meropenem and Critical-Illness

Meropenem, as a carbapenem antibiotic, is commonly used in critically ill pediatric patients with severe infection because of its broad antimicrobial spectrum, high penetration into tissues, and favorable safety profile. Due to pathophysiological changes in critically ill children, the available evidence has demonstrated that the standard dosage regimens of meropenem could not meet an appropriate pharmacodynamic (PD) target attainment in severely infected children. Therefore, we reviewed the pharmacokinetic (PK) profile of meropenem in critically ill children, therapeutic drug monitoring (TDM), and dose optimization based on PK/PD. Meropenem kills bacteria in a timedependent manner and its efficacy is positively correlated with the percentage of the time of dosing interval during which the free serum concentration of meropenem remains above the minimum inhibitory concentration (MIC) of the pathogen (%fT>MIC), which is related to PK/PD targets. For critically ill children, TDM-based dosage optimization and setting even higher PK/PD targets seem necessary to be considered. The currently available studies have revealed that increasing the dose and the application of the extended or continuous infusion of meropenem were able to achieve better PK/PD targets. According to limited clinical data on efficacy and safety, these treatment measures cannot yet be adopted as routine regimens only when serious infections caused by drug-resistant bacteria or strains with high values of MIC are suspected. Further high-quality randomized controlled trials (RCTs) or observational studies with sufficient sample sizes are required to confirm the efficacy and safety of these modes of administration.

Topics: Anti-Bacterial Agents; Carbapenems; Child; Critical Illness; Humans; Meropenem

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.. 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.. 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.. 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.

Topics: Anti-Bacterial Agents; Continuous Renal Replacement Therapy; Critical Illness; Humans; Meropenem; Monte Carlo Method; Renal Replacement Therapy

Meropenem is frequently used to treat severe infections in critically ill children. However, pharmacokinetic data on meropenem in children with end-stage renal disease (ESRD) undergoing prolonged intermittent renal replacement therapy (PIRRT) is limited. Our objectives were to evaluate meropenem clearance in a child with ESRD with and without PIRRT, compare the results to previous continuous renal replacement therapy studies in children, toddlers and neonates, and assess whether the currently used dose of meropenem is sufficient.. A 5-year-old girl with an estimated glomerular filtration rate of 12.8 mL/min/1.73 m 2 was diagnosed with pulmonary infection and treated with 300 mg meropenem once a day. PIRRT was performed for 8 hours every 2 days. We used WinNonlin to evaluate meropenem clearance with and without PIRRT.. Our case showed that PIRRT increased the clearance of meropenem from 1.39 (1.3) to 2.42 L/h (2.3 mL/kg/min) and caught up 42.6% of the total clearance. This result is in accordance with previous studies in children but slightly less than seen in toddlers and neonates under continuous renal replacement therapy. The current dose of 300 mg once a day is not sufficient to reach the therapeutic target.. Predicting meropenem clearance in children with ESRD undergoing PIRRT is difficult as clearance will be affected by renal function, PIRRT settings and other factors. Further studies are needed to explore the individual variability of meropenem clearance and optimize the dosing regimen.

Topics: Anti-Bacterial Agents; Child, Preschool; Continuous Renal Replacement Therapy; Critical Illness; Drug Elimination Routes; Female; Humans; Intermittent Renal Replacement Therapy; Kidney Failure, Chronic; Meropenem

Augmented renal clearance (ARC), which is commonly defined as increased renal clearance above 130 ml/min/1.73 m. This article is a narrative review of the articles that evaluated different dosing regimens of antibiotics in patients with ARC. The keywords "Augmented Renal Clearance," "Critically ill patients," "Drug dosing," "Serum concentration," "Beta-lactams," "Meropenem," "Imipenem," "Glycopeptide," "Vancomycin," "Teicoplanin," "Linezolid," "Colistin," "Aminoglycosides," "Amikacin," "Gentamycin," "Fluoroquinolones," "Ciprofloxacin," and "Levofloxacin" were searched in Scopus, Medline, PubMed, and Google Scholar databases, and pediatric, nonhuman, and non-English studies were excluded.. PK properties of antibiotics including lipophilicity or hydrophilicity, protein binding, the volume of distribution, and elimination rate that affect drug concentration should be considered along with PD parameters for drug dosing in critically ill patients with ARC.. This review recommends a dosing protocol for some antibiotics to help the appropriate dosing of antibiotics in ARC and decrease the risk of subtherapeutic exposure that may be observed while receiving conventional dosing regimens in critically ill patients with ARC.

Topics: Anti-Bacterial Agents; Child; Critical Illness; Humans; Kidney; Meropenem

The optimal dosing regimen for meropenem in critically ill patients undergoing continuous renal replacement therapy (CRRT) remains undefined due to small studied sample sizes and uninformative pharmacokinetic (PK)/pharmacodynamic (PD) analyses in reported studies. The present study aimed to perform a population PK/PD meta-analysis of meropenem using available literature data to suggest the optimal treatment regimen. A total of 501 meropenem concentration measurements from 78 adult CRRT patients pooled from nine published studies were used to develop the population PK model for meropenem. PK/PD target (40% and 100% of the time with the unbound drug plasma concentration above the MIC) marker-based efficacy and risk of toxicity (trough concentrations of >45 mg/L) for short-term (30 min), prolonged (3 h), and continuous (24 h) infusion dosing strategies for meropenem were investigated. The impact of CRRT dose and identified covariates on the PD probability of target attainment (PTA) and predicted toxicity was also examined. Meropenem concentration data were adequately described by a two-compartment model with linear elimination. Trauma was identified as a pronounced modifier for endogenous clearance of meropenem. Simulations demonstrated that adequate PK/PD targets and low risk of toxicity could be achieved in non-trauma CRRT patients receiving meropenem regimens of 1 g every 6 h infused over 30 min, 1 g every 8 h infused over 3 h, and 2 to 4 g every 24 h infused over 24 h. The impact of CRRT dose (25 to 50 mL/kg/h) on PTA was clinically irrelevant, and continuous infusion of 3 to 4 g every 24 h was suitable for trauma CRRT patients (MICs of ≤0.5 mg/L). A population PK model was developed for meropenem in CRRT patients, and different dosing regimens were proposed for non-trauma and trauma CRRT patients.

Topics: Adult; Anti-Bacterial Agents; Continuous Renal Replacement Therapy; Critical Illness; Humans; Meropenem; Microbial Sensitivity Tests; Prospective Studies; Renal Replacement Therapy

Intermittent hemodialysis, continuous hemofiltration and prolonged daily dialysis are used for renal replacement therapy in the intensive care units. Independent of the replacement modality, antibiotic therapy must start with a high loading dose. Dose adjustment to the kidneys must follow 48 h later to prevent toxic accumulation. Dose recommendations on product labels are often underdosed. On continuous hemofiltration, meanwhile many intensivists administer a normal standard dose because the high filtration rate corresponds to a half-normal glomerular filtration rate. After intermittent hemodialysis, a dose similar to the loading dose will be needed. On day off dialysis, the maintenance dose must be adjusted to the failing kidney function. Immediately after prolonged daily dialysis, a loading dose should be given; with twice daily dosing the maintenance dose needs to be adjusted to kidney function. Therapeutic drug monitoring is recommended for gentamicin, vancomycin, piperacillin, meropenem and voriconazole. Due to pharmacodynamic reasons, the target concentration corresponds to the concentration producing the half-maximum effect. Accordingly, the target concentration is the normal peak for concentration-dependent action with bolus dosing. The target is the average steady-state concentration for antibiotics with time-dependent action and continuous infusion.. Zur Nierenersatztherapie auf der Intensivstation werden die intermittierende Hämodialyse, die kontinuierliche Hämofiltration und die prolongierte Tankdialyse eingesetzt. Unabhängig vom Nierenersatzverfahren beginnt die Antibiotikatherapie mit einer hohen Startdosis. Die Dosisanpassung an die Niere wird erst nach 48 h erforderlich, wenn toxische Spiegel akkumulieren könnten. Empfehlungen zur Dosisanpassung in den Fachinformationen sind häufig unterdosiert. Bei kontinuierlicher Hämofiltration geben viele Intensivmediziner inzwischen eine normale Standarddosis, da die Filtrationsrate oft schon einer halbnormalen glomerulären Filtrationsrate entspricht. Die Dosis nach intermittierender Hämodialyse orientiert sich an der Startdosis. Am Nichtdialysetag muss die Erhaltungsdosis der Nierenfunktion angepasst werden. Unmittelbar nach prolongierter Tankdialyse wird jeweils wieder eine Startdosis gegeben; die Erhaltungsdosis bei 12-stündigem Dosierungsintervall muss ebenfalls der Nierenfunktion angepasst werden. Ein therapeutisches Drugmonitoring empfiehlt sich bei Gentamicin, Vancomycin, Piperacillin, Meropenem und Voriconazol. Aus pharmakodynamischen Gründen sollte als Zielspiegel die Konzentration des halbmaximalen Effekts gewählt werden. Der Zielspiegel entspricht so den normalen Spitzenspiegeln bei konzentrationsabhängiger Wirkung mit Bolusdosierung. Die Zielspiegel bei zeitabhängiger Wirkung und kontinuierlicher Infusion entsprechen dann der mittleren Gleichgewichtskonzentration.

Topics: Anti-Bacterial Agents; Critical Illness; Humans; Meropenem; Piperacillin; Renal Dialysis; Renal Replacement Therapy; Vancomycin

Meropenem, a carbapenem antibiotic, is widely prescribed for the treatment of life-threatening infections. The main parameter associated with its therapeutic success is the percentage of time that the levels remain above the minimum inhibitory concentration. Inadequate levels of meropenem can lead to therapeutic failure and increase the possibility of microbial resistance. The employment of strategies involving dose regimens and drug pharmacodynamics has become increasingly important to optimize therapies. In the present study, we conducted a review with the purpose of assembling information about the clinical use of meropenem and therapeutic drug monitoring.. A literature review emphasizing the application of therapeutic drug monitoring (TDM) of meropenem in clinical practice has been done. To identify articles related to the topic, we performed a standardized search from January 21, 2020 to December 21, 2020, using specific descriptors in PubMed, Lilacs and Embase.. In total, 35 studies were included in the review. The daily dose of meropenem commonly ranged from 3 to 6 g/day. Critically ill patients and those with impaired renal function appear to be the most suitable patients for the application of meropenem TDM, in order to guide therapy. We observed that most of the studies recommend TDM and that, in nine locations, the TDM of meropenem and of other beta-lactams is a routine practice. TDM data can help to maximize the clinical outcomes of the treatment with meropenem. It can also improve the patient care by providing suitable levels of meropenem, guiding the most appropriate dose regimens, which is the main parameter associated with therapeutic success.. The findings from this review suggest that the therapeutic monitoring of meropenem can be beneficial, since it adjusts the treatment and aids clinical outcomes. It does so by indicating the appropriate dosage and preventing failure, toxicity and possible antimicrobial resistance. The multidisciplinary effort, basic knowledge and communication among the medical team are also essential.

Topics: Anti-Bacterial Agents; Critical Illness; Drug Monitoring; Drug Resistance, Microbial; Humans; Meropenem; Microbial Sensitivity Tests; Severity of Illness Index

To summarize the current literature on the use and clinical efficacy of extended-infusion (EI) beta-lactam antibiotics, including piperacillin-tazobactam, meropenem, and cefepime.. Gram-negative infections are a serious concern among hospitalized patients and require innovative pharmacokinetic dosing strategies to achieve clinical success, especially as the emergence of resistant gram-negative pathogens has outpaced the development of new antibiotics. Beta-lactam antibiotics exhibit time-dependent activity, which means that optimal efficacy is achieved when free drug concentrations stay above the minimum inhibitory concentration for an extended duration of the recommended dosage interval. EI piperacillin-tazobactam therapy has demonstrated improved clinical outcomes and decrease mortality in critically ill patients with gram-negative infections, particularly Pseudomonas aeruginosa infections. EI meropenem has shown higher therapeutic success rates for patients with febrile neutropenia and shorter intensive care unit (ICU) length of stay (LOS) with a reduction in ventilator days in patients with multidrug-resistant ventilator-associated pneumonia. However, a larger study showed no difference in clinical outcomes between standard-infusion and EI meropenem. EI cefepime has been associated with decreased mortality and shorter ICU LOS in patients with Pseudomonas aeruginosa infections. Common challenges associated with EI beta-lactam antibiotics include Y-site incompatibilities, lack of intravenous access, and tubing residuals. It is important to note that factors such as diverse patient populations and study methodology, along with various antibiotic dose regimens, may have contributed to conflicting data on EI beta-lactam therapy.. Based on most published literature, there appears to be a favorable trend toward use of EI beta-lactam therapy in clinical practice, particularly in critically ill patients with gram-negative infections.

Topics: Anti-Bacterial Agents; Cefepime; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Multiple, Bacterial; Humans; Infusions, Intravenous; Intensive Care Units; Length of Stay; Meropenem; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination; Pseudomonas aeruginosa; Pseudomonas Infections; Time Factors; Treatment Outcome

Essential for drug dose adjustment is the glomerular filtration rate (GFR) not the serum creatinine level. In acute disease, a loading dose must be given that usually corresponds to the normal dose. The eliminated half-life is used to estimate the administration interval. For anti-infective drugs with a concentration-dependent effect, the target is the high peak such as for daptomycin, linezolide, and colistin. For anti-infective drugs with a time-dependent effect, the target is the high trough such as for piperacillin, meropenem and vancomycin. Such drugs with a time-dependent action should best be administered by infusion not by bolus dosing. With continuous renal replacement therapy (CRRT), the total filtration rate corresponds to a GFR of 30-50 ml/min and many antibiotics will not need a dose reduction on CRRT. After intermittent hemodialysis, a new loading dose should be given to ascertain sufficiently high concentrations in the interval until the next dose or next dialysis.

Topics: Anti-Bacterial Agents; Critical Illness; Glomerular Filtration Rate; Humans; Kidney Diseases; Meropenem; Pharmacokinetics; Piperacillin; Vancomycin

Beta-lactam dose optimization in critical care is a current priority. We aimed to review the pharmacokinetics (PK) of three commonly used beta-lactams (amoxicillin ± clavulanate, piperacillin-tazobactam and meropenem) to compare PK parameters reported in critically and noncritically ill neonates, children and adults, and to investigate whether allometric and maturation scaling principles could be applied to describe changes in PK parameters through life.. A systematic review of PK studies of the three drugs was undertaken using MEDLINE and EMBASE. PK parameters and summary statistics were extracted and scaled using allometric principles to 70 kg individual for comparison. Pooled data were used to model clearance maturation and decline using a sigmoidal (Hill) function.. A total of 130 papers were identified. Age ranged from 29 weeks to 82 years and weight from 0.9-200 kg. PK parameters from critically ill populations were reported with wider confidence intervals than those in healthy volunteers, indicating greater PK variability in critical illness. The standard allometric size and sigmoidal maturation model adequately described increasing clearance in neonates, and a sigmoidal model was also used to describe decline in older age. Adult weight-adjusted clearance was achieved at approximately 2 years postmenstrual age. Changes in volume of distribution were well described by the standard allometric model, although amoxicillin data suggested a relatively higher volume of distribution in neonates.. Critical illness is associated with greater PK variability than in healthy volunteers. The maturation models presented will be useful for optimizing beta-lactam dosing, although a prospective, age-inclusive study is warranted for external validation.

Topics: Adult; Age Factors; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Bacterial Infections; beta-Lactamase Inhibitors; Biological Variation, Population; Child; Critical Illness; Dose-Response Relationship, Drug; Healthy Volunteers; Humans; Infant, Newborn; Meropenem; Microbial Sensitivity Tests; Piperacillin, Tazobactam Drug Combination

Appropriate antibiotic dosing is critical to improve outcomes in critically ill patients with sepsis. The addition of continuous renal replacement therapy makes achieving appropriate antibiotic dosing more difficult. The lack of continuous renal replacement therapy standardization results in treatment variability between patients and may influence whether appropriate antibiotic exposure is achieved. The aim of this study was to determine if continuous renal replacement therapy effluent flow rate impacts attaining appropriate antibiotic concentrations when conventional continuous renal replacement therapy antibiotic doses were used. This study used Monte Carlo simulations to evaluate the effect of effluent flow rate variance on pharmacodynamic target attainment for cefepime, ceftazidime, levofloxacin, meropenem, piperacillin, and tazobactam. Published demographic and pharmacokinetic parameters for each antibiotic were used to develop a pharmacokinetic model. Monte Carlo simulations of 5000 patients were evaluated for each antibiotic dosing regimen at the extremes of Kidney Disease: Improving Global Outcomes guidelines recommended effluent flow rates (20 and 35 mL/kg/h). The probability of target attainment was calculated using antibiotic-specific pharmacodynamic targets assessed over the first 72 hours of therapy. Most conventional published antibiotic dosing recommendations, except for levofloxacin, reach acceptable probability of target attainment rates when effluent rates of 20 or 35 mL/kg/h are used.

Topics: Anti-Bacterial Agents; Cefepime; Ceftazidime; Cephalosporins; Computer Simulation; Critical Illness; Humans; Levofloxacin; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method; Penicillanic Acid; Piperacillin; Renal Replacement Therapy; Sepsis; Tazobactam; Thienamycins

Carbapenem-resistant Enterobacteriaceae (CRE) is a worldwide challenge and associated with a high mortality rate in critically ill patients. This review focused on rapid diagnosis, optimization of antimicrobial therapy, and implication of effective infection control precautions to reduce impact of CRE on vulnerable patients.. Several new diagnostic assays have recently been described for the early diagnosis of CRE. Retrospective studies are supportive for colistin plus meropenem combination for the treatment of CRE infections; however, solid evidence is still lacking. Ceftazidime-avibactam may be an effective therapeutic agent for infections caused by carbapenem-hydrolyzing oxacillinase-48 and Klebsiella pneumoniae carbapenamase-producing Enterobacteriaceae, but not for New Delhi metallo-β-lactamase producers. Gastrointestinal screening may permit early identification of patients with CRE infections. There is not enough evidence to recommend selective digestive decontamination for CRE carriers.. The information for rapid diagnosis of CRE is accumulating. There are new agents with high in-vitro activity against CRE, but clinical experience is limited to case reports. Active surveillance with a high rate of compliance to basic infection control precautions seems to be the best approach to reduce the impact of CRE on vulnerable patients.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactam Resistance; beta-Lactamases; Carbapenems; Ceftazidime; Colistin; Critical Illness; Drug Combinations; Drug Therapy, Combination; Enterobacteriaceae; Enterobacteriaceae Infections; Humans; Meropenem; Retrospective Studies; Thienamycins

Although early and appropriate antibiotic therapy remains the most important intervention for successful treatment of septic shock, data guiding optimization of beta-lactam prescription in critically ill patients prescribed with continuous renal replacement therapy (CRRT) are still limited. Being small hydrophilic molecules, beta-lactams are likely to be cleared by CRRT to a significant extent. As a result, additional variability may be introduced to the per se variable antibiotic concentrations in critically ill patients. This article aims to describe the current clinical scenario for beta-lactam dosing in critically ill patients with septic shock and CRRT, to highlight the sources of variability among the different studies that reduce extrapolation to clinical practice, and to identify the opportunities for future research and improvement in this field. Three frequently prescribed beta-lactams (meropenem, piperacillin and ceftriaxone) were chosen for review. Our findings showed that present dosing recommendations are based on studies with drawbacks limiting their applicability in the clinical setting. In general, current antibiotic dosing regimens for CRRT follow a one-size-fits-all fashion despite emerging clinical data suggesting that drug clearance is partially dependent on CRRT modality and intensity. Moreover, some studies pool data from heterogeneous populations with CRRT that may exhibit different pharmacokinetics (for example, admission diagnoses different to septic shock, such as trauma), which also limit their extrapolation to critically ill patients with septic shock. Finally, there is still no consensus regarding the %T>MIC (percentage of dosing interval when concentration of the antibiotic is above the minimum inhibitory concentration of the pathogen) value that should be chosen as the pharmacodynamic target for antibiotic therapy in patients with septic shock and CRRT. For empirically optimized dosing, during the first day a loading dose is required to compensate the increased volume of distribution, regardless of impaired organ function. An additional loading dose may be required when CRRT is initiated due to steady-state equilibrium breakage driven by clearance variation. From day 2, dosing must be adjusted to CRRT settings and residual renal function. Therapeutic drug monitoring of beta-lactams may be regarded as a useful tool to daily individualize dosing and to ensure optimal antibiotic exposure.

Topics: Anti-Bacterial Agents; beta-Lactams; Ceftriaxone; Critical Illness; Humans; Meropenem; Piperacillin; Renal Replacement Therapy; Shock, Septic; Thienamycins

Several reports have shown marked heterogeneity of antibiotic pharmacokinetics (PK) in patients admitted to ICUs, which might potentially affect outcomes. Therefore, the pharmacodynamic (PD) parameter of the efficacy of β-lactam antibiotics, that is, the time that its concentration is above the bacteria minimal inhibitory concentration (T > MIC), cannot be safely extrapolated from data derived from the PK of healthy volunteers.. We performed a full review of published studies addressing the PK of intravenous β-lactam antibiotics given to infected ICU patients. Study selection comprised a comprehensive bibliographic search of the PubMed database and bibliographic references in relevant reviews from January 1966 to December 2010. We selected only English-language articles reporting studies addressing β-lactam antibiotics that had been described in at least five previously published studies. Studies of the PK of patients undergoing renal replacement therapy were excluded.. A total of 57 studies addressing six different β-lactam antibiotics (meropenem, imipenem, piperacillin, cefpirome, cefepime and ceftazidime) were selected. Significant PK heterogeneity was noted, with a broad, more than twofold variation both of volume of distribution and of drug clearance (Cl). The correlation of antibiotic Cl with creatinine clearance was usually reported. Consequently, in ICU patients, β-lactam antibiotic half-life and T > MIC were virtually unpredictable, especially in those patients with normal renal function. A better PD profile was usually obtained by prolonged or even continuous infusion. Tissue penetration was also found to be compromised in critically ill patients with septic shock.. The PK of β-lactam antibiotics are heterogeneous and largely unpredictable in ICU patients. Consequently, the dosing of antibiotics should be supported by PK concepts, including data derived from studies of the PK of ICU patients and therapeutic drug monitoring.

Topics: Anti-Bacterial Agents; beta-Lactams; Cefepime; Cefpirome; Ceftazidime; Cephalosporins; Critical Illness; Humans; Imipenem; Infections; Meropenem; Piperacillin; Thienamycins

Augmented renal clearance (ARC) defined as creatinine clearance (Clcr) above 130 mL/min/1.73m. In this randomized clinical trial, patients with VAP and high risk for ARC were recruited. An 8-h urine collection was performed on the 1st, 3rd, and 5th days of study to measure Clcr. Included patients were divided into three groups: (1) 1 g meropenem, 3-h infusion, (2) 2 g meropenem, 3-h infusion, (3) 1 g meropenem, 6-h infusion. On the 2nd, 3rd, and 5th days of treatment, peak and trough blood samples were collected to undergo HPLC assay. MICs were assessed using microdilution method. Patients were also clinically monitored for 14 days.. Forty-five patients were included. Group 3 showed significanty higher rate of patients achieving fT > MIC > 50% (100% for group 3 versus 40% for group 2 and 13% for group 1; p = 0.0001). Mean fT > MIC% was significantly higher in group 3 (78.77 ± 5.87 for group 3 versus 49.6 ± 7.38 for group 2 and 43.2 ± 7.98 for group 1; p = 0.0001). Statistical analysis showed no significant differences among groups regarding clinical improvement.. According to the findings of this trial, prolonged meropenem infusion is an appropriate strategy compared to dose elevation among ARC patients.

Topics: Anti-Bacterial Agents; Critical Illness; Humans; Meropenem; Microbial Sensitivity Tests; Pneumonia, Ventilator-Associated; Renal Insufficiency

Sepsis and continuous renal replacement therapy (CRRT) are both responsible for the alterations of the pharmacokinetics of antibiotics. For patients with sepsis receiving CRRT, the serum concentrations of meropenem in the early phase (< 48 h) was significantly lower than that in the late phase (> 48 h). This current trial aimed to investigate whether administration of a loading dose of meropenem results in a more likely achievement of the pharmacokinetic (PK)/pharmacodynamics (PD) target (100% fT > 4 × MIC) and better therapeutic results in the patients with sepsis receiving CRRT.. This is a single-blinded, single-center, randomized, controlled, two-arm, and parallel-group trial. This trial will be carried out in Guangzhou First People's Hospital, School of Medicine, South China University of Technology Guangdong, China. Adult patients (age ≥ 18 years) with critical sepsis or sepsis-related shock receiving CRRT will be included in the study. The subjects will be assigned to the control group and the intervention group (LD group) randomly at a 1:1 ratio, the estimated sample size should be 120 subjects in each group. In the LD group, the patient will receive a loading dose of 1.5-g meropenem resolved in 30-ml saline which is given via central line for 30 min. Afterward, 0.75-g meropenem will be given immediately for 30 min every 8 h. In the control group, the patient will receive 0.75-g meropenem for 30 min every 8 h. The primary objective is the probabilities of PK/PD target (100% fT > 4 × MIC) achieved in the septic patients who receive CRRT in the first 48 h. Secondary objectives include clinical cure rate, bacterial clearance rate, sepsis-related mortality and all-cause mortality, the total dose of meropenem, duration of meropenem treatment, duration of CRRT, Sequential Organ Failure Assessment (SOFA), C-reactive protein levels, procalcitonin levels, white blood cell count, and safety.. This trial will assess for the first time whether administration of a loading dose of meropenem results in a more likely achievement of the PK/PD target and better therapeutic results in the patients with sepsis receiving CRRT. Since CRRT is an important therapeutic strategy for sepsis patients with hemodynamic instability, the results from this trial may help to provide evidence-based therapy for septic patients receiving CRRT.. Chinese Clinical Trials Registry, ChiCTR2000032865 . Registered on 13 May 2020, http://www.chictr.org.cn/showproj.aspx?proj=53616 .

Topics: Adolescent; Adult; Anti-Bacterial Agents; Critical Illness; Humans; Meropenem; Prospective Studies; Randomized Controlled Trials as Topic; Sepsis; Shock, Septic

In critically ill children, severely altered pharmacokinetics may result in subtherapeutic β-lactam antibiotic concentrations when standard pediatric dosing regimens are applied. However, it remains unclear how to recognize patients most at risk for suboptimal exposure and their outcome. This study aimed to: 1) describe target attainment for β-lactam antibiotics in critically ill children, 2) identify risk factors for suboptimal exposure, and 3) study the association between target nonattainment and clinical outcome.. Post hoc analysis of the "Antibiotic Dosing in Pediatric Intensive Care" study (NCT02456974, 2012-2019). Steady-state trough plasma concentrations were classified as therapeutic if greater than or equal to the minimum inhibitory concentration of the (suspected) pathogen. Factors associated with subtherapeutic concentrations and clinical outcome were identified by logistic regression analysis.. The pediatric and cardiac surgery ICU of a Belgian tertiary-care hospital.. One hundred fifty-seven patients (aged 1 mo to 15 yr) treated intravenously with amoxicillin-clavulanic acid, piperacillin-tazobactam, or meropenem.. None.. Three hundred eighty-two trough concentrations were obtained from 157 patients (median age, 1.25 yr; interquartile range, 0.4-4.2 yr). Subtherapeutic concentrations were measured in 39 of 60 (65%), 43 of 48 (90%), and 35 of 49 (71%) of patients treated with amoxicillin-clavulanic acid, piperacillin-tazobactam, and meropenem, respectively. Estimates of glomerular filtration rate (eGFR; 54% increase in odds for each sd increase in value, 95% CI, 0.287-0.736; p = 0.001) and the absence of vasopressor treatment (2.8-fold greater odds, 95% CI, 1.079-7.253; p = 0.034) were independently associated with target nonattainment. We failed to identify an association between antibiotic concentrations and clinical failure.. Subtherapeutic β-lactam concentrations are common in critically ill children and correlate with renal function. eGFR equations may be helpful in identifying patients who may require higher dosing. Future studies should focus on the impact of subtherapeutic concentrations on clinical outcome.

Topics: Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; beta-Lactams; Child; Critical Illness; Humans; Infant; Meropenem; Piperacillin, Tazobactam Drug Combination; Risk Factors

No study has been evaluated pharmacokinetic (PK) and pharmacodynamic (PD) properties of β-lactam antibiotics in patients with acute kidney injury (AKI), not requiring renal replacement therapy (RRT). We evaluated the time that plasma concentrations remain above four times the MIC (ft > 4MIC) and PK parameters of meropenem in this population.. In this prospective, randomized clinical trial (RCT), all patients received standard dose (3 g daily) of meropenem for 48 h, then randomly allocated in standard or adjusted groups. The standard group received meropenem without dose adjustment. In the adjusted group, the meropenem dose was adjusted based on the Cockcroft-Gault(C-G) equation. Meropenem concentrations were measured at the peak and trough times on the 2nd and 5th days of the study.. On the 2nd day of the study, 3 out of 10 (30%) of patients attained the PD target (≥ 80%ft > 4MIC). In the 5th day of the study, the PD target was attained in 2 out of 10 (20%) and 1 out of 5 (20%) of patients who received standard and adjusted doses of meropenem, respectively (p = 1). In all samples, increased volume of distribution (Vd) (median; IQR) (46.04; 23.06-103.18 L), terminal half-life (T1/2) (4.51; 2.67-8.88 h) and decreased clearance (6.52; 4.43-10.16 L/h) have been shown.. In critically ill patients with AKI, who not receive RRT, standard doses, and adjusted according to renal function of meropenem failed to achieve PD target of ≥ 80%ft > 4MIC. Higher doses are required for this target.. The study protocol with registered retrospectively and approved on January 19, 2019, with the number of IRCT20160412027346N5.

Topics: Acute Kidney Injury; Adult; Aged; Anti-Bacterial Agents; Critical Illness; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Male; Meropenem; Metabolic Clearance Rate; Microbial Sensitivity Tests; Middle Aged; Prospective Studies

Meropenem is a β-lactam, carbapenem antibacterial agent with antimicrobial activity against gram-negative, gram-positive and anaerobic micro-organisms and is important in the empirical treatment of serious infections in Intensive Care Unit (ICU) patients. Multi-drug resistant gram-negative organisms, coupled with scarcity of new antibiotic classes, forced healthcare community to optimize the therapeutic potential of available antibiotics. Our aim is to investigate the effect of continuous infusion of meropenem against bolus administration, as indicated by a composite outcome of reducing death and emergence of extensive or pan drug-resistant pathogens in a population of ICU patients.. Double blind, double dummy, multicenter randomized controlled trial (1:1 allocation ratio).. Tertiary and University hospitals.. 600 ICU patients with sepsis or septic shock, needing by clinical judgment antibiotic therapy with meropenem, will be randomized to receive a continuous infusion of meropenem 3 g/24 h or an equal dose divided into three daily boluses (i.e. 1g q8h).. The primary endpoint will be a composite outcome of reducing death and emergence of extensive or pan drug-resistant pathogens. Secondary endpoints will be death from any cause at day 90, antibiotic-free days at day 28, ICU-free days at day 28, cumulative SOFA-free (Sequential Organ Failure Assessment) score from randomization to day 28 and the two, separate, components of the primary endpoint. We expect a primary outcome reduction from 52 to 40% in the continuous infusion group.. The trial will provide evidence for choosing intermittent or continuous infusion of meropenem for critically ill patients with multi-drug resistant gram-negative infections.

Topics: Anti-Bacterial Agents; Critical Care; Critical Illness; Humans; Meropenem; Sepsis

Topics: Anti-Bacterial Agents; Critical Illness; Dose-Response Relationship, Drug; Humans; Length of Stay; Meropenem; Organ Dysfunction Scores; Sepsis; Shock, Septic

To evaluate the effect of direct hemoperfusion with polymyxin B immobilized cartridge (DHP-PMX) on meropenem pharmacokinetics in critically ill patients with sepsis requiring continuous venovenous hemofiltration (CVVH).. After intravenous infusion of 1 g meropenem over 3 h repeated every 8 h for at least 3 doses, 2 serial blood and ultrafiltration fluid samples were collected: one over a dose interval of meropenem with DHP-PMX therapy; and the other on the following day over a dose interval of meropenem with no DHP-PMX therapy. Meropenem concentrations were measured by high performance liquid chromatography. Pharmacokinetic parameters of meropenem and extraction ratio of DHP-PMX were calculated.. No significant effect of DHP-PMX on meropenem pharmacokinetics was observed among severe sepsis/septic shock patients during CVVH treatment.. Clinical Trial Registry detail: NCT registry: 02413541 (First registered March 3, 2015, last update October 16, 2017).

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Critical Illness; Female; Hemoperfusion; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Meropenem; Middle Aged; Polymyxin B; Prospective Studies; Shock, Septic; Treatment Outcome

β-Lactam antibiotics display a time-dependent mechanism of action, with evidence suggesting improved outcomes when administering these drugs via continuous infusion compared with standard intermittent infusion. However, there is no phase 3 randomised controlled trial (RCT) evidence to support one method of administration over another in critically ill patients with sepsis.. The β-Lactam Infusion Group (BLING) III study is a prospective, multicentre, open, phase 3 RCT to compare continuous infusion with standard intermittent infusion of β-lactam antibiotics in critically ill patients with sepsis. The study will be conducted in about 70 intensive care units (ICUs) in Australia, New Zealand, the United Kingdom, Belgium and selected other countries, from 2018 to 2021.. BLING III will recruit 7000 critically ill patients with sepsis being treated with one of two β-lactam antibiotics (piperacillin-tazobactam or meropenem) to receive the β-lactam antibiotic by either continuous or intermittent infusion.. The primary outcome is allcause mortality within 90 days after randomisation. Secondary outcomes are clinical cure at Day 14 after randomisation, new acquisition, colonisation or infection with a multiresistant organism or Clostridium difficile diarrhoea up to 14 days after randomisation, all-cause ICU mortality and all-cause hospital mortality. Tertiary outcomes are ICU length of stay, hospital length of stay and duration of mechanical ventilation and duration of renal replacement therapy up to 90 days after randomisation.. The BLING III study will compare the effect on 90-day mortality of β-lactam antibiotics administered via continuous versus intermittent infusion in 7000 critically ill patients with sepsis.. ClinicalTrials.gov Registry (NCT03213990).

Topics: Anti-Bacterial Agents; Australia; beta-Lactams; Critical Illness; Drug Administration Schedule; Humans; Infusions, Intravenous; Meropenem; New Zealand; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Sepsis; Treatment Outcome; United Kingdom

Meropenem is frequently prescribed in critically ill children receiving continuous renal replacement therapy (CRRT). We previously used clinical trial simulations to evaluate dosing regimens of meropenem in this population and reported that a dose of 20 mg/kg every 12 hours optimizes target attainment. Meropenem pharmacokinetics were investigated in this prospective, open-label study to validate our previous in silico predictions. Seven patients received meropenem (13.8-22 mg/kg) administered intravenously every 12 hours as part of standard care. A mean dose of 18.6 mg/kg of meropenem was administered, resulting in a mean peak concentration of 80.1 μg/mL. Meropenem volume of distribution was 0.35 ± 0.085 L/kg. CRRT clearance was 40.2 ± 6.6 mL/(min · 1.73 m(2) ) and accounted for 63.4% of the total clearance of 74.8 ± 36.9 mL/(min · 1.73 m(2) ). Simulations demonstrated that a dose of 20 mg/kg every 12 hours resulted in a time above the minimum inhibitory concentration (%fT > MIC) of 100% in 5 out of 7 subjects, with a %fT > MIC of 93% and 43% in the remaining 2 subjects. We conclude that CRRT contributed significantly to the total clearance of meropenem. A dosing regimen of 20 mg/kg achieved good target attainment in critically ill children receiving CRRT, which is consistent with our previously published in silico predictions.

Topics: Administration, Intravenous; Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Computer Simulation; Critical Illness; Female; Hemodiafiltration; Humans; Male; Meropenem; Microbial Sensitivity Tests; Prospective Studies; Renal Replacement Therapy; Thienamycins; Young Adult

Patients admitted to intensive care unit (ICU) with Klebsiella pneumoniae infections are characterized by high mortality. The aims of the present study were to investigate the population pharmacokinetics parameters and to assess the probability of target attainment of meropenem in critically ill patients to provide information for more effective regimens.. Twenty-seven consecutive patients were included in the study. Meropenem was administered as 3-h intravenous (i.v.) infusions at doses of 1-2 g every 8 or 12 h. Meropenem plasma concentrations were measured by a high-performance liquid chromatography (HPLC) method, and a population pharmacokinetics analysis was performed using NONMEM software. Meropenem plasma disposition was simulated for extended (3 h; 5 h) or continuous i.v. infusions, and the following parameters were calculated: time during which free drug concentrations were above minimum inhibitory concentration (MIC) (fT > MIC), free minimum plasma concentrations above 4× MIC (fCmin > 4× MIC), probability of target attainment (PTA), and cumulative fraction of response (CFR).. Gender and severity of sepsis affected meropenem clearance, whose typical population values ranged from 6.22 up to 12.04 L/h (mean ± standard deviation (SD) value, 9.38 ± 4.47 L/h). Mean C min value was 7.90 ± 7.91 mg/L, suggesting a high interindividual variability. The simulation confirmed that 88 and 97.5 % of patients achieved effective C min > 4× MIC values after 3- and 5-h i.v. infusions of meropenem 2 g × 3/day, respectively. On the contrary, the same total daily doses reached the target C min > 4× MIC values in 100 % of patients when administered as continuous i.v. infusions.. Several factors may influence meropenem pharmacokinetics in ICU patients. Continuous i.v. infusions of meropenem seem to be more effective than standard regimens to achieve optimal therapeutic targets.

Topics: Adult; Aged; Anti-Bacterial Agents; Critical Illness; Cross Infection; Female; Humans; Infusions, Intravenous; Klebsiella Infections; Klebsiella pneumoniae; Male; Meropenem; Middle Aged; Models, Biological; Sepsis; Thienamycins

The objective of this study was to describe the pharmacokinetics of meropenem, administered by continuous infusion (CI) or intermittent bolus (IB), in critically ill patients receiving continuous venovenous haemofiltration (CVVH) and to evaluate the frequency of pharmacokinetic/pharmacodynamic target attainment with each dosing strategy. This was a prospective, randomised controlled trial in critically ill patients receiving CVVH and administered meropenem by CI or IB. Serial meropenem concentrations in plasma and ultrafiltrate were measured after administration of a standard total daily dose (4 g/day on Day 1, followed by 3g/day thereafter) on two occasions during antibiotic therapy. Meropenem pharmacokinetic parameters were calculated using a non-compartmental approach. Sixteen critically ill patients receiving CVVH concurrently treated with meropenem were randomised to CI (n = 8) or IB dosing (n = 8). IB administration resulted in higher maximum concentrations (C(max)) [64.7 (58.9-80.3) and 64.8 (48.5-81.8) mg/L, respectively] on both sampling occasions compared with CI (P < 0.01 and P = 0.04, respectively). CI resulted in a higher meropenem steady-state concentration (Css) on occasion 1 [26.0 (24.5-41.6) mg/L] compared with the minimum concentration (C(min)) observed for IB patients [17.0 (15.7-19.8)mg/L; P < 0.01]. CVVH contributed to ca. 50% of meropenem total clearance in these patients. The administered meropenem doses resulted in plasma drug concentrations that were >4× the targeted susceptibility breakpoint (2mg/L) for 100% of the dosing interval, for both groups, on both occasions. CI could be an alternative to IB for meropenem administration in critically ill patients receiving CVVH.

Topics: Administration, Intravenous; Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Critical Illness; Female; Hemofiltration; Humans; Male; Meropenem; Middle Aged; Plasma; Prospective Studies; Thienamycins; Young Adult

Use of antibiotics in critically ill patients may increase the risk of invasive Candida infection. The objective of this study was to determine whether increased exposure to antibiotics is associated with increased prevalence of invasive Candida infection.. Substudy using data from a randomized controlled trial, the Procalcitonin And Survival Study 2006-2010.. Nine multidisciplinary ICUs across Denmark.. A total of 1,200 critically ill patients.. Patients were randomly allocated to either a "high exposure" antibiotic therapy (intervention arm, n = 604) or a "standard exposure" guided by current guidelines (n = 596).. Seventy-four patients met the endpoint, "invasive Candida infection," 40 in the high exposure arm and 34 in standard exposure arm (relative risk = 1.2; 95% CI, 0.7-1.8; p = 0.52). Among medical patients in the high exposure arm, the use of ciprofloxacin and piperacillin/tazobactam was 51% and 75% higher than in the standard exposure arm; no difference in antibiotic exposure was observed between the randomized arms in surgical patients. Among medical intensive care patients, invasive Candida infection was more frequent in the high exposure arm (6.2%; 27/437) than in standard exposure arm (3.3%; 14/424) (hazard ratio = 1.9; 95% CI, 1.0-3.6; p = 0.05). Ciprofloxacin used at study entry independently predicted invasive Candida infection (adjusted hazard ratio = 2.1 [1.1-4.1]); the risk gradually increased with duration of ciprofloxacin therapy: six of 384 in patients not exposed (1.6%), eight of 212 (3.8%) when used for 1-2 days (hazard ratio = 2.5; 95% CI, 0.9-7.3), and 31 of 493 (6.3%) when used for 3 days (hazard ratio = 3.8; 95% CI, 1.6-9.3; p = 0.002). Patients with any ciprofloxacin-containing antibiotic regimen the first 3 days in the trial had a higher risk of invasive Candida infection than did patients on any antibiotic regimen not containing ciprofloxacin (unadjusted hazard ratio = 3.7; 95% CI, 1.6-8.7; p = 0.003; adjusted hazard ratio, 3.4; 95% CI, 1.4-8.0; p = 0.006).. High exposure to antibiotics is associated to increased risk of invasive Candida infection in medical intensive care patients. Patients with ciprofloxacin-containing regimens had higher risk of invasive Candida infection. Other antibiotics, such as meropenem, piperacillin/tazobactam, and cefuroxime, were not associated with such a risk.

Topics: Age Factors; Aged; Anti-Bacterial Agents; APACHE; Candidiasis, Invasive; Cefuroxime; Ciprofloxacin; Critical Illness; Denmark; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Intensive Care Units; Male; Meropenem; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Single-Blind Method; Thienamycins

There is variability in the pharmacokinetics (PK) of antibiotics (AB) in critically ill patients. Therapeutic drug monitoring (TDM) could overcome this variability and increase PK target attainment. The objective of this study was to analyse the effect of a dose-adaption strategy based on daily TDM on target attainment.. This was a prospective, partially blinded, and randomised controlled trial in patients with normal kidney function treated with meropenem (MEM) or piperacillin/tazobactam (PTZ). The intervention group underwent daily TDM, with dose adjustment when necessary. The predefined PK/pharmacodynamic (PK/PD) target was 100% fT>4MIC [percentage of time during a dosing interval that the free (f) drug concentration exceeded 4 times the MIC]. The control group received conventional treatment. The primary endpoint was the proportion of patients that reached 100% fT>4MIC and 100 % fT>MIC at 72 h.. Forty-one patients (median age 56 years) were included in the study. Pneumonia was the primary infectious diagnosis. At baseline, 100% fT>4MIC was achieved in 21% of the PTZ patients and in none of the MEM patients; 100% fT>MIC was achieved in 71% of the PTZ patients and 46 % of the MEM patients. Of the patients in the intervention group, 76 % needed dose adaptation, and five required an additional increase. At 72 h, target attainment rates for 100% fT>4MIC and 100% fT>MIC were higher in the intervention group: 58 vs. 16%, p = 0.007 and 95 vs. 68%, p = 0.045, respectively.. Among critically ill patients with normal kidney function, a strategy of dose adaptation based on daily TDM led to an increase in PK/PD target attainment compared to conventional dosing.

Topics: beta-Lactamase Inhibitors; Creatine; Critical Illness; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Meropenem; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Thienamycins

Meropenem is a carbapenem antibiotic commonly used in critically ill patients to treat severe infections. The available pharmacokinetic (PK) data has been mostly obtained from healthy volunteers as well as from clinical studies addressing selected populations, often excluding the elderly and also patients with renal failure. Our aim was to study PK of meropenem in a broader population of septic critically ill patients.. We characterized the PK of meropenem in 15 critically ill patients during the first 36 hrs of therapy. Aditionally, whenever possible, we collected a second set of late plasma samples after 5 days of therapy to evaluate PK intra-patient variability and its correlation with clinical course.Patients received meropenem (1 g every 8 hrs IV). Drug plasma profiles were determined by high-performance liquid chromatography. The PK of meropenem was characterized and compared with clinical parameters.. Fifteen septic critically ill patients (8 male, median age 73 yrs) were included. The geometric mean of the volume of distribution at the steady state (Vss)/weight was 0.20 (0.15-0.27) L/kg. No correlation of Vss/weight with severity or comorbidity scores was found. However the Sequential Organ Failure Assessment score correlated with the Vss/weight of the peripheral compartment (r2 = 0.55, p = 0.021). The median meropenem clearance (Cl) was 73.3 (45-120) mL/min correlated with the creatinine (Cr) Cl (r2 = 0.35, p = 0.033).After 5 days (N = 7) although Vss remained stable, a decrease in the proportion of the peripheral compartment (Vss2) was found, from 61.3 (42.5-88.5)% to 51.7 (36.6-73.1)%. No drug accumulation was noted.. In this cohort of septic, unselected, critically ill patients, large meropenem PK heterogeneity was noted, although neither underdosing nor accumulation was found. However, Cr Cl correlated to meropenem Cl and the Vss2 decreased with patient's improvement.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Critical Illness; Female; Humans; Male; Meropenem; Middle Aged; Sepsis; Thienamycins

To test whether a prolonged 3-hour infusion of meropenem 500mg achieves an equivalent proportion of time above the minimal inhibitory concentration (MIC) (%TMIC) to that of meropenem 1000mg given over 30 minutes.. A randomised crossover study in 10 critically ill patients.. We administered meropenem as a 1000mg, 30-minute infusion or as a 500mg, 3-hour infusion. We determined serial plasma concentrations for each dosing episode and performed comparisons of %TMIC at different MICs.. The percentage of time that meropenem was above its MIC.. For low MICs (≤2 mg/L), both regimens attained a %TMIC >40% in all patients. For an MIC of 4mg/L, this target was attained in all but one patient, but with an MIC of 8mg/L, three patients in each group had a %TMIC <40%. There was no difference in target attainment between the two regimens for MICs up to 8mg/L. There was marked variability in the pharmacokinetic and hence the pharmacokinetic-pharmacodynamic parameters between individuals. Several patients had elevated creatinine clearances and, with both regimens, their target attainment was poor.. Meropenem at 1000mg over 30 minutes achieved a similar %TMIC to meropenem at 500mg given over 3 hours. Meropenem pharmacokinetics were highly variable from individual to individual.

Topics: Adult; Aged; Anti-Bacterial Agents; Critical Illness; Cross-Over Studies; Female; Humans; Infusions, Intravenous; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Pilot Projects; Prospective Studies; Thienamycins

To Compare the clinical efficacy and safety of meropenem with a 3-hour extended infusion or conventional 30-minute infusion regimen in treatment of hospital acquired pneumonia (HAP) in intensive care unit (ICU) patients.. An open-label randomized controlled clinical trial was conducted. 100 HAP patients, admitted to ICU of Qilu Hospital of Shandong University, who needed meropenem therapy were enrolled from September 1st, 2012 to September 30th, 2013. The patients were randomly divided into two groups. Patients who did not conform to the study protocol were excluded. A total of 78 patients were included for the study of clinical efficacy evaluation, with 38 cases in study group, and 40 in control group. The patients in study group received intravenous 1 g of meropenem (dissolved in 40 mL saline) within 10 minutes, and followed by the remaining 750 mg by continuous intravenous infusion for 3 hours, and the treatment was repeated every 8 hours. The patients in control group received meropenem by injection of 1 g (dissolved in 40 mL saline), i.e. by intravenous infusion within 30 minutes every 8 hours. This regime was carried out for at least 7 days. Clinical efficacy, bacterial clearance rate, improvement of critical illness scoring, and safety were observed and compared after meropenem withdrawal between two groups.. Compared with control group, the clinical cure rate and 28-day survival rate in study group were significantly increased [clinical cure rate: 71.1% (27/38) vs. 42.5% (17/40), χ² = 6.461, P=0.011; survival rate: 81.6% (31/38) vs. 60.0% (24/40), χ² = 4.364, P=0.037]. The improvement of clinical pulmonary infection score (CPIS) and sequential organ failure assessment (SOFA) score in study group were more marked than those in control group (difference of CPIS score: -3.47 ± 2.48 vs. -1.50 ± 2.48, t=-3.513, P=0.001; difference of SOFA score: -2.10 ± 2.38 vs. -1.00 ± 2.21, t=-0.800, P=0.037). There were no significant differences in duration of meropenem treatment, acute physiology and chronic health evaluation II (APACHEII) score, procalcitonin (PCT), duration of mechanical ventilation, ICU stay days, secondary infection, and bacterial clearance rate between two groups. The main adverse reactions observed were transient elevation of liver enzymes and diarrhea in both groups, but no significant difference in their incidence was found between study and control groups [elevated liver enzymes: 28.9% (11/38) vs. 30.0% (12/40), χ² = 0.010, P=0.919; diarrhea: 7.9% (3/38) vs. 10.0% (4/40), χ² = 0.000, P=1.000].. Compared with conventional regime of 30-minute infusion of meropenem in the treatment of HAP in ICU patients, the clinical efficacy can be improved, the severity of the disease can be reduced, the recovery of organ failure and long-term prognosis can be improved with 3 hour extended infusion of meropenem.

Topics: Calcitonin; Calcitonin Gene-Related Peptide; Critical Illness; Humans; Infusions, Intravenous; Intensive Care Units; Meropenem; Pneumonia; Protein Precursors; Respiration, Artificial; Thienamycins; Time Factors

Pharmacokinetic changes have been found in critically ill patients, including ventilator-associated pneumonia (VAP) when compared with healthy volunteers leading to fluctuation of plasma concentrations.. To compare the probability of target attainment (PTA) and cumulative fraction of response (CFR) for meropenem between administration by a bolus injection and a 3-hour infusion.. The study was a randomized three-way crossover in nine patients with VAP. Each patient received meropenem in three regimens consecutively: (i) a bolus injection of 1 g every eight hours (q8h) for 24 hours; (ii) a 3-hour infusion of 1 g q8h for 24 hours; and (iii) a 3-hour infusion of 2 g q8h for 24 hours. The pharmacodynamic analysis of meropenem was performed to determine the PTA by using the Monte Carlo simulation and the study used susceptibility patterns obtained from EUCAST and MYSTIC for assessment of CFR.. For an MIC of 4 microg/ml, the PTAs achieving 40% T > MIC following a bolus injection of 1 g q8h, a 3-hour infusion of 1 g q8h, and a 3-hour infusion of 2 g q8h were 87.71%, 98.80%, and 99.90%, respectively. Only the 3-hour infusion regimens were predicted to achieve a CFR > or = 90% against E. coli, Klebsiella spp., P. aeruginosa, and Acinetobacter spp.. A 3-hour infusion of 2 g of meropenem regimen was predicted to have the highest PTA rates. Only the prolonged infusion regimens achieved a high CFR against E. coli, Klebsiella spp., P. aeruginosa, and Acinetobacter spp.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Critical Illness; Cross-Over Studies; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Injections; Male; Meropenem; Middle Aged; Monte Carlo Method; Pneumonia, Ventilator-Associated; Thienamycins; Treatment Outcome

The study aimed to characterize the pharmacokinetics (PK) of four β-lactams (piperacillin, ceftazidime, cefepime, and meropenem) in patients comedicated with amikacin (AMK), and to confirm the predictive performance of AMK data, obtained from therapeutic drug monitoring (TDM), on these PK, using a population modeling approach.. Serum samples were collected in 88 critically ill septic patients. For each β-lactam, the covariate model was optimized using renal function. Furthermore, predictive performance of AMK concentrations and PK parameters was assessed on β-lactam PK.. A two-compartment model with first-order elimination best fitted the β-lactam data. Results supported the superiority of AMK concentrations, over renal function and AMK PK parameters, to assess the β-lactam PK.. The study confirmed the significant link between the exposure to AMK and to β-lactams, and presented population models able to guide β-lactam dosage adjustments using renal biomarkers or TDM-related aminoglycoside data.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Amikacin; Anti-Bacterial Agents; beta-Lactams; Cefepime; Ceftazidime; Cephalosporins; Critical Illness; Drug Monitoring; Female; Humans; Male; Meropenem; Metabolic Clearance Rate; Middle Aged; Models, Biological; Piperacillin; Sepsis; Thienamycins; Tissue Distribution; Treatment Outcome

Meropenem bactericidal activity depends on the time when the free drug concentrations remain above the minimum inhibitory concentration of pathogens. The goal of this study was to compare clinical and bacteriological efficacy of continuous meropenem infusion versus bolus administration in critically ill patients with severe infection, and to evaluate the safety of both dosing regimens.. Patients admitted to the interdisciplinary Intensive Care Unit (ICU) who suffered from severe infections and received meropenem were randomized either in the Infusion group (n = 120) or in the Bolus group (n = 120). Patients in the Infusion group received a loading dose of 2 g of meropenem followed by a continuous infusion of 4 g of meropenem over 24 hours. Patients in the Bolus group were given 2 g of meropenem over 30 minutes every 8 hours. Clinical and microbiological outcome, safety, meropenem-related length of ICU and hospital stay, meropenem-related length of mechanical ventilation, duration of meropenem treatment, total dose of meropenem, and ICU and in-hospital mortality were assessed.. Clinical cure at the end of meropenem therapy was comparable between both groups (83.0% patients in the Infusion vs. 75.0% patients in the Bolus group; P = 0.180). Microbiological success rate was higher in the Infusion group as opposed to the Bolus group (90.6% vs. 78.4%; P = 0.020). Multivariate logistic regression identified continuous administration of meropenem as an independent predictor of microbiological success (OR = 2.977; 95% CI = 1.050 to 8.443; P = 0.040). Meropenem-related ICU stay was shorter in the Infusion group compared to the Bolus group (10 (7 to 14) days vs. 12 (7 to 19) days; P = 0.044) as well as shorter duration of meropenem therapy (7 (6 to 8) days vs. 8 (7 to 10) days; P = 0.035) and lower total dose of meropenem (24 (21 to 32) grams vs. 48 (42 to 60) grams; P < 0.0001). No severe adverse events related to meropenem administration in either group were observed.. Continuous infusion of meropenem is safe and, in comparison with higher intermittent dosage, provides equal clinical outcome, generates superior bacteriological efficacy and offers encouraging alternative of antimicrobial therapy in critically ill patients.

Topics: Adult; Anti-Bacterial Agents; Colony Count, Microbial; Critical Illness; Drug Administration Schedule; Female; Hospital Mortality; Humans; Infusions, Intravenous; Intensive Care Units; Male; Meropenem; Middle Aged; Prospective Studies; Thienamycins; Treatment Outcome

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 1g 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 24h. 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 1g q8h, a 3-h infusion of 1 g q8h and a 3-h infusion of 2g 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 8μg/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.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacteremia; Critical Illness; Escherichia coli; Female; Humans; Infusions, Intravenous; Injections, Intravenous; Klebsiella pneumoniae; Male; Meropenem; Middle Aged; Neutropenia; Thienamycins; Treatment Outcome; Young Adult

To compare the plasma and subcutaneous tissue concentration-time profiles of meropenem administered by intermittent bolus dosing or continuous infusion to critically ill patients with sepsis and without renal dysfunction, and to use population pharmacokinetic modelling and Monte Carlo simulations to assess the cumulative fraction of response (CFR) against Gram-negative pathogens likely to be encountered in critical care units.. We randomized 10 patients with sepsis to receive meropenem by intermittent bolus administration (n = 5; 1 g 8 hourly) or an equal dose administered by continuous infusion (n = 5). Serial subcutaneous tissue concentrations were determined using microdialysis and compared with plasma data for first-dose and steady-state pharmacokinetics. Population pharmacokinetic modelling of plasma data and Monte Carlo simulations were then undertaken with NONMEM.. It was found that continuous infusion maintains higher median trough concentrations, in both plasma (intermittent bolus 0 versus infusion 7 mg/L) and subcutaneous tissue (0 versus 4 mg/L). All simulated intermittent bolus, extended and continuous infusion dosing achieved 100% of pharmacodynamic targets against most Gram-negative pathogens. Superior obtainment of pharmacodynamic targets was achieved using administration by extended or continuous infusion against less susceptible Pseudomonas aeruginosa and Acinetobacter species.. This is the first study to compare the relative concentration-time data of bolus and continuous administration of meropenem at the subcutaneous tissue and plasma levels. We found that the administration of meropenem by continuous infusion maintains higher concentrations in subcutaneous tissue and plasma than by intermittent bolus dosing. Administration by extended or continuous infusion will achieve superior CFR against less-susceptible organisms in patients without renal dysfunction.

Topics: Acinetobacter Infections; Anti-Bacterial Agents; Critical Illness; Female; Humans; Male; Meropenem; Middle Aged; Models, Statistical; Monte Carlo Method; Plasma; Pseudomonas Infections; Sepsis; Subcutaneous Tissue; Thienamycins; Treatment Outcome

Meropenem is a carbapenem antibacterial frequently prescribed for the treatment of severe infections in critically ill patients, including those receiving continuous renal replacement therapy (CRRT). The objective of this study was to develop a population pharmacokinetic model of meropenem in critically ill patients undergoing CRRT.. A prospective, open-label study was conducted in 20 patients undergoing CRRT. Blood and dialysate-ultrafiltrate samples were obtained after administration of 500 mg, 1000 mg or 2000 mg of meropenem every 6 or 8 hours by intravenous infusion. The data were analysed under the population approach using NONMEM version V software. Age, bodyweight, dialysate plus ultrafiltrate flow, creatinine clearance (CL(CR)), the unbound drug fraction in plasma, the type of membrane, CRRT and the patient type (whether septic or severely polytraumatized) were the covariates studied.. The pharmacokinetics of meropenem in plasma were best described by a two-compartment model. CL(CR) was found to have a significant correlation with the apparent total clearance (CL) of the drug during the development of the covariate model. However, the influence of CL(CR) on CL differed between septic and polytraumatized patients (CL = 6.63 + 0.064 x CL(CR) for septic patients and CL = 6.63 + 0.72 x CL(CR) for polytraumatized patients). The volume of distribution of the central compartment (V(1)) was also dependent on the patient type, with values of 15.7 L for septic patients and 69.5 L for polytraumatized patients. The population clearance was 15 L/h, and the population apparent volume of distribution of the peripheral compartment was 19.8 L. From the base to the final model, the interindividual variabilities in CL and the V(1) were significantly reduced. When computer simulations were carried out and efficacy indexes were calculated, it was shown that polytraumatized patients and septic patients with conserved renal function may not achieve adequate efficacy indexes to deal with specific infections. Continuous infusion of meropenem is recommended for critically septic patients and polytraumatized patients when pathogens with a minimum inhibitory concentration (MIC) of > or =4 mg/L are isolated. Infections caused by pathogens with an MIC of > or =8 mg/L should not be treated with meropenem in polytraumatized patients without or with moderate renal failure because excessive doses of meropenem would be necessary.. A population pharmacokinetic model of meropenem in intensive care patients undergoing CRRT was developed and validated. CL(CR) and the patient type (whether septic or polytraumatized) were identified as significant covariates. The population pharmacokinetic model developed in the present study has been employed to recommend continuous infusion protocols in patients treated with CRRT.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Creatinine; Critical Illness; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Meropenem; Middle Aged; Models, Biological; Prospective Studies; Renal Replacement Therapy; Thienamycins; Tissue Distribution

To evaluate and compare the pharmacokinetic profiles of imipenem and meropenem in a population of critically ill patients with sepsis to find possible differences that may help in selecting the most appropriate drug and/or dosage in order to optimise empiric antimicrobial therapy.. This was a single-centre, randomised, nonblind study of the pharmacokinetics of both intravenous imipenem 1g and meropenem 1g in 20 patients admitted to an intensive care unit with sepsis in whom antimicrobial therapy was indicated on clinical grounds. Patients were divided into two groups: group I received intravenous imipenem 1g plus cilastatin 1g, and group II received intravenous meropenem 1g over 30 minutes. Peripheral blood samples were collected at 0, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4, 6 and 8 hours after the first dose and were centrifuged for 10 minutes at 4 masculineC. Urine samples were collected during the 8 hours after antimicrobial administration at 2-hour intervals: 0-2, 2-4, 4-6 and 6-8 hours. The total volume of urine was recorded; the serum and urine samples were immediately frozen and stored at -80 masculineC until assayed. Pharmacokinetic analysis was carried out through computerised programs using the least-square regression method and a two-compartment open model. Statistical differences were evaluated by means of one-way ANOVA.. The following pharmacokinetic differences between the two drugs were observed: the imipenem mean peak serum concentration was significantly higher than for meropenem (90.1 +/- 50.9 vs 46.6 +/- 14.6 mg/L, p < 0.01); the area under the serum concentration-time curve was significantly higher for imipenem than for meropenem (216.5 +/- 86.3 vs 99.5 +/- 23.9 mg . h/L, p < 0.01), while the mean volume of distribution and mean total clearance were significantly higher for meropenem than for imipenem (25 +/- 4.1 vs 17.4 +/- 4.5L, p < 0.01 and 191 +/- 52.2 vs 116.4 +/- 42.3 mL/min, p < 0.01, respectively).. The more favourable pharmacokinetic profile of imipenem compared with meropenem in critically ill patients with sepsis might balance the possibly greater potency demonstrated in vitro for meropenem against Gram-negative strains. Hence, the clinical efficacy of the two carbapenems depends mostly on their correct dosage.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Area Under Curve; Critical Illness; Female; Humans; Imipenem; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Sepsis; Thienamycins

In patients with acute renal failure, the pharmacokinetics of meropenem depend on the operational characteristics of the renal replacement therapy. Dosage recommendations are based on the correlation of plasma levels with pharmacodynamic requirements.. Eight critically ill patients with acute renal failure were treated by continuous veno-venous hemofiltration with a filtrate flow of 1,600 ml/h and received 500 mg of meropenem every 12 h. Plasma and hemofiltrate concentrations of meropenem at steady state were determined by HPLC.. Peak levels in plasma amounted to 39.5 +/- 10.5 mg/l (mean +/- SD) and trough levels were 2.4 +/- 1.5 mg/l. The minimal inhibitory concentration (MIC) for susceptible bacteria (4 mg/l) was covered for 40% of the dosing interval or longer in all patients. The MIC for intermediately susceptible organisms (8 mg/l) was covered for 33% in 6 of the 8 patients. The elimination half-life was prolonged to 3.63 +/- 0.77 h. The sieving coefficient of meropenem was 0.91 +/- 0.10 and the recovery in hemofiltrate amounted to 30.9 +/- 11.5% of the dose.. A dosage of 500 mg twice daily provides appropriate serum levels for the treatment of infections caused by susceptible bacteria. A higher dosage is adequate for infections by intermediately susceptible bacteria or for renal replacement therapies with markedly higher filtrate flow rates.

Topics: Acute Kidney Injury; Aged; Bacterial Infections; Critical Illness; Drug Administration Schedule; Female; Half-Life; Hemofiltration; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Thienamycins

The pharmacokinetics and pharmacodynamics of meropenem were investigated in 14 critically ill patients with sepsis. Patients with creatinine clearance (CrCl) higher than 50 ml/min received 1 g meropenem three times daily (Group I) and patients with CrCl lower than 50 ml/min received 1 g meropenem twice daily (Group II). Meropenum concentrations in plasma were determined by high performance liquid chromatography with UV detection. The pharmacokinetic parameters differed between the two groups as follows, Group I, maximal concentration 56.3 +/- 19.1 microg/ml; trough concentration 3.3 +/- 2.5 microg/ml; elimination half life 2.5 +/- 1.2 h; clearance (Cl) 155.8 +/- 40.6 ml/min; MRT 2.2 +/- 0.4 h; steady state volume of distribution (V(ss)) 21.7 +/- 5.7 l, and AUC(-8) 119.4 +/- 32.6 microg/ml h. Group II, maximal concentration 71.1 +/- 5.1 microg/ml; trough concentration 3.4 +/- 1.8 microg/ml; elimination half life 3.9 +/- 1.6 h; Cl 77.7 +/- 15.8 ml/min; MRT 3.5 +/- 0.6 h; V(ss), 17.1 +/- 2.1 l, and AUC(0-12) 230.2 +/- 43.3 microg/ml h. The most frequently isolated bacteria from blood and wound infections were Acinetobacter baumanii, Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli; their meropenem minimal inhibitory concentrations (MICs) ranged from 0.064 to 3.0 mg/l. In most cases the pharmacodynamic parameters, measured as T>MIC index, were higher than 75%. In both groups, patients with susceptible pathogens (MIC<1 mg/l) had meropenem plasma levels which exceeded the MIC for the whole dosing interval. When pathogens were highly resistant (A. baumanii or P. aeruginosa) the T>MIC indices were lower.

Topics: Aged; Creatinine; Critical Illness; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Sepsis; Thienamycins

To study the pharmacokinetics of meropenem in critically ill patients with acute renal failure receiving continuous venovenous hemofiltration (CWHF).. Prospective, open-labeled study.. Medical intensive care unit of the University Medical Center Utrecht.. Five critically ill patients receiving CWHF for acute renal failure treated with meropenem for documented or suspected bacterial infection.. All patients received meropenem (500 mg) administered intravenously every 12 hrs. Plasma samples and ultrafiltrate aliquots were collected during one dosing interval.. Mean age and body weight of the patients studied were 46.6 yrs (range, 28-61 yrs) and 85.8 kg (range, 70-100 kg), respectively. The following pharmacokinetic variables for meropenem were obtained: mean peak plasma concentration was 24.5 +/- 7.2 mg/L, mean trough plasma concentration was 3.0 +/- 0.9 mg/L, mean terminal elimination half-life was 6.37 +/- 1.96 hrs, mean total plasma clearance was 4.57 +/- 0.89 L/hr, mean CWHF clearance was 1.03 +/- 0.42 L/hr, mean nonrenal clearance was 3.54 +/- 1.06 L/hr, and mean volume of distribution was 0.37 +/- 0.15 L/kg.. In critically ill patients with acute renal failure, nonrenal clearance became the main elimination route. CWHF substantially contributed to the clearance of meropenem (23% of mean total plasma clearance). We recommend meropenem to be dosed at 500 mg intravenously every 12 hrs in patients receiving CWHF, according to our operational characteristics. This dosing regimen resulted in adequate trough plasma levels for susceptible microorganisms.

Topics: Acute Kidney Injury; Adult; Bacterial Infections; Critical Illness; Drug Monitoring; Female; Hemofiltration; Humans; Infusions, Intravenous; Least-Squares Analysis; Male; Meropenem; Metabolic Clearance Rate; Middle Aged; Prospective Studies; Thienamycins; Time Factors; Tissue Distribution

This prospective crossover study compared the pharmacokinetics of meropenem by continuous infusion and by intermittent administration in critically ill patients. Fifteen patients were randomized to receive meropenem either as a 2 g iv loading dose, followed by a 3 g continuous infusion (CI) over 24 h, or by intermittent administration (IA) of 2 g iv every 8 h (q8h). Each regimen was followed for a period of 2 days, succeeded by crossover to the alternative regimen for the same period. Pharmacokinetic parameters (mean +/- SD) of CI included the following: concentration at steady state (Css) was 11.9+/-5.0 mg/L; area under the curve (AUC) was 117.5+/-12.9 mg/L x h. The maximum and minimum serum concentrations of meropenem (Cmax, Cmin) and total meropenem clearance (CItot) for IA were 110.1+/-6.9 mg/L, 8.5+/-1.0 mg/L and 9.4+/-1.2 L/h, respectively. The AUC during the IA regimen was larger than the AUC during CI (P < 0.001). In both treatment groups, meropenem serum concentrations remained above the MICs for the most common bacterial pathogens. We conclude that CI of meropenem is equivalent to the IA regimen and is therefore suitable for treating critically ill patients. Further studies are necessary to compare the clinical effects of CI and IA in this patient group.

Topics: Adolescent; Adult; Aged; Bacterial Infections; Critical Illness; Cross-Over Studies; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Intensive Care Units; Male; Meropenem; Middle Aged; Pneumonia; Sepsis; Thienamycins

The Seraph® 100 Microbind® Affinity Blood Filter (Seraph 100) is a hemoperfusion device that can remove pathogens from central circulation. However, the effect of Seraph 100 on achieving pharmacodynamic (PD) targets is not well described. We sought to determine the impact of Seraph 100 on ability to achieve PD targets for commonly used antibiotics.. Estimates of Seraph 100 antibiotic clearance were obtained via literature. For vancomycin and gentamicin, published pharmacokinetic models were used to explore the effect of Seraph 100 on ability to achieve probability of target attainment (PTA). For meropenem and imipenem, the reported effect of continuous kidney replacement therapy (CKRT) on achieving PTA was used to extrapolate decisions for Seraph 100.. Seraph 100 antibiotic clearance is likely less than 0.5 L/h for most antibiotics. Theoretical Seraph 100 clearance up to 0.5 L/h and 2 L/h had a negligible effect on vancomycin PTA in virtual patients with creatinine clearance (CrCl) = 14 mL/min and CrCl >14 mL/min, respectively. Theoretical Seraph 100 clearance up to 0.5 L/h and 2 L/h had a negligible effect on gentamicin PTA in virtual patients with CrCl = 120 mL/min and CrCl <60 mL/min, respectively. CKRT intensity resulting in antibiotic clearance up to 2 L/h generally does not require dose increases for meropenem or imipenem. As Seraph 100 is prescribed intermittently and likely contributes far less to antibiotic clearance, dose increases would also not be required.. Seraph 100 clearance of vancomycin, gentamicin, meropenem, and imipenem is likely clinically insignificant. There is insufficient evidence to recommend increased doses. For aminoglycosides, we recommend extended interval dosing and initiating Seraph 100 at least 30 min to 1 h after completion of infusion to avoid the possibility of interference with maximum concentrations.

Topics: Anti-Bacterial Agents; Critical Illness; Gentamicins; Hemoperfusion; Humans; Imipenem; Meropenem; Vancomycin

Creatinine clearance (CCr) and pharmacokinetic parameters are markedly affected by pathophysiological changes in patients with sepsis. However, only a few reports have assessed renal function in patients with sepsis using the measured CCr. Furthermore, the administration regimen has not been sufficiently evaluated using a population PK (PPK) model across renal function broad ranges. Therefore, this study was performed to construct a meropenem PPK model for patients with sepsis using the measured CCr and evaluate the optimized meropenem dosing regimen based on the CCr.. Patients with sepsis who received intravenous meropenem at the Showa University Hospital were enrolled in this prospective observational study. The PPK model was constructed using blood samples and clinical information of patients. The probability of target attainment (PTA) indicates the likelihood of achieving 50% time above the minimum inhibitory concentration (% T > MIC) based on 10,000 virtual patients using Monte Carlo simulations. The PTA for each meropenem regimen was 50% T > MIC based on different renal functions using the Monte Carlo simulation.. One hundred samples were collected from 31 patients. The final PPK model incorporating the measured CCr as a covariate in CL displayed the best fit. The recommended dosing regimen to achieve a PTA of 50% T > MIC of 4 mcg/mL was 1 g every 8 hours as a 3-hour prolonged infusion for patients with CCr 85-130 mL/min and 1 g every 8 hours as an 8-hour continuous infusion for patients with CCr ≥ 130 mL/min.. This model precisely predicted meropenem concentrations in patients with sepsis by accurately evaluating renal function using the measured CCr. Extended dosing was demonstrated to be necessary to achieve a PTA of 50% T > MIC for patients with CCr ≥ 85 mL/min. Meropenem effectiveness can be maximized in patients with sepsis by selecting the appropriate dosing regimen based on renal function and the MIC.

Topics: Anti-Bacterial Agents; Creatinine; Critical Illness; Humans; Meropenem; Microbial Sensitivity Tests; Sepsis; Thienamycins

Meropenem is a wide inter-individual variability in the pharmacokinetic, and standard dosing may not be adequate in critically ill patients. Therapeutic drug monitoring is a useful tool to optimize dosing. Meropenem is the amphoteric compound with an isoelectric point of 5.15. The secondary amino group of meropenem is positively charged when pH ≤ 5.4, thus we attempted to separate by strong cation exchange (SCX) column using acetonitrile/25-mM potassium dihydrogen phosphate (pH 3.0; 60:40) as mobile phase, and good peak shape and effective separation obtained. Generally, meropenem were unstable in plasma. We try to investigate stability of plasma samples using the medium QC sample with or without 3-(N-morpholino) propanesulfonic acid (MOPS) as stabilizer solutions at possible conditions during handling and storage. Meropenem showed higher stability at -80°C, and addition of MOPS might increase the short-term and extracted samples stability. This method is suitable for the quantification of meropenem in human plasma from 0.5 to 100 μg/mL. The accuracy was ranged from 96.53 to 101.11% with relative standard deviation ≤ 4.76%. The method has been used for determined 63 critically ill patients treated with meropenem. During the first measurement, 11 patients showed trough levels below the target ranges despite standard dosing. Through continuous or prolonged infusion, 8/11 patients (72.73%) led to adequate trough levels. The described SCX-high-performance liquid chromatography method for meropenem in human plasma is a powerful tool for therapeutic drug monitoring.

Topics: Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Critical Illness; Drug Monitoring; Humans; Meropenem

The aim of this study was to assess the pharmacokinetic (PK) exposure and clinical toxicity for three beta-lactams: cefotaxime, piperacillin/tazobactam, and meropenem, depending on two lengths of infusion: continuous and intermittent, in critically ill children. This single center observational prospective study was conducted in a pediatric intensive care unit. All hospitalized children who had one measured plasma concentration of the investigated antibiotics were included. Plasma antibiotic concentrations were interpreted by a pharmacologist, using a Bayesian approach based on previously published population pharmacokinetic models in critically ill children. Exposure was considered optimal, low, or high according to the PK target 100% fT. CI provided a higher probability to attain an optimal PK target compared to II, but also a higher risk for overexposure. Regular therapeutic drug monitoring is recommended in critically ill children receiving beta-lactams, regardless of the length of infusion.. • Since beta-lactams are time-dependent antibiotics, the probability to attain the pharmacokinetic target is higher with continuous infusion compared to that with intermittent infusion. • In daily practice, continuous or extended infusions are rarely used despite recent guidelines, and toxicity is hardly reported.. • Continuous infusion provided a higher probability to attain an optimal pharmacokinetic target compared to intermittent infusion, but also a higher risk of overexposure. • Regular therapeutic drug monitoring is recommended in critically ill children receiving beta-lactams, regardless of the length of infusion.

Topics: Anti-Bacterial Agents; Bayes Theorem; beta-Lactams; Cefotaxime; Child; Critical Illness; Humans; Infusions, Intravenous; Meropenem; Piperacillin; Prospective Studies

Critically ill patients with sepsis are predisposed to physiological changes that can reduce the probability of achieving target antibiotic exposures. Precision dosing software programs may be used to improve probability of obtaining these target exposures.. To quantify the accuracy of a precision dosing software program for predicting antibiotic concentrations as well as to assess the impact of using software predictions on actual dosing adjustments.. The software program ID-ODS was used to predict concentrations for piperacillin, meropenem and vancomycin using patient covariate data with and without the use of therapeutic drug monitoring (TDM) data. The impact of these predictions on actual dosage adjustments was determined by using software predicted concentrations versus measured concentrations.. Software predictions for piperacillin and meropenem exhibited large bias that improved with the addition of TDM data (bias improved from -28.8 to -2.0 mg/L for piperacillin and -3.0 to -0.1 mg/L for meropenem). Dosing changes using predicted concentrations of piperacillin and meropenem with TDM data versus measured concentrations were matched on 89.2% (107/120) and 71% (9/69) occasions, respectively. Although vancomycin predictions demonstrated good accuracy with and without TDM, these findings were limited by our small sample size.. These data demonstrate that precision dosing software programs may have scope to reasonably predict antibiotic concentrations in critically ill patients with sepsis. The addition of TDM data improves the predictive performance of the software for all three antibiotics and the ability to anticipate the correct dose change required.

Topics: Anti-Bacterial Agents; Critical Illness; Drug Monitoring; Humans; Meropenem; Piperacillin; Sepsis; Software; Vancomycin

The aim of this study was to compare the achievement of therapeutic pharmacokinetic-pharmacodynamic (PK-PD) exposure targets for beta-lactam antibiotics using product information dosing or guideline-based dosing for the treatment of serious infections.. In silico study.. ID-ODS. None.. In silico product information and guideline-based dosing simulations for cefepime, ceftazidime, flucloxacillin, meropenem, and piperacillin/tazobactam were performed using pharmacokinetic models from seriously ill patient populations. The median simulated concentration at 48 and 96 h was used to measure the probability of target attainment (PTA) to achieve predefined therapeutic and toxicity PK-PD targets. A multiple linear regression model was constructed to identify the effect of guideline-based dosing covariates on achieving pre-defined therapeutic targets. In total, 480 dosing simulations were performed. The PTA percentage with guideline-based dosing at 48 and 96 h was 80% and 68%, respectively, yielding significantly higher results when compared to product information dosing (48.45% and 49%, respectively), p < 0.001 at both time points. At 48 h, predefined toxicity thresholds were exceeded in 4.7% and 0% of simulations for guideline-based and product information-based dosing, respectively (p = 0.002). eGFR was significantly associated with the % PTA by guideline-based dosing, with eGFR values of 20 and 50 ml/min both statistically significant in leading to an increase in PTA.. Our study demonstrated that achievement of PK-PD exposures associated with an increased likelihood of effectiveness was more likely to occur with guideline-based dosing; especially at 48 h.

Topics: Adult; Anti-Bacterial Agents; Cefepime; Ceftazidime; Critical Illness; Humans; Lactams; Meropenem; Microbial Sensitivity Tests

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.

Topics: Anti-Bacterial Agents; Bayes Theorem; Creatinine; Critical Illness; Humans; Intensive Care Units; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method; Prospective Studies

To evaluate the association between early and cumulative beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) parameters and therapy outcomes in bloodstream infection (BSI).. Early and cumulative achievement of fT

Topics: Adult; Anti-Bacterial Agents; beta-Lactams; Critical Illness; Humans; Meropenem; Microbial Sensitivity Tests; Middle Aged; Piperacillin, Tazobactam Drug Combination; Sepsis

Evidence regarding acute kidney injury associated with concomitant administration of vancomycin and piperacillin-tazobactam is conflicting, particularly in patients in the ICU.. Does a difference exist in the association between commonly prescribed empiric antibiotics on ICU admission (vancomycin and piperacillin-tazobactam, vancomycin and cefepime, and vancomycin and meropenem) and acute kidney injury?. This was a retrospective cohort study using data from the eICU Research Institute, which contains records for ICU stays between 2010 and 2015 across 335 hospitals. Patients were enrolled if they received vancomycin and piperacillin-tazobactam, vancomycin and cefepime, or vancomycin and meropenem exclusively. Patients initially admitted to the ED were included. Patients with hospital stay duration of < 1 h, receiving dialysis, or with missing data were excluded. Acute kidney injury was defined as Kidney Disease: Improving Global Outcomes stage 2 or 3 based on serum creatinine component. Propensity score matching was used to match patients in the control (vancomycin and meropenem or vancomycin and cefepime) and treatment (vancomycin and piperacillin-tazobactam) groups, and ORs were calculated. Sensitivity analyses were performed to study the effect of longer courses of combination therapy and patients with renal insufficiency on admission.. Thirty-five thousand six hundred fifty-four patients met inclusion criteria (vancomycin and piperacillin-tazobactam, n = 27,459; vancomycin and cefepime, n = 6,371; vancomycin and meropenem, n = 1,824). Vancomycin and piperacillin-tazobactam was associated with a higher risk of acute kidney injury and initiation of dialysis when compared with that of both vancomycin and cefepime (Acute kidney injury: OR, 1.37 [95% CI, 1.25-1.49]; dialysis: OR, 1.28 [95% CI, 1.14-1.45]) and vancomycin and meropenem (Acute kidney injury: OR, 1.27 [95%, 1.06-1.52]; dialysis: OR, 1.56 [95% CI, 1.23-2.00]). The odds of acute kidney injury developing was especially pronounced in patients without renal insufficiency receiving a longer duration of vancomycin and piperacillin-tazobactam therapy compared with vancomycin and meropenem therapy.. VPT is associated with a higher risk of acute kidney injury than both vancomycin and cefepime and vancomycin and meropenem in patients in the ICU, especially for patients with normal initial kidney function requiring longer durations of therapy. Clinicians should consider vancomycin and meropenem or vancomycin and cefepime to reduce the risk of nephrotoxicity for patients in the ICU.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Cefepime; Critical Illness; Drug Therapy, Combination; Humans; Meropenem; Piperacillin; Piperacillin, Tazobactam Drug Combination; Retrospective Studies; Vancomycin

Critically ill patients undergoing continuous renal replacement therapy (CRRT) have medical conditions requiring extensive pharmacotherapy. Continuous renal replacement therapy impacts drug disposition. Few data exist regarding drug dosing requirements with contemporary CRRT modalities and effluent rates. The practical limitations of pharmacokinetic studies requiring numerous plasma and effluent samples, and lack of generalizability of observations from specific CRRT prescriptions, highlight gaps in bedside assessment of CRRT drug elimination and individualized dosing needs. We employed a porcine model using transdermal fluorescence detection of the glomerular filtration rate fluorescent tracer agent MB-102, with the aim to assess the relationship between systemic exposure of MB-102 and meropenem during CRRT. Animals underwent bilateral nephrectomies and received intravenous bolus doses of MB-102 and meropenem. Once MB-102 equilibrated in the animal, CRRT was initiated. Continuous renal replacement therapy prescriptions comprised four combinations of blood pump (low versus high) and effluent (low versus high) flow rates. Changes in transdermal detected MB-102 clearance occurred immediately with a change in CRRT rates. Blood side meropenem clearance mirrored transdermal MB-102 clearance ( r2 : 0.95-0.97, p value all <0.001). We suggest transdermal MB-102 clearance provides real-time personalized assessment of drug elimination and could optimize prescription of drugs for critically ill patients requiring CRRT.

Topics: Animals; Anti-Bacterial Agents; Continuous Renal Replacement Therapy; Critical Illness; Meropenem; Renal Replacement Therapy; Swine

The altered pharmacokinetics of renally cleared drugs such as meropenem in critically ill patients receiving continuous renal replacement therapy (CRRT) might impact target attainment. Model-informed precision dosing (MIPD) is applied to individualize meropenem dosing. However, most population pharmacokinetic (PopPK) models developed to date have not yet been evaluated for MIPD. Eight PopPK models based on adult CRRT patients were identified in a systematic literature research and encoded in NONMEM 7.4. A data set of 73 CRRT patients from two different study centers was used to evaluate the predictive performance of the models using simulation and prediction-based diagnostics for i)

Topics: Adult; Anti-Bacterial Agents; Bayes Theorem; Continuous Renal Replacement Therapy; Critical Illness; Humans; Meropenem; Renal Replacement Therapy

To demonstrate the feasibility of continuous infusion of meropenem-vaborbactam to optimize the treatment of carbapenem-resistant Enterobacterales.. Report of a case of a Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae bloodstream infection comfirmed by whole genome sequencing and therapeutic drug monitoring (TDM) of meropenem.. A patient with augmented renal clearance (ARC) went into septic shock caused by an ST11 KPC-3-producing K. pneumoniae bloodstream infection that was successfully treated with a continuous infusion of meropenem-vaborbactam at a dosage of 1 g/1 g q4h as a 4-h infusion. TDM confirmed sustained concentrations of meropenem ranging from 8 to 16 mg/L throughout the dosing interval.. Continuous infusion of meropenem-vaborbactam was feasible. It could be appropriate for optimizing the management of critically ill patients with ARC, as it resulted in antibiotic concentrations above the minimum inhibitory concentration for susceptible carbapenem-resistant Enterobacterales (up to 8 mg/L) throughout the dosing interval.

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Critical Illness; Drug Combinations; Humans; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Sepsis

Meropenem is a widely prescribed β-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes.. To determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis.. A double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022.. Patients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304).. The primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events.. All 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96 [95% CI, 0.81-1.13], P = .60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients).. In critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28.. ClinicalTrials.gov Identifier: NCT03452839.

Topics: Anti-Bacterial Agents; Critical Illness; Double-Blind Method; Female; Humans; Hypersensitivity; Male; Meropenem; Middle Aged; Monobactams; Sepsis; Shock, Septic

In recent years, numerous dosing studies have been conducted to optimize therapeutic antibiotic exposures in patients with serious infections. These studies have led to the inclusion of dose optimization recommendations in international clinical practice guidelines. The last international survey describing dosing, administration and monitoring of commonly prescribed antibiotics for critically ill patients was published in 2015 (ADMIN-ICU 2015). This study aimed to describe the evolution of practice since this time.. A cross-sectional international survey distributed through professional societies and networks was used to obtain information on practices used in the dosing, administration and monitoring of vancomycin, piperacillin/tazobactam, meropenem and aminoglycosides.. A total of 538 respondents (71% physicians and 29% pharmacists) from 409 hospitals in 45 countries completed the survey. Vancomycin was mostly administered as an intermittent infusion, and loading doses were used by 74% of respondents with 25 mg/kg and 20 mg/kg the most favoured doses for intermittent and continuous infusions, respectively. Piperacillin/tazobactam and meropenem were most frequently administered as an extended infusion (42% and 51%, respectively). Therapeutic drug monitoring was undertaken by 90%, 82%, 43%, and 39% of respondents for vancomycin, aminoglycosides, piperacillin/tazobactam, and meropenem, respectively, and was more frequently performed in high-income countries. Respondents rarely used dosing software to guide therapy in clinical practice and was most frequently used with vancomycin (11%).. We observed numerous changes in practice since the ADMIN-ICU 2015 survey was conducted. Beta-lactams are more commonly administered as extended infusions, and therapeutic drug monitoring use has increased, which align with emerging evidence.

Topics: Adult; Aminoglycosides; Anti-Bacterial Agents; Critical Illness; Cross-Sectional Studies; Humans; Intensive Care Units; Meropenem; Piperacillin; Piperacillin, Tazobactam Drug Combination; Surveys and Questionnaires; Vancomycin

Antibiotics are among the most utilized drugs in pediatrics. Nonetheless, there is a lack in pharmacokinetics information for this population, and dosing criteria may vary between healthcare centers. Physiological variability associated with maturation in pediatrics makes it challenging to reach a consensus on adequate dosing, which is further accentuated in more vulnerable groups, such as critically ill or oncology patients. Model-informed precision dosing is a useful practice that allows dose optimization and attainment of antibiotic-specific pharmacokinetic/pharmacodynamic targets. The aim of this study was to evaluate the needs of model-informed precision dosing of antibiotics in a pediatrics unit, at a pilot scale. Pediatric patients under antibiotic treatment were monitored with either a pharmacokinetic/pharmacodynamic optimized sampling scheme or through opportunistic sampling. Clindamycin, fluconazole, linezolid, meropenem, metronidazole, piperacillin, and vancomycin plasma concentrations were quantified through a liquid chromatography coupled to mass spectrometry method. Pharmacokinetic parameters were estimated using a Bayesian approach to verify pharmacokinetic/pharmacodynamic target attainment. A total of 23 pediatric patients aged 2 to 16 years were included, and 43 dosing regimens were evaluated; 27 (63%) of them required adjustments as follows: 14 patients were underdosed, 4 were overdosed, and 9 patients needed infusion rate adjustments. Infusion rate adjustments were mostly recommended for piperacillin and meropenem; daily doses were augmented for vancomycin and metronidazole, meanwhile linezolid was adjusted for under- and overdosing. Clindamycin and fluconazole regimens were not adjusted at all.  Conclusion: Results showcase a lack of antibiotic pharmacokinetic/pharmacodynamic target attainment (particularly for linezolid, vancomycin, meropenem, and piperacillin), and the need for model-informed precision dosing in pediatrics. This study provides pharmacokinetic evidence which can further improve antibiotic dosing practices. What is Known: • Model-informed precision dosing is performed in pediatrics to optimize the treatment of antimicrobial drugs such as vancomycin and aminoglycosides, while its usefulness is debated for other groups (beta-lactams, macrolides, etc.). What is New: • Vulnerable pediatric subpopulations, such as critically ill or oncology patients, can benefit the most from model-informed precision dosing of antibiotics.

Topics: Anti-Bacterial Agents; Bayes Theorem; Child; Clindamycin; Critical Illness; Fluconazole; Humans; Linezolid; Meropenem; Metronidazole; Neoplasms; Piperacillin; Vancomycin

It is well documented that inappropriate use of antimicrobials is the major driver of antimicrobial resistance. To combat this, antibiotic stewardship has been demonstrated to reduce antibiotic usage, decrease the prevalence of resistance, lead to significant economic gains and better patients' outcomes. In Nigeria, antimicrobial guidelines for critically ill patients in intensive care units (ICUs), with infections are scarce. We set out to develop antimicrobial guidelines for this category of patients.. A committee of 12 experts, consisting of Clinical Microbiologists, Intensivists, Infectious Disease Physicians, Surgeons, and Anesthesiologists, collaborated to develop guidelines for managing infections in critically ill patients in Nigerian ICUs. The guidelines were based on evidence from published data and local prospective antibiograms from three ICUs in Lagos, Nigeria. The committee considered the availability of appropriate antimicrobial drugs in hospital formularies. Proposed recommendations were approved by consensus agreement among committee members.. Candida albicans and Pseudomonas aeruginosa were the most common microorganisms isolated from the 3 ICUs, followed by Klebsiella pneumoniae, Acinetobacter baumannii, and Escherichia coli. Targeted therapy is recognized as the best approach in patient management. Based on various antibiograms and publications from different hospitals across the country, amikacin is recommended as the most effective empiric antibiotic against Enterobacterales and A. baumannii, while colistin and polymixin B showed high efficacy against all bacteria. Amoxicillin-clavulanate or ceftriaxone was recommended as the first-choice drug for community-acquired (CA) CA-pneumonia while piperacillin-tazobactam + amikacin was recommended as first choice for the treatment of healthcare-associated (HA) HA-pneumonia. For ventilatorassociated pneumonia (VAP), the consensus for the drug of first choice was agreed as meropenem. Amoxycillin-clavulanate +clindamycin was the consensus choice for CAskin and soft tissue infection (SSIS) and piperacillin-tazobactam + metronidazole ±vancomycin for HA-SSIS. Ceftriaxone-tazobactam or piperacillin-tazobactam + gentamicin was consensus for CA-blood stream infections (BSI) with first choice+regimen for HA-BSI being meropenem/piperacillin-tazobactam +amikacin +fluconazole. For community-acquired urinary tract infection (UTI), first choice antibiotic was ciprofloxacin or ceftriaxone with a catheter-associated UTI (CAUTI) regimen of first choice being meropenem + fluconazole.. Data from a multicenter three ICU surveillance and antibiograms and publications from different hospitals in the country was used to produce this evidence-based Nigerian-specific antimicrobial treatment guidelines of critically ill patients in ICUs by a group of experts from different specialties in Nigeria. The implementation of this guideline will facilitate learning, continuous improvement of stewardship activities and provide a baseline for updating of guidelines to reflect evolving antibiotic needs.. Il est bien établi que l’utilisation inappropriée des antimicrobiens est le principal moteur de la résistance aux antimicrobiens. Pour lutter contre ce phénomène, il a été démontré que la bonne gestion des antibiotiques permettait de réduire l’utilisation des antibiotiques, de diminuer la prévalence de la résistance, de réaliser des gains économiques significatifs et d’améliorer les résultats pour les patients. Au Nigéria, les directives antimicrobiennes pour les patients gravement malades dans les unités de soins intensifs (USI), souffrant d’infections, sont rares. Nous avons entrepris d’élaborer des lignes directrices sur les antimicrobiens pour cette catégorie de patients.. Un comité de 12 experts, composé de microbiologistes cliniques, d’intensivistes, de médecins spécialistes des maladies infectieuses, de chirurgiens et d’anesthésistes, a collaboré à l’élaboration de lignes directrices pour la prise en charge des infections chez les patients gravement malades dans les unités de soins intensifs nigérianes. Les lignes directrices sont basées sur des données publiées et des antibiogrammes prospectifs locaux provenant de trois unités de soins intensifs de Lagos, au Nigeria. Le comité a pris en compte la disponibilité des médicaments antimicrobiens appropriés dans les formulaires des hôpitaux. Les recommandations proposées ont été approuvées par consensus entre les membres du comité.. Candida albicans et Pseudomonas aeruginosa étaient les microorganismes les plus fréquemment isolés dans les trois unités de soins intensifs, suivis par Klebsiella pneumoniae, Acinetobacter baumannii et Escherichia coli. La thérapie ciblée est reconnue comme la meilleure approche pour la prise en charge des patients. Sur la base de divers antibiogrammes et publications provenant de différents hôpitaux du pays, l'amikacine est recommandée comme l'antibiotique empirique le plus efficace contre les entérobactéries et A. baumannii, tandis que la colistine et la polymixine B se sont révélées très efficaces contre toutes les bactéries. L'amoxicilline-clavulanate ou la ceftriaxone ont été recommandées comme médicaments de premier choix pour les pneumonies communautaires, tandis que la pipéracilline-tazobactam + amikacine ont été recommandées comme médicaments de premier choix pour le traitement des pneumonies associées aux soins. Pour les pneumonies acquises sous ventilation mécanique (PAV), le consensus sur le médicament de premier choix est le méropénem. L'amoxycilline-clavulanate +clindamycine était le choix consensuel pour les infections de la peau et des tissus mous et la pipéracilline-tazobactam + métronidazole ±vancomycine pour les infections de la peau et des tissus mous. HA-SSIS. Ceftriaxone-tazobactam ou pipéracilline-tazobactam + gentamicine a fait l'objet d'un consensus pour les infections de la circulation sanguine de l'AC (BSI), le premier choix de régime pour les HA-BSI étant le méropénem/pipéracilline-tazobactam +amikacine +fluconazole. Pour les infections urinaires communautaires, l'antibiotique de premier choix était la ciprofloxacine ou la ceftriaxone, le régime de premier choix pour les infections urinaires associées à un cathéter étant le meropenem +fluconazole.. Les données issues d’une surveillance multicentrique de trois unités de soins intensifs, d’antibiogrammes et de publications de différents hôpitaux du pays ont été utilisées par un groupe d’experts de différentes spécialités nigérianes pour élaborer ces lignes directrices sur le traitement antimicrobien des patients gravement malades dans les unités de soins intensifs, fondées sur des données probantes et spécifiques au Nigeria. La mise en œuvre de ces lignes directrices facilitera l’apprentissage, l’amélioration continue des activités de gestion et fournira une base de référence pour la mise à jour des lignes directrices afin de refléter l’évolution des besoins en antibiotiques.. Antimicrobiens, Résistance aux antimicrobiens, Gestion des antibiotiques, Lignes directrices, Soins intensifs, Unité de soins intensifs, Infections associées aux soins de santé.

Topics: Amikacin; Anti-Bacterial Agents; Anti-Infective Agents; Ceftriaxone; Clavulanic Acid; Community-Acquired Infections; Critical Illness; Cross Infection; Fluconazole; Humans; Meropenem; Microbial Sensitivity Tests; Nigeria; Piperacillin, Tazobactam Drug Combination; Pneumonia; Prospective Studies; Urinary Tract Infections

Topics: Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Critical Illness; Drug Combinations; Humans; Klebsiella Infections; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Pneumonia, Ventilator-Associated

Topics: Anti-Bacterial Agents; Critical Illness; Humans; Meropenem; Sepsis

Topics: Anti-Bacterial Agents; Critical Illness; Humans; Meropenem; Sepsis

β-Lactams are the most commonly used antibiotics in intensive care units (ICUs). As critically ill patients often experience pharmacokinetic aberrations, and rates of antimicrobial resistance vary between hospital settings, reliance on tertiary sources or package labeling to guide empiric dosing often results in suboptimal β-lactam exposure. The primary objective was to identify β-lactam regimens capable of achieving ≥90% cumulative fraction of response (CFR) against 7 Gram-negative pathogens within 4 ICUs at our institution. Unit-specific minimal inhibitory concentration (MIC) distribution data was used in combination with published pharmacokinetic parameters in critically ill patients to perform Monte Carlo simulations. The percentage of time for which the unbound concentration of antibiotic remained above the MIC (%ƒT > MIC) was used as the pharmacodynamic target: 70%ƒT >MIC for cefepime, 40%ƒT > MIC for meropenem, and 50%ƒT > MIC for piperacillin/tazobactam. Regimens were modeled to determine the likelihood of achieving ≥90% CFR. Overall, intermittently dosed cefepime, meropenem, and piperacillin/tazobactam failed to achieve ≥90% CFR for every organism. Cefepime 2 g intermittent bolus every 8 hours failed to achieve ≥90% CFR for Klebsiella pneumoniae or Enterobacter cloacae despite susceptibility rates exceeding 90%. Piperacillin/tazobactam 4.5 g prolonged infusion (PI) every 6 hours achieved <85% CFR for Pseudomonas aeruginosa and <50% CFR for Acinetobacter baumannii in every ICU. Meropenem 2 g PI every 8 hours and meropenem 2 g PI every 6 hours were the only regimens capable of achieving ≥90% CFR for P aeruginosa in all units. Use of Monte Carlo simulations, with incorporation of local MIC distribution data, provides a mechanism to effectively predict optimal agent and dose selection within specific hospital systems, thereby enhancing pharmacokinetic/pharmacodynamic optimization and improving clinical efficacy.

Topics: Anti-Bacterial Agents; beta-Lactams; Cefepime; Critical Illness; Humans; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method; Piperacillin; Pseudomonas aeruginosa; Tazobactam

Beta-lactam dosing is challenging in critically ill patients with slow extended daily dialysis (SLEDD). This prospective observational study aimed to investigate meropenem and piperacillin concentrations and half-lives during SLEDD and in SLEDD-free intervals. Critically ill patients with SLEDD-therapy and meropenem or piperacillin therapy were included. Breakpoints of target attainment were defined as 2 and 20.8 mg/L for meropenem and piperacillin, respectively. Daily TDM was performed and therapies were adapted based on the measured concentrations. Elimination rate constants were determined by using nonlinear regression analysis. Seventeen patients were included (48 SLEDD intervals; median SLEDD-duration: 7.25 h). The median antibiotic trough concentrations and half-lives were significantly (p < 0.001) lower during and after the SLEDD-therapy compared to SLEDD-free intervals (median meropenem: 22.3 (IQR: 12.8, 25.6) vs. 28.3 mg/L (IQR: 16.9, 37.4); median piperacillin: 55.8 (IQR: 45.1, 84.9) vs. 130 mg/L (IQR: 91.5, 154.5); relative change: -48.0% each, IQR meropenem: -33.3, -58.5%; IQR piperacillin: -36.3, -52.1%). However, none of the measured trough concentrations were subtherapeutic during SLEDD. SLEDD leads to a reduction in meropenem and piperacillin concentrations of approximately 50% independently of the initial concentration. If the concentration is twice as high as the breakpoint of target attainment before SLEDD-therapy, subtherapeutic levels can be avoided.

Topics: Anti-Bacterial Agents; Critical Illness; Humans; Meropenem; Piperacillin; Renal Dialysis

The risk of acute kidney injury (AKI) associated with concomitant vancomycin and piperacillin/tazobactam in the intensive care unit (ICU) remains controversial. The aim of this study was to compare the AKI incidence associated with concomitant vancomycin and piperacillin/tazobactam compared to either cefepime or meropenem with vancomycin in the ICU.. A multicenter, retrospective, propensity score-matched cohort study was conducted in adult ICU patients administered vancomycin in combination with either piperacillin/tazobactam, cefepime, or meropenem were included. Patients developing AKI ≤48 h following combination therapy initiation were excluded. The primary endpoint was to compare the incidence of AKI associated with concomitant antimicrobial therapy. Multivariable Cox regression modeling in predicting AKI was also conducted.. A total of 1044 patients were matched. The AKI incidence in vancomycin- piperacillin/tazobactam and vancomycin-cefepime/meropenem groups were 21.9% and 16.8%, respectively (p = 0.068). Multivariable prediction models showed concomitant vancomycin-piperacillin/tazobactam was an independent risk factor of AKI using serum creatinine only (HR 1.52, 1.10-2.10, p = 0.011) and serum creatinine with urine output-based KDIGO criteria (HR 1.77, 1.18-2.67, p = 0.006). No significant differences between groups were observed for AKI recovery patterns or mortality.. Concomitant vancomycin and piperacillin/tazobactam administration in adult ICU patients was independently associated with an increased risk of AKI.

Topics: Acute Kidney Injury; Adult; Anti-Bacterial Agents; Cefepime; Cohort Studies; Critical Illness; Drug Therapy, Combination; Humans; Meropenem; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Propensity Score; Retrospective Studies; Vancomycin

We hypothesized that a protocol of standardized fixed dose using prolonged infusion during the early phase of sepsis may avoid insufficient β-lactam concentrations.. In this single center prospective study, patients with sepsis and vasopressors were enrolled if they were treated by either piperacillin-tazobactam, meropenem or cefepime. Βeta-lactams were administered at fixed dose by prolonged infusion. Targeted plasma concentrations for piperacillin, meropenem and cefepime were above 80 mg/L, 8 mg/L and 38 mg/L respectively. Three blood samples were collected per patient over the first 48 h of treatment. Primary endpoint was target concentration achievement during the 48 first hours, defined as all plasma concentrations above the targeted threshold.. Among the 89 patients completing the three samples, target concentrations were achieved for 61 (69%). Target concentrations were achieved in 20 (53%), 32 (89%), and 9 (60%) of the patients treated with piperacillin, meropenem and cefepime, respectively. By multivariate analysis, lower APACHE 2 score, higher baseline MDRD creatinine clearance, and piperacillin use were independently associated with insufficient β-lactam concentrations.. Despite a fixed dose antibiotic administration protocol with prolonged infusion insufficient β-lactam concentration was frequent at the early phase of sepsis, especially in less severe patients, without renal failure, and treated with piperacillin. In septic patients with vasopressors, piperacillin dosing higher than 16 g may be needed to achieve the recommended target concentration.. NCT02820987.

Topics: Anti-Bacterial Agents; beta-Lactams; Critical Illness; Humans; Meropenem; Piperacillin; Prospective Studies; Sepsis

Severe burn injury involves widespread skin and tissue damage leading to systemic inflammation, hypermetabolism and multi-organ failure. The hypermetabolic phase of burn injury has been associated with increased systemic antibiotic clearance; however, critical illness in the absence of burn may also induce similar physiologic changes. Continuous renal replacement therapy (CRRT) is often implemented in critically ill patients and may also affect antibiotic clearance. Although the pharmacokinetics (PK) of meropenem has been described in both the burn and non-burn critically ill populations, direct comparative data is lacking.. For this study, we evaluated PK parameters of meropenem from 23 critically ill patients, burn or non-burn, treated with or without continuous veno-venous haemofiltration (CVVH) to determine the contribution of burn and CVVH to the variability of therapeutic meropenem levels.. A two-compartment model best described the data and revealed creatinine clearance (CrCl) and total burn surface area (TBSA) as significant covariates on clearance (CL) and peripheral volume of distribution (Vp), respectively. Of interest, non-burn patients on CVVH displayed an overall lower inherent CL as compared to burn patients on CVVH (6.43 vs. 12.85 L/h). Probability of target attainment (PTA) simulations revealed augmented renal clearance (ARC) may necessitate dose adjustments, but TBSA and CVVH would not.. We recommend a standard dose of 1000 mg every 8 hours; however, if ARC is suspected, or the severity of illness requires a more stringent therapeutic target, we recommend a loading dose of 1000-2000 mg infused over 30 minutes to 1 hour followed by continuous infusion (3000-6000 mg over 24 hours), or intermittent infusion of 2000 mg every 8 hours.

Topics: Anti-Bacterial Agents; Burns; Continuous Renal Replacement Therapy; Critical Illness; Humans; Meropenem; Renal Insufficiency

The purpose of this study was to explore factors influencing meropenem pharmacokinetics (PKs) in critically ill patients by developing a population PK model and to determine the optimal dosing strategy.. This prospective observational study involved 12 critically ill patients admitted to the intensive care unit and treated with meropenem 1 g infused over 1 h every 8 h. Blood samples were collected on days 1, 2, and 5 immediately prior to dosing, and at 1, 2, 4, and 6 h after the start of infusion. Population PK parameters were estimated using nonlinear mixed-effects model software.. Meropenem PK was adequately described using a two-compartment model. Typical values of total and inter-compartmental clearance were 9.30 L/h and 9.70 L/h, respectively, and the central and peripheral compartment volumes of distribution were 12.61 L and 7.80 L, respectively. C-reactive protein (CRP) was identified as significant covariate affecting total meropenem clearance. The probability of target attainment (PTA) predicted by Monte Carlo simulations varied according to the patients' CRP. The PTA of 100% time above the minimum inhibitory concentration ≤2 mg/L for bacteria was achieved after a dose of 1 and 2 g infused over 4 h every 8 h in patients with CRP of 30 and 5 mg/dL, respectively.. The findings of this study suggest that CRP might be helpful in managing meropenem dosing in critically ill patients. Higher doses and extended infusion may be required to achieve optimal pharmacodynamic targets.

Topics: Anti-Bacterial Agents; Critical Illness; Humans; Inflammation; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method

To determine percentage of patients with sub-therapeutic beta-lactam exposure in our intensive care units (ICU) and to correlate target attainment with clinical outcomes.. Multi-centre, prospective, observational study was conducted in ICUs from three hospitals in Singapore from July 2016 to May 2018. Adult patients (≥21 years) receiving meropenem or piperacillin-tazobactam were included. Four blood samples were obtained during a dosing interval to measure and determine attainment of therapeutic targets: unbound beta-lactam concentration above (i) minimum inhibitory concentration (MIC) at 40% (meropenem) or 50% (piperacillin) of dosing interval (40-50%fT > MIC) and (ii) 5 × MIC at 100% of dosing interval (100%fT > 5 × MIC). Correlation to clinical outcomes was evaluated using Cox regression.. Beta-lactam levels were highly variable among 61 patients, with trough meropenem and piperacillin levels at 21.5 ± 16.8 mg/L and 101.6 ± 81.1 mg/L respectively. Among 85 sets of blood samples, current dosing practices were able to achieve 94% success for 40-50%fT > MIC and 44% for 100%fT > 5 × MIC. Failure to achieve 40-50%fT > MIC within 48 h was significantly associated with all-cause mortality (HR: 9.0, 95% CI: 1.8-45.0), after adjustment for APACHE II score. Achievement of 100%fT > 5 × MIC within 48 h was significantly associated with shorter length of hospital stay.. Current dosing practices may be suboptimal for ICU patients. Beta-lactam TDM may be useful.

Topics: Adult; Anti-Bacterial Agents; beta-Lactams; Critical Illness; Drug Monitoring; Humans; Meropenem; Microbial Sensitivity Tests; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Singapore

The aim of this prospective cohort study was to evaluate the therapeutic target attainment of 3-hour extended infusion of meropenem in patients with septic burns in the early and late periods of septic shock.. Meropenem serum levels were determined by liquid chromatography from blood samples collected within 48 hours (early period) of therapy and 10 to 14 days afterward (late period). Pharmacokinetic properties were investigated by noncompartmental analysis, and the therapeutic target was defined as 100% of the time above the MIC (100%fT> MIC).. Fifteen patients with 90 measured meropenem concentrations were included. Throughout the entire course of antimicrobial therapy, the therapeutic target was attained against gram-negative pathogens with an MIC ≤ 2 mg/L. Pathogens with intermediate susceptibility to meropenem were only covered in the early phase of therapy.. Higher-dose regimens or continuous infusions may be necessary to guarantee antimicrobial coverage of meropenem against less sensitive pathogens in patients with septic burns.

Topics: Anti-Bacterial Agents; Burns; Critical Illness; Humans; Infusions, Intravenous; Meropenem; Microbial Sensitivity Tests; Prospective Studies; Shock, Septic; Thienamycins

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.. 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.. Two guidelines and two labels were included in the Monte Carlo simulations. For 70% fT. 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.

Topics: Anti-Bacterial Agents; Critical Illness; Humans; Infant, Newborn; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method; Neonatal Sepsis

Topics: Anti-Bacterial Agents; Critical Illness; Humans; Infusions, Intravenous; Meropenem; Piperacillin; Renal Dialysis; Thienamycins

Topics: Anti-Bacterial Agents; Critical Illness; Humans; Infusions, Intravenous; Meropenem; Piperacillin; Renal Dialysis; Thienamycins

Therapeutic drug monitoring (TDM) may represent an invaluable tool for optimizing antimicrobial therapy in septic patients, but extensive use is burdened by barriers. The aim of this study was to assess the impact of a newly established expert clinical pharmacological advice (ECPA) program in improving the clinical usefulness of an already existing TDM program for emerging candidates in tailoring antimicrobial therapy among critically ill patients.. This retrospective observational study included an organizational phase (OP) and an assessment phase (AP). During the OP (January-June 2021), specific actions were organized by MD clinical pharmacologists together with bioanalytical experts, clinical engineers, and ICU clinicians. During the AP (July-December 2021), the impact of these actions in optimizing antimicrobial treatment of the critically ill patients was assessed. Four indicators of performance of the TDM-guided real-time ECPA program were identified [total TDM-guided ECPAs July-December 2021/total TDM results July-December 2020; total ECPA dosing adjustments/total delivered ECPAs both at first assessment and overall; and turnaround time (TAT) of ECPAs, defined as optimal (< 12 h), quasi-optimal (12-24 h), acceptable (24-48 h), suboptimal (> 48 h)].. The OP allowed to implement new organizational procedures, to create a dedicated pathway in the intranet system, to offer educational webinars on clinical pharmacology of antimicrobials, and to establish a multidisciplinary team at the morning bedside ICU meeting. In the AP, a total of 640 ECPAs were provided for optimizing 261 courses of antimicrobial therapy in 166 critically ill patients. ECPAs concerned mainly piperacillin-tazobactam (41.8%) and meropenem (24.9%), and also other antimicrobials had ≥ 10 ECPAs (ceftazidime, ciprofloxacin, fluconazole, ganciclovir, levofloxacin, and linezolid). Overall, the pre-post-increase in TDM activity was of 13.3-fold. TDM-guided dosing adjustments were recommended at first assessment in 61.7% of ECPAs (10.7% increases and 51.0% decreases), and overall in 45.0% of ECPAs (10.0% increases and 35.0% decreases). The overall median TAT was optimal (7.7 h) and that of each single agent was always optimal or quasi-optimal.. Multidisciplinary approach and timely expert interpretation of TDM results by MD Clinical Pharmacologists could represent cornerstones in improving the cost-effectiveness of an antimicrobial TDM program for emerging TDM candidates.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Critical Illness; Drug Monitoring; Humans; Meropenem

Carbapenemase-producing Enterobacterales (CPE) represent a public health concern. The limited antimicrobial options against CPE have led to the development of novel antimicrobial molecules. In the present study, we characterized the genetic determinants associated with the resistance to ceftazidime/avibactam (CAZ-AVI), meropenem/vaborbactam (MER-VAB), imipenem/relebactam (IMI-REL) and cefiderocol (CFD) in a carbapenemase-producing Klebsiella pneumoniae strain isolated from a critically ill patient.. Genomic DNA was sequenced using Illumina iSeq 100 and Minion Oxford Nanopore platforms. Assemblies were performed with a de novo approach using short-read, hybrid and long-lead assembly approaches. Final assembly was manually curated and carefully verified. Circular elements were screened for antimicrobial-resistance genes, porins, virulence factors and prophage regions.. KPC-Kp (KPC-producing Klebsiella pneumoniae) BO743 was resistant to all novel β-lactams including CAZ-AVI, MER-VAB, IMI-REL and CFD. The genome of strain BO743 is composed of a single chromosome of 5 347 606 bp and three circular plasmids of 363 634 bp (pBO743-363Kb), 120 290 bp (pBO743-120Kb) and 54 339 bp (pBO743-54Kb). Sequence analysis demonstrated that KPC-Kp BO743 co-harboured bla. The description of the genome of KPC-Kp cross-resistant to novel βL-βLICs and cefiderocol reveals the presence of numerous antimicrobial resistance genes including bla

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Boronic Acids; Cefiderocol; Ceftazidime; Cephalosporins; Critical Illness; Humans; Imipenem; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests

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

Topics: Anti-Bacterial Agents; Brain; Critical Illness; Humans; Meropenem; Monte Carlo Method; Prospective Studies; Thienamycins

Morbidity and mortality related to ventriculitis in neurocritical care patients remain high. Antibiotic dose optimization may improve therapeutic outcomes. In this study, a population pharmacokinetic model of meropenem in infected critically ill patients was developed. We applied the final model to determine optimal meropenem dosing regimens required to achieve targeted cerebrospinal fluid exposures. Neurocritical care patients receiving meropenem and with a diagnosis of ventriculitis or extracranial infection were recruited from two centers to this study. Serial plasma and cerebrospinal fluid samples were collected and assayed. Population pharmacokinetic modeling and Monte Carlo dosing simulations were performed using Pmetrics. We sought to determine optimized dosing regimens that achieved meropenem cerebrospinal fluid concentrations above pathogen MICs for 40% of the dosing interval, or a higher target ratio of meropenem cerebrospinal fluid trough concentrations to pathogen MIC of ≥1. In total, 53 plasma and 34 cerebrospinal fluid samples were obtained from eight patients. Meropenem pharmacokinetics were appropriately described using a three-compartment model with linear plasma clearance scaled for creatinine clearance and cerebrospinal fluid penetration scaled for patient age. Considerable interindividual pharmacokinetic variability was apparent, particularly in the cerebrospinal fluid. Percent coefficients of variation for meropenem clearance from plasma and cerebrospinal fluid were 41.7% and 89.6%, respectively; for meropenem, the volume of distribution in plasma and cerebrospinal fluid values were 63.4% and 58.3%, respectively. High doses (up to 8 to 10 g/day) improved attainment of meropenem cerebrospinal fluid target exposures, particularly for less susceptible organisms (MICs, ≥0.25 mg/L). Standard meropenem doses of 2 g every 8 h may not achieve effective concentrations in cerebrospinal fluid in all critically ill patients. Higher doses, or alternative dosing methods (e.g., loading dose followed by continuous infusion) may be required to optimize cerebrospinal fluid exposures. Doses of up to 8 to 10 g/day either as intermittent boluses or continuous infusion would be suitable for patients with augmented renal clearance; lower doses may be considered for patients with impaired renal function as empirical suggestions. Ongoing dosing should be tailored to the individual patient circumstances. Notably, the study population was small and dosing recom

Topics: Anti-Bacterial Agents; Cerebral Ventriculitis; Critical Illness; Humans; Meropenem; Prospective Studies; Renal Insufficiency; Thienamycins

Critical illness reduces β-lactam pharmacokinetic/pharmacodynamic (PK/PD) attainment. We sought to quantify PK/PD attainment in patients with hospital-acquired pneumonia.. Meropenem plasma PK data (n = 70 patients) were modelled, PK/PD attainment rates were calculated for empirical and definitive targets, and between-patient variability was quantified [as a coefficient of variation (CV%)].. Attainment of 100% T>4×MIC was variable for both empirical (CV% = 92) and directed (CV% = 33%) treatment.. Individualization is required to achieve suggested PK/PD targets in critically ill patients.

Topics: Anti-Bacterial Agents; Critical Illness; Hospitals; Humans; Intensive Care Units; Meropenem; Microbial Sensitivity Tests; Pneumonia; Prospective Studies

Optimization of antimicrobial therapy is a challenge in critically ill patients who develop extreme interindividual and intraindividual pharmacokinetic variability. Therapeutic drug monitoring is a valuable tool for maximizing the effect of a drug and minimizing its adverse and unwanted effects. The aim of the current work was to develop and validate an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to determine multiple antibiotics in clinical plasma samples from critically ill patients; low sample volume and rapid processing of samples were considered the main criteria.. A separation method based on an online combination of UHPLC-MS/MS was developed for the simultaneous determination of 4 β-lactam antibiotics (cefepime, meropenem, cefotaxime, and piperacillin), tazobactam, and linezolid in human plasma samples. The volume of plasma sample used for analysis was 20 µL. The developed method was validated according to Food and Drug Administration guidelines.. The chromatographic run time was 8 minutes. Calibration curves were linear for concentration ranges of 0.1-100 mcg/mL (r 2 > 0.99) for tazobactam, meropenem, cefotaxime, linezolid, and piperacillin and 1-100 mcg/mL (r 2 > 0.99) for cefepime. The intraday and interday accuracy of the method ranged from 92.4% to 110.7% and 93.6% to 113.3%, respectively. The intraday and interday precision values were ≤17.3% and ≤17.4%, respectively. No interfering and carryover analytes were observed.. The developed UHPLC-MS/MS method is an appropriate and practical tool for therapeutic drug monitoring of the selected antibiotics. Owing to its rapidity, requirement of low sample volume, and high selectivity, sensitivity, and reliability, it can be effectively implemented in routine clinical laboratory tests for critically ill patients.

Topics: Anti-Bacterial Agents; Cefepime; Cefotaxime; Chromatography, High Pressure Liquid; Critical Illness; Drug Monitoring; Humans; Linezolid; Meropenem; Monobactams; Piperacillin; Reproducibility of Results; Tandem Mass Spectrometry; Tazobactam

Linezolid, vancomycin, teicoplanin, tigecycline, imipenem, meropenem, voriconazole, and micafungin are eight special-grade antimicrobials commonly used for patients with severe infections. Changes in the pharmacodynamics and pharmacokinetics of critically ill patients severely affect the efficacy of antimicrobial drugs. Therefore, conventional or standard dosing regimens do not achieve satisfactory anti-infective effects. In the current study a simple and specific ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for simultaneously determining the concentrations of the above-mentioned eight antimicrobials in human plasma only 3 min after one-step magnetic solid phase extraction pre-treatment. Multiple-reaction monitoring and positive ion modes were used for detection. The calibration curves were established over a concentration range of 0.1-25.0 μg/mL for teicoplanin, linezolid, micafungin, voriconazole, imipenem, igecyclin, and meropenem, and 0.2-50.0 μg/mL for vancomycin; the coefficient of correlation was > 0.9971 for all the compounds. The inter- and intra-day coefficients of variation were < 6.88% at the lower limit of quantification and quality control (QC) levels (low concentration-QC, medium concentration-QC, and high-concentration QC). The UPLC-MS/MS method was successfully used for clinical therapeutic drug monitoring of linezolid, vancomycin, teicoplanin, tigecycline, imipenem, meropenem, voriconazole, and micafungin for critically ill patients.

Topics: Anti-Infective Agents; Chromatography, High Pressure Liquid; Chromatography, Liquid; Critical Illness; Drug Monitoring; Humans; Imipenem; Linezolid; Meropenem; Micafungin; Reproducibility of Results; Tandem Mass Spectrometry; Teicoplanin; Tigecycline; Vancomycin; Voriconazole

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.

Topics: Anti-Bacterial Agents; Critical Illness; Humans; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method

The average body weight is smaller in Asian patients compared with Western patients, but influence of body weight in antibiotic dosing is unknown. This study was to predict the optimal ceftazidime, cefepime, meropenem, piperacillin/tazobactam doses in Asian patients undergoing continuous venovenous hemofiltration (CVVH).. Monte Carlo simulations (MCS) were performed using published Asian demographics and pharmacokinetics parameters in 5000 virtual patients at three CVVH effluent rates (Qeff; 20, 30, 40 mL/kg/h). Various dosing regimens were assessed for the probability of target attainments using 60% fT > 1 × MIC or 4xMIC and neurotoxicity risk at 48-h using suggested neurotoxicity thresholds.. Ceftazidime 1 g q12h, meropenem 1 g q12h, and piperacillin/tazobactam 3.375 g q6h were optimal for all Qeff settings against fT > 1 × MIC. Cefepime 2 g q24h and 2 g q12h were optimal at 20 and 30-40 mL/kg/h respectively. For the aggressive PD target (4 × MIC), optimal ceftazidime regimens were 1.25 g q8h (20-30 mL/kg/h) and 1.5 g q8h (40 mL/kg/h). Cefepime 2 g q8h and meropenem 1 g q8h were optimal at all Qeff settings. No simulated piperacillin doses attained the aggressive PD target. Increased neurotoxicity risk was predicted with ceftazidime and cefepime doses attaining the efficacy.. MCS enabled the prediction of optimal β-lactam dosing regimens for Asian patients receiving CVVH at varying Qeff. Clinical validation is warranted.

Topics: Anti-Bacterial Agents; Body Weight; Cefepime; Ceftazidime; Critical Illness; Humans; Lactams; Meropenem; Microbial Sensitivity Tests; Piperacillin; Piperacillin, Tazobactam Drug Combination

Therapeutic drug monitoring (TDM) of β-lactam antibiotics may be used to optimize dosing for patients in the intensive care unit (ICU). A noninvasive matrix such as oral fluid may be interesting in selected patient groups. We compared the oral fluid concentrations of piperacillin and meropenem with the respective unbound and total concentrations in plasma. A secondary objective was to evaluate feasibility of the collection of oral fluid samples in this specific patient population.. The study included 20 non-intubated ICU patients, age 22 to 77 y, receiving piperacillin or meropenem via continuous intravenous infusion. The standard protocol consisted of collecting a paired plasma-oral fluid sample for 3 consecutive days. Oral fluid was obtained from the patients using a standardized procedure by spitting in a plastic container after 2 min of gathering oral fluid in the mouth.. Antibiotic concentrations of piperacillin and meropenem are measurable, albeit very low, in unstimulated oral fluid of ICU patients. For piperacillin, a poor correlation was found between oral fluid and both total and unbound plasma concentrations (Spearman's correlation coefficients (Rs) 0.46 and 0.48 respectively). For meropenem this correlation was better (Rs for oral fluid versus total and unbound plasma meropenem concentration 0.92 and 0.93 respectively). Dispersion of antibiotic concentrations was greater in oral fluid than in blood. Collecting oral fluid samples was difficult in non-intubated ICU patients.. Oral fluid from non-intubated ICU patients, obtained through a standardized procedure, cannot be recommended as an alternative matrix for quantitative meropenem or piperacillin TDM.

Topics: Adult; Aged; Anti-Bacterial Agents; Critical Illness; Humans; Intensive Care Units; Meropenem; Middle Aged; Pilot Projects; Piperacillin; Young Adult

Topics: Critical Illness; Cytokines; Humans; Meropenem; Sepsis; Shock, Septic

The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets.. We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations.. We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4-8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35-65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P < .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9-18.8), piperacillin was 78.6 mg/L (49.5-127.3), tazobactam was 9.5 mg/L (6.3-14.2), and vancomycin was 14.3 mg/L (11.6-21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively.. In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.

Topics: Anti-Bacterial Agents; Critical Illness; Humans; Meropenem; Piperacillin; Prospective Studies; Renal Replacement Therapy

There has been increasing interest in incorporating β-lactam precision dosing into routine clinical care, but robust population pharmacokinetic models in critically ill children are needed for these purposes. The objective of this study was to demonstrate the feasibility of an opportunistic sampling approach that utilizes scavenged residual blood for future pharmacokinetic studies of cefepime, meropenem, and piperacillin. We aimed to show that opportunistic samples would cover the full concentration-versus-time profiles and to evaluate stability of the antibiotics in whole blood and plasma to optimize future use of the opportunistic sampling approach. A prospective observational study was conducted in a single-center pediatric intensive care unit, where pediatric patients administered at least 1 dose of cefepime, meropenem, or piperacillin/tazobactam and who had residual blood scavenged from samples obtained for routine clinical care were enrolled. A total of 138 samples from 22 pediatric patients were collected in a 2-week period. For all 3 antibiotics, the samples collected covered the entire dosing intervals and were not clustered around specific times. There was high variability in the free concentrations and in the percentage of drug bound to protein. There was less than 15% degradation for meropenem or piperacillin when stored in whole blood or plasma at 4°C after 6 days. Cefepime degraded by more than 15% after 3 days. The opportunistic sampling approach is a powerful and feasible method to obtain sufficient samples to study the variability of drug concentrations and protein binding for future pharmacokinetic studies in the pediatric critical care population.

Topics: Adolescent; Anti-Bacterial Agents; beta-Lactams; Cefepime; Child; Child, Preschool; Comorbidity; Critical Illness; Feasibility Studies; Female; Humans; Intensive Care Units, Pediatric; Male; Meropenem; Piperacillin; Prospective Studies

The proper dosage of antibiotics is a key element in the effective treatment of infection, especially in critically ill patients. This study aimed to evaluate the efficacy of optimized meropenem regimens based on pharmacokinetic/pharmacodynamic criteria in patients admitted to the intensive care unit.. This observational, naturalistic, retrospective, unicentric cohort study was performed between May 2011 and December 2017. The clinical and bacteriologic responses of 77 control intensive care unit patients receiving meropenem were compared with those of 77 propensity score-balanced patients who received meropenem dose adjusted by therapeutic drug monitoring. The primary end point of clinical response was a reduction at the end of treatment of at least 80% of the maximum procalcitonin (PCT) value recorded during the meropenem treatment.. The primary end point was met by 55 patients (71.4%) in the adjusted group compared with 41 (53.3%) patients in the control group (mean difference 18.1%, P = 0.02). Fifty-one patients (66.2%) in the adjusted group required a meropenem dose adjustment, being necessary in 46 of them (90.2%) to decrease the dose. The reduction of PCT was the greatest in the adjusted group compared with the unadjusted group (93% versus 85%, P = 0.004); a greater percentage of patients reached a PCT level < 0.5 ng/mL (63.6% versus 41.6%, P = 0.006), and there was a trend toward an improved bacteriologic response (relative risk = 1.27; 95% confidence interval: 0.92-1.56). There were no differences in early mortality or safety between groups.. Adjustment of meropenem therapy by monitoring is a useful strategy for improving meropenem effectiveness in the treatment of infection in critically ill patients, with no impact on safety.

Topics: Anti-Bacterial Agents; Critical Illness; Humans; Intensive Care Units; Meropenem; Retrospective Studies

Meropenem, a broad-spectrum carbapenem, is frequently used to treat severe bacterial infections in critically ill children. Recommendations for meropenem doses in adult infections are available; however, few studies have been published regarding the use of meropenem in children with sepsis, especially in those receiving continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO). We aimed to investigate the pharmacokinetic (PK) parameters of meropenem in children with sepsis receiving extracorporeal life support (ECLS).. This was a prospective observational clinical study of children with sepsis receiving ECMO or CRRT in the paediatric intensive care unit (PICU) of a children's hospital. The enrolled children received 20 mg/kg meropenem infusion over 1 hour, every 8 hours, and were grouped into children receiving ECMO, children receiving CRRT and children receiving neither ECMO nor CRRT. Plasma meropenem concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The key PK parameters were determined using the non-compartmental approach.. Twenty-seven patients were finally enrolled. The eCLCR of the CRRT group was lower than that of the ECMO group. The values of elimination half-life (t. No significant alterations in the PK parameters of meropenem occurred in children with sepsis administered ECMO and/or CRRT. Further investigations including PK modelling could provide evidence for appropriate meropenem dosing regimens during ECLS administration.

Topics: Anti-Bacterial Agents; Area Under Curve; Child; Child, Preschool; Creatinine; Critical Illness; Extracorporeal Membrane Oxygenation; Female; Half-Life; Humans; Infant; Male; Meropenem; Metabolic Clearance Rate; Prospective Studies; Sepsis

Topics: Anti-Bacterial Agents; Child; Continuous Renal Replacement Therapy; Critical Illness; Humans; Meropenem; Thienamycins

Topics: Anti-Bacterial Agents; Child; Continuous Renal Replacement Therapy; Critical Illness; Humans; Meropenem; Thienamycins

Augmented renal clearance (ARC, creatinine clearance > 130 mL/minute) makes difficult achievement of effective concentrations of renally cleared antibiotics in critically ill patients. This study examined the synergistic killing and resistance suppression for meropenem-ciprofloxacin combination dosage regimens against Pseudomonas aeruginosa isolates within the context of ARC. Clinically relevant meropenem and ciprofloxacin concentrations, alone and in combinations, were studied against three clinical isolates with a range of susceptibilities to each of the antibiotics. Isolate Pa1280 was susceptible to both meropenem and ciprofloxacin, Pa1284 had intermediate susceptibility to meropenem and was susceptible to ciprofloxacin, and CR380 was resistant to meropenem and had intermediate susceptibility to ciprofloxacin. Initially, isolates were studied in 72-hour static-concentration time-kill (SCTK) studies. Subsequently, the pharmacokinetic profiles expected in patients with ARC receiving dosage regimens, including at the highest approved daily doses (meropenem 6 g daily divided and administered as 0.5-hour infusions every 8 hours, or as a continuous infusion; ciprofloxacin 0.4 g as 1-hour infusions every 8 hours), were examined in a dynamic hollow-fiber infection model (HFIM) over 7-10 days. In both SCTK and HFIM, combination regimens were generally synergistic and suppressed growth of less-susceptible subpopulations, these effects being smaller for isolate CR380. The time-courses of total and less-susceptible bacterial populations in the HFIM were well-described by mechanism-based models, which enabled conduct of Monte Carlo simulations to predict likely effectiveness of approved dosage regimens at different creatinine clearances. Optimized meropenem-ciprofloxacin combination dosage regimens may be a viable consideration for P. aeruginosa infections in critically ill patients with ARC.

Topics: Anti-Bacterial Agents; Bacteriological Techniques; Ciprofloxacin; Creatinine; Critical Illness; Dose-Response Relationship, Drug; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Kidney Function Tests; Meropenem; Monte Carlo Method; Pseudomonas aeruginosa

To improve the predictive ability of literature models for model-informed therapeutic drug monitoring (TDM) of meropenem in intensive care units, we propose to tweak the literature models with the "prior approach" using a subset of the data. This study compares the predictive ability of both literature and tweaked models on TDM concentrations of meropenem in critically ill patients.. Blood samples were collected from patients of an intensive care unit treated with intravenous meropenem. Data were split six times into an "estimation" and a "prediction" datasets. Population pharmacokinetic (popPK) models of meropenem were selected from literature. These models were run on the "estimation" dataset with the $PRIOR subroutine in NONMEM to obtain tweaked models. The literature and tweaked models were used a priori (with covariate only) and with Bayesian fitting to predict each individual concentration from the previous concentration(s). Their respective predictive abilities were compared using median relative prediction error (MDPE%) and median absolute relative prediction error (MDAPE%).. The total dataset was composed of 115 concentrations from 58 patients. For each of the six splits, the "estimation" and the "prediction" datasets were respectively composed of 44 and 14 patients or 45 and 13 patients. Six popPK models were selected in the literature. MDPE% and MDAPE% were globally lower for the tweaked than for the literature models, especially for a priori predictions.. The "prior approach" could be a valuable tool to improve the predictive ability of literature models, especially for a priori predictions, which are important to optimize dosing in emergency situations.

Topics: Administration, Intravenous; Aged; Anti-Bacterial Agents; Critical Illness; Drug Monitoring; Female; Humans; Intensive Care Units; Male; Meropenem; Middle Aged; Models, Biological; Retrospective Studies

The advanced organ support (ADVOS) system allows to eliminate water-soluble as well as protein-bound molecules. Despite its clinical features, to date nothing is known about the elimination of clinically relevant drugs such as antiinfectives. Therefore, we report a case treated with ADVOS, continuous renal replacement therapy (CRRT), and meropenem (1 g 8-hourly) for empiric sepsis therapy monitored by meropenem drug levels. ADVOS showed more efficient elimination of meropenem compared to CRRT which has to be considered when evaluating dosing regimens.

Topics: Anti-Bacterial Agents; Continuous Renal Replacement Therapy; Critical Illness; Humans; Meropenem; Renal Replacement Therapy

Meropenem is frequently used for the treatment of severe bacterial infections in critically ill patients. Because critically ill patients are more prone to pharmacokinetic variability than other patients, ensuring an effective blood concentration can be complex. Therefore, describing this variability to ensure a proper use of this antibiotic drug limits the rise and dissemination of antimicrobial resistance, and helps preserve the current antibiotic arsenal. The aims of this study were to describe the pharmacokinetics of meropenem in critically ill patients, to identify and quantify the patients' characteristics responsible for the observed pharmacokinetic variability, and to perform different dosing simulations in order to determine optimal individually adapted dosing regimens.. A total of 58 patients hospitalized in the medical intensive care unit and receiving meropenem were enrolled, including 26 patients with renal replacement therapy. A population pharmacokinetic model was developed (using NONMEM software) and Monte Carlo simulations were performed with different dosing scenarios (bolus-like, extended, and continuous infusion) exploring the impact of clinical categories of residual diuresis (anuria, oliguria, and preserved diuresis) on the probability of target attainment (MIC: 1-45 mg/L).. The population pharmacokinetic model included five covariates with a significant impact on clearance: glomerular filtration rate, dialysis (continuous and semi-continuous), renal function status, and volume of residual diuresis. The clearance for a typical patient in our population is 4.20 L/h and volume of distribution approximately 44 L. Performed dosing regimen simulations suggested that, for equivalent doses, the continuous infusion mode (with loading dose) allowed the obtaining of the pharmacokinetic/pharmacodynamic target for a larger number of patients (100% for MIC ≤ 20 mg/L). Nevertheless, for the treatment of susceptible bacteria (MIC ≤ 2 mg/L), differences in the probability of target attainment between bolus-like, extended, and continuous infusions were negligible.. Identified covariates in the model are easily accessible information in patient health records. The model highlighted the importance of considering the patient's overall condition (renal function and dialysis) and the pathogen's characteristics (MIC target) during the establishment of a patient's dosing regimen.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Infections; Critical Illness; Drug Administration Schedule; Female; Humans; Intensive Care Units; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Models, Biological; Monte Carlo Method; Retrospective Studies; Tissue Distribution; Young Adult

The aim of this study was to investigate optimal loading doses prior to continuous infusion of meropenem in critically ill patients. A previously published and successfully evaluated pharmacokinetic model of critically ill patients was used for stochastic simulations of virtual patients. Maintenance doses administered as continuous infusion of 1.5-6 g/24 h with preceding loading doses (administered as 30 min infusion) of 0.15-2 g were investigated. In addition to the examination of the influence of individual covariates, a best-case and worst-case scenario were simulated. Dosing regimens were considered adequate if the 5th percentile of the concentration-time profile did not drop at any time below four times the S/I breakpoint (= 2 mg/L) of Pseudomonas aeruginosa according to the EUCAST definition. Low albumin concentrations, high body weight and high creatinine clearances increased the required loading dose. A maximum loading dose of 0.33 g resulted in sufficient plasma concentrations when only one covariate showed extreme values. If all three covariates showed extreme values (= worst-case scenario), a loading dose of 0.5 g was necessary. Higher loading doses did not lead to further improvements of target attainment. We recommend the administration of a loading dose of 0.5 g meropenem over 30 min immediately followed by continuous infusion.

Topics: Anti-Bacterial Agents; Body Weight; Critical Illness; Dose-Response Relationship, Drug; Humans; Infusions, Intravenous; Meropenem; Microbial Sensitivity Tests; Patient Simulation; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections

There have historically been concerns of acute kidney injury (AKI) with the use of aminoglycosides. The present study aimed to compare the AKI incidence and mortality rate between critically ill patients treated with aminoglycoside or meropenem in the intensive care unit setting using a propensity score matching approach. This cross-sectional study was conducted at two university hospitals from January 2011 to October 2017. Clinical and laboratorial data were evaluated to exclude potential confounders and to calculate the Charlson index. AKI was classified according to the Acute Kidney Injury Network criteria. All tests were two-tailed, and a p value ≤ 0.05 was considered significant in the univariate and multivariate analyses. We included 494 patients, 95 and 399 of whom used meropenem and aminoglycoside, respectively. Patients in the subgroup that used meropenem were matched with controls (aminoglycoside). Among the 494 patients, 120 developed any grade of AKI (24.2%). After propensity score matching, there were no significant differences in AKI incidence and mortality rate between the aminoglycoside and meropenem groups (p = 0.324 and 0.464, respectively). Patients on the aminoglycoside regimen neither presented a higher AKI incidence nor mortality rate when compared with those on the meropenem regimen. Aminoglycosides may be a safe option for the treatment of critically ill patients on carbapenem sparing antimicrobial stewardship programs.

Topics: Acute Kidney Injury; Aged; Aminoglycosides; Anti-Bacterial Agents; Critical Illness; Cross Infection; Cross-Sectional Studies; Female; Hospitals, University; Humans; Incidence; Intensive Care Units; Male; Meropenem; Middle Aged; Propensity Score; Retrospective Studies; Risk Factors

The effect of renal replacement therapy on drug concentrations in patients with sepsis has not been fully elucidated because the pharmacokinetic properties of many antimicrobials are influenced by both pathophysiological and treatment-related factors. The aim of this study was to determine meropenem concentrations in patients with sepsis before and after the initiation of continuous venovenous hemodialysis with regional citrate anticoagulation (RCA-CVVHD).. The study included 15 critically ill patients undergoing RCA-CVVHD due to sepsis-induced acute kidney injury. All participants received 2 g of meropenem every 8 h in a prolonged infusion lasting 3 h. Meropenem concentrations were measured in blood plasma using high-performance liquid chromatography coupled with tandem mass spectrometry. Blood samples were obtained at six-time points prior to and at six-time points after introducing RCA-CVVHD.. The median APACHE IV and SOFA scores on admission were 118 points (interquartile range [IQR] 97-134 points) and 19.5 points (IQR 18-21 points), respectively. There were no significant differences in the plasma concentrations of meropenem measured directly before RCA-CVVHD and during the first 450 min of the procedure. The drug concentration reached its peak 2 h after initiating the infusion and then steadily declined.. The concentration of high-dose meropenem (2 g every 8 h) administered in a prolonged infusion was similar before and after the introduction of RCA-CVVHD in patients with sepsis who developed acute kidney injury.

Topics: Acute Kidney Injury; Aged; Anti-Bacterial Agents; Anticoagulants; Chromatography, High Pressure Liquid; Citric Acid; Cohort Studies; Continuous Renal Replacement Therapy; Critical Illness; Female; Humans; Male; Meropenem; Middle Aged; Prospective Studies; Sepsis; Tandem Mass Spectrometry

The aim of this study was to conduct a population pharmacokinetic (PK) analysis of meropenem and to explore the optimal dosing strategy for meropenem in critically ill patients with acute kidney injury receiving treatment with continuous hemodiafiltration (CHDF).. Blood samples were obtained on days 1, 2, and 5 after the start of meropenem administration, immediately before dosing, and at 1, 2, 6, and 8 hours after dosing. Population PK model analysis was performed and concentration-time profiles were simulated using the Nonlinear Mixed Effects Model software.. Twenty-one patients receiving CHDF in our intensive care unit were enrolled and 350 serum concentration-time data points were obtained. The PKs of meropenem were best described using a 2-compartment model. Typical total and intercompartmental clearance values were 4.22 L/h and 7.84 L/h, respectively, whereas the central and peripheral compartment volumes of distribution were 14.82 L and 11.75 L, respectively. Estimated glomerular filtration rate was identified as a significant covariate of meropenem total clearance. In simulations of patients with renal failure receiving CHDF, the dose was affected by estimated glomerular filtration rate; a dose of 0.5 g every 8 hours or 1 g every 12 hours showed the probability of target attainment of achieving 100% time above the minimum inhibitory concentration for bacteria with a minimum inhibitory concentration ≤2 mg/L.. A population PK model was developed for meropenem in critically ill patients with acute kidney injury receiving CHDF. Our results indicated that a meropenem dosage of 0.5 g every 8 hours or 1 g every 12 hours was suitable in this population and for susceptible bacteria.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Critical Illness; Female; Hemodiafiltration; Humans; Infusions, Intravenous; Intensive Care Units; Male; Meropenem; Metabolic Clearance Rate; Microbial Sensitivity Tests; Middle Aged; Prospective Studies; Renal Dialysis; Young Adult

Critically ill patients show several pathophysiological alterations that can complicate antibiotic dosing. Hence, there is a strong rationale to individualize anti-infective dosing in these patients by using therapeutic drug monitoring (TDM). The current study aimed to develop and validate a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of total and unbound plasma concentrations of 3 commonly used antibiotics (meropenem, imipenem/cilastatin, and cefoperazone/sulbactam) in the treatment of infections in critically ill patients in China, which could be suitable for routine TDM in hospital laboratories.. The unbound drug was separated from the bound drug by ultrafiltration. Simple protein precipitation was used for sample preparation. Meropenem, imipenem/cilastatin, cefoperazone/sulbactam, and their corresponding internal standards were then resolved using the Waters CORTECS C18 column. All the compounds were detected using electrospray ionization in the positive/negative ion-switching mode.. The calibration curves were linear for all compounds, with correlation coefficients (R) above 0.99 for total concentrations in human plasma and unbound concentrations in the plasma ultrafiltrate. For both total and unbound drugs, the relative errors and intra-assay/interassay relative standard deviations were below 15%. The limit of quantification was 0.05 mcg/mL for both total plasma concentrations and plasma ultrafiltrate concentrations of all compounds.. The method was simple, rapid, and reliable and is currently being used to provide a TDM service to enhance the efficacious use of the 3 antibiotics.

Topics: Cefoperazone; Chromatography, High Pressure Liquid; Cilastatin; Cilastatin, Imipenem Drug Combination; Critical Illness; Drug Monitoring; Humans; Imipenem; Meropenem; Plasma; Sulbactam; Tandem Mass Spectrometry

Antibiotic dosing is challenge in critically ill patients undergoing renal replacement therapy. Our aim was to evaluate the pharmacokinetic and pharmacodynamic (PK/PD) characteristics of meropenem and vancomycin in patients undergoing SLED.. Consecutive ICU patients undergoing SLED and receiving meropenem and/or vancomycin were prospectively evaluated. Serial blood samples were collected before, during, and at the end of SLED sessions. Antimicrobial concentrations were determined using a validated HPLC method. Noncompartmental PK analysis was performed. AUC was determined for vancomycin. For meropenem, time above MIC was calculated.. SLED clearances of meropenem and vancomycin were 3-fold higher than the clearance described by continuous methods. Despite this finding, overall high PK/PD target attainments were obtained, except for at higher MICs. We suggest a maintenance dose of 1 g TID or BID of meropenem. With vancomycin, a more individualized approach using therapeutic drug monitoring should be used, as commercial assays are available.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Critical Illness; Female; Humans; Hybrid Renal Replacement Therapy; Intensive Care Units; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Vancomycin; Young Adult

Beta-lactam anti-infective levels after standard dosing have been shown to be subtherapeutic when renal clearance is augmented.. To determine if piperacillin and meropenem are found to be in their therapeutic range in infected critically ill patients when administered by continuous intravenous infusion (CII) assisted by a therapeutic drug monitoring (TDM) report issued by the pharmacy service.. This prospective non-controlled intervention study evaluated septic patients in an intensive care unit. Patients received a loading dose of meropenem or piperacillin-tazobactam and the antibiotics were afterwards administered by CII. Blood concentrations were determined by high-performance liquid chromatography assays. The adequacy of β-lactam therapy in the cohort subjected to intervention was assessed by determining whether plasma levels during CII were >4 times the informed minimum inhibitory concentration during the first 96 hours of treatment.. A total of 124 patients were subject to TDM during antibiotic treatment but, for the analysis of the fulfilment of pharmacodynamic requirements, data from 31/124 (25%) were excluded. Of the whole cohort of treatment courses, 57/93 (61.3%) reached the target level. Plasma levels were adequate in 41/70 (58.6%) and 16/23 (69.6%) of the patients treated with piperacillin-tazobactam and meropenem, respectively. Globally, recommendations based on TDM results were followed in 35/93 (37.6%) of the treatment courses.. The results of the study show that, in critically ill patients with sepsis, there is a significant proportion of treatment courses where target levels are not reached even if the antibiotics are administered by CII and TDM support is provided by the pharmacy service. This TDM support should be offered on a real-time basis to be really useful.

Topics: Aged; Anti-Bacterial Agents; Cohort Studies; Critical Illness; Drug Monitoring; Female; Humans; Infusions, Intravenous; Male; Meropenem; Middle Aged; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Sepsis

Topics: Anti-Bacterial Agents; Critical Illness; Cross Infection; Humans; Meropenem; Pneumonia; Thienamycins

Beta-lactams (BL), the most commonly prescribed class of antibiotics, are recommended as the first-line therapy for multiple indications in infectious disease guidelines. Meropenem (MERO) is frequently used in intensive care units (ICU) to treat bacterial infections with or without sepsis. The pharmacokinetics of MERO display a large variability in patients admitted to ICUs due to altered pathophysiology. The aim of this study was to perform an external evaluation of published population pharmacokinetic models of MERO in order to test their predictive performance in a cohort of ICU adult patients.. A literature search in PubMed/Medline database was made following the PRISMA statement. External evaluation was performed using NONMEM software, and the bias and inaccuracy values were calculated.. An external validation dataset from the Timone Hospital in Marseille, France, included 84 concentration samples from 27 patients. Four models of MERO were identified according to the inclusion criteria of the study. None of the models presented acceptable values of bias and inaccuracy.. While performing external evaluations on some populations may confirm a model's suitability to diverse groups of patients, there is still some variability that cannot be explained nor solved by the procedure. This brings to light the difficulty to develop only one model for ICU patients and the need to develop one specific model to each population of critically ill patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Critical Illness; Female; Humans; Intensive Care Units; Male; Meropenem; Middle Aged; Models, Biological; Prospective Studies; Young Adult

Data of developmental pharmacokinetics (PK) of meropenem in critically ill infants and children with severe infections are limited. We assessed the population PK and defined the appropriate regimen to optimize treatment in this population based on developmental PK-pharmacodynamic (PD) analysis. Blood samples were collected from pediatric intensive care unit patients with severe infection treated with standard dosage regimens for meropenem. Population PK data were analyzed using NONMEM software. Fifty-seven patients (mean age, 2.96 years [range, 0.101 to 14.4]; mean body weight, 15.8 kg [range, 5.0 to 65.0]) were included. A total of 135 meropenem concentrations were obtainable for population PK modeling. The median number of samples per patients was 2 (range, 1 to 4). A two-compartment model with first-order elimination was optimal for PK modeling. Weight and creatinine clearance (estimated by the Schwartz formula) were significantly correlated with the PK parameters of meropenem. The probabilities of target attainment for pathogens with low MICs of 1 and 2 μg/ml were 87.5% and 68.6% following administration of 40 mg/kg/dose (every 8 h [q8h]) as a 4-h infusion and 98.0% and 73.3% with high MICs of 4 and 8 μg/ml following administration of 110 mg/kg/day as a continuous infusion in critically ill infants and children under 70%

Topics: Anti-Bacterial Agents; Child; Child, Preschool; Critical Illness; Humans; Infant; Meropenem; Microbial Sensitivity Tests; Thienamycins

Meropenem pharmacokinetics (PK) may be altered in patients with cirrhosis, hampering target attainment. We aimed to describe meropenem PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target.. Serum concentrations and covariates were obtained from patients with severe infections under meropenem treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate meropenem exposure to assess the PTA.. Fifty-four patients were enrolled in the study. Data were best described by a one-compartment linear model. The estimated typical mean value for clearance (CL) was 8.35 L/h and the estimated volume of distribution (V) was 28.2 L. Creatinine clearance (CLCR) and MELD score significantly influenced meropenem CL, and acute-on-chronic liver failure (ACLF) significantly affected V. Monte Carlo simulations showed that a lower meropenem dose would be needed as CLCR decreases and as the MELD score increases. Patients with ACLF would have lower peak meropenem concentrations but similar steady-state concentrations compared with patients with no ACLF.. Our study identified two new covariates that influence meropenem PK in patients with decompensated cirrhosis in addition to CLCR: MELD score and ACLF. Dosing regimens are recommended to reach several PK/PD targets considering these clinical variables and any MIC within the susceptibility range.

Topics: Anti-Bacterial Agents; Critical Illness; Humans; Liver Cirrhosis; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method

Optimization of antibiotic therapy is still urgently needed in critically ill patients. The aim of the ONTAI survey (online survey on the use of Therapeutic Drug Monitoring of antibiotics in intensive care units) was to evaluate which strategies intensive care physicians in Germany use to improve the quality of antibiotic therapy and what role a Therapeutic Drug Monitoring (TDM) plays.. Among the members of the German Society for Anaesthesiology and the German Society for Medical Intensive Care Medicine and Emergency Medicine, a national cross-sectional survey was conducted using an online questionnaire.. The questionnaire was completely answered by 398 respondents. Without TDM, prolonged infusion was judged to be the most appropriate dosing regimen for beta lactams. A TDM for piperacillin, meropenem and vancomycin was performed in 17, 22 and 75% of respondents, respectively. For all beta lactams, a TDM was requested more often than it was available. There was great uncertainty as to the optimal pharmacokinetic/pharmacodynamic index for beta-lactams. 86% of the respondents who received minimal inhibitory concentrations adapted the therapy accordingly.. German intensive care physicians are convinced of TDM for dose optimization. However, practical implementation, the determination of MICs and defined target values are still lacking.

Topics: Anti-Bacterial Agents; Critical Care; Critical Illness; Cross-Sectional Studies; Drug Monitoring; Germany; Humans; Intensive Care Units; Meropenem; Microbial Sensitivity Tests; Physicians; Piperacillin; Surveys and Questionnaires; Treatment Outcome; Vancomycin

To gather available meropenem pharmacokinetics and define drug dosing regimens for Asian critically ill patients receiving CRRT.. All necessary pharmacokinetic and pharmacodynamic data from Asian population were gathered to develop mathematic models with first order elimination. Meropenem concentration-time profiles were calculated to evaluate efficacy based on the probability of target attainment (PTA) of 40%fT. The recommended meropenem dosing regimen for Asian critically ill patients receiving CRRT with standard (20-25 mL/kg/h) and high (35 mL/kg/h) effluent rates was 750 mg q 8 h to manage Gram negative infections with expected MIC < 2 mg/L in virtual Asian patients. Some meropenem dosages from available clinical resources could not achieve the aforementioned target. The volume of distribution, body weights and nonrenal clearance significantly contributed to drug dosing adaptation especially in the specific population.. A meropenem regimen of 750 mg q 8 h was recommended for Asian critically ill patients receiving 2 different CRRT modalities with standard and high effluent rates. Clinical validation of these results is needed.

Topics: Acute Kidney Injury; Aged; Anti-Bacterial Agents; Asian People; Body Weight; Continuous Renal Replacement Therapy; Critical Care; Critical Illness; Drug Dosage Calculations; Female; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Models, Theoretical; Monte Carlo Method; Prospective Studies

Topics: Aged; Anti-Bacterial Agents; Critical Care Outcomes; Critical Illness; Drug Administration Schedule; Female; Hospital Mortality; Humans; Infusions, Intravenous; Intensive Care Units; Male; Meropenem; Microbial Sensitivity Tests; Proportional Hazards Models; Retrospective Studies; Sepsis

To determine the percentage of patients given standard doses of piperacillin/tazobactam or meropenem by continuous  infusion who achieved the target pharmacokinetic/pharmacodynamic  (PK/PD) index, which was defined as free concentrations four times  more than the minimum inhibitory concentration (CMI) for 100% of the  dosing interval (100% fT≥ 4 x MIC).. Preliminary data from a larger prospective clinical study  analysing the PK/PD behaviour of β-lactams antibiotics continuous  infusion (CI) in critical patients. The study was conducted in the  intensive care units of a tertiary university hospital for adults (June  2015-May 2017). Inclusion criteria: normal renal function (glomerular  renal function (GFR) CKD-EPI formula ≥ 60 mL/min/1.73 m2) and  treatment with standard dose β-lactams CI. Concentrations at steady  state (Css) conditions were determined using UHPLC-MS/MS. We  selected the highest susceptible MIC for all likely organisms according to  European Commitee on Antimicrobial Susceptibility Testing's (i.e.  piperacillin/tazobactam: 8 mg/L for enterobacteriaceae and 16 mg/L for  Pseudomonas aeruginosa; meropenem: 2 mg/L for any  microorganism). In addition, a subanalysis of patients was conducted using actual MIC values.. 61 patients were enrolled (25 to meropenem and 36 to  piperacillin/tazobactam). Average age was 59 (15) years and median  GFR rate was 95 mL/min/1.73 m2 (83-115). Median meropenem and  piperacillin free concentrations were 16 mg/L (11-29) and 40 mg/L (21- 51), respectively. 88% of patients treated with meropenem reached the  PK/PD target, without differences between both microorganisms. For  piperacillin/tazobactam, 61% and 11% of patients reached the target,  with enterobacteriaceae and Pseudomonas as suspected  microorganisms, respectively. The pathogen was isolated in 35 (57%)  patients: 94% reached the target PK/PD, without differences between  both antibiotic therapies.. Standard doses of meropenem CI are sufficient to  achieve a PK/PD target of 100% fT≥ 4 x MIC in suspected infections  with high MICs (Pseudomonas aeruginosa or enterobacteriaceae).  However, higher doses of piperacillin/tazobactam could be considered to  achieve this goal. In patients with isolated microorganisms, a  standard dose of both antibiotic therapies would be sufficient to achieve  the target. Therapeutic drug monitoring is highly recommended for  therapeutic optimization.. Objetivo: Determinar el porcentaje de pacientes, a los que se les  administró dosis estándar de piperacilina/tazobactam o meropenem en  perfusión continua, que alcanzaban el índice  farmacocinético/farmacodinámico diana definido como el 100% del  intervalo de administración en que las concentraciones de antibiótico  libre fueron cuatro veces iguales o superiores a la concentración mínima  inhibitoria (100% fT ≥ 4 x CMI).Método: Datos preliminares obtenidos de un estudio clínico prospectivo que analiza el comportamiento  farmacocinético/farmacodinámico de los antibióticos betalactámicos  administrados en perfusión continua en pacientes críticos. Se realizó en  unidades de cuidados intensivos de un hospital universitario de tercer  nivel, desde junio de 2015 a mayo de 2017. Criterios de inclusión:  adultos con función renal correcta (filtrado glomerular según la fórmula  CKD-EPI ≥ 60 ml/min/1,73 m2) y tratados con dosis estándar de  antibióticos betalactámicos en perfusión continua. Las concentraciones  en estado de equilibrio estacionario fueron determinadas mediante  cromatografía líquida acoplada a espectrometría de masas (UHPLC- MS/MS). Se utilizaron valores de concentración mínima  inhibitoria  teóricos para microorganismos más resistentes (piperacilina/ tazobactam: 16 mg/l para Pseudomonas aeruginosa y 8 mg/l para Enterobacteriaceae; meropenem: 2 mg/l, independientemente del  microorganismo). Además, se realizó un subanálisis de los pacientes con aislamiento microbiológico (concentraciones mínimas inhibitorias  reales).Resultados: Se incluyeron 61 pacientes (25 meropenem y 36  piperacilina/ tazobactam). Edad media 59 años (15), mediana de  filtrado glomerular 95 ml/min/1,73 m2 (83-115). Mediana de  concentraciones en estado de equilibrio estacionario libre: 16 mg/l (11- 29) meropenem y 40 mg/l (21-51) piperacilina. El 88% de los pacientes  tratados con meropenem alcanzaron el objetivo  farmacocinético/farmacodinámico, sin diferencias entre Enterobacteriaceae y Pseudomonas. En el caso de  piperacilina/tazobactam, el 61% y el 11% de los pacientes alcanzaron la  diana, considerando Enterobacteriaceae y Pseudomonas como  microorganismo sospechoso. Un total de 35 (57%) pacientes  presentaron aislamiento microbiológico. El 94% de ellos alcanzaron la  diana, sin diferencias entre los dos antibióticos.Conclusiones: Ante la sospecha de infecciones por microorganismos con concentraciones mínimas inhibitorias elevadas  (Pseudomonas aeruginosa o enterobacterias),

Topics: Adult; Aged; Anti-Bacterial Agents; Clinical Studies as Topic; Critical Illness; Cross Infection; Enterobacteriaceae Infections; Female; Hospitals, University; Humans; Infusions, Intravenous; Intensive Care Units; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Pseudomonas Infections; Tertiary Care Centers

Among long-stay critically ill patients in the adult intensive care unit (ICU), there are often marked changes in the complexity of the gut microbiota. However, it remains unclear whether such patients might benefit from enhanced surveillance or from interventions targeting the gut microbiota or the pathogens therein. We therefore undertook a prospective observational study of 24 ICU patients, in which serial faecal samples were subjected to shotgun metagenomic sequencing, phylogenetic profiling and microbial genome analyses. Two-thirds of the patients experienced a marked drop in gut microbial diversity (to an inverse Simpson's index of <4) at some stage during their stay in the ICU, often accompanied by the absence or loss of potentially beneficial bacteria. Intravenous administration of the broad-spectrum antimicrobial agent meropenem was significantly associated with loss of gut microbial diversity, but the administration of other antibiotics, including piperacillin/tazobactam, failed to trigger statistically detectable changes in microbial diversity. In three-quarters of ICU patients, we documented episodes of gut domination by pathogenic strains, with evidence of cryptic nosocomial transmission of

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Biodiversity; Critical Illness; Enterococcus faecium; Feces; Female; Gastrointestinal Microbiome; Humans; Intensive Care Units; Male; Meropenem; Metagenomics; Middle Aged; Prospective Studies

Therapeutic drug monitoring (TDM) of beta-lactam antibiotics has become a valuable tool to guide dosing in critically ill patients. The main goal of the study was to compare two routinely used techniques for beta-lactam TDM in intensive care unit (ICU) patient samples, namely isotope dilution liquid chromatography tandem mass spectrometry (ID-LC-MS/MS) and high-performance liquid chromatography combined with ultra-violet detection (HPLC-UV).. A set of 80 sera/plasma samples from ICU patients receiving therapeutic meropenem or piperacillin dosage was investigated. Sample duplicates and quality assessment samples were assayed in parallel with an in-house LC-MS/MS and a commercially available IVD HPLC-UV kit. A pharmacokinetic and pharmacodynamic (PK/PD) target with ≥ 22.5 mg/L for piperacillin and ≥ 8.0 mg/L for meropenem was used for medical assessment of trough sample (n = 40) antibiotic concentrations.. There was no difference between serum and Li-heparin plasmas. Concentration deviations were found for 4% of meropenem and 17% of piperacillin samples. Eliminating the influence of the systemic bias of approximately 10% for piperacillin, measurement discrepancies ≥ 25% between LC-MS/MS and HPLC-UV analyses were only observed for ≈ 4 - 6% of all samples. In the same way, identical PK/PD target attainment rates of 50 - 60% could be obtained.. After correction of the analytical bias for piperacillin measurements, both methods showed comparable results, also with respect to clinical decision limits. HPLC-UV analysis is an adequate TDM methodology for testing of beta-lactam antibiotics in centers where no special knowledge in LC-MS/MS based TDM is present. However, potential matrix effects, interferences, and calibration issues for both methods must be taken into account.

Topics: Anti-Bacterial Agents; Chromatography, High Pressure Liquid; Chromatography, Liquid; Critical Care; Critical Illness; Drug Monitoring; Humans; Meropenem; Piperacillin; Reproducibility of Results; Tandem Mass Spectrometry; Ultraviolet Rays

Nephrotoxins contribute to 20%-40% of acute kidney injury (AKI) cases in the intensive care unit (ICU). The combination of piperacillin-tazobactam (PTZ) and vancomycin (VAN) has been identified as nephrotoxic, but existing studies focus on extended durations of therapy rather than the brief empiric courses often used in the ICU. The current study was performed to compare the risk of AKI with a short course of PTZ/VAN to with the risk associated with other antipseudomonal β-lactam/VAN combinations.. The study included a retrospective cohort of 3299 ICU patients who received ≥24 but ≤72 hours of an antipseudomonal β-lactam/VAN combination: PTZ/VAN, cefepime (CEF)/VAN, or meropenem (MER)/VAN. The risk of developing stage 2 or 3 AKI was compared between antibiotic groups with multivariable logistic regression adjusted for relevant confounders. We also compared the risk of persistent kidney dysfunction, dialysis dependence, or death at 60 days between groups.. The overall incidence of stage 2 or 3 AKI was 9%. Brief exposure to PTZ/VAN did not confer a greater risk of stage 2 or 3 AKI after adjustment for relevant confounders (adjusted odds ratio [95% confidence interval] for PTZ/VAN vs CEF/VAN, 1.11 [.85-1.45]; PTZ/VAN vs MER/VAN, 1.04 [.71-1.42]). No significant differences were noted between groups at 60-day follow-up in the outcomes of persistent kidney dysfunction (P = .08), new dialysis dependence (P = .15), or death (P = .09).. Short courses of PTZ/VAN were not associated with a greater risk of short- or 60-day adverse renal outcomes than other empiric broad-spectrum combinations.

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cefepime; Cohort Studies; Critical Illness; Female; Humans; Intensive Care Units; Kidney Function Tests; Male; Meropenem; Middle Aged; Piperacillin, Tazobactam Drug Combination; Pseudomonas; Pseudomonas Infections; Severity of Illness Index; Vancomycin

Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Anti-Bacterial Agents; Critical Illness; Hemofiltration; Humans; Hydrostatic Pressure; Male; Meropenem

Several population pharmacokinetic (PopPK) models for meropenem dosing in ICU patients are available. It is not known to what extent these models can predict meropenem concentrations in an independent validation dataset when meropenem is infused continuously.. A PopPK model was developed with concentration-time data collected from routine care of 21 ICU patients (38 samples) receiving continuous infusion meropenem. The predictability of this model and seven other published PopPK models was studied using an independent dataset that consisted of 47 ICU patients (161 samples) receiving continuous infusion meropenem. A statistical comparison of imprecision (mean square prediction error) and bias (mean prediction error) was conducted.. A one-compartment model with linear elimination and creatinine clearance as a covariate of clearance best described our data. The mean ± SD parameter estimate for CL was 9.89 ± 3.71 L/h. The estimated volume of distribution was 48.1 L. The different PopPK models showed a bias in predicting serum concentrations from the validation dataset that ranged from -8.76 to 7.06 mg/L. Imprecision ranged from 9.90 to 42.1 mg/L.. Published PopPK models for meropenem vary considerably in their predictive performance when validated in an external dataset of ICU patients receiving continuous infusion meropenem. It is necessary to validate PopPK models in a target population before implementing them in a therapeutic drug monitoring program aimed at optimizing meropenem dosing.

Topics: Adult; Aged; Anti-Bacterial Agents; Critical Illness; Drug Monitoring; Female; Humans; Infusions, Intravenous; Male; Meropenem; Middle Aged; Models, Biological

Individualizing drug dosing regimens in critically ill patients on renal replacement therapy is a challenge to clinicians as guidelines are often imprecise and specific-validated pharmacokinetic software is unavailable.. A case of a septic patient on hemodialysis is presented, where a quick solution for antibiotic dose adjustment based on the application of pharmacokinetic principles was found.. The dose adjustment was made in two steps-the first step was to calculate total antibiotic clearance (using the formula: total drug clearance = dialysate flow rate × fraction of unbound drug in plasma + extrarenal clearance), and the second step was to calculate maintenance dose based on target plasma concentrations in steady-state (using the formula: maintenance dose = target plasma concentration × total drug clearance × dose interval).. After the doses of antibiotics were adjusted, the patient's condition gradually improved, with a drop in body temperature to normal values, a decrease in plasma levels of inflammatory parameters, and the emergence of spontaneous diuresis. The plasma concentration of vancomycin was within the recommended therapeutic range.. Specific pharmacokinetic software and measuring plasma concentrations of the drugs should be used for calculation of total drug clearance and dose adjustment whenever possible. However, if unavailable, basic pharmacokinetic formulas and principles could be successfully used instead to adjust the dose in critically ill patients on hemodialysis.

Topics: Aged; Anti-Bacterial Agents; Area Under Curve; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Male; Meropenem; Metabolic Clearance Rate; Renal Dialysis; Sepsis; Time Factors; Treatment Outcome; Vancomycin

Measurement of antibiotic concentrations is increasingly used to optimize antibiotic therapy. Plasma samples are typically used for this, but other matrices such as exhaled air could be an alternative.. We studied 11 spontaneously breathing intensive care unit patients receiving either piperacillin/tazobactam or meropenem. Patients exhaled in the ExaBreath® device, from which the antibiotic was extracted. The presence of antibiotics was also determined in the condensate found in the device and in the plasma.. Piperacillin or meropenem could be detected in the filter in 9 patients and in the condensate in 10. Seven patients completed the procedure as prescribed. In these patients the median quantity of piperacillin in the filter was 3083 pg/filter (range 988-203,895 pg/filter), and 45 pg (range 6-126 pg) in the condensate; meropenem quantity was 21,168 pg/filter, but the quantity in the condensate was below the lower limit of quantification. There was no correlation between the concentrations in the plasma and quantities detected in the filter or condensate.. Piperacillin and meropenem can be detected and quantified in exhaled air of non-ventilated intensive care unit patients; these quantities did not correlate with plasma concentrations of these drugs.

Topics: Anti-Bacterial Agents; Breath Tests; Chromatography, Liquid; Critical Illness; Exhalation; Feasibility Studies; Humans; Meropenem; Piperacillin, Tazobactam Drug Combination; Proof of Concept Study

Critically ill patients are frequently treated with empirical antibiotic therapy, including vancomycin and β-lactams. Recent evidence suggests an increased risk of acute kidney injury (AKI) in patients who received a combination of vancomycin and piperacillin-tazobactam (VPT) compared with patients who received vancomycin alone or vancomycin in combination with cefepime (VC) or meropenem (VM), but most studies were conducted predominately in the non-critically ill population. A retrospective cohort study that included 2,492 patients was conducted in the intensive care units of a large university hospital with the primary outcome being the development of any AKI. The rates of any AKI, as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, were 39.3% for VPT patients, 24.2% for VC patients, and 23.5% for VM patients (

Topics: Acute Kidney Injury; Aged; Cefepime; Critical Illness; Female; Humans; Incidence; Male; Meropenem; Middle Aged; Multivariate Analysis; Piperacillin; Retrospective Studies; Tazobactam; Vancomycin

To evaluate target attainment of empirically dosed continuous infusion piperacillin/tazobactam (TZP) and meropenem (MER) in critically ill patients.. Patients were sampled on a daily basis. TZP or MER concentrations were evaluated during the first two days antibiotic therapy. The lower limit of the target range was defined as unbound concentrations equaling 4 times the epidemiological cutoff value of P. aeruginosa. The upper limit of the target range was based on the risk of toxicity, i.e. unbound concentrations >160 mg/L for TZP and > 45 mg/L for MER. Multivariable logistic regression was used to evaluate factors associated with target attainment.. Data from 253 patients were analyzed. Overall, 76/205 (37.1%) and 36/48 (75%) of the patients receiving TZP or MER respectively, attained target concentrations. In multivariable analysis, estimated creatinine clearance was identified as a risk factor for target non-attainment (OR 0.988, 95%CI [0.982;0.994]). Patients receiving MER were more likely to attain target concentrations compared with patients receiving TZP (OR 6.02, 95%CI [2.12;18.4]).. Target attainment of empiric antibiotic therapy in critically ill patients was low (37%) for TZP and moderate (75%) for MER, despite the use of a loading dose and despite optimization of the mode of infusion.

Topics: Adult; Aged; Anti-Bacterial Agents; Creatinine; Critical Illness; Female; Humans; Kidney Function Tests; Meropenem; Middle Aged; Multivariate Analysis; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Risk Factors; Treatment Outcome

Topics: Aged; Anti-Bacterial Agents; beta-Lactamases; Chromatography, Liquid; Colistin; Critical Illness; Drug Therapy, Combination; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Meropenem; Microbial Sensitivity Tests; Microbial Viability; Middle Aged; Serum; Tandem Mass Spectrometry; Tigecycline

The pharmacokinetics (PK) of antibiotics change during sepsis and continuous renal replacement therapies in critically ill patients. Limited evidence exists on the use of the oXiris® high-adsorbent membrane.. To develop a PK/pharmacodynamic (PD) model for meropenem in critically ill sepsis patients undergoing continuous venovenous haemodiafiltration (CVVHDF) with the oXiris® membrane, and to design an optimal dosing regimen assessed according to the PTA.. A prospective, open-label, observational PK trial was performed (EUDRACT 2011-005902-30). We conducted PK studies (plasma and ultrafiltrate) for at least 24 h after concomitant administration of CVVHDF and meropenem 1 g q8h. We constructed a PK model using the non-linear mixed-effects approach (NONMEM 7.3). We evaluated the suitability of different dosage regimens using Monte Carlo simulations and calculated the PTA as the percentage of subjects achieving a given percentage of time above the MIC (fT>MIC).. The PK of meropenem was best captured by a two-open-compartment model with zero-order input kinetics and first-order elimination. Extracorporeal CL was 7.78 L/h [relative standard error (RSE) 16.45 L/h] and central compartment V (Vc) was 24.9 L (RSE 13.73 L). Simulations showed that, for susceptible Pseudomonas aeruginosa isolates (EUCAST MIC ≤2 mg/L) and attainment of 100%fT>MIC, 500 mg q8h given as extended (EI) or continuous infusion (CI) would be sufficient. For a target of 100%fT>4×MIC, CI of 3000 mg q24h or 2000 mg q8h administered as EI or CI would be required.. We have constructed a PK model of meropenem in sepsis patients undergoing CVVHDF using the oXiris® membrane. This tool will support physicians when calculating the optimal initial dose.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Continuous Renal Replacement Therapy; Critical Illness; Female; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Prospective Studies; Pseudomonas aeruginosa; Sepsis

In critically ill patients treated with meropenem, the proposed pharmacokinetics/pharmacodynamics (PK/PD) efficacy index is to keep the free drug concentration 4-5 times above the minimum inhibitory concentration (MIC) of the germ isolated, for 100% of the interval regimen. The objectives were to design a population pharmacokinetics model for meropenem in critically ill patients and to evaluate different dosage schemes that achieve the optimal PK/PD objectives.. This retrospective, observational, single-centre study included 80 critically ill patients (154 samples) treated with meropenem between May 2011 and December 2017. Patient data, concentrations, treatment and bacteriological variables were collected from electronic medical records. Total and free concentrations of meropenem were modelled in Pmetrics. Monte Carlo simulations were performed to assess the probability of achieving the PK/PD target for different dosage regimens. For patients with available data, the number of patients with a free concentration 4 times higher or lower than the observed MIC for the P. aeruginosa and E. coli was investigated.. A one-compartment model with first-order elimination adequately described serum total and free meropenem concentrations. The only variable that significantly influenced the elimination constant of meropenem was the creatinine clearance (CLcr) calculated using the CKD-EPI formula. The highest probability of achieving the pharmacodynamic objective was with 3-h infusion dosage regimens. Sixty percent and 89% of patients attained a free drug concentration 4 times above the MIC for P. aeruginosa and E. coli respectively.. This study proposed different dosing regimens depending on renal clearance strata and the MIC of the germ targeted.

Topics: Aged; Anti-Bacterial Agents; Computer Simulation; Critical Illness; Escherichia coli; Female; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Models, Biological; Monte Carlo Method; Pseudomonas aeruginosa; Statistics, Nonparametric

Optimal antibiotic exposure is a vital but challenging prerequisite for achieving clinical success in ICU patients.. To develop and externally validate a population pharmacokinetic model for continuous-infusion meropenem in critically ill patients and to establish a nomogram based on a routinely available marker of renal function.. A population pharmacokinetic model was developed in NONMEM® 7.3 based on steady-state meropenem concentrations (CSS) collected during therapeutic drug monitoring. Different serum creatinine-based markers of renal function were compared for their influence on meropenem clearance (the Cockcroft-Gault creatinine clearance CLCRCG, the CLCR bedside estimate according to Jelliffe, the Chronic Kidney Disease Epidemiology Collaboration equation and the four-variable Modification of Diet in Renal Disease equation). After validation of the pharmacokinetic model with independent data, a dosing nomogram was developed, relating renal function to the daily doses required to achieve selected target concentrations (4/8/16 mg/L) in 90% of the patients. Probability of target attainment was determined for efficacy (CSS ≥8 mg/L) and potentially increased likelihood of adverse drug reactions (CSS >32 mg/L).. In total, 433 plasma concentrations (3.20-48.0 mg/L) from 195 patients (median/P0.05 - P0.95 at baseline: weight 77.0/55.0-114 kg, CLCRCG 63.0/19.6-168 mL/min) were used for model building. We found that CLCRCG best described meropenem clearance (CL = 7.71 L/h, CLCRCG = 80 mL/min). The developed model was successfully validated with external data (n = 171, 73 patients). According to the nomogram, daily doses of 910/1480/2050/2800/3940 mg were required to reach a target CSS = 8 mg/L in 90% of patients with CLCRCG = 20/50/80/120/180 mL/min, respectively. A low probability of adverse drug reactions (<0.5%) was associated with these doses.. A dosing nomogram was developed for continuous-infusion meropenem based on renal function in a critically ill population.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Critical Illness; Female; Humans; Infusions, Intravenous; Male; Meropenem; Middle Aged; Nomograms; Retrospective Studies

Topics: Anti-Bacterial Agents; Cefepime; Critical Illness; Female; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Tazobactam

To describe the achievement of unbound β-lactam antibiotic concentration targets in a therapeutic drug monitoring (TDM) programme in critically ill patients, and the factors associated with failure to achieve a target concentration.. Plasma samples and clinical data were obtained for analysis from a single centre prospectively. Unbound concentrations of ceftriaxone, cefazolin, meropenem, ampicillin, benzylpenicillin, flucloxacillin and piperacillin were directly measured using ultracentrifugation. Factors associated with the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets or negative clinical outcomes were evaluated with binomial logistic regression.. TDM data from 330 patients, and 369 infection episodes, were included. The range of doses administered was 99.4% ± 45.1% relative to a standard daily dose. Dose increases were indicated in 33.1% and 63.4% of cases to achieve PK/PD targets of 100% fT>MIC and 100% fT>4×MIC, respectively. Dose reduction was indicated in 17.3% of cases for an upper PK/PD threshold of 100% fT>10×MIC. Higher protein bound β-lactams (ceftriaxone and benzylpenicillin) had better therapeutic target attainment (P < 0.01), but were prone to excessive dosing. Augmented renal clearance (calculated CLCR >130 mL/min) increased the odds of failure to achieve 100% fT>MIC and 100% fT>4×MIC (OR 2.47 and 3.05, respectively; P < 0.01).. Measuring unbound concentrations of β-lactams as part of a routine TDM programme is feasible and demonstrates that a large number of critically ill patients do not achieve predefined PK/PD targets. The clinical significance of this finding is unknown due to the lack of correlation between PK/PD findings and clinical outcomes.

Topics: Adult; Aged; Anti-Bacterial Agents; beta-Lactams; Ceftriaxone; Critical Illness; Drug Monitoring; Female; Humans; Logistic Models; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Piperacillin; Prospective Studies; Treatment Outcome

Meropenem plasma concentration above a pathogen's MIC over the whole dosing interval (100% ƒT>MIC) is a determinant of outcome in severe infections. Significant variability of meropenem pharmacokinetics is reported in ICU patients.. To characterize meropenem pharmacokinetics in variable CLCR or renal replacement therapy and assess the appropriateness of recommended regimens for MIC coverage.. A pharmacokinetic analysis (NONMEM) was conducted with external model validation. Patient characteristics were tested on meropenem clearance estimates, differentiated according to the presence/absence of continuous renal replacement therapy (CRRT, CLCRRT or CLno-CRRT). Simulations evaluated the appropriateness of recommended dosing for achieving 100% fT>MIC in 90% of patients.. A total of 101 patients were studied: median 63 years (range 49-70), 56% male, SAPS II 38 (27-48). 32% had a CLCR >60 mL/min, 49% underwent CRRT and 32% presented severe sepsis or septic shock. A total of 127 pathogens were documented: 76% Gram-negatives, 24% Gram-positives (meropenem MIC90 2 mg/L, corresponding to EUCAST susceptibility breakpoint). Three hundred and eighty plasma and 129 filtrate-dialysate meropenem concentrations were analysed: two-compartment modelling best described the data. Predicted meropenem CLno-CRRT was 59% lower in impaired (CLCR 30 mL/min) compared to normal (CLCR 100 mL/min) renal function. Simulations showed that recommended regimens appropriately cover MIC90 in patients with CLCR <60 mL/min. Patients with CLCR of 60 to <90 mL/min need 6 g/day to achieve appropriate coverage. In patients with CLCR ≥90 mL/min, appropriate exposure is achieved with increased dose, frequency of administration and infusion duration, or continuous infusion.. Recommended meropenem regimens are suboptimal in ICU patients with normal or augmented renal clearance. Modified dosing or infusion modalities achieve appropriate MIC coverage for optimized antibacterial efficacy in meropenem-susceptible life-threatening infections.

Topics: Aged; Anti-Bacterial Agents; Bacterial Infections; Computer Simulation; Critical Illness; Female; Humans; Male; Meropenem; Metabolic Clearance Rate; Middle Aged; Plasma; Prospective Studies; Renal Insufficiency; Renal Replacement Therapy

The objective of this study was to assess the achievement of pharmacokinetic/pharmacodynamic (PK/PD) targets of meropenem (MEM) in critically-ill patients with bloodstream infections (BSI) due to Klebsiella pneumoniae-carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) with MEM minimum inhibitory concentrations (MICs) ≥16 mg/L. Nineteen critically-ill patients with KPC-Kp BSI were given combination therapy including MEM, tigecycline, plus colistin or gentamicin (according to susceptibility testing). MEM was administered as an extended 3-hour infusion of 2 g every 8 hours, or adjusted according to renal function. MEM plasma concentrations were determined by high-performance liquid chromatography. PK/PD targets for MEM were defined as T > 40% 1×MIC and T > 40% 4×MIC. Possible synergisms between MEM and coadministered agents were assessed by time-kill assays based on plasma levels for MEM and on fixed plasma concentrations for the other agents. In none of 19 patients MEM reached any PK/PD target. The actual MEM MICs were 256, 512, and 1024 mg/L in 1, 3, and 15 isolates, respectively. However, theoretically, the PK/PD target of T > 40% 1×MIC could have been achieved in 95%, 68%, 32% and 0% of the isolates for MIC equal to 8, 16, 32, and 64 mg/L, respectively. No synergisms were observed between MEM and coadministered agents. In conclusion, high-dose MEM failed to reach PK/PD targets in 19 patients with BSI due to KPC-Kp with very high MEM MICs. On a theoretical basis, our results suggest a possible usefulness of MEM against resistant blood isolates with MICs up to 32 mg/L.

Topics: Aged; Anti-Bacterial Agents; Bacteremia; Bacterial Proteins; beta-Lactamases; Colistin; Critical Illness; Drug Synergism; Drug Therapy, Combination; Female; Gentamicins; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Minocycline; Thienamycins; Tigecycline

Since 2013, wounded and ill children from Syria have received treatment in Israel. Screening cultures indicated that multidrug-resistant (MDR) pathogens colonized 89 (83%) of 107 children. For 58% of MDR infections, the pathogen was similar to that identified during screening. MDR screening of these children is valuable for purposes of isolation and treatment.

Topics: Adolescent; Amikacin; Anti-Bacterial Agents; Armed Conflicts; Bacterial Infections; Child; Child, Preschool; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Hospitalization; Humans; Infant; Infant, Newborn; Israel; Male; Meropenem; Multiple Trauma; Syria; Thienamycins

Continuous infusion of meropenem is a candidate strategy for optimization of its pharmacokinetic/pharmacodynamic profile. However, plasma concentrations are difficult to predict in critically ill patients. Steady-state concentrations of meropenem were determined prospectively during continuous infusion in 32 surgical ICU patients (aged 21-85 years, body weight 55-125 kg, APACHE II 5-29, measured creatinine clearance 22.7-297 mL/min). Urine was collected for the quantification of renal clearance of meropenem and creatinine. Cystatin C was measured as an additional marker of renal function. Population pharmacokinetic models were developed using NONMEM(®) , which described total meropenem clearance and its relationship with several estimates of renal function (measured creatinine clearance CLCR , Cockcroft-Gault formula CLCG , Hoek formula, 1/plasma creatinine, 1/plasma cystatin C) and other patient characteristics. Any estimate of renal function improved the model performance. The strongest association of clearance was found with CLCR (typical clearance = 11.3 L/h × [1 + 0.00932 × (CLCR  - 80 mL/min)]), followed by 1/plasma cystatin C; CLCG was the least predictive covariate. Neither age, weight, nor sex was found to be significant. These models can be used to predict dosing requirements or meropenem concentrations during continuous infusion. The covariate CLCR offers the best predictive performance; if not available, cystatin C may provide a promising alternative to plasma creatinine.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Creatinine; Critical Illness; Cystatin C; General Surgery; Humans; Infusions, Intravenous; Kidney Function Tests; Meropenem; Middle Aged; Models, Biological; Prospective Studies; Thienamycins; Young Adult

We utilized the database of the Defining Antibiotic Levels in Intensive care unit patients (DALI) study to statistically compare the pharmacokinetic/pharmacodynamic and clinical outcomes between prolonged-infusion and intermittent-bolus dosing of piperacillin/tazobactam and meropenem in critically ill patients using inclusion criteria similar to those used in previous prospective studies.. This was a post hoc analysis of a prospective, multicentre pharmacokinetic point-prevalence study (DALI), which recruited a large cohort of critically ill patients from 68 ICUs across 10 countries.. Of the 211 patients receiving piperacillin/tazobactam and meropenem in the DALI study, 182 met inclusion criteria. Overall, 89.0% (162/182) of patients achieved the most conservative target of 50% fT>MIC (time over which unbound or free drug concentration remains above the MIC). Decreasing creatinine clearance and the use of prolonged infusion significantly increased the PTA for most pharmacokinetic/pharmacodynamic targets. In the subgroup of patients who had respiratory infection, patients receiving β-lactams via prolonged infusion demonstrated significantly better 30 day survival when compared with intermittent-bolus patients [86.2% (25/29) versus 56.7% (17/30); P = 0.012]. Additionally, in patients with a SOFA score of ≥9, administration by prolonged infusion compared with intermittent-bolus dosing demonstrated significantly better clinical cure [73.3% (11/15) versus 35.0% (7/20); P = 0.035] and survival rates [73.3% (11/15) versus 25.0% (5/20); P = 0.025].. Analysis of this large dataset has provided additional data on the niche benefits of administration of piperacillin/tazobactam and meropenem by prolonged infusion in critically ill patients, particularly for patients with respiratory infections.

Topics: Aged; Anti-Bacterial Agents; Blood Chemical Analysis; Critical Illness; Female; Humans; Infusions, Intravenous; Intensive Care Units; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Thienamycins; Treatment Outcome

Pseudallescheria boydii is a fungal organism known to affect immunocompromised patients. This organism is known to cause, in severe cases, invasive infection of various organs such as the central nervous, cardiovascular, and respiratory systems. We report an unusual case of pulmonary P. boydii pneumonia in an immunocompromised critically ill patient with a co-infection of Aspergillus fumigatus and Aspergillus terreus with ARDS. This case highlights the importance of a high index of suspicion for superimposed fungal infections in patients who are critically ill and immunocompromised. Uncommon fungal pathogens should be considered in the differential diagnosis of respiratory failure, especially if diagnostic markers such as galactomannan (from BAL and serum) or 1,3-beta-D-glucan are elevated. Further diagnostic interventions are warranted when insufficient clinical improvement is observed to prevent treatment failure and adverse outcomes.

Topics: Aged; Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; beta-Glucans; Clarithromycin; Coinfection; Critical Illness; Extracorporeal Membrane Oxygenation; Galactose; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Linezolid; Male; Mannans; Meropenem; Pneumonia; Pseudallescheria; Severe Acute Respiratory Syndrome; Thienamycins; Transplant Recipients; Voriconazole

The pharmacokinetics of β-lactam antibiotics have not been well defined in critically ill patients with cirrhosis.. We reviewed data from critically ill patients with cirrhosis and matched controls in whom routine therapeutic drug monitoring of two broad-spectrum β-lactam antibiotics (piperacillin/tazobactam and meropenem) had been performed. Serum drug concentrations were measured twice by high-performance liquid chromatography. Antibiotic pharmacokinetics were calculated using a one-compartment model. We considered that therapy was adequate when serum drug concentrations were between 4 and 8 times the minimal inhibitory concentration of Pseudomonas aeruginosa during optimal periods of time for each drug (≥ 50% for piperacillin/tazobactam; ≥ 40% for meropenem).. We studied 38 patients with cirrhosis (16 for piperacillin/tazobactam and 22 for meropenem) and 38 matched controls. Drug dosing was similar in the two groups. The pharmacokinetics analysis showed a lower volume of distribution of meropenem (P = 0.05) and a lower antibiotic clearance of piperacillin/tazobactam (P = 0.009) in patients with cirrhosis than in the matched controls. Patients with cirrhosis were more likely than those without cirrhosis to have excessive serum β-lactam concentrations (P = 0.015), in particular for piperacillin/tazobactam.. Standard β-lactam antibiotics regimens resulted in excessive serum concentrations in two thirds of the patients with cirrhosis. This was particularly true for piperacillin/tazobactam, probably because of reduced drug clearance.

Topics: Aged; Anti-Bacterial Agents; Belgium; Case-Control Studies; Chromatography, High Pressure Liquid; Critical Illness; Databases, Factual; Drug Monitoring; Female; Humans; Liver Cirrhosis; Logistic Models; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Multivariate Analysis; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Sepsis; Thienamycins

The objectives of this study were to determine the effects of obesity on unbound trough concentrations and on the achievement of pharmacokinetic (PK)/pharmacodynamic (PD) targets of piperacillin and meropenem in critically ill patients.. This study retrospectively analysed therapeutic-drug-monitoring data from ICU databases in Australia, Germany and Spain, as well as from a large PK study. The presence of obesity was defined as a BMI ≥30 kg/m(2), and patients were also categorized based on level of renal function. The presence of obesity was compared with unbound piperacillin and meropenem trough concentrations. We also used logistic regression to describe factors associated with the achievement of the PK/PD targets, an unbound concentration maintained above the MIC breakpoint (100% fT>MIC and 100% fT>4×MIC) of Pseudomonas aeruginosa.. In all, 1400 patients were eligible for inclusion in the study. The median age and weight were 67 years (IQR 52-76 years) and 79 kg (69-90 kg), respectively, and 65% of participants were male. Significantly lower median piperacillin trough concentrations [29.4 mg/L (IQR 17.0-58.0 mg/L)] were found in obese patients compared with non-obese patients [42.0 mg/L (21.5-73.5 mg/L)] (P = 0.001). There was no difference for meropenem trough concentrations [obese 10.3 mg/L (IQR 4.8-16.0 mg/L) versus non-obese 11.0 mg/L (4.3-18.5 mg/L); P = 0.296]. Using logistic regression, we found that the presence of obesity was not associated with achievement of 100% fT>MIC, but the use of prolonged infusion, a creatinine clearance ≤100 mL/min, increasing age and female gender were for various PK/PD targets for both piperacillin and meropenem (P < 0.05).. This large dataset has shown that the presence of obesity in critically ill patients may affect piperacillin, but not meropenem, unbound trough concentrations.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Australia; Critical Illness; Female; Germany; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Obesity; Piperacillin; Plasma; Pseudomonas aeruginosa; Retrospective Studies; Spain; Thienamycins; Young Adult

The aim of this study was the evaluation of the influence of the susceptibility patterns of Escherichia coli and Klebsiella pneumoniae isolates, specifically the presence of extended-spectrum β-lactamases and the geographical area (Europe and USA), on the meropenem dosing requirements in critically ill patients with different degrees of renal function by estimation of the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment. Additionally, estimation of the PK/PD breakpoints according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) approach was also an objective. Six dosing regimens were evaluated: 0.5 g, 1 g and 2 g every 8 h given as 0.5-h or 3-h infusions. Pharmacokinetic data were obtained from the literature, and susceptibility data to meropenem for E. coli and K. pneumoniae were collected from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) surveillance study. For the same dose level, the 3-h infusion provided a probability of target attainment (PTA) ≥90 % for minimum inhibitory concentration (MIC) values up to two-fold dilution higher than those obtained with the 0.5-h infusion. For E. coli, the cumulative fraction of response (CFR) was 100 % in most cases, and neither the dose nor the infusion length nor the geographical area significantly affected the probability to reach the target. With regards to K. pneumoniae, the CFR increased when increasing the dose and decreasing the creatinine clearance (CLCR). The CFR for Spanish and USA strains was higher than that calculated for European strains. Meropenem PK/PD breakpoints are dependent on the dose, infusion length and CLCR, ranging from 2 to 32 mg/L. Based on our results, meropenem administered as a extended infusion is the best option to treat infections due to E. coli and K. pneumoniae.

Topics: Algorithms; Anti-Bacterial Agents; beta-Lactamases; Critical Illness; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Europe; Female; Geography; Humans; Kidney Function Tests; Male; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method; Risk Factors; Thienamycins; United States

Melioidosis is increasing in incidence with newly recognized foci of melioidosis in the Americas, Africa, and elsewhere. This review describes the demographics, management, and outcomes of a large cohort of critically ill patients with melioidosis.. Data were extracted from two prospective databases-the Menzies School of Health Research Melioidosis Database (1989-2013) and the Royal Darwin Hospital ICU Melioidosis Database (2001-2013).. The Royal Darwin Hospital ICU is the only ICU in the tropical Top End of Northern Territory of Australia, an endemic area for melioidosis. The study included all patients with melioidosis admitted to Royal Darwin Hospital ICU from 1989 to 2013.. From 1989 to 2013, 207 patients with melioidosis required admission to ICU. Mortality reduced from 92% (1989-1997) to 26% (1998-2013) (p < 0.001). The reduced mortality coincided with the introduction of an intensivist-led service, meropenem, and adjuvant granulocyte colony-stimulating factor for confirmed melioidosis sepsis in 1998. Pneumonia was the presenting illness in 155 of 207 (75%). ICU melioidosis patients (2001-2013) had an Acute Physiology and Chronic Health Evaluation II score of 23, median length of stay in the ICU of 7 days, and median ventilation hours of 130 and one third required renal replacement therapy.. The mortality for critically ill patients with melioidosis in the Top End of the Northern Territory of Australia has substantially reduced over the past 24 years. The reduction in mortality coincided with the introduction of an intensivist-led model of care, the empiric use of meropenem, and adjunctive treatment with granulocyte colony-stimulating factor in 1998.

Topics: Anti-Bacterial Agents; APACHE; Australia; Comorbidity; Critical Illness; Female; Granulocyte Colony-Stimulating Factor; Humans; Incidence; Intensive Care Units; Length of Stay; Male; Melioidosis; Meropenem; Middle Aged; Prospective Studies; Residence Characteristics; Respiration, Artificial; Socioeconomic Factors; Thienamycins

β-lactam antibiotics may necessitate higher than licensed drug doses to achieve therapeutic exposures in critically ill patients. Therapeutic drug monitoring can be used to guide dosing so as to maximise therapeutic effect whilst reducing the likelihood of exposure-related toxicity.. A retrospective review of critically ill patients identified those that received higher than licensed doses of either meropenem (3-6 g/day) or piperacillin-tazobactam (16 g-2 g/day) (i.e. high-dose group) guided by therapeutic drug monitoring. β-lactam-associated toxicities were compared with a patient group of similar age, sex, body mass index and admission diagnosis that received licensed doses of either antibiotic.. Mean daily doses were more than 40% higher in the high-dose groups for each antibiotic. There were no significant differences between the high-dose and licensed-dose groups in terms of hepatocellular derangement (17.9% vs. 31.8%, P=0.25 for meropenem and 17.4% vs. 16.0%, P=0.90 for piperacillin-tazobactam), cholestasis (28.0% vs. 13.6%, P=0.32 for meropenem and 13.0% vs. 4.0%, P=0.26 for piperacillin-tazobactam), need for continuous renal replacement therapy (0% vs. 9.1%, P=0.10 for meropenem and 0% vs. 8.0%, P=0.16 for piperacillin-tazobactam), seizure incidence (7.1% vs. 4.5%, P=0.70 for meropenem and nil for either piperacillin-tazobactam group), thrombocytopenia (9.1% vs. 10.7%, P=0.85 for meropenem and 4.0% vs. 4.3% for piperacillin-tazobactam), or neutropenia (4.5% vs. 3.6%, P=0.95 for meropenem and 0.0% vs. 4.3% for piperacillin-tazobactam).. Higher than licensed doses of meropenem and piperacillin-tazobactam guided by therapeutic drug monitoring were not associated with additional toxicities. Larger prospective studies are required to confirm the clinical utility of higher than licensed dosing.

Topics: Adult; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Chemical and Drug Induced Liver Injury; Cholestasis; Critical Illness; Drug Monitoring; Female; Humans; Male; Meropenem; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Renal Replacement Therapy; Retrospective Studies; Seizures; Thienamycins; Thrombocytopenia

Severe pathophysiological changes in critical illness can lead to dramatically altered antimicrobial pharmacokinetics (PK). The additional effect of obesity on PK potentially increases the challenge for effective dosing. The aim of this prospective study was to describe the population PK of meropenem for a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients prescribed meropenem were recruited into the following three body mass index (BMI) groups: nonobese (18.5 to 29.9 kg/m(2)), obese (30.0 to 39.9 kg/m(2)), and morbidly obese (≥40 kg/m(2)). Serial plasma samples were taken, and meropenem concentrations were determined using a validated chromatographic method. Population PK analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Nineteen critically ill patients with different BMI categories were enrolled. The patients' mean ± standard deviation (SD) age, weight, and BMI were 49 ± 15.9 years, 95 ± 22.0 kg, and 33 ± 7.0 kg/m(2), respectively. A two-compartment model described the data adequately. The mean ± SD parameter estimates for the final covariate model were as follows: clearance (CL), 15.5 ± 6.0 liters/h; volume of distribution in the central compartment (V1), 11.7 ± 5.8 liters; intercompartmental clearance from the central compartment to the peripheral compartment, 25.6 ± 35.1 liters h(-1); and intercompartmental clearance from the peripheral compartment to the central compartment, 8.32 ± 12.24 liters h(-1) Higher creatinine clearance (CLCR) was associated with a lower probability of target attainment, with BMI having little effect. Although obesity was found to be associated with an increased V1, dose adjustment based on CLCR appears to be more important than patient BMI.

Topics: Adult; Aged; Anti-Bacterial Agents; Body Mass Index; Critical Illness; Female; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Obesity; Prospective Studies; Thienamycins

This study aimed to describe the pharmacokinetic (PK) characteristics of meropenem in children with severe infections and to assess the pharmacokinetic/pharmacodynamic (PK/PD) profiles of various meropenem dosage regimens in these patients. Fourteen children with severe infections received intravenous (i.v.) bolus doses of meropenem (20 mg/kg/dose) every 8 h (q8h). Serum samples were obtained before and serially after the second dose of meropenem, and a population PK analysis was performed. The final model was used to simulate serum concentration-time profiles with various dosage regimens. The PK/PD target was to achieve a serum meropenem concentration higher than the minimum inhibitory concentration (MIC) of the causative organism (i.e. Pseudomonas aeruginosa and Enterobacteriaceae) for ≥40% of the dosing interval (40%T>MIC). The median age and weight of the children were 6.0 years and 20.0 kg, respectively. Meropenem serum concentration-time profiles were best described by a two-compartmental model with first-order elimination. The simulations showed that the probabilities of target attainment (PTAs) for organisms with an MIC of 1 mg/L were 0.678 and 1.000 following i.v. bolus and 3-h infusion of meropenem (20 mg/kg/dose), respectively. Using a 3-h infusion of a 20 mg/kg/dose, the PTA was 0.999 and 0.765 for organisms with MICs of 4 mg/L and 8 mg/L, respectively. Meropenem given as i.v. bolus doses of 20 mg/kg/dose q8h appeared to be inadequate for PK/PD target attainment for organisms with an MIC of 1 mg/L. The simulations showed that meropenem administration via a 3-h infusion using the same dose improved the PTA.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Child; Child, Preschool; Computer Simulation; Critical Illness; Enterobacteriaceae; Enterobacteriaceae Infections; Female; Humans; Male; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Serum; Thienamycins; Time Factors

Pharmacokinetics of meropenem differ widely in the critically ill population. It is imperative to maintain meropenem concentrations above the inhibitory concentrations for most of the interdose interval. A population pharmacokinetic/pharmacodynamic model was developed to determine the probability of target attainment for 3-hour and 30-minute infusion regimens in this population.. This study was performed in an intensive care setting among adult patients who were initiated on meropenem at a dose of 1000 mg. Multiple blood specimens were collected at predetermined time points during the interdose period, and meropenem concentrations were measured using high performance liquid chromatography. Using Pmetrics, a pharmacokinetic/pharmacodynamic model was developed and validated. Monte Carlo simulation was performed, and probability of target attainment (100% T > minimum inhibitory concentration (MIC), with a probability >0.9) for doubling MICs was determined for different regimens of meropenem.. A 2-compartment multiplicative gamma error model best described the population parameters from 34 patients. The pharmacokinetic parameters used in the final model were Ke (elimination rate constant from the central compartment), Vc (volume of distribution of central compartment), KCP and KPC (intercompartmental rate constants), and IC2 (the fitted amount of meropenem in the peripheral compartment). Inclusion of creatinine clearance (CLcreat) and body weight as covariates improved the model prediction (Ke = Ke0 × (Equation is included in full-text article.), Vc = Vc0 × Weight). The Ke and Vc [geometric mean (range)] of the individuals were 0.54 (0.01-2.61)/h and 9.36 (4.35-21.62) L, respectively. The probability of attaining the target, T > MIC of 100%, was higher for 3-hour infusion regimens compared with 30-minute infusion regimens for all ranges of CLcreat.. This study emphasizes that extended regimens of meropenem are preferable for treating infections caused by bacteria with higher MICs. The nonparametric analysis using body weight and CLcreat as covariate adequately predicted the pharmacokinetics of meropenem in critically ill patients with a wide range of renal function.

Topics: Anti-Bacterial Agents; Computer Simulation; Critical Illness; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Meropenem; Monte Carlo Method; Statistics, Nonparametric; Thienamycins

Recent studies show that suboptimal blood levels of β-lactam antibiotics are present in intensive care unit (ICU) patients. A common reference method for assessing drug concentrations is liquid chromatography coupled with mass-spectrometry (LC-MS) which is highly accurate but rarely available outside reference centres. Thus, our aim was to develop a microbiological method for monitoring β-lactam antibiotic serum levels which could be used at any hospital with a microbiological laboratory.. The method was developed as a 96-well broth microdilution format to assess the concentrations of cefotaxime (CTX), meropenem (MER), and piperacillin (PIP). Patient serum containing antibiotics were diluted in suspensions of bacteria with known minimal inhibitory concentrations (MICs). Serum antibiotic concentrations were calculated by dividing the MIC with the dilution factor at which the serum inhibited growth of the bacterial suspension. Serum (n=88) from ICU patients at four hospitals in south-east Sweden were analysed and compared to LC-MS analysis.. The overall accuracy and precision for spiked samples and patient samples was within the pre-set target of ±20.0% for all drugs. There was a significant correlation between the microbiological assay and LC-MS for the patient samples (CTX: r=0.86, n=31; MER: r=0.96, n=11; PIP: r=0.88, n=39) and the agreement around the clinical cut-off for CTX (4.0mg/l), MER (2.0mg/l) and PIP (16.0mg/l) was 90%, 100% and 87%, respectively.. The microbiological method has a performance for determination of serum levels of meropenem, piperacillin and cefotaxime suitable for clinical use. It is an inexpensive method applicable in any microbiology laboratory.

Topics: Anti-Bacterial Agents; Bacteria; Bacteriological Techniques; beta-Lactams; Chromatography, Liquid; Critical Illness; Humans; Mass Spectrometry; Meropenem; Microbial Sensitivity Tests; Sweden; Thienamycins

The objective of this study was to propose an optimal treatment regimen of meropenem in critically ill patients with severe nosocomial pneumonia.. Among 55 patients in intensive care treated with 1 g of meropenem every 8 h for severe nosocomial pneumonia, 30 were assigned to intermittent infusion (II; over 0.5 h) and 25 to extended infusion (EI; over 3 h) groups. Based on plasma and epithelial lining fluid (ELF) concentrations determined at steady-state, pharmacokinetic modelling and Monte Carlo simulations were undertaken to assess the probability of attaining drug concentrations above the MIC for 40%-100% of the time between doses (%T > 1-fold and 4-fold MIC), for 1 or 2 g administered by either method.. Penetration ratio, measured by the ELF/plasma ratio of AUCs, was statistically higher in the EI group than in the II group (mean ± SEM: 0.29 ± 0.030 versus 0.20 ± 0.033, P = 0.047). Considering a maximum susceptibility breakpoint of 2 mg/L, all dosages and modes of infusions achieved 40%-100% T > 1-fold MIC in plasma, but none did so in ELF, and only the 2 g dose over EI achieved 40%-100% T > 4-fold MIC in plasma.. The optimum regimen to treat severe nosocomial pneumonia was 2 g of meropenem infused over 3 h every 8 h. This regimen achieved the highest pharmacodynamic targets both in plasma and in ELF.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Critical Illness; Cross Infection; Female; Humans; Infusions, Intravenous; Male; Meropenem; Middle Aged; Plasma; Pneumonia, Bacterial; Prospective Studies; Respiratory Mucosa; Thienamycins; Young Adult

To describe the interstitial fluid (ISF) and plasma pharmacokinetics of meropenem in patients on continuous venovenous haemodiafiltration (CVVHDF).. This was a prospective observational pharmacokinetic study. Meropenem (500 mg) was administered every 8 h. CVVHDF was targeted as a 2-3 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m2 and a blood flow rate of 200 mL/min. Serial blood (pre- and post-filter), filtrate/dialysate and ISF concentrations were measured on 2 days of treatment (Profiles A and B). Subcutaneous tissue ISF concentrations were determined using microdialysis.. A total of 384 samples were collected. During Profile A, the comparative median (IQR) ISF and plasma peak concentrations were 13.6 (12.0-16.8) and 40.7 (36.6-45.6) mg/L and the trough concentrations were 2.6 (2.4-3.4) and 4.9 (3.5-5.0) mg/L, respectively. During Profile B, the ISF trough concentrations increased by ∼40%. Meropenem ISF penetration was estimated at 63% (60%-69%) and 69% (65%-74%) for Profiles A and B, respectively, using comparative plasma and ISF AUCs. For Profile A, the plasma elimination t1/2 was 3.7 (3.3-4.0) h, the volume of distribution was 0.35 (0.25-0.46) L/kg, the total clearance was 4.1 (4.1-4.8) L/h and the CVVHDF clearance was 2.9 (2.7-3.1) L/h.. This is the first known report of concurrent plasma and ISF concentrations of a meropenem antibiotic during CVVHDF. We observed that the ISF concentrations of meropenem were significantly lower than the plasma concentrations, although the present dose was appropriate for infections caused by intermediately susceptible pathogens (MIC≤4 mg/L).

Topics: Aged; Anti-Bacterial Agents; Area Under Curve; Critical Illness; Extracellular Fluid; Female; Hemodiafiltration; Humans; Intensive Care Units; Male; Meropenem; Middle Aged; Plasma; Prospective Studies; Renal Replacement Therapy; Thienamycins

Population pharmacokinetic analyses can be applied to predict optimized dosages for individual patients. The aim of this study was to compare the prediction performance of the published population pharmacokinetic models for meropenem in critically ill patients. We coded the published population pharmacokinetic models with covariate relationships into dosing software to predict unbound meropenem concentrations measured in a separate cohort of critically ill patients. The agreements between the observed and predicted concentrations were evaluated with Bland-Altman plots. The absolute and relative bias and precision of the models were determined. The clinical implications of the results were evaluated according to whether dose adjustments were required from the predictions to achieve a meropenem concentration of >2 mg/liter throughout the dosing interval. A total of 157 free meropenem concentrations from 56 patients were analyzed. Eight published population pharmacokinetic models were compared. The models showed an absolute bias in predicting the unbound meropenem concentrations from a mean percent difference (95% confidence interval [CI]) of -108.5% (-119.9% to -97.3%) to 19.9% (7.3% to 32.7%), while absolute precision ranged from -249.1% (-263.4% to -234.8%) to 31.9% (17.6% to 46.2%) and -178.9% (-196.9% to -160.9%) to 175.0% (157.0% to 193.0%). A dose change was required in 44% to 64% of the concentration results. Seven of the eight equations evaluated underpredicted free meropenem concentrations. In conclusion, the overall accuracy of these models supports their inclusion in dosing software and application for individualizing meropenem doses in critically ill patients to increase the likelihood of achievement of optimal antibiotic exposures.

Topics: Adult; Anti-Bacterial Agents; Critical Illness; Drug Monitoring; Humans; Meropenem; Middle Aged; Models, Biological; Thienamycins

Adequate empirical antibiotic dose selection for critically ill burn patients is difficult due to extreme variability in drug pharmacokinetics. Therapeutic drug monitoring (TDM) may aid antibiotic prescription and implementation of initial empirical antimicrobial dosage recommendations. This study evaluated how gradual TDM introduction altered empirical dosages of meropenem and imipenem/cilastatin in our burn ICU.. Imipenem/cilastatin and meropenem use and daily empirical dosage at a five-bed burn ICU were analyzed retrospectively. Data for all burn admissions between 2001 and 2011 were extracted from the hospital's computerized information system. For each patient receiving a carbapenem, episodes of infection were reviewed and scored according to predefined criteria. Carbapenem trough serum levels were characterized. Prior to May 2007, TDM was available only by special request. Real-time carbapenem TDM was introduced in June 2007; it was initially available weekly and has been available 4 days a week since 2010.. Of 365 patients, 229 (63%) received antibiotics (109 received carbapenems). Of 23 TDM determinations for imipenem/cilastatin, none exceeded the predefined upper limit and 11 (47.8%) were insufficient; the number of TDM requests was correlated with daily dose (r=0.7). Similar numbers of inappropriate meropenem trough levels (30.4%) were below and above the upper limit. Real-time TDM introduction increased the empirical dose of imipenem/cilastatin, but not meropenem.. Real-time carbapenem TDM availability significantly altered the empirical daily dosage of imipenem/cilastatin at our burn ICU. Further studies are needed to evaluate the individual impact of TDM-based antibiotic adjustment on infection outcomes in these patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Infections; Body Surface Area; Burn Units; Burns; Carbapenems; Cilastatin; Cilastatin, Imipenem Drug Combination; Cohort Studies; Computer Systems; Critical Illness; Drug Combinations; Drug Monitoring; Female; Humans; Imipenem; Length of Stay; Male; Meropenem; Middle Aged; Retrospective Studies; Thienamycins; Young Adult

Pathophysiological changes during the early phase of severe sepsis and septic shock in critically ill patients, resulting in altered pharmacokinetic (PK) patterns for antibiotics, are important factors influencing therapeutic success. The aims of this study were (i) to reveal the population PK parameters and (ii) to assess the probability of target attainment (PTA) for meropenem. The PK studies were carried out following administration of 1 g of meropenem every 8 h during the first 24 h of severe sepsis and septic shock in nine patients, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the free plasma drug concentration remains above the MIC (fT>MIC) and 80% fT>MIC. The volume of distribution (V) and total clearance (CL) of meropenem in these patients were 23.7 liters and 7.82 liters/h, respectively. For pathogens with MICs of 4 μg/ml, the PTAs of 40% fT>MIC following administration of meropenem as a 1-h infusion of 1 g every 8 h and a 4-h infusion of 0.5 g every 8 h were 92.52% and 90.29%, respectively. For pathogens with MICs of 2 μg/ml in immunocompromised hosts, the PTAs of 80% fT>MIC following administration of 1-h and 4-h infusions of 2 g of meropenem every 8 h were 84.32% and 94.72%, respectively. These findings indicated that the V of meropenem was greater and the CL of meropenem was lower than the values obtained in a previous study with healthy subjects. The maximum recommended dose, i.e., 2 g of meropenem every 8 h, may be required for treatment of life-threatening infections in this patient population.

Topics: Adult; Aged; Critical Illness; Female; Humans; Intensive Care Units; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Monte Carlo Method; Sepsis; Shock, Septic; Thienamycins

A 35-year-old patient in intensive care with severe burn injury developed episodes of sepsis. Blood culture yielded a multidrug-resistant Pseudomonas aeruginosa and treatment was commenced with amikacin (minimum inhibitory concentration (MIC) 2-4 mg/L, dose 20 mg/kg adjusted body weight 24-hourly) and meropenem (MIC 8 mg/L, dose 2 g IV 8-hourly and later 6-hourly). Despite the use of extended infusions with β-lactam therapeutic drug monitoring and doses that were more than 2.5 times higher than standard meropenem doses, resistance emerged. This case report describes the application of therapeutic drug monitoring to optimize β-lactam therapy in a difficult-to-treat critically ill patient.

Topics: Adult; Amikacin; Anti-Bacterial Agents; beta-Lactams; Critical Illness; Dose-Response Relationship, Drug; Drug Monitoring; Drug Resistance, Bacterial; Female; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Sepsis; Thienamycins

The pharmacokinetics of meropenem have not yet been examined in Japanese patients receiving Continuous venovenous hemodialysis (CVVHD). The aim of this clinical investigation was to determine the pharmacokinetic parameters of meropenem in critically ill patients receiving CVVHD in order to estimate dosing regimens for the patient population in Japan. The values of pharmacokinetic parameters were 17.5 ± 5.6 l for V1, 1.27 ± 0.38 h(-1) for K12, 0.71 ± 0.40 h(-1) for K21 and 0.17 ± 0.02 h(-1) for K10. Based on these mean parameters (V1, K12, K21 and K10), time above MIC (T > MIC) values were estimated at different MICs using various meropenem regimens. For bacteria with a meropenem MIC of ≤ 2 μg/ml, a dosing regimen of 0.25 g every 24 h achieved more than 40% T > MIC. For a MIC of 4 μg/ml, all the regimens tested, except for 0.25 g every 24 h, achieved more than 40% T > MIC. For a MIC of 16 μg/ml, dosing regimens of 0.5 g every 8 h, 1 g every 12 h, and 1 g every 8 h achieved 40% T > MIC, reaching the pharmacokinetic-pharmacodynamic target range. This is the first study to examine the pharmacokinetics of meropenem under a CVVHD setting in Japan. The pharmacokinetic-pharmacodynamic profile of dosing regimens tested in this study will assist in selecting the appropriate meropenem regimens for patients receiving CVVHD.

Topics: Adult; Aged; Anti-Bacterial Agents; Asian People; Critical Illness; Female; Humans; Male; Meropenem; Middle Aged; Renal Dialysis; Thienamycins

Meropenem dosing in critically ill patients with septic shock and continuous renal replacement therapy (CRRT) is complex, with the recommended maintenance doses being 500 mg to 1,000 mg every 8 h (q8h) to every 12 h. This multicenter study aimed to describe the pharmacokinetics (PKs) of meropenem in this population to identify the sources of PK variability and to evaluate different dosing regimens to develop recommendations based on clinical parameters. Thirty patients with septic shock and CRRT receiving meropenem were enrolled (153 plasma samples were tested). A population PK model was developed with data from 24 patients and subsequently validated with data from 6 patients using NONMEM software (v.7.3). The final model was characterized by CL = 3.68 + 0.22 · (residual diuresis/100) and V = 33.00 · (weight/73)(2.07), where CL is total body clearance (in liters per hour), residual diuresis is the volume of residual diuresis (in milliliters per 24 h), and V is the apparent volume of distribution (in liters). CRRT intensity was not identified to be a CL modifier. Monte Carlo simulations showed that to maintain concentrations of the unbound fraction (fu ) of drug above the MIC of the bacteria for 40% of dosing interval T (referred to as 40% of the ƒ uT >MIC), a meropenem dose of 500 mg q8h as a bolus over 30 min would be sufficient regardless of the residual diuresis. If 100% of the ƒ uT >MIC was chosen as the target, oligoanuric patients would require 500 mg q8h as a bolus over 30 min for the treatment of susceptible bacteria (MIC < 2 mg/liter), while patients with preserved diuresis would require the same dose given as an infusion over 3 h. If bacteria with MICs close to the resistance breakpoint (2 to 4 mg/liter) were to be treated with meropenem, a dose of 500 mg every 6 h would be necessary: a bolus over 30 min for oligoanuric patients and an infusion over 3 h for patients with preserved diuresis. Our results suggest that residual diuresis may be an easy and inexpensive tool to help with titration of the meropenem dose and infusion time in this challenging population.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Critical Illness; Female; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Prospective Studies; Renal Replacement Therapy; Shock, Septic; Thienamycins

Ex vivo experiments in extracorporeal membrane oxygenation (ECMO) circuits have identified octanol-water partition coefficient (logP, a marker of lipophilicity) and protein binding (PB) as key drug factors affecting pharmacokinetics (PK) during ECMO. Using ovine models, in this study we investigated whether these drug properties can be used to predict PK alterations of antimicrobial drugs during ECMO.. Single-dose PK sampling was performed in healthy sheep (HS, n = 7), healthy sheep on ECMO (E24H, n = 7) and sheep with smoke inhalation acute lung injury on ECMO (SE24H, n = 6). The sheep received eight study antimicrobials (ceftriaxone, gentamicin, meropenem, vancomycin, doripenem, ciprofloxacin, fluconazole, caspofungin) that exhibit varying degrees of logP and PB. Plasma drug concentrations were determined using validated chromatographic techniques. PK data obtained from a non-compartmental analysis were used in a linear regression model to predict PK parameters based on logP and PB.. We found statistically significant differences in pH, haemodynamics, fluid balance and plasma proteins between the E24H and SE24H groups (p < 0.001). logP had a strong positive linear relationship with steady-state volume of distribution (Vss) in both the E24H and SE24H groups (p < 0.001) but not in the HS group (p = 0.9) and no relationship with clearance (CL) in all study groups. Although we observed an increase in CL for highly PB drugs in ECMO sheep, PB exhibited a weaker negative linear relationship with both CL (HS, p = 0.01; E24H, p < 0.001; SE24H, p < 0.001) and Vss (HS, p = 0.01; E24H, p = 0.004; SE24H, p = 0.05) in the final model.. Lipophilic antimicrobials are likely to have an increased Vss and decreased CL during ECMO. Protein-bound antimicrobial agents are likely to have reductions both in CL and Vss during ECMO. The strong relationship between lipophilicity and Vss seen in both the E24H and SE24H groups indicates circuit sequestration of lipophilic drugs. These findings highlight the importance of drug factors in predicting antimicrobial drug PK during ECMO and should be a consideration when performing and interpreting population PK studies.

Topics: Animals; Anti-Infective Agents; Carbapenems; Caspofungin; Ceftriaxone; Ciprofloxacin; Critical Illness; Doripenem; Echinocandins; Extracorporeal Membrane Oxygenation; Fluconazole; Gentamicins; Lipopeptides; Meropenem; Models, Theoretical; Sheep; Sheep, Domestic; Thienamycins; Vancomycin

Topics: Anti-Bacterial Agents; Critical Illness; Drug Dosage Calculations; Female; Gram-Negative Bacterial Infections; Humans; Imipenem; Male; Medication Errors; Meropenem; Metabolic Clearance Rate; Middle Aged; Renal Dialysis; Thienamycins

To describe the effect of different renal replacement therapy modalities and settings on the clearance of meropenem, piperacillin, and vancomycin in critically ill patients and to evaluate the frequency with which current dosing regimens achieve therapeutic concentrations.. Regression analyses of published pharmacokinetic data.. Pubmed was searched for relevant articles published between 1952 and 2013.. Original research articles describing the pharmacokinetics of meropenem, piperacillin, and vancomycin in critically ill patients receiving renal replacement therapy.. None.. Data from 30 studies were analyzed. The mean age of the patient groups involved in studies of meropenem, piperacillin, and vancomycin were 55.3, 60.3, and 56.9 years, respectively. The mean blood and effluent flow rates used for each antibiotic were 151.3 and 33.8 mL/min, 131.8 and 27.3 mL/min, and 189.3 and 35.6 mL/min, respectively, in continuous renal replacement therapy studies. Correlations existed between effluent flow rate in continuous renal replacement therapy and extracorporeal clearance for meropenem (rs = 0.43; p = 0.12), piperacillin (rs = 0.77; p = 0.10), and vancomycin (rs = 0.90; p = 0.08). Current dosing regimens achieved target concentrations for meropenem (89%), piperacillin (83%), and vancomycin (60%) against susceptible pathogens.. Effluent flow rate appears to be a reliable predictor of antibiotic clearance in critically ill patients despite significantly altered pharmacokinetics in these patients. Higher dosing regimens maybe required in critically ill patients receiving renal replacement therapy, in the presence of high effluent flow rates and/or the presence of poorly susceptible pathogens, particularly for vancomycin.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Intensive Care Units; Male; Meropenem; Metabolic Clearance Rate; Middle Aged; Piperacillin; Renal Replacement Therapy; Thienamycins; Vancomycin

Meropenem is a broad-spectrum antibiotic, often used for the empirical treatment of infections in critically ill patients with acute kidney injury. Meropenem has clinically insignificant protein binding and, as a carbapenem antibiotic, shows time-dependent bacterial killing, meaning that the unbound or free antibiotic concentration in blood should be maintained above the minimal inhibitory concentration of the pathogen for at least 40 % of the dosing interval. We developed and validated simple chromatographic methods by ultra-performance liquid chromatography-tandem mass spectrometry to measure plasma, filtrate-dialysate, and urine concentrations of meropenem. Chromatographic separation was achieved using an Acquity(®) UPLC(®) BEH(TM) (2.1 × 100 mm id, 1.7 μm) reverse-phase C(18) column, with a water/acetonitrile linear gradient containing 0.1 % formic acid at a 0.4-mL/min flow rate. Meropenem and its internal standard (ertapenem) were detected by electrospray ionization mass spectrometry in positive ion multiple reaction monitoring mode. The limits of quantification were 0.27, 0.24, and 1.22 mg/L, and linearity was observed between 0.27-150, 0.24-150, and 1.22-2,000 mg/L for plasma, filtrate-dialysate, and urine samples, respectively. Coefficients of variation and relative biases were less than 13.5 and 8.0 % for all biological fluids. Recovery values were greater than 68.3 %. Evaluation of the matrix effect showed ion suppression for meropenem and ertapenem. No carry-over was observed. The validated methods are useful for both therapeutic drug monitoring and pharmacokinetic studies. It could be applied to daily clinical laboratory practice to measure the concentration of meropenem in plasma, filtrate-dialysate, and urine.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Body Fluids; Chromatography, Liquid; Critical Illness; Drug Monitoring; Humans; Meropenem; Renal Replacement Therapy; Sepsis; Spectrometry, Mass, Electrospray Ionization; Thienamycins

The scope of extracorporeal membrane oxygenation (ECMO) is expanding; however, optimal drug prescription during ECMO remains a developing science. Currently, there are no clear guidelines for antibiotic dosing during ECMO. This open-label, descriptive, matched-cohort pharmacokinetics (PK) study aimed to compare the PK of meropenem in ECMO patients to critically ill patients with sepsis not receiving ECMO (controls).. Eleven adult patients on ECMO (venovenous (VV) ECMO, n = 6; venoarterial (VA) ECMO, n = 5) receiving intravenous (IV) meropenem were included. Meropenem plasma concentrations were determined using validated chromatography. Population PK analysis was performed using non-linear mixed effects modelling. This data was compared with previously published meropenem PK data from 10 critically ill adult patients not on ECMO (preserved renal function (n = 5) or receiving renal replacement therapy (RRT) (n = 5). Using these data, we then performed Monte Carlo simulations (n = 1,000) to describe the effect of creatinine clearance on meropenem plasma concentrations.. In total, five (two VV, three VA) out of eleven ECMO patients received RRT. The other six patients (four VV, two VA) had no significant impairment in renal function. A two-compartment model adequately described the data. ECMO patients had numerically higher volume of distribution (0.45 ± 0.17 versus 0.41 ± 0.13 L/kg, P = 0.21) and lower clearance compared to controls (7.9 ± 5.9 versus 11.7 ± 6.5 L/h, P = 0.18). Variability in meropenem clearance was correlated with creatinine clearance or the presence of RRT. The observed median trough concentrations in the controls were 4.2 (0.0 to 5.7) mg/L. In ECMO patients, while trough meropenem concentrations >2 mg/L were achieved in all patients, a more aggressive target of >8 mg/L for less susceptible microorganisms was observed in only eight out of eleven patients, with five of them being on RRT.. ECMO patients exhibit high PK variability. Decreased meropenem CL on ECMO appears to compensate for ECMO and critical illness-related increases in volume of distribution. Routine target concentrations >2 mg/L are maintained with standard dosing (1 g IV 8-hourly). However, an increase in dose may be necessary when targeting higher concentrations or in patients with elevated creatinine clearance.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Cohort Studies; Critical Illness; Extracorporeal Membrane Oxygenation; Female; Humans; Male; Meropenem; Middle Aged; Monte Carlo Method; Renal Replacement Therapy; Sepsis; Thienamycins; Young Adult

Meropenem and piperacillin are two commonly prescribed antibiotics in critically ill surgical patients. To date, the pharmacokinetics of these antibiotics in the presence of indwelling abdominal surgical drains is poorly defined. This was a prospective pharmacokinetic study of meropenem and piperacillin. Serial plasma, urine and surgical drain fluid samples were collected over one dosing interval of antibiotic treatment in ten patients (meropenem, n = 5; piperacillin n = 5). Drug concentrations were measured using a validated high-performance liquid chromatography assay. Median (interquartile range) pharmacokinetic parameter estimates for meropenem were as follows: area under concentration-time curve (AUC), 128.7 mgh/L (95.3-176.7 mgh/L); clearance (CL), 5.7 L/h (5.1-10.5 L/h); volume of distribution (Vd), 0.41 L/kg (0.35-0.56 L/kg); AUC ratio (drain:plasma), 0.2 (0.1-0.2); and calculated antibiotic clearance via surgical drain, 3.8% (2.8-5.4%). For piperacillin, unbound pharmacokinetic results were as follows; AUC, 344.3 mgh/L (341.1-348.4 mgh/L); CL, 13.1 L/h (12.9-13.2 L/h); Vd, 0.63 L/kg (0.38-1.28 L/kg); AUC ratio (drain:plasma), 0.2 (0.2-0.3); and calculated antibiotic clearance via surgical drain 8.2% (3.3-14.0%). A linear correlation was present between the percentage of antibiotic cleared through the drain and the volume of surgical drain fluid output for meropenem (r(2) = 0.89; P = 0.05) and piperacillin (r(2) = 0.63; P = 0.20). Meropenem and piperacillin have altered pharmacokinetics in critically ill patients with indwelling surgical drains. We propose that only when very high drain fluid output is present (>1000 mL/day) would an additional dose of antibiotic be necessary.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Chromatography, Liquid; Critical Illness; Drainage; Exudates and Transudates; Female; Humans; Male; Meropenem; Middle Aged; Piperacillin; Plasma; Prospective Studies; Thienamycins; Urine

Correct antibiotic dosing remains a challenge for the clinician. The aim of this study was to assess the influence of augmented renal clearance on pharmacokinetic/pharmacodynamic target attainment in critically ill patients receiving meropenem or piperacillin/tazobactam, administered as an extended infusion.. This was a prospective, observational, pharmacokinetic study executed at the medical and surgical intensive care unit at a large academic medical center. Elegible patients were adult patients without renal dysfunction receiving meropenem or piperacillin/tazobactam as an extended infusion. Serial blood samples were collected to describe the antibiotic pharmacokinetics. Urine samples were taken from a 24-hour collection to measure creatinine clearance. Relevant data were drawn from the electronic patient file and the intensive care information system.. We obtained data from 61 patients and observed extensive pharmacokinetic variability. Forty-eight percent of the patients did not achieve the desired pharmacokinetic/pharmacodynamic target (100% fT>MIC), of which almost 80% had a measured creatinine clearance>130 mL/min. Multivariate logistic regression demonstrated that high creatinine clearance was an independent predictor of not achieving the pharmacokinetic/pharmacodynamic target. Seven out of nineteen patients (37%) displaying a creatinine clearance>130 mL/min did not achieve the minimum pharmacokinetic/pharmacodynamic target of 50% fT>MIC.. In this large patient cohort, we observed significant variability in pharmacokinetic/pharmacodynamic target attainment in critically ill patients. A large proportion of the patients without renal dysfunction, most of whom displayed a creatinine clearance>130 mL/min, did not achieve the desired pharmacokinetic/pharmacodynamic target, even with the use of alternative administration methods. Consequently, these patients may be at risk for treatment failure without dose up-titration.

Topics: Adult; Aged; Anti-Bacterial Agents; Creatinine; Critical Illness; Drug Delivery Systems; Female; Humans; Infusions, Intravenous; Kidney; Male; Meropenem; Metabolic Clearance Rate; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Thienamycins

Critically ill patients with infection provide a number of challenges to clinicians in terms of optimizing their antimicrobial treatment. Of foremost importance, initial antibiotic treatment should be selected as to provide coverage for the causative pathogens. However, the administration of those antibiotics (dosing, interval of administration, duration of infusion, route of administration) should be prescribed in a manner to ensure optimal drug delivery to the site of infection. This is a challenge given the characteristics of many infected critically ill patients (shock, elevated cardiac output in the resuscitated state, supranormal creatinine clearance, increased volume of distribution). Intensive care unit practitioners should utilize treatment strategies that strive to deliver antibiotics in an individualized manner aimed at attaining desired pharmacokinetic/pharmacodynamic targets. The goal of such a treatment strategy is to maximize the likelihood of curing the infection and allowing the critically ill patient the best opportunity for recovery. Effective implementation of antimicrobial optimization delivery strategies will likely require a multi-disciplinary approach including intensivists, pharmacists, and infectious disease specialists.

Topics: Critical Illness; Drug Delivery Systems; Female; Humans; Kidney; Male; Meropenem; Metabolic Clearance Rate; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Thienamycins

Meropenem is an effective β-lactam antibiotic that is frequently used to treat serious infections in both intensive care unit (ICU) and febrile neutropenic hematology/oncology (Hem/Onc) patients. Studies suggest that to be effective, meropenem concentrations must be maintained above the inhibitory concentrations for the majority of a dosing interval. However, the pharmacokinetics (PK) of meropenem seem to differ in critically ill patients compared with healthy or less ill subjects used to select labeled dosing regimens.. This study was designed to investigate meropenem PK in critically ill patients and to see how often standard dosing regimens produced adequate plasma concentrations. A secondary objective was to investigate how achieved concentrations were related to outcomes (morbidity and mortality) in these patients.. Meropenem plasma concentrations over time were measured using a high pressure liquid chromatography assay in febrile Hem/Onc and ICU patients who were treated with standard meropenem dosing schedules. Outcomes such as fever control and survival were assessed in these patients and compared with individual meropenem PK data and with recommended target concentrations.. A total of 25 subjects including 10 febrile Hem/Onc and 15 ICU patients with a variety of serious illnesses and baseline renal function were studied. Mean peak concentrations were less variable than were pre-dose concentrations. Post peak and trough concentrations were often below recommended minimum inhibitory concentrations. Both clearance and volumes of distribution were greater than reported in less ill subjects, only in part explained by increased renal clearance. Therefore, serum concentrations often did not exceed recommended concentration targets even for moderately sensitive organisms. Inadequate concentrations were especially common in the mostly ill, febrile neutropenic Hem/Onc subjects and seemed to explain at least some therapeutic failures. Conversely, drug accumulation occurred in ICU subjects with decreased renal function.. Standard meropenem dosing regimens were inadequate in many critically ill febrile, neutropenic Hem/Onc, and septic ICU patients. These data suggest a role for meropenem concentration monitoring in such patients.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Critical Illness; Female; Humans; Infections; Intensive Care Units; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Prospective Studies; Retrospective Studies; Thienamycins

In critically ill patients receiving continuous renal replacement therapy, we aimed to assess the variability of antibiotic trough concentrations, the influence of effluent flow rates on such concentrations, and the incidence of suboptimal antibiotic dosage.. Prospective, observational, multicenter, pharmacokinetic study.. Four tertiary intensive care units within the multicenter RENAL randomized controlled trial of continuous renal replacement therapy intensity.. Twenty-four critically ill adult patients with acute kidney injury receiving ciprofloxacin, meropenem, piperacillin/tazobactam, or vancomycin during continuous renal replacement therapy.. We obtained trough blood samples and measured antibiotic concentrations.. We obtained data from 40 dosing intervals and observed wide variability in trough concentrations (6.7-fold for meropenem, 3.8-fold for piperacillin, 10.5-fold for tazobactam, 1.9-fold for vancomycin, and 3.9-fold for ciprofloxacin). The median (interquartile range) trough concentrations (mg/L) for meropenem was 12.1 (7.8-18.4), 105.0 (74.4-204.0)/3.8 (3.4-21.8) for piperacillin/tazobactam, 12.0 (9.8-16.0) for vancomycin, and 3.7 (3.0-5.6) for ciprofloxacin. Overall, 15% of dosing intervals did not meet predetermined minimum therapeutic target concentrations, 40% did not achieve the higher target concentration, and, during 10% of dosing intervals, antibiotic concentrations were excessive. No difference, however, was found between patients on the basis of the intensity of continuous renal replacement therapy; this effect may have been obscured by differences in dosing regimens, time off the filter, or altered pharmacokinetics.. There is significant variability in antibiotic trough concentrations in critically ill patients receiving continuous renal replacement therapy, which did not only appear to be influenced by effluent flow rate. Here, empirical dosing of antibiotics failed to achieve the target trough antibiotic concentration during 25% of the dosing intervals.

Topics: Acute Kidney Injury; Aged; Anti-Bacterial Agents; Ciprofloxacin; Critical Illness; Female; Hemofiltration; Humans; Male; Meropenem; Middle Aged; Penicillanic Acid; Piperacillin; Tazobactam; Thienamycins; Vancomycin

Intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial with excellent activity against pathogens associated with intra-abdominal infections. The purpose of this study was to determine the safety and effectiveness of meropenem in young infants with suspected or complicated intra-abdominal infections.. Preterm and term infants <91 days of age with suspected or confirmed intra-abdominal infections hospitalized in 24 neonatal intensive care units were studied in an open-label, multiple-dose study. Adverse events and serious adverse events were collected through 3 and 30 days following the last meropenem dose, respectively. Effectiveness was assessed by 3 criteria: death, bacterial cultures, and presumptive clinical cure score.. Of 200 subjects enrolled in the study, 99 (50%) experienced an adverse event, and 34 (17%) had serious adverse events; no adverse events were probably or definitely related to meropenem. The most commonly reported adverse events were sepsis (6%), seizures (5%), elevated conjugated bilirubin (5%), and hypokalemia (5%). Only 2 of the serious adverse events were determined to be possibly related to meropenem (isolated ileal perforation and an episode of fungal sepsis). Effectiveness was evaluable in 192 (96%) subjects, and overall treatment success was 84%.. Meropenem was well tolerated in this cohort of critically ill infants, and the majority of infants treated with meropenem met the definition of therapeutic success.. NCT00621192.

Topics: Anti-Bacterial Agents; Cohort Studies; Critical Illness; Female; Humans; Infant; Infant, Newborn; Intraabdominal Infections; Male; Meropenem; Thienamycins

The worrisome increase in Gram-negative bacteria with borderline susceptibility to carbapenems and of carbapenemase-producing Enterobacteriaceae has significantly undermined their efficacy. Continuous infusion may be the best way to maximize the time-dependent activity of meropenem. The aim of this study was to create dosing nomograms in relation to different creatinine clearance (CL(Cr)) estimates for use in daily clinical practice to target the steady-state concentrations (C(ss)s) of meropenem during continuous infusion at 8 to 16 mg/liter (after the administration of an initial loading dose of 1 to 2 g over 30 min). The correlation between meropenem clearance (CL(m)) and CL(Cr) was retrospectively assessed in a cohort of critically ill patients (group 1, n = 67) to create a formula for dosage calculation to target C(ss). The performance of this formula was validated in a similar cohort (group 2, n = 56) by comparison of the observed and the predicted C(ss)s. A significant relationship between CL(m) and CL(Cr) was observed in group 1 (r = 0.72, P < 0.001). The application of the formula to meropenem dosing in group 2, infusion rate (g/24 h) = [0.078 × CL(Cr) (ml/min) + 2.85] × target C(ss) × (24/1,000), led to a significant correlation between the observed and the predicted C(ss)s (r = 0.92, P < 0.001). Dosing nomograms based on CL(Cr) were created to target the meropenem C(ss) at 8, 12, and 16 mg/liter in critically ill patients. These nomograms could be helpful in improving the treatment of severe Gram-negative infections with meropenem, especially in the presence of borderline susceptible pathogens or even of carbapenemase producers and/or of pathophysiological conditions which may enhance meropenem clearance.

Topics: Aged; Algorithms; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Chromatography, High Pressure Liquid; Cohort Studies; Creatinine; Critical Illness; Enterobacteriaceae; Female; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Nomograms; Spectrophotometry, Ultraviolet; Thienamycins

To develop a meropenem population pharmacokinetic model in critically ill patients with particular focus on optimizing dosing regimens based on renal function.. Population pharmacokinetic analysis was performed with creatinine clearance (CrCl) and adjusted body weight to predict parameter estimates. Initial modeling was performed on 21 patients (55 samples). Validation was conducted with 12 samples from 5 randomly selected patients excluded from the original model. A 5,000-patient Monte Carlo simulation was used to ascertain optimal dosing regimens for three CrCl ranges.. Mean ± SD age, APACHE, and CrCl were 59.2 ± 16.8 years, 13.6 ± 7, and 78.3 ± 33.7 mL/min. Meropenem doses ranged from 0.5 g every 8 h (q8h)-2 g q8h as 0.5-3 h infusions. Median estimates for volume of the central compartment, K₁₂ and K₂₁ were 0.24 L/kg, 0.49 h⁻¹, and 0.65 h⁻¹, respectively. K₁₀ was described by the equation: K₁₀= 0.3922 + 0.0025 × CrCl. Model bias and precision were -1.9 and 8.1 mg/L. R², bias, and precision for the validation were 93%, 1.1, and 2.6 mg/L. At minimum inhibitory concentrations (MICs) up to 8 mg/L, the probability of achieving 40% fT > MIC was 96, 90, and 61% for 3 h infusions of 2 g q8h, 1 g q8h, and 1 g q12h in patients with CrCl ≥50, 30-49, and 10-29, respectively. Target attainment was 75, 65, and 44% for these same dosing regimens as 0.5 h infusions.. This pharmacokinetic model is capable of accurately estimating meropenem concentrations in critically ill patients over a range of CrCl values. Compared with 0.5 h infusions, regimens employing prolonged infusions improved target attainment across all CrCl ranges.

Topics: Adult; Aged; Anti-Bacterial Agents; Connecticut; Creatinine; Critical Illness; Dose-Response Relationship, Drug; Female; Hospitals, Urban; Humans; Kidney; Kidney Function Tests; Male; Meropenem; Middle Aged; Monte Carlo Method; Thienamycins

Use of high ultrafiltrate flow rates with continuous venovenous hemofiltration (CVVHF) in critically ill patients is an emerging setting, for which there are few data to guide drug dosing. The objectives of this study were, firstly, to investigate the pharmacokinetics of meropenem in critically ill patients with severe sepsis who are receiving high-volume CVVHF with high-volume exchanges (> or = 4 liters/h); secondly, to determine whether standard dosing regimens (1,000 mg intravenously [i.v.] every 8 h) are sufficient for treatment of less susceptible organisms such as Burkholderia pseudomallei (MIC, 4 mg/liter); and, finally, to compare the clearances observed in this study with data from previous studies using lower-volume exchanges (1 to 2 liters/h). We recruited 10 eligible patients and collected serial pre- and postfilter blood samples and ultrafiltrate and urine samples. A noncompartmental method was used to determine meropenem pharmacokinetics. The cohort had a median age of 56.6 years, a median weight of 70 kg, and a median APACHE II (acute physiology and chronic health evaluation) score of 25. The median (interquartile range) values for meropenem were as follows: terminal elimination half-life, 4.3 h (2.9 to 6.0); terminal volume of distribution, 0.2 liters/kg (0.2 to 0.3); trough concentration, 7.7 mg/liter (6.2 to 12.9); total clearance, 6.0 liters/h (5.2 to 6.2); hemofiltration clearance, 3.5 liters/h (3.4 to 3.9). In comparing the meropenem clearance here with those in previous studies, ultrafiltration flow rate was found to be the parameter that accounted for the differences in clearance of meropenem (R(2) = 0.89). In conclusion, high-volume CVVHF causes significant clearance of meropenem, necessitating steady-state doses of 1,000 mg every 8 h to maintain sufficient concentrations to treat less susceptible organisms such as B. pseudomallei.

Topics: Anti-Bacterial Agents; Critical Illness; Hemofiltration; Humans; Meropenem; Prospective Studies; Sepsis; Thienamycins

De-escalation of antimicrobial therapy is often advocated to reduce the use of broad-spectrum antibiotics in critically ill patients. However, little data are available on the application of this strategy in daily clinical practice.. This is a retrospective analysis of all meropenem prescriptions in a surgical intensive care unit (ICU) during 1 year. Age, Acute Physiology and Chronic Health Evaluation II score on admission to the ICU, site of infection, causative organism, duration of meropenem administration, other antibiotic prescription for the same infectious episode for which meropenem was administered, and ICU mortality were recorded. De-escalation was defined as the administration of an antibiotic with a narrower spectrum within 3 days of the start of meropenem.. Data from 113 meropenem prescriptions were available for analysis. Pulmonary (46%) and complicated intraabdominal (31%) infections were the most frequent infections. In 37 patients, meropenem was used after identification of a multiresistant gram-negative organism (MRGN), whereas in 76 patients, empirical treatment with meropenem was started. Empirical prescription of meropenem was de-escalated in 42% of the patients. In the majority of the patients in whom de-escalation was not done, no conclusive cultures were available to guide treatment; also, colonization with MRGN at other sites was frequently associated with non-de-escalation. Patients in whom antibiotics were de-escalated had a trend toward a lower mortality rate (7% vs 21%, P = .12).. De-escalation after empirical treatment with meropenem was performed in less than half of the patients. Reasons for not de-escalating included the absence of conclusive microbiology and colonization with MRGN.

Topics: Adult; Aged; Anti-Bacterial Agents; Critical Care; Critical Illness; Drug Administration Schedule; Drug Resistance, Microbial; Empirical Research; Hospital Mortality; Humans; Intensive Care Units; Meropenem; Middle Aged; Practice Patterns, Physicians'; Respiratory Tract Infections; Retrospective Studies; Surgical Wound Infection; Thienamycins

The purpose of this study was to examine the removal of meropenem during an 8-h sustained low-efficiency dialysis (SLED) session. Using a minimum inhibitory concentration (MIC) = 2 microg/mL as our reference point, we also evaluated the therapeutic adequacy of dosing meropenem as 1 g every 12 h during SLED.. This was a prospective, open-label study involving 10 intensive care unit patients with renal failure needing SLED. Meropenem was dosed as 1 g every 12 h. To ensure a steady state, the patients received at least two doses prior to the study. SLED was initiated at least 2 h after the last meropenem dose, and each session was at least 8 h. Blood samples were collected during SLED at 0, 2, 4 and 8 h. The 8-h sample approximated the trough level. After centrifuging the samples, the supernatants were analysed by high-performance liquid chromatography.. Most patients were male with a mean age of 63.7 years and a mean weight of 88.9 kg. The SLED prescription was based on each patient's needs, and the blood flow, dialysate flow and ultrafiltration rates varied by up to 150 mL/min. The mean reduction of plasma meropenem concentration was 79.1 +/- 7.3%, and the mean half-life was 3.6 +/- 0.8 h during the 8-h SLED. Significantly more meropenem was removed in the first 4 h of SLED compared with the rest of the sessions. The mean plasma trough concentration was 4 +/- 1.6 microg/mL.. Meropenem was significantly removed from the blood compartment during SLED. Dosing 1 g of meropenem every 12 h during a typical 8-h SLED session maintains adequate plasma concentrations.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Cohort Studies; Critical Illness; Dose-Response Relationship, Drug; Female; Humans; Intensive Care Units; Kidney Failure, Chronic; Male; Meropenem; Middle Aged; Prospective Studies; Regional Blood Flow; Renal Dialysis; Thienamycins; Time Factors; Ultrafiltration

Topics: Antibiotic Prophylaxis; Child; Child, Preschool; Critical Illness; Cross Infection; Female; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Incidence; Infant; Intensive Care Units, Pediatric; Male; Meropenem; Risk Assessment; Sensitivity and Specificity; Survival Analysis; Thienamycins

To describe the effectiveness and tolerability of the dose adjustment of meropenem in empirical treatment of nosocomial infections in critically-ill patients admitted to intensive care medicine services.. Prospective, observational and multicenter study in patients admitted to 17 intensive care medicine services with nosocomial infection, who were initially treated with meropenem, 1 g every 8 h, were eligible. The initial dose was adjusted to 0.5 g every 8 h if there were: a) a favorable clinical course, and b) microbiological isolation of meropenem-susceptible pathogens or absence of pathogens in cultures.. Ninety-two patients in whom meropenem doses were adjusted to 0.5 g every 8 h were included. Ventilator-associated pneumonia followed by bacteremia was the most frequently treated infections. Microbiological studies were positive in 53 patients, with a predominance of gram-positive bacteria (53.7%), especially methicillin-susceptible Staphylococcus aureus, followed by gram-negative bacteria (42.7 %). A total of 18 patients were not evaluable at the end of treatment. Sixty-seven (90.5 %) of the 74 evaluable patients had a favorable clinical course (54 patients cured and 13 improved). In 50 out of 53 microbiologically evaluable cases, eradication or apparent eradication of initial microorganisms was achieved. In 3 cases, the initial pathogen persisted: Acinetobacter baumannii (2 cases) and Pseudomonas aeruginosa (1 case). On three occasions, new pathogens developed during treatment: A. baumannii (2 cases) and methicillin-resistant S. aureus (1 case). Adverse events occurred in 3 patients (4%), none of which was considered severe, and withdrawal of meropenem was not necessary. A total of 25 (27.2 %) patients died, three of them in relation to the infectious process.. Dose adjustment of meropenem to 0.5 g every 8 h is a useful tool in the treatment of severe nosocomial infections in patients admitted to services of intensive care medicine except in cases in which causative pathogens are non-fermenting Gram-negative bacteria.

Topics: Anti-Bacterial Agents; Critical Illness; Cross Infection; Female; Humans; Male; Meropenem; Middle Aged; Prospective Studies; Severity of Illness Index; Thienamycins

Topics: Alkalosis; Anti-Bacterial Agents; Critical Care; Critical Illness; Humans; Meropenem; Thienamycins

To determine the epidemiology and risk factors for carbapenem-resistant Pseudomonas aeruginosa (CR-PA) digestive tract colonization, weekly rectal and pharyngeal swabs were obtained in two serial incidence surveys (266 patients). Forty-two (16%) patients were CR-PA colonized (12 [29%] on admission and 30 [71%] in intensive care units). Pulsed-field gel electrophoresis showed extensive clonal diversity, although one specific clone (type B) was isolated from 11 patients. The presence of similar genotypes of CR-PA colonizing 30% of the CR-PA-colonized patients suggests the occurrence of cross-colonization; in addition, 10 pairs of carbapenem-susceptible P. aeruginosa (CS-PA) and subsequent CR-PA strains isolated from the same patients were found to be clonally identical and were considered to have been endogenously acquired (33%). All endogenously acquired CR-PA strains were isolated after exposure to a carbapenem, and 80% showed a phenotype of imipenem resistance (IR pattern) alone, while 67% of the CR-PA strains acquired by cross-transmission exhibited a multiresistant (MR) phenotype, with previous carbapenem exposure in 44%. Logistic regression analysis identified severity of acute illness (odds ratio [OR], 1.0; 95% confidence interval [CI], 1.0 to 1.1), prior carbapenem use (OR, 7.8; 95% CI, 1.7 to 35.3), and prior use of fluoroquinolones (OR, 11.0; 95% CI, 1.7 to 67.9) as independent risk factors for CR-PA digestive tract colonization. Overall, the local epidemiology of CR-PA digestive tract colonization was characterized by polyclonal endemicity with phenotype patterns of IR and MR divided evenly between patients. Restricting the use of particular agents, such as carbapenems and fluoroquinolones, should be considered advisable to minimize the problem of this antibiotic resistance. However, the possible risk for development of collateral unexpected bacterial resistance patterns should be accurately monitored.

Topics: Adult; Aged; Anti-Bacterial Agents; beta-Lactam Resistance; Carbapenems; Carrier State; Critical Illness; Endemic Diseases; Female; Gastrointestinal Tract; Humans; Imipenem; Incidence; Intensive Care Units; Male; Middle Aged; Pharynx; Pseudomonas aeruginosa; Pseudomonas Infections; Rectum; Risk Factors

Infections caused by multidrug-resistant Acinetobacter baumannii have become a therapeutic challenge for clinicians worldwide. Although colistin and tigecycline have been successful in treating patients with these infections, these agents are not available on a worldwide basis. We describe four critically ill patients in Taiwan who were diagnosed with multidrug-resistant Acinetobacter baumannii bacteremia. All bacterial isolates from these patients were resistant to commonly available antibiotics, including carbapenems and sulbactam; however, combination therapy with a carbapenem and sulbactam led to favorable clinical outcomes in all four patients. We also conducted an in vitro study using isolates from these patients that showed that this drug combination had a synergistic effect with enhanced antibacterial activity against the isolates. Thus, a carbapenem-sulbactam combination may be a therapeutic alternative for multidrug-resistant Acinetobacter baumannii bacteremia in countries where colistin and tigecycline are not available for clinical use.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Aged; Anti-Bacterial Agents; Bacteremia; Cilastatin; Cilastatin, Imipenem Drug Combination; Critical Illness; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Female; Humans; Imipenem; Male; Meropenem; Microbial Sensitivity Tests; Sulbactam; Taiwan; Thienamycins

Antimicrobial resistance of isolates and risk factors for mortality were retrospectively investigated in 71 adult patients with Serratia marcescens bacteremia. During the 4-year study period, 78 clinically significant episodes of S. marcescens bacteremia occurred in 71 patients. The mean age of the patients was 65 years (range, 25-86 years) with a male predominance (45 patients, 63%). Most of the bacteremic episodes were nosocomial (78%), and 34% were polymicrobial. The overall mortality rate within 2 weeks after the onset of bacteremia was 41%. The presence of malignancy and critical illness at initial presentation were independent risk factors for mortality. By disk susceptibility test, 72 isolates were resistant to cefotaxime (92%) but susceptible to ceftazidime (99%). All isolates were susceptible to meropenem. Among the 47 patients with monomicrobial S. marcescens bacteremia, the mortality rate within 5 days of onset in patients receiving appropriate empirical antimicrobial therapy was lower than that in patients receiving inappropriate therapy although this difference was not significant (14% vs 28%, p = 0.27). Among the patients with cefotaxime-resistant but ceftazidime-susceptible S. marcescens bacteremia treated with ceftazidime, 6 of 7 patients (86%) survived for more than 2 weeks, suggesting the potential effectiveness of ceftazidime in the treatment of cefotaxime-resistant Serratia infections. Further clinical studies are required to delineate the clinical role of ceftazidime therapy for infections caused by S. marcescens with this resistant phenotype.

Topics: Adult; Aged; Anti-Bacterial Agents; Bacteremia; Cefotaxime; Ceftazidime; Critical Illness; Cross Infection; Drug Resistance, Bacterial; Female; Humans; Male; Meropenem; Middle Aged; Neoplasms; Retrospective Studies; Risk Factors; Serratia Infections; Serratia marcescens; Taiwan; Thienamycins

Meropenem is a broad-spectrum antibiotic used for severe infections. In patients with chronic end-stage renal failure, meropenem clearance is reduced and doses must be adjusted according to the creatinine clearance. The aim of this study was to assess pharmacokinetic data of meropenem in patients with acute renal failure and to determine the amount of drug removed by continuous venovenous hemofiltration, an often-used renal replacement therapy in patients with acute renal failure.. Nine critically ill anuric patients with acute renal failure undergoing continuous venovenous hemofiltration received 500 mg meropenem 2 or 3 times daily. Plasma and hemofiltrate concentrations were determined during 1 dosing interval at steady state. Pharmacokinetic parameters were calculated for a 2-compartment open model and dose requirements were calculated.. The total meropenem clearance was 52.0 +/- 8.4 mL/min, with a hemofiltration clearance of 22.0 +/- 4.7 mL/min and a nonrenal-nonhemofiltration clearance of 29.9 +/- 5.4 mL/min; 235.9 +/- 88.6 mg, or 47.2% +/- 17.7%, of the dose were removed through continuous venovenous hemofiltration. The terminal elimination half-life was 8.7 +/- 3.5 hours and the volume of distribution at steady state was 12.4 +/- 1.8 L. Peak and trough concentrations for a dosing interval of 12 hours were 38.9 +/- 9.7 mg/L and 7.3 +/- 1.3 mg/L, respectively. The corresponding concentrations for a dosing interval of 8 hours were 44.7 +/- 10.4 mg/L and 11.9 +/- 0.7 mg/L, respectively.. Pharmacokinetic data of anuric patients with acute renal failure were similar to those of patients with end-stage renal failure. Because hemofiltration contributes significantly to meropenem elimination, the recommended dose for critically ill anuric patients receiving continuous venovenous hemofiltration should be increased by 100% to avoid potential underdosing.

Topics: Acute Kidney Injury; Adult; Aged; Anuria; Creatinine; Critical Illness; Drug Administration Schedule; Female; Hemofiltration; Humans; Male; Meropenem; Middle Aged; Thienamycins

Serious infections in children represent unique challenges for the treating physician. For the pediatric patient, considerations of drug toxicity are especially critical to avoid potential long-term complications of therapy. There are several advantages associated with using single, broad-spectrum, empiric antibiotic therapy, including reduced potential for drug-mediated toxicity or drug interactions and facilitation of home therapy. Of the antibiotics available for monotherapy, the carbapenems have the broadest spectrum of activity. However, a major obstacle toward the use of the carbapenems in pediatrics has been the risk of seizures occurring during therapy with imipenem/cilastatin. In clinical studies of meningitis and other infections in children, no drug-related seizures were reported when treated with the carbapenem meropenem. Meropenem monotherapy has been shown to be similar to ceftriaxone- and cefotaxime-based single or multiple antibiotic regimens, in terms of clinical and microbiologic efficacy and tolerability. Thus, meropenem represents a favorable treatment choice for the seriously ill child, either as empiric monotherapy or as definitive therapy of polymicrobial or nosocomial infections.

Topics: Child; Critical Illness; Fusobacterium Infections; Fusobacterium necrophorum; Humans; Male; Meropenem; Thienamycins

Topics: Anti-Bacterial Agents; Ceftazidime; Cephalosporins; Critical Illness; Cross Infection; Drug Therapy, Combination; Humans; Meropenem; Pneumonia, Bacterial; Severity of Illness Index; Thienamycins; Tobramycin; Treatment Outcome

The pharmacokinetics of meropenem were studied in nine anuric critically ill patients treated by continuous venovenous hemodiafiltration. Peak levels after infusion of 1,000 mg over 30 min amounted to 103.2 +/- 45.9 microgram/ml, and trough levels at 12 h were 9.6 +/- 3.8 microgram/ml. A dosage of 1,000 mg of meropenem twice a day provides plasma drug levels covering intermediately susceptible microorganisms. Further reductions of the dosage might be appropriate for highly susceptible bacteria or when renal replacement therapies with lower clearances are applied.

Topics: Acute Kidney Injury; Adult; Aged; Critical Illness; Female; Hemodiafiltration; Humans; Male; Meropenem; Middle Aged; Thienamycins

The use of meropenem, a new antibiotic from the carbapenemic family, was analyzed in the treatment of all types of serious infections in patients in critical condition. The global clinical response was satisfactory in 85.4% of the 178 assessable cases, with no significant differences being found in the form of treatment (monotherapy or combination therapy with aminoglycosides and/or glycopeptides) or in the type of infection treated, although the patients that received three or more antibiotics had more treatment failure. In the case of pneumonia, a better clinical response was observed with the use of monotherapy (38/40, 95% vs. 38/47, 80.8%, p = 0.049). The microbiological response was satisfactory in 72.7% of the 110 assessable cases. Initial pathogens persisted in just 8.2% of the cases, with superinfection in 12.7% and colonization in 6.4%. Differences relating to the form of treatment or the area of infection were not detected. The severity of the patient's condition influenced the choice of the form of meropenem treatment (monotherapy or combined therapy). Such factors as the patient's severity, the presence of hypotension or shock, and the need for mechanical ventilation were indicators for the use of two or more antibiotics. The severity also influenced the use of a larger average daily dose, as well as the length of treatment. Adverse reactions were detected in 6 of the 178 (3.37%) assessable patients, with 4 cases of nephrotoxicity, and 2 of hepatotoxicity. Global mortality was 14%, while infection-related mortality was 8.43%.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aminoglycosides; Anti-Bacterial Agents; APACHE; Bacterial Infections; Child; Child, Preschool; Critical Illness; Data Interpretation, Statistical; Drug Therapy, Combination; Female; Glycopeptides; Humans; Male; Meropenem; Middle Aged; Sepsis; Shock, Septic; Thienamycins

Pneumonia in critical ill patients, most of them associated with insaturation of an artificial a way and the use of mechanical ventilation, involves important morbi/mortality in the Intensive Care Units. Knowledge of pathogenesis, risk factors, and implicated microorganisms in developing of this major infectious complication, in the context of infections which rise in the critically ill patients, allow us to apply prophylaxis measures which could decrease its incidence, and establish antimicrobial therapy, which permit us to cover all the etiologic possibilities. Availability in the arsenal of the powerful antimicrobial, of a new carbapenemic, meropenem, and based on the different studies and clinic assays, allow to recommend its use with warranties and efficacy, in the empirical or's in concretely those due to Pseudomonas aeruginosa, enterobacteriaceae, (in general or producers of ample spectrum beta-lactamases), and Acinetobacter spp., in monotherapy or combined therapy, with aminoglycosides.

Topics: Clinical Protocols; Critical Illness; Humans; Meropenem; Pneumonia, Bacterial; Thienamycins