Population Pharmacokinetics Analysis and Dosing Simulations Of Meropenem in Critically Ill Patients with Pulmonary Infection

PurposeThis study aimed to develop a population pharmacokinetic (PPK) model for meropenem to optimize dosing regimens for critically ill patients with pulmonary infection.Patients and methodsThis prospective PPK study of meropenem was conducted on a pooled dataset of 236 blood samples obtained from 48 patients with pulmonary infection in the intensive care unit. Meropenem plasma concentrations were measured by a validated high-performance liquid chromatography-tandem mass spectrometry method, and the data were analyzed using NONMEM. The effect of covariates on meropenem pharmacokinetics was investigated. The probability of target attainment (PTA) to achieve the target of 100% fT_>MIC at the proposed dosage regimens were investigated by Monte Carlo simulations.ResultsA two-compartment model adequately described the data with estimated glomerular filtration rate (eGFR) as a covariate significantly associated with the clearance (CL) from the central compartment. The typical value of CL was 7.48 L/h, with an eGFR adjustment factor of 0.0103 mL?1.73 m²/min, and the typical values of volume of the central compartment (V₁), peripheral compartmental clearance (Q), and volume of the peripheral compartment (V₂) were 15.9 L, 15.8 L/h, and 14.8 L, respectively. The goodness-of-fit plots, normalized prediction distribution error, and visual predictive checks showed good fitting and predictability of the final PPK model. When eGFR was >90 mL/min/1.73 m^2, and there was a short duration of infusion (<60min), it was difficult for the probability target attainment (PTA) to reach >90% for MIC ≥ 2. Continuous infusion and frequent administration were necessary to achieve the target of 100% fT_>MIC for critically ill patients with pulmonary infection.ConclusionTo achieve the optimal PTA, meropenem must be administered by frequent administration or continuously by an intravenous infusion. Our findings provide important information to optimize the meropenem regime in critically ill patients with pulmonary infection depending on eGFR values.     

Beta-lactam target attainment and associated outcomes in patients with bloodstream infections

ObjectivesTo evaluate the association between early and cumulative beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters and therapy outcomes in bloodstream infection (BSI).MethodsAdult patients who received cefepime, meropenem, or piperacillin/tazobactam for BSI and had concentrations measured were included. Beta-lactam exposure was generated and the time that free concentration remained above the minimum inhibitory concentration (fT_>MIC) and four multiples of MIC (fT_>4 × MIC) were calculated for times 0-24 h and 0-7 days of therapy. Multiple regression analysis was performed to evaluate the impact of PK/PD on microbiological and clinical outcomes.ResultsA total of 204 patients and 213 BSI episodes were included. The mean age was 58 years and weight 83 kg. Age, Sequential Organ Failure Assessment (SOFA) score, haemodialysis, Pitt bacteraemia score, and hours of empiric antibiotic therapy were significantly associated with certain outcomes and retained in the final model. In multiple regression analysis, fT_>4 × MIC at 0-24 h and 0-7 days was a significant predictor of negative blood culture on day 7 (P=0.0161 and 0.0068, respectively). In the time-to-event analysis, patients who achieved 100% fT_>4 × MIC at 0-24 h and 0-7 days had a shorter time to negative blood culture compared with those who did not (log-rank P=0.0004 and 0.0014, respectively). No significant associations were identified between PK/PD parameters and other outcomes, including improvement in symptoms at day 7 and 30-day mortality.ConclusionEarly and cumulative achievement of fT_>4 × MIC was a significant predictor of microbiological outcome in patients with BSI.     

Pharmacokinetic modeling and simulation for dose rationale of doripenem in neonates and infants

The aims of this study were to construct a population pharmacokinetic model of doripenem in neonates and infants and to assess the dosing regimen for patients <3 months of age using Monte-Carlo pharmacokinetic/pharmacodynamic (PKPD) simulations. In the population pharmacokinetic analysis using 187 plasma concentrations from 47 neonates and infants, a two-compartment model well described plasma doripenem concentrations with the most significant covariates of chronological age and gestational age identified for the pharmacokinetics of doripenem. Monte-Carlo simulations suggested that the selected dosages for neonates and infants based on chronological age and gestational age (5 or 10 mg/kg) would provide ≥90% target attainment of 40%fT_>MIC against MIC of 2 μg/mL in all age groups. These results would be useful for understanding the PKPD characteristics of doripenem, which could provide essential information on optimal therapeutic treatment for neonates and infants.     

Frequency of pharmacological target attainment with flucloxacillin and cefazolin in invasive methicillin-susceptible Staphylococcus aureus infection: a prospective cohort study in hospitalized patients

BackgroundThe proportion of patients with invasive methicillin-susceptible Staphylococcus aureus (MSSA) infection who achieve target concentrations of flucloxacillin or cefazolin with standard dosing regimens is uncertain. This study measured drug concentrations in a prospective cohort of patients with invasive S. aureus infections to determine the frequency of target concentration attainment, and risk factors for failure to achieve target concentrations.Patients and methodsUnbound flucloxacillin and cefazolin plasma concentrations were measured at the midpoint between intravenous doses. Adequate and optimal targets were defined as an unbound plasma concentration of ≥1 and ≥2 times the minimum inhibitory concentration (MIC) (flucloxacillin 0.5 mg/L, cefazolin 2 mg/L), respectively (50%fT_≥1MIC, 50%fT_≥2MIC).ResultsThere were 50 patients in each of the flucloxacillin and cefazolin groups. Eighty-five (85%) patients met the target of 50%fT_≥2MIC and 95 (95%) patients met the target of 50%fT_≥1MIC. The median unbound flucloxacillin concentration was 2.6 mg/L [interquartile range (IQR) 1.0–8.1]. The median unbound cefazolin concentration was 15.4 mg/L (IQR 8.8–28.2). A higher proportion of patients in the flucloxacillin group failed to achieve the optimal target compared with the cefazolin group [13 (26%) vs 2 (4%); P=0.002]. Younger age and higher creatinine clearance were associated with lower plasma concentrations.ConclusionsStandard dosing of flucloxacillin and cefazolin in the treatment of invasive MSSA infections may not achieve target plasma concentrations for a subgroup of patients. Measuring drug concentrations identifies this subgroup and facilitates dose individualization.     

Piperacillin/tazobactam as an alternative antibiotic therapy to carbapenems in the treatment of urinary tract infections due to extended-spectrum β-lactamase-producing Enterobacteriaceae: an in silico pharmacokinetic study

Piperacillin/tazobactam (TZP) as an alternative treatment to carbapenems for infections involving extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-PE) remains debated. In this study, the probabilities of pharmacodynamic (PD) target attainment with different TZP regimens in ESBL-producing Escherichia coli (ESBL-Ec) and Klebsiella pneumoniae (ESBL-Kp) were evaluated in the context of pyelonephritis. Minimum inhibitory concentrations (MICs) of 144 ESBL-Ec and 111 ESBL-Kp from pyelonephritis were measured, and two previously published population pharmacokinetic models were used to determine by Monte Carlo simulation the probabilities of reaching two PD targets (50%fT_>MIC and 100%fT_>MIC) with TZP doses of 4?g three times daily and 4.5?g four times daily given as short (1?h) or prolonged (4?h) infusions or as 12–18?g/day continuous infusions. Only MICs of the 133 ESBL-Ec and 74 ESBL-Kp strains susceptible to TZP according to inhibition zone diameter were considered for the simulations. Results were similar with the two models, and only prolonged and continuous infusions allowed to reach 50%fT_>MIC with a probability of >90% irrespective of bacterial species. Continuous infusion and prolonged infusion combined with the maximum dosage were the only condition allowing to achieve 100%fT_>MIC with a probability of >70% with this population of ESBL-Ec. A probability of >90% to reach 100%fT_>MIC with ESBL-Kp could be obtained only with the 18?g/day continuous-infusion regimen. TZP may be used for treatment for mild pyelonephritis involving susceptible ESBL-Ec provided that administration modalities are optimised. Conversely, for ESBL-Kp the risk of treatment failure may be higher, supporting the use of continuous infusion.     

Application of pharmacokinetic/pharmacodynamic modelling and simulation for the prediction of target attainment of ceftobiprole against meticillin-resistant Staphylococcus aureus using minimum inhibitory concentration and time–kill curve based approaches

The purpose of this report was to compare two different methods for dose optimisation of antimicrobials. The probability of target attainment (PTA) was calculated using Monte Carlo simulation to predict the PK/PD target of fT_>MIC or modelling and simulation of time–kill curve data. Ceftobiprole, the paradigm compound, activity against two MRSA strains was determined, ATCC 33591 (MIC = 2 mg/L) and a clinical isolate (MIC = 1 mg/L). A two-subpopulation model accounting for drug degradation during the experiment adequately fit the time–kill curve data (concentration range 0.25–16× MIC). The PTA was calculated for plasma, skeletal muscle and subcutaneous adipose tissue based on data from a microdialysis study in healthy volunteers. A two-compartment model with distribution factors to account for differences between free serum and tissue interstitial space fluid concentration appropriately fit the pharmacokinetic data. Pharmacodynamic endpoints of fT_>MIC of 30% or 40% and 1- or 2-log kill were used. The PTA was >90% in all tissues based on the PK/PD endpoint of fT_>MIC >40%. The PTAs based on a 1- or 2-log kill from the time–kill experiments were lower than those calculated based on fT_>MIC. The PTA of a 1-log kill was >90% for both MRSA isolates for plasma and skeletal muscle but was slightly below 90% for subcutaneous adipose tissue (both isolates ca. 88%). The results support a dosing regimen of 500 mg three times daily as a 2-h intravenous infusion. This dose should be confirmed as additional pharmacokinetic data from various patient populations become available.     

In vitro activity of the siderophore monosulfactam BAL30072 against contemporary Gram-negative pathogens from New York City,including multidrug-resistant isolates

The in vitro activity of BAL30072 was assessed against clinical isolates from NYC hospitals, including isolates from a citywide surveillance study and a collection of isolates with well-characterised resistance mechanisms. BAL30072 was the most active β-lactam against Pseudomonas aeruginosa (MIC_50/90, 0.25/1 μg/mL), Acinetobacter baumannii (MIC_50/90, 4/>64 μg/mL) and KPC-possessing Klebsiella pneumoniae (MIC_50/90, 4/>64 μg/mL). Combining BAL30072 with meropenem resulted in a ≥4-fold decrease in the BAL30072 MIC₉₀ both for A. baumannii and K. pneumoniae. For isolates with a BAL30072 MIC > 4 μg/mL, addition of a sub-MIC concentration of colistin resulted in a four-fold decrease in the BAL30072 MIC in 44% of P. aeruginosa, 82% of A. baumannii and 23% of K. pneumoniae. Using sub-MIC concentrations, BAL30072 plus colistin was bactericidal against 4 of 11 isolates in time–kill studies. BAL30072 MICs were frequently lower for P. aeruginosa and K. pneumoniae when tested using Mueller–Hinton agar versus Iso-Sensitest agar or Mueller–Hinton broth. Against the well-characterised isolates, reduced susceptibility to BAL30072 correlated with mexA and mexX expression (P. aeruginosa), adeB expression (A. baumannii) and presence of SHV-type ESBLs (A. baumannii and K. pneumoniae). BAL30072 shows promising activity against contemporary Gram-negatives, including MDR P. aeruginosa, A. baumannii and K. pneumoniae. Enhanced activity was often present when BAL30072 was combined with meropenem or colistin. BAL30072 MICs were influenced by the testing method, particularly for P. aeruginosa and K. pneumoniae. Further in vivo studies are warranted to determine the potential clinical utility of BAL30072 alone and combined with other agents.     

First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis

The objectives of this study were (i) to compare the plasma concentration–time profiles for first-dose and steady-state piperacillin administered by intermittent or continuous dosing to critically ill patients with sepsis and (ii) to use population pharmacokinetics to perform Monte Carlo dosing simulations in order to assess the probability of target attainment (PTA) by minimum inhibitory concentration (MIC) for different piperacillin dosing regimens against bacterial pathogens commonly encountered in critical care units. Plasma samples were collected on Days 1 and 2 of therapy in 16 critically ill patients, with 8 patients receiving intermittent bolus dosing and 8 patients receiving continuous infusion of piperacillin (administered with tazobactam). A population pharmacokinetic model was developed using NONMEM^®, which found that a two-compartment population pharmacokinetic model best described the data. Total body weight was found to be correlated with drug clearance and was included in the final model. In addition, 2000 critically ill patients were simulated for pharmacodynamic evaluation of PTA by MIC [free (unbound) concentration maintained above the MIC for 50% of the dosing interval (50% f_T>MIC)] and it was found that continuous infusion maintained superior free piperacillin concentrations compared with bolus administration across the dosing interval. Dosing simulations showed that administration of 16 g/day by continuous infusion vs. bolus dosing (4 g every 6 h) provided superior achievement of the pharmacodynamic endpoint (PTA by MIC) at 93% and 53%, respectively. These data suggest that administration of piperacillin by continuous infusion, with a loading dose, both for first dose and for subsequent dosing achieves superior pharmacodynamic targets compared with conventional bolus dosing.     

Evaluating biapenem dosage regimens in intensive care unit patients with Pseudomonas aeruginosa infections: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation

This study was conducted to identify optimal dosage regimens and estimate pharmacokinetic/pharmacodynamic (PK/PD) characteristics of short-infusion (SI) versus extended-infusion (EI) biapenem against Pseudomonas aeruginosa infections in Chinese intensive care unit (ICU) patients. A total of 85 strains of P. aeruginosa were collected, and the minimum inhibitory concentration (MIC) of biapenem was measured by the serial two-fold agar dilution method. We designed four frequently used clinical regimens: biapenem 300?mg I.V. q12h, q8h, and q6h, and 600?mg q12h. The Monte Carlo Simulation (MCS) was performed using previously published pharmacokinetic data to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of these regimens as an SI (0.5?h) and an EI (1?h, 2?h, 3?h, and 4?h).For a target of 40%fT_>MIC (serum drug concentration remains above the MIC for a dosing period), none of the regimens achieved any CFRs>90% for P. aeruginosa, multidrug–resistant P. aeruginosa (MDR-PA) and even non–MDR-PA. The traditional biapenem SI regimens most commonly seen in clinical practice were insufficient in treating both MDR and non-MDR P. aeruginosa in ICU patients. However, biapenem 600?mg q12h over 2–4?h EI regimens could achieve CFR>90% with 20%fT_>MIC. Clinical trials should aim to validate the potentially greater PK/PD index with higher, more frequent doses and longer extended infusions.     

基于PK/PD模型结合蒙特卡洛模拟评价3种抗菌药物对铜绿假单胞菌感染延长输注给药方案

目的： 应用PK/PD模型结合蒙特卡洛模拟评价3种抗菌药物对铜绿假单胞菌感染的延长输注给药方案。方法： 收集广州市中西医结合医院2020年铜绿假单胞菌对头孢他啶、哌拉西林钠他唑巴坦（8∶1）、美罗培南的药敏报告,制订3种抗菌药物的3 h延长输注及两步法延长输注共12种给药方案,根据各抗菌药物的药动学/药效学（PK/PD）模型参数,应用蒙特卡洛模拟（Monte Carlo simulation,MCS）计算3种抗菌药物不同给药方案对10 000例感染患者的达标概率（probability of target attainment,PTA）及累积反应分数（cumulative fraction of response,CFR）,对各延长输注给药方案进行评价及临床验证。结果： 临床标本共分离出296株铜绿假单胞菌,经MCS模拟3种抗菌药物所有延长输注给药方案的CFR均小于90%,CFR最高的为哌拉西林钠他唑巴坦2.25 g/0.5 h+2.25 g/3 h q6h给药方案（88.10%）;哌拉西林钠他唑巴坦、美罗培南比头孢他啶对MIC中介的铜绿假单胞菌有更高的PTA及CFR,其中美罗培南1 g/0.5 h+1 g/3 h q8h给药方案对MIC=8 μg·mL^-1的耐药铜绿假单胞菌仍有一定的PTA （60.21%）;临床病例验证与MCS结果相仿。结论： 该院铜绿假单胞菌中介/耐药率较高,针对MIC中介以上的铜绿假单胞菌感染,可选择哌拉西林钠他唑巴坦或美罗培南,通过增加给药剂量、频次并使用两步法延长输注给药方式优化抗感染方案。     

Pharmacokinetics and Pharmacodynamics of Ceftolozane/Tazobactam in Critically Ill Patients With Augmented Renal Clearance

ObjectiveTo determine whether established ceftolozane/tazobactam (C/T) dosing is adequate for patients with augmented renal clearance (ARC) and bacterial infection.MethodsARC (creatinine clearance [CrCl] ≥ 130 mL/min) was confirmed by directly measured CrCl in 11 critically ill patients in a phase 1 pharmacokinetics study. Patients received 3 g C/T (ceftolozane 2 g/tazobactam 1 g) as a 60-minute intravenous infusion. Pharmacokinetic sampling occurred at 0 (predose), 1, 2, 4, 6, and 8 hours after the start of the infusion. Noncompartmental analyses were conducted on concentration data. The following pharmacodynamic targets were evaluated: time that free (unbound) drug concentrations exceeded the minimum inhibitory concentration (fT>MIC) of 4 μg/mL for ceftolozane and time that the unbound concentration exceeded the 1 μg/mL target threshold (fT>threshold = 1 µg/mL) for > 20% of the dosing interval for tazobactam. Safety was evaluated.ResultsMean (SD) area under the plasma concentration-time curve from 0 to infinity, clearance and volume of distribution at steady state (V_ss) were 236 (118) h*µg/mL, 10.4 (4.5) L/h and 30.8 (10.8) L, respectively, for ceftolozane; and 35.5 (18.5) h*µg/mL, 35.3 (16.5) L/h and 54.8 (20.1) L, respectively, for tazobactam. Clearance and V_ss were higher for both ceftolozane and tazobactam in patients with ARC compared with healthy individuals. The mean estimated ceftolozane fT>MIC at 4 µg/mL was 86.4%; the mean estimated tazobactam fT>threshold = 1 µg/mL was 54.9%. Treatment-emergent adverse events were mild to moderate.ConclusionsIn patients with ARC, a 3 g C/T dose met respective pharmacodynamic targets for ceftolozane and tazobactam.ClinicalTrials.gov identifierNCT02387372     

Pharmacokinetics,pharmacokinetic–pharmacodynamic relationship,and withdrawal period of amoxicillin sodium in olive flounder (Paralichthys olivaceus)

1.?The pharmacokinetics (PK) and withdrawal period of amoxicillin sodium in olive flounder and its activity against pathogenic bacteria of olive flounder were investigated.

2.?Intramuscular administration (12.5 or 125?mg/kg, n?=?160) and HPLC analysis of sera were used.

3.?Rapid absorption (T_max 2.6 and 2.2?h), prolonged action (terminal half-life, 15.52 and 10.42?h; MRT, 18.79 and 14.44?h), and dose-proportional exposure (AUC_0–∞, 273.69 and 2755.37?h. μg/ml) were observed after 12.5 and 125?mg/kg doses.

4.?The withdrawal period of amoxicillin sodium from muscle plus skin of olive flounder (n?=40, water temperature, 23?°C) was 12 d (276 degree days).

5.?Amoxicillin sodium had small MICs against Streptococcus iniae (0.008–0.06?μg/ml) and Streptococcus parauberis (0.03–1.0?μg/ml), whereas higher concentrations were required to inhibit Edwardsiella tarda isolates (0.06–16?μg/ml).

6.?While large AUC_0–24?h/MIC₉₀ and C_max/MIC₉₀ ratios were obtained for S. iniae and S. parauberis, with drug concentrations in serum greater than MICs for the entire dosing interval (T?>?MIC₉₀ of 100%), the lower dose (12.5?mg/kg) could not achieve target values of the PK–pharmacodynamic (PD) indices for E. tarda isolates, suggesting the need for higher doses to combat pathogenic bacteria with large MICs.     

Meropenem–nacubactam activity against AmpC-overproducing and KPC-expressing Pseudomonas aeruginosa in a neutropenic murine lung infection model

Nacubactam is a novel non-β-lactam diazabicyclooctane β-lactamase inhibitor under development for the treatment of serious Gram-negative infections. This study assessed the efficacy of human-simulated epithelial lining fluid (ELF) exposure of nacubactam in combination with meropenem against AmpC-overproducing (n=4) and Klebsiella pneumoniae carbapenemase (KPC)-expressing (n=3) Pseudomonas aeruginosa isolates in the neutropenic murine lung infection model. Meropenem, nacubactam and meropenem–nacubactam (1:1 concentration ratio) minimum inhibitory concentrations (MICs) were determined in triplicate using broth microdilution. Regimens that provided ELF profiles mimicking those observed in humans given nacubactam 2 g q8h (1.5-h infusion) alone and in combination with a subtherapeutic ELF exposure of meropenem were administered 2 h after inoculation. Efficacy was assessed as the change in log₁₀ colony-forming units (CFU)/lung at 24 h compared with 24-h meropenem monotherapy. Meropenem, nacubactam and meropenem–nacubactam MICs were 8–>64, 128–>256 and 2–16 mg/L, respectively. Meropenem and nacubactam monotherapy groups demonstrated bacterial growth over 24 h for each isolate. Against AmpC-overproducing and KPC-expressing P. aeruginosa isolates, meropenem–nacubactam resulted in −2.73±0.93 and −4.35±1.90 log₁₀CFU/lung reduction, respectively, relative to meropenem monotherapy. Meropenem–nacubactam showed promising in-vivo activity against meropenem-resistant P. aeruginosa, indicative of a potential role for the treatment of infections caused by these challenging pathogens.     

Pharmacokinetic and pharmacodynamic optimisation of intravenous tobramycin dosing among children with cystic fibrosis

This study aimed to characterize the pharmacokinetics of tobramycin administered one, two, or three times daily and to develop an optimal dosing scheme for children with cystic fibrosis. Therapeutic drug monitoring data were obtained from children hospitalized at three academic medical centres from 2006 to 2012. Population pharmacokinetic models were constructed using NONMEM 7.2. Model-based simulations were performed in Matlab R2012b to identify optimal dosing regimens using pharmacodynamic targets. The pharmacokinetic analysis involved 257 patients with a median age of 8.1 years (range 0.1–18.8). Clearance was estimated as 5.59 L/h and the volume of distribution was 18.90 L. Mean (±SD) maximum serum concentrations were highest among patients dosed once per day (24.1 ± 8.9 μg/mL) and were lower among patients dosed two and three times per day (11.2 ± 1.4 and 8.1 ± 2.4 μg/mL, respectively). Simulations revealed that once daily dosing was the only effective regimen for a Pseudomonas aeruginosa MIC of 1.5 μg/mL and none of the tested regimens reliably achieved the pharmacodynamic target for MICs ≥2 μg/mL. Once daily dosing resulted in higher maximum serum concentrations when compared to multiple-daily dosing. In simulations, once daily dosing was the only regimen to achieve the pharmacodynamic target for all subjects with MICs <2 μg/mL.     

Continuous versus intermittent infusion of cefepime in neurosurgical patients with post-operative intracranial infections

Cefepime is administered as an intermittent infusion (II); however, continuous infusion (CI) may be advantageous because β-lactam antibiotics exhibit time-dependent antibacterial activity. This retrospective, non-randomised, comparative study included 68 neurosurgical patients with post-operative intracranial infections treated with 4 g/day cefepime over 24 h as a CI (n = 34) or 2 g every 12 h as II (n = 34). CI controlled the intracranial infection more rapidly and effectively than II (6.6 ± 1.9 days vs. 7.8 ± 2.6 days; P = 0.036). By considering the minimum inhibitory concentrations (MICs) to be 4 μg/mL and 8 μg/mL, the percentage of time when the cefepime plasma or CSF concentrations were higher than the MIC (%T_>MIC) was calculated for each patient. For plasma cefepime concentrations, the %T_>MIC in the CI group was higher than in the II group (for MICs of 8 μg/mL, 100% vs. 75%, respectively). The mean calculated area under the curve (AUC) in the CI group was similar to the II group (1197.99 ± 72.15 μg h/mL vs. 890.84 ± 140.78 μg h/mL; P = 0.655). For CSF cefepime concentrations, the %T_>MIC in the CI group was higher than in the II group (for MICs of 4 μg/mL and 8 μg/mL, 83.3% and 75% vs. 25% and 0%, respectively). The mean calculated AUC for the CI group was higher than the II group (220.56 ± 13.59 μg h/mL vs. 86.34 ± 5.69 μg h/mL; P = 0.003). Therefore, CI of cefepime significantly enhanced the antibacterial effect and reduced the treatment duration in neurosurgical patients with post-operative intracranial infections.     

基于PK/PD效应相关的目标获得概率论述美罗培南延长输注给药的适宜性

目的： 探讨美罗培南延长输注给药的适宜性。方法： 以美罗培南0.5 g q 8 h、1 g q 8 h和2 g q 8 h为模型方案，以40%、60%和80%fT>MIC为PK/PD靶标，以目标获得概率（PTA）为PK/PD效应指标，通过蒙特卡洛模拟计算各方案对MIC分别为0.125，0.25，0.5，1，2，4，8，16，32，64 mg·L^-1分别通过0.5，1，2，4，6 h输注给药达到各靶标的PTA。同一方案对同一MIC在2种不同的输注时间下可得到2个PTA值，结果组成一个对子，对所有MIC可组成10个对子。对所有对子进行配对资料检验，考察输注时间对PTA的影响。结果： 无论PK/PD靶标和给药方案如何，均存在这样一个MIC临界值，使得对于那些小于该值的MIC，即使美罗培南0.5 h输注，PTA也远远大于90%；而对于那些大于该值的MIC，即使美罗培南6 h输注，PTA也远远小于90%；对于这些非临界值上的MIC，延长输注给药并不能有效增加PTA。但对于部分处在临界值上的MIC，美罗培南延长输注可大大增加PTA。但任何2个不同时间的输液组的PTA进行比较，统计学分析结果显示差异均无统计学意义（P>0.05）。结论： 美罗培南延长输注给药获得的PK/PD增效对分离菌株或MIC具有一定的选择性，并非所有菌株均适宜采用延长输注给药。对处于MIC临界值上的分离菌株，更适合延长输注给药；对处于非MIC临界值上的分离菌株，无需采用延长输注给药。     

Pharmacokinetics of meropenem in critically ill patients in Saudi Arabia

BackgroundMeropenem is commonly used in the ICU to treat gram-negative infections. Due to various pathophysiological changes, critically ill patients are at higher risk of having subtherapeutic concentrations and hence have a higher risk of treatment failure—especially in regions where gram-negative drug resistance is increasing, such as Saudi Arabia. No studies have evaluated the pharmacokinetics of meropenem in critically ill patients in Saudi Arabia. Our primary objective is to assess the percentage of patients achieving the therapeutic target for meropenem.MethodsThis prospective observational study was conducted in the ICUs of King Khalid University Hospital. Patient were included if >18 years-of-age and received meropenem for a clinically suspected or proven bacterial infection. The primary outcome was to assess the percentage of patients who achieved the pharmacokinetic/pharmacodynamic (PKPD) therapeutic target of a free trough concentration four times the MIC. The secondary outcome was to estimate the pharmacokinetics of meropenem. Pharmacokinetic analysis was performed using Monolix Suite 2020R1 (Lixoft, France).ResultsTrough concentrations were highly variable and ranged from <0.5 µg/mL to 39 µg/mL, with a mean ± SD trough concentration of 8.5 ± 8 µg/mL. Only 46% of patients achieved the therapeutic target. The only significant predictor of failing to achieve the PKPD target was augmented renal clearance.ConclusionIn conclusion, more than half of our patients did not achieve the PKPD target. Thus, there is a need for better dosing strategies of meropenem in critically ill patients in Saudi Arabia such as extended and continuous infusion.     

Pharmacodynamics of meropenem in critically ill patients with febrile neutropenia and bacteraemia

The bactericidal activity of β-lactams is determined by the time that concentrations in tissue and serum are above the minimum inhibitory concentration (T > MIC) for the pathogen. The aim of this study was to compare the probability of target attainment (PTA) and the cumulative fraction of response (CFR) for meropenem between administration by bolus injection and a 3-h infusion. The study was a randomised, three-way, cross-over design in eight febrile neutropenic patients with bacteraemia. Each subject received meropenem in three regimens consecutively: (i) a bolus injection of 1 g every 8 h (q8h) for 24 h; (ii) a 3-h infusion of 1 g q8h for 24 h; and (iii) a 3-h infusion of 2 g q8h for 24 h. For pathogens with an MIC of 4 μg/mL, the PTA of achieving 40% T > MIC following administration of meropenem by a bolus injection of 1 g q8h, a 3-h infusion of 1 g q8h and a 3-h infusion of 2 g q8h was 75.7%, 99.24% and 99.96%, respectively. Only the 3-h infusion of 2 g q8h achieved a PTA >99% for 40% T > MIC for a MIC of 8 μg/mL. By referral to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) MIC distributions, the three regimens of meropenem were predicted to achieve a CFR ≥ 90% against Escherichia coli and Klebsiella spp. In conclusion, a 3-h infusion of 2 g of meropenem q8h resulted in the highest PTA rates. The three regimens of meropenem had high probabilities of achieving optimal impact against E. coli and Klebsiella spp.     

Individualising netilmicin dosing in neonates

Purpose  The aim of this study was develop an optimal dosing regimen for netilmicin in neonates. Methods  This was a population pharmacokinetic study in 97 neonates aged from 2 to 28 days after the due date who were being treated with netilmicin for suspected sepsis. The model was used to simulate dosing regimens. Results  The principle factors influencing netilmicin clearance (CL) were postmenstrual age (PMA) and current body weight (CWT), and the principal determinant of volume of distribution (V) was CWT. The final covariate model was CL = 0.192 × (CWT/2)^1.35 × (PMA/40)^1.03, V = 1.5 × (CWT/2)^0.3. The optimal dosing was 5 mg/kg ever 36 h, 5 mg/kg every 24 h, 6 mg/kg every 24 h and 7 mg/kg every 24 h for neonates ≤27, 28–30, 31–33 and ≥34 weeks PMA, respectively. Conclusion  Individualisation of netilmicin dosing in neonates requires adjustment of dose by body weight, and dosing interval by both PMA and CWT.     

Class-dependent relevance of tissue distribution in the interpretation of anti-infective pharmacokinetic/pharmacodynamic indices

The pharmacokinetic/pharmacodynamic (PK/PD) indices useful for predicting antimicrobial clinical efficacy are well established. The most common indices include the time free drug concentration in plasma is above the minimum inhibitory concentration (MIC) (fT_>MIC) expressed as a percent of the dosing interval, the ratio of maximum concentration to MIC (C_max/MIC), and the ratio of the area under the 24-h concentration–time curve to MIC (AUC_0–24/MIC). A single PK/PD index may correlate well with an entire antimicrobial class. For example, the β-lactams correlate well with the fT_>MIC. However, other classes may be more complex and a single index cannot be generalised to the class, e.g. the macrolides. The rationale behind which PK/PD index best correlates with efficacy depends on several factors, including the mechanism of action, the microbial kill kinetics, the degree of protein binding and the degree of tissue distribution. Studies have traditionally emphasised the first two factors, whilst the significance of protein binding and tissue distribution is increasingly appreciated. In fact, the latter two factors may partially elucidate why the magnitude of reported target indices are not always as expected. For example, tigecycline and telithromycin are clinically efficacious with average serum concentrations below their MICs over a 24-h period. Therefore, to understand more fully the PK/PD relationship of antibiotics and to better predict the clinical efficacy of antibiotic dosing regimens, assessment of free drug concentrations at the site of action is warranted.