Abstract
Background. To explore the use of teicoplanin among Chinese patients with Gram-positive infections in a tertiary hospital. Methods. The medical records of patients, who were monitored for teicoplanin plasma concentration (TPC) from December 2017 to February 2019, were collected. By combining the therapeutic drug monitoring (TDM) and nonlinear mixed-effects model, a population pharmacokinetic (PPK) model of teicoplanin was established. Results. The proportions of TPCs lower and higher than 10 mg/L were nearly the same (102 vs. 108 cases). A two-compartment model of teicoplanin PPK in Chinese patients was established. Compared with 400 mg, the 600 mg regimen was more able to reach the target concentration (10 mg/L), especially for high-weight patients. Conclusions. The standard regimen of teicoplanin, 400 mg, failed to reach the target value in the present population. Moreover, the 600 mg regimen was feasible for high-weight patients based on TDM and individualized pharmacokinetic dosing adjustment.
1. Background
Entering the 21st Century, multidrug-resistant Gram-negative bacteria are becoming an increasingly global threat, while methicillin-resistant Staphylococcus aureus (MRSA) remains one of the most persistent drug-resistant bacteria in hospital and community environments. It is urgently necessary to eliminate MRSA infections in the community environment [1]. Compared with vancomycin, teicoplanin has received more widespread clinical attention due to its lower nephrotoxicity and longer half-life [2]. Teicoplanin, a glycopeptide antibiotic, has antibacterial activity against aerobic or anaerobic gram-positive bacteria, especially for methicillin-sensitive Staphylococcus aureus (MSSA) and MRSA, with rare drug resistance. Teicoplanin is not absorbed orally. Intravenous or intramuscular administration is generally used in clinical, with 94% bioavailability. The binding rate of serum albumin (ALB) in teicoplanin reaches 90%. Teicoplanin is mainly eliminated by the kidneys, with a half-life of nearly 170 h [3].
In September 2017, the drug instruction of teicoplanin for injection (manufacturer: Sanofi S.p. A) has been updated by adding indications, increasing dosage appropriately, and redefining the standard of plasma concentration. Administrating different regimens, teicoplanin concentrations are expected to be of great variation [4], leading to the difference in clinical response and adverse drug reactions (ADRs) [5]. Though its characteristics of pharmacokinetic parameters have been studied, the process of teicoplanin in vivo varies a lot due to the differences among individuals. Individualized treatment of teicoplanin is of the utmost importance to achieve sufficient drug concentrations and maximize the therapeutic effect. In such a situation, we aimed to obtain evidence of clinical effectiveness and safety for the use of teicoplanin in our hospital and assess the effects of different factors on plasma concentrations, such as dosage, weight, and other biochemical test indicators.
2. Methods
The medical records of inpatients, who used teicoplanin for injection in our hospital and whose teicoplanin plasma concentration (TPC) was monitored by high-performance liquid chromatography (HPLC) at least once from December 2017 to February 2019, were collected, including basic information, diagnosis, and testing, medication, plasma concentration, and so on. Those patients, whose therapeutic drug monitoring (TDM) was twice or more, were used to establish a population pharmacokinetic (PPK) model of teicoplanin. Patients who had TDM once were also included to provide further pharmacokinetic information.
2.1. Ethics Approval
This study was approved by the Medical Ethics Committee of Chinese PLA General Hospital (No. S2018-179-01). The Medical Ethics Committee waived the need for informed consent as no private health information was collected.
2.2. HPLC Determining TPC
Each patient using teicoplanin extracted 3-4 ml of venous blood in an anticoagulant tube, which was sent for testing. The trough concentration was generally recommended to be sampled at 24 h after the first dose or 30 min before the sixth dose. The blood sample was centrifuged at 4000 r/min for 10 min to obtain plasma. A Waters Symmetry C18 column (4.6 mm × 250 mm, 5 μm) was used as an analytical column, at 35°C. The mobile phase used for chromatography was composed of 0.01 mol/L NaH2PO4 (pH 3.3) and acetonitrile (74 : 26 v/v) using a flow rate of 1.0 ml/min. 20 μl samples were injected into an Agilent 1260 series chromatographic system. The analytes were detected using a UV detector with a wavelength set at 215 nm. The linearity was established between 3.125 and 100.000 mg/L. The precision and accuracy were reported to meet biological testing standards.
2.3. Inclusion and Exclusion Criteria
The age of patients was above 18 years old. Patients were suspected or confirmed Gram-positive bacterial infections. The medical records of patients were sufficient to evaluate the effectiveness and safety. If the same patient was treated with teicoplanin twice or more and the interval between two treatments exceeded 7 days, the medical information could be recorded and reincluded. Patients who were not administered intravenously were excluded. Patients who were allergic to teicoplanin or excipients were excluded. Pregnant or lactating women were also excluded. Samples with a monitoring time before the 3rd dose were excluded in the establishment of the PPK model.
2.4. Data Extraction
By consulting Hospitalized Information System (HIS) in our hospital, the following basic information of patients taking teicoplanin was extracted retrospectively: characteristics of patients (gender, age, height, and weight), department, length of stay; clinical diagnosis, outcomes, type of infection, blood routine, blood biochemistry, etiological examination; usage of teicoplanin, medication duration, combined medication, TPC, and other available medical records. The evaluation was carried out in terms of drug application, medication dosage, therapeutic effect, and ADRs.
2.5. Definitions and Outcomes
According to drug instructions, the standard regimen of teicoplanin is a loading dose of 400 mg every 12 h (q12 h), followed by a maintenance dose of 400 mg once a day (QD). The regimen here was a sequential treatment of maintained or gradually reduced dose or frequency. To investigate the compliance status, the teicoplanin trough concentration of the therapeutic drug recommended in the instructions is 10 mg/L, which is determined by the HPLC approach.
The treatment effectiveness included clinical response and microbiological response. The clinical response was defined as the resolution of clinical signs and symptoms of the infections or infection indicators returning to normal by therapy completion [6]. The microbiological response was defined as the eradication of pathogens from subsequent specimen cultures [7]. The outcome of “cured” referred to clinical success and complete microbiological response. The outcome of “improvement” referred to clinical improvement and/or microbiological response. The outcome of “failure” referred to worsening or no improvement of clinical features and microbiological cultures after medication administration, with no deaths.
Safety outcomes evaluated included nephrotoxicity and hepatotoxicity, as well as hypersensitivity and neutropenia reactions at the end of teicoplanin therapy. The decrease in renal function was evaluated by a 50% increase in serum creatinine (Scr) from the baseline [8]. Abnormal liver function was evaluated by the level of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at or above three times the upper limit of normal. If the baseline of ALT or AST was abnormal, hepatotoxicity was defined as ALT or AST at or above three times the baseline [9].
2.6. PPK Model Establishment
Combined with the steady-state data of TDM, the PPK model was established using a nonlinear mixed-effects model (NONMEM7.4). The initial model was a single-compartment or two-compartment model evaluated by objective function value (OFV). Interindividual and intraindividual variations were introduced into the initial structure model to construct a random-effects model. Off-diagonals were tested for potential correlation. In the basic model above-mentioned, gender, age, height, weight, and biochemical test indicators, such as ALT, AST, ALB, Scr, urea, total bilirubin (TBil), direct bilirubin (DBil), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT) were analyzed as covariates one by one. The final regression model was established through forward inclusion and backward elimination which were evaluated by value. By drawing the diagnostic curve of plot distribution, the goodness of fit plots of the final model was investigated [10]. The robustness and accuracy of the final model were tested by nonparametric bootstrap. Based on the final model, after the patients were administered with different doses of teicoplanin, the in-vivo process was simulated to predict the variation of TPC.
2.7. Statistical Analysis
The data were analyzed by Microsoft Excel 2016 and IBM SPSS Statistics 26.0. Measurement data were statistically described by ± s and compared by t-test between groups. Counting data were expressed by case number and percentage (%), while comparisons between groups were performed using the χ2 test. Odds ratios (ORs) were calculated as effect measures, including a 95% confidence interval (CI) [11]. was considered statistically significant.
3. Results
3.1. Basic Characteristics of Patients
A total of 212 patients and 341 samples were included in the test of TPC. Table 1 shows the basic characteristics of patients. For 341 plasma samples, the TPCs ranged from <3.125 mg/L to 127.34 mg/L. 186 samples (54.55%) were below 10 mg/L and 155 samples (45.45%) reached 10 mg/L. Figure 1 illustrates the distribution of TPC values.
3.2. Diagnosis of Infection and Outcomes
Among 212 patients, 153 patients (72.17%) had at least one definite diagnosis of infection (Tuberculosis was excluded). The rest were administered with teicoplanin empirically. The diagnosis of infection types was classified as shown in Table 2. Moreover, 52 patients (24.53%) were cured of the infection. The largest proportion of outcomes was patients with improved outcomes (129 cases, 60.85%). Patients of treatment failure and decease were eight (3.77%) and 23 (10.85%), respectively.
3.3. Medication Usage of Teicoplanin
The initial regimen of teicoplanin included four doses, 200 mg, 400 mg, 600 mg, and 800 mg. There were four medication frequencies, including q12 h, QD, every other day (qod), and once every 3 days (q3d). Among 212 patients, 87 patients (41.04%) were monitored for TPCs at least twice. Two patients were not monitored for TPC before the dose or frequency was increased. Besides, the other 210 patients were included to observe the compliance status of the recommended therapeutic concentration. Table 1 of Supplemental Materials lists the detailed medication regimens in 212 patients and TPCs in 210 patients. The two excluded patients were shown in red in the table.
As the regimens in Table 1 of Supplemental Materials contained sequential usages of maintained or gradually reduced dose or frequency, the increasing dose or frequency was excluded. Moreover, 15 patients were administered with the increasing dose or frequency after the sequential usages were maintained or gradually reduced. Table 2 of Supplemental Materials shows the changed dose or frequency of teicoplanin. Only five out of seven patients, whose TDM were before and after the increasing dose, reached the target concentration, and they were shown in red in the table.
Among 212 patients, 208 patients (98.11%) also received other antibiotics, and 150 patients (70.75%) received two or more antibiotics. The combined antibiotics mainly included carbapenems, β-lactams/β-lactamase inhibitors, and azole antifungals. Figure 2 shows the top 10 combined antibiotics.
3.4. TDM and Outcomes
Among 210 patients, the TPCs of 108 patients (51.43%) reached 10 mg/L, while 29 patients (13.81%) reached 20 mg/L. χ2 test showed that outcomes were not significantly influenced by TPCs (χ2 = 4.48, ). Table 3 shows different outcomes, cured cases, improvement, failure, deceased cases, and corresponding TPCs.
3.5. ADRs
ADRs were evaluated in all 212 patients. Scr levels of nine patients (4.25%) were found to increase lower than 50%, while the increased Scr levels were still in the range of normal. No impaired renal functions were found. ALT or AST levels of eight patients (3.77%) increased to above the upper limit of normal. They returned to normal at the end of teicoplanin therapy. These patients were all administered with other antibiotics. Other ADRs, such as rash and neutropenia, were not found.
3.6. PPK Model of Teicoplanin
A total of 87 patients were monitored for TPC twice or more. The TPCs of 87 patients and 213 samples were used to establish a PPK model. Among these 87 patients, there were 69 males and 18 females. Table 4 shows the basic characteristics of patients. In these patients, the regimens of teicoplanin, including dose and frequency, were shown in Table 3 of Supplemental Materials. For 213 plasma samples, the TPCs ranged from <3.125 mg/L to 87.93 mg/L. 122 samples (57.28%) were below 10 mg/L and 91 samples (42.72%) reached 10 mg/L. Figure 3 illustrates the characteristic curve between TPC and monitoring time.
(a)
(b)
The OFV of the single-compartment model for teicoplanin was 901.158, and that of the two-compartment model was 865.112. Figures 4 and 5 illustrate the evaluation plots of the single-compartment model and two-compartment model, respectively. The two-compartment model was selected as the basic model of teicoplanin due to its lower value of OFV and better effect of fit. The covariate parameters were gradually introduced to the screen. The weight, ranging from 38 to 115 kg, could affect the clearance rate (CL) significantly. Figure 6 shows the correction plots of CL residual error. In the equation of the covariate model, CLi and Weighti were the values of Group i made up of every individual, 3.97 was the correction factor of weight to parameter CL, and 0.239 (unit: L/h) was the typical value of CL.
Figure 7 shows the goodness of fit plots of the final teicoplanin model. After the covariate model was added, the OFV of the final teicoplanin model became 847.357. The data points were evenly distributed, and no obvious deviation in the diagnostic curve was found. In 1000 times of verification, 743 times were successful. Table 5 shows the model parameters and verified results of the final model, indicating that the final model had good accuracy and stability.
A standard loading dose regimen and a high loading dose regimen were simulated by the final teicoplanin model as follows: 400 and 600 mg q12 h for 72 h, followed by the same dose administered once daily for 4 weeks. Patients were simulated with the covariate of weight ranging from 38 to 115 kg. 40, 50, 65, 80, 105, and 115 kg were selected to compare the concentration-time curves (Figures 8 and 9). For patients with a weight above 105 kg, when administered with 400 mg, it was difficult to reach the target of recommended TPC, while patients administered with 600 mg could mostly reach the target.
4. Discussion
The medication instructions for teicoplanin for injection have been updated in 2017. Besides adding indications and increasing dosage, the target trough plasma concentration of 10 mg/L was extended from patients with severe infections to common infections. The latest guideline for the clinical practice of teicoplanin made by the Japanese Society recommends 15–30 mg/L as the target concentration for the treatment of common MRSA infections in patients [12]. However, the instructions for teicoplanin in Chinese have not added the standard of plasma concentration. A British study [13] lasting 13 years has analyzed the TPC of 1,007 blood samples from 121 hospitals. The plasma concentrations of 13% of samples are lower than 10 mg/L and 35% of samples are within the range of 10–20 mg/L. Furthermore, 49% of samples are between 20 to 60 mg/L. The others are higher than 60 mg/L. About half of the samples are above 20 mg/L, while 87% of samples are over 10 mg/L. However, the proportion of concentrations of more than 10 mg/L in our study was 51.43% (108/210). Nah et al. [14] have explored the TPCs from 61 patients in a Korean hospital. With the standard regimen recommended by medication instructions, patients with plasma concentrations lower than 10 mg/L constituted almost half of the whole population (29 cases, 47.5%). The median plasma concentration was 6.8 mg/L. Another Chinese study [15] has analyzed the TPCs in 542 patients, showing that 42% of patients (230/542) have a plasma concentration below 10 mg/L, and 77% of patients (419/542) have a plasma concentration lower than 15 mg/L. Meanwhile, the medication instructions of teicoplanin in Japanese recommend that it is a guideline for common infections to keep trough plasma concentrations at 5–10 mg/L. Whether 10 mg/L is suitable as the target for Chinese patients remains controversial and needs to be further validated. It was highly necessary to perform TDM routinely and to adjust the dose or frequency of teicoplanin based on the monitoring results, especially for patients who did not reach the target concentration initially.
As the plasma concentration in our study was mostly the trough concentration of patients, the teicoplanin samples were loosely collected 2-3 times from each patient. Cazaubon et al. [16] investigated the teicoplanin PPK model in 98 French patients through NONMEM. The estimated CL is 0.305 L/h, and intercompartmental clearance is 4.42 L/h. The central and peripheral volumes of distribution are 10.3 L and 97.4 L, respectively. Another study [17] in Japanese hospitals performed teicoplanin PPK and pharmacodynamic analyses on 237 patients. CL and intercompartmental clearance are 0.211 L/h and 2.42 L/h. The volumes of the central and peripheral compartments are 38.2 L and 106 L, respectively. In our present study, the values of CL and intercompartmental clearance were similar to those of Japanese patients. The differences might be attributed to ethnic populations. Though the OFVs between the single-compartment and two-compartment models were not drastically different, taking evaluation plots into account, our study preferred the two-compartment model for teicoplanin concentrations, which had been described in previous studies [18].
Our study found that the administration regimen and plasma concentration were not suitable for high-weight patients. The weight significantly affected the teicoplanin pharmacokinetic parameters, resulting in a changed TPC. As weight is increased, the in-vivo distribution of teicoplanin, a water-soluble drug, is changed [3]. Meanwhile, renal blood flow and glomerular filtration rates of patients are increased at different degrees, leading to an increase in the parameter of CL [19]. Recent studies have reported that increasing times of loading doses are beneficial for achieving the target of TPC. A Chinese study [20] consisting of 113 patients at one hospital has found that compared with patients treated with three loading doses, those treated with 3–6 loading doses have a higher mean trough concentration (). Teicoplanin trough concentration is strongly correlated with the probable success of clinical effectiveness (OR = 2.049, ). Furthermore, TPCs are not only related to loading dose and weight [21], but also related to levels of Scr and ALB [22]. Teicoplanin CL is correlated to Scr, adjusted or individualized dosing approach should be adopted in patients with renal insufficiency or hematological malignancies [23]. Except for weight, our study found that no other covariates could significantly affect PPK parameters, resulting in the diversification of TPC. As teicoplanin, a drug of kidney excretion, has a high rate of protein binding, the doctors would adjust the Scr or ALB levels of patients to normal before using teicoplanin [24]. If not, patients would be treated with other antibiotics instead of teicoplanin. As few patients included in our study had high levels of Scr or low levels of ALB, Scr, or ALB could not be significant () covariates in the teicoplanin PPK model.
Several limitations of this study warrant mention. First, the etiological evidence, including data on minimum inhibitory concentration (MIC) and microbiological response, was not obtained. It was impossible to perform pharmacodynamic research and to further explore the relationship between plasma concentration and treatment outcomes. Secondly, the population included was not diversified enough. Because few patients had abnormal values of biochemical test indicators, such as Scr or ALB, no significant correlation was found in some vital variates. At last, the data in our study were collected retrospectively. Because of the retrospective character, the grade of evidence was insufficient. Thus, prospective administration based on the PPK model was required to explore the compliance of plasma concentration and therapeutic effectiveness.
5. Conclusions
The standard regimen of 400 mg teicoplanin failed to reach the target value in the present population. The dose of 600 mg was feasible to be administered based on TDM, especially for high-weight patients. A PPK-based individualized pharmacokinetic dosing adjustment was advisable to guarantee TPC achieving the target of the therapeutic level.
Abbreviations
| TPC: | Teicoplanin plasma concentration |
| TDM: | Therapeutic drug monitoring |
| PPK: | Population pharmacokinetic |
| MRSA: | Methicillin-resistant Staphylococcus aureus |
| HIS: | Hospitalized information system |
| MSSA: | Methicillin-sensitive Staphylococcus aureus |
| ALB: | Serum albumin |
| ADR: | Adverse drug reaction |
| HPLC: | High-performance liquid chromatography |
| Scr: | Serum creatinine |
| ALT: | Alanine aminotransferase |
| AST: | Aspartate aminotransferase |
| NONMEM: | Nonlinear mixed-effects model |
| OFV: | Objective function value |
| OR: | Odds ratio |
| CI: | Confidence interval |
| TBil: | Total bilirubin |
| DBil: | Direct bilirubin |
| ALP: | Alkaline phosphatase |
| GGT: | γ-glutamyltransferase |
| CL: | Clearance rate |
| MIC: | Minimum inhibitory concentration |
| BMI: | Body mass index |
| BSI: | Bloodstream infection |
| CI: | Chest infection |
| HBI: | Hepatobiliary infection |
| ITI: | Intestinal infection |
| OI: | Oral infection |
| UTI: | Urinary tract infection |
| PNA: | Pneumonia |
| CRI: | Catheter-related infection |
| FNP: | Febrile neutropenia |
| SSTI: | Skin and soft tissue infection |
| IAI: | Intraabdominal infection |
| MSI: | Multiple site infections |
| q12 h: | Once every 12 h |
| QD: | Once a day |
| qod: | Once every other day |
| q3d: | Once every 3 days |
| Vc: | Central volume of distribution |
| Q: | Intercompartmental clearance |
| Vp: | Peripheral volume of distribution |
| PRED: | Predictive value |
| OBS: | Observed value |
| IPRED: | Individual predictive value |
| CWRES: | Conditional weighted residues. |
Data Availability
The datasets used or analyzed during this study are available from the corresponding author upon reasonable request.
Ethical Approval
The study involving human participants was reviewed and approved by the Medical Ethics Committee of Chinese PLA General Hospital (No. S2018-179-01).
Consent
Written informed consent for participation was not required for this study in accordance with national legislation and institutional requirements.
Disclosure
The funders have no roles in study design, data collection, analysis, the decision to publish, or the preparation of the manuscript.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors’ Contributions
JW, NB, and YC conceived and designed the study. YYL, GXZZ, JW, and NB made contributions to the acquisition and performed analysis and interpretation of data. YYL, GXZZ, JW, and YC drafted the article. YYL, GXZZ, NB, and YC revised the study critically for important intellectual content. All authors read and approved the final manuscript. Yuan-Yuan Li and Guan-Xuan-Zi Zhang authors contributed equally to this work.
Acknowledgments
This work was supported by the National Natural Science Foundations of China (82073894), Cultivation Project of PLA General Hospital for Distinguished Young Scientists (2020-JQPY-004), and New Medicine Clinical Research Fund (246Z512).
Supplementary Materials
The Supplementary Material of tables about teicoplanin regimens for this article is available as Supplementary data at Hindawi Online. (Supplementary Materials)