We disagree with the conclusions presented by Jacob E Choby and coworkers1Choby JE Ozturk T Satola SW Jacob JT Weiss DS Widespread cefiderocol heteroresistance in carbapenem-resistant Gram-negative pathogens. in their Correspondence, in which they postulated a causal link between the in-vitro observation of heteroresistance to cefiderocol in Gram-negative bacteria and the imbalance in all-cause mortality observed in the CREDIBLE-CR (NCT02714595) clinical trial.In their Correspondence, the authors attempt to quantify and compare the frequency of heteroresistant subpopulations in clinical isolates collected from a surveillance study in Georgia, USA, with clinical outcomes from the international CREDIBLE-CR study.1Choby JE Ozturk T Satola SW Jacob JT Weiss DS Widespread cefiderocol heteroresistance in carbapenem-resistant Gram-negative pathogens. The authors propose that numerical similarities in the relative frequency of heteroresistance between pathogens in their study and the rates of mortality reported in CREDIBLE-CR suggest that heteroresistance might have contributed to deaths.

Although the observation of heteroresistance to cefiderocol is interesting, the standard in-vitro methodology used, population analysis profiling, is not clinically validated as predictive of clinical or microbiological outcomes in vivo, and as such is not used by clinical diagnostic laboratories to inform patient care, even for the drug–bug combinations for which heteroresistance is well characterised. Therefore, the experimental study design described by Choby and coworkers is not sufficient to test the hypothesis of a link between an in-vitro phenomenon and clinical or microbiological outcomes reported in patients.

Moreover, Choby and colleagues ignore the fact that 25 of 38 patients in the best-available therapy (BAT) comparator group received a colistin-based regimen.2Bassetti M Echols R Matsunaga Y et al.Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Within Gram-negative pathogens, heteroresistance has been most fully documented to occur within the polymyxin class, including colistin, and is reported to manifest at a high rate among Acinetobacter spp.3Karakonstantis S Saridakis I Colistin heteroresistance in Acinetobacter spp: systematic review and meta-analysis of the prevalence and discussion of the mechanisms and potential therapeutic implications. As such, if heteroresistance had contributed to treatment failure and mortality, we would have also expected it to have contributed to mortality in colistin-treated patients in the BAT group, which paradoxically was unusually low. Although fully explaining the mortality observations in CREDIBLE-CR might not be possible, imbalances in patient factors at baseline among patients infected with Acinetobacter baumannii—for instance, shock and location of intensive care unit—might provide the most plausible explanation for the mortality difference.2Bassetti M Echols R Matsunaga Y et al.Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial.Addressing the wider question of development of resistance to cefiderocol during therapy, here too Choby and colleagues point to observations with cefiderocol but ignore those in the BAT comparator group. Shifts in minimum inhibitory concentration (MIC) were observed and reported during therapy with both cefiderocol and BAT from CREDIBLE-CR.2Bassetti M Echols R Matsunaga Y et al.Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial., 4Takemura M Yamano Y Matsunaga Y Ariyasu M Echols R Den Nagata T Characterization of shifts in minimum inhibitory concentrations during treatment with cefiderocol or comparators in the phase 3 CREDIBLE-CR and APEKS-NP studies. We found that the frequency of MIC shifts were similar for cefiderocol and comparator antibiotics including colistin, and resistance was not markedly higher for Acinetobacter spp than in other pathogen groups. Furthermore, almost all isolates that showed increased cefiderocol MIC during therapy remained susceptible (MIC 4Takemura M Yamano Y Matsunaga Y Ariyasu M Echols R Den Nagata T Characterization of shifts in minimum inhibitory concentrations during treatment with cefiderocol or comparators in the phase 3 CREDIBLE-CR and APEKS-NP studies., 5Kawaguchi N Katsube T Echols R Wajima T Population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses of cefiderocol, a parenteral siderophore cephalosporin, in patients with pneumonia, bloodstream infection/sepsis, or complicated urinary tract infection. Most importantly, in the APEKS-NP study (NCT03032380),6Wunderink RG Matsunaga Y Ariyasu M et al.Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. a randomised, double-blind, controlled trial in patients with nosocomial pneumonia for which mortality was the primary endpoint, no mortality imbalance was observed between the cefiderocol or high-dose meropenem groups among patients, including those with infections involving Acinetobacter spp, Pseudomonas spp, or Enterobacterales. Publications reporting early clinical experience of cefiderocol in non-trial settings provide further evidence of good clinical and microbiological responses in complex, critically ill patients, including those with A baumannii infections and in patients treated for prolonged periods of time for osteomyelitis or endocarditis, in whom heteroresistance might be expected to cause treatment failure or persistence.7Falcone M Tiseo G Nicastro M et al.Cefiderocol as rescue therapy for Acinetobacter baumannii and other carbapenem-resistant Gram-negative infections in ICU patients., 8Dagher M Ruffin F Marshall S et al.Case report: successful rescue therapy of extensively drug-resistant Acinetobacter baumannii osteomyelitis with cefiderocol.

AKo, AKa, CL, YY, and TDN are employees of Shionogi. RE is a consultant for Shionogi and received a consultancy fee. MB has participated in advisory boards or received speaker honoraria from Angelini, Astellas, Bayer, Basilea, bioMérieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer, Roche, and Shionogi, and has received study grants from Gilead, MSD, Pfizer, and Shionogi.

References1.Choby JE Ozturk T Satola SW Jacob JT Weiss DS

Widespread cefiderocol heteroresistance in carbapenem-resistant Gram-negative pathogens.

Lancet Infect Dis. 21: 597-5982.Bassetti M Echols R Matsunaga Y et al.

Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial.

Lancet Infect Dis. 21: 226-2403.Karakonstantis S Saridakis I

Colistin heteroresistance in Acinetobacter spp: systematic review and meta-analysis of the prevalence and discussion of the mechanisms and potential therapeutic implications.

Int J Antimicrob Agents. 561060654.Takemura M Yamano Y Matsunaga Y Ariyasu M Echols R Den Nagata T

Characterization of shifts in minimum inhibitory concentrations during treatment with cefiderocol or comparators in the phase 3 CREDIBLE-CR and APEKS-NP studies.

Open Forum Infect Dis. 7: S649-S6505.Kawaguchi N Katsube T Echols R Wajima T

Population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses of cefiderocol, a parenteral siderophore cephalosporin, in patients with pneumonia, bloodstream infection/sepsis, or complicated urinary tract infection.

Antimicrob Agents Chemother. 65: e01437-e015206.Wunderink RG Matsunaga Y Ariyasu M et al.

Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial.

Lancet Infect Dis. 21: 213-2257.Falcone M Tiseo G Nicastro M et al.

Cefiderocol as rescue therapy for Acinetobacter baumannii and other carbapenem-resistant Gram-negative infections in ICU patients.

Clin Infect Dis. ()8.Dagher M Ruffin F Marshall S et al.

Case report: successful rescue therapy of extensively drug-resistant Acinetobacter baumannii osteomyelitis with cefiderocol.

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DOI: https://doi.org/10.1016/S1473-3099(21)00328-5

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We read with interest the CREDIBLE-CR study on cefiderocol treatment of carbapenem-resistant infections by Matteo Bassetti and colleagues.1 Cefiderocol had similar efficacy to best available therapy but a higher rate of all-cause mortality, particularly in infections with Acinetobacter spp, despite 95% of bacterial isolates exhibiting a minimum inhibitory concentration of 4 μg/mL or less. We hypothesise that these discrepant data might be due to undetected cefiderocol heteroresistance.

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