Optimal Teicoplanin Trough Concentration With Therapeutic Drug Monitoring in Children: A Systematic Review and Meta-analysis.

BACKGROUND: Teicoplanin is used to treat serious Gram-positive bacterial infections. However, the optimal trough concentrations for pediatric patients remain unclear owing to the lack of monitoring guidelines. This study aimed to determine the optimal teicoplanin trough concentration for treating Gram-positive bacterial infections in children. METHODS: A systematic review was conducted using 4 databases. Stepwise cutoffs within the range of 10-30 mcg/mL were used for efficacy and safety. Studies were included if they reported treatment success rates and/or all-cause mortality, nephrotoxicity, hepatotoxicity, and thrombocytopenia according to the trough concentration. RESULTS: The meta-analysis included 12 studies involving 830 pediatric patients. Teicoplanin cutoff values of 10, 15, 20, and 30 mcg/mL were reported in 9, 8, 9, and 2 studies, respectively. Trough concentrations <10 mcg/mL significantly reduced the treatment success rate, with an odds ratio of 0.07 and a 95% confidence interval ranging from 0.01 to 0.40. The overall treatment success rate was 50.0% versus 95.7% observed at concentrations ≥10 mcg/mL. However, no significant difference was observed at the 15-, 20-, and 30-mcg/mL cutoffs, when compared with lower concentrations. Trough concentrations <20 mcg/mL were associated with a decreased risk of nephrotoxicity (odds ratio = 0.21; 95% confidence interval, 0.08-0.55). However, hepatotoxicity and thrombocytopenia showed no significant associations with trough concentration ranges between 10 and 30 mcg/mL. CONCLUSIONS: Although further prospective studies are required for validation, the authors' findings suggest that 10- to 20-mcg/mL teicoplanin is the optimal trough concentration for enhanced clinical success and reduced toxicity in pediatric patients.

Difference in the impact of coinfections and secondary infections on antibiotic use in patients hospitalized with COVID-19 between the Omicron-dominant period and the pre-Omicron period.

INTRODUCTION: This study evaluated the effect of coinfections and/or secondary infections on antibiotic use in patients hospitalized with coronavirus disease 2019 (COVID-19). METHOD: Days of therapy per 100 bed days (DOT) in a COVID-19 ward were compared between 2022 (Omicron period) and 2021 (pre-Omicron period). Antibiotics were categorized as antibiotics predominantly used for community-acquired infections (CAIs) and antibiotics predominantly used for health care-associated infections (HAIs). Bacterial and/or fungal infections which were proved or assumed on admission were defined as coinfections. Secondary infections were defined as infections that occurred following COVID-19. RESULTS: Patients with COVID-19 during the Omicron period were older and had more comorbidities. Coinfections were more common in the Omicron period than in the pre-Omicron period (44.4% [100/225] versus 0.8% [2/257], respectively, p < 0.001), and the mean DOT of antibiotics for CAIs was significantly increased in the Omicron period (from 3.60 to 17.84, p < 0.001). Secondary infection rate tended to be higher in the Omicron period (p = 0.097). Mean DOT of antibiotics for HAIs were appeared to be lower in the COVID-19 ward than in the general ward (pre-Omicron, 3.33 versus 6.37, respectively; Omicron, 3.84 versus 5.22, respectively). No multidrug-resistant gram-negative organisms were isolated in the COVID-19 ward. CONCLUSION: Antibiotic use for CAIs was limited in the pre-Omicron period but increased in the Omicron period because of a high coinfection rate on admission. With the antimicrobial stewardship, excessive use of antibiotics for HAIs was avoided in the COVID-19 ward during both periods.

Validation and development of population pharmacokinetic model of vancomycin using a real-world database from a nationwide free web application.

INTRODUCTION: Vancomycin requires a population pharmacokinetic (popPK) model to estimate the area under the concentration-time curve (AUC), and an AUC-guided dosing strategy is necessary. This study aimed to develop a popPK model for vancomycin using a real-world database pooled from a nationwide web application (PAT). METHODS: In this retrospective study, the PAT database between December 14, 2022 and April 6, 2023 was used to develop a popPK model. The model was validated and compared with six existing models based on the predictive performance of datasets from another PAT database and the Kumamoto University Hospital. The developed model determined the dosing strategy for achieving the target AUC. RESULTS: The modeling populations consisted of 7146 (13,372 concentrations from the PAT database), 3805 (7540 concentrations from the PAT database), and 783 (1775 concentrations from Kumamoto University Hospital) individuals. A two-compartment popPK model was developed that incorporated creatinine clearance as a covariate for clearance and body weight for central and peripheral volumes of distribution. The validation demonstrated that the popPK model exhibited the smallest mean absolute prediction error of 5.07, outperforming others (ranging from 5.10 to 5.83). The dosing strategies suggested a first dose of 30 mg/kg and maintenance doses adjusted for kidney function and age. CONCLUSIONS: This study demonstrated the updating of PAT through the validation and development of a popPK model using a vast amount of data collected from anonymous PAT users.

Influence of easing COVID-19 strategies following downgrading of the national infectious disease category on COVID-19 occurrence among hospitalized patients in Japan.

PURPOSE: We aimed to evaluate the influence of easing COVID-19 preventive measures following its downgrading to a common infectious disease on COVID-19 occurrence among hospitalized patients. METHODS: Nosocomial occurrence of COVID-19 was compared between periods with national infectious disease category 5 versus the preceding category 2 equivalent. Changes in the revised manual included a shorter duration of work restrictions for infected health care practitioners (HCPs); no work restriction for HCPs exposed to SARS-CoV-2 with a negative test on days 1, 3 and 5; discontinuation of universal pre-admission screening; and pre-emptive isolation of patients without screening. Wearing an N95 mask and face shield was required in procedure/care with moderate-to high-risk contact. RESULTS: Although the mean monthly number of infected HCPs increased from 8.1 to 12.7 in the category 5 period (p = 0.034) and that of pre-admission screening decreased to one-fourth, the COVID-19 incidence in hospitalized patients remained similar between the two study periods (1.60 ± 5.59/month versus 1.40 ± 2.63/month, p = 0.358). Clusters, defined as ≥3 COVID-19 patients on the ward, were experienced twice in the preceding period and only once in the category 5 period. The index cases causing nosocomial SARS-CoV-2 transmission mostly involved rehabilitation therapists in the preceding period; five of six index cases were patients in the category 5 period. Following the expanded indication for N95 masks, neither SARS-CoV-2 transmission to patients nor transmission from infected patients was observed in HCPs for 1 year. CONCLUSION: With sustained, enhanced standard precautions, easing prevention strategies could limit nosocomial SARS-CoV-2 infections.

Clinical features of pasteurellosis without an animal bite or scratch in comparison with bite/scratch pasteurellosis.

Pasteurellosis is a common zoonotic infection that occurs after an animal bite or scratch (B/S). We compared the clinical features of six patients with non-B/S pasteurellosis with those of 14 patients with B/S infections. Pasteurella multocida was identified with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in all six non-B/S infections, whereas 13 of the 14 B/S infections were identified with diagnostic kits. The non-B/S infections were pneumonia (n = 3), skin and soft tissue infections (n = 2), and bacteremia (n = 1). Pneumonia occurred in two patients with underlying pulmonary disease, whereas ventilator-associated pneumonia developed in one patient with cerebral infarction. Pasteurella multocida was isolated from a blood specimen and nasal swab from a patient with liver cirrhosis (Child-Pugh class C) and diabetes. Cellulitis developed in one patient with diabetes and normal-pressure hydrocephalus, who had an open wound following a fall, and in one patient with diabetes and a foot ulcer. Three patients with non-B/S infections had no pet and no episode of recent animal contact. The rate of moderate-to-severe comorbidities was significantly higher in patients with non-B/S infections than in those with B/S infections (100% and 14.3%, respectively, p < 0.001). In conclusion, non-B/S infections can develop in patients with chronic pulmonary disease, invasive mechanical ventilation, or open wounds, or who are immunocompromised, irrespective of obvious animal exposure. In contrast to B/S infections, non-B/S pasteurellosis should be considered opportunistic.

Association between the hypokalaemia index based on area over the serum potassium concentration curve and occurrence of acute kidney injury in patients administered liposomal amphotericin B.

BACKGROUND: Acute kidney injury (AKI) and hypokalaemia are common adverse events after treatment with liposomal amphotericin B (L-AMB). OBJECTIVES: Because excess potassium (K) leakage occurs during renal tubular injury caused by L-AMB, measuring the decrease in rate of serum K concentration might be more useful to assess the renal impact of L-AMB than hypokalaemia identified from a one-point measurement. The effects of a decrease in K concentration and duration of hypokalaemia on AKI were investigated. METHODS: A ≥ 10% decrease in K concentration from the reference concentration within a 7-day timeframe was evaluated. The hypokalaemia index, which combines the duration of K concentration lower than the reference and a marked low K concentration, was calculated from the area over the concentration curve. RESULTS: Eighty-six patients were included in the study. The incidences of AKI and decrease in K concentration were 36.0% and 63.9%, respectively. Of patients who developed both adverse events, a decrease in K concentration occurred first in 22 of 26 patients, followed by AKI 7 days later. Hypokalaemia did not increase AKI risk whereas a decrease in K concentration was an independent risk factor for AKI. The hypokalaemia index in patients with AKI was significantly higher than those without AKI (5.35 vs. 2.50 points, p = 0.002), and ≥3.45 points was a significant predictor for AKI. CONCLUSION: A ≥ 10% decrease in the K concentration was a significant factor for AKI in patients receiving L-AMB therapy. In such patients, dose reduction or alternative antifungals could be considered based on the hypokalaemia index.

Comparison of the efficacy and safety of standard- and high-dose daptomycin: A systematic review and meta-analysis.

AIMS: Standard doses of daptomycin at 4 and 6 mg/kg were used for the treatment of skin and soft tissue for infections and bacteraemia, respectively. However, increased doses of daptomycin are recommended for complicated infections by Gram-positive organisms. METHODS: A systematic review was conducted using 4 databases. We compared treatment success between standard-dose (SD, 4-6 mg/kg) and high-dose (HD, >6 mg/kg) daptomycin in patients with all-cause bacteraemia, complicated bacteraemia, infective endocarditis, osteomyelitis and foreign body/prosthetic infection as the primary outcome. We also compared the success between SD and HD2 (≥8 mg/kg) daptomycin treatments in patients with these diseases as the secondary outcome. The incidence of creatine phosphokinase (CPK) elevation was evaluated as safety. RESULTS: In patients with complicated bacteraemia and infective endocarditis, the treatment success was significantly lower in the SD group than in the HD group (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.30-0.76 and OR 0.50, 95% CI 0.30-0.82) and HD2 group (OR 0.38, 95% CI 0.21-0.69 and OR 0.30, 95% CI 0.15-0.60), respectively. A significant difference was demonstrated only in the HD2 group in patients with bacteraemia, including simple infection. SD did not decrease the success rate for the treatment of osteomyelitis and foreign body/prosthetic infection. The incidence of elevated CPK was significantly lower in SD group than in HD group. CONCLUSION: SD daptomycin was associated with significantly lower treatment success than HD in patients with complicated bacteraemia/infective endocarditis. The CPK elevation should be considered in patients treated with high daptomycin doses.

Judicious ending of isolation based on reverse transcription-polymerase chain reaction (RT-PCR) cycle threshold only for patients with coronavirus disease 2019 (COVID-19) requiring in-hospital therapy for longer than 20 days after symptom onset.

BACKGROUND: For patients with coronavirus disease 2019 (COVID-19) requiring hospitalization, extending isolation is warranted. As a cautious protocol, ending isolation based on polymerase chain reaction cycle threshold (Ct) value was introduced for patients requiring therapy for >20 days after symptom onset. METHOD: We compared a Ct-based strategy using Smart Gene® between March 2022 and January 2023 with a preceding control period (March 2021 to February 2022) when two consecutive negative reverse transcription-polymerase chain reaction tests using FilmArray® were required for ending isolation. Ct was evaluated on day 21, and ending isolation was permitted in patients with Ct ≥ 38. Although patients with Ct 35-37 were transferred to a non-COVID-19 ward, isolation was continued. RESULTS: The duration of stay on a COVID-19 ward in the Ct group was 9.7 days shorter than that in controls. The cumulative number of tests was 3.7 in controls and 1.2 in the Ct group. There was no nosocomial transmission after ending isolation in either group. The number of days from symptom onset to testing was 20.7 ± 2.1 in Ct group, and five patients had Ct < 35, nine Ct 35-37, and 71 Ct ≥ 38. No patients were moderately or severely immunocompromised. Steroid use was an independent risk factor for prolonged low Ct (odds ratio 9.40, 95% confidence interval 2.31-38.15, p = 0.002) CONCLUSIONS: The efficacy of ending isolation based on Ct values could improve bed utilization without the risk of transmission among patients with COVID-19 requiring therapy for >20 days after symptom onset.

Optimal timing for therapeutic drug monitoring of voriconazole to prevent adverse effects in Japanese patients.

BACKGROUND: The optimal timing for therapeutic drug monitoring (TDM) of voriconazole in Asians, who have higher rates of poor metabolisers than non-Asians, is unclear. This can cause unexpectedly high concentrations and delays in reaching steady-state levels. OBJECTIVES: To determine the appropriate timing of TDM in Japanese patients receiving voriconazole. PATIENTS/METHODS: Trough levels (Cmin ) were measured on days 3-5 (recommended timing, RT) and days 6-14 (delayed timing, DT) after starting voriconazole in patients receiving an appropriate dosage. Considering bioavailability, Cmin was only compared in patients receiving oral voriconazole. RESULTS: A total of 289 and 186 patients were included in the safety and pharmacokinetic analyses, respectively. There was a significant difference in Cmin measured no later than and after day 5 (3.59 ± 2.12 [RT] vs. 4.77 ± 3.88 µg/mL [DT], p = .023), whereas no significant difference was observed on cutoff day 6 (3.91 ± 2.60 vs. 4.40 ± 3.94 µg/mL, p = .465), suggesting that Cmin close to the steady-state was achieved after day 5. DT causes a delay in achieving the therapeutic range. The hepatotoxicity rates were 21.5% and 36.8% in the RT and DT groups, respectively (p = .004); DT was an independent risk factor for hepatotoxicity. CONCLUSION: Although steady-state concentrations may not be achieved by day 5, early dose optimisation using RT can prevent hepatotoxicity in Japanese patients. TDM should be performed on days 3-5 to ensure safety. However, subsequent TDM may be necessary due to a possible further increase in Cmin .

Clinical practice guidelines for therapeutic drug monitoring of teicoplanin: a consensus review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring.

BACKGROUND: Owing to its low risk of adverse effects, teicoplanin has been extensively used in patients with infections caused by MRSA. To promote the better management of patients receiving teicoplanin, we have updated the guidelines for therapeutic drug monitoring (TDM). METHODS: The guidelines were developed by a committee following the methodology handbook published by the Japanese Medical Information Distribution Service. Nine clinical questions were selected. The committee conducted a systematic review and meta-analysis to establish evidence-based recommendations for the target trough concentration (Cmin). An initial electronic database search returned 515 articles, and 97 articles qualified for a full review. Four and five studies were included for the efficacy evaluation of cut-off Cmin values of 15 and 20 mg/L, respectively. RESULTS: Compared with Cmin < 15 mg/L, a target Cmin value of 15-30 mg/L resulted in increased clinical efficacy in patients with non-complicated MRSA infections (OR = 2.68; 95% CI = 1.14-6.32) without an increase in adverse effects. Although there was insufficient evidence, target Cmin values of 20-40 mg/L were suggested in patients with complicated or serious MRSA infections. A 3 day loading regimen followed by maintenance treatment according to renal function was recommended to achieve the target trough concentrations. Because of the prolonged half-life of teicoplanin, measurement of the Cmin value on Day 4 before reaching steady state was recommended. CONCLUSIONS: The new guideline recommendations indicate the target Cmin value for TDM and the dosage regimen to achieve this concentration and suggest practices for specific subpopulations.

Effect of Changing Surgical Instruments Before Wound Closure to Prevent Wound Infection in Lower GI Surgery: A Randomized Controlled Trial.

BACKGROUND: Surgical site infection is a major surgical complication and has been studied extensively. However, the efficacy of changing surgical instruments before wound closure remains unclear. OBJECTIVE: The aim of this study was to investigate the efficacy of changing surgical instruments to prevent incisional surgical site infection during lower GI surgery. DESIGN: This was a randomized controlled trial. SETTINGS: This study was conducted at the Hyogo College of Medicine in Japan. PATIENTS: Patients undergoing elective lower GI surgery with open laparotomy were included. INTERVENTIONS: Patients were randomly assigned to 1 of 2 groups. In group A, the surgeon changed surgical instruments before wound closure, and in group B, the patients underwent conventional closure. MAIN OUTCOME MEASURES: The primary end point was the incidence of incisional surgical site infection. The secondary end point was the incidence of surgical site infection restricted to clean-contaminated surgery. RESULTS: A total of 453 patients were eligible for this trial. The incidence of incisional surgical site infection was not significantly different between group A (18/213; 8.5%) and group B (24/224; 10.7%; p = 0.78). In the clean-contaminated surgery group, the incidence of incisional surgical site infection was 13 (6.8%) of 191 in group A and 9 (4.7%) of 190 in group B (p = 0.51). LIMITATIONS: This was a single-center study. CONCLUSIONS: Changing surgical instruments did not decrease the rate of incisional surgical site infection in patients undergoing lower GI surgery in either all wound classes or clean-contaminated conditions. See Video Abstract at http://links.lww.com/DCR/B701. EFECTO DE REALIZAR CAMBIO DE LOS INSTRUMENTOS QUIRRGICOS ANTES DEL CIERRE DE LA INCISIN EN LA INFECCIN DE LA HERIDA DEL SITIO QUIRRGICO EN CIRUGA DEL TUBO DIGESTIVO BAJO ESTUDIO ALEATORIO CONTROLADO: ANTECEDENTES:La infección del sitio quirúrgico es una complicación importante y se ha estudiado ampliamente. Sin embargo, la eficacia de cambiar los instrumentos quirúrgicos antes del cierre de la herida sigue sin estar clara.OBJETIVO:El objetivo de este estudio es investigar la eficacia de cambiar el instrumental quirúrgico en la prevención de la infección del sitio quirúrgico en cirugía gastrointestinal inferior.DISEÑO:Estudio aleatorio controlado.AJUSTE:Este estudio se realizó en la Facultad de Medicina de Hyogo en Japón.PACIENTES:Se incluyeron pacientes sometidos a cirugía electiva de tubo digestivo bajo con laparotomía abierta.INTERVENCIONES:Los pacientes fueron asignados aleatoriamente a uno de dos grupos. En el grupo A, el cirujano cambió el instrumental quirúrgico antes del cierre de la herida, y en el grupo B, los pacientes se sometieron a un cierre convencional.PRINCIPALES MEDIDAS DE RESULTADO:El criterio de valoración principal fue la incidencia de infección del sitio quirúrgico de la incisión. El criterio de valoración secundario fue la incidencia de infección del sitio quirúrgico restringida a la cirugía limpia contaminada.RESULTADOS:Un total de 453 pacientes fueron elegibles para este ensayo. La incidencia de infección del sitio quirúrgico no fue significativamente diferente entre el grupo A (18/213; 8,5%) y el grupo B (24/224; 10,7%) (p = 0,78). En el grupo de cirugía limpia-contaminada, la incidencia de infección del sitio quirúrgico incisional fue 13/191 (6,8%) en el grupo A y 9/190 (4,7%) en el grupo B (p = 0,51).LIMITACIÓN:Estudio de un solo centro.CONCLUSIÓNES:El cambio de instrumentos quirúrgicos no disminuyó la tasa de infección del sitio quirúrgico en todas las clases de heridas o condiciones limpias-contaminadas. Consulte Video Resumen en http://links.lww.com/DCR/B701.

Correction of thrombocytopenia caused by linezolid with scheduled sequential tedizolid use in patients with vertebral osteomyelitis by antibiotic resistant Gram-positive organisms.

INTRODUCTION: Because of thrombocytopenia, linezolid treatment tends to be stopped before the completion of therapy for complicated infections that require prolonged antimicrobial administration. In contrast, tedizolid shows a favorable hematologic profile. The primary end-point of this study was to evaluate the efficacy of switching treatment to tedizolid in patients who developed thrombocytopenia during linezolid therapy. METHODS: This retrospective study was conducted in patients with vertebral osteomyelitis (VO) caused by antibiotic-resistant Gram-positive bacteria. Treatment failure was defined as the reappearance of infection signs within 2 weeks after stopping tedizolid and discontinuation of tedizolid because of continued thrombocytopenia or other adverse effects. RESULTS: Eight patients with native VO (n = 3) and postoperative VO (n = 5) were included in the study. The causative organisms were MRSA in all patients except one. Platelet counts decreased from 35.2 ± 11.5 × 104/mm3 to 17.8 ± 6.2 × 104/mm3 during linezolid therapy and improved without washout period in all patients after switching to tedizolid on days 5-7 (28.6 ± 4.9 × 104/mm3, p = 0.002). Tedizolid therapy was completed and treatment failure was not observed in any patient. The duration of treatment was 20.0 ± 11.2 days for linezolid and 30.3 ± 9.5 days for tedizolid (total, 50.3 ± 10.7 days). One patient died because of underlying disease, and there was no recurrence in the remaining 7 patients (median follow-up 501 days). CONCLUSIONS: Switching therapy to tedizolid improved thrombocytopenia that occurred during linezolid therapy, and it enabled the completion of therapy for VO patients.

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.

Survey on the current status of the indication and implementation protocols for bile replacement in patients with external biliary drainage with special reference to infection control.

PURPOSE: This survey of bile replacement (BR) was conducted on patients with external biliary drainage to assess the current status of indication and implementation protocol of BR with special reference to infection control. METHODS: A 12-item questionnaire regarding the performance of perioperative BR was sent to 124 institutions in Japan. RESULTS: BR was performed in 29 institutions, and the indication protocol was introduced in 19. BR was performed preoperatively in 11 institutions, pre- and postoperatively in 12, and postoperatively in 6. The methods used for BR administration included oral intake (n = 10), nasogastric tube (n = 1), enteral nutrition tube (n = 3), oral intake and enteral nutrition tube (n = 6), oral intake or nasogastric tube (n = 2), nasogastric tube and enteral nutrition tube (n = 2), and oral intake or nasogastric tube and enteral nutrition tube (n = 5). In 10 of 29 institutions, isolation of multidrug-resistant organisms and a high bacterial load were considered contraindications for the use of BR. Seven institutions experienced environmental contamination. CONCLUSIONS: Given the different implementation of BR among institutions, the appropriate indication and protocols for BR should be established for infection control.

Performance of Area under the Concentration-Time Curve Estimations of Vancomycin with Limited Sampling by a Newly Developed Web Application.

PURPOSE: Therapeutic drug monitoring guided by the area under the concentration-time curve (AUC-guided TDM) is recommended for vancomycin. However, validated efficient software remains elusive to popularize AUC-guided TDM in Japan. The aim of this study was to validate a newly developed web application, PAT, for AUC estimation. METHODS: PAT was developed on the R ver. 3.6.2 platform for use with mobile phones and personal computers. AUC estimated by PAT (AUCPAT) was evaluated against the reference AUC (AUCREF) calculated with the log-linear trapezoidal rule using eight measured concentrations, or against AUC (AUCBM-P) calculated using an evaluated available software with clinical data. RESULTS: Investigating the best sampling points with limited sampling, PAT produced the least bias using two concentrations at 1 h and 11 h after the end of infusion (slope 1.18, intercept -15.57, median AUCPAT/AUCREF 0.93 [range 0.81-1.24]), where only one estimation (6%) was out of the predetermined acceptable range of 0.8-1.2. Employment of only a trough concentration was more biased (AUCPAT/AUCREF range 0.73-1.30 for 11 h, AUCPAT/AUCREF range 0.62-1.40 for 23 h). In comparison with the evaluated software, AUCPAT was not biased against the AUCBM-P (slope 1.04, intercept -15.80, median AUCPAT/AUCBM-P 1.00 [range 0.86-1.10]). CONCLUSIONS: The new application using two concentrations was appropriately validated and might be efficient in popularizing the AUC-guided TDM of vancomycin.

The monitoring of vancomycin: a systematic review and meta-analyses of area under the concentration-time curve-guided dosing and trough-guided dosing.

BACKGROUND: This systematic review and meta-analysis explored the relationship between vancomycin (VCM) monitoring strategies and VCM effectiveness and safety. METHODS: We conducted our analysis using the MEDLINE, Web of Sciences, and Cochrane Register of Controlled Trials electronic databases searched on August 9, 2020. We calculated odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Adult patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia with VCM trough concentrations ≥15 µg/mL had significantly lower treatment failure rates (OR 0.63, 95% CI 0.47-0.85). The incidence of acute kidney injury (AKI) increased with increased trough concentrations and was significantly higher for trough concentrations ≥20 µg/mL compared to those at 15-20 µg/mL (OR 2.39, 95% CI 1.78-3.20). Analysis of the target area under the curve/minimum inhibitory concentration ratios (AUC/MIC) showed significantly lower treatment failure rates for high AUC/MIC (cut-off 400 ± 15%) (OR 0.28, 95% CI 0.18-0.45). The safety analysis revealed that high AUC value (cut-off 600 ± 15%) significantly increased the risk of AKI (OR 2.10, 95% CI 1.13-3.89). Our meta-analysis of differences in monitoring strategies included four studies. The incidence of AKI tended to be lower in AUC-guided monitoring than in trough-guided monitoring (OR 0.54, 95% CI 0.28-1.01); however, it was not significant in the analysis of mortality. CONCLUSIONS: We identified VCM trough concentrations and AUC values that correlated with effectiveness and safety. Furthermore, compared to trough-guided monitoring, AUC-guided monitoring showed potential for decreasing nephrotoxicity.

A meta-analysis of the target trough concentration of gentamicin and amikacin for reducing the risk of nephrotoxicity.

INTRODUCTION: Antimicrobial resistance is one of the biggest threats to public health systems worldwide, and aminoglycosides are key drugs for treating drug-resistant infections. Because of the nephrotoxicity of aminoglycosides, therapeutic drug monitoring is recommended, but few studies of the target trough concentration (Cmin) have been reported. To address the problem, we performed a meta-analysis to confirm the target Cmin of aminoglycosides for minimizing the risk of nephrotoxicity. METHODS: We conducted a literature search using MEDLINE, the Cochrane Library, and Ichushi-Web. In the meta-analysis, nephrotoxicity was compared between the Cmin ≥2 mg/L and Cmin <2 mg/L groups for gentamicin and between the Cmin ≥10 mg/L and Cmin <10 mg/L groups for amikacin. RESULTS: No randomized controlled trials were reported for any of the drugs. Five observational studies involving 615 patients were reported for gentamicin, and two observational studies involving 159 patients were identified for amikacin. For gentamicin, Cmin <2 mg/L was linked to a significantly lower rate of nephrotoxicity than Cmin ≥2 mg/L (odds ratio [OR] = 0.22, 95% confidence interval [CI] = 0.12-0.40). For amikacin, Cmin <10 mg/L was associated with a significantly lower rate of nephrotoxicity than Cmin ≥10 mg/L (OR = 0.05, 95% CI = 0.01-0.21). CONCLUSIONS: Although further well-controlled studies with a low risk of bias are needed, the current meta-analysis demonstrated that Cmin <2 mg/L and Cmin <10 mg/L may reduce the risk of nephrotoxicity linked to gentamicin and amikacin, respectively.

Evaluation of once-daily dosing and target concentrations in therapeutic drug monitoring for arbekacin: A meta-analysis.

INTRODUCTION: Arbekacin is the first aminoglycoside antibacterial agent approved for treating methicillin-resistant Staphylococcus aureus infection in Japan. Although therapeutic drug monitoring (TDM) is recommended during arbekacin treatment, little evidence for the target exposure and once-daily dosing has been reported. This study aimed to clarify the target peak/trough concentrations and the effectiveness of once-daily dosing of arbekacin against nephrotoxicity or treatment failure via meta-analysis. METHODS: A literature search was performed using MEDLINE, Cochrane Library, and Ichushi-Web. RESULTS: Nine observational cohort studies met the inclusion criteria. A peak arbekacin concentration of ≥15-16 µg/mL did not exhibit a statistically significant lower risk of treatment failure (risk ratio [RR] = 0.61, 95% confidence interval [CI] = 0.30-1.24). A trough arbekacin concentration of <2 µg/mL resulted in a significantly lower risk of nephrotoxicity (RR = 0.30, 95% CI = 0.15-0.61). Once-daily dosing significantly reduced the risk of treatment failure (RR = 0.61, 95% CI = 0.39-0.97) but not nephrotoxicity (RR = 0.54, 95% CI = 0.16-1.75). CONCLUSIONS: Once-daily dosing can improve the therapeutic efficacy of arbekacin, and a trough arbekacin concentration of <2 µg/mL can reduce the risk of nephrotoxicity. A peak arbekacin concentration of ≥15-16 µg/mL did not exhibit the significant lower risk of treatment failure. Additional clinical trials are required to confirm these findings.

Optimal trough concentration of voriconazole with therapeutic drug monitoring in children: A systematic review and meta-analysis.

OBJECTIVES: This systematic review and meta-analysis was designed to determine the optimal trough concentration of voriconazole for children with invasive fungal infections (IFIs). METHODS: We searched electronic databases (PubMed, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and Japana Centra Revuo Medicina) for clinical studies describing the voriconazole trough concentration. We used stepwise cut-off values of 1.0-2.0 mg/L for efficacy and 3.0-6.0 mg/L for safety. The efficacy outcomes were treatment success and all-cause mortality, and the safety outcomes were hepatotoxicity, neurotoxicity and all-cause adverse events. RESULTS: Nine studies involving 211 patients were included in the analysis. The probability of treatment success against IFIs was significantly increased at cut-off values of ≥1.0 mg/L (odds ratio [OR] = 2.65, 95% confidence interval [CI] = 1.20-5.87). Our analysis did not find any relationship between the trough concentration and survival. Concerning safety, the occurrence of any outcomes did not significantly differ according to the voriconazole trough concentrations at any cut-off value. However, in a subgroup analysis of Asian study locations, a significantly higher risk of hepatotoxicity was demonstrated at voriconazole trough cut-off values ≥ 3.0 mg/L (OR = 8.40, 95% CI = 1.36-51.92). Although a significant correlation between the voriconazole concentration and hepatotoxicity was evident in regression curve analysis, (y = 0.1198e0.2298x), no correlation was demonstrated for neurotoxicity (y = 0.3913e-0.008x). CONCLUSION: Our findings suggest that the optimal trough concentration for increasing clinical success and minimizing hepatotoxicity during voriconazole therapy in children with IFIs, particularly for Asian populations, is 1.0-3.0 mg/L.

The optimal trough-guided monitoring of vancomycin in children: Systematic review and meta-analyses.

We carried out a systematic review and meta-analysis exploring the relationship between vancomycin (VCM) trough concentrations and its effectiveness and nephrotoxicity in pediatric patients. We conducted our analysis using MEDLINE, Web of Sciences, and Cochrane Register of Controlled Trials as electronic databases (June 29, 2019). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. We identified 16 studies that were eligible for the meta-analysis. A total of 351 and 3,266 patients were included in the analysis for effectiveness and nephrotoxicity, respectively. Pediatric MRSA infection patients with VCM trough concentrations ≥ 10 µg/mL had significantly lower treatment failure rates (OR 0.54, 95% CI 0.30-0.96). The incidence of nephrotoxicity was significantly higher in trough concentrations ≥ 15 µg/mL than when they were < 15 µg/mL (OR 3.02, 95% CI 2.08-4.38). We identified the optimal VCM trough concentrations associated with effectiveness and nephrotoxicity in pediatric patients with MRSA infection. Further prospective studies are needed to find optimal dosing and monitoring strategy on VCM in pediatric population.