Therapeutic Drug Level Monitoring of Teicoplanin in Korean Pediatric Patients with Normal versus Impaired Renal Function.

BACKGROUND: Teicoplanin is used to treat serious gram-positive infections. Optimal teicoplanin trough levels are considered to be ≥ 10 µg/mL. Despite its wide use in various clinical settings, data on teicoplanin trough level in pediatric patients are limited. Therefore, the aim of this study was to investigate the therapeutic drug level monitoring of teicoplanin in Korean pediatric patients, including those with impaired renal function. METHODS: A retrospective study was performed in pediatric patients (age ≤ 18 years old) who received teicoplanin from September 2014 to April 2018. The regimen included a loading dose of 10 mg/kg/dose at 12 hours' interval three times in a row, and a maintenance dose of 10 mg/kg/dose commenced at 24 hours of interval after the loading dose, with a maximum of 400 mg/dose, respectively. The first therapeutic drug levels were measured. Distribution and characteristics of trough levels in patients with decreased renal function and those with bacteremia were also assessed. RESULTS: A total of 187 trough levels were collected from 143 patients. Hematologic and oncologic diseases were the most common underlying diseases (83.2%, n = 119). One hundred eighty trough levels were first measured, and their median value was 16.2 µg/mL (range, 2.3-100 µg/mL) and the median interval between initial teicoplanin injection and 1st trough level was 96.5 hours (range 47.6-179.3 hours). Lower steady-state levels were observed in younger age group (median, 13.5 vs. 18.0 µg/mL, P = 0.038). Median trough levels were higher in patients with decreased renal functions (P < 0.001). In addition, among eight with gram-positive bacteremia, seven of them had a favorable outcome. CONCLUSION: This study provides additive information on trough level monitoring of teicoplanin in children with impaired renal function and treatment effect in patients with gram-positive bacteremia. Careful monitoring for steady state trough levels of teicoplanin is warranted.

Interlaboratory analysis of teicoplanin plasma concentration assays among Chinese laboratories.

WHAT IS KNOWN AND OBJECTIVE: Teicoplanin is widely used for the treatment of infections caused by drug-resistant Gram-positive bacteria. Since there is a good correlation between trough levels and clinical outcome, therapeutic drug monitoring (TDM) is recommended to achieve better clinical curative effects. However, TDM of teicoplanin is not routine in China. So, a programme was initiated in 2017, including both HPLC method establishment and interlaboratory quality assessment, for the measurement of teicoplanin. METHODS: A main centre and a quality control centre were set up in the study. An HPLC-based method of teicoplanin determination in plasma was developed by the main centre. Analysis was performed using a Waters Symmetry C18 column (250 mm × 4.6 mm, 5 µm). The mobile phase was NaH2 PO4 (0.01 mol/L) and acetonitrile (75:25 v/v; pH 3.3), with a flow rate of 1.0 mL/min and a detection wavelength of 215 nm. Piperacillin sodium was selected as an internal standard (IS). Twenty-six additional TDM centres were then recruited to adopt this method. Then, all the centres were asked to take part in a quality control assessment evaluated by the quality control centre. RESULTS: For all TDM centres, linearity of teicoplanin concentration ranges was between 3.125 and 100 µg/mL. Intraday and interday accuracies ranged from 87.1% to 118.4%. Intraday and interday precision ranged from 0.3% to 13.8%. Therapeutic drug monitoring centres all passed inter-room quality assessment. All samples tested met the acceptance criteria. Then, 542 samples were collected. Patients with sub-optimal (≤10 mg/L) plasma teicoplanin concentrations constituted 42% of the total study population. WHAT IS NEW AND CONCLUSIONS: For the first time, a simple, rapid and accurate HPLC method for determining teicoplanin levels was successfully applied to therapeutic drug monitoring in clinical practice for twenty-seven TDM centres in China. The results demonstrated excellent interlaboratory agreement for teicoplanin testing and provide support for clinical laboratory quality management and results inter-accreditation.

Population pharmacokinetics of teicoplanin in hospitalized elderly patients using cystatin C as an indicator of renal function.

OBJECTIVE: Serum cystatin C (CysC) has recently been proposed as an alternative marker to serum creatinine (SCR) for estimating renal clearance. In the present study, we performed a population pharmacokinetic analysis of teicoplanin (TEIC), which is mainly eliminated through the kidneys, using CysC as a predictor for renal clearance. METHODS: Thirty-six patients with MRSA infections who were administrated to the National Hospital Organization Beppu Medical Center between January 2012 and December 2013 were enrolled and gave 123 sets of blood TEIC concentration data. Renal clearance was estimated by the Hoek equation using CysC, by creatinine clearance predicted by the Cockcroft-Gault equation using SCR, or directly by CysC. One compartment open model with inter-individual variabilities for renal clearance and the volume of distribution as well as an additional residual error model was used to estimate population pharmacokinetic parameters for TEIC. RESULTS: The model with the best predictability was that with CysC as a predictor for renal clearance; it showed better significance than the models using estimated the glomerular filtration rate by the Hoek equation or CLcr. The final model was as follows: CL (L/hr) = 0.510 × (CysC/1.4)-0.68 × Total body weight/600.81, omega (CL) = 19.8% CV, VC (L) = 78.1, omega (V) = 42.7% CV. CONCLUSION: The present results show the usefulness of CysC to more accurately predict the pharmacokinetics of drugs mainly eliminated through the kidneys, such as TEIC. However, since the sample size in this study was relatively small, further investigations on renal clearance predictability using CysC are needed.

Optimal Trough Concentration of Teicoplanin in Febrile Neutropenic Patients with Hematological Malignancy.

BACKGROUND: Teicoplanin is a glycopeptide antibiotic currently used for the treatment of methicillin-resistant Staphylococcus aureus. The need for therapeutic drug monitoring of teicoplanin has been increasingly highlighted as important. It is generally accepted that whereas a plasma trough concentration (Cmin) of ≥10 mg/L is appropriate for the majority of infections, it should exceed 20 mg/L for severe infections. The target Cmin of teicoplanin in patients with febrile neutropenia (FN) has not been reported. The aim of this study was to estimate the target Cmin for the treatment of FN in patients with hematological malignancy. METHODS: In this retrospective, single-center, observational cohort study, the records of 52 hospitalized patients with hematological malignancy who were treated with teicoplanin for FN due to bacteriologically documented or presumptive gram-positive infections were analyzed. RESULTS: A significant difference in the first Cmin of teicoplanin was observed between the response and nonresponse groups in patients with bacteremia. The areas under the receiver operating characteristic curves were 0.80 for clinical efficacy. The cut-off value of teicoplanin Cmin on days 4-6 was 15.2 mg/L (sensitivity 80.0%, specificity 75.0%). CONCLUSIONS: The authors propose a target teicoplanin Cmin of ≥15.2 mg/L for FN in patients with hematological malignancy.

Population pharmacokinetics of teicoplanin and attainment of pharmacokinetic/pharmacodynamic targets in adult patients with haematological malignancy.

OBJECTIVES: To describe the population pharmacokinetics of teicoplanin in adult patients with haematological malignancies receiving higher than standard doses, and to perform Monte Carlo simulations to determine dosing regimens associated with optimal teicoplanin concentrations. METHODS: This was a hospital-based clinical trial (EudraCT 2013-004535-72). Nine blood samples were collected on Day 3, plus single trough samples on Days 7 and 10, and 24 and 48 hours after the last dose. Teicoplanin minimum inhibitory concentrations were determined for Gram-positive isolates from study patients. Population pharmacokinetic analyses and Monte Carlo dosing simulations were undertaken using Pmetrics. RESULTS: Thirty adult haematological malignancy patients were recruited with a mean (SD) loading dose, age, total body weight, and creatinine clearance of 9.5 (1.9) mg/kg, 63 (12) years, 69.1 (15.8) kg, and 72 (41) mL/min, respectively. A three-compartment linear pharmacokinetic model best described the teicoplanin concentration data. Covariates supported for inclusion in the final model were creatinine clearance for clearance and total body weight for volume of the central compartment. The median (IQR) area under the concentration-time curve from 48 to 72 hours (AUC48-72h) was 679 (319) mg.h/L. There was a strong correlation between the AUC48-72h and trough concentration at 72 hours (Pearson correlation coefficient 0.957, p <0.001). Dosing simulations showed that administration of five loading doses at 12-hourly intervals, stratified by total body weight and creatinine clearance, increased the probability of achieving target concentrations within 72 hours. CONCLUSIONS: To increase the number of patients achieving optimal teicoplanin concentrations an individualized dosing approach, based on body weight and creatinine clearance, is recommended.

Comparison of predictive accuracy of teicoplanin concentration using creatinine clearance and glomerular filtration rate estimated by serum creatinine or cystatin C.

We compared the predictive accuracy of TEIC concentrations (TEIC_conc) calculated using either serum cystatin C (CysC) or serum creatinine (SCr) and the population mean method using the mean population parameter of TEIC_conc for Japan. We also compared the predicted TEIC_conc to measured TEIC_conc. Creatinine clearance (CLCr) predicted using the Cockcroft-Gault (C&G) equation with SCr was 45.23 mL/min (interquartile range [IQR]: 32.12-58.28), and the glomerular filtration rate (GFR) predicted using the Hoek equation with CysC was 45.23 mL/min (IQR: 35.40-53.79). The root mean-squared prediction error (IQR) based on CLCr predicted using the C&G equation with SCr was 6.88 (3.80-9.96) µg/mL, and that based on GFR predicted using the Hoek equation with CysC was 6.72 (3.77-9.68) µg/mL. Predicted TEIC_conc did not differ significantly between the two methods. The predictive accuracy of the TEIC_conc using the Hoek equation with CysC was similar to that of CLCr using the C&G equation with SCr. These findings suggest that the predictive accuracy of the TEIC_conc using CLCr based on the G&G equation and SCr might be sufficient for the initial dose adjustment of TEIC. Given that we were unable to confirm that CysC is the optimal method for predicting TEIC_conc, the expensive measurement of CysC might not be necessary.

Population pharmacokinetics and dosing optimization of teicoplanin in children with malignant haematological disease.

AIM: Children with haematological malignancy represent an identified subgroup of the paediatric population with specific pharmacokinetic parameters. In these patients, inadequate empirical antibacterial therapy may result in infection-related morbidity and increased mortality, making optimization of the dosing regimen essential. As paediatric data are limited, our aim was to evaluate the population pharmacokinetics of teicoplanin in order to define the appropriate dosing regimen in this high risk population. METHODS: The current dose of teicoplanin was evaluated in children with haematological malignancy. Population pharmacokinetics of teicoplanin were analyzed using nonmem software. The dosing regimen was optimized based on the final model. RESULTS: Eighty-five children (age range 0.5 to 16.9 years) were included. Therapeutic drug monitoring and opportunistic samples (n = 143) were available for analysis. With the current recommended dose of 10 mg kg(-1) day(-1) , 41 children (48%) had sub-therapeutic steady-state trough concentrations (Css,min <10 mg l(-1) ). A two compartment pharmacokinetic model with first order elimination was developed. Systematic covariate analysis identified that bodyweight (size) and creatinine clearance significantly influenced teicoplanin clearance. The model was validated internally. Its predictive performance was further confirmed in an external validation. In order to reach the target AUC of 750 mg l(-1) h 18 mg kg(-1) was required for infants, 14 mg kg(-1) for children and 12 mg kg(-1) for adolescents. A patient-tailored dose regimen was further developed and reduced variability in AUC and Css,min values compared with the mg kg(-1) basis dose, making the modelling approach an important tool for dosing individualization. CONCLUSIONS: This first population pharmacokinetic study of teicoplanin in children with haematological malignancy provided evidence-based support to individualize teicoplanin therapy in this vulnerable population.

Dalbavancin: Quantification in human plasma and urine by a new improved high performance liquid chromatography-tandem mass spectrometry method.

Dalbavancin is a novel second-generation lipoglycopeptide antibiotic with activity against broad range of Gram-positive pathogens. In order to determine the pharmacokinetics (PK) of dalbavancin in pediatric patients, a new High Performance Liquid Chromatography-Tandem Mass Spectrometry (HPLC-MS/MS) bioanalytical method has been developed for quantification of dalbavancin in plasma and in urine. The plasma method was validated for dalbavancin in the linear range from 0.5 µg/mL to 500 µg/mL using 50 µL of K(2) EDTA plasma. For dalbavancin spiked in urine, non-specific binding (NSB) of the drug to polypropylene (PP) urine collection containers was observed. The loss amounted to about 10% per transfer. After successfully establishing the collection/sampling procedure for urine by addition of Triton X-100 to the collection vessels (with a purpose of preventing NSB), the method was validated for dalbavancin in the range from 0.05 µg/mL to 50 µg/mL, using 100 µL of urine. These methods were used to quantify dalbavancin in plasma and urine of hospitalized children in a pediatric dalbavancin PK study. Eighteen percent of the total number of plasma study samples was reassayed for incurred samples reproducibility (ISR) and all the reassayed dalbavancin concentrations were within the ± 20% limits. For urine, all the collected samples were reassayed for ISR and the original dalbavancin concentration was confirmed within the ± 20% limits for 17 (94%) samples; the one remaining urine sample had its reassayed concentration confirmed within ± 25% of the original result.

Glycopeptide bone penetration in patients with septic pseudoarthrosis of the tibia.

BACKGROUND AND OBJECTIVE: In the treatment of bone infections, a major determinant of the clinical response is the active drug concentration at the infected site. Because of the high prevalence of meticillin (methicillin)-resistant staphylococci and enterococci, glycopeptides are widely used for the treatment of bone and joint infections, but data on their penetration into human bone are lacking. The aim of our study was to measure vancomycin and teicoplanin concentrations in infected human bone under steady-state conditions and verify their relationship with inflammatory markers, patient demographic characteristics and pharmacodynamic microbiological markers. METHODS AND PATIENTS: Twenty-seven adult orthopaedic patients undergoing surgical debridement for septic pseudoarthrosis of the tibia and receiving either intravenous vancomycin (Vancocina) 1 g twice daily) or teicoplanin (Targosid) 10 mg/kg/day) were studied from January 2004 to January 2008. Plasma and bone specimens were simultaneously collected during surgery for pharmacokinetic and microbiological assays at a variable interval after antimicrobial administration. Bone samples were dissected into cortical and cancellous bone, cleaned of soft tissues, crushed and eluted into phosphate buffer. Necrotic samples and sequestra were not analysed.Plasma and bone antimicrobial concentrations were measured by a validated method of high-performance liquid chromatography with UV detection, and bone/plasma concentration ratios were calculated. Cortical and cancellous bone area under the concentration-time curve (AUC) over 24 hours (AUC(24)) values were measured by the linear-log trapezoidal rule, using WinNonlin) software, and were compared with the minimum inhibitory concentrations (MICs) of the infecting agents. RESULTS: For vancomycin, the mean +/- SD concentrations were 2.66 +/- 1.2 mg/L in cortical bone and 11.53 +/- 7.8 mg/L in cancellous bone (corresponding to 20.67% and 89.39% of intraoperative plasma concentrations), and the mean +/- SD tissue AUC(24) values were 55.15 +/- 25.26 h . mg/L for cortical bone and 299.16 +/- 299.54 h . mg/L for cancellous bone. For teicoplanin, the mean +/- SD concentrations were 2.01 +/- 1.7 and 7.51 +/- 7.0 mg/L in cortical and cancellous bone, respectively (12.35% and 48.6% of intraoperative plasma concentrations), and the mean +/- SD teicoplanin tissue AUC(24) values were 34.08 +/- 23.6 h . mg/L and 155.17 +/- 132.8 h . mg/L for cortical bone and cancellous bone, respectively. The mean vancomycin AUC(24)/MIC ratios were 215.02 for plasma, 47.14 for cortical bone and 268.95 for cancellous bone. The mean teicoplanin AUC(24)/MIC ratios were 336.48, 36.27 and 197.21 for plasma, cortical bone and cancellous bone, respectively. CONCLUSIONS: Bone penetration of both glycopeptides ranged from poor (<15%) to satisfactory (15-30%) in the cortical compartment, while it was far higher into the highly vascularized cancellous tissue. Vancomycin bone penetration was slightly higher than with teicoplanin, but the difference was not statistically significant. Higher bone concentrations were observed with higher inflammatory markers, possibly as a result of increased vascularization and vascular permeability under inflammatory conditions. Bone concentrations over the MIC and AUC/MIC ratios suggested that both glycopeptides achieve a satisfactory pharmacokinetic exposure in the cancellous bone, as far as Gram-positive pathogens are concerned. On the other hand, cortical bone exposure was suboptimal in most patients. Furthermore, as antimicrobial penetration may be affected by impaired blood supply, the role of radical surgical removal of purulent and necrotic tissues appears to be essential in order to shorten treatment duration and to reduce the risk of treatment failure.

Comparative efficacy of topical versus systemic teicoplanin in experimental model of wound infections.

INTRODUCTION: Surgical site infections are the second most common cause of nosocomial infections and, typically, gram-positive pathogens are involved. MATERIALS AND METHODS: A mouse model was used to investigate the efficacy of different methods for the treatment of wound infections. A full thickness wound was established on the back subcutaneous tissue of adult male BALB/c mice. A small gauze was placed over each wound and then inoculated with 5 x 10(7) colony-forming units of Staphylococcus aureus. The study included a control group that did not receive any treatment and four contaminated groups treated, respectively, with: (1) drug-free Allevyn (Smith and Nephew Healthcare, Yorkshire, United Kingdom), (2) teicoplanin-soaked Allevyn, (3) drug-free Allevyn and daily intraperitoneal teicoplanin (7 mg/kg) and, finally, (4) teicoplanin-soaked Allevyn and daily intraperitoneal teicoplanin (7 mg/kg). Main outcome measures were quantitative bacterial culture, assessment of vascular endothelial growth factor (VEGF) plasma levels, histological examination with assessment of microvessel density, and of VEGF expression in tissue sections. RESULTS: Data analysis showed that strong inhibition of bacterial growth was achieved in any group treated with intraperitoneal teicoplanin. However, the highest inhibition of bacterial growth was obtained in the group that received teicoplanin-soaked Allevyn and intraperitoneal teicoplanin. Histological examination showed that each treatment modality was able to reduce the delay in wound repair. The most effective treatment appeared to be the local application of teicoplanin-soaked hydro gel foam. The tissue effects were associated with an increase in neovascularization and VEGF expression by endothelial cells and fibroblasts in the granulation tissue. Bacterial colonies also were reduced, especially when teicoplanin was given parenterally. CONCLUSIONS: Soaking a hydro cellular foam with an antistaphylococcal agents, such as teicoplanin, may be useful for the management of infected wounds.

Steady-state trough serum and epithelial lining fluid concentrations of teicoplanin 12 mg/kg per day in patients with ventilator-associated pneumonia.

OBJECTIVE: To determine the steady-state trough serum and epithelial lining fluid (ELF) concentrations of teicoplanin 12 mg/kg per day in critically ill patients with ventilator associated pneumonia. DESIGN AND SETTING: Prospective, pharmacokinetic study in the surgical intensive care unit in a university hospital. PATIENTS: Thirteen adult patients with nosocomial bacterial pneumonia on mechanical ventilation were enrolled. INTERVENTIONS: All subjects received a 30-min intravenous infusion of 12 mg/kg teicoplanin every 12 h for 2 consecutive days followed by 12 mg/kg once daily. Teicoplanin concentrations in serum and ELF were determined simultaneously 4-6 days after antibiotic administration started. MEASUREMENTS AND RESULTS: The median total and free concentrations of teicoplanin in serum at trough were 15.9 microg/ml (range 8.8-29.9) and 3.7 (2.0-5.4), respectively. The concentration in ELF was 4.9 (2.0-11.8). CONCLUSIONS: In critically ill patients with ventilator-associated pneumonia the administration of high teicoplanin doses is required to reach sufficient trough antibiotic concentrations in lung tissues at steady state. At that time trough-free concentrations of teicoplanin in serum and ELF are comparable.

Pharmacokinetic-pharmacodynamic aspects of antimicrobial prophylaxis with teicoplanin in patients undergoing major vascular surgery.

A prospective, two-arm, open study assessing plasma exposure to teicoplanin with two different prophylactic regimens (Group A (n = 23), 800 mg pre-operatively versus Group B (n = 24), 400 mg pre-operatively plus two doses of 200 mg 24 h apart) was carried out in patients undergoing major vascular surgery. The intent was to define the feasibility and the possible advantages of the single pre-operative high dose in ensuring therapeutically effective plasma concentrations (>10 mg/L) of teicoplanin even during long-lasting operations. At the end of the intervention, mean teicoplanin concentrations (+/-S.D.) were 14.05 +/- 5.13 mg/L and 5.39 +/- 2.13 mg/L in Groups A and B, respectively. At 24 h, average teicoplanin levels were 5.10 +/- 1.25 mg/L and 2.08 +/- 0.73 mg/L in Groups A and B, respectively; at 48 h they declined to 2.86 +/- 0.70 mg/L in Group A, whereas they rose to 2.67 +/- 0.82 mg/L after administration of 2.63 +/- 0.51 mg/kg at 24 h in Group B. Single pre-operative high-dose teicoplanin may ensure effective plasma levels even in cases of very long-lasting operations (>8 h) with no need for intraoperative re-dosing and may enable more appropriate prophylactic exposure than that achievable with the same total dose given in three administrations 24 h apart.

Teicoplanin in patients with acute leukaemia and febrile neutropenia: a special population benefiting from higher dosages.

OBJECTIVE: To define the optimal dosage regimen of teicoplanin that ensures early therapeutically relevant trough concentrations (C(min)) [>10 mg/L at 24 hours and possibly close to 20 mg/L at 48 hours] in patients with acute leukaemia who develop febrile neutropenia after chemotherapy. DESIGN: Prospective observational pharmacokinetic study. PARTICIPANTS: Adult patients (n = 33) with normal renal function previously treated with antineoplastic chemotherapy because of acute lymphocytic or acute nonlymphocytic leukaemia, and subsequently developing febrile neutropenia treated with empirical antimicrobial therapy. DESIGN: First, the standard dosage group (n = 11) was administered standard loading and maintenance doses of teicoplanin (400 mg every 12 hours for three doses followed by 400 mg once daily). Blood samples were collected at defined times as part of routine monitoring and assessed for teicoplanin plasma concentration by fluorescence polarisation immunoassay. Secondly, the high dosage group (n = 22) received a high loading regimen (800 + 400 mg 12 hours apart on day 1, 600 + 400mg 12 hours apart on day 2) followed by a high maintenance regimen (400 mg every 12 hours) from day 3 on. RESULTS: In the standard dosage group, no patient had the recommended teicoplanin C(min) of >or=10 mg/L within the first 72 hours, and only five of the 11 patients (45%) had a C(min) of >or=10 mg/L after 120 hours. No patient had a C(min) of >or=20 mg/L. In the high dosage group, teicoplanin C(min) averaged >or=10 mg/L within 24 hours, and this value was achieved within 48 hours in all but one patient. Of note, C(min) at 72 hours exceeded 20 mg/L in ten of the 22 patients (45%). No patient experienced significant impairment of renal function. CONCLUSIONS: In this patient group, therapeutically relevant C(min) may be achieved very early in the treatment period with loading doses of 12 mg/kg and 6 mg/kg 12 hours apart on day 1, and 9 mg/kg and 6 mg/kg 12 hours apart on day 2, regardless of renal function. Subsequently, in patients with normal renal function a maintenance dosage of 6 mg/kg every 12 hours may be helpful in ensuring C(min) close to 20 mg/L. Assessment of C(min) after 48-72 hours may be useful to individualise teicoplanin therapy. Factors increasing volume of distribution and/or renal clearance of teicoplanin (fluid load, hypoalbuminaemia, leukaemic status) may explain the need for higher dosages.

Serum and bone concentrations of teicoplanin and vancomycin: study in an animal model.

Teicoplanin and vancomycin are antibiotics widely used in the therapy of bone and joint infections. The aim of this study was to compare bone and serum concentrations of each antibiotic in guinea pigs after administration of 50 mg/kg of teicoplanin or vancomycin by the intravenous route. Serum and bone concentrations were determined immediately before and 0.5, 1, 2, 6, 12 and 24 h after drug administration by means of high performance liquid chromatography. Teicoplanin concentrations were always higher than vancomycin levels. Area under the concentration/time curve was significantly greater for teicoplanin than for vancomycin. In bone, teicoplanin concentration increased up to 6 h, while vancomycin reached its peak after 2 h. Moreover, teicoplanin showed markedly higher levels at 6, 12 and 24 h than vancomycin. In conclusion, the ability of teicoplanin to penetrate bone in greater amount than vancomycin confirms the potential use of teicoplanin in the treatment of bone infections and in the prophylaxis of orthopedic surgery.

Penetration of teicoplanin into heart valves and subcutaneous and muscle tissues of patients undergoing open-heart surgery.

Penetration of teicoplanin into serum, heart valves, and subcutaneous and muscle tissues was determined in 22 patients undergoing open-heart surgery. Each patient received 12 mg of teicoplanin per kg of body weight as a 30-min intravenous infusion preoperatively. Within 10 h, serum concentrations of teicoplanin declined from 43.1 to 2.8 microg/ml. Teicoplanin concentrations in subcutaneous tissues reached their peak of 9.2 microg/g after 2 to 3 h and decreased slowly to 2.3 microg/g after 9 to 10 h. Concentrations in muscle decreased from 8.7 microg/g to nondetectable levels. Teicoplanin concentrations in cardiac valvular tissue reached their peak of 6.1 microg/g and decreased thereafter to 1.7 microg/g. Teicoplanin concentrations in heart valves were high enough to inhibit methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci, which are known to cause postoperative wound infections and infective endocarditis.

Variations of teicoplanin concentrations in neutropenic patients.

The aim of this study was to measure the trough plasma concentrations of teicoplanin in neutropenic patients with a view to optimizing the loading dose. Teicoplanin trough plasma concentrations were followed in 11 neutropenic patients after repeated administration of a 6 mg/kg i.v. bolus. The first three injections were given at 12-h intervals, and the rest every 24 h. Trough plasma concentrations at 48 h varied from 5.6 to 13.1 mg/I. The mean trough plasma concentration-time curve indicated a trend towards accumulation. In conclusion, the loading dose of teicoplanin should be tailored to individual neutropenic patients.

Teicoplanin in cardiac surgery: intraoperative pharmacokinetics and concentrations in cardiac and mediastinal tissues.

The concentrations of teicoplanin in the sera and mediastinal and heart tissues of 23 patients undergoing cardiac surgery were measured after two regimens of teicoplanin administration. Intraoperative pharmacokinetic parameters were also obtained. Patients were randomized into two groups. Those in group 1 were given teicoplanin at 6 mg x kg(-1) intravenously at the time of induction of anesthesia. Patients in group 2 were given teicoplanin at 12 mg x kg(-1) during the same period. The maximum concentration in serum (71 +/- 20 and 131 +/- 44 mg x l(-1)), the minimum concentration in serum (3.6 +/- 1.3 and 6.8 +/- 2.1 mg x l(-1)), the area under the concentration-time curve (AUC) from 0 to 12 h (108 +/- 20 and 217 +/- 38 microg x h x ml(-1)), and the AUC from 0 h to infinity (154 +/- 36 and 292 +/- 77 microg x h x ml(-1)) were twice as high after 12-mg x kg(-1) injections as after 6-mg x kg(-1) injections. No differences in mean residence time (9.7 +/- 4.9 and 8.4 +/- 2.7 h) or terminal half-life (8.5 +/- 3.8 and 7.5 +/- 2.3 h) were observed. Teicoplanin penetrated mediastinal and heart tissues but not sternal bone, where the antibiotic was detectable in only 1 of 13 patients in group 1 and 2 of 10 patients in group 2. In group 1, 7 of 13 patients had teicoplanin concentrations in tissue that were lower than the MIC for 90% of the strains of potential pathogens tested (MIC90) that cause infection after cardiac surgery. All of the patients in group 2 but one had teicoplanin concentrations in tissue (other than in sternal bone) far in excess of the MIC90 for the potential pathogens. In conclusion, the 12-mg x kg(-1) regimen of teicoplanin is followed by a significant increase in teicoplanin concentrations in heart and mediastinal tissues and should be preferred to the 6-mg x kg(-1) regimen if teicoplanin is selected for antimicrobial prophylaxis in open heart surgery.

Teicoplanin pharmacokinetics in pediatric patients.

BACKGROUND: The incidence of methicillin-resistant Gram-positive bacteria infections in febrile neutropenic children is high. Teicoplanin is an alternative treatment to vancomycin in these patients but few pharmacokinetic studies of teicoplanin in children have been conducted and optimal dosages have not been well-established. OBJECTIVES: To assess the pharmacokinetics of teicoplanin in combination with another antibiotic in Gram-positive infections in pediatric patients undergoing bone marrow transplantation and to determine the most appropriate dosage regimen for this type of patient. METHODS: We studied 21 patients divided into 2 groups. In Group A (n = 9) the dosage regimen consisted of 3 loading doses of 10 mg/kg at 12-h intervals, followed by a maintenance dosage of 10 mg/kg/day. Group B (n = 12) received the same loading dose and a maintenance dosage of 20 mg/kg/day. Plasma teicoplanin concentrations were monitored in all patients from the second day after the start of treatment and periodically thereafter. Serum concentrations above 10 mg/l were established as desirable trough values. RESULTS: In Group A trough values > 10 mg/l were not reached in five patients and treatment was modified owing to persistent fever. In Group B all patients attained trough values > 10 mg/l. Tolerance to treatment was excellent. CONCLUSION: In febrile neutropenic pediatric patients undergoing bone marrow transplantation, maintenance dosages of teicoplanin between 15 and 20 mg/kg/day assure serum concentrations above 10 mg/l. Dosages of 10 mg/kg/day do not assure serum through values above 10 mg/l.

Population pharmacokinetic study of teicoplanin in severely neutropenic patients.

The teicoplanin pharmacokinetics (PK) of 30 febrile and severely neutropenic patients (polymorphonuclear count, < 500/mm3) with hematologic malignancies were compared with those determined for five healthy volunteers (HV). Neutropenic patients were given piperacillin combined with amikacin, and teicoplanin was added to the regimen the day fever developed in patients suspected of having a staphylococcal infection or 48 h later. Teicoplanin was given intravenously at a dosage of 6 mg/kg of body weight at 0, 12, and 24 h and once a day thereafter. Five to eleven blood samples per patient were collected. Teicoplanin concentrations were measured by liquid chromatography. A bicompartmental model was fitted to the data by a nonlinear mixed-effect-model approach. Multiple-linear regression analysis was applied in an attempt to correlate PK parameters to nine covariates. The mean trough concentrations of teicoplanin 48 h after the onset of treatment and 24 h after the last injection (last trough) +/- standard deviations were 8.8 +/- 4.1 and 17.5 +/- 13.5 mg/liter, respectively. A significant increase was noted in the mean rate of elimination clearance of teicoplanin in neutropenic patients compared with that of HV (0.86 versus 0.73 liter/h, P = 0.002), as was the case with rates of distribution clearance (5.89 versus 4.94 liter/h, P = 0.002); the mean half-life of distribution was significantly shorter in patients than in HV (0.43 versus 0.61 h, P = 0.002). In contrast, the volumes of the central compartment (ca. 5.8 liters for both groups), the volumes of distribution at steady state (HV, 37.6 liters; patients, 55.9 liters), and the elimination half-lives (HV, 39.6 h; patients, 52.7 h) were not significantly different between HV and neutropenic patients. Interindividual variabilities of rates of clearance (coefficient of variation [CV], 43%) and elimination half-lives (CV, 56%) were mainly explained by the variabilities among rates of creatinine clearance. Interindividual variabilities of the volumes of the central compartment (CV, 33%) and the volumes of distribution at steady state (CV = 51%) were correlated to interindividual variabilities among numbers of leukocytes and the ages of patients, respectively. On the basis of the population PK model of teicoplanin, simulations were made to optimize the dosing schedule. A supplemental 6 mg/kg dose of teicoplanin at 36 h resulted in a trough concentration at 48 h of 16.0 +/- 4.5 mg/liter, with only 7% of patients having a trough concentration of less than 10 mg/liter, compared with 46% of patients on the usual schedule.

Effects of cardiopulmonary bypass on teicoplanin serum disposition.

The time course of teicoplanin (T) serum concentrations was determined in 6 patients who had undergone cardiopulmonary bypass (CPB). The drug was given i.v. (12 mg/kg) 85-140 min before starting CPB. Serum concentrations of T were measured with an automated fluorescence polarization immunoassay, at appropriate times before, during and after CPB (total sampling interval: 12 h). Five min after initiating CPB, T serum concentrations decreased, on average, by 29% and remained less than the expected values (values extrapolated from the decay curve, measured excluding the CPB period) over the subsequent 60 min. When CPB was discontinued, the T serum concentrations rebounded to the expected values within 5 min. The mean area under the curve (AUC) during CPB was significantly lower than the mean extrapolated AUC. It was concluded that CPB reversibly reduced T serum concentrations, probably due to drug redistribution. Nevertheless, T serum levels were always above the mean inhibitory concentration (MIC) of the most common pathogenic organisms associated with CPB surgery infections.