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  Georges Sadaka, Cyrille Fauchard, Raphaël Antoine, Olivier Maquaire, Stéphane Costa, Antoine Tonnoir To cite this version: Thomas Junique, Georges Sadaka, Cyrille Fauchard, Raphaël Antoine, Olivier Maquaire, et al.. DEFHY3GEO French Regional project Detection and Study of Fracturing by HYdrological, GEOmorphodynamic, geological and geophysical approach. Polder2C's Conference, Mar 2024, Anvers, Belgium. hal-04394357

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Romaric Larcher
email: romaric.larcher@chu-nimes.fr

Paul Laffont-Lozes

Paul Loubet

Didier Laureillard

Tayma Naciri

Albert Sotto

Re: 'real world clinical outcome of cefiderocol for treatment of multidrug resistant non-fermenting gram

Keywords: Antimicrobial susceptibility testing, Bloodstream infection, Cefiderocol, Combination therapy, Heteroresistance, Immunocompromised patient, Nonfermenters. Outcomes BJI, bone and joint infection, BSI, bloodstream infection, CNSI, central nervous system infection, IAI, intra-abdominal infection, ICU, intensive care unit, LRTI, low respiratory tract infection, MDR, multidrug-resistant, MDR-NFGNB, multidrug-resistant non-fermenting gram-negative bacilli, NA, not applicable, SSTI, skin and soft tissue infection, UTI, urinary tract infection

Re: 'Real world clinical outcome of cefiderocol for treatment of multidrug-resistant nonfermenting gramnegative bacilli infections' by Hoellinger et al.

Multidrug-resistant (MDR) non-fermenting gram-negative bacilli infections were reported. In this work, patients treated with cefiderocol exhibited dramatically high 30-day mortality, clinical failure, and microbiological failure rates at 60%, 80%, and 60%, respectively. The authors stated that the high rate of treatment failure could be explained by a delayed effective antimicrobial therapy in most of the patients (8/10), the risk of error in cefiderocol susceptibility assessment, the high rate of hetero-resistance to cefiderocol, and the high proportion of bloodstream infections (BSIs) and immunocompromised patients.

Here, we would like to provide some comments on why the data reported by Hoellinger et al. [START_REF] Hoellinger | Realworld clinical outcome of cefiderocol for treatment of multidrug-resistant non-fermenting, gram negative bacilli infections: a case series[END_REF] should not discourage clinicians from using cefiderocol for the treatment of MDR-nonfermenting gram-negative bacilli infections, including in immunocompromised patients or those with BSI, pointing out that the outcomes in their case series are not consistent with those reported in the literature [2e11] (Table 1).

Indeed, many studies on the use of cefiderocol in real-life situations have reported similar BSI rates but better outcomes [2,4e7]. Furthermore, it should be noted that most of the BSIs (4/6) reported by Hoellinger et al. [START_REF] Hoellinger | Realworld clinical outcome of cefiderocol for treatment of multidrug-resistant non-fermenting, gram negative bacilli infections: a case series[END_REF] were related to the catheter or urinary tract infections. These sources of BSI are those associated with the best outcomes [START_REF] Leligdowicz | Association between source of infection and hospital mortality in patients who have septic shock[END_REF], making a deleterious effect on prognosis less likely.

We would also like to temper the idea expressed by the authors that the high proportion of immunocompromised patients could explain such poor outcomes because the 30-day mortality rate was lower than 25% in the largest cohort, including 17 immunocompromised patients treated with cefiderocol [START_REF] Meschiari | Reallife experience with compassionate use of cefiderocol for difficult-to-treat resistant Pseudomonas aeruginosa (DTR-P) infections[END_REF]. However, it has come to our attention that patients included in their analysis [START_REF] Hoellinger | Realworld clinical outcome of cefiderocol for treatment of multidrug-resistant non-fermenting, gram negative bacilli infections: a case series[END_REF] were not simply immunocompromised, but presented with severe comorbidities, which could have a greater influence on prognosis than the acute infectious event [START_REF] Ahlstreom | A comparison of impact of comorbidities and demographics on 60-daymortality in ICU patients with COVID-19, sepsis and acute respiratory distress syndrome[END_REF], such as allogeneic stem cell transplant with graft-versus-host disease, prolonged neutropenia after chemotherapy for acute myeloid leukemia or Burkitt lymphoma, metastatic stomach cancer, pulmonary fibrosis, or lung transplantation.

The authors also reported a risk of a major error in the detection of strains resistant to cefiderocol, which is a relevant concern [START_REF] Devoos | Performance of discs, sensititre EUMDROXF microplates and MTS gradient strips for the determination of the susceptibility of multidrug resistant Pseudomonas aeruginosa to cefiderocol[END_REF]. The determination of susceptibility to cefiderocol should be carried out with the reference method by broth microdilution [START_REF] Devoos | Performance of discs, sensititre EUMDROXF microplates and MTS gradient strips for the determination of the susceptibility of multidrug resistant Pseudomonas aeruginosa to cefiderocol[END_REF], which was not systematically done in their study. Thus, as the authors acknowledged, some patients may have received inadequate antibiotic therapy, including one patient who eventually died of an infection caused by a cefiderocol-resistant strain of Stenotrophomonas maltophilia [START_REF] Hoellinger | Realworld clinical outcome of cefiderocol for treatment of multidrug-resistant non-fermenting, gram negative bacilli infections: a case series[END_REF].

Finally, we would like to point out that two patients requiring continuous venovenous hemofiltration received 1 g of cefiderocol every 12 hour, whereas recent data suggested using doses ranging from 1.5 g every 12 hour to 2 g every 8 hour in patients undergoing continuous renal replacement therapy [START_REF] Wenzler | Pharmacokinetics, pharmacodynamics, and dose optimization of cefiderocol during continuous renal replacement therapy[END_REF]. Inadequate dosage regimens may have led to nonattainment of cefiderocol pharmacokinetic/ pharmacodynamic targets, which has been associated with treatment failure [START_REF] Gatti | A descriptive case series of pharmacokinetic/pharmacodynamic target attainment and microbiological outcome in critically ill patients with documented severe extensively drug-resistant Acinetobacter baumannii bloodstream infection and/or ventilator-associated pneumonia treated with cefiderocol[END_REF]. Optimizing pharmacokinetic/pharmacodynamic target attainment with therapeutic drug monitoring, and combination therapy [6e8] could limit treatment failure caused by a high incidence of hetero-resistance to cefiderocol [START_REF] Choby | Does cefiderocol heteroresistance explain the discrepancy between the APEKS-NP and CREDIBLE-CR clinical trial results?[END_REF], and overall improve the outcomes.

In conclusion, the results of other real-world studies temper those of Hoellinger et al. [START_REF] Hoellinger | Realworld clinical outcome of cefiderocol for treatment of multidrug-resistant non-fermenting, gram negative bacilli infections: a case series[END_REF], highlighting that cefiderocol appeared to be safe and effective for the treatment of most MDR-non-fermenting gram-negative bacilli infections, although patients involved were often frail, critically ill, and had severe comorbidities. Further studies are now mandatory to assess if combination therapy and therapeutic drug monitoring could improve the outcomes of such patients.

Funding

No funding has been received by any of the authors for this work.

Author contributions

The first draft of the letter was written by RL. Critical revision of the letter was performed by PLL, PL, DL, TN, and AS. All authors read and approved the final version of the manuscript.

Transparency declaration

RL has received consulting fees from MSD, payment or honoraria for lectures, presentations, speakers' bureaus, or educational events from BioMérieux and MSD, and support for attending meetings and/or travel from BioMérieux, MSD, and Pfizer. PL has received payment or honoraria for lectures, presentations, speakers' bureaus, or educational events from AstraZeneca, GSK, Janssen, MSD, Moderna, Pfizer, Sanofi Pasteur, and support for attending meetings and/or travel from AstraZeneca, Pfizer, andSanofiPasteur.AS has received consulting fees from Besins Healthcare and Karo Pharma, support for attending meetings and/or travel from Pfizer and MSD, and participates free of charge on advisory boards of Biofilm Control and CTX Laboratory. All other authors declare that they have no conflict of interest.