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Antibiotics
Volume 11
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10.3390/antibiotics11010054
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Article

Quantification of Fosfomycin in Combination with Nine Antibiotics in Human Plasma and Cation-Adjusted Mueller-Hinton II Broth via LCMS

by
Kelvin Kau-Kiat Goh
1,2,
Wilson Ghim-Hon Toh
1,†,
Daryl Kim-Hor Hee
3,‡,
Edwin Zhi-Wei Ting
3,
Nathalie Grace Sy Chua
1,
Farah Iffah Binte Zulkifli
1,
Li-Jiao Sin
1,
Thuan-Tong Tan
4,5,
Andrea Lay-Hoon Kwa
1,4,6,* and
Tze-Peng Lim
1,2,4,*
1
Department of Pharmacy, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
2
SingHealth Duke-NUS Pathology Academic Clinical Programme, 8 College Road, Singapore 169857, Singapore
3
Shimadzu (Asia Pacific) Pte Ltd., 79 Science Park Dr, #02-01/08 Cintech IV, Singapore 118264, Singapore
4
SingHealth Duke-NUS Medicine Academic Clinical Programme, 8 College Road, Singapore 169857, Singapore
5
Department of Infectious Diseases, Singapore General Hospital, Outram Road, Singapore 169608, Singapore
6
Emerging Infectious Diseases Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore
*
Authors to whom correspondence should be addressed.
†
Wilson Ghim-Hon TOH is no longer at the institution where the work was performed. Current email address: wilsontgh113@hotmail.com.
‡
Daryl Kim-Hor HEE is no longer at the institution where the work was performed. Current email address: daryl_hee@cgh.com.sg.
Antibiotics 2022, 11(1), 54; https://doi.org/10.3390/antibiotics11010054
Submission received: 6 December 2021 / Revised: 28 December 2021 / Accepted: 29 December 2021 / Published: 2 January 2022
(This article belongs to the Section Antibiotics Use and Antimicrobial Stewardship)
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Abstract

Fosfomycin-based combination therapy has emerged as an attractive option in our armamentarium due to its synergistic activity against carbapenem-resistant Gram-negative bacteria (CRGNB). The ability to simultaneously measure fosfomycin and other antibiotic drug levels will support in vitro and clinical investigations to develop rational antibiotic combination dosing regimens against CRGNB infections. We developed an analytical assay to measure fosfomycin with nine important antibiotics in human plasma and cation-adjusted Mueller–Hinton II broth (CAMHB). We employed a liquid-chromatography tandem mass spectrometry method and validated the method based on accuracy, precision, matrix effect, limit-of-detection, limit-of-quantification, specificity, carryover, and short-term and long-term stability on U.S. Food & Drug Administration (FDA) guidelines. Assay feasibility was assessed in a pilot clinical study in four patients on antibiotic combination therapy. Simultaneous quantification of fosfomycin, levofloxacin, meropenem, doripenem, aztreonam, piperacillin/tazobactam, ceftolozane/tazobactam, ceftazidime/avibactam, cefepime, and tigecycline in plasma and CAMHB were achieved within 4.5 min. Precision, accuracy, specificity, and carryover were within FDA guidelines. Fosfomycin combined with any of the nine antibiotics were stable in plasma and CAMHB up to 4 weeks at −80 °C. The assay identified and quantified the respective antibiotics administered in the four subjects. Our assay can be a valuable tool for in vitro and clinical applications.
Keywords: fosfomycin; LCMS/MS; antibiotics; plasma; TDM; validation fosfomycin; LCMS/MS; antibiotics; plasma; TDM; validation

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MDPI and ACS Style

Goh, K.K.-K.; Toh, W.G.-H.; Hee, D.K.-H.; Ting, E.Z.-W.; Chua, N.G.S.; Zulkifli, F.I.B.; Sin, L.-J.; Tan, T.-T.; Kwa, A.L.-H.; Lim, T.-P. Quantification of Fosfomycin in Combination with Nine Antibiotics in Human Plasma and Cation-Adjusted Mueller-Hinton II Broth via LCMS. Antibiotics 2022, 11, 54. https://doi.org/10.3390/antibiotics11010054

AMA Style

Goh KK-K, Toh WG-H, Hee DK-H, Ting EZ-W, Chua NGS, Zulkifli FIB, Sin L-J, Tan T-T, Kwa AL-H, Lim T-P. Quantification of Fosfomycin in Combination with Nine Antibiotics in Human Plasma and Cation-Adjusted Mueller-Hinton II Broth via LCMS. Antibiotics. 2022; 11(1):54. https://doi.org/10.3390/antibiotics11010054

Chicago/Turabian Style

Goh, Kelvin Kau-Kiat, Wilson Ghim-Hon Toh, Daryl Kim-Hor Hee, Edwin Zhi-Wei Ting, Nathalie Grace Sy Chua, Farah Iffah Binte Zulkifli, Li-Jiao Sin, Thuan-Tong Tan, Andrea Lay-Hoon Kwa, and Tze-Peng Lim. 2022. "Quantification of Fosfomycin in Combination with Nine Antibiotics in Human Plasma and Cation-Adjusted Mueller-Hinton II Broth via LCMS" Antibiotics 11, no. 1: 54. https://doi.org/10.3390/antibiotics11010054

APA Style

Goh, K. K.-K., Toh, W. G.-H., Hee, D. K.-H., Ting, E. Z.-W., Chua, N. G. S., Zulkifli, F. I. B., Sin, L.-J., Tan, T.-T., Kwa, A. L.-H., & Lim, T.-P. (2022). Quantification of Fosfomycin in Combination with Nine Antibiotics in Human Plasma and Cation-Adjusted Mueller-Hinton II Broth via LCMS. Antibiotics, 11(1), 54. https://doi.org/10.3390/antibiotics11010054

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