Imipenem/relebactam pharmacokinetics in critically ill patients supported on extracorporeal membrane oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a life-saving modality but has the potential to alter the pharmacokinetics (PK) of antimicrobials. Imipenem/cilastatin/relebactam is an antibiotic with utility in treating certain multi-drug resistant Gram-negative infections. Herein, we describe the population pharmacokinetics of imipenem and relebactam in critically ill patients supported on ECMO. METHODS: Patients with infection supported on ECMO received 4-6 doses of imipenem/cilastatin/relebactam per current prescribing information based on estimated creatinine clearance. Blood samples were collected following the final dose of the antibiotic. Concentrations were determined via LC-MS/MS. Population PK models were fit with and without covariates using Pmetrics. Monte Carlo simulations of 1000 patients assessed joint PTA of fAUC0-24/MIC ≥ 8 for relebactam, and ≥40% fT > MIC for imipenem for each approved dosing regimen. RESULTS: Seven patients supported on ECMO were included in PK analyses. A two-compartment model with creatinine clearance as a covariate on clearance for both imipenem and relebactam fitted the data best. The mean ±â€Šstandard deviation parameters were: CL0, 15.21 ±â€Š6.52 L/h; Vc, 10.13 ±â€Š2.26 L; K12, 2.45 ±â€Š1.16 h-1 and K21, 1.76 ±â€Š0.49 h-1 for imipenem, and 6.95 ±â€Š1.34 L/h, 9.81 ±â€Š2.69 L, 2.43 ±â€Š1.13 h-1 and 1.52 ±â€Š0.67 h-1 for relebactam. Simulating each approved dose of imipenem/cilastatin/relebactam according to creatinine clearance yielded PTAs of ≥90% up to an MIC of 2 mg/L. CONCLUSIONS: Imipenem/cilastatin/relebactam dosed according to package insert in patients supported on ECMO is predicted to achieve exposures sufficient to treat susceptible Gram-negative isolates, including Pseudomonas aeruginosa.

Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Children with Confirmed or Suspected Gram-Negative Bacterial Infections: A Phase 1b, Open-Label, Single-Dose Clinical Trial.

Imipenem/cilastatin/relebactam is approved for the treatment of serious gram-negative bacterial infections in adults. This study assessed the pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (with a fixed 2:1 ratio of imipenem/cilastatin to relebactam, and with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram-negative bacterial infections receiving standard-of-care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), PK parameters from 46 children were analyzed using both population modeling and noncompartmental analysis. The PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%fT>MIC) of ≥30% (MIC = 2 mcg/mL). For relebactam, the PK/PD target was a free drug area under the plasma concentration-time curve (AUC) normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to an AUC from time zero extrapolated to infinity of ≥20.52 mcg·h/mL). Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges for the geometric mean %fT>MIC and maximum concentration (Cmax ) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean Cmax and AUC from 0 to 6 hours across age cohorts were 16.9-21.3 mcg/mL and 26.1-55.3 mcg·h/mL, respectively. In total, 8/46 (17%) children experienced ≥1 adverse events (AEs) and 2/46 (4%) children experienced nonserious AEs that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation.

Beneficial herb-drug interaction of rhein in Jinhongtang and Imipenem/Cilastatin mediated by organic anion transporters.

ETHNOPHARMACOLOGICAL RELEVANCE: Jinhongtang as a traditional Chinese medicine (TCM) formula, has been widely used as a clinical adjuvant in the treatment of acute abdominal diseases and sepsis. Clinical benefits of the concurrent use of Jinhongtang and antibiotics have been observed, however, the mechanism has not been fully understood. AIM OF THE STUDY: The present study aimed to explore the effect of Jinhongtang on the antibacterial activity of Imipenem/Cilastatin and to clarify the underlying mechanism of herb-drug interaction (HDI). MATERIALS AND METHODS: A mouse model of sepsis induced by Staphylococcus aureus (S. aureus) was used to evaluate the pharmacodynamic interaction in vivo. In vitro antibacterial activity of Imipenem/Cilastatin was studied by determining minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). Pharmacokinetic interaction was investigated by pharmacokinetic studies in rats and uptake assays using OAT1/3-HEK293 cells. The main constituents ingested into blood of rats were qualitatively identified by UHPLC-Q-TOF-MS. RESULTS: Mice treated by Imipenem/Cilastatin and Jinhongtang exhibited higher survival rate, lower bacteria load and less inflammation in blood and lung tissues, compared with those treated by Imipenem/Cilastatin alone after injection of S. aureus. However, MIC and MBC of Imipenem/Cilastatin against S. aureus in vitro were not significantly changed in the presence of Jinhongtang. On the contrary, Jinhongtang increased the plasma concentration of Imipenem and decreased its urinary excretion in rats. CLr of Imipenem was reduced by 58.5%, while its half-life (t1/2) was prolonged for approximate 1.2 times after coadministered Jinhongtang. Furthermore, the extracts of Jinhongtang, single herb in the prescription, and main absorbable constituents inhibited cellular uptake of probe substrates and Imipenem by OAT1/3-HEK293 cells to different extents. Among them, rhein exhibited the strongest inhibition capacity with IC50 values of 0.08 ± 0.01 µM (OAT1) and 2.86 ± 0.28 µM (OAT3). Moreover, coadministration of rhein also significantly enhanced the antibacterial activity of Imipenem/Cilastatin in sepsis mice. CONCLUSION: Concomitant administration of Jinhongtang enhanced antibacterial activity of Imipenem/Cilastatin in sepsis mice induced by S. aureus through reducing renal elimination of Imipenem via inhibition of OATs. Our investigation provided the insight of Jinhongtang as an effective supplement to enhance the antibacterial activity of Imipenem/Cilastatin and can be useful for future clinical studies.

Population pharmacokinetics and pharmacodynamics of imipenem in neutropenic adult patients.

OBJECTIVE: Imipenem is recommended in patients with chemotherapy-induced febrile neutropenia. Although alterations of antibiotic pharmacokinetic parameters have been reported in such patients, little data is available on imipenem. METHODS: Prospective, single-center, non-interventional pharmacokinetic cohort study in adults with chemotherapy-induced febrile neutropenia. Critically ill patients were excluded. Imipenem was administered as a 30-min infusion of 1000 mg/8h. Total imipenem plasma concentrations were assayed by high-performance liquid chromatography during neutropenia and just after neutrophil recovery. We estimated population pharmacokinetic parameters of imipenem by non-linear mixed-effect modelling using the SAEM algorithm. RESULTS: Sixteen patients were included in the study, including nine women (56.3%), median age 37 years (range, 18.3; 78.3). Eight patients had an hematological malignancy (50.0%) and seven had a solid tumor (43.8%). Imipenem pharmacokinetics were best described by a one-compartment model with first-order elimination. Mean values for imipenem were: clearance 14.3L/h and 10.9L/h and volume of distribution 20.7L and 14.5 L during neutropenia and after recovery, respectively. Imipenem plasma area under the curve at steady state was reduced by 23% during neutropenia. However, all patients achieved a pharmacodynamic target of %fT>MIC ≥ 40% with a regimen of 1000 mg/8 h or 500 mg/6 h, for MICs up to 2 mg/L. The pharmacodynamics profile for a target of %fT > MIC = 100% was however less favorable with 500 mg/6 h or 1000 mg/8 h either during or after neutropenia. CONCLUSION: Pharmacokinetic/pharmacodynamic goals for imipenem were similar in patients during and after neutropenia, despite reduced plasma exposure.

Evaluating the usefulness of the estimated glomerular filtration rate for determination of imipenem dosage in critically ill patients.

BACKGROUND: Antibiotic dosing in critically ill patients is complicated by variations in the pharmacokinetics of antibiotics in this group. The dosing of imipenem/cilastatin is usually determined by severity of illness and renal function. OBJECTIVES: To determine the correlation between estimated glomerular filtration rates (eGFRs) calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and imipenem trough levels in critically ill patients. METHODS: This prospective observational study was done in the surgical intensive care unit (ICU) at Steve Biko Academic Hospital, Pretoria, South Africa. Imipenem trough levels were measured by high-performance liquid chromatography and compared with eGFRs calculated with the CKD-EPI equation. Correlation was evaluated by the Pearson product-moment correlation coefficient. RESULTS: The study population consisted of 68 critically ill patients aged between 18 and 81 years; 43 (63%) were male, and the mean weight was 78 kg (range 40 - 140). On admission, 30 patients (44%) had sepsis, 16 (24%) were admitted for trauma, and 22 (32%) were admitted for miscellaneous surgical conditions. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores ranged from 4 to 39 (mean 18). The 28-day mortality rate was 29%. The mean albumin level was 16 g/L (range 7 - 25), the mean creatinine level 142 µmol/L (range 33 - 840), and the mean eGFR 91 mL/min/1.73 m2 (range 6 - 180). Imipenem trough levels ranged between 3.6 and 92.2 mg/L (mean 11.5). The unadjusted Pearson product-moment correlation coefficient between eGFR and imipenem trough level was -0.04 (p=0.761). CONCLUSION: Considering the high mortality rate of sepsis in ICUs and the rapid global increase in antimicrobial resistance, it is crucial to dose antibiotics appropriately. Owing to the variability of antibiotic pharmacokinetics in critically ill patients, this task becomes almost impossible when relying on conventional dosing guidelines. This study found that eGFRs do not correlate with imipenem blood levels in critically ill patients and should not be used to determine the dose of imipenem/cilastatin. Instead, the dose should be individualised for patients through routine therapeutic drug monitoring.

Simultaneous determination of meropenem and imipenem in rat plasma by LC-MS/MS and its application to a pharmacokinetic study.

An efficient and reliable method using LC-MS/MS was established and validated for the simultaneous quantification of meropenem and imipenem in rat plasma. An electronic spray ion source in the positive multiple reaction monitoring mode was used for the detection and the transitions were m/z 384.6 → m/z 141.2 for meropenem, m/z 300.1 → m/z 141.8 for imipenem and m/z 423.4 → m/z 207.1 for matrine (IS). The calibration curves of meropenem and imipenem were linear in the range of 0.50-200 µg/mL. Satisfactory separation was achieved with a total run time of 3.0 min, the injection volume was 3 µl. The retention times of meropenem, imipenem and IS were 1.19, 1.14 and 1.13 min, respectively. Meropenem and imipenem are easily hydrolyzed in plasma. HEPES was used as a stabilizer and added to the plasma samples immediately after centrifugation. Extractions of meropenem, imipenem and IS were carried out by protein precipitation with acetonitrile. The specificity, precision and accuracy, stability, recovery and matrix effects were within acceptance limits. This method was successfully applied to investigate the pharmacokinetics of intravenous injection of meropenem and imipenem single administration or combined with sulbactam in rats. We found that sulbactam has no influence on the pharmacokinetics behavior of meropenem or imipenem.

NONMEM population pharmacokinetics and Monte Carlo dosing simulations of imipenem in critically ill patients with life-threatening severe infections during support with or without extracorporeal membrane oxygenation in an intensive care unit.

STUDY OBJECTIVES: The objectives of this study were (i) to determine the population pharmacokinetic (PK) of imipenem in critically ill patients with life-threatening severe infections, (ii) to investigate the impact of extracorporeal membrane oxygenation (ECMO) on the population PK of imipenem during support with ECMO compared to those without ECMO support, and (iii) to assess the probability of target attainment (PTA) for finding the optimal dosage regimens of imipenem in critically ill patients with life-threatening severe infections. DESIGN: Open-label, PK study. SETTING: Academic tertiary care medical center. PATIENTS: Fifty critically ill patients with or without ECMO by pooling data from previously published studiesand unpublished data from 14 patients. INTERVENTION AND MEASUREMENTS: The population PK of imipenem was determined using NONMEM and a Monte Carlo simulation was performed to determine the PTAs of achieving 40% and 75% exposure times during which the plasma drug concentrations remained above the MIC. MAIN RESULTS: The values of volume of distribution and total clearance were 30.5 L and 13.3 L/h, respectively. The ECMO circuit did not show a significant influence on the PK parameters of imipenem. For pathogens with a MIC of 4 mg/L, the PTA target of 75% fT>MIC in patients with normal renal function was achieved when the imipenem was administered by a 4-h infusion of 1 g q6h. CONCLUSION: The ECMO circuit had little effect on enhancing the PK changes of imipenem that had already occurred in these patients. A high dosage of imipenem may be required for achieving the PK/pharmacodynamic targets against less susceptible pathogens, however, the dosage regimens in patients with renal impairment may not need to be as high as those required in patients with normal renal function. ClinicalTrials.gov: NCT03858387.

Population Pharmacokinetic Modeling and Simulations of Imipenem in Burn Patients With and Without Continuous Venovenous Hemofiltration in the Military Health System.

Continuous venovenous hemofiltration (CVVH) is a life-sustaining procedure in patients with severe burns and acute kidney injury. Physiologic changes from burn injury and use of CVVH may alter imipenem pharmacokinetics (PK). We aimed to compare imipenem clearance (CL) in burn patients with and without CVVH, determine the effect of burn on imipenem volume of distribution (CVVH, n = 12; no CVVH, n = 11), in combination with previously published models. Model qualification was performed with standard diagnostics and comparing predicted PK parameters/time-concentration profiles with those in the existing literature. Monte Carlo simulations were conducted to evaluate the probability of target attainment. A 2-compartment model best described the data. Utilizing albumin as a covariate on volume parameters and leveraging the clearance model from prior literature, our model predicted imipenem central volume and CL within a 10% margin of error across healthy, renally impaired, and burn populations. We provide direct comparison of imipenem CL in burn patients with and without CVVH. Notably, there was no significant difference. Large imipenem Vd in patients with severe burns is likely explained by increased capillary permeability, for which serum albumin may be a reasonable surrogate. Dosing 500 mg every 6 hours is adequate for burn patients on renally dosed CVVH; however, suspicion of augmented renal clearance or patients placed on CVVH without renal impairment may necessitate dosing of 1000 mg every 6 hours.

Pharmacokinetics and Monte Carlo Dosing Simulations of Imipenem in Critically Ill Patients with Life-Threatening Severe Infections During Support with Extracorporeal Membrane Oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO), a cardiopulmonary bypass device, has been found to increase the profound pathophysiological changes associated with life-threatening severe infections in patients with multiple comorbidities, which results in alterations of pharmacokinetic patterns for antibiotics. OBJECTIVES: The aims of this study were (1) to determine the pharmacokinetics of imipenem and (2) to assess the probability of target attainment (PTA) for imipenem in critically ill patients with life-threatening severe infections during support with ECMO. METHODS: The pharmacokinetic studies were carried out following administration of 0.5 g of imipenem every 6 h on the 4th dose of drug administration in 10 patients and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the plasma drug concentrations remained above minimum inhibitory concentration (T > MIC) and 80% T > MIC. RESULTS: The median values of volume of distribution and total clearance (CL) of imipenem in these patients were 13.98 L and 9.78 L/h, respectively. A high PTA (≥ 90%) for a target of 80% with a MIC of 4 µg/mL in patients with CLCR 60-120 mL/min and flow rate of ECMO circuit 3-5.5 L/min was observed when imipenem was administered by a 4-h infusion of 1 g every 6 h. CONCLUSIONS: A high dosage regimen such as 1 g every 6 h of imipenem may be required to achieve pharmacodynamic targets against less susceptible pathogens in this patient population. CLINICALTRIAL. GOV IDENTIFIER: NCT03776305, date of registration: 11 December 2018.

Evaluating imipenem + cilastatin + relebactam for the treatment of complicated urinary tract infections.

INTRODUCTION: The addition of the ß-lactamase inhibitor relebactam to imipenem restores the antibacterial activity against the majority of multidrug resistant Gram-negative bacteria. Complicated urinary tract infections (UTIs) are predominantly caused by Gram-negative uropathogens. The rise in antibiotic resistance, including to carbapenems, is an increasing challenge in daily practice. AREAS COVERED: In the current review, the use of imipenem/relebactam in complicated UTI is evaluated by discussing its chemistry, pharmacokinetics/dynamics, microbiology, safety, and clinical efficacy. The authors also provide their expert perspectives onto its use and its future place in the treatment armamentarium. EXPERT OPINION: With respect to complicated UTI, it should be noted that, to our knowledge, there are no data yet upon the clinical efficacy of imipenem/relebactam in patients with severe urosepsis or men with suspected prostatitis. Further studies upon these specific groups of UTI patients are needed including additional pharmacokinetic studies upon its tissue penetration of the prostate which is currently unknown. However, in our opinion, imipenem/relebactam can be used in complicated UTI when other treatment options are limited.

Pharmacokinetic and Pharmacodynamic Analysis of Critically Ill Patients Undergoing Continuous Renal Replacement Therapy With Imipenem.

PURPOSE: This study explores factors that affect behavior in critically ill patients receiving continuous renal replacement therapy (CRRT) with imipenem and provides dosing regimens for these patients. METHODS: A prospective, open-label study was conducted in a clinical setting. Both blood and effluent samples were collected pairwise at the scheduled time points. Plasma and effluent imipenem concentrations were determined by HPLC-UV. A population pharmacokinetic model was developed using a nonlinear mixed-effects modeling method. The final model was evaluated by a bootstrap and visual predictive check. A population pharmacokinetic and pharmacodynamic analysis using Monte Carlo simulations was performed to explore the effects of empirically used dosing regimens (0.5 g q6h, 0.5 g q8h, 0.5 g q12h, 1 g q6h, 1 g q8h, and 1 g q12h) on the probability of target attainment. FINDINGS: Thirty patients were included in the population model analysis. Imipenem concentration data were best described by a 3-compartment model (central, peripheral, and dialysis compartments). The clearance of the dialysis compartment (CLd) was used to characterize drug elimination from the dialyzer. Creatinine clearance (CrCl) was the covariate that influenced the central clearance (CLc), and the effects of dialysate flow (Qd) was significant for CLd. Model validation revealed that the final model had qualified stability and acceptable predictive properties. A pharmacokinetic and pharmacodynamic analysis was conducted by Monte Carlo simulation, and patients were categorized into 12 subgroups based on different CrCl values (<30, 31-60, 61-90, and >90 mL/min) and Qd values (300, 500, and 1000 mL/h). Under the same MIC value and administration regimen, probability of target attainment values decreased with an increase of CrCl and Qd. IMPLICATIONS: CrCl and Qd had significant effects on CLc and CLd, respectively. The proposed final model may be used to guide practitioners in imipenem dosing in this specific patient population.

Preliminary physiologically based pharmacokinetic modeling of renally cleared drugs in Chinese pregnant women.

AIM: The aim of this study was to build and verify a preliminary physiologically based pharmacokinetic (PBPK) model of Chinese pregnant women. The model was used to predict maternal pharmacokinetics (PK) of 6 predominantly renally cleared drugs. METHOD: Based on SimCYP Caucasian pregnancy population dataset, the preliminary Chinese pregnant population was built by updating several key parameters and equations according to physiological parameters of Chinese (or Japanese) pregnant women. Drug-specific parameters of 6 renally cleared drugs were validated through PBPK modeling of Caucasian non-pregnant, Caucasian pregnant and Chinese non-pregnant population. The preliminary PBPK model of Chinese pregnant population was then developed by integrating the preliminary Chinese pregnant population and the drug-specific parameters. This model was verified by comparing the predicted maternal PK of these 6 drugs with the observed in vivo data from the literature. RESULTS: The preliminary Chinese pregnant population PBPK model successfully predicted the PK of 6 target drugs for different pregnancy stages. The predicted plasma concentrations time profiles fitted the observed data well, and most predicted PK parameters were within 2-fold of observed data. CONCLUSIONS: The preliminary Chinese pregnant population PBPK model provided a useful tool to predict the maternal PK of 6 predominantly renally cleared drugs in Chinese pregnant women.

HILIC LC-MS/MS method for the quantification of cefepime, imipenem and meropenem.

A high performance hydrophilic interaction chromatography method combined with tandem-mass spectrometry for the quantification of cefepime, meropenem and imipenem in plasma and cerebrospinal fluid is presented. A solution of 0.5 M 3-Morpholinopropanesulfonic acid and ethylene glycol (1:1) was added to the samples before analysis to ensure stability of analytes during work up and storage. Deuterated forms of cefepime and meropenem were used as internal standards. Protein precipitation prior to injection into the LC-MS/MS system provided a fast and easy sample preparation. For online extraction, a Turboflow Cyclone-MCX column was used and the chromatographic separation was carried out on a Hypersil GOLD HILIC column. Linear calibration curves were obtained in the concentration range of 0.4-40 mg/l, 0.6-60 mg/l and 1-100 mg/l for meropenem, imipenem and cefepime, respectively. The intra- and interday imprecision and inaccuracy values were below 10 % for plasma and 13 % for cerebrospinal fluid using a calibration in plasma. The method was employed for therapeutic drug measurements in a university hospital.

Comparable Effect of Two-Step Versus Extended Infusions on the Pharmacokinetics of Imipenem in Patients with Sepsis and Septic Shock.

INTRODUCTION: The present study aimed to compare the pharmacokinetic/pharmacodynamic (PK/PD) parameters of imipenem administered by two-step (50% delivered in a 30-min bolus, 50% for the following 90 min) or extended (administered continuously for 2 h) infusion. METHODS: Patients with sepsis and septic shock were prospectively enrolled and randomized into four groups. Subjects in the two-step or extended groups were given two doses of imipenem (0.5 g q6h and 1.0 g q8h). The plasma imipenem concentrations were measured at given time points after the fifth dose. The PK/PD target was defined as the achievement of a fractional time above the minimal inhibitory concentration (MIC) of > 40%. RESULTS: Thirty-five patients were eventually enrolled. No significant difference was observed in the percentage of patients achieving 40% T > MIC between the different infusion modes with the same dosage, although the two-step groups exhibited a significantly shorter Tmax compared with the extended groups (0.5 g q6h: 1.5 ± 0.8 vs. 2.0 ± 0.0 h; 1.0 g q8h: 1.0 ± 0.6 vs. 2.0 ± 0.0 h; both, p < 0.05). All four groups achieved 40% T > MIC when MIC was 0.5-4.0 µg/ml, but only regimens with a higher dose (1.0 g q8h) achieved target when MIC was 8 µg/ml. CONCLUSION: The two-step and extended regimens of imipenem are comparable to the PK/PD target in the treatment of sepsis and septic shock. A higher dose (1.0 g q8h) should be considered for target achievement at an MIC of > 8 µg/ml. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02616354.

Association Between Pathophysiology and Volume of Distribution Among Patients With Sepsis or Septic Shock Treated With Imipenem: A Prospective Cohort Study.

BACKGROUND: This study was performed to explore the apparent volume of distribution (Vd) of imipenem in patients with sepsis or septic shock. METHODS: A prospective, observational, single-center study was conducted in patients with sepsis or septic shock. The patients were treated with 1 g of imipenem mixed with 200 mL of normal saline infused intravenously over a 3-hour period at 8-hour intervals. The concentration of imipenem was 5 mg/mL, and the rate of infusion was 5.5 mg/min. Blood samples for measuring imipenem serum concentrations with high-performance liquid chromatography were obtained before and at 0, 1, 2, 3, and 5 hours after drug infusion on study days 1 and 3. Pharmacokinetic parameters were calculated according to a noncompartment model. RESULTS: A total of 25 adult patients were enrolled in this study, of whom 15 were diagnosed with sepsis and 10 with septic shock. The initial Vd (Vc) of imipenem was significantly lower in the sepsis than that in the septic shock group (mean [standard deviation], 26.5 [7.1] vs 40.7 [11.0] L; P = .001). The Vc of imipenem was significantly related to serum albumin levels (r = -0.517; P = .008) as well as Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (r = 0.606; P = .001). Multivariate linear regression identified serum albumin levels and APACHE II scores on day 1 as independent factors influencing the Vc of imipenem (P < .05). The difference in Vd between the imipenem steady state and the initial state was significantly higher in nonsurvivors than in survivors (mean [standard deviation], 1.7 [21.5] vs -13.1 [11.4] L; P = .046). CONCLUSIONS: APACHE II scores and serum albumin levels were found in this study to be independent factors that may affect the Vc of imipenem in patients with sepsis or septic shock. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov, NCT03308214.

Population Pharmacokinetics of Imipenem in Critically Ill Patients: A Parametric and Nonparametric Model Converge on CKD-EPI Estimated Glomerular Filtration Rate as an Impactful Covariate.

BACKGROUND: Population pharmacokinetic (popPK) models for antibiotics are used to improve dosing strategies and individualize dosing by therapeutic drug monitoring. Little is known about the differences in results of parametric versus nonparametric popPK models and their potential consequences in clinical practice. We developed both parametric and nonparametric models of imipenem using data from critically ill patients and compared their results. METHODS: Twenty-six critically ill patients treated with intravenous imipenem/cilastatin were included in this study. Median estimated glomerular filtration rate (eGFR) measured by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 116 mL/min/1.73 m2 (interquartile range 104-124) at inclusion. The usual dosing regimen was 500 mg/500 mg four times daily. On average, five imipenem levels per patient (138 levels in total) were drawn as peak, intermediate, and trough levels. Imipenem concentration-time profiles were analyzed using parametric (NONMEM 7.2) and nonparametric (Pmetrics 1.5.2) popPK software. RESULTS: For both methods, data were best described by a model with two distribution compartments and the CKD-EPI eGFR equation unadjusted for body surface area as a covariate on the elimination rate constant (Ke). The parametric population parameter estimates were Ke 0.637 h-1 (between-subject variability [BSV]: 19.0% coefficient of variation [CV]) and central distribution volume (Vc) 29.6 L (without BSV). The nonparametric values were Ke 0.681 h-1 (34.0% CV) and Vc 31.1 L (42.6% CV). CONCLUSIONS: Both models described imipenem popPK well; the parameter estimates were comparable and the included covariate was identical. However, estimated BSV was higher in the nonparametric model. This may have consequences for estimated exposure during dosing simulations and should be further investigated in simulation studies.

Antimicrobial susceptibilities of the ertapenem-non-susceptible non-carbapenemase-producing Enterobacterales isolates causing intra-abdominal infections in the Asia-Pacific region during 2008-2014: Results from the Study for Monitoring the Antimicrobial Resistance Trends (SMART).

OBJECTIVES: To investigate the susceptibility profiles amongst ertapenem-non-susceptible non-carbapenemase-producing Enterobacterales (ETP-NS-non-CPE) isolates. METHODS: Minimum inhibitory concentrations (MICs) of 404 ETP-NS-non-CPE isolates collected from different intra-abdominal infection (IAI) sites amongst patients in the Asia-Pacific region during 2008-2014 were determined using the broth microdilution method. The susceptibility results were interpreted according to the MIC breakpoints recommended by the Clinical and Laboratory Standards Institute (CLSI) in 2018. The MICs data of several agents were evaluated based on their published pharmacokinetic/pharmacodynamic (PK/PD) profiles. RESULTS: The majority (>84%) of IAI-ETP-NS-non-CPE isolates - including Escherichia coli (n=83), Klebsiella pneumoniae (n=91) and Enterobacter species (n=210) - were susceptible to imipenem and amikacin. The 193 hepatobiliary ETP-NS-non-CPE isolates exhibited a trend of lower cefepime MIC (≤4mg/L) distribution than those (n=145) cultured from the peritoneal space (P=0.058). Amongst the ETP-NS-non-CP Enterobacter isolates, 65.7% displayed a cefepime MIC≤4mg/L. In addition, compared with Escherichia coli and Klebsiella pneumoniae isolates, 82.9% and 72.9% of the ETP-NS-non-CP Enterobacter isolates were susceptible to levofloxacin and ciprofloxacin, respectively. Of note, 74.5% and 70.3% of the ETP-NS-non-CP Enterobacter isolates cultured from the hepatobiliary tract and peritoneal space exhibited a ciprofloxacin MIC≤2mg/L and ≤0.25mg/L, respectively. Imipenem and amikacin showed good in vitro susceptibility rates against the IAI-ETP-NS-non-CPE isolates. The hepatobiliary ETP-NS-non-CPE displayed lower cefepime MICs than those cultured from the peritoneal space. Additionally, a significant fraction of IAI-ETP-NS-non-CP Enterobacter isolates exhibited ciprofloxacin MIC ≤ 2mg/L. CONCLUSION: Based upon the PK/PD analyses, ciprofloxacin, imipenem and cefepime are probably effective against IAI-ETP-NS-non-CPE isolates.

Population Pharmacokinetic Analysis for Imipenem-Relebactam in Healthy Volunteers and Patients With Bacterial Infections.

Relebactam is a small-molecule ß-lactamase inhibitor developed as a fixed-dose combination with imipenem/cilastatin. The pharmacokinetics of relebactam and imipenem across 10 clinical studies were analyzed using data from adult healthy volunteers and patients with bacterial infections. Renal function estimated by creatinine clearance significantly affected the clearance of both compounds, whereas weight and health status were of less clinical significance. Simulations were used to calculate probability of joint target attainment (ratio of free drug area under the curve from 0 to 24 hours to minimum inhibitory concentration (MIC) for relebactam and percentage of time the free drug concentration exceeded the MIC for imipenem) for the proposed imipenem/relebactam dose of 500/250 mg, with adjustments for patients with renal impairment, administered as a 30-minute intravenous infusion four times daily. These dosing regimens provide sufficient antibacterial coverage (MIC ≤ 4 µg/mL) for all renal groups.

A translational pharmacokinetic/pharmacodynamic model to characterize bacterial kill in the presence of imipenem-relebactam.

OBJECTIVES: Relebactam is a small molecule ß-lactamase inhibitor under clinical investigation for use as a fixed-dose combination with imipenem/cilastatin. Here we present a translational pharmacokinetic/pharmacodynamic mathematical model to support optimal dose selection of relebactam. METHODS: Data derived from in vitro checkerboard and hollow fiber infection studies of imipenem-resistant strains of Pseudomonas aeruginosa were incorporated into the model. The model integrates the effect of relebactam concentration on imipenem susceptibility in a semi-mechanistic manner using the checkerboard data and characterizes the bacterial time-kill profiles from the hollow fiber infection model data. RESULTS: Simulations demonstrated that the ratio of the area under the concentration-time curve for free drug to the minimum inhibitory concentration (fAUC/MIC) was the pharmacokinetic driver for relebactam, with a target fAUC/MIC=7.5 associated with 2-log kill. At a clinical dose of 250mg relebactam, greater than 2-log reductions in bacterial load are projected for imipenem-resistant strains with an imipenem/relebactam MIC≤4µg/mL. CONCLUSIONS: The study confirms that the pharmacokinetic/pharmacodynamic driver for relebactam is fAUC/MIC, that an fAUC/MIC ratio of 7.5 is associated with 2-log kill in vitro, and that a 250mg clinical dose of relebactam achieves this target value when delivered in combination with imipenem/cilastatin.

Pharmacokinetics of Imipenem in Critically Ill Patients with Life-threatening Severe Infections During Support with Extracorporeal Membrane Oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has become increasingly used for lifesaving respiratory and/or cardiac failure support in critically ill patients, including those with life-threatening severe infections. This cardiopulmonary bypass device has been shown to enhance the profound pathophysiological changes in this patient population, resulting in an alteration of the pharmacokinetics of antimicrobial agents. OBJECTIVE: The aim of this study was to determine the effect of ECMO on the pharmacokinetics of imipenem in critically ill patients supported by this cardiopulmonary bypass device. METHODS: The study was conducted in critically ill patients with respiratory and/or cardiac failure and severe infections who were supported by ECMO. All patients received a 1-h infusion of 0.5 g of imipenem every 6 h and imipenem pharmacokinetics studies were carried out on the fourth dose of drug administration. RESULTS: Ten patients were enrolled in this study. The pharmacokinetics parameters of imipenem were found to be highly variable. The volume of distribution, total clearance, elimination half-life and the area under the concentration-time curve between 0 and 6 h were 33.38 ± 13.89 L, 9.99 ± 10.47 L/h, 12.01 ± 29.63 h and 88.93 ± 54.07 mg∙h/L, respectively. CONCLUSIONS: Pathophysiological changes in critically ill patients with severe infections during support with ECMO had a greater impact on altered pharmacokinetic patterns of imipenem than those that occur in critically ill patients without ECMO support. Therefore, the largest licensed dose, 1 g every 6 h, of imipenem, may be required to maintain adequate drug concentrations to achieve the pharmacokinetic/pharmacodynamic targets for effective antimicrobial therapy in this patient population.