A retrospective analysis to estimate trough concentrations of teicoplanin in patients with suspected or documented Gram-positive infections

Abstract Teicoplanin is a glycopeptide antibiotic commonly used to treat Gram-positive bacterial infections in the clinic. The aim of this study was to provide a therapeutic reference for the clinical application and dosage regimen adjustment of teicoplanin by identifying factors associated with its plasma trough concentration (Ctrough). A retrospective study was performed on patients with suspected or documented Gram-positive infections who were hospitalized from November 2017 to January 2020 and treated with teicoplanin while undergoing routine therapeutic drug monitoring (TDM). A total of 112 Ctrough trough measurements were obtained from 72 patients were included in this study. SPSS software was used for correlation analysis and receiver operator characteristic curve (ROC) analysis. The Ctrough for teicoplanin showed statistically significant relationships (P<0.05) with PLT, Scr, CLcr, eGFR, BUN and Cys-C. ROC curve analysis revealed that CLcr and eGFR were more sensitive and specific for Ctrough compared to the other factors. These findings should be considered in the clinical application of teicoplanin and for its dosage adjustment.


INTRODUCTION
Teicoplanin is a glycopeptide antibiotic developed after the discovery of vancomycin and is composed of structurally similar compounds (Marcone et al., 2018).It has similar antibacterial activity and mechanism of action to vancomycin, mainly by blocking the biosynthesis of cell walls.Teicoplanin is recommended for the treatment of infections caused by Gram-positive bacteria such as Staphylococcus epidermidis (MRSE), Streptococcus, Enterococcus and the majority of anerobic positive bacteria (Tascini et al., 2012;Sader et al., 2019).
Teicoplanin, cannot be absorbed orally and, is thus usually administered by intramuscular or intravenous injection.It binds strongly to plasma proteins and has a binding rate of approximately 90%.It also has good tissue permeability and is distributed mainly in the lung, myocardium and bone tissues, but has poor penetrateion into the cerebrospinal fluid (CSF).Teicoplanin has a long plasma half-life and its non-metabolic form is excreted mainly through the kidneys.Compared to vancomycin, teicoplanin needs a longer time period to achieve the steady-state concentration (Takechi et al., 2017;Electronic Medicines Compendium, 2017).
Glycopeptide antibiotics are time-dependent and have long post-antibiotic effects (PAE).The ratio of the area under the drug concentration-time curve (AUC) to the minimum inhibitory concentration (MIC) is refered Page 2/9 Braz.J. Pharm.Sci.2023;59: e21077 Luo Yi-Fan, Wang Yi-Dan, Ren Li-Xiang, Chu Yang to as the pharmacokinetic-pharmacodynamic (PK/PD) parameter, and is correlated with antibacterial efficacy and clinical outcomes (Craig, 2003;Ramos-Martín et al., 2017).The PK/PD parameter for teicoplanin is the AUC during 24 h (AUC 24 /MIC).Clinical targets for the treatment of general and severe infections are AUC 24 /MIC ≥125 and AUC 24 /MIC ≥345, respectively (Ahn et al., 2011;Matsumoto et al., 2016).For clinical treatment, the plasma trough concentrations (C trough ) for teicoplanin as measured by high-performance liquid chromatography (HPLC) is >10 mg/L for most Gram-positive bacterial infections and 15-30 mg/L for severe infections such as endocarditis or bloodstream infection.When measured by fluorescence polarization immunoassay (FPIA), the C trough is >15 mg/L for most infections, >20 mg/L for bone or prosthetic infections, and 30-40 mg/L for endocarditis (Roberts et al., 2012;Ueda et al., 2012;Kato et al., 2016;Electronic Medicines Compendium, 2017).
The aim of this study was therefore to evaluate the relationship between various physiological factors and the C trough for teicoplanin.

Patient enrollment
Patients, suspected or documented Gram-positive infections enrolled in this study were admitted to the First Hospital of China Medical University between November 2017 and January 2020.They received intravenous teicoplanin treatment and TDM was performed at least 24 h afterwards, with at least more than one C trough measurement obtained from each patient.
Exclusion criteria: were (1) patients who were younger than 18 years old; (2) patients undergoing renal replacement therapy; and (3) patients for which clinical data was unavailable.

Chromatography conditions
An Agilent 1100 HPLC system (Agilent Technologies, Japan) was adopted for sample analysis.An ODS Hypersil column (250 mm×4.6 mm, 5μm) was used for separation and the temperature was maintained at 40 ºC.The mobile phase consisted of 10 mM sodium dihydrogen phosphate buffer (pH=2.3):acetonitrile at 75:25 (v/v) with a flow rate of 1.2 ml/min.Ultraviolet measurements were carried out at 215 nm.The linear range of the calibration standard curve was 3.125-100 mg/L and the intra-and inter-coefficients of variation were all < 11.0%.This method was suitable for the clinical TDM of teicoplanin.

Sample preperation
Blood samples were collected into EDTA tubes just before the next teicoplanin administration.Plasma samples were obtained after centrifuging at 4,500 rpm for 10 min.Aliquots of 50 μl of internal standard (piperacillin sodium) and 400 μl of plasma were placed into a 2.0 ml microtube and 600 μl of acetonitrile was then added.After vortex-mixing for 30 s and centrifugation at 13,000 rpm for 5 min, 900 μl of the supernatant was placed into another microtube.Dichloromethane (400 μl) was then added, the mixture was vortexed for 30 s and then centrifuged at 13,000 rpm for 5 min again.The supernatant was carefully collected and a volume of 20 μl was injected for HPLC analysis.

Statistical analysis
Continuous variables were expressed as the mean±standard deviation (SD) or as the median and interquartile (IQR) range.The Spearman method was used for correlation analysis.A P value of <0.05 was considered to represent statistical significance.Regression analysis was performed to evaluate the relationship between C trough and defferent variables.

RESULTS AND DISCUSSION
The demographic and clinical data of patients in this study are shown in Table I  The heatmap shown in Figure 2 clearly displays the correlation matrix for the different variables.As listed in Table II, C trough had a significant positive correlation with S cr , BUN and Cys-C, but a negative correlation with PLT, CL cr and eGFR.Higher C trough was collected with higher values of S cr , BUN and Cys-C, but with lower values of PLT, eGFR and CL cr .Only CL cr and eGFR were significantly different between  In total, 112 Ctrough measurements were obtained.There were 46, 38 and 28 concentrations that were collected on days 2 to 4, days 5 to 10 and days >10 of therapy, the mean±SD of the C trough were 15.46±7.90,14.63±6.97and 15.94±4.66respectely (Figure 1).There was no statistical significance of C trough among different sampled days of therapy.0.705 [95% confidence interval (CI), 0.577-0.832],with cut-offs of 123.8 ml/min and 161.55 ml/min/1.73m 2 respectively.The AUC of all other factors were all less than < 0.50.
the two groups (P<0.05) as shown in Table III.ROC analysis curves (Figure 3) revealed that the area under the curve (AUC) of CL cr and eGFR for C trough were 0.678 [95% confidence interval (CI), 0.555-0.802]and This retrospective analysis was carried out on patients who were suspected or documented as having with Gram-positive infections and who received treatment with teicoplanin.Correlation analysis revealed that PLT, S cr , CL cr , eGFR, BUN and Cys-C were the main factors associated with teicoplanin C trough .Several previous studies have also analyzed factors that may influence teicoplanin C trough .Wang et al. (2015) reported that dosage (mg/kg) and CL cr were significant factors in their study.Pea et al. (2003) found that teicoplanin C trough was correlated with dose/kg on the second or third day of therapy, and with dose/kg, age and CL cr on the fourth day of therapy.
In their study, the mean C trough was 15.3 mg/L and the range was 4.9-36.3mg/L.In the present study, 28/112 (25%) of the teicoplanin C trough measurements were <10 mg/L.Moreover, all C trough values were > 10 mg/L when the loading dose was 800 mg, even 24 h after the first administration, while the time to reach target C trough was longer in patients with a 400 mg loading dose.The teicoplanin C trough is associated with efficacy and antibacterial response, hence trough levels of > 10 mg/L are required for general or severe infections.Higher loading doses and longer therapy durations are also needed.
The present results also showed that higher C trough was associated with lower PLT.Previous studies also reported that teicoplanin treatment might cause thrombocytopenia (Hsiao et al., 2012;Wang et al., 2013), and specifically immune thrombocytopenia.The proposed mechanism is that drug-dependent anti-platelet antibodies produced by the body which can recognize and react with the platelet membrane glycoprotein complexes IIb/IIa or Ib/IX/V (Kroll, Sun, Santoso, 2000;Garner et al., 2005).The adverse reactions of teicoplanin involving thrombocytopenia are reported as being low probability.However, routine blood tests are still recommended during teicoplanin treatment.
Teicoplanin has antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), Streptococcus and Enterococcus.Because some of the patients in this study were infected with two or more pathogenic organisms, combined antibacterial treatments with penicillin/cephalosporin+enzyme inhibitor, carbapenem or quinolone antibiotics were combined used.
Several studies on the comparative efficacy and safety of teicoplanin versus vancomycin have been conducted since the 1990s.Most showed that teicoplanin had similar efficacy, less adverse reactions and less serious adverse events compared to vancomycin.Some researchers have suggested that teicoplanin could be used as an alternative to vancomycin to treat infections caused by MRSA or other resistant gram-positive organisms (Wood, 1996;Wood, 2000;Svetitsky, Leibovici, Paul, 2009;Yoon et al., 2014).Both teicoplanin and vancomycin are mainly excreted through the kidney and hence their elimination half-life is prolonged in patients with renal failure (Li et al., 2017;Ponce et al., 2018).Considering that the maintenance dose of teicoplanin is onceper day and that it has a lower rate of dose-related nephrotoxicity, teicoplanin is likely to be superior to vancomycin for clinical antibacterial application (Svetitsky, Leibovici, Paul, 2009;Shime et al., 2018).
Several limitations of this study should be considered.First, this was a retrospective analysis conducted at a single center, with some missing data.Second, CL cr and eGFR were calculated using Cockroft -Gault formula and abbreviated MDRD formula, which may be inconsistent with the measured value.Third, comparisons of teicoplanin C trough between different gender and age groups were not performed due to the limited data, and will require investigation in lager patient cohorts.

CONCLUSIONS
Clinical TDM can help monitor teicoplanin concentrations in order to maintain effective concentrations and thus ensure clinical efficacy.The trough concentrations of teicoplanin were mainly related to markers of renal function, especially eGFR and CL cr , and were usually associated with lower PLT during therapy.These findings should be considered during the clinical application and dosage adjustment of teicoplanin.

FIGURE 1 -
FIGURE 1 -Trough concentration of teicoplanin of patients measured on days 2 to 4, days 5 to 10 and days >10 of therapy.

FIGURE 2 -
FIGURE 2 -Heatmap of the correlation matrix for variables.

FIGURE 3 -
FIGURE 3 -ROC plot of CL cr and eGFR (the diagonal is the indifference line).
Luo Yi-Fan, Wang Yi-Dan, Ren Li-Xiang, Chu YangPARTICIPATEThe present study was approved by the First Hospital of China Medical University(approval no.[2020]244; Shenyang, China).Page 9/9This is an open-access article distributed under the terms of the Creative Commons Attribution License.Wang JT, Wu HS, Weng CM, Hsu LY, Wang FD.Prognosis of patients with methicillin-resistant Staphylococcus aureus bloodstream infection treated with teicoplanin: a retrospective cohort study investigating effect of teicoplanin minimum inhibitory concentrations.BMC Infectious Diseases.2013;13:182.Wood MJ.The comparative efficacy and safety of teicoplanin and vancomycin.J Antimicrob Chemother.1996;37(2):209-22.Wood MJ.Comparative safety of teicoplanin and vancomycin.J Chemother.2000;12 (Suppl 5): 21-5.Yoon YK, Park DW, Sohn JW, Kim HY, Kim YS, Lee CS, et al.Multicenter prospective observational study of the comparative efficacy and safety of vancomycin versus teicoplanin in patients with health care-associated methicillin-resistant staphylococcus aureus bacteremia.Antimicrob Agents Chemother.2014;58(1):317-24.Received for publication on 11 th February 2021 Accepted for publication on 08 th June 2021

TABLE I -
Demographic and clinical data of patients

TABLE I -
Demographic and clinical data of patients

TABLE II -
Correlation analysis of the relationship of variables with C trough

TABLE III -
Characteristics of patients in groups a CL cr was calculated by Cockroft -Gault formula; b eGFR was calculated by abbreviated MDRD formula;PLT=platelet; S cr =serum creatinine concentration; CL cr =creatinine clearance; eGFR=estimated glomerular filtration rate; BUN=blood urea nitrogen; Cys-C=cystatin C; c n=23; d n=83 ; e n=77.