Patients
This retrospective study was conducted between June 2015 and May 2019, and was approved by the Institutional Review Board of Hyogo College of Medicine (No. 3266). Adult patients who were treated with teicoplanin, and in whom therapeutic drug monitoring (TDM) was performed, were included in the study. Exclusion criteria were patients with known hypersensitivity to teicoplanin, pregnancy, below the age of 18 years, and requirement of intermitted hemodialysis and continuous renal replacement therapy. The analysis of Cmin and the safety population included all eligible patients. The analysis of the clinical efficacy population included patients 1) who had bacteremia or complicated infections [ventilator associated pneumonia (VAP), osteomyelitis and arthritis infection, and central nervous system infection] by MRSA, 2) who received at least 4 days of teicoplanin treatment, 3) who did not receive any concomitant antibiotics with anti-MRSA activity, and 4) who did not receive the above mentioned antibiotics for > 24 h within the previous 3 days.
A diagnosis for each infection was based on definitions in the guidelines issued by the National Healthcare Safety Network [13]. Infections with at least one of the following signs were analyzed: core temperature >37.8°C, total peripheral white blood cell (WBC) count >10,000/mm3, or C-reactive protein (CRP) >3.0 mg/dL. The minimum inhibitory concentration (MIC) of teicoplanin was measured by microdilution methods in accordance with the Clinical and Laboratory Standards Institute testing guidelines (M02 and M07, 2018) [14]. MIC break-points set by the European Committee on Antimicrobial Susceptibility Testing were adopted in this study, and antimicrobial resistance was defined as MIC ≥4 μg/mL. The estimated glomerular filtration rate (eGFR) was calculated using the following formula developed by the Japanese Society of Nephrology [eGFR (mL/min/1.73 m2) = 194 × serum creatinine (−1.094) × age (−0.287) × 0.739 (for females)] [15].
Administration plan in patients with conventional and enhanced high loading dose regimens
The target initial trough concentration (Cmin) was 15–30 µg/mL between June 2015 and May 2018, and 20–40 µg/mL in patients with bacteremia/complicated MRSA infections between June 2018 and May 2019. According to these target Cmin, we conducted two different teicoplanin dose regimens for 3 consecutive days as follows. A conventional high loading dose regimen was used for patients with a target Cmin 15–30 µg/mL, and the enhanced high loading dose regimen was used for patients with a target Cmin 20–40 µg/mL.
- Conventional high loading dose regimen: a loading dose of 10 mg/kg twice daily on the first and second days, followed by 10 mg/kg once daily on the third day in patients whose eGFR was ≥60 ml/min/1.73 m2; a loading dose of 10 mg/kg twice daily on the first day, followed by 10 mg/kg once daily on the second and third days in patients whose eGFR was 40–60 mL/min/1.73 m2; and a loading dose of 10 mg/kg twice daily on the first day, followed by 6.7 mg/kg once daily on the second and third days in patients whose eGFR was <40 mL/min/1.73 m2. Maintenance dosing after the fourth day was 6.7 mg/kg once daily in patients whose eGFR was ≥60 ml/min/1.73 m2; 3.3 mg/kg once daily in patients whose eGFR was 40–60 mL/min/1.73 m2; and 5.0 mg/kg every 2 days in patients whose eGFR was <40 mL/min/1.73 m2.
- Enhanced high loading dose regimen: a loading dose of 12 mg/kg twice daily on the first and second days, followed by 12 mg/kg once daily on the third day in patients whose eGFR was ≥60 ml/min/1.73 m2; a loading dose of 12 mg/kg twice daily on the first day, followed by 12 mg/kg once daily on the second and third days in patients whose eGFR was 30–60 mL/min/1.73 m2; and a loading dose of 12 mg/kg twice daily on the first day, followed by 12 mg/kg once daily on the second day and 6.7 mg/kg once daily on the third day in patients whose eGFR was <30 mL/min/1.73 m2. The maintenance dosing regimen after the fourth day was 6.7 mg/kg once daily in patients whose eGFR was ≥60 ml/min/1.73 m2; 5.0 mg/kg once daily in patients whose eGFR was 30–60 mL/min/1.73 m2; and 6.7 mg/kg every 2 days in patients whose eGFR was <30 mL/min/1.73 m2.
Therapeutic drug monitoring and dosage adjustment
An initial Cmin sample was obtained prior to the administration of teicoplanin on the fourth day (at 72 h after the first dose). The target Cmin was defined as 20–40 μg/mL. The dose of teicoplanin was adjusted according to the initial Cmin. Additional loading doses were administered on the fourth day if the initial Cmin was lower than the target Cmin. Blood samples were collected in blood-collection tubes without a blood coagulation accelerator and immediately centrifuged at 3000 rpm for 10 min. Teicoplanin was measured using a fluorescence polarization immunoassay with a TDXFLX analyzer (Abbott Japan Co., Tokyo, Japan) and a teicoplanin TDM kit-IBL (OXIS International Inc., Beverly Hills, CA, USA).
Clinical efficacy
The primary endpoint was an early clinical response at 72–96 h after the start of teicoplanin therapy. We defined patients as responders if they had a 30% or greater decrease in total peripheral WBC count or CRP, decline of fever (defined as a daily maximum temperature decrease of > 0.3°C for at least two consecutive days in febrile patients), without worsening of clinical features, and did not die within 96 h [16]. Secondary efficacy end points were clinical success at the end of teicoplanin therapy (EOT), which was defined as survival with the resolution or improvement of all core symptoms and signs of infection in each infection to the extent that further antibacterial therapy with anti-MRSA activity was unnecessary. Microbiological assessments were conducted using cultures taken before the start of teicoplanin administration and at the completion of treatment, and microbiological success was defined as “eradication” (pathogen absent in culture) or “presumed eradication” (no material available for culture because the infection was cured or attenuated).
Adverse events
Adverse events of nephrotoxicity and hepatotoxicity were evaluated on the fourth day of therapy and at the end of teicoplanin therapy. Nephrotoxicity was defined as a serum creatinine (Cre) increase >0.5 mg/L or 50% increase from the baseline [17]. Hepatotoxicity was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels at or above three times the upper limit of normal. If the AST or ALT baseline was abnormal, hepatotoxicity was defined as AST or ALT at or above three times the baseline [18].
Statistical analysis
Parametric variables were analyzed using the Student’s t-test, while nonparametric variables were analyzed using the Mann–Whitney U-test or Fisher’s exact test. Multivariate analyses were performed to determine the odds ratio (OR) to achieve the target Cmin (≥20 μg/mL) and early clinical responses. The crude OR in univariate analysis was estimated for each variable using the chi-squared test, and potential confounders were examined by cross tabulation. Variables selected by univariate analysis (p < 0.1) were subsequently entered into a stepwise logistic regression model to estimate the magnitude of association [adjusted OR and 95% confidence interval (CI)]. The level of significance was set at p < 0.05. SPSS ver. 24 (SPSS Inc., Chicago, IL, USA) was used to perform statistical analyses.