A Single-Run HPLC–MS Multiplex Assay for Therapeutic Drug Monitoring of Relevant First- and Second-Line Antibiotics in the Treatment of Drug-Resistant Tuberculosis
Abstract
:1. Introduction
2. Materials and Methods
2.1. The Definition of an Assay Target Profile
2.2. Chemicals
2.3. Sample Preparation
2.4. HPLC–MS/MS
2.4.1. MS/MS
2.4.2. HPLC
2.5. Extraction Procedure
2.6. Validation
2.6.1. Calibration
2.6.2. Carry-Over, Selectivity, and Specificity
2.6.3. Recovery and Matrix Effect
2.6.4. Accuracy and Precision
2.7. Clinical Application
2.7.1. Patient Histories
2.7.2. Sample Collection and Management
3. Results
3.1. Definition of an Assay Target Profile
3.2. HPLC-MS/MS
3.2.1. MS/MS
3.2.2. HPLC
3.3. Validation
3.3.1. Calibration
3.3.2. Carry-Over, Selectivity, and Specificity
3.3.3. Recovery and Matrix Effect
3.3.4. Accuracy and Precision
- Linezolid, delamanid, meropenem, and prothionamide were strictly within the EMA/FDA-recommended range of 85–115% accuracy and 0–15% within-day and between day precision [14,15]. The expected deviation from the nominal concentration in the form of the 80% beta-expectation tolerance interval was up to ±30% in meropenem and up to approximately ±40% in linezolid, delamanid, and prothionamide (linezolid: −19.3% to +40.4%, ethambutol: −9.7% to +41.0%, both at QClow).
- Moxifloxacin, clofazimine, cycloserine, and ethambutol showed accuracy of 80–120% and precision of approximately 0–20% (moxifloxacin between-day precision: 20.6%, ethambutol accuracy: 123.4%, both at QCmed). 80% beta-expectation tolerance intervals were within approximately ±40% (moxifloxacin: −26.9% to +40.3% at QCmed, ethambutol: −9.7% to +41.0% at QClow).
- Rifampicin, rifabutin, levofloxacin, bedaquiline, pyrazinamide, and PAS showed accuracy of approximately 80–120% and precision of approximately 0–20% with higher deviations at QClow: rifampicin with an accuracy of 122.2%, rifabutin with a between-day precision of 20.8%, and bedaquiline with a between-day precision of 24.4%. Correspondingly, rifampicin, rifabutin, levofloxacin, bedaquiline, pyrazinamide, and PAS showed higher expected deviations at low concentrations, with an 80% beta-expectation tolerance interval of up to ±60% at QClow and ±30% at QCmed and QChigh for bedaquiline and pyrazinamide, as well as ±40% at QCmed and QChigh for rifampicin, rifabutin, levofloxacin, and PAS (PAS: −23.3% to +42.9% and −40.3% to +21.9% at QCmed and QChigh, respectively).
- Amikacin was evaluated based on only one set of QClow, QCmed, and QChigh, hence stratified between-day precision could not be calculated and overall accuracy (93.5%), within-day (6.3%), and between-day precision (6.3%) were determined instead. The overall 80% beta-expectation tolerance interval was −15.2% to +2.2%.
- Isoniazid, pretomanid, streptomycin, capreomycin IB and IA, as well as kanamycin showed inadequate accuracy and/or within- and between-day precision. 80% beta-expectation tolerance intervals of isoniazid, pretomanid, streptomycin, capreomycin IB and IA, and kanamycin partly exceeded 100%. Quantification of isoniazid showed systematic deviations, with accuracies of 141.2% to 160.3%.
3.4. Clinical Application
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Criterion | Sufficient and Ideal Performance |
---|---|
Analyte panel | |
Platform |
|
Throughput |
|
Sensitivity | LLOQ: cover pharmacokinetics from lower Cmax over five half-lives: ULOQ:
|
Validation |
|
WHO Group | Analyte | Panel | TDM Recommended [10] | TDM Priority | Toxicity Target [10] [µg/mL] | Efficacy Target [10] | Cmax [10] [µg/mL] | Target Calibration LLOQtarget-ULOQtarget [µg/mL] | QClow [µg/mL] | QCmed [µg/mL] | QChigh [µg/mL] |
---|---|---|---|---|---|---|---|---|---|---|---|
First-line | rifampicin | 2 | toxicity/efficacy | ++ | - | AUC/MIC > 271 | 8–24 | 0.2–10 | 0.6 | 1.5 | 7.5 |
rifabutin | 5 | toxicity [17] | ++ | - | - | 0.45–0.9 [18] | 0.01–0.5 | 0.03 | 0.075 | 0.4 | |
isoniazid | 2 | toxicity/efficacy | ++ | - | AUC/MIC > 567 | 3–6 | 0.1–5 | 0.3 | 0.75 | 3.75 | |
Group A | levofloxacin | 1, 5 | efficacy | +++ | - | AUC/MIC > 146 | 8–13 | 0.25–2.5 | 0.75 | 1.25 | 2 |
moxifloxacin | 1, 3 | efficacy | +++ | - | fAUC/MIC > 53 | 3–5 | 0.1–1 | 0.3 | 0.5 | 0.75 | |
bedaquiline | 1, 4 | toxicity/efficacy [19] | +++ | - | AUC/MIC > 74.6 * [19] | 0.9–4.3 | 0.01–1 | 0.03 | 0.15 | 0.75 | |
linezolid | 1, 4 | toxicity/efficacy [20] | +++ | Cmin > 2–2.5 | fAUC/MIC > 125 [20] | 12–26 | 0.1–5 | 0.3 | 0.75 | 4 | |
Unclassified | pretomanid | 5 | - | ++ | - | - | 1.4–4.3 [21] | 0.01–1 | 0.03 | 0.15 | 0.75 |
Group B | clofazimine | 1, 3 | - | ++ | - | - | 0.5–2 | 0.01–0.5 | 0.03 | 0.075 | 0.4 |
cycloserine | 1, 3 | toxicity/efficacy | +++ | - | %T > MIC > 30% | 20–35 | 0.5–10 | 1.5 | 2 | 7.5 | |
Group C | ethambutol | 1, 2, 3 | toxicity | ++ | - | AUC/MIC > 119 | 2–6 | 0.062–2.5 | 0.18 | 0.4 | 1.9 |
delamanid | 1, 5 | - | ++ | - | - | 0.3–0.9 [22] | 0.005–0.5 | 0.015 | 0.075 | 0.4 | |
pyrazinamide | 1, 2 | toxicity/efficacy | +++ | - | AUC/MIC > 8.42 | 20–60 | 0.5–10 | 1.5 | 2 | 7.5 | |
meropenem | 1, 4 | - | ++ | - | %T > MIC > 60% [22] | 50–100 [23] | 0.1–10 | 0.3 | 1.5 | 7.5 | |
clavulanic acid | 1, 4 | - | ++ | - | - | 2.5–4 [24] | 1–10 | 1.5 | 2 | 7.5 | |
amikacin | 1, 4 | toxicity/efficacy | ++ | Cmin > 2 | Cmax/MIC > 75 | 35–45 | 1–10 | 3 | 5 | 7.5 | |
streptomycin | 2, 3 | - | + | - | fCmax/MIC > 20 [25] | 35–45 [25] | 1–10 | 3 | 5 | 7.5 | |
prothionamide | 1, 3 | - | ++ | - | AUC/MIC > 56.2 | 2–5 | 0.05–1 | 0.15 | 0.2 | 0.75 | |
PAS | 1, 5 | - | + | - | fCmin > 1 | 20–60 | 0.5–10 | 1.5 | 2 | 7.5 | |
Excluded | capreomycin | 3 | - | + | - | fCmax/MIC > 20 [25] | 35–45 [25] | 1–10 | 3 | 5 | 7.5 |
kanamycin | 5 | - | + | - | fCmax/MIC > 20 [25] | 35–45 [25] | 1–10 | 3 | 5 | 7.5 |
WHO Group | Analyte | Precursor [m/z] | → | Fragment [m/z] | Ion Mode | Cone Voltage [eV] | Collision Energy [eV] | Retention Time [min] Median (90% RT Range) | Channel Start [min] | Channel Stop [min] | Dwell [s] |
---|---|---|---|---|---|---|---|---|---|---|---|
First-line | rifampicin | 823.46 | → | 791.01 | [M + H]+ | 30 | 20 | 2.60 (2.43–2.89) | 1.75 | 4.5 | 0.05 |
D-rifampicin | 830.25 | → | 798.69 | [M + H]+ | 30 | 20 | 2.61 (2.44–2.89) | 1.75 | 4.5 | 0.05 | |
rifabutin | 847.02 | → | 815.52 | [M + H]+ | 40 | 35 | 2.91 (2.79–3.61) | 1.75 | 3.75 | 0.05 | |
D-rifabutin | 852.59 | → | 821.16 | [M + H]+ | 40 | 35 | 2.92 (2.79–3.62) | 1.75 | 3.75 | 0.05 | |
isoniazid | 137.68 | → | 78.50 | [M + H]+ | 25 | 25 | 2.81 (2.70–3.40) | 2 | 4.5 | 0.10 | |
D-isoniazid | 141.72 | → | 82.60 | [M + H]+ | 25 | 25 | 2.89 (2.78–3.47) | 2 | 4.5 | 0.10 | |
Group A | levofloxacin | 361.82 | → | 261.17 | [M + H]+ | 40 | 30 | 4.25 (4.08–4.51) | 2 | 5 | 0.05 |
D-levofloxacin | 366.04 | → | 261.04 | [M + H]+ | 40 | 30 | 4.25 (3.63–4.42) | 2 | 5 | 0.05 | |
moxifloxacin | 401.67 | → | 364.21 | [M + H]+ | 40 | 35 | 3.18 (2.77–4.20) | 2 | 4.8 | 0.05 | |
D-moxifloxacin | 407.30 | → | 369.08 | [M + H]+ | 40 | 35 | 3.20 (2.77–4.20) | 2 | 4.8 | 0.05 | |
bedaquiline | 555.14 | → | 58.16 | [M + H]+ | 30 | 35 | 2.52 (2.08–3.15) | 1.5 | 4 | 0.05 | |
D-bedaquiline | 561.13 | → | 64.13 | [M + H]+ | 30 | 35 | 2.52 (2.08–3.16) | 1.5 | 4 | 0.05 | |
linezolid | 337.17 | → | 195.20 | [M + H]+ | 40 | 25 | 1.06 (0.96–1.10) | 0.5 | 1.5 | 0.05 | |
D-linezolid | 345.10 | → | 203.20 | [M + H]+ | 40 | 25 | 1.07 (1.03–1.10) | 0.5 | 1.5 | 0.05 | |
Un-clssfd | pretomanid | 359.00 | → | 174.82 | [M + H]+ | 35 | 25 | 1.00 (0.95–1.05) | 0 | 2 | 0.05 |
Group B | clofazimine | 471.61 | → | 395.25 | [M + H]+ | 60 | 45 | 2.41 (2.02–2.88) | 1.5 | 4 | 0.05 |
D-clofazimine | 480.00 | → | 396.15 | [M + H]+ | 60 | 45 | 2.29 (2.02–2.87) | 1.5 | 4 | 0.05 | |
cycloserine | 102.88 | → | 75.03 | [M + H]+ | 25 | 10 | 4.99 (4.92–5.10) | 4.6 | 5.3 | 0.05 | |
D-cycloserine | 106.22 | → | 78.85 | [M + H]+ | 25 | 10 | 4.99 (4.92–5.10) | 4.6 | 5.3 | 0.05 | |
Group C | ethambutol | 204.78 | → | 44.29 | [M + H]+ | 20 | 25 | 5.48 (5.45–5.62) | 5.2 | 6 | 0.05 |
D-ethambutol | 208.78 | → | 48.29 | [M + H]+ | 20 | 25 | 5.50 (5.45–5.67) | 5.2 | 6 | 0.05 | |
delamanid | 534.37 | → | 352.07 | [M + H]+ | 35 | 25 | 1.87 (1.70–2.51) | 1.2 | 3.3 | 0.05 | |
D-delamanid | 538.30 | → | 356.07 | [M + H]+ | 35 | 25 | 1.95 (1.73–2.62) | 1.2 | 3.3 | 0.05 | |
pyrazinamide | 123.68 | → | 78.88 | [M + H]+ | 20 | 20 | 1.19 (1.16–1.21) | 0 | 2 | 0.05 | |
D-pyrazinamide | 127.21 | → | 82.85 | [M + H]+ | 20 | 20 | 1.19 (1.09–1.21) | 0 | 2 | 0.05 | |
meropenem | 383.95 | → | 68.04 | [M + H]+ | 25 | 30 | 4.58 (4.43–4.68) | 4 | 5 | 0.05 | |
D-meropenem | 389.96 | → | 68.06 | [M + H]+ | 25 | 30 | 4.59 (4.44–4.68) | 4 | 5 | 0.05 | |
clavulanic acid * | 198.00 | → | 136.00 | [M − H]− | 20 | 10 | 1.17 * | 0 | 4 | 0.10 | |
amikacin | 586.06 | → | 163.07 | [M + H]+ | 30 | 30 | 6.94 (6.62–7.29) | 6 | 8 | 0.50 | |
D-amikacin | 590.11 | → | 162.52 | [M + H]+ | 30 | 30 | 6.93 (6.60–7.28) | 6 | 8 | 0.50 | |
streptomycin | 582.03 | → | 263.10 | [M + H]+ | 65 | 35 | 6.12 (6.07–6.35) | 5.7 | 6.8 | 0.50 | |
prothionamide | 180.57 | → | 120.94 | [M + H]+ | 35 | 25 | 1.76 (1.65–2.25) | 1.2 | 3 | 0.05 | |
D-prothionamide | 187.58 | → | 127.38 | [M + H]+ | 35 | 25 | 1.79 (1.70–2.31) | 1.2 | 3 | 0.05 | |
PAS | 153.64 | → | 91.17 | [M + H]+ | 25 | 25 | 1.09 (0.98–1.21) | 0.7 | 1.4 | 0.05 | |
D-PAS | 159.94 | → | 96.09 | [M + H]+ | 25 | 25 | 1.07 (1.04–1.12) | 0.7 | 1.4 | 0.05 | |
Excluded | capreomycin IB § | 326.21 | → | 70.18 | [M + 2H]2+ | 25 | 20 | 7.60 (7.45–8.70) | 6.5 | 10 | 0.50 |
capreomycin IA § | 334.27 | → | 70.24 | [M + 2H]2+ | 25 | 20 | 7.79 (7.61–8.97) | 6.5 | 10 | 0.50 | |
kanamycin | 484.46 | → | 162.48 | [M + H]+ | 35 | 25 | 7.55 (7.46–8.27) | 5 | 9 | 0.50 | |
D-kanamycin | 490.63 | → | 162.52 | [M + H]+ | 35 | 25 | 7.31 (7.24–7.95) | 5 | 9 | 0.50 | |
gentamicin | 477.43 | → | 157.15 | [M + H]+ | 30 | 20 | 12.07 (10.21–13.81) | 9 | 22 | 0.50 |
WHO Group | Analyte | Calibration Range [µg/mL] | R2 | Carry-Over [% LLOQ] | Sample Sets nlow; nmed; nhigh | Recovery [%] (%CV) | Matrix Effect [%] (%CV) |
---|---|---|---|---|---|---|---|
First-line | rifampicin | 0.1–10 | 0.9935 | 1.3 | 1; 1; 1 | 102.6 (7.5) | 135.4 (13.1) |
rifabutin | 0.005–0.5 | 0.9952 | 2.4 | 2; 2; 2 | 96.9 (6.1) | 106.3 (6.4) | |
isoniazid | 0.05–5 | 0.9951 | 0.0 | 1; 1; 1 | 101.2 (6.7) | 101.3 (3.9) | |
Group A | levofloxacin | 0.025–2.5 | 0.9947 | 6.3 | 2; 2; 2 | 98.0 (4.2) | 98.2 (7.8) |
moxifloxacin | 0.01–1 | 0.9916 | 0.0 | 3; 3; 4 | 96.2 (7.6) | 107.3 (5.1) | |
bedaquiline | 0.01–1 | 0.9969 | 0.6 | 1; 1; 1 | 86.2 (5.5) | 96.6 (4.6) | |
linezolid | 0.05–5 | 0.9968 | 4.1 | 1; 1; 1 | 93.3 (6.0) | 96.9 (4.9) | |
Unclassified | pretomanid * | 0.015–1 | 0.9902 | 0.0 | 2; 2; 2 | 97.2 (13.4) | 106.7 (35.5) |
Group B | clofazimine | 0.005–0.5 | 0.9974 | 0.0 | 3; 3; 4 | 96.1 (7.7) | 102.1 (3.9) |
cycloserine | 0.1–10 | 0.9914 | 0.0 | 3; 3; 4 | 94.6 (10.3) | 116.2 (4.8) | |
Group C | ethambutol | 0.025–2.5 | 0.9919 | 8.4 | 1; 1; 1 | 91.8 (9.2) | 103.6 (6.6) |
delamanid | 0.005–0.5 | 0.9959 | 0.0 | 3; 3; 3 | 83.0 (9.8) | 101.1 (16.4) | |
pyrazinamide | 0.1–10 | 0.9953 | 19.0 | 1; 1; 1 | 105.6 (6.7) | 97.2 (3.3) | |
meropenem | 0.1–10 | 0.9916 | 6.7 | 1; 1; 1 | 76.1 (10.3) | 105.9 (6.1) | |
clavulanic acid | – | - | - | - | - | - | |
amikacin | 0.1–10 | 0.9835 | 0.0 | 1; 1; 1 | 47.8 (13.3) | 139.8 (11.3) | |
Streptomycin $ | 0.2–10 | 0.9913 | 0.0 | 1; 1; 1 | 56.3 (28.1) | 183.6 (35.8) | |
prothionamide | 0.01–1 | 0.9974 | 1.0 | 3; 3; 4 | 97.0 (7.8) | 98.9 (12.7) | |
PAS | 0.1–10 | 0.9957 | 1.2 | 2; 2; 2 | 95.8 (4.0) | 100.7 (7.3) | |
excluded | capreomycin IB $ | 0.2–10 | 0.9903 | 0.0 | 3; 3; 4 | 49.9 (24.1) | 231.7 (32.6) |
capreomycin IA $ | 0.1–10 | 0.9879 | 0.0 | 3; 3; 4 | 47.7 (23.6) | 206.5 (30.2) | |
kanamycin | 0.25–10 | 0.9910 | 16.7 | 2; 2; 2 | 63.9 (15.3) | 153.5 (12.2) |
WHO Group | Analyte | Sample Sets nlow; nmed; nhigh | Val. | Accuracy [%] (wthn−Day Prec. [%]; btw−Day prec. [%]) | 80 % Beta−Expectation Tolerance Interval [%] | Accuracy [%] (Precision [%CV]) | ||||
---|---|---|---|---|---|---|---|---|---|---|
QClow | QCmed | QChigh | QClow | QCmed | QChigh | Patient Samples | ||||
First−line | rifampicin | 2; 2; 2 | ext | 122.2 (1.9; 9.7) | 113.0 (3.4; 5.6) | 114.5 (2.4; 1.5) | −14.9; +59.4 | −10.6; +36.7 | +9.9; +19.2 | - |
rifabutin | 3; 3; 2 | int | 103.8 (2.1; 20.8) | 103.0 (3.5; 14.4) | 102.1 (3.3; 3.4) | −41.7; +49.3 | −29.0; +35.1 | −8.1; +12.3 | - | |
isoniazid | 2; 2; 2 | ext | 160.3 (2.2; 14.8) | 141.2 (1.0; 0.7) | 146.9 (4.6; 7.6) | +4.2; +116.4 | +39.1; +43.3 | +14.8; +78.9 | - | |
Group A | levofloxacin | 3; 3; 3 | ext | 95.7 (5.8; 17.8) | 97.1 (6.8; 14.4) | 105.0 (4.5; 13.4) | −44.7; +36.1 | −36.9; +31.1 | −25.5; +35.5 | - |
moxifloxacin | 5; 6; 6 | int | 113.8 (9.0; 12.9) | 106.7 (4.9; 20.6) | 114.9 (4.6; 11.0) | −10.0; +37.6 | −26.9; +40.3 | −3.5; +33.2 | 113.6 (7.5) | |
bedaquiline | 3; 3; 3 | ext | 97.2 (6.2; 24.4) | 94.3 (3.5; 3.9) | 102.0 (4.9; 10.1) | −57.2; +51.7 | −14.5; +3.1 | −21.9; +25.9 | 106.5 (11.2) | |
linezolid | 3; 3; 3 | ext | 110.5 (5.3; 12.9) | 108.3 (3.5; 12.9) | 106.3 (3.6; 14.2) | −19.3; +40.4 | −20.5; +37.1 | −25.5; +38.1 | 102.6 (8.4) | |
Unclassified | pretomanid * | 3; 3; 3 | int | 91.5 (20.0; 37.6) | 96.1 (19.3; 29.2) | 96.7 (13.3; 38.3) | −99.1; +82.1 | −67.9; +60.0 | −90.6; +84.1 | - |
Group B | clofazimine | 5; 6; 6 | int | 108.6 (8.2; 13.1) | 106.2 (3.5; 15.8) | 113.2 (3.4; 11.7) | −15.3; +32.5 | −19.6; +32.0 | −6.1; +32.5 | 90.1 (9.6) |
cycloserine | 4; 5; 5 | int | 103.3 (14.7; 11.9) | 97.7 (6.7; 17.3) | 95.9 (8.4; 17.6) | −24.2; +30.8 | −32.0; +27.4 | −35.2; +27.1 | 105.7 (11.7) | |
Group C | ethambutol | 2; 5; 5 | int | 115.6 (7.7; 8.8) | 123.4 (5.0; 8.1) | 114.1 (4.8; 10.3) | −9.7; +41.0 | +8.7; +38.2 | −4.0; +32.3 | - |
delamanid | 3; 4; 3 | int | 114.0 (5.0; 9.4) | 113.0 (4.4; 13.5) | 107.4 (6.1; 13.2) | −8.6; +36.6 | −12.8; +38.7 | −23.6; +38.4 | 113.6 (16.4) | |
pyrazinamide | 2; 2; 2 | ext | 116.1 (2.0; 9.5) | 108.1 (1.1; 4.1) | 113.6 (2.8; 2.2) | −20.5; +52.7 | −7.9; +24.0 | +7.0; +20.1 | − | |
meropenem | 2; 2; 2 | int | 101.5 (6.7; 1.7) | 95.4 (7.1; 4.7) | 101.1 (8.5; 0.0) | −8.6; +11.6 | −18.9; +9.8 | −11.1; +13.4 | 92.3 (10.8) | |
clavulanic acid | - | - | - | - | - | - | - | - | ||
amikacin | 1; 1; 1 | int | 93.5 (6.3; 6.3) § | −15.2; +2.2 § | - | |||||
streptomycin $ | 3; 4; 4 | int | 131.8 (19.0; 13.0) | 106.1 (16.3; 60.2) | 82.5 (23.6; 37.3) | −2.5; +66.1 | −107.5; +119.7 | −88.5; +53.5 | - | |
prothionamide | 3; 4; 3 | int | 113.6 (10.2; 6.1) | 111.1 (5.5; 11.5) | 111.2 (10.4; 6.2) | −3.7; +31.0 | −10.3; +32.5 | −6.5; +28.9 | - | |
PAS | 3; 3; 3 | int | 109.0 (2.5; 16.4) | 109.8 (1.9; 15.1) | 90.8 (2.5; 14.1) | −27.1; +45.2 | −23.3; +42.9 | −40.3; +21.9 | - | |
Excluded | capreomycin IB $ | 3; 4; 4 | int | 71.0 (13.5; 43.9) | 46.2 (12.7; 29.4) | 33.5 (19.5; 32.5) | −128.2; +70.2 | −111.8; +4.2 | −130.0; −3.0 | - |
capreomycin IA $ | 3; 4; 4 | int | 61.5 (12.6; 47.0) | 38.6 (12.4; 29.5) | 27.7 (20.0; 34.7) | −143.8; +66.8 | −119.4; −3.4 | −139.5; −5.0 | - | |
kanamycin | 3; 3; 3 | int | 103.7 (5.6; 6.8) | 114.7 (3.7; 10.4) | 95.8 (10.6; 30.0) | −11.2; +18.6 | −9.1; +38.5 | −72.8; +64.4 | - |
TDM Target | Patient 1 T1 | Patient 2 T3 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Drug | Parameter | Value | DST § | MIC § | Dose [mg] § | TDM1 | DST | MIC | Dose [mg] | TDM3 | |
Group A | levofloxacin | AUC/MIC | >146 | R | 4 | - | - | R | 7.5 | - | - |
moxifloxacin | fAUC/MIC | >53 | r | 2 | 1200 | 21.26 | r | 2 | 1600 | 18.49 | |
bedaquiline | AUC/MIC | >74.6 | S | 0.015 | 200 | 2703.33 | r | 2 | 300 | 54.03 | |
linezolid | fAUC/MIC | >125 | S | 0.25 | 600 | 273.53 | R | >1 | - | - | |
Unclassified | pretomanid | - | - | - | - | - | - | - | - | - | - |
Group B | clofazimine | Cmin; Cmax * [µg/mL] | 0.52; 0.79 | S | 0.12 | 100 | 0.25; 0.52 | r | 2 | 200 | 0.54; 0.68 |
cycloserine $ | % T > MIC [%] | >30 | - | 4 | 750 | 100 | - | 30 | 1000 | 80.67 | |
Group C | ethambutol | AUC/MIC | >119 | R | 10 | - | - | R | 7.5 | - | - |
delamanid | Cmin; Cmax * [µg/mL] | 0.17; 0.31 | R | >0.48 | - | - | S | <0.06 | 2 × 100 | 0.32; 0.58 | |
pyrazinamide | AUC/MIC | >8.42 | R | >100 | - | - | R | >100 | - | - | |
meropenem | % T > MIC [%] | >60 % | - | - | 3 × 2000/2 h | 62.3 (MIC:8) § | R | 16 | 3 × 2000/3 h | 46.30 | |
clavulanic acid | - | - | - | - | 3 × 125 | - | - | - | 3 × 125 | - | |
amikacin | Cmax/MIC | >75 | S | <0.25 | - | - | R | >1 | - | - | |
streptomycin | fCmax/MIC | >20 | S | - | - | - | R | - | - | - | |
prothionamide | AUC/MIC | >56.2 | R | 2 | - | - | R | >5 | - | - | |
PAS | Cmax * [µg/mL] | 300–500 | S | <4 | - | - | R | >16 | 11820 | 440.38 |
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Köhler, N.; Karaköse, H.; Grobbel, H.-P.; Hillemann, D.; Andres, S.; König, C.; Kalsdorf, B.; Brehm, T.T.; Böttcher, L.; Friesen, I.; et al. A Single-Run HPLC–MS Multiplex Assay for Therapeutic Drug Monitoring of Relevant First- and Second-Line Antibiotics in the Treatment of Drug-Resistant Tuberculosis. Pharmaceutics 2023, 15, 2543. https://doi.org/10.3390/pharmaceutics15112543
Köhler N, Karaköse H, Grobbel H-P, Hillemann D, Andres S, König C, Kalsdorf B, Brehm TT, Böttcher L, Friesen I, et al. A Single-Run HPLC–MS Multiplex Assay for Therapeutic Drug Monitoring of Relevant First- and Second-Line Antibiotics in the Treatment of Drug-Resistant Tuberculosis. Pharmaceutics. 2023; 15(11):2543. https://doi.org/10.3390/pharmaceutics15112543
Chicago/Turabian StyleKöhler, Niklas, Hande Karaköse, Hans-Peter Grobbel, Doris Hillemann, Sönke Andres, Christina König, Barbara Kalsdorf, Thomas Theo Brehm, Laura Böttcher, Inna Friesen, and et al. 2023. "A Single-Run HPLC–MS Multiplex Assay for Therapeutic Drug Monitoring of Relevant First- and Second-Line Antibiotics in the Treatment of Drug-Resistant Tuberculosis" Pharmaceutics 15, no. 11: 2543. https://doi.org/10.3390/pharmaceutics15112543
APA StyleKöhler, N., Karaköse, H., Grobbel, H.-P., Hillemann, D., Andres, S., König, C., Kalsdorf, B., Brehm, T. T., Böttcher, L., Friesen, I., Hoffmann, H., Strelec, D., Schaub, D., Peloquin, C. A., Schmiedel, S., Decosterd, L. A., Choong, E., Wicha, S. G., Aarnoutse, R. E., ... Sánchez Carballo, P. M. (2023). A Single-Run HPLC–MS Multiplex Assay for Therapeutic Drug Monitoring of Relevant First- and Second-Line Antibiotics in the Treatment of Drug-Resistant Tuberculosis. Pharmaceutics, 15(11), 2543. https://doi.org/10.3390/pharmaceutics15112543