A cohort study of the risk factors and the target AUC to avoid vancomycin-associated acute kidney injury in pediatric patients.

OBJECTIVES: In recent years, Vancomycin (VCM) dosing design using area under the concentration-time curve (AUC) has been recommended as a measure of efficacy and safety, but there are fewer reports on pediatric patients than on adults. In this study, we evaluated the threshold of AUC for AKI occurrence in pediatric patients and investigated the factors that contribute to the occurrence of AKI. METHODS: Pediatric patients aged 1-15 years on VCM treatment who underwent TDM at Kagoshima University Hospital from April 2016 to March 2022 were included in the computation of AUC using pediatric population pharmacokinetic parameters. RESULTS: The ROC curve showed that the AUC threshold for the risk of developing AKI was 583.0 µg・h/mL, and the AUC-ROC curve was 0.873 (sensitivity 0.930, specificity 0.750). Univariate analysis showed that factors associated with AKI incidence were the duration of VCM administration, ICU admission, and AUCSS. Concomitant medications identified as risk factors for AKI incidence were tazobactam/piperacillin, liposomal amphotericin B, calcineurin inhibitors, contrast agents, and H2-receptor blockers. The multivariate analysis showed that AUC ≧ 583.0 µg・h/mL (odds ratio 20.14, 95% CI 3.52-115.22, p < 0.001) and H2-receptor blockers (odds ratio 8.70, 95% confidence interval = 1.38-54.87, p = 0.02) were independent factors for AKI incidence. CONCLUSIONS: We showed that in pediatric patients receiving VCM, the risk of AKI increases as AUC increases. The findings imply that concurrent use of VCM and H2-receptor blockers may increase the risk of AKI.

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.

Enhanced measures, including PCR-based screening and syndromic surveillance for nosocomial outbreaks of the COVID-19 Omicron variant, using descriptive epidemiology and whole-genome sequencing in a Japanese tertiary care hospital.

INTRODUCTION: In this study, we aimed to analyze the effectiveness of enhanced preventive measures against nosocomial COVID-19 Omicron outbreaks based on those encountered. METHODS: We introduced PCR-based screening and syndromic surveillance, in addition to standard and transmission-based precautions, during a COVID-19 outbreak in three wards of Kagoshima University Hospital, a Japanese tertiary care hospital, in February 2022, amid the Omicron variant endemic. Furthermore, we analyzed the descriptive epidemiology and whole-genome sequencing (WGS) of positive SARS-CoV-2 PCR samples from this outbreak. RESULTS: PCR-based screening tests were conducted following the identification of three cases through syndromic surveillance. As a result, 30 individuals tested positive for SARS-CoV-2, including 13 inpatients, five attendant family members, and 12 healthcare workers across the three wards. Notably, no new infections were observed within eight days following the implementation of preventive measures. Among the SARS-CoV-2 genomes analyzed (n = 16; 53.3%), all strains were identified as belonged to BA.1.1 variant. Detailed analysis of descriptive and molecular epidemiology, incorporating single-nucleotide polymorphism analysis of WGS and clarification of transmission links, considering two potential entry routes to the hospital. CONCLUSIONS: Introduction of additional preventive measures, including PCR-based screening and syndromic surveillance, in addition to WGS and descriptive epidemiology, is useful for the early intervention of nosocomial outbreaks and for revealing the transmission route of the COVID-19 Omicron variant.

Dosing Optimization of Ampicillin-Sulbactam Based on Cystatin C in Elderly Patients with Pneumonia.

Ampicillin-sulbactam is a first-line therapy for pneumonia and is mainly excreted by the kidney. It is important to optimize the dose and dosing interval of ampicillin-sulbactam because in patients with decreased renal function and low skeletal muscle mass, such as the elderly, excess drug may burden renal function. In this study, we evaluated indices of renal function and optimized the dose and dosing interval of ampicillin-sulbactam based on pharmacokinetics (PK) and pharmacodynamics theory in elderly patients. The serum concentrations of ampicillin and sulbactam were measured by HPLC, and PK parameters were calculated. Correlations between the clearance of ampicillin or sulbactam and renal function were evaluated, and dosing optimization was calculated based on PK parameters. The PK parameters of ampicillin were CL = 6.5 ± 4.0 L/h, Vd = 19.3 ± 0.2 L, Ke = 0.4 ± 0.2, and t1/2 = 2.7 ± 1.6 h. The most correlated renal function index was estimated glomerular filtration rate (eGFRcys-c) calculated by serum cystatin-c (r = 0.7374, correlation formula; CL of ampicillin = 0.1937 × eGFRcys-c-0.6726). Based on this formula, we calculated the clearance of ampicillin and developed dosing regimens for the elderly. Serum cystatin-c concentration is an ideal index to optimize ampicillin-sulbactam antimicrobial therapy in elderly patients with pneumonia.

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.

Effects of antifungal stewardship using therapeutic drug monitoring in voriconazole therapy on the prevention and control of hepatotoxicity and visual symptoms: A multicentre study conducted in Japan.

BACKGROUND: Hepatotoxicity and visual symptoms are common adverse effects (AEs) of voriconazole therapy. OBJECTIVE: To retrospectively evaluate the effects of treatment modification based on therapeutic drug monitoring on AEs in patients undergoing voriconazole therapy. METHODS: The target voriconazole trough concentration (Cmin ) was 1-5 µg/mL. Receiver operating characteristic curves were used to determine Cmin cut-offs for AEs. RESULTS: A total of 401 patients were included. Among 108 patients with high initial Cmin , voriconazole was discontinued in 32 and the dose was reduced in 71. Among 44 patients with low initial Cmin , voriconazole was discontinued in 4 and the dose was increased in 19. Hepatotoxicity occurred in 6.0% of patients, after a median of 10 days. Visual symptoms were evident in 9.5% of patients after a median of 4 days. Initial Cmin was significantly associated with visual symptoms but not hepatotoxicity, which suggested the effect of treatment modification on hepatotoxicity. However, both hepatotoxicity and visual symptoms were significantly correlated with Cmin at the onset of AEs, and the Cmin cut-offs were 3.5 µg/mL for hepatotoxicity and 4.2 µg/mL for visual symptoms. Voriconazole was discontinued after the occurrence of AEs in 62.5% of patients with hepatotoxicity but only 26.3% of patients with visual symptoms. With dose adjustment, treatment was completed in 8/9 patients with hepatotoxicity and 27/28 patients with visual symptoms. CONCLUSIONS: A significant preventive effect was demonstrated on hepatotoxicity, but not on visual symptoms because of earlier occurrence. With treatment modification after the occurrence of AEs, most patients completed therapy.

Influence of GST polymorphisms on busulfan pharmacokinetics in Japanese children.

BACKGROUND: Fatal adverse effects or relapse can occur with excessive or insufficient busulfan exposure in hematopoietic stem cell transplantation. Given that busulfan is mainly metabolized by glutathione S-transferase (GST), we investigated the influence of GST polymorphisms on busulfan pharmacokinetics in Japanese pediatric patients. METHODS: Blood samples were taken from patients receiving high-dose i.v. busulfan as the first dose. Plasma busulfan concentration was measured using high-performance liquid chromatography. The area under the plasma busulfan concentration-time curve (AUC) was calculated. The genotype of GSTA1 was determined on polymerase chain reaction (PCR)-restriction fragment length polymorphism. Multiplex PCR was used to detect the presence or absence of GSTM1 and GSTT1 in the genomic DNA samples. RESULTS: Twenty patients were consecutively enrolled. Phenotype prediction was defined as follows: poor metabolizer (n = 4), one or more GSTA1*B haplotype or GSTM1/GSTT1 double-null genotypes; and extensive metabolizer (n = 16), other genotypes. GSTA1, M1, and T1 independently had no significant differences in AUC0-∞ , clearance or elimination rate constant. For the infant with unexpectedly high AUC0-∞ (2,591 µmol/L min), the GSTA1, M1, and T1 polymorphisms were wild type. On further analysis, the poor metabolizer group had lower clearance and higher AUC0-∞, except for the aforementioned patient, compared with the extensive metabolizer group (1,531 vs 1,010 µmol/L min; P < 0.01). CONCLUSIONS: GST polymorphisms may have affected busulfan pharmacokinetics, but these effects were obscured by other factors, such as underlying disease, systemic conditions, treatment history, and race.

Risk factors for ganciclovir-induced thrombocytopenia and leukopenia.

Ganciclovir is a nucleoside guanosine analogue that exhibits therapeutic activity against human cytomegalovirus infection, and is primarily excreted via glomerular filtration and active tubular secretion. The adverse effects induced by ganciclovir therapy are generally of a hematological nature and include thrombocytopenia and leukopenia. Low marrow cellularity and elevated serum creatinine have been identified as risk factors for ganciclovir-induced neutropenia. However, the risk factors for thrombocytopenia have yet to be determined. Therefore, this study investigated patients administered ganciclovir to determine the risk factors for thrombocytopenia and leukopenia. Thrombocytopenia occurred in 41 of these patients (30.6%). Multivariate logistic regression analysis identified three independent risk factors for thrombocytopenia: cancer chemotherapy (odds ratio (OR)=3.1), creatinine clearance (<20 mL/min) (OR=12.8), and the ganciclovir dose (≥12 mg/kg/d) (OR=15.1). Leukopenia occurred in 36 patients (28.6%), and white blood cell count (<6000 cells/mm(3)) (OR=3.7) and the ganciclovir dose (≥12 mg/kg/d) (OR=7.8) were identified as risk factors. These results demonstrated that several factors influenced the occurrence of ganciclovir-induced thrombocytopenia and leukopenia, and suggest that special attention should be paid to patients receiving cancer chemotherapy with a low creatinine clearance (<20 mL/min) and high dose (≥12 mg/kg/d) in order to avoid ganciclovir-induced thrombocytopenia.

Linezolid dosage in pediatric patients based on pharmacokinetics and pharmacodynamics.

Linezolid pharmacokinetic profile in pediatric patients has not been fully characterized, and the dose needed to achieve a pharmacokinetic-pharmacodynamic (PK-PD) target has yet to be established because its efficacy is associated with the area under the plasma drug concentration-time curve (AUC24)/minimum inhibitory concentration (MIC) ratio. The present study aimed to define the pharmacokinetic parameters of intravenous linezolid in pediatric patients and assess the rationale for the approved dosage recommendations. Linezolid was safe, tolerated well, and clinically effective for treating Gram-positive bacteria in five pediatric patients (3-11 years). The mean values for the volume of distribution and total clearance (CL) in a one-compartment model were estimated to be 0.646 ± 0.239 l/kg and 0.171 ± 0.068 l/h/kg, respectively (mean ± S.D.). Based on this analysis, the AUC24 and trough drug concentration in plasma (C(min)) for linezolid doses were predicted to be 175.4 µg h/ml and 3.4 µg/ml for 30 mg/kg/day, 204.7 µg h/ml and 4.3 µg/ml for 35 mg/kg/day, and 263.2 µg h/ml and 6.2 µg/ml for 45 mg/kg/day, respectively. Taking into account that AUC24 should be ≥ 200 µg h/ml for MIC of 2.0 µg/ml (to achieve an AUC24/MIC ratio of ≥ 100) and C(min) should be approximately 7 µg/ml (to avoid thrombocytopenia), we consider the approved dosage of 30 mg/kg/day to be fundamentally rational, but can be underdosed against bacteria with MIC of 2.0 µg/ml; therefore, a dose of 35-45 mg/kg/day is more appropriate to ensure the efficacy and safety of linezolid in pediatric patients.

Factors affecting treatment and recurrence of Clostridium difficile infections.

The antimicrobial agents vancomycin and metronidazole have been used to treat Clostridium difficile infections (CDIs). However, it remains unclear why patients are at risk of treatment failure and recurrence. Therefore, this study retrospectively examined 98 patients with CDIs who were diagnosed based on the detection of toxin-positive C. difficile to determine the risk factors affecting drug treatment responses and the recurrence of CDI. No significant difference was observed in the cure rate or dosage between the vancomycin and metronidazole groups. The 90-d mortality rate and total number of drugs associated with CDIs, including antiinfective agents used within 2 months before the detection of toxin-positive C. difficile, were significantly lower in the treatment success group than in the failure group. The total number of antiinfective agents and gastric acid-suppressive agents used during CDI therapy was also significantly lower in the success group than in the failure group. The period from the completion of CDI therapy to restarting the administration of anticancer agents and steroids was significantly longer in patients without than in patients with recurrence. These results indicate that the total number of drugs associated with CDIs should be minimized to reduce the risk of CDIs, that not only antibiotics but also gastric acid-suppressive agents should be discontinued during CDI therapy to increase therapeutic efficacy, and that the use of anticancer agents and steroids should be delayed as long as possible after patients are cured by CDI therapy to prevent recurrence.

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.

Reduction in the incidence of MRSA with use of alcohol-based hand rub solutions and gloves.

Methicillin-resistant Staphylococcus aureus (MRSA) is highly contagious. It is spread by direct contact with MRSA-infected people or objects. Healthcare workers' hands are the most common vehicle for the transmission of healthcare-associated pathogens from patient to patient and within the healthcare environment. The present study aimed to investigate the correlation between the incidence of MRSA among Staphylococcus aureus recovered from clinical culture and the use of alcohol-based hand rub solutions or gloves and antimicrobial use density (AUD). All data were examined every 6 months between January 2005 and June 2008. The increasing use of alcohol-based hand rub solutions was correlated with a decreasing incidence of recovery of MRSA from clinical cultures (r(2) = 0.58). A statistically significant (P < 0.05) correlation (r(2) = 0.68) was observed between glove use and the incidence of MRSA. On the other hand, we did not find any correlation between the AUD of each antibiotic group and the incidence of MRSA. Thus, we suggest that it is important to use not only alcohol-based hand rubs, but also gloves, because MRSA is transmitted from patient to patient by the hands of healthcare workers.

Concentration-Dependent Activity of Pazufloxacin against Pseudomonas aeruginosa: An In Vivo Pharmacokinetic/Pharmacodynamic Study.

The bacterium Pseudomonas aeruginosa is known to be associated with nosocomial infections around the world. Pazufloxacin, a potent DNA gyrase inhibitor, is known to be an effective drug candidate. However, it has not been clarified whether the pharmacokinetic (PK)/pharmacodynamic (PD) of pazufloxacin was effective against P. aeruginosa. Herein, we demonstrated that the PK/PD index of pazufloxacin against P. aeruginosa infection is used to optimize the dosing regiments. We constructed an in vivo infection model by infecting P. aeruginosa into the thigh of a mouse to determine the PD, and we measured the serum concentration of pazufloxacin to construct the PK model using high-performance liquid chromatography. The therapeutic efficacy of pazufloxacin was correlated with the ratio of the area under the free concentration time curve at 24 h to the minimum inhibitory concentration (fAUC24/MIC), and the maximum free concentration to the MIC (fCmax/MIC). Each contribution rate (R2) was 0.72 and 0.65, respectively, whereas the time at which the free drug concentration remained above the MIC (R2 = 0.28). The target value of pazufloxacin fAUC24/MIC for stasis was 46.1, for 1 log10 it was 63.8, and for 2 log10 it was 100.8. Moreover, fCmax/MIC for stasis was 5.5, for 1 log10 it was 7.1, and for 2 log10 it was 10.8. We demonstrated that the in vivo concentration-dependent activity of pazufloxacin was effective against the P. aeruginosa infection, and successfully made the PK/PD model sufficiently bactericidal. The PK/PD model will be beneficial in preventing the spread of nosocomial infections.

An initial dosing method for teicoplanin based on the area under the serum concentration time curve required for MRSA eradication.

Teicoplanin is a glycopeptide antibacterial agent that has a long serum half-life and therefore takes time to achieve steady-state conditions. An appropriate initial dosing is needed for teicoplanin to promptly reach an effective serum trough concentration. However, little information is available on tailoring the initial dosing for patients with various characteristics. The objective of this study was to develop a nomogram for determining teicoplanin initial dose to promptly reach an effective trough concentration (≥ 13 µg/mL). A logistic regression analysis was performed to test whether the area under the concentration time curve (AUC) is a significant predictor of microbiological response (persistence 0; eradication 1). The study included 24 adult patients with methicillin-resistant Staphylococcus aureus infections [minimal inhibitory concentration (MIC) for the isolates was <2 µg/mL). Each AUC was estimated using individual dose, creatinine clearance (CL(cr)), and body weight data. The target value, which gives about a 0.9 microbiological eradication probability, was 750 µg h/mL for AUC from zero to 24 h (AUC(0-24 h)). Using published population pharmacokinetic parameters, the dose required to achieve the AUC(0-24 h) target was calculated as dose (mg) = 750 × (0.00498 × CL(cr) (mL/min) + 0.00426 × body weight (kg). For various combinations of CL(cr) and body weight, we checked the calculated doses using a therapeutic drug monitoring (TDM)-supporting software and developed a nomogram. The nomogram would be useful for initial dose adjustment to promptly reach an effective serum trough concentration and avoid adverse events of teicoplanin.

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.

Pharmacokinetic/pharmacodynamic evaluation of teicoplanin against Staphylococcus aureus in a murine thigh infection model.

OBJECTIVES: Pharmacokinetic/pharmacodynamic (PK/PD) analysis using murine infection models is a well-established methodology for optimising antimicrobial therapy. Therefore, we investigated the PK/PD indices of teicoplanin againstStaphylococcus aureus using a murine thigh infection model. METHODS: Mice were rendered neutropenic by administration of a two-step dosing of cyclophosphamide. Then, isolates of methicillin-susceptibleS. aureus (MSSA) or methicillin-resistant S. aureus (MRSA) were inoculated into the thighs of neutropenic mice. PK/PD analyses were performed by non-linear least-squared regression using the MULTI program. RESULTS: Target values offCmax/MIC (r2 = 0.94) of teicoplanin for static effect and 1 log10 kill against MSSA were 4.44 and 15.44, respectively. Target values of fAUC24/MIC (r2 = 0.92) of teicoplanin for static effect and 1 log10 kill against MSSA were 30.4 and 70.56, respectively. Target values of fCmax/MIC (r2 = 0.91) of teicoplanin for static effect and 1 log10 kill against MRSA were 8.92 and 14.16, respectively. Target values of fAUC24/MIC (r2 = 0.92) of teicoplanin for static effect and 1 log10 kill against MRSA were 54.8 and 76.4, respectively. CONCLUSION: These results suggest thatfCmax/MIC and fAUC24/MIC are useful PK/PD indices of teicoplanin against MSSA and MRSA.

Determination of teicoplanin trough concentration target and appropriate total dose during the first 3 days: a retrospective study in patients with MRSA infections.

An initial loading procedure has been recommended to enable teicoplanin to promptly reach an effective serum concentration for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to retrospectively evaluate the pharmacokinetics and pharmacodynamics of teicoplanin to determine the therapeutic target for the teicoplanin trough concentration and an appropriate dosing method during the first 3 days. The mean trough concentrations were 13.2 mg/L for patients with eradication of MRSA. Moreover, logistic regression analysis showed that the teicoplanin trough concentration was 13 mg/L to achieve MRSA eradication with a probability of 89.0%. The rates of achieving >or=13 mg/L in or=36 mg/kg (total dose during the first 3 days) groups were 9.1, 48.4 and 87.5%, respectively. These results suggest that the administration of >or=36 mg/kg during the first 3 days is appropriate to promptly obtain a trough concentration target of >or=13 mg/L for the initial treatment of MRSA infections.

Therapeutic drug monitoring of voriconazole in Japanese patients: analysis based on clinical practice data.

The aim of this study was to investigate whether routine therapeutic drug monitoring (TDM) of voriconazole (VRCZ) reduced discontinuation due to hepatotoxicity. Hepatotoxicity was observed in 15 (51.7%) out of 29 patients. The percentages of patients who developed hepatotoxicity within 4 days and 1 week were 26.7 and 46.7%, respectively. The drug trough concentrations in patients with and without hepatotoxicity were 5.55 ± 2.73 and 2.36 ± 1.67 µg/ml (P < 0.01, the two-sided Student's t-test), respectively. Trough concentrations reached the target of 1-5 µg/ml in patients with gradual dose reductions based on TDM, and, consequently, liver enzyme levels returned to the original levels before the VRCZ treatment. All patients eventually continued effective VRCZ therapy despite its hepatotoxicity. Thus, dose adjustments by TDM to achieve the target trough concentrations is useful in order to avoid hepatotoxicity and enable continued effective VRCZ therapy for Japanese patients with invasive fungal infections.

Pharmacokinetic/pharmacodynamic analysis of teicoplanin in patients with MRSA infections.

BACKGROUND: Teicoplanin is a glycopeptide antibiotic that has been used to treat serious, invasive infections caused by Gram-positive bacteria. The area under the drug concentration-time curve (AUC)/minimum inhibitory concentration (MIC) was identified as a pharmacokinetic-pharmacodynamic (PK-PD) parameter of glycopeptide antibiotics that correlated with bacteriological responses and clinical outcomes. Although optimized dosing regimens based on PK-PD are needed, a PK-PD analysis of teicoplanin against methicillin-resistant Staphylococcus aureus (MRSA) infections has not yet been performed. Thus, this study examined patients with MRSA infections, who were administered with teicoplanin in order to determine the target AUC/MIC ratio. METHODS: This study retrospectively assessed data obtained as part of our routine therapeutic drug monitoring (TDM) of teicoplanin therapy in 46 patients with MRSA infections at Kagoshima University Hospital. Serum concentrations of teicoplanin were determined using a fluorescence polarization immunoassay system and used for a Bayesian PK estimation to estimate AUC for 24 hours (AUC24). The MIC value for teicoplanin was determined using a standardized agar dilution method. The effects of teicoplanin were evaluated in terms of bacteriological responses by a quantitative assessment. RESULTS: The estimated AUC24/MIC ratios with and without bacteriological responses were 926.6±425.2 µg·h/mL (n=34) and 642.2±193.9 µg·h/mL, respectively (n=12; P<0.05). On the basis of a logistic regression analysis, AUC24/MIC ratios of 500 µg·h/mL, 700 µg·h/mL, and 900 µg·h/mL gave probabilities of treatment success of 0.50, 0.72, and 0.87, respectively. Furthermore, using the Kaplan-Meier curve analysis, an AUC24/MIC ratio of ≥900 led to a significantly stronger bacteriological response than an AUC24/MIC ratio of <900. CONCLUSION: These results suggest that an AUC24/MIC ratio of ≥900 µg·h/mL is required to ensure a sufficient bacteriological response.