Quantitative Determination of Unbound Piperacillin and Imipenem in Biological Material from Critically Ill Using Thin-Film Microextraction-Liquid Chromatography-Mass Spectrometry
Abstract
:1. Introduction
2. Results and Discussion
2.1. LC-MS Conditions Optimization
2.1.1. Chromatographic Column Selection
2.1.2. Mobile Phase Gradient Selection
2.1.3. MS Conditions Optimization
2.1.4. Quality Control of TFME Blades Preparation
2.2. TFME Procedure Optimization
2.2.1. Solid Phase and Desorption Solvent Selection
2.2.2. Extraction and Desorption Time
2.3. Method Validation
2.3.1. Linearity Range
2.3.2. LLOQ and Sensitivity
2.3.3. Accuracy and Precision
2.3.4. Selectivity and Specificity
2.3.5. Carryover
2.3.6. Recovery
2.4. Application in Biological Samples
2.4.1. Patient Characteristics
2.4.2. Concentration of Piperacillin and Imipenem in Plasma
2.4.3. Degree of Penetration of Piperacillin and Imipenem to BAL
3. Materials and Methods
3.1. Chemicals and Reagents
3.2. Instrumentation
3.2.1. Optimization of LC-MS Conditions
3.2.2. Final LC-MS Conditions
3.2.3. Preparation of TFME Coating
3.2.4. Quality Control of TFME Blades
3.3. Optimization of TFME Procedure
3.4. Method Validation
3.4.1. Linearity Range
3.4.2. LLOQ and Sensitivity
3.4.3. Accuracy and Precision
3.4.4. Selectivity and Specificity
3.4.5. Carry-Over
3.4.6. Recovery
3.5. Blood and BAL Sampling from VAP Patients
4. Study Limitations
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Time (min) | % A Phase | % B Phase |
---|---|---|
0.01 | 95.00 | 5.00 |
0.20 | 95.00 | 5.00 |
1.00 | 60.00 | 40.00 |
2.00 | 60.00 | 40.00 |
3.50 | 5.00 | 95.00 |
5.00 | 5.00 | 95.00 |
5.01 | 95.00 | 5.00 |
7.20 | 95.00 | 5.00 |
Compounds | Parent Ion m/z | Product Ions m/z | Collision Energy (V) | Q1 (V) | Q3 (V) | Retention Time (min) |
---|---|---|---|---|---|---|
Imipenem | 300.00 | 141.85 | −28.00 | −10.00 | −14.00 | 1.76 |
98.05 | −28.00 | −10.00 | −19.00 | |||
125.95 | −20.00 | −13.00 | −19.00 | |||
Piperacillin | 518.05 | 143.00 | −20.00 | −22.00 | −15.00 | 2.53 |
159.95 | −19.00 | −22.00 | −30.00 | |||
359.00 | −10.00 | −22.00 | −12.00 |
Compounds | Concentration [mg/L] | Within-Run [%] | Between-Run [%] | ||
---|---|---|---|---|---|
1st Run | 2nd Run | 3rd Run | |||
Imipenem | 0.05 | 110.54–115.53 | 109.07–112.82 | 88.52–92.87 | 88.52–115.53 |
0.15 | 102.02–112.09 | 99.88–106.51 | 88.60–108.93 | 88.60–112.09 | |
0.5 | 85.19–98.33 | 71.47–92.74 | 94.83–102.00 | 71.47–102.00 | |
1.0 | 91.68–100.12 | 93.65–86.91 | 97.33–107.89 | 86.91–107.89 | |
Piperacillin | 0.02 | 83.26–118.56 | 83.93–113.37 | 78.14–100.68 | 79.14–118.56 |
0.06 | 88.25–111.57 | 90.36–111.57 | 81.82–116.08 | 81.82–116.08 | |
0.25 | 96.13–117.56 | 88.65–107.25 | 86.49–102.08 | 88.65–117.56 | |
0.5 | 95.15–103.52 | 85.08–103.78 | 92.68–99.15 | 85.08–103.78 |
Compounds | Concentration [mg/L] | Within-Run [%] | Between-Run [%] | ||
---|---|---|---|---|---|
1st Run | 2nd Run | 3rd Run | |||
Imipenem | 0.05 | 1.81 | 1.35 | 2.06 | 10.59 |
0.15 | 3.67 | 2.77 | 9.05 | 6.91 | |
0.5 | 5.90 | 10.49 | 2.79 | 11.48 | |
1.0 | 3.38 | 2.72 | 4.54 | 6.47 | |
Piperacillin | 0.02 | 14.73 | 13.12 | 11.51 | 13.43 |
0.06 | 10.43 | 9.32 | 10.38 | 10.72 | |
0.25 | 9.29 | 8.09 | 7.64 | 9.74 | |
0.5 | 3.38 | 7.81 | 2.87 | 5.08 |
Compounds | Peak Area for Blank | Peak Area for LLOQ | % of LLOQ |
---|---|---|---|
Imipenem | 4.40 × 103 | 2.09 × 105 | 2.10% |
7.73 × 102 | 0.37% | ||
3.24 × 103 | 1.55% | ||
4.05 × 103 | 1.94% | ||
Piperacillin | 2.82 × 104 | 6.84 × 105 | 4.13% |
8.61 × 103 | 1.26% | ||
1.56 × 104 | 2.28% | ||
2.77 × 104 | 4.05% |
Pat. # | Age [years] | Body Weight [kg] | Microorganisms Found | Other Drugs | Renal Impairment Therapy | PCT [ng/mL] | CRP [mg/L] | Albumins [g/L] | Urea [mmol/L] | Creatinine [µmol/L] |
---|---|---|---|---|---|---|---|---|---|---|
Patients receiving PIPERACILLIN | ||||||||||
1 | 89 | 88 | P. aeruginosa, P. mirabilis, Enterococcus spp. | - | - | 1.27 | 88.69 | 34.68 | 9.4 | 82.06 |
2 | 28 | 78 | P. aeruginosa, S. marcescens | - | - | 0.13 | 35.66 | 33.1 | 11.6 | 29.36 |
3 | 60 | 71 | P. mirabilis, E. coli | - | - | 1.4 | 69.56 | 29.1 | 5.3 | 61.71 |
- | 0.69 | 51.08 | - | 4.3 | 61.2 | |||||
- | 0.39 | 53.65 | 32.54 | 3.6 | 54.36 | |||||
4 | 73 | 64 | - | - | - | 0.59 | 76.48 | 29.37 | 8.6 | 50.87 |
0.45 | 42.08 | 28.99 | 9.3 | 55.67 | ||||||
5 | 83 | 82 | - | - | - | 0.3 | 133.56 | 24.9 | 13.5 | 82.31 |
6 | 66 | 86 | P. mirabilis, E. faecalis | - | CVVHD | 0.67 | 179.61 | - | 10.3 | 96.98 |
7 | 64 | 88 | E. coli | - | - | 0.19 | 109.19 | 29.89 | 4.1 | 54.7 |
8 | 69 | 86 | E. coli, Candida spp. | - | - | 0.06 | 60.14 | 31.64 | 4 | 28.72 |
9 | 68 | 68 | S. hominis | - | - | 0.15 | 6.26 | 37.67 | 3 | 46.89 |
10 | 46 | 76 | K. pneumoniae | - | - | 0.28 | 184.35 | 32.86 | 10.1 | 53.53 |
11 | 77 | 62 | C. albicans | - | - | 2.37 | 195.97 | 28.58 | 13.6 | 105.33 |
Patients receiving IMIPENEM | ||||||||||
1 | 71 | 83 | E.coli | piperacillin | diuresis supported with FSD | 24.39 | 105.11 | 31.73 | 11 | 72.62 |
2.88 | 26.4 | 30.95 | 6.4 | 40.82 | ||||||
2 | 57 | 75 | P. mirabilis | piperacillin | CVVHD | 10.04 | 241.85 | - | 12.1 | 118.62 |
5.2 | 297.15 | 32.45 | 11.6 | 111.15 | ||||||
3 | 77 | 91 | E.coli, C. albicans | - | diuresis supported with FSD | 2.09 | 231.29 | 28.33 | 4.8 | 66.99 |
1.21 | 140.11 | - | 5.1 | 58.17 | ||||||
1.1 | 124.79 | 30.78 | 6.9 | 63.08 | ||||||
4 | 59 | 84 | S. marcescens, S. aureus | - | - | 30.2 | 78.93 | 23.4 | 18.3 | 109.19 |
5 | 71 | 78 | S. aureus | ceftriaxone | CVVHD | 4.72 | 369.99 | 27.64 | 11.1 | 220.28 |
6.24 | 366.4 | 34.44 | 16 | 196.23 | ||||||
6 | 92 | 68 | K. pneumoniae | piperacillin | diuresis supported with FSD | 2.64 | 377.4 | - | 23.3 | 198.76 |
2.47 | 324.75 | 21.52 | 27 | 197.61 | ||||||
7 | 30 | 78 | Candida spp. | Piperacillin | diuresis supported with FSD | 2.36 | 327.57 | 39.73 | 14.4 | 178.12 |
Pat. # | Age [years] | Body Weight [kg] | Microorganisms Found | Other Drugs | Renal Impairment Therapy | PCT [ng/mL] | CRP [mg/L] | Albumins [g/L] | Urea [mmol/L] | Creatinine [µmol/L] |
---|---|---|---|---|---|---|---|---|---|---|
Patients receiving PIPERACILLIN | ||||||||||
1 | 66 | 86 | P. mirabilis, E. faecalis | - | CVVHD | 0.71 | 263 | 31.57 | 16 | 164 |
2 | 28 | 76 | P. aeruginosa, S. marcescens | - | - | 0.13 | 35.66 | 33.1 | 11.6 | 29.36 |
3 | 68 | 84 | C. freundi | - | - | 37.96 | 61 | 22.56 | 9.1 | 117 |
4 | 69 | 78 | E. coli, Candida sp. | - | - | 0.06 | 60.14 | 31.64 | 4 | 28.72 |
5 | 46 | 67 | K. pneumoniae | - | - | 0.28 | 184.35 | 32.86 | 10.1 | 53.53 |
6 | 77 | 79 | C. albicans | - | - | 2.37 | 195.97 | 28.58 | 13.6 | 105.33 |
Patients receiving IMIPENEM | ||||||||||
1 | 71 | 78 | S. aureus | ceftriaxone | CVVHD | 4.72 | 369.99 | 27.64 | 11.1 | 220.28 |
6.24 | 366.4 | 34.44 | 16 | 196.23 | ||||||
2 | 92 | 68 | K. pneumoniae | piperacillin | diuresis supported with FSD | 2.64 | 377.4 | - | 23.3 | 198.76 |
2.47 | 324.75 | 21.52 | 27 | 197.61 | ||||||
3 | 30 | 78 | Candida spp. | piperacillin | diuresis supported with FSD | 2.36 | 327.57 | 39.73 | 14.4 | 178.12 |
Pat. # | Sample Number | Antibiotic Treatment before Sampling [days] | Concentration in Plasma before Infusion [mg/L] | Concentration in Plasma after Infusion [mg/L] |
---|---|---|---|---|
Patients receiving PIPERACILLIN | ||||
1 | PIP-1 | 1 | 162.869 | 307.806 |
2 | PIP-2 | 7 | 115.500 | 286.148 |
3 | PIP-3 | 3 | 61.603 | 133.925 |
PIP-4 | 4 | 58.241 | 138.191 | |
PIP-5 | 5 | 44.869 | 203.747 | |
4 | PIP-6 | 6 | 54.496 | 278.231 |
PIP-7 | 7 | 62.556 | 198.964 | |
5 | PIP-8 | 1 | 215.263 | 461.537 |
6 | PIP-9 | 1 | 166.428 | 370.821 |
7 | PIP-10 | 3 | 92.074 | 189.133 |
8 | PIP-11 | 0 | 14.533 | 109.166 |
9 | PIP-12 | 2 | 53.270 | 130.710 |
10 | PIP-13 | 1 | 22.617 | 98.457 |
11 | PIP-14 | 2 | 183.280 | 307.027 |
Patients receiving IMIPENEM | ||||
1 | IMI-1 | 2 | 0.918 | 15.344 |
IMI-2 | 4 | 1.646 | 16.283 | |
2 | IMI-3 | 4 | 0.756 | 8.176 |
IMI-4 | 5 | 0.293 | 17.185 | |
3 | IMI-5 | 4 | 1.650 | 18.394 |
IMI-6 | 5 | 0.835 | 5.627 | |
IMI-7 | 6 | 1.157 | 12.919 | |
4 | IMI-8 | n.a. | 15.034 | 38.816 |
5 | IMI-9 | 0 | 7.001 | 25.113 |
IMI-10 | 3 | 2.958 | 10.219 | |
6 | IMI-11 | 1 | 5.067 | 13.399 |
IMI-12 | 2 | 5.291 | 13.164 | |
7 | IMI-13 | 0 | 0.707 | 5.852 |
Pat. # | Sample Number | Concentration after Infusion in PLASMA [mg/L] | Concentration after Infusion in BAL [mg/L] | BAL/Plasma % |
---|---|---|---|---|
Patients receiving PIPERACILLIN | ||||
1 | PIP-I | 201.687 | 3.794 | 1.88 |
2 | PIP-II | 263.928 | 6.271 | 2.38 |
3 | PIP-III | 309.428 | 6.995 | 2.26 |
4 | PIP-IV | 109.166 | 2.236 | 2.05 |
5 | PIP-V | 98.457 | 2.673 | 2.71 |
6 | PIP-VI | 307.027 | 7.711 | 2.51 |
Patients receiving IMIPENEM | ||||
1 | IMI-I | 25.113 | 2.801 | 11.15 |
2 | IMI-II | 10.219 | 0.576 | 5.64 |
IMI-III | 13.399 | 0.298 | 2.22 | |
3 | IMI-IV | 13.164 | 1.189 | 9.03 |
IMI-V | 5.852 | 0.087 | 1.49 |
Type of Sorbent | Number of Layers | Oven Temperature (°C) | Curing Time (min) |
---|---|---|---|
C18 | 10 | 180 °C | 2 min |
DVB | 8 | 110 °C | 3 min |
PCA | 10 | 110 °C | 3 min |
SCX | 10 | 110 °C | 3 min |
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Włodarski, R.; Żuchowska, K.; Filipiak, W. Quantitative Determination of Unbound Piperacillin and Imipenem in Biological Material from Critically Ill Using Thin-Film Microextraction-Liquid Chromatography-Mass Spectrometry. Molecules 2022, 27, 926. https://doi.org/10.3390/molecules27030926
Włodarski R, Żuchowska K, Filipiak W. Quantitative Determination of Unbound Piperacillin and Imipenem in Biological Material from Critically Ill Using Thin-Film Microextraction-Liquid Chromatography-Mass Spectrometry. Molecules. 2022; 27(3):926. https://doi.org/10.3390/molecules27030926
Chicago/Turabian StyleWłodarski, Robert, Karolina Żuchowska, and Wojciech Filipiak. 2022. "Quantitative Determination of Unbound Piperacillin and Imipenem in Biological Material from Critically Ill Using Thin-Film Microextraction-Liquid Chromatography-Mass Spectrometry" Molecules 27, no. 3: 926. https://doi.org/10.3390/molecules27030926