Spider chart, greenness and whiteness assessment of experimentally designed multivariate models for simultaneous determination of three drugs used as a combinatory antibiotic regimen in critical care units: Comparative study.

In this study, five earth-friendly spectrophotometric methods using multivariate techniques were developed to analyze levofloxacin, linezolid, and meropenem, which are utilized in critical care units as combination therapies. These techniques were used to determine the mentioned medications in laboratory-prepared mixtures, pharmaceutical products and spiked human plasma that had not been separated before handling. These methods were named classical least squares (CLS), principal component regression (PCR), partial least squares (PLS), genetic algorithm partial least squares (GA-PLS), and artificial neural network (ANN). The methods used a five-level, three-factor experimental design to make different concentrations of the antibiotics mentioned (based on how much of them are found in the plasma of critical care patients and their linearity ranges). The approaches used for levofloxacin, linezolid, and meropenem were in the ranges of 3-15, 8-20, and 5-25 µg/mL, respectively. Several analytical tools were used to test the proposed methods' performance. These included the root mean square error of prediction, the root mean square error of cross-validation, percentage recoveries, standard deviations, and correlation coefficients. The outcome was highly satisfactory. The study found that the root mean square errors of prediction for levofloxacin were 0.090, 0.079, 0.065, 0.027, and 0.001 for the CLS, PCR, PLS, GA-PLS, and ANN models, respectively. The corresponding values for linezolid were 0.127, 0.122, 0.108, 0.05, and 0.114, respectively. For meropenem, the values were 0.230, 0.222, 0.179, 0.097, and 0.099 for the same models, respectively. These results indicate that the developed models were highly accurate and precise. This study compared the efficiency of artificial neural networks and classical chemometric models in enhancing spectral data selectivity for quickly identifying three antimicrobials. The results from these five models were subjected to statistical analysis and compared with each other and with the previously published ones. Finally, the whiteness of the methods was assessed by the recently published white analytical chemistry (WAC) RGB 12, and the greenness of the proposed methods was assessed using AGREE, GAPI, NEMI, Raynie and Driver, and eco-scale, which showed that the suggested approaches had the least negative environmental impact. Furthermore, to demonstrate solvent sustainability, a greenness index using a spider chart methodology was employed.

Cost-effectiveness analysis of CTZ/TAZ for the treatment of ventilated hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia in Japan.

BACKGROUND: Resistant bacterial infections, particularly those caused by gram-negative pathogens, are associated with high mortality and economic burdens. Ceftolozane/tazobactam demonstrated efficacy comparable to meropenem in patients with ventilated hospital-acquired bacterial pneumonia in the ASPECT-NP study. One cost-effectiveness analysis in the United States revealed that ceftolozane/tazobactam was cost effective, but no Japanese studies have been conducted. Therefore, the objective of this study was to assess the cost-effectiveness of ceftolozane/tazobactam compared to meropenem for patients with ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia from a health care payer perspective. METHODS: A hybrid decision-tree Markov decision-analytic model with a 5-year time horizon were developed to estimate costs and quality-adjusted life-years and to calculate the incremental cost-effectiveness ratio associated with ceftolozane/tazobactam and meropenem in the treatment of patients with ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. Clinical outcomes were based on the ASPECT-NP study, costs were based on the national fee schedule of 2022, and utilities were based on published data. One-way sensitivity analysis and probabilistic sensitivity analysis were also conducted to assess the robustness of our modeled estimates. RESULTS: According to our base-case analysis, compared with meropenem, ceftolozane/tazobactam increased the total costs by 424,731.22 yen (£2,626.96) and increased the quality-adjusted life-years by 0.17, resulting in an incremental cost-effectiveness ratio of 2,548,738 yen (£15,763.94) per quality-adjusted life-year gained for ceftolozane/tazobactam compared with meropenem. One-way sensitivity analysis showed that although the incremental cost-effectiveness ratio remained below 5,000,000 yen (£30,925) for most of the parameters, the incremental net monetary benefit may have been less than 0 depending on the treatment efficacy outcome, especially the cure rate and mortality rate for MEPM and mortality rate for CTZ/TAZ. 53.4% of the PSA simulations demonstrated that CTZ/TAZ was more cost-effective than MEPM was. CONCLUSION: Although incremental cost-effectiveness ratio was below ï¿¥5,000,000 in base-case analysis, whether ceftolozane/tazobactam is a cost-effective alternative to meropenem for ventilated hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia in Japan remains uncertain. Future research should examine the unobserved heterogeneity across patient subgroups and decision-making settings, to characterise decision uncertainty and its consequences so as to assess whether additional research is required.

Intravenous push antibiotics in the emergency department: Education and implementation.

PURPOSE: Intravenous push antibiotics can serve as an alternative to intravenous piggyback antibiotics while providing the same pharmacodynamics and adverse effect profile, easing shortage pressures and decreasing order to administration time, as well as representing a potential cost savings. The purpose of this study was to determine whether intravenous push antibiotics could decrease the time from an order to the start of administration compared to piggyback antibiotics in emergency departments. This study also measured the cost savings of antibiotic preparation and administration and assessed nursing satisfaction when using intravenous push antibiotics. METHODS: Sample instances of use of intravenous push and piggyback antibiotics were identified. Patients were included if they were 18 years of age or older and received at least a single dose of intravenous push or piggyback ceftriaxone, cefepime, cefazolin, or meropenem in one of the institution's emergency departments. The primary outcome of the study was to compare the time from the order to the start of administration of intravenous push vs piggyback antibiotics. The secondary outcome was to compare the cost of antibiotic preparation for the 2 methods. RESULTS: The intravenous push and piggyback groups each had 43 patients. The time from the order to the start of administration decreased from 74 (interquartile range, 29-114) minutes in the piggyback group to 31 (interquartile range, 21-52) minutes in the push group (P = 0.003). When the estimated monthly cost savings for ceftriaxone, cefepime, and meropenem were added together, across the emergency departments, an estimated $227,930.88 is saved per year when using intravenous push antibiotics. CONCLUSION: Intravenous push antibiotics decrease the time from ordering to the start of administration and result in significant cost savings.

Assessment of antibiotic release and antibacterial efficacy from pendant glutathione hydrogels using ex vivo porcine skin.

Acute bacterial skin and skin structure infections (ABSSSIs) confer a substantial burden on the healthcare system. Local antibiotic delivery systems can provide controlled drug release directly to the site of infection to maximize efficacy and minimize systemic toxicity. The purpose of this study was to examine the antibacterial activity of antibiotic-loaded glutathione-conjugated poly(ethylene glycol) hydrogels (GSH-PEG) against ABSSSIs utilizing an ex vivo porcine dermal explant model. Vancomycin- or meropenem-loaded GSH-PEG hydrogels at 3 different dose levels were loaded over 1 h. Drug release was monitored in vitro under submerged conditions, by the Franz cell diffusion method, and ex vivo utilizing a porcine dermis model. Antibacterial activity was assessed ex vivo on porcine dermis explants inoculated with Staphylococcus aureus or Pseudomonas aeruginosa isolates treated with vancomycin- or meropenem-loaded GSH-PEG hydrogels, respectively. Histological assessment of the explants was conducted to evaluate tissue integrity and viability in the context of the experimental conditions. A dose-dependent release was observed from vancomycin and meropenem hydrogels, with in vitro Franz cell diffusion data closely representing ex vivo vancomycin release, but not high dose meropenem release. High dose vancomycin-loaded hydrogels resulted in a >3 log10 clearance against all S. aureus isolates at 48 h. High dose meropenem-loaded hydrogels achieved 6.5, 4, and 2 log10 reductions in CFU/ml against susceptible, intermediate, and resistant P. aeruginosa isolates, respectively. Our findings demonstrate the potential application of GSH-PEG hydrogels for flexible, local antibiotic delivery against bacterial skin infections.

Severity assessment to guide empiric antibiotic therapy for cholangitis in children after Kasai portoenterostomy: a multicenter prospective randomized control trial in China.

BACKGROUND: Cholangitis is common in patients with biliary atresia following Kasai portoenterostomy (KPE). The prompt use of empiric antibiotics is essential due to the lack of identified microorganisms. The authors aimed to validate a severity grading system to guide empiric antibiotic therapy in the management of post-KPE cholangitis. MATERIALS AND METHODS: This multicenter, prospective, randomized, open-label study recruited patients with post-KPE cholangitis and was conducted from January 2018 to December 2019. On admission, patients were categorized into mild, moderate, and severe cholangitis according to the severity grading system. Patients in the mild cholangitis group were randomized to receive cefoperazone sodium tazobactam sodium (CSTS) or meropenem (MEPM). Patients with severe cholangitis were randomized to treatment with MEPM or a combination of MEPM plus immunoglobulin (MEPM+IVIG). Patients with moderate cholangitis received MEPM. RESULTS: The primary endpoint was duration of fever (DOF). Secondary outcomes included blood culture, length of hospital stay, incidence of recurrent cholangitis, jaundice clearance rate, and native liver survival (NLS). For mild cholangitis, DOF, and length of hospital stay were similar between those treated with CSTS or MEPM (all P >0.05). In addition, no significant difference in recurrence rate, jaundice clearance rate, and NLS was observed between patients treated with CSTS and MEPM at 1-month, 3-month, and 6-month follow-up. In patients with moderate cholangitis, the DOF was 36.00 (interquartile range: 24.00-48.00) h. In severe cholangitis, compared with MEPM, MEPM+IVIG decreased DOF and improved liver function by reducing alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and direct bilirubin at 1-month follow-up. However, recurrence rate, jaundice clearance rate, and NLS did not differ significantly between MEPM+IVIG and MEPM at 1-month, 3-month, and 6-month follow-up. CONCLUSIONS: In patients with post-KPE cholangitis, MEPM is not superior to CSTS for the treatment of mild cholangitis. However, MEPM+IVIG treatment was associated with better short-term clinical outcomes in patients with severe cholangitis.

Mathematical pharmacodynamic modeling for antimicrobial assessment of ceftazidime/colistin versus gentamicin/meropenem combinations against carbapenem-resistant Pseudomonas aeruginosa biofilm.

BACKGROUND: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) represents an escalating healthcare hazard with high mortality worldwide, especially in presence of biofilm. The current study aimed to evaluate the anti-biofilm potentials of ceftazidime, colistin, gentamicin, and meropenem alone and in combinations against biofilm-forming CRPA. METHODS: Biofilm killing and checkerboard assay were performed to detect the effectiveness of combined antibiotics against biofilms and planktonic cells, respectively. The bacterial bioburden retrieved from the established biofilms following treatment with combined antibiotics was utilized to construct a three-dimensional response surface plot. A sigmoidal maximum effect model was applied to determine the pharmacodynamic parameters (maximal effect, median effective concentration, and Hill factor) of each antibiotic to create a mathematical three-dimensional response surface plot. RESULTS: Data revealed statistically significant (p < 0.05) superior anti-biofilm potential in the case of colistin followed by a lower effect in the case of gentamicin and meropenem, while ceftazidime exhibited the least anti-biofilm activity. The fractional inhibitory concentration index (FICI ≤ 0.5) indicated synergism following treatment with the combined antibiotics. An elevated anti-biofilm activity was recorded in the case of gentamicin/meropenem compared to ceftazidime/colistin. Synergistic anti-biofilm potentials were also detected via the simulated pharmacodynamic modeling, with higher anti-biofilm activity in the case of the in vitro observation compared to the simulated anti-biofilm profile. CONCLUSIONS: The present study highlighted the synergistic potentials of the tested antibiotic combinations against P. aeruginosa biofilms and the importance of the mathematical pharmacodynamic modeling in investigating the efficacy of antibiotics in combination as an effective strategy for successful antibiotic therapy to tackle the extensively growing resistance to the currently available antibiotics.

Optimal Meropenem Dosing Regimens in Patients Undergoing Continuous Renal Replacement Therapy: Systematic Review and Monte Carlo Simulations.

INTRODUCTION: The optimal meropenem dosing regimens in critically ill patients receiving continuous renal replacement therapy (CRRT) based on pharmacokinetic and pharmacodynamic (PD) concepts are not well established. This study aimed to (1) gather the available published pharmacokinetic studies conducted in septic patients receiving CRRT and (2) to define the optimal meropenem dosing regimens in these populations via Monte Carlo simulations. METHODS: We used Medical Subject Headings "meropenem," "continuous renal replacement therapy," and "pharmacokinetics" or related terms to identify studies for systematic review. A one-compartment pharmacokinetic model was conducted to predict meropenem levels for the initial 48 h of therapy. The PD targets were 40% of free drug above a threshold of 1 times the minimum inhibitory concentration (MIC) (40% fT > MIC), 4 times the MIC (40% fT > 4MIC), and an additional target of free drug level above 1 times MIC 100% of the time (fT > MIC). The dose that achieved at least 90% of the probability of target attainment (PTA) was defined as an optimal dose. RESULTS: Twenty-one articles were included for our systematic review. The necessary pharmacokinetic parameters such as volume of distribution and CRRT clearance were cited in 90.5 and 71.4% of articles, respectively. None of the published studies reported completed necessary parameters. A regimen of 750 mg q 8 h was found to be the optimal dose for pre-dilution continuous venovenous hemofiltration and continuous venovenous hemodialysis modality using two effluent rates (25 and 35 mL/kg/h) which achieved the PD target of 40% fT > 4MIC. CONCLUSION: None of the published studies showed the necessary pharmacokinetic parameters. PD target significantly contributed to meropenem dosage regimens in these patients. Differing effluent rates and types of CRRT shared similar dosing regimens. Clinical validation of the recommendation is suggested.

Optimization of ß-Lactam Dosing Regimens in Neonatal Infections: Continuous and Extended Administration versus Intermittent Administration.

BACKGROUND AND OBJECTIVE: In neonates, ß-Lactam antibiotics are almost exclusively administered by intermittent infusion. However, continuous or prolonged infusion may be more beneficial because of the time-dependent antibacterial activity. In this pharmacokinetic/pharmacodynamic simulation study, we aimed to compare treatment with continuous, extended and intermittent infusion of ß-lactam antibiotics for neonates with infectious diseases. METHODS: We selected population pharmacokinetic models of penicillin G, amoxicillin, flucloxacillin, cefotaxime, ceftazidime and meropenem, and performed a Monte Carlo simulation with 30,000 neonates. Four different dosing regimens were simulated: intermittent infusion in 30 min, prolonged infusion in 4 h, continuous infusion, and continuous infusion with a loading dose. The primary endpoint was 90% probability of target attainment (PTA) for 100% ƒT>MIC during the first 48 h of treatment. RESULTS: For all antibiotics except cefotaxime, continuous infusion with a loading dose resulted in a higher PTA compared with other dosing regimens. Sufficient exposure (PTA >90%) using continuous infusion with a loading dose was reached for amoxicillin (90.3%), penicillin G (PTA 98.4%), flucloxacillin (PTA 94.3%), cefotaxime (PTA 100%), and ceftazidime (PTA 100%). Independent of dosing regimen, higher meropenem (PTA for continuous infusion with a loading dose of 85.5%) doses might be needed to treat severe infections in neonates. Ceftazidime and cefotaxime dose might be unnecessarily high, as even with dose reductions, a PTA > 90% was retained. CONCLUSIONS: Continuous infusion after a loading dose leads to a higher PTA compared with continuous, intermittent or prolonged infusion, and therefore has the potential to improve treatment with ß-lactam antibiotics in neonates.

Impact of an antibiotic stewardship program on antibiotic utilization, bacterial susceptibilities, and cost of antibiotics.

Antimicrobial misuse is a worldwide issue, and antimicrobial resistance is considered the most challenging aspect of health care. It has been reported that as much as 30-50% of antimicrobials prescribed in hospitals are deemed unnecessary or inappropriate. Antibiotic stewardship programs (ASPs) include policies that apply continuous management of judicious anti-infectious treatment in the clinical setting. Therefore, the objectives of this study were to evaluate the effect of ASPs on antibiotic consumption, the costs of antibiotic expenditure, and the sensitivity of antimicrobials. A retrospective, quasi-experimental study was performed to assess the effect of ASP at An-Najah National University Hospital, a tertiary care hospital in the West Bank, Palestine, over a period of 20 months before and 17 months after the implementation of the ASP. Data on antibiotic consumption were reported monthly as days of therapy per 1000 patient-days and monthly costs (USD/1000 patient-days). A total of 2367 patients who received one or more of the targeted antibiotics (meropenem, colistin and tigecycline) during their hospital stay were included in the study. They have split into two groups: 1710 patients in the pre-ASP group, and 657 patients in the post ASP group. The most significant reduction in DOT per 1000 patient-days was seen with tigecycline, with a percentage of change of - 62.08%. Furthermore, the mean cost of the three antibiotics decreased significantly by 55.5% in the post-ASP phase compared to the pre-ASP phase. After the implementation of ASP, there was a statistically significant increase in susceptibility to meropenem, piperacillin and piperacillin/tazobactam with respect to Pseudomonas aeruginosa. However, changes in mortality rates were not statistically significant (p = 0.057). ASP positively reduced costs and antimicrobial consumption, with no statistically significant effect on the overall mortality rate. However, a long-term evaluation of the ASP's impact is needed to conclude its lasting impact on infection-related mortality and antimicrobial susceptibility pattern.

Phenotypes, genotypes and breakpoints: an assessment of ß-lactam/ß-lactamase inhibitor combinations against OXA-48.

BACKGROUND: Two of the three recently approved ß-lactam agent (BL)/ß-lactamase inhibitor (BLI) combinations have higher CLSI susceptibility breakpoints (ceftazidime/avibactam 8 mg/L; meropenem/vaborbactam 4 mg/L) compared with the BL alone (ceftazidime 4 mg/L; meropenem 1 mg/L). This can lead to a therapeutic grey area on susceptibility reports depending on resistance mechanism. For instance, a meropenem-resistant OXA-48 isolate (MIC 4 mg/L) may appear as meropenem/vaborbactam-susceptible (MIC 4 mg/L) despite vaborbactam's lack of OXA-48 inhibitory activity. METHODS: OXA-48-positive (n = 51) and OXA-48-negative (KPC, n = 5; Klebsiella pneumoniae wild-type, n = 1) Enterobacterales were utilized. Susceptibility tests (broth microdilution) were conducted with ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam, as well as their respective BL partner. Antimicrobial activity of all six agents was evaluated in the murine neutropenic thigh model using clinically relevant exposures. Efficacy was assessed as the change in bacterial growth at 24 h, compared with 0 h controls. RESULTS: On average, the three BL/BLI agents resulted in robust bacteria killing among OXA-48-negative isolates. Among OXA-48-positive isolates, poor in vivo activity with imipenem/relebactam was concordant with its resistant phenotypic profile. Variable meropenem/vaborbactam activity was observed among isolates with a 'susceptible' MIC of 4 mg/L. Only 30% (7/23) of isolates at meropenem/vaborbactam MICs of 2 and 4 mg/L met the ≥1-log bacterial reduction threshold predictive of clinical efficacy in serious infections. In contrast, ceftazidime/avibactam resulted in marked bacterial density reduction across the range of MICs, and 96% (49/51) of isolates exceeded the ≥1-log bacterial reduction threshold. CONCLUSIONS: Data demonstrate that current imipenem/relebactam and ceftazidime/avibactam CLSI breakpoints are appropriate. Data also suggest that higher meropenem/vaborbactam breakpoints relative to meropenem can translate to potentially poor clinical outcomes in patients infected with OXA-48-harbouring isolates.

Evaluation of Empirical Dosing Regimens for Meropenem in Intensive Care Unit Patients Using Population Pharmacokinetic Modeling and Target Attainment Analysis.

In the present study, population pharmacokinetic (PK) analysis was performed based on meropenem data from a prospective study conducted in 114 critically ill patients with a wide range of renal functions and various disease conditions. The final model was a one-compartment model with linear elimination, with creatinine clearance and continuous renal replacement therapy affecting clearance, and total bodyweight impacting the volume of distribution. Our model is a valuable addition to the existing meropenem population PK models, and it could be particularly useful during implementation of a therapeutic drug monitoring program combined with Bayesian forecasting. Based on the final model developed, comprehensive Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) of 16 different dosing regimens. Simulation results showed that 2 g administered every 8 h with 3-h prolonged infusion (PI) and 4 g/day by continuous infusion (CI) appear to be two empirical dosing regimens that are superior to many other regimens when both target attainment and potential toxicity are considered and renal function information is not available. Following a daily CI dose of 6 g or higher, more than 30% of the population with a creatinine clearance of <60 mL/min is predicted to have neurotoxicity. With the availability of institution- and/or unit-specific meropenem susceptibility patterns, as well as an individual patient's renal function, our PTA results may represent useful references for physicians to make dosing decisions.

Cost-effectiveness of ceftazidime/avibactam plus metronidazole versus meropenem as first-line empiric therapy for the treatment of complicated intra-abdominal infections: A study based on the in-vitro surveillance data in China.

BACKGROUND: With the increase in drug resistance rates of pathogens isolated from complicated intra-abdominal infections (cIAIs), ceftazidime/avibactam (CAZ-AVI) is increasingly used clinically. However, given the high drug cost and the fact that not yet covered by the health insurance payment, this study evaluated the cost-effectiveness of CAZ-AVI plus metronidazole versus meropenem as a first-line empiric treatment for cIAIs from the perspective of the Chinese healthcare system. METHODS: A decision analytic model with a one-year time horizon was constructed to assess the cost-effectiveness based on the entire disease course. Model inputs were mainly obtained from clinical studies, published literature, and publicly available databases. Primary outcomes were cost, quality-adjusted life years (QALYs), life years (Lys), and incremental cost-effectiveness ratio (ICER). One-way sensitivity analysis and probabilistic sensitivity analysis were also performed. RESULTS: In the base cases, compared to meropenem, CAZ-AVI plus metronidazole had a shorter mean hospital length of stay (-0.77 days per patient) and longer life expectancy (+0.05 LYs and +0.06 QALYs). CAZ-AVI plus metronidazole had an ICER of $25517/QALY, which is well below the threshold of $31509 per QALY in China. The one-way sensitivity analysis showed that the change of the treatment duration of CAZ-AVI plus metronidazole was the parameter that most influenced the results of the ICER. In probabilistic sensitivity analysis, CAZ-AVI plus metronidazole was the optimal strategy in 75% of simulations at $31510/QALY threshold. CONCLUSIONS: CAZ-AVI plus metronidazole could be considered as a cost-effective option for the empiric treatment of patients with cIAIs in China, and this benefit will be more evident when the price of CAZ-AVI decreases by 23.8%.

Population Pharmacokinetics/Pharmacodynamics and Clinical Outcomes of Meropenem in Critically Ill Patients.

Several pathophysiological changes can alter meropenem pharmacokinetics in critically ill patients, thereby increasing the risk of subtherapeutic concentrations and affecting therapeutic outcomes. This study aimed to characterize the population pharmacokinetic (PPK) parameters of meropenem, evaluate the relationship between the pharmacokinetic/pharmacodynamic index of meropenem and treatment outcomes, and evaluate the different dosage regimens that can achieve 40%, 75%, and 100% of the dosing interval for which the free plasma concentrations remain above the MIC of the pathogens (fT>MIC) targets. Critically ill adult patients treated with meropenem were recruited for this study. Five blood samples were collected from each patient. PPK models were developed using a nonlinear mixed-effects modeling approach, and the final model was subsequently used for Monte Carlo simulations to determine the optimal dosage regimens. A total of 247 concentrations from 52 patients were available for analysis. The two-compartment model with linear elimination adequately described the data. The mean PPK parameters were clearance (CL) of 4.8 L/h, central volume of distribution (VC) of 11.4 L, peripheral volume of distribution (VP) of 14.6 L, and intercompartment clearance of 10.5 L/h. Creatinine clearance was a significant covariate affecting CL, while serum albumin level and shock status were factors influencing VC and VP, respectively. Although 75% of the drug-resistant infection patients had fT>MIC values of >40%, approximately 83% of them did not survive the infection. Therefore, 40% fT>MIC might not be sufficient for critically ill patients, and a higher target, such as 75 to 100% fT>MIC, should be considered for optimizing therapy. A 75% fT>MIC could be reached using approved doses administered via a 3-h infusion.

Optimizing Meropenem in Highly Resistant Klebsiella pneumoniae Environments: Population Pharmacokinetics and Dosing Simulations in Critically Ill Patients.

Critically ill patients are characterized by substantial pathophysiological changes that alter the pharmacokinetics (PK) of hydrophilic antibiotics, including carbapenems. Meropenem is a key antibiotic for multidrug-resistant Gram-negative bacilli, and such pathophysiological alterations can worsen treatment outcomes. This study aimed to determine the population PK of meropenem and to propose optimized dosing regimens for the treatment of multidrug-resistant Klebsiella pneumoniae in critically ill patients. Two plasma samples were collected from eligible patients over a dosing interval. Nonparametric population PK modeling was performed using Pmetrics. Monte Carlo simulations were applied to different dosing regimens to determine the probability of target attainment and the cumulative fraction of response, taking into account the local MIC distribution for K. pneumoniae. The targets of 40% and 100% for the fraction of time that free drug concentrations remained above the MIC (ƒT>MIC) were tested, as suggested for critically ill patients. A one-compartment PK model using data from 27 patients showed high interindividual variability. Significant PK covariates were the 8-h creatinine clearance for meropenem and the presence of an indwelling catheter for pleural, abdominal, or cerebrospinal fluid drainage for the meropenem volume of distribution. The target 100% ƒT>MIC for K. pneumoniae, with a MIC of ≤2 mg/liter, could be attained by the use of a continuous infusion of 2.0 g/day. Meropenem therapy in critically ill patients could be optimized for K. pneumoniae isolates with an MIC of ≤2 mg/liter by using a continuous infusion in settings with more than 50% isolates have a MIC of ≥32mg/L.

Assessment of Antibacterial Efficacy of Callistemon viminalis (Sol. ex Gaertn.) G. Don against Some Isolates Obtained from Urinary Tract Infections.

This study aimed to examine the antibacterial effects of constituents obtained from Callistemon viminalis leaves. This goal was achieved by using three organic solvents, namely Ethanol, Ethyl acetate, and Hexane to prevent the growth of the causative urinary tract infections isolates, such as Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia, and Proteus sp. in Iraq. The C. viminalis fresh leaves collected from different regions of Hillah City, during March 2020, were classified according to the taxonomic features of Iraqi Flora. Extractions were completed by a method of digestion and then the stock solution of 200 mg/mL was prepared in 10% of Dimethylsulfoxide. A Millipore filter (0.22 µm) was used for the sterilization of all the extracts used in this study. Agar well diffusion method was utilized to test the antibacterial effects of the constituents separated from the dried leaves of C. viminalis against the urinary tract infection bacteria at three concentrations of 50, 100, and 200 mg/mL for each extracted constitute by the three different solvents. Dimethylsulfoxide 10% and the meropenem were utilized as the negative and positive controls. Constituents separated by ethanol solvent at 200 mg/mL exhibited significant supremacy (P≤0.05) over the meropenem against Proteus sp. isolate, and exhibited the same significant difference (P≤0.05), compared to the meropenem drug against E. coli. Constituents extracted by Ethyl acetate organic solvent at a concentration of 200 mg/mL exhibited a similarly significant effect (P≤0.05), compared to the meropenem against Proteus sp. isolate. However, the hexane extract was the least effective among the other solvents utilized in this study. The results of the current study revealed that constituents in the leaves of C. viminalis could be considered a valuable herbal remedy for controlling urinary tract infections pathogenic bacteria.

In vivo translational assessment of the GES genotype on the killing profile of ceftazidime, ceftazidime/avibactam and meropenem against Pseudomonas aeruginosa.

OBJECTIVES: To evaluate the in vivo killing profile of human-simulated exposures of ceftazidime, ceftazidime/avibactam and meropenem against GES-harbouring Pseudomonas aeruginosa in the murine thigh infection model. METHODS: Five P. aeruginosa isolates [three isogenic (GES-1, GES-5 and GES-15) and two clinical (GES-5 and GES-15)] were evaluated. MICs were determined using broth microdilution. Human-simulated regimens (HSRs) of ceftazidime 2 g IV q8h as a 2 h infusion, ceftazidime/avibactam 2.5 g IV q8h as a 2 h infusion and meropenem 2 g IV q8h as a 3 h infusion were administered. Change in bacterial burden relative to baseline was assessed. RESULTS: Modal MICs ranged from 8 to >64 mg/L for ceftazidime, from 1 to 16 mg/L for ceftazidime/avibactam and from 1 to >64 mg/L for meropenem. In vivo, for the isogenic strains, avibactam augmented ceftazidime activity against the GES-1- and GES-15-harbouring isolates. Both ceftazidime and ceftazidime/avibactam resulted in significant kill against the GES-5 isogenic isolate. The meropenem HSR produced >1 log10 kill against each isogenic isolate (MICs of 1-4 mg/L). Against the GES-5 clinical isolate, ceftazidime and ceftazidime/avibactam resulted in >1 log10 kill compared with bacterial growth with the meropenem HSR. In the clinical isolate harbouring GES-15, the elevated MICs of ceftazidime and ceftazidime/avibactam reduced the effectiveness of both compounds, while the observed reduction in meropenem MIC translated into in vivo efficacy of the HSR regimen, predictive of clinical efficacy. CONCLUSIONS: In GES-harbouring P. aeruginosa, quantitative reductions in bacterial density observed with the translational murine model suggest that the phenotypic profile of ceftazidime, ceftazidime/avibactam and meropenem is predictive of clinical efficacy when using the evaluated dosing regimens.

Meropenem Population Pharmacokinetics and Simulations in Plasma, Cerebrospinal Fluid, and Brain Tissue.

Meropenem is a broad spectrum carbapenem used for the treatment of cerebral infections. There is a need for data describing meropenem pharmacokinetics (PK) in the brain tissue to optimize therapy in these infections. Here, we present a meropenem PK model in the central nervous system and simulate dosing regimens. This was a population PK analysis of a previously published prospective study of patients admitted to the neurointesive care unit between 2016 and 2019 who received 2 g of meropenem intravenously every 8 h. Meropenem concentration was determined in blood, cerebrospinal fluid (CSF), and brain microdialysate. Meropenem was described by a six-compartment model: two compartments in the blood, two in the CSF, and two in the brain tissue. Creatinine clearance and brain glucose were included as covariates. The median elimination rate constant was 1.26 h-1, the central plasma volume was 5.38 L, and the transfer rate constants from the blood to the CSF and from the blood to the brain were 0.001 h-1 and 0.02 h-1, respectively. In the first 24 h, meropenem 2 g, administered every 8 h via intermittent and extended infusions achieved good target attainment in the CSF and brain, but continuous infusion (CI) was better at steady-state. Administering a 3 g loading dose (LD) followed by 8 g CI was beneficial for early target attainment. In conclusion, a meropenem PK model was developed using blood, CSF, and brain microdialysate samples. An 8 g CI may be needed for good target attainment in the CSF and brain. Giving a LD prior to the CI improved the probability of early target attainment.

Therapeutic drug monitoring of meropenem and pharmacokinetic-pharmacodynamic target assessment in critically ill pediatric patients from a prospective observational study.

OBJECTIVES: To compare the unbound plasma meropenem concentrations at mid-dosing intervals (Cmid, 50%fT), end-dosing intervals (Ctrough, 100%fT), and proportions of patients achieving 50%fT and 100%fT above minimum inhibitory concentration (MIC) (50%fT>MIC and 100%fT>MIC) between extended infusion (EI) and intermittent bolus (IB) administration in a therapeutic drug monitoring (TDM) program in children. METHODS: A prospective observational study was conducted in children aged 1 month to 18 years receiving meropenem every 8 hours by either EI or IB. Meropenem Cmid, Ctrough, and proportions of patients achieving 50%fT>MIC and 100%fT>MIC were compared. RESULTS: TDM data from 72 patients with a median age (interquartile range [IQR]) of 12 months (3-37) were used. Meropenem dose was 120 and 60 mg/kg/day in EI and IB groups, respectively. Geometric mean (95% confidence interval [CI]) Cmid of EI versus IB was 17.3 mg/L (13.7-21.8) versus 3.4 mg/L (1.7-6.7) (P <0.001). Geometric mean (95% CI) Ctrough of EI versus IB was 2.3 mg/L (1.6-3.4) versus 0.8 mg/L (0.4-1.5) (P=0.005). Greater proportions of patients achieving 50%fT>MIC and 100%fT>MIC were observed in the EI group. CONCLUSIONS: A meropenem dose of 20 mg/kg/dose given by IB should not be used in critically ill children, even if they are not suspected of having a central nervous system infection. A dose of 40 mg/kg/dose given by EI resulted in higher Cmid, Ctrough, and proportions of patients achieving 50%fT>MIC and 100%fT>MIC.

In vivo exposure-response relationship of meropenem against metallo-ß-lactamase-harbouring Pseudomonas aeruginosa: an assessment using MICs from conventional and zinc-limited broth.

OBJECTIVES: Previous investigations into metallo-ß-lactamase (MBL)-harbouring Enterobacterales suggest that susceptibility testing in zinc-limited media may be more appropriate in predicting ß-lactam in vivo activity. There are limited data with MBL-harbouring Pseudomonas aeruginosa. METHODS: Forty-three MBL-harbouring P. aeruginosa isolates (IMP, n = 11; VIM, n = 12; NDM, n = 10; SPM, n = 10) and two P. aeruginosa control isolates (KPC, n = 1; WT, n = 1) were evaluated. Meropenem activity was evaluated in the murine neutropenic thigh model using humanized exposures. Susceptibility testing was conducted in conventional CAMHB, EDTA-supplemented CAMHB (3-300 mg/L EDTA) and Chelex-treated CAMHB (0-1.0 mg/L re-supplemented zinc), resulting in a range of meropenem MIC values for each isolate. A sigmoidal Emax model was fitted to fT>MIC versus change in log10 cfu/thigh to estimate the goodness of fit (R2). RESULTS: Increasing EDTA concentrations or limiting the amount of zinc in broth resulted in several-fold reductions in MIC among the majority of the MBL-harbouring P. aeruginosa while the MICs for the KPC and WT isolates were unchanged. Bacterial killing in vivo was variable, with the range of killing spanning -3.29 to +4.81 log10 change in cfu/thigh. Addition of 30 mg/L EDTA and Chelex-treated CAMHB (with no zinc supplementation) provided broth conditions for susceptibility testing that best predicted in vivo efficacy (R2 > 0.7). CONCLUSIONS: Among MBL-harbouring P. aeruginosa, meropenem in vivo efficacy is best represented by the pharmacodynamic profile generated using MICs determined in EDTA-supplemented or zinc-limited broth. In addition to previous data with Enterobacterales, antibiotic susceptibility testing in media that approximates physiological conditions makes it possible to uncover potential and existing therapeutic agents.

Optimal dose of meropenem for the treatment of neonatal sepsis: Dosing guideline variations and clinical practice deviations.

AIMS: Meropenem is increasingly used to treat neonatal sepsis. There are several guidelines recommending different dosing regimens of meropenem in neonates. Furthermore, deviations from these guidelines regularly occur in daily clinical practice. Therefore, the current study aimed to evaluate the variations of meropenem dosing guidelines and compare the difference between guideline and clinical practice in terms of the probability of target attainment. METHODS: This study is based on a population pharmacokinetic model. After defining the predictive performance of the model, Monte Carlo simulations were used to calculate the probability of target attainment of the currently existing dosing guidelines of meropenem and their use in daily clinical practice. RESULTS: Two guidelines and two labels were included in the Monte Carlo simulations. For 70% fT>MIC (fraction of time when the free meropenem concentration exceeded the minimum inhibitory concentration during the dosing interval), the probability of target attainment of four recommended doses ranged from 59% to 88% (MIC = 2 mg·L-1 ) and from 17% to 47% (MIC = 8 mg·L-1 ). At the clinical practice evaluation, only 20% of patients attained target exposure for the MIC of 8 mg·L-1 with 70% fT>MIC , which was much less than those found in the Food and Drug Administration labels (40%). CONCLUSION: This model-based population pharmacokinetics simulation showed that improper guidelines and/or clinical practice deviations will result in low probability of target attainment for patients infected with resistant bacteria and critically ill patients. It is important to develop and adhere to evidence-based and clinically pragmatic guidelines.