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What Is Known and Objective: Vancomycin therapeutic guidelines suggest a loading dose of 25-30 mg/kg for seriously ill patients. However, high-quality data to guide the use of loading doses are lacking. We aimed to evaluate whether a loading dose (a) achieved a target trough concentration at steady state and (b) improved early clinical response., Methods: Patients with an estimated glomerular filtration rate ≥ 90 mL/min/1.73 m 2 were included. A loading dose of 25 mg/kg vancomycin followed by 15 mg/kg twice daily was compared with traditional dosing. A C min sample was obtained before the fifth dose. An early clinical response 48-72 hours after the start of therapy and clinical success at end of therapy (EOT) was evaluated in patients with methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative Staphylococci or Enterococcus faecium., Results: There was no significant difference in C min between the regimen with and without a loading dose (median: 10.4 and 10.2 µg/mL, P = .54). Proportions of patients achieving 10-20 and 15-20 µg/mL were 56.9% and 5.6%, respectively, in patients with a loading dose. Although there was no significant difference in success rate at EOT between groups, a loading dose was associated with increased early clinical response for all infections (adjusted odds ratio [OR]: 4.588, 95% confidence interval [CI]: 1.373-15.330) and MRSA infections (OR: 12.065, 95% CI: 1.821-79.959). Study limitations included no C min measurements within 24 hours and the inclusion of less critically ill patients., What Is New and Conclusion: A loading dose of 25 mg/kg followed by 15 mg/kg twice daily did not achieve the optimal Cmin at steady state in patients with normal renal function. However, more early clinical responses were obtained with a loading dose compared with traditional dosing, possibly because of a prompt albeit temporary achievement of a more effective concentration., (© 2020 John Wiley & Sons Ltd.)

Background: A trough concentration (C min ) ≥20 μg/mL of teicoplanin is recommended for the treatment of serious methicillin-resistant Staphylococcus aureus (MRSA) infections. However, sufficient clinical evidence to support the efficacy of this target C min has not been obtained. Even though the recommended high C min of teicoplanin was associated with better clinical outcome, reaching the target concentration is challenging., Methods: Pharmacokinetics and adverse events were evaluated in all eligible patients. For clinical efficacy, patients who had bacteremia/complicated MRSA infections were analyzed. The primary endpoint for clinical efficacy was an early clinical response at 72-96 h after the start of therapy. Five dosed of 12 mg/kg or 10 mg/kg was administered as an enhanced or conventional high loading dose regimen, respectively. The C min was obtained at 72 h after the first dose., Results: Overall, 512 patients were eligible, and 76 patients were analyzed for treatment efficacy. The proportion of patients achieving the target C min range (20-40 μg/mL) by the enhanced regimen was significantly higher than for the conventional regimen (75.2% versus 41.0%, p < 0.001). In multivariate analysis, C min  ≥ 20 μg/mL was an independent factor for an early clinical response (odds ratio 3.95, 95% confidence interval 1.25-12.53). There was no significant difference in the occurrence of adverse events between patients who did or did not achieve a C min  ≥ 20 μg/mL., Conclusion: A target C min  ≥ 20 μg/mL might improve early clinical responses during the treatment of difficult MRSA infections using 12 mg/kg teicoplanin for five doses within the initial 3 days.

In the treatment of severe MRSA infections such as endocarditis, more than 20 mg/L of plasma trough concentration (C(min)) is recommended for teicoplanin; however, in the treatment of common MRSA infections, recommended C(min) remains more than 10 mg/L. In this study, we set C(min) as 15-30 mg/L to obtain a favorable clinical outcome in the treatment of common MRSA infections, and investigated the optimal loading regimen that achieved the target C(min) in patients with normal renal function. Seventy-eight patients received the high-dose regimen A (6 mg/kg every 12-h for initial two days) and 60 patients received the high-dose regimen B (the first five loading doses of 10-12 mg/kg at 12-h intervals for initial three days, followed by 6 mg/kg once daily). The mean C(min) on the 4th day was 13.7 ± 5.3 mg/L in regimen A, and 20.0 ± 6.6 mg/L in regimen B (P < 0.001), and the proportion of patients achieving the 15-30 mg/L was 25.6% and 68.3% (P < 0.001). Clinical response at end-of treatment were 66.7% and 85.0% (P = 0.014). The patients of initial C(min) with ≥15 mg/L had tended to be higher clinical response than those with <15 mg/L (80.9% vs 68.6%, P = 0.084). There were no significant differences in the occurrence of adverse effects in regimen A and B (nephrotoxicity; 1.3% vs 3.3%, P = 0.413, hepatotoxicity; 5.1% vs 3.3%, P = 0.608). In conclusion, to obtain C(min) 15-30 mg/L, the first five loading doses of 10-12 mg/kg at 12-h intervals was required in patients with normal renal function., (Copyright © 2013 Japanese Society of Chemotherapy and the Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The aim of this study was to investigate the timing of therapeutic drug monitoring (TDM) in patients with impaired renal function treated with once-daily administration of vancomycin (VCM). Once-daily administration was selected for patients whose creatinine clearance (Ccr) was <80 ml/min. TDM was conducted on day 3 or on day 4. Adult patients whose VCM dosage was not altered according to initial C min and for whom subsequent follow-up TDM was performed within 1 week were entered into the study. Patients whose renal function deteriorated at follow-up TDM were excluded. One hundred sixty-five patients were eligible for analysis. Among patients with once-daily dosing, relative increases of C min at follow-up TDM compared with initial TDM were 34.5 ± 39.2 % in TDM on day 3 and 16.6 ± 20.6 % in TDM on day 4 (P = 0.016). In contrast, there was no significant difference in the relative increase of C min between TDM on days 3 and 4 (26.1 ± 39.6 vs. 18.4 ± 25.6 %, P = 0.551) in the twice-daily regimen. On multivariate analysis, TDM on day 3 alone (odds ratio, 4.93; 95 % confidence interval, 1.71-14.2) was selected as an independent risk factor associated with a relative increase of C min by >30 % in the once-daily regimen. Steady-state VCM serum concentration was not achieved on day 3 in the once-daily regimen in patients with impaired renal function, and TDM on day 3 caused underestimation of C min.

Minimum inhibitory concentration (MIC) creep in vancomycin has prompted guidelines that recommend a target trough concentration (C (min)) of 15-20 mg/L, and it is also considered necessary to set a C (min) of >15 mg/L for teicoplanin (TEIC), especially in patients with complicated methicillin-resistant Staphylococcus aureus (MRSA) infections. The aim of this study was to investigate the appropriate TEIC regimen for reaching the revised target C (min) (15-30 mg/L) in patients with normal renal function and those with renal dysfunction. We analyzed patients with MRSA infections who were treated with TEIC between July 2006 and December 2009. Two-day loading regimen was studied in patients with non-renal-dysfunction (group 1). The 1-day loading regimen was studied in patients with non-renal-dysfunction (group 2, control) and in patients with renal dysfunction (group 3). The 178 patients in the study consisted of 76, 28, and 74 patients in groups 1, 2, and 3, respectively. C (min) on day 4 was 14.6 ± 5.6, 11.9 ± 4.1, and 13.5 ± 4.2 mg/L, and the proportion of patients achieving the revised target range was 34.2%, 17.9%, and 20.3%, respectively. Only one patient in group 1 revealed C (min) of >30 mg/L. Treatment success rates, nephrotoxicity, and hepatotoxicity were similar among the three groups. It was difficult to achieve the revised target C (min) with the 2-day loading regimen in patients without renal dysfunction and with the standard TEIC regimen, even in patients with renal dysfunction. Further investigation of an even higher TEIC dosing regimen is considered necessary.

Recent studies demonstrated that mortality associated with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia was high when vancomycin was used to treat infections with strains that had a high vancomycin minimum inhibitory concentration (MIC). This study compared several characteristics of vancomycin MIC 2 μg/ml strains isolated from bacteremia with those isolated from infections other than bacteremia. A total of 128 episodes of MRSA bacteremia between 2005 and 2008 were followed-up, and compared with 631 MRSA infections other than bacteremia. The isolation of strains with a 2 μg/ml MIC accounted for 32.0% of isolates from MRSA bacteremia, whereas strains with a 2 μg/ml MIC comprised 9.0% of MRSA isolated from other sites (p < 0.001). The incidence of pneumonia as the source of infection was significantly higher in patients with bacteremia from strains with a 2 μg/ml MIC than in those with ≤1 μg/ml MIC. Prior vancomycin use did not correlate with the isolation of 2 μg/ml strains. The efficacy of glycopeptides as 1st line therapy in patients infected with 2 μg/ml strains was significantly lower than that for patients infected with ≤1 μg/ml strains (30.0 vs. 78.8%, p < 0.001) in bacteremia. In the analysis of infections other than bacteremia, efficacy did not reveal a significant difference according to MIC (69.0 vs. 79.6%, p = 0.109). In bacteremia, mortality was 65.8% in patients with 2 μg/ml strains and 19.5% in patients with ≤1 μg/ml strains (p < 0.001), whereas there was no significant difference in mortality from infections other than bacteremia (10.7 vs. 7.8%, p = 0.617). In multivariate analysis, bacteremia with 2 μg/ml strains, intensive care unit (ICU) stay, and liver cirrhosis were independent risk factors for death in patients with bacteremia, and initial appropriate therapy lowered the risk. Several characteristics such as a higher incidence than at other infection sites, a high incidence of pneumonia as a source of infection, a low success rate of vancomycin therapy, and poor prognosis were confirmed in 2 μg/ml MIC MRSA isolated from bacteremia; however, a low success rate of vancomycin and poor prognosis were not apparent in 2 μg/ml MIC MRSA strains isolated from infections other than bacteremia.