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.
Heteroresistance is a form of antibiotic resistance in which a bacterial isolate harbours a minority resistant subpopulation of cells that coexists with a majority susceptible population, and it is often undetected by standard antimicrobial susceptibility testing (AST; appendix pp 1–2).2 In the presence of the relevant antibiotic, the resistant subpopulation is selected for and predominates; however, after antibiotic removal, the resistant subpopulation returns to baseline (appendix p 3). Isolates exhibiting undetected heteroresistance can cause treatment failure in in-vivo models.3,4
We surveyed for cefiderocol heteroresistance among carbapenem-resistant bacteria collected in the Georgia Emerging Infections Program, GA, USA, including Acinetobacter baumannii (2012–15), Klebsiella spp (2011–15), Pseudomonas aeruginosa (2015–16), and Stenotrophomonas maltophilia (2018–21; appendix p 1). By standard disk diffusion AST, the vast majority of isolates were classified as susceptible to cefiderocol, consistent with the CREDIBLE-CR trial and the SIDERO-CR surveillance study of 1873 carbapenem non-susceptible, Gram-negative pathogens.1,5 However, sensitive testing by population analysis profile identified cefiderocol heteroresistance in each pathogen, with particularly high rates in Acinetobacter (table; appendix pp 1, 4). Importantly, these data indicate that cefiderocol heteroresistance was present in the USA before clinical approval of this drug by the US Food and Drug Administration in 2019. The frequency of heteroresistance was far greater than that of detected resistance for all four pathogens and was similar to the all-cause mortality rate, suggesting that heteroresistance might have contributed to cefiderocol treatment failure in the CREDIBLE-CR study.
Table 1:
All-cause mortality and cefiderocol non-susceptibility among carbapenem-resistant pathogens
| Acinetobacter | Klebsiella | Pseudomonas | Stenotrophomonas | |
|---|---|---|---|---|
| CREDIBLE-CR trial1 | ||||
| All-cause mortality* | 49% (19/39) | 21% (6/28) | 18% (2/11) | 67% (2/3) |
| Detected resistance† | 3% (1/36) | 0% (0/27) | 0% (0/12) | 0% (0/5) |
| SIDERO-CR study5 | ||||
| Detected resistance | 10% (38/368) | 2% (12/720) | 1% (2/262) | 0% (0/217) |
| GA, USA, surveillance | ||||
| Detected resistance | 8% (9/108) | 6% (5/89) | 0% (0/69) | 0% (0/29) |
| Heteroresistance | 59% (64/108) | 30% (27/89) | 9% (6/69) | 48% (14/29) |
All-cause mortality data are from the CREDIBLE-CR trial.1 Detected resistance data (minimum inhibitory concentration >4 μg/mL) are from the CREDIBLE-CR trial1 or SIDERO-CR study,5 or were generated by disk diffusion assay on carbapenem-resistant isolates from GA, USA, according to Clinical and Laboratory Standards Institute guidance. Heteroresistance data were established by population analysis profile to identify minority resistant subpopulations within an isolate.
All-cause mortality data for Klebsiella, Pseudomonas, and Stenotrophomonas spp are for patients who did not have Acinetobacter spp coinfection.
Data not available for all isolates in the CREDIBLE-CR trial.
Hallmarks of heteroresistance are the resistant subpopulation increasing in frequency with antibiotic treatment and decreasing in frequency after removal from the drug. We observed both effects in a representative carbapenem-resistant A baumannii isolate (appendix pp 3, 5). In the CREDIBLE-CR study, the minimum inhibitory concentration of some isolates exposed to cefiderocol increased after treatment, which might be consistent with heteroresistance.1
CREDIBLE-CR involved isolates from 16 countries and SIDERO-CR involved those from 52 countries, with similar frequencies of detected cefiderocol resistance (by standard AST) as observed in our research, suggesting that the GA, USA, isolates are representative. Therefore, the widespread and undetected cefiderocol heteroresistance among carbapenem-resistant pathogens observed here might explain the discordance between this drug’s excellent susceptibility profile in vitro and its association with increased patient mortality.
Supplementary Material
Acknowledgments
DSW reports grants from National Institutes of Health, Veterans Health Administration, and Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease award. DSW also has a pending patent for exploitation of heteroresistance for combination therapy. JTJ reports grants from Centers for Disease Control and Prevention. JEC reports grants from the Cystic Fibrosis Foundation and National Institutes of Health (T32 DK108735). All other authors declare no competing interests. We would like to thank the Georgia Emerging Infections Program led by Monica Farley, and its Multi-Site Gram-negative Surveillance Initiative, as well as the Emory Antibiotic Resistance Center’s Investigational Clinical Microbiology Core, for providing isolates. This work was supported by the National Institutes of Health (AI141883, AI148661, AI158080) and the Department of Veteran’s Affairs (BX002788). The Georgia Emerging Infections Program and the Multi-Site Gram-negative Surveillance Initiative are funded by the Centers for Disease Control and Prevention.
Footnotes
See Online for appendix
This online publication has been corrected. The corrected version first appeared at thelancet.com/infection on
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