Therapeutic drug monitoring of cefiderocol in a patient with sepsis in a children’s oncohematology hospital

Objective. To evaluate the pharmacokinetic features of cefiderocol in a patient with sepsis.
Materials and methods. In this research, we studied the pharmacokinetics of cefiderocol in a patient who was admitted to an oncohematology hospital for the treatment of primary immunodeficiency — chronic granulomatous disease with a concomitant diagnosis of sepsis caused by Burkholderia cepacia. Cefiderocol was administered in three different doses: 3 times a day at 30, 45 and 60 mg/kg. The serum concentration of the antibiotic was determined by high-performance liquid chromatography — tandem mass spectrometry (HPLC-MS/MS) with subsequent construction of a pharmacokinetic curve and calculation of pharmacokinetic parameters.
Results. The studied B. cepacia strain showed a high level of resistance to standard antibiotics. The prescribed cefiderocol had a shortened half-life, which could probably be due to increased values of the glomerular filtration rate (GFR) and massive infusion therapy (3 l/m² /day). The obtained values of the area-under-the-time-versus-concentration curve (AUC) AUC = 362.1 mg^×h/l and Cmax = 117.1 mg/l were closest to the data given in the instructions (AUC = 394.7 mg^×h/l and Cmax = 138 mg/l) only in the case of the prescribed dose of 60 mg/kg 3 times a day. Moreover, in the case of prescribing this dose, a decrease in the time of serum concentration below four times the minimum inhibitory concentration (MIC) (fT < 4 × MIC) was observed — 17.4 %, against 39.9 % and 40.2 % at a dose of 30 mg/kg and 45 mg/kg and an increase in the time of serum concentration above (fT > 10 × MIC) — 50.2 %, against 11.4 % and 13.4 %.
Conclusion. The use of HPLC-MS/MS to determine the serum concentration of cefiderocol is an effective approach to therapeutic drug monitoring of cefiderocol. Its use can be a useful tool for selecting an effective and safe dose, which allows for timely dose adjustments, especially for critically ill patients.

1. Результаты аллогенной трансплантации гемопоэтических стволовых клеток у пациентов с хронической гранулематозной болезнью в Российской детской клинической больнице / Е. Б. Мачнева, Е. А. Пристанскова, Л. В. Ольхова [и др.] // Российский журнал детской гематологии и онкологии. — 2020. — Т. 7, № 2. — С. 23—34 .

2. Burkholderia cepacia Sepsis in a Previously Healthy Full-Term Infant / C. A. Carmona, A. Marante, F. Levent, S. Marsicek // Case reports in pediatrics. — 2020. — Vol. 105. — P. 126—131.

3. The Sanford Guide to Antimicrobial Therapy 2022 / D. N. Gilbert, H. F. Chambers, M. S. Saag. [et al.]. — 52th ed. — 2022. — 340 p.

4. Naturally occurring Class A βlactamases from the Burkholderia cepacia complex / L. Poirel, J.-M. Rodriguez-Martinez, P. Plesiat, P. Nordmann // Antimicrob Agents Chemother. — 2009. — Vol. 53, № 3. — P. 876—882.

5. Podnecky, N. L. Efflux pump mediated drug resistance in Burkholderia / N. L. Podnecky, K. A. Rhodes, H. P. Schweizer // Case Reports in Pediatrics. — 2015. — № 6. — DOI: 10.3389/fmicb.2015.00305.

6. Rhodes, K. A. Antibiotic resistance in Burkholderia species / K. A. Rhodes, H. P. Schweizer // Drug Resistance Updates. — 2016. — № 28. — P. 82—90.

7. Shommu, N. S. Potential of metabolomics to reveal Burkholderia cepacia complex pathogenesis and antibiotic resistance / N. S. Shommu, H. J. Vogel, D. G. Storey // Frontiers in Microbiology. — 2015. — № 6. — DOI: 10.3389/fmicb.2015.00668.

8. Butt, A. T. Iron acquisition mechanisms and their role in the virulence of Burkholderia species / A. T. Butt, M. S. Thomas // Frontiers in Cellular and Infection Microbiology. — 2017. — № 7. — DOI: 10.3389/fcimb.2017.00460.

9. Microcalorimetric investigation of the toxic action of ammonium ferric (III) sulfate on the metabolic activity of pure microbes / F. Wang, J. Yao, L. Tian [et al.] // Environmental Toxicology and Pharmacology. — 2008. — Vol. 25, № 3. — P. 351—357.

10. Successful Use of Cefiderocol to Treat a Multidrug-resistant Stenotrophomonas maltophilia Ventilator-associated Pneumonia in an Extremely Preterm Neonate / A. Koirala, B. Krishnappa, C. Banh [et al.] // Environmental Toxicology and Pharmacology. — 2023. — Vol. 42, № 11. — P. 1012—1016.

11. Novel Beta Lactam Antibiotics for the Treatment of Multidrug-Resistant Gram-Negative Infections in Children : a narrative review / F. Venuti, L. Romani, M. De Luca [et al.] // Microorganisms. — 2023. — Vol. 11, № 7. — DOI: 10.3390/microorganisms11071798.

12. Pharmacokinetics, safety and tolerability of single-dose or multiple-dose cefiderocol in hospitalized pediatric patients three months to less than eighteen years old with infections treated with standardof-care antibiotics in the PEDI-CEFI Phase 2 Study / F. Venuti, E. Orchiston, S. Portsmouth [et al.] // The Pediatric infectious disease journal. — 2025. — Vol. 44, № 2. — P. 136—142

13. Cockcroft, D. W. Prediction of creatinine clearance from serum creatinine / D. W. Cockcroft, M. H. Gault, D. G. Storey // Nephron. — 1976. — № 16. — P. 31—41.

14. Du Bois, D. A formula to estimate the approximate surface area if height and weight be known / D. Du Bois, E. F. Du Bois, D. G. Storey // Nephron. — 1989. — № 5. — P. 303—311.

15. Gatti, M. 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 / M. Gatti, M. Bartoletti, G. Cojutti // Journal of global antimicrobial resistance. — 2021. — № 27. — P. 294—298.