Efficacy of Humanized Cefiderocol Exposures over 72 Hours against a Diverse Group of Gram-Negative Isolates in the Neutropenic Murine Thigh Infection Model

Stainton, Sean M.; Monogue, Marguerite L.; Tsuji, Masakatsu; Yamano, Yoshinori; Echols, Roger; Nicolau, David P.

doi:10.1128/aac.01040-18

Cited by 27 publications

(25 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to the iron depletion model, pharmacokinetic profiles of cefiderocol and meropenem were unaltered in the iron overload model. Plasma concentrations of both drugs were comparable to those previously observed in the standard thigh infection model using these regimens (1,26,27), permitting a direct comparison of efficacy between iron-overloaded and standard murine thigh infection models.…”

Section: Discussionsupporting

confidence: 63%

Development of Neutropenic Murine Models of Iron Overload and Depletion To Study the Efficacy of Siderophore-Antibiotic Conjugates

Kidd

Abdelraouf

Nicolau

2019

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Siderophore-antibiotic conjugates have increased in vitro activity in low-iron environments where bacteria express siderophores and associated transporters. The host immune hypoferremic response reduces iron availability to bacteria; however, patients with iron overload or deficiency may have altered ability to restrict iron, which may affect the efficacy of siderophore-antibiotic conjugates. In vivo models of infection with iron overload and deficiency are needed to perform this assessment. The standard neutropenic murine thigh infection model was supplemented with iron-altering treatments: iron dextran at 100 mg/kg of body weight daily for 14 days to load iron or deferoxamine at 100 mg/kg daily plus a low-iron diet for up to 30 days to deplete iron. Human-simulated regimens of cefiderocol and meropenem were administered in both models to assess any impact of iron alteration on plasma pharmacokinetics. Median iron in overloaded mice was significantly higher than that of controls in plasma (1,657 versus 336 μg/dl; P < 0.001), liver (2,133 versus 11 μg/g; P < 0.001), and spleen (473 versus 144 μg/g; P < 0.001). At 30 days, depleted mice had significantly lower iron than controls in liver (2.4 versus 6.5 μg/g; P < 0.001) and spleen (72 versus 133 μg/g; P = 0.029) but not plasma (351 versus 324 μg/dl; P = 0.95). Cefiderocol and meropenem plasma concentrations were similar in iron overloaded and control mice but varied in iron-depleted mice. The iron-overloaded murine thigh infection model was established, and human-simulated regimens of cefiderocol and meropenem were validated therein. While deferoxamine successfully reduced liver and splenic iron, this depleting treatment altered the pharmacokinetics of both antimicrobials.

show abstract

Section: Discussionsupporting

confidence: 63%

Development of Neutropenic Murine Models of Iron Overload and Depletion To Study the Efficacy of Siderophore-Antibiotic Conjugates

Kidd

Abdelraouf

Nicolau

2019

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is important to note that while regrowth did occur in some isolates, the pattern of regrowth in their study was inconsistent with the emergence of resistance observed with other siderophores and the phenomenon of adaptive resistance was not observed over the 72 h period. In isolates that were retested for MICs after cefiderocol exposure, only one isolate (1/54 samples, 1.8%) demonstrated an increase in MIC from 1 to 4 lg/mL for an E. coli isolate at 72 h [36]. This is notable as adaptive resistance has been well documented in other siderophore compounds.…”

Section: Animal Efficacy Modelsmentioning

confidence: 92%

Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms

2020

View full text Add to dashboard Cite

Cefiderocol, formerly S-649266, is a first in its class, an injectable siderophore cephalosporin that combines a catechol-type siderophore and cephalosporin core with side chains similar to cefepime and ceftazidime. This structure and its unique mechanism of action confer enhanced stability against hydrolysis by many b-lactamases, including extended spectrum b-lactamases such as CTX-M, and carbapenemases such as KPC, NDM, VIM, IMP, OXA-23, OXA-48-like, OXA-51-like and OXA-58. Cefiderocol's spectrum of activity encompasses both lactosefermenting and non-fermenting Gram-negative pathogens, including carbapenem-resistant Enterobacterales. Cefiderocol recently received US Food and Drug Administration approval for the treatment of complicated urinary tract infections, including pyelonephritis, and is currently being evaluated in phase III trials for nosocomial pneumonia and infections caused by carbapenem-resistant Gram-negative pathogens. The purpose of this article is to review existing data on the mechanism of action, microbiology, pharmacokinetics, pharmacodynamics, efficacy, and safety of cefiderocol to assist clinicians in determining its place in therapy.

show abstract

“…Thirty-one clinical Gram-negative isolates, including 16 Enterobacterales, 7 P. aeruginosa, and 8 A. baumannii isolates, were studied. MICs to cefiderocol in iron-depleted cationadjusted Mueller-Hinton broth (CAMHB) and meropenem in standard CAMHB for each isolate were previously determined in triplicate (17); cefiderocol MICs ranged from 0.25 to 16 mg/liter in Enterobacterales, 0.5 to 8 mg/liter in P. aeruginosa, and 0.25 to 64 mg/liter in A. baumannii. All isolates were previously frozen in skim milk at -80°C.…”

Section: Methodsmentioning

confidence: 99%

“…Neutropenic thigh infection models. The standard murine thigh infection model was utilized as previously described (16,17). In brief, neutropenia was produced with 150 mg/kg cyclophosphamide at day 4 and 100 mg/kg at day 1 prior to inoculation, and 5 mg/kg uranyl nitrate was used at day 3 prior to inoculation to decrease renal elimination of the study compounds.…”

Section: Methodsmentioning

confidence: 99%

“…The present results from the 24-h standard thigh infection model reproduce these observations with remarkable agreement on the magnitude of killing for individual isolates between both studies. Additional investigation on a subset of these isolates using 72 h of human-simulated cefiderocol exposure was performed by Stainton and colleagues, finding that during an extended treatment period, efficacy was sustained, and only one isolate had a significant (two 2-fold dilutions) increase in postexposure cefiderocol MIC, which the authors interpreted as evidence against adaptive resistance (17). Three isolates (KP 539, ACB 87, and PSA 1595) from this study were included in the present experiments, where similar magnitudes of killing at 72 h were seen in both standard and iron-overloaded models.…”

Section: Figmentioning

confidence: 99%

See 1 more Smart Citation

Efficacy of Humanized Cefiderocol Exposure Is Unaltered by Host Iron Overload in the Thigh Infection Model

Kidd

Abdelraouf

Nicolau

2019

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Cefiderocol is a siderophore-cephalosporin conjugate with greater in vitro potency under iron-depleted conditions. During infection, iron is scarce in host tissue; however, it is not known whether iron overload in the host, such as in cases of hereditary hemochromatosis, alters the efficacy of cefiderocol. We compared cefiderocol efficacy between iron-overloaded and standard murine thigh infection models. Female CD-1 mice rendered neutropenic received 2 weeks of iron dextran at 100 mg/kg of body weight/day intraperitoneally (iron-overloaded model) or no injections (standard model). Mice were inoculated (107 CFU/ml) with Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa with previously determined cefiderocol MICs from 0.25 to 64 mg/liter. Human-simulated regimens of cefiderocol or meropenem (2 g every 8 h [q8h], 3-h infusion) were administered for 24 h (31 strains) or 72 h (15 strains; cefiderocol only). Procedures were simultaneously performed in standard and iron-overloaded models. Mean bacterial burdens (log10 CFU/thigh) at baseline were 5.75 ± 0.47 versus 5.81 ± 0.51 in standard versus iron-overloaded models, respectively. At 24 h, mean burdens in standard versus iron-overloaded models decreased by −0.8 ± 1.9 versus −1.2 ± 2.0 (P = 0.25) in meropenem-treated mice and by −1.5 ± 1.4 versus −1.6 ± 1.5 (P = 0.54) in cefiderocol-treated mice. At 72 h, mean burdens in cefiderocol-treated mice decreased by −2.5 ± 1.5 versus −2.5 ± 1.4. No overall differences in efficacy between the models were observed for meropenem or cefiderocol. Human-simulated exposure of cefiderocol is equally efficacious in iron-overloaded and normal hosts. The potential clinical use of cefiderocol to treat Gram-negative infections in patients with iron overload is supported.

show abstract

Efficacy of Humanized Cefiderocol Exposures over 72 Hours against a Diverse Group of Gram-Negative Isolates in the Neutropenic Murine Thigh Infection Model

Cited by 27 publications

References 15 publications

Development of Neutropenic Murine Models of Iron Overload and Depletion To Study the Efficacy of Siderophore-Antibiotic Conjugates

Development of Neutropenic Murine Models of Iron Overload and Depletion To Study the Efficacy of Siderophore-Antibiotic Conjugates

Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms

Efficacy of Humanized Cefiderocol Exposure Is Unaltered by Host Iron Overload in the Thigh Infection Model

Contact Info

Product

Resources

About