arpi.unipi.it€¦ · Web viewGiacomo Luci1,#,*, Federico Cucchiara1,#, Laura Ciofi2, Marianna...
Transcript of arpi.unipi.it€¦ · Web viewGiacomo Luci1,#,*, Federico Cucchiara1,#, Laura Ciofi2, Marianna...
A new validated HPLC-UV method for therapeutic monitoring of daptomycin in comparison
with reference Mass Spectrometry
Giacomo Luci1,#,*, Federico Cucchiara1,#, Laura Ciofi2, Marianna Lastella2, Romano Danesi1,2,
Antonello Di Paolo1,2
Affiliations
1, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126,
Pisa, Italy.
2, Unit of Clinical Pharmacology and Pharmacogenetics, University Hospital, Via Roma 55, 56126,
Pisa, Italy.
# = The two authors equally contributed to the paper
* = Corresponding Author:
Giacomo Luci
Department of Clinical and Experimental Medicine
University of Pisa
Via Roma 55, 56126, Pisa, Italy
Tel: +39 0502218755
E-mail: [email protected]
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Abstract
Daptomycin, a cyclic lipopeptide antibiotic with a broad spectrum of activity against Gram-positive
bacteria, is also active against multi-resistant bacterial strains, as well as methicillin-resistant S.
aureus, vancomycin-resistant enterococci or penicillin-resistant S. pneumoniae. For these reasons it
is a viable alternative for the treatment of persisting infections. However, the therapeutic drug
monitoring of daptomycin is recommended because the known variability in drug disposition and
the severe clinical conditions of patients. Therefore, we developed a simple and fast UV-HPLC
method according to FDA guidelines to monitor plasma concentrations of the drug. Briefly, after a
liquid-liquid extraction, plasma calibration samples, quality controls and patients’ samples were
injected in a HPLC instrument and peaks of daptomycin and gentamicin (internal standard) were
resolved by a C18 250 x 4.6 mm, 5 µm stationary phase and peaks were monitored at UV=262 nm.
Mobile phase (isocratic flow of 1 mL/min) consisted of acetonitrile-buffer (KH2PO4 20 mM
pH=3.2) 46:54, vol/vol. Under these conditions, IS and daptomycin peaked at 4.1 and 5.8 min after
injection. Values of limits of detection and quantitation accounted for 1.65 and 5.00 (g/ml),
respectively. Values of method linearity (r2) in range 5-100 mg/L were 0.9975 and 0.9956 plasma
samples and solvent standard, respectively. Inter- and intra-day variability coefficients were lower
than 15%. The comparison with a reference, commercially-available LC-MS/MS method on 122
patient plasma samples returned excellent correlation (r2=0.9474). In conclusion, the present
method demonstrated to be reliable and suitable for daptomycin TDM in clinical routine.
Keywords
Daptomycin; HPLC-UV; Plasma; Chromatography; Automatic integration; TDM
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Highlights
Daptomycin displays a non-negligible pharmacokinetic variability among patients
Therapeutic drug monitoring may reduce interpatient variability
A robust HPLC-UV method was developed and validated in comparison with a reference
LC-MS/MS method
The availability of such a method may improve daptomycin efficacy and tolerability
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1. Introduction
Daptomycin is one of cyclic lipopeptide antibiotics drugs, with broad spectrum against gram-
positive bacteria [1] that are responsible for severe and difficult-to-treat infections, characterized by
high mortality rate in hospital settings. [2]. For these reasons, the antibiotic has been increasingly
used to treat skin infections, [3], bacterial endocarditis [4], as well as infections caused by
methicillin-resistant S. aureus (MRSA) [5] and vancomycin-resistant enterococcus (VRE) [6].
Although the standard doses ranged from 4 to 6 mg/kg, in several cases physicians are prescribing
higher dosages up to 10 or 12 mg/kg [7]. Daptomycin is characterised by linear pharmacokinetics in
healthy volunteers, and with a plasma half-life of about 9 h, while drug excretion occurs mainly via
the kidneys as parent compound [8]. Only a small fraction of the drug (approximately 3%) is
excreted into the bile [5,9]. However, some factors may influence daptomycin pharmacokinetics
[10]. For example, the dose adjustment is required in patients with chronic kidney disease stages 4
and 5 (glomerular filtration rate, GFR <30 ml/min) [10]. Moreover, the renal replacement therapies
eliminates only a minimal part (about 15%) of drug, depending on the dialysis method applied and
the high plasma protein binding of about 92% [11].
In turn, these alterations can cause changes in plasma concentrations and, consequently, the
occurrence of adverse reactions, such as muscle toxicity with possible rhabdomyolysis, acute renal
failure [12], and hepatotoxicity [13] that could be exaggerated by other drugs [14]. Due to the
severity of these adverse reactions, the therapeutic monitoring (TDM) of drug plasma
concentrations is important to personalize the dosage. Indeed, it has been demonstrated that
daptomycin pharmacokinetics is variably changing according to the severity of the infection and
diseases, with significant changes over time [15] that justify the adoption of TDM protocols
[16,17].
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In recent years, the improving knowledge and technical possibilities have significantly increased the
development of chromatographic methods to identify and quantitate toxic substances, as well as
residues of xenobiotics in food and drugs [18–20]. In particular, new antibiotics as well as
daptomycin have become increasingly prescribed given their efficacy in the presence of resistant
bacteria and difficult-to-treat infections, despite their non-negligible risk of potentially severe toxic
effects. Therefore, the availability of a chromatographic method for therapeutic drug monitoring
(TDM) has been perceived as a need for physicians and laboratory staff. The literature reports
different methods based on mass spectrometry [21], UPLC-PDA [22] and UPLC-UV [23], which
are characterized by high costs and need high degrees of sample purification in order to solve
instrumental problems. In the present study, we describe the development and validation of a new
chromatographic method for the measurement of daptomycin plasma concentrations according to
for Industry FDA guidelines [24]. Moreover, an automatic detection and quantification of peaks
without user input was developed (patent pending). Finally, the validated method was compared
with a liquid-chromatography-mass spectrometry (LC-MS/MS) method that is commercially
available.
2. Materials
2.1 Chemicals
Acetonitrile (CH3CN), phosphoric acid 85% (H3PO4 85%), trichloroacetic acid (TCA), water and
methanol (CH3OH), all reagents of HPLC grade, were purchased from Merck (Merck, Darmstadt,
Germany). Potassium phosphate (KH2PO4), daptomycin and gentamicin sulfate (internal standard)
were purchased from Merck. The Mass spectrometry (LC-MS/MS) kit for the measurement of
antibiotic concentrations in plasma was purchased from Eureka-Lab Division (Eureka One, Ancona,
Italy) and considered as the reference method.
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2.2 Instrumentation
The HPLC-UV method was developed using a Waters 2695 Separations Module equipped with a
Waters 2487 Dual Absorbance Detector (Waters Corporation, Milford, CT) and controlled by the
Empower software version Pro (Waters Corporation). HPLC separation was accomplished on a
HAISIL HL C18 250 mm x 4.6 mm x 5 m (Higgins Analytical Inc., USA). Moreover, plasma
samples were assayed for daptomycin concentrations by the reference LC-MS/MS method using an
Acquity UPLC Binary Solvent Manager pump with Sample Manager autosampler equipped with a
Triple Quadrupole Detector (TQD, Waters Corporation). LC-MS/MS system was controlled by
MassLynx software (version V4.1, Waters Corporation, USA).
Finally, MATLAB R2016b with the bioinformatic toolbox (MathWorks Inc., USA) was used to
process data.
2.3 Methods
2.3.1 Calibration and quality control samples
A daptomycin stock solution was prepared by dissolving 10 mg of daptomycin in 10 ml of water
(final concentration, 1000 g/ml). Calibration and quality control samples were obtained by serial
dilution of drugs (from stock solution aliquots) in human plasma, obtained from healthy volunteers.
From this stock solution, 100 l was diluted with 900 l of blank human plasma (obtained from
healthy volunteers), obtaining a working solution of 100 g/ml. Serial dilutions for calibration
standards were made in blank plasma up to final concentrations of 5, 10, 25, 50, 100 g/ml. For
method validation and intra/inter-day variability the following concentrations were used 5, 50, 100
g/ml. Internal standard validation was performed on gentamycin spiked plasma samples.
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Daptomycin and gentamicin stock solutions (in water) were stored at -20 °C for maximum 7 days,
while spiked plasma was conserved at -20 °C for 3 consecutive days for intra- and inter-day
validation [23].
2.3.2 Sample preparation
To 200 l of quality control, calibration or patient samples, 20 l of gentamicin (IS) 100 g/ml
were added, then samples were vortexed for 30 sec. Samples were treated to remove proteins by
adding different chemicals (i.e., , CH3OH, etc.) and the final choice was based on percentage of
absolute recovery. Samples were vortexed for 30 sec and centrifuged at 7700 g for 15 min; the clear
supernatant was transferred into HPLC autosampler vials for HPLC-UV analysis. Sample
preparations for LC-MS/MS analysis were made according to Eureka® KIT protocol.
2.3.3 HPLC-UV and LC-MS/MS conditions and detection
The HPLC mobile phase consisted of organic solvent (i.e., CH3CN and/or MeOH) plus buffer
KH2PO4 20 mM pH=3.2. The choice of final pH was dependent on the chemical structure of
daptomycin and gentamycin in order to optimize the interaction of analytes with stationary phase.
Moreover, in order to expedite the chromatographic runs, an isocratic elution of the mobile phase
was chosen with chromatographic column maintained at controlled temperature (35 °C). Finally,
because of the chromatographic column size (250 mm x 4.6, 5 µm), the volume of injection was
fixed at 50 l.
Samples analysis by LC-MS/MS was made according to Eureka® Kit procedure and parameters
setting [25].
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2.3.4 Validation studies
The method validation was made according to FDA guidelines through the evaluating of precision
and accuracy. In particular, a limit for intra-day precision was defined as 2(1-0.5logConc)2/3, while a
limit for inter-day precision was calculated as 2(1-0.5logConc). Accuracy was the percentage of results
not deviating more than 15% of nominal concentrations and 20% at LOQ. Quality control
samples were analysed in triplicate at each of the three concentration levels. Samples were
quantified in a single batch, considering mean concentration, standard deviation and percentage
coefficient of variation. Inter-day precision and accuracy were calculated with the same parameters
and quality controls, in triplicate at three different concentrations for three consecutive days. To
evaluate specificity, blank samples of human plasma were analyzed to check for the presence of
interfering peaks at the elution time points of daptomycin and gentamicin. Potential interferences
caused by endogenous and chemically-related compounds, were studied to evaluate the selectivity
of the method and for internal standard. The signal-to-noise ratio of a possible interfering peak in a
blank plasma sample should be below the signal-to-noise ratio of daptomycin and gentamicin in the
same elution sector at the limit of detection (LOD) level. The LOD was evaluated as a signal-to-
noise ratio ≥ 3 while limit of quantification (LOQ) was calculated as 3.04LOD.
The last step of method validation did concern every possible interference by drugs co-administered
with daptomycin. To do this, drugs other than daptomycin were selected on the basis of
concomitant therapies prescribed in patients.
2.3.5 Application of the method and comparison
From November 2018 to February 2019, blood samples from hospital units (i.e., infectious diseases,
cardiovascular diseases, orthopaedics, general medicine and neurosurgery) were dispatched to TDM
laboratory of the Clinical Pharmacology Unit for daptomycin monitoring. Samples were rapidly
processed to measure plasma drug concentration by the commercially-available LC-MS/MS method
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(Eureka One, Ancona, Italy) on the Waters TQD instrument (Waters, Milford, CT). After the
completion of laboratory activities, aliquots of plasma samples (1 mL) were stored at -80 °C for
further processing by using the developed method. The collection and analysis of samples were part
of the DAPTOLIN protocol [protocol number 55945, Pisa University Hospital Ethics Committee],
but none of patients’ information nor clinical data were registered or used for the present work. Raw
results were then analysed by a custom-made MATLAB method® – patent pending (MatLab®, The
Math Works Inc, USA) in order to obtain retention times and area values of analytes peaks. The
linear correlation of peak area values obtained by the developed HPLC-UV method and the LC-
MS/MS kit was investigated.
2.3.6 Statistical calculations
Statistical calculations were performed with Graph Pad Prism version 5.0a (Graph Pad Software®,
USA). Correlation analysis were done between daptomycin concentrations of HPLC-UV data and
LC-MS/MS reference method, that was performed to evaluate the significance of equivalence.
Level of significance was set at p < 0.05.
3. Results
3.1 Sample extraction and HPLC-UV analysis
The sample preparation procedure was chosen after various tests, with same volumetric ratios,
vortexing and centrifugation times. The following solvents were tested for preanalytical preparation
of plasma samples: CH3CN - H3PO4 85% (95:5 v/v), CH3CN, water - TCA (90:10 v/v) and CH3OH.
For every experimental condition, 10 human plasma samples from healthy volunteers were spiked
with daptomycin and gentamicin then they were analysed. Protein precipitation was obtained by
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adding 200 L of each solvent/mixture to 200 L of spiked human plasma. Table 1 reports the
average percentage recovery of plasma samples extracted in different conditions. The highest
recovery of daptomycin and gentamicin was obtained with CH3CN - H3PO4 85% (95:5 v/v).
Table 2 and Figure 1 report retention times of analytes with different mobile phases made by
CH3CN and phosphate buffer KH2PO4 20 mM, pumped with a flow of 1 mL/min in isocratic mode.
The best separation of peaks with a short chromatographic run (i.e., ≤10 min) was obtained with a
mobile phase consisting of CH3CN-phosphate buffer KH2PO4 20 mM pH=3.2 46:54, vol/vol.
Furthermore, temperature of column oven and UV wavelength were set at 35 °C and 262 nm,
respectively. With these chromatographic conditions, the run time was 10 min while daptomycin
and gentamycin have a retention time of 4.1 and 5.8 minutes, respectively. Representative sample
chromatograms with analytes extracted from a human plasma sample are shown in Figure 2.
Noteworthy, average recovery from plasma samples was > 95% for both daptomycin and
gentamicin.
3.2 Validation studies
Validation parameters are reported in Tables 3 and 4, and they completely fulfilled the requirements
of the FDA 2018 analytical parameters guideline [24]. The method was proven to be linear in the
full range of 5-100 mg/L in both plasma samples (r2 > 0.9975) and solvent standards (r2 > 0.9956).
The intra- and inter-day variability values were <12% and < 15%, respectively, at three different
concentrations. The LOQ and LOD values of the method were 5.00 and 1.65 mg/L, respectively.
The results of the selectivity study showed no interferences between endogenous compounds and
the analysed compounds (daptomycin and gentamicin). The average internal standard response in
samples was +3.45% compared to average internal standard response of calibrators. The analysis of
more than 30 different drugs (Table 5) suggested only one probably interference between
daptomycin peak (RT = 4.1 min.) and piperacillin.
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Accuracy and precision values were within acceptable range of variability with respect nominal
concentrations at 5-50-100 mg/L (15%) and LOQ (20%) as per FDA guidelines (Tables 3 and
4).
Finally, the LOD value and calibration range were acceptable on the basis of TDM routine and
therapeutic range. Indeed, the efficacy of daptomycin is associated with maximal plasma
concentrations (Cmax) higher than 60 mg/L, while the risk of drug-associated toxicities increases
when minimum plasma concentrations (Cmin) are higher than 24 mg/L. In particular, only 5 pre-dose
samples had daptomycin concentrations lower than 5.00 mg/L, whereas drug concentrations higher
than 100 mg/L were measured in 2 samples (i.e., 103 and 109 mg/L). Interestingly, the
corresponding Cmin values were 30.8 and 34.5 mg/L.
3.3 Comparison between HPLC-UV and LC-MS/MS analyses on plasma samples and
possible interfering drugs
In order to establish the reliability of the developed HPLC-UV method, the latter was compared
with a LC-MS/MS reference method by measuring daptomycin concentrations in 122 human
plasma samples using both methods. When HPLC-UV results were plotted against those obtained
with mass spectrometry, the correlation analysis returned values of highly statistical significance,
with a r2 value of 0.9474, a slope of 1.052 and a y-intercept of 0.8543 ± 0.9368 mg/L (Figure 3).
Moreover, the Mann-Whitney test and unpaired t test with Welch’s correction returned not
significant differences between results obtained by the two techniques (p values, 1.000 and 0.9927,
respectively).
4. Discussion
The presented manuscript describes the development and the validation of an HPLC-UV method for
the determination of daptomycin in human plasma. The method was then applied to measure
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daptomycin concentration in 122 plasma samples from patients treated with the drug. The findings
showed that the method is precise and reproducible, being able to quantitate plasma concentrations
of daptomycin within the minimum-maximum range of values that are expected after the
administration of the drug at the prescribed doses (4-6 mg/kg/day i.v.). Furthermore, to our
knowledge this is the first HPLC-UV method for daptomycin that has been compared with a LC-
MS/MS reference method. For these reasons, the method is currently used to monitor all plasma
samples dispatched to our Clinical Pharmacology Unit.
The need for therapeutic monitoring of daptomycin is based on the severity of infections that
require the drug and on the interindividual variability observed in pharmacokinetics across several
physio-pathological conditions [26] , as well as the influence of renal function [27]. Therefore, the
optimization of drug dosage within the first days is a fundamental prerequisite to improve cure rate
[27], to diminish the risk of severe toxicities [12,13] and to shorten the stay in intensive care or
infectious disease units. Our method allows the measurement of daptomycin concentration in
plasma samples adopting a liquid-liquid extraction procedure, which is advantageous for the highest
recovery achieved and reduced time needed to sample preparation. The latter characteristic, together
with a 10-min chromatographic run, does ensure the analysis of at least 5 samples per hour. The
sample rate is lower than that of LC-MS/MS methods, however the HPLC-UV platform is simpler
from a technical point of view and less expensive than the mass spectrometry. In terms of
sensitivity, our method has a LOQ of 5.00 mg/L, which is well above the LOQ of a corresponding
LC-MS/MS method. However, TDM of daptomycin is based on two pharmacokinetic endpoints,
significantly associated with efficacy and tolerability. In particular, Cmax values should be higher
than 60 mg/L to achieve a Cmax/MIC (Minimal Inhibitory Concentration) ratio of at least 100 based
on the clinical breakpoint values for daptomycin in sensitive species [28] to reduce the selection of
resistant clones [29]. In our series of patients’ samples, we observed only 2 concentrations higher
than 100 mg/L. Moreover, Cmin values should be lower than 24.3 mg/L to reduce the risk of adverse
drug reactions, especially skeletal muscle toxicity [26,30]. Interestingly, the two samples with the
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highest drug concentrations were correlated with Cmin values higher than 24.3 mg/L, hence
suggesting that TDM of both peak and through samples is appropriate to identify patients at risk of
severe toxicities. Based on these assumptions and observation, the measurement of daptomycin
concentrations lower than the LOQ in 6 samples was not considered an issue for the validation of
the present HPLC-UV method. Therefore, the linearity of the present method in the range 5.00-100
mg/L well encompasses the full window of plasma concentrations measured in patients who
received daptomycin at doses of 4-6 mg/kg/day i.v. or higher [27], while the accuracy and precision
further strengthen the reliability of the present method.
In conclusion, we developed a reliable and rapid HPLC-UV method for the measurement of
daptomycin concentrations in plasma samples using an internal standard for better accuracy and
precision over the range of drug concentrations expected after the administration of daptomycin at
standard doses. Moreover, the simple preanalytical preparation of samples and the reduced costs of
HPLC platform certainly ensure a wide diffusion of the present method.
Conflict of Interest
The authors haven’t conflict of interest.
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References
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Legends of Figures
Figure 1. Analytes retention time. Changes in retention time of analytes (daptomycin and
gentamicin) at different percentages of acetonitrile and phosphate buffer (KH2PO4 20 mM). The pH
of the mobile phase (MP) was 3.2 and it was pumped within the HPLC system at flow of 1 mL/min.
The temperature of column oven was set at 35 °C.
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Figure 2. Chromatograms. Sample chromatograms obtained from extracted plasma samples. A,
blank plasma sample, without interfering peaks detected at retention times of daptomycin (RT=4.1
min) and gentamicin (RT=5.8 min). B and C, chromatograms from plasma samples spiked with
gentamicin and daptomycin together with gentamicin, respectively.
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Figure 3. Methods linear correlation. Linear correlation of daptomycin concentration values
obtained with HPLC-UV and LC-MS/MS methods in 122 plasma samples. The linear correlation
analysis returned a r2 value of 0.9474 (p < 0.0001)
Table 1. Tests with different solvents for plasma proteins precipitation. Summary of percentage
recovery of 10 human plasma samples spiked with daptomycin and gentamycin and extracted with
different solvents.
SolventsPercentage recovery(mean SD, n = 10)
CH3CN - H3PO4 85% (95:5 v/v) 98.2 4.57
CH3CN 85.1 5.47
CH3OH 70.6 3.67
TCA 10 % 45.9 4.65
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Abbreviations: TCA, trichloroacetic acid
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Table 2. Tests with different mobile phases to obtain non-overlapping peaks of daptomycin and
gentamicin. The pH of mobile phase was 3.2 and the chromatographic run was 10 minutes
Mobile phase (% v/v)KH2PO4, 20mM – CH3CN
Optimal separation of analytes
60 - 40 No
55 - 45 No
54 - 46 Yes
50 - 50 No
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Table 3. Inter-day validation parameters. The inter-day parameters were calculated on 3
consecutive days and 6 set of samples per day. Measured concentrations are meanSD values
Concentration (mg/L)Accuracy
(%)Precision
(%)CV(%)DAY Theoretical Measured
1
5 4.77 ± 0.70 4.64 0.88 14.61
50 49.32 ± 2.26 2.20 0.20 0.00
100 98.29 ± 2.78 1.71 0.05 2.83
2
5 4.77 ± 0.69 4.58 0.88 14.39
50 48.80 ± 2.26 2.40 0.21 4.64
100 97.76 ± 3.99 2.24 0.01 4.08
3
5 4.62 ± 0.46 1.41 0.87 0.00
50 50.41 ± 3.34 -0.81 0.20 6.62
100 99.75 ± 0.76 0.25 0.001 0.77
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Table 4. Intra-day validation parameters. The intra-day parameters were calculated on 6 set of
samples per day. Measured concentrations are meanSD values. The table also reports the limits
of detection (LOD), quantitation (LOD) and r 2 of linear regression analysis for daptomycin spiked in
blank human plasma samples.
Concentration (mg/L)Accuracy
(%)Precision
(%)CV(%)
LOD (mg/L)
LOQ (mg/L)
r2
Theoretical Measured
5 4.77 ± 0.83 3.19 1.32 11.65
1.65 5.00
0.9975
±
0.0009
50 49.74 ± 2.39 0.53 0.30 4.80
100 98.60 ± 2.86 1.40 0.01 2.90
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Table 5. Drugs that do not interfere with the identification and quantitation of daptomycin and
gentamicin peaks in chromatograms. Piperacillin/tazobactam may be able to alter
chromatographic peaks.
Drugs not interfering with the identification and quantitation of daptomycin and gentamycin peaksA - Acamprosate, Acetil salicylic acid, Aldactone, Allopurinol, Alprazolam, Amiodarone
B - Bisoprolol, Bromazepam
C - Canrenoate potassium, Canrenone, Carvedilol, Clindamycin, Clopidogrel, Carbidopa,
Codeine, Colchicine
D-F - Delorazepam, Diazepam, Enoxaparin sodium, Entecapone, Fluconazole, Furosemide
I - Isosorbide mononitrate
L-O - Lansoprazole, Levodopa, Levothyroxine, Linezolid, Lorazepam, Omeprazole, Oxacillin,
Oxycodone
P-R - Pantoprazole, Prednisone, Ramipril, Rifampicin
S-T-W - Sertraline, Sulfamethoxazole, Tamsulosin, Tazobactam, Teicoplanin, Tigecycline,
Triazolam, Trimetoprim, Warfarin
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