Breaking Down the Barrier to Rapid Anti-bacterial Drug Levels with Paper Spray-Mass Spectrometry: Simultaneous Quantitation of Five βeta-lactams from Plasma

Importance of the Topic

Precise measurement of antibacterial drug levels is critical for effective therapy, especially in vulnerable populations such as children, where pharmacokinetics and pharmacodynamics differ greatly from adults.
Therapeutic drug monitoring (TDM) supports dosing decisions, reduces toxicity, and improves clinical outcomes.

Objectives and Study Overview

This study aimed to evaluate paper spray–mass spectrometry (PS-MS/MS) for the simultaneous quantitation of five β-lactam antibiotics in plasma.
Target compounds included ampicillin, piperacillin, meropenem, cefazolin, cefepime, and ceftriaxone.
Performance goals were a limit of detection (LOD) of 0.25 µg/mL, a lower limit of quantitation (LLOQ) of 1 µg/mL, and an upper limit of quantitation (ULOQ) of 50 µg/mL.

Methodology and Instrumentation

PS-MS/MS combines ambient ionization and mass analysis without chromatographic separation.
Plasma aliquots (1–3 µL) were applied to a paper substrate, extracted with 40–100 µL of organic solvent, and ionized at ~4 kV.
Optimization used a fractional factorial design to vary paper type, pore size, solvent composition, sample volume, and paper pretreatment.

• Primary instrument: Thermo Fisher TSQ Altis triple quadrupole with Verispray source.
• Supplemental tests: Thermo Fisher LTQ with Velox source.

Main Results and Discussion

Optimization reduced experimental runs from thousands to fewer than 200, identifying critical factors for signal and signal‐to‐blank ratio.
Achieved LODs ranged from 0.03 to 0.09 µg/mL and LOQs from 0.09 to 0.28 µg/mL for the five β-lactams, surpassing initial targets.
Fractional factorial analysis highlighted solvent volume and substrate characteristics as key drivers of sensitivity.
Feasibility studies showed glass fiber–based paper substrates provided the best performance for hydrophilic agents.

Benefits and Practical Applications

PS-MS/MS delivers rapid analysis (<5 minutes) with minimal sample (1–3 µL) and solvent consumption, no carryover, and no column maintenance.
Direct analysis from crude plasma simplifies workflow, enabling potential near–point-of-care TDM in hospital laboratories.
Applications include antimicrobial dosing, immunosuppressant monitoring, toxicology, and other drug panels.

Future Trends and Applications

Further clinical validation of β-lactam and triazole antifungal methods in pediatric settings will support physiologically based PK/PD modeling and precision dosing.
Advances in automation may yield integrated paper spray cartridges and plug-and-play sources.
Emerging micro-sampling techniques (e.g., heel‐stick, VP shunt sampling, volumetric absorptive microsampling) will expand applicability.
Extension to proteomics, lipidomics, biomarker quantitation, and microbial identification is anticipated.

Conclusion

Paper spray-MS offers a fast, robust, and resource-efficient approach for multi-drug quantitation from plasma.
Optimized methodology achieved sub-microgram per milliliter sensitivity, meeting clinical TDM requirements.
Its simplicity and speed position it as a promising tool for on-site drug monitoring and personalized therapy.

Reference

Manicke, N., et al. Anal. Methods, 2017, 9, 5037–5043.