Therapeutics for Vancomycin-Resistant Enterococcal Bloodstream Infections.

Vancomycin-resistant enterococci (VRE) are common causes of bloodstream infections (BSIs) with high morbidity and mortality rates. They are pathogens of global concern with a limited treatment pipeline. Significant challenges exist in the management of VRE BSI, including drug dosing, the emergence of resistance, and the optimal treatment for persistent bacteremia and infective endocarditis. Therapeutic drug monitoring (TDM) for antimicrobial therapy is evolving for VRE-active agents; however, there are significant gaps in the literature for predicting antimicrobial efficacy for VRE BSIs. To date, TDM has the greatest evidence for predicting drug toxicity for the three main VRE-active antimicrobial agents daptomycin, linezolid, and teicoplanin. This article presents an overview of the treatment options for VRE BSIs, the role of antimicrobial dose optimization through TDM in supporting clinical infection management, and challenges and perspectives for the future.

Model-based dosing optimization and therapeutic drug monitoring practices of teicoplanin in patients with complicated or non-complicated methicillin-resistant staphylococcus aureus infection.

AIMS: This study aims to establish a population pharmacokinetic (PK) model of teicoplanin in Chinese adult patients to evaluate the dosing regimen in the label sheet and optimize it. METHODS: Nonlinear mixed-effects modelling was used to estimate PK parameters. Monte Carlo simulations were used to evaluate the attainment of various dosing regimens in achieving the target trough concentrations in patients with normal or decreased renal function. RESULTS: A total of 115 patients were enrolled in this retrospective study. Creatinine clearance (CrCL) and albumin (ALB) were identified as covariates on the clearance of teicoplanin. For the treatment of non-complicated methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with normal renal function and serum ALB concentration, the recommended dosing regimen was 600 mg q12h with five administrations as the loading dose followed by 600 mg qd as the maintenance dose; for the treatment of serious and/or complicated MRSA infections, the recommended dosing regimen was 800 mg q12h with five administrations as the loading dose followed by 800 mg qd as the maintenance dose. It is worth noting that both the loading and maintenance doses ought to be modified based on the patient's renal function and serum ALB concentration. In addition, trough concentrations of teicoplanin were significantly increased every other week. CONCLUSIONS: Both loading dosing and maintenance dosing regimens were recommended to be adjusted according to patient's renal function and serum ALB concentration. In addition, it is necessary to perform follow-up therapeutic drug monitoring of teicoplanin at least once every week.

Association of the predicted free blood concentration of teicoplanin with the development of renal dysfunction.

PURPOSE: In clinical practice, teicoplanin (TEIC) is typically administered at a trough concentration of 15-40 µg/mL. TEIC has a protein binding rate of approximately 90%, and its concentration rarely exceeds 40 µg/ml. Nevertheless, an increase in the free blood trough concentration may result in renal dysfunction. However, the relationship between the free blood trough concentration and the occurrence of renal dysfunction remains unclear. This study aimed to examine the impact of the predicted free blood concentration on the development of renal dysfunction. METHODS: This retrospective study included patients who underwent TEIC and had at least one trough concentration measurement. The association between the frequency of renal dysfunction occurrence and the predicted free blood concentration was evaluated using the following equation: free TEIC concentration = total TEIC concentration/(1 + 1.78 × serum albumin level). RESULTS: Of the 170 patients included in this study, 18% (31/170) developed renal dysfunction. The predicted free trough concentration was significantly higher in the renal dysfunction onset group than in the nononset group. However, the total trough concentration was not significantly associated with the development of renal dysfunction. The odds ratio for developing renal dysfunction was 4.5 (95% confidence interval, 1.9-10.5; P < 0.001) when the predicted free trough concentration was > 4.0 µg/mL. CONCLUSION: Elevated free trough concentrations of TEIC were associated with an increased risk of renal dysfunction. Controlling the increase in the predicted free blood concentration may effectively prevent the development of renal dysfunction.

Fitness costs of Tn1546-type transposons harboring the vanA operon by plasmid type and structural diversity in Enterococcus faecium.

BACKGROUND: This study analyzed the genetic traits and fitness costs of vancomycin-resistant Enterococcus faecium (VREfm) blood isolates carrying Tn1546-type transposons harboring the vanA operon. METHODS: All E. faecium blood isolates were collected from eight general hospitals in South Korea during one-year study period. Antimicrobial susceptibility testing and vanA and vanB PCR were performed. Growth rates of E. faecium isolates were determined. The vanA-positive isolates were subjected to whole genome sequencing and conjugation experiments. RESULTS: Among 308 E. faecium isolates, 132 (42.9%) were positive for vanA. All Tn1546-type transposons harboring the vanA operon located on the plasmids, but on the chromosome in seven isolates. The plasmids harboring the vanA operon were grouped into four types; two types of circular, nonconjugative plasmids (Type A, n = 50; Type B, n = 46), and two types of putative linear, conjugative plasmids (Type C, n = 16; Type D, n = 5). Growth rates of vanA-positive E. faecium isolates were significantly lower than those of vanA-negative isolates (P < 0.001), and reduction in growth rate under vancomycin pressure was significantly larger in isolates harboring putative linear plasmids than in those harboring circular plasmids (P = 0.020). CONCLUSIONS: The possession of vanA operon was costly to bacterial hosts in antimicrobial-free environment, which provide evidence for the importance of reducing vancomycin pressure for prevention of VREfm dissemination. Fitness burden to bacterial hosts was varied by type and size of the vanA operon-harboring plasmid.

Risk Factors for Teicoplanin-Associated Acute Kidney Injury in Patients with Hematological Malignancies: Focusing on Concomitant Use of Tazobactam/Piperacillin.

Patients with hematological malignancies (HM) often receive tazobactam/piperacillin (TAZ/PIPC) and glycopeptide antibiotics for febrile neutropenia. The effect of concomitant use of TAZ/PIPC on risk of teicoplanin (TEIC)-associated acute kidney injury (AKI) remains unclear. We investigated the impact of concomitant TAZ/PIPC use on TEIC-associated AKI in HM patients and identified the risk factors. In this retrospective, single-center, observational cohort study, 203 patients received TEIC, 176 of whom satisfied the selection criteria and were divided into TEIC cohort (no TAZ/PIPC; n = 118) and TEIC + TAZ/PIPC cohort (n = 58). AKI was defined as serum creatinine increase ≥0.3 mg/dL within 48 h or ≥50% from baseline. Incidence of AKI in TEIC cohort before and after propensity score matching was 9.3 and 5.9%, respectively, and that in TEIC + TAZ/PIPC cohort was 10.3 and 11.8%. AKI incidence and risk were not significantly different between two cohorts before (p = 0.829; odds ratio (OR) 1.122, 95% confidence interval (CI) 0.393-3.202) and after matching (p = 0.244; OR 2.133, 95% CI 0.503-9.043). Logistic regression analysis with factors clinically or mechanistically potentially related to TEIC-associated AKI, including concomitant TAZ/PIPC use, as independent variables identified baseline hemoglobin level as the only significant risk factor for TEIC-associated AKI (p = 0.011; OR 0.484, 95% CI 0.276-0.848). In HM patients treated with TEIC, concomitant TAZ/PIPC use did not increase AKI risk whereas lower hemoglobin levels had higher risk for TEIC-associated AKI development, suggesting the necessity to monitor serum creatinine when using TEIC in patients with anemia.

Necessity for higher teicoplanin doses in older adults: a multicenter prospective observational study in China.

BACKGROUND: Many older adult patients receive low-dose teicoplanin with varied regimens, leading to a lack of clarity on its optimal regimens and toxicity profiles in China. This study aimed to clarify these aspects by analyzing teicoplanin treatment concentrations and toxicities. METHODS: We included older adult patients administered teicoplanin at four tertiary hospitals in Beijing from June 2021 to July 2023, targeting a trough concentration (Cmin) ≥ 10 mg/L. Teicoplanin concentrations and toxicities were monitored dynamically. RESULTS: From 204 patients, we obtained 632 teicoplanin concentrations. Most patients (83.3%) received low-dose regimens. Suboptimal concentrations were found in 66.4% of patients within 7 days of treatment and 17.0% after 15 days. Cmin gradually increased with treatment duration and was influenced initially by creatinine and by both body weight and creatinine from days 8 to 14. The target concentration was achieved in 53.1%, 33.9%, 15.6%, and 5.5% of patients at 3, ≤ 7, 8-14, and ≥ 15 days after withdrawal, respectively. Slow elimination was associated with average Cmin and eGFR. Nephrotoxicity, hepatotoxicity, and thrombocytopenia occurred in 12.5%, 4.1%, and 31.5% of patients, respectively, without significant differences between concentrations. CONCLUSIONS: Most older adult patients were underdosed, indicating a need for dose adjustment. Given the varied risk factors for suboptimal concentrations in different treatment stages, a one-size-fits-all regimen was ineffective. We recommend an initial dose of 400 mg at 12-h intervals for the first three days, with subsequent doses from days 4 to 14 adjusted based on creatinine and body weight; after day 14, a maintenance dose of 200 mg daily is advised. TRIAL REGISTRATION: ChiCTR2100046811; 28/05/2021.

Comparative activities of ampicillin and teicoplanin against Enterococcus faecalis isolates.

BACKGROUND: Enterococcus faecalis remains one of the most common pathogens causing infection in surgical patients. Our goal was to evaluate the antibiotic resistance of E. faecalis, causing infections in a surgical clinic, against two antibacterial drugs, ampicillin and teicoplanin. One commonly administered in the past for such infections, ampicillin, and another newer, teicoplanin, which demonstrated exceptionally good efficacy. METHODS: Data from 1882 isolates were retrieved from the microbiology department database during two 5-year periods. Standard biochemical methods were employed for the identification of the isolates. The prevalence of E. faecalis among patients with clinical evidence of infection in a surgical oncology ward was assessed. Confidence interval (CI) as well as standard error (SE) were calculated. Moreover, the annual incidence of E. faecalis infections in this surgical ward was recorded. The susceptibility of E. faecalis to ampicillin and teicoplanin was studied and compared using Fisher's exact test. RESULTS AND CONCLUSION: Results showed that the incidence of E. faecalis infections in the surgical clinic was increasing. Ampicillin, in the later year period, was not statistically different from teicoplanin in treating E. faecalis infections. Consequently, ampicillin seems currently to be an effective antibiotic against such infections that could be used as empiric therapy.

Staphylococcus haemolyticus attenuates the antibacterial effect of teicoplanin via aggregates and biofilms.

OBJECTIVES: This study aimed to determine the inhibitory and bactericidal effects of teicoplanin (TEC) on TEC-susceptible Staphylococcus haemolyticus isolated from a patient with cancer in whom infection persisted despite TEC therapy. We also focused on the biofilm-forming ability of the isolate in vitro. METHODS: S. haemolyticus clinical isolate (strain 1369A) and its control strain, ATCC 29970 were cultured in Luria-Bertani (LB) broth with TEC. The inhibitory and bactericidal effects of TEC on planktonic, adherent, biofilm-dispersed, and biofilm-embedded cells of these strains were analyzed by using a biofilm formation/viability assay kit. The expression of biofilm-related genes was measured using quantitative real-time polymerase chain reaction (qRT-PCR). Biofilm formation was determined by using scanning electron microscopy (SEM). RESULTS: The clinical isolate of S. haemolyticus had enhanced ability to bacterial growth, adherence, aggregation, and biofilm formation, thus the inhibitory and bactericidal effects of TEC on planktonic, adherent, biofilm-dispersed, and biofilm-embedded cells of the isolate were attenuated. Additionally, TEC induced cell aggregation, biofilm formation, and some biofilm-related gene expression of the isolate. CONCLUSION: The clinical isolate of S. haemolyticus is resistant to TEC treatment due to cell aggregation and biofilm formation.

Comparison of core-shell versus fully porous particle packings for chiral liquid chromatography productivity.

A loading and productivity study was done using three racemates on vancomycin and teicoplanin-bonded chiral stationary phases of different particle formats. Two columns were packed with 2.7 µm superficially porous particles and two columns were packed with identically bonded 5 µm fully porous particles. The last two columns were packed with specially synthesized 4.5 µm vancomycin and teicoplanin superficially porous particles. The loading of different chiral compounds showed that the columns filled with 2.7-µm chiral stationary phases were inappropriate for preparative separations due to their very low permeability which precluded high flow rates. However, columns containing 4.5 µm superficially porous (core-shell) particles were as effective for small-scale preparative chiral separations as columns filled with classical 5 µm fully porous particles. Comparing the 4.5 µm superficially porous particles and 5 µm fully porous particles teicoplanin columns, the observed respective productivities of 270 and 265 mg/g chiral phase/h for 5-methyl-5-phenyl hydantoin enantiomers were obtained. Particular attention was given to the peculiar case of the mianserin enantiomeric separation on vancomycin columns that gave observed productivities of 200 and 205 mg/g chiral phase/h on the 4.5 µm superficially porous particles and 5 µm fully porous particles, respectively.

In vitro analysis of factors affecting the continuous hemodiafiltration clearance of teicoplanin.

BACKGROUND: In the treatment of sepsis, continuous hemodiafiltration (CHDF) and the administration of antibiotics such as teicoplanin (TEIC) are frequently performed in parallel. We aimed to clarify the factors influencing the CHDF clearance (CLCHDF ) of TEIC using a polymethylmethacrylate (PMMA) membrane or a polyacrylonitrile and sodium methallyl sulfonate copolymer membrane coated with polyethylenimine (AN69ST). We also investigated whether the adsorption of TEIC onto the hemofilters inhibits the adsorption of interleukin (IL)-6 onto the membranes. METHODS: TEIC, human serum albumin (HSA), and IL-6 were incubated with pieces of hemofilter membranes and adsorption rates were calculated. The CLCHDF , diafiltration rate, and adsorption rate of TEIC were calculated using an in vitro CHDF circuit model. RESULTS: The adsorption rates of TEIC onto the pieces of PMMA and AN69ST membranes ranged from 15.0% to 100% and from -10% to 5%, respectively. The adsorption rate of IL-6 was similar with or without TEIC. The CLCHDF and adsorption rate of TEIC under PMMA-CHDF depended on HSA, but not on effluent flow rate (Qe). The CLCHDF under AN69ST-CHDF depended on HSA and Qe. The observed CLCHDF under AN69ST-CHDF was similar to the predicted value (the product of Qe and the plasma unbound fraction). The observed CLCHDF under PMMA-CHDF was 2.0-7.8 times greater than the predicted value. CONCLUSIONS: Adsorption mainly contributes to the CLCHDF of TEIC using PMMA membranes, whereas diafiltration mainly contributes to the CLCHDF of TEIC using AN69ST membranes. TEIC adsorption might not affect the adsorption of IL-6 onto PMMA membrane.

Optimal Use and Need for Therapeutic Drug Monitoring of Teicoplanin in Children: A Systematic Review.

BACKGROUND: Teicoplanin is a glycopeptide antimicrobial that treats serious invasive infections caused by gram-positive bacteria, such as the methicillin-resistant Staphylococcus aureus. Despite some comparable advantages, there is no guideline or clinical recommendation for teicoplanin in the pediatric population, unlike vancomycin where abundant studies and the recently revised guideline on therapeutic drug level monitoring (TDM) exist. METHODS: The systematic review was performed in accordance with the preferred reporting items for systematic reviews. Two authors (JSC and SHY) searched PubMed, Embase, and Cochrane Library databases using relevant terms independently. RESULTS: Fourteen studies were finally included with a total of 1,380 patients. TDM was available in 2,739 samples collected in the nine studies. Dosing regimens varied widely, and eight studies used recommended dosing regimens. Timing for measuring TDM was mostly 72-96 hours or longer after the initiation of the first dose, which was expected to be a steady-state. The majority of studies had target trough levels of 10 µg/mL or above. Three studies reported that the clinical efficacy and treatment success rate of teicoplanin was 71.4%, 87.5%, and 88%. Adverse events associated with teicoplanin use were described in six studies with a focus on renal and/or hepatic impairment. Except for one study, no significant relation was noted between the incidence of adverse events and trough concentration. CONCLUSION: Current evidence on teicoplanin trough levels in pediatric populations is insufficient due to heterogeneity. However, target trough levels with favorable clinical efficacy are achievable by recommended dosing regimen in the majority of patients.

Oral teicoplanin administration suppresses recurrence of Clostridioides difficile infection: Proof of concept.

OBJECTIVES: Teicoplanin is a potential antimicrobial candidate for Clostridioides difficile infection (CDI) treatment. However, the therapeutic potential of teicoplanin against severe CDI has not been clinically proven. In the present study, we investigated the efficacy of oral teicoplanin administration against severe CDI and the recurrence of severe CDI after teicoplanin treatment in a mouse model. METHODS: A lethal CDI mouse model was established by colonizing the mice with C. difficile ATCC® 43255; they were orally administered teicoplanin (128 mg/kg/d) or vancomycin (160 mg/kg/d) for 10 d, 24 h after C. difficile spore challenge, and physiological and biological responses were monitored for 20 d after the initial antibiotic treatment. We also performed the in vitro time-kill assay and determined minimum inhibitory concentration (MIC), post-antibiotic effect, and toxin production with antibiotic exposure. RESULTS: The therapeutic response (survival rates, body weight change, clinical sickness score grading, C. difficile load, and toxin titer in feces) of oral teicoplanin administration was comparable to that of oral vancomycin administration in the lethal CDI mouse model. Moreover, teicoplanin treatment suppressed the re-onset of diarrhea and re-increase in toxin titer 10 d after treatment compared with that by vancomycin treatment. In in vitro experiments, teicoplanin exhibited time-dependent antibacterial activity and possessed lower MIC and longer post-antibiotic effect than vancomycin against C. difficile. C. difficile toxin production was numerically lower with teicoplanin exposure than with vancomycin exposure. CONCLUSIONS: The results obtained from the present basic experiments could suggest that teicoplanin is a potential antibiotic for the treatment of severe CDI with recurrence-prevention activity.

Accuracy of Therapeutic Drug Monitoring of Teicoplanin at the Onset of Febrile Neutropenia.

Background and Objectives: Teicoplanin (TEIC) is an effective drug for patients with febrile neutropenia (FN); however, it has been reported that these patients may have increased TEIC clearance compared with patients who do not have FN. The purpose of this study was to study therapeutic drug monitoring in patients with FN when the TEIC dosing design was based on the population mean method. Materials and Methods: Thirty-nine FN patients with hematological malignancy were included in the study. To calculate the predicted blood concentration of TEIC, we used the two population pharmacokinetic (population PK) parameters (parameters 1 and 2) reported by Nakayama et al. and parameter 3, which is a modification of the population PK of Nakayama et al. We calculated the mean prediction error (ME), an indicator of prediction bias, and the mean absolute prediction error (MAE), an indicator of accuracy. Furthermore, the percentage of predicted TEIC blood concentration within 25% and 50% of the measured TEIC blood concentration was calculated. Results: The ME values were -0.54, -0.25, and -0.30 and the MAE values were 2.29, 2.19, and 2.22 for parameters 1, 2, and 3, respectively. For all of the three parameters, the ME values were calculated as minus values, and the predicted concentrations tended to be biased toward smaller values relative to the measured concentrations. Patients with serum creatinine (Scr) < 0.6 mg/dL and neutrophil counts < 100/µL had greater ME and MAE values and a smaller percentage of predicted TEIC blood concentration within 25% of measured TEIC blood concentrations compared with other patients. Conclusions: In patients with FN, the accuracy of predicting TEIC blood concentrations was good, with no significant differences between each parameter. However, patients with a Scr < 0.6 mg/dL and a neutrophil count < 100/µL showed slightly inferior prediction accuracy.

Effectiveness, safety, and cost of vancomycin and linezolid in Kuwait: A retrospective cohort study.

Background: The effectiveness, safety, and cost of vancomycin and linezolid for managing gram-positive bacterial infections in Kuwait are unknown. This study assessed the effectiveness, safety, and cost of vancomycin, teicoplanin and linezolid for managing gram-positive bacterial infections in Kuwait. Research design and methods: This retrospective study included adult patients who were prescribed antibiotics (vancomycin, teicoplanin, and linezolid) for the treatment of gram-positive infections at five hospitals in Kuwait. Descriptive statistics were used to assess the effectiveness and safety outcomes. A cost analysis was performed on the patients hospitalised for gram-positive infections. Results: Among 116 patients, 42.2 % (n = 49) received glycopeptides (vancomycin [n = 45] and teicoplanin [n = 4]) or linezolid (n = 67). Clinical cure was achieved in 100 patients without significant intergroup differences (p = 0.34). Thrombocytopenia and acute kidney injury occurred in 19 and 20 patients (p = 0.82 and 0.96), respectively, and their incidence was similar with all the studied agents. The average cost per patient was USD 983.70. The estimated total direct medical costs were USD 894,570.6, the cost was highest for linezolid (USD 469,682.30) and vancomycin (USD 370,342.5), and lowest for teicoplanin (USD 20,799.9). Conclusions: Glycopeptides and linezolid were highly effective. Linezolid was the most frequently prescribed agent; its effectiveness and safety were similar according to the antibiotic class. However, treatment with linezolid and vancomycin were associated with considerable costs.

Replacing Commercial 6-Phosphofructokinase in an Online Pyrophosphate Detection Assay.

Detection of pyrophosphate is important in quantifying enzyme activity, particularly adenylation domain activity during non-ribosomal peptide synthesis. The previous development of an enzyme coupled PPi /NADH assay allowed the measurement of such activity in an online fashion using commercially available components. Now, with a key enzyme - 6-phosphofructokinase - no longer available, we have screened and identified viable replacement enzymes that can be expressed in high yield and that are far superior in activity to the now discontinued commercial product. This will support the ability of groups to continue to use this established online assay for pyrophosphate detection.

Comparison of mortality and clinical failure rates between vancomycin and teicoplanin in patients with methicillin-resistant Staphylococcus aureus pneumonia.

BACKGROUND: Very few studies have compared the effects and side effects of vancomycin and teicoplanin in patients with methicillin-resistant Staphylococcus aureus pneumonia. This study aimed to compare the efficacy and safety of vancomycin and teicoplanin in patients with methicillin-resistant Staphylococcus aureus pneumonia. METHODS: This study examined 116 patients with methicillin-resistant Staphylococcus aureus pneumonia who met the inclusion criteria and were treated with either vancomycin (n = 54) or teicoplanin (n = 62). The primary (i.e., clinical failure during treatment) and secondary outcomes (i.e., mortality rates, discontinuation of study drugs due to treatment failure, side effects, and clinical cure) were evaluated. RESULTS: The vancomycin group presented lower clinical failure rates (25.9% vs. 61.3%, p < 0.001), discontinuation due to treatment failure (22.2% vs. 41.9%, p = 0.024), and mortality rates (3.7% vs 19.4%, p = 0.010). The Cox proportional hazard model revealed that teicoplanin was a significant clinical failure predictor compared with vancomycin (adjusted odds ratio, 2.198; 95% confidence interval 1.163-4.154). The rates of drug change due to side effects were higher in the vancomycin group than in the teicoplanin group (24.1% vs. 1.6%, p < 0.001). CONCLUSIONS: Vancomycin presented favorable treatment outcomes and more side effects compared with teicoplanin, which suggests that clinicians would need to consider the efficacy and potential side effects of these drugs before prescription.

Thrombocytopenia Associated With Teicoplanin Use: A Retrospective Observational Study.

BACKGROUND: Contradictory studies reporting vast heterogeneity in the teicoplanin-induced thrombocytopenia (TIT) incidence exist. OBJECTIVE: To identify the incidence of TIT associated with teicoplanin dosing range (6-12 mg/kg/dose) and the risk factors of TIT. METHODS: This retrospective observational study included adult patients who received teicoplanin for ≥3 consecutive days over a period of 3.5 years. Thrombocytopenia was defined as a platelet count of <100 × 103/µL coupled with at least a 25% drop from the baseline count. The TIT incidence was assessed using the adverse drug reaction probability scale (Naranjo scale). RESULTS: Data from 482 patients who received teicoplanin and met the predefined inclusion criteria were included in the analyses. The cohort presented a mean age of 53.5 ± 19 years, where 72.4% were male, and 49.2% exhibited normal baseline renal function. Teicoplanin was most commonly used for bacteremia (n = 134), and the most common isolated pathogen being Staphylococcus aureus (n = 221). The TIT incidence was 4.6% (the possible and probable category using the Naranjo scale; 22/482). The median time to first platelet count dropped to <100 × 103/µL after teicoplanin initiation was 5 (interquartile range [IQR], 3-10) days and 8 (IQR, 5-14) days till the maximum platelet count dropped. None of the tested patient variables were found to be independently associated with an increased risk of thrombocytopenia. CONCLUSION AND RELEVANCE: The overall TIT incidence was low across our study cohort, including critically ill patients. Our study results may aid in the optimal monitoring of such serious teicoplanin-induced adverse effects.

A novel sensitive analytical method for the simultaneous analysis of vancomycin and teicoplanin in human urine via single high-performance liquid chromatography coupled with photodiode array and mass spectrometry in series.

Analysis of vancomycin and teicoplanin in biological fluids is vital since they are used in the treatment of hospital infections. For the determination of both glycopeptides in urine, a sensitive and accurate analytical method using high-performance liquid chromatography coupled with photodiode array and mass spectrometry was developed and validated. This research work is the first attempt to develop a chromatographic method for the determination of two glycopeptides with structural similarities. Moreover, the used non-invasive sampling method is an advantage of this research effort, especially when the blood sampling is difficult. Urine was treated with acetonitrile and 5% trichloroacetic acid, followed by solid-phase extraction. The chromatographic separation was established at a C18 column (4.6 × 150 mm, 5 µm), using a gradient method and an electrospray ionization source in a positive mode. The linearity of the method was R2 ≥ 0.9900. The precision was estimated with a maximum coefficient of variation below 15%, while the accuracy ranged from 64 to 121%. The limit of detection and quantification of both glycopeptides ranged from 0.076 up to 0.33 mg/L and 0.33 up to 2.1 mg/L, respectively, showing the same sensitivity as the triple quadrupole mass spectrometry, which is the most frequently used method.

Therapeutic drug monitoring status of four common antibiotics: vancomycin, meropenem, linezolid and teicoplanin.

Accurate therapeutic drug monitoring (TDM) of vancomycin, meropenem, linezolid and teicoplanin are conducive to developing optimal therapeutic regimes for patients. However, the measurement status of those drugs in different laboratories has not been reported. In this study, four samples including two frozen plasma samples and two lyophilized plasma samples were measured by over 35 laboratories across China. The inter- and intra-laboratory %CV, biases (%) of laboratories and intra- and inter-measurement-system %CV were calculated and analyzed. The short-term stability and homogeneity of those drugs in samples were studied. The results of frozen and lyophilized samples were also compared to determine whether there were significant differences in their matrix effects on various measurement systems. Results showed most laboratories' intra-laboratory %CVs were less than 9% for all drugs, and the mean inter-laboratory %CVs were 18.4%, 86.4%, 19.1% and 37.1% for vancomycin, meropenem, linezolid and teicoplanin measurements, respectively. For vancomycin, the intra-measurement %CV of commercial measurement systems was found to be smaller than that of other measurement systems. For meropenem, linezolid and teicoplanin, the agreement among laboratories using self-developed methods (Liquid chromatography-mass spectrometry [LC-MS] or high-performance liquid chromatography [HPLC]) was not satisfactory as most intra-measurement system CVs% were over 20%. Drugs in lyophilized samples were found to be more stable than in frozen samples, and no obvious differences in matrix effects were found for those two kinds of processed samples on most measurement systems. In conclusion, this study depicted the measurement status of those drugs in clinical laboratories, and found the lyophilized samples were more suitable EQA material for those drugs.

Enhanced loading dose of teicoplanin for three days is required to achieve a target trough concentration of 20 µg/mL in patients receiving continuous venovenous haemodiafiltration with a low flow rate.

INTRODUCTION: Because of its lower risk of renal toxicity than vancomycin, teicoplanin is the preferred treatment for methicillin-resistant Staphylococcus aureus infection in patients undergoing continuous venovenous haemodiafiltration (CVVHDF) in whom renal function is expected to recover. The dosing regimen for achieving a trough concentration (Cmin) of ≥20 µg/mL remains unclear in patients on CVVHDF using the low flow rate adopted in Japan. METHODS: The study was conducted in patients undergoing CVVHDF with a flow rate of <20 mg/kg/h who were treated with teicoplanin. We adopted three loading dose regimens for the initial 3 days: the conventional regimen, a high-dose regimen (four doses of 10 mg/kg), and an enhanced regimen (four doses of 12 mg/kg). The initial Cmin was obtained at 72 h after the first dose. RESULTS: Overall, 60 patients were eligible for study inclusion. The proportion of patients achieving the Cmin target was significantly higher for the enhanced regimen than for the high-dose regimen (52.9% versus 8.3%, p = 0.003). In multivariate analysis, the enhanced regimen (odds ratio [OR] = 39.93, 95% confidence interval [CI] = 5.03-317.17) and hypoalbuminaemia (OR = 0.04, 95% CI = 0.01-0.44) were independent predictors of the achievement of Cmin ≥ 20 µg/mL. CONCLUSIONS: An enhanced teicoplanin regimen was proposed to treat complicated or invasive infections by methicillin-resistant Staphylococcus aureus in patients receiving CVVHDF even with a low flow rate.