PAP assay, this method is not feasible for clinical use, and heteroresistance often remains undetected [ 15 , 20 ]. Alternative methods to PAP are the disc diffusion assay and Etests ( Figure 1 a).…”

Section: Heteroresistance: Definition Detection Methods and Underlying Mechanismsmentioning

confidence: 99%

“…Heteroresistance may lead to antibiotic treatment failure due to the misclassification of heteroresistant isolates as susceptible strains. Consequently, inappropriate therapies fail to eradicate infections and facilitate the selection of resistant mutants [ 19 , 20 , 43 , 44 ]. It has been demonstrated that different antibiotics at levels below the MIC of the susceptible clinical isolates of E. coli and Salmonella enterica can cause the enrichment of resistant subpopulations with an increased copy number of resistance genes [ 19 ].…”

Section: Heteroresistance: Definition Detection Methods and Underlying Mechanismsmentioning

confidence: 99%

Antibiotic Heteroresistance in Klebsiella pneumoniae

Stojowska-Swędrzyńska

Łupkowska

Kuczyńska-Wiśnik

et al. 2021

IJMS

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Klebsiella pneumoniae is one of the most common pathogens responsible for infections, including pneumonia, urinary tract infections, and bacteremias. The increasing prevalence of multidrug-resistant K. pneumoniae was recognized in 2017 by the World Health Organization as a critical public health threat. Heteroresistance, defined as the presence of a subpopulation of cells with a higher MIC than the dominant population, is a frequent phenotype in many pathogens. Numerous reports on heteroresistant K. pneumoniae isolates have been published in the last few years. Heteroresistance is difficult to detect and study due to its phenotypic and genetic instability. Recent findings provide strong evidence that heteroresistance may be associated with an increased risk of recurrent infections and antibiotic treatment failure. This review focuses on antibiotic heteroresistance mechanisms in K. pneumoniae and potential therapeutic strategies against antibiotic heteroresistant isolates.

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Widespread cefiderocol heteroresistance in carbapenem-resistant Gram-negative pathogens

Cited by 78 publications

References 5 publications

Mechanisms of Reduced Susceptibility to Cefiderocol Among Isolates from the CREDIBLE-CR and APEKS-NP Clinical Trials

Mechanisms of Reduced Susceptibility to Cefiderocol Among Isolates from the CREDIBLE-CR and APEKS-NP Clinical Trials

Durlobactam, a New Diazabicyclooctane β-Lactamase Inhibitor for the Treatment of Acinetobacter Infections in Combination With Sulbactam

Antibiotic Heteroresistance in Klebsiella pneumoniae

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