High rates of cefidercol plasma target attainment: results of a retrospective cohort study in 31 critically ill ICU patients

Cefiderocol is a catechol-conjugated cephalosporin indicated for adults with limited treatment options, which suffer from systemic infections with aerobic Gram-negative bacteria. These include nosocomial pathogens such as Enterobacterales, Stenotrophomonas maltophilia and extensively drug-resistant bacteria like carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa [1]. Cefiderocol displays linear pharmacokinetics, as both the plasma concentration area under the curve and the maximum plasma concentration increase proportionally with the dosage, ranging from 100 to 2000 mg.

We conducted a retrospective therapeutic drug monitoring (TDM) study for cefiderocol including 31 intensive care patients with bacterial infections that were treated at ICUs at Klinikum Nürnberg, Nuremberg, Germany between April 2021 and October 2023. This study was approved by the institutional review board at Klinikum Nürnberg (IRB-2024-15). Key patients’ clinical and demographic data are provided in Table 1, further details are found in additional file 1.

Table 1 Key demographic and clinical characteristics of the patients included

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Twenty-one patients of this study were infected with multidrug-resistant Gram-negative bacteria. P. aeruginosa was by far the most prevalent isolate (n = 12), four others were Enterobacterales, one isolate each was identified as A. baumannii and four as S. maltophilia. The remaining ten patients were treated with cefiderocol empirically after multiple antibiotic pre-therapies.

Patients were given cefiderocol for 1–10 days with one patient being treated for 43 days (median: 5 days, interquartile range (IQR): 2–8). Based upon a standard dosing regimen of 2000 mg for 3 h every 8 h (with an upfront loading dose administered in 60 min), the patients received adjusted amounts of cefiderocol, taking TDM and creatinine clearance (CrCl) into account. Thus, individual patients were administered one to four doses of 750–2000 mg of cefiderocol, resulting in total daily doses ranging from 750 to 8000 mg (median: 3000 mg, IQR: 2000–4000).

Cefiderocol concentrations were analysed from blood samples taken 30–60 min before administration of the next dose, defining them as C_min values (trough levels). Analytics was performed by liquid chromatography with tandem mass spectrometry, with a turnaround time of less than 2 h. According to EUCAST we assumed a minimal inhibitory concentrations (MIC) breakpoint of cefiderocol of 2 µg/mL irrespective of the specific bacterium in our study. A C_min above 8 µg/mL of total cefiderocol (4 × minimum inhibitory concentration) was defined as sufficient target attainment. Considering an average of 42% of unbound cefiderocol [2], the free C_min (fC_min)/MIC ratio ≥ 4 (equalling to a calculated fC_min ≥ 8 µg/mL or C_min ≥ 19 µg/mL) was regarded as optimal. Previously, König et al. calculated that an fC_min of about 2 µg/mL of cefiderocol would be adequate to maintain a PK/PD target of 100% fT > MIC [3]. For an elevated target attainment of 100% fT > 4xMIC, in turn, an fC_min of 8 µg/mL would be sufficient, which corresponds to the “optimal “ threshold we set.

We analysed a total of 108 cefiderocol trough levels with one to 11 data points per patient (median: 3, IQR: 1–5). The median C_min of the cohort was 40.99 µg/mL (IQR: 23.56–64.54, Fig. 1A). Daily dosage of cefiderocol was positively correlated to the C_min in all patients (Pearson correlation r = 0.301 (95% CI: 0.119–0.463), p = 0.0016, Fig. 1B). Of all plasma levels, 99.1% were above the C_min target of 8 µg/mL. Consequently, 84.3% of the levels of the cohort were above the calculated fC_min target. We also investigated six subcohorts, according to the variables sex, renal replacement therapy (RRT), and body-mass index (BMI). The median C_min levels of these subcohorts were in the range of 31.27 µg/mL (women) to 46.61 µg/mL (RRT). No statistical differences in C_min levels were found within associated subcohorts (additional file 1).

Fig. 1

A C_min values of the study cohort. Each symbol of the scatter plot represents one C_min level. The bold and broader lines within the plots represent the median, the thinner and shorter lines denote the 25th and 75th percentiles. The fine line marks the target of 8 µg/mL of cefiderocol corresponding to four-fold MIC for relevant bacteria according to EUCAST. B relation between daily dose and measured plasma concentration. Each symbol represents one C_min level. The fine line marks the target of 8 µg/mL of cefiderocol. The solid line shows a simple linear regression of daily dosage vs. C_min with dotted lines showing the 95% confidence intervals. C and D Spaghetti-plots to illustrate dynamics in dose adjustment on plasma concentration in two sub-cohorts. Each pair of symbols represents one patient. Error bars are present in case of more than one level for the respective condition. C five patients with a dose reduction scheme from 6000 to 3000 mg per day, D five other patients with a dose reduction scheme from 6000 to 3000 mg per day. The fine line marks the target of 8 µg/mL of cefiderocol

Full size image

During therapy, dosing of cefiderocol was reduced in 21 patients. Among these, five patients first received 6000 mg and later 3000 mg per day. Five others first received 3000 and later 2000 mg per day. Both reduction schemes yielded decreased plasma levels of the drug (Fig. 1C and 1D). In all of these cases, total C_min levels were above the 8 µg/mL threshold anytime.

Generally, the levels we measured in this real-world setting fit well to previously published results. In our cohort, the median C_min of total cefiderocol was 40.99 µg/mL (IQR 23.56–64.54) translating to ca. 17 µg/mL of fC_min. The fC_min/MIC ration we observed was 8.61 (IQR 4.94–13.56) with 84.3% of target attainment. This is in line with different clinical trials, where fT > MIC was 100% in most cases [4]. In another study with 13 patients, the median fC_min of cefiderocol was 2.39 µg/mL (IQR 0.68–6.47) and the fC_min/MIC ratio was ≥ 4 in 38% of the cases [5].

We could show that following recommendations on dosing of cefiderocol ensures high rates of target attainment in a large and diverse patient collective. This was true for the entire cohort and the subcohorts that include patients with RRT and high BMI. While TDM may not be generally be required for cefiderocol, further studies investigating tissue penetration like in the lungs are warranted.

Raw data are available in pseudonymized form.

BMI:

Body-mass index

C_min :

Trough concentration

CrCl:

Creatinine clearance

EUCAST:

European committee on antimicrobial susceptibility testing

fC_min :

Free C_min

IQR:

Interquartile range

MIC:

Minimal inhibitory concentration

RRT:

Renal replacement therapy

TDM:

Therapeutic drug monitoring

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Members of the TDM study group are: Arnim Geise, Department for Respiratory Medicine; Golo-Sung Haarmeyer, Department for Respiratory Medicine; Matthias Baumgärtel, Department for Respiratory Medicine; Jens Nentwich, Department of Cardiology, Intensive Care Medicine; Axel von Fragstein, Department of Anaesthesiology and Operative Intensive Medicine, Anke Jensen, Department of Anaesthesiology and Operative Intensive Medicine (all from Klinikum Nürnberg, Paracelsus Medical University, Nuremberg, Germany).

This research received no external funding.

Author notes

1. Hans Theodor Naumann and Rainer Höhl have contributed equally to this work.

Authors and Affiliations

1. Institute of Clinical Microbiology, Infectious Diseases and Infection Control, Nuremberg General Hospital, Paracelsus Medical University, Nuremberg, Germany

   Hans Theodor Naumann, Rainer Höhl, Ralph Bertram & Joerg Steinmann

2. Intensive Care Unit, Department of Medicine 1, University Hospital Carl Gustav Carus, TU, Dresden, Dresden, Germany

   Hans Theodor Naumann

3. Institute for Biomedical and Pharmaceutical Research, Nuremberg-Heroldsberg, Germany

   Martina Kinzig & Fritz Sörgel

4. Study Program in Human Medicine, Paracelsus Medical University, Nuremberg, Germany

   Sophie Salat & Vanessa Bartsch

5. Institute of Pharmacology, West German Heart and Vascular Centre, University of Duisburg-Essen, Essen, Germany

   Fritz Sörgel

6. Department for Respiratory Medicine, Klinikum Nürnberg, Paracelsus Medical University, Nuremberg, Germany

   Arnim Geise, Golo-Sung Haarmeyer & Matthias Baumgärtel

7. Department of Cardiology, Intensive Care Medicine, Klinikum Nürnberg, Paracelsus Medical University, Nuremberg, Germany

   Jens Nentwich

8. Department of Anaesthesiology and Operative Intensive Medicine, Klinikum Nürnberg, Paracelsus Medical University, Nuremberg, Germany

   Axel von Fragstein & Anke Jensen

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Consortia

Therapeutic Drug Monitoring study group

• Arnim Geise
• , Golo-Sung Haarmeyer
• , Matthias Baumgärtel
• , Jens Nentwich
• , Axel von Fragstein
•  & Anke Jensen

Contributions

HTN performed investigation, data curation and writing of the manuscript. RH supervised and conceptualized the work and provided resources. MK analysed the samples for drug levels and was involved in writing the manuscript. SS and VB curated data. FS was involved in analytics and administration of the project. RB curated data, performed formal analysis and wrote large parts of the manuscript. JS performed conceptualization, supervision and writing of the manuscript. Members of the Therapeutic Drug Monitoring (TDM) study group provided resources. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ralph Bertram or Joerg Steinmann.

Ethics approval and consent to participate

This study was approved by the institutional review board at Klinikum Nürnberg (IRB-2024–15).

Competing interests

RH was active in the Advisory Board of Shionogi, the supplier of cefiderocol. JS received speaker’s honorarium from Gilead, Pfizer and bioMérieux.

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Naumann, H.T., Höhl, R., Kinzig, M. et al. High rates of cefidercol plasma target attainment: results of a retrospective cohort study in 31 critically ill ICU patients. Crit Care 28, 438 (2024). https://doi.org/10.1186/s13054-024-05214-5

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• Received: 18 October 2024

• Accepted: 12 December 2024

• Published: 30 December 2024

• DOI: https://doi.org/10.1186/s13054-024-05214-5

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Keywords

• Cefiderocol
• Therapeutic drug monitoring
• Antibiotics
• Antiinfectives
• Pharmacokinetics
• Pharmacodynamics