Contribution of Iron-Transport Systems and β-Lactamases to Cefiderocol Resistance in Clinical Isolates of Acinetobacter baumannii Endemic to New York City

Asrat, Habtamu; Samaroo-Campbell, Jevon; Ata, Shingo; Quale, John

doi:10.1128/aac.00234-23

Cited by 9 publications

(10 citation statements)

References 26 publications

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“…Such a large repertoire of iron-acquisition systems in A baumannii implies an even larger repertoire of possible combinations of iron-acquisition systems, whose expression can be tuned according to the energetic status of the cell, the available iron source(s) and the physicochemical conditions of the growth environment. While the natural substrate specificity of the additional TonB-dependent receptors is still unclear, the piuA (DMO12_RS02620) and pirA (DMO12_RS05030) xenosiderophore receptors have recently been associated with the transport of cefiderocol, a siderophore–cefalosporin conjugate endowed with good activity on MDR P. aeruginosa and A. baumannii [ 67, 68 ].…”

Section: Discussionmentioning

confidence: 99%

Genomics of Acinetobacter baumannii iron uptake

et al. 2023

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Iron is essential for growth in most bacteria due to its redox activity and its role in essential metabolic reactions; it is a cofactor for many bacterial enzymes. The bacterium Acinetobacter baumannii is a multidrug-resistant nosocomial pathogen. A. baumannii responds to low iron availability imposed by the host through the exploitation of multiple iron-acquisition strategies, which are likely to deliver iron to the cell under a variety of environmental conditions, including human and animal infection. To date, six different gene clusters for active iron uptake have been described in A. baumannii , encoding protein systems involved in (i) ferrous iron uptake (feo); (ii) haem uptake (hemT and hemO); and (iii) synthesis and transport of the baumannoferrin(s) (bfn), acinetobactin (bas/bau) and fimsbactin(s) (fbs) siderophores. Here we describe the structure, distribution and phylogeny of iron-uptake gene clusters among >1000 genotypically diverse A. baumannii isolates, showing that feo, hemT, bfn and bas/bau clusters are very prevalent across the dataset, whereas the additional haem-uptake system hemO is only present in a portion of the dataset and the fbs gene cluster is very rare. Since the expression of multiple iron-uptake clusters can be linked to virulence, the presence of the additional haem-uptake system hemO may have contributed to the success of some A. baumannii clones.

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Section: Discussionmentioning

confidence: 99%

Genomics of Acinetobacter baumannii iron uptake

et al. 2023

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“…Nearly all Bcc isolates with high cefiderocol MIC values belonged to the same species (i.e., B. multivorans ). Previous studies on cefiderocol susceptibility suggest that the presence of different resistance mechanisms, including mutations in iron transport-related proteins, defects in porin channels, and expression of certain β-lactamases, is needed to confer cefiderocol resistance in non-fermenter pathogens such as A. baumannii or P. aeruginosa ( 23 – 26 ). Thus, it may be possible that cefiderocol resistance in Achromobacter spp.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo activity of cefiderocol against Achromobacter spp. and Burkholderia cepacia complex, including carbapenem-non-susceptible isolates

Takemura,

Nakamura,

Ota

et al. 2023

Antimicrob Agents Chemother

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Achromobacter spp. and Burkholderia cepacia complex (Bcc) are rare but diverse opportunistic pathogens associated with serious infections, which are often multidrug resistant. This study compared the in vitro antibacterial activity of the siderophore antibiotic cefiderocol against Achromobacter spp. and Bcc isolates with that of other approved antibacterial drugs, including ceftazidime-avibactam, ciprofloxacin, colistin, imipenem-relebactam, and meropenem-vaborbactam. Isolates were collected in the SIDERO multinational surveillance program. Among 334 Achromobacter spp. isolates [76.6% from respiratory tract infections (RTIs)], cefiderocol had minimum inhibitory concentration (MIC) 50/90 of 0.06/0.5 µg/mL overall and 0.5/4 µg/mL against 52 (15.6%) carbapenem-non-susceptible (Carb-NS) isolates. Eleven (3.3%) Achromobacter spp. isolates overall and 6 (11.5%) Carb-NS isolates were not susceptible to cefiderocol. Among 425 Bcc isolates (73.4% from RTIs), cefiderocol had MIC 50/90 of ≤0.03/0.5 µg/mL overall and ≤0.03/1 µg/mL against 184 (43.3%) Carb-NS isolates. Twenty-two (5.2%) Bcc isolates overall and 13 (7.1%) Carb-NS isolates were not susceptible to cefiderocol. Cumulative MIC distributions showed cefiderocol to be the most active of the agents tested in vitro against both Achromobacter spp. and Bcc. In a neutropenic murine lung infection model and a humanized pharmacokinetic immunocompetent rat lung infection model, cefiderocol showed significant bactericidal activity against two meropenem-resistant Achromobacter xylosoxidans strains compared with untreated controls ( P < 0.05) and vehicle-treated controls ( P < 0.05), respectively. Meropenem, piperacillin-tazobactam, ceftazidime, and ciprofloxacin comparators showed no significant activity in these models. The results suggest that cefiderocol could be a possible treatment option for RTIs caused by Achromobacter spp. and Bcc.

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“…The transport of FDC from the outer membrane to the periplasmic space is mediated by passive diffusion via porin channels or active transport linked to TonB-dependent siderophore receptors PiuA and PirA [6] (Figure 1A). Thus, a positive correlation has been demonstrated between FDC susceptibility and the expression of PiuA and PirA TonB-dependent receptors (TBDRs) in A. baumannii [17,18]. Also, the high affinity of PiuA and PirA transporters for siderophores allows the transport of FDC in the periplasmic space even at low concentrations (Figure 1B) [19,20].…”

Section: Cefiderocol Is a Novel Siderophore Cephalosporin 21 Chemical...mentioning

confidence: 94%

“…FDC resistance has been associated with the reduced expression of the siderophore receptor pirA and piuA genes in several A. baumannii strains [17,18]. Also, Malik et al showed that two mutations in the midst of a beta strand of PirA diminished the functionality of this receptor protein in two FDC-resistant A. baumannii strains [17].…”

Section: Mechanisms Of Resistancementioning

confidence: 99%

Cefiderocol and Sulbactam-Durlobactam against Carbapenem-Resistant Acinetobacter baumannii

Karruli,

Migliaccio,

Pournaras

et al. 2023

Antibiotics

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Infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) remain a clinical challenge due to limited treatment options. Recently, cefiderocol, a novel siderophore cephalosporin, and sulbactam-durlobactam, a bactericidal β-lactam–β-lactamase inhibitor combination, have been approved by the Food and Drug Administration for the treatment of A. baumannii infections. In this review, we discuss the mechanisms of action of and resistance to cefiderocol and sulbactam-durlobactam, the antimicrobial susceptibility of A. baumannii isolates to these drugs, as well as the clinical effectiveness of cefiderocol and sulbactam/durlobactam-based regimens against CRAB. Overall, cefiderocol and sulbactam-durlobactam show an excellent antimicrobial activity against CRAB. The review of clinical studies evaluating the efficacy of cefiderocol therapy against CRAB indicates it is non-inferior to colistin/other treatments for CRAB infections, with a better safety profile. Combination treatment is not associated with improved outcomes compared to monotherapy. Higher mortality rates are often associated with prior patient comorbidities and the severity of the underlying infection. Regarding sulbactam-durlobactam, current data from the pivotal clinical trial and case reports suggest this antibiotic combination could be a valuable option in critically ill patients affected by CRAB infections, in particular where no other antibiotic appears to be effective.

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Contribution of Iron-Transport Systems and β-Lactamases to Cefiderocol Resistance in Clinical Isolates of Acinetobacter baumannii Endemic to New York City

Abstract: The development of resistance to cefiderocol among multidrug resistant Acinetobacter baumannii has been attributed to downregulation in iron transport systems and a variety of β-lactamases. However, the precise contribution of each in clinical isolates remains to be determined.

Cited by 9 publications

References 26 publications

Genomics of Acinetobacter baumannii iron uptake

Genomics of Acinetobacter baumannii iron uptake

In vitro and in vivo activity of cefiderocol against Achromobacter spp. and Burkholderia cepacia complex, including carbapenem-non-susceptible isolates

Cefiderocol and Sulbactam-Durlobactam against Carbapenem-Resistant Acinetobacter baumannii

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