Predictive Value of Vancomycin AUC24/MIC Ratio for 30-day Mortality in Patients with Severe or Complicated Methicillin-Resistant Staphylococcus aureus Infections: A Multicenter Retrospective Study.

BACKGROUND: Although vancomycin is typically employed against methicillin-resistant Staphylococcus aureus (MRSA) infections, the optimal ratio of 24-h area under the concentration-time curve to minimum inhibitory concentration (AUC24/MIC) for severe or complicated infections lacks clear guideline recommendations. This study aimed to determine the target AUC24/MIC ratio associated with treatment outcomes of infections treated with vancomycin. METHODS: This retrospective multicenter cohort study included adult patients receiving ≥ 5 days of vancomycin for severe/complicated MRSA infections (e.g., osteoarticular, pulmonary, endocarditis, etc.) between January 2018 and December 2023. The primary outcome was 30-day mortality, with secondary outcomes including clinical success, microbiological eradication, and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis was used to identify the AUC24/MIC cutoff for 30-day mortality. Multivariate regression analysis was used to determine association between AUC24/MIC and outcomes. RESULTS: This study included 82 patients. ROC identified a target AUC24/MIC of ≥ 505 for 30-day mortality. The overall 30-day mortality rate (22.0%) was significantly higher for below average AUC24/MIC cutoff (34.1%) than for above AUC24/MIC cutoff group (9.8%). Multivariate analysis confirmed AUC24/MIC of < 505 as an independent predictor (adjusted odds ratio, 5.001; 95% confidence interval, 1.335-18.75). The clinical success rate differed significantly between below- and above-cutoff groups, whereas microbiological eradication tended to favor the above-cutoff group. The nephrotoxicity rates were comparable between groups. CONCLUSIONS: In treating severe/complicated MRSA infections, vancomycin AUC24/MIC ratio ≥ 505 was independently associated with favorable 30-day mortality. Given the retrospective nature of this study, further prospective studies are essential to confirm the reliability of the target AUC24/MIC ratios.

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.

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 .

Vancomycin Hydrochloride as a Risk Factor for Acute Kidney Injury: A Retrospective Study.

INTRODUCTION: The incidence of acute kidney injury (AKI) caused by vancomycin hydrochloride (VCM) was reported to be 5-43%. VCM-induced AKI was reported to be more likely to occur 4-17 days after initiating VCM treatment; however, it may occur earlier. The aim of this study was therefore to investigate risk factors for the development of AKI within two (AKI2days) and seven (AKI7days) days of VCM administration. METHODS: This was a single-center, retrospective study including patients who underwent VCM therapy between April 1, 2013, and December 31, 2019. AKI was evaluated based on the Kidney Disease: Improving Global Outcomes criteria. RESULTS: In total, 287 patients were enrolled. The incidence of VCM-induced AKI within 7 days was 10.8% (31/286 cases), and the incidence of AKI within 2 days was 5.9% (15/252 cases). Serum VCM trough concentrations and tazobactam-piperacillin (TZP) were shown to be a risk factor for VCM-induced AKI. The serum VCM trough concentration was 12.67 µg/mL within the 48 h threshold (AKI2days) and 19.03 µg/mL within the 7-day threshold (AKI7days). CONCLUSION: Our study demonstrated that high serum VCM trough concentrations and the combination of VCM and TZP were independent risk factors for VCM-induced AKI. Avoiding the concomitant use of TZP, or thorough monitoring of renal function with the concomitant use of TZP, may be helpful in reducing the occurrence of AKI. Furthermore, monitoring serum VCM trough concentrations within 2 days may effectively reduce the incidence of AKI.

Risk Factors for Lenvatinib-Induced High-Grade Hypothyroidism in Patients with Hepatocellular Carcinoma: A Retrospective Study.

INTRODUCTION: Lenvatinib mesylate (LEN) is an orally administered tyrosine kinase inhibitor used for the treatment of various cancers, including hepatocellular carcinoma (HCC). HCC treatment with LEN is associated with a very high incidence of adverse events, especially hypothyroidism. This study investigated the incidence of hypothyroidism due to LEN and the relationships between hypothyroidism incidence and patient demographics by analyzing clinical laboratory data from HCC patients treated with LEN. METHODS: This was a single-center, retrospective study of HCC patients who received LEN between April 19, 2018, and September 30, 2020. The observation period was from 1 week before the start of LEN administration to 1 month after the end of administration. RESULTS: In total, 61 patients with HCC were enrolled. High-grade hypothyroidism (CTCAE Grade 2-3) was found in 36.1% (22/61 patients). In high-grade hypothyroidism, eosinophil (EOSINO) count was significantly low (p = 0.029). The cutoff value of EOSINO count was estimated to be approximately 150/µL. The adjusted odds ratios of high-grade hypothyroidism for current smoking and EOSINO count <150/µL were 0.237 (95% confidence interval: 0.063-0.893) and 4.219 (95% confidence interval: 1.119-15.92), respectively. CONCLUSION: The results showed that noncurrent smoking and EOSINO count <150/µL are risk factors for LEN-induced high-grade hypothyroidism.

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.

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.

Optimal trough concentration of teicoplanin for the treatment of methicillin-resistant Staphylococcus aureus infection: A systematic review and meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: It has been recommended that the trough concentration (Cmin ) of teicoplanin should be maintained at ≥20 µg/ml for difficult-to-treat complicated infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Conversely, Cmin of teicoplanin of at least 10 µg/ml is required for non-complicated MRSA infections. Considering the low incidence of nephrotoxicity for teicoplanin, Cmin  = 15-30 µg/ml has been suggested for most MRSA infections. Thus, we assessed the clinical efficacy and adverse effects of teicoplanin at this target Cmin . METHODS: We searched electronic databases (PubMed, Cochrane Central Register of Controlled Trials and Ichushi-Web) to identify eligible studies. Studies were included if they provided the incidence of treatment success, mortality in patients with MRSA infection, and/or hepatotoxicity and nephrotoxicity according to the Cmin range. RESULTS AND DISCUSSION: Four trials assessing clinical success (n = 299) and three studies assessing adverse effects (n = 546) were included. Cmin  = 15-30 µg/ml significantly increased the probability of treatment success compared with Cmin  < 15 µg/ml (odds ratio [OR] = 2.68, 95% confidence interval [CI] = 1.14-6.32, p = 0.02). The all-cause mortality rate did not differ between the groups (OR = 0.46, 95% CI = 0.13-1.61, p = 0.22). Cmin  = 15-30 µg/ml did not increase the risks of nephrotoxicity (OR = 0.91, 95% CI = 0.49-1.69, p = 0.76) or hepatotoxicity (OR = 0.67, 95% CI = 0.18-2.44, p = 0.54). WHAT IS NEW AND CONCLUSION: Teicoplanin therapy using a Cmin target of 15-30 µg/ml is likely to be associated with better clinical responses than Cmin  < 15 µg/ml without increasing the risk of adverse effects.

A new carbapenem drug dosage metric for carbapenem usage and correlation with carbapenem resistance of Pseudomonas aeruginosa.

The emergence and dissemination of antimicrobial resistance is a worldwide problem. Inappropriate antimicrobial use contributes to this resistance, and several metrics of drug usage have been used to monitor their consumption and rational use. We examined several existing drug metrics, and developed a new one, dose/duration-density (D/d2), for a the best correlation between carbapenem usage and carbapenem resistance of Pseudomonas aeruginosa. The annual changes of antimicrobial use density (AUD), days of therapy (DOT), daily dose (DD) and D/d2 for meropenem, imipenem and total carbapenems was analyzed for a correlation with carbapenem susceptibility of P. aeruginosa from 2006 through 2015 at a university hospital. The substitution of meropenem for imipenem usage, and an approximate 10% increase in carbapenem susceptibility of P. aeruginosa occurred over the study period. There were significant correlations of the meropenem susceptibility of P. aeruginosa and meropenem usage as measured by the meropenem DD, of imipenem susceptibility and imipenem AUD and DOT, and overall carbapenem susceptibility and imipenem DOT. The D/d2 for meropenem, imipenem and total carbapenems had significant correlations with individual and all carbapenem susceptibility of P. aeruginosa. These D/d2 is the best single carbapenem use metric for correlating carbapenem usage with P. aeruginosa resistance. Further studies are warranted to consider the value of D/d2 for other antimicrobials and bacteria.

A retrospective study of the risk factors for linezolid-induced thrombocytopenia and anemia.

Myelosuppression is major treatment-related adverse events of linezolid therapy and result in treatment termination in some cases. We aimed to identify the risk factors for linezolid-induced thrombocytopenia and anemia. We retrospectively retrieved demographic and laboratory data from the medical records of 221 Japanese patients who were undergoing linezolid therapy. Thrombocytopenia and anemia were defined as an unexplained reduction of >30% in the patient's platelet count and hemoglobin level, respectively, from the baseline. Thrombocytopenia developed in 48.4% of patients, and anemia developed in 10.4% of patients during linezolid therapy. In multivariate analysis, creatinine clearance (adjusted odds ratio = 0.94 [0.92-0.95], P < 0.001), hemodialysis (3.32 [1.14-9.67], P = 0.011), and the duration of linezolid therapy (1.14 [1.07-1.21], P < 0.001) were found to be significant risk factors for linezolid-induced thrombocytopenia. Patients with creatinine clearance rates of <60 mL/min and those on hemodialysis were found to be at high risk of linezolid-induced thrombocytopenia. In addition, a high incidence of linezolid-induced thrombocytopenia was even detected among the patients that had received linezolid therapy for <7 days. As for anemia, the duration of linezolid therapy (1.04 [1.01-1.07], P = 0.011) was shown to be a risk factor for anemia, and a high incidence of anemia was seen among the patients who received linezolid for >15 days. In conclusion, we recommend that among patients receiving linezolid therapy the platelet counts of those with risk factors for linezolid-induced thrombocytopenia should be monitored closely throughout treatment, and the hemoglobin levels of patients that receive linezolid for >15 days should be carefully monitored on a weekly basis to detect anemia.

Changes in psychopharmacotherapy for patients with schizophrenia in a psychiatric institution in Japan: A 12-year prescription survey pre- and post-introduction of clozapine.

Psychopharmacotherapy for patients with schizophrenia in Japan has a long history of polypharmacy, which is rare worldwide but remains a critical problem. One reason for this is that clozapine was not available in Japan until 2009. We aimed to investigate the changes in psychopharmacotherapy in patients with schizophrenia over 12 years pre- and post-introduction of clozapine to clarify how psychopharmacotherapy for patients with schizophrenia has changed with the introduction of clozapine. We retrospectively collected data from the medical records of inpatients diagnosed with schizophrenia at the Okayama Psychiatric Medical Center. Chlorpromazine equivalent (CP-eq) decreased from 1276.6 mg/day in 2009 to 613.9 mg/day in 2020. The prescribed daily dose/defined daily dose (PDD/DDD) decreased from 3.0 in 2009 to 1.2 in 2020. The monotherapy rate increased from 24.4 % in 2009 to 74.6 % in 2020. Our institution began using clozapine in 2010, and the prescription rate for clozapine increased to 37.3 % in 2020. The prescription rate for more than three antipsychotics decreased from 27.8 % in 2009 to 0.8 % in 2020. The increase in clozapine prescription has contributed to an increased rate of antipsychotic monotherapy and a decreased rate of polypharmacy, promoting the optimization of schizophrenia medication. Clozapine therapy should be further promoted in Japan to reduce treatment-resistant schizophrenia due to polypharmacy as much as possible.

Model-informed precision dosing of teicoplanin for the rapid achievement of the target area under the concentration-time curve: A simulation study.

Teicoplanin, a glycopeptide antimicrobial, is recommended for therapeutic drug monitoring, but it remains unclear how to target the area under the concentration-time curve (AUC). This simulation study purposed to demonstrate the potential of the Bayesian forecasting approach for the rapid achievement of the target AUC for teicoplanin. We generated concordant and discordant virtual populations against a Japanese population pharmacokinetic model. The predictive performance of the Bayesian posterior AUC in limited sampling on the first day against the reference AUC was evaluated as an acceptable target AUC ratio within the range of 0.8-1.2. In the concordant population, the probability for the maximum a priori or Bayesian posterior AUC on the first day (AUC0-24 ) was 61.3% or more than 77.0%, respectively. The Bayesian posterior AUC on the second day (AUC24-48 ) was more than 75.1%. In the discordant population, the probability for the maximum a priori or Bayesian posterior AUC0-24 was 15.5% or 11.7-80.7%, respectively. The probability for the maximum a priori or Bayesian posterior AUC24-48 was 23.4%, 30.2-82.1%. The AUC at steady-state (AUCSS ) was correlated with trough concentration at steady-state, with a coefficient of determination of 0.930; the coefficients on days 7 and 4 were 0.442 and 0.125, respectively. In conclusion, this study demonstrated that early sampling could improve the probability of AUC0-24 and AUC24-48 but did not adequately predict AUCSS . Further studies are necessary to apply early sampling-based model-informed precision dosing in the clinical settings.

Model-informed precision dosing of vancomycin for rapid achievement of target area under the concentration-time curve: A simulation study.

In this study, we aimed to evaluate limited sampling strategies for achieving the therapeutic ranges of the area under the concentration-time curve (AUC) of vancomycin on the first and second day (AUC0-24 , AUC24-48 , respectively) of therapy. A virtual population of 1000 individuals was created using a population pharmacokinetic (PopPK) model, which was validated and incorporated into our model-informed precision dosing tool. The results were evaluated using six additional PopPK models selected based on a study design of prospective or retrospective data collection with sufficient concentrations. Bayesian forecasting was performed to evaluate the probability of achieving the therapeutic range of AUC, defined as a ratio of estimated/reference AUC within 0.8-1.2. The Bayesian posterior probability of achieving the AUC24-48 range increased from 51.3% (a priori probability) to 77.5% after using two-point sampling at the trough and peak on the first day. Sampling on the first day also yielded a higher Bayesian posterior probability (86.1%) of achieving the AUC0-24 range compared to the a priori probability of 60.1%. The Bayesian posterior probability of achieving the AUC at steady-state (AUCSS ) range by sampling on the first or second day decreased with decreased kidney function. We demonstrated that second-day trough and peak sampling provided accurate AUC24-48 , and first-day sampling may assist in rapidly achieving therapeutic AUC24-48 , although the AUCSS should be re-estimated in patients with reduced kidney function owing to its unreliable predictive performance.

Clinical Practice Guideline for the Therapeutic Drug Monitoring of Voriconazole in Non-Asian and Asian Adult Patients: Consensus Review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring.

PURPOSE: Voriconazole, an antifungal drug, is metabolized by a cytochrome P450 isozyme. Increased adverse effects are observed in Asians because of the high rate of poor metabolizers. In this therapeutic drug monitoring (TDM) guideline, recommendations were made according to ethnic group. METHODS: Five clinical questions were used. For the preparation of the guideline, the performance of TDM in multicenter studies was surveyed (study 1). We also conducted a systematic review and meta-analysis (study 2) to establish recommendations for non-Asians and Asians. FINDINGS: In study 1, 401 patients were surveyed. A risk of supratherapeutic concentrations was found in Japanese patients who adhered to the recommended dose. Target trough levels were achieved in 87% of patients with dose reductions. Although the trough level measured at the onset of adverse effects (AEs) was significantly associated with hepatotoxicity, no significant correlation was found between the initial trough level and hepatotoxicity, which indicated that hepatotoxicity was successfully prevented by the trough-guided dosing. In study 2, 22 studies (11 Asian locations and 11 non-Asian locations) were included in meta-analysis for the relationship between trough cutoff level (3, 4, 5, 5.5, and 6 µg/mL) and AEs. Significant differences were found for all cutoff levels, with the highest odds ratio for 4.0 µg/mL in Asian locations. In contrast, in non-Asian locations, no more than 1 study was available for any trough cutoff level, except for 5.5 µg/mL, at which level a significant increase in AEs was found. These findings indicate that TDM is strongly recommended to prevent AEs in Asians, and TDM is generally recommended for non-Asians to address subtherapeutic concentrations. TDM on day 3 is recommended to assess pharmacokinetic properties, including loading and maintenance doses. If the patient condition permits, delaying until day 5 is suggested for Asians because of the prolonged t½ in poor metabolizers. A trough level ≥1.0 µg/mL is strongly recommended to improve efficacy. Trough levels ≥2.0 µg/mL are suggested for invasive aspergillosis. To decrease adverse effects, trough levels <4.0 µg/mL are strongly recommended in Asians, whereas trough levels <5.5 µg/mL are generally recommended in non-Asians. Maintenance doses of 4 and 3 mg/kg twice daily are recommended in non-Asians and Asians, respectively. IMPLICATIONS: Different indications, timings, and target trough levels for TDM and different regimens are suggested for Asians and non-Asians.

Evaluation of risk factors for uric acid elevation in COVID-19 patients treated with favipiravir.

The objective of this retrospective study was to identify the clinical risk factor associated with uric acid elevation in coronavirus disease (COVID-19) patients treated with favipiravir. Uric acid elevation was defined as an unexplained increase of ≥1.5 times in the patient's uric acid level from baseline. Twenty-nine COVID-19 patients were included in the study. Uric acid elevation developed during favipiravir therapy in 12 (41.4%) patients and the median onset time was 4.5 days after starting favipiravir. In multiple logistic regression analysis, the favipiravir dosage (adjusted OR = 1.69 [1.02-2.81], P = 0.044) and younger patient age (adjusted OR = 0.91 [0.83-0.99], P = 0.040) were significant clinical risk factors for uric acid elevation. No significant between-group difference was noted in the uric acid elevation and non-elevation groups in the clinical recovery after favipiravir therapy. The uric acid levels of patients administered with favipiravir should be monitored closely.

Clinical Practice Guidelines for Therapeutic Drug Monitoring of Vancomycin in the Framework of Model-Informed Precision Dosing: A Consensus Review by the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring.

BACKGROUND: To promote model-informed precision dosing (MIPD) for vancomycin (VCM), we developed statements for therapeutic drug monitoring (TDM). METHODS: Ten clinical questions were selected. The committee conducted a systematic review and meta-analysis as well as clinical studies to establish recommendations for area under the concentration-time curve (AUC)-guided dosing. RESULTS: AUC-guided dosing tended to more strongly decrease the risk of acute kidney injury (AKI) than trough-guided dosing, and a lower risk of treatment failure was demonstrated for higher AUC/minimum inhibitory concentration (MIC) ratios (cut-off of 400). Higher AUCs (cut-off of 600 µg·h/mL) significantly increased the risk of AKI. Although Bayesian estimation with two-point measurement was recommended, the trough concentration alone may be used in patients with mild infections in whom VCM was administered with q12h. To increase the concentration on days 1-2, the routine use of a loading dose is required. TDM on day 2 before steady state is reached should be considered to optimize the dose in patients with serious infections and a high risk of AKI. CONCLUSIONS: These VCM TDM guidelines provide recommendations based on MIPD to increase treatment response while preventing adverse effects.

Comparison of thoracic and abdominal deep inspiration breath holds in whole-breast irradiation for patients with left-sided breast cancer.

BACKGROUND: The deep inspiration breath hold (DIBH) technique is effective for heart dose reduction in patients with left-sided breast cancer. In deep breathing, some women breathe in thoracic respiration; and others, in abdominal respiration. This study evaluated differences in dose reduction in organs at risk (OAR) and reproducibilities of the target and OAR between thoracic DIBH (T-DIBH) and abdominal DIBH (A-DIBH). METHODS: Fourteen patients with left-sided breast cancer who had planned to receive whole-breast irradiation were included. Computed tomography (CT) was performed in free breathing (FB), T-DIBH, and A-DIBH, and the dosimetric indexes of the target and OAR for three treatment plans were compared. In T-DIBH and A-DIBH, two series CTs were taken in each breathing method and the displacements of the target and heart were calculated. RESULTS: The averaged mean heart doses (MHDs) were 1.5 Gy and 1.6 Gy in T-DIBH and A-DIBH, respectively, significantly lower than 2.7 Gy in FB (p < 0.001 for both breathing methods). Between T-DIBH and A-DIBH, no significant difference in MHD was found (p = 0.95); however, the percentage increase in lung volume positively moderately correlated with the reduction in MHD (R = 0.68). The three-dimensional target displacements were 2.3 mm in T-DIBH and 2.0 mm in A-DIBH (p = 0.64). The three-dimensional heart displacements were 1.7 mm in T-DIBH and 1.8 mm in A-DIBH (p = 0.85). CONCLUSION: The present study demonstrates that the MHD and reproducibility did not differ between T-DIBH and A-DIBH. However, the superior breathing method for increasing lung volume should be determined for each patient.

Favorable Effects of Voriconazole Trough Concentrations Exceeding 1 µg/mL on Treatment Success and All-Cause Mortality: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis examined the optimal trough concentration of voriconazole for adult patients with invasive fungal infections. We used stepwise cutoffs of 0.5-2.0 µg/mL for efficacy and 3.0-6.0 µg/mL for safety. Studies were included if they reported the rates of all-cause mortality and/or treatment success, hepatotoxicity, and nephrotoxicity according to the trough concentration. Twenty-five studies involving 2554 patients were included. The probability of mortality was significantly decreased using a cutoff of ≥1.0 µg/mL (odds ratio (OR) = 0.34, 95% confidence interval (CI) = 0.15-0.80). Cutoffs of 0.5 (OR = 3.48, 95% CI = 1.45-8.34) and 1.0 µg/mL (OR = 3.35, 95% CI = 1.52-7.38) also increased the treatment success rate. Concerning safety, significantly higher risks of hepatotoxicity and neurotoxicity were demonstrated at higher concentrations for all cutoffs, and the highest ORs were recorded at 4.0 µg/mL (OR = 7.39, 95% CI = 3.81-14.36; OR = 5.76, 95% CI 3.14-10.57, respectively). Although further high-quality trials are needed, our findings suggest that the proper trough concentration for increasing clinical success while minimizing toxicity is 1.0-4.0 µg/mL for adult patients receiving voriconazole therapy.

Candidates for area under the concentration-time curve (AUC)-guided dosing and risk reduction based on analyses of risk factors associated with nephrotoxicity in vancomycin-treated patients.

OBJECTIVES: Compared with vancomycin trough concentration (Cmin)-guided dosing, area under the concentration-time curve (AUC)-guided dosing is associated with decreased acute kidney injury (AKI). However, whether Cmin-guided or AUC-guided dosing should be used in patients other than those with serious MRSA infections remains uncertain. The purposes of this multicentre study were to identify risk factors for early- and late-phase vancomycin-induced AKI and to identify candidates for AUC-guided dosing, rather than Cmin-guided dosing, who require a more accurate dose titration to reduce the AKI risk. METHODS: A multivariate logistic regression analysis was applied to identify risk factors for AKI. Additionally, the cut­off day for AKI onset, cut-off Cmin for AKI, safe Cmin for reduced AKI risk and probability of AKI were calculated. RESULTS: In total, 8.4% (159/1882) of patients developed AKI. AKI occurred within the first 7 days of therapy (early phase) in the vast majority of patients. Significant risk factors for AKI during the early phase were identified as Cmin > 20 mg/L, ICU stay, concurrent diuretic or piperacillin/tazobactam use, and pre-existing renal dysfunction. A temporarily elevated Cmin (>15-20 mg/L) was not associated with a greater risk of AKI. In patients with risk factors, the cut-off Cmin for AKI and the estimated safe Cmin for reduced AKI risk were 18.8-21.0 mg/L and <11.7-13.5 mg/L, respectively. CONCLUSION: Patients with known AKI risk factors require a low target Cmin. The presence of several risk factors for AKI may indicate a need for more accurate dose titration using AUC-guided dosing.

[Systematic review on the short-term efficacy and safety of nicorandil for stable angina pectoris in comparison with those of ß-blockers, nitrates and calcium antagonists].

Nicorandil significantly reducted the incidence of major coronary events in patients with stable angina in a long-term trial, although there are few reports on its short-term efficacy in the treatment and prevention of angina symptoms. We performed a meta-analysis of the short-term efficacy of nicorandil compared with antianginal drugs for stable angina. We selected 20 reports (vs. ß-blockers, n=6; vs. nitrates, n=6; vs. calcium antagonists, n=8) of prospective controlled trials from MEDLINE, the Cochrane Library, and Japana Centra Revuo Medicina. The trials were short in duration (median 5 weeks). We combined the results using odds ratios (OR) for discrete data and weighted mean differences (WMD) for continuous data. Compared with antianginal drugs, nicorandil did not show significant reduction of angina episodes per week (vs. ß-blockers, -1.50 [95% confidence interval (CI): -4.09, 1.09]; vs. nitrates, 0.22 [95% CI: -1.22, 1.65]; vs. calcium antagonists, -0.23 [95% CI: -1.37, 0.90]). Furthermore, there were no significant differences in time to ischemia (total exercise duration, time to 1-mm ST depression, time to onset of pain). Although the total numbers of adverse events with each antianginal drug were similar, heart rate and blood pressure were significantly decreased by calcium antagonists but not changed by nicorandil (8.09 [95% CI: 3.20, 12.98] and 8.64 [95% CI: 3.28, 13.99], respectively). Thus this study suggests that short-term therapy with nicorandil is as effective as standard therapy and that nicorandil can also be used as a first-line agent in patients with stable angina.