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 ≥13 mg/L in ≤24, 24–36 and ≥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 ≥36 mg/kg during the first 3 days is appropriate to promptly obtain a trough concentration target of ≥13 mg/L for the initial treatment of MRSA infections.     

Exploration of optimal teicoplanin dosage based on pharmacokinetic parameters for the treatment of intensive care unit patients infected with methicillin-resistant Staphylococcus aureus

Severely ill intensive care unit (ICU) patients are frequently at risk of developing methicillin-resistant Staphylococcus aureus (MRSA) infections. It is generally accepted that a trough level of >10 μg/mL teicoplanin (TEC) is appropriate for most such infections. The present study was designed to determine how TEC exposure and patient characteristics affect microbiological response in the treatment of MRSA infections. All patients studied were admitted to Aichi Medical University Hospital ICU between May 2005 and April 2010. Fifty-nine patients were prescribed TEC and 33 of those patients used to treat MRSA infection. Outcome was classified as either cure or failure, and logistic regression analysis was performed to determine which covariates, including severity, significantly influenced the microbiological response. Satisfactory outcomes were obtained in 19 of the 33 patients. Although the cured and failed groups showed adequate trough concentrations, the area under the serum concentration curve (AUC_0–24) on the third day was significantly higher for the cured group (897.6 ± 71.7) than for the failed group (652.9 ± 83.4) (p < 0.05). The results suggested that at least 800 μg h/mL TEC AUC_0–24 were required to obtain microbiological cure. The higher AUC_0–24, the better the outcome. In our study, higher initial AUC_0–24 was associated with a better microbiological outcome, which demonstrates the importance of the loading dose of TEC, especially for ICU patients. Moreover, the present findings are useful for optimizing the individual dose of TEC using AUC_0–24 in the treatment of MRSA-infected patients.     

Development and evaluation of a vancomycin dosing nomogram to achieve the target area under the concentration-time curve. A retrospective study

Although the superiority of vancomycin dosing based on area under the concentration-time curve (AUC_0-24) over that based on trough concentration has been reported, a dosing strategy to achieve the target AUC_0-24 has yet to be developed. The objective of this study was to develop a convenient useable nomogram for vancomycin dosing to obtain the target AUC_0-24 (400 μg h/mL). The nomogram was pharmacokinetically developed in a retrospective manner. The number of enrolled patients and concentrations was 166 and 309 for development of the nomogram, 99 and 181 for evaluation of the nomogram, respectively. The nomogram was developed as doses per personal body weight corresponding to each range of estimated glomerular filtration rate (eGFR), which was identified to be the covariate for vancomycin clearance by non-linear mixed effect modeling. The nomogram described the surrogate trough concentration for the target AUC_0-24 was calculatedly different for each eGFR range (9.3–15.0 μg/mL). The rate of attainment of therapeutic range using surrogate trough concentration to obtain the target AUC_0-24 was 63.8% in the evaluation period. We have developed and evaluated the first convenient useable nomogram of vancomycin dosing to obtain the target AUC_0-24.     

A Simulated Application of the Hartford Hospital Aminoglycoside Dosing Nomogram for Plazomicin Dosing Interval Selection in Patients With Serious Infections Caused by Carbapenem-Resistant Enterobacterales

PurposeIn the Phase III Study of Plazomicin Compared With Colistin in Patients With Infection Due to Carbapenem-Resistant Enterobacteriaceae (CARE), plazomicin was studied for the treatment of critically ill patients with infections caused by carbapenem-resistant Enterobacterales. Initial plazomicin dosing was guided by creatinine clearance (CrCl) and subsequent doses adjusted by therapeutic drug monitoring to achieve AUC_0–24 exposures within a target range (210–315 mg?h/L). We applied the Hartford nomogram to evaluate whether this clinical tool could reduce plazomicin troughs levels and increase the proportion of patients within the target AUC range.MethodsThirty-seven patients enrolled in cohorts 1 or 2 of CARE were eligible for analyses. Observed 10-hour concentrations after the initial dose were plotted on the Hartford nomogram to determine an eligible dosing interval group (q24h, q36h or q48h). On the basis of baseline CrCl, a 15- or 10-mg/kg dose was simulated with the nomogram-recommended dosing interval. The proportion of patients in each dosing interval group with a trough ≥3 mg/L (trough threshold associated with serum creatinine increases ≥0.5 mg/dL in product label) was quantified. Simulated interval-normalized AUC_0–24 was compared with the target AUC range.FindingsAmong the 28 patients with a CrCl ≥60 mL/min, the nomogram recommended every-24-hour dosing in 61% and an extended-interval (q36h or q48h) in 39% of patients. For patients with a CrCl ≥30–59 mL/min (n = 9), the nomogram recommended every-24-hour dosing and an extended-interval in 22% and 78% of patients, respectively. Among both renal function cohorts, exposure simulation with the nomogram significantly reduced the proportion of patients with trough concentrations ≥3 mg/L (CrCl ≥60 mL/min cohort: 91% vs 9%, P < 0.001; CrCl ≥30–59 mL/min cohort, 100% vs 0%, P < 0.001). Relative to the observed mean (SD) AUC_0–24 of 309 mg?h/mL (96 mg?h/mL), simulation of extended intervals resulted in a mean interval-normalized AUC_0–24 of 210 mg?h/mL (40 mg?h/mL) in all patients eligible for an extended interval, resulting in a similar proportion (49% vs 54%) of patients within the target AUC_0–24 range after the first dose.ImplicationsApplication of the Hartford nomogram successfully reduced the likelihood of elevated plazomicin trough concentrations while improving AUC exposures in these patients with carbapenem-resistant Enterobacterales infections.     

Pharmacokinetic study of antimicrobial agents in patients undergoing continuous ambulatory peritoneal dialysis

A pharmacokinetic study was done in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) to establish an appropriate treatment for bacterial peritonitis. Twenty-nine CAPD patients were randomized to receive either oral ofloxacin (OFLX) 300 mg, followed by 200 mg once a day; intraperitoneal vancomycin (VCM) 30 mg/kg once a week; or intravenous imipenem/cilastatin (IPM/CS) 1000 mg once a day. Pharmacokinetic simulation models were determined according to changes of doses and duration. The time to reach the maximum plasma concentration (t _max), the maximum plasma concentration (C _max), the plasma elimination half-life (t _1/2), and area under the curve (AUC) were, respectively, 5.2 hours, 4.7 μg/mL, 20.4 hours and 80.5 μg/mL/h (AUC_0–24) for OFLX, 7.0 h, 26.4 μg/mL, 92.0 hours, and 1641 μg/mL/h (AUC_0–120) for VCM, 1.1 hour, 62.3 μg/ml, 3.76 hours, and 229.3 μg/mL/h (AUC₀₋₁) for IPM/CS. Twenty-three of 27 (85%) strains of clinical isolates were gram-positive cocci; 20 strains (74%) consisted of staphylococci or streptococci. The MIC₉₀ of OFLX, VCM, and IPM was 3.13, 1.56, and 0.78 μg/mL, respectively. When the minimum concentration in the dialysate during the initial 5 days was higher than the MIC, all the isolates (7 out of 7) were eradicated, when it was lower, only half of the isolates (3 out of 6) were eradicated. The simulation study suggested a significant drug accumulation in response to shortening the dosing duration.     

Pharmacokinetics and pharmacodynamics of sequential intravenous and subcutaneous teicoplanin in critically ill patients without vasopressors

Objective To compare the pharmacokinetic parameters of sequential intravenous and subcutaneous teicoplanin in the plasma of surgical intensive care unit patients.Design and setting Prospective, randomized, crossover study in the surgical ICU of a university hospital.Patients Twelve patients with a suspected nosocomial infection, a serum albumin level higher than 10 g/l, body mass index less than 28 kg/m², and estimated creatinine clearance higher than 70 ml/min.Interventions Teicoplanin was first administered intravenously as a loading dose of 6 mg/kg per 12 h for 48 h and then continued at a daily dose of 6 mg/kg. On the fourth day patients were randomized in two groups according to the order of the pharmacokinetic studies.Measurements and results Serial plasma samples were obtained to measure teicoplanin levels. Compared with a 30-min intravenous infusion the peak concentration of teicoplanin after a 30-min subcutaneous administration occurred later (median 7 h, range 5–18) and was lower (16 µg/ml, 9–31; vs. 73, 53–106). Despite large and unpredictable interindividual differences no significant differences between subcutaneous and intravenous administration were observed in: trough antibiotic concentrations (10 µg/ml, 6–24; vs. 9, 5–30), the area under the teicoplanin plasma concentration vs. time curves from 0 to 24 h (AUC_0–24h; 309 µg/ml per minute, 180–640; vs. 369, 171–955), the proportion of the dosing interval during which the plasma teicoplanin concentration exceeded 10 µg/ml (96%, 0–100%; vs. 79%, 13–100%), and the ratio of AUC_0–24h to 10 (77, 45–160; vs. 92, 43–239).Conclusions In critically ill patients without vasopressors a switch to the subcutaneous teicoplanin after an initial intravenous therapy seems to give comparable pharmacodynamic indexes of therapeutic success.     

Penetration of pazufloxacin into the fluid of suction blisters induced in human skin

We investigated the pharmacokinetics of pazufloxacin (PZFX) in the fluid of suction blisters induced in the skin of 6 healthy male volunteers after a 200 mg oral dose of PZFX. The time to reach the maximum concentration (t _max) of PZFX in plasma was 0.7 hours, and the maximum concentration (C _max) was 2.95 μg/mL. The half-life of the elimination phase (t _1/2) in plasma was 1.75 hours, and the area under the concentration-time curve (AUC) was 6.70 μg·h/mL. Thet _max,C _max,t _1/2 and AUC values in the suction blister fluid were 2.0 hours, 1.52 μg/mL, 1.95 hours and 6.28 μg·h/mL, respectively. The ratio of the AUC of PZFX in blister fluid to the AUC in plasma was almost 1.0. Thus, excellent penetration of PZFX into suction blister fluid was observed.     

Pharmacokinetics and pharmacodynamics of daptomycin in a clinical setting

We investigated achievement of a target 24-h area under the concentration-time curve to minimum inhibitory concentration ratio (AUC/MIC) ≥666 and the factors influencing this ratio in patients who received daptomycin (DAP) for infectious disease treatment in a clinical setting. The target AUC/MIC was obtained in 6 patients (35.3%) at a 4–6 mg/kg dose (Group_{_4–6 mg/kg}) and in 4 (18.2%) at a >6 mg/kg dose (Group_{_>6 mg/kg}). There was a significant difference in clearance of DAP (CL_{_DAP}) between these groups, but no other difference in characteristics. Multiple linear regression analysis was performed for prediction of AUC ≥666 based on patient factors and the presence or absence of sepsis. In a stepwise analysis, serum creatinine (SCr) was a significant predictor of AUC, but this parameter explained only 13% of the variance in achievement of the target AUC. These results show that the target AUC/MIC may or may not be achieved at the doses used in Group_{_4–6 mg/kg} and Group_{_>6 mg/kg}. Receiver operating characteristic analysis suggested that a CL_{_DAP} >0.450 L/hr may lead to failure to reach the target AUC/MIC. Therefore, regardless of dose, the efficacy of DAP should be monitored closely to prevent failure of infectious disease treatment, particularly because therapeutic drug monitoring of DAP is limited by difficulty measuring the DAP serum concentration at many medical facilities. Our findings are preliminary, and a further study is required to identify factors that increase CL_{_DAP} and to enable dose adjustment of DAP.     

Evaluation by Monte Carlo simulation of levofloxacin dosing for complicated urinary tract infections caused by Escherichia coli or Pseudomonas aeruginosa

We evaluated, by Monte Carlo simulation, 500-mg once-daily, 100-mg thrice-daily, 200-mg twice-daily, and 200-mg thrice-daily dose regimens of levofloxacin (LVFX), for the ratio of area under the concentration–time curve for 24 h (AUC_0–24) to minimum inhibitory concentration (MIC) (AUC_0–24/MIC) and the ratio of maximum plasma concentration (C _max) to MIC (C _max/MIC), which predict microbiological outcomes, and the C _max/MIC, which inhibits fluoroquinolone resistance selection, in complicated urinary tract infections (UTIs) with Escherichia coli or Pseudomonas aeruginosa. Monte Carlo simulation was performed for 10000 cases using the pharmacokinetic data of patients with complicated UTIs and the LVFX MIC distributions for E. coli or P. aeruginosa clinical strains. The probabilities of achieving the AUC_0–24/MIC target (66.2–67.9%) and the C _max/MIC target (64.5–67.5%) to eradicate E. coli were similar among the 4 regimens. In eradication of P. aeruginosa, the 200-mg thrice-daily and the once-daily dose regimens produced higher probabilities of achieving the AUC_0–24/MIC target (57.5%) and C _max/MIC target (55.1%), respectively. For the probabilities of achieving the C _max/MIC targets that prevent the emergence of fluoroquinolone resistance, the once-daily dose regimen (66.8%) did not differ from the other multiple-dose regimens (62.3–66.2%) in E. coli, whereas the former regimen (44.2%) was superior to the latter regimens (10.8–31.7%) in P. aeruginosa. The 500-mg once-daily dose regimen of LVFX, which produced the larger AUC_0–24 and higher C _max, could ensure the efficacy of eradication of uropathogens and reduce the risk of fluoroquinolone resistance selection in complicated UTIs.     

Telavancin pharmacokinetics and pharmacodynamics in patients with complicated skin and skin structure infections and various degrees of renal function

This study characterized the pharmacokinetic/pharmacodynamic profiles of the Food and Drug Administration (FDA)-approved telavancin renal dose adjustment schemes. A previously published two-compartment open model with first-order elimination and a combined additive and proportional residual error model derived from 749 adult subjects in 11 clinical trials was used to simulate the individual concentration-time profiles for 10,260 subjects (NONMEM). The dosing regimens simulated were 10 mg/kg of body weight once daily for individuals with creatinine clearances (CL_CRs) of >50 ml/min, 7.5 mg/kg once daily for individuals with CL_CRs of 30 to 50 ml/min, and 10 mg/kg every 2 days for those with CL_CRs of <30 ml/min. The area under the concentration-time curve (AUC) under one dosing interval (AUC_τ) was computed as dose/CL. The probability of achieving an AUC_τ/MIC ratio of ≥219 was evaluated separately for each renal dosing scheme. Evaluation of the dosing regimens demonstrated similar AUC values across the different renal function groups. For all renal dosing strata, >90% of the simulated subjects achieved an AUC_τ/MIC ratio of ≥219 for MIC values as high as 2 mg/liter. For patients with CL_CRs of <30 ml/min, the probability of target attainment (PTA) exceeded 90% for both the AUC_0–24 (AUC from 0 to 24 h) and AUC_24–48 intervals for MICs of ≤1 mg/liter. At a MIC of 2 mg/liter, the PTAs were 89.3% and 23.6% for the AUC_0–24 and AUC_24–48 intervals, respectively. The comparable PTA profiles for the three dosing regimens across their respective dosing intervals indicate that the dose adjustments employed in phase III trials for complicated skin and skin structure infections were appropriate.     

Effect of renal clearance on vancomycin area under the concentration–time curve deviations in critically ill patients

IntroductionAugmented renal clearance (ARC) increases vancomycin (VCM) clearance. Therefore, higher VCM doses are recommended in patients with ARC; however, impacts of ARC on the area under the concentration–time curve (AUC) discrepancies between initial dosing design and therapeutic drug monitoring (TDM) period remains unclear.MethodsWe retrospectively collected data from critically ill patients treated with VCM. The primary endpoint was the association between ARC and AUC_24–48h deviations. ARC and AUC deviation were defined as a serum creatinine clearance (CCr) ≥130 mL/min/1.73 m² and an AUC at TDM 30% or more higher than the AUC at the initial dosing design, respectively. The pharmacokinetic profiles of VCM were analyzed with the trough levels or peak/trough levels using the Bayesian estimation software Practical AUC-guided TDM (PAT).ResultsAmong 141 patients (median [IQR]; 66 [58–74] years old; 30% women), 35 (25%) had ARC. AUC deviations were significantly more frequent in the ARC group than in the non-ARC group (20/35 [57.1%] and 17/106 [16.0%] patients, respectively, p < 0.001). Age- and sex-adjusted multivariate analyses revealed that the number of VCM doses before TDM ≥5 (odds ratio, 2.56; 95% confidence interval [CI]: 1.01–6.44, p = 0.047) and CCr ≥130 mL/min/1.73 m² were significantly associated with AUC deviations (odds ratio, 7.86; 95%CI: 2.91–21.19, p < 0.001).ConclusionOur study clarifies that the AUC of VCM in patients with ARC is higher at the time of TDM than at the time of dosage design.     

Population pharmacokinetics of oral levofloxacin 500 mg once-daily dosage in community-acquired lower respiratory tract infections: results of a prospective multicenter study in China

This study aimed to explore the pharmacokinetic features of levofloxacin (LVFX) in Chinese patients with infections and to confirm oral LVFX 500 mg once daily as an optimal treatment regimen based on pharmacokinetic-pharmacodynamic (PK-PD) analysis. A total of 1052 plasma samples from 164 Chinese adult patients with communityacquired lower respiratory tract infections (CALRTIs) and 18 healthy volunteers were used for population PK analysis. LVFX 500-mg tablets were given once daily. A nonlinear mixed effects model (NONMEM) program was used for population PK model-building and a two-compartment model with first-order absorption process was established. Creatinine clearance (CL_cr) and body weight were identified as intrinsic factors which significantly affected oral clearance (CL_t/F) and the apparent volume of distribution of the central compartment (V1/F), respectively. The final model is described as follows: CL_t/F (l/h) = (8.97 + 0.917 × (CL_cr (ml/min) ? 100.92) × 60/1000) × exp (η_CLt/F). V1/F (l) = (85.3 + 1.22 × (weight (kg) ? 60.75)) × exp (η_V1/F). Q/F (l/h) = 0.351. V2/F (l) = 6.81. k_a (h^?1) = 1.44 × exp(η_ka). Based on the population PK model, mean C_max and AUC_0–24h in CALRTI patients were estimated as 5.13 µg/ml and 58.98 µg·h/ml, respectively. A subgroup analysis showed that patients with mild renal dysfunction (50 ml/min ≤ CL_cr < 80 ml/min) had 34% higher AUC_0–24h values compared to patients with normal renal function (CL_cr ≥ 80 ml/min). Postmodeling simulation using final population PK estimates also showed that C_max and AUC_0–24h increased markedly in patients with severe renal dysfunction. The results indicate that LVFX dosage adjustment should be individualized on the basis of the CL_cr, especially in those with CL_cr less than 50 ml/min. None of the PK parameters had any correlation with the occurrence of adverse events. PK-PD analysis indicated that, in patients treated with LVFX 500 mg once daily, the AUC_0–24h/MIC ratio exceeded the target for those major CALRTI pathogens isolated. In addition, the C_max/MIC ratio reached 5 for Streptococcus pneumoniae, indicating that the emergence of LVFX-resistant S. pneumoniae could be prevented during the therapy with this dosage regimen. These results demonstrate that oral LVFX 500 mg once daily has favorable PK parameters and PK-PD features in patients with CALRTIs, and the results strongly support this dosage regimen for the treatment of CALRTI.     

Thrombocytopenia and anemia caused by a persistent high linezolid concentration in patients with renal dysfunction

It has been proposed that it is not necessary to adjust the dose of linezolid (LZD) in patients with reduced renal function. However, significantly lower platelet counts and hemoglobin levels have been reported in such patients compared to those in patients with normal renal function. This suggests that the appropriate dose and administration method for LZD are yet to be established in patients with renal dysfunction. The subjects in this study were patients with renal dysfunction who developed adverse effects of thrombocytopenia and anemia during treatment with LZD. We investigated the association of these adverse effects with the blood LZD concentration and the area under the concentration–time curve from zero to 24 h (AUC_0–24), determined using a one-compartment Bayesian model (n = 20). The measured blood LZD concentration was significantly higher than the predicted concentration in a population pharmacokinetics approach (p < 0.01), and severe thrombocytopenia developed as the blood LZD concentration increased. The platelet count and hemoglobin level decreased as the AUC_0–24 of LZD increased in patients with renal dysfunction, and the correlations were significant: r = 0.593 and r = 0.783, respectively (p < 0.01). These findings suggest that LZD administered to patients with renal dysfunction may reach a high blood level and subsequently increase the AUC_0–24, which may then induce adverse effects of severe thrombocytopenia and anemia.     

Population Pharmacokinetics and AUC-Guided Dosing of Tobramycin in the Treatment of Infections Caused by Glucose-Nonfermenting Gram-Negative Bacteria

PurposeTobramycin (TOB) exhibits variable pharmacokinetic properties due to the clinical condition of patients. This study aimed to investigate the AUC-guided dosing of TOB based on population pharmacokinetic analysis in the treatment of infections caused by Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia.MethodsThis retrospective study was conducted between January 2010 and December 2020 after obtaining approval from our institutional review board. For 53 patients who received therapeutic drug monitoring of TOB, a population pharmacokinetic model was developed with covariates of estimated glomerular filtration rate using serum creatinine (eGFRcre) on clearance (CL) and weight on both CL and V_d in exponential error modeling (CL = 2.84 × [weight/70] × eGFRcre^0.568, interindividual variability [IIV] = 31.1%; V_d = 26.3 × [weight/70], IIV = 20.2%; residual variability = 28.8%).FindingsThe final regression model for predicting 30-day mortality was developed with risk factors of AUC during a 24-hour period after the first dose to MIC ratio (odds ratio [OR] = 0.996; 95% CI, 0.968–1.003) and serum albumin (OR = 0.137; 95% CI, 0.022–0.632). The final regression model for predicting acute kidney injury was developed with the risk factors of C-reactive protein (OR = 1.136; 95% CI, 1.040–1.266) and AUC during a 72-hour period after the first dose (OR = 1.004; 95% CI, 1.000–1.001). A dose of 8 or 15 mg/kg was beneficial for achievement of AUC during a 24-hour period after the first dose/MIC >80 and trough concentration <1 µg/mL in patients with preserved kidney function and TOB CL >4.47 L/h/70 kg in the events of MIC of 1 or 2 µg/mL, respectively. We propose that the first dose of 15, 11, 10, 8, and 7 mg/kg for eGFRcre >90, 60 to 89, 45 to 59, 30 to 44, and 15 to 29 mL/min/1.73 m² be followed by therapeutic drug monitoring at peak and 24 hours after the first dose.ImplicationsThis study suggests that TOB use encourages the replacement of trough- and peak-targeted dosing with AUC-guided dosing.     

Safety,Tolerability, Pharmacokinetics,and Pharmacodynamics of SPH3127: A Phase I,Randomized, Double-Blind,Placebo-Controlled Trial

PurposeTo evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of single- and multiple-dose SPH3127 in healthy individuals.MethodsThis was a randomized, double-blind, placebo-controlled, Phase I dose-escalation study.FindingsSPH3127 exposure, expressed as C_max, AUC_0–t, and AUC_0–∞, was proportionally increased with dose for a range of 25–800 mg (single ascending dose [SAD]) and 100–400 mg daily (multiple ascending doses [MADs]). In an SAD, the C_max values with 25, 50, 100, 200, 400, and 800 mg of SPH3127 were 90.67, 344.50, 523.50, 1239.50, 2445.00, and 5753.33 ng/mL, respectively. The corresponding AUC_0–t values were 294.48, 843.62, 1109.33, 2858.56, 6697.50, and 13057.83 h × ng/mL. In MADs, after the first dose of SPH3127, the C_max values with 100, 200, and 400 mg of SPH3127 were 421.50, 969.00, and 2468.33 ng/mL, respectively. The corresponding AUC_0–t values were 1279.28, 2275.77, and 5934.26 h × ng/mL. At steady state, the C_max values with 100, 200, and 400 mg of SPH3127 were 514.67, 1419.17, and 2513.33 ng/mL, respectively. The corresponding AUC_0–24 values were 1638.14, 3096.20, and 7577.70 h × ng/mL. The median T_max range from 0.33 to 1.0 h and the median t_1/2 from 3 to 4 h. In an SAD, when the dose was >100 mg, plasma renin activity inhibition of up to 90% lasted up to 24 h. In MADs, renin activity was continuously inhibited by up to 90% in each group for 24 h after the last administration. Treatment-emergent adverse events (AEs) were reported in 29.2% of individuals receiving the SAD and 33.3% of those receiving MADs. Only mild adverse events occurred.ImplicationsSPH3127 was well tolerated and had robust and sustained suppression of plasma renin activity.Clinicaltrials.gov identifiersNCT03128138 (SAD study) and NCT03255993 (MAD study).     

Antibacterial effects of brand-name teicoplanin and generic products against clinical isolates of methicillin-resistant <Emphasis Type="Italic">Staphylococcus aureus</Emphasis>

Glycopeptide antibiotics, such as vancomycin and teicoplanin, have been used worldwide to treat infection caused by methicillin-resistant Staphylococcus aureus (MRSA). Generic teicoplanin products were manufactured by many companies in 2009. We investigated the susceptibility of 147 MRSA strains to brand-name teicoplanin (TEIC-1) and seven generic products (TEIC-2 to TEIC-8). The MIC₉₀ of generic TEIC-5 and TEIC-7 was 8 μg/ml whereas that of TEIC-1 and other generic products was 4 μg/ml. The potency equivalent of generic TEIC-5 and TEIC-7 was lower than that of TEIC-1, and TEIC content (%) per potency equivalent (200 mg) in a vial of these two generic products varied greatly compared with the other products. Although the potency equivalent of the TEIC used in this study was within the range stipulated in the Japanese Pharmacopeia, these results showed that the potency equivalent and susceptibility of two of the seven generic products differed from that of TEIC-1. The predicted AUC_0–72 value of those two generic products was 84–85% in comparison with that of TEIC-1. Among generic drugs, there may be products whose antimicrobial effect is not equal to that of the brand teicoplanin.     

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

IntroductionBecause 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 (C_min) of ≥20 μg/mL remains unclear in patients on CVVHDF using the low flow rate adopted in Japan.MethodsThe 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 C_min was obtained at 72 h after the first dose.ResultsOverall, 60 patients were eligible for study inclusion. The proportion of patients achieving the C_min 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 C_min ≥ 20 μg/mL.ConclusionsAn 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.     

Comparison of single trough-based area under the concentration–time curve versus trough concentration for the incidence of vancomycin-associated nephrotoxicity

IntroductionWhile the revised 2020 consensus guideline recommends the use of area under the concentration–time curve (AUC)-guided vancomycin monitoring, collecting multiple vancomycin serum samples to calculate the AUC may cause clinical complications. The aim of the present retrospective study was to evaluate whether AUC-guided vancomycin monitoring, in which AUC was calculated based on a single trough concentration, is a better predictor of nephrotoxicity than trough-guided monitoring in patients receiving vancomycin therapy.MethodsA single-center, retrospective cohort study was conducted at the 614-bed Gifu University Hospital in Japan. Patients who received intravenous vancomycin for a documented or suspected infection and had their serum vancomycin trough concentration monitored between October 1, 2016 and September 30, 2020 were enrolled in the present study.ResultsMultivariate Cox proportional hazard analysis indicated that AUC (>600 μg?h/mL) was a significant risk factor for the incidence of acute kidney injury (AKI), while trough concentration (≥15 μg/mL) was not. Moreover, the AUC (>600 μg?h/mL) showed higher specificity and similar sensitivity to the trough concentration (≥15 μg/mL). Kaplan-Meier plots of the cumulative incidence of the AKI-free rate in patients indicated that the onset of AKI was significantly longer in patients with AUC ≤600 μg?h/mL than in patients with AUC >600 μg?h/mL (HR, 16.1; 95% CI, 6.3–41.2; p < 0.001).ConclusionAUC based on a single trough concentration was a better predictor of nephrotoxicity than trough concentration.     

Steady-state trough serum and epithelial lining fluid concentrations of teicoplanin 12 mg/kg per day in patients with ventilator-associated pneumonia

Objective To determine the steady-state trough serum and epithelial lining fluid (ELF) concentrations of teicoplanin 12 mg/kg per day in critically ill patients with ventilator associated pneumonia.Design and setting Prospective, pharmacokinetic study in the surgical intensive care unit in a university hospital.Patients Thirteen adult patients with nosocomial bacterial pneumonia on mechanical ventilation were enrolled.Interventions All subjects received a 30-min intravenous infusion of 12 mg/kg teicoplanin every 12 h for 2 consecutive days followed by 12 mg/kg once daily. Teicoplanin concentrations in serum and ELF were determined simultaneously 4–6 days after antibiotic administration started.Measurements and results The median total and free concentrations of teicoplanin in serum at trough were 15.9 μg/ml (range 8.8–29.9) and 3.7 (2.0–5.4), respectively. The concentration in ELF was 4.9 (2.0–11.8).Conclusions In critically ill patients with ventilator-associated pneumonia the administration of high teicoplanin doses is required to reach sufficient trough antibiotic concentrations in lung tissues at steady state. At that time trough-free concentrations of teicoplanin in serum and ELF are comparable.This work was financially supported by a grant from Laboratoires Aventis, Paris, France     

Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling

Because of the recent awareness that vancomycin doses should aim to meet a target area under the concentration-time curve (AUC) instead of trough concentrations, more aggressive dosing regimens are warranted also in the pediatric population. In this study, both neonatal and pediatric pharmacokinetic models for vancomycin were externally evaluated and subsequently used to derive model-based dosing algorithms for neonates, infants, and children. For the external validation, predictions from previously published pharmacokinetic models were compared to new data. Simulations were performed in order to evaluate current dosing regimens and to propose a model-based dosing algorithm. The AUC/MIC over 24 h (AUC₂₄/MIC) was evaluated for all investigated dosing schedules (target of >400), without any concentration exceeding 40 mg/liter. Both the neonatal and pediatric models of vancomycin performed well in the external data sets, resulting in concentrations that were predicted correctly and without bias. For neonates, a dosing algorithm based on body weight at birth and postnatal age is proposed, with daily doses divided over three to four doses. For infants aged <1 year, doses between 32 and 60 mg/kg/day over four doses are proposed, while above 1 year of age, 60 mg/kg/day seems appropriate. As the time to reach steady-state concentrations varies from 155 h in preterm infants to 36 h in children aged >1 year, an initial loading dose is proposed. Based on the externally validated neonatal and pediatric vancomycin models, novel dosing algorithms are proposed for neonates and children aged <1 year. For children aged 1 year and older, the currently advised maintenance dose of 60 mg/kg/day seems appropriate.